{"Disease Name": "10q22.3q23.3 microdeletion syndrome", "Disease Definition": "10q22.3q23.3 microdeletion syndrome is a rare partial autosomal monosomy characterized by a mild facial dysmorphism variably including macrocephaly, broad forehead, hypertelorism or hypotelorism, deep-set eyes, upslanting or downslanting palpebral fissures, low-set ears, flat nasal bridge, smooth philtrum, thin upper lip), cleft palate, cerebellar and cardiac malformations, psychomotor development delay, and behavioral abnormalities (attention deficit hyperactivity disorder, autism). Other rare features may include congenital breast aplasia, arachnodactyly, joint hyperlaxity, club feet, feeding difficulties, failure to thrive.", "ORPHA ID": 276413, "Summary": ""}
{"Disease Name": "10q22.3q23.3 microduplication syndrome", "Disease Definition": "A rare, chromosomal anomaly characterized by variable clinical features that may include developmental delay, mild intellectual disability and dysmorphic facial features. In some cases, microcephaly, growth retardation and congenital heart defects have been reported.", "ORPHA ID": 276422, "Summary": ""}
{"Disease Name": "11p15.4 microduplication syndrome", "Disease Definition": "A rare partial autosomal trisomy/tetrasomy characterized by obesity, global developmental delay and intellectual disability, facial dysmorphism (synophrys, high-arched eyebrows, large posteriorly rotated ears, upturned nose, long smooth philtrum, overbite and high palate), large hands and limb hypotonia. Additional features include seizures and behavioral abnormalities.", "ORPHA ID": 300305, "Summary": ""}
{"Disease Name": "11q22.2q22.3 microdeletion syndrome", "Disease Definition": "A rare chromosomal anomaly characterized by mild intellectual disability, developmental delay, short stature, hypotonia and dysmorphic facial features. Anxiety and short attention span have also been reported.", "ORPHA ID": 444002, "Summary": ""}
{"Disease Name": "12p12.1 microdeletion syndrome", "Disease Definition": "A rare chromosomal anomaly syndrome, resulting from the partial deletion of the short arm of chromosome 12, characterized by intellectual disability, global developmental delay with prominent language impairment, behavioral abnormalities and mild facial dysmorphism (incl. frontal bossing, downslanting palpebral fissures, epicanthal folds, broad, depressed nasal bridge with bulbous nasal tip, low-set ears with underdeveloped helices). Other associated features may include skeletal abnormalities (butterfly vertebrae, scoliosis), strabismus, optic nerve hypoplasia, and brain malformations.", "ORPHA ID": 313884, "Summary": ""}
{"Disease Name": "12q14 microdeletion syndrome", "Disease Definition": "12q14 microdeletion syndrome is characterised by mild intellectual deficit, failure to thrive, short stature and osteopoikilosis. It has been described in four unrelated patients. The syndrome appears to be caused by a heterozygous deletion at chromosome region 12q14, which was detected in three of the four patients. The deleted region contains the LEMD3 gene: mutations in this gene have already been implicated in osteopoikilosis.", "ORPHA ID": 94063, "Summary": ""}
{"Disease Name": "12q15q21.1 microdeletion syndrome", "Disease Definition": "12q15q21.1 microdeletion syndrome is a rare chromosomal anomaly syndrome resulting from a partial deletion of the long arm of chromosome 12, with a highly variable phenotype, typically characterized by developmental delay, learning disability, intra-uterine and postnatal growth retardation, and mild facial dysmorphism that changes with age. Nasal speech and hypothyroidism are also associated.", "ORPHA ID": 289513, "Summary": ""}
{"Disease Name": "13q12.3 microdeletion syndrome", "Disease Definition": "13q12.3 microdeletion syndrome is a rare chromosomal anomaly characterized by moderate intellectual disability, speech delay, postnatal microcephaly, eczema or atopic dermatitis, characteristic facial features (malar flattening, prominent nose, underdeveloped alae nasi, smooth philtrum, and thin vermillion of the upper lip), and reduced sensitivity to pain.", "ORPHA ID": 412035, "Summary": ""}
{"Disease Name": "14q11.2 microdeletion syndrome", "Disease Definition": "14q11.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay, hypotonia and facial dysmorphism.", "ORPHA ID": 261120, "Summary": "Epidemiology\nIt has been clinically and molecularly characterized in 3 patients.\nClinical description\nAll three children have similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow, full lower lip and similar auricular anomalies.\nEtiology\nThis syndrome is caused by an interstitial deletion encompassing 14q11.2. These de novo deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size with the smallest region of overlap of 35 kb including only two genes, SUPT16H and CHD8, which are good candidate genes for the phenotype.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "14q11.2 microduplication syndrome", "Disease Definition": "14q11.2 microduplication syndrome is a rare chromosomal anomaly characterized by developmental delay, mild to severe intellectual disability with speech impairment and epilepsy. Additionally, it may include dysmorphic features (such as hypo- or hypertelorism, dysplastic ears, short palpebral fissures), microcephaly or macrocephaly, behavioral abnormalities, stereotyped hand movements, ataxia, hypotonia, cleft palate.", "ORPHA ID": 261229, "Summary": ""}
{"Disease Name": "14q22q23 microdeletion syndrome", "Disease Definition": "14q22q23 microdeletion syndrome is a rare partial deletion of the long arm of chromosome 14 characterized by ocular anomalies (anopthalmia/microphthalmia, ptosis, hypertelorism, exophthalmos), pituitary anomalies (pituitary hypoplasia/aplasia with growth hormone deficiency and growth retardation) and hand/foot anomalies (polydactyly, short digits, pes cavus). Other clinical features may include muscular hypotonia, psychomotor development delay/intellectual disability, dysmorphic signs (facial asymmetry, microretrognathia, high-arched palate, ear anomalies), congenital genitourinary malformations, hearing impairment. Smaller 14q22 deletions may have variable expression.", "ORPHA ID": 264200, "Summary": ""}
{"Disease Name": "14q24.1q24.3 microdeletion syndrome", "Disease Definition": "14q24.1q24.3 microdeletion syndrome is a rare, genetic, syndromic intellectual disability characterized by mild intellectual disability, delayed speech development, congenital heart defects, brachydactyly and dysmorphic facial features.", "ORPHA ID": 401935, "Summary": ""}
{"Disease Name": "14q32 duplication syndrome", "Disease Definition": "14q32 duplication syndrome is a rare chromosomal anomaly syndrome resulting from the partial duplication of the long arm of chromosome 14 that results in a predisposition to a number of adult-onset myeloproliferative neoplasms, including acute myeloid leukemia, chronic myelomonocytic leukemia, and especially essential thrombocythemia. Progression to myelofibrosis and secondary acute myeloid leukemia can be observed.", "ORPHA ID": 488280, "Summary": ""}
{"Disease Name": "15q overgrowth syndrome", "Disease Definition": "A rare partial autosomal trisomy/tetrasomy characterized by facial dysmorphism (long thin face, prominent forehead, down-slanting palpebral fissures, prominent nose with broad nasal bridge, prominent chin), pre- and postnatal overgrowth, renal anomalies (e.g. horseshoe kidney, renal agenesis, hydronephrosis), mild to severe learning difficulties and behavioral abnormalities. Additional features may include craniosynostosis and macrocephaly.", "ORPHA ID": 314585, "Summary": ""}
{"Disease Name": "15q11.2 microdeletion syndrome", "Disease Definition": "15q11.2 microdeletion syndrome is a rare partial autosomal monosomy with a variable phenotypic expression and reduced penetrance associated with an increased susceptibility to neuropsychiatric or neurodevelopmental disorders including delayed psychomotor development, speech delay, autism spectrum disorder, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, epilepsy or seizures. It may also include mild non-specific dysmorphic features (such as dysplastic ears, broad forehead, hypertelorism), cleft palate, neurological and neuroimaging abnormalities (such as ataxia and muscular hypotonia).", "ORPHA ID": 261183, "Summary": ""}
{"Disease Name": "15q11q13 microduplication syndrome", "Disease Definition": "The 15q11-q13 microduplication (dup15q11-q13) syndrome is characterized by neurobehavioral disorders, hypotonia, cognitive deficit, language delay and seizures. Prevalence is unknown.", "ORPHA ID": 238446, "Summary": "Epidemiology\nTo date, about 30 cases with syndrome of maternal origin have been reported.\nClinical description\nThe syndrome of maternal origin manifests in early childhood by developmental delay particularly in language, hypotonia, seizures often resistant, behavioral problems sometimes falling within the autism spectrum disorders (ASDs), and subtle or no dysmorphic features (macrocephaly, down-slanting palpebral fissures, epicanthal folds, expressionless face, clinodactyly, syndactyly) and short stature. A late-onset Lennox-Gastaut syndrome has been described. Cardiac defects have occasionally been reported. The clinical picture is highly variable even within the same family. Paternal duplications are rarely symptomatic (developmental delay/ behavioral disorders).\nEtiology\nThe syndrome is due to interstitial duplications that encompass the imprinted Prader-Willi/Angelman critical region (PWACR), of which deletions lead to Prader-Willi and Angelman syndromes (see these terms). The chromosome 15q proximal region is unstable and rich in low-copy repeat (LCR) sequences that are often substrates of clinically relevant rearrangements with various parent-of-origin effects, including duplications that occur preferentially on the maternal chromosome. The causative genes are imprinted and expressed from the maternal allele. Only two maternally expressed genes, UBE3A and ATP10C, are located in the imprinted domain. Interstitial duplications are of an almost uniform 4 Mb size, sharing the same breakpoints with deletions, and about 2/3 of them appear to arise from an interchromosomal event, the remaining being intrachromosomal. Interstitial triplications have rarely been reported. Interstitial duplications occur usually de novo and are much less frequent than inverted duplications leading to the inv dup(15) syndrome (see this term).\nDiagnostic methods\nDiagnosis should be suspected in any child with early hypotonia, minor dysmorphic features, developmental delay/intellectual disability, ASD and seizures. Diagnosis is confirmed by standard cytogenetics (G-R-banding, able to identify most but not all duplications) and interphase fluorescence in situ hybridization (FISH) using probes from both proximal chromosome 15 and the PWACR, which shows the dup15q11-q13 encompassing the PWACR. Molecular studies (microsatellite analysis on parental DNA and methylation-specific PCR on proband DNA) are needed to detect the parent-of-origin. Comparative genomic hybridization microarray (aCGH) is a powerful method to detect the duplication extent.\nDifferential diagnosis\nDifferential diagnosis includes the other causes of developmental delay, ASD, and epilepsy. Severe early hypotonia may lead to genetic evaluation for PWS, showing the dup15q11-q13. Genetic testing rules out other disorders with a similar clinical picture and associated with supernumerary marker chromosome (SMC) derived from 15, such as inv dup(15) or, more rarely, double SMC resulting in partial hexasomy of the maternally inherited PWACR.\nAntenatal diagnosis\nPrenatal diagnosis is possible. Cells, obtained by choriocentesis or amniocentesis, can be analyzed by a combination of cytogenetic (G-R-banding, FISH), and molecular (methylation analysis) methods.\nGenetic counseling\nGenetic counseling should be cautious as the dup15q11-q13 syndrome is usually sporadic and rarely familial.\nManagement and treatment\nThe multidisciplinary management includes a comprehensive neurological and developmental evaluation. A video-EEG study is recommended to characterize the seizures and to determine the first choice pharmacotherapy. Regular follow-up is essential, as the seizures may be hard to control. Developmental evaluations allow planning early physical, occupational and speech interventions. Cardiac ultrasound should be performed in all carriers to exclude a cardiac defect.\nPrognosis\nSurvival is not significantly reduced.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Marie-France PORTNOI"}
{"Disease Name": "15q13.3 microdeletion syndrome", "Disease Definition": "15q13.3 microdeletion (microdel15q13.3) syndrome is characterized by a wide spectrum of neurodevelopmental disorders with no or subtle dysmorphic features.", "ORPHA ID": 199318, "Summary": "Epidemiology\nIts prevalence is unknown; nearly 150 cases have been reported, including a subset of healthy relatives of affected individuals. Males are more likely to be symptomatic.\nClinical description\nThe syndrome manifests in childhood or later in life. Patients present with developmental delay, mainly in speech acquisition, cognitive impairment in about half of the cases (usually mild, sometimes moderate to severe), idiopathic generalized epilepsy (IGE, including childhood or juvenile absence epilepsy, juvenile myoclonic epilepsy (see these terms) and epilepsies with generalized tonic-clonic seizures), neurobehavioral disorders of the autistic or psychotic spectrum (including impaired expressive language, poor eye contact, repetitive movements, hyperactivity, impulsive and/or aggressive behavior, and disturbed social interactions). Subtle dysmorphic features may be present (down-slanting palpebral fissures, prominent nasal tip, large ears, strabismus, clinodactyly of the 5th finger, pigmented naevi). Short stature, macrocephaly and hypotonia are common. Congenital heart defects are rare. Asymptomatic carriers may have a history of learning difficulties.\nEtiology\nThe syndrome is due to submicroscopic deletions in the proximal 15q region, known for its instability and high density of low-copy repeat (LCR) sequences mediating non-allelic homologous recombination (NAHR), resulting in genomic rearrangements. Six breakpoints (BPs), clustered in LCRs, are mapped to the 15q11q14 region. 15q13.3 recurrent 1.5 Mb deletion between BP4 and BP5, results in loss of six known genes including CHRNA7. Haplo-insufficiency of CHRNA7 might be responsible for most of the neurodevelopmental disorders associated with the deletion. Occasional larger BP3-BP5 deletions do not seem to differ clinically.\nDiagnostic methods\nDiagnosis should be suspected in any infant or child with developmental delay/intellectual disability, autism, schizophrenia, seizures, hypotonia, and/or minor dysmorphic features. Microdel15q13.3 is not detected using conventional karyotyping (G-banding) but can be detected by fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridization (aCGH).\nDifferential diagnosis\nDifferential diagnosis comprises the other causes of intellectual deficit, schizophrenia, autism and epilepsy. Genetic testing rules out the other 15q proximal anomalies associated with a similar clinical picture.\nAntenatal diagnosis\nPrenatal diagnosis is possible through chorionic villus sampling or amniocentesis analyzed by cytogenetic (FISH) and molecular methods.\nGenetic counseling\nAround 25% of deletions occur de novo while 75% are inherited in an autosomal dominant manner with variable expressivity and incomplete penetrance. Of the inherited cases, approximately 25% are inherited paternally and 75% maternally. Genetic counseling should be offered cautiously as the syndrome may be either sporadic or familial. In cases where the deletion is inherited, siblings have a 50% risk of inheriting the deletion. However, not all carriers will develop the syndrome.\nManagement and treatment\nThe clinical picture should guide treatment. Early educational interventions are recommended in patients with cognitive impairment and autism. Epilepsy, autism and/or schizophrenia should be treated according to standard guidelines. Cardiac ultrasound should be performed in all carriers to exclude a congenital heart defect. Management in healthy carriers is not necessary, although medical awareness of signs that may become apparent later in life, e.g. schizophrenia, is recommended.\nPrognosis\nPrognosis depends on the clinical features. Carriers with learning difficulties in childhood often function normally in adulthood. Survival does not seem to be reduced in the absence of a congenital heart defect.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Dr B. [Boukje] DE VRIES  - Dr Marie-France PORTNOI"}
{"Disease Name": "15q24 microdeletion syndrome", "Disease Definition": "15q24 microdeletion syndrome is a rare chromosomal anomaly characterized cytogenetically by a 1.7-6.1 Mb deletion in chromosome 15q24 and clinically by pre- and post-natal growth retardation, intellectual disability, distinct facial features, and genital, skeletal, and digital anomalies.", "ORPHA ID": 94065, "Summary": "Epidemiology\nThe prevalence of 15q24 deletion syndrome is unknown. To date, 19 cases with clinical data and detailed mapping of genomic breakpoints have been reported.\nClinical description\nAt birth, approximately 1/3 of patients have low birth weight consistent with intrauterine growth retardation. Feeding difficulties and failure to thrive are reported in about 20%. In later childhood, 30% show growth retardation and short stature and 17% obesity. Growth hormone (GH) deficiency may be present. Growth delay, feeding difficulties, and distinct facial features (long face with high anterior hairline, epicanthal folds, hypertelorism, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, long smooth philtrum, and small mouth with full lower lip) are the most common early presenting symptoms. Most patients (90%) have digital deformities (proximally implanted and/or hypoplastic thumbs, clinodactyly, brachydactyly, overriding toes, toe syndactyly, small hands). Approximately 60% have skeletal complications (joint laxity and scoliosis). Hernias are found as well as hypotonia (60%). Eye abnormalities are common (nystagmus and strabismus). Ear abnormalities are variable but common (large ears, ear lobe pits, anteverted ear lobes, and protuberant ears). Genital abnormalities are common in males (60%). Mild to moderate developmental delay is found in all patients. Behavior abnormalities, such as autism, hyperactivity, aggression, and attention deficit are reported in 37%. Approximately 50% of patients have abnormal brain imaging on magnetic resonance imaging (MRI). Nearly 40% have a history of recurrent infections. Recurrent ear infections may be a predisposing factor to hearing loss (25%). Microcephaly is uncommon (20%). Other congenital malformations, while rare, can be severe and include cardiovascular malformations, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and myelomeningocele (see these terms).\nEtiology\nThe syndrome is caused by a microdeletion of 1.7 to 6.1 Mb in size in chromosome 15q24 which usually results from nonallelic homologous recombination (NAHR). The smallest region of overlap (SRO) spans a 1.2 Mb region including several candidate genes that may predispose to many of the clinical features: CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK.\nDiagnostic methods\nOligonucleotide array CGH (aCGH) with confirmation by fluorescent in-situ hybridization (FISH) detects most, if not all, deletions of 15q24. Karyotypes are typically normal.\nDifferential diagnosis\nDifferential diagnoses include other genetic syndromes, particularly monosomy 22q11, Prader-Willi, and Noonan syndromes (see these terms).\nAntenatal diagnosis\nDeletion of 15q24 can be detected in amniotic fluid or chorionic villi samples. Since routine karyotyping is not sufficient to detect the deletion, aCGH should be performed.\nGenetic counseling\nThe deletion occurred as a de novo event in all reported patients when parents were available for testing. Parental aCGH and/or FISH studies are recommended to provide accurate genetic counseling.\nManagement and treatment\nManagement should be multi-disciplinary with the primary care physician and clinical geneticist playing crucial roles in appropriate screening, surveillance, and care. At the time of diagnosis, baseline echocardiograms, audiologic, ophthalmologic, and developmental assessments are needed. Growth and feeding should be monitored closely.\nPrognosis\nThe prognosis is variable and depends on the severity and extent of congenital malformations.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Ayman EL-HATTAB"}
{"Disease Name": "16p11.2p12.2 microdeletion syndrome", "Disease Definition": "16p11.2-p12.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay and facial dysmorphism.", "ORPHA ID": 261211, "Summary": "Epidemiology\nIt has been clinically and molecularly characterized in 5 patients.\nClinical description\nFacial features include flat facies, downslanting palpebral fissures, low-set and malformed ears. Orofacial clefting, heart defects, short stature, feeding difficulties and hypotonia can be observed.\nEtiology\nThis syndrome is caused by an interstitial deletion encompassing 16p11.2-p12.2. These deletions arise de novo and are flanked by segmental duplications suggesting that the underlying mechanism is non-allelic homologous recombination (NAHR). They were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH).\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "16p11.2p12.2 microduplication syndrome", "Disease Definition": "16p11.2p12.2 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from the partial duplication of the short arm of chromosome 16 with a highly variable phenotype typically characterized by developmental/psychomotor delay (particularly of speech), intellectual disability, autism spectrum disorder and/or obsessive and repetitive behavior, behavioral problems (such as aggression and outbursts), dysmorphic facial features (triangular face, deep set eyes, broad and prominent nasal bridge, upslanting or narrow palpebral features, hypertelorism). Additionally, finger/hand anomalies, short stature, microcephaly and slender build are frequently described.", "ORPHA ID": 261204, "Summary": ""}
{"Disease Name": "16p12.1p12.3 triplication syndrome", "Disease Definition": "16p12.1p12.3 triplication syndrome is a rare chromosomal anomaly syndrome resulting from the partial triplication of the short arm of chromosome 16 characterized by global developmental delay, pre- or post-natal growth delay and distinctive craniofacial features, including short palpebral fissures, epicanthal folds, bulbous nose, thin upper vermillion border, apparently low-set ears and large ear lobes. Variable clinical features that have been reported include congenital heart disease, genitourinary abnormalities, visual anomalies or, less commonly, infantile hepatic disease. Patients are also reported to have tapered fingers.", "ORPHA ID": 485405, "Summary": ""}
{"Disease Name": "16p13.11 microdeletion syndrome", "Disease Definition": "16p13.11 microdeletion syndrome is a recently described syndrome characterized by developmental delay, microcephaly, epilepsy, short stature, facial dysmorphism and behavioral problems.", "ORPHA ID": 261236, "Summary": "Epidemiology\nIt has been clinically and molecularly characterized in fewer than 15 patients.\nClinical description\nFacial features include down-slanting palpebral fissures, short nose, low-set ears, wide mouth and thin upper lip. Variable congenital anomalies can also be observed.\nEtiology\nThis syndrome is caused by an interstitial deletion encompassing 16p13.11. The deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). The underlying mechanism is non-allelic homologous recombination (NAHR).\nGenetic counseling\nMicrodeletions appear de novo or are inherited from mildly affected or completely normal parents in an autosomal dominant manner, suggesting that the microdeletion has incomplete penetrance and variable expressivity. Two genes within the deleted region, NDE1 (nudE nuclear distribution gene E homolog 1) and NTAN1 (N-terminal asparagine amidase) may contribute to the neuro-cognitive phenotype.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "16p13.11 microduplication syndrome", "Disease Definition": "16p13.11 microduplication syndrome is a recently described syndrome associated with variable clinical features including behavioral abnormalities, developmental delay, congenital heart defects and skeletal anomalies.", "ORPHA ID": 261243, "Summary": "Epidemiology\nIt has been clinically and molecularly characterized in fewer than 20 patients.\nClinical description\nBehavioral abnormalities include attention deficit/hyperactivity disorder, aggression and disruptive temperament, and autistic spectrum disorders. Skeletal manifestations include hypermobility, craniosynostosis and polydactyly.\nEtiology\nThis syndrome is caused by interstitial duplications encompassing 16p13.11. The size of the rearrangements is variable. The duplications were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). The underlying mechanism is non-allelic homologous recombination (NAHR). The microduplications appear de novo or are inherited from mildly affected or completely normal parents, suggesting that the microduplication has incomplete penetrance and variable expressivity. Two genes, NDE1 (nudE nuclear distribution gene E homolog 1) and NTAN1 (N-terminal asparagine amidase) included in the duplicated region may contribute to the neurobehavioral phenotype. As the duplication is present in phenotypically normal parents of patients, as well as in the general population, the clinical significance of the 16p13.11 microduplication is still unclear.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "16p13.3 microduplication syndrome", "Disease Definition": "16p13.3 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from a partial duplication of the short arm of chromosome 16 and manifesting with a variable phenotype which is mostly characterized by: mild to moderate intellectual deficit and developmental delay (particularly speech), normal growth, short, proximally implanted thumbs and other hand and feet malformations (such as camptodactyly, syndactyly, club feet), mild arthrogryposis and characteristic facies (upslanting, narrow palpebral fissures, hypertelorism, mid face hypoplasia, bulbous nasal tip and low set ears). Other reported manifestations include cryptorchidism, inguinal hernia and behavioral problems.", "ORPHA ID": 96078, "Summary": ""}
{"Disease Name": "16q24.1 microdeletion syndrome", "Disease Definition": "A partial autosomal monosomy characterized clinically by lethal pulmonary disease that presents as severe respiratory distress and refractory pulmonary hypertension within a few hours after birth and typically results in death from respiratory failure within the first months of life. Characteristic histological features of lung tissue include paucity of alveolar wall capillaries, alveolar wall thickening, muscular hypertrophy of the pulmonary arteries, and malposition of the small pulmonary veins. Various additional congenital malformations may be associated, mostly gastrointestinal (intestinal malrotation and atresias, anular pancreas), genitourinary (dilatation of urinary tracts, duplicated uterus) and cardiovascular anomalies (hypoplastic left heart and other congenital heart defects).", "ORPHA ID": 352629, "Summary": ""}
{"Disease Name": "16q24.3 microdeletion syndrome", "Disease Definition": "16q24.3 microdeletion syndrome is a recently described syndrome associated with variable developmental delay, facial dysmorphism, seizures and autistic spectrum disorder.", "ORPHA ID": 261250, "Summary": "Epidemiology\nIt has been clinically and molecularly characterized in 4 patients.\nClinical description\nFacial dysmorphism includes high forehead, large ears, smooth philtrum, pointed chin and wide mouth. Anomalies of the brain and neonatal thrombocytopenia can be observed.\nEtiology\nThis syndrome is caused by an interstitial deletion encompassing 16q24.3. These de novo deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They vary in size, the common region of overlap is only 90 kb and comprises two candidates genes, ANKRD11 (Ankyrin Repeat Domain 11) and ZNF778 (Zinc Finger 778).\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "17p11.2 microduplication syndrome", "Disease Definition": "17p11.2 microduplication syndrome is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 17, typically characterized by hypotonia, poor feeding, failure to thrive, developmental delay (particularly cognitive and language deficits), mild-moderate intellectual deficit, and neuropsychiatric disorders (behavioral problems, anxiety, attention deficit hyperactivity disorder, autistic spectrum disorder, bipolar disorder). Structural cardiovascular anomalies (dilated aortic root, bicommissural aortic valve, atrial/ventricular and septal defects) and sleep disturbance (obstructive and central sleep apnea) are also frequently associated.", "ORPHA ID": 1713, "Summary": ""}
{"Disease Name": "17p13.3 microduplication syndrome", "Disease Definition": "17p13.3 microduplication syndrome is characterized by variable psychomotor delay and dysmorphic features.", "ORPHA ID": 217385, "Summary": "Epidemiology\nIt has been recently described in less than ten patients.\nClinical description\nClinical presentation is variable but it is possible to delineate a common clinical spectrum comprising mild to moderate psychomotor delay, hypotonia and discrete craniofacial dysmorphic features including a high forehead with frontal bossing, a small nose and a small mouth.\nEtiology\nThe microduplication was identified by microarray-based comparative genomic hybridization (a-CGH). It encompasses the same region that is deleted in Miller-Dieker (17p13 deletion) syndrome (see this term).. The variable size of this de novo duplication indicates that mechanisms other than nonallelic homologous recombination (NAHR) may be responsible. Additional patients will further substantiate the significance of 17p13.3 duplication and contribute to delineation of the clinical spectrum.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "17q11 microdeletion syndrome", "Disease Definition": "17q11 microdeletion syndrome is a rare severe form of neurofibromatosis type 1 (NF1; see this term) characterized by mild facial dysmorphism, developmental delay, intellectual disability, increased risk of malignancies, and a large number of neurofibromas.", "ORPHA ID": 97685, "Summary": "Epidemiology\nThe prevalence of 17q11 microdeletion syndrome is not known. About 5% of NF1 cases are reported to have deletions of the entire NF1 gene. More than 170 affected patients have been reported to date.\nClinical description\nAffected individuals often have unusual body habitus and facial dysmorphism including facial coarsening, prominent forehead, ptosis, down-slanting palpebral fissures, hypertelorism, broad nose and nasal bridge, low set ears, and micrognathia. Patients develop a large number of neurofibromas, often with early onset, including multiple cutaneous neurofibromas, and less commonly plexiform neurofibromas. Other characteristic features include attention deficit/hyperactivity disorder (AD/HD), delayed cognitive development and intellectual disability. Some patients are reported to have microcephaly or macrocephaly, optic pathway glioma, iris coloboma (see these terms), heart defects (mitral valve prolapse, aortic dilatation), large hands and feet, connective tissue dysplasia (joint hyperflexibility, soft palm skin), muscular hypotonia, scoliosis, pectus excavatum, and bone cysts. A higher risk of malignancy for NF1 and non-NF1 tumors is reported: malignant peripheral nerve sheath tumors (lifetime risk of 16-26%), retroperitoneal fibrosarcoma, and medulloblastoma with extensive nodularity (see this term).\nEtiology\nGermline and mosaic microdeletions of the NF1 gene and its flanking regions caused by non-allelic homologous recombination are reported in patients with this disorder. Most occur de novo.\nGenetic counseling\nAs most cases are de novo, recurrence risk for offspring of unaffected parents is very low. Affected individuals have a 50% risk of transmitting the microdeletion, and prenatal and preimplantation genetic diagnosis is possible.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Eric LEGIUS"}
{"Disease Name": "17q11.2 microduplication syndrome", "Disease Definition": "17q11.2 microduplication syndrome is characterized by dysmorphic features and intellectual deficit.", "ORPHA ID": 139474, "Summary": "Epidemiology\nIt has been described in seven patients within one family.\nClinical description\nThere is a marked clinical heterogeneity between patients. Striking findings are intellectual deficit, early onset of baldness (15 years of age) and dental enamel hypoplasia. Craniofacial dysmorphic features include microcephaly, long midface, malar hypoplasia, sparse eyebrows and thin upper lip. Short stature is common.\nEtiology\n17q11.2 microduplication encompasses the NF1 region. This region is involved in the NF1 microdeletion syndrome (neurofibromatosis type 1, see this term). The microduplication was recently identified by microarray-based comparative genomic hybridization (array-CGH). The underlying mechanism may be non-allelic homologous recombination (NAHR). The study of pedigree suggests that this microduplication segregates within the family for at least two generations.\nGenetic counseling\nTwo patients displayed a normal clinical presentation, suggesting an autosomal dominant pattern of inheritance with incomplete penetrance.\n\n                            Last update: \n                            November 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "17q12 microdeletion syndrome", "Disease Definition": "17q12 microdeletion syndrome is a rare chromosomal anomaly syndrome resulting from the partial deletion of the long arm of chromosome 17 characterized by renal cystic disease, maturity onset diabetes of the young type 5, and neurodevelopmental disorders, such as cognitive impairment, developmental delay (particularly of speech), autistic traits and autism spectrum disorder. Müllerian aplasia in females, macrocephaly, mild facial dysmorphism (high forehead, deep set eyes and chubby cheeks) and transient hypercalcaemia have also been reported.", "ORPHA ID": 261265, "Summary": ""}
{"Disease Name": "17q12 microduplication syndrome", "Disease Definition": "17q12 microduplication syndrome is a rare chromosomal anomaly with variable phenotypic expression and reduced penetrance associated with developmental delay, mild to severe intellectual disability, speech delay, seizures, microcephaly, behavioral abnormalities, autism spectrum disorder, eye or vision defects (such as strabismus, astigmatism, amblyopia, cataract, coloboma, and microphthalmia), non-specific dysmorphic features, hypotonia, cardiac and renal anomalies, schizophrenia.", "ORPHA ID": 261272, "Summary": ""}
{"Disease Name": "17q21.31 microduplication syndrome", "Disease Definition": "The newly described 17q21.31 microduplication syndrome is associated with a broad clinical spectrum, of which behavioral disorders and poor social interaction seem to be the most consistent.", "ORPHA ID": 217340, "Summary": "Epidemiology\nOnly five patients have been reported to date.\nClinical description\nAll patients have behavioral disorders suggesting that some of the genes within the duplication interval may be candidates for the autistic spectrum. Intellectual skills range from normal to mild intellectual deficiency. Other features are variable with no striking common phenotypic features.\nEtiology\nThis microduplication syndrome was identified by microarray-based comparative genomic hybridization (aCGH). It seems reasonable to postulate that the underlying mechanism is a non-allelic homologous recombination (NAHR). Moreover, an inversion within 17q21.31, present in the Western European population at a frequency of 20%, was shown to be closely associated with the rearrangement. Parental origin was investigated in 3 patients. In all cases duplication was of maternal origin.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "17q23.1q23.2 microdeletion syndrome", "Disease Definition": "17q23.1q23.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay, microcephaly, short stature, heart defects and limb abnormalities.", "ORPHA ID": 261279, "Summary": "Epidemiology\nIt has been clinically and molecularly characterized in 7 patients.\nClinical description\nAll individuals had mild to moderate developmental delay, in particular speech delay. All except one had heart defects, including mainly patent ductus arteriosus or atrial septal defect. Limb abnormalities include long, thin fingers and toes, and hypoplasia of patellae. Scoliosis is also present. Patients had some mild and unspecific dysmorphic facial features.\nEtiology\nThe syndrome is caused by an interstitial deletion encompassing 17q23.1q23.2. The deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). The underlying mechanism is non-allelic homologous recombination (NAHR). Parental FISH testing in five of the seven cases confirmed a de novo origin. The minimal deletion region of 2.2 Mb encompasses 2 transcription factors, TBX2 and TBX4, which are good candidate genes for explaining the phenotype.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "17q24.2 microdeletion syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic features-intellectual disability syndrome characterized by developmental and speech delay, intellectual disability, feeding difficulties, failure to thrive, growth retardation, and associated malformations such as abnormality of fingers and toes (i.e. clinodactyly of the 5th finger, 2-3 toe syndactyly), microcephaly, heart defects, and upper airways anomalies. Observed facial dysmorphism includes hypertelorism, small, narrow or downslanting palpebral fissures, ptosis, epicanthus, ear malformations, broad nasal bridge, bulbous/prominent nose, short philtrum, thin lips, retrognathia/micrognathia, arched/cleft palate, and dental anomalies. Additional variable manifestations include hearing and visual impairment, seizures, joint anomalies, obesity, and behavioral/psychiatric disorders.", "ORPHA ID": 529962, "Summary": ""}
{"Disease Name": "19p13.12 microdeletion syndrome", "Disease Definition": "19p13.12 microdeletion syndrome is a newly described syndrome characterized by moderate to severe developmental delay, language delay, bilateral sensorineural and/or conductive hearing loss and facial dysmorphism.", "ORPHA ID": 254346, "Summary": "Epidemiology\nIt has been reported in 6 patients to date.\nClinical description\nFacial dysmorphism includes brachycephaly, anteverted nares, and ear malformations. Cardiac defects and abnormal behavior characterized by auto- and hetero-aggressivity and hyperactivity can be observed.\nEtiology\nThis interstitial microdeletion was identified by comparative genomic hybridization (CGH) microarray and its size is variable.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "19p13.13 microdeletion syndrome", "Disease Definition": "A rare partial autosomal monosomy characterized by global developmental delay, moderate intellectual disability, macrocephaly, overgrowth, hypotonia, and facial dysmorphism (frontal bossing, down-slanting palpebral fissures). Other associated features variably include ataxia, seizures, ventriculomegaly, ocular abnormalities (strabismus, optic nerve hypoplasia) and gastrointestinal problems (abdominal pain, vomiting, constipation).", "ORPHA ID": 357001, "Summary": ""}
{"Disease Name": "19p13.3 microduplication syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability characterized by intrauterine growth retardation, microcephaly, hypotonia, motor and neurodevelopmental delay, speech delay, intellectual disability, and mild dysmorphic features.", "ORPHA ID": 447980, "Summary": ""}
{"Disease Name": "19q13.11 microdeletion syndrome", "Disease Definition": "The 19q13.11 microdeletion is characterized by several major features including pre and postnatal growth retardation, slender habitus, severe postnatal feeding difficulties, microcephaly, intellectual deficit with speech disturbance, hypospadias and ectodermal dysplasia presented by scalp aplasia, thin and sparse hair, eyebrows and eyelashes, thin and dry skin and dysplasic nails.", "ORPHA ID": 217346, "Summary": "Epidemiology\nTo date, the syndrome has been identified in five patients.\nClinical description\nMinor dysmorphic features include a long face, high forehead, retrognathia, thin lips, V shaped nasal tip, hypoplastic alae nasi, prominent columella, and large and simple ears.\nEtiology\nThe microdeletion was identified by microarray-based comparative genomic hybridization (aCGH). Haploinsufficiency of one or more genes in the 19q13.11 region could cause this microdeletion syndrome. The careful clinical examination and the molecular characterization of additional patients with a similar chromosomal anomaly are needed to further delineate the clinical features and refine the minimal critical region.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "1p21.3 microdeletion syndrome", "Disease Definition": "1p21.3 microdeletion syndrome is an extremely rare chromosomal anomaly characterized by severe speech and language delay, intellectual deficiency, autism spectrum disorder(see this term).", "ORPHA ID": 293948, "Summary": "Epidemiology\nLess than 10 cases have been reported to date.\nClinical description\n1p21.3 microdeletion syndrome is characterized by severe speech and language delay, a borderline-mild to mild-moderate intellectual deficiency, autism spectrum disorder (see this term) features, and minor dysmorphic facial features such as long ears, deep set eyes, a broad nasal tip and a thick lower lip. Affected individuals have normal gross motor development without major abnormalities, they are often very shy and friendly with a tendency to overeat.\nEtiology\n1p21.3 microdeletion syndrome is caused by a hemizygous interstitial microdeletion on the short arm of chromosome 1, occurring mostly de novo, that implicates DPYD (dihydropyrimidine dehydrogenase) and MIR137 genes associated with miRNA pathways.\n\n                            Last update: \n                            November 2012\n\n\n                            - Expert reviewer(s): \n                            Pr T. [Tjitske] KLEEFSTRA"}
{"Disease Name": "1p31p32 microdeletion syndrome", "Disease Definition": "1p31p32 microdeletion syndrome is a rare chromosomal anomaly syndrome, resulting from the partial deletion of the short arm of chromosome 1, characterized by developmental delay, corpus callosum agenesis/hypoplasia and craniofacial dysmorphism, such as macrocephaly (caused by hydrocephalus or ventriculomegaly), low-set ears, anteverted nostrils and micrognathia. Urinary tract defects (e.g. vesicoureteral reflux, urinary incontinence) are also frequently associated. Other reported variable manifestations include hypotonia, tethered spinal cord, Chiari type I malformation and seizures.", "ORPHA ID": 401986, "Summary": ""}
{"Disease Name": "1p35.2 microdeletion syndrome", "Disease Definition": "A rare chromosomal anomaly characterized by an intrauterine and postnatal growth retardation, short stature, developmental delay, learning difficulties, hearing loss, hypermetropia,and a recognisable facial dysmorphism including prominent forehead, long, myopathic facies, fine eyebrows, small mouth and micrognathia.", "ORPHA ID": 456298, "Summary": ""}
{"Disease Name": "1p36 deletion syndrome", "Disease Definition": "A rare chromosomal anomaly characterized by distinctive facial dysmorphic features, hypotonia, developmental delay, intellectual disability, seizures, heart defects, poor/absent speech, and prenatal onset growth deficiency.", "ORPHA ID": 1606, "Summary": "Epidemiology\n1p36 deletion syndrome is considered one of the most common chromosome deletion syndromes; in the USA, the birth prevalence is estimated at 1/ 5,000. A higher frequency is observed among females.\nClinical description\nPatients share recognizable craniofacial dysmorphism with microbrachycephaly, a large, late-closing anterior fontanel (>3 cm at birth), straight eyebrows, deep-set eyes, broad and depressed nasal bridge, midface retrusion, posteriorly rotated, low-set, abnormal ears, long philtrum, and pointed chin. Brachydactyly, camptodactyly and short feet are also characteristic. Almost all patients suffer from congenital hypotonia, contributing to feeding difficulties, delay in motor development and fine motor skills, and delayed or absent speech. A variable level of intellectual disability is observed in all patients. Other symptoms include prenatal-onset growth deficiency, structural brain abnormalities, seizures, congenital heart defects, eye/vision problems, hearing loss (sensorineural or conductive/glue ear), skeletal anomalies, abnormalities of the external genitalia and, less frequently, renal abnormalities and hypothyroidism.\nEtiology\n1p36 deletion syndrome is caused by a partial heterozygous deletion that primarily involves the distal part of the short arm of chromosome 1, with breakpoints ranging from 1p36.13 to 1p36.33. About 50% of cases are due to a de novo terminal 1p36 deletion, around 29% to an interstitial deletion; remaining cases comprise more complex chromosome rearrangements.\nDiagnostic methods\nDiagnosis is based on the clinical picture and is confirmed by chromosomal analysis. Molecular techniques are used for the genetic characterization of the deletion (fluorescence in situ hybridization, comparative genomic hybridization array). An evaluation for congenital heart defects with an echocardiogram and electrocardiagram; brain abnormalities with magnetic resonance imaging; seizures with an electroencephalogram; a neurodevelopmental assessment, and standard examinations for eye/vision problems, hearing loss, and skeletal and renal abnormalities are recommended.\nDifferential diagnosis\nDifferential diagnosis includes Rett syndrome, Angelman syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, Cohen syndrome, and Aicardi syndrome.\nAntenatal diagnosis\nAntenatal testing is feasible when a 1p36 chromosome rearrangement is already identified in a family member.\nGenetic counseling\nMost cases are sporadic, but an unbalanced translocation may be inherited from a parent with a balanced rearrangement.\nManagement and treatment\nManagement should be multi-disciplinary and include a regular follow-up. Early diagnosis and access to personalized rehabilitation therapies focusing on motor development, cognition, communication, and social skills are highly recommended. The use of sign language is helpful. Some congenital heart defects may resolve on their own, others may require medication or surgery. Epileptic seizures are treated with standard antiepileptics. Infantile spasms are responsive to corticotrophin. Feeding and growth should be monitored as feeding difficulties are common early on. Triiodothyronine, thyroxine, and thyrotropin levels should be evaluated at diagnosis, and, then, once a year.\nPrognosis\nThe severity of the 1p36 deletion syndrome varies between affected individuals. Seizures and other medical issues seem to improve with time. Patients will remain dependent on others for most activities of daily living and will require medical support throughout life. Individuals with 1p36 deletion syndrome survive well into adult life.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Agatino BATTAGLIA"}
{"Disease Name": "1q21.1 microdeletion syndrome", "Disease Definition": "1q21.1 microdeletion syndrome is a newly described recurrent deletion syndrome with variable clinical manifestations but without the clinical picture of thrombocytopenia - absent radius (TAR) syndrome.", "ORPHA ID": 250989, "Summary": "Epidemiology\nIt has been described in 46 patients to date.\nClinical description\nThe clinical phenotype is extremely variable; the most common but non-constant clinical findings include microcephaly, developmental delay or mild intellectual deficit, slight facial dysmorphic features and eye abnormalities. Congenital malformations are not common. Autism spectrum disorders, schizophrenia or attention deficit hyperactivity disorder have been noted occasionally.\nEtiology\nThis syndrome is caused by a recurrent 1.35Mb deletion in the distal 1q21.1 region distinct from the deletion region implicated in TAR syndrome (see this term).\nDiagnostic methods\nThis microdeletion was identified by comparative genomic hybridization (CGH) microarray and is only diagnosed by molecular cytogenetics. It cannot be identified by routine chromosome analysis.\nGenetic counseling\nThe underlying mechanism is non-allelic homologous recombination (NAHR). Deletions appear de novo or can be inherited in an autosomal dominant manner from mildly affected or completely normal parents. This suggests that the distal 1q21.1 microdeletion has incomplete penetrance and variable expressivity.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "1q21.1 microduplication syndrome", "Disease Definition": "1q21.1 microduplication syndrome is a rare partial autosomal trisomy/tetrasomy with incomplete penetrance and variable expression characterized by macrocephaly, developmental delay, intellectual disability, psychiatric disturbances (autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, mood disorders) and mild facial dysmorphism (high forehead, hypertelorism). Other associated features include congenital heart defects, hypotonia, short stature, scoliosis.", "ORPHA ID": 250994, "Summary": ""}
{"Disease Name": "1q41q42 microdeletion syndrome", "Disease Definition": "1q41q42 microdeletion syndrome is a chromosomal anomaly characterized by a severe developmental delay and/or intellectual disability, typical facial dysmorphic features, brain anomalies, seizures, cleft palate, clubfeet, nail hypoplasia and congenital heart disease.", "ORPHA ID": 250999, "Summary": ""}
{"Disease Name": "1q44 microdeletion syndrome", "Disease Definition": "1q44 microdeletion syndrome is a newly described syndrome associated with facial dysmorphism, developmental delay, in particular of expressive speech, seizures and hypotonia.", "ORPHA ID": 238769, "Summary": "Epidemiology\nIt has been reported in four unrelated patients.\nClinical description\nThe most common facial features include microcephaly, hypertelorism and thin upper lip. An abnormal corpus callosum (agenesis, hypogenesis or slightly reduced thickness) is observed in all affected patients.\nEtiology\nThis microdeletion was identified by array CGH (comparative genomic hybridization).\n\n                            Last update: \n                            October 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "2-aminoadipic 2-oxoadipic aciduria", "Disease Definition": "A rare disorder of lysine and tryptophan metabolism characterized by 2-aminoadipic and 2-oxoadipic aciduria. Patients may also present with increased urinary excretion of alpha-hydroxyadipic acid. Variable clinical presentations have been found in patients including hypotonia, developmental delay, mild to severe intellectual disability, ataxia, epilepsy, and behavioral disorders (most commonly attention deficit hyperactivity disorder). However, many individuals with the biochemical phenotype are completely asymptomatic and thus the clinical significance of the condition is questionable.", "ORPHA ID": 79154, "Summary": ""}
{"Disease Name": "2-hydroxyglutaric aciduria", "Disease Definition": "2-Hydroxyglutaric aciduria is a group of neurometabolic disorders with a wide clinical spectrum ranging from severe neonatal presentations to progressive forms, and asymptomatic cases, characterized biochemically by increased levels of 2-hydroxyglutaric acid in the plasma, cerebrospinal fluid and urine.", "ORPHA ID": 19, "Summary": "Epidemiology\nThe exact prevalence and incidence of the disorders are not known, but fewer than 300 patients have been reported to date.\nClinical description\nThere are two enantiomeric forms of 2-hydroxyglutaric acid, i.e. D-2-hydroxyglutaric acid and L-2-hydroxyglutaric acid. L-2-hydroxyglutaric aciduria (see this term) is characterized by psychomotor retardation, cerebellar ataxia and epilepsy, and D-2-hydroxyglutaric aciduria (see this term) is characterized by variable metabolic, neurological and dysmorphic manifestations.\nEtiology\nMutations in the L2HGDH gene (14q22.1) gene have been implicated in L-2-hydroxyglutaric aciduria, and mutations in the D2HGDH (2q37.3) and IDH2 (15q26.1) genes in D-2-hydroxyglutaric aciduria.\nGenetic counseling\nL-2-hydroxyglutaric aciduria and D-2-hydroxyglutaric aciduria caused by mutations in the L2HGDH and D2HGDH genes, respectively, follow an autosomal recessive pattern of inheritance. In contrast, D-2-hydroxyglutaric aciduria caused by a specific heterozygous gain-of-function mutation in the IDH2 gene, is an autosomal dominant trait and is usually caused by de novo mutations.\n\n                            Last update: \n                            June 2012\n\n\n                            - Expert reviewer(s): \n                            Dr E.A. [Eduard] STRUYS"}
{"Disease Name": "2-methylbutyryl-CoA dehydrogenase deficiency", "Disease Definition": "A rare organic aciduria characterized by impaired isoleucine degradation with increased plasma or whole blood C5 acylcarnitine levels (typically observed in newborn screening) and increased urinary excretion of N-methylbutyrylglycine. The condition is usually clinically asymptomatic, although patients with muscular hypotonia, developmental delay, and seizures (among others) have been reported.", "ORPHA ID": 79157, "Summary": ""}
{"Disease Name": "20p12.3 microdeletion syndrome", "Disease Definition": "20p12.3 microdeletion syndrome is a recently described syndrome characterized by Wolff-Parkinson-White syndrome (see this term), variable developmental delay and facial dysmorphism.", "ORPHA ID": 261295, "Summary": "Epidemiology\nIt has been clinically and molecularly characterized in 3 patients.\nClinical description\nDysmorphic features include macrocephaly, hypertelorism, down-slanting palpebral fissures and microstomia.\nEtiology\nThis syndrome is caused by an interstitial deletion encompassing 20p12.3. All these deletions except one occurred de novo and were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size with the smallest region of overlap including only one gene, BMP2, which is a good candidate gene for explaining the phenotype of Wolff-Parkinson-White syndrome.\n\n                            Last update: \n                            June 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "20p13 microdeletion syndrome", "Disease Definition": "20p13 microdeletion syndrome is a rare chromosomal anomaly characterized by developmental delay, mild to moderate intellectual disability, epilepsy, and unspecific dysmorphic signs. High palate, delayed permanent tooth eruption, hypoplastic fingernails, clinodactyly and short fingers have also been reported.", "ORPHA ID": 313781, "Summary": ""}
{"Disease Name": "20q11.2 microdeletion syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability characterized by psychomotor delay, hypotonia, feeding difficulties, failure to thrive, anomalies of the hands and feet (clinodactyly, camptodactyly, brachydactyly, feet malposition), and craniofacial dysmorphism. Associated prenatal growth retardation, and gastrointestinal, heart and eye anomalies have been reported.", "ORPHA ID": 444051, "Summary": ""}
{"Disease Name": "20q11.2 microduplication syndrome", "Disease Definition": "20q11.2 microduplication syndrome is a rare chromosomal anomaly syndrome, due to partial duplication of the long arm of chromosome 20, characterized by psychomotor and developmental delay, moderate intellectual disability, metopic ridging/trigonocephaly, short hands and/or feet and distinctive facial features (epicanthus, hypoplastic supraorbital ridges, horizontal/downslanting palpebral fissures, small nose with depressed nasal bridge and anteverted nostrils, prominent cheeks, retrognathia and small, thick ears). Growth delay and cryptororchidism are often associated features.", "ORPHA ID": 363659, "Summary": ""}
{"Disease Name": "20q13.33 microdeletion syndrome", "Disease Definition": "A rare chromosomal anomaly syndrome resulting from the partial deletion of the long arm of chromosome 20 with a highly variable phenotype typically characterized by hypotonia, intellectual disability, cognitive and language deficits (including decreased or absent speech), pre and post-natal growth retardation, feeding difficulties, microcephaly, and malformed hands and feet. Neurodevelopmental disorders (including hyperactivity, social interactive problems and autism spectrum disorder), seizures and dysmorphic facial features (high forehead, hypertelorism, malformed ears, broad nasal bridge, bulbous nasal tip, thin upper lip, small chin) are frequently associated.", "ORPHA ID": 261311, "Summary": ""}
{"Disease Name": "21q deletion syndrome", "Disease Definition": "Monosomy 21 is a chromosomal anomaly characterized by the loss of variable portions of a segment of the long arm of chromosome 21 that leads to an increased risk of birth defects, developmental delay and intellectual deficit.", "ORPHA ID": 574, "Summary": "Epidemiology\nMonosomy 21 is a very rare condition with less than 50 cases described in the literature. Full monosomy 21 is probably not compatible with life.\nClinical description\nThe severity of the phenotype depends on the location and size of the deleted area. In general, proximal and distal deletions lead to a milder phenotype (e.g. few dysmorphic features or congenital anomalies, and mild to moderate intellectual deficit), whereas deletions involving band 21q22 have a more severe effect on the phenotype. In the later case, the most common clinical features include intrauterine and postnatal growth retardation, microcephaly, prominent occiput, and facial dysmorphism characterized by up or down-slanted small palpebral fissures, prominent nasal bridge with a broad nose, and large ears. Multiple malformations including structural brain malformations (e.g. cerebral atrophy, cortical dysplasia, and corpus callosum dysgenesis) and heart defects (e.g. patent ductus arteriosus, septal defects) are also frequently observed. Severe intellectual deficit is common. Joints may be stiff and held in an unusual position. Abnormal muscle tone, respiratory infections and seizures are usual. Specific blood disorders (e.g. thrombocytopenia, myelodysplasia) have been reported.\nEtiology\nThe disease is due to the loss of variable portions of the long arm of chromosome 21. Partial 21q deletions are interstitial or terminal. They occur de novo or as the result of a parental rearrangement. Monosomy due to malsegregation of a parental rearrangement is usually associated with another imbalance that could complicate the phenotype. Some cases result from formation of a ring chromosome 21.\nDiagnostic methods\nDiagnosis is based on clinical findings that lead to chromosomal analysis. Depending on their size, partial 21q deletions may be diagnosed by classical or molecular karyotyping. Molecular techniques are necessary for the genetic characterization of the deletion.\nAntenatal diagnosis\nPrenatal diagnosis of 21q deletion is possible by amniocentesis or chorionic villus sampling and cytogenetic analysis.\nGenetic counseling\nThe risk of having another affected child is higher if a chromosomal rearrangement is present in one of the parents.\nManagement and treatment\nManagement is multi-disciplinary and requires evaluation and treatment by a general pediatrician, and relevant specialists. Children will benefit from early assessment and access to the major developmental therapies. Physiotherapy may be important to improve both the muscle tone and the joints flexibility.\nPrognosis\nPrognosis depends on the size and location of the deletion. It is severe if band 21q22 is involved, with vital prognosis depending on the severity of congenital malformations.\n\n                            Last update: \n                            January 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Catherine TURLEAU"}
{"Disease Name": "21q22.11q22.12 microdeletion syndrome", "Disease Definition": "A rare, genetic, chromosomal anomaly syndrome resulting from a partial deletion of the long arm of chromosome 21 characterized by pre- and post-natal growth delay, short stature, intellectual disability, developmental delay with severe language impairment, thrombocytopenia, and craniofacial dysmorphism which may include microcephaly, downslanted palpebral fissures, low-set ears, broad nose, thin upper vermillion, and downturned corners of the mouth. Brain MRI abnormalities (such as agenesis of the corpus callosum), behavioral problems and seizures may be associated.", "ORPHA ID": 261323, "Summary": ""}
{"Disease Name": "22q11.2 deletion syndrome", "Disease Definition": "A rare chromosomal anomaly which causes a congenital malformation disorder that is typically characterized by cardiac defects, palatal anomalies, facial dysmorphism, developmental delay and immune deficiency.", "ORPHA ID": 567, "Summary": "Epidemiology\nThe worldwide prevalence at birth is estimated at 1/4,500-1/10,000.\nClinical description\n22q11.2 deletion syndrome shows a variable clinical phenotype that can range from mild to severe. Congenital heart defects (two-thirds of cases) include mainly conotruncal malformations such as ventricular septal defect, truncus arteriosus, tetralogy of Fallot and interrupted aortic arch. Anomalies of the aortic arch and vascular ring are frequent. More than 65% of patients present with palatal anomalies (e.g. velopharyngeal incompetence, submucous cleft palate or bifid uvula) that may lead to hypernasal speech and feeding difficulties. Overt cleft palate and cleft lip are less frequent. Most patients display subtle but recognizable facial features (e.g. ptosis, hypertelorism, epicanthal folds, prominent nasal root, malar flatness, small ears). Immune deficiency is the consequence of thymic aplasia/hypoplasia and improvement in T-cell production occurs over time. Patients have a higher risk of developing an autoimmune disease such as idiopathic thrombocytopenic purpura and juvenile idiopathic arthritis. Hypocalcemia as a consequence of hypoparathyroidism is frequent in the neonatal period and usually resolves but can reappear at any age. Additional clinical findings may include gastrointestinal anomalies (intestinal malrotation, imperforate anus), hearing loss, renal anomalies (renal agenesis), dental anomalies (enamel hypoplasia), and skeletal anomalies (scoliosis, clubfoot). Learning difficulties and developmental delay are almost always present. Psychiatric illness (anxiety, depression, schizophrenia) and Parkinson's disease are more frequent than in the general population.\nEtiology\nIn most cases, the syndrome is due to a 3 million base pair (Mb) deletion on the chromosomal region 22q11.2 that is flanked by low copy number repeats. The deletion is due to a non-allelic meiotic recombination during spermatogenesis or oogenesis. In ~15% of cases, the deletion is nested within the 3 Mb DiGeorge critical region and varies in size. Most deletions include the TBX1 gene that has been shown to be implicated in cardiac, parathyroid, thymus and facial structure development. The variable expression of the 22q11.2 phenotype is thought to be due to genetic modifiers on either the other 22q11.2 allele or on other chromosomes.\nDiagnostic methods\nDiagnosis is suspected upon clinical examination and confirmed by detection of the 22q11.2 deletion, using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH) or genome-wide SNP (single nucleotide polymorphism) microarrays.\nDifferential diagnosis\nDifferential diagnosis includes Smith-Lemli-Opitz syndrome, CHARGE syndrome, Alagille syndrome, VATER syndrome, Goldenhar syndrome and isotretinoin embryopathy.\nAntenatal diagnosis\nPrenatal diagnosis is possible in familial cases by chorionic villus sampling or amniocentesis, and in pregnancies where associated anomalies have been noted by fetal echocardiography. Preimplantation genetic diagnosis is possible.\nGenetic counseling\nThe deletion arises de novo in ~90% of the cases. The recurrence risk in the sibship of a de novo case is 2-3% due to of low-grade germline parental mosaicism. Affected individuals have a 50% risk of having an affected child.\nManagement and treatment\nManagement is symptom-based and requires a multidisciplinary approach. It may consist of heart and/or palate surgery, nasogastric feeding, calcium supplementation, occupational, physical, and speech therapy, educational and behavioral therapy, as well as support and treatment for psychiatric disease. Tonsillectomy is not recommended unless indicated by a center of expertise. A regular surveillance of calcium, thyroid function and blood cell count is necessary. Immune function must be evaluated before administering live vaccines.\nPrognosis\nThe prognosis is variable and depends on the severity of the disease. The infant mortality rate is relatively low (~4%); in adults mortality is higher than that of the rest of the adult population. Most congenital malformations and medical problems can be managed. Prognosis in adults depends on the degree of autonomy.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Tiffany BUSA | ITHACA* - Pr Nicole PHILIP | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "22q11.2 duplication syndrome", "Disease Definition": "A rare chromosomal anomaly characterized by an extremely variable clinical phenotype and may include heart defects, urogenital abnormalities, velopharyngeal insufficiency with or without cleft palate, and ranging from multiple defects to mild learning difficulties with some individuals being essentially normal.", "ORPHA ID": 1727, "Summary": "Epidemiology\nUp till now more than 50 unrelated cases have been reported with a high frequency of familial duplications.\nClinical description\nThe age at diagnosis is variable and depends on the clinical manifestations. The clinical presentation of patients shares features with 22q11.2 deletion syndrome (DG/VCFS), including heart defects, velopharyngeal insufficiency with or without cleft palate. The clinical picture is highly variable with incomplete penetrance, ranging from multiple defects with severe intellectual disability to mild learning difficulties with some individuals being essentially normal. Bladder exstrophy, a very rare malformation in the general population, is significantly associated with the duplication. A high rate of autism spectrum disorder is found. Congenital heart defects and urogenital anomalies can be detected in utero, whereas asymptomatic individuals are usually diagnosed after the birth of a severely affected relative.\nEtiology\nThe basis of this clinical variability remains unclear. The low-copy repeats spanning the region 22q11.2 (LCR22) predispose to homologous recombination events, often nonallelic, that result in rearrangements of 22q11.2. The large majority of affected individuals have identical 3Mb microduplications; however, proximal nested 1.5 Mb duplications or larger duplications are also reported. The 3Mb duplication encompasses a region containing 40 genes including the TBX1 gene that has been shown to be the major disease gene responsible for DG/VCFS. Interestingly, TBX1 gain-of-function mutations resulting in the same phenotypic spectrum as haploinsufficiency have been observed, and suggests that TBX1 overexpression might be responsible for the 22q11.2 duplication syndrome.\nDiagnostic methods\nThe 22q11.2 duplication is detected by fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification, array comparative genome hybridization (aCGH) or genome-wide SNP (single nucleotide polymorphism) microarrays.\nDifferential diagnosis\nThe main differential diagnosis is DG/VCFS.\nAntenatal diagnosis\nDetection of the duplication on fetal sample by FISH or a-CGH should be discussed with the parents of an index case during subsequent pregnancies or when a parent carries the microduplication.\nGenetic counseling\nTransmission is autosomal dominant. Most cases are inherited from a pauci or asymptomatic parent. An affected individual has a 50% risk of transmitting the duplication.\nManagement and treatment\nSymptomatic treatment should be proposed by a multidisciplinary team including pediatricians, child psychiatrists.\nPrognosis\nPrognosis is variable. Marked inter and intrafamilial variability is observed among patients. Some patients have been reported to have significant cardiovascular malformations leading to early death.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Tiffany BUSA | ITHACA* - Pr Nicole PHILIP | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "2p13.2 microdeletion syndrome", "Disease Definition": "A rare partial autosomal monosomy characterized by global development delay, intellectual disability, behavioral abnormalities (hyperactivity, attention deficit and autistic behaviors), brachycephaly and variable facial dysmorphism. Other associated features may include vertebral fusions, mild contractures of knees and elbows, and feeding difficulties during infancy.", "ORPHA ID": 363680, "Summary": ""}
{"Disease Name": "2p15p16.1 microdeletion syndrome", "Disease Definition": "2p15p16.1 microdeletion syndrome is a recently described syndrome characterized by developmental delay and facial dysmorphism.", "ORPHA ID": 261349, "Summary": "Epidemiology\nIt has been clinically and molecularly characterized in 5 patients.\nClinical description\nDysmorphic features include receding forehead, telecanthus, epicanthic fold, short and down-slanting palpebral fissures, ptosis, broad and high nasal bridge, retrognathia, flat philtrum, small mouth with high, narrow palate and everted lower lip. Ophthalmologic examination in 4 patients revealed bilateral optic atrophy/hypoplasia. Microcephaly, short stature, genitourinary abnormalities and behavioral problems are common.\nEtiology\nThis syndrome is caused by an interstitial deletion 2p15p16.1 (present in mosaic in one patient). These de novo deletions were characterized by comparative genomic hybridisation (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size from 570 kb to 5.7 Mb and encompass several genes. Haploinsufficiency of these genes could contribute to the phenotype.\n\n                            Last update: \n                            June 2011"}
{"Disease Name": "2p21 microdeletion syndrome without cystinuria", "Disease Definition": "2p21 microdeletion syndrome without cystinuria is a rare partial autosomal monosomy characterized by weak fetal movements, severe infantile hypotonia and feeding difficulties that spontaneously improve with time, urogenital abnormalities (hypospadias or hypoplastic labia majora), global development delay, mild intellectual disability and facial dysmorphism (dolichocephaly, frontal bossing, bilateral ptosis, midface retrusion, open mouth with tented upper lip vermilion). Affected individuals have borderline elevated serum lactate but no cystinuria.", "ORPHA ID": 369881, "Summary": ""}
{"Disease Name": "2p21 microdeletion syndrome", "Disease Definition": "The 2p21 microdeletion syndrome consists of cystinuria, neonatal seizures, hypotonia, severe growthand developmental delay, facial dysmorphism, and lactic acidemia.", "ORPHA ID": 163693, "Summary": "Epidemiology\nIt has been described in seven patients from three families of a small Bedouin clan.\nClinical description\nDysmorphic features include frontal bossing, almond-shaped eyes, long eyelashes, depressed nasal bridge, and large, posteriorly rotated ears. Renal lithiasis occurs at an early age in all patients. Reduced activity of the respiratory chain complexes I, III, IV and V was found in patients examined.\nEtiology\nThe syndrome is caused by homozygous deletion of at least four contiguous genes on chromosome 2: SLC3A1, PREPL, PPM1B and C2orf34 (2p21).\n\n                            Last update: \n                            November 2010"}
{"Disease Name": "2q23.1 microdeletion syndrome", "Disease Definition": "The newly described 2q23.1 microdeletion syndrome includes severe intellectual deficit with pronounced speech delay, behavioral abnormalities including hyperactivity and inappropriate laughter, short stature and seizures.", "ORPHA ID": 228402, "Summary": "Epidemiology\nTo date, fifteen patients have been reported.\nClinical description\nDysmorphic features include microcephaly, wide and open mouth, a tented upper lip, and prominent incisors. The majority of cases present with stereotypic repetitive behavior, a disturbed sleep pattern and a broad-based gait. Skeletal abnormalities include generalized brachydactyly with small hands and feet.\nEtiology\nThe microdeletion was identified by microarray based comparative genomic hybridization (aCGH). The size of the deletions is variable; the critical region includes a single gene, MBD5. Another gene, EPC2, is deleted in patients who have a broader phenotype than those with a deletion of MBD5 only.\n\n                            Last update: \n                            May 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "2q23.1 microduplication syndrome", "Disease Definition": "2q23.1 microduplication syndrome is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 2, primarily characterized by global developmental delay, hypotonia, autistic-like features and behavioural problems. Craniofacial dysmorphism (arched eyebrows, hypertelorism, bilateral ptosis, prominent nose, wide mouth, micro/retrognathia) and an affable personality are also commonly associated. Minor digital anomalies (fifth finger clinodactyly and large, broad first toe) have occasionally been reported.", "ORPHA ID": 313947, "Summary": ""}
{"Disease Name": "2q31.1 microdeletion syndrome", "Disease Definition": "2q31.1 microdeletion syndrome is a well-defined and clinically recognisable syndrome characterized by moderate to severe developmental delay, short stature, facial dysmorphism and variable limb defects.", "ORPHA ID": 251014, "Summary": "Epidemiology\nIt has been reported in 20 patients.\nClinical description\nDysmorphic features include microcephaly, downslanting palpebral fissures, flat and long philtrum, micrognathia and low-set and dysplastic ears. The spectrum of limb defects ranges from monodactylous ectrodactyly, brachydactyly and syndactyly to camptodactyly. The lower limbs tend to be more often and more severely affected than the upper limbs.\nEtiology\nThis microdeletion was identified by comparative genomic hybridization (CGH) microarray and its size is variable. The critical region encompasses the HOXD genes, haploinsufficiency of which results in the skeletal phenotype.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "2q32q33 microdeletion syndrome", "Disease Definition": "A rare autosomal monosomy characterized by a variable phenotype with moderate to severe intellectual disability, behavioral problems, short stature, microcephaly, dysplastic nails, sparse hair, cleft palate and dysmorphic craniofacial features.", "ORPHA ID": 251019, "Summary": ""}
{"Disease Name": "2q37 microdeletion syndrome", "Disease Definition": "A rare chromosomal anomaly involving deletion of chromosome band 2q37 and characterized by a broad spectrum of clinical findings including mild-moderate developmental delay/intellectual disability, brachymetaphalangy of digits 3-5, short stature, obesity, hypotonia, specific facial dysmorphism, abnormal behavior, autism or autism spectrum disorder, joint hypermobility/dislocation, and scoliosis.", "ORPHA ID": 1001, "Summary": "Epidemiology\nTo date, more than 150 individuals have been reported worldwide. Females are more frequently affected (60%).\nClinical description\nA congenital malformation syndrome with a variable presentation. The phenotype includes mild-to-moderate developmental delay or intellectual deficit, hypotonia (50 to 65% of patients), seizures (20%-35%), brachymetaphalangism (50%), short stature (23%), characteristic facial dysmorphism (sparse scalp hair, round face, prominent forehead, upslanting palpebral fissures, sparse and arched eyebrows, deep-set eyes, midface hypoplasia, a depressed nasal bridge, deficient nasal alae and prominent columella, V-shaped appearance of the nasal tip, thin vermillion border of the lips, and a high-arched palate) and a tendency toward obesity with age. Behavioral disorders are common and may include repetitive behavior, severe communication and social interaction deficits, stereotypic movements, intermittent aggressiveness, hyperactivity, attention deficit disorder, obsessive-compulsive disorder and sleep disturbances. The following clinical features are also frequent: widely set, distally placed or supernumerary nipples, fifth finger clinodactyly, syndactyly, and small hands/feet, syndactyly of the fingers or toes, persistent fetal finger pads and a single palmar crease, and microcephaly or macrocephaly. Eczema is often present. Major malformations occur in 30% of patients with 2q37 deletions and may include congenital heart, gastrointestinal (30% of patients), genitourinary (11% of cases) and central nervous system malformations (6% of patients).\nEtiology\nThe deletion involves the terminal region of chromosome 2 with breakpoints at or within band 2q37. A few genotype-phenotype correlations have been identified including a critical region for the Albright hereditary osteodystrophy-like phenotype. The genes in 2q37 involved in the clinical signs previously mentioned include CAPN10, PRLH, HDLBP, PER2 for the weight, GBC1, GPR35, STK25, PDCD1, GBX2, TWIST2, FARP2, PER2 for skeletal disorders, GBX2, TWIST2, FARP2, PER2, PRLH, HDLBP, TRPM8, AGAP1, KIF1A, PASK, ATG4B for behavioral disorders, and HDAC4 which is essential for the development of the brain, muscle, and bone. The deletion of Mir-562 is linked to Wilms tumor.\nDiagnostic methods\nDiagnosis relies on cytogenetic analysis and molecular characterization. Screening for a translocation should also be conducted as the deletion may be the result of the transmission of a derivative chromosome.\nDifferential diagnosis\nThe differential diagnosis should include other segmental aneusomy syndromes and Prader-Willi syndrome. The group of pseudohypoparathyroidism with Albright hereditary osteodystrophy should also be included in the differential diagnosis but calcium, phosphorus, and parathyroid hormone levels are in the normal range in patients with deletion 2q37.\nAntenatal diagnosis\nGenetic antenatal diagnosis is feasible where the deletion or associated rearrangement has previously been identified in a family member. A prenatal diagnosis might be proposed as for any de novo abnormal chromosomal rearrangement because of potential germinal mosaicism.\nGenetic counseling\nMost cases arise de novo; however, familial chromosomal rearrangements have been identified in a small proportion of cases. The subsequent risk to siblings of a proband depends on the specific chromosome rearrangement in the parent. Theoretically, a patient with pure 2q37 deletion will have a 50% risk to transmit the deletion.\nManagement and treatment\nManagement should be multidisciplinary and include a comprehensive evaluation of the major clinical criteria. Speech, physical and occupational therapy are required. The patients will need careful medical screening between birth and 5 years, for potential associated malformation, and follow up in referal centers for intellectual disabled patients.\nPrognosis\nThe prognosis is very different between children some are mildly affected and other have severe intellectual disability. They have often cognitive difficulties and most of them attend special schools. At the age of 20 most of them are not autonomous and some develop psychiatric disorders.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Martine DOCO-FENZY | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "3-hydroxy-3-methylglutaric aciduria", "Disease Definition": "A rare organic aciduria, due to deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase characterized by episodes of metabolic decompensation with hypoketotic hypoglycemia triggered by periods of fasting or infections.", "ORPHA ID": 20, "Summary": "Epidemiology\n3-hydroxy-3-methylglutaric aciduria (3HMG) occurs in all ethnic groups. The conditions is extremely rare in the United States, Taiwan and mainland China where incidence is estimated at less than 1/1,000,000; however, it is more frequently observed in Saudi Arabia, Portugal and Spain. In Portugal, the birth prevalence is estimated at 1/125,000 live births.\nClinical description\nThe clinical presentation is heterogeneous, ranging from severe neonatal onset with potentially fatal outcome to presentation in adulthood. Most patients became symptomatic within the first year of life (50% in neonatal period) with episodes of metabolic decompensation triggered by periods of fasting or infections, which when left untreated may lead to neurological sequelae. Newborns or infants present with acidosis and hypoglycemia, accompanied by vomiting, dehydration, hypotonia and lethargy. Acute decompensation is triggered by infections, vaccinations, and dietary changes. The typical laboratory findings include hypoglycemia, acidosis, an increased anion gap, hyperammonemia and elevated transaminases. Long-term neurological complications are common. Half of the patients have a normal cognitive development while the remainder shows psychomotor deficits. Speech and motor developmental delay are frequent. Cerebral MRI frequently reveals diffuse abnormality in signal intensity of the cerebral white matter, thalami and basal ganglia. Other manifestations may include macrocephaly, dilated cardiomyopathy, arrhythmias, hepatomegaly and acute pancreatitis. Children are usually healthy between episodes; subsequent acute crises may be preceded by anorexia, lethargy, behavioral changes, irritability and muscle weakness. Hypoketotic hypoglycemia is characteristic.\nEtiology\n3HMG is caused by mutations of the gene HMGCL (1p36.11).\nDiagnostic methods\nDiagnosis is based on the tandem mass spectrometry profile of plasmatic acylcarnitines (increased C5OH and C6DC) and urinary organic acid (high levels of acids: 3-hydroxy-3-methylglutaric, 3-hydroxyisovaleric, 3-methylglutaconic and 3-methyglutaric). The diagnosis can be confirmed by mutation analysis.\nDifferential diagnosis\nDifferential diagnosis includes sepsis, fatty acid oxidation disorders, organic acidurias and Reye's syndrome.\nAntenatal diagnosis\nDuring the third trimester of gestation, amniotic fluid organic acid levels, as well as maternal urinalysis may indicate 3HMG; confirmation requires testing of cultured amniocytes or chorionic villi for molecular study.\nGenetic counseling\n3HMG is an autosomal recessive genetic disorder. Genetic counselling should be offered to all families.\nManagement and treatment\nPatients must be treated by intravenous 10% glucose and supportive treatment during acute metabolic crises. Maintenance treatment requires protein/leucine-restricted diet with a leucine free amino acid mixture, restricted fat intake and regular feeding (every 3-6 hours). Carnitine supplementation is often given.\nPrognosis\nPrognosis is good for those patients who are rapidly diagnosed and survive past childhood.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Anabela BANDEIRA  - Dr Laura VILARINHO"}
{"Disease Name": "3-hydroxy-3-methylglutaryl-CoA synthase deficiency", "Disease Definition": "3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMG-CoA synthase deficiency) is a rare autosomal recessively inherited disorder of ketone body metabolism (see this term), reported in less than 20 patients to date, characterized clinically by episodes of decompensation (often associated with gastroenteritis or fasting) that present with vomiting, lethargy, hepatomegaly, non ketotic hypoglycemia and, in rare cases, coma. Patients are mostly asymptomatic between acute epidodes. HMG-CoA synthase deficiency requires an early diagnosis in order to avoid hypoglycemic crises that can lead to permanent brain damage or death.", "ORPHA ID": 35701, "Summary": ""}
{"Disease Name": "3-hydroxyisobutyric aciduria", "Disease Definition": "A rare classic organic aciduria characterized by tissue accumulation and elevation of urinary excretion of 3-hydroxyisobutyric acid. The clinical phenotype ranges from recurrent mild episodes of vomiting with normal cognitive development, to massive acidosis, seizures, and failure to thrive with profound intellectual disability and early death. Dysmorphic craniofacial features (such as microcephaly, triangular face, short, sloping forehead, long, prominent philtrum, and micrognathia) and variable cerebral anomalies have also been described.", "ORPHA ID": 939, "Summary": ""}
{"Disease Name": "3-methylcrotonyl-CoA carboxylase deficiency", "Disease Definition": "A rare inherited disorder of leucine metabolism characterized by a highly variable clinical picture ranging from metabolic crisis in infancy to asymptomatic adults.", "ORPHA ID": 6, "Summary": "Epidemiology\nThe birth prevalence in Europe is estimated at 1/50,000-1/30,000. The introduction of neonatal screening programs based on tandem mass spectrometry has revealed a high frequency of this disorder, and it now appears to be the most common organic aciduria in some populations.\nClinical description\nPatients with 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) have a variable clinical phenotype with the vast majority of patients being asymptomatic and a small subgroup displaying symptoms of an organic aciduria, usually in association with environmental triggering factors. Many newborns now diagnosed through expanded newborn screening tests remain asymptomatic, indicating that the disease has a very low clinical penetrance. Most symptomatic patients have normal growth and development until presenting with an acute metabolic crisis, usually following a minor infection, fasting or introduction of a protein-rich diet, between the ages of 2-33 months. Symptoms include vomiting, coma and apnea. Rarely, neurological abnormalities (i.e. metabolic stroke, hemiparesis, and encephalopathy), weakness, muscular hypotonia and developmental delay have been reported. Between episodes of metabolic crisis patients are usually asymptomatic. Some patients with 3-MCCD may not develop symptoms until adulthood, manifesting with weakness and fatigue, while others may never show symptoms.\nEtiology\n3-MCCD is due to mutations in the MCCC1 (3q27.1) or MCCC2 (5q12-q13) genes. These two genes encode MCCase subunit alpha and MCCase subunit beta, which together catalyze the fourth step in the leucine catabolic pathway. Mutations in these genes lead to reduced or absent 3-MCC activity, thereby allowing the toxic byproducts of leucine processing to build up and cause clinical symptoms. Evidence is emerging that consanguinity with homozygosity for damaging mutations in a second rare disease gene may be associated with non-specific severe phenotypes of 3-MCCD.\nDiagnostic methods\nNewborn screening using tandem mass spectrometry reveals an elevation of C5-hydroxy acylcarnitine on blood spots. Urine organic acid analysis shows elevation of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. Carnitine serum levels can be decreased. Lymphocyte and fibroblast assays show low to absent 3-MCC activity while other carboxylase enzymes have normal activity. Laboratory findings during an acute metabolic crisis include metabolic acidosis, hypoglycemia, and in some cases, mild hyperammonemia. Molecular genetic testing identifying two disease causing alleles confirms diagnosis. Newborn screening programs are available in the U.S. and some European countries.\nDifferential diagnosis\nThe differential diagnosis includes other organic acidurias such as multiple carboxylase deficiency as well as Reye's syndrome.\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with known disease causing mutations.\nGenetic counseling\n3-MCCD is inherited autosomal recessively and genetic counseling is recommended.\nManagement and treatment\nEarly diagnosis may help in properly managing 3-MCCD and reducing the risk of severe metabolic crisis. Treatment is often not necessary in asymptomatic individuals. Some patients may require oral L-carnitine supplementation. A diet restricted in leucine is usually not warranted. Avoidance of fasting and of other precipitating stresses is recommended (mainly in infants and young children), as is the regular monitoring of free carnitine concentrations. An emergency regimen (IV glucose and the correction of acidosis) is recommended during intercurrent illness.\nPrognosis\nThe prognosis is usually good but depends on the severity of symptoms experienced.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Matthias BAUMGARTNER"}
{"Disease Name": "3-methylglutaconic aciduria type 1", "Disease Definition": "3-methylglutaconic aciduria (3-MGA) type I is an inborn error of leucine metabolism with a variable clinical phenotype ranging from mildly delayed speech to psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia.", "ORPHA ID": 67046, "Summary": "Epidemiology\nThe disorder is very rare with less than 20 cases reported in the literature.\nClinical description\nClinical manifestations usually become apparent in the neonatal period or during infancy but the diagnosis may not be made until childhood. Some of the reported patients also displayed hypoglycaemia, spastic quadriparesis, microcephaly, progressive neurological deficit, seizures, vomiting, atrophy of the basal ganglia, severe hypotonia and hepatomegly.\nEtiology\nThe syndrome is caused by mutations in the AUH gene (chromosome 9) encoding 3-methylglutaconyl-CoA hydratase, an enzyme involved in leucine degradation.\nDiagnostic methods\nAs the clinical picture is variable and nonspecific, diagnosis can be made by assay of 3-methylglutaconyl-CoA hydratase activity in fibroblasts or leukocytes, quantitative analysis of urinary organic acid excretion or, more recently, analysis of bodily fluids by NMR spectroscopy.\nDifferential diagnosis\nPatients with 3-MGA type I can be distinguished from those with other forms of 3-MGA (types II, III and IV; see these terms) by the distinctive pattern of metabolite excretion: 3-methylglutaconic acid levels are highly elevated (higher than those detected in other forms of 3-MGA) whereas methylglutaric acid levels are usually only slightly elevated, and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other forms of 3-MGA).\nAntenatal diagnosis\nPrenatal diagnosis should be possible through detection of high levels of 3-hydroxyisovaleric acid in the amniotic fluid or through enzyme analysis of cultured amniocytes.\nGenetic counseling\nThe syndrome is inherited as an autosomal recessive trait.\nManagement and treatment\nTreatment is largely symptomatic but dietary management with a modest leucine restriction and supplementation with L-carnitine may be beneficial in some cases.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Pascale DE LONLAY"}
{"Disease Name": "3-methylglutaconic aciduria type 3", "Disease Definition": "3-methylglutaconic aciduria type III (MGA III) is an organic aciduria characterised by the association of optic atrophy and choreoathetosis with 3-methylglutaconic aciduria.", "ORPHA ID": 67047, "Summary": "Epidemiology\nThe vast majority of reported cases involved the Iraqi-Jewish population, in which the prevalence of the disorder has been estimated at around 1 in 10 000.\nClinical description\nOnset of the optic atrophy occurs during infancy with a progressive decrease in visual acuity. The choreoathetoid movement disorder manifests later, usually within the first ten years of life. Other clinical features may include spastic paraparesis, mild ataxia and cognitive deficit, dysarthria, and nystagmus.\nEtiology\nMGA III is caused by mutations in the OPA3 gene (19q13.2-q13.3). The biological function of the OPA3 gene product remains to be defined but MGA III is hypothesised to be a primary mitochondrial disorder.\nDiagnostic methods\nDiagnosis may be suspected up on presentation with early-onset optic atrophy and choreoathetosis (particularly in individuals of Iraqi-Jewish origin) and by detection of an elevation in the levels of 3-methylglutaconic and 3-methylglutaric acid in the urine. Diagnosis can be confirmed by detection of mutations in the OPA3 gene.\nDifferential diagnosis\nMGA type III can be distinguished from other forms of MGA (types I, II and IV; see these terms) on the basis of the clinical phenotype and, more specifically, from 3-MGA type I by the absence of an elevation in 3-hydroxyisovaleric acid levels and normal 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts. The differential diagnosis may also include Behr syndrome (see this term) and cerebral palsy.\nAntenatal diagnosis\nPrenatal testing is clinically available for affected families through molecular analysis of amniocytes or chorionic villus samples.\nGenetic counseling\nMGA III is transmitted as an autosomal recessive trait.\nManagement and treatment\nTreatment is symptomatic only and should be managed by a multidisciplinary team.\nPrognosis\nThe long-term prognosis remains unknown: although the disease progresses during childhood, it appears to stabilise during early adulthood.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Pascale DE LONLAY"}
{"Disease Name": "3-methylglutaconic aciduria type 4", "Disease Definition": "3-methylglutaconic aciduria (3-MGA) type IV, or unclassified 3-MGA, is a clinically heterogeneous disorder characterised by increased 3-methylglutaconic acid excretion in individuals that cannot be classified as having one of the other forms of 3-MGA (3-MGA I, II or III).", "ORPHA ID": 67048, "Summary": "Epidemiology\nThe prevalence of this disorder is unknown.\nClinical description\nPatients usually present during the first year of life with neurological findings including psychomotor retardation, hypotonia, developmental delay, seizures and progressive spasticity, together with severe failure to thrive. Cardiomyopathy, hepatic dysfunction, eye anomalies, microcephaly, deafness, dysmorphism, neonatal hypoglycaemia, thrombocytopaenia and lactic acidosis have also been reported. Cerebellar dysgenesis may be revealed by magnetic resonance imaging. In contrast, a small number of asymptomatic patients have been diagnosed as having 3-MGA type IV.\nEtiology\nThe aetiology remains unknown: unlike patients with 3-MGA type I, individuals with 3MGA type IV display normal 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts. Mitochondrial respiratory chain abnormalities have been detected in some 3MGA type IV patients but the clinical heterogeneity associated with this disorder suggests that the 3-methylglutaconic aciduria seen in 3-MGA type IV patients may result from a variety of causes and genetic factors.\nDiagnostic methods\n3-methylglutaconic aciduria can be diagnosed by analysis of urinary organic acid excretion but specific diagnosis of 3-MGA type IV requires exclusion of all other forms of 3-MGA. As the genetic factors responsible for the other forms of 3-MGA have now been determined, molecular analysis provides a valuable tool for accurate diagnosis.\nDifferential diagnosis\n3-MGA type IV can be distinguished from the type I disorder by normal excretion of 3-hydroxyisovaleric acid. 3-MGA type II may be excluded by the mode of inheritance (transmission is X-linked recessive in 3-MGA type II) and on the basis of the clinical phenotype (the type II disorder is characterised by neutropaenia, skeletal myopathy, dilated cardiomyopathy and growth delay). Depending on the manifestations present, clinical differentiation of types III and IV may be more problematic, but the occurrence of 3-MGA type III is largely restricted to the Iraqi-Jewish population. In addition to other forms of 3-MGA, the differential diagnosis should also include cerebral palsy, dilated cardiomyopathy with ataxia (see this term) and other organic acidurias.\nGenetic counseling\nThe disorder has been reported to be inherited as an autosomal recessive trait.\nManagement and treatment\nAt present there is no effective treatment for 3-MGA type IV and a leucine-restricted diet appears to be of no benefit.\nPrognosis\nThe prognosis depends on the clinical phenotype but the neurological complications can be severe with a potentially fatal disease course.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Pascale DE LONLAY"}
{"Disease Name": "3-methylglutaconic aciduria type 8", "Disease Definition": "A rare organic aciduria characterized by neonatal onset of hypotonia, recurrent apneic episodes, lack of psychomotor development, feeding difficulties, extrapyramidal signs, and seizures. Other reported features include microcephaly, sensorineural deafness, bradycardia, and neutropenia. Laboratory studies show increased serum lactate and urinary excretion of 3-methylglutaconic acid. Brain imaging may reveal progressive cerebral atrophy. The disease is lethal in infancy.", "ORPHA ID": 505208, "Summary": ""}
{"Disease Name": "3-methylglutaconic aciduria type 9", "Disease Definition": "A rare organic aciduria characterized by early onset of global developmental delay with severe intellectual disability, seizures, and 3-methylglutaconic aciduria. Additional features are hypotonia, hyperactivity and aggressive behavior, optic atrophy, or spasticity. Brain imaging may show generalized cerebral atrophy and white matter abnormalities.", "ORPHA ID": 505216, "Summary": ""}
{"Disease Name": "3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome", "Disease Definition": "A rare organic aciduria characterized by increased urinary excretion of 3-methylglutaconic acid, variably associated with neutropenia (sometimes causing recurrent severe infections and potentially resulting in leukemia) and progressive neurologic manifestations, such as global developmental delay, intellectual disability, hypotonia, movement disorder, and seizures. Microcephaly, cataract, facial dysmorphism, growth retardation, endocrine abnormalities, and cardiomyopathy have also been reported. Brain imaging may show cerebral or cerebellar atrophy, or abnormalities of the basal ganglia.", "ORPHA ID": 445038, "Summary": ""}
{"Disease Name": "3-phosphoglycerate dehydrogenase deficiency, infantile/juvenile form", "Disease Definition": "3-Phosphoglycerate dehydrogenase deficiency (3-PGDH deficiency) is an autosomal recessive form of serine deficiency syndrome (see this term) characterized clinically in the few reported cases by congenital microcephaly, psychomotor retardation and intractable seizures in the infantile form and by absence seizures, moderate developmental delay and behavioral disorders in the juvenile form", "ORPHA ID": 79351, "Summary": ""}
{"Disease Name": "3-phosphoserine phosphatase deficiency, infantile/juvenile form", "Disease Definition": "3-Phosphoserine phosphatase deficiency is an extremely rare form of serine deficiency syndrome (see this term) characterized clinically by congenital microcephaly and severe psychomotor retardation in the single reported case to date, which was associated with Williams syndrome (see this term).", "ORPHA ID": 79350, "Summary": ""}
{"Disease Name": "3C syndrome", "Disease Definition": "Cranio-cerebello-cardiac (3C) syndrome is a rare multiple congenital anomalies syndrome characterized by craniofacial (prominent occiput and forehead, hypertelorism, ocular coloboma, cleft palate), cerebellar (Dandy-Walker malformation, cerebellar vermis hypoplasia) and cardiac (tetralogy of Fallot, atrial and ventricular septal defects) anomalies (see these terms).", "ORPHA ID": 7, "Summary": "Epidemiology\nTo date < 50 cases have been described. The syndrome appears to be panethnic.\nClinical description\n3C syndrome is a congenital disorder characterized by distinctive craniofacial features including, in decreasing frequency, low-set ears, hypertelorism, down-slanting palpebral fissures, depressed nasal bridge, prominent occiput, prominent forehead, cleft palate, micrognathia, ocular coloboma. Additional craniofacial features encompass nevus flammeus (on forehead), low posterior hairline, sparse scalp hair, eyebrows and eyelashes, open mouth with protruding tongue, and short neck. In 80% of cases, cerebellar anomalies are present and include primarily Dandy-Walker malformation or Dandy-Walker variant, cerebellar vermis hypoplasia and enlargement of cisterna magma. Affected individuals have gross motor and speech delay and intellectual disability. The cardiovascular anomalies include atrial and ventricular septal defects, patent arterial duct, tetralogy of Fallot, double outlet right ventricle, hypoplastic left heart syndrome (see these terms), aortic or pulmonary stenosis, and other valvular anomalies. Postnatal short stature is noted in most patients, and growth hormone deficiency has been reported in two patients. Additional anomalies, noted in >10% of patients, include feeding difficulties, single umbilical artery, small hands with single transverse crease, camptodactyly, equinovarus deformity, hydronephrosis, shallow scrotum, undescended testis, cryptorchidism, micropenis, hypospadias, nail hypoplasia, hearing loss, malrotation of the gut. Skeletal defects may be present with rib and vertebral anomalies (hemivertebrae). Rarely observed features include ocular (congenital glaucoma, optic nerve atrophy with eyelid ptosis, heteochromatic iris, posterior embryotoxon), renal (multicystic dysplastic kidney, horseshoe kidneys, unilateral renal agenesis) and anal (anal atresia, anteriorly placed anus malformations) anomalies. Single occurrences of renal hypoplasia, nipple hypoplasia, penile hypoplasia, unilateral adrenal aplasia, immunodeficiency have also been reported.\nEtiology\nThe exact etiology is still unknown but mutations in KIAA0196 (8q24.13; coding for strumpellin) have been identified in a First Nations cohort and these mutations may be involved in the pathophysiology of 3C syndrome.\nDiagnostic methods\nThe diagnostic criteria for 3C syndrome include congenital heart malformation(s) other than isolated patent arterial duct; Dandy-Walker malformation, cerebellar vermis hypoplasia, or enlarged cisterna; and cleft palate, ocular coloboma or four of the following: prominent occiput, prominent forehead, hypertelorism, micrognathia, downslanting palpebral fissures, depressed nasal bridge, low-set ears.\nDifferential diagnosis\nDifferential diagnosis includes Joubert syndrome, Ellis Van Creveld syndrome, Cornelia de Lange syndrome, distal monosomy 6p (see these terms) and Dandy Walker malformation.\nAntenatal diagnosis\nPrenatal diagnosis may be suspected after an ultrasound examination revealing characteristic major structural anomalies of 3C syndrome. Prenatal testing is available for families in which the disease-causing mutations have been previously identified.\nGenetic counseling\nSporadic and familial cases have been reported. Transmission is autosomal recessive. Phenotypic variability exists between siblings.\nManagement and treatment\nManagement is mainly symptomatic and multidisciplinary approaches including educational programs, physical, occupational, and speech therapy may help to improve hypotonia and reduce motor developmental delay. Cardiac malformation requires specific care, often surgery.\nPrognosis\nPrognosis is determined by the cardiovascular malformation. Motor delay is common and associated with hypotonia secondary to cerebellar anomalies.\n\n                            Last update: \n                            September 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Marlène RIO"}
{"Disease Name": "3M syndrome", "Disease Definition": "A rare primordial growth disorder characterized by low birth weight, reduced birth length, severe postnatal growth restriction, large head size, a spectrum of minor anomalies (including facial dysmorphism) and normal intelligence.", "ORPHA ID": 2616, "Summary": "Epidemiology\nApproximately 200 cases have been reported to date and the condition is rare. However, the phenotype is likely under-recognized.\nClinical description\nInfants present with severe prenatal and postnatal growth retardation, birth weight usually at or below the 2nd centile. Growth impairment is greater in those with CUL7 variants. The head circumference is relatively large. Characteristic facial features include: triangular-shaped face, pointed chin, frontal bossing, hypoplastic midface, fleshy, upturned nose , prominent mouth and lips. These features often become less noticeable with age. Short broad neck and thorax, prominent trapezii, winged scapulae, square shoulders, hyperlordosis and clinodactyly of the fifth finger are seen in some children. Prominent fleshy heels in infancy are a common and distinctive feature. Joint hypermobility and an increased risk of congenital hip dislocation may be present. Hyperlordosis can cause back pain. Intelligence is unaffected and development is usually normal. Some cases of impaired fertility and hypospadias have been noted in males , though this is not universal, while females have normal ovarian function. Patients reach a final adult height of about 120-130 cm (5-6 standard deviations below the mean).\nEtiology\nPathogenic variants in three different genes are known to cause 3M syndrome. Variants in in the CUL7 at 6p21.1 are found in around 75% patients. Other genes known to be involved are OBSL1 (2q35), in 20% of cases and CCDC8 (19q13.33) in 5% of cases. The precise mechanisms leading to growth failure in 3M syndrome remain unclear although the poor response to growth hormone in many patients indicates a degree of resistance to the GH/IGF1 pathway.\nDiagnostic methods\nDiagnosis is based primarily on clinical features (e.g. low birth weight, severe growth retardation, prominent fleshy heels). In some, specific radiological findings will be found including slender/ 'gracile' long bones, relatively tall vertebral bodies, foreshortening of vertebral bodies with increasing age, small pelvic bones and a broad thorax with slender and horizontal ribs. The occurrence of these radiological findings, however, is highly variable. Children with 3M syndrome usually have normal GH levels. Molecular genetic testing can identify pathogenic variants in one of the causal genes, confirming diagnosis in the majority of cases. Some children with 3M syndrome demonstrate normal-high baseline insulin-like growth factor (IGF-I) concentrations.\nDifferential diagnosis\nDifferential diagnoses include Silver-Russell syndrome, Dubowitz syndrome, Mulibrey nanism, fetal alcohol syndrome, and microdeletion of chromosome 20p13p12.\nAntenatal diagnosis\nPrenatal and preimplantation diagnosis is possible in families with a known disease causing variant.\nGenetic counseling\n3M syndrome is inherited autosomal recessively and genetic counseling is recommended for affected families. In a family with an index patient, the sibling recurrence risk is 25%.\nManagement and treatment\nOnce diagnosed the child should be seen by a pediatric endocrinologist for monitoring of growth and pubertal progress and for consideration of recombinant human growth hormone (GH) therapy. Monitoring of growth every 6-12 months is recommended until achievement of final height. Adaptive aids for people with short stature and physiotherapy are possible treatment options. Newborns should have a hip ultrasound scan to screen for developmental dysplasia of the hip. Children can be treated with recombinant human growth hormone. In general, the response to treatment is relatively poor, however a trial of treatment over 1 year may show a reasonable response. Overall treatment with growth hormone is more successful if started early and continued long term. The issue of fertility should be discussed with male patients at the end of puberty and semen analysis offered.\nPrognosis\n3M syndrome is not a life-threatening condition and the prognosis is good.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jill CLAYTON-SMITH | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "3MC syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by a spectrum of developmental anomalies including cleft lip and/or palate, craniosynostosis, intellectual disability and/or learning disability, radioulnar synostosis, genital and vesicorenal anomalies. Observed facial dysmorphism includes hypertelorism, blepharophimosis, blepharoptosis, high arched eyebrows. Less common features reported include anterior chamber defects, cardiac anomalies (e.g. ventricular septal defect; see this term), caudal appendage, umbilical hernia/omphalocele and diastasis recti.", "ORPHA ID": 293843, "Summary": "Epidemiology\nPrevalence data is limited. To date less than 35 cases have been reported in the literature worldwide.\nClinical description\nDiagnosis is often made at birth, in newborns presenting with craniosysnostosis, cleft lip and/or palate and typical facial dysmorphism. Diagnosis could be made antenatally if the fetus presents omphalocele, facial cleft, caudal appendage or sacral anomalies. Children have psychomotor and growth delay. Intellectual disability forms part of the spectrum, and when present is typically moderate; however, patients are sometimes only limited by learning difficulties. Hearing loss is possible and should be monitored. Radioulnar synostosis, vesicorenal and genital anomalies can also occur.\nEtiology\n3MC syndrome is due to biallelic point mutations or deletions in one of the 3 known causative genes COLEC10 (8q24.12), COLEC11 (2p25.3), and MASP1 (3q27.3). These genes code for factors involved in the activation of complement via the lectin or alternative pathways.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation (particularly by the association of craniosynostosis, intellectual disability and typical facial dysmorphism) and confirmed by genetic testing including targeted sequencing of the 3 genes COLEC10, COLEC11 and MASP1/3.\nDifferential diagnosis\nDifferential diagnosis includes syndromic craniosynostoses, such as Crouzon disease.\nAntenatal diagnosis\nPrenatal diagnosis is possible if a pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy. Consanguineous families are more prone to present this rare disorder.\nManagement and treatment\nEarly surgical repair is provided for craniosynostosis, cleft lip/palate, caudal appendage.\nPrognosis\nPrognosis is linked to visceral malformations, growth restriction and intellectual disability.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Caroline ROORYCK-THAMBO | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "3p25.3 microdeletion syndrome", "Disease Definition": "3p25.3 microdeletion syndrome is a rare chromosomal anomaly characterized by intellectual disability, epilepsy or EEG abnormalities, poor speech, ataxia, and stereotypic hand movements.", "ORPHA ID": 435638, "Summary": ""}
{"Disease Name": "3q13 microdeletion syndrome", "Disease Definition": "3q13 microdeletion syndrome is a rare chromosomal anomaly syndrome resulting from a partial deletion of the long arm of chromosome 3. Phenotype can be highly variable, but it is primarily characterized by significant developmental delay, postnatal growth above the mean, muscular hypotonia and distinctive facial features (such as broad and prominent forehead, hypertelorism, epicantic folds, anti-mongloid slanted eyes, ptosis, short philtrum, protruding lips with a full lower lip, high arched palate). Abnormal hypoplastic male genitalia and skeletal abnormalities are frequently present.", "ORPHA ID": 1621, "Summary": ""}
{"Disease Name": "3q26 microduplication syndrome", "Disease Definition": "A rare chromosomal anomaly characterized by prenatal and postnatal growth retardation, developmental delay, intellectual impairment, dysmorphic signs and variable combination of congenital anomalies, including cardiovascular, genitourinary and skeletal anomalies and spectrum of caudal malformations.", "ORPHA ID": 96095, "Summary": ""}
{"Disease Name": "3q26q27 microdeletion syndrome", "Disease Definition": "A rare partial autosomal microdeletion syndrome characterized by neonatal hypotonia, prenatal and postnatal growth deficiency, severe feeding difficulties, global developmental delay and intellectual disability, dental anomalies (delayed tooth eruption, delayed loss of primary teeth, dental crowding), recurrent respiratory infections, thrombocytopenia and facial dysmorphism (flat facial profile, medially sparse eyebrows, epicanthal folds, flat nasal bridge and tip, short philtrum). Behavioral abnormalities (ADHD, Asperger syndrome) have also been reported.", "ORPHA ID": 356947, "Summary": ""}
{"Disease Name": "3q27.3 microdeletion syndrome", "Disease Definition": "3q27.3 microdeletion syndrome is a rare chromosomal anomaly syndrome, resulting from the partial deletion of the long arm of chromosome 3, characterized by mild to severe intellectual disability, neuropsychiatric disorders of the psychotic and dysthymic spectrum, mild distinctive facial dysmorphism (incl. slender face, deep-set eyes, high nasal bridge with a hooked nose, small, low- set ears, short philtrum, small mouth with thin upper lip, prognathism) and a marfanoid habitus.", "ORPHA ID": 397695, "Summary": ""}
{"Disease Name": "3q29 microdeletion syndrome", "Disease Definition": "A recurrent subtelomeric deletion syndrome with variable clinical manifestations including intellectual deficit and dysmorphic features.", "ORPHA ID": 65286, "Summary": "Epidemiology\nIt has been described in 23 patients.\nClinical description\nThe clinical phenotype is extremely variable. The most common features include mild-to-moderate intellectual deficit and slightly dysmorphic facial features: microcephaly, long and narrow face, short philtrum, large posteriorly rotated ears and high nasal bridge. Autism and gait ataxia have been noted occasionally. Congenital malformations are not common: there are only rare reports of horseshoe kidney, hypospadias and congenital heart defects (patent ductus arteriosus).\nEtiology\nThe syndrome is caused by a recurrent deletion of the 3q subtelomeric region. The microdeletion is commonly 1.6 Mb in length and encompasses more than 20 genes. It was identified by comparative genomic hybridization (CGH) microarray or fluorescence in situ hybridization (FISH) and the underlying mechanism is likely non-allelic homologous recombination (NAHR). Most of the deletions appear de novo  but a few of them were inherited from mildly or non-affected parents. More recently an infant and his father, both with 3q29 microdeletion and cardiac defects, were described as intellectually normal.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "3q29 microduplication syndrome", "Disease Definition": "3q29 microduplications are recently described chromosomal abnormalities with unclear clinical significance.", "ORPHA ID": 251038, "Summary": "Epidemiology\nThey have been reported in fewer than 30 patients.\nClinical description\nThe clinical phenotype is extremely variable and the most consistent features are mild or moderate intellectual deficit and microcephaly.\nEtiology\nAmong duplications, only some appear to be the reciprocal duplication products of 3q29 microdeletion (see this term) and the others flank, span, or partially overlap the common deletion region. These results suggest that other mechanisms in addition to non-allelic homologous recombination (NAHR) mediate rearrangements of 3q29. These microduplications appear de novo or are inherited from mildly affected or completely normal parents. The clinical significance of reciprocal 3q29 microduplication is still unclear.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "45,X/46,XY mixed gonadal dysgenesis", "Disease Definition": "A rare disorder/difference of sex development (DSD) associated with a numerical sex chromosome abnormality resulting from Y-chromosome mosaicism and associated to abnormal gonadal development and features of Turner-Syndrome.", "ORPHA ID": 1772, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe clinical manifestations are highly variable, ranging from partial virilization and ambiguous genitalia at birth to people with a completely male or female phenotype. The most common feature of 45,X/46,XY mixed gonadal dysgenesis (MGD) is asymmetric development of testes, often with a dysgenic testis on one side and a streak gonad on the other. Asymmetry of the external and internal genitalia may also be present. Infants may have frank genital ambiguity and sex assignment may be postponed or left open. Some infants may present with cryptorchidism, partial testicular dysgenesis, and hypospadias... Affected children may show manifestations of other clinical features of Turner syndrome (e.g. short stature, kidney malformations etc.). There may be persistence of Müllerian structures, depending on the degree of dysgenesis. The uterus is of variable size and the degree of differentiation of the internal genitalia varies. Short stature may be present in both sexes and patients are at increased risk of developing gonadoblastomas and dysgerminomas. Global development is normal.\nEtiology\nPatients with 45,X/46,XY mixed gonadal dysgenesis (45,X/46,XY MGD) mostly have a 45,X/46,XY karyotype, with the phenotype of the gonads and the external genitalia depending on the proportion of monosomic cells. The presence of 45,X cell lines is frequently associated with Y chromosome rearrangements (commonly dicentric and ring Y chromosomes), which may also have an impact on the phenotype. All cases are sporadic. Several genotype-phenotype correlations have been established: partial expression of the SRY gene (leading to partial testicular dysgenesis and resulting in diminished testosterone synthesis and hence to the androgenization deficit), presence of the gonadoblastoma (TSPY1) locus on the Y-chromosome in females (associated with an increased risk for the development of neoplasms), and dosage loss of the SHOX gene leading to short stature. The formation of the uterus is due to lack of production of anti-Müllerian hormone.\nDiagnostic methods\nDiagnosis is made by cytogenetic analysis of chromosome status. Karyotype analysis may be conducted prenatally after amniocentesis or chorionic villus sampling, postnatally in patients with ambiguous genitalia, or later in life in patients with fertility problems.\nDifferential diagnosis\nThe differential diagnosis should include 46,XY partial gonadal dysgenesis (46,XY PGD) and syndromic 46,XY gonadal dysgenesis (such as Frasier syndrome, campomelic dysplasia and 46,XY DSD with adrenal insufficiency).\nAntenatal diagnosis\nAntenatal diagnosis is possible if a genital atypia is suspected with imaging.\nGenetic counseling\nGenetic counseling should be provided to parents with a prenatal diagnosis of 45,X/46,XY mosaicism but is complicated by the broad phenotypic spectrum associated with this condition.\nManagement and treatment\nMultidisciplinary management in a center for DSDs should be favored in cases of obvious ambiguous genitalia, allowing informed decisions for sex assignment and planning of procedures. Surgical reconstruction of genital status may be performed in due course if medically necessary and legally approved. Gonadectomy may be considered in patients with a female sex assignment due to the increased risk of gonadoblastoma. In patients with male sex assignment, orchidopexy is required for fixation of the testes in the scrotum and functional assessment including biopsy may be recommended at the time of puberty. Usually, the more dysgenic gonad needs to be removed. Due to the increased risk of malignancy, ultrasound of the gonads should be performed on a regular basis. In some patients, the possibility of growth hormone treatment needs to be discussed if short stature is found.\nPrognosis\nClinical and psychological outcomes depend on the quality of care and level support provided.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Olaf HIORT | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "46,XX difference of sex development-anorectal anomalies syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by a normal female karyotype, normal ovaries, male or ambiguous genitalia, urinary tract malformations (ranging from bilateral renal agenesis to mild unilateral hydronephrosis), Müllerian duct anomalies (e.g. complete absence of the uterus and vagina, bicornuate uterus), and imperforate anus. Additional features may include tracheoesophageal fistula, radial aplasia, and malrotation of the gut.", "ORPHA ID": 2973, "Summary": ""}
{"Disease Name": "46,XX difference of sex development-skeletal anomalies syndrome", "Disease Definition": "A rare difference of sex development characterized by primary amenorrhea and ambiguous external genitalia (enlarged clitoris with marked fusion of the labioscrotal folds) in association with skeletal anomalies (such as hypoplasia of the mandibular condyles and the maxilla, and ulnar dislocation of the radial heads), in the presence of a 46,XX karyotype and regular ovaries, fallopian tubes, and uterus. There have been no further descriptions in the literature since 1972.", "ORPHA ID": 2975, "Summary": ""}
{"Disease Name": "46,XX gonadal dysgenesis", "Disease Definition": "A rare disorder/difference of sex development characterized by a primary ovarian defect, either a failure of the gonads to develop or resistance to gonadotrophin stimulation which leads to premature ovarian failure (POF) in otherwise phenotypically female 46,XX individuals.", "ORPHA ID": 243, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nPatients are born with typical female sex characteristics without ambiguity. However, affected individuals present during adolescence or young adulthood with either delayed or absent puberty resulting in primary or sometimes secondary amenorrhea. The internal and external genitalia are typically developed. 46,XX gonadal dysgenesis can occur as part of Perrault syndrome (ovarian dysgenesis and deafness with or without cerebellar ataxia), as well as other rare syndromes such as lung fibrosis-immunodeficiency-gonadal dysgenesis.\nEtiology\nOvarian dysgenesis results from genetic defects of ovarian development. Although the underlying etiology remains unknown in most cases, several genes have been implicated including homozygous or compound heterozygous inactivating mutations of the follicle-stimulating hormone receptor gene (FSHR; 2p21-p16), mutations in the BMP15 gene (Xp11.2) and mutations in the NR5A1 gene (9q33), amongst others.\nDiagnostic methods\nDiagnosis requires an evaluation of hormonal status (gonadal and adrenal), laboratory investigations to screen for infectious or autoimmune disorders, karyotype analysis, molecular studies and sometimes laparoscopy with biopsy of ovarian tissue.\nDifferential diagnosis\nThe differential diagnosis should include other causes of POF, as well as 46,XY complete gonadal dysgenesis. In addition, secondary ovarian hypoplasia has been described in association with infectious agents (HIV) or autoimmunity (APECED syndrome associated with AIRE gene mutations).\nAntenatal diagnosis\nPrenatal molecular diagnosis is feasible in cases where a mutation has been identified in the family.\nGenetic counseling\nGenetic counseling may be offered. Inactivating FSHR mutations are inherited in an autosomal recessive manner, BMP15 mutations are inherited in an X-linked manner and NR5A1 mutations are autosomal dominant in the great majority of cases.\nManagement and treatment\nManagement should include hormone replacement therapy. Calcium and vitamin D supplements may also be proposed. Psychological support should also be offered to patients and their families in a difference/disorder of sexual development-center setting. Infertility is an important management issue; however, pregnancy may be feasible through zygote egg donation.\nPrognosis\nWith appropriate management, the physiological and clinical outcome for patients is good.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Olaf HIORT | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "46,XX ovarian dysgenesis-short stature syndrome", "Disease Definition": "A rare genetic disorder with difference of sex development characterized by primary amenorrhea, short stature, delayed bone age, decreased levels of estradiol, elevated levels of follicle-stimulating hormone and luteinizing hormone, absent or underdeveloped uterus and ovaries, delayed development of pubic and axillary hair, and normal 46,XX karyotype.", "ORPHA ID": 444048, "Summary": ""}
{"Disease Name": "46,XX ovotesticular difference of sex development", "Disease Definition": "A rare difference of sex development (DSD) characterized by histologically confirmed testicular and ovarian tissue in an individual with a 46,XX karyotype.", "ORPHA ID": 2138, "Summary": "Epidemiology\nEstimated prevalence is approximately 1/20,000 births. The disorder may account for less than 3-10% of all DSD.\nClinical description\nAbout 20% of affected individuals are diagnosed before 5 years of age. Diagnosis is commonly made during the neonatal period due to atypical genitalia. Some present later with abnormal pubertal development. Signs include: lower abdominal pain, gynecomastia, inguinal hernia, an inguinoscrotal mass, cryptorchidism or amenorrhea/periodic hematuria depending on sex assignment. Most affected individuals have female internal genitalia (uterus, hemi-uterus or rudimentary uterus). Development of external genitalia ranges from apparent female to male genitalia with hypospadias or isolated bilaterally undescended ovotestes (gonads containing ovarian and testicular elements). Infertility is common in men whereas women have some potential for fertility. Malignant gonadal tumors are rare (less than 3% of cases).\nEtiology\nThe cause of 46,XX ovotesticular DSD is not elucidated for the majority of cases. A small proportion of individuals have a translocation of a Y chromosome fragment, including the SRY gene, to an X or another chromosome but most individuals (65%) are SRY negative. Copy number variations, resulting in duplication or deletion of regulatory genes, have been described for SOX9 (4 families), SOX3 (1 individual) and NR0B1 (1 individual). A recurrent NR5A1 variant has been reported in a number of unrelated individuals. Some individuals may have a chromosomal mosacism or a chimerism that results in the presence of Y chromosome containing cells in the gonad.\nDiagnostic methods\nThe assessment and diagnosis of DSD is complex. Consensus guidelines recommend referral to a specialist center for examination and treatment. Initial investigations include chromosome analysis and an ultrasound scan to check the internal reproductive organs. Patients who present later in life have higher differentiation of genitalia. Diagnosis requires careful anatomical assessment via imaging modalities and/or laparoscopy. Biochemical endocrine investigation, cytogenetic and molecular genetic tests are required. Definitive diagnosis is based on gonadal histology (testicular and ovarian tissue).\nDifferential diagnosis\nDifferential diagnoses include other DSD, including mixed gonadal dysgenesis and 46,XX testicular DSD. NR2F2 gene variants have been described in individuals with a 46,XX testicular / ovotesticular DSD phenotype associated with cardiac defects, some with congenital diaphramatic hernia and blepharophimosis-ptosis-epicanthis inversus. Rarely, others include palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (caused by biallelic RSPO1 gene variants), SERKAL syndrome (recessive WNT4 variants).\nAntenatal diagnosis\nPrenatal diagnosis may be possible following demonstration of atypical genitalia on ultrasound and amniocentesis revealing a 46,XX karyotype.\nGenetic counseling\nGenetic counseling should be offered to families of affected children. Recurrence risk depends on the type of genetic alteration found. The majority arise as de novo gene variants.\nManagement and treatment\nThe patient and family must be provided with psychological support. Other treatments primarily involve hormone replacement. The need for and timing of surgical treatment is complex, depending on sex assignment and gonadal configuration. Management needs to balance the risks and benefits of gonadectomy and reconstructive surgery.\nPrognosis\nPatients usually have normal life expectancy.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Faisal AHMED  - Pr Kenneth MCELREAVEY  - Dr Ruth MCGOWAN  - Pr Edward TOBIAS"}
{"Disease Name": "46,XX testicular difference of sex development", "Disease Definition": "A rare difference of sex development (DSD) associated with a 46, XX karyotype and characterized by male external genitalia, ranging from normal to atypical with associated testosterone deficiency.", "ORPHA ID": 393, "Summary": "Epidemiology\nThe estimated prevalence is 1/20,000 males.\nClinical description\nThe clinical phenotype is variable, with features that include: normal male external to atypical genitalia, undescended testes with absent Müllerian structures and infertility. Presentation depends on the presence of the SRY gene (sex determining region of the Y chromosome). SRY positive cases (80-90%) are usually otherwise normal men who present after puberty with short stature, normal pubic hair and penile size but small testes, gynecomastia and azoospermia-related sterility. Undescended testes and hypospadias are also reported. There are usually no concerns about gender role and identity. SRY negative individuals (10-20%) usually present at birth with features such as penoscrotal hypospadias and undescended testes. Long-term complications due to male hypogonadism include: low libido, erectile dysfunction, decreased secondary sexual characteristics, osteopenia and depression.\nEtiology\nIn most patients, the condition is caused by translocation of a small Y chromosome fragment, including SRY onto an X or other chromosome. In SRY negative cases, copy number variations, involving regulatory genes (SOX3, SOX9) and a common recurrent NR5A1 variant are reported.\nDiagnostic methods\nDiagnosis is based on clinical signs and endocrine testing showing hypergonadotrophic hypogonadism and cytogenetic or molecular testing (SNP array) confirming an XX genome. Fluorescence hybridization (FISH) or polymerase chain reaction (PCR) techniques may detect the SRY gene.\nDifferential diagnosis\nThe main differential diagnoses are 45,X/46,XY mixed gonadal dysgenesis, 47,XXY Klinefelter syndrome, 46,XX ovotesticular DSD and sex chromosome mosaicisms. NR2F2 gene variants have been described in individuals with a 46,XX testicular / ovotesticular DSD phenotype associated with cardiac defects, some with congenital diaphramatic hernia and blepharophimosis-ptosis-epicanthis inversus. Rarely, others include palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (caused by biallelic RSPO1 gene variants), SERKAL syndrome (recessive WNT4 variants) and microphthalmia with linear skin defects (MIDAS) syndrome.\nAntenatal diagnosis\nPrenatal testing in pregnancies may be possible if the underlying genetic cause has been identified.\nGenetic counseling\nGenetic counseling should be offered to affected individuals and their families. Recurrence risk depends on the type of genetic alteration found. SRY positive cases are generally not inherited because this is usually associated with infertility. In SRY negative cases, the pattern of inheritance depends on the genetic cause, if known.\nManagement and treatment\nThe mainstay of treatment is testosterone replacement therapy to correct hormonal imbalance, prevent gynecomastia and to induce development of male secondary sex characteristics. Hypergonadotrophic hypogonadism is uncommon prior to adulthood. Reduction mammoplasty may be considered in some cases. Psychological support and timely referral to an assisted conception service should be offered.\nPrognosis\nManagement of male hypogonadism reduces complications. Affected individuals are typically infertile. Tumorigenic risk is low.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Faisal AHMED  - Pr Kenneth MCELREAVEY  - Dr Ruth MCGOWAN  - Pr Edward TOBIAS"}
{"Disease Name": "46,XY complete gonadal dysgenesis", "Disease Definition": "A rare disorder/difference of sex development (DSD) associated with absence in gonadal development that results in the presence of female appearing external and internal genitalia in presence of a 46,XY karyotype.", "ORPHA ID": 242, "Summary": "Epidemiology\nThe prevalence of 46,XY complete gonadal dysgenesis ( 46,XY CGD) is unknown.\nClinical description\nPatients are born with typical female appearing external genitalia as well as the presence of a uterus and fallopian tubes. They often present during adolescence or early adulthood with lack of pubertal development although adrenarche is normal. Completely undeveloped streak gonads are present and are associated with an increased risk of abdominal tumors (most commonly dysgerminoma), which may be the presenting feature in some cases. Stature is normal or above normal, and features of Turner syndrome are absent.\nEtiology\nAlthough the etiology is not completely understood, 46,XY CGD results from failure of testicular development due to disruption of the underlying genetic pathways. Several genes have been implicated: SRY (gene deletion or loss-of-function mutations; Yp11.3), NR5A1 (9q33) and DHH (homozygous or compound heterozygous mutations; 12q13.1). In addition, patients with partial duplications of Xp (including the NR0B1 gene) and chromosome 9p deletions (involving the DMRT1) may also present with isolated 46, XY CGD. Mutations in the CBX2 gene have been rarely reported, namely in a patient with development of ovarian tissue despite 46,XY karyotype. Mutations in the MAP3K1 gene (5q11.2) that cause downstream alterations in the MAP kinase signaling pathway have recently been identified in two familial and two sporadic cases. Of high clinical relevance, 46,XY CGD is a feature of Frasier syndrome (caused by WT1 variants). Environmental factors (maternal progesterone intake during pregnancy), and impaired prenatal growth have also been associated with 46,XY CGD. In the majority of cases, the genetic etiology remains unclear.\nDiagnostic methods\nDiagnosis is made on the basis of the clinical findings together with cytogenetic analysis, endocrine investigations, molecular genetic studies, and sometimes surgical exploration with biopsy and removal of streak gonads.\nDifferential diagnosis\nThe differential diagnosis should include hypergonadotropic ovarian dysgenesis (46,XX GD) and all forms of syndromic 46,XY CGD (for example, Frasier syndrome, campomelic dysplasia and 46,XY DSD with adrenal insufficiency).\nAntenatal diagnosis\nPrenatal diagnosis is feasible for families in which the genetic anomaly has been confirmed but is only recommended in syndromic cases.\nGenetic counseling\nAlthough some cases of 46,XY CGD occur sporadically, genetic counseling may be offered to affected families and should be adapted depending on the mode of inheritance associated with the genetic anomaly identified.\nManagement and treatment\nManagement may involve removal of streak gonadal tissue as there is a risk for malignancy, which may depend on the underlying etiology. Possible associated health issues (e.g. associated malformations) need to be addressed according to the genetic diagnosis. Hormone substitution is recommended at the time of puberty. Psychological support should also be offered to patients and their families in a specialized DSD-center. Infertility is an important management issue; however, pregnancy may be feasible through zygote egg donation.\nPrognosis\nWith appropriate management, the risk of malignancy is low and the psychological and clinical outcome for patients is good.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Olaf HIORT | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "46,XY difference of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency", "Disease Definition": "A rare difference of sex development characterized by 17-beta hydroxysteroid dehydrogenase 3 deficiency that affects individuals with a 46,XY karyotype leading to underandrogenization of the genitalia.", "ORPHA ID": 752, "Summary": "Epidemiology\nEstimated prevalence at birth has been reported to be 1/147,000 in the Netherlands; the prevalence may be higher elsewhere, especially in populations with high consanguinity.\nClinical description\nThe clinical presentation is variable. Atypical external genitalia with variable phallic size and posterior labioscrotal fusion are often noticed at birth. Patients with typical female-appearing external genitalia may present with inguinal hernia in childhood. Although some patients, with less severe enzyme defiency, are assigned males at birth, affected individuals are often assigned females at birth. However, at puberty, a portion of these patients develop signs of unusual androgenization (phallic enlargement, male secondary sexual characteristics) as the result of increased testosterone (due to conversion of androstenedione by 17-beta-hydroxysteroid dehydrogenase isoenzymes). Testes can be abdominal, inguinal, or in the labioscrotal folds. The internal urogenital tract is developed to a variable extent, and Müllerian structures are absent. All affected individuals are infertile.\nEtiology\nThe condition is caused by mutations in the HSD17B3 gene (9q22) encoding an enzyme expressed predominantly in the testes that converts androstenedione to testosterone. The variable clinical phenotype may be related to partial activity of the enzyme or activity of isoenzymes.\nDiagnostic methods\nHormonal evaluation demonstrates increased androstenedione and low testosterone levels, with an elevated androstenedione/testosterone ratio. The Sertoli cell markers, serum AMH and inhibin B, are usually in the typical age-related reference range for males. Before puberty, an hCG (human chorionic gonadotropin) stimulation test is often necessary for diagnosis, since basal levels may be uninformative. Therefore, recent consensus statements recommend the molecular genetic analysis of the HSD17B3 gene as a primary diagnostic approach.\nDifferential diagnosis\nThe differential diagnosis includes disorders of androgen synthesis such as 5-alpha-reductase 2 deficiency, complete and partial androgen insensitivity syndromes and partial gonadal dysgenesis (caused by NR5A1 mutations for example).\nAntenatal diagnosis\nPrenatal diagnosis is available for the kindred of affected patients if causal pathogenic variants have been identified. Atypical fetal genitalia may be seen on prenatal ultrasound.\nGenetic counseling\nThe condition follows an autosomal recessive inheritance pattern. Parents of an affected individual should be informed that there is a 25% of chance of having an affected child at each pregnancy.\nManagement and treatment\nIf diagnosed at birth, gender assignment should be discussed openly with the family and an evaluation should be done at a DSD center. Any genital surgery demands a thorough assessment and is restricted in several countries in childhood. Early gonadectomy is unnecessary. Depending on gender identity development, some adolescents may demand a gender change whereas others may request treatment to prevent pubertal androgenization and to induce female puberty.\nPrognosis\nLife expectancy and overall morbidity (other than related to untreated hormone deficiency) are not altered. The impact on genital development, puberty and adult sexual functioning is usually severe and may require endocrine and/or surgical treatment, as well as psychological counseling.\n\n                            Last update: \n                            June 2023\n\n\n                            - Expert reviewer(s): \n                            Dr S.E. [Sabine] HANNEMA  - Pr Olaf HIORT | Endo-ERN* - Pr Luca PERSANI \n\n\n                                * European Reference Network"}
{"Disease Name": "46,XY difference of sex development due to 5-alpha-reductase 2 deficiency", "Disease Definition": "A rare difference of sex development (DSD) due to a defect in metabolizing testosterone to dihydrotestosterone and characterized by incomplete intrauterine masculinization which ranges from a female genitalia with a blind vaginal pouch to a fully male phenotype with pseudovaginal posterior hypospadias and micropenis.", "ORPHA ID": 753, "Summary": "Epidemiology\nThe disease has been described in large pedigrees from the Dominican Republic, Southern Lebanon and the Eastern Highlands Province of Papua New Guinea. It is relatively rare among Caucasians, but is recognized as a significant cause of DSD and mutational analysis is part of initial investigations.\nClinical description\nPatients present at birth with characteristics of dihydrotestosterone (DHT) deficiency, such as posterior hypospadias, micropenis/clitoris-like phallus, bifid scrotum, cryptorchid testes (with normal or reduced spermatogenesis), and rudimentary prostate. The clinical spectrum is heterogeneous, ranging from a female with a blind vaginal pouch to a fully male phenotype with hypospadias and micropenis. Two-thirds of patients are initially assigned female gender, and thus clinical presentation maybe later during childhood with abnormal genitalia or during puberty with scarce facial and body hair (with normal sebum production) and virilization without breast development. Wolffian duct differentiation (testosterone-dependent) and regression of Müllerian structures (AMH-dependent) are not involved.\nEtiology\nThe disease is caused by mutations in the SRD5A2-gene (2p23.1) leading to a reduced or absent function of the steroid 5 alpha-reductase type 2 enzyme which converts testosterone into DHT in the external genitalia. As a result, male differentiation fails to occur during fetal development, despite high circulating testosterone levels. Manifestations at birth vary according to the levels of residual enzymatic function.\nDiagnostic methods\nDiagnostic criteria include genital ambiguity, a family history of DSD, and genital/karyotype discordance. Biochemical findings reveal increase in the testosterone/DHT ratio after human chorionic gonadotropin stimulation and normal testosterone and anti-Müllerian hormone concentration. Diagnosis also relies on 5-alpha-reductase activity assessment using the urinary steroid profiling (ratio of androsterone to etiocholanolone and 5-alpha-tetrahydrocortisol/tetrahydrocortisol and 5-alpha-tetrahydrocorticosterone to tetrahydrocorticosterone below the lower limit of normal). Nowadays, the diagnosis is most commonly determined directly by genetic screening.\nDifferential diagnosis\nDifferential diagnosis includes many other causes of severe hypospadias like partial androgen insensitivity syndrome, 17-beta-hydroxysteroid dehydrogenase 3 deficiency and Leydig cell hypoplasia.\nAntenatal diagnosis\nPrenatal diagnosis with ultrasound is uncommon but may occur in families with a previously diagnosed child.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling should be offered to at-risk couples. The parents are almost always carriers and without symptoms, but 25% of their boys will be affected. Girls with 46,XX karyotype and who are homozygous for mutations in the gene, will have no symptoms, but will transmit the mutation to their children.\nManagement and treatment\nFor patients raised as male, the main concern is to keep the testis for later hormone production. Topical DHT cream on the pubic area can be applied neonatally after diagnosis at least during the minipuberty. Surgical repair of hypospadias (chordee correction, urethral reconstruction and orchidopexia with or without scrotalplasty,) should be performed at 6-18 months of age. For patients raised as female, management may include surgical correction of the external genitalia (vaginal opening into the perineum with early separation of the vagina and urethra), early removal of gonadal tissue to prevent masculinization before puberty, clitoral reduction (if severe masculinization) and cyclic hormonal therapy at puberty for development of secondary sexual characteristics. Choosing a female sex is nowadays only an option in XY children with a total deficiency.\nPrognosis\nThe risk of gonadal tumors in individuals with SRD5A2 mutations is quite low. Prostate diseases (prostate cancer, benign prostate hyperplasia) have not been reported in affected males. Most men are infertile due to the small prostate gland causing diminished semen volume and lack of spontaneous fertility; however, artificial reproductive techniques are a possibility.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Agneta NORDENSKJÖLD"}
{"Disease Name": "46,XY difference of sex development due to isolated 17,20-lyase deficiency", "Disease Definition": "A rare difference of sex development due to reduced 17,20-lyase activity that affects individuals with 46,XY karyotype and is characterized by female or atypical external genitalia with reduced phallic size, hypospadias, incomplete fusion of the labioscrotal swellings, cryptorchidism, and a blind vaginal pouch. Blood pressure and electrolytes are normal whilst hormonal investigations show normal basal and stimulated levels of cortisol, and low basal and stimulated androgen levels.", "ORPHA ID": 90796, "Summary": ""}
{"Disease Name": "46,XY difference of sex development-adrenal insufficiency due to CYP11A1 deficiency", "Disease Definition": "A rare, genetic, developmental defect during embryogenesis disorder characterized by severe, early-onset, salt-wasting adrenal insufficiency and ambiguous/female external genitalia (irrespective of chromosomal sex) due to mutations in the CYP11A1 gene. Milder cases may present delayed onset of adrenal gland dysfunction and genitalia phenotype may range from normal male to female in individuals with 46,XY karyotype. Imaging studies reveal hypoplastic/absent adrenal glands and biochemical findings include low serum cortisol, mineralocorticoids, androgens, and sodium, with elevated potassium levels.", "ORPHA ID": 168558, "Summary": ""}
{"Disease Name": "46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome", "Disease Definition": "46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome is a rare, genetic, developmental defect during embryogenesis disorder characterized by partial (unilateral testis, persistence of Müllerian duct structures) or complete (streak gonads only) gonadal dysgenesis, usually manifesting with primary amenorrhea in individuals with female phenotype but 46,XY karyotype, and sensorimotor dysmyelinating minifascicular polyneuropathy, which presents with numbness, weakness, exercise-induced muscle cramps, sensory disturbances and reduced/absent deep tendon reflexes. Germ cell tumors (seminoma, dysgerminoma, gonadoblastoma) may develop from the gonadal tissue.", "ORPHA ID": 168563, "Summary": ""}
{"Disease Name": "46,XY ovotesticular difference of sex development", "Disease Definition": "46,XY ovotesticular disorder of sex development is a rare, genetic disorder of sex development characterized by either the coexistence of both male and female reproductive gonads or, more frequently, by the presence of one or both gonads containing a mixture of both testicular and ovarian tissue (ovotestes) in an individual with a normal male 46, XY karyotype. External genitalia are usually ambiguous, but can range from normal male to normal female and if a uterus and/or fallopian tubes are present, they are generally hypoplastic. Cryptorchidism, hypospadias, infertility and increased risk of gonadal tumours are frequently associated.", "ORPHA ID": 325345, "Summary": ""}
{"Disease Name": "46,XY partial gonadal dysgenesis", "Disease Definition": "A rare disorder/difference of sex development (DSD) characterized by atypical gonadal development that results in genital ambiguity of variable degree ranging from almost female phenotype to almost male phenotype in a patient carrying a 46,XY karyotype.", "ORPHA ID": 251510, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\n46,XY partial gonadal dysgenesis (46,XY PGD) is characterized by ambiguous external genitalia with or without Müllerian structures. The degree of genital ambiguity varies along a spectrum, ranging from an almost female phenotype with clitoromegaly at one extreme to an almost male phenotype with isolated hypospadias at the other. Many patients present ambiguous genitalia or severe micropenis and cryptorchidism associated with complete regression of testicular tissue in one or both sides. Testicular regression syndrome (ETRS) is considered as part of the clinical spectrum of 46,XY PGD. Patients with NR5A1 variants can have adrenal insufficiency. Gonadoblastomas or dysgerminomas may occur in a significant proportion of patients, but may depend on the genetic origin.\nEtiology\n46,XY PGD is a heterogeneous disorder associated with partial absence of both Leydig cell and Sertoli cell function that may result from a variety of genetic events. Rarely, deletions or point mutations in the SRY gene or dose sensitive sex locus (NR0B1) duplication on the X chromosome have been described. Most SRY mutations are de novo mutations, however some cases of X-linked inheritance have been observed. More important are mutations in steroidogenic factor 1 (NR5A1; SF-1). SF-1 is a nuclear receptor and regulator of multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Therefore, affected patients may also have adrenal insufficiency. 46,XY PGD may be a feature of many syndromes (e.g Denys-Drash syndrome) and other genetic conditions.\nDiagnostic methods\nDiagnosis is made on the basis of clinical findings with cytogenic analysis, endocrine investigations, molecular genetic studies, and sometimes surgical exploration with biopsy.\nDifferential diagnosis\nDifferential diagnoses include all forms of syndromic 46,XY gonadal dysgenesis (for example, Denys-Drash syndrome, campomelic dysplasia and 46,XY DSD with adrenal insufficiency) and similar phenotypes that can also result from a 45,X/46,XY karyotype, known as 45,X/46,XY mixed gonadal dysgenesis (45,X/46,XY MGD). The absence of a 45,X lineage is of importance for the management and prognosis.\nAntenatal diagnosis\nAntenatal diagnosis is possible if a genital malformation is suspected with imaging and if a familial background exists.\nGenetic counseling\nGenetic counseling is mandatory.\nManagement and treatment\nManagement of patients requires a multi-disciplinary team in a designated DSD centre. Psychological evaluation and counseling of parents is necessary. The determination of social sex should consider etiological diagnosis, clinical evaluation, ethnic traditions, sexual identity and the acceptance of assigned social sex by the parents. Hormone therapy in patients with female social sex at the time of puberty is based on estrogen and progesterone for those patients where uterus is present in order to induce menses, and estrogen alone in patients without a uterus. Androgen replacement, including testosterone injections, may be appropriate for patients who choose a male social sex in adolescence. Surgery may be considered to allow sex appropriate functionality. This may require legal approval in some countries. Previously, gonadectomy was widely performed in children assigned to female sex, but is nowadays often postponed to allow an informed consent policy. However, due to the increased risk for the development of gonadal tumors, regular clinical assessment and diagnostic visualization of the gonads should be recommended.\nPrognosis\nWith early diagnosis, surgery and hormone treatment can result in good outcome, both functionally and phenotypically. Infertility is almost always present.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Olaf HIORT | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "47,XYY syndrome", "Disease Definition": "A rare sex chromosome aneuploidy where males receive an additional Y chromosome, that is characterized clinically by tall stature evident from childhood, macrocephaly, facial features (mild hypertelorism, low set ears, a mildly flat malar region), speech delay and an increased risk for social and emotional difficulties, attention deficit hyperactive disorder and autistic spectrum disorder.", "ORPHA ID": 8, "Summary": ""}
{"Disease Name": "48,XXXY syndrome", "Disease Definition": "The 48,XXXY syndrome represents a chromosomal anomaly of the aneuploidic type characterized by the presence of two extra X chromosomes in males.", "ORPHA ID": 96263, "Summary": "Epidemiology\nThere is an annual incidence of 1/50,000 male births.\nClinical description\nThe 48,XXXY syndrome differs from Klinefelter syndrome by the presence of moderate intellectual deficit (average IQ of 50), more marked genital hypoplasia (microorchidism, micropenis, hypoplasia of the scrotum) and by more frequently observed facial dysmorphism (flat nose, epicanthus, prognathism, short neck, hypertelorism, facial asymmetry). Other dysmorphic characteristics (clinodactyly of the fifth finger, coxa valga, etc.) are often associated with this syndrome. Congenital skeletal malformations (kyphoscoliosis, radioulnar synostosis, epiphyseal dysplasia) canalso be present in addition to genital anomalies (cryptorchidism) and gynecomastia. With age, other manifestations can also appear such as arthropathies, obesity, behavioral problems (hyperactivity, irritability, anxiety, immaturity, passivity, anger, communication and socialization problems) and language retardation.\nEtiology\nThe most likely etiology is the non disjunction of homologous chromosomes (during the first meiotic division) or sister chromatids (during the second meiotic division) in the parental germ cells. There is no known factor responsible for or favoring the development of this syndrome.\nDiagnostic methods\nThe metaphase karyotype allows for the confirmation of a clinical diagnosis. Mosaicism with other polygonosomies is not uncommon (48,XXXY/ 48,XXYY/ 49,XXXXY).\nDifferential diagnosis\nDifferential diagnoses include other aneuploidies, such as Klinefelter syndrome (47,XXY), 48,XXYY syndrome and 49,XXXXY syndrome (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible by amniocentesis.\nGenetic counseling\nThe risk of recurrence is very low as cases of 48,XXXY are sporadic.\nManagement and treatment\nManagement needs to be handled by a multidisciplinary team and includes the treatment of cardiac and skeletal malformations, management of sensory, neurological, hormonal (testosterone-based hormone therapy), metabolic (supervising obesity), psychological and psychiatric care and dental follow-up.\nPrognosis\nPatients have an essentially normal life expectancy but will need to attend regular medical visits, in particular for their endocrine and infectious problems, and to undergo regular psychiatric monitoring.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Carole CORSINI  - Pr Pierre SARDA"}
{"Disease Name": "48,XXYY syndrome", "Disease Definition": "A rare sex chromosome number anomaly disorder characterized, genetically, by the presence of an extra X and Y chromosome in males and, clinically, by tall stature, dysfunctional testes associated with infertility and insufficient testosterone production, cognitive, affective and social functioning impairments, global developmental delay, and an increased risk of congenital malformations.", "ORPHA ID": 10, "Summary": "Epidemiology\nThe estimated prevalence is between 1/18,000 to 1/50,000 male births.\nClinical description\nPresentation is often in infancy or early childhood with hypotonia and global development delay, sometimes accompanied by mild dysmorphic facies, plagiocephaly, and flat feet. Testicular hypogonadism, starting in adolescence and persisting throughout adulthood, is nearly universal. Cryptorchidism, micropenis, and gynecomastia have been occasionally reported. Overall, cognitive abilities tend to be in the borderline range (70-80) with about 1/3 of males with full scale IQ in the intellectually disabled range. Significantly lower verbal reasoning skills are often present. Relative to IQ, adaptive functioning is significantly impaired, with common deficits in communication, social skills, self-care, and self-direction. Many medical conditions are frequently associated, including significant dental problems (~90%), tremor (~60% of adults), asthma/allergies (~60%), skeletal anomalies (club foot, radioulnar synostosis, prominent elbows with cubitus varus, scoliosis, and kyphosis), type 2 diabetes (~20% in adulthood), thrombosis (~18%), epilepsy (~15%), strabismus (~15%), gastrointestinal problems (feeding intolerance, reflux, constipation), congenital heart defects, and renal abnormalities. Non-specific dysmorphic features may include epicanthal folds, hypertelorism, and clinodactyly. Behavioral patterns can include characteristics of attention-deficit/hyperactivity disorder and autism spectrum disorder, in addition to mood instability, anxiety, obsessive-compulsive behaviors, and emotional immaturity.\nEtiology\n48,XXYY syndrome results from a nondisjunction event of sex chromosomes during spermatogenesis or, less often, from post-zygotic mitotic nondisjunction during cell division. There are no known predisposing factors.\nDiagnostic methods\nDiagnosis is often made during childhood evaluation of physical and/or developmental concerns. Diagnosis is confirmed with standard karyotype or chromosomal microarray.\nDifferential diagnosis\nMain differential diagnoses include 47,XXY syndrome; 48,XXXY syndrome; 49,XXXXY syndrome; 45,X/46,XY mosaicism and 46,XX males. Other possible overlapping conditions include Fragile X, Jacob, Prader-Willi, Soto, Börjeson-Forssman Lehman, Weaver, and Cohen syndromes.\nAntenatal diagnosis\nNon-invasive prenatal screening through cell-free fetal DNA can identify a fetus with 48,XXYY but this test is not diagnostic. Antenatal diagnosis is possible by amniocentesis or chorionic villus sampling.\nGenetic counseling\n48,XXYY is typically due to a sporadic aneuploidy event with an estimated recurrence risk of <1%. Genetic counseling should include a review of the potential physical, medical, developmental and psychological features.\nManagement and treatment\nComprehensive interdisciplinary care is important to evaluate and manage the associated developmental, medical, and psychological conditions. A thorough physical exam, renal ultrasound and echocardiography should be performed to evaluate for congenital defects. Vision/hearing screenings and routine dental care are important throughout life. Comorbidities, such as asthma and epilepsy, should be diagnosed and managed as they would be in individuals without 48,XXYY. Pubertal examinations and serum hormone profiles should be monitored beginning around age 10, and testosterone supplementation should be considered for hypogonadism. Annual screening for hyperlipidemia, diabetes, and autoimmune thyroid disease is recommended starting in adolescence. Comprehensive, interdisciplinary neurodevelopmental and behavioral evaluation is warranted throughout childhood. Interventions targeting psychological functioning (including emotional and behavioral disorders) and speech/language, motor, and self-care skills should be evidence-based and individualized. School- and community-based supports and services frequently form part of the treatment plan.\nPrognosis\nWhile there is no cure, with appropriate treatment for associated medical and psychiatric conditions, life expectancy is typically normal. Health-related quality of life and degree of independence varies depending on the severity of symptoms and access to appropriate health care and support services.\n\n                            Last update: \n                            January 2019\n\n\n                            - Expert reviewer(s): \n                             Catherine BUCHANAN  - Dr Shanlee DAVIS  - Dr Susan HOWELL  - Dr Nicole TARTAGLIA  - Dr Adrianne VILLAGOMEZ"}
{"Disease Name": "48,XYYY syndrome", "Disease Definition": "A rare Y chromosome number anomaly that affects only males and is characterized by mild-moderate developmental delay (especially speech), normal to mild intellectual disability, large, irregular teeth with poor enamel, tall stature and acne. Radioulnar synostosis and clinodactyly have also been associated. Boys generally present normal genitalia, while hypogonadism and infertility is frequently reported in adult males.", "ORPHA ID": 99329, "Summary": ""}
{"Disease Name": "49,XXXXY syndrome", "Disease Definition": "The 49,XXXXY syndrome represents a chromosomal anomaly of the aneuploidic type characterized by the presence of three extra X chromosomes in males.", "ORPHA ID": 96264, "Summary": "Epidemiology\nIt has an annual incidence of 1/85,000 to 1/100,000 male births.\nClinical description\nThe 49,XXXXY syndrome differs from Klinefelter syndrome by its variable IQ with an often subtle intellectual deficit in childhood but a progressive (moderate to severe) deterioration with age (IQ varying between 70 and 20), by the absence of tall stature with delayed growth often already visible in utero and under the third percentile after birth, and sometimes by a small stature and a deficit in growth hormones. Hypogonadism is severe with a micropenis, microorchidism, hypoplasia of the scrotum and cryptorchidism. Gynecomastia is uncommon. Remarkable facial dysmorphism (hypertelorism, large flat nose with a depressed nasal curvature, upslanting palpebral fissures, epicanthus, prognathism, folded-over ears, short neck) and other dysmorphic characteristics (cubitus valgus, flat feet, clinodactyly of the fifth finger, joint laxity) appear frequently. Congenital heart defects (arterial canal) as well as skeletal defects (radioulnar synostosis, epiphyseal dysplasia, coxa valga, kyphoscoliosis, hip and knee dislocation), cerebral (hypoplastic corpus callosum, arhinencephaly) and renal defects (renal hypoplasia) can also be present. Axial hypotonia is often seen in children. With age, the intellectual deficit worsens and is associated with a major delay in language development. Strabismus or severe and progressive myopia can occur which can lead to declining vision. Behavioral problems such as shyness can also become apparent.\nEtiology\nThe etiology is the non disjunction of homologous chromosomes (during the first meiotic division) or of sister chromatids (during the second meiotic division) in the maternal germ cells. There is no known factor responsible for or favoring the appearance of this syndrome.\nDiagnostic methods\nThe metaphase karyotype allows for the confirmation of a clinical diagnosis.\nAntenatal diagnosis\nAntenatal diagnosis is possible by an amniocentesis screening for a wide range of conditions.\nGenetic counseling\nThe risk of recurrence is very unlikely as cases of 49,XXXXY are sporadic.\nManagement and treatment\nManagement needs to be handled by a multidisciplinary team and includes the treatment of cardiac and skeletal defects, the monitoring of psychomotor development with physiotherapy, psychomotricity, speech therapy, orthopedic and sensory management (ophthalmological examination), neurological, hormonal (if necessary) and psychological care and regular dental follow-up.\nPrognosis\nPatients have an essentially normal life expectancy but will need to attend regular medical visits.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Carole CORSINI  - Pr Pierre SARDA"}
{"Disease Name": "49,XXXYY syndrome", "Disease Definition": "49,XXXYY syndrome is a rare gonosome anomaly syndrome characterized by a eunuchoid habitus with gynecoid fat distribution and shape, normal to tall stature, moderate to severe intellectual disability, distinctive facial features (e.g. prominent forehead, epicanthic folds, broad nasal bridge, prognathism), gynecomastia, hypogonadism, cryptorchidism, small penis and behavioral abnormalities (incl. solitary, passive disposition but prone to aggressive outbursts, autistic). Skeletal malformations, such as delayed bone age, fifth finger clinodactyly, elbow malformations and slow molar development, may also be associated.", "ORPHA ID": 261534, "Summary": ""}
{"Disease Name": "49,XYYYY syndrome", "Disease Definition": "A rare Y chromosome number anomaly with a variable phenotype mainly characterized by moderate to severe intellectual disability, speech delay, hypotonia, and mild dysmorphic features, including facial asymmetry, hypertelorism, bilateral low set 'lop' ears, and micrognatia. Skeletal abnormalities (such as skull deformities, radioulnar synostosis, elbow flexion, clinodactyly, brachydactyly) and behavourial problems have also been associated with this condition. Genitalia are normal at birth, although hypogonadism and azoospermia has been reported in adults.", "ORPHA ID": 99330, "Summary": ""}
{"Disease Name": "4H leukodystrophy", "Disease Definition": "A rare hypomyelinating leukodystrophy disorder characterized by the association of dental abnormalities (delayed dentition, abnormal order of dentition, hypodontia), hypogonadotropic hypogonadism, and hypomyelinating leukodystrophy manifesting with neurodevelopmental delay or regression and/or progressive cerebellar symptoms.", "ORPHA ID": 289494, "Summary": "Epidemiology\nTo date, more than 200 cases have been reported worldwide.\nClinical description\nAge of onset typically ranges from infancy to childhood but exceptionally may occur in late adolescence or early adulthood. The clinical phenotype is variable with about half of affected individuals presenting global developmental delay, which usually presents in infancy. Cerebellar signs frequently include intention tremor, dysmetria, absence of smooth pursuit and gaze-evoked nystagmus and, more variably, gait ataxia and vertical gaze limitation. Pyramidal signs are typically absent in young children and may develop slowly in older patients. Extrapyramidal signs, typically dystonia, are prominent in only a few patients. Wheelchair dependence typically occurs from the end of the first decade, although half of patients remain ambulatory as adults. Cognition varies from normal to learning difficulties or mild to moderate intellectual disability (most frequent), with slow deterioration in the second decade. Expressive language and swallowing is present until late but deteriorates over time. Dental abnormalities include delayed dentition with abnormal order of deciduous teeth eruption, hypodontia and, less frequently, natal teeth. Delayed puberty or primary amenorrhea is frequent. Most patients have high myopia; optic atrophy is present in older individuals. About half of patients have short stature, and may have growth hormone deficiency. Central hypothyroidism is present in a few patients. Brain magnetic resonance imaging (MRI) shows hypomyelination along with relative T2 hypointensity of optic radiation, posterior limb of internal capsule, anterolateral thalamus, and dentate nucleus.\nEtiology\nMutations of the genes encoding POLR3 (RNA polymerase III) subunits, POLR3A, POLR3B and POLR1C, have been identified. POLR3 is an enzyme responsible for transcription of specific noncoding small RNAs involved in the regulation of transcription, RNA processing, and translation. It is suggested that these mutations lead to abnormal POLR3 function and abnormal production of proteins important for development of central nervous system white matter. Despite the overlap in causal genes, no genotype-phenotype correlation has been identified.\nDiagnostic methods\nDiagnosis is suspected based on the clinical presentation and the characteristic hypomyelination findings on brain MRI. Blood tests for levels of thyroid, growth and puberty hormones can be helpful. Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nOther hypomyelinating leukodystrophies, especially when there are no typical dental abnormalities.\nAntenatal diagnosis\nGenetic prenatal diagnosis is possible when causal mutations have previously been identified in an affected family.\nGenetic counseling\nThe disease is inherited in an autosomal recessive manner and genetic counseling should be offered to affected families. Where both parents are unaffected carriers, the risk of inheriting the disease is 25%. POLR3A pathogenic variants tend to correspond with an earlier disease onset, more rapid neurological decline and shorter life expectancy than POLR3B pathogenic variants.\nManagement and treatment\nManagement and treatment should be multidisciplinary and tailored to the individual. Regular monitoring by an endocrinologist is required. The decision to treat sex and growth hormone deficiency, when present, is individually based. Physical aids and therapy may be required to support motor function. Good dental hygiene and monitoring is recommended to preserve teeth. Regular ophthalmologic follow-up is also necessary, as in most patients, especially with POLR3B mutations, myopia continues to increase.\nPrognosis\nPrognosis depends primarily on disease severity. At the severe end, affected individuals do not achieve independent walking and have mild to moderate intellectual disability.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Pr N.I. [Nicole] WOLF"}
{"Disease Name": "4p16.3 microduplication syndrome", "Disease Definition": "4p16.3 microduplication syndrome is a rare genetic syndrome that results from the partial duplication of the short arm of chromosome 4. It has a highly variable phenotype, principally characterized by psychomotor and language delay, seizures and dysmorphic features such as high forehead with frontal bossing, hypertelorism, prominent glabella, long narrow palpebral fissures, low set ears and short neck. Eye abnormalities (glaucoma, irregular iris pigmentation, hyperopia) have also been reported.", "ORPHA ID": 96072, "Summary": ""}
{"Disease Name": "4q21 microdeletion syndrome", "Disease Definition": "The 4q21 microdeletion syndrome is a newly described syndrome associated with facial dysmorphism, progressive growth restriction, severe intellectual deficit and absent or severely delayed speech.", "ORPHA ID": 238750, "Summary": "Epidemiology\nIt has been reported in nine unrelated patients.\nClinical description\nThe most common facial feature includes high or broad forehead, hypertelorism and short philtrum. Short hands and feet are frequently observed.\nEtiology\nThis microdeletion was identified by comparative genomic hybridisation (CGH) microarray. The critical region encompasses two candidate genes, PRKG2 and RASGEF1B, in which haploinsufficiency could participate to the phenotype.\n\n                            Last update: \n                            October 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "4q25 proximal deletion syndrome", "Disease Definition": "A partial deletion of the long arm of chromosome 4 characterized by complex behavioral difficulties, developmental and delay/ intellectual disability, and minor dysmorphic features, including subtle facial asymmetry (most prominent in the mandible), mild hypotelorism, long nasal bridge, small low-set ears, narrow mouth, and mild hand deformities, such as bilateral short 5th metacarpals, and short hands.", "ORPHA ID": 502437, "Summary": ""}
{"Disease Name": "5-fluorouracil poisoning", "Disease Definition": "A rare intoxication caused by the prolonged, low-dose administration of 5-fluorouracil, which is the mainstay of both adjuvant and advanced-disease chemotherapy regimens in colon cancer. 5-fluorouracil poisoning is characterized by gastrointestinal (nausea, emesis, diarrhea, anorexia, stomatitis) and hematologic (myelosuppression) toxicities as well as mucositis, alopecia and, occasionally, palmar-plantar dysesthesia (more commonly known as hand-foot syndrome). Women have been reported to experience more 5-fluorouracil-related toxicity than men.", "ORPHA ID": 217064, "Summary": ""}
{"Disease Name": "5-oxoprolinase deficiency", "Disease Definition": "A very heterogeneous condition characterized by 5-oxoprolinuria.", "ORPHA ID": 33572, "Summary": "Epidemiology\nIt has been detected in eight patients worldwide. All affected patients have been identified because of 5-oxoprolinuria.\nClinical description\nSymptoms reported in individual patients include renal stone formation, enterocolitis, intellectual deficiency, neonatal hypoglycemia, microcytic anemia and microcephaly.\nEtiology\n5-Oxoprolinase catalyses a step in the gamma-glutamyl cycle (glutathione metabolism).\nDiagnostic methods\nThe diagnosis is based on the finding of 5-oxoprolinuria and on the low activity of 5-oxoprolinase.\nDifferential diagnosis\nOther causes of 5-oxoprolinuria include glutathione synthetase deficiency (see this term), diet (certain infant formulas and tomato juice), severe burns, Stevens-Johnson syndrome (see this term), inborn errors of metabolism not involving the gamma-glutamyl cycle, e.g. X-linked ornithine trancarbamylase deficiency, urea cycle defects, or tyrosinemia, as well as homocystinuria (see these terms), drug metabolism (paracetamol, vigabatrin, flucloxacillin, netilmicin), prematurity, malnutrition, pregnancy and nephropatic cystinosis.\nGenetic counseling\nThe disease is transmitted as an autosomal recessive trait.\nManagement and treatment\nNo specific treatment has been proposed or tested.\nPrognosis\nThe prognosis is difficult to predict as only eight patients with different clinical symptoms have been described.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Agne LARSSON  - Dr Ellinor RISTOFF"}
{"Disease Name": "5p13 microduplication syndrome", "Disease Definition": "A rare partial autosomal trisomy/tetrasomy characterized by global developmental delay, intellectual disability, autistic behavior, muscular hypotonia, macrocephaly and facial dysmorphism (frontal bossing, short palpebral fissures, low set, dysplastic ears, short or shallow philtrum, high arched or narrow palate, micrognathia). Other associated clinical features include sleep disturbances, seizures, aplasia/hypoplasia of the corpus callosum, skeletal abnormalities (large hands and feet, long fingers and toes, talipes).", "ORPHA ID": 329802, "Summary": ""}
{"Disease Name": "5q14.3 microdeletion syndrome", "Disease Definition": "The newly described 5q14.3 microdeletion syndrome includes severe intellectual deficit with no speech, stereotypic movements and epilepsy.", "ORPHA ID": 228384, "Summary": "Epidemiology\nTo date, fourteen patients have been reported.\nClinical description\nMiscellaneous dysmorphic facial features are present in all cases, but some common features are noticed, high and wide forehead, pronounced eyebrows, anteverted nostrils, short and prominent philtrum, down-turned corners of the mouth and small chin. Stereotypic movements and poor eye contact are present in many patients, suggesting the diagnosis of autism spectrum disorder. In most patients brain imaging is reported to be abnormal, including anomalies of the corpus callosum, enlarged ventricles, periventricular white matter, hyperintensities and cortical atrophy.\nEtiology\nThe microdeletion was identified by microarray-based comparative genomic hybridization (CGH). The size of deletions varies, the minimal common deleted region encompasses only MEF2C, suggesting that haploinsufficiency of MEF2C is responsible for the phenotype.\n\n                            Last update: \n                            May 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "5q35 microduplication syndrome", "Disease Definition": "The newly described 5q35 microduplication syndrome is associated with microcephaly, short stature, developmental delay and delayed bone maturation.", "ORPHA ID": 228415, "Summary": "Epidemiology\nIt has been reported in two unrelated patients.\nClinical description\nThere is no remarkable facial dysmorphism. The clinical picture is opposite to that of patients with Sotos syndrome (macrocephaly, overgrowth and advanced bone age; see this term).\nEtiology\nThis microduplication was identified by microarray-based comparative genomic hybridization (aCGH). The breakpoints of the duplication in both patients map to the proximal and distal low-copy repeats (LCRs), which flank the Sotos critical region. These findings support a non-allelic homologous recombination (NAHR) as the mechanism of duplication, and a dosage effect of the Sotos gene NSD1 (5q35).\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "6-phosphogluconate dehydrogenase deficiency", "Disease Definition": "A rare constitutional hemolytic anemia characterized by a low 6-phosphogluconate dehydrogenase activity in the erythrocytes, which clinically manifests with a well-compensated chronic nonspherocytic hemolytic anemia and transient hemolytic periods with jaundice.", "ORPHA ID": 99135, "Summary": ""}
{"Disease Name": "6-pyruvoyl-tetrahydropterin synthase deficiency", "Disease Definition": "A rare form of hyperphenylalaninemia due to tetrahydropterin (BH4) biosynthesis deficiency, leading to central dopamine and serotonin deficiency, and characterized by infantile-onset neurological disease of variable severity ranging from mild forms with normal neurological development to severe forms with hypotonia, developmental delay, complex movement disorder dominated by dystonia or dystonia parkinsonism.", "ORPHA ID": 13, "Summary": "Epidemiology\nThe global prevalence of BH4 deficiencies remains unknown and great variance can be found among different countries. European newborn screening programs (NBS) reveal that the mean incidence of all hyperphenylalaninemias (HPA) is approximately 1/10,000, with BH4 deficiencies representing 1-2% of cases. 6-pyruvoyl-tetrahydropterin synthase deficiency (PTPSD) is the most frequent of all HPA-associated BH4 deficiencies, representing approximately half of cases.\nClinical description\nWhen left untreated, the deficiency leads to neurological symptoms starting at 4-5 months of age. Very frequent symptoms (>50% of patients) are developmental delay and (axial) hypotonia. Frequent symptoms (25-50% of patients) are hypertonia of the extremities, impaired speech development and being small for gestational age. There are no consistent reports on genotype-phenotype correlation.\nEtiology\nPTPSD is caused by variants in the PTS gene, which encodes 6-pyruvoyl-tetrahydropterin synthase. BH4 is an essential cofactor for phenylalanine hydroxylase (PAH), tyrosine (TH) and tryptophan hydroxylase (TPH). Therefore, the tetrahydrobiopterin deficiency causes not only HPA, but also a central dopamine and serotonin deficiency.\nDiagnostic methods\nPTPSD should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when HPA is moderate. The analysis of pterins in urine or dried blood spot (DBS) in patients and the analysis of dihydropteridine reductase (DHPR) enzyme activity in DBS has to follow in all patients with HPA on NBS. The suspected diagnosis can be further confirmed by genetic evaluation of the PTS gene and/or the measuring of the neurotransmitters 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and pterins in cerebrospinal fluid. Clinical consensus guidelines on the different diagnostic options are available with open access.\nDifferential diagnosis\nThe differential diagnosis includes classic phenylketonuria and hyperphenylalaninemia due to autosomal recessive GTP cyclohydrolase I, pterin-4-alpha-carbinolamine dehydratase, dihydropteridine reductase, and DNAJC12 deficiencies.\nAntenatal diagnosis\nPrenatal diagnosis is possible by molecular analysis where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nPTPS deficiency is an autosomal recessive genetic disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of sapropterin hydrochlorid) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophan). In case of insufficient clinical response or L-dopa-induced hyperkinesia, long-acting dopamine agonists (e.g. pramipexole) can be used to stabilize the clinical and biochemical picture. Monoamino oxidase inhibitors (selegiline) are also useful to prolong the action of neurotransmitter precursors.\nPrognosis\nLevodopa/carbidopa supplementation drastically improves, often even reconstitutes motor function. However, long-term prognosis correlates with early diagnosis and treatment initiation.\n\n                            Last update: \n                            April 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Oya KUSEYRI HÜBSCHMANN | MetabERN* - Pr Thomas OPLADEN | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "6p22 microdeletion syndrome", "Disease Definition": "6p22 microdeletion syndrome is a newly described syndrome associated with a variable clinical phenotype including developmental delay, facial dysmorphism, short neck and diverse malformations.", "ORPHA ID": 251046, "Summary": "Epidemiology\nEight cases have been reported to date.\nClinical description\nThe most common facial features include eye anomalies: strabismus, deeply set eyes, and epicanthic folds and ear anomalies such as over-folded helices and low-set ears. This microdeletion was identified by fluorescence in situ hybridization (FISH) or comparative genomic hybridisation (CGH) microarray. Reported patients have deletions of variable size. The critical region for the 6p22 deletion phenotype is 2.2 Mb and encompasses 12 genes; their function is still largely unknown.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "6q terminal deletion syndrome", "Disease Definition": "A rare partial deletion of the long arm of chromosome 6 characterized by a variable clinical phenotype that includes a characteristic craniofacial dysmorphism (including microcephaly, broad nose with prominent nasal root and bulbous nasal tip, large ears that may be malformed and low-set, characteristic downturned mouth, and short neck), global development delay, intellectual disability, and variable, non-specific, congenital malformations. Muscular hypotonia, seizures, retinal anomalies, and variable brain abnormalities have been reported in association.", "ORPHA ID": 75857, "Summary": ""}
{"Disease Name": "6q16 microdeletion syndrome", "Disease Definition": "A rare Prader-Willi like syndrome due to an interstitial deletion located at 6q16.1q16.2 and characterized by obesity, hyperphagia, hypotonia, small hands and feet, eye/vision anomalies, and global developmental delay.", "ORPHA ID": 171829, "Summary": ""}
{"Disease Name": "6q25.2q25.3 microdeletion syndrome", "Disease Definition": "6q25 microdeletion syndrome is a recently described syndrome characterized by developmental delay, facial dysmorphism and hearing loss.", "ORPHA ID": 251056, "Summary": "Epidemiology\nIt has been clinically and molecularly characterized in 4 patients.\nClinical description\nAll of them presented with microcephaly, developmental delay, dysmorphic features and hearing loss, whereas two of them had agenesis of the corpus callosum. Dysmorphic features include midface hypoplasia, hypertelorism, broad nasal root and posteriorly rotated ears.\nEtiology\nThis syndrome is caused by an interstitial deletion encompassing 6q25.2-q25.3. These de novo deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size with the smallest region of overlap (SRO) of 3.52 Mb.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "7p22.1 microduplication syndrome", "Disease Definition": "7p22.1 microduplication syndrome is a rare chromosomal anomaly syndrome, resulting from a partial interstitial microduplication of the short arm of chromosome 7, characterized by intellectual disability, psychomotor and speech delays, craniofacial dysmorphism (including macrocephaly, frontal bossing, hypertelorism, abnormally slanted palpebral fissures, anteverted nares, low-set ears, microretrognathia) and cryptorchidia. Cardiac (e.g., patent foramen ovale and atrial septal defect), as well as renal, skeletal and ocular abnormalities may also be associated.", "ORPHA ID": 314034, "Summary": ""}
{"Disease Name": "7q11.23 microduplication syndrome", "Disease Definition": "7q11.23 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from the partial duplication of the long arm of chromosome 7 characterized by a highly variable phenotype that typically manifests with mild-moderate intellectual delay (patients could be in the normal range), speech disorders (particularly of expressive language), and distinctive craniofacial features (brachycephaly, broad forehead, straight eyebows, broad nasal tip, short philtrum, thin upper lip and facial asymmetry). Hypotonia, developmental coordination disorders, behavioral problems (such as anxiety, ADHD and oppositional disorders) and various congenital anomalies, such as heart defects, diaphragmatic hernia, renal malformations and cryptorchidism, are frequently presented. Neurological abnormalities (visible on MRI) have been reported.", "ORPHA ID": 96121, "Summary": ""}
{"Disease Name": "7q31 microdeletion syndrome", "Disease Definition": "7q31 microdeletion syndrome is a rare chromosomal anomaly characterized by speech and language disorder, predominantly presenting as an apraxia of speech, sometimes associated with oral motor dyspraxia, dysarthria, receptive and expressive language disorder, and hearing loss. Individuals with larger deletions in this region have also been reported to display intellectual disability and autism.", "ORPHA ID": 251061, "Summary": ""}
{"Disease Name": "8p inverted duplication/deletion syndrome", "Disease Definition": "A rare chromosomal anomaly clinically characterized by mild to severe intellectual disability, severe developmental delay (psychomotor and speech development), hypotonia with tendency to later develop progressive hypertonia, and characteristic facial features. The main congenital anomalies associated include central nervous system (CNS) malformations such as hypoplasia/agenesis of the corpus callosum (80%), skeletal abnormalities such as scoliosis/kyphosis or dislocated hips (60%), and congenital heart defects (25%).", "ORPHA ID": 96092, "Summary": "Epidemiology\nAbout 60 patients have been reported. Whilst epidemiological data is limited, the prevalence at birth has been estimated between 1/10,000-30,000 in Europe.\nClinical description\nThe most common clinical manifestations include developmental delay, mild to severe degree of cognitive deficit, lack or delay of expressive speech and language and hypotonia, contributing to a mild-severe global developmental delay. Most children with invdupdel(8p) have been reported to be happy natured, sociable and communicative albeit non-verbal, but some may exhibit attention deficits, impulsivity and hyperactivity. In this view, it has been also estimated that between thirty to fifty percent of individuals with invdupdel(8p) may develop a neurodevelopmental disorder during infancy. Facial dysmorphism, more noticeable in childhood, is subtle and frequently includes a prominent forehead, temporal baldness, anteverted nostrils, eversion of the lower lip, large mouth and ears and a short neck. Adults with invdupdel(8p) have height ranging from normal to exceptionally tall, and have a tendency to develop progressive hypertonia, spastic quadriplegia and orthopedic conditions like contracted joints and scoliosis. Albeit, a wide range of congenital malformations (such as cardiac defects, eye and urinary system anomalies) and other skeletal abnormalities have also been reported, the most common congenital malformation being corpus callosum hypoplasia/agenesis.\nEtiology\nThe invdupdel(8p) consists of a deletion distal to the 8p23 region followed by an intermediate intact segment, and a proximal inverted duplication of various extensions. These rearrangements are mediated mainly by two olfactory receptor gene clusters or defensin repeat (ORDRs) at the breakpoints; the polymorphic 8p23 inversion between these clusters increases the susceptibility on 8p to rearrangements. Thus, the inverted duplication with a terminal deletion of the short arm of chromosome 8 mostly occurs as either an inverted duplication from centromere to D8S552 with a pter deletion from D8S349 or as an inverted duplication from 8p11.2 or 8p21 to D8S552, with a telomeric deletion from D8349. To date, all invdupdel(8p) occurred de novo, but the inversion allele is frequently found in one of the parents, and has an estimated allele frequency of 27% in the general Japanese population.\nDiagnostic methods\nDiagnosis is based on clinical manifestations and agenesis of the corpus callosum on brain magnetic resonance imaging (MRI) leading to chromosomal analysis. Molecular techniques (FISH, MLPA, CGH array) can be used for the genetic characterization of the above-mentioned rearrangements.\nDifferential diagnosis\nDifferential diagnosis includes other multiple congenital anomalies/intellectual deficit syndromes such as Trisomy 8p, in particular those carrying an 8p21-p22 duplication.\nAntenatal diagnosis\nAntenatal diagnosis is based on ultrasound detection of fetal abnormalities (e.g. agenesis of corpus callosum) and cytogenetic analysis after amniocenteses or chorionic villus sampling.\nGenetic counseling\nGenetic counseling is recommended. Invdupdel(8p) rearrangements occur de novo; however, parents can carry a harmless common inversion involving the 8p23.1 segment (prevalence 1/4 to 1/5) which on rare occasions might lead to the more complex invdupdel(8p) rearrangement in their offspring.\nManagement and treatment\nPhysiotherapy from an early age as well as occupational therapy and speech therapy are recommended. Some patients benefit from music therapy. No gross orthopedic complications are noted. However, regular follow-up is needed.\nPrognosis\nThere is no report on life expectancy. The majority of invdupdel(8p) individuals will need lifelong, full-time care. Spastic quadriplegia may be slowly progressive with age.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Andrea BARTULI | ITHACA* - Dr Marina MACCHIAIOLO | ITHACA* - Dr Davide VECCHIO | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "8p11.2 deletion syndrome", "Disease Definition": "8p11.2 deletion syndrome is a contiguous gene syndrome characterized by the association of congenital spherocytosis, dysmorphic features, growth delay and hypogonadotropic hypogonadism.", "ORPHA ID": 251066, "Summary": "Epidemiology\nIt has been described in 8 patients to date.\nClinical description\nCommon dysmorphic features include micrognathia, microcephaly, preauricular pits, high-arched palate and abnormal ears. All patients except one have intellectual deficit. In one patient, the association of anosmia was suggestive of Kallmann syndrome (see this term).\nEtiology\nThe syndrome is caused by deletions of the proximal part of the short arm of chromosome 8 (8p11.1 to 8p21). The deletions can be cytogenetically detected and their size is variable. The loss of the ankyrin-1 gene (ANK1) results in congenital spherocytosis.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "8p23.1 duplication syndrome", "Disease Definition": "8p23.1 duplication syndrome is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 8, with a highly variable phenotype, principally characterized by mild to moderate developmental delay, intellectual disability, mild facial dysmorphism (incl. prominent forehead, arched eyebrows, broad nasal bridge, upturned nares, cleft lip and/or palate) and congenital cardiac anomalies (e.g., atrioventricular septal defect). Other reported features include macrocephaly, behavioral abnormalities (e.g., attention deficit disorder), seizures, hypotonia and ocular and digital anomalies (poly/syndactyly).", "ORPHA ID": 251076, "Summary": ""}
{"Disease Name": "8p23.1 microdeletion syndrome", "Disease Definition": "8p23.1 deletion involves a partial deletion of the short arm of chromosome 8 characterized by low birth weight, postnatal growth deficiency, mild intellectual deficit, hyperactivity, craniofacial abnormalities, and congenital heart defects.", "ORPHA ID": 251071, "Summary": "Epidemiology\nThe prevalence is unknown but 8p23.1 deletions are rare. To date, over 50 cases of interstitial or terminal 8p23.1 have been reported without a notable gender discrepancy.\nClinical description\nThe clinical manifestations are variable and do not depend on the size of the deletion, since this is the same in the majority of patients. Most common manifestations include prenatal and postnatal growth retardation, low birth weight, mild to moderate intellectual deficit, psychomotor retardation, poor speech, seizures, behavioral problems such as hyperactivity and impulsiveness. Frequent craniofacial abnormalities include microcephaly, high and narrow forehead, broad nasal bridge, epicanthic folds, high arched palate, short neck and low set unusually shaped ears. Furthermore congenital heart defects (atrioventricular, septal defects, pulmonary stenosis), congenital diaphragmatic hernia and in boys cryptorchidism and hypospadias have been frequently reported. Some affected individuals have been reported to have normal intelligence.\nEtiology\nThe 8p23.1 deletion is likely to arise through non-allelic homologous recombination mediated by flanking low-copy repeats (LCRs), explaing the common size of approximately 3.4 Mb. The congenital heart defects and diaphragmatic hernia are most likely explained by haploinsufficiency for GATA4.\nDiagnostic methods\nDiagnosis is based on clinical manifestations leading to chromosomal analysis. 8p23.1 deletions are often missed by standard karyotyping, and mostly detected by molecular karyotyping. Molecular techniques may be used for the genetic characterization of the deletion (FISH, MLPA, aCGH).\nDifferential diagnosis\nDifferential diagnosis includes monosomy 22q11 (velocardiofacial syndrome; see this term). Accurate chromosomal analysis confirms the differential diagnosis.\nAntenatal diagnosis\nPrenatal diagnosis is possible by amniocentesis or chorionic villus sampling and molecular cytogenetic analysis.\nGenetic counseling\nGenetic counseling is recommended. Most 8p23.1 deletions occur de novo. However, parents can carry and transmit the chromosomal rearrangement to their children as well, with a risk of 50% for each child.\nManagement and treatment\nManagement involves assessment, treatment and a regular follow-up by appropriate specialists, including a general practitioner, pediatrician and cardiologists. Early diagnosis and access to major developmental therapies aiming at obtaining the best developmental outcome have been proven beneficial.\nPrognosis\nLife expectancy is considered normal provided that there is no major congenital heart anomaly or a diaphragmatic hernia.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Koenraad DEVRIENDT"}
{"Disease Name": "8q12 microduplication syndrome", "Disease Definition": "The newly described 8q12 microduplication syndrome is associated with unusual and characteristic multi-organ clinical features, which include hearing loss, congenital heart defects, intellectual disability, hypotonia in infancy, and Duane anomaly (see this term).", "ORPHA ID": 228399, "Summary": "Epidemiology\nIt has been described in two patients.\nClinical description\nThe mild facial dysmorphism is characterized by high, arched eyebrows and unilateral narrowing of the palpebral fissure and retraction of the globe caused by Duane anomaly (Duane anomaly is a form of complex strabismus characterized by limited ocular abduction and variably limited adduction accompanied by retraction of the globe, which narrows the palpebral fissure).\nEtiology\nThis microduplication was identified by microarray-based comparative genomic hybridization (aCGH). The lack of recurrent breakpoints in these two cases and the absence of any low-copy repeats (LCR) pairs that flank these de novo events do not support non-allelic homologous recombination as the mutation mechanism. The 8q12 region includes CHD7 and it is proposed that this gene, associated with CHARGE syndrome by haploinsufficiency, causes a different phenotype by gain-of-dosage.\n\n                            Last update: \n                            May 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "8q21.11 microdeletion syndrome", "Disease Definition": "8q21.11 microdeletion syndrome encompasses heterozygous overlapping microdeletions on chromosome 8q21.11 resulting in intellectual disability, facial dysmorphism comprising a round face, ptosis, short philtrum, Cupid's bow and prominent low-set ears, nasal speech and mild finger and toe anomalies.", "ORPHA ID": 284160, "Summary": "Epidemiology\nThe prevalence is unknown but 8q21.11 microdeletion syndrome is rare. To date, 13 cases, of which 5 from the same family, have been clinically and molecularly characterized without a notable gender discrepancy.\nClinical description\nVery frequent facial anomalies in patients with 8q21.11 microdeletions include a round face with full cheeks, ptosis, short philtrum, small mouth with downturned corners and a Cupid's bow of the upper lip, low-set and prominent ears and nasal speech. Mild to moderate intellectual disability is present in all affected individuals. Mild finger and toe anomalies such as camptodactyly, syndactyly of the 3rd and 4th fingers, and broadening of the first rays are relatively common. Most also suffer from hypotonia. Other features comprise a high forehead, short palpebral fissures, wide nasal bridge, underdeveloped alae, micrognathia, short neck, hearing loss and ophthalmic manifestations including strabismus, sclerocornea and microphthalmia.\nEtiology\nThe syndrome is caused by a heterozygous deletion at chromosome region 8q21.11, reported in the majority of patients. The constant microdeletion overlap region contains the ZFHX4 gene, a microRNA gene of unknown function, as well as a pseudogene and in 7 cases heterozygous deletions of PEX2 were noted. Microdeletions appear de novo or are inherited from affected parents in an autosomal dominant manner.\nDiagnostic methods\nDiagnosis is based on clinical manifestations leading to cytogenetic analysis. The 8q21.11 microdeletion can be detected using a range of molecular techniques including array based comparative genomic hybridization (array CGH) and fluorescence in situ hybridization (FISH).\nDifferential diagnosis\nDifferential diagnosis includes Schilbach-Rott syndrome, auriculo-condylar (question mark ear) syndrome, Frydman syndrome, Kabuki syndrome (see these terms). The syndrome also bares resemblance with distal 22q11.2 microdeletion syndrome and 10p13 microdeletion syndrome. The entity should not be confused with the 8q22.1 microdeletion (see this term) found in patients with Nablus mask-like facial syndrome.\nAntenatal diagnosis\nAntenatal diagnosis of 8q21.11 microdeletion is possible by amniocentesis or chorionic villus sampling and cytogenetic analysis. Preimplantation genetic diagnosis should be available for at risk couples.\nGenetic counseling\nCytogenetic testing and genetic counseling should be offered to parents of affected individuals, informing them of the 50% risk of recurrence. Although the 8q21.11 microdeletion occurs sporadically, most deletions appearing de novo, a small number of patients have been inherited from affected parents.\nManagement and treatment\nManagement involves assessment, developmental therapies and a regular follow-up by a primary care physician and if required by appropriate specialists. Affected children almost invariably need special education. Early diagnosis and access to therapies with attention to speech and language, motor development and cognition are recommended.\nPrognosis\nPrognosis depends on clinical features. Adult affected individuals, despite their learning difficulties specifically regarding abstract thinking and planning ahead, function normally in everyday life. Fertility and life expectancy does not seem to be reduced.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM"}
{"Disease Name": "8q22.1 microdeletion syndrome", "Disease Definition": "The 8q22.1 microdeletion syndrome or Nablus mask-like facial syndrome is a rare microdeletion syndrome associated with a distinct facial appearance.", "ORPHA ID": 178303, "Summary": "Epidemiology\nIt has been reported in four unrelated patients.\nClinical description\nA mask-like facial appearance is the most characteristic feature with blepharophimosis, tight appearing glistening facial skin, flat and broad nose, dysplastic ears and unusual scalp hair pattern. Camptodactyly, joint contractures, unusual dentition and mild developmental delay can be observed. Cryptorchidism in boys and a happy disposition are constant.\nEtiology\nThis microdeletion was identified by comparative genomic hybridisation (CGH) microarray.\n\n                            Last update: \n                            October 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "8q24.3 microdeletion syndrome", "Disease Definition": "A multiple congenital anomalies/dysmorphic - intellectual disability syndrome characterized by feeding problems, growth retardation, microcephaly, developmental delay, digital and vertebral anomalies, joint laxity/dislocation, cardiac and renal defects, and dysmorphic facial features (including plagiocephaly, prominent forehead, bitemporal narrowing, bilateral coloboma, epicanthal folds, malformations of the outer and middle ear, wide nasal bridge, anteverted nares, prominent and bulbous nose tip, long philtrum, thin lips, high and narrow palate, micrognathia with prognathism/retrognathism, full cheeks, and short, broad neck). Additional variable manifestations include obstructive apneas, recurrent pneumonia, and seizures.", "ORPHA ID": 508488, "Summary": ""}
{"Disease Name": "9p13 microdeletion syndrome", "Disease Definition": "9p13 microdeletion syndrome is a rare chromosomal anomaly syndrome, resulting from a partial interstitial deletion of the short arm of chromosome 9, characterized by mild to moderate developmental delay, hand tremors, myoclonic jerks, attention deficit-hyperactivity disorder and a social personality. Patients also present bruxism, short stature and minor facial dysmorphic features (e.g., bilateral epicantic folds, broad, flat nasal bridge, anteverted nares, low-set ears micro/retro-gnathia).", "ORPHA ID": 324313, "Summary": ""}
{"Disease Name": "9q21.13 microdeletion syndrome", "Disease Definition": "A rare, genetic, intellectual disability malformation syndrome characterized by global developmental delay, intellectual disability, delayed speech and language development, epilepsy, autistic behavior, and moderate facial dysmorphism (including elongated face, narrow forehead, arched eyebrows, horizontal palpebral fissures, hypertelorism, epicanthus, midface flattening, short nose, long and featureless philtrum, thin upper lip, macrostomia, and prominent chin). Additional variable manifestations include microcephaly, hypotonia, hypertrichosis, and strabismus.", "ORPHA ID": 531151, "Summary": ""}
{"Disease Name": "9q31.1q31.3 microdeletion syndrome", "Disease Definition": "9q31.1q31.3 microdeletion syndrome is a rare, genetic, syndromic intellectual disability characterized by mild intellectual disability, short stature with high body mass index, short neck with cervical gibbus and dysmorphic facial features. A metabolic syndrome, including type 2 diabetes, hypercholesterolemia and hypertension has also been reported.", "ORPHA ID": 401923, "Summary": ""}
{"Disease Name": "9q33.3q34.11 microdeletion syndrome", "Disease Definition": "A partial monosomy of the long arm of chromosome 9 characterized by intellectual disability, developmental delay with pronounced speech delay, short stature, and muscular hypotonia. Common craniofacial dysmorphic features consist of microcephaly, prominent forehead, round face, arched eyebrows, upslanting palpebral fissures, strabismus, short nose, and thin upper lip. Other clinical findings include epilepsy, ataxia, unspecific brain MRI findings, early-onset primary dystonia, nail dysplasia, and bone malformations, in particular patellar abnormalities, epistaxis, and cutaneous-mucous telangiectasias.", "ORPHA ID": 495818, "Summary": ""}
{"Disease Name": "AA amyloidosis", "Disease Definition": "A rare amyloidosis that complicates chronic inflammatory disorders and is characterized by the aggregation and deposition of amyloid fibrils composed of serum amyloid A protein, an acute phase reactant. The kidney is involved in virtually all patients and dominates the clinical picture. Other frequently involved sites are the liver, the spleen, suprarenal gland, gut and less frequently the heart.", "ORPHA ID": 85445, "Summary": "Epidemiology\nThe exact prevalence is not known. AA amyloidosis occurs in less than 5% of patients with chronic inflammatory disorders. The disease is more frequent in certain countries like Finland, Japan, Turkey and the Middle East.\nClinical description\nThe predominant feature of AA amyloidosis at diagnosis is renal dysfunction, proteinuria and nephrotic syndrome. AA amyloidosis complicates chronic inflammatory disorders and is typically preceded by many years of active inflammatory disease. These may include chronic inflammatory arthritis, (rheumatoid arthritis, juvenile idiopathic arthritis), chronic infections (bronchiectasis, osteomyelitis, tuberculosis), auto-inflammatory diseases (familial mediterranean fever (FMF), TRAPS syndrome), Crohn's disease and less commonly Castleman's disease, Schnitzler syndrome, vasculitis or neoplasias (lymphoma, mesothelioma). In almost 25% of cases with AA, the cause of inflammation remains unclear (idiopathic AA amyloidosis) and it has been proposed that obesity may have a role in these cases. In the last decades, the progressive improvement of treatment for rheumatic diseases has reduced the number of cases driven by inflammatory arthritis and, in parallel, increased the number of patients with an underlying chronic infectious disease or idiopathic AA amyloidosis.\nEtiology\nChronic inflammatory disorders are associated with elevated levels of the acute-phase reactant, serum amyloid A protein (SAA) protein. AA amyloid fibrils are derived from SAA through a process of cleavage, misfolding, and aggregation. Amyloid fibrils associate with other moieties, including glycosaminoglycans and serum amyloid P component (SAP), forming deposits that disrupt structure and function of tissues and organs.\nDiagnostic methods\nDiagnosis of AA amyloidosis requires the demonstration of amyloid deposits on tissue biopsy revealed by Congo red staining on light microscopy and apple green birefringence on polarized light microscopy and amyloid typing by light microscopy, immunoelectron microscopy or proteomic analysis. Amyloidosis is suspected when signs of renal dysfunction (renal failure and proteinuria) are noted in the background of a chronic inflammatory disease with persistent elevated SAA concentration.\nDifferential diagnosis\nDifferential diagnoses include AL amyloidosis, familial renal amyloidosis and other causes of renal dysfunction like membranous glomerulonephritis and renal vein thrombosis.\nManagement and treatment\nTreatment of AA amyloidosis relies on treating the underlying inflammatory disease (antimicrobial therapy in chronic infections, colchicine in FMF, immunosuppressive agents in chronic arthritis). The aim of therapy is the reduction of SAA concentration (ideally <10 mg/L) in order to minimize the risk of disease progression and possibly to reverse organ dysfunction. Successful treatment of the underlying inflammatory disorders reduces SAA concentrations. In patients with end stage renal disease and controlled underlying disease, renal transplantation could be considered as a valuable treatment option.\nPrognosis\nFactors associated with a poor prognosis are older age, a reduced serum albumin concentration, end-stage renal failure at baseline, and the degree by which the SAA concentration is elevated during follow-up. Patients with underlying chronic infectious diseases have a worse outcome. Twenty-four hour proteinuria and estimated glomerular filtration rate (eGFR) can identify patients with higher risk of end-stage renal failure at diagnosis.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanni PALLADINI | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "AApoAI amyloidosis", "Disease Definition": "A rare, hereditary amyloidosis with primary renal involvement characterized by renal interstitial and medullary deposition of amyloid, low plasma levels of ApoA-1 and slow disease progression. Main clinical signs and symptoms are hypertension, proteinuria, hematuria and edema due to chronic renal insufficiency leading to end stage renal disease. Hepatosplenomegaly, progressive cardiomyopathy and involvement of skin, testes and adrenals (hypergonadotropic hypogonadism) have also been reported.", "ORPHA ID": 93560, "Summary": ""}
{"Disease Name": "AApoAII amyloidosis", "Disease Definition": "A rare hereditary amyloidosis with primary renal involvement characterized by variable onset of renal insufficiency with edema, hypertension, proteinuria, and azotemia, eventually leading to end-stage renal disease. Amyloid cardiomyopathy and histopathological evidence of amyloid deposition in other organs, such as the spleen, liver, adrenal glands, and pancreas, among others, have also been described.", "ORPHA ID": 238269, "Summary": ""}
{"Disease Name": "AApoAIV amyloidosis", "Disease Definition": "A rare nonhereditary systemic amyloidosis characterized by slowly progressive renal dysfunction, increased serum creatinine, mostly normal urine analysis with no significant proteinuria and associated heart disease. Cardiac involvement presents as hypertrophic obstructive cardiomyopathy, left ventricular outflow tract obstruction, coronary artery disease and conduction system abnormalities. Histology reveals medullar amyloid deposits, renal tubular atrophy, interstitial fibrosis, and glomerular sclerosis.", "ORPHA ID": 439232, "Summary": ""}
{"Disease Name": "Aarskog-Scott syndrome", "Disease Definition": "A rare developmental disorder characterized by facial, limbs and genital features, and a disproportionate acromelic short stature.", "ORPHA ID": 915, "Summary": "Epidemiology\nAAS prevalence is not known, but less than 100 cases have been reported in the literature since the first description in 1970. However, prevalence estimates are thought to be around 1/25,000. About 40 molecularly proven cases are published worldwide.\nClinical description\nAAS predominantly concerns males. Facial features include widow's peak and hypertelorism, both observed in female carriers, and downslanting palpebral fissures, broad nasal bridge, anteversed nostrils, low set and protuberant ears, maxillary hypoplasia and transverse crease below the lower lip. AAS patients have short and broad hands and feet, interdigital webbing, clinodactyly, and hyperextension of proximal interphalangeal joints and flexion at distal interphalangeal joints causing swan neck deformity of fingers. Size is generally normal at birth, but growth is slow in infancy and childhood, leading to short stature until puberty, which is often delayed. A growth spurt in late teens, generally, results in a moderate short stature. Genital anomalies may include cryptorchidism, macroorchidism, shawl scrotum and, more rarely, hypospadias. Fertility is normal. Female carriers may have only a subtle phenotype with hypertelorism and widow's peak. Patients may present a neurodevelopmental phenotype with learning and behavioural disabilities that are often confined to early childhood. When present, mental impairment is rarely severe.\nEtiology\nAlthough clinically and genetically heterogeneous, the best characterized form of the disorder is caused by mutations in the FGD1 gene (faciogenital dysplasia 1 gene; Xp11.21). Other gene(s) might be involved since most familial cases still do not have identified genetic cause.\nDiagnostic methods\nClinical diagnosis is based on physical examination and the recognition of the most distinctive clinical hallmarks. Molecular genetics, based on analysis of the FGD1 gene, may confirm diagnosis.\nDifferential diagnosis\nWhen molecular diagnosis is not conclusive, all possible options for differential diagnosis should still be considered, including Noonan syndrome, SHORT syndrome, pseudohypoparathyroidism and Robinow syndrome (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis for pregnancies at increased risk is technically possible when the disease-causing mutation in the family is known (the majority of mutations are family specific). However, prenatal testing is unlikely to be requested frequently, because usually physical signs can be mild and the clinical heterogeneity makes difficult a prediction of the phenotype, even within the same family.\nGenetic counseling\nAAS is an X-linked disease, but autosomal dominant and autosomal recessive transmissions have also been reported. Genetic counseling thus requires in depth investigation of patient's family history.\nManagement and treatment\nThere is no curative treatment for AAS. Preliminary results of growth hormone administration in childhood do not seem to show a significant effect. Learning problems and attention deficit and hyperactivity disorder (ADHD), in case, may require a neuropsychiatric intervention.\nPrognosis\nThe majority of patients present a good prognosis. Typically, they have a good evolution into adulthood with an age-related improvement of mental status.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Alfredo ORRICO"}
{"Disease Name": "Aase-Smith syndrome", "Disease Definition": "A very rare genetic disorder characterised by the following congenital malformations: hydrocephalus (due to Dandy-Walker anomaly), cleft palate, and severe joint contractures.", "ORPHA ID": 916, "Summary": "Epidemiology\nLess than 20 cases have been reported in the literature.\nClinical description\nThe fingers are thin with absent knuckles and reduced creases over the joints, and patients show an inability to make a full fist. Additional findings may include deformed ears, ptosis, an inability to open the mouth fully, heart defects, and clubfoot.\nEtiology\nThe aetiology remains unknown. There are currently no human genes associated with this disease.\nDiagnostic methods\nThe features of the hand are especially important for the diagnosis.\nDifferential diagnosis\nClinical overlap between Aase-Smith syndrome I and Gordon syndrome (see this term) has been suggested, due to the presence of distal arthrogryposis and cleft palate in both syndromes.\nGenetic counseling\nAutosomal dominant inheritance is suggested.\nManagement and treatment\nIn the absence of a specific treatment, supportive care and surgical correction should be offered.\n\n                            Last update: \n                            July 2007"}
{"Disease Name": "ABeta amyloidosis, Arctic type", "Disease Definition": "A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset of 54-61 years and progressive Alzheimer's disease-like dementia. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels.", "ORPHA ID": 324723, "Summary": ""}
{"Disease Name": "ABeta amyloidosis, Dutch type", "Disease Definition": "A form of hereditary cerebral hemorrhage with amyloidosis characterized by severe cerebral amyloid angiopathy (CAA), predominantly hemorrhagic strokes and dementia.", "ORPHA ID": 100006, "Summary": "Epidemiology\nThe prevalence is unknown. It has been seen in three Dutch families, that are most likely related (before 17th century), to date. Approximately 200-300 patients are known to be affected.\nClinical description\nHCHWA-D presents with hemorrhagic stroke between the ages of 39-76 years (average age 50 years). In one third of cases, the initial stroke is fatal, recurrent strokes are seen in those who survive and patients often suffer from serious disability. Cognitive decline can be a presenting symptom in some cases but often occurs after the initial or recurrent strokes. Dementia is seen in the majority of patients with HCHWA-D over the age of 40. Epilepsy is also seen in half of patients who have already experienced a previous stroke.\nEtiology\nHCHWA-D is due to a mutation in the APP gene on chromosome 21q21.2, encoding the beta-amyloid precursor protein. The mutation leads to extensive amyloid-beta deposition in the meningocortical arterioles, causing them to weaken and rupture.\nDiagnostic methods\nThe diagnosis is clear when a patient presents with a lobar hemorrhage and is known to come from an affected family. Imaging studies show diffuse white matter damage as well as hemorrhages. Genetic testing reveals a mutation in the APP gene.\nDifferential diagnosis\nDifferential diagnoses include other conditions that could cause intracerebral hemorrhage such as coagulopathies, vasculitis (see these terms), CNS neoplasms, cerebral vascular malformations, ischemic stroke and antecedent trauma.\nAntenatal diagnosis\nAntenatal diagnosis is possible but is rarely performed.\nGenetic counseling\nAs HCHWA-D is inherited autosomal dominantly, genetic counseling is possible when a family member is diagnosed with the disease. Pre-symptomatic genetic testing is possible.\nManagement and treatment\nThere is currently no acute or preventive treatment for HCHWA-D. Symptomatic treatment (with corticosteroids and antiepileptic drugs) can be given. On pragmatic grounds, antihypertensive treatment is recommended for those with mild to moderate hypertension.\nPrognosis\nThe prognosis is poor. HCHWA-D is often fatal, either acutely at first presentation or, on average, 10 years after symptom onset and after multiple strokes.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Joost HAAN  - Pr G.M. [Gisela] TERWINDT"}
{"Disease Name": "ABeta amyloidosis, Iowa type", "Disease Definition": "A form of hereditary cerebral hemorrhage with amyloidosis characterized by age of onset between 50-66 years of age, memory impairment, myoclonic jerks, expressive dysphagia, short-stepped gait, personality changes, and lobar intracerebral hemorrhages. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels.", "ORPHA ID": 324708, "Summary": ""}
{"Disease Name": "ABeta amyloidosis, Italian type", "Disease Definition": "A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset of 50 years of age, dementia and lobar intracerebral hemorrhage. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels.", "ORPHA ID": 324713, "Summary": ""}
{"Disease Name": "ABetaA21G amyloidosis", "Disease Definition": "A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset of 45 years of age, progressive Alzheimer's disease-like dementia, and lobar intracerebral hemorrhage in some patients. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels.", "ORPHA ID": 324718, "Summary": ""}
{"Disease Name": "ABetaL34V amyloidosis", "Disease Definition": "A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset between 50-70 years of age, recurrent lobar intracerebral hemorrhages and cognitive decline. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels.", "ORPHA ID": 324703, "Summary": ""}
{"Disease Name": "Abetalipoproteinemia", "Disease Definition": "A severe, familial hypobetalipoproteinemia characterized by permanently low levels (below the 5th percentile) of apolipoprotein B and LDL cholesterol, and by growth delay, malabsorption, hepatomegaly, and neurological and neuromuscular manifestations.", "ORPHA ID": 14, "Summary": "Epidemiology\nIt is very rare, with an estimated prevalence of less than 1/1,000,000.\nClinical description\nAbetalipoproteinemia manifests during the first year of life or in young childhood. It is often associated with growth delay, hepatomegaly with steatosis, diarrhea with steatorrhea, and fat malabsorption. Spastic ataxia, atypical retinitis pigmentosa, acanthocytosis, a low level of liposoluble vitamins, and major cytolysis and even cirrhosis can occur.\nEtiology\nAbetalipoproteinemia is a result of mutations of two alleles of the MTTP gene (MTP; 4q24). Other severe early familial hypobetalipoproteinemias are inherited in a codominant manner and are a result of mutations of two alleles of the APOB gene (2p24-p23).\nDiagnostic methods\nDiagnosis is based on lipid analysis, after 12 hours of fasting, carried out on the patient and their parents to measure serum levels of LDL (<0.10g/L), triglycerides (<0.20 g/L), and apolipoprotein B (<0.10g/L). Identification of steatorrhea and truncated apolipoprotein B after oral lipid intake, measurement of liposoluble vitamins (A, E, K), testing for acanthocytosis (on blood smears), complete neurological examination, hepatic ultrasound and eye examination can also be carried out. Identification of mutations of the MTTP or APOB genes confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include metabolic diseases with hepatic overload, with steatosis and/or hepatomegaly, atypical diseases of the central and peripheral nervous system, and secondary causes of hypocholesterolemia (iatrogenic or systemic).\nAntenatal diagnosis\nPrenatal diagnosis is possible when the causal mutations in both parents are known.\nGenetic counseling\nAbetalipoproteinemia is inherited in a recessive manner.\nManagement and treatment\nManagement should be undertaken in specialized centers.\nPrognosis\nThe prognosis is severe, with a significantly reduced life expectancy.\n\n                            Last update: \n                            May 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Pascale BENLIAN"}
{"Disease Name": "Ablepharon macrostomia syndrome", "Disease Definition": "An extremely rare multiple congenital malformation syndrome characterized by the association of ablepharon, macrostomia, abnormal external ears, syndactyly of the hands and feet, skin findings (such as dry and coarse skin or redundant folds of skin), absent or sparse hair, genital malformations and developmental delay (in 2/3 of cases). Other reported manifestations include malar hypoplasia, absent or hypoplastic nipples, umbilical abnormalities and growth retardation. It is a mainly sporadic disorder, although a few familial cases having been reported, and it displays significant clinical overlap with Fraser syndrome.", "ORPHA ID": 920, "Summary": ""}
{"Disease Name": "Abnormal number of coronary ostia", "Disease Definition": "A rare, congenital, non-syndromic heart malformation characterized by more or less than one coronary ostium at the left and at the right aortic sinus of Valsalva. It may be asymptomatic or it leads to myocardial ischemia and technical difficulties during coronary angiography.", "ORPHA ID": 99089, "Summary": ""}
{"Disease Name": "Abnormal origin of right or left pulmonary artery from the aorta", "Disease Definition": "A rare, congenital, heart malformation characterized by anomalous origin of one branch of the pulmonary arteries directly from the aorta and a normal origin of the other pulmonary artery from the main pulmonary artery coming from the right ventricular outflow tract. Patients present respiratory distress, congestive heart failure and failure to thrive within the first days/months of life.", "ORPHA ID": 99050, "Summary": "Epidemiology\nThe incidence is estimated at 0.1% of all congenital cardiac anomalies.\nClinical description\nAbnormal origin of right or left pulmonary artery from aorta usually occurs in infants or in the newborns where it manifests by respiratory distress, recurrent respiratory infection, moderate to severe pulmonary hypertension, congestive heart failure, and failure to thrive within the first months of life. Infants are usually cyanotic and may present chest pain and dyspnea on exertion. Two forms may be distinguished: anomalous origin of the left pulmonary artery from the aorta (AOLPA; about 25% of cases) and anomalous origin of the right pulmonary artery from the aorta (AORPA; about 75% of cases). Abnormal origin of right or left pulmonary artery from aorta frequently occurs as an isolated form with or without patent arterial duct. However, AOLPA may be associated with Tetralogy of Fallot, Right aortic arch, aortopulmonary window and anomalous subclavian arteries. On the contrary, patent ductus arteriosus and aortic coarctation or interruption (type A) may be associated with AORPA. Atrial and ventricular septal defects may be also present.\nEtiology\nThe pathogenesis still remains unknown, although an association has been reported with 22q11.2 deletion syndrome in children with AOLPA, usually associated with Right aortic arch, Tetralogy of Fallot and Absent pulmonary valve. Indeed, deletions 22q11.2 may impair the second heart field causing anomalies of development of the pharyngeal pouch derivate, aortic arches and conotruncal part of the heart.\nDiagnostic methods\nInitial diagnosis is made with 2D-echocardiography which allows the definition of morphology and the detection of systemic or supra-systemic pressures in the right ventricle. Diagnosis is confirmed by catheterization, angiocardiography, MRI and CT angiography.\nDifferential diagnosis\nOccasionally, one pulmonary artery (more frequently the left one) can origin via a patent ductus arteriosus coming from the aorta, however this morphological anomaly should be differentiated from Abnormal origin of right or left pulmonary artery from aorta.\nGenetic counseling\nAbnormal origin of right or left pulmonary artery from aorta is usually non-syndromic and sporadic. However, association with the 22q11.2 deletion syndrome is described in patients with AOLPA. Familial recurrence has also been reported.\nManagement and treatment\nEarly diagnosis and surgical treatment are mandatory in order to prevent cardiac failure and pulmonary hypertension. Treatment involves different techniques to implant the anomalous pulmonary artery branch to the main pulmonary artery. This includes direct implantation, end-to-end anastomosis with a synthetic graft, homograft patch, and an \"aortic-ring\" flap. In cases with AOLPA, the direct implantation technique is the strategy of choice, while for AORPA, different technique employing autologous tissues for increasing the length of the pulmonary artery branch may be used. Postoperative restenosis across the anastomotic site is frequently observed. Postoperative echocardiographic study is thus recommended to detect presence of stenosis.\nPrognosis\nPatients treated early in life have good short and long-term outcome. If left untreated, the disease may lead to congestive cardiac failure and pulmonary hypertension, with 30% of infants dying within 3 months. Palliative treatment such as pulmonary artery banding, ligation of the associated ductus arteriosus and aortopulmonary shunt, increases mortality substantially.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Bruno MARINO"}
{"Disease Name": "ABri amyloidosis", "Disease Definition": "A rare, neurodegenerative disease characterized by progressive cognitive impairment, spastic tetraparesis, and cerebellar ataxia resulting from amyloid deposits in the brain. Spasticity with increased deep tendon reflexes and tone are early symptoms, muscular rigidity evolves later. Progressive mental deterioration usually starts with apathy and impaired memory with progression to complete disorientation.", "ORPHA ID": 97345, "Summary": ""}
{"Disease Name": "Abruzzo-Erickson syndrome", "Disease Definition": "An orofacial clefting syndrome that is characterized by a cleft palate, ocular coloboma, hypospadias, mixed conductive-sensorineural hearing loss, short stature, and radio-ulnar synostosis.", "ORPHA ID": 921, "Summary": "Epidemiology\nTo date, 4 cases from a single family have been described in the literature.\nClinical description\nAbruzzo-Erickson syndrome is a congenital disorder characterized by a cleft palate, ocular coloboma, hypospadias, mixed conductive-sensorineural hearing loss, short stature, and radio-ulnar synostosis. Additional features include ear malformation, a wide gap between the second and third metacarpals, ulnar deviation, facial asymmetry, dental abnormalities and congenital heart malformation (such as interauricular communication). These manifestations overlap with those of CHARGE syndrome, however, in contrast to CHARGE syndrome; patients with Abruzzo-Erickson syndrome do not show intellectual disability nor choanal atresia or genital hypoplasia.\nEtiology\nThe complete etiology of Abruzzo-Erickson syndrome is still unknown but the recent identification of a novel mutation in the gene TBX22 (Xq21.1) (a gene known to cause X-linked cleft palate and ankyloglossia (CPX) co-segregating in the family strongly indicates that it is a mutation partially responsible for the phenotypic variation.\nDiagnostic methods\nDiagnosis is based upon clinical observations. Genetic and molecular testing allow to complete the diagnosis.\nDifferential diagnosis\nDifferential diagnosis include CHARGE syndrome.\nAntenatal diagnosis\nAntenatal diagnosis is theoretically possible by DNA analysis of fetal cells in maternal blood.\nGenetic counseling\nAbruzzo-Erickson syndrome is inherited in an X-linked recessive manner, with a carrier female having a 50 % risk of transmitting the mutation to her offspring.\nManagement and treatment\nCorrection of some abnormalities require extensive multidisciplinary craniofacial surgery.\nPrognosis\nLife expectancy seems normal based on long-term observations of three affected individuals in the family.\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Michael ABRUZZO  - Dr Robert ERICKSON"}
{"Disease Name": "Absence deformity of leg-cataract syndrome", "Disease Definition": "A very rare congenital limb malformation syndrome characterized by absence deformity of one leg, progressive scoliosis, short stature, and congenital cataract associated with dysplasia of the optic nerve. No intellectual deficit has been reported. There have been no further descriptions in the literature since 1968.", "ORPHA ID": 2310, "Summary": ""}
{"Disease Name": "Absence of fingerprints-congenital milia syndrome", "Disease Definition": "A rare syndrome characterized by neonatal blisters and milia (small white papules, especially on the face) and congenital absence of dermatoglyphics on the hands and feet. It has been reported in two kindreds (one of which contained 13 affected individuals spanning three generations) and in an unrelated individual. Some affected patients also showed bilateral partial flexion contractures of the fingers and toes, and webbing of the toes. The syndrome is inherited as an autosomal dominant trait.", "ORPHA ID": 1658, "Summary": ""}
{"Disease Name": "Absence of innominate vein", "Disease Definition": "A rare congenital anomaly of the great veins characterized by absence of the left brachiocephalic vein (or innominate vein), resulting in an anomalous venous vasculature. Patients are usually asymptomatic and the anomaly is typically discovered intraoperatively. An association with persistence of left superior vena cava, permanent levoatrial cardinal vein or anomaly of the inferior vena cava has been reported in some cases.", "ORPHA ID": 99112, "Summary": ""}
{"Disease Name": "Absence of the pulmonary artery", "Disease Definition": "A rare vascular anomaly characterized by congenital absence of the right or left pulmonary artery, usually ending within 2 cm of its expected origin from the pulmonary trunk. Patients often also have other cardiovascular abnormalities and respective symptoms and are then typically diagnosed in infancy or childhood, while isolated cases generally present with a mild clinical course and may go undiagnosed until adulthood. Presenting clinical features in isolated cases include hemoptysis, exertional dyspnea, and recurrent respiratory infections. The condition is typically accompanied by marked changes of lung tissue and may, if unrecognized, result in massive hemoptysis and pulmonary hypertension.", "ORPHA ID": 980, "Summary": ""}
{"Disease Name": "Absence of uterine body", "Disease Definition": "A rare, non-syndromic, uterovaginal malformation characterized by underdevelopment of the uterus, ranging from complete absence to the presence of bilateral rudimentary horns with or without a cavity. Patients usually present with primary amenorrhea, abdominal/pelvic pain and/or infertility.", "ORPHA ID": 180142, "Summary": ""}
{"Disease Name": "Absent radius-anogenital anomalies syndrome", "Disease Definition": "A rare, genetic limb reduction defects syndrome characterized by bilateral radial aplasia/hypoplasia manifesting with absent/short forearms in association with anogenital abnormalities (e.g. hypospadias or imperforate anus). Additional features reported include hydrocephalus and absent preaxial digits. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 3016, "Summary": ""}
{"Disease Name": "Absent thumb-short stature-immunodeficiency syndrome", "Disease Definition": "An exceedingly rare, autosomal recessive immune disease characterized by thumb aplasia, short stature with skeletal abnormalities, and combined immunodeficiency described in three sibships from two possibly related families. The skeletal abnormalities included unfused olecranon and the immunodeficiency manifested with severe chickenpox and chronic candidiasis. No new cases have been reported since 1978.", "ORPHA ID": 2951, "Summary": ""}
{"Disease Name": "Absent tibia-polydactyly-arachnoid cyst syndrome", "Disease Definition": "Tibia absent - polydactyly - arachnoid cyst syndrome is a very rare constellation of multiple anomalies, including absence or hypoplasia of the tibia.", "ORPHA ID": 3328, "Summary": "Epidemiology\nIt has been described in 3 sibs (two males and one female).\nClinical description\nThe syndrome is characterized by absence or hypoplasia of the tibia, pre and postaxial polydactyly of the hands and/or feet, syndactyly of the toes, shortening and bowing of other long bones, and retrocerebellar arachnoid cyst.\nGenetic counseling\nParental consanguinity reported in the family suggests an autosomal recessive pattern of inheritance.\n\n                            Last update: \n                            December 2010"}
{"Disease Name": "Acalvaria", "Disease Definition": "A rare congenital malformation characterized by the absence of calvarial bones, dura mater and associated muscles while skull base, facial bones and brain structures are normal. Central nervous system is usually unaffected, however some neuropathological abnormalities such as holoprosencephaly, hydrocephalus, micropolygyria and gyration anomalies can be present. Prenatal diagnosis by ultrasonography is usually confirmed by magnetic resonance imaging as it can be confused with anencephaly or encephalocele.", "ORPHA ID": 945, "Summary": ""}
{"Disease Name": "Acanthosis nigricans-insulin resistance-muscle cramps-acral enlargement syndrome", "Disease Definition": "This syndrome is characterised by the association of acanthosis nigricans, insulin resistance, severe muscle cramps and acral hypertrophy.", "ORPHA ID": 90301, "Summary": "Epidemiology\nAt least five cases have been described in the literature so far.\nClinical description\nEnlargement of the kidneys was also reported in some cases.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            April 2008"}
{"Disease Name": "Acatalasemia", "Disease Definition": "A rare inborn error of metabolism characterized by a deficiency in erythrocyte catalase, an enzyme responsible for the breakdown of hydrogen peroxide. The disorder is usually asymptomatic but may be associated with oral ulcerations and gangrene, or diabetes mellitus and atherosclerosis in certain populations.", "ORPHA ID": 926, "Summary": ""}
{"Disease Name": "Accessory mitral valve tissue", "Disease Definition": "A rare congenital non-syndromic heart malformation characterized by an accessory mitral valve leaflet or various accessory mitral valve structures. It may be asymptomatic or present at various ages with symptoms of left ventricular outflow tract obstruction, low cardiac output due to subaortic obstruction or congestive heart failure. In some cases, it may be a source of cardioembolism. The malformation may be isolated or associated with other congenital heart malformations.", "ORPHA ID": 99061, "Summary": ""}
{"Disease Name": "Accessory pancreas", "Disease Definition": "A rare asymptomatic embryopathy characterized by the presence of pancreatic tissue in other sites of the body such as the splenic pedicle, gonadic pedicles, intestinal mesentery, duodenum wall, upper jejunum, or, more rarely, the gastric wall, ileum, gallbladder or spleen.", "ORPHA ID": 674, "Summary": "Epidemiology\nPrevalence is unknown and only a few cases have been reported in the literature so far.\nEtiology\nThe anomaly is caused by migration of pancreatic cells during embryogenesis.\n\n                            Last update: \n                            April 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Frédéric BARGY"}
{"Disease Name": "Accessory tricuspid valve tissue", "Disease Definition": "A rare, congenital, atrioventricular valve malformation characterized by fixed or mobile accessory tissue on the tricuspid valve, usually associated with other complex congenital heart anomalies (atrial septal defect, ventricular septal defect, transposition of great arteries, tetralogy Fallot). It may present clinically with systolic murmur, dyspnea, cyanosis, depending also on accompanying congenital heart anomaly.", "ORPHA ID": 95462, "Summary": ""}
{"Disease Name": "Aceruloplasminemia", "Disease Definition": "A rare adult-onset disorder of neurodegeneration with brain iron accumulation (NBIA) characterized by anemia, retinal degeneration, diabetes and various neurological symptoms.", "ORPHA ID": 48818, "Summary": "Epidemiology\nTo date 56 cases have been reported and prevalence has been estimated at about 1/1,000,000-1/1,200,000.\nClinical description\nAceruloplasminemia presents in adulthood with neurological symptoms including ataxia, involuntary movements (blepharospasm, grimacing, facial and neck dystonia, tremors, and chorea), parkinsonism, depression, and cognitive dysfunction accompanied by retinal degeneration, diabetes mellitus, and iron-refractory anemia.\nEtiology\nAceruloplasminemia is caused by a complete absence of ceruloplasmin ferroxidase activity caused by homozygous mutation of the ceruloplasmin (CP) gene (3q23-q24).\nDiagnostic methods\nDiagnosis is based on the absence of serum ceruloplasmin and some combination of low serum copper concentration, low serum iron concentration, high serum ferritin concentration as well as hepatic iron overload. The diagnosis is strongly supported by characteristic MRI findings of abnormal low intensities reflecting iron accumulation on the brain (striatum, thalamus, dentate nucleus) and liver on both T1- and T2- weighted images. Genetic testing can confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other forms of later-onset, slowly progressing NBIA including atypical pantothenate kinase-associated neurodegeneration (PKAN) and neuroferritinopathy, hereditary hemochromatosis, Wilson disease, Huntington disease, dentatorubral pallidoluysian atrophy (DRPLA), juvenile Parkinson disease, hereditary spinocerebellar ataxias (see these terms) and drug effects or toxicity.\nAntenatal diagnosis\nPrenatal testing for pregnancies at increased risk may be available through laboratories offering custom prenatal testing if the disease-causing mutations have been identified in an affected family member.\nGenetic counseling\nAceruloplasminemia is inherited in an autosomal recessive manner.\nManagement and treatment\nTreatment is based on intravenous and oral iron chelators (deferiprone or deferasirox), which have been associated with improvement in diabetes and neurological symptoms. Combined IV desferrioxamine and fresh-frozen human plasma (FFP) is effective in decreasing iron content in the liver. Antioxidants such as vitamin E and oral administration of zinc may prevent tissue damage.\nPrognosis\nPrognosis may include heart failure due to cardiac iron overload. To date five patients with aceruloplasminemia are known to have died from heart failure probably due to cardiac iron overload in their sixties. In the absence of heart failure and with good treatment of diabetes, the prognosis is good.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Hiroaki MIYAJIMA"}
{"Disease Name": "Acetazolamide-responsive myotonia", "Disease Definition": "A form of potassium-aggravated myotonia (PAM) which shows dramatic improvement with the use of acetazolamide (ACZ).", "ORPHA ID": 99736, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nSymptoms generally manifest during childhood (before 10 years old), with myotonia of the facial, limbs and/or intercostal muscles that is triggered by potassium ingestion, fasting and mildly by cold exposure and exercise. Muscle stiffness is generally painful. Additional clinical signs include generalized muscle hypertrophy, percussion myotonia of proximal upper extremity muscles, thenar eminence and tongue and myotonia in the eyelids. Paralysis or weakness is never observed.\nEtiology\nACZ-responsive myotonia is a sodium muscle channelopathy due to missense mutations of the SCN4A gene, encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4.\nGenetic counseling\nTransmission is autosomal dominant.\nManagement and treatment\nMyotonia is dramatically improved with ACZ but when ACZ does not control myotonia or when side-effects occur such as kidney stone formation, mexiletine can be used as replacement therapy.\n\n                            Last update: \n                            October 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Savine VICART"}
{"Disease Name": "Achalasia-microcephaly syndrome", "Disease Definition": "An extremely rare genetic syndrome characterized by the association of microcephaly, intellectual deficit and achalasia (with symptoms of coughing, dysphagia, vomiting, failure to thrive and aspiration appearing in infancy/early-childhood). Antenatal exposure to Mefloquine was reported in one simplex case.", "ORPHA ID": 929, "Summary": ""}
{"Disease Name": "Achondrogenesis type 1A", "Disease Definition": "A rare, lethal type of achondrogenesis characterized by dwarfism with extremely short limbs, narrow chest, short ribs that are easily fractured, soft skull bones and distinctive histological features of the cartilage.", "ORPHA ID": 93299, "Summary": ""}
{"Disease Name": "Achondrogenesis type 1B", "Disease Definition": "A rare, lethal type of achondrogenesis characterized by severe micromelia with very short fingers and toes, a flat face, a short neck, thickened soft tissue around the neck, hypoplasia of the thorax, protuberant abdomen, a hydropic fetal appearance and distinctive histological features of the cartilage.", "ORPHA ID": 93298, "Summary": ""}
{"Disease Name": "Achondrogenesis type 2", "Disease Definition": "A rare, lethal type of achondrogenesis, and part of the spectrum of type 2 collagen-related bone disorders, characterized by severe micromelia, short neck with large head, small thorax, protuberant abdomen, underdeveloped lungs, distinctive facial features such as a prominent forehead, a small chin, a cleft palate (in some) and distinctive histological features of the cartilage.", "ORPHA ID": 93296, "Summary": ""}
{"Disease Name": "Achondrogenesis", "Disease Definition": "A rare group of lethal skeletal dysplasias characterized by an endochondral ossification deficiency that leads to dwarfism with extreme micromelia, a small thorax, a prominent abdomen, anasarca and polyhydramnios. There are three types of achondrogenesis that exist and that differ clinically, radiologically, histologically and genetically: achondrogensis type 1a, type 1b and type 2.", "ORPHA ID": 932, "Summary": ""}
{"Disease Name": "Achondroplasia", "Disease Definition": "A primary bone dysplasia with micromelia characterized by rhizomelia, exaggerated lumbar lordosis, brachydactyly, and macrocephaly with frontal bossing and midface hypoplasia.", "ORPHA ID": 15, "Summary": "Epidemiology\nAchondroplasia estimated incidence is at about 1/25,000 live births worldwide.\nClinical description\nCharacteristic clinical features (short limbs with rhizomelia, long and narrow trunk and macrocephaly with frontal bossing and midfacial hypoplasia with depressed nasal bridge) are often times visible at birth. Hands are broad, short and trident shaped. Hypotonia is common, leading to hypermobile joints particularly in the lower extremities. A smaller foreamen magnum or abnormal shape can lead to serious sequelae in infancy like spinal cord compression or vertebral artery compression leading to central apnea. Thoracolumbar kyphosis is very common in infancy, with 90% resolving over time. Midface hypoplasia in combination with adenoid and tonsil hypertrophy can lead to obstructive sleep apnea. Chronic otitis media can lead to conductive hearing loss. Achievement of gross motor skills is slower than typical due to short limbs, short neck, and large head, in addition to hypotonia. Dental crowding is common. Genu varum often occurs in childhood. Lower lumbar spinal stenosis with accompanying neurological deficits, has an increased frequency in adulthood, as does cardiovascular disease. Obesity is a common issue. Adults reach a height of 131±5.6 cm (men) and 124±5.9 cm (women). Affected women must deliver by caesarian section due to small pelvis size.\nEtiology\nAchondroplasia is due to a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, encoding a transmembrane receptor that is important in regulating linear bone growth, among other functions. Almost all mutations affect a specific glycine that is substituted to an arginine (G380R), leading to a gain of function mutation.\nDiagnostic methods\nThere are no clinical diagnostic criteria for achondroplasia. Diagnosis is based on radiological and clinical findings. A skeletal survey will demonstrate generalized metaphyseal irregularities. Molecular genetic testing can confirm a diagnosis by the presence of a FGFR3 mutation in almost all individuals.\nDifferential diagnosis\nDifferential diagnoses include hypochondroplasia, thanatophoric dwarfism (types I and II), and SADDAN.\nAntenatal diagnosis\nPrenatal diagnosis can occur incidentally during routine prenatal ultrasound examination in the 3rd trimester when shortened long bones are noted. In these cases or when a parent is known to have achondroplasia, fetal DNA can be tested for the FGFR3 mutation to confirm diagnosis. Pre-implantation genetic diagnosis is possible in specialized laboratories.\nGenetic counseling\nInheritance is autosomal dominant so genetic counseling is warranted. In 80% of cases, it is due to a de novo mutation in children with parents of average stature. If one parent has achondroplasia there is a 50% risk at each pregnancy of passing it on to offspring. If both parents have achondroplasia, there is another 25% risk that the offspring will have homozygous achondroplasia which is incompatible with life.\nManagement and treatment\nManagement is multidisciplinary and anticipatory care is essential. Neonates should have imaging of the brain and cervical spine to access the foreamen magnum and check for hydrocephalus as well as polysomnography to check for central sleep apnea. Abnormalities in either study should warrant a prompt referral to neurosurgical colleagues for evaluation and possible surgical treatment. Regardless of imaging, activities which lead to a risk of injury to the craniocervical junction should be avoided. Treatment of ear infections and serous otitis media, along with assessment of any hearing problems is needed. Speech therapy can be offered if concerns arise. Treatment of obstructed sleep apnea may include adenotonsillectomy, weight loss, and/or continuous positive airway pressure. Weight gain should be monitored in childhood to avoid later complications. Social and psychological support should be offered. Progressive and symptomatic leg bowing can be treated surgically. Adult patients may require a lumbar laminectomy to treat spinal stenosis. Some may choose controversial limb lengthening procedures.\nPrognosis\nThere is only a slight decrease in life expectancy compared to the general population, potentially due to cardiovascular disease.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Elaine PEREIRA"}
{"Disease Name": "Achromatopsia", "Disease Definition": "A rare autosomal recessive retinal disorder characterized by color blindness, nystagmus, photophobia, and severely reduced visual acuity due to the absence or impairment of cone function.", "ORPHA ID": 49382, "Summary": "Epidemiology\nThe prevalence is estimated to be 1/30,000-1/50,000 worldwide.\nClinical description\nACHM is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, and reduced or complete loss of color discrimination. Most individuals have complete ACHM, with total lack of function in all three types of cones. Rarely, individuals have incomplete ACHM, with similar, but generally less severe symptoms.\nEtiology\nFive genes (GNAT2 (1p13), PDE6C (10q24), PDE6H (12p13), CNGA3 (2q11.2), and CNGB3 (8q21.3)) have been associated with ACHM, all encoding key components of the cone phototransduction cascade (G-protein GNAT2 > phosphodiesterase PDE6C/PDE6H > cyclic nucleotide gated channel CNGA3/CNGB3). Mutations in CNGB3 are the most prevalent, followed by CNGA3, while the others are rare causes of ACHM.\nDiagnostic methods\nThe diagnosis of ACHM is based on clinical ophthalmological examination, psychophysical testing (i.e. color vision) and electrophysiological testing (electroretinography - ERG) where a loss of photopic but normal scotopic responses is observed. Optical coherence tomography shows progressive disruption and/or loss of the inner/outer segment junction of the photoreceptors and an attenuation of the retinal pigment epithelium (RPE) within the macular region. The diagnosis is verified by molecular genetic analysis of the causative genes.\nDifferential diagnosis\nDifferential diagnosis includes blue cone monochromatism (BCM), Leber congenital amaurosis, other cone dystrophies (see these terms), and cerebral achromatopsia\nAntenatal diagnosis\nPrenatal diagnosis may be offered by specialized laboratories to at-risk couples.\nGenetic counseling\nACHM is transmitted in an autosomal recessive manner. Carrier testing for family members at risk of mutations is possible once the disease-causing mutations have been identified in the family. Furthermore, genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\nManagement and treatment\nThere is no specific therapy available. Management is symptomatic and includes regular ophthalmological follow-up examination. Patients should be informed about the possibility of using filtering glasses or contact lenses (red tinted or brown) to reduce photophobia and to improve contrast sensitivity. Low-vision aids include high-powered magnifiers for reading.\nPrognosis\nACHM is usually a stationary disease, yet macular degeneration can occur.\n\n                            Last update: \n                            August 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Susanne KOHL"}
{"Disease Name": "Acinar cell carcinoma of pancreas", "Disease Definition": "A very rare, malignant, epithelial tumor of the pancreas characterized, macroscopically, by a usually large, well-circumscribed, fully or partially encapsulated, solid mass, often with hemorrhage, necrosis and cystic changes, in any portion of the pancreas and, histologically, by neoplastic cells with variable degrees of differentiation and morphology, ranging from acinar structures similar to normal pancreatic acini to large sheets of poorly differentiated neoplastic cells. Presenting symptoms are typically non-specific and include abdominal pain, weight loss, vomiting, nausea, and/or, less commonly, jaundice. Immunohistochemical evidence of acinar-specific products is observed. Association with Lynch syndrome, familial adenomatous polyposis, and pancreatic panniculitis has been reported.", "ORPHA ID": 424046, "Summary": ""}
{"Disease Name": "Acitretin/etretinate embryopathy", "Disease Definition": "A rare teratogenic disorder due to acitretin or etretinate exposure during the first trimester of pregnancy, carrying a risk of fetal malformations of approximately 20%, including central nervous system, craniofacial, ear, thymic, cardiac and limb anomalies.", "ORPHA ID": 40366, "Summary": "Epidemiology\nTo date, 3 infants/fetuses with anomalies indicative or possibly indicative for the embryopathy whose mothers were treated with acitretin during the first trimester of pregnancy have been reported in the literature. In addition, 23 infants/fetuses with anomalies indicative or possibly indicative for the embryopathy whose mothers were treated with etretinate during the first trimester or before pregnancy have been reported in the literature.\nClinical description\nAcitretin/Etretinate embryopathy is characterized by multiple congenital anomalies involving the central nervous system (with neurodevelopmental delay), retinal or optic-nerve, craniofacial (microcephaly, facial dysmorphism displaying epicanthal folds, low nasal bridge, anteverted nostrils, high and cleft palate, micrognathia) and ear abnormalities (microtia/anotia, cup-shaped ears, bilateral sensorineural deafness). Thymic and cardiac defects (atrioventricular canal defect, conotruncal heart malformation, aortic-arch defect) are also observed. Severe anomalies of upper and lower limbs have also been described.\nEtiology\nAcitretin/etretinate embryopathy is due to acitretin or etretinate exposure during the first trimester of pregnancy. Acitretin is an aromatic retinoid analog of vitamin A used for the treatment of severe forms of psoriasis and disorders of keratinization. Acitretin/etretinate have a teratogenic potential since it affects cellular differentiation and proliferation.\n\n                            Last update: \n                            August 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Christof SCHAEFER"}
{"Disease Name": "Acquired aneurysmal subarachnoid hemorrhage", "Disease Definition": "A rare, life threatening rare neurologic disease characterized by a sudden rupture of an intracranial aneurysm into the subarachnoid space. It usually presents with a sudden, severe, excruciating headache accompanied by nausea, vomiting and syncope. Other features may include focal neurological signs, third and sixth nerve palsies, seizures and cardiac failure. Early complications include rebleeding, hydrocephalus, and seizures.", "ORPHA ID": 90065, "Summary": ""}
{"Disease Name": "Acquired angioedema type 1", "Disease Definition": "A type of acquired angioedema (AAE) characterized by acute edema in subcutaneous tissues, viscera and/or the upper airway.", "ORPHA ID": 100056, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nLike other forms of AAE it has a later onset than HAE (see this term) and occurs generally in adults over the age of 50 where there is no family history of the disease.\nEtiology\nThe disease occurs due to an acquired C1-INH deficiency. It is often associated with lymphoproliferative or autoimmune diseases which produce immune factors that destroy C1-INH leading to low levels of C1-INH, C1q complement and C4 complement.\nManagement and treatment\nThe treatments used for HAE can be effective for AAE but the most effective strategy is the treatment of the associated disease.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence BOUILLET"}
{"Disease Name": "Acquired angioedema type 2", "Disease Definition": "A type of acquired angioedema (AAE) characterized by acute edema in subcutaneous tissues, viscera and/or the upper airway.", "ORPHA ID": 100055, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nLike other forms of AAE, it has a later onset than HAE (see this term) and occurs generally in adults over the age of 50 and there is no family history of the disease.\nEtiology\nThe disease occurs due to an acquired C1-INH deficiency caused by malfunctioning B cells that secrete autoantibodies to the C1-INH molecule that neutralize C1-INH activity. AAE type 2 is often associated with dysglobulinemia of unknown origin.\nManagement and treatment\nThe treatments used for HAE can be effective for AAE but the most effective strategy is to decrease C1-INH antibody level with corticosteroids or rituximab.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence BOUILLET"}
{"Disease Name": "Acquired angioedema with C1Inh deficiency", "Disease Definition": "A rare non-histaminic angioedema characterized by potentially life-threatening episodes of edema of subcutaneous and/or mucosal tissues without urticaria, caused by excessive consumption of C1 esterase inhibitor (C1-INH) in the context of lymphoproliferative or autoimmune diseases. Patients typically present in the fourth decade of life or later and without a family history of angioedema. Clinical manifestation includes nonpitting edema of the skin predominantly involving the face, but also the limbs or genitals, as well as abdominal pain due to involvement of the gastrointestinal mucosa, and severe edema of the upper airway and oral mucosa. Laboratory examination shows low C1-INH activity and low C3, C4, and C1q levels. Autoantibodies to C1-INH are frequently detectable.", "ORPHA ID": 528663, "Summary": ""}
{"Disease Name": "Acquired angioedema", "Disease Definition": "A rare disease characterized by the occurrence of transitory and recurrent subcutaneous and/or submucosal edemas resulting in swelling and/or abdominal pain due to an acquired C1 inhibitor (C1-INH) deficiency.", "ORPHA ID": 91385, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nOnset most commonly occurs after 50 years of age. Patients present with white, circumscribed nonpruritic edemas that remain for a period of 48 to 72 hours and recur with variable frequency. The edemas may involve the digestive tract resulting in a clinical picture similar to that seen in intestinal occlusion syndrome, sometimes associated with ascites and hypovolemic shock. Laryngeal edema can be life-threatening with a risk of death of 25% in the absence of appropriate treatment. Dental procedures are a triggering factor for laryngeal edema. Edemas of the face are a risk factor for laryngeal involvement.\nEtiology\nThe edemas are triggered by increased permeability of the blood vessels in response to elevated levels of bradykinin as a result of the C1-INH deficiency. Type 1 AAE (see this term) is frequently associated with lymphoproliferative syndromes and accelerated consumption of C1-INH, and with autoimmune diseases that may manifest several years after the initial episodes of angioedema. Type 2 AAE (see this term) is associated with the presence of autoantibodies to the C1-INH that neutralize C1-INH activity and are often associated with dysglobulinemia of unknown origin. AAE can also be induced by renin-angiotensin-aldosterone system blockers (RAAS-blocker-induced angioedema; see this term).\nDiagnostic methods\nDiagnosis relies on clinical findings, measurement of C4 concentrations and on quantitative and functional analysis of C1-INH. C1q levels are low in patients with AAE but are normal in patients with hereditary angioedema (see this term).\nDifferential diagnosis\nThe differential diagnosis should include intestinal occlusion syndrome, hereditary angioedema and histamine-induced angioedema (of allergenic or nonallergenic origin) generally associated with urticaria.\nManagement and treatment\nTreatment of the associated disease should generally allow episodes to be controlled and lead to normalization of C1-INH levels. In the absence of an associated disease, the treatments used to manage the hereditary forms of angioedema may be of benefit.\nPrognosis\nThe prognosis depends on the risk of developing hematological manifestations. Rituximab can be an alternative treatment in cases of AAE associated with C1-INH antibodies.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence BOUILLET"}
{"Disease Name": "Acquired arginine vasopressin deficiency", "Disease Definition": "A subtype of central diabetes insipidus (CDI) characterized by polyuria and polydipsia, due to an idiopathic or secondary decrease in vasopressin (AVP) production.", "ORPHA ID": 95626, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nIt occurs equally in both sexes and in all age groups but most often has an onset around the ages of 10-20. Symptoms include polyuria, polydipsia, usually associated with weight loss, and nocturia.\nEtiology\nAcquired CDI is secondary to a condition damaging the central nervous system or it is idiopathic (unknown etiology). Causes that lead to damage of the hypothalamus-neurohypophyseal brain region include head trauma (resulting from an accident or surgery), congenital abnormalities (pituitary stalk interruption syndrome (PSIS, see this term), infections (meningitis, encephalitis), autoimmune disorders (primary hypophisitis, see this term) and inflammatory (sarcoidosis and Wegener's granulomatosis, see these terms) or neoplastic (germinoma, meningioma, Langerhans cell histiocytosis, craniopharyngioma (see these terms), Rathke cleft cysts and metastasis). Up to 50% of CDI cases are idiopathic and the cause is unknown but autoimmunity is suspected to be involved in a number of them.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Stefano GHIRARDELLO"}
{"Disease Name": "Acquired Creutzfeldt-Jakob disease", "Disease Definition": "A group of human prion diseases characterized by progressive, invariably fatal neurodegeneration resulting from accidental transmission of prions. The group comprises iatrogenic Creutzfeldt-Jakob disease (CJD), which results from transmission of CJD prions in the course of medical procedures or treatments, and variant CJD (transmission via consumption of products from prion-diseased cows or via blood transfusion from an affected individual).", "ORPHA ID": 454700, "Summary": ""}
{"Disease Name": "Acquired cystic disease-associated renal cell carcinoma", "Disease Definition": "A rare subtype of renal cell carcinoma, ocurring in the context of end-stage kidney disease and acquired cystic kidney disease, characterized by a usually well circumscribed, solid, multifocal, bilateral tumor with inter- or intracellular microlumen formation (leading to cribiform architecture). Tumors are often diagnosed incidentally in early stages, although complications caused by renal cysts (dull flank or abdominal pain, fever) or renal parenchymal bleeding may mask the underlying neoplastic process. Most have an indolent behavior.", "ORPHA ID": 404514, "Summary": ""}
{"Disease Name": "Acquired generalized lipodystrophy", "Disease Definition": "A rare lipodystrophic syndrome characterized by loss of adipose tissue, and is a syndrome of insulin resistance that leads to increased cardiovascular risk. Acquired generalized lipodystrophy is related to a selective loss of subcutaneous adipose tissue occurring exclusively at the extremities (face, legs, arms, palms and sometimes soles).", "ORPHA ID": 79086, "Summary": "Epidemiology\nMore than 100 cases have been described and the female to male ratio is 3:1.\nClinical description\nThe clinical phenotype is similar to that of Berardinelli-Seip syndrome (see this term), but lipoatrophy appears secondarily during childhood, adolescence or adulthood, and as a result the syndrome is thought to be acquired. In some cases, loss of adipose tissue is localized, especially if it is preceded by a panniculitis. The syndrome is associated with a voracious appetite and an acceleration of growth in adolescents. One third of cases are accompanied by acanthosis nigricans and a polycystic ovary syndrome (see these terms). Hepatomegaly with steatosis and a risk of cirrhogenous progression is common. Biologically, hyperinsulinemia and insulin-resistant diabetes are observed, often associated with severe hypertriglyceridemia with low plasma levels of leptin and adiponectin. Proteinuria associated with focal segmental glomerulosclerosis or with membranoproliferative glomerulonephritis have been reported recently, as well as dysregulation of growth hormone. Three types of the disease have been described: 1) a form with panniculitis (inflammatory nodules followed by lipoatrophy), 2) an autoimmune form that is readily associated with other syndromes such as chronic active hepatitis, Hashimoto struma and hemolytic anemia, but also with dermatomyositis and Sjogren's syndrome (see these terms), 3) idiopathic.\nEtiology\nThe cause of the disease remains unknown. There may be infectious triggering factors (there was a recent case of the panniculitis type that appeared after tuberculosis) or an autoimmune mechanism. A recent publication showed activation of the classical complement pathway (low C4). This is in contrast to acquired partial lipodystrophy (see this term) which affects the upper half of the body and is characterized by an activation of the alternative complement pathway (low C3). Progression towards partial lipoatrophy, focal or generalized, has been reported in patients with dermatomyositis, amongst whom this could be a late relapse, and it is more common that the antibody anti-p155 is present. The hypothesis of an underlying genetic factor has not been rejected.\nDiagnostic methods\nDiagnosis is clinical and should be confirmed by an assessment of body fat, in particular by biphotonic absorptiometry and magnetic resonance imaging.\nDifferential diagnosis\nDifferential diagnoses include other forms of extreme insulin resistance (Rabson-Mendenhall syndrome, leprechaunism, Berardinelli type lipodystrophy and insulin resistance syndromes types A and B; see these terms) and other lipodystrophies.\nManagement and treatment\nThe treatment of the metabolic manifestations is a priori no different to the treatment of other forms of insulin resistance: physical exercise, insulin sensitizers such as metformin or pioglitazone, insulin (or preferably insulin analogues), antihypertensives, and monitoring and treatment of hypertriglyceridemia. The efficacy of recombinant human leptin has been demonstrated on the metabolic level but this therapy is not available in all countries. In serious autoimmune forms of the disease, immunosuppressive therapy may be indicated.\nPrognosis\nThe prognosis is not well known but is probably related to cardiovascular risk (linked to the insulin-resistance syndrome) and to the underlying cause of the disease.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Marie-Christine VANTYGHEM"}
{"Disease Name": "Acquired hemophagocytic lymphohistiocytosis associated with malignant disease", "Disease Definition": "A rare, secondary hemophagocytic lymphohistiocytosis characterized by occurring as either initial presentation of a malignant disease or at any stage during chemotherapy. The common associated malignancies are lukemias, B-cell, T-cell or NK-cell lymphomas, and Hodgkin lymphoma. Typical clinical manifestation includes fever, hepatosplenomegaly and cytopenias, combined with specific laboratory findings.", "ORPHA ID": 158057, "Summary": ""}
{"Disease Name": "Acquired hypertrichosis lanuginosa", "Disease Definition": "A rare cutaneous paraneoplastic disease characterized by the presence of excessive lanugo-type hair on the glabrous skin of face, neck, trunk and limbs that can be associated with additional clinical features such as burning glossitis, papillary hypertrophy of the tongue, diarrhea, dysgeusia, and/or weight loss. It is associated with lymphoma or cancer of the gastrointestinal system, urinary tract, lung, breast, uterus or ovary.", "ORPHA ID": 2221, "Summary": ""}
{"Disease Name": "Acquired ichthyosis", "Disease Definition": "A rare epidermal disease characterized by rough, dry skin with prominent, plate-like scaling. It is non-hereditary and usually arises during adulthood in the context of a variety of diseases or conditions, like various types of cancer, autoimmune diseases, endocrine disorders, nutritional deficiencies, but also as a side effect of certain medications. Severity depends on the underlying disease or condition.", "ORPHA ID": 454, "Summary": ""}
{"Disease Name": "Acquired idiopathic sideroblastic anemia", "Disease Definition": "A rare myelodysplastic syndrome (MDS) characterized by ineffective hemopoiesis affecting one or more blood cell lineages (myeloid, erythroid or megakaryocytic) leading to peripheral blood cytopenias and an increased risk of developing leukaemia.", "ORPHA ID": 75564, "Summary": "Epidemiology\nIn Europe, the incidence of new cases of RARS is estimated at around 1 per 100,000 people per year but precise values are not available. Incidence increases with age by a factor of around 10 in those aged 70 and over.\nClinical description\nIt occurs mainly in elderly people or people of late middle age at a rate that varies somewhat around the world.\nEtiology\nThe cause is not known. It appears to be a clonal disorder arising from a haemopoetic stem cell abnormality but is not associated with any particular cytogenetic change except for a few reports of chromosomal rearrangements involving Xq13.\nDiagnostic methods\nDiagnosis requires examination of both blood and bone marrow, investigation into possible secondary acquired causes and careful attention to any family and clinical history that would suggest an inherited type of sideroblastic anaemia (see these terms).\nDifferential diagnosis\nRARS can be separated from other categories of MDS by the presence in the bone marrow of more than 15% of ringed sideroblasts in the erythroid cells, an absence of dysplasia in the other cell lineages and a low percentage of myeloid blasts (<5%).\nManagement and treatment\nTreatment is mainly supportive and directed towards alleviating the symptoms of anaemia and avoidance or treatment of iron overload that results from any blood transfusion. Regular full blood count monitoring is important.\nPrognosis\nThe risk of transformation to leukaemia is low (between 5 to 10% at 10 years in those with a normal karyotype and no dependence on blood transfusion) compared with other groups of MDS (for example 50% at 8 months in the group with thehighest risk), and the prognosis is good. Life expectancy in those over 70 years of age with RARS may be no different to that of the general population. The development of bi-lineage or multi-lineage dysplasia, the emergence of cells which are karyotypically abnormal, or an increased dependency on blood transfusions herald a worse prognosis and may indicate more vigorous intervention.\n\n                            Last update: \n                            May 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Ala AL-SABAH  - Dr Alison MAY"}
{"Disease Name": "Acquired kinky hair syndrome", "Disease Definition": "A rare hair disorder characterized by the appearance of lustreless, curly, frizzy, and coarse hair generally during adolescence predominantly in the frontal, temporal, and vertex regions of the scalp. Eyelashes, as well as growth and pigmentation of the hair, may also be affected.", "ORPHA ID": 37559, "Summary": ""}
{"Disease Name": "Acquired methemoglobinemia", "Disease Definition": "A rare hematologic disease characterized by increased levels of methemoglobin in the blood due to exposure to oxidizing agents like nitrates or nitrites, a variety of medications (most commonly local anesthetics), or aniline dyes, among others. Clinical manifestations include cyanosis, dizziness, headache, dyspnea, confusion, and coma. The severity of symptoms ranges from mild to life-threatening, depending on the percentage of methemoglobin.", "ORPHA ID": 464453, "Summary": ""}
{"Disease Name": "Acquired monoclonal Ig light chain-associated Fanconi syndrome", "Disease Definition": "A rare monoclonalgammopathy characterized by renal proximal tubule dysfunction secondary to monoclonal kappa light chain deposits in proximal tubular cells. Clinical presentation is with variable chronic kidney disease, low molecular weight proteinuria, aminoaciduria, hyperphosphaturia, uricosuria, bicarbonaturia, and non-diabetic glycosuria. Renal phosphate and urate wasting may cause hypophosphatemia and hypouricaemia.", "ORPHA ID": 91136, "Summary": "Epidemiology\nTo date, less than 100 cases have been reported in the medical literature.\nClinical description\nPresentation is often in patients over 50 years of age with a degree of chronic kidney disease (CKD). There will be low molecular weight proteinuria, generalised aminoaciduria, uricosuria, phosphaturia, bicarbonaturia (which may cause a mild metabolic acidosis) and normoglycemic glycosuria. Low molecular weight proteinuria is the most sensitive test, and non-diabetic glycosuria is the most specific. There may be hypophosphatemia and hypouricemia and/or a mild metabolic acidosis. Urinary phosphate wasting may be severe enough to cause bone demineralization and rickets in children or osteomalacia in adults. Bone pain or pathological fractures are a possible presentation of this condition. The disease often occurs in the setting of monoclonal gammopathy of undetermined significance and less commonly in multiple myeloma or Waldenstrom macroglobulinemia.\nEtiology\nTypically, the monoclonal light chains are of the variable kappa-1 (VK1) subgroup which resist proteolysis in the proximal tubular cells, and results in self-aggregation and crystal formation in the endolysosomal compartment.\nDiagnostic methods\nDiagnosis is made by demonstrating the renal Fanconi syndrome with the presence of low molecular weight proteinuria (and phosphaturia or glycosuria, if present) along with a monoclonal gammopathy. The diagnosis may be confirmed by a kidney biopsy (which may be indicated when establishing the diagnosis of myeloma). Findings on light microscopy include atrophy, dedifferentiation and intracytoplasmic inclusions in the proximal tubule epithelium. Proximal tubule cells are typically positive for kappa LCs (and less frequently lambda LCs) on immunofluorescence. Ultrastructural studies reveal crystals (rhomboid), located in proximal tubular cells lysosomes or free in the cytoplasm. Additional investigations required include bone marrow aspiration or biopsy to identify the clone, and evaluation of serum and urine immunoglobulin free light chains.\nDifferential diagnosis\nDifferential diagnosis should include other types of monoclonal gammopathy of renal significance (AL amyloidosis, monoclonal immunoglobulin deposition disease, and myeloma cast nephropathy), in addition to other causes of FS (including autoimmune disorders, drugs, or heavy metal poisoning).\nManagement and treatment\nIf there is severe urinary phosphate wasting, or osteomalacia (low bone mineral density) then phosphate supplements should be given. Bone demineralization starts before the serum phosphate falls. All patients with an associated overt lymphoid disorder should receive appropriate chemotherapy. Otherwise, treatment should be adapted to the degree of renal failure. CKD 1-3 stages: chemotherapy should be considered to slow progression to ESRD. Cyclophosphamide, bortezomib or thalidomide-based treatment are the best options. High dose melphalan (HDM) supported by autologous peripheral blood cell transplantation (ASCT) may be performed in selected nonresponding patients, although the benefit of this strategy remains to be proven. CKD 4-5 stages: patients who are eligible for renal allograft, chemotherapy (including HDM/ASCT) should be considered prior to transplantation. In patients not eligible for renal transplantation, introduction of chemotherapy has no benefit.\nPrognosis\nProgression of CKD is slow.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen WALSH | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Acquired partial lipodystrophy", "Disease Definition": "A rare acquired lipodystrophy characterized by bilateral, symmetrical lipoatrophy of the upper body (face, neck, arms, thorax and sometimes upper abdomen) with sparing of the lower extremities and cephalothoracic progression. The disease may be associated with low serum levels of C3 and presence of C3-nephritic factor.", "ORPHA ID": 79087, "Summary": "Epidemiology\nThe prevalence in Europe is less than 1/100 000. There is a female predominance with a female-to-male ratio of 4:1.\nClinical description\nOnset typically occurs during childhood or adolescence but may occur as late as the fourth or fifth decade of life. Lipoatrophy is slowly progressive, starts on the face and then extends downwards to the neck, shoulders, upper limbs and/or thorax. The hips, thighs, distal legs and gluteal regions are initially normal, however, lipohypertrophy may present post-puberty, especially in females. Mesangiocapillary glomerulonephritis is reported in one third of patients and is associated with low complement-component 3 (C3) serum levels and the presence of C3-nephritic factor. Whilst there is an increased risk of insulin resistance and metabolic complications (including menstrual irregularities, hirsutism, diabetes mellitus, dyslipidemia, hypertension and hepatic steatosis), these are less frequently observed compared to other types of lipodystrophies. Occasionally, functional anomalies including sensorineural deafness, epilepsy, intellectual deficit, myopathy and retinal changes may be associated.\nEtiology\nWhilst the etiology is unknown, susceptibility has been linked to heterozygous mutations in the LMNB2 (19p12.3) gene, encoding the lamin B2 nuclear envelope protein. Nevertheless, this mutation is very inconstant. Moreover, the frequently early occurrence of the disease suggests yet unknown genetic causes, perhaps involved in the innate immunity.\nDiagnostic methods\nDiagnosis is essentially based on the characteristic subcutaneous fat loss pattern. Physical examination (including skin fold thickness measurements) and MRI studies are important to assess fat loss distribution. Measurement of serum complements and autoantibodies (low C3 and presence of C3-nephritic factor), absence of family history of lipodystrophy, an onset during childhood/adolescence, and biopsy may support diagnosis. Clinical judgement should be used for screening for co-morbidities.\nDifferential diagnosis\nDifferential diagnosis includes anorexia nervosa, cachexia, starvation, diencephalic syndrome, multiple symmetric lipomatosis and other rare progeroid syndromes and disorders affecting growth and development. In addition, other forms of acquired lipodystrophy observed may be associated with a broad spectrum of autoimmune diseases, including systemic lupus erythematosus, juvenile dermatomyositis, celiac disease, or pernicious anemia and vasculitis.\nManagement and treatment\nSurgical management of the lipodystrophy is feasible, and is mainly aimed at aesthetic improvement. Treatment of the metabolic manifestations, if present, should follow the same guidelines as those used for other forms of insulin resistance: physical exercise, insulin-sensitizing medication (metformin or, if available, glitazones), agonists of GLP1 receptor, and finally insulin (or preferably insulin analogues)) and management of the hypertension and hypertriglyceridemia. Nephrological follow-up should also be recommended. Metreleptin, indication authorized in Europe, may be considered for hypoleptinemic patients with severe metabolic derangements, where other treatments have failed to achieve adequate metabolic control.\nPrognosis\nThe prognosis is largely unknown but greatly depends on the extent of the nephropathy, which may progress to renal insufficiency.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Marie-Christine VANTYGHEM"}
{"Disease Name": "Acquired prothrombin deficiency", "Disease Definition": "A rare hemorrhagic disorder characterized by decreased factor II plasma levels in association with severe liver disease, vitamin K deficiency, or vitamin K antagonist treatment, or in the context of other conditions such as systemic lupus erythematosus, primary antiphospholipid syndrome, or infections. Patients present with increased bleeding tendency leading to easy bruising, frequent nosebleeds, hemorrhaging after surgery or trauma, and heavy menstrual bleeding, among others. Joint bleeding is uncommon.", "ORPHA ID": 26348, "Summary": ""}
{"Disease Name": "Acquired pseudoxanthoma elasticum", "Disease Definition": "A rare acquired dermis elastic tissue disorder characterized by clinical and histopathologic evidence of pseudoxanthoma elasticum in the absence of a family history or specific mutation. Patients present with predominantly cutaneous manifestations consisting of yellowish papules which coalesce into large plaques and are most commonly localized on the neck, axillae, groin, and flexural surfaces. Skin biopsy shows accumulation of clumped, calcified elastic fibers in the mid-dermis. Reported underlying factors include previous liver transplantation, exposure to penicillamine, or concomitant beta-thalassemia.", "ORPHA ID": 228247, "Summary": ""}
{"Disease Name": "Acquired purpura fulminans", "Disease Definition": "A life-threatening, rapidly progressive thrombotic disorder affecting mainly neonates and children that is characterized by purpuric skin lesions and disseminated intravascular coagulation. It may progress rapidly to multi-organ failure caused by thrombotic occlusion of small and medium-sized blood vessels. There are two forms of the disorder that are classified according to triggering mechanisms: acute infectious (the most common form), and idiopathic purpura fulminans.", "ORPHA ID": 49566, "Summary": ""}
{"Disease Name": "Acquired von Willebrand syndrome", "Disease Definition": "A rare bleeding disorder marked by the same biological anomalies as those seen in hereditary von Willebrand disease (VWD) but which occurs in association with another underlying pathology, generally in elderly patients without any personal or family history of bleeding anomalies.", "ORPHA ID": 99147, "Summary": "Epidemiology\nPrevalence is unknown, but Acquired von Willebrand syndrome (AVWS) is a rare disease that is underdiagnosed, with just over 300 cases reported in the literature so far.\nClinical description\nThe bleeding manifestations are similar to those occurring in hereditary VWD (prolonged bleeding after trauma, epistaxis, ecchymoses and gastrointestinal bleeding associated with angiodysplasia).\nEtiology\nThree principle pathogenic mechanisms have been described: 1) the presence of autoantibodies (inhibiting or noninhibiting) that form immune complexes with the von Willebrand factor (VWF) leading to rapid clearance of VWF from the circulation (the mechanism most commonly implicated in AVWS associated with monoclonal gammapathies and autoimmune diseases); 2) absorption of VWF onto malignant cell clones (the mechanism implicated in AVWS associated with neoplasia); 3) increased proteolysis of high molecular weight VWF multimers under abnormal hemorheologic conditions caused by cardiovascular malformations (such as aortic valve stenosis).\nDiagnostic methods\nThe most accurate diagnostic tests rely on detection of abnormally low levels of VWF activity (ristocetin cofactor or collagen binding assays) in comparison to VWF antigen levels, and on demonstration of a selective deficiency of high molecular weight VWF multimers. Measurement of VWF propeptide levels may also be useful as they reflect the abnormally rapid clearance of VWF from the circulation. However, none of these tests allow AVWS to be distinguished from hereditary VWD. Detection of anti-VWF antibodies is pathognomonic of the acquired mechanism of VWF deficiency; however, these antibodies are only detected in 14% of suspected cases of AVWS. The finding of a monoclonal protein detected by serum protein electrophoresis is an argument for AVWS. Thus, it is the presentation of an acute bleeding disorder, in association with an underlying pathology (such as lympho- or myeloproliferative disorders, solid tumors, immunological or cardiovascular disorders) which generally leads to the diagnosis of acquired VWF deficiency.\nManagement and treatment\nManagement relies on identification and then treatment of the underlying pathology usually involving corticosteroids or immunosuppressors, chemotherapy, plasmapheresis or valve replacement. In cases when these treatments are not rapidly efficient, symptomatic treatment aiming to correct the VWF deficiency is used to prevent or to cure abnormal bleeding. The choice of treatment depends on the suspected physiopathology and clinical status: intravenous immunoglobulins (in case of IgG monoclonal gammopathy of undetermined significance), desmopressin or VWF concentrates (although pharmacokinetic studies may be required before any major surgical intervention as the half-life of endogenous or exogenous VWF may be significantly reduced), recombinant factor VIII concentrates (completely depleted of VWF) or, as a last-resort treatment option, recombinant activated factor VII.\nPrognosis\nThe prognosis depends on the underlying pathology associated with the disease.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND  - Pr Agnès VEYRADIER"}
{"Disease Name": "Acral peeling skin syndrome", "Disease Definition": "A rare peeling skin syndrome characterized by superficial peeling of the skin predominantly affecting the dorsa of the hands and feet.", "ORPHA ID": 263534, "Summary": "Epidemiology\nAcral PSS is rare, the prevalence is unknown. Few cases have been described in the literature.\nClinical description\nThe disease manifests shortly after birth or in early childhood with superficial painless peeling on the palmar, plantar and dorsal surfaces of the hands and feet, that leaves residual erythema. Superficial blisters may be seen. Palmoplantar skin may also be hyperkeratotic. Seasonal variations are generally observed. Heat, humidity, occlusion, exposure to water and friction or minor trauma can induce exfoliation. The lesions are usually not painful and heal without scarring but a burning sensation may be experienced before or after peeling.\nEtiology\nSome cases result from mutations in the TGM5 gene or CSTA gene, encoding, respectively, transglutaminase-5 (one of the three transglutaminase isoforms involved in the cross-linking of the cornified cell envelope) or cystatin A (a protease inhibitor crosslinked to the cornified envelope).\nDiagnostic methods\nClinical presentation is highly suggestive of the disease. Histological examination of skin lesion biopsies reveals tissue separation at the stratum granulosum-stratum corneum junction. Molecular analysis, if performed, may reveal a mutation in TGM5 or CSTA.\nDifferential diagnosis\nDifferential diagnosis includes epidermolysis bullosa simplex, keratolytic winter erythema, exfoliative ichthyosis, keratolysis exfoliativa, fungal infection (dermatophytes), psoriasis and dyshidrosis.\nAntenatal diagnosis\nThe disease is not severe enough to justify prenatal screening.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThere is no effective treatment. Emollients are often used to reduce skin peeling. Patients must avoid immersion in water and are recommended to use absorbing powders or aluminum antiperspirants.\nPrognosis\nLife expectancy is normal. No significant impairment in quality of life is reported.\n\n                            Last update: \n                            January 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Acral persistent papular mucinosis", "Disease Definition": "A rare chronic form of localized lichen myxedematosus characterized by the development of multiple symmetrical skin-colored mucinous papules exclusively on the extensor surface of the hands and distal forearms.", "ORPHA ID": 90396, "Summary": ""}
{"Disease Name": "Acral self-healing collodion baby", "Disease Definition": "A variant of self-healing collodion baby (SHCB) characterized by the presence at birth of a collodion membrane only at the extremities.", "ORPHA ID": 281127, "Summary": "Epidemiology\nOnly 2 cases were described in the literature.\nClinical description\nIn both cases, the babies healed soon after birth.\nEtiology\nIn one case, molecular analysis was performed that revealed mutations in the TGM1 gene encoding transglutaminase 1, an enzyme involved in the cornification of the stratum corneum.\n\n                            Last update: \n                            January 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Juliette MAZEREEUW-HAUTIER"}
{"Disease Name": "Acro-renal-mandibular syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by limb deficiencies and renal anomalies that include split hand-split foot malformation, renal agenesis, polycystic kidneys, uterine anomalies and severe mandibular hypoplasia. An autosomal recessive mode of inheritance has been suggested.", "ORPHA ID": 958, "Summary": ""}
{"Disease Name": "Acro-renal-ocular syndrome", "Disease Definition": "A rare syndrome of multiple congenital anomalies characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesico-ureteral reflux, bladder diverticula), and ophthalmological abnormalities (mainly colobomas, but also microphthalmia, ptosis, and Duane anomaly). The phenotype overlaps with other SALL4-related disorders including Okihiro syndrome and Holt-Oram syndrome.", "ORPHA ID": 959, "Summary": ""}
{"Disease Name": "Acrocallosal syndrome", "Disease Definition": "A rare polymalformative syndrome characterized by agenesis of corpus callosum (CC), distal anomalies of limbs, minor craniofacial anomalies and intellectual disability.", "ORPHA ID": 36, "Summary": "Epidemiology\nThe prevalence is not known but fewer than 50 cases have been published since the first description in 1979.\nClinical description\nIn acrocallosal syndrome (ACS), craniofacial anomalies include macrocephaly with prominent forehead and occiput, hypertelorism, large anterior fontanel, short nose with broad nasal bridge and anteverted nostrils, and short mandible. Cases of anencephaly were observed as well as an extra bone within the anterior fontanel, a calvarian defect or a Dandy-Walker malformation. CC hypoplasia or agenesis is the main distinctive feature of ACS. It may be associated with arachnoidal cysts in about one third of cases and with various other brain abnormalities (medulla oblongata, temporal lobe or pons hypoplasia, micropolygyria and hypoplasia or agenesis of cerebellar vermis with a molar tooth sign). Distal anomalies of limbs include preaxial or postaxial polydactyly or polysyndactyly of toes and/or hands. The large majority of ACS patients have intellectual disability that is severe in 80% of cases, and substantial global developmental delay. Additional malformations have been described occasionally: short philtrum/upper lip, high-arched palate, cleft lip/palate, heart defects, hypospadias and inguinal and umbilical hernias.\nEtiology\nMutations in kinesin KIF7 (15q26.1) and, rarely, in the transcriptional activator GLI3 (7p14.1) are responsible for ACS. Both genes are involved in the ciliary sonic hedgehog pathway and their mutations most likely influences the early development of midline structures during embryogenesis.\nDiagnostic methods\nGiven the high variability of phenotypes, any two of the following criteria evokes the ACS diagnosis: (1) total or partial absence of the CC, (2) minor craniofacial anomalies, (3) moderate to severe global developmental delay with hypotonia and (4) polydactyly. Molecular genetic testing can be used to confirm the diagnosis and to guide genetic counseling.\nDifferential diagnosis\nDifferential diagnosis includes Greig cephalopolysyndactyly syndrome, syndrome orofaciodigital type I, Smith-Lemli-Opitz syndrome, Rubinstein-Taybi syndrome, Gorlin syndrome, Aicardi syndrome, as well as Meckel-Gruber syndrome and hydrolethalus in the extreme forms.\nAntenatal diagnosis\nAntenatal diagnosis is based on ultrasonography examination from the 20th week of gestation and magnetic resonance imaging (MRI) of the fetus.\nGenetic counseling\nACS is an autosomal recessive disease. For parents of an affected individuals, there is therefore a 25% recurrence risk for a subsequent pregnancy. If the gene mutation in the kinesin/transcriptional activator genes has been identified in an affected sibling, molecular genetic diagnosis can be offered after chorionic villus sampling.\nManagement and treatment\nSurgical intervention may be considered for the polydactyly. Management is otherwise supportive with periodical evaluation by a child neurologist/neuropsychiatrist in order to monitor the evolution of the intellectual development or onset of seizures, as well as enabling and supporting therapies (including non-verbal communication) and special education programs.\nPrognosis\nPrognosis depends on the severity of malformations and hypotonia, and on the occurrence of seizures.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Tania ATTIE-BITACH | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Acrocapitofemoral dysplasia", "Disease Definition": "A rare skeletal dysplasi, characterized clinically by short stature of variable degrees with short limbs, brachydactyly and narrow thorax.", "ORPHA ID": 63446, "Summary": "Epidemiology\nIt has been described in 5 individuals in 2 families.\nClinical description\nAffected patients have normal intelligence. Radiographically, cone-shaped epiphyses are observed in the hands, the proximal part of the femur, and, to a variable degree, at the shoulders, knees, and ankles.\nEtiology\nHomozygous mutations in the Indian hedgehog homolog gene (IHH; 2q33-q35), outside the region where brachydactyly type A-1 mutations are clustered, have been identified in affected patients.\nGenetic counseling\nThe condition is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            February 2011"}
{"Disease Name": "Acrocardiofacial syndrome", "Disease Definition": "A rare genetic disorder characterized by split-hand/split-foot malformation (SHFM), facial anomalies, cleft lip/palate, congenital heart defect (CHD), genital anomalies, and intellectual deficit.", "ORPHA ID": 2008, "Summary": "Epidemiology\nThe incidence of ACFS has not been determined due to the low number of reported cases (9 to date). A similar occurrence among genders is expected.\nClinical description\nThe spectrum of defects occurring in ACFS is wide, and both interindividual variability and clinical differences among sibs have been reported. Bilateral or unilateral cleft hand is a constant feature. Cleft foot and cutaneous finger and toe syndactyly have been reported in some cases. Congenital heart defects of varying types have been detected in two thirds of patients. Facial anomalies are not specific for the syndrome, and clinical expression appears to be variable. Male patients manifest different genital anomalies, ranging from micropenis to cryptorchidism and hypospadias. Growth retardation is a common prenatal and postnatal finding. The frequency of intellectual deficit in ACFS is at present unknown due to the early death of most patients. Neurological anomalies such as hypotonia, hypertonia, and seizures have been reported in the first days and months of life.\nEtiology\nThe genetic mechanism underlying ACFS is still unknown. Isolated or syndromic SHFM has been linked to different loci or genes. Mutations in the p63 gene, responsible for ectrodactyly - ectodermal dysplasia - cleft lip palate (EEC) syndrome (see this term) and related disorders with SHFM, have been excluded in a patient with ACFS.\nDiagnostic methods\nDiagnosis is based solely on clinical characteristics. The major diagnostic criteria include SHFM and CHD. Cleft lip/palate and genital anomalies are less common features. Although facial anomalies are not specific to this disorder, low-set dysmorphic ears appear to be a constant feature.\nDifferential diagnosis\nDifferential diagnosis includes other ectrodactyly syndromes and clefting conditions associated with genital anomalies. However, EEC syndrome, Rapp-Hodgkin syndrome (see these terms) and ectrodactyly-cleft lip/palate-hand/foot deformities-intellectual deficit can be ruled out based on lack of ectodermal involvement. Malpuech syndrome (see this term) can also be excluded based on distinct facial features and absent limb defects. CHD, cleft palate, and genital anomalies are features of genito-palato-cardiac syndrome, but none of the reported cases had ectrodactyly.\nAntenatal diagnosis\nThe major features of ACFS can be detected prenatally by ultrasonography. A second trimester scan, including echocardiography and upper/lower limb evaluation, is recommended for monitoring pregnancies when parents have had a child with the disorder.\nGenetic counseling\nACFS follows an autosomal recessive pattern of inheritance. The risk of transmitting the disease for the parents of an affected child seems to be up to 1 in 4.\nManagement and treatment\nPatients are at high risk of death in the first months of age. Cardiac and respiratory problems should be treated by specialists. A nutrition specialist should be consulted for feeding problems. Surviving patients will benefit from physical therapy, which should start in the first months of life in babies manifesting hypotonia/hypertonia and motor delays. In surviving patients, neuropsychological assessment should be performed every year to check for developmental and cognitive delay.\nPrognosis\nLife expectancy is very low. Most reported patients survived only a few hours or months. Cardiopulmonary complications were the main cause of death.\n\n                            Last update: \n                            December 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Bruno DALLAPICCOLA  - Dr Maria Cristina DIGILIO"}
{"Disease Name": "Acrocephalopolydactyly", "Disease Definition": "An extremely rare lethal autosomal recessive disorder characterized by massive birth weight, swollen globular body, generalized edema, short limbs, postaxial polydactyly, thick skin, facial dysmorphism (slanted palpebral fissures, hypertelorism, epicanthic folds, dysplastic ears), excessive connective tissue, renal dysplasia, and in some patients, organomegaly, craniosynostosis with acrocephaly, omphalocele, cleft palate, and cryptorchidism. Fewer than 10 cases have been reported to date.", "ORPHA ID": 221054, "Summary": ""}
{"Disease Name": "Acrocraniofacial dysostosis", "Disease Definition": "A very rare acrofacialdyosotosis characterized by short stature, acrocephaly, ocular hypertelorism, ptosis of eyelids, ocular proptosis, downslanting palpebral fissures, high nasal bridge, anteverted nostrils, short philtrum, cleft palate, micrognathia, abnormal external ears, preauricular pits, mixed hearing loss, bulbous digits, metatarsus varus, pectus excavatum and various radiological abnormalities. Features of this syndrome were reported to overlap with otopalatodigital syndrome types 1 and 2. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 949, "Summary": ""}
{"Disease Name": "Acrodermatitis continua of Hallopeau", "Disease Definition": "A rare, genetic, chronic, recurrent, slowly progressive, epidermal disease characterized by small, sterile, pustular eruptions, involving the nails and surrounding skin of the fingers and/or toes, which coalesce and burst, leaving erythematous, atrophic skin where new pustules develop. Onychodystrophy is frequently associated and anonychia and osteolysis are reported in severe cases. Local expansion (to involve the hands, forearms and/or feet) and involvement of mucosal surfaces (e.g. conjunctiva, tongue, urethra) may be observed.", "ORPHA ID": 163931, "Summary": ""}
{"Disease Name": "Acrodermatitis enteropathica", "Disease Definition": "A rare inherited inborn error of metabolism resulting in a severe zinc deficiency and characterized by acral dermatitis, alopecia, diarrhea and growth failure.", "ORPHA ID": 37, "Summary": "Epidemiology\nThe prevalence of Acrodermatitis enteropathica (AE) is unknown. It is more common in the North-West of Tunisia.\nClinical description\nAE usually presents in the first 4-10 weeks of life in infants that are not breast-fed and at around the time of weaning in breast-fed infants, as cow's milk contains more zinc-binding phytates that impede zinc absorption. AE is characterized by eczematous pink scaly plaques that can become pustular, vesiculobullous, psoriasisform or crusted. Lesions usually involve the acral, periorificial and typically the anogenital areas. Skin lesions may evolve into erosions without treatment and are susceptible to secondary staphylococcal and candidal infections. Diarrhea, generalized alopecia and Beau-Reil lines on the nails are frequent manifestations. Paronychia, conjunctivitis, blepharitis and erythematous oral mucous membranes are also sometimes observed. Other features associated with severe and chronic zinc deficiency include failure to thrive, mental slowness, photophobia, hypogeusia, anemia, poor wound healing, hypogonadism in males, and delayed puberty.\nEtiology\nAE is due to a mutation in the SLC39A4 gene (8q24.3) that encodes a zinc transporter protein (called the Zip4 transporter). Zip4 is needed for the transcellular absorption of zinc into the enterocytes of the duodenum and jejunum where the ZnT-zinc transporters (that are not affected) allow for the transport of zinc into the bloodstream. Mutations in the SLC39A4 lead to zinc malapsorption. This can only be corrected by a high dietary intake of zinc that allows for a small fraction of zinc to be absorbed paracellularly, without the aid of Zip4.\nDiagnostic methods\nDiagnosis is based on clinical findings (diarrhea and acral dermatitis) as well as laboratory testing. Patients have low plasma zinc concentrations and low levels of serum alkaline phosphatase. Molecular genetic testing can identify a mutation in the SLC39A4 gene, confirming diagnosis of AE.\nDifferential diagnosis\nDifferential diagnoses include impetigo contagiosa, candidiasis, psoriasis, and other pathogen-related skin diseases. Sickle cell disease and related diseases, non-genetic or acquired causes of zinc deficiency such as glucagonoma (see these terms), chronic liver and renal diseases, nutritional deficiency, chronic inflammatory bowel diseases, AIDS, burn injuries, and excessive perspiration in hot climates should also be excluded.\nGenetic counseling\nAE is inherited autosomal recessively. Genetic counseling is recommended to identify other affected family members before the onset of symptoms.\nManagement and treatment\nThere is no cure for AE. In the majority of cases, zinc supplementation therapy results in the disappearance of AE symptoms, but this treatment is life-long and relapses can occur. Initial dosages of 5-10 mg/kg/day of elemental zinc, followed by maintenance doses of 1-2 mg/kg/day are recommended and are taken orally. Zinc sulphate is the best tolerated preparation, in most cases, but it can also be administered as acetate, gluconate and amino acid chelates. Zinc and copper levels should be monitored regularly. Dosages need to be increased during periods of growth, such as adolescence and during pregnancy, when relapses can occur.\nPrognosis\nWith adherence to life-long zinc substitution therapy, the prognosis is good. Only when infants are left untreated can the disease be fatal.\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Brigitte DRÉNO"}
{"Disease Name": "Acrodysostosis", "Disease Definition": "An acromelic dysplasia that is characterized by severe brachydactyly, peripheral dysostosis with facial dysostosis, nasal hypoplasia, and developmental delay.", "ORPHA ID": 950, "Summary": "Epidemiology\nLess than 80 cases of Acrodysostosis (ACRDYS) have been reported in the literature to date.\nClinical description\nTypical clinical features include severe peripheral dysostosis (short stature and brachydactyly affecting metacarpals, metatarsals and phalanges), facial dysostosis (broad face, widely spaced eyes and maxillonasal hypoplasia), and developmental delay. Advanced skeletal maturation, decreased vertebral interpedicular distance, and obesity are also frequently observed. Several features of acrodysostosis are similar to those present in patients with Albright's hereditary osteodystrophy (AHO) such as short stature, obesity and brachydactyly (in AHO, only 4th and 5th metacarpals and metatarsals). Prenatal onset, and multiple hormonal resistance, most frequently to parathyroid hormone (PTH) and thyroid stimulating hormone (TSH), are reported in approximately half of ACRDYS patients. While patients with PRKAR1A mutations (referred to as ACRDYS type 1) constantly present with significant hormonal resistance, hormonal resistance in patients with PDE4D mutations (referred to as ACRDYS type 2) is rare, and when present, is relatively mild. Various degrees of intellectual disability and/or behavioral disorders have also been reported in ACRDYS patients.\nEtiology\nAcrodysostosis is caused by heterozygous mutations in either the PRKAR1A (17q24.2) or PDE4D (5q11.2-q12.1) genes. PRKAR1A mutations are gain-of-function leading to a constitutive loss of function in protein kinase A (by reducing the affinity of the protein subunits for cAMP, thereby hampering the dissociation from the catalytic subunit). A functional defect of PDE4D has not been characterized, but is expected to also be gain-of-function, leading to a constitutive loss of function in protein kinase A, at least in skeletal tissues.\nDiagnostic methods\nDiagnosis is based on the clinical, biochemical and radiological (i.e. cone-shaped epiphyses) characteristics. It is confirmed by the genetic screening of PRKAR1A or PDE4D genes. Basal urinary cAMP levels normalized by creatininuria, a reflection of PTH biological activity in the renal proximal tubule, have been found significantly increased in patients with PRKAR1A mutations, but not in patients with PDE4D mutations.\nDifferential diagnosis\nDifferential diagnosis includes brachydactyly type E, pseudohypoparathyroidism 1a or pseudopseudohypoparathyroidism.\nAntenatal diagnosis\nIn families with a known disease causing mutation, prenatal diagnosis is possible.\nGenetic counseling\nMost cases occur sporadically but autosomal dominant inheritance has been reported in some families, and in these cases genetic counseling is possible.\nManagement and treatment\nThere is no specific treatment for acrodysostosis. Patients should be screened for hormonal resistances, in particular to PTH and TSH, and treated appropriately following the same criteria, doses, and follow-up as in any other form of hypoparathyroidism and hypothyroidism, and eventually treated for any associated endocrinopathy. Dietary and lifestyle measures to prevent obesity and supportive care for cognitive functions are recommended. Attention must be given in children to height, growth velocity, and pubertal development.\nPrognosis\nPrognosis is unknown due to a lack of long-term patient data. Functional consequences, however, can decrease a patient's quality of life.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Maria Luisa BRANDI"}
{"Disease Name": "Acrodysplasia scoliosis", "Disease Definition": "A rare, genetic dysostosis disorder characterized by brachydactyly and other finger/toe anomalies (short and/or wide metacarpals, abnormal or absent metatarsals, broad halluces), carpal synostosis, fused cervical vertebrae, scoliosis and spina bifida occulta. There have been no further descriptions in the literature since 1984.", "ORPHA ID": 2956, "Summary": ""}
{"Disease Name": "Acrofacial dysostosis, Catania type", "Disease Definition": "A rare congenital acrofacial dysostosis characterized by mild intrauterine growth retardation, postnatal short stature, microcephaly, intellectual disability, moderate mandibulofacial dysostosis (including dental anomalies and/or malpositioning, microretrognathia, and malar hypoplasia), and mild pre- and postaxial limb hypoplasia with generalized brachydactyly, mild interdigital webbing, single transverse palmar creases and clinodactyly. Reported facial features include high forehead, widow's peak, downslanted palpebral fissures, sparse lateral eyebrows, and small or dysplastic ears. Variably associated features include frequent caries, preauricular fistulae, inguinal hernia, spina bifida occulta, and cryptorchidism and hypospadias in males.", "ORPHA ID": 1786, "Summary": ""}
{"Disease Name": "Acrofacial dysostosis, Kennedy-Teebi type", "Disease Definition": "A rare acrofacial dysostosis due to the presence of manifestations not usually seen in Nager syndrome (NS) such as microcephaly, blepharophimosis, microtia, a peculiar beakednose, cleft lip and palate, symmetrical involvement of the thumbs and great toes and developmental delay. It has since been suggested that these features can also be a part of the NS phenotype.", "ORPHA ID": 64542, "Summary": ""}
{"Disease Name": "Acrofacial dysostosis, Palagonia type", "Disease Definition": "A rare acrofacial dysostosis characterized by normal intelligence, shortness of stature, and mild acrofacial dysostosis (malar hypoplasia, micrognathia and webbing of digits with shortening of the fourth metacarpals) associated with oligodontia, normal or high arched palate, aplasia cutis verticis with pili torti, mild cutaneous syndactyly of digits 2-5, and unilateral cleft lip. Features are similar to those seen in Zlotogora-Ogur syndrome, although the latter shows no sign of acrofacial dysostosis. There have been no further reports in the literature since 1997.", "ORPHA ID": 1787, "Summary": ""}
{"Disease Name": "Acrofacial dysostosis, Rodríguez type", "Disease Definition": "A rare, severe, multiple congenital anomalies syndrome characterized by severe mandibular hypoplasia, upper limb phocomelia with olygodactyly, absent fibula, and a number of additional skeletal (hypoplastic scapula and ischii, 11 ribs, clubfeet), facial (hypertelorism, hypoplastic supraorbital ridges, wide nasal bridge, microtia with low-set ears) and variable internal organ abnormalities (including arhinencephaly, hypolobulated lungs, and congenital cardiac defects), which usually lead to perinatal death. Surviving patients show features similar to Nagel syndrome.", "ORPHA ID": 1788, "Summary": ""}
{"Disease Name": "Acrofacial dysostosis, Weyers type", "Disease Definition": "A rare ectodermal dysplasia syndrome with bone abnormalities characterized by onychodystrophy; anomalies of the lower jaw, oral vestibule and dentition; post-axialpolydactyly; moderately restricted growth with short limbs; and normal intelligence. Although it closely resembles Ellis-van Creveld syndrome (see this term), an allelic disorder and another type of ciliopathy, WAD is usually a milder disease without the presence of heart abnormalities and is inherited in an autosomal dominant manner.", "ORPHA ID": 952, "Summary": ""}
{"Disease Name": "Acrofrontofacionasal dysostosis", "Disease Definition": "A rare congenital malformation syndrome characterized by the association of facial and skeletal anomalies with severe intellectual deficit and occasional genitourinary anomalies.", "ORPHA ID": 1784, "Summary": "Epidemiology\nOnly 12 patients have been reported since the first description in 1985, 7 originate from Brazil.\nClinical description\nThe cranio-facial malformations are numerous and variable. They include brachycephaly or microbrachycephaly, prominent forehead with low frontal and occipital hairline, wide anterior fontanel, hypertelorism, large philtrum, broad notched nasal tip, cleft lip, highly-arched palate, small ears with prominent helix, hypoplasia of mid-face, and prognathism. Other skeletal malformations are also present, with syndactyly of fingers 3 and 4, hypoplastic 3rd, 4th and 5th toes, anomalies of feet structure and fibular hypoplasia. Short stature may be observed. Eye anomalies include bilateral ptosis, coloboma of the upper lids, cataract, congenital glaucoma and iris atrophy. In some male patients, hypospadias, with or without cleft glans, and bifid scrotum are reported. Patients suffer from potentially severe intellectual deficit and present with anomalies of the cortical gyration (without any corpus callosum abnormality). Encephalocele may occur.\nEtiology\nThe etiology of acro-fronto-facio-nasal dysostosis is unknown.\nGenetic counseling\nAutosomal recessive transmission is probable.\n\n                            Last update: \n                            April 2012"}
{"Disease Name": "Acrogeria", "Disease Definition": "A rare premature aging syndrome characterized by atrophy of the skin and subcutaneous tissue involving predominantly the distal parts of the extremities, resulting in prematurely aged appearance of the hand and feet. Another prominent feature is the characteristic facies with hollow cheeks, beaked nose, and owl-like eyes. Additional, non-dermatological manifestations, like bone anomalies have been described in some patients. Mode of inheritance has not been definitively established.", "ORPHA ID": 2500, "Summary": ""}
{"Disease Name": "Acrokeratoelastoidosis of Costa", "Disease Definition": "A rare punctate palmoplantar keratoderma characterized by multiple small, round to oval or rhomboid, yellowish, hyperkeratotic papules and plaques most commonly localized to the palms of the hands and soles of the feet, potentially extending to the dorsum of the hands and feet in severe cases. Histopathological analysis shows hyperkeratosis, epidermal hypertrophy, and fragmentation and rarefaction of elastic fibers. The condition can be sporadic or familial.", "ORPHA ID": 38, "Summary": ""}
{"Disease Name": "Acrokeratosis verruciformis of Hopf", "Disease Definition": "A rare, genetic, acrokeratoderma disease characterized by multiple, symmetrical, asymptomatic, skin-colored (rarely, brownish), flat-topped, wart-like papules located on the dorsal aspects of the hands and feet (occasionally found on other parts of the body, such as knees, elbows and forearms), typically associated with palmoplantar punctate keratosis and variable nail involvement (including leukonychia, thickening, ridging, longitudinal striations and splitting). Histology reveals undulating hyperkeratosis, papillomatosis, hypergranulosis, and acanthosis, creating a characteristic 'church spire' appearance, with no acantholysis nor dyskeratosis associated.", "ORPHA ID": 79151, "Summary": ""}
{"Disease Name": "Acromegaly", "Disease Definition": "A rare acquired endocrine disease related to excessive production of growth hormone (GH) and characterized by progressive somatic disfigurement (mainly involving the face and extremities) and systemic manifestations.", "ORPHA ID": 963, "Summary": "Epidemiology\nWorldwide, the prevalence is 1/7,500 to 1/35,800. The annual incidence is 1/91,000 to 1/526,000.\nClinical description\nDue to its insidious onset and slow progression, acromegaly is often diagnosed from four to more than ten years after its onset, and is most often diagnosed in middle age (average age 40-50 years). The main clinical features are broadened extremities (hands and feet), widened, thickened and stubby fingers, and thickened soft tissue. The facial aspect is characteristic and includes a widened and thickened nose, prominent cheekbones, forehead bulges, thick lips and marked facial lines. The forehead and overlying skin is thickened, sometimes leading to frontal bossing. There is a tendency towards mandibular overgrowth with prognathism, maxillary widening, tooth separation and jaw malocclusion. The disease also has rheumatologic, cardiovascular, respiratory and metabolic consequences which determine its prognosis.\nEtiology\nIn the majority of cases, acromegaly is related to a pituitary adenoma, either purely GH-secreting (60%) or mixed. In very rare cases, acromegaly is due to ectopic secretion of growth hormone-releasing hormone (GHRH), responsible for pituitary hyperplasia. The gene aryl hydrocarbon receptor interacting protein, AIP (11q13.3), has been identified as a major susceptibility factor, particularly when acromegaly begins in childhood or adolescence. Acromegaly may also be part of multiple endocrine neoplasia syndromes such as MEN1 (MEN1; gene MEN1, 11q13), Carney complex (gene  PRKAR1A , 17q24.2) or familial isolated pituiatary adenoma (FIPA; gene AIP, 11q13.2). Very rarely it may be secondary to Xq26.3 chromosomal microduplications, responsible for X-linked acrogigantism due to Xq26 microduplication (XLAG), a very early-onset gigantism syndrome. Acromegaly may also be part of McCune-Albright syndrome.\nDiagnostic methods\nThe clinical diagnosis is confirmed biochemically by detection of increased serum of insulin-like growth factor-I (IGF-I) concentrations (screening test) and an increased serum GH concentration not suppressed following an oral glucose tolerance test (OGTT; confirmation test). Assessment of tumor volume and extension is based on imaging studies. Echocardiography and sleep apnea testing are used to determine the clinical impact of acromegaly.\nDifferential diagnosis\nDifferential diagnosis includes other causes of acromegaly (FIPA, MEN1, Carney complex and XLAG) as well as pachydermoperiostosis and acromegaloid features of severe insulin resistance.\nGenetic counseling\nThis form of acromegaly is sporadic; a causal genetic mutation has not been identified.\nManagement and treatment\nTreatment is aimed at correcting (or preventing) tumor compression by excising the disease-causing lesion, and at reducing GH and IGF-I levels to normal values. Transsphenoidal surgery is often the first-line treatment. When surgery fails to correct GH/IGF-I hypersecretion, medical treatment with dopamine agonists and/or somatostatin analogs is proposed. The GH antagonist (pegvisomant) is used in patients that are resistant to somatostatin analogs. Radiotherapy may be discussed as a third line of treatment in cases of medical treatment failure.\nPrognosis\nAdequate hormonal disease control is achieved in most cases, allowing a life expectancy similar to that of the general population. However, even if patients are cured or well-controlled, sequelae (joint pain, deformities and altered quality of life) often remain.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe CHANSON"}
{"Disease Name": "Acromelanosis", "Disease Definition": "A rare pigmentation anomaly of the skin characterized by otherwise asymptomatic hyperpigmentation of the skin over the dorsal side of fingers and toes which may rapidly spread towards proximal regions, like genitals, abdomen, and thighs. It is mostly seen in newborns or during the first years of life.", "ORPHA ID": 39, "Summary": ""}
{"Disease Name": "Acromelic frontonasal dysplasia", "Disease Definition": "A rare frontonasal dysplasia characterized by distinct craniofacial (large fontanelle, hypertelorism, bifid nasal tip, nasal clefting, brachycephaly, median cleft face, carp-shaped mouth), brain (interhemispheric lipoma, agenesis of the corpus callosum), and limb (tibial hypoplasia/aplasia, club foot, symmetric preaxial polydactyly of the feet and bilateral clubbed and thickened nails of halluces) malformations as well as intellectual disability. Other manifestations sometimes reported include absent olfactory bulbs, hypopituitarism and cryptorchidism.", "ORPHA ID": 1827, "Summary": ""}
{"Disease Name": "Acromesomelic dysplasia, Grebe type", "Disease Definition": "A rare autosomal recessive acromesomelic dysplasia characterized by severe dwarfism at birth, abnormalities confined to limbs, severe shortening and deformity of long bones, fusion or absence of carpal and tarsal bones, ball shaped fingers and, occasionally, polydactyly and absent joints. As seen in acromesomelic dysplasia, Hunter-Thomson type and acromesomelic dysplasia, Maroteaux Type, facial features and intelligence are normal.", "ORPHA ID": 2098, "Summary": ""}
{"Disease Name": "Acromesomelic dysplasia, Hunter-Thompson type", "Disease Definition": "A rare autosomal recessive acromesomelic dysplasia characterized by severe dwarfism (adult height approximately 120 cm) with abnormalities limited to the limbs (affecting the lower limbs more than upper limbs, with middle and distal segments being the most affected), severe shortening, absence or fusion of tubular bones of hands and feet and large joint dislocations. As seen in acromesomelic dysplasia, Grebe type and acromesomelic dysplasia, Maroteaux type, facial features and intelligence are normal.", "ORPHA ID": 968, "Summary": ""}
{"Disease Name": "Acromesomelic dysplasia, Maroteaux type", "Disease Definition": "A rare autosomal recessive acromesomelic dysplasia characterized by severe dwarfism (adult height <120 cm), both axial and appendicular involvement (shortening of the middle and distal segments of limbs and vertebral shortening), and with normal facial appearance and intelligence. It is a less severe form than acromesomelic dysplasia, Grebe type and acromesomelic dysplasia, Hunter-Thomson type .", "ORPHA ID": 40, "Summary": ""}
{"Disease Name": "Acromicric dysplasia", "Disease Definition": "A rare bone dysplasia characterized by short stature, short hands and feet, mild facial dysmorphism, and characteristic X-ray abnormalities of the hands.", "ORPHA ID": 969, "Summary": "Epidemiology\nThe prevalence is unknown. Fewer than 60 patients with this condition have been reported to date.\nClinical description\nLength is usually normal at birth but postnatal height falls progressively below the normal percentiles. The mean adult height is 130 cm (133 cm in males, 129 cm in females). The hands, feet, and limbs are short and occipitofrontal circumference is normal. There is no intellectual deficit. Mild dysmorphic features have been noted, including a round face, narrow palpebral fissures, well-defined eyebrows, long eyelashes, a bulbous nose with anteverted nostrils, a long and prominent philtrum, and thick lips with a small mouth. Other features include well-developed muscles, a hoarse voice, generalized joint limitations in some patients, frequent ear, tracheal, and respiratory complications, and spine abnormalities. Long-term follow-up shows that facial dysmorphism becomes less obvious in adults and that carpal tunnel syndrome is frequent in older patients. The entity known as Moore-Federman syndrome (see this term) characterized by short stature (with disproportionately short legs), joint stiffness, ocular abnormalities (hypermetropia, glaucoma) and thickened skin on the forearms, is believed to represent a variable clinical expression of acromicric dysplasia.\nEtiology\nThe disease is caused by heterozygous mutations in the FBN1 gene. Mutations are all located in exon 41-42, encoding TGFβ binding protein-like domain 5.\nDiagnostic methods\nDiagnosis of acromicric dysplasia can be suspected on association of severe postnatal short stature, short hands and feet, normal intelligence and mild facial dysmorphism. X-rays show delayed carpal bone age, cone shaped epiphyses, short metacarpals and phalanges with an internal notch of the second metacarpal, an external notch of the fifth metacarpal, as well as an internal notch of the femoral heads. Notches of the hands disappear in adulthood.\nDifferential diagnosis\nOverlapping syndromes include geleophysic dysplasia, Weill-Marchesani syndrome, and Myhre syndrome (see these terms). Geleophysic dysplasia can be distinguished from acromicric dysplasia by the presence of cardiac abnormalities (e.g. cardiac valvular thickening), Weill-Marchesani syndrome by the presence of microspherophakia, and Myhre syndrome by the presence of prognathism, deafness, developmental delay, and a thick calvarium.\nGenetic counseling\nTransmission is autosomal dominant. Affected individuals have a 50% risk of transmitting the disease to their offspring.\nManagement and treatment\nOrthopedic management may be needed for hip dysplasia during childhood and for carpal tunnel syndrome in older patients. Physical therapy is required to prevent progressive joint limitation. In a few cases, children have been treated with growth hormone therapy. Regular multidisciplinary follow-up is required, especially for respiratory abnormalities.\nPrognosis\nThe prognosis for affected individuals is usually good with a normal life expectancy. However, complications may occur, such as respiratory disorders, which may worsen the prognosis.\n\n                            Last update: \n                            June 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Valérie CORMIER-DAIRE"}
{"Disease Name": "Acroosteolysis-keloid-like lesions-premature aging syndrome", "Disease Definition": "A rare, genetic, progeroid syndrome disorder characterized by a prematurely aged appearance (including lipoatrophy, thin, translucent skin, sparse, thin hair, and skeletal muscle atrophy), delayed tooth eruption, keloid-like lesions on pressure regions, and skeletal abnormalities including marked acroosteolysis, brachydactyly with small hands and feet, kyphoscoliosis, osteopenia, and progressive joint contractures in the fingers and toes. Craniofacial features include a thin calvarium, delayed closure of the anterior fontanel, flat occiput, shallow orbits, malar hypoplasia and narrow nose.", "ORPHA ID": 363665, "Summary": ""}
{"Disease Name": "Acrootoocular syndrome", "Disease Definition": "A very rare disorder associating pseudopapilledema (optic disc swelling not secondary to increased intracranial pressure), mixed hearing loss, facial dysmorphism and limb extremity anomalies.", "ORPHA ID": 2980, "Summary": "Epidemiology\nOnly 4 cases have been reported in the literature from 3 inbred sibships.\nClinical description\nFacial dysmorphism is characterized by small head, downslanting palpebral fissures, broad base of the nose, micrognathia and malformed ears. Hand anomalies include short fingers, hypoplasia of thenar and hypothenar eminences and cutaneous syndactyly. Feet are small with a peculiar shape, wide space between toes 1 and 2 and syndactyly type 1 (see this term). The affected patients have no intellectual deficit.\nGenetic counseling\nThe condition is most probably hereditary, transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "Acropectoral syndrome", "Disease Definition": "A rare syndrome characterized by a combination of distal limb abnormalities (syndactyly of all fingers and toes, preaxial polydactyly in the feet and/or hands) and upper sternum malformations.", "ORPHA ID": 85203, "Summary": ""}
{"Disease Name": "Acropectorovertebral dysplasia", "Disease Definition": "A rare skeletal dysplasia characterized by fusion of the carpal and tarsal bones, with complex anomalies of the fingers and toes (preaxial polydactyly of the hands and/or feet, syndactyly of fingers and toes, hypoplasia and dysgenesis of metatarsal bones).", "ORPHA ID": 957, "Summary": "Epidemiology\nIt has been described in less than 30 patients from three unrelated families.\nClinical description\nOther manifestations include prominence of the sternum with variable pectus excavatum, lumbosacral spina bifida occulta, minor craniofacial anomalies and mild intellectual deficit.\nEtiology\nThe causative gene has been mapped to chromosome region 2q36.\nGenetic counseling\nThis syndrome is transmitted as an autosomal dominant trait with full penetrance.\n\n                            Last update: \n                            January 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Acrorenal syndrome", "Disease Definition": "A spectrum of congenital malformative disorders characterized by the co-occurrence of distal limb anomalies (usually bilateral cleft feet and/or hands) and renal defects (e.g. unilateral or bilateral agenesis), that can be associated with a variety of other anomalies such as those of genitourinary tract (genital anomalies, ureteral hypoplasias, vesicoureteral reflux), abdominal well defects, intestinal atresias, and lung malformations. Familial cases have been reported in which an autosomal recessive inheritance was suspected.", "ORPHA ID": 971, "Summary": ""}
{"Disease Name": "ACTH-dependent Cushing syndrome", "Disease Definition": "A group of endogenous Cushing syndrome (CS) caused by abnormal production of ACTH due, in 80% of cases, to adrenocorticotropic hormone (ACTH) oversecretion by a pituitary adenoma (Cushing disease, CD) and in 20% of cases to ectopic ACTH secretion (CS due to EAS) by an extrapituitary tumor or very rarely due to a tumor secreting both ACTH and corticotrophin-releasing hormone (CRH).", "ORPHA ID": 99892, "Summary": ""}
{"Disease Name": "Actinic lichen planus", "Disease Definition": "A rare cutaneous lichen planus characterized by the development of photo-distributed lichenoid lesions.", "ORPHA ID": 254395, "Summary": "Epidemiology\nThe exact prevalence is unknown. It is extremely rare in Caucasians but it is more common in dark-skinned populations, particularly in young adults.\nClinical description\nIndurated plaques or papules erupt on the face, neck, and the dorsal surface of hands after exposure to ultraviolet (UV) light. Different morphological subtypes have been described: the classic form (violaceous papules), a granuloma annular-like form (annular erythematous hyperpigmented plaques), a dyschromic form (white angular coalescent papules on the neck and dorsa of the hands), and a pigmented melasma-like form (dark patches on the face and neck). There is no mucosal or nail involvement. Histology is characterized by more marked melanin incontinence than in classical lichen planus; there may also be a lighter inflammatory cell infiltrate and focal areas of parakeratosis.\nEtiology\nEtiology is unknown.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Stephanie ARNOLD  - Dr Susan COOPER"}
{"Disease Name": "Actinic prurigo", "Disease Definition": "A rare, chronic, photodermatosis disease characterized by intensely pruritic, polymorphic, erythematous, excoriated and/or lichenified papules, macules, plaques and nodules, occurring on sun-exposed areas of the skin (particularly face, nose, lips, and ears), frequently associating cheilitis (especially of the lower lip) and conjuctivitis, which are present year-round or only in the spring/summer (depending on geographic location), observed mainly in Native Americans and Mestizos. Cheilitis may be the sole clinical presentation. Histologically, the presence of lymphoid follicles in mucosa is pathognomonic.", "ORPHA ID": 330061, "Summary": ""}
{"Disease Name": "Actinomycosis", "Disease Definition": "A rare bacterial infectious disease characterized by a chronic granulomatous infection by Actinomyces species which are commensals in the human gastrointestinal and urogenital tract and oropharynx. Corresponding to the affected site, the disease presents as cervicofacial, respiratory tract, genitourinary tract, digestive tract, central nervous system, or cutaneous actinomycosis and leads to the formation of abscesses and fistulae in the respective region.", "ORPHA ID": 457095, "Summary": ""}
{"Disease Name": "Action myoclonus-renal failure syndrome", "Disease Definition": "A rare epilepsy syndrome characterized by progressive myoclonus epilepsy in association with primary glomerular disease. Patients present with neurologic symptoms (including tremor, action myoclonus, tonic-clonic seizures, later ataxia and dysarthria) that may precede, occur simultaneously or be followed by renal manifestations including proteinuria that progresses to nephrotic syndrome and end-stage renal disease. In some patients, sensorimotor peripheral neuropathy, sensorineural hearing loss and dilated cardiomyopathy are associated symptoms.", "ORPHA ID": 163696, "Summary": ""}
{"Disease Name": "Activated PI3K-delta syndrome", "Disease Definition": "A rare, genetic, primary immunodeficiency disease characterized by increased susceptibility to recurrent and/or severe bacterial and viral infections (in particular, sinopulmonary bacterial and herpesvirus infections), chronic benign lymphoproliferation (manifesting as lymphadenopathy, hepatosplenomegaly and focal nodular lymphoid hyperplasia), and/or autoimmune disease (including immune cytopenias, juvenile arthritis, glomerulonephritis and sclerosing cholangitis). Immunophenotypically, variable degrees of agammaglobulinemia with increased IgM levels, increased circulating transitional B cells, decreased naïve CD4 and CD8 T-cells with increased CD8 effector/memory T cells are observed.", "ORPHA ID": 397596, "Summary": ""}
{"Disease Name": "Acute ackee fruit intoxication", "Disease Definition": "A rare disorder due to poisoning caused by the ingestion of unripe Blighia sapida fruits, clinically characterized by toxic hypoglycaemia and inhibition of neoglucogenesis.", "ORPHA ID": 73423, "Summary": "Epidemiology\nThe true incidence is unknown and most likely underreported. It is relatively frequent in the Caribbean and Western Africa where the fruit is consumed. In contrast, it is rare in France and other Western countries.\nClinical description\nThe clinical manifestations are severe and rapidly progressing (delirium, toxic hepatitis, acute dehydration and a state of shock, convulsions, coma) and may lead to death.\nEtiology\nThe hypoglycaemia is caused by the effect of hypoglycin A, which is found in the arils of the Blighia sapida fruit. When ingested, hypoglycin A is metabolized into (methylenecyclopropyl)acetyl-CoA, which inhibits several enzymes required for beta oxidation of fatty acids and gluconeogenesis.\nDiagnostic methods\nDiagnosis is based on clinical presentation following consumption of ackee fruit.\nDifferential diagnosis\nOther acute poisonings and acute gastritis are among the differential diagnoses.\nManagement and treatment\nTreatment is symptomatic (administration of glucose, IV or per os)\nPrognosis\nAlthough the intoxication is generally benign or has a favourable outcome, ingestion of large doses may lead to death: ackee fruit intoxication lead to 29 deaths in 1998 and more than 50 in 2001.\n\n                            Last update: \n                            October 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Bruno MÉGARBANE  - Pr Dabor RÉSIÈRE"}
{"Disease Name": "Acute adrenal insufficiency", "Disease Definition": "A primary adrenal insufficiency caused by a sudden defective production of adrenal steroids (cortisol and aldosterone). It represents an emergency, thus the rapid recognition and prompt therapy are critical for survival even before the diagnosis is made.", "ORPHA ID": 95409, "Summary": "Epidemiology\nAcute adrenal insufficiency (AAI) exact prevalence is unknown.\nClinical description\nThe disease may occur at any age. The onset is often sudden. The initial presentation may be non specific and may be limited to abdominal pain, nausea, vomiting, weight loss, tachycardia, and fever. Asymptomatic hypoglycemia, Hypoglycemic seizures or symptoms of dehydration are common manifestations seen in children. If untreated, shock and bilateral adrenal hemorrhage can rapidly lead to death.\nEtiology\nSteroid withdrawal is the most common cause of AAI in patients with chronic adrenal insufficiency. A precipitating illness (severe infection, acute myocardial infarction, stroke), surgery without adrenal support, pregnancy, any acute or chronic disease, or acute trauma are other potential causes of an acute adrenal crisis. AAI may result from an acute exacerbation of chronic primary adrenal insufficiency (CPAI). Adrenal destruction may be associated with autoimmune adrenalitis (Addison disease), isolated or in the context of autoimmune polyendocrinopathy type 1, 2 or 4. It can also be caused by medications that reduce steroid metabolism for patients with tuberculosis, opportunistic mycoses and viral infections in immunocompromised patients and adrenal metastases. Adrenal destruction may occur in the absence of CPAI history and may be due to bilateral massive adrenal hemorrhage (BMAH) as seen in Waterhouse-Friderichsen syndrome. AAI may also result from corticotroph insufficiency, either isolated or more often resulting from complete anterior pituitary insufficiency. Chronic glucocorticoid therapy (exogenous steroid such oral prednisolone or inhaled steroid) is also a cause of adrenal insufficiency (secondary adrenal insufficiency). Abrupt withdrawal of treatment may result in acute adrenal insufficiency.\nDiagnostic methods\nThe clinical signs are nonspecific but the diagnosis of AAI is suspected if a patient presents with hypotonia or shock that responds poorly to catecholamines. Laboratory exams show signs of adrenal insufficiency (hypoglycemia, hyponatremia and elevated natriuresis, hyperkaliemia, hemoconcentration, metabolic acidosis and functional renal failure) confirmed by hypocortisolemia, increased ACTH (Adreno CorticoTropic Hormone), and an insufficient response to rapid ACTH stimulation testing that leads to the diagnosis of absolute and peripheral AAI. The mineralocorticoid insufficiency, when present, can be confirmed by low aldosterone levels and high plasma renin activity (PRA). The etiological diagnosis is based on various imaging exams (CT-scan, ultrasound, or MRI). In case of anterior pituitary insufficiency, ACTH is low.\nDifferential diagnosis\nSecondary adrenal insufficiency needs to be eliminated. Peritonitis is often a differential diagnosis as well as other causes of adrenal destruction such as bilateral adrenalectomy, Waterhouse-Friderichsen syndrome, autoimmune adrenalitis, infectious adrenalitis.\nManagement and treatment\nImmediate treatment in an intensive care unit is necessary. Administration of 100 mg hydrocortisone i.v. (followed by 100-200 mg over 24 hours) combined with fluid resuscitation (1L saline solution during first hour, 500ml during second hour) is the standard treatment for an adrenal crisis. In children the dosage is based on 2 mg/kg/every 6 hours and hydroelectrolytic re-equilibration based on 3l/m2/d. During this time cardiac monitoring is essential. Antibiotics, vasopressors, heparin, packed red blood cells, platelets, cryoprecipitates and fresh frozen plasma are also administered if needed. Preventive strategies include dosage increase of oral steroid hormones during times of stress in those with CPIA or intramuscular, intraveinous or sub cutaneous injection. Patients and their families should also be educated on what to do during an adrenal crisis.\nPrognosis\nPrognosis varies depending on the etiologies, but is generally correlated with the rapidity of diagnosis and medical assistance. Death is rare when the patients receive appropriate medical assistance.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Juliane LEGER"}
{"Disease Name": "Acute annular outer retinopathy", "Disease Definition": "A rare, acquired retinal disorder characterized by unilateral, acute onset, rapidly progressive visual field loss. Sometimes patients have photopsia and complain of floaters. Typical ophthalmoscopic finding is a unilateral, yellowish-white annular intraretinal line, splitting the retinal field to affected outer retina with thinning, and normal retina. Gradual spontaneous visual recovery has been observed.", "ORPHA ID": 284460, "Summary": ""}
{"Disease Name": "Acute basophilic leukemia", "Disease Definition": "A rare acute myeloid leukemia characterized by primary differentiation to basophils. Microscopically, peripheral blood and bone marrow blasts contain coarse cytoplasmic basophilic granules which are positive with metachromatic staining (toluidine blue). Electron microscopy confirms that granules show features characteristic of basophil precursors. Mature basophils are usually sparse. Patients may present with manifestations related to bone marrow failure, as well as hepatosplenomegaly, cutaneous involvement, lytic lesions, and hyperhistaminemia. The disease is associated with a poor prognosis.", "ORPHA ID": 86849, "Summary": ""}
{"Disease Name": "Acute bilirubin encephalopathy", "Disease Definition": "A rare neurologic disease characterized by lethargy, hypotonia, poor feeding, opisthotonus, and a typical high-pitched cry due to bilirubin accumulation in the globus pallidus, sub-thalamic nuclei, and other brain regions, resulting from severe neonatal unconjugated hyperbilirubinemia. Onset of symptoms is typically within the first three to five days of life. Additional features include fever, apnea, seizures, and coma. Especially respiratory failure or refractory seizures may lead to a fatal outcome.", "ORPHA ID": 529799, "Summary": ""}
{"Disease Name": "Acute disseminated encephalomyelitis", "Disease Definition": "A demyelinating disorder of the central nervous system.", "ORPHA ID": 83597, "Summary": "Epidemiology\nThe incidence rate has been estimated at 1 in 125,000-250,000 per year.\nClinical description\nChildren younger than 10 years are predominantly affected. A seasonal winter and spring peaks have been registered. The disease usually develops after acute viral or bacterial infection or vaccination, with a sudden onset of irritability and lethargy after a prodromal period of 1-4 weeks. Major symptoms include fever, headache, drowsiness, changes in mental status, seizures and coma. Weakness, vomiting, weight loss, stiff neck, ataxia, bilateral optic neuritis and delirium are common. Peripheral nervous system involvement (paralysis of a single limb or hemiplegia) occurs in 5-45% of cases, according to literature data. Although initially the symptoms of ADEM may be mild, they worsen rapidly within several hours to four days. Pathologically, ADEM is characterized by bilateral large and confluent lesions in cerebral and cerebellar white matter; basal ganglia and gray matter may also be involved. ADEM lesions in the spinal cord are continuous and extending to multiple levels. Some authors consider the disease as a variant or borderline form of multiple sclerosis (MS) (see this term).\nEtiology\nADEM is considered as an immune-mediated disorder of the central nervous system. It can arise spontaneously but in most cases the disease is triggered by infectious disease or vaccinations. Links between the Pasteur rabies vaccine and ADEM have been documented. Immunizations less frequently associated with ADEM include pertussis, measles, Japanese B virus, tetanus, influenza.\nDiagnostic methods\nDiagnosis is based on the clinical history and magnetic resonance imaging, which is the diagnostic modality of choice.\nDifferential diagnosis\nMS is the main differential diagnosis. The differentiation between ADEM and a first episode of MS can be very difficult but has important prognostic and treatment implications. Differential diagnosis also includes infectious encephalitis, Guillain-Barré syndrome, glioblastoma multiforme, Schilder's disease (see these terms), psychotic disorders with acute onset, toxic/metabolic encephalopathy, vasculitis, nonvasculitic autoimmune encephalopathy, meningitis, metastatic tumor.\nManagement and treatment\nCurrently, immunosuppression with corticosteroids for the acute events is the mainstay of treatment. In patients refractory to steroid therapy, plasmapheresis or intravenous immunoglobulin therapy can be used. Symptomatic and supportive treatments are recommended.\nPrognosis\nADEM is typically a monophasic (single episode) disease with generally favorable outcome. Average time to recover is one to six months. Relapses may occur in 5-25% of cases, generally 6-18 months after the onset. Fulminant presentation with cerebral edema requiring critical intensive care is rare.\n\n                            Last update: \n                            July 2009"}
{"Disease Name": "Acute encephalopathy with biphasic seizures and late reduced diffusion", "Disease Definition": "A rare childhood-onset epilepsy syndrome associated with infection and characterized by a biphasic clinical course. The initial symptom is a prolonged febrile seizure on day 1 (the first phase). Afterwards, patients have variable levels of consciousness from normal to coma. Irrespective of the consciousness levels, magnetic resonance imaging (MRI) during the first 2 days shows no abnormality. During the second phase (usually days 4 - 6), patients show a cluster of seizures and deterioration of consciousness. Diffusion-weighted images (DWI) on MRI reveal the brain lesions with reduced diffusion predominantly in the subcortical white matter. After the second acute phase, consciousness levels improve with the emerging focal neurological signs. Neurological outcomes of AESD vary from normal to mild or severe sequelae including cerebral atrophy, mental retardation, paralysis and epilepsy.", "ORPHA ID": 363549, "Summary": ""}
{"Disease Name": "Acute erythroid leukemia", "Disease Definition": "A rare unclassified acute myeloid leukemia characterized by a proliferation of immature cells exclusively of the erythroid lineage without a significant myeloblastic component. Microscopically, the cells may be undifferentiated or proerythroblastic in appearance. Patients may present with pancytopenia with fatigue, infections, and mucocutaneous bleedings, as well as weight loss, fever, and night sweats. Prognosis is poor.", "ORPHA ID": 318, "Summary": ""}
{"Disease Name": "Acute fatty liver of pregnancy", "Disease Definition": "A rare, severe complication occurring in the third trimester of pregnancy or in early postpartum period bearing a risk for perinatal and maternal mortality and characterized by jaundice, rise of hepatic injuries and evolving to acute liver failure and encephalopathy.", "ORPHA ID": 243367, "Summary": ""}
{"Disease Name": "Acute generalized exanthematous pustulosis", "Disease Definition": "A rare hypersensitivity reaction characterized by the rapid development of numerous, nonfollicular, sterile, pinhead-sized pustules on an erythematous base, predominantly occurring on the trunk, intertriginous and flexural areas, with rare, mostly oral, mucosal involvement. Fever, peripheral blood leukocytosis, and mild eosinophilia are accompanying features. Systemic involvement, with hepatic, renal or pulmonary dysfunction, occasionally occurs. Onset usually occurs 1-12 days after administration of the causal medication and is most frequently associated with beta‐lactam antibiotics, macrolides (including pristinamycin and clindamycin), diltiazem, terbinafine, (hydroxy‐)chloroquine but many other medications have also been implicated. Histology reveals spongiform, subcorneal and/or intraepidermal, pustules but this pattern is not specific (same in pustular psoriasis).", "ORPHA ID": 293173, "Summary": ""}
{"Disease Name": "Acute hepatic porphyria", "Disease Definition": "A subgroup of porphyria characterized by the occurrence of neurovisceral attacks with or without cutaneous signs. They encompass four diseases: acute intermittent porphyria (PAI; the most common), variegate porphyria (VP), hereditary coproporphyria (HC), and hereditary delta-aminolevulinic acid dehydratase deficiency (ADP; extremely rare).", "ORPHA ID": 95157, "Summary": "Epidemiology\nIn most European countries, the prevalence of acute hepatic porphyria (AHP) is about 1/75,000.\nClinical description\nIn 80% of cases, patients are women between 20 and 45 years old. In all acute hepatic porphyrias, neurovisceral attacks may occur and manifest by intense abdominal pain (85-95% of cases) lasting one to two weeks, neurological disorders (muscle weakness, sensory disturbance or convulsions), and psychological disturbances (irritability, anxiety, auditory or visual hallucinations, mental confusion). The episodes are most commonly triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, a low caloric diet, stress), and/or endogenous factors (hormonal, linked to menstrual cycle). In the majority of VP patients and in less than 15% of HC patients, skin lesions are present.\nEtiology\nEach of the acute hepatic porphyrias is due to a deficiency of one of the enzymes in the heme biosynthesis pathway. These deficiencies lead to an accumulation of porphyrin precursors (delta aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver, and also, in the case of VP and HC, to an accumulation of porphyrins inducing cutaneous symptoms.\nDiagnostic methods\nDiagnosis is based on the demonstration of significantly elevated ALA levels, and above all, PBG (pathognomonic of acute porphyria attack) and, occasionally, porphyrins in urine, stool and/or plasma. Biochemical and enzymatic assays followed by characterization of mutations in the corresponding gene help defining the type of porphyria.\nDifferential diagnosis\nThe differential diagnosis includes Guillain-Barré syndrome and all causes of acute abdominal pain. For VP and HC, the differential diagnosis also includes photodermatoses. For ADP, the differential diagnosis must include type I tyrosinemia and lead poisoning.\nAntenatal diagnosis\nAntenatal diagnosis may be proposed in families at risk of homozygous acute hepatic porphyrias.\nGenetic counseling\nAcute hepatic porphyrias are monogenic disorders with autosomal dominant pattern of inheritance (except for ADP, which is autosomal recessive). There is a 50% risk of transmitting the pathogenic variant from an affected individual to their offspring. Genetic counseling is recommended to patients and families to identify individuals at risk of developing or transmitting the disease.\nManagement and treatment\nAcute attacks must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Management includes attacks prevention (avoidance of triggers) and skin protection against light in the case of cutaneous symptoms.\nPrognosis\nIn most cases, acute attacks do not recur throughout adult life, and the disease is rarely progressive. However, in some patients, episodes can reoccur necessitating repeated injections of human hemin. A new treatment based on ALAS1 siRNA, which prevents the recurrence of crippling acute episodes, may be proposed, thus removing the need for liver transplantation. AHP is a risk factor for the long-term development of hepatocellular carcinoma and chronic renal failure. Annual monitoring is proposed to detect these chronic complications.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Neila TALBI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins", "Disease Definition": "A rare mitochondrial respiratory chain deficiency due to TRMU deficiency leading to mitochondrial tRNA synthesis defect and characterized clinically by transient, but life-threatening acute liver failure episodes.", "ORPHA ID": 217371, "Summary": "Epidemiology\nTo date, more than 30 cases have been reported.\nClinical description\nClinical presentation is typically with acute liver failure (hepatomegaly, jaundice, irritability, feeding difficulties, vomiting, coagulopathy) occurring between 1 and 6 months of age. Patients present with hypoglycemia and hyperlactatemia, consistent with a defect in mitochondrial respiratory chain function. Uncommon clinical features including muscular involvement, mainly cardiac, have also been reported.\nEtiology\nThis disease is due to biallelic pathogenic variants in the (TRMU, 22q13.31) gene. This gene encodes for the tRNA mitochondrial 2-thiouridylase that is responsible for the 2-thiolation of uridine at the first anticodon position of the mitochondrial tRNALys, tRNAGlu, and tRNAGln. Mutations in this gene impair the translation of mtDNA-dependent complexes and cause combined respiratory chain defects.\nDiagnostic methods\nDiagnosis is based on the clinical evaluation of liver failure symptoms and on metabolic tests evaluating the mitochondrial function. Abdominal ultrasound usually disclosed hyperechogenic liver. When performed, liver biopsy analysis showed microvesicular steatosis and oncocytic hepatocytes, suggesting mitochondrial disease. Molecular genetic analysis searching for mitochondrial diseases establishes the diagnosis by identifying pathogenic TRMU variants.\nDifferential diagnosis\nDifferential diagnoses include mainly: other mitochondrial respiratory chain diseases involving the liver, especially hepatocerebral depletion syndromes (POLG, DGUOK, MPV17); adenosine kinase deficiency; recurrent acute liver failure triggered by infections or hyperthermia (NBAS, SCYL1, RINT1); aminoacyl-tRNA synthetase deficiencies (LARS, MARS, IARS). Molecular genetic testing rules out the diagnosis of these diseases.\nAntenatal diagnosis\nPrenatal testing is possible if pathogenic variants have been previously identified in the family.\nGenetic counseling\nThe disorder follows an autosomal recessive inheritance pattern. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nNon-specific supportive care including treatment and prevention of hypoglycemia is provided to patients undergoing an episode of acute liver failure. While cysteine supplementation efficacy is not demonstrated, supplementation with N-acetylcysteine or L-cysteine should be considered. Given the absence of significant neurological involvement reported so far, when indicated, a liver transplantation could be considered in these patients.\nPrognosis\nAccording to published data, 8 out of 32 patients (25%) died during the first year of life. In patients who survive the acute liver failure episodes, a full recovery occurs within months. Currently, no prognostic factor has been identified.\n\n                            Last update: \n                            December 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Pauline GAIGNARD  - Pr Emmanuel GONZALES | RARE-LIVER*\n\n\n                                * European Reference Network"}
{"Disease Name": "Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome", "Disease Definition": "A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by infantile onset of recurrent episodes of acute liver failure (resulting in chronic liver fibrosis and hepatosplenomegaly), delayed motor development, cerebellar dysfunction presenting as gait disturbances and intention tremor, neurogenic stuttering, and motor and sensory neuropathy with muscle weakness especially in the lower legs, and numbness. Mild intellectual disability was reported in some patients. MRI of the brain shows non-progressive atrophy of the cerebellar vermis and thinning of the optic nerve.", "ORPHA ID": 466794, "Summary": ""}
{"Disease Name": "Acute infantile liver failure-multisystemic involvement syndrome", "Disease Definition": "A rare, genetic, parenchymal hepatic disease characterized by acute liver failure, that occurs in the first year of life, which manifests with failure to thrive, hypotonia, moderate global developmental delay, seizures, abnormal liver function tests, microcytic anemia and elevated serum lactate. Other associated features include hepatosteatosis and fibrosis, abnormal brain morphology, and renal tubulopathy. Minor illness exacerbates deterioration of liver failure.", "ORPHA ID": 370088, "Summary": ""}
{"Disease Name": "Acute inflammatory demyelinating polyradiculoneuropathy", "Disease Definition": "A rare inflammatory neuropathy belonging to the clinical spectrum of Guillain-Barré syndrome (GBS).", "ORPHA ID": 98916, "Summary": "Epidemiology\nOverall annual incidence of GBS is estimated at between 1/91,000 and 1/55,000. AIDP accounts for around 90% of GBS cases in Europe and North America and thus the term GBS is often synonymous with AIDP in Western countries. The disease occurs in patients of all ages and men are affected about 1.5 times more often than women.\nClinical description\nThe clinical course of AIDP is divided into three phases. The first phase (lasting a few weeks) is characterized by rapidly progressive muscle weakness (usually appearing first in the feet and progressing upwards). It is symmetrical and may cause acute neuromuscular paralysis. Sensory disturbances (tingling and numbness), intense pains, and cramps may also occur. Other sites involved may include the respiratory muscles (leading to acute respiratory failure, with 20-30% of patients needing mechanical ventilation), the deglutition muscles (leading to life-threatening aspiration) and the eye muscles (leading to ophthalmoplegia). Deep-tendon reflexes may be decreased or absent. During the second phase (variable duration), symptoms become stable but other manifestations (cardiac arrhythmias, hyper/hypotension and gastric dysmotility) may occur. During the third (recovery) phase, lasting a few months or longer, symptoms slowly regress. Many patients have residual findings (weakness, sensory disturbances, fatigue or pain) for many months or even years.\nEtiology\nIn the majority of cases, an infectious disease precedes the onset of limb weakness, with Campylobacter jejuni infection being the most frequent initiating event. Cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae, and Haemophilus influenza have also been implicated. Onset of AIDP has also been reported after vaccination and surgical intervention. Although the exact pathological mechanisms remain to be discovered, AIDP is associated with activated macrophage infiltration of myelin sheaths, leading to myelin damage and demyelination. Other immunological mechanisms are also likely to play a role.\nDiagnostic methods\nDiagnosis is based on the clinical picture and can be difficult to establish. Lumbar puncture and cerebrospinal fluid (CSF) examination should be performed and electromyography can be helpful for confirming the diagnosis and identifying the GBS subtype: AIDP, or the axonal (AMAN, AMSAN) forms (see these terms).\nDifferential diagnosis\nThe differential diagnosis is wide and includes drug-induced neuropathy, critical illness polyneuropathy, carcinomatosis, metabolic disturbances, acute rhabdomyolysis, and cord and spinal nerve root compression or inflammation. Porphyria, vasculitis, diphtheria,, myasthenia gravis, botulism, polymyositis, dermatomyositis, brainstem encephalitis, meningitis, transverse myelitis, poliomyelitis (see these terms) as well as vitamin B1 deficiency may also be considered.\nManagement and treatment\nOptimal care from a multidisciplinary team providing intensive-care facilities is essential for management. Treatment consists of rapid administration of intravenous immunoglobulin (IVIg) or plasma exchange. Physiotherapy and rehabilitation are important.\nPrognosis\nGBS patients have a variable prognosis: it is estimated that around 50% of patients recover completely or have only minor sequelae, 20% are unable to walk after 6 months and 3% die. Multiple clinical, electrophysiological, serological and laboratory factors have been identified as predictors of a poor outcome. Fatigue and endurance intolerance may persist for years.\n\n                            Last update: \n                            December 2009\n\n\n                            - Expert reviewer(s): \n                            Pr P.A. [Pieter] VAN DOORN"}
{"Disease Name": "Acute intermittent porphyria", "Disease Definition": "A form of acute hepatic porphyria characterized by the occurrence of neurovisceral attacks without cutaneous symptoms.", "ORPHA ID": 79276, "Summary": "Epidemiology\nThis is the most frequent and severe form of acute hepatic porphyria. Its prevalence in Europe is about 1/75,000. The disease generally manifests after puberty, predominantly affecting women (80% of cases).\nClinical description\nPatients suffer intermittent neurovisceral attacks lasting several days and repeat over several weeks. They manifest as severe abdominal pain (>95% of patients), neurological disorders, and/or psychological disturbances. Abdominal pain is very often associated with low back pain irradiating to the legs, nausea, vomiting, and severe constipation. Several psychological disturbances can be observed: irritability, emotional sensitivity, depressive disorder, anxiety and, more rarely, auditory or visual hallucinations, disorientation, and mental confusion. Neurological manifestations can affect both the central and peripheral nervous systems (myalgia, paresis, ascending flaccid paralysis of the limbs or convulsions), and can lead to severe complications such as motor paralysis. Tachycardia and hyponatremia are common during attacks. In the rare case of cardiac arrhythmia or respiratory paralysis, the attacks can be fatal. The attacks are most commonly triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, a low caloric diet, stress), and/or endogenous factors (hormonal, linked to menstrual cycle).\nEtiology\nThe disease is caused by a deficiency in porphobilinogen deaminase (PBG-D, the third enzyme in the heme biosynthesis pathway), which leads to an accumulation of porphyrins and their precursors (aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver. The enzyme deficiency is due to mutations of the HMBS gene (11q23.3; NM_000190.4) coding for PBGD.\nDiagnostic methods\nReddish or brown coloration of urine following exposure to warm light is suggestive of the disease. Diagnosis is based on significantly elevated concentrations of PBG (pathognomonic of acute porphyria) and ALA in urine, and 50% residual PBGD activity in red blood cells (but not always found during attacks). Identification of a causal mutation of the HMBS gene confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other acute hepatic porphyrias, and is based on porphyrin analysis in urine, stool, and plasma.\nAntenatal diagnosis\nAntenatal diagnosis may be offered in families at risk of homozygous acute intermittent porphyria (AIP).\nGenetic counseling\nTransmission is autosomal dominant, with very low penetrance. Genetic counselling is recommended to patients and their families to identify individuals at risk of developing or transmitting the disease.\nManagement and treatment\nAcute attacks must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Management includes elimination of one or more triggers, relief of pain (opioids), vomiting, and anxiety, and prevention of attacks (avoidance of triggers, particularly drugs).\nPrognosis\nIn most cases, acute attacks of AIP do not recur throughout adult life, and the disease is rarely progressive. However, in some patients, attacks can reoccur, necessitating repeated injections of human hemin. A new ALAS1 siRNA-based treatment to prevent the recurrence of crippling acute attacks may be proposed, thereby delaying the need for liver transplantation. AIP is a risk factor for the long-term development of hepatocellular carcinoma and chronic renal failure. Annual monitoring is proposed to detect these chronic complications.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Neila TALBI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Acute interstitial pneumonia", "Disease Definition": "A rare, rapidly progressive, and histologically distinct, form of idiopathic interstitial pneumonia.", "ORPHA ID": 79126, "Summary": "Epidemiology\nPrevalence of acute interstitial pneumonia (AIP) is estimated at 1 in 25,000.\nClinical description\nAIP occurs over a wide age range, with a mean age of approximately 50 years. There is no sex predominance or association with smoking. The onset is acute/subacute (1±3 weeks), with dyspnoea and cough followed by rapid development of respiratory failure and the need for mechanical ventilation in the vast majority of the patients. Fever is present in almost half of the patients on presentation and a history of viral-like symptomatology exists in most cases but extensive investigations for bacterial and viral agents are negative.\nEtiology\nNo etiology is known for AIP. There is no genetic predisposition identified.\nDiagnostic methods\nThe chest radiograph and high-resolution computed tomography (HRCT) scan is abnormal; chest CT manifestations of AIP are bilateral, extensive, and sometimes patchy. They show alveolar densities associated with areas of ground glass attenuation. Consolidation is seen in the majority of cases, but is not as common as ground glass attenuation. Lung biopsies from patients with AIP show histologic features of the acute and/or organising phases of diffuse alveolar damage (DAD). The exudative phase shows oedema, hyaline membranes, and microvascular thrombi. The organising phase shows loose organising fibrosis, mostly within alveolar septa, and type II pneumocyte hyperplasia. The diagnosis of AIP is made in the appropriate clinical setting in a patient who has a clinical, radiological and histopathological presentations compatible with acute respiratory distress syndrome (ARDS) but without a clear etiology.\nDifferential diagnosis\nThe differential diagnosis, histologically and clinically, includes acute exacerbation of pulmonary fibrosis, DAD in patients with collagen vascular diseases, DAD of known cause (ARDS), infection (especially Pneumocystis jiroveci pneumonia and legionellosis) and drug-induced pneumonitis, as well as hypersensitivity pneumonitis and acute eosinophilic pneumonia.\nManagement and treatment\nThere is no proven treatment, however supportive care with mechanical ventilation, occasionally extracorporeal membrane oxygenation, high-dose corticosteroids, and often intravenous pulse cyclophosphamide, are usually provided.\nPrognosis\nThe prognosis is severe and early mortality is high, with a mortality rate over 50% within six months after onset.\n\n                            Last update: \n                            January 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Vincent COTTIN"}
{"Disease Name": "Acute liver failure", "Disease Definition": "A rare hepatic disease characterized by acute onset of severe liver dysfunction without evidence of underlying chronic liver disease. Patients present with nonspecific symptoms like jaundice, upper right abdominal pain, nausea, vomiting, pruritus, fatigue, and fever. The condition may rapidly progress to hepatic encephalopathy, coagulopathy, and life-threatening multiorgan failure. Liver biopsy typically shows massive hepatic necrosis.", "ORPHA ID": 90062, "Summary": ""}
{"Disease Name": "Acute lymphoblastic leukemia", "Disease Definition": "A rare disease characterized by malignant proliferation of lymphoid cells blocked at an early stage of differentiation and accounts for 75% of all cases of childhood leukaemia.", "ORPHA ID": 513, "Summary": "Epidemiology\nAbout 3,000 children in the United States and 5,000 children in Europe are diagnosed with ALL per year.\nClinical description\nThe peak incidence occurs between 2 and 5 years of age. ALL may be either asymptomatic or acute with a life-threatening haemorrhage, infection, or episode of respiratory distress. Although ALL primarily affects the bone marrow and peripheral blood, any organ or tissue may be infiltrated by the abnormal cells. The most frequent signs are lymphadenopathies, hepatosplenomegaly, fever, signs of haemorrhage, and bone pain.\nEtiology\nMost cases show chromosomal and genetic abnormalities, occurring spontaneously in genes playing important regulatory roles in controlling the lymphoid cell population. The most common ALL translocation, the t(12;21), appears to have good prognostic implications.\nDiagnostic methods\nALL is biologically heterogeneous and morphologic, immunologic, cytogenetic, biochemical, and molecular genetic characterisation of leukaemia lymphoblasts is needed to establish the diagnosis or to exclude other possible causes of bone marrow failure and, finally, to classify ALL subtypes. Biological findings include hyperleukocytosis due to circulating lymphoblasts, anaemia and thrombocytopaenia. Diagnosis is established by bone marrow biopsy revealing leukaemic cell infiltration.\nManagement and treatment\nThe chemotherapy protocols adopted by international cooperative groups have four main objectives: induction with the aim of complete remission, preventative therapy to avoid central nervous system involvement, consolidation/re-induction, and maintenance therapy. Although management of relapse remains largely controversial, high dose chemotherapy blocks and stem cell transplantation are approaches increasingly adopted in most cases. In 2006, clofarabine obtained EU marketing authorisation as an Orphan drug for second line treatment of paediatric ALL patients. A novel tyrosine-kinase inhibitor, dasatinib, has been shown to be a safe and effective treatment option for adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia and resistance or intolerance to imatinib. Clinical trials with this inhibitor are ongoing in the paediatric population. With the need to stratify patients into risk groups and to provide risk-adapted therapy, treatment requires high levels of organisation, expertise and knowledge.\nPrognosis\nThe increase in the survival rate for children younger than 15 years of age has been dramatic, moving from less than 10% in the early 60's to about 75% in the late 90's. Unfortunately, however, results are still rather poor in countries with limited resources, which are home to around 80% of the child population.\n\n                            Last update: \n                            August 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Andrea BIONDI  - Dr Roberto CHIESA  - Dr C CITTERIO  - Dr Valentino CONTER  - Pr Carmelo RIZZARI  - Dr Arturo SALA"}
{"Disease Name": "Acute macular neuroretinopathy", "Disease Definition": "A rare, acquired retinal disorder characterised by transient or permanent visual impairment accompanied by the presence of reddish-brown, wedge-shaped lesions in the macula, the apices of which tend to point towards the fovea. The lesions usually appear in a petalloid or tear-drop configuration. Patients tend to be young, Caucasian, and female.", "ORPHA ID": 488239, "Summary": ""}
{"Disease Name": "Acute mast cell leukemia", "Disease Definition": "A rare systemic mastocytosis characterized by the presence of at least 20% usually immature and atypical mast cells in bone marrow aspirate smears. In classic mast cell leukemia, mast cells account for at least 10% of peripheral white blood cells, although the aleukemic variant with less than 10% mast cells is more common. C-findings (cytopenias, hepatomegaly, ascites, portal hypertension, splenomegaly, skeletal lesions, malabsorption), indicative of organ damage due to mast cell infiltration, are usually present at diagnosis, while skin lesions are absent in most cases. Prognosis is generally poor.", "ORPHA ID": 566393, "Summary": ""}
{"Disease Name": "Acute megakaryoblastic leukemia", "Disease Definition": "A rare acute myeloid leukemia that occurs predominantly in childhood and particularly in children with Down syndrome (DS-AMKL). Nonspecific symptoms may be irritability, weakness, and dizziness while specific symptoms include pallor, fever, mucocutaneous bleeding, hepatosplenomegaly, neurological manifestations and rarely lymphadenopathy. Acute panmyelosis with myelofibrosis may also be associated with AMKL. In contrast to DS-AMKL (around 80 % survival), non-DS-AMKL is an AML subgroup associated with poor prognosis.", "ORPHA ID": 518, "Summary": ""}
{"Disease Name": "Acute monoblastic/monocytic leukemia", "Disease Definition": "A form of acute myeloid leukemia that is either comprised of more than 80% of monoblasts or 30-80% monoblasts with (pro)monocytic differentiation. It presents with asthenia, pallor, fever, and dizziness. Specific features include hyperleukocytosis, propensity for extramedullary infiltrates, coagulation abnormalities including disseminated intravascular coagulation and neurological disorders. Leukemia cutis and gingival infiltration can also be seen. A characteristic translocation observed is t(9;11).", "ORPHA ID": 514, "Summary": ""}
{"Disease Name": "Acute motor and sensory axonal neuropathy", "Disease Definition": "A rare motor-sensory, axonal form of Guillain-Barré syndrome (GBS).", "ORPHA ID": 98917, "Summary": "Epidemiology\nThe overall annual incidence of GBS is estimated at between 1/91,000 and 1/55,000. The axonal (AMSAN and acute motor axonal neuropathy, AMAN; see this term), forms account for only 3-5% of cases of GBS in Western countries but are much more frequent (30%-50% of GBS cases) in Asia and Latin America.\nClinical description\nPatients present with a clinical picture (muscle weakness and sensory deficits) similar to that of the more frequent demyelinating form of GBS, acute inflammatory demyelinating polyradiculoneuropathy (AIDP; see this term) but the disease course in AMSAN tends to be more severe. As in other types of GBS, an infectious disease precedes the onset of limb weakness in the majority of cases.\nEtiology\nAlthough the exact pathological mechanism is poorly understood, both AMAN and AMSAN are associated with the presence of antiganglioside antibodies (anti-GM1/GD1a/GM1b/GalNAc-GD1a) and may be caused by antibody-mediated primary axonal degeneration or antibody-mediated inhibition of voltage-gated sodium channels.\nPrognosis\nAMSAN is generally a severe form of GBS and recovery is often poor.\n\n                            Last update: \n                            December 2009\n\n\n                            - Expert reviewer(s): \n                            Pr P.A. [Pieter] VAN DOORN"}
{"Disease Name": "Acute motor axonal neuropathy", "Disease Definition": "A rare pure motor axonal form of Guillain-Barré syndrome (GBS).", "ORPHA ID": 98918, "Summary": "Epidemiology\nThe overall annual incidence of GBS is estimated at between 1/91,000 and 1/55,000. The axonal forms (AMAN and acute motor-sensory axonal neuropathy, AMSAN; see this term) account for only 3-5% of cases in Western countries but are much more frequent (30%-50% of GBS cases) in Asia and Latin America.\nClinical description\nAMAN presents with rapid onset of muscle weakness and absent reflexes. The clinical course in AMAN tends to be more severe than in the more frequent, demyelinating form of GBS, acute inflammatory demyelinating polyradiculoneuropathy (AIDP; see this term), with an increased number of patients requiring artificial ventilation due to respiratory involvement. However, there is no sensory deficit in AMAN and cranial nerve involvement is rare.\nEtiology\nIn the majority of cases, AMAN occurs following Campylobacter jejuni infection, in particular following infection with strains of C jejuni that cause enteritis. Although the exact pathological mechanism is not fully understood, AMAN is associated with the presence of antiganglioside antibodies (primarily, anti-GM1/GD1a) and may be caused by antibody-mediated primary axonal degeneration or antibody-mediated inhibition of voltage-gated sodium channels.\nPrognosis\nAlthough the clinical course initially can be severe in AMAN, recovery can be rapid. However, recovery may be significantly prolonged in patients with extensive axonal degeneration.\n\n                            Last update: \n                            December 2009\n\n\n                            - Expert reviewer(s): \n                            Pr P.A. [Pieter] VAN DOORN"}
{"Disease Name": "Acute myeloblastic leukemia with maturation", "Disease Definition": "A rare, acute myeloid leukemia characterized by evidence of granulocytic maturation and more than 20% of blast cells in the bone marrow and/or peripheral blood. The maturing non-blast granulocytic cells account for greater than or equal to 10% and monocytic cells less than or equal to 20% of the bone marrow cells. Various degrees of anemia, thrombocytopenia, or pancytopenia are present. Frequent clinical manifestations include fatigue, fever, bleeding disorders, and organomegaly, especially hepatosplenomegaly.", "ORPHA ID": 98834, "Summary": ""}
{"Disease Name": "Acute myeloblastic leukemia without maturation", "Disease Definition": "A rare, acute myeloid leukemia characterized by no significant myeloid maturation and more than 90% blast cells in the non-erythroid population. Various degrees of anemia, thrombocytopenia, or pancytopenia are present. Frequent clinical manifestations include fatigue, fever, bleeding disorders, and organomegaly, especially hepatosplenomegaly.", "ORPHA ID": 98833, "Summary": ""}
{"Disease Name": "Acute myeloid leukaemia with myelodysplasia-related features", "Disease Definition": "A rare acute myeloid leukemia (AML) characterized by the presence of acute leukemia with at least 20% peripheral blood or bone marrow blasts with morphological features of myelodysplasia, or occurrence in patients with a prior history of a myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm, with MDS-related cytogenetic abnormalities, in the absence of specific genetic abnormalities characteristic of AML with recurrent genetic abnormalities. Prior cytotoxic or radiation therapy for an unrelated disease must be excluded. The condition occurs mainly in elderly patients and is rare in children. Patients often present with severe pancytopenia. Prognosis is generally poor.", "ORPHA ID": 86845, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia and myelodysplastic syndromes related to alkylating agent", "Disease Definition": "A subgroup of therapy-related myeloid neoplasms (t-MN), associated with a treatment of an unrelated neoplastic or autoimmune disease with cytotoxic agents, like cyclophosphamid, platins, melphalan and others. The neoplastic cells typically harbor unbalanced aberrations of chromosomes 5 and 7 (monosomy 5/del(5q) and monosomy 7/del(7q)) or a complex karyotype. It usually presents with multilineage dysplasia and cytopenias 5-10 years after exposure, with symptoms related to the degree of bone marrow failure and the corresponding cytopenia (fatigue, bleeding and bruising, recurrent infections, bone pain).", "ORPHA ID": 102379, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia and myelodysplastic syndromes related to radiation", "Disease Definition": "A subgroup of therapy-related myeloid neoplasms (t-MN), associated with treatment of an unrelated neoplastic disease with radiation. The neoplastic cells typically harbor unbalanced aberrations of chromosomes 5 and 7 (monosomy 5/del(5q) and monosomy 7/del(7q)) or a complex karyotype. Patients frequently present with multilineage dysplasia and cytopenias 5-10 years after exposure.", "ORPHA ID": 164726, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia and myelodysplastic syndromes related to topoisomerase type 2 inhibitor", "Disease Definition": "A subgroup of therapy-related myeloid neoplasms (t-MN), associated with treatment of an unrelated neoplastic disease with cytotoxic agents, like etoposid, doxorubicin, daunorubicin and others. The neoplastic cells often show rearrangements involving the mixed lineage leukemia gene at 11q23. This subgroup of t-MN is typically associated with overt leukemia, without preceding myelodysplastic syndrome, developing 2-3 years after exposure, presenting with non-specific symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement.", "ORPHA ID": 102381, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia with 11q23 abnormalities", "Disease Definition": "A rare tumor arising from hematopoietic and lymphoid tissues characterized by abnormal proliferation and differentiation of a clonal population of myeloid stem cells carrying unspecific 11q23 abnormalities. Clinical manifestations result from accumulation of malignant myeloid cells within the bone marrow, peripheral blood and other organs, and include leukocytosis, anemia, thrombocytopenia, fatigue, anorexia and weight loss.", "ORPHA ID": 98831, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)", "Disease Definition": "A rare acute myeloid leukemia (AML) with recurrent genetic anomaly disorder characterized by an inv(16)(p13q22) or t(16;16)(p13;q22) cytogenic abnormality, which generates a CBFB-MYH11 fusion gene, presenting with typical morphologic features of AML as well as abnormal bone marrow eosinophils (seen in all stages of maturation with no significant signs of maturation arrest). Myeloid sarcoma and involvement of the central nervous system is relatively common. Cytology reveals myeloblasts, a significant monocytic component and variable numbers of immature eosinophils with atypical purple-violet granules in addition to eosinophilic granules. Presence of the fusion gene is sufficent for diagnosis irrespective of blast count.", "ORPHA ID": 98829, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia with CEBPA somatic mutations", "Disease Definition": "A subtype of acute myeloid leukemia with recurrent genetic abnormalities, characterized by clonal proliferation of myeloid blasts harboring somatic mutations of the CEBPA gene in the bone marrow, blood and, rarely, other tissues. It can present with anemia, thrombocytopenia, and other nonspecific symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement (gingivitis, splenomegaly).", "ORPHA ID": 319480, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2)", "Disease Definition": "A subtype of acute myeloid leukemia with recurrent genetic abnormalities characterized by clonal proliferation of myeloid blasts in the bone marrow, blood and, rarely, other tissues. Bone marrow typically shows small, hypolobated megakaryocytes and multilineage dysplasia. Patients typically present with leukocytosis, anemia, variable platelet counts and a variety of nonspecific symptoms related to ineffective hematopoesis (fatigue, bleeding, bruising, recurrent infections, bone pain) and/or extramedullary site involvement (gingivitis, splenomegaly). High resistance to conventional chemotherapy is reported.", "ORPHA ID": 402020, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia with minimal differentiation", "Disease Definition": "A rare subtype of acute myeloid leukemia characterized by clonal proliferation of poorly differentiated myeloid blasts in the bone marrow, blood or other tissues. It usually presents with anemia, thrombocytopenia and other nonspecific symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement (gingivitis, splenomegaly). Low remission rates are reported.", "ORPHA ID": 98832, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia with NPM1 somatic mutations", "Disease Definition": "A subtype of acute myeloid leukemia with recurrent genetic abnormalities characterized by leukocytosis, thrombocytosis and nonspecific symptoms related to ineffective hematopoiesis (fatigue, bleeding and bruising, recurrent infections, bone pain), with frequent extramedullary involvement typically presenting as gingival hyperplasia and lymphadenopathy. The disease is characterized by clonal proliferation of myeloid blasts harboring mutations of the NPM1 gene in the bone marrow, blood and other tissues. It is associated with multilineage dysplasia, involving the myeloid, monocytic, erythroid, and megakaryocytic cell lineages.", "ORPHA ID": 402026, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia with t(6;9)(p23;q34)", "Disease Definition": "A rare subtype of acute myeloid leukemia with recurrent genetic abnormalities characterized by clonal proliferation of poorly differentiated myeloid blasts in the bone marrow, blood, or other tissues in patients who present the t(6;9)(p23;q34) translocation. Frequently associated with multilineage bone marrow dysplasia, it usually presents with anemia, thrombocytopenia (often pancytopenia), and other nonspecific symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement (gingivitis, splenomegaly). Basophilia, as well as poor response to chemotherapy, has been reported.", "ORPHA ID": 402014, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia with t(8;16)(p11;p13) translocation", "Disease Definition": "A distinct form of Acute myeloid leukemia (AML) in which this chromosomal anomaly is found de novo or in therapy-related AML cases, and is characterized by frequent extramedullary involvement (mainly hepatomegaly, splenomegaly, lymphadenopathies, cutaneous infiltration, but also gum, bone, central nervous system, testicles involvement), severe coagulation disorder (disseminated intravascular coagulopathy or primary fibrinolysis) and poor prognosis. Morphologically, a blast population with a myelomonocytic stage of differentiation is observed.", "ORPHA ID": 370026, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia with t(8;21)(q22;q22) translocation", "Disease Definition": "A rare acute myeloid leukemia with recurrent genetic anomaly disorder characterized by a t(8;21)(q22;q22) balanced translocation cytogenetic abnormality, forming a RUNX1-RUNX1T1 fusion gene, presenting with morphological characteristics which include myeloblasts with indented nuclei, basophilic cytoplasm with a prominent paranuclear hof that may contain a few azurophilic granules, prominent and possibly large promyelocytes, myelocytes and metamyelocytes, easily identifiable Auer rods and, more variably, bone marrow eosinophilia. Myeloid sarcoma is frequently present at diagnosis. Detection of the t(8;21)(q22;22) translocation is sufficient for diagnosis irrespective of blast count.", "ORPHA ID": 102724, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia with t(9;11)(p22;q23)", "Disease Definition": "A tumor of hematopoietic and lymphoid tissues characterized by the most common AML-causing MLL translocation, resulting in the MLL-MLLT3-fusion protein. It can occur either as a primary neoplasm or secondary to previous chemo-/radiation therapy. Clinical manifestations result from accumulation of malignant myeloid cells within the bone marrow, peripheral blood and other organs and include leukocytosis, anemia, thrombocytopenia, fever, bone pain, fatigue, pallor, easy bruising and frequent bleeding.", "ORPHA ID": 402017, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia with t(9;22)(q34.1;q11.2)", "Disease Definition": "A rare acute myeloid leukemia (AML) with recurrent genetic anomaly characterized by the presence of bone marrow and peripheral blood myeloblasts with features ranging from those of minimal differentiation to granulocytic maturation, demonstrating t(9;22)(q34.1;q11.2) or molecular genetic evidence of BCR-ABL1 fusion. Evidence of chronic myeloid leukemia (CML) is absent. Patients most commonly present with leukocytosis with blast predominance and variable anemia and thrombocytopenia. Splenomegaly is less frequent and peripheral blood basophilia lower than in patients with myeloid blast transformation of CML. The disease occurs primarily in adults, and response to traditional AML therapy or tyrosine kinase inhibitor therapy alone is typically poor.", "ORPHA ID": 585867, "Summary": ""}
{"Disease Name": "Acute myeloid leukemia", "Disease Definition": "A group of neoplasms arising from precursor cells committed to the myeloid cell-line differentiation. All of them are characterized by clonal expansion of myeloid blasts. They manifest by fever, pallor, anemia, hemorrhages and recurrent infections.", "ORPHA ID": 519, "Summary": "Epidemiology\nAnnual incidence rate of AML is estimated to be 1/33,000-1/25,000 in Europe.\nClinical description\nAlthough, AML can occur at any age, it is typically a disease affecting elder people, usually more than 65 years. The main clinical picture consists of a short time period with pallor, fatigue, fever, infections and hemorrhages. Presence of all these features is not compulsory. Central nervous system infiltration is uncommon and mainly related with monocytic variants. Extramedullary accumulation of myeloid blasts in different tissues, mainly skin, can be observed and is known as myeloid sarcoma (see this term). Testes are usually not affected.\nEtiology\nPathogenesis of AML is still unclear but a two-hit model has been suggested as the probable mechanism for leukemogenesis. That means that AML could be the consequence of at least 2 different types of gene mutations. Class I mutations resulting in proliferative advantage while the class II mutations alter the normal hematopoietic differentiation. Examples of class I mutations are those of FLT3-ITD or KIT mutations. Class II mutations include CEBPA mutations. Controversy is also still in the type of cell from which AML arises. While data supporting progenitor cells committed to specific myeloid cell type has been reported, other studies argue in favor for a more immature stem.\nDiagnostic methods\nDiagnosis relies on laboratory findings showing anemia, thrombocytopenia and leucopenia or leukocytosis which result from disturbed hematopoietic function due to bone marrow and peripheral blood infiltration by immature blast cells. Diagnosis of AML also relies on bone marrow aspirate or biopsy after the disease has been suspected. Bone marrow should have at least 20% of myeloid blasts to be considered as AML. After morphological examination, immunophenotyping of leukemic cells, cytogenetic and molecular analysis should be performed.\nDifferential diagnosis\nDifferential diagnosis includes megaloblastic anaemia, myelodysplastic syndromes, acute lymphoblastic leukemia, acute biphenotypic leukemia, chronic myeloid leukemia (myeloid blast phase), and metastases of tumors such rhabdomyosarcoma and neuroblastoma (see these terms).\nManagement and treatment\nFor young patients, treatment consists of an induction cycle with cytarabine plus idarubicin or daunorubicin in a typical 3 + 7 schedule with the first objective to reach complete response (CR). About 75% of the patients achieve CR, but virtually all of them will relapse if additional treatment (consolidation therapy) is not given. Based on stratification, patients can be treated with chemotherapy consolidation or allogenic hematopoietic stem cell transplantation (HSCT). Refractory or relapsed AML is treated with a second induction course adding new drugs (such gemtuzumab ozogamicin) to the standard treatment. Some drugs such as azacitidine or decitabine are available for the treatment of elderly AML patients under specific circumstances.\nPrognosis\nPrognosis varies widely according to cytogenetics, molecular findings, response to induction treatment and age, between others. Overall, long-term survivors account for 40% of young patients. For children less than 15 years, overall survival rates are 60-70%. Prognosis of elder patients is rather poor.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Federico MOSCARDÓ"}
{"Disease Name": "Acute myelomonocytic leukemia", "Disease Definition": "A rare acute myeloid leukemia disorder characterized by increased blast cells (myeloblasts, monoblast, and/or promonoblasts), representing more than 20% of the total bone marrow (BM) or peripheral blood differential counts, with 20-80% of BM cells being of monocytic lineage. Clinical presentation is the result of bone marrow involvement and extramedullary infiltration by the leukemic cells and includes asthenia, pallor, fever, dizziness, respiratory symptoms, easy bruising, bleeding disorders, and neurological deficits. Gingival hyperplasia, organomegaly, especially hepatosplenomegaly, and lymphadenopathy may also be associated.", "ORPHA ID": 517, "Summary": ""}
{"Disease Name": "Acute necrotizing encephalopathy of childhood", "Disease Definition": "A rare neurologic disease characterized by a rapid onset of seizures, an altered state of consciousness, neurologic decline, and variable degrees of hepatic dysfunction following a respiratory or gastrointesitnal infection (e.g. mycoplasma, influenza virus) in a previously healthy child. Brain MRI of patients reveals bilateral, multiple, symmetrical lesions predominantly observed in thalami and brainstem, but also in periventricular white matter and cerebellum in some cases.", "ORPHA ID": 263524, "Summary": ""}
{"Disease Name": "Acute neonatal citrullinemia type I", "Disease Definition": "A severe form of citrullinemia type 1 characterized biologically by hyperammonemia and clinically by progressive lethargy, poor feeding and vomiting, seizures and possible loss of consciousness, within one to a few days of birth, with variable signs of increased intracranial pressure. The condition can lead to significant neurologic deficits.", "ORPHA ID": 247546, "Summary": ""}
{"Disease Name": "Acute opioid intoxication", "Disease Definition": "A rare intoxication with opioids, a large group of alkaloid analgesics, mainly characterized by miosis (pinpoint pupil), respiratory depression (bradypnea/apnea) and central nervous system depression (sedation or coma). Other manifestations include hypotension, reduced bowel motility, hypothermia and hypoglycemia. Naloxone, a competitive inhibitor of the mu-opioid receptor, is a potent antagonist and is used as the antidote for opioid intoxication.", "ORPHA ID": 35889, "Summary": ""}
{"Disease Name": "Acute pandysautonomia", "Disease Definition": "A rare variant of Guillain-Barré syndrome characterized by acute post-ganglionic sympathetic and parasympathetic failure presenting several weeks after acute infection with gastrointestinal symptoms (abdominal pain, vomiting, constipation, diarrhea, gastroparesis, ileus), orthostatic hypotension, erectile dysfunction, urinary frequency, urgency or retention, vasomotor instability with acrocyanosis and reduced salivation, lacrimation and sweating.", "ORPHA ID": 231457, "Summary": ""}
{"Disease Name": "Acute panmyelosis with myelofibrosis", "Disease Definition": "A rare unclassified acute myeloid leukemia characterized by an acute panmyeloid proliferation with blasts constituting more than 20% of cells in the bone marrow or peripheral blood, accompanied by fibrosis of the bone marrow. Patients typically present with acute onset of severe constitutional symptoms, bone pain, and pancytopenia. Splenomegaly is minimal or absent. The disease is rapidly progressive with poor therapy response.", "ORPHA ID": 86843, "Summary": ""}
{"Disease Name": "Acute peripheral arterial occlusion", "Disease Definition": "A rare vascular condition characterized by the sudden blockage of an artery supplying blood to the limbs by a blood clot, causing acute limb ischemia. The clinical presentation is variable and depends on the time course of vessel occlusion, the presence of an underlying vascular disease, and the recruitment of collateral circulation. Symptoms can develop over a period of hours to days and typically include limb pain, pallor, absent pulse, poikilothermia, paresthesia, and limb paralysis. The condition can quickly progress to infarction and loss of the limb.", "ORPHA ID": 90064, "Summary": ""}
{"Disease Name": "Acute poisoning by drugs with membrane-stabilizing effect", "Disease Definition": "A rare clinical situation characterized by acute, potentially life-threatening toxic effects of drugs acting on voltage-gated sodium or calcium channels, such as tricyclic antidepressants, anticonvulsants, local anesthetics and antiarrhythmics, some beta-blockers, and chloroquine. Clinical manifestations include abnormal ECG findings (intraventricular conduction block with widening of the QRS complex, T wave flattening, prolongation of the QT interval) and variable signs and symptoms depending on the drug, typically involving the cardiovascular and central nervous system, among others.", "ORPHA ID": 43119, "Summary": ""}
{"Disease Name": "Acute pure sensory neuropathy", "Disease Definition": "A rare, acquired, demyelinating neuropathy disease characterized by acute, symmetric, monophasic sensory neuropathy without motor involvement, typically manifesting with numbness in the distal lower limbs which progressively extends to all the limb, tingling sensation in the distal lower limbs, generalized areflexia, and unsteady gait, as well as clumsiness of the upper limbs, pseudoathetosis and loss of vibration sense.", "ORPHA ID": 231450, "Summary": ""}
{"Disease Name": "Acute radiation syndrome", "Disease Definition": "A rare radiation-induced disorder resulting from whole body exposure to large doses of penetrating radiation (>0.7 Gray) within a very short period of time (usually minutes) and characterized by bone marrow syndrome with pancytopenia (mild symptoms of which may occur already at 0.3 Gray), gastrointestinal syndrome resulting in mostly fatal infection, dehydration, and electrolyte imbalance (occurring at doses >10 Gray), and cardiovascular/central nervous system syndrome with watery diarrhea, convulsions, coma, and death within three days of exposure (occurring at doses >50 Gray). The syndrome develops in four clinical stages (prodromal/latent/manifest illness/recovery or death) of variable duration.", "ORPHA ID": 454831, "Summary": ""}
{"Disease Name": "Acute sensory ataxic neuropathy", "Disease Definition": "A rare variant of Guillain-Barré syndrome characterized by acute onset monophasic sensory neuropathy with diminished or absent tendon reflexes, loss of proprioception, positive Romberg sign and nerve conduction features of demyelination. It presents several weeks after acute infection with paresthesias, ataxia and neuropathic pain.", "ORPHA ID": 231466, "Summary": ""}
{"Disease Name": "Acute transverse myelitis", "Disease Definition": "A rare inflammatory demyelinating disorder of the spinal cord that can be either idiopathic (IATM) or secondary to a known cause (SATM).", "ORPHA ID": 139417, "Summary": "Epidemiology\nAnnual incidence of IATM is estimated between 1/1,000,000 and 1/250,000. Incidence of SATM is variable and depends of the underlying disease.\nClinical description\nAge of onset and clinical course vary depending on the form. The clinical manifestations common to both forms include motor involvement (limb weakness, stiffness and muscle spasms with impaired respiratory function in cases with involvement of the upper spinal cord), sensory manifestations (back pain, paresthesia, numbness and neuropathic pain) and autonomic findings (sexual dysfunction, urinary urge/retention, bowel urge/retention and autonomic dysreflexia). Other signs depend on the associated diseases in SATM, with involvement of cranial and peripheral nerves. IATM has a monophasic course whereas SATM may be relapsing.\nEtiology\nIATM is believed to be an immune-mediated disease, due to a late immune response against a recent infection that inadvertently targets the spinal cord. SATM is due to an inflammatory disease: multiple sclerosis (MS), neuromyelitis optica (NMO), systemic lupus erythematosus (SLE) and Sjögren's syndrome (see these terms), and may also be due to an infectious disease (bacterial, parasitic or viral).\nDiagnostic methods\nDiagnosis requires MRI of the spinal cord to confirm the presence of Acute transverse myelitis and cause, if any. Laboratory tests are also essential for identifying the cause of SATM: analysis of the cerebrospinal fluid may reveal the presence of oligoclonal bands (commonly seen in MS) or bacterial/viral/parasitic infections; serology may reveal the presence of autoantibodies to aquaporin-4 (NMO), anti-double-stranded DNA antibodies (SLE) or anti-Ro/SS-A antibodies (Sjögren's syndrome).\nDifferential diagnosis\nThe differential diagnosis includes acute transverse myelopathy associated with fistulae, trauma, acute compressive lesions (such as metastases and epidural abscess) and infarction of the spinal cord.\nManagement and treatment\nTreatment approaches depend on the presence of an associated disease. Acute treatment may include corticosteroids and plasma exchange in steroid-resistant patients. The benefit of intravenous immunoglobulins and cyclophosphamide remains to be established. Long-term care includes symptomatic management, rehabilitative therapy, and, in case of SATM, long-term maintenance treatment to prevent relapses or disease progression.\nPrognosis\nThe prognosis is variable, unpredictable and depends on the response to treatment. SATM is often relapsing and prognosis depends on prevention of further episodes.\n\n                            Last update: \n                            June 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Anu JACOB  - Dr Alison L JONES"}
{"Disease Name": "Acute tricyclic antidepressant poisoning", "Disease Definition": "A rare, potentially lethal intoxication characterized by life-threatening arrhythmias (sinus tachycardias, premature ventricular contractions, ventricular arrhythmias), anticholinergic toxidrome (mydriasis, dry mucous membrane, tachycardia, hypertension), central nervous system toxicity (lethargy, coma, myoclonic jerks), refractory hypotension and sudden death.", "ORPHA ID": 43117, "Summary": ""}
{"Disease Name": "Acute undifferentiated leukemia", "Disease Definition": "A rare acute leukemia of ambiguous lineage characterized by clonal proliferation of primitive hematopoietic cells, primarily in the bone marrow and blood, lacking lineage-specific markers and detectable genotypic alterations. The patients present with leukocytosis, anemia, variable platelet count and a variety of nonspecific symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement (lymphadenopathy, splenomegaly, hepatomegaly).", "ORPHA ID": 98835, "Summary": ""}
{"Disease Name": "Acute zonal occult outer retinopathy", "Disease Definition": "A rare acquired retinal disorder characterised by sequential focal degeneration of photoreceptors, retinal pigment epithelium and choroid, with the majority of patients experiencing sudden onset photopsia and acute scotomas. Although patients typically retain decent visual acuity, blind spot enlargement and retinal pigment epithelial disturbances tend to develop over time. Individuals also often complain of distortion of central vision, photophobia and difficulty with night vision, with more advanced cases reporting loss of peripheral vision.", "ORPHA ID": 284454, "Summary": ""}
{"Disease Name": "Acyl-CoA dehydrogenase 9 deficiency", "Disease Definition": "A rare disorder characterized by neurological dysfunction, hepatic failure and cardiomyopathy due to a deficiency of complex I of the respiratory chain.", "ORPHA ID": 99901, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nPatients present predominantly with neurological, hepatic and /or cardiomyopathic disease with isolated NADH-CoQ reductase deficiency (see this term). Manifestations include failure to thrive, hypertrophic cardiomyopathy, exercise intolerance, liver disease and mild to severe neurological dysfunction.\nEtiology\nACAD9 deficiency is caused by a mutation in the  ACAD9 gene (3q21.3) that encodes the protein ACAD9. This protein has only relatively recently been described but is quite widely expressed in tissues and has activity as an acyl-CoA dehydrogenase with overlapping substrate specificity with very long-chain acyl-CoA dehydrogenase (VLCAD). It also acts an assembly factor for complex I of the respiratory chain and therefore has a vital role in the production of a functioning mitochondrial respiratory chain.\nGenetic counseling\nThe mode of inheritance is autosomal recessive and genetic counseling is possible.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Simon OLPIN"}
{"Disease Name": "ACys amyloidosis", "Disease Definition": "A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset of 20-30 years, major systemic amyloidosis and recurrent lobar intracerebral hemorrhages. Unlike other forms of hereditary cerebral hemorrhage with amyloidosis, this subtype is due to a mutation in the CST3 gene (20p11.2), encoding the precursor protein cystatin C.", "ORPHA ID": 100008, "Summary": ""}
{"Disease Name": "Adamantinoma", "Disease Definition": "A rare, primary low-grade malignant bone tumor that occurs in more than 80% of cases on the anterior surface of the tibia (tibial dyaphysis). Most cases are symptomatic or present with pain, swelling, bowing deformity or pathological fracture. Metastases especially in the lungs may be observed.", "ORPHA ID": 55881, "Summary": "Epidemiology\nAD represent between 0.1 and 0.5% of all primary malignant bone tumors. The life time prevalence in Europe is estimated to be 1/900,000. Males are more commonly affected and in the latter case the tumor is more aggressive.\nClinical description\nAD affects individuals over a wide age range (2-86 years), but 75% occurs in the mature skeleton within the second and third decades. AD has an insidious onset and the typical presentation is that of a slow growing and painless swelling on the anterior side of the tibia. Localized pain, pathological fracture and bone deformity are other features which lead the patient to seek medical attention. Most tumors are located in the middle third of the tibial anterior cortex but involvement of bones other than the tibia has been reported and includes the humerus (6 %), ulna (4 %), fibula (3 %), femur (3 %) and radius (1 %). In rare cases, the tumor can be located in the ribs, pelvis, spine, carpus and tarsus. Multiple locations or purely within the cortex may be observed.\nEtiology\nThe etiology of AD is unknown and to date, no known genetic mutations have been identified. A translocation t(7;13)(q32;q14) has been reported in a lung metastasis from an AD of the tibia in a boy. However, an identical translocation was found in his normal father.\nDiagnostic methods\nOn conventional radiography, early stage AD appears as a cortical lucency without a significant periosteal. Cortical thickening, although seen after fracture and presence of a soft tissue mass are rare findings. Detection of tumors at this stage is rare and usually fortuitous, with most patients being diagnosed in more advanced stages. The typical tumors are multiloculated cystic/sclerotic lesions with a characteristic `soap bubble like' appearance. In some cases, the cortex may eventually be disrupted and a soft-tissue component can be found. Lesions are mostly eccentric, expansile and cortically located. AD show low signal intensity on T-1 weighted MRI and high signal intensity on T-2 weighted images. In histopathological terms, AD is characterized by the presence of a variable proportion of epithelial cells within osteofibrous tissue that may be intermingled with each other in various proportions resulting in 2 differentiating patterns: osteofibrous dysplasia-like AD (with a predominance of the osteofibrous component) with intermediate malignancy potential; and classic AD with a predominance of the epithelial component and low grade malignancy.\nDifferential diagnosis\nThe main differential diagnosis for AD is fibrous dysplasia of bone but chondrosarcoma, langerhans cell histiocytosis, haemangioendothelioma (see these terms), fibroma (non-ossifying as well as ossifying), and bone cyst should also be excluded.\nManagement and treatment\nDefinitive cure can only be achieved after gross total resection with wide resection margins. Chemotherapy and radiotherapy do not play a role in the treatment of ADs. Long-term clinical and radiological monitoring is necessary because of the risk of local recurrence or metastasis, which can occur many years after the initial treatment.\nPrognosis\nIn general ADs have a good outcome. Complete remission can be achieved in around 70% of the cases. However, in 10-50% of cases, the disease may be fatal due to metastases (occuring most often in the lungs and in the lymph nodes, although metastases to liver, bone and brain have been reported). Mean survival of patients with metastatic disease is reported to be 12 years.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Pr M. [Mario] MAAS  - Pr R.R. [Rick] VAN RIJN"}
{"Disease Name": "Adams-Oliver syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by the combination of congenital distal limb reduction and scalp defects, often accompanied by skull ossification defects.", "ORPHA ID": 974, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nThe severity of the disorder varies greatly among affected individuals. Aplasia cutis congenita, transverse limb defects and cutis marmorata telangiectasia congenita are characteristic of this condition. The affected patients typically have malformations of the hands and/or feet that range from hypoplastic phalanges to absent fingers and/or toes. AOS may be associated with a variety of physical anomalies including congenital cataract, strabismus and microphthalmia, congenital heart malformations (including tetralogy of Fallot and pulmonary atresia), and hepatoportal sclerosis. Hydrocephalus is the principal cerebral feature and epilepsy may be associated. Extensive lethal anomalies are possible but very rare. Most frequent signs are vertex aplasia, distal limb reduction, intrauterine growth retardation, and neurodevelopmental delay. The penetrance of the disease seems decreased in AOS of autosomal recessive transmission, with intrafamilial variability, and rare patients may present without aplasia cutis congenita and/or limb reduction.\nEtiology\nThe etiopathogenesis remains unclear, but 2 pathways are implied: NOTCH pathway and RAC1/CDC42 pathway. To date, 6 genes have been described in Adams-Oliver syndrome: ARHGAP31 (autosomal dominant; AD), DLL4 (AD), RBPJ (AD), NOTCH1 (AD), EOGT (autosomal recessive; AR), and DOCK6 (AR). An important inter- and intra-familial variability in expression is described, and an incomplete penetrance. Surprisingly, the penetrance seems to be decreased for recessive transmission. There is no obvious phenotypic difference between those who have missense variations and those who have frameshift or stop-gain variations.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation, with the association of aplasia cutis congenita and distal limb reduction. It can be confirmed by genetic testing (genes panel, exome or genome sequencing).\nDifferential diagnosis\nThe principal differential diagnosis is the recently described FOSL2-related neurodevelopmental disorder with scalp and enamel defects (also presenting sometimes with distal limb reduction). Other genetic differential diagnoses present with scalp defects or distal limb reduction associated syndrome such as Poland sequence, SCALP syndrome, or aplasia cutis congenita (non-exhaustive list). This kind of distal limb defects can also be due to constriction rings of amniotic membranes.\nAntenatal diagnosis\nAntenatal diagnosis can be performed when ultrasounds reveal distal limb anomalies and/or vertex defects. When a pathogenic variant is identified in a family, antenatal diagnosis is possible depending on the severity of the malformations in the family. Antenatal testing is based on DNA analysis of amniocentesis and chorionic villus sampling and may be useful to confirm ultrasound and echocardiography findings in families with a known Adams Oliver syndrome variant.\nGenetic counseling\nOccurrence can be familial or sporadic. Transmission depends on the affected genes; most cases are transmitted as an autosomal dominant trait (ARHGAP31, DLL4, RBPJ, NOTCH1), but some show autosomal recessive transmission (EOGT and DOCK6). Genetic counseling should be offered to at-risk couples: when the transmission is autosomal recessive, there is a 25% risk of having an affected child at each pregnancy, whereas when the transmission is autosomal dominant, there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nLimb and scalp defects require orthopedic treatment. Management is multidisciplinary and includes geneticists, orthopedic surgeons and pediatric orthopedics, cardiologists, as well as social support networks.\nPrognosis\nLife expectancy mostly depends on the severity of the vertex aplasia and of the heart malformation(s). Functionality in everyday life depends on the type and severity of upper-limb anomalies, cerebral malformations, heart and kidney defects, and eyes anomalies.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Perrine BRUNELLE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "ADan amyloidosis", "Disease Definition": "A rare, neurodegenerative disease characterized by progressive cataracts, hearing loss, cerebellar ataxia, paranoid psychosis and dementia. Neuropathological features are diffuse atrophy of all parts of the brain, chronic diffuse encephalopathy and the presence of extremely thin and almost completely demyelinated cranial nerves.", "ORPHA ID": 97346, "Summary": ""}
{"Disease Name": "Addison disease", "Disease Definition": "A chronic and rare endocrine disorder due to autoimmune destruction of the adrenal cortex and resulting in a glucocorticoid and mineralocorticoid deficiency. Properly speaking, it designates autoimmune adrenalitis, but it is a term commonly used to describe any form of chronic primary adrenal insufficiency (CPAI).", "ORPHA ID": 85138, "Summary": "Epidemiology\nThe prevalence of AD is 1/9,000-1/6,900 in the developed countries.\nClinical description\nDisease onset peaks around 40 but it can occur at any age. It presents insidiously with nonspecific symptoms that can be mistaken for other more prevalent conditions. Common manifestations include fatigue, loss of energy, malaise, weight loss, nausea, anorexia (failure to thrive in children), muscle and joint pain. Pigmentation of skin and mucous membranes (darkening of the skin especially in the palmar creases, knuckles, scars, oral mucosa and sites of friction) is a cardinal sign of AD. Symptoms of postural hypotension and hypoglycemia are late manifestations. Patients may also crave salt. Vitiligo and alopecia areata are often present. AD also causes dehydroepiandrosterone deficiency causing additional symptoms seen only in women (loss of axillary/pubic hair, absence of pubarch in children, reduced libido and dry skin). Acute primary adrenal insufficiency (AAI; see this term), also called an adrenal crisis, can occur if treatment is not followed or during precipitating illnesses and is a life threatening medical emergency.\nEtiology\nAD results from autoimmune destruction of the adrenal cortex and can be isolated or seen as part of an autoimmune disorder (autoimmune polyendocrine syndrome type 1, 2 or 4, see these terms).\nDiagnostic methods\nBiochemical tests are needed to diagnose AD. Early morning serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels are measured. Plasma ACTH is much higher in individuals with AD (>22 pmol/L) and morning serum cortisol levels are usually low (<83nmol/L) but can fluctuate. A stimulation test observing the cortisol response to exogenous ACTH is a useful tool in confirming a diagnosis. In healthy subjects serum cortisol concentrations increase (>500 nmol/L) after exogenous ACTH administration but no increase is seen in AD patients. Raised plasma ACTH levels confirm AD diagnosis.\nDifferential diagnosis\nSecondary adrenal insufficiency needs to be eliminated. Causes include pituitary tumors, lymphatic hypophystitis, pituitary tuberculosis and sarcoidosis, all of which are differential diagnoses. Infiltrative disorders and other causes of CPAI should be excluded and include tuberculosis (see this term), fungal infections and AIDS-associated opportunistic infections. Genetic disorders, tumors, and treatment with certain drugs are other less common causes of CPAI.\nManagement and treatment\nManagement is life-long and requires a multidisciplinary team. Glucocorticoid replacement with oral hydrocortisone (10-25 mg daily taken in 2-3 doses) is given to mimic physiological cortisol secretion patterns. Oral fludrocortisone is given to replace mineralocorticoid hormones. Dehydroepiandrosterone replacement is optional. Glucocorticoid levels can be adjusted during times of stress to prevent AAI. The dose of hydrocortisone is maintained on the basis of clinical assessment and responses, taking into account a patient's well-being and presence of signs of over-replacement or under-replacement. An assessment of plasma renin activity is helpful in optimizing the dose of fludrocortisone. Growth and development in children must be monitored. Patients should carry a ready to inject hydrocortisone preparation and carry a medical alert card, in case of adrenal crisis.\nPrognosis\nThere is no cure for AD but with proper treatment and care taken to prevent AAI there is no decrease in life expectancy. AD is only life threatening when ignored.\n\n                            Last update: \n                            November 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Anne BACHELOT"}
{"Disease Name": "Adducted thumbs-arthrogryposis syndrome, Christian type", "Disease Definition": "A type of arthrogryposis characterized by congenital cleft palate, microcephaly, craniostenosis and arthrogryposis (limitation of extension of elbows, flexed adducted thumbs, camptodactyly and clubfeet). Additional features include facial dysmorphism ('myopathic' stiff face, antimongoloid slanting, external ophthalmoplegia, telecanthus, low-set large malrotated ears, open mouth, mierogenia and high arched palate). Velopharyngeal insufficiency with difficulties in swallowing, increased secretion of the nose and throat, prominent occiput, generalized muscular hypotonia with mild cyanosis and no spontaneous movements, seizures, torticollis, areflexia, intellectual disability, hypertrichosis of the lower extremities, and scleredema (in the first days of life; see this term) are also observed. The disease often leads to early death. Transmission is autosomal recessive. No new cases have been described since 1983.", "ORPHA ID": 2952, "Summary": ""}
{"Disease Name": "Adenine phosphoribosyltransferase deficiency", "Disease Definition": "A rare genetic nephropathy secondary to a disorder of purine metabolism characterized by the formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine, causing urolithiasis and crystalline nephropathy.", "ORPHA ID": 976, "Summary": "Epidemiology\nPrevalence is estimated at 1/50,000 to 1/100,000 in Caucasian, 1/27,000 in Japanese and > 1/15,000 in Icelandic populations. Adenine phosphoribosyltransferase deficiency (APRT) deficiency appears to equally affect children and adults, male or female. In Caucasian populations, heterozygous prevalence is estimated between 0.4% and 1.2%.\nClinical description\nClinical manifestations include symptoms usually associated with urolithiasis. Stones are typically radiolucent. Onset can be between infancy and the 4th decade of life, or sometimes even later. A small portion of patients remain asymptomatic. The disease can present not only as urolithiasis but also as crystalline nephropathy secondary to the precipitation of 2,8-DHA into renal parenchyma (DHA nephropathy). DHA nephropathy occurs most often in patients with repeated misdiagnosed episodes of urolithiasis and progressive worsening of renal function, but it may also present as acute renal failure. Rarely, DHA nephropathy may occur in patients who experienced only a few stone episodes. DHA nephropathy can evolve to end stage renal disease requiring dialysis and transplantation and can recur after transplantation causing rapid loss of graft function if left untreated.\nEtiology\nAPRT deficiency is an autosomal recessive (AR) disorder caused by mutations in the APRT gene (16q24) encoding the APRT enzyme catalyzing AMP synthesis from adenine and 5'-phosphoribosyl-1-pyrophosphate. Two types of APRT deficiencies have been described, according to APRT activity in vitro; type I characterized by a total lack of APRT activity, found primarily in Caucasians, and type II, found only in Japan, characterized by a 10-25% APRT activity. This in vitro distinction has no known clinical significance.\nDiagnostic methods\nLack of awareness of APRT deficiency often causes a significant delay between the onset of symptoms and a proper diagnosis. Diagnosis is primarily based on identifying 2,8-DHA by examination of crystals or stones. Crystalluria examination can be used for diagnosis. In DHA nephropathy patients, crystals may also be identified in renal biopsy, although this invasive test is theoretically unnecessary. Crystals and stones should be analyzed by morphologic examination combined with infrared spectrometry and/or x-ray crystallography. Diagnosis can be confirmed by enzyme activity analysis in erythrocyte lysates. Genetic testing may be used for diagnosis but may be useful for familial screening.\nDifferential diagnosis\nConfusion frequently occurs between 2,8-DHA and uric acid stones, which are typically both radiolucent. Contrary to uric acid, 2,8-DHA stones do not respond to alkali therapy. Differential diagnosis also includes other radiolucent stones, such as cystine, xanthine and drugs.\nGenetic counseling\nGenetic counseling is possible but rarely indicated. However, given the AR transmission, siblings of the affected individual, even if they are asymptomatic, should be screened through DNA analysis or APRT activity.\nManagement and treatment\nTo prevent further 2,8-DHA formation, treatment consists of allopurinol daily (usually 10mg/kg per day in children and 300 mg per day in adults) together with a high fluid intake and low purine diet. In cases of acute or chronic renal failure, allopurinol doses should be reduced. Asymptomatic individuals should be treated by allopurinol to prevent renal complications. Febuxostat, another xanthine oxydase inhibitor, may be even more efficacious than allopurinol in reducing DHA excretion. It remains unknown how this translates into improved patient outcomes. Febuxostat should be recommended in allopurinol-intolerant patients and also in rare patients who do not respond well to allopurinol.\nPrognosis\nEarly diagnosis is the key and prognosis depends on progression of this treatable disorder. Allopurinol therapy effectively prevents stone recurrence and can lead to an improvement or stabilization of renal function in most patients. Stone recurrence and renal complications are rare in patients who remain compliant with allopurinol therapy.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Guillaume BOLLEE"}
{"Disease Name": "Adenocarcinoma of the anal canal", "Disease Definition": "A very rare tumor of the intestine, originating from the epithelium of the anal canal (including the mucosal surface, anal glands, and lining of fistulous tracts), macroscopically appearing as a nodular, often ulcerated, invasive mass located in the anal canal. Patients often present with rectal bleeding, as well as difficulty and pain during defecation. Inguinal lymphadenopathy, if present, usually indicates metastatic spread.", "ORPHA ID": 424016, "Summary": ""}
{"Disease Name": "Adenocarcinoma of the esophagus", "Disease Definition": "Esophageal adenocarcinoma (EAC) is a sub-type of esophageal carcinoma (EC; see this term) affecting the glandular cells of the lower esophagus at the junction with the stomach.", "ORPHA ID": 99976, "Summary": "Epidemiology\nIt has an estimated annual incidence of 1/35,000.\nClinical description\nThe age of onset is between 50-60 years and it is more frequently seen in males. EAC is usually asymptomatic until an advanced disease stage with common presenting symptoms being dysphagia and unintentional weight loss. There is often a history of chronic gastroesophageal reflux disease (GERD). When symptoms are present it often has advanced locally and may have spread through the lining of the esophagus and involve lymph nodes or more distant sites.\nEtiology\nThe exact etiology is unknown. There is a strong association with GERD and obesity. There is no specific, known genetic link. The principal pathologic precursor is Barrett's esophagus (BE; see this term) which is characterized by metaplasia in the lining of the esophagus for variable distances above the stomach, and is identified through endoscopy and pathology. A high percentage of cases of EAC arise in a background of BE.\nDiagnostic methods\nEndoscopy and a biopsy establish the diagnosis. For staging, a computed tomography (CT) scan of the neck, chest and abdomen, or CT combined with a positron emission tomography (CT-PET) scan will identify the primary tumor in most cases as well as any spread to the lymph nodes and organs such as the liver, lungs and bone. Endoscopic ultrasound (EUS) is also increasingly used for staging, and is of particular value for early cancers. Laparoscopy is used in selected cases for further staging.\nDifferential diagnosis\nDifferential diagnoses include idiopathic achalasia, gastric cancer (see these terms) and a benign esophageal stricture.\nManagement and treatment\nTreatment may be with curative intent when the disease is confined to the esophagus and even when local nodes of the primary tumor are involved, and when the patient is fit enough for treatment. The mainstay of treatment of EAC is surgical resection, usually via a transthoracic resection, and occasionally a neck incision. In selected cases a transhiatal esophagectomy (without opening the chest) is performed. In patients diagnosed with early cancers, in particular patients undergoing surveillance for BE, the use of endoscopic surgery, often in combination with radiofrequency ablation (RFA), may supplant the need for open surgery. There is also an increasing use of chemotherapy or of the combination of chemotherapy and radiation therapy before and after surgery. A number of clinical trials support this practice, particularly where the tumor is locally advanced, and this is increasingly the standard of care in Europe and North America. The chemotherapeutic drugs most often used in combination are epirubicin, cisplatin and 5-fluorouracil (known as ECF). Capecitabine and oxaliplatin are less toxic agents that can be used in those with cardiac and renal problems. In patients who are unsuitable for approaches involving surgery, high-dose radiotherapy and chemotherapy is an increasingly used alternative. For palliative approaches, self-expanding metal stents (SEMS) can relieve dysphagia, and chemotherapy, radiation therapy and laser-based approaches are also considered.\nPrognosis\nAs diagnosis often occurs at an advanced disease stage, the prognosis is poor with the overall estimated 5-year survival rate of 10-20%. However, the cure rate is now approximately 40% for patients treated with curative intent, in part because of increased early diagnoses, and in part because of improved treatments.\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Claire DONOHOE  - Dr John REYNOLDS"}
{"Disease Name": "Adenocarcinoma of the gallbladder and extrahepatic biliary tract", "Disease Definition": "A rare epithelial carcinoma, arising either in the gallbladder itself or from the epithelium lining the extrahepatic biliary tree, cystic duct and/or peribiliary gland, characterized by nonspecific symptoms, such as abdominal pain, jaundice and vomiting and sometimes mimicking benign biliary diseases. Chronic biliary epithelial inflammation (e.g. primary sclerosing cholangitis, cholelithiasis, choledocholithiasis, liver fluke infestation) is a major risk factor.", "ORPHA ID": 424991, "Summary": ""}
{"Disease Name": "Adenocarcinoma of the liver and intrahepatic biliary tract", "Disease Definition": "A rare hepatic and biliary tract tumor characterized by a growth pattern ressembling that found in hepatocellular carcinomas and cholangiocarcinomas but presenting atypical histological and immunohistochemical features (such as trabecular, organoid, microcystic and/or blastemal-like architecture and inhibin A, cytokeratin 7 and/or cytokeratin 19 positivity) that do not allow a formal diagnosis of the more common aforementioned liver cancers. Patients may present abdominal distension and pain, a palpable abdominal mass and elevated liver enzymes.", "ORPHA ID": 424943, "Summary": ""}
{"Disease Name": "Adenocarcinoma of the penis", "Disease Definition": "An extremely rare penile epithelial neoplasm, histologically composed of nests of epithelilal cells floating in lakes of extracellular, PAS-positive mucin, clinically characterized by a nonhealing ulcer or soft mass in the preputium or glans area, with itching and burning often preceding appearance of the lesion. Lymphadenopathy may indicate dissemination. Mucinous metaplasia of the penis may be a risk factor.", "ORPHA ID": 398053, "Summary": ""}
{"Disease Name": "Adenocarcinoma of the small intestine", "Disease Definition": "Small bowel adenocarcinoma (SBA) is a rare small intestinal malignancy, most commonly located in the duodenum (55% of cases) but also rarely in the jejunum and ileum, which is usually discovered at an advanced stage in the 6th to 7th decade of life due to non-specific symptoms at presentation such as nausea, abdominal pain and weight loss. In some cases it is asymptomatic, and therefore usually has a poor prognosis.", "ORPHA ID": 104075, "Summary": ""}
{"Disease Name": "Adenohypophysitis", "Disease Definition": "A rare, acquired pituitary hormone deficiency, a type of primary hypophysitis characterized by an inflammation of anterior pituitary. Clinical presentation is variable and includes headaches, visual disturbances, symptoms of adrenal insufficiency, hyperprolactinemia, hypothyroidism and hypogonadism. It most commonly affects young women during pregnancy or postpartum period.", "ORPHA ID": 95512, "Summary": ""}
{"Disease Name": "Adenoid basal carcinoma of the cervix uteri", "Disease Definition": "A rare, slow-growing uterine cancer characterized, histologically, by small, well differentiated nests of basaloid cells resembling basal cell carcinoma of the skin, commonly associated with squamous cell carcinoma or squamous intraepithelial lesions. Patients are usually asymptomatic or present with dysfunctional vaginal bleeding, often with no observable lesion on the cervix. Infection with high-risk HPV-types (16 and 33) has been reported in some cases.", "ORPHA ID": 213828, "Summary": ""}
{"Disease Name": "Adenoid cystic carcinoma of the cervix uteri", "Disease Definition": "A rare, highly aggressive uterine cancer, macroscopically appearing as an irregular, slow-growing, non-friable, polypoid mass on the uterine cervix and histologically showing a pseudoglandular or cribriform growth pattern. It presents with vaginal bleeding and discharge and abdominal or pelvic pain. The tumor is highly infiltrative, often associated with vascular, lymphatic and perineural invasion, with subsequent haematogenous spread and early recurrence.", "ORPHA ID": 213823, "Summary": ""}
{"Disease Name": "Adenoma of pancreas", "Disease Definition": "A rare, benign tumor of the pancreas characterized by variable number and size of the cysts lined with glycogen rich epithelial cells. Clinical manifestation may include epigastric or abdominal pain, weight loss, diabetes, jaundice and palpable abdominal mass. Some patients have no symptoms and the tumor is discovered incidentally.", "ORPHA ID": 93292, "Summary": ""}
{"Disease Name": "Adenosarcoma of the cervix uteri", "Disease Definition": "A rare subtype of malignant mixed epithelial and mesenchymal tumor composed of benign or mildly atypical glandular elements and a surrounding low-grade malignant stroma, often containing heterologous elements, such as areas of sex-cord-like or smooth muscle differentiation. It usually presents with vaginal bleeding or discharge, lower abdominal pain and/or a cervical mass or polyp. The tumor may arise from pre-existing endometriosis and patients may have a history of recurrent cervical polyps.", "ORPHA ID": 213792, "Summary": ""}
{"Disease Name": "Adenosarcoma of the corpus uteri", "Disease Definition": "A rare subtype of mixed epithelial-mesenchymal tumor, often presenting as a large, exophytic polypoid lesion, which may extend through the cervix, composed of benign or atypical epithelium and low-grade malignant stroma. It usually presents with dysfunctional bleeding or vaginal discharge and less often abdominal pain. Association with long-term unopposed estrogen therapy, tamoxifen therapy and a history of pelvic radiation has been reported.", "ORPHA ID": 213600, "Summary": ""}
{"Disease Name": "Adenosine deaminase 2 deficiency", "Disease Definition": "Vasculitis due to ADA2 deficiency is a rare, genetic, systemic and rheumatologic disease due to adenosine deaminase-2 inactivating mutations, combining variable features of autoinflammation, vasculitis, and a mild immunodeficiency. Variable clinical presentation includes chronic or recurrent systemic inflammation with fever, livedo reticularis or racemosa, early-onset ischemic or hemorrhagic strokes, peripheral neuropathy, abdominal pain, hepatosplenomegaly, portal hypertension, cutaneous polyarteritis nodosa, variable cytopenia and immunoglobulin deficiency.", "ORPHA ID": 404553, "Summary": ""}
{"Disease Name": "Adenosine monophosphate deaminase deficiency", "Disease Definition": "A rare metabolic disorder for which two forms have been described. Lack of activity of the erythrocyte isoform of adenosine monophosphate (AMP) deaminase has been described in subjects with low plasma uric acid levels without obvious clinical relevance and will not be described further. Myoadenylate deaminase deficiency is an inherited disorder of muscular energy metabolism with a lack of AMP deaminase activity in skeletal muscle. It is characterised by exercise-induced muscle pain, cramps and/or early fatigue.", "ORPHA ID": 45, "Summary": "Epidemiology\nAbout 1-2% of the Caucasian population carries the genetic defect causing myoadenylate deaminase deficiency, but only a minority of carriers develop symptoms. The prevalence is unknown but several hundred patients with the disorder have been reported in case reports and patient series. Men and women are equally affected.\nClinical description\nThe vast majority of patients suffer from post-exercise symptoms: rapid fatigue, cramps or myalgias. Approximately equal proportions of the patients first develop symptoms during childhood, adolescence, or as young or older adults. After progression of the symptoms over the first few years, the clinical course usually stabilises. There is no evidence of muscular dystrophy or muscular wasting. The disorder exclusively affects skeletal muscle. Smooth muscle or other organs are not affected as the disorder is associated with a specific lack of skeletal muscle adenylate deaminase activity.\nEtiology\nThe vast majority of patients with this disease are homozygous for the nonsense C34-T mutation in the AMPD1 (adenosine monophosphate deaminase 1) gene. This mutation creates an early stop codon thus preventing the synthesis of an enzymatically active protein. The deficiency disrupts the purine nucleotide cycle, and thus muscle energy production. Surprisingly, however, asymptomatic AMP deaminase-deficient subjects have been reported, indicating that additional factors are likely to be involved in the development of myopathic symptoms.\nDiagnostic methods\nThe diagnosis is based on histochemical staining or biochemical analysis of a muscle biopsy showing a lack of muscle adenylate deaminase activity, or on molecular identification of the disease-causing mutation.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nUnfortunately, there is no medical cure for this disorder. Symptoms improve with administration of D-ribose. However, the effects of this sugar are only short-tem and it has no beneficial effect during subsequent days.\n\n                            Last update: \n                            February 2007"}
{"Disease Name": "Adenovirus infection in immunocompromised patients", "Disease Definition": "A rare viral disease characterized by invasive and/or disseminated adenovirus infection in immunocompromised patients, either acquired de novo or arising from reactivation of persistent latent infection. The clinical picture comprises a wide range of manifestations including pneumonia, colitis, hepatitis, hemorrhagic cystitis, tubulointerstitial nephritis, encephalitis, and disseminated disease, among others. Severity varies with age and immune status, and life-threatening courses may occur.", "ORPHA ID": 91127, "Summary": ""}
{"Disease Name": "Adenylosuccinate lyase deficiency", "Disease Definition": "A disorder of purine metabolism characterized by intellectual disability, psychomotor delay and/or regression, seizures, and autistic features.", "ORPHA ID": 46, "Summary": "Epidemiology\nThe prevalence and incidence of ADSL deficiency are unknown. More than 80 cases have been reported to date, mostly from Europe and the Mediterranean region. The disorder may be underdiagnosed as it is probably panethnic.\nClinical description\nADSL covers a continuous clinical spectrum with three major forms: fatal neonatal, severe (type I), and mild to moderate form (type II). Clinical variability is found, even in patients from the same family. Onset is generally between birth and early childhood. Cases ranging from fatal neonatal encephalopathy (presenting with hypokinesia, intractable seizures and respiratory failure) to mild intellectual disability have been reported. Intellectual disability is found in all patients, epilepsy of various types in most, and autistic features in about one third (failure to make eye contact, hypersensitivity to noise and light, repetitive behavior, agitation, temper tantrums, autoaggression and self-mutilation). Other less common manifestations include psychomotor delay, hyperactivity, speech impairment, muscular hypotonia, muscle wasting, and spasticity. Severely affected patients often have microcephaly. Prenatal manifestations are also reported: impaired intrauterine growth, microcephaly, fetal hypokinesia, and loss of fetal heart rate variability.\nEtiology\nADSL is a defect of purine metabolism affecting purinosome assembly and reducing metabolite fluxes through purine de novo synthesis and purine nucleotide recycling pathways. Biochemically, this defect manifests by the presence in the biologic fluids of two dephosphorylated substrates of ADSL enzyme: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). The underlying defect is associated with mutations in the ADSL gene (22q13.1). No strict genotype-phenotype correlations have been found.\nDiagnostic methods\nFinal diagnosis requires demonstration of succinylpurines in extracellular fluids such as plasma, cerebrospinal fluids (CSF) and/or urine using HPLC or HPLC-MS and/or genomic cDNA sequencing of the ADSL gene and characterization of mutant proteins. For selective screening, rapid methods are used (Bratton-Marshall or TLC). Reported findings on brain magnetic resonance imaging (MRI) include white matter anomalies, atrophy of the cerebral cortex, corpus callosum, cerebellar vermis, lack of myelination, delayed myelination, and lissencephaly (see this term).\nDifferential diagnosis\nThe differential diagnoses include neurological disorders with intractable seizures and encephalopathy, and other inborn errors of purine and pyrimidine metabolism with neurological manifestations.\nAntenatal diagnosis\nPrenatal diagnosis is possible when a disease-causing mutation has been identified in an affected family.\nGenetic counseling\nADSL deficiency follows an autosomal recessive pattern of inheritance.\nManagement and treatment\nThere is currently no effective treatment for ADSL deficiency. Treatment is primarily supportive, aimed at controlling seizures. The aim of treating epilepsy is to control or at least decrease seizure frequency with minimal side effects. Treatment with anticonvulsive drugs (e.g. valproic acid, phenobarbital, carbamazepine, topiramate, levetiracetam, phenitoin, clobazam) depends on the type of seizures. Patients often require polypharmacy with the use of two or more anticonvulsants. Drug resistance is common.\nPrognosis\nLife expectancy in ADSL deficiency is variable. Neonatal forms may lead to early death, whereas onset in early childhood usually entails a stable course.\n\n                            Last update: \n                            March 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Agnieszka JURECKA  - Pr Anna TYLKI-SZYMANSKA"}
{"Disease Name": "Adenylosuccinate synthetase-like 1-related distal myopathy", "Disease Definition": "A rare autosomal recessive distal myopathy characterized by slowly progressive diffuse muscle weakness in childhood, followed by predominantly distal muscle weakness in adolescence, and quadriceps muscle weakness in the fourth decade. Facial muscle weakness is commonly reported. Muscle biopsy shows fiber size variation, increased internal nuclei, fiber splitting, rimmed vacuoles, and focal endomysial fibrosis.", "ORPHA ID": 482601, "Summary": ""}
{"Disease Name": "Adiposis dolorosa", "Disease Definition": "A rare disorder of subcutaneous tissue characterized by the development of painful, adipose tissue with multiple subcutaneous lipomas, in association with overweight or obesity.", "ORPHA ID": 36397, "Summary": "Epidemiology\nPrevalence is unknown. It is 5-30 times more common in women.\nClinical description\nThe onset may be abrupt or indolent and most commonly occurs between 35 and 50 years of age. The main symptoms are obesity and painful adipose tissue. The most common locations for lipomas are the extremities, the trunk, the pelvic area, and the buttocks. The pain is often described as burning or aching but the pain experience varies between different individuals. A number of associate symptoms have been described. Some of them can be induced by obesity per se, such as weakness and susceptibility to fatigue. Others, such as depression and psychiatric manifestations, are common in all diseases involving pain. Therefore, such symptoms should not be seen as diagnostic for the disease. Other symptoms, such as easy bruisability, rapid heartbeat, shortness of breath, thyroid disease, diabetes and constipation have only been described in case reports and in a questionnaire study; however there is no evidence to support the association with adiposis dolorosa. Adiposis dolorosa can clinically be classified into: i) generalised diffuse form with diffusely widespread painful adipose tissue without clear lipomas ii) generalised nodular form with general pain in the adipose tissue as well as in and around lipomas iii) localised nodular form with pain in and around lipomas iv) juxta-articular form with solitary deposits of excess fat around one or several joints.\nEtiology\nThe etiology remains unknown but several hypotheses have been proposed including endocrine dysfunction, nervous system dysfunction, mechanical pressure on the nerves, adipose tissue dysfunction, inflammation, infection and induced by trauma or medications. Most of the hypotheses are based on case reports and there is no convincing evidence for any of the etiologies.\nDiagnostic methods\nThe basic diagnostic criteria for adiposis dolorosa are i) generalised overweight or obesity and ii) chronic pain (for greater than 3 months) in the adipose tissue. The diagnosis should be based on systemic physical examination and thorough exclusion of differential diagnoses. There are no laboratory markers for the disease. The pathohistological picture of adipose biopsies is generally indistinguishable from that of lipomas. Radiological findings overlap with other lipodystrophies, although lymphovascular anomalies and MRI patterns with fatty lesions in the subcutaneous fat have been described in single cases. Laboratory tests, biopsies, and radiology can be useful to exclude differential diagnoses.\nDifferential diagnosis\nIn cases of general diffuse forms of adiposis dolorosa, the differential diagnosis should include other conditions with general pain, such as fibromyalgia, lipoedema, panniculitits, endocrine disorders comprising pain and obesity, and psychiatric conditions comprising pain, especially in combination with obesity. In nodular forms of adiposis dolorosa, the differential diagnosis should include other multiple lipoma syndromes such as familial multiple lipomatosis, multiple symmetric lipomatosis, myoclonic epilepsy with red ragged fibres (MERRF) syndrome, neurofibromatosis type 1, and multiple endocrine neoplasia type 1 (MEN1). In case of single lesions, adipose tissue tumors, such as sarcoma, have to be excluded.\nGenetic counseling\nThe majority of reported cases are sporadic. Autosomal dominant inheritance has been suggested in several case reports; however, there are no described mutations.\nManagement and treatment\nTreatment is symptomatic. Few convincing larger studies have been conducted. Methods that have been described for pain relief include liposuction or surgical resection of lipomas and traditional analgesics (NSAIDs). The following treatments have only been described in case reports or case series: lidocaine, corticosteroids, combinations of mexiletine and amitriptyline, or infliximab, calcium-channel modulators, D-thyroxine interferon alfa-2b, methotrexate, metformin, deoxycholic acid, rapid cycling hypobaric pressure, and transcutaneous electrical stimulations. Only one case of treatment with bariatric surgery in adiposis dolorosa has been described. There are no studies on the effect of weight loss in adiposis dolorosa.\nPrognosis\nThe disease course is chronic. Case reports have suggested that pain increases with time. A study with a five-year follow-up has suggested that the average pain is relatively constant over time.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Håkan BRORSON  - Pr Emma HANSSON"}
{"Disease Name": "ADNP syndrome", "Disease Definition": "A rare syndromic intellectual disability characterized by global developmental delay, gastrointestinal problems, hypotonia, delayed speech, behavioral and sleep problems, pain insensitivity, seizures, structural brain anomalies, dysmorphic features, visual problems, early tooth eruption and autistic features.", "ORPHA ID": 404448, "Summary": "Epidemiology\nThe point prevalence of ADNP syndrome is approximately 1-2/100,000 individuals. The syndrome represents 0.17% of the autism spectrum disorder cases.\nClinical description\nThe ADNP syndrome phenotype includes intellectual disability (ID) of various severities, severely delayed speech including oral apraxia, behavioral problems (anxiety, obsessive compulsive disorder, aggressive behavior, temper tantrums, attention deficit hyperactivity disorder), motor development delays of various severities. ADNP patients have higher rates of ID but less severe social affect symptoms and high levels of stereotyped motor behaviors compared to high levels of restricted interests in idiopathic ASD. Other ADNP symptoms may include delayed toilet training, pain insensitivity, sleep problems, seizures, structural brain anomalies, distinct dysmorphic facial features, sensory problems including mostly visual problems, occasional hearing problems, autistic traits and hypotonia or in rare cases, hypertonia. Gastrointestinal problems are most frequently encountered. Congenital heart defects, short stature, skin cell deficiencies and hormonal deficiencies/abnormalities as well as recurrent infections are also apparent. About 80% of the children harboring ADNP mutations show early deciduous dentation.\nEtiology\nA single de novo ADNP mutation presumably occurs during the formation of the sperm/egg or during early embryonic development. The condition occurs in families with no history of the disease. Most frequent ADNP protein coding mutations include STOP or frameshift-STOP autosomal dominant mutations.\nDiagnostic methods\nWhole exome sequencing, or specific ADNP gene sequencing for mutation. Early deciduous tooth eruption (almost fully erupted dentition by 1 year of age).\nDifferential diagnosis\nSome similarities are found with Okihiro syndrome plus developmental delay, Angelman syndrome, Rett syndrome, Noonan syndrome, Kleefstra syndrome, Smith-Magenis syndrome, and other Coffin-Siris syndrome related disorders.\nAntenatal diagnosis\nPrenatal testing and preimplantation genetic diagnosis (PGD) are possible options.\nGenetic counseling\nThe ADNP syndrome is expressed in an autosomal dominant manner. Given that affected individuals were reported to have the disorder as a result of a de novo ADNP pathogenic variant, the risk to other family members is presumed to be low. C-terminal mutations were reported to be inherited, the severity of these mutations (if any) is yet to be explored.\nManagement and treatment\nRoutine symptomatic care by primary care professionals is recommended and includes: speech, occupational, and physical therapy, specialized individualized learning programs, treatment of neuropsychiatric features including sleep disorders, behavioral problems, and/or seizures. Nutritional/hormonal support, routine treatment of cardiac, ophthalmologic and auditory findings are also recommended.\nPrognosis\nWith developmental delays, it is expected that children with ADNP syndrome will start walking and talking relatively late. Depending on the precise ADNP mutation, independent walking can be established at 3.5 years of age or later. Speech may be acquired even later. However, in longitudinal observations, progress is noticed over the years. To date, there is only a paucity of adults that are known to have the ADNP syndrome.\n\n                            Last update: \n                            January 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Illana GOZES  - Pr Frank KOOY"}
{"Disease Name": "Adrenocortical carcinoma with pure aldosterone hypersecretion", "Disease Definition": "A very rare surgically-correctable form of primary aldosteronism (PA) due to an aldosterone-secreting adrenal malignancy.", "ORPHA ID": 231625, "Summary": "Epidemiology\nThe prevalence of adrenocortical carcinoma with pure aldosterone hypersecretion is unknown.\nClinical description\nPure APAC is characterized by renin suppression, unilateral aldosterone hypersecretion and moderate to severe hypertension that may be associated with hypokalemia, and the presence of a large adrenal tumor. Hypokalemia may be symptomatic and present as muscular weakness, cramps, paresthesia or palpitations with or without atrial fibrillation.\nEtiology\nEtiology is unknown.\nDiagnostic methods\nThe diagnosis of carcinoma is suggested by CT scan, showing a tumor exceeding 4 cm in diameter, and possible metastases and/or invasion of the inferior vena cava.\nManagement and treatment\nOpen laparotomy enables resection of the tumor and possible metastases or adjacent organs. Unless unresectable tumor or metastases are present, adrenalectomy abolishes aldosterone hypersecretion and hypokalemia in most patients. Adjuvant mitotane therapy may be indicated based on tumor scoring using the Weiss score or ENS@T score.\nPrognosis\nThe prognosis of pure APAC is the same as for others adrenocortical carcinomas: 5-year survival is 15% in patients with metastatic adrenocortical carcinomas.\n\n                            Last update: \n                            July 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence AMAR  - Pr Pierre-François PLOUIN  - Dr Olivier STEICHEN"}
{"Disease Name": "Adrenocortical carcinoma", "Disease Definition": "A rare cancer that arises from the adrenal cortex.", "ORPHA ID": 1501, "Summary": "Epidemiology\nIt represents 0.2% of childhood malignancies and has an international incidence of 1 in 2,000,000. It is more frequent in girls than in boys (ratio 1.5:1).\nClinical description\nAdrenocortical carcinoma (ACC) occurs in childhood with a peak incidence at 3.5 years of age. Most ACCs in children and adolescents are hormone-secreting and the clinical presentation reflects the pattern of adrenocortical hormones secreted by the tumor. Signs and symptoms of virilisation are present in over 90% of cases, hypertension may also be present. Hirsutism, acne and deepening of the voice may be apparent in both sexes. Girls may also present with cliteromegaly and facial hair, while boys present with phallomegaly and early virilisation. Cushing's syndrome (see this term) occurs in a third of cases with the most common signs being a moon-like facies, centripetal fat distribution and plethora. There is an increased incidence of ACC in patients with isolated hemihypertrophy, Wiedemann-Beckwith syndrome, congenital adrenal hyperplasia (CAH) and Li-Fraumeni syndrome (LFS) (see these terms).\nDiagnostic methods\nDiagnosis is based on the results of urine and blood tests, dexamethasone suppression tests, abdominal ultrasound, CT and MRI scans.\nDifferential diagnosis\nDifferential diagnosis should include phaeochromocytoma and neuroblastoma (see these terms).\nGenetic counseling\nAt least 50 % of ACCs have an inherited basis and hence referral to a cancer genetics service is recommended.\nManagement and treatment\nComplete, radical surgical resection is the treatment of choice and may be curative, especially for small tumors. In patients with incomplete resection or metastatic spread, treatment options include chemotherapy and/or mitotane, which obtained EU marketing authorisation in 2004 as an Orphan drug for symptomatic treatment of advanced (unresectable, metastatic or relapsed) ACC.\nPrognosis\nACC has a poor prognosis (5-year actuarial survival is 36%) except in case of small tumours that are completely resected.\n\n                            Last update: \n                            June 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Bernadette BRENNAN"}
{"Disease Name": "Adrenomyeloneuropathy", "Disease Definition": "A form of the peroxisomal disease X-linked adrenoleukodystrophy, characterized by progressive myelopathy and peripheral neuropathy, and often associated with peripheral adrenal insufficiency in males. Onset is typically in adulthood.", "ORPHA ID": 139399, "Summary": ""}
{"Disease Name": "Adrenomyodystrophy", "Disease Definition": "An extremely rare genetic endocrine disease characterized by primary adrenal insufficiency, dystrophic myopathy, hepatic steatosis, severe psychomotor delay, megalocornea, failure to thrive, chronic constipation, and terminal bladder ectasia which can lead to death. There have been no further descriptions in the literature since 1982.", "ORPHA ID": 977, "Summary": ""}
{"Disease Name": "Adult acute respiratory distress syndrome", "Disease Definition": "A very severe form of acute pulmonary failure secondary to capillary permeability impairment. The symptoms include dyspnea, hypotension and multivisceral failure. The disease is characterized by bilateral pulmonary infiltrates and severe hypoxemia due to increased alveolar-capillary permeability. The severity depends on the degree of alveolar epithelial injury, with a mortality rate of 30-50%.", "ORPHA ID": 70578, "Summary": ""}
{"Disease Name": "Adult familial nephronophthisis-spastic quadriparesia syndrome", "Disease Definition": "A rare, genetic, renal disease characterized by the association of familial adult medullary cystic disease with spastic quadriparesis. There have been no further descriptions in the literature since 1990.", "ORPHA ID": 2666, "Summary": ""}
{"Disease Name": "Adult hepatocellular carcinoma", "Disease Definition": "A rare carcinoma of the liver characterized by one to several or many nodules occurring anywhere within the liver, composed of neoplastic epithelial cells with hepatocellular differentiation. The vast majority of tumors are associated with chronic liver disease (such as hepatitis B or C, or steatohepatitis) or exposure to a variety of exogenous agents. Patients may present with signs and symptoms related to the tumor, as well as to the underlying condition. Common manifestations include right upper quadrant abdominal pain, weight loss, hepatosplenomegaly, jaundice, and ascites. Symptomatic tumors generally have poor prognosis.", "ORPHA ID": 210159, "Summary": ""}
{"Disease Name": "Adult hypophosphatasia", "Disease Definition": "A moderate form of hypophosphatasia (HPP) characterized by adult onset osteomalacia, chondrocalcinosis, osteoarthropathy, stress fractures and dental anomalies.", "ORPHA ID": 247676, "Summary": "Epidemiology\nThe prevalence of adult hypophosphatasia is not known. However the prevalence of moderate HPP (childhood, adult and odontoHPP) cases taken together has been estimated at 1/6300.\nClinical description\nAdult HPP is clinically very heterogeneous. In its mildest form it is the least severe form of hypophosphatasia (HPP), characterized by non-specific symptoms in later age, such as osteoporosis, musculoskeletal pain, chondrocalcinosis. Most patients present features during middle age but some may have had a history of mild rickets or other musculoskeletal manifestations in childhood. Cardinal features include stress fractures and pseudo-fractures of the lower limbs, along with foot, thigh, and hip pain. The most common fracture types are metatarsal and tibial and femoral pseudofractures. Osteomalacia, chondrocalcinosis, and osteoarthropathy may develop with age. Some patients report history of early loss of primary dentition. Loss of permanent dentition is also common and some cases of enamel hypoplasia and tooth mobility are described. Patients with the adult form of HPP may have had some manifestations in early life between the prenatal period and childhood (prenatal benign HPP or childhood HPP). The presence of bone symptoms (osteomalacia, fractures) distinguish adult HPP from odontohypophosphatasia.\nEtiology\nMutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia.\nDiagnostic methods\nDiagnosis is based on clinical presentation, alkaline phosphatase assay and confirmed by genetic testing.\nDifferential diagnosis\nThe main differential diagnosis is osteogenesis imperfecta.\nGenetic counseling\nInheritance may be autosomal recessive (rare) or autosomal dominant (the vast majority of cases).\nManagement and treatment\nManagement is typically supportive.\nPrognosis\nOverall prognosis is typically good, although affected individuals may experience some physical limitations depending on the extent and progression of the disease.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Severine BACROT  - Dr Etienne MORNET"}
{"Disease Name": "Adult idiopathic neutropenia", "Disease Definition": "A rare acquired immunodeficiency disease characterized by adult-onset absolute neutrophil counts less than 1.5 x 10^9/L on at least 3 occasions in a 3 month period that cannot be attributable to drugs or a specific genetic, infectious, inflammatory, autoimmune or malignant cause. Recurrent aphtous stomatitis and a history of mild bacterial infections are typically associated. A benign outcome with a low rate of severe infections and no secondary malignancies is observed.", "ORPHA ID": 2688, "Summary": ""}
{"Disease Name": "Adult intestinal botulism", "Disease Definition": "A very rare form of botulism, a rare acquired neuromuscular junction disease with descending flaccid paralysis caused by botulinum neurotoxins (BoNTs), and is due to intestinal colonization by Clostridium botulinum leading to toxin-mediated infection with toxemia.", "ORPHA ID": 178487, "Summary": "Epidemiology\nExact prevalence is unknown. To date, about 20 cases have been reported.\nClinical description\nThe disease affects adults and older children. Clinical manifestations are similar to other forms of botulism (flaccid and symmetrical cranial nerve palsy, followed by symmetrical flaccid descending motor paralysis). Compared to foodborne botulism (see this term), the onset is generally gradual and less dramatic. In some cases, diarrhea due to C. difficile co-infection has been reported.\nEtiology\nThe disease results from prolonged intestinal absorption of small quantities of BoNTs produced in situ by C. botulinum type A and B, or rarely by C.botulinum type C (one case) or by neurotoxigenic strains of C. baratiitype F or C. butyricum type E, that can temporarily colonize the intestinal tract. Colonization is generally associated with anatomical abnormalities of the gastrointestinal tract or alteration of protective endogenous microflora by broad-spectrum antibiotics following inflammatory intestinal disease or surgery. Some patients who underwent laparotomy for suspected appendicitis have shown worsening paralysis probably due to the post-surgical antibiotic therapy. Presence of Meckel's diverticulum may be a predisposing factor for intestinal colonization by C. butyricum.\nDiagnostic methods\nDiagnosis is based on clinical presentation. Confirmation of adult intestinal botulism is based on the detection of BoNTs in serum and stools. In addition, stools can be screened for BoNT-producing Clostridia. Diagnosis is also performed by demonstration of prolonged excretion of microorganisms and toxin in the stool in patients with sporadic botulism and no known contaminated food or wound.\nDifferential diagnosis\nDifferential diagnosis includes myasthenia gravis, Guillain-Barré syndrome (Miller Fisher syndrome), Lambert-Eaton syndrome and foodborne and wound botulism (see these terms).\nManagement and treatment\nThe antitoxin therapy must be associated with supportive care in an intensive care unit (ICU). Equine antitoxin treatment for adults has a half-life of 5-8 days. In Europe, the formulation currently available for adults is trivalent (anti A, B, E). A heptavalent (anti A to G) product is also available. In the USA, a bivalent (anti A, B) and a monovalent (anti E) antitoxin are available. Antibiotic therapy is ineffective on the toxin action and can exacerbate the neuromuscular blockade, but it is useful when secondary infections are present. In the severe forms, respiratory failure and paralysis may require ventilation for weeks as well as intensive care.\nPrognosis\nWhen treatment is administered early and with appropriate intensive care, the prognosis is generally good, no long-term side effects have been observed, and death resulting from respiratory failure is extremely rare. Complications can occur during hospitalization including nosocomial adverse events.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Lucia FENICIA"}
{"Disease Name": "Adult polyglucosan body disease", "Disease Definition": "A glycogen storage disease of adults characterized by progressive upper and lower motor neuron dysfunction, progressive neurogenic bladder and cognitive difficulties that can lead to dementia.", "ORPHA ID": 206583, "Summary": "Epidemiology\nThe prevalence is unknown. More than 50 cases have been described to date in Ashkenazi (in most cases) and non-Ashkenazi Jewish individuals.\nClinical description\nAPBD presents after the age of 40, with urinary incontinence (indicative of neurogenic bladder) often being the first manifestation. Progressive spasticity and weakness are also present due to upper and lower motor neuron involvement and patients have difficulty walking. Severity of gait difficulties varies between patients with some requiring a wheelchair at an advanced disease stage. Sensory loss in the distal lower extremities occurs in most individuals and can lead to foot injuries. Cognitive difficulties (such as problems with executive functioning) can be mild but in some cases can lead to dementia.\nEtiology\nAPBD is caused by a mutation in the GBE1 gene, encoding the glucan (1, 4-alpha-) branching enzyme 1 (GBE). Without this enzyme, glycogen is not synthesized properly, regulation of glycogen synthase is dysfunctional and deposition of amylopectin-like polyglucosan bodies in neural tissue occurs. Other mutations in this gene are responsible for a more severe and earlier onset form of the disease known as glycogen storage disease type IV (see this term).\nDiagnostic methods\nDiagnosis is based on the presence of clinical manifestations of the disease along with the characteristic laboratory findings. Typically, magnetic resonance imaging (MRI) demonstrates cerebral white matter changes in the subcortical and periventricular areas, the posterior limb of the internal capsule and in the brainstem. Cerebral, cerebellar and spinal cord atrophy may also be seen at various stages of the disease. Reduced GBE activity is observed in cultured skin fibroblasts and peripheral blood lymphocytes of patients with APBD and sural nerve biopsy shows the presence of polyglucosan bodies in the nerve. Genetic testing is essential for the diagnosis and makes nerve biopsy unnecessary.\nDifferential diagnosis\nThe motor neuron dysfunction seen in APBD may be similar to that seen in amyotrophic lateral sclerosis (see this term). Primary urologic dysfunction, multiple sclerosis and Alzheimer's disease should also be considered, as well as other causes of adult onset myeloneuropathy and leukoencephalopathy.\nAntenatal diagnosis\nAntenatal diagnosis can be performed but is rarely done as the disease has an adult onset.\nGenetic counseling\nAPBD is inherited autosomal recessively and genetic counseling can be given to those with the GBE1 gene mutations in the family. Pre-symptomatic testing can be performed if considered essential for genetic counseling.\nManagement and treatment\nTreatment requires a multidisciplinary team including specialists in physical medicine rehabilitation, psychology and urology. Urologic management may require antispasmodic bladder medications as well as an indwelling or an in-and-out bladder catheter. Ambulation aids such as canes, walkers and wheelchairs may be needed depending on the severity of gait dysfunction in order to move around safely. A neuropsychometric analysis can identify any cognitive impairment and appropriate cognitive aids and behavioural modification can be given. Follow up is needed to monitor bladder function and prevent urosepsis as well as assess levels of cognition, sensation in the distal lower extremities and gait function. Triheptanoin diet therapy is another possible treatment but, as of yet, the clinical benefits observed have been limited.\nPrognosis\nThe prognosis is variable depending on the severity of the disease and the level of care given to patients. In most cases it does not decrease life-expectancy but quality of life is most definitely affected.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Alexander LOSSOS"}
{"Disease Name": "ADULT syndrome", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by ectrodactyly, syndactyly, mammary hypoplasia, and excessive freckling as well as other typical ectodermal defects such as hypodontia, lacrimal duct anomalies, hypotrichosis, and onychodysplasia.", "ORPHA ID": 978, "Summary": ""}
{"Disease Name": "Adult T-cell leukemia/lymphoma", "Disease Definition": "A rare, virus associated tumor due to human T-cell leukemia virus type 1 or human T-cell lymphotropic virus type 1 (HTLV-1) and is characterized by the presence of anti-HTLV-1 antibodies, and malignant, mature, medium-sized T cells with condensed chromatin and polylobated nuclei. The malignant cells exhibit a mature CD4+ T cells phenotype and express CD2, CD5, CD25, CD45RO, HLA-DR, and T-cell receptor αβ. Presentation is heterogeneous and is typically of aggressive leukemia or lymphoma, variable skin eruptions, and visceral organ involvement.", "ORPHA ID": 86875, "Summary": ""}
{"Disease Name": "Adult-onset autosomal dominant leukodystrophy", "Disease Definition": "A rare, slowly progressive neurological disorder involving central nervous system demyelination, leading to autonomic dysfunction, ataxia and mild cognitive impairment.", "ORPHA ID": 99027, "Summary": "Epidemiology\nMore than 20 families in different ethnic groups have been reported to date. Exact prevalence and incidence data are however lacking.\nClinical description\nUnlike most forms of leukodystrophy which appear in childhood, ADLD occurs in the 4th to 6th decade of life. ADLD may clinically resemble multiple sclerosis in the initial phase. In most patients, the initial manifestation of the disease is autonomic dysfunction resulting in micturition urgency, bladder retention, constipation, postural hypotension and erectile dysfunction in affected males. Decreased sweating is reported in some cases. Some patients develop autonomic dysfunction later in the disease course. The other features are cerebellar dysfunction (gait ataxia, nystagmus, dysmetria, loss of fine motor control, and action tremors), pyramidal signs (spasticity, weakness of both upper and lower extremities, hyperreflexia), and cognitive impairment possibly with personality changes. These manifestations may not develop for years following initial presentation. Neuroradiological characteristics include extensive symmetrical white matter changes, corpus callosum atrophy, and brain stem and spinal cord atrophy. The disease follows a slow progressive course with an eventual loss of walking ability and slightly shortened lifespan.\nEtiology\nADLD is caused by chromosomal rearrangements with duplications of the LMNB1 gene (5q23.2) or a ''position effect'' due to a genomic deletion upstream of the gene causing its upregulation. Overexpression of LMNB1 causes myelin disruption in the central nervous system for which the precise underlying pathogenic mechanisms have not been elucidated. Alteration of splicing patterns suggests that ADLD is a spliceopathy.\nGenetic counseling\nGenetic counseling should be provided to affected families indicating the autosomal dominant pattern of inheritance.\n\n                            Last update: \n                            July 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Alfredo BRUSCO"}
{"Disease Name": "Adult-onset autosomal recessive cerebellar ataxia", "Disease Definition": "A rare, genetic, autosomal recessive cerebellar ataxia disease characterized by adulthood-onset of slowly progressive spinocerebellar ataxia, manifesting with gait and appendicular ataxia, dysarthria, ocular movement anomalies (e.g. horizontal, vertical, and/or downbeat nystagmus, hypermetric saccades), increased deep tendon reflexes and progressive cognitive decline. Additional variable features may include proximal leg muscle wasting and fasciculations, pes cavus, inspiratory stridor, epilepsy, retinal degeneration and cataracts. Brain imaging reveals marked cerebellar atrophy and electromyography shows evidence of lower motor neuron involvement.", "ORPHA ID": 284289, "Summary": ""}
{"Disease Name": "Adult-onset autosomal recessive sideroblastic anemia", "Disease Definition": "A very rare non-syndromic autosomal recessive pyridoxine-refractory sideroblastic anemia due to a splice defect of glutaredoxin-5 (GLRX5) described in a single patient with adult onset microcytic hypochromic anemia with liver iron overload and type 2 diabetes.", "ORPHA ID": 255132, "Summary": ""}
{"Disease Name": "Adult-onset cervical dystonia, DYT23 type", "Disease Definition": "A rare, genetic, isolated dystonia characterized by adult-onset, non-progressive, focal cervical dystonia typically manifesting with torticollis and occasionally accompanied by mild head tremor and essential-type limb tremor.", "ORPHA ID": 420492, "Summary": ""}
{"Disease Name": "Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy", "Disease Definition": "A rare mitochondrial disease characterized by adult onset of progressive external ophthalmoplegia, exercise intolerance, muscle weakness, manifestations of spinocerebellar ataxia (e.g. impaired gait, dysarthria) and mild motor peripheral neuropathy. Respiratory insufficiency has been reported in some cases.", "ORPHA ID": 329336, "Summary": ""}
{"Disease Name": "Adult-onset distal myopathy due to VCP mutation", "Disease Definition": "A rare, genetic distal myopathy disorder characterized by middle age-onset of distal leg muscle weakness, atrophy in the anterior compartment resulting in foot drop, without proximal or scapular skeletal muscle weakness. Rapidly progressive dementia, Paget disease of bone and hand weakness have been reported. Muscle biopsy shows pronounced myopathic changes with rimmed vacuoles.", "ORPHA ID": 329478, "Summary": ""}
{"Disease Name": "Adult-onset dystonia-parkinsonism", "Disease Definition": "A rare neurodegenerative disease usually presenting before the age of 30 and which is characterized by dystonia, L-dopa-responsive parkinsonism, pyramidal signs and rapid cognitive decline.", "ORPHA ID": 199351, "Summary": "Epidemiology\nPrevalence is unknown. Only 14 cases have been reported to date.\nClinical description\nDisease onset occurs in late adolescence or early adulthood (usually before the age of 30) and usually presents with parkinsonism (tremor, rigidity, bradykinesia), dystonia and rapid cognitive decline. Eye movement abnormalities (supranuclear vertical gaze palsy, eyelid opening apraxia), pyramidal tract signs, and psychiatric features such as depression and personality changes have also been reported in some patients. Dopaminergic treatment is initially successful with regard to parkinsonism, but the development of prominent dyskinesias often follows.\nEtiology\nAdult-onset dystonia-parkinsonism is caused by mutations in the phospholipase A2, group VI (PLA2G6) gene located on chromosome 22q13.1.\nGenetic counseling\nAdult-onset dystonia-parkinsonism is inherited in an autosomal recessive manner, and genetic counseling is possible and recommended.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "Adult-onset foveomacular vitelliform dystrophy", "Disease Definition": "A rare, genetic, macular dystrophy characterized by blurred vision, metamorphopsia and mild visual impairment secondary to a slightly elevated, yellow, egg yolk-like lesion located in the foveal or parafoveal region.", "ORPHA ID": 99000, "Summary": "Epidemiology\nThe prevalence of AOFVD is unknown.\nClinical description\nThe clinical onset is typically between the fourth and sixth decade of life. In the early stages of AOFVD, patients are visually asymptomatic or have mild complaints of scotoma, visual blur or metamorphopsia in one or both eyes. The visual acuity usually ranges from 20/50 to 20/25. As the disease progresses, vision loss may become more severe. Choroidal neovascularization (CNV) or central retinal pigment epithelium (RPE) atrophy may result. Color vision has been reported to be slightly impaired (tritan defect).\nEtiology\nThe mechanism underlying the physiopathology of AOFVD is still unknown but it has been postulated that there is an abnormal accumulation of lipofuscin that may be caused by the increased workload of metabolism and phagocytosis on the RPE cells in conjunction with other disease-related factors (such as age, genetic predisposition, and environmental causes). As a result, the RPE layer is separated from the photoreceptor layer by hyper-reflective material. Mutations in the genes BEST1 (11q12), PRPH2 (6p21.1) or IMPG1 (6q14.2-q15) (encoding bestrophin-1, peripherin and SPACR respectively) have been found in some individuals with AOFVD.D.\nDiagnostic methods\nDiagnosis of AOFVD relies on complete ophthalmologic examination, including measurement of best-corrected visual acuity (values range between 20/20-20/100), fundus biomicroscopy, fundus autofluorescence (FAF) imaging, and fluorescein angiography of optical coherent tomography when choroidal neovascularization is suspected. The minimal criteria for AOFVD diagnosis is the presence of a macular round, yellowish, more or less homogeneous lesion with fundus examination, showing hyper-autofluorescence. Electrooculogram (EOG) and electroretinogram (ERG) show normal or subnormal results (normal Arden ratio). Optical coherence tomography (OCT) reveals a vitelliform lesion located at the level of RPE or between the RPE and photoreceptors. This technique is extremely helpful in differentiating AOFVD from age-related macular degeneration (AMD; see this term).\nDifferential diagnosis\nThe differential diagnosis of AOFVD includes Best vitelliform macular dystrophy, Stargardt disease, central areolar choroidal dystrophy, central serous retinopathy (CSR), pigmented epithelial detachment (PED), basal laminar drusen, acute exudative polymorphous vitelliform maculopathy (AEPVM) (see these terms) and occult CNV secondary to AMD.\nGenetic counseling\nAn autosomal dominant inheritance with variable expression and incomplete penetrance is suggested but AOFVD can also be sporadic without evidence of a familial inheritance pattern.\nManagement and treatment\nThere is no effective therapy for AOVFD and patients should be managed with a comprehensive eye examination, including dilation, once or twice a year to rule out any possible complications, such as CNV, full-thickness macular holes, or retinal detachments. If vision is impaired, patients should be referred for low vision testing and rehabilitation. Ranibizumab intravitreal injections may be effective in the short-term.\nPrognosis\nThe visual prognosis of AOVFD is relatively good because the disease typically causes slow progressive vision loss, and most patients maintain decent vision in at least one eye until very late in the disease evolution. The vitelliform lesion typically disappears later in life; however, vision loss, development of a full-thickness macular hole or a retinal detachment in the late atrophic stages of the disease may be observed.\n\n                            Last update: \n                            December 2013\n\n\n                            - Expert reviewer(s): \n                             Stephanie CHAN  - Pr Ian MACDONALD"}
{"Disease Name": "Adult-onset immunodeficiency with anti-interferon-gamma autoantibodies", "Disease Definition": "A rare acquired immunodeficiency disorder characterized by the appearance of susceptibility to disseminated opportunistic infections (in particular, disseminated nontuberculous mycobacterial infection, salmonellosis, penicillosis, and varicella zoster virus infection) in previously healthy (HIV-negative) adults, associated with the presence of acquired autoantibodies to interferon gamma. Typical clinical manifestation includes lymphadenopathy (cervical or generalized), fever, weight loss and/or reactive skin lesions.", "ORPHA ID": 306431, "Summary": ""}
{"Disease Name": "Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia", "Disease Definition": "Hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia is a rare autosomal dominant disease characterized by a complex phenotype including progressive dementia, apraxia, apathy, impaired balance, parkinsonism, spasticity and epilepsy.", "ORPHA ID": 313808, "Summary": ""}
{"Disease Name": "Adult-onset multiple mitochondrial DNA deletion syndrome due to DGUOK deficiency", "Disease Definition": "An extremely rare multiple mitochondrial DNA deletion syndrome with markedly decreased deoxyguanosine kinase (DGUOK) activity in skeletal muscle characterized by a highly variable phenotype. Clinical manifestations include progressive external ophthalmoplegia, mitochondrial myopathy, recurrent rhabdomyolysis, lower motor neuron disease, mild cognitive impairment, sensory axonal neuropathy, optic atrophy, ataxia, hypogonadism and/or parkinsonism.", "ORPHA ID": 329314, "Summary": ""}
{"Disease Name": "Adult-onset myasthenia gravis", "Disease Definition": "A rare autoimmune disorder of the neuromuscular junction characterized by fatigable muscle weakness with frequent ocular signs and/or generalized muscle weakness, and occasionally associated with thymoma.", "ORPHA ID": 391490, "Summary": "Epidemiology\nEstimated prevalence varies geographically: 1/5,000 in the USA, about 1/3,000 in the UK in adults. Adult-onset represents 85-90% of MG forms in Europe and USA. The male:female sex ratio is 1:3 in patients below 40 years of age, equal in those aged 40 to 50, and about 1.5:1 in elderly patients.\nClinical description\nPatients typically present with ocular symptoms, specifically diplopia and unilateral or bilateral ptosis. About 15% of patients with ocular signs do not progress to generalized myasthenia. Within 2 to 3 years of initial manifestations, a majority of patients (about 80%) develop generalized fluctuating muscle weakness, worsening with exertion and improving with rest. Symptoms, often exacerbated at the end of the day, include fatigue, dysphagia, dysphonia, exertional dyspnea or orthopnea; in severe cases difficulty chewing, choking, and nasal regurgitation may be observed. Upper limb weakness is more common than lower limb weakness. Head drop, expressionless face, and neck pain may also be found. In severe cases, a myasthenic crisis may develop, involving acute respiratory failure requiring mechanical ventilation and nasogastric tube feeding. Myasthenic crisis occurs in about 20% of affected patients, mainly in the absence of treatment. 10-15% of patients have associated thymoma, which is malignant in most cases, and more than 50% of young patients (especially females) present a thymic follicular hyperplasia.\nEtiology\nThe exact pathogenesis is not known, but MG is mediated by circulating antibodies to various muscle receptors, including acetylcholine receptor (AChR), muscle-specific receptor tyrosine kinase (MuSK), and low density lipoprotein receptor-related protein 4 (LRP4). The thymus is thought to trigger antibody production in the form with anti-AChR antibodies. The disorder can also be drug-induced.\nDiagnostic methods\nThe diagnosis is suspected on the basis of fluctuating muscle weakness. A thorough history to identify this pattern is essential. Easy fatigability is a classic sign. Applying ice to the eye in patients with ptosis (ice test) leads to improvement of the condition in most patients. The diagnosis can be confirmed through specific laboratory tests for antibodies to AChR or to MuSK, present in 85% and about 6% of patients, respectively. Some patients display antibodies to LRP4. Antibody-negative cases are however found. Radiography, computed tomography (CT) or magnetic resonance imaging (MRI) are required to detect thymoma or thymic follicular hyperplasia.\nDifferential diagnosis\nDifferential diagnoses include congenital MG, Lambert-Eaton myasthenic syndrome, ALS, mitochondrial myopathy, botulism and polymyositis (see these terms).\nManagement and treatment\nThe vast majority of MG patients respond well to treatment. A wide range of drugs can be used to control the disease symptoms and to suppress autoimmune response. These include acetylcholinesterase inhibitors (patients with AChR antibodies), immunosuppressants such as oral steroids, azathioprine, mycophenolate mofetil, methotrexate, and tacrolimus. Ciclosporin and cyclophosphamide have been used, as well as rituximab in severe cases. Myasthenic crisis and rapid deterioration can be treated with intravenous immunoglobulins (IVIg) and plasmapheresis. Thymectomy is indicated for young patients with anti-AChR antibodies, and for patients with thymoma.\nPrognosis\nThe natural course of MG is gradual improvement but rare severe cases may be life-threatening. The overall prognosis with treatment is however excellent.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Sonia BERRIH-AKNIN  - Pr Bruno EYMARD"}
{"Disease Name": "Adult-onset nemaline myopathy", "Disease Definition": "A rapidly progressive type of nemaline myopathy (NM) characterized by a very late onset.", "ORPHA ID": 171442, "Summary": "Epidemiology\nThe annual incidence of NM has been estimated at 1/50,000 live births. Adult-onset NM represents <5% of total cases.\nClinical description\nAdult onset NM occurs sporadically between 20 and 50 years of age. It presents with a generalized weakness, myalgia and rapid progression. Several cases have been associated with cardiomyopathy, dropped head syndrome and respiratory involvement. Muscle biopsy can reveal inflammatory changes. Monoclonal gammopathy and paresthesiae may be a marker of poor prognosis.\nEtiology\nThis form of NM is due to mutations in the ACTA1 (1q42.13), NEB (2q22), TPM2 (9p13.3) or TPM3 (1q21.2) genes.\nGenetic counseling\nAdult onset NM is usually sporadic and no familial history of neuromuscular diseases is found.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Monique RYAN"}
{"Disease Name": "Adult-onset Still disease", "Disease Definition": "A rare inflammatory multisystem disorder characterized clinically by four cardinal signs: fever of unknown origin, arthralgia or arthritis, hyperleucocytosis, and typical skin rash.", "ORPHA ID": 829, "Summary": "Epidemiology\nPrevalence and incidence data are difficult to determine given the broad, non-specific clinical presentation of adult-onset Still disease (AOSD). The estimated prevalence of AOSD is more than 1/100,000 population. There is a slightly higher number of affected women than affected men.\nClinical description\nAOSD primarily affects young adults, although older patients have been reported. The presenting features are variable and may include high fever (>39°C) with daily spikes, sore throat or pharyngitis, arthralgia or arthritis (>65% of patients), transient maculopapular rash, and more rarely myalgia, lymphadenopathy, hepatosplenomegaly, and serositis. Arthritis may involve any joint and can migrate in early disease and then stabilize with time. Arthralgia is usually correlated with fever spikes. Rash mostly consists of transient, small, discrete, salmon-pink, non-pruritic macules or maculopapules that often occur concomitantly with fever and generally spare the face, palms and soles of the feet. Pleuritis or pericarditis are commonly found. Patients may lose weight and have a generally poor overall health status. Three different disease courses have been described: self-limited, systemic course with a single flare and complete remission within 2 to 4 weeks, intermittent course with recurrence of systemic or articular flares after remission of 2 weeks to 2years, and a primarily articular chronic course (with erosions in a 1/3 patients). Some affected individuals have a history of systemic juvenile idiopathic arthritis.\nEtiology\nThe etiology of AOSD and its underlying pathogenetic mechanisms are not known. No risk factors for the disease have been identified so far, but environmental factors are suspected. Several infectious conditions have been reported to be associated with onset of the disease (e.g. Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, Coxsackie virus, hepatitis A, B, and C viruses, and Mycoplasma pneumoniae).\nDiagnostic methods\nThe non-specific clinical features of AOSD make diagnosis difficult. No serological marker is currently available. AOSD is a diagnosis of exclusion. Two sets of classification criteria, Yamaguchi and Fautrel, exist. Major diagnostic criteria include arthralgia for more than 2 weeks, intermittent high fever for more than 1 week, characteristic rash, and white blood cell count above 10,000. Minor criteria include sore throat, lymphadenopathy and/or splenomegaly, abnormal liver function tests, and negative rheumatoid factor and ANA. Elevated ferritin is often found and may assist in diagnosis, especially if it is associated with a low level of glycosylated ferritin.\nDifferential diagnosis\nMany other inflammatory, neoplastic, and infectious conditions with a similar presentation must be ruled out in order to diagnose AOSD. Differential diagnoses include infections (endocarditis, occult infections, secondary syphilis, viral rash), malignancies (lymphoma) or autoimmune diseases (such as polyarteritis nodosa, vasculitis, or polymyositis).\nGenetic counseling\nAOSD is a sporadic non-inheritable disease and genetic counseling is therefore not needed.\nManagement and treatment\nThe aim is to achieve complete remission and prevent joint damage through treatment. Treatment-free remission is possible but the risk of relapse remains present throughout life Multidisciplinary rounds in contact with a reference center are highly recommended. The mainstay of first-line treatment is prednisone, and most guidelines tend to recommend an early association with biologic therapies (anti-IL1 agents (anakinra, canakinumab), and anti-IL-6 agents (tocilizumab)), in order to allow a rapid tapering of prednisone and hence prevent steroid-induced complications. Methotrexate and tumor necrosis factor blockers may be used in chronic articular forms, but have limited efficacy in systemic forms. Regular clinical and biological monitoring (initially tight) is necessary.\nPrognosis\nThe overall prognosis is generally good, but acute life-threatening manifestations may occur in rare cases. The most classical complication is macrophage activation syndrome but blood coagulation disorders, fulminant hepatitis, cardiac and pulmonary complications may occur. Some patients with chronic disease and major joint involvement may have significantly altered quality of life, but this tends to disappear thanks to a better and earlier management with biologics.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Bruno FAUTREL  - Dr Stéphane MITROVIC"}
{"Disease Name": "AFib amyloidosis", "Disease Definition": "A rare, hereditary amyloidosis with primary renal involvement characterized by fibrinogen A-alpha-chain amyloid deposition predominantly in the kidney glomeruli and clinically presenting with hypertension, uremia, nephrotic syndrome slowly progressing to end-stage renal disease. Extra-renal involvement is possible, due to neurological, cardiac, visceral and vascular amyloid deposition.", "ORPHA ID": 93562, "Summary": ""}
{"Disease Name": "African tick typhus", "Disease Definition": "A rare bacterial infectious disease caused by the tick-borne bacterium Rickettsia africae, characterized by acute onset of fever accompanied by myalgia, localized lymphadenitis, and a papulovesicular rash. In most cases at least one, sometimes multiple, inoculation eschars are observed. Clustering of cases is frequent.", "ORPHA ID": 101334, "Summary": ""}
{"Disease Name": "African trypanosomiasis", "Disease Definition": "A rare parasitic disease characterized by infection with the protozoans Trypanosoma brucei rhodesiense (East African trypanosomiasis) or T. brucei gambiense (West African trypanosomiasis), usually due to the bite of an infected tsetse fly. The first, hemolymphatic stage presents with fever, headaches, fatigue, lymphadenopathy, and aching muscles and joints. In East African trypanosomiasis, the fly bite may develop into a red sore or chancre. This form then progresses to CNS invasion with somnolence and other neurologic and psychiatric symptoms within a few weeks, while West African trypanosomiasis slowly progresses within about 3 years. Both forms are fatal if left untreated.", "ORPHA ID": 3385, "Summary": ""}
{"Disease Name": "Agammaglobulinemia-microcephaly-craniosynostosis-severe dermatitis syndrome", "Disease Definition": "A rare syndromic agammaglobulinemia characterized by profound B-cell depletion (with normal T-cell numbers) resulting in agammaglobulinemia, associated with severe developmental delay, microcephaly, craniosynostosis, cleft palate, narrowing of the choanae, blepharophimosis, and severe dermatitis. Additional reported features include distal joint contractures, renal/genitourinary anomalies, and mild cerebral atrophy, among others.", "ORPHA ID": 83617, "Summary": ""}
{"Disease Name": "AGel amyloidosis", "Disease Definition": "A rare, systemic amyloidosis characterized by a triad of ophthalmologic, neurologic and dermatologic findings due to the deposition of gelsolin amyloid fibrils in these tissues. Clinical manifestations include corneal lattice dystrophy, cranial neuropathy, especially affecting the facial nerve, bulbar signs, cutis laxa, increased skin fragility, and less commonly peripheral neuropathy and renal failure.", "ORPHA ID": 85448, "Summary": ""}
{"Disease Name": "Agenesis of the superior vena cava", "Disease Definition": "A rare congenital anomaly of the great veins characterized by unilateral or bilateral complete absence of the superior vena cava (SVC). Unilateral agenesis is mainly asymptomatic (most of the time diagnosed incidentally) and patients usually have otherwise normal heart structure. Bilateral agenesis, however, is frequently associated with other congenital cardiac anomalies and/or conduction abnormalities (such as tetralogy of Fallot, atrial septal defect) and typically present symptoms of SVC syndrome.", "ORPHA ID": 99114, "Summary": ""}
{"Disease Name": "Aggressive NK-cell leukemia", "Disease Definition": "An extremely rare and highly aggressive neoplasm, usually manifesting in the third to fourth decade of life, affecting males and females equally, and characterized by the onset of high fever, weight loss, jaundice, skin infiltration, lymphadenopathy, hepatosplenomegaly, and severe anemia. It has a fulminant and rapidly fatal disease course with the progressive appearance of multiorgan failure and disseminated intravascular coagulation.", "ORPHA ID": 86873, "Summary": ""}
{"Disease Name": "Aggressive systemic mastocytosis", "Disease Definition": "A rare, aggressive form of advanced systemic mastocytosis (advSM) characterized by massive infiltration of mast cells (MC) in different tissues and presence of extracutaneous organ dysfunction, but without evidence of mast cell leukemia or another hematologic neoplasm.", "ORPHA ID": 98850, "Summary": "Epidemiology\nIt represents less than 10% of all SM cases and the global prevalence is estimated in the order of between 1/250,000-400,000.\nClinical description\nAggressive systemic mastocytosis (ASM) may occur at any age, occurring predominantly in adults and very rarely in pediatric patients. Presentation is with organ dysfunction related to mast cell invasion (C-findings) and the intense release of mediators including syncope, recurrent flushing, diarrhea, pain, organomegaly. C-findings include bone marrow (BM) dysfunction, palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension, skeletal involvement with large osteolytic lesions and/or pathological fractures, palpable splenomegaly with hypersplenism and malabsorption with ascites. Patients do not show signs of non-mast cell hematological disease. Cutaneous involvement is slightly less frequent than in indolent SM. The most serious complications include potentially fatal anaphylactic shock and transformation to mast cell leukemia (MCL). Disease progression can be either slow or rapid. In patients with rapid progression, serum tryptase levels increase rapidly, multi-organ damage occurs (or worsens) within a short time, and rapid progression to MCL is frequent. Due to the latter, ASM with >5% MC in BM smears is termed ASM in transformation.\nEtiology\nThe etiology is not well understood but there is evidence of an activating mutation of KIT, usually D816V, in the mast cells and sometimes in non-MC hematopoietic lineages. Additional and recurrent somatic mutations of other genes have been reported in ASM; the genes most frequently affected includeTET2, SRSF2, ASXL1, RUNX1, JAK2, N/KRAS, and CBL and, less frequently,EZH2, IDH2, ETV6, U2AF, or SF3B1. These defects contribute to aggressiveness of the disease, particularly in multi-mutated patients.\nDiagnostic methods\nDiagnosis of SM is established using the WHO (World Health Organization) consensus criteria. The disease is then categorized according to the presence of B- and C-findings. The characteristics of ASM includes BM smear with <20% MC, and one or more C-findings. In rapidly progressive cases, the percentage of MC in the BM smears is of major prognostic significance and is usually elevated substantially (>5%).\nDifferential diagnosis\nDifferential diagnoses include all causes of cytopenias (myelofibrosis, myelodysplasia and other hematological malignancies) and other abnormal types of mutation in JAK2, that are excluded by the detection of bone marrow infiltration by neoplastic mast cells with an activation mutation of KIT.\nManagement and treatment\nTreatment is constant with non-targeted or targeted cytoreductive therapy. Non-targeted therapies include interferon-(IFNalpha), which may be effective in a subset of patients, and cladribine (2CdA) which provides high, and sometimes long lasting, response rates. Allogeneic stem cell transplantation (allo-SCT) is rarely used and reserved for fit patients with a suitable donor. However, when applicable, allo-SCT provides frequently good response rates and complete remission. Targeted therapy is with KIT tyrosine kinase inhibitors (KIT TKIs) Midostaurin which inhibits the D816V mutant (approved in Europe and the USA), is regarded as the standard first-line therapy in ASM. Whilst it is efficacious, it does not induce complete hematologic remissions. Midostaurin may also be useful for patients who need debulking prior to allo-SCT or those who fail treatment with 2CdA or IFNalpha. Other TKIs included imatinib mesylate or masitinib and may be indicated for the few patients without the KITD816V mutation. Symptomatic treatment is mainly with antihistamines (anti-H1 and anti-H2). The use of iodinated contrast agents should be limited.\nPrognosis\nThe prognosis is usually poor with a median survival of 2 to 4 years. Due to rapid progression to MCL, ASM patients with a MC count in the BM smears >5% have a worse outcome with reduced survival and progression-free survival compared to patients with <5%. Furthermore, the presence of mutations in other critical target genes, in particular SRSF2, ASXL1, RUNX1, is associated with progression and poor outcome.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Michel AROCK"}
{"Disease Name": "Agnathia-holoprosencephaly-situs inversus syndrome", "Disease Definition": "An extremely rare and fatal association syndrome, characterized by absence of the mandible, cerebral malformations with facial anomalies related to a defect in cleavage in the embryonic brain (e.g. synophthalmia, malformed and low-set ears fused in midline (otocephaly), agenesis of the olfactory bulbs, microstomia, hypoglossia/aglossia) and situs inversus partialis or totalis.", "ORPHA ID": 990, "Summary": ""}
{"Disease Name": "AH amyloidosis", "Disease Definition": "A rare, systemic amyloidosis characterized by the aggregation and deposition of amyloid fibrils composed of monoclonal immunoglobulin heavy-chain fragments, usually produced by a plasma cell neoplasm. Amyloid fibrils deposit in various organs, most commonly in the kidneys. It typically affects older patients and clinical presentation includes signs and symptoms of renal dysfunction, sometimes leading to nephrotic syndrome and end stage renal disease. Cardiac, liver and nerves involvement has also been described.", "ORPHA ID": 442582, "Summary": ""}
{"Disease Name": "AHDC1-related intellectual disability-obstructive sleep apnea-mild dysmorphism syndrome", "Disease Definition": "A rare, syndromic intellectual disability characterized by hypotonia, developmetal delay, absent or severly delayed speech development, intellectual disability, obstructive sleep apnea, mild dysmorphic facial features and behavioral abnormalities. Epilepsy, ataxia and nystagmus have also been reported.", "ORPHA ID": 412069, "Summary": ""}
{"Disease Name": "AICA-ribosiduria", "Disease Definition": "A rare and severe inborn metabolic disease characterized clinically by the association of severe-to-profound neurodevelopmental impairment, severe visual impairment, ante-postnatal growth impairment, severe scoliosis and, frequently, early-onset epilepsy.", "ORPHA ID": 250977, "Summary": "Epidemiology\nTo date only 4 affected individuals from 3 independent families have been reported worldwide.\nClinical description\nThere are no specific fetal abnormalities. However, during pregnancy, intrauterine growth retardation and low amniotic fluid are noted frequently. The newborns usually display a marked global hypotonia and global developmental delay is usually noticeable during the first year. Affected children are able to learn some skills but most of them will remain unable to walk and speak. No structural brain abnormalities are noted. Epilepsy of variable type and severity is frequent and usually noticeable during the first year of life. Visual issues are also usually noticeable during the first year of life, characterized mainly by severe hypermetropia and chorio-retinal atrophy. Some individuals can see close objects whereas others are blind. Severe scoliosis usually appears during childhood. Growth remains delayed to approximately -2 to -4 standard deviations, with normal cranial circumference. Affected individuals share common inconspicuous facial features (short and upturned nose, brushy eyebrows, and long eyelashes). Other clinical features that may be related to the disease include chronic hepatic cytolysis with recurrent acute aggravations and hepatomegaly , aortic coarctation of the newborn, and nephrocalcinosis. A less severe phenotype is possible.\nEtiology\nAICA-ribosiduria is caused by germline defects in the ATIC gene (2q35). The pathogenesis seems to involve a cytotoxic effect of abnormally accumulated substrates of ATIC enzyme: AICAR and AICA-riboside. No genotype-phenotype relationship has been identified.\nDiagnostic methods\nThe diagnostic is not usually suspected on clinical grounds, although theoretically recognizable. It is more realistically suspected after exome-, genome-, or gene-panel- sequencing, in the presence of two pathogenic loss of function variations in the gene ATIC, with a bi-allelic pattern. The diagnosis can also be suspected in the presence of a positive urine Bratton-Marshall test suggesting an accumulation AICA-riboside. The diagnosis may be definitively confirmed by HPLC (High Performance Liquid Chromatography) analysis.\nDifferential diagnosis\nThere is no true differential diagnosis. However, each of the core features has numerous differential diagnoses.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variants have been previously identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. For the parents of an affected child, the risk of recurrence for each future pregnancy is 25%. Genetic counseling is highly recommended for affected families.\nManagement and treatment\nManagement is multidisciplinary. There is no preventive, curative, or specific treatment to date. Epilepsy should be sought, and when present should be treated by an experienced neuropediatrician according to the standard protocols. It may become pharmacoresistant. The patient should be referred to an experienced ophthalmologist. Hypermetropia can be treated according to standard procedures; however, chorio-retinal atrophy has no specific treatment. The presence of scoliosis should be assessed and treated aggressively if present. Neurodevelopment should be supported through an early intervention program. Growth retardation is not usually subject to specific measures.\nPrognosis\nTo date all individuals affected by AICA-ribosiduria require extensive support. Life expectancy is unknown (oldest individual is 20 years of age).\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Francis RAMOND"}
{"Disease Name": "Aicardi syndrome", "Disease Definition": "A rare neurodevelopmental disorder characterized by the classic triad of agenesis of the corpus callosum (total or partial), central chorioretinal lacunae and infantile spasms that affects almost exclusively females.", "ORPHA ID": 50, "Summary": "Epidemiology\nAbout 200 individuals with Aicardi syndrome have been reported in North America and Europe, but the true prevalence is unknown. Single cases in males with 47, XXY chromosome constitution have been reported.\nClinical description\nIndividuals typically present within the first few months of life with infantile spasms and low muscle tone. In addition to the classic triad (agenesis of the corpus callosum, central chorioretinal lacunae and infantile spasms), other characteristics have been identified. All individuals manifest additional developmental brain abnormalities, with most presenting periventricular nodular heterotopias, brain cysts and polymicrogyria or pachygyria. While infantile spasms are the most common initial seizure type, most evolve into a complex pattern of partial and generalized seizures that are typically very difficult to control. In addition to chorioretinal lacunae, microphthalmia, retinal and optic nerve colobomas can be seen. Facial features, including prominent premaxilla, upturned nasal tip, decreased angle of the nasal bridge, and sparse lateral eyebrows have been described. Scoliosis is present in up to one third of affected individuals. Gastrointestinal disorders such as reflux, discomfort and constipation are nearly universal. Less common findings include cutaneous vascular malformations and pigmentary skin lesions. Vascular tumors have been reported in a few individuals.\nEtiology\nIt is believed that Aicardi syndrome is a sporadic disorder caused by heterozygous pathogenic variants in an X-linked gene in females, with early embryonic lethality in hemizygous males; however, a candidate region on the X chromosome has not yet been identified due to the sporadic nature of the condition. Some groups have reported potential causative genes in single individuals but these have not been confirmed in larger studies.\nDiagnostic methods\nDiagnosis is based on clinical features, brain imaging and skeletal findings. There is no blood test or other clinical diagnostic test to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes microcephaly-chorioretinopathy with or without lymphedema (in this disorder, the lacunae are peripheral and the microcephaly is significant ; girls with Aicardi syndrome typically do not have microcephaly), oculocerebrocutaneous syndrome, neuronal migration disorders and numerous syndromes that present with one or more of the features characteristic for Aicardi syndrome.\nAntenatal diagnosis\nPrenatal diagnosis may be suspected based upon fetal brain imaging.\nGenetic counseling\nAicardi syndrome appears to be a de novo, X-linked dominant disorder with lethality in males. There are no confirmed cases of familial recurrence.\nManagement and treatment\nLong-term follow-up by a pediatric neurologist is necessary for management of seizures. Seizures are often refractory to multiple medication regimens and no single medication works for all; some have reported improvement with vagal nerve stimulators. Physical, occupational, speech and vision therapy should begin at diagnosis. Appropriate musculoskeletal support and treatment for prevention of scoliosis-related complications is indicated. Immunizations, infection control measures and therapy for pulmonary toilet are important to reduce the risk of pneumonia, a major cause of mortality.\nPrognosis\nDifficult-to-control seizures and significant neurodevelopmental disorders are the primary challenge for individuals with Aicardi syndrome. Most are not able to sit independently, walk or speak. The 5-, 10- and 20-year survival rates are 90%, 80% and 50%, respectively. Pulmonary infections, presumed secondary to hypotonia, are the most common cause of death.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr V. Reid SUTTON"}
{"Disease Name": "Aicardi-Goutières syndrome", "Disease Definition": "A rare inherited subacute encephalopathy characterized by the variable association of basal ganglia calcification, leukodystrophy, cerebrospinal fluid (CSF) lymphocytosis and evidence of enhanced type I interferon signaling in blood and CSF.", "ORPHA ID": 51, "Summary": "Epidemiology\nMore than 500 cases of Aicardi-Goutières syndrome (AGS) have been reported in the literature to date.\nClinical description\nThe majority of affected infants are born at full term with normal growth parameters. In its classic form, onset occurs within the first few days or months of life with severe, subacute encephalopathy (feeding problems, irritability and psychomotor regression or delay) associated with epilepsy, chilblain skin lesions on the extremities and episodes of aseptic febrile illness. These features can continue over several weeks/months (with the development of microcephaly and pyramidal signs) before the disease apparently stabilizes. Less severe forms have been described with onset after 1 year of age, and relative preservation of communication skills, cognitive function and head circumference. The phenotype can manifest with marked inter- and intrafamilial variation. Less frequently still, mutations in AGS-related genes can be associated with other distinct phenotypes, including bilateral striatal necrosis, non-syndromic spastic paraparesis of the lower limbs with normal intellect and neuroradiology, cerebrovascular disease similar to Moyamoya, and even complete clinical non-penetrance.\nEtiology\nSince 2006, causative mutations have been identified in nine genes encoding: (i) the 3'->5' exonuclease TREX1; (ii) the three components of the RNase H2 endonuclease complex (RNASEH2A, RNASEH2B and RNASEH2C), (iii) SAMHD1, which functions as a deoxynucleoside triphosphate triphosphohydrolase; (iv) ADAR1, which catalyzes the hydrolytic deamination of adenosine to inosine in RNA; (v) MDA5, (encoded by IFIH1) a cytosolic double stranded RNA sensor; and (vi) two components of the histone pre-mRNA processing complex (RNU7-1 and LSM11). Mutations in TREX1, RNASEH2C and RNASEH2A are more often associated with severe neurological problems, whereas mutations in RNASEH2B, SAMHD1, IFIH1 and ADAR1 can be associated with a relative preservation of skills. The phenotype associated with mutations in LSM11 and RNU7-1 have yet to be fully determined.\nDiagnostic methods\nCalcification (involving the basal ganglia and white matter), cystic leukodystrophy (predominantly frontotemporal in very early onset cases) and cortical-subcortical atrophy are cardinal features of typical AGS, sometimes associated with atrophy of the corpus callosum, the brain stem and cerebellum. Elevated IFN-alpha activity and lymphocytosis in the CSF are frequent but not constant findings in the initial stage of the disease, but tend to normalize or resolve within a few years. The expression of interferon stimulated genes (ISGs)—a so-called interferon signature—can be recorded in the blood of the majority of cases, except in patients carrying RNASEH2B variants (where ~ 20% of patients have normal ISG expression after age 4 years). The diagnosis is confirmed by detection of mutations in one of the nine disease-associated genes.\nDifferential diagnosis\nThe principle differential diagnoses are TORCH congenital infections (toxoplasma, rubella, cytomegalovirus, HSV1 and HSV2), and other diseases associated with white matter abnormalities and/or intracranial calcification.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nDisease due to mutations in TREX1, RNASEH2A/B/C, SAMHD1, ADAR, LSM11 and RNU7-1 are almost always inherited as an autosomal recessive trait, although rare dominant mutations in TREX1 and ADAR —affecting highly specific residues— are well recognized. In contrast, mutations in IFIH1 are always inherited as an autosomal dominant trait.\nManagement and treatment\nTo date, treatment has been mostly symptomatic (management of feeding problems, tone, epilepsy etc.). However, JAK1 inhibition (JAKi) is a therapeutic option for the systemic features of AGS, such as recurrent fevers and chilblains. The efficacy of JAKi on the neurological features of the disease is less evident. Side effects of such targeted therapies should be considered.\nPrognosis\nAround 10% of patients die within the first 5 years of life, but prolonged survival into the third and fourth decades of life is well recognized.\n\n                            Last update: \n                            May 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Yanick CROW | RITA* - Pr Marie-Louise FRÉMOND | RITA* - Pr Bénédicte NEVEN \n\n\n                                * European Reference Network"}
{"Disease Name": "AIDS wasting syndrome", "Disease Definition": "A rare condition associated with acquired immunodeficiency syndrome (AIDS) and characterized by unwanted weight loss (involving both fat and muscle) of more than ten percent of body weight, with either diarrhea or weakness and fever which have lasted at least 30 days and are not related to an infection.", "ORPHA ID": 90081, "Summary": ""}
{"Disease Name": "Airway infantile hemangioma", "Disease Definition": "A rare benign vascular tumor characterized by rapid growth after birth (followed by spontaneous partial regression over the course of years), potentially leading to life-threatening airway obstruction due to the subglottic location. Patients present with respiratory symptoms including biphasic stridor, recurrent croup, cyanosis, apnea, and sternal and intercostal retractions. The tumor may be accompanied by cutaneous hemangiomata, especially in the lower facial (\"beard\") distribution.", "ORPHA ID": 137935, "Summary": ""}
{"Disease Name": "AKT2-related familial partial lipodystrophy", "Disease Definition": "A rare familial partial lipodystrophy characterized by adult onset of distal lipoatrophy and severe insulin resistance in the liver and peripheral tissues, hyperinsulinemia, and diabetes mellitus. Acanthosis nigricans and hypertension have been reported in association.", "ORPHA ID": 79085, "Summary": ""}
{"Disease Name": "AL amyloidosis", "Disease Definition": "A clonal B-cell disorder characterized by the aggregation and deposition of insoluble amyloid fibrils derived from misfolding of monoclonal immunoglobulin light chains. It usually presents as systemic AL amyloidosis with involvement of one or more parenchymal organ(s) and, less frequently, as localized amyloidosis with usually nodular deposits restricted to a single organ and/or system.", "ORPHA ID": 85443, "Summary": "Epidemiology\nIt represents the most common type of systemic amyloidosis in western countries; in Europe and the USA the incidence ranges from 1/80,000-330,000 and prevalence between 1/17,000-50,000. AL amyloidosis affects men slightly more often than women.\nClinical description\nThe average age of diagnosed patients is 63 years. The clinical manifestations depend on organ involvement and general symptoms, such as fatigue and weight loss, can also occur. The heart (approximately 80%) and the kidneys (65%) are the most commonly involved organs, followed by soft tissues, liver, peripheral and autonomic nervous system, and gastrointestinal tract. This can result in fluid retention, dyspnea, arrhythmias, liver enlargement, macroglossia, swelling if the submandibular glands, carpal tunnel syndrome, peripheral neuropathy, hypotension, diarrhea or constipation. Localized AL amyloidosis can affect the skin, the respiratory, gastrointestinal and urinary tract, and the eye.\nEtiology\nAL amyloidosis results from conformational changes of monoclonal immunoglobulin light chains produced by a usually small B-cell (most commonly plasma cell) clone. These light chains misfold, aggregate, and deposit in tissue in the form of fibrils. Organ dysfunction and damage is dependent on a direct toxic effect of monoclonal light chains, particularly in the heart, and on the mechanical effect of deposits.\nDiagnostic methods\nDiagnosis of systemic AL amyloidosis is established by demonstrating amyloid deposits (red-green birefringence with Congo red staining under cross-polarized light) in the affected organ by biopsy or other less invasive alternatives (e.g. subcutaneous fat aspirate) and by demonstrating that amyloid fibrils are formed by immunoglobulin light chains (amyloid typing). Amyloid typing can be achieved by immunohistochemical staining, immunofluorescence on renal biopsies in patients with kidney involvement, and mass spectrometry. A B-cell clone producing a light chain of the same isotype as that documented in the deposits should be searched for and demonstrated. The presence and severity of organ involvement should be assessed (by echocardiography, cardiac magnetic resonance imaging, measurement of proteinuria and renal and liver function parameters) and graded. Cardiac and renal staging systems based on natriuretic peptide type-B or its N-terminal pro-hormone, troponin, free light chain proteinuria, and glomerular filtration rate accurately predict the risk of death and progression to dialysis. Localized AL amyloidosis is diagnosed by biopsy of the deposits.\nDifferential diagnosis\nSystemic AL amyloidosis should be distinguished from other forms of systemic amyloidosis and from non-amyloid light chain deposition disease.\nManagement and treatment\nTreatment of systemic AL amyloidosis is based on therapies targeting the underlying plasma clone aiming at reducing the supply of the amyloid-forming light chain. Successful treatment can improve organ involvement and extend survival. The only licensed therapy is the combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD). Other effective regimens are bortezomib, melphalan, dexamethasone (BMDex) and CyBorD. Autologous stem cell transplant is effective and induces long term survival in responders, but only a minority of patients (approximately 20%) are fit enough to safely undergo this procedure. Relapsed and refractory patients are usually rescued with immunomodulatory drugs, such as lenalidomide and pomalidomide. Patients in whom the disease is not caused by a plasma cell clone are treated with regimens used in the corresponding B cell malignancy. Localized AL amyloidosis is treated by surgical removal of the amyloid deposits when this is necessary and possible.\nPrognosis\nThe prognosis of systemic AL amyloidosis depends on the presence and severity of heart involvement and on response to therapy. Patients who are diagnosed when advanced heart involvement is already established are at high risk of early death (within a few months), whereas patients who attain rapid and deep response to therapy can enjoy a prolonged survival. Localized AL amyloidosis has a largely better outcome and only exceptionally is it life threatening.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanni PALLADINI | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Alacrimia-choreoathetosis-liver dysfunction syndrome", "Disease Definition": "A rare, genetic, inborn error of metabolism disorder characterized by global developmental delay, hypotonia, choreoathetosis, hypo-/alacrimia, and liver dysfunction which manifests with elevated liver transaminases and hepatocyte cytoplasmic storage material or vacuolization on liver biopsy. Additional features reported include acquired microcephaly, hypo-/areflexia, seizures, peripheral neuropathy, intellectual and language/speech disability, additional ocular anomalies and EEG and brain imaging abnomalities.", "ORPHA ID": 404454, "Summary": ""}
{"Disease Name": "Alagille syndrome", "Disease Definition": "A rare syndrome variably characterized by chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, vertebrae segmentation anomalies, characteristic facies, posterior embryotoxonterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys.", "ORPHA ID": 52, "Summary": "Epidemiology\nThe prevalence is approximately 1/70,000.\nClinical description\nThe disease may manifest in newborns by prolonged jaundice due to conjugated hyperbilirubinemia, and/or cardiac signs and symptoms. Cardiac abnormalities include pulmonary atresia or stenosis, atrial and/or ventricular septal defects, tetralogy of Fallot, and patent ductus arteriosus (see these terms). Cholestasis manifests by conjugated hyperbilirubinemia, hepatosplenomegaly, hypercholesterolemia, hypertriglyceridemia, and coagulopathy. Pruritus and xanthomas may occur. Minor skeletal abnormalities include butterfly hemivertebrae (around 50% of cases), and shortening of the radius, ulna, and phalanges. Characteristic facial features, if present, are usually apparent from childhood and include prominent forehead, deep-set eyes, upslanting palpebral fissures, hypertelorism, flat nasal root, and pointed chin. Ophthalmic anomalies include posterior embryotoxon (75% of cases), Axenfeld anomaly (see this term), pigmentary retinopathy, papillary and optic disc anomalies. Growth delay, fat malabsorption (rickets may occur), and sometimes developmental delay occur. Small and dysplastic kidneys (common in AGS type 2), and hypothyroidism may be present.\nEtiology\nAGS is most commonly due to JAG1 (20p12) gene mutations (AGS type 1), encoding a Notch signaling pathway ligand. AGS type 2 is due to NOTCH2 gene mutations (1p12).\nDiagnostic methods\nThe diagnosis is based on the clinical picture and liver biopsy revealing chronic cholestasis and paucity of interlobular bile ducts. Imaging (abdominal ultrasonography, cholangiography) helps to identify biliary anatomy. Screening for ophthalmic, skeletal, vascular and endocrine (thyroid) abnormalities should be performed. DNA sequencing may confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include biliary atresia, congenital hepatic fibrosis, cystic fibrosis, neonatal jaundice, polycystic kidney disease, progressive familial intrahepatic cholestasis, and tyrosinemia (see these terms).\nAntenatal diagnosis\nIf a pathogenic mutation has been identified, prenatal genetic diagnosis is possible on DNA from chorionic villous tissue or cultured amniocytes. Otherwise, detailed fetal ultrasonography may identify cardiac and/or renal anomalies if present.\nGenetic counseling\nTransmission is autosomal dominant, but reduced penetrance (up to 50% of cases) and somatic mosaicism (~8%) are common.\nManagement and treatment\nTreatment is non-specific and includes high-carbohydrates and high-medium chain triglyceride diets and vitamin supplementation. Pruritus may be reduced by cholestyramine or rifampin. Liver transplantation may be necessary for patients with refractory disease. Cardiac or vascular procedures may be required for significant symptomatic lesions.\nPrognosis\nThe prognosis is usually favorable, but complications such as cirrhosis, variceal hemorrhage, refractory ascites, and spontaneous bacterial peritonitis may occur. The disease usually stabilizes between ages 4 and 10 years. When hepatic failure and/or cardiac lesions are present, mortality risk is increased.\n\n                            Last update: \n                            March 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Peter TURNPENNY"}
{"Disease Name": "Alar cartilages hypoplasia-coloboma-telecanthus syndrome", "Disease Definition": "A very rare dysmorphic disorder characterized by hypoplasia and coloboma of the alar cartilages and telecanthus described in 2 sisters. No new cases with similar features have been reported since 1976.", "ORPHA ID": 2007, "Summary": ""}
{"Disease Name": "Alazami syndrome", "Disease Definition": "A rare form of primordial dwarfism, often microcephalic, characterized by short stature, global developmental delay, variable intellectual disability and recognizable dysmorphic facial features (triangular face, prominent forehead, deeply set eyes, low-set ears, wide nose, malar hypoplasia, wide mouth, thick lips, and widely spaced teeth).", "ORPHA ID": 319671, "Summary": "Epidemiology\nTo date, less than 30 affected individuals reported worldwide, about half of which belong to a few consanguineous families.\nClinical description\nAlazami syndrome is a genetic developmental defect characterized by mild to severe short stature, head circumference below the 50th centile, microcephaly in half of the individuals, and global developmental delay with moderate to severe intellectual disability. Speech can be absent or delayed (mainly expressive rather than receptive language delay in milder cases). Short stature and reduced head circumference are progressive, but usually already apparent at birth; endocrinological testing is normal in the majority of examined patients, with only a slight reduction of IGF-1 in some. Most individuals have distinctive facial features: triangular face, prominent forehead, deeply set eyes (often with narrow palpebral fissures), low-set ears, wide nose, malar hypoplasia, wide mouth, thick lips, widely spaced teeth. Scoliosis and strabismus are reported in one third of affected individuals. Several patients display autistic and/or maladaptive behaviors, including stereotypies similar to hand-washing. All features show inter- and intrafamilial variability. Additional, variable features may also include congenital heart defects such as pulmonary artery stenosis or atrial septal defect, seizures, aplasia/hypoplasia of the corpus callosum or other brain MRI anomalies, and accelerated skeletal maturation. Features more rarely reported include cleft palate, brachydactyly, prominent interphalangeal joints, 2-3 toe syndactyly, metaphyseal dysplasia, hydronephrosis due ureteropelvic junction stenosis, and hypospadias.\nEtiology\nThe syndrome is caused by biallelic loss-of-function variants in the LARP7 gene (4q25), which encodes a protein involved in the regulation of RNA transcription and splicing. At least one variant retaining partial protein function has been described, but no specific genotype-phenotype correlation could be established.\nDiagnostic methods\nDiagnosis is based on clinical examination and can be confirmed by molecular testing through sequencing. Chromosomal microarrays may also be considered since large deletions encompassing LARP7 cannot be excluded, although none have been reported in affected individuals to date.\nDifferential diagnosis\nDifferential diagnosis includes other syndromes characterized by intellectual disability and short stature.\nAntenatal diagnosis\nPrenatal diagnosis is available for at-risk pregnancies, if a pathogenic variant has been identified in a member of the affected family.\nGenetic counseling\nAlazami syndrome is an autosomal recessive disorder, with homozygous and compound heterozygous variants described. It is expected to have increased frequency in populations where consanguineous couples are frequent. Genetic counseling should be offered to at-risk couples (both carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement is multidisciplinary, based on the clinical manifestations, with lifelong follow-up. Most patients will require various degrees of assistance with day-to-day activities. Neuropsychiatric assistance, speech therapy and educational support may be effective.\nPrognosis\nLife expectancy is currently unknown. Affected individuals have been reported to live into early adulthood, and only a few of the known associated clinical features can pose a life-threatening risk. There is only one report indicating a possible increase in tumor susceptibility. The level of autonomy is dependent on the severity of intellectual disability and language delay.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Stefano Giuseppe CARAFFI | ITHACA* - Dr Livia GARAVELLI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Albers-Schönberg osteopetrosis", "Disease Definition": "A sclerosing disorder of the skeleton characterized by increased bone density that classically displays the radiographic sign of ''sandwich vertebrae'' (dense bands of sclerosis parallel to the vertebral endplates).", "ORPHA ID": 53, "Summary": "Epidemiology\nThe prevalence is estimated to be 1/20,000.\nClinical description\nOnset of the disease is typically in late childhood or adolescence. The main manifestations are confined to the skeleton, including fractures, scoliosis, hip osteoarthritis and osteomyelitis, particularly affecting the mandible in association with dental abscess or caries. Cranial nerve compression is a rare but important complication, with hearing and visual loss affecting around 5% of individuals. Moderate bone marrow failure is described occasionally.\nEtiology\nThe disease is caused by heterozygous mutations in the chloride channel 7 (ClCN7) gene (16p13).\nDiagnostic methods\nDiagnosis is based on clinical findings and largely depends on the radiographic appearance of the skeleton. Genetic testing is available and can be used to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other subtypes of osteopetrosis, fluorosis, beryllium, lead and bismuth poisoning, myelofibrosis, Paget's disease (sclerosing form) and malignancies (lymphoma, osteoblastic cancer metastases) (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible if the mutation causing the condition in the family is known.\nGenetic counseling\nAlbers-Schönberg osteopetrosis is transmitted in an autosomal dominant manner. Genetic counseling should be offered to families. Each child of an affected individual has 50% risk of being affected. The parents of the proband should be carefully evaluated for signs of osteopetrosis, including radiographic studies of the skeleton.\nManagement and treatment\nAt present, there is no effective medical treatment for osteopetrosis. Management is supportive and aims at providing multidisciplinary surveillance and symptomatic treatment.\nPrognosis\nClinical manifestations may worsen over time but life expectancy is usually normal.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Ravi SAVARIRAYAN  - Dr Zornitza STARK"}
{"Disease Name": "Albinism-deafness syndrome", "Disease Definition": "A rare disorder characterised by congenital nerve deafness and piebaldness with no ocular albinism. It has been described in one large pedigree. Transmission is X-linked with affected males presenting with profound sensorineural deafness and severe pigmentary abnormalities of the skin, and carrier females presenting with variable hearing impairment without any pigmentary changes. The causative gene has been mapped to Xq26.3-q27.1.", "ORPHA ID": 998, "Summary": ""}
{"Disease Name": "ALDH18A1-related De Barsy syndrome", "Disease Definition": "A rare, genetic, neurometabolic disease characterized by prenatal and postnatal growth retardation, hypotonia, failure to thrive, large and late-closing fontanel, development delay, cutis laxa, joint laxity, progeroid appearance, and dysmorphic facial features. In addition, corneal opacities, cataracts, myopia, seizures, hyperreflexia and athetoid movements have also been associated.", "ORPHA ID": 35664, "Summary": ""}
{"Disease Name": "ALECT2 amyloidosis", "Disease Definition": "A rare, systemic amyloidosis characterized by slowly progressive renal disease presenting with proteinuria, hypertension and decreased glomerular filtration rate leading to progressive renal failure. Histology reveals amyloid deposits of leukocyte chemotactic factor-2 protein in the renal cortical interstitium, tubular basement membranes, glomeruli and the vessel walls. Extra-renal deposits can be seen in the liver, lungs, spleen and adrenal glands.", "ORPHA ID": 439224, "Summary": ""}
{"Disease Name": "Alexander disease type I", "Disease Definition": "An astrogliopathy and the most severe and common form of Alexander disease (AxD), presenting before the age of 4 and characterized by seizures, megalencephaly and developmental delay with progressive deterioration.", "ORPHA ID": 363717, "Summary": "Epidemiology\nThe prevalence is unknown. This form accounts for approximately 60% of AxD cases.\nClinical description\nAxD type I typically presents between birth and the age of 4. Those with a neonatal onset (within the first 30 days) usually have a more severe disease course presenting with symptoms of generalized, frequent, and often intractable seizures, aqueductal stenosis (leading to hydrocephalus with raised intracranial pressure) and severe motor and intellectual disability. In infantile-onset cases, ataxia, hyperreflexia and pyramidal signs are seen along with seizures. Megalencephaly and frontal bossing are further manifestations of the disease. In all infants there is a loss of developmental milestones with progressive psychomotor retardation. The disease course is severe with death usually, but not always, occurring in the first two decades after diagnosis. In the neonatal form the disease progresses even faster with severe disability or death occurring within the first years of life.\nEtiology\nAxD is caused by gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene (17q21). This gene encodes GFAP, the major intermediate filament protein found in astrocytes. The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the CNS. It is currently unknown how Rosenthal fibers are involved in disease pathogenesis.\nDiagnostic methods\nMRI shows characteristic leukodystrophy with frontal, basal ganglia signal abnormality, brainstem signal abnormality and contrast enhancement. Molecular genetic testing for a mutation in the GFAP gene confirms diagnosis. The presence of Rosenthal fibers in astrocytes can also be seen in other diseases and is therefore not diagnostic.\nDifferential diagnosis\nDifferential diagnoses include: peroxisomal biogenesis disorders, Zellweger syndrome spectrum, glutaric aciduria type I, Aicardi-Goutières syndrome, the frontal variant of adrenoleukodystrophy and megalencephalic leukoencephalopathy with subcortical cysts (see these terms).\nAntenatal diagnosis\nAlthough most cases of AxD type I are sporadic, antenatal diagnosis is possible if a disease causing mutation has been identified in an affected family member.\nGenetic counseling\nAxD type I typically occurs sporadically and is associated with the occurrence of de novo  mutations. Most patients do not reproduce. Gonadal mosaicism should be considered in advising families of the risk of recurrence when a de novo mutation is identified. Genetic counseling can be proposed to families with a history of the disease and family members can be tested for the disease-causing mutation. Penetrance is complete.\nManagement and treatment\nThere is no cure for AxD type I. Treatment is symptomatic and focuses on seizure control, maintenance of pulmonary function and nutrition. Those with severe feeding difficulties and recurrent vomiting may require a percutaneous gastrostomy tube or the placement of a nasogastric tube. Antibiotics can be given to treat intercurrent infections and antiepileptic drugs are given to control seizures. Orthopedic complications should be prevented, in particular scoliosis, and the management of spasticity by a multidisciplinary team is an important component of care. Psychological counseling can also be proposed to families of infants with the disease.\nPrognosis\nThe prognosis is poor but with supportive therapies some patients have lived into adolescence and adulthood.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Albee MESSING  - Dr Adeline VANDERVER"}
{"Disease Name": "Alexander disease type II", "Disease Definition": "An astrogliopathy and a form of Alexander disease (AxD) characterized by ataxia, bulbar symptoms, spastic paraparesis, palatal myoclonus, and autonomic symptoms.", "ORPHA ID": 363722, "Summary": "Epidemiology\nPrevalence is unknown. It accounts for approximately 40% of AxD cases.\nClinical description\nAxD type II can present throughout life, most commonly in late adolescence or adulthood (over the age of 12) and more rarely in childhood, with the age of onset ranging from 4-62 in published cases. It presents most commonly with bulbar symptoms (dysarthria, dysphonia, dysphagia), pyramidal signs and gait difficulties due to ataxia and/or spastic paraparesis. Unlike AxD type I (see this term), seizures are rarely seen and cognitive impairment is sometimes absent. Abnormalities of ocular movements are common and include saccadic pursuit, nystagmus, mild upper lid ptosis or diplopia. Sleep disorders (apneas and snoring) due to brainstem involvement are common as are urinary disturbances. Palatal myoclonus is also common. Other manifestations may include hypothermia episodes, sweating disturbances, constipation, pupillary abnormalities, impotence, kyphosis and scoliosis. Progression is slow and disease course is less severe than AxD type I but eventually muscle wasting and weakness often lead to motor impairment and dysphagia. Death is often due to aspiration pneumonia and respiratory insufficiency.\nEtiology\nAxD type II is caused by gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene (17q21). Both sporadic cases with de novo mutations and familial cases have been reported. This gene encodes GFAP, the major intermediate filament protein found in astrocytes. The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the CNS. It is currently unknown how Rosenthal fibers are involved in disease pathogenesis.\nDiagnostic methods\nMRI is the most useful diagnostic tool as AxD type II characteristically shows a predominance of hindbrain lesions with mild to severe atrophy of the medulla oblongata and upper spinal cord. Molecular genetic testing for a mutation in the GFAP gene confirms diagnosis. Pathological findings of Rosenthal fibers do not determine diagnosis as they are present in other conditions.\nDifferential diagnosis\nDifferential diagnoses include: peroxisomal biogenesis disorders, Zellweger syndrome spectrum, glutaric aciduria type I, megalencephalic leukoencephalopathy with subcortical cysts as well as other leukodystrophies such as Canavan disease, X-linked adrenoleukodystrophy and Krabbe disease (see these terms). AxD type II can also be misdiagnosed as primary lateral sclerosis, multiple sclerosis, spinocerebellar ataxia and amyotrophic lateral sclerosis (see these terms) or one of numerous types of neoplasms (ex. spinal cord lesions, focal brain stem glioma, focal posterior fossa lesions).\nAntenatal diagnosis\nAntenatal diagnosis is possible if a disease causing mutation has been identified in a family member.\nGenetic counseling\nThe disease is transmitted autosomal dominantly. Both de novo and familial cases have been reported. Genetic counseling can be offered to those with a family member with a mutation in the GFAP gene but is difficult as penetrance is sometimes incomplete.\nManagement and treatment\nThere is no cure for AxD type II. Treatment is symptomatic and supportive. Monitoring and assessment of speech and swallowing difficulties is necessary. Evaluation and management of sleep apnea can greatly improve quality of life. Early recognition of scoliosis can prevent long term complications. As the disease progresses most patients require walking aids and/or wheelchairs. Patients with dysphagia may require a percutaneous gastrostomy tube or the placement of a nasogastric tube. Psychological assessment of patients along with counseling for patients and their families can be offered.\nPrognosis\nThe prognosis is quite poor with median survival time after disease onset being 25 years.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Albee MESSING  - Dr Adeline VANDERVER"}
{"Disease Name": "Alexander disease", "Disease Definition": "A rare neurodegenerative disorder of the astrocytes comprised of two clinical forms: Alexander disease (AxD) type I and type II manifesting with various degrees of macrocephaly, spasticity, ataxia and seizures and leading to psychomotor regression and death.", "ORPHA ID": 58, "Summary": "Epidemiology\nThe prevalence is unknown. One population based study in Japan estimated an annual incidence of 1/ 2.7 million.\nClinical description\nThe clinical presentation depends on the subtype. Previously, AxD was classified either as infantile, juvenile or adult, based simply on age of onset. The currently used classification system is based on a constellation of clinical and radiologic features and includes AxD type I and AxD type II (see these terms). AxD type I is more likely to be of early onset (mean 1.74 years) and shorter survival (median 14 years) whereas type II exhibits onset throughout the lifespan (mean 21.64 years, but can occur in early childhood) and has longer survival (median 25 years). The two types also differ in their clinical symptoms. AxD type I manifests with symptoms of encephalopathy, epilepsy and failure to thrive and has an infantile presentation, while patients with AxD type II manifest with bulbar, autonomic and motor signs such as dysarthria, dysphonia, dysphagia, ataxia, spastic paraparesis and palatal myoclonus. AxD type II also has a slower progression and cognitive impairment can be completely absent.\nEtiology\nIn the vast majority (95%) of patients, AxD is caused by gain-of-function de novo mutations in the glial fibrillary acidic protein (GFAP) gene. Several familial cases have also been reported with autosomal dominant transmission. This gene encodes GFAP, the major intermediate filament protein found in astrocytes. The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the central nervous system (CNS). It is currently unknown how Rosenthal fibers are involved in disease pathogenesis.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Albee MESSING  - Dr Adeline VANDERVER"}
{"Disease Name": "ALG1-CDG", "Disease Definition": "A severe form of congenital disorders of N-linked glycosylation characterized by severe developmental and psychomotor delay, muscular hypotonia, intractable early-onset seizures, and microcephaly. Additional features include altered blood coagulation with a high probability of hemorrhages or thromboses, nephrotic syndrome, ascites, hepatomegaly, cardiomyopathy, ocular manifestations (strabismus, nystagmus), and immunodeficiency. The disease is caused by loss-of-function mutations in the gene ALG1 (16p13.3).", "ORPHA ID": 79327, "Summary": ""}
{"Disease Name": "ALG11-CDG", "Disease Definition": "A form of congenital disorders of N-linked glycosylation characterized by facial dysmorphism (microcephaly, high forehead, low posterior hairline, strabismus), hypotonia, failure to thrive, intractable seizures, developmental delay, persistent vomiting and gastric bleeding. Additional features that may be observed include fat pads anomalies, inverted nipples, and body temperature oscillation. The disease is caused by mutations in the gene ALG11 (13q14.3).", "ORPHA ID": 280071, "Summary": ""}
{"Disease Name": "ALG12-CDG", "Disease Definition": "A form of congenital disorders of N-linked glycosylation characterized by facial dysmorphism (prominent forehead, large ears, thin upper lip), generalized hypotonia, feeding difficulties, moderate to severe developmental delay, progressive microcephaly, frequent upper respiratory tract infections due to impaired immunity with decreased immunoglobulin levels, and decreased coagulation factors. Additional features include hypogonadism with or without hypospadias in males, skeletal anomalies, seizures and cardiac anomalies in some cases. The disease is caused by loss of function mutations of the gene ALG12 (22q13.33).", "ORPHA ID": 79324, "Summary": ""}
{"Disease Name": "ALG13-CDG", "Disease Definition": "A form of congenital disorders of N-linked glycosylation characterized by microcephaly, hepatomegaly, edema of the extremities, intractable seizures, recurrent infections and increased bleeding tendency. The disease is caused by mutations in the gene ALG13 (Xq23).", "ORPHA ID": 324422, "Summary": ""}
{"Disease Name": "ALG2-CDG", "Disease Definition": "A form of congenital disorders of N-linked glycosylation characterized by iris coloboma, cataract, infantile spasms, developmental delay and abnormal coagulation factors. The disease is caused by loss-of-function mutations in the gene ALG2 (9q31.1). Transmission is autosomal recessive.", "ORPHA ID": 79326, "Summary": ""}
{"Disease Name": "ALG3-CDG", "Disease Definition": "A form of congenital disorders of N-linked glycosylation characterized by severe neurological involvement, including hypotonia, developmental delay, intellectual disability, postnatal microcephaly, and progressive brain and cerebellar atrophy. Epilepsy with hypsarrythmia is frequently reported. Additional features that may be observed include failure to thrive, arthrogryposis multiplex congenita (AMC), vision impairment (optic atrophy, iris coloboma) and facial dysmorphism (hypertelorism with a broad nasal bridge, large and thick ears, thin lips, micrognathia). The disease is caused by loss of function mutations of the gene ALG3 (3q27.3).", "ORPHA ID": 79321, "Summary": ""}
{"Disease Name": "ALG6-CDG", "Disease Definition": "A form of congenital disorders of N-linked glycosylation characterized by feeding problems, mild-to-moderate neurologic involvement with hypotonia, poor head control, developmental delay, ataxia, strabismus, and seizures, ranging from febrile convulsions to epilepsy. Retinal degeneration has also been reported. A minority of patients show other manifestations, particularly intestinal (such as protein-losing enteropathy) and liver involvement. The disease is caused by loss of function mutations of the gene ALG6 (1p31.3).", "ORPHA ID": 79320, "Summary": ""}
{"Disease Name": "ALG8-CDG", "Disease Definition": "A rare form of congenital disorders of N-linked glycosylation characterized by gastrointestinal symptoms (diarrhea, vomiting, feeding problems with failure to thrive, protein-losing enteropathy), edema and ascites (including hydrops fetalis), hepatomegaly, renal tubulopathy, coagulation anomalies due to thrombocytopenia, brain involvement (psychomotor delay, seizures, ataxia), facial dysmorphism (low-set ears and retrognathia), pes equinovarus, and muscular hypotonia. Cataracts may also be observed. Prognosis is usually poor. The disease is caused by loss-of-function mutations in the gene ALG8 (11q14.1), resulting in a block in the initial step of protein glycosylation.", "ORPHA ID": 79325, "Summary": ""}
{"Disease Name": "ALG9-CDG", "Disease Definition": "A rare form of congenital disorders of N-linked glycosylation characterized by progressive microcephaly, hypotonia, developmental delay, drug-resistant infantile epilepsy, and hepatomegaly. Additional features that may be observed include failure to thrive, pericardial effusion, renal cysts, skeletal dysplasia, facial dysmorphism (frontal bossing, hypertelorism, depressed nasal bridge, low-seated ears, large mouth) and hydrops fetalis. The disease is caused by loss-of-function mutations in the gene ALG9 (11q23).", "ORPHA ID": 79328, "Summary": ""}
{"Disease Name": "ALK-negative anaplastic large cell lymphoma", "Disease Definition": "A type of ALCL, a rare and aggressive peripheral T-cell non-Hodgkin lymphoma affecting lymph nodes and extranodal sites, which is characterized by the lack of expression of a protein called anaplastic lymphoma kinase (ALK).", "ORPHA ID": 300903, "Summary": "Epidemiology\nThe prevalence of ALK- ALCL is unknown. This subtype is more commonly found in patients over the age of 40.\nClinical description\nALK- ALCL is characterized by peripheral, mediastinal, or abdominal lymph node involvement. It manifests with the development of painless,enlarged lymph nodes, especially in the neck or armpit (axillary lymph nodes). General symptoms include loss of appetite and fatigue as well as fever, weight loss, and night sweats (B symptoms). Mediastinal involvement manifests as cough, dypsnea and/or edema. ALK- ALCL can also extend to extranodal sites such as the bones, bone marrow, subcutaneous tissue, lungs, spleen and liver. The 5-year survival for ALK-negative patients is of 33-49%.\nEtiology\nEtiology is unknown.\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Pauline BRICE"}
{"Disease Name": "ALK-positive anaplastic large cell lymphoma", "Disease Definition": "A type of ALCL, a rare and aggressive peripheral T-cell non-Hodgkin lymphoma affecting lymph nodes and extranodal sites, which is characterized by the expression of a protein called anaplastic lymphoma kinase (ALK).", "ORPHA ID": 300895, "Summary": "Epidemiology\nThe prevalence of ALK+ ALCL is unknown. This subtype usually affects children and young adults.\nClinical description\nALK+ ALCL is characterized by peripheral, mediastinal, or abdominal lymph node involvement. It manifests with the development of painless, enlarged lymph nodes, especially in the neck or armpit (axillary lymph nodes). General symptoms include loss of appetite and fatigue as well as fever, weight loss, and night sweats (B symptoms). Mediastinal involvement manifests as cough, dypsnea and/or edema. ALK+ ALCL can also extend to extranodal sites such as the bones, bone marrow, subcutaneous tissue, lungs, spleen and liver. The 5-year survival rate of ALK-positive patients is 70-80%.\nEtiology\nIn ALK+ ALCL, the anaplastic lymphoma receptor tyrosine kinase ALK>/i> gene is overexpressed due to a t(2;5) (p23;q35) translocation.\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Pauline BRICE"}
{"Disease Name": "ALK-positive large B-cell lymphoma", "Disease Definition": "A very rare variant of diffuse large B-cell lymphoma (DLBCL) mainly affecting middle-aged immunocompetent men and characterized by a consistent primary involvement of lymph nodes (mainly in the cervical and mediastinum lymph nodes) and with infrequent extra nodal involvement of the bone marrow and other extra-nodal sites (head and neck region, liver, spleen, and gastrointestinal tract). It has an aggressive disease course, and is associated with a poor prognosis.", "ORPHA ID": 364043, "Summary": ""}
{"Disease Name": "Alkaline ceramidase 3 deficiency", "Disease Definition": "A rare genetic leukodystrophy characterized by infantile onset of stagnation and regression of motor and language development resulting in complete lack of communication and purposeful movement. Further neurological manifestations include truncal hypotonia, appendicular spasticity, dystonia, optic disc pallor, peripheral neuropathy, and neurogenic bladder. Patients also present multiple contractures, late-onset relative macrocephaly, short stature, and facial dysmorphism (including coarse facial features, sloping forehead, thick eyebrows, low-set ears, prominent nose, flat philtrum, and prominent lower lip). Brain imaging at advanced stages shows diffuse abnormal white matter signal and severe atrophy. Sural nerve biopsy reveals decreased myelination.", "ORPHA ID": 502444, "Summary": ""}
{"Disease Name": "Alkaptonuria", "Disease Definition": "A rare disorder of phenylalanine and tyrosine metabolism characterized by the accumulation of homogentisic acid (HGA) and its oxidized product, benzoquinone acetic acid (BQA), in various tissues (e.g. cartilage, connective tissue) and body fluids (urine, sweat), causing urine to darken when exposed to air as well as grey-blue coloration of the sclera and ear helix (ochronosis), and a disabling joint disease involving both the axial and peripheral joints (ochronotic arthropathy).", "ORPHA ID": 56, "Summary": "Epidemiology\nBirth prevalence is estimated at around 1/250,000 to 1/1,000,000 in most ethnic groups. The condition is more common in Slovakia and the Dominican republic where it affects up to 1 in 19,000 newborns.\nClinical description\nMany affected individuals are asymptomatic and unaware of their condition until adulthood, however, homogentisic aciduria may be recognized early in infancy by dark-stained diapers. After the third decade, unusual pigmentation of the sclera and the skin overlying cartilage begins to be observed, as well as muscular-skeletal symptoms such as back pain and stiffness. Involvement of the large peripheral joints usually occurs several years after spinal changes, often leading to end-stage joint disease. Ochronotic peripheral arthropathy is generally degenerative in nature. From the fourth decade, joint mobility diminishes. Ankylosis may be present. Fractures of the vertebrae and long bones are also possible. Other features may include genitourinary (e.g. renal, bladder, prostatic stones) and cardiac (mitral valvulitis, arrhythmias) complications as well as respiratory insufficiency due to musculoskeletal involvement.\nEtiology\nPatients are homozygous or compound heterozygous for loss-of-function mutations (more than 200 different variants described worldwide) in the HGD gene, encoding homogentisate 1,2-dioxygenase, an enzyme of the phenylalanine and tyrosine catabolic pathway. The inability to break down HGA leads to its accumulation. Tissue damage results from the deposition of a melanin-like pigment, which is a polymerized form of BQA, that has a high affinity for connective tissue. This pigment is able to trigger numerous redox reactions and induce free radical production, causing further damage to the connective tissue.\nDiagnostic methods\nDiagnosis is suspected upon clinical examination and is based on the amount of HGA found in the urine using gas chromatography-mass spectroscopy. As many patients present without dark urine, it may be advisable to look for HGA in all patients with radiographic evidence of osteoarthritis. A spinal x-ray will reveal disk degeneration combined with dense calcification, particularly in the lumbar area. Genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes acute intermittent porphyria, rheumatoid arthritis, ankylosing spondylitis and osteoarthritis.\nGenetic counseling\nTransmission is autosomal recessive, there is a 25% risk of disease transmission to offspring where both parents are unaffected carriers.\nManagement and treatment\nTreatment is palliative. Dietary restriction (low protein diet) is beneficial, but compliance is often limited. Medical therapy (paracetamol, non-steroidal anti-inflammatory drugs) associated with physiotherapy help to minimize pain and improve the range of joint motion. Older individuals may require removal and fusion of lumbar discs. Hip or knee joint replacement may be necessary. Therapeutic strategies aimed at perturbing the altered phenylalanine-tyrosine pathway have been devised (e.g. nitisinone). Off-label usage of nitisinone has been shown to slow the rate of disease progression; however, the long-term effectiveness and safety in adult patients with alkaptonuria, as well as the most suitable age for intervention, remains to be evaluated (currently an open-label clinical trial and observation study are under way).\nPrognosis\nLife expectancy is not significantly reduced but pain can be constant and progressive functional decline is observed with a loss of mobility; patients often require the use of physical aids (crutches, wheelchair). Cardiac complications are often life-threatening and may worsen the prognosis.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Berardino PORFIRIO"}
{"Disease Name": "Allan-Herndon-Dudley syndrome", "Disease Definition": "An X-linked intellectual disability syndrome with neuromuscular involvement characterized by infantile hypotonia, muscular hypoplasia, spastic paraparesis with dystonic/athetoic movements, and severe cognitive deficiency.", "ORPHA ID": 59, "Summary": "Epidemiology\nAt least 132 families with 320 affected individuals have been reported in the literature to date. Although the prevalence is unknown, one study identified AHDS in 1.4% of males with intellectual disability of unknown etiology. Only males are affected.\nClinical description\nThe disease manifests as congenital hypotonia (appearing at birth or in the first weeks/months of life) that progresses to spasticity (contractures, Babinski sign, and clonus), and is usually detectable early in life. Hyperreflexia appears later in life. Affected males also present, in infancy and early childhood, with muscle hypoplasia and generalized muscle weakness that manifests as difficulty in supporting the head and delayed motor milestones. Hypotonia and severe intellectual deficit are present in 100% of patients. Severe psychomotor delay is present from the outset (delay of motor and language milestones) and autonomy is never reached. The face has distinctive features that evolve over time: open mouth, tented upper lip, ptosis, abnormal folding of the ears, thickening of the soft tissue of the nose and ears, and upturned earlobes. Long, thin everted feet are also typical. Ocular manifestations (i.e. rotary nystagmus and disconjugate eye movements) are rare. Seizures and poor weight gain are reported in some patients. Pectus excavatum and scoliosis are sometimes present, perhaps as a result of the hypotonia and muscle hypoplasia.\nEtiology\nAHDS is caused by mutations in the SLC16A2 gene (Xq13.2), which encodes for monocarboxylate transporter 8 (MCT8), a specific transporter for thyroid hormone T3. Identified mutations include truncations, in-frame deletions, nonsense and missense mutations. Neurological problems may be due to an inability to transport thyroid hormone T3 into some neuronal cells.\nDiagnostic methods\nDiagnosis is based on clinical findings and on the presence of altered thyroid- hormone serum levels: males have abnormally high 3,3',5'-triiodothyronine (T3), low to normal free tetraiodothyronine (T4) levels, and normal to slightly elevated thyroid stimulating hormone (TSH) levels. Molecular genetic testing revealing mutations in the SLC16A2 gene confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include X-linked intellectual disability conditions associated with ataxia, spastic paraplegia or muscle hypoplasia such as X-linked intellectual disability-spastic paraplegia with iron deposits syndrome, X-linked progressive cerebellar ataxia, and spastic paraplegia type 2. Pelizaeus-Merzbacher disease and Snyder-Robinson syndrome should also be considered.\nAntenatal diagnosis\nAntenatal diagnosis of a male with AHDS is possible if the mother is a carrier of a specific SLC16A2 mutation.\nGenetic counseling\nTransmission is X-linked recessive. Affected families should be offered genetic counseling and informed that boys have a 50% risk of being affected if the mother is a carrier of a SLC16A2 mutation and that girls have a 50% risk of inheriting the SLC16A2 mutation if their mother is a SLC16A2 mutation carrier.\nManagement and treatment\nAt present, no treatment is available for AHDS and management consists of supportive measures. Physical, occupational, and speech therapy may be beneficial. Dystonia may be treated with certain medications, including anticholinergics, L-DOPA, carbamazepine, or lioresol. Seizures, when present, can be controlled with standard antiepileptic drugs. Treatment for hypothyroidism does not appear to be beneficial.\nPrognosis\nAlthough several patients have survived into their 60s, overall life expectancy is compromised and quality of life is severely affected as most patients are unable to sit, stand or walk independently.\n\n                            Last update: \n                            March 2017\n\n\n                            - Expert reviewer(s): \n                            Dr Charles SCHWARTZ"}
{"Disease Name": "Allergic bronchopulmonary aspergillosis", "Disease Definition": "A rare immunologic pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus, clinically manifesting with poorly controlled asthma and recurrent pulmonary infiltrates.", "ORPHA ID": 1164, "Summary": "Epidemiology\nThe prevalence of ABPA in the general population is unknown.\nClinical description\nABPA is most commonly diagnosed in adults although it is increasingly being diagnosed in children. Although affected individuals can occasionally be asymptomatic, most of them present with wheezing, bronchial hyperreactivity, hemoptysis, productive cough, low-grade fever, malaise, weight loss, and/or worsening symptoms of asthma and cystic fibrosis (see this term), the two underlying diseases of most of the ABPA patients (about 2% of patients with asthma and 1 to 15% of patients with cystic fibrosis develop ABPA).\nEtiology\nABPA is an immunologic disorder due to a predominant T-helper 2 lymphocyte response to Aspergillus fumigatus infection without tissue invasion. The resulting lung inflammation induces mucus production, airway hyperactivity and, finally, bronchiectasis. Its increased frequency in patients with asthma or cystic fibrosis is consistent with a genetic susceptibility to ABPA.\nDiagnostic methods\nDiagnostic findings of ABPA include immediate cutaneous hyperreactivity to A. fumigatus antigen, elevated A. fumigatus specific IgE levels and total serum IgE levels over 1,000 IU/mL. High levels of A. fumigatus-specific IgG antibodies and eosinophils can also be observed. Chest radiographs and thoracic high-resolution computed tomography (HRCT) can reveal fleeting pulmonary parenchymal opacities, central bronchiectasis, high attenuation mucus, air trapping and centrilobular nodules. Pulmonary function tests may detect airflow obstruction. According to laboratory and imaging findings, five stages of the disease have been defined: acute, remission, recurrent exacerbation (with presence of pulmonary infiltrates, elevation of total serum IgE), corticosteroid-dependent asthma (severe wheezing resulting from discontinuation of the treatment) and fibrotic (irreversible pulmonary function abnormalities). However, the disease usually does not progress through these successive stages.\nDifferential diagnosis\nDifferential diagnosis includes severe asthma with fungal sensitization, newly diagnosed cystic fibrosis, tuberculosis, infectious pneumonia (especially during exacerbations) and other causes of eosinophilic pneumonia like Churg-Strauss syndrome (see this term), and bronchocentric granulomatosis.\nManagement and treatment\nThe best treatment approach is not currently established. Therapeutic options include oral corticosteroids (e.g: prednisolone, prednisone) and antifungal agents (like itraconazole, voriconazole or posaconazole). Other treatments that have been tried include pulse doses of methylprednisolone, and nebulized amphotericin B and omalizumab (antifungal agents). The duration of corticosteroid therapy ranges from several weeks to several months after an acute episode but corticosteroid-dependent asthma patients are very difficult to wean off steroids. The duration of the antifungal therapy has yet to be established. However, if tolerated, it can be used for years.\nPrognosis\nThe clinical course of ABPA is variable. Many ABPA patients can be stabilized for long periods when treated. However, long-lasting remissions are seen in only 50% of patients and many patients require recurrent courses of therapy. Central bronchiectasis, high-attenuation mucus and concomitant aspergilloma at diagnosis identify a patient with a propensity for recurrent relapses and chronicity, which requires close monitoring.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Ritesh AGARWAL"}
{"Disease Name": "Alobar holoprosencephaly", "Disease Definition": "A severe form of holoprosencephaly characterized by a single brain ventricle and no interhemispheric fissure. Severe craniofacial features may manifest as cyclopia, ethmocephaly or cebocephaly.", "ORPHA ID": 93925, "Summary": ""}
{"Disease Name": "Alopecia antibody deficiency", "Disease Definition": "A rare primary immunodeficiency disorder characterized by the association of alopecia areata totalis and antibody deficiency (congenital agammaglobulinemia or incomplete antibody deficiency syndrome), manifesting with recurrent infections. There have been no further descriptions in the literature since 1976.", "ORPHA ID": 1006, "Summary": ""}
{"Disease Name": "Alopecia totalis", "Disease Definition": "A form of alopecia areata, an inflammatory disease of the hair follicle, characterized by a complete loss of hair of the entire scalp which becomes glabrous.", "ORPHA ID": 700, "Summary": ""}
{"Disease Name": "Alopecia universalis", "Disease Definition": "A disorder of most severe form of alopecia areata, an inflammatory disease of the hair follicle, which is characterized by a complete loss of hair of the scalp and all the hair-bearing areas of the body.", "ORPHA ID": 701, "Summary": ""}
{"Disease Name": "Alopecia-contractures-dwarfism-intellectual disability syndrome", "Disease Definition": "A form of ectodermal dysplasia syndrome characterized by a short stature of prenatal onset, alopecia, ichthyosis, photophobia, ectrodactyly, seizures, scoliosis, multiple contractures, fusions of various bones (particularly elbows, carpals, metacarpals, and spine), intellectual disability, and facial dysmorphism (microdolichocephaly, madarosis, large ears and long nose). ACD syndrome overlaps with ichthyosis follicularis-alopecia-photophobia syndrome.", "ORPHA ID": 1005, "Summary": ""}
{"Disease Name": "Alopecia-epilepsy-pyorrhea-intellectual disability syndrome", "Disease Definition": "A rare genetic syndromic intellectual disability that is characterized by congenital permanent alopecia universalis, intellectual disability, psychomotor epilepsy and periodontitis (pyorrhea). Total permanent alopecia and pyorrhea are invariably concomitant while intellectual disability and psychomotor epilepsy are observed in most patients. No other abnormality of nails or skin (apart from absence of hair) has been reported. Transmission is autosomal dominant.", "ORPHA ID": 1008, "Summary": ""}
{"Disease Name": "Alopecia-intellectual disability syndrome", "Disease Definition": "An extremely rare genetic syndromic intellectual disability described in less than 20 families to date and characterized by total or partial alopecia associated with intellectual deficit. The syndrome can be associated with other anomalies such as seizures, sensorineural hearing loss, delayed psychomotor development, and/or hypertonia.", "ORPHA ID": 2850, "Summary": ""}
{"Disease Name": "Alopecia-intellectual disability-hypergonadotropic hypogonadism syndrome", "Disease Definition": "A rare multiple congential anomalies syndrome characterized by association of congenital total alopecia, mild intellectual deficit and hypergonadotropic hypogonadism.", "ORPHA ID": 1014, "Summary": ""}
{"Disease Name": "Alpers-Huttenlocher syndrome", "Disease Definition": "A cerebrohepatopathy and a rare and severe form of mitochondrial DNA (mtDNA) depletion syndrome characterized by the triad of progressive developmental regression, intractable seizures, and hepatic failure.", "ORPHA ID": 726, "Summary": "Epidemiology\nThe incidence of AHS is estimated to be between 1/100,000 and 1/250,000.\nClinical description\nDevelopment is usually normal until disease onset and presentations are highly variable. The most common age of onset is between 2-4 years (ranges from 3 months to 36 years). Seizures (mainly partial, secondary generalized tonic-clonic, or myoclonic) are often the presenting feature, evolving into focal status epilepticus, epilepsia partialis continua, and/or multifocal myoclonic epilepsy. Seizures may respond to treatment initially but usually become intractable. Headaches, visual disturbances and movement disorders (e.g. myoclonus and choreoathetosis) are also common. Cerebellar ataxia develops in most patients. Peripheral neuropathy develops in many and becomes increasingly common in older children and young adults. Loss of cognitive function progresses with varying rates (rapid regression seen during infectious diseases) with manifestations including somnolence, irritability, loss of concentration, loss of language skills and memory deficits, ending in dementia and visual loss. Gastrointestinal involvement (i.e. swallowing dysfunction, intestinal dysmotility) is also noted. Liver disease may be indolent for years before the first acute exacerbation, but may be the first presenting symptom in some children. The clinical course of both brain and liver abnormalities is often episodic with acute exacerbations followed by periods of partial recovery.\nEtiology\nAHS is due to mutations in the polymerase gamma (POLG) gene (15q24). This gene encodes DNA polymerase subunit gamma-1, which is involved in the replication and repair of mtDNA. Ecogenetic and epigenetic stressors, including incidental infections and drugs like valproic acid, can accelerate the onset of symptoms and modify how the phenotype unfolds.\nDiagnostic methods\nDiagnosis is based on clinical and laboratory findings. Electroencephalogram findings include explosive seizures with asymmetric occipital lobe predominance of epileptiform discharges, evolving into epilepsia partialis continua or status epilepticus. Neuroimaging may show neuronal loss/gliosis and generalized brain atrophy. Mitochondrial respiratory chain deficiencies and low levels of mtDNA are noted in the liver and muscle as the disease progresses. Molecular genetic testing revealing a POLG mutation confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses are numerous with some examples being disease phenocopies caused by mutations in the C10ORF2 gene (10q24), which can cause autosomal dominant progressive external ophthalmoplegia (adPEO) as well as recessive mutations that can lead to other phenotypes that may overlap with AHS. Others disorders include infantile neuronal ceroid-lipofuscinosis, late-infantile neuronal ceroid lipofuscinosis, MERRF and MELAS. Other POLG-related disorders include recessive mitochondrial ataxia syndrome (MIRAS), ataxia neuropathy spectrum (ANS), and autosomal recessive PEO.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease-causing mutation.\nGenetic counseling\nAHS is inherited in an autosomal recessive manner. Genetic counseling is possible.\nManagement and treatment\nThere is no cure for AHS and treatment is symptomatic and palliative. Anticonvulsive therapy is prescribed for the management of epileptic seizures but is not always successful. As valproic acid may trigger or worsen liver disease, it is contraindicated. Occupational, physical, and/or speech therapy may be offered to maintain neurologic function as long as possible. Tracheostomy placement, artificial ventilation and placement of a gastric feeding tube may all be necessary as the disease progresses.\nPrognosis\nThe prognosis is severe with life-expectancy in patients ranging from 3 months to 12 years, after disease onset.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Robert NAVIAUX  - Dr Russell SANETO"}
{"Disease Name": "Alpha delta granule deficiency", "Disease Definition": "A rare hemorrhagic disorder due to a constitutional platelet anomaly characterized by moderate to severe deficiency in both platelet alpha-granules and dense bodies, resulting in impaired platelet function and decreased aggregation responses. Patients present increased bleeding tendency with symptoms like easy bruising, or menorrhagia.", "ORPHA ID": 734, "Summary": ""}
{"Disease Name": "Alpha-1-antitrypsin deficiency", "Disease Definition": "A rare hereditary, metabolic disease characterized by serum levels of alpha-1-antitrypsin (AAT) that are well below the normal range. In the most severe form, the disease can clinically manifest with chronic liver disorders (cirrhosis, fibrosis), respiratory disorders (emphysema, bronchiectasis), and rarely panniculitis or vasculitis.", "ORPHA ID": 60, "Summary": "Epidemiology\nPrevalence of the genetic condition at birth is estimated between 1/1,600-5,000 in Western Europe and in the USA.\nClinical description\nThe severe form, caused by homozygous Z variant in the gene SERPINA1, is the most clinically relevant and referred to here as Z-AATD. Z-AATD has an extraordinary heterogeneous disease course. Some individuals remain healthy, while others develop a severe lung or liver disease, rarely both. The age of onset is variable in Z-AATD, liver disease presents typically in newborn/early childhood age or later on in adult life (typically at ≥ 40 years of age). Z-AATD can lead to neonatal cholestasis in about 10 % of the affected infants and about 30-50% of these will develop chronic progressive liver disease. About 10% of adults develop liver cirrhosis. Onset of lung disease is generally between 20 and 50 years of age. The main pulmonary manifestations include early onset panacinar emphysema, bronchiectasis, bronchial asthma or vasculitis presenting with persistent, dyspnea, cough, wheezing, and production of sputum. Smoking is a major factor affecting the course of the pulmonary manifestations, and is associated with earlier onset. Other features include weight loss, recurrent respiratory infections, and fatigue. Panniculitis of variable severity and developing at any age is a rare disease manifestation. A strongly increased risk of developing liver cirrhosis and hepatocellular carcinoma has been reported. The course may be severe in the absence of appropriate treatment and continued tobacco smoking.\nEtiology\nThe disease is due to variants in SERPINA1 (14q32.13). Major gene sequencing efforts carried out in disease populations disclosed more than 100 rare SERPINA1 variants which may cause the absence of circulating AAT (null alleles), poor AAT secretion from hepatocytes (deficiency alleles) or even form a modified enzyme inhibitory activity (dysfunctional alleles). The low levels of the serine protease inhibitor alpha-1-antitrypsin, involved in regulation of neutrophil elastase and proteinase 3, leads to alveolar damage. The pathophysiology of lung alveolar damage is based on the protease-antiprotease balance hypothesis.\nDiagnostic methods\nManifestations are non-specific and therefore may lead to delayed diagnosis. Liver and lung diseases are investigated with imaging and biopsies. The diagnosis is based on detection of low serum concentrations of AAT and molecular genetic testing.\nDifferential diagnosis\nThe main differential diagnoses include asthma in younger patients and chronic obstructive pulmonary disease (COPD) in older individuals. Chronic viral hepatitis, hemochromatosis, Wilson disease, non-alcoholic/alcoholic fatty liver and primary biliary cirrhosis should be considered as alternative causes of liver disease.\nAntenatal diagnosis\nWhen mutations have been identified in an affected family, prenatal diagnosis is possible.\nGenetic counseling\nInheritance is autosomal recessive and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThere is currently no curative treatment. Treatment is similar to that used for COPD and emphysema and aims at reducing symptoms and slowing progression. Long-acting bronchodilators, antibiotics, corticosteroid inhalations, and long-acting beta-agonists are the mainstay of treatment. Another treatment option in severe cases involves augmentation therapy with administration of purified human AAT to reach normal physiological levels. Smoking and exposure to tobacco smoke should be avoided. Vaccines for common respiratory disorders may be beneficial. Lung transplantation may be required for end-stage lung disease. Likewise, liver transplantation can be considered for advanced liver disease. Panniculitis usually responds to treatment with intravenous augmentation of AAT. Several treatments for lung and liver disease are currently in clinical trials.\nPrognosis\nThe prognosis is generally very good in non-smokers. Smoking is known to exacerbate the disease and leads to poorer outcomes. Obesity, diabetes, alcohol misuse, metabolic syndrome and male sex are risk factors for liver disease.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr J. [Jan] STOLK | ERN-LUNG* - Pr Pavel STRNAD | RARE-LIVER*\n\n\n                                * European Reference Network"}
{"Disease Name": "Alpha-B crystallin-related late-onset myopathy", "Disease Definition": "A rare, genetic, alpha-crystallinopathy disease characterized by adult-onset myofibrillar myopathy, variably associated with cardiomyopathy and/or posterior polar cataracts. Patients typically present progressive proximal and distal muscle weakness and wasting of lower and upper limbs, often with velopharyngeal involvement including dysphagia, dysphonia and ventilatory insufficiency. Electromyography shows myopathic features and muscle biopsy reveals myofibrillar myopathy changes.", "ORPHA ID": 399058, "Summary": ""}
{"Disease Name": "Alpha-dystroglycan-related limb-girdle muscular dystrophy R16", "Disease Definition": "A form of limb-girdle muscular dystrophy characterized by slowly-progressive, mainly proximal, muscle weakness presenting in early childhood (with difficulties walking and climbing stairs) and mild to severe intellectual disability. Additional manifestations reported include microcephaly, mild increase in thigh or calf muscles, and contractures of the ankles.", "ORPHA ID": 280333, "Summary": ""}
{"Disease Name": "Alpha-heavy chain disease", "Disease Definition": "A type of HCD characterized by the production of incomplete monoclonal alpha-heavy chains without associated light chains. Alpha-HCD is considered to be a subtype of immunoproliferative small intestinal disease (IPSID). The clinical presentation includes chronic diarrhea with evidence of malabsorption.", "ORPHA ID": 100025, "Summary": "Epidemiology\nThe prevalence of the disease is unknown but most cases have been from North African and Middle Eastern/Mediterranean countries and have been associated with poor sanitation. There have been more than 400 cases reported in the world literature.\nClinical description\nAlpha-HCD has a predilection for young age groups (20-30 years). Patients present with symptoms of malabsorption. Diarrhea, weight loss and abdominal pain are common. Parasitic infections are often present. Infiltration of the jejunal mucosa with plasmacytoid cells is the most frequent pathologic feature. Immunoblastic lymphoma occurs as the disease progresses.\nEtiology\nThe exact cause of alpha-HCD is unknown. The lymphoplasmacytic infiltration of the intestinal mucosa is felt to be a response of the alimentary tract immune system to prolonged luminal antigenic stimulation by intestinal organisms.\nDiagnostic methods\nThe diagnosis of alpha-HCD is based on identification of free alpha-heavy chains without associated light chains. Truncated alpha-heavy chains can be detected in biological fluids (serum, urine, jejunal secretions) by immunoelectrophoresis, immunoselection, or immunofixation.\nDifferential diagnosis\nAlpha-HCD disease must be differentiated from non-Hodgkin lymphoma (NHL; see this term), although this is an uncommon diagnosis in the age range typical of alpha-HCD. Other causes of small bowel malabsorption need to be considered, especially celiac disease (see this term).\nManagement and treatment\nInitial treatment consists of eradication of any concurrent infection (e.g., parasites, viruses, Helicobacter pylori, Campylobacter jejuni) with appropriate antibiotics. For patients with symptomatic disease not responding adequately to antibiotics, chemotherapy similar to that used to treat NHL is recommended. Surgical resection is sometimes needed when bulky masses are present.\nPrognosis\nThe disease course of alpha-HCD is variable and long-term prognosis of the disease is imprecise. Without antibiotics and chemotherapy the disease progresses rapidly and prognosis is poor.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Robert KYLE  - Dr Dietlind WAHNER-ROEDLER"}
{"Disease Name": "Alpha-mannosidosis", "Disease Definition": "An inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual deficit.", "ORPHA ID": 61, "Summary": "Epidemiology\nIt occurs in approximately 1 in 500,000 live births.\nClinical description\nAffected infants often appear normal at birth but their condition worsens progressively. However, some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial dysmorphism is marked by a large head with a prominent forehead, rounded eyebrows, a flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity.\nEtiology\nThe disorder is caused by lysosomal alpha-mannosidase deficiency. It is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12).\nDiagnostic methods\nDiagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic.\nDifferential diagnosis\nThe principle differential diagnoses are other lysosomal storage diseases, such as the various forms of mucopolysaccharidosis (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible, based on both biochemical and genetic methods.\nGenetic counseling\nAlpha-mannosidosis is inherited in an autosomal recessive fashion. Genetic counseling should be provided to explain the nature of the disease and to detect carriers.\nManagement and treatment\nManagement should be proactive, preventing complications and treating manifestations. Infections must be treated frequently. Otolaryngological treatment of fluid in the middle ear is often needed and use of hearing aids is invariably required. Early educational intervention for development of social skills is needed and physiotherapy is important to improve bodily function. Orthopedic surgery may be necessary.\nPrognosis\nThe long-term prognosis is poor. There is an insidiously slow progression of neuromuscular and skeletal deterioration over several decades, making most patients wheel-chair dependent. No patients manage to be completely socially independent. However, many patients survive to over 50 years of age.\n\n                            Last update: \n                            July 2016\n\n\n                            - Expert reviewer(s): \n                            Pr Dag MALM  - Pr Oivind NILSSEN"}
{"Disease Name": "Alpha-N-acetylgalactosaminidase deficiency type 1", "Disease Definition": "A very rare and severe type of NAGA deficiency characterized by infantile neuroaxonal dystrophy.", "ORPHA ID": 79279, "Summary": "Epidemiology\nPrevalence of this disorder is not known but less than 20 cases have been reported to date for NAGA deficiency\nClinical description\nThe disease presents with psychomotor retardation at around 9 months of age and later, at the age of 2, with developmental retrogression. Further manifestations follow between the ages of 4-10 years, including muscular hypotonia, spasticity, nystagmus, strabismus, myoclonic jerks, grand-mal seizures, cortical blindness and deafness, optic and brain atrophy, loss of environmental contact and decorticate posturing. No visceromegaly or coarsening of features has been reported.\nEtiology\nNAGA deficiency type 1 is caused by a homozygous NAGA gene (22q13.2) mutation resulting in a Glu325-to-Lys (E325K) substitution and the dysfunction, instability and rapid degradation of the lysosomal protein NAGA.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling is possible.\n\n                            Last update: \n                            June 2013"}
{"Disease Name": "Alpha-N-acetylgalactosaminidase deficiency type 2", "Disease Definition": "A very rare mild adult type of NAGA deficiency with the features of angiokeratoma corporis diffusum and mild sensory neuropathy.", "ORPHA ID": 79280, "Summary": "Epidemiology\nPrevalence of this disorder is not known but less than 20 cases have been reported to date for NAGA deficiency.\nClinical description\nThis disorder is clinically heterogeneous. Some patients have been reported to have, in addition to angiokeratoma, mild intellectual impairment, but no neurologic signs. Another patient had lymphedema, cardiomegaly, corneal opacity and slight facial coarsening including thick lips, a depressed nasal bridge and an enlarged tip of the nose. Other facultative features consist of tinnitus, hearing loss and vertigo (Meniere disease) (see this term). Pathological characteristics are comprised of vacuolization seen in the blood and dermal cells including the endothelial cells of blood and lymphatic vessels, pericytes, fibrocytes, fat cells, Schwann cells, axons, arrector pili smooth muscle cells, and eccrine sweat gland cells. Vacuolization is most prominent in vascular endothelial cells and the secretory portion of sweat glands.\nEtiology\nDifferent causal homozygous mutations of the NAGA gene (22q13.2) have been described in the reported patients. These mutations lead to the dysfunction, instability and rapid degradation of the lysosomal protein, NAGA. Lack of this enzyme activity leads to impaired catabolism and accumulation of undegraded glycoconjugates in the tertiary lysosomes.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling is possible.\n\n                            Last update: \n                            June 2013"}
{"Disease Name": "Alpha-N-acetylgalactosaminidase deficiency type 3", "Disease Definition": "A rare clinically heterogeneous type of NAGA deficiency with developmental, neurologic and psychiatric manifestations presenting at an intermediate age.", "ORPHA ID": 79281, "Summary": "Epidemiology\nPrevalence of this disorder is not known but less than 20 cases have been reported to date for NAGA deficiency\nClinical description\nA very wide spectrum of signs, with a juvenile onset, has been described including asymptomatic patients at the time of diagnosis. Manifestations seen in clinically overt cases may include epilepsy of variable severity, psychomotor retardation, intellectual impairment, autism, strabismus and cataract.\nEtiology\nCompound heterozygous or homozygous mutations of the alpha-N-acetylgalactosaminidase gene (NAGA; 22q13.2) have been reported in affected patients but also occasionally in their healthy siblings. These mutations lead to the dysfunction, instability and rapid degradation of the lysosomal protein NAGA.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling is possible.\n\n                            Last update: \n                            June 2013"}
{"Disease Name": "Alpha-N-acetylgalactosaminidase deficiency", "Disease Definition": "A very rare lysosomal storage disease that is clinically and pathologically heterogeneous and is characterized by deficient NAGA activity.", "ORPHA ID": 3137, "Summary": "Epidemiology\nExact prevalence of NAGA deficiency is unknown but fewer than 20 cases have been reported to date in patients of German, Dutch, Spanish, Japanese, French and Moroccan origin.\nClinical description\nExtreme clinical variability has been reported. Cases of NAGA deficiency have been divided into 3 clinical subtypes: NAGA deficiency type 1, type 2 and type 3 (see these terms). Type 1 is characterized by infantile-onset neuroaxonal dystrophy, type 2 is described in adult patients with angiokeratoma corporis diffusum and minimal involvement of the nervous system and type 3 is an intermediate clinical form with manifestations ranging from intellectual impairment, neurological dysfunction and seizures to milder neurological and psychiatric issues such as speech and language delays or mild autism-like symptoms.\nEtiology\nAll individuals with NAGA deficiency have mutations in the alpha-N-acetylgalactosaminidase gene (NAGA; 22q13.2) but not all develop neurological symptoms. A number of different NAGA mutations have been identified. There is however no direct genotype-phenotype correlation in view of the clinical heterogeneity of the reported cases. It has been suggested that other factors or genes contribute to the occurrence of neurological symptoms but there is no conclusive evidence to confirm this theory.\nDiagnostic methods\nThe currently known cases were identified through reduced activity of the NAGA enzyme assessed by enzyme tests (assays) on white blood cells (leukocytes), blood plasma or cultured lymphoblasts or fibroblasts, or through urinalysis by thin layer chromatography for oligosaccharide and glycopeptide profiles that revealed increased levels of these complex compounds. Confirmation may be sought by mutation analysis of the NAGA gene.\nDifferential diagnosis\nDifferential diagnosis depends on the type of NAGA deficiency and may include infantile neuroaxonal dystrophy, associated with mutations in the PLA2G6 gene, pantothenate kinase-associated neurodegeneration, associated with mutations in the PANK2 gene and other lysosomal diseases, including Fabry disease, due to different lysosomal enzyme defects or unknown factors (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is theoretically possible by mutation analysis of the NAGA gene after amniocentesis or chorionic villus sampling but as the clinically different forms of the disease have been mapped to the same gene they cannot be determined prenatally.\nGenetic counseling\nNAGA deficiency follows an autosomal recessive pattern of inheritance. Genetic counseling should therefore be offered to affected families.\nManagement and treatment\nTreatment of this disorder is symptomatic and supportive. It includes the maintenance of satisfactory nutrition and hydration, management of infectious diseases (possibly by antibiotic shielding), control of seizures by anti-epileptic drugs, reduction of spasticity or pain with medication, adequate positioning, physiotherapy to prevent joint contractures or pneumonia, and aspiration prophylaxis potentially including tube feeding. Recent studies identify NAGA deficiency as a typical protein folding disorder. As such, investigational studies are examining whether it is amenable to pharmacological chaperone approaches or enzyme replacement therapy. Gene therapy is being studied as another possible approach to therapy for some lysosomal storage disorders.\nPrognosis\nPrognosis is variable depending on the type of NAGA deficiency, with type 1 having the worst and the other types having fairer outcomes. Evidence-based mortality rates or life expectancy figures are not available due to the very small number of patients.\n\n                            Last update: \n                            June 2013"}
{"Disease Name": "Alpha-sarcoglycan-related limb-girdle muscular dystrophy R3", "Disease Definition": "A subtype of autosomal recessive limb-girdle muscular dystrophy characterized by childhood onset of progressive proximal weakness of the shoulder and pelvic girdle muscles, resulting in difficulty walking, scapular winging, calf hypertrophy and contractures of the Achilles tendon, which lead to a tiptoe gait pattern. Cardiac and respiratory involvement is rare.", "ORPHA ID": 62, "Summary": ""}
{"Disease Name": "Alpha-thalassemia-intellectual disability syndrome linked to chromosome 16", "Disease Definition": "A rare developmental defect during embryogenesis, a contiguous gene deletion syndrome, is a form of alpha-thalassemia characterized by microcytosis, hypochromia, normal hemoglobin (Hb) level or mild anemia, associated with developmental abnormalities.", "ORPHA ID": 98791, "Summary": "Epidemiology\nAlpha-thalassemia-intellectual disability syndrome linked to chromosome 16 (ATR-16) prevalence is unknown. More than 20 cases have been reported to date.\nClinical description\nATR-16 is a congenital disease. Patients present with either alpha-thalassemia trait or mild hemoglobin H disease (HbH disease) associated with a mild to profound (in most cases) intellectual disability and, in some cases, with mild, nonspecific dysmorphic features (mild hypertelorism, down slanted palpebral fissures, broad or prominent nasal bridge, small ears, short neck), microcephaly and short stature. Genital abnormalities (hypospadias and cryptorchidism) have been reported in males. Club foot is common.\nEtiology\nATR-16 is due to large deletions on chromosome band 16p13.3 which remove the alpha-globin genes (HBA1 and HBA2), and many other flanking genes. The gene(s) responsible for intellectual deficiency and other developmental abnormalities has not been clearly identified. All cases are due to de novo deletions or segregation for parental translocations inherited in an unbalanced manner.\nDiagnostic methods\nDiagnosis is based on the clinical picture and confirmed by cytogenetic testing. Routine cytogenetic studies may be sufficient to identify the deletion. However, in some instances other methods such as comparative genomic hybridization (CGH) arrays are used to detect cryptic subtelomeric deletions.\nDifferential diagnosis\nDifferential diagnosis includes Alpha thalassemia - X-linked intellectual deficit syndrome, and the co-occurrence of common alpha-thalassemia trait and an intellectual deficiency of another cause.\nAntenatal diagnosis\nAntenatal diagnosis is indicated in cases of parental translocations but it can also be offered to parents of a patient with de novo deletions to prevent recurrence due to germline mosaicism.\nGenetic counseling\nGenetic counseling is possible when parents are known carriers of the chromosomal translocation.\nManagement and treatment\nThere is no treatment for ATR-16. Management is symptom-based and requires a multidisciplinary approach. Management of intellectual deficiency usually includes speech therapy and individualized educational plans. In case of anemia, specific treatment may include occasional red blood cell transfusions, iron chelation and other supportive measures.\nPrognosis\nThe prognosis is highly variable, depending on the degree of intellectual deficiency.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Catherine BADENS"}
{"Disease Name": "Alpha-thalassemia-myelodysplastic syndrome", "Disease Definition": "An acquired form of alpha-thalassemia characterized by a myelodysplastic syndrome (MDS) or more rarely a myeloproliferative disease (MPD) associated with hemoglobin H disease (HbH).", "ORPHA ID": 231401, "Summary": "Epidemiology\nAbout 80 cases have been identified to date and most involved patients are of northern European descent. Some cases have been reported in patients from Asia and the Mediterranean area.\nClinical description\nATMDS occurs predominantly in males during the 7th decade of life (male-to-female ratio greater than 6:1). The main clinical features include anemia and other signs associated with MDS such as shortness of breath, weakness, tendency to bruise or bleed and an increased susceptibility to infections. It has occasionally been associated with MPD and in these cases, splenomegaly frequently co-occurs. MDS progresses to leukemia in about 25% of cases and HbH is usually no longer detectable at this time.\nEtiology\nATMDS is due to acquired somatic mutations in the ATRX gene (Xq21.1). There is also evidence that acquired deletions of chromosome 16p may be causative. These defects result in significant down-regulation of alpha-globin gene expression.\nDiagnostic methods\nTypical hematological findings show hypochromic microcytic red blood cells and striking anisopoikilocytosis, and the presence of HbH inclusions in a proportion of red blood cells that varies depending on the patients. Cytological and cytogenetic analysis of bone marrow cells is required to confirm the diagnosis and to classify the underlying MDS. Direct sequencing of the ATRX gene in DNA samples from blood or bone marrow usually indicates a mosaicism, identified by a single nucleotide mutation.\nDifferential diagnosis\nDifferential diagnoses include other causes of anemia, cytopenia or microcytosis. It is especially important to exclude an inherited form of alpha-thalassemia by molecular analysis of the HBA locus.\nManagement and treatment\nTreatment depends on the underlying MDS. Stem cell transplantation is the only curative treatment but it is rarely feasible. Other treatment options may include hypomethylant (azacitabine) therapy and lenalinomide. Supportive care includes blood transfusions, erythropoietin stimulating agents, growth factors, antibiotics (if infections are present), and iron chelation therapy in those undergoing long term transfusion therapy.\nPrognosis\nPrognosis depends on the sub-type of MDS according to the International scoring system (ISS). The scoring system takes into account the percentage of marrow blasts, the severity of cytopenia, and cytogenetic analysis of bone marrow cells. Death is usually due to leukemic transformation, infections due to neutropenia, bleeding related to thrombocytopenia and, in some cases, to other co-morbidities such as cardiovascular disease.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Catherine BADENS  - Pr Christian ROSE"}
{"Disease Name": "Alpha-thalassemia", "Disease Definition": "A rare inherited hemoglobinopathy characterized by impaired synthesis of two to all four alpha-globin chains leading to a variable clinical picture depending on the number of affected alleles.", "ORPHA ID": 846, "Summary": "Epidemiology\nLike other globin gene disorders, alpha-thalassemia is highly prevalent in all tropical and subtropical regions (around 1/10,000), particularly in the African equatorial belt. Intermediate and severe forms of alpha-thalassemia are very rare in North America and Northern Europe (about 1/1,000,000), but predominantly seen in immigrant populations from South-East Asia or Mediterranean countries.\nClinical description\nDisease expression varies according to the level of alpha-globin chain deficiency. Alpha thalassemia trait (or alpha thalassemia minor) causes microcytosis and hypochromia with absent or mild anemia (often detected on routine blood tests), generally with no other symptoms. Hemoglobin H disease (HbH) is characterized by moderate hemolytic anemia with variable amounts of hemoglobin H along with occasionally severe splenomegaly, sometimes complicated by hypersplenism. Hb Bart's hydrops fetalis involves a severe deficiency in alpha-globin chains with serious developmental implications.\nEtiology\nAlpha globin synthesis is regulated by four alpha-globin genes, two on each copy of chromosome 16 (16p13.3). Alpha-thalassemia most frequently results from deletion of two or more alleles (HBA1 and HBA2). More rarely, point mutations in critical regions of these genes may cause non-deletional alpha-thalassemia. Deletions of regulatory elements located upstream of the alpha-globin genes have also been found. The severity of the clinical picture is correlated with the degree of alpha-globin chain deficiency. It has been found that interactions involving non-deletional forms lead to more severe manifestations than those involving deletional forms. Deletion of 1 allele results in the silent form, 2 alleles in alpha-thalassemia trait, 3 alleles in HbH and 4 alleles in Hb Bart's hydrops fetalis.\nDiagnostic methods\nDiagnosis is based on hematologic testing of red blood cell (RBC) indices, peripheral blood smear, supravital stain to detect RBC inclusion bodies, and qualitative and quantitative hemoglobin analysis. Confirmation of diagnosis is based on molecular genetic testing.\nDifferential diagnosis\nDifferential diagnosis should include iron deficiency anemia and defects in heme synthesis. An acquired form known as alpha-thalassemia-myelodysplastic syndrome (ATMDS) has been described mainly in adult males and should also be considered; it is characterized by myelodysplasia (MD) associated with HbH. A syndromic form, alpha-thalassemia-intellectual deficit syndrome, is characterized by very mild to severe anemia associated with developmental abnormalities.\nAntenatal diagnosis\nPrenatal diagnosis is possible when Hb Bart's hydrops fetalis or a severe form of Hb H disease has previously been identified in a family member.\nGenetic counseling\nCarriers of a single allelic variant are asymptomatic (silent alpha-thalassemia) but pose a risk of transmission to their offspring. The pattern of inheritance is autosomal recessive and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nPatients with silent alpha-thalassemia or thalassemia trait do not require treatment. Specific treatment is however required for other forms of the disease and may include occasional or regular red blood cell transfusions, iron chelation, and other supportive measures.\nPrognosis\nThe prognosis for carriers of silent alpha-thalassemia or alpha-thalassemia trait is very good. Neonates with Hb Bart's hydrops fetalis usually die in the perinatal period. In patients with hemoglobin H disease, the prognosis is usually good, but depends on complications and care.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Corinne PONDARRE"}
{"Disease Name": "ALPI-related inflammatory bowel disease", "Disease Definition": "A rare genetic gastroenterological disease characterized by severe, refractory intestinal inflammation with mucosal erosions and ulcerations potentially involving the small and large intestine. Epithelioid granulomas are typically absent. Patients present with severe diarrhea, abdominal pain, vomiting, rectal bleeding, and weight loss.", "ORPHA ID": 597887, "Summary": ""}
{"Disease Name": "Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome", "Disease Definition": "A rare constitutional hemolytic anemia that is characterised by the association of Alport syndrome, midface hypoplasia, intellectual deficit and elliptocytosis. It has been described in two families. The syndrome is transmitted as an X-linked trait is caused by a contiguous gene deletion in Xq22.3 involving several genes including COL4A5, FACL4 and AMMECR1.", "ORPHA ID": 86818, "Summary": ""}
{"Disease Name": "Alport syndrome", "Disease Definition": "A rare renal disease characterized by glomerular nephropathy with hematuria progressing to end-stage renal disease (ESRD), frequently associated with sensorineural deafness, and occasionally with ocular anomalies.", "ORPHA ID": 63, "Summary": "Epidemiology\nThe global prevalence of Alport syndrome (AS) is unknown. The prevalence at birth in Finland is estimated at 1/53,000. In the USA, Alport syndrome reportedly accounts for up to 2% of new cases of pediatric ESRD.\nClinical description\nThe clinical subtypes of AS include X-linked (XL), autosomal recessive (AR) and autosomal dominant (AD) AS and count for about 80%, 15% and 5% of all AS cases, respectively. AS can present anywhere from childhood to elderly age, although it generally manifests earlier (during childhood or adolescence) in XL and AR forms. Males are severely affected in XLAS and present with microhematuria very early in life, followed by micro-albuminuria, macroproteinuria and progression to ESRD before the age of 40 years old. XLAS is highly variable in females, ranging from an asymptomatic disease to lifelong microscopic hematuria (with preserved renal function), or renal failure at a young age. Sensorineural hearing loss is common. Occasional ocular anomalies (e.g. anterior lenticonus, retinal flecks, corneal lesions) may develop in late childhood or early adulthood, males being more commonly affected than females. Rarely, leiomyomatosis (esophagus, tracheobronchial tree or female genitalia) can be associated, forming the X-linked diffuse leiomyomatosis-AS (XL-DLAS). ARAS is similar to XLAS in males, but presents without any gender differentiation in the disease course and the family history. ADAS varies from an asymptomatic disease (mostly presenting as a familial benign hematuria) to AD forms of proteinuria and focal segmental glomerulosclerosis (in cases without hematuria or not as a first line presentation). The progression to ESRD is usually slower than in XLAS, and extra-renal manifestations are less common.\nEtiology\nAS involves a structural defect of type IV collagen, an essential component of the glomerular basal membrane. XLAS is due to mutations in COL4A5 (Xq22.3) gene coding for the alpha 5 chain of type IV collagen. ARAS and ADAS are due to mutations in both COL4A3 (2q36.3) and COL4A4 (2q36.3) genes coding for the alpha 3 and 4 chains of type IV collagen, respectively. XL-DLAS is due to COL4A5 (Xq22.3) and COL4A6 (Xq22.3).\nDiagnostic methods\nThe diagnosis is based on familial history, clinical signs, electron microscopy examination of renal biopsy (showing abnormalities of the glomerular basal membrane), and immunohistochemical findings on renal and cutaneous biopsy (even if it cannot establish the diagnosis in all the patients). Molecular genetic testing can confirm the diagnosis.\nDifferential diagnosis\nThe differential diagnoses include hematuria related to urologic diseases and cancer, IgA nephropathy, nephropathy related to MYH9 mutation, and familial benign hematuria.\nAntenatal diagnosis\nA prenatal and pre-implantation diagnosis is possible for at-risk pregnancies, if a causative mutation has been found in a member of the affected family.\nGenetic counseling\nMost AS cases follow an X-linked dominant mode of inheritance, but AR and AD cases have also been reported. A genetic counseling should be proposed to affected families.\nManagement and treatment\nThe management of AS is only symptomatic, mainly aiming at slowing the progression to ESRD. It includes angiotensin blockade (e.g. angiotensin converting enzyme inhibitors, angiotensin receptor blockers), diuretics, and a salt-restricted diet. The most severe cases require dialysis and renal replacement therapy. Regular hearing and ocular follow-up are recommended. Hearing aids should be prescribed when needed, and surgical intervention for ocular anomalies can be considered.\nPrognosis\nThe prognosis of AS is poor due to the progression to ESRD (often affecting young adults). However, renal transplantation is usually successful, since the development of anti-type IV collagen antibodies is a rare event. The extra-renal features can affect the quality of life.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Laurence HEIDET | ERKNet* - Pr Rachel LENNON | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Alström syndrome", "Disease Definition": "A rare multisystemic disorder characterized by cone-rod dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy (DCM), and progressive hepatic and renal dysfunction.", "ORPHA ID": 64, "Summary": "Epidemiology\nAlström syndrome (AS) has a suggested prevalence of 1/1000,000 in Europe and North America. A much higher frequency was reported in some populations with a high level of consanguinity or those that are geographically isolated. More than 950 cases have been identified worldwide.\nClinical description\nThe clinical features, age of onset, and severity can vary greatly among and within families. Cone-rod retinal dystrophy usually develops within a few weeks after birth, with the first symptoms being nystagmus and extreme photodysphoria or light sensitivity. It is progressive and leads to blindness, usually by the second decade of life. Most patients develop mild-to-moderate slowly progressive bilateral sensorineural hearing loss. There is evidence of multi-organ fibrosis in AS. DCM manifests in approximately 2/3 of patients, either as infants or as adolescents. Patients are at risk of sudden congestive heart failure at any age. Obesity with hyperphagia, insulin resistance and hyperinsulinemia are early and consistent features. Liver dysfunction usually begins in childhood with steatosis (fatty liver). In some cases, cirrhosis, portal hypertension and liver failure can occur. Chronic respiratory illness (bronchitis/pneumonia), pulmonary hypertension, recurrent otitis media, and hypertriglyceridemia are frequent. Slowly progressive nephropathy can lead to end stage renal failure. Patients have distinctive facial characteristics ( thin hair, premature frontal balding, deep-set eyes with a rounded face and thick ears,). Most children have characteristic wide, thick, flat feet, and short stubby fingers and toes with no polydactyly or syndactyly. Hypogonadism in males/hyperandrogenism in females is also reported. Most patients have normal intelligence, although some reports have indicated delayed global development and intellectual disability. As some phenotypes develop slowly over time, non-classical presentations have also been reported.\nEtiology\nAS is caused by mutations in the ALMS1 gene (2p13.1). Its molecular function is currently unknown, although roles in ciliary function, cell cycle control, and intracellular transport have been suggested.\nDiagnostic methods\nDiagnosis is made on the basis of the clinical features observed (major/minor), and typically confirmed with genetic testing. Family history is considered a major criteria in the diagnosis of AS.\nDifferential diagnosis\nDifferential diagnoses include Bardet-Biedl syndrome, Biemond syndrome type 2, Wolfram syndrome, Cohen syndrome, familial isolated DCM and mitochondrial disorders.\nAntenatal diagnosis\nPrenatal testing can be offered if the ALMS1 mutations have been previously identified in a family member.\nGenetic counseling\nAS is transmitted autosomal recessively and genetic counseling is recommended.\nManagement and treatment\nManagement should include vigilant monitoring and treatment of the emerging clinical manifestations. Red-orange tinted prescription lenses can reduce photophobia. As blindness occurs in all cases, early educational planning to teach patients Braille, computing skills and adaptive living skills is essential. Bilateral digital hearing aids and cochlear implants can increase hearing capabilities. Heart failure is mainly treated with angiotensinogen-converting enzyme (ACE) inhibitors, beta-blockers, diuretics, and digoxin. Heart transplantation could be also considered. Diabetes can be managed with a low-fat, low sugar diet, exercise, metformin, glitazones, incretin analogues, and SGLT2 inhibitors (beneficial in 2/3 of cases). Beta-blockers, sclerotherapy of the esophageal veins, and banding usually treat portal hypertension. In unsuccessful cases a transjugular intrahepatic portosystemic shunt may be needed. In those with renal disease, ACE inhibitors can be considered. In several cases, renal transplantation has been successful. New medications are in clinical trials, and include PBI-4050 (phase 2 completed), a compound with anti-fibrotic and anti-inflammatory properties, and setmelanotide for the treatment of hyperphagia in rare forms of genetic obesity including AS.\nPrognosis\nAlthough the life span of AS patients can be shortened, early diagnosis and intervention can moderate the progression and improve the longevity and quality of life of patients.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Pietro MAFFEI"}
{"Disease Name": "Alternating hemiplegia of childhood", "Disease Definition": "A rare, genetic, neurodevelopmental disorder characterized by early-onset of recurrent, transient episodes of hemiplegia (including quadriplegia), which typically disappear upon sleep.", "ORPHA ID": 2131, "Summary": "Epidemiology\nAlternating hemiplagia of childhood (AHC) prevalence is estimated at 1/100,000 in children under 16 years old, although underdiagnosis is probable.\nClinical description\nPatients usually present in infancy with episodic hemiplegia involving one or alternating sides of the body which typically disappear upon sleep. Episodes occur with variable frequency and may last a few minutes to several days. Isolated or associated episodes of bilateral hemiplegia may also be observed. Early signs of the disease are often noted, in some cases shortly after birth, associating paroxysmal involuntary movements (including tonic-dystonic movements) nystagmus, choreoathetosis, dyskinesia and autonomic abnormalities. Various triggers may precipitate symptoms, including exposure to heat or cold, emotional stress, fatigue, excessive light and sound stimuli, trauma, and bathing. Psychomotor delay, ranging from mild to severe, is common. Additional features include cerebellar signs, speech disorders and behavioral disturbances, such as mood changes, aggressiveness, impulsivity and attention deficit. A considerable number of AHC patients develop epilepsy and cardiac conduction abnormalities.\nEtiology\nAlthough the exact pathophysiological mechanism of AHC remains unclear, de novo heterozygous mutations in the ATP1A3 (19q13.2) gene, encoding a subunit of the Na+/K+ ATPase pump, have been implicated as causative for the majority of screened AHC cases. Over 60 different AHC mutations have been identified so far in the ATP1A3 gene as the most frequent mutations are D801N (43%), E815K (16%), and G947R (11%) Some cases with alternating hemiplegia and atypical features have been reported with mutations in the ATP1A2 (1q23.2),CACNA1A,ADCY5, TANGO2 and SLC1A3 genes.\nDiagnostic methods\nDiagnosis is based on characteristic clinical manifestations using Aicardi's diagnostic criteria. ATP1A3 gene testing would be recommended to support clinical diagnosis of AHC.\nDifferential diagnosis\nDifferential diagnoses includes infantile epilepsy syndrome, benign nocturnal alternating hemiplegia of childhood, as well as allelic disorders with overlapping clinical features, such as rapid-onset dystonia-parkinsonism, familial or sporadic hemiplegic migraine and Moyamoya disease. Neurological, metabolic and vascular syndromes with similar clinical features should also be excluded.\nAntenatal diagnosis\nPrenatal diagnosis for pregnancies at increased risk is possible if a causative mutation has been previously identified in the family.\nGenetic counseling\nAHC is inherited in an autosomal dominant manner as most cases are sporadic. However, parental germline mosaicism has also been reported in couple of cases with familial recurrence. Therefore genetic counseling should be provided to parents with an affected child and should take into account the risk of recurrence in the family.\nManagement and treatment\nThere is no regulatory approved treatment for AHC. Flunarizine has been widely prescribed during the past 30 years to reduce the frequency, severity and duration of hemiplegic episodes. Other commonly used drugs are topiramate, benzodiazepines, chloral hydrate. Seizures and ECG abnormalities should be properly treated and monitored while triggers and irregular sleeping patterns should be avoided as much as possible.\nPrognosis\nPsychomotor outcome is highly variable as some patients may be wheelchair-bound while others are able to live independent lives in adulthood. Frequency and duration of acute manifestations generally decrease with age, however sudden deterioration can occur in the late course of the disease. Status epilepticus in alternating hemiplegia is linked to severe outcome.\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Tsveta SCHYNS-LIHARSKA"}
{"Disease Name": "Alveolar echinococcosis", "Disease Definition": "A rare parasitic disorder that occurs after ingestion of eggs of Echinococcus multilocularis and characterized by an initial asymptomatic incubation period of many years followed by a chronic course where the clinical manifestations include epigastric pain and jaundice.", "ORPHA ID": 284, "Summary": "Epidemiology\nE.multilocularis is endemic in the northern hemisphere and central Europe and the incidence in Europe is estimated to range between 1/10,000,000-1/330,000. Hot spots are in Western parts of China and Central Asia. People at high risk include dog-owners, including farmers, or others who have contact with wild foxes, or their stool.\nClinical description\nThe peak age group in Europe is 50-60 years. After an asymptomatic period of >10 years, the parasite invades mainly the liver forming slow-growing, minute vesicles comparable to a sponge. As the lesion gets larger, the central part may become necrotic, and appears as a pseudocyst. Calcifications can frequently be seen. The clinical manifestations include epigastric pain and jaundice which may be followed by fever, anemia and weight loss. Invasion of the bile ducts leads to cholangitis, portal hypertension, and biliary cirrhosis. The disease can progress to the cirrhotic stage after a long latent, asymptomatic period. Extrahepatic manifestation as primary disease is very rare (1%). 13% of cases present as multiorgan disease where the metacestode infiltrates the neighborhood of the liver, and/or sets metastasis involving the lungs, spleen, bones and/or brain. Lung or brain involvement is characterized by exertional dyspnea, dysarthria, hemiparesis and cranial nerve palsies.\nEtiology\nAlveolar echinococcosis (AE) occurs after ingestion of eggs of the parasite E.multilocularis. Wild carnivores, mainly foxes, are the most important definitive hosts but domestic dogs and cats may also serve as definite hosts by ingestion of infected wild rodents. Human are accidental intermediate hosts and are affected by the intermediate metacestode stage of the parasite.\nDiagnostic methods\nDiagnosis of AE is based on: typical organ lesions detected by imaging techniques such as ultrasound (large hepatic mass with juxtaposed areas of internal hyper- and hypoechogenicity, irregular margins, and scattered calcification, and/or a pseudocyst with a large area of central necrosis surrounded by an irregular ring-like region of hyperechogenicity representing fibrous tissue), CT (indistinct solid tumors with central necrotic areas, plaque like calcifications), and MRI; detection of specific serum antibodies by ELISA or by immunochromatographic test; specific staining of metacestode in histo-or immunohistopathology; and detection of E. multilocularis nucleic acid in a clinical specimen.\nDifferential diagnosis\nDifferential diagnosis includes benign or malignant neoplasms, focal hepatic lesions, and abscesses.\nManagement and treatment\nThe mainstay for AE treatment remains an interdisciplinary management guided by gastroenterologists, surgeons, radiologists and parasitologists. Radical surgery is indicated if lesion can be excised with safety margins. Long-term antiparasitic treatment with albendazole is mandatory. Preventive measures include avoidance of contact with fox feces, use of praziquantel-impregnated baits, regular treatment of dogs or cats with praziquantel, as well as hand washing and improved hygiene.\nPrognosis\nAE is one of the most dangerous zoonotic diseases in the world and if untreated prognosis is poor. Early diagnosis and treatment of AE, especially during the asymptomatic period, are important for reducing morbidity and mortality. Patients succumb to hepatic failure, invasion of contiguous structures, or, less frequently, involvement of the brain. Mortality rates have traditionally been high, ranging between 50% and 75%. However, in recent years major achievement has been reached by careful management of AE cases, and life-expectancy of patients is approaching that of the general population.\n\n                            Last update: \n                            June 2014"}
{"Disease Name": "Alveolar soft tissue sarcoma", "Disease Definition": "A rare soft tissue sarcoma characterized by a slowly growing, painless space-occupying lesion, composed of large, uniform, epithelioid cells arranged in solid nests and/or alveolar structures, separated by thin, sinusoidal vessels. The tumor mostly affects adolescents and young adults. Early metastasis, most commonly to the lung, bones, and brain, is a characteristic feature and relevant prognostic factor, together with age at presentation and tumor size, while histological features have no prognostic significance.", "ORPHA ID": 163699, "Summary": ""}
{"Disease Name": "ALys amyloidosis", "Disease Definition": "A rare, hereditary amyloidosis with primary renal involvement characterized by amyloid deposition in the kidney glomeruli and medulla, gastrointestinal tract, liver, spleen and slow disease progression. Symptoms and signs include nausea, vomiting, dyspepsia, gastritis, gastrointestinal hemorrhage, abdominal pain, hepatic rupture, sicca syndrome, purpura and petechiae, lymphadenopathy and renal dysfunction.", "ORPHA ID": 93561, "Summary": ""}
{"Disease Name": "Amaurosis-hypertrichosis syndrome", "Disease Definition": "A rare, syndromic, inherited retinal disorder characterized by cone-rod type congenital amaurosis, severe retinal dystrophy leading to visual impairment and profound photophobia (without night blindness), and trichomegaly (bushy eyebrows with synophrys, excessive facial and body hair (including marked circumaleolar hypertrichosis). There have been no further descriptions in the literature since 1989.", "ORPHA ID": 1021, "Summary": ""}
{"Disease Name": "Amelo-onycho-hypohidrotic syndrome", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by the association of hypocalcified and hypoplastic tooth enamel, distal finger and toenail onycholysis with subungueal hyperkeratosis, and functional hypohidrosis. Additional manifestations include seborrheic scalp dermatitis and rough, dry skin. Lacrymal punctae may be occasionally absent. There have been no further descriptions in the literature since 1975.", "ORPHA ID": 1028, "Summary": ""}
{"Disease Name": "Ameloblastic carcinoma", "Disease Definition": "A rare odontogenic tumor characterized by aggressive clinical course and local destruction, occurring in mandible more often than in maxilla. The most common symptom is a rapidly progressing painful swelling, but it may present as a benign cystic lesion or as a large, rapidly growing mass with ulceration, bone resorption and teeth mobility, as well. The tumor may metastasize, most commonly to the cervical lymph nodes and the lungs.", "ORPHA ID": 314422, "Summary": ""}
{"Disease Name": "Ameloblastoma", "Disease Definition": "A rare, benign, slow-growing odontologic tumor located in the mandible, and on occasion the maxilla, characterized by painless, variable-sized jaw swelling, which if left untreated may lead to a grotesque facial appearance. Occasionally, paresthesias, tooth displacement and adjacent root resorption may be associated. Local invasion is frequently observed, but malignant transformation and metastasis are not common.", "ORPHA ID": 314419, "Summary": ""}
{"Disease Name": "Amelocerebrohypohidrotic syndrome", "Disease Definition": "A genetically heterogeneous autosomal recessive syndrome characterized by the triad of amelogenesis imperfect, infantile onset epilepsy, intellectual disability with or without regression and dementia.", "ORPHA ID": 1946, "Summary": ""}
{"Disease Name": "Amelogenesis imperfecta", "Disease Definition": "A rare genetic odontal or periodontal disorder that represents a group of developmental conditions affecting the structure and clinical appearance of the enamel of all or nearly all the teeth in a more or less equal manner, and which may be associated with morphologic or biochemical changes elsewhere in the body.", "ORPHA ID": 88661, "Summary": "Epidemiology\nThe prevalence varies from 1:700 to 1:14,000, according to the populations studied.\nClinical description\nThe enamel may be hypoplastic, hypomineralised or both, and affected teeth may be discoloured, sensitive or prone to disintegration. Amelogenesis imperfecta (AI) exists in isolation or associated with other abnormalities as part of a syndrome.\nEtiology\nIn families with an X-linked form, it has been shown that the disorder may result from mutations in the amelogenin gene, AMELX. The enamelin gene, ENAM, is implicated in the pathogenesis of the dominant forms of AI. Autosomal recessive AI has been reported in families with known consanguinity.\nDiagnostic methods\nDiagnosis is based on the family history, pedigree plotting and meticulous clinical observation. At present, genetic diagnosis is only available as a research tool.\nGenetic counseling\nIt may be sporadic or show autosomal dominant, autosomal recessive or sex-linked inheritance.\nManagement and treatment\nThe condition presents social and functional problems and leads to discomfort, but it may be managed by early vigorous intervention, both preventively and restoratively, with treatment continued throughout childhood and into adult life. In infancy, the primary dentition may be protected by the use of preformed metal crowns on posterior teeth. Longer-term care involves either crowns or, more frequently these days, adhesive, plastic restorations.\n\n                            Last update: \n                            April 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Michael ALDRED  - Pr Agnès BLOCH-ZUPAN  - Pr Peter CRAWFORD"}
{"Disease Name": "American trypanosomiasis", "Disease Definition": "A tropical disease mainly found in latin America and transmitted by triatomine insects (mostly Triatoma infestans and Rhodnius prolixus and Panstrongylus megistus) harboring the hemoflagellate protozoan parasite Trypanosoma cruzi. The disease is characterized by an acute phase which is either asymptomatic or manifest with fever, inflammation at the inoculation site (inoculation chancre or chagoma), unilateral palpebral edema called the Romaña sign (when the triatomine bite occurs near the eye), enlarged lymph nodes, and splenomegaly. The chronic phase is lifelong and development of chagasic cardiomyopathy (30%; complex arrhythmias, heart failure, and thromboembolic events), digestive (10%; megaoesophagus and megacolon), neurological (10%; stroke, peripheral neuropathy and autonomic dysfunction), or mixed alterations (10%) may be observed. These can all lead to high morbidity and mortality rates.", "ORPHA ID": 3386, "Summary": ""}
{"Disease Name": "Aminoacylase 1 deficiency", "Disease Definition": "An inborn error of metabolism marked by a characteristic pattern of urinary N-acetyl amino acid excretion and neurologic symptoms.", "ORPHA ID": 137754, "Summary": "Epidemiology\nPrevalence is unknown but less than 20 cases have been reported in the literature so far.\nClinical description\nMost individuals with ACY1D identified so far are children who underwent selective screening tests for inborn errors of metabolism prompted mainly by delayed psychomotor development or by the occurrence of seizures. However, there is a considerable phenotypic variability between ACY1D individuals.\nEtiology\nACY1D is caused by biallelic mutations in the ACY1 gene (3p21.2). ACY1 catalyzes the formation of free amino acids from N-acetylated precursors. The enzyme is strongly expressed in the human brain and is a potential modifier affecting the severity or manifestation of different neurologic diseases.\nDiagnostic methods\nDiagnosis is made by gas chromatography-mass spectrometry (GC-MS) analysis of urinary organic acids revealing increased levels of N-acetylated amino acids, including methionine, glutamine, alanine, leucine, glycine, valine, and isoleucine derivatives, or by NMR spectroscopy of urine. The diagnosis can be confirmed by identification of mutations in the ACY1 gene and by detection of reduced ACY1 enzyme activity in Epstein-Barr virus (EBV)-transformed lymphoblasts or in fibroblasts.\nGenetic counseling\nACY1D is transmitted as an autosomal recessive trait.\nManagement and treatment\nManagement is symptomatic only.\nPrognosis\nDue to the small number of individuals known to have ACY1D and due to the young age of the reported patients, the clinical course cannot be fully predicted and the prognosis is unknown. Characterization of additional patients and long-term follow-up are indicated.\n\n                            Last update: \n                            August 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Jörn Oliver SASS"}
{"Disease Name": "Aminopterin/methotrexate embryofetopathy", "Disease Definition": "A syndrome of developmental anomalies characterized by growth deficiency, facial dysmorphism and skull, limb and neural defects secondary to maternal exposure to aminopterin or methotrexate (MTX) during pregnancy.", "ORPHA ID": 1908, "Summary": "Epidemiology\nAt least 51 cases have been reported in the last decades; prevalence and incidence values are not available.\nClinical description\nFetuses and neonates present with short stature, skull anomalies (delayed calvarial ossification, craniosynostosis and cloverleaf skull), facial dysmorphism (hypertelorism, broad nasal bridge, prominent eyes, micrognathia, abnormal external ears), cleft palate, hydrocephalus, limb anomalies (shortness, ossification defects, talipes equinovarus, hypodactyly, syndactyly, hypoplastic toes, hypoplastic nails) and neural tube defects. In some cases, cardiac malformations such as tetralogy of Fallot, pulmonary atresia or ventricular septal defects have been reported. Occasional encephalic anomalies are absent corpus callosum, hypoplastic cerebellum and, more rarely, holoprosencephaly. Psychomotor development is usually normal, but cases with mild to severe intellectual deficit are reported.\nEtiology\nThe syndrome is caused by exposure during the first trimester of pregnancy to aminopterin or MTX, two folate antagonists. Aminopterin is no longer used, but MTX is used as an abortifacient (especially in case of suspected ectopic pregnancy), in inflammatory diseases (Crohn's disease, psoriasis, rheumatoid arthritis) and in malignancies (at higher doses). The teratogenic effect was described very early, given the anti-mitotic activity. The malformation rate after in utero exposure to aminopterin or MTX is not known, but it is dose- and time-related. It has been suggested that the critical period for MTX-induced teratogenicity is from 6 to 8 weeks after conception. Paternal MTX exposure at the time of conception does not seem to raise any major concern for offspring, but therapy discontinuation 3-6 months before conception is usually advised.\nDiagnostic methods\nDiagnosis is based on clinical examination and a history of maternal/paternal exposure.\nDifferential diagnosis\nDifferential diagnosis includes various genetic diseases presenting with one of the following signs: anomalies of the developing calvaria, micrognathia with cleft palate (including Pierre Robin syndrome - see this term), limb reduction defects and hand/feet anomalies. An \"aminopterin syndrome sine aminopterin (ASSA) syndrome\" (see this term) has been described..\nAntenatal diagnosis\nAntenatal diagnosis can be oriented by 2nd-3rd trimester ultrasound if intrauterine growth retardation (IUGR), oligo-polyhydramnios and/or malformations are seen in an at-risk pregnancy.\nManagement and treatment\nMTX and aminopterin should not be administered in pregnant women. A pregnancy could be considered, 3-6 months after MTX treatment has been stopped by women or men. Women with chronic diseases should be counseled to plan their pregnancies. In case of exposure during the 6 months preceding conception, folic acid supplementation (5 mg/day) is recommended in the preconception period (1-3 months) and for the whole first trimester of pregnancy. Folic acid supplementation (5 mg/day) is recommended throughout pregnancy for women exposed to aminopterin or MTX during pregnancy. Pregnancies exposed to aminopterin or MTX should be carefully monitored with second level ultrasounds and fetal heart ultrasound to control potential anomalies. Cardiac malformations can be corrected by surgery.\nPrognosis\nPrognosis depends on the extent and severity of malformations.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Matteo CASSINA  - Pr Maurizio CLEMENTI  - Dr Elena DI GIANANTONIO"}
{"Disease Name": "Amish lethal microcephaly", "Disease Definition": "A very rare syndrome characterized by extreme microcephaly and early death, within the first year.", "ORPHA ID": 99742, "Summary": "Epidemiology\nIt has been described only in the Old Order Amish of Lancaster County Pennsylvania. In this population, birth prevalence is about 1/500.\nClinical description\nMicrocephaly is a microcephalia vera (MV), evident at birth or through 22-week fetal ultrasound. Affected children have high urinary levels of alpha-ketoglutaric acid.\nEtiology\nAll affected infants are homozygous for the same mutation of the SLC25A19 gene on chromosome 17 (17q25.3).\nGenetic counseling\nThe condition follows an autosomal recessive pattern of inheritance.\nPrognosis\nPrognosis is very poor: the average life span of affected infants is between five and six months.\n\n                            Last update: \n                            December 2010"}
{"Disease Name": "Amish nemaline myopathy", "Disease Definition": "A type of nemaline myopathy (NM) only observed in several families of the Amish community.", "ORPHA ID": 98902, "Summary": "Clinical description\nIt has a neonatal onset and patients present with hypotonia associated to contractures, a severe pectus carinatum, and tremor that subsides after 2-3 months of age.\nEtiology\nTNNT1 (19q13.4) is the causative gene of the Amish NM.\nGenetic counseling\nTransmission follows an autosomal recessive pattern.\nPrognosis\nLife expectancy rarely exceeds 2 years as a consequence of severe respiratory insufficiency.\n\n                            Last update: \n                            October 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Monique RYAN"}
{"Disease Name": "Amniotic band syndrome", "Disease Definition": "Constriction rings syndrome is a congenital limb malformation disorder with an extremely variable clinical presentation characterized by the presence of partial to complete, congenital, fibrous, circumferential, constriction bands/rings on any part of the body, although a particular predilection for the upper or lower extremities is seen. Phenotypes range from only a mild skin indentation to complete amputation of parts of the fetus (e.g. digits, distal limb). Compression from the rings may lead to edema, skeletal anomalies (e.g. fractures, foot deformities) and, infrequently, neural compromise.", "ORPHA ID": 295000, "Summary": ""}
{"Disease Name": "Amoebiasis due to Entamoeba histolytica", "Disease Definition": "A parasitic disease caused by the protozoa, Entamoeba histolytica, mainly occurring in tropical regions after the ingestion of an amoebic cyst, and resulting in clinical manifestations that may range from an asymptomatic state to amoebic colitis (violent abdominal pain, a painful contracted feeling around the anal sphincter, blood and mucus in the stools but without the presence of fever), or amoebic liver abscesses (fever, chills, abdominal pain, weight loss, hepatomegaly) that can be fatal if not immediately treated. Extraintestinal involvement elsewhere (i.e. thoracic, hepatic) is extremely rare.", "ORPHA ID": 67, "Summary": ""}
{"Disease Name": "Amoebiasis due to free-living amoebae", "Disease Definition": "A rare parasitic disease caused by free-living amoebae belonging to the Acanthamoeba, Naegleria and Balamuthia genera, that are able to survive in an autonomous state in all natural environments and can also parasitize humans. In immunosuppressed individuals Acanthamoeba genus contamination leads to granulomatous amoebic encephalitis (also reported in association with species of the Balamuthia genus) together with other problems including cardiac, cutaneous and pulmonary manifestations, all of which influence the prognosis. In immunocompetent individuals, the Naegleria fowleri species is responsible for primary amoebic meningoencephalitis, the evolution of which is rapidly fatal.", "ORPHA ID": 68, "Summary": ""}
{"Disease Name": "Amoebic keratitis", "Disease Definition": "A rare corneal infection due to the protozoan Acanthamoeba that generally occurs in contact lens wearers and that is characterized by severe ocular pain, blepharospasm, photophobia, eye tearing, blurred vision and foreign body sensation. It can lead to impaired visual acuity if not treated promptly.", "ORPHA ID": 67043, "Summary": ""}
{"Disease Name": "Amyloidosis cutis dyschromia", "Disease Definition": "A rare primary cutaneous amyloidosis characterized by macular or reticulate hyperpigmentation with symmetrically distributed guttate hypo- and hyperpigmented lesions which progress gradually over the years to involve almost the entire body (with relative sparing of the face, hands, feet and neck). Patients are usually asymptomatic, however mild pruritus may be associated. Amyloid deposition in the papillary dermis is observed on skin biopsy. Systemic amyloidosis is not present and association with generalized morphea, atypical Parkinsonism, spasticity, motor weakness or colon carcinoma is rare.", "ORPHA ID": 319635, "Summary": ""}
{"Disease Name": "Amyloidosis", "Disease Definition": "A vast group of rare systemic diseases characterized by the presence of insoluble fibrillar protein deposits in tissues. Amyloidoses are classified according to biochemical type of amyloid protein involved.", "ORPHA ID": 69, "Summary": "Epidemiology\nAL amyloidosis's estimated global incidence of 1/95,800 people, with males preponderance. Hereditary ATTR amyloidosis (or ATTRv) mid-global prevalence estimate is of 1/450,000 people (range 1/120,000-830,000). In Tuscany, the incidence of ATTR wild type (ATTRwt) and ATTRv is 1/37,500 and 1/370,000, respectively, with male preponderance. AA amyloidosis estimated incidence is 1-2/1,000,000, but is decreasing.\nClinical description\nThe most frequent forms are AL amyloidosis, involving all organs except the brain, ATTR amyloidosis, ATTRwt involving the heart and ATTRv involving nerves and heart, and AA amyloidosis involving mainly kidneys, thyroid and GI tract. Progression is usually severe, as affected organs' functions are progressively destroyed. Localized amyloidosis usually has a benign course.\nEtiology\nAL amyloidosis is caused by plasma cell clone producing misfolded immunoglobulin LC that deposits as fibrils in vital organs. ATTR amyloidosis is caused by transthyretin, produced mainly by the liver, the retina epithelial cells and choroid plexus. ATTRv is associated with >130 mutations in the transthyretin gene. In the elderly, particularly in men, ATTRwt causes cardiac amyloidosis. AA amyloidosis is caused by persistent high concentration of serum amyloid A (SAA) in chronic inflammatory diseases.\nDiagnostic methods\nDiagnosis can be facilitated by clinical red flags. Once the suspicion of amyloidosis is made, the first step is the search for the monoclonal protein. In the presence of a monoclonal protein, a biopsy of abdominal fat, or salivary glands, or target organs is necessary. Typing of amyloid deposits is mandatory, using mass spectrometry, or immunoelectron-microscopy and immunohistochemistry. In the absence of monoclonal protein, scintigraphy with bone tracers can diagnose cardiac ATTR.\nDifferential diagnosis\nThe various types of systemic amyloidosis have a similar clinical presentation, and can be misdiagnosed as each other with catastrophic therapeutic consequences. Misdiagnosis with common diseases, such as type 2 diabetes and congestive heart failure, can occur. ATTRv amyloidosis can be misdiagnosed with chronic inflammatory demyelinating polyneuropathy.\nAntenatal diagnosis\nPrenatal diagnosis is available for severe forms, mainly Portuguese amyloid neuropathies.\nGenetic counseling\nGenetic counseling is recommended in patients with hereditary forms of amyloidosis and in their at-risk relatives. Pre-symptomatic genetic testing can be offered in the context of genetic counseling. Clinical monitoring of asymptomatic TTR mutation carriers should start ten years before the predicted age of onset of the disease according to genotype.\nManagement and treatment\nEffective therapies are now available for the three major types of amyloidosis. Frontline treatments vary greatly depending on the type of amyloidosis; careful diagnosis must be performed beforehand. For all types of amyloidosis, supportive therapy plays a fundamental role. Appropriate management of the cardiac, renal, liver, gastrointestinal, nutritional, and neurological manifestations requires concerted action with specialists.\nPrognosis\nThe recent development of effective therapies has dramatically improved the outlook of patients with the most common systemic amyloidosis. For AL amyloidosis patients, the median survival is >6 years, with ∼1/3 of patients achieving long-term survival (>10 years) without sign of active disease. The same applies to ATTR amyloidosis. The median survival of patients presenting with polyneuropathy is ∼10 years, and ∼4-5 years for those presenting with cardiac involvement. Disease-modifying therapies recently introduced are expected to significantly improve outcomes. In AA amyloidosis, the prognosis depends on the nature of the underlying disease. Biologic therapies have dramatically improved the prognosis.\n\n                            Last update: \n                            April 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Giampaolo MERLINI | RITA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Amyotrophic lateral sclerosis type 4", "Disease Definition": "A rare, genetic motor neuron disease characterized by late childhood- or adolescent-onset of slowly progressive, severe, distal limb muscle weakness and wasting, in association with pyramidal signs, normal sensation, and absence of bulbar involvement, leading to degeneration of motor neurons in the brain and spinal cord.", "ORPHA ID": 357043, "Summary": ""}
{"Disease Name": "Amyotrophic lateral sclerosis", "Disease Definition": "A neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord.", "ORPHA ID": 803, "Summary": "Epidemiology\nIncidence (average around 1/50,000 per year) and prevalence (average around 1/20,000) are relatively uniform in Western countries, although foci of higher frequency have been reported in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male preponderance (male to female ratio of around 1.5:1).\nClinical description\nApproximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, in which onset of symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solids or liquids. Limb symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1-2 years. Paralysis is progressive and leads to death due to respiratory failure within 2-3 years for bulbar onset cases and 3-5 years for limb onset ALS cases.\nEtiology\nMost ALS cases are sporadic but 5-10% of cases are familial, and of these 20% involve a mutation of the SOD1 gene (21q22.11), about 2-5% involve mutations of the TARDBP gene (1p36.22) encoding the TAR DNA-binding protein 43 (TDP-43) and 1-2% involve mutations of the VCP gene (9p13.3) coding for the Valosin Containing Protein. Two percent of apparently sporadic cases involve SOD1 mutations, and TARDBP mutations have also been identified in sporadic cases.\nDiagnostic methods\nThe diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. multifocal motor neuropathy, Kennedy's disease (seethese terms) and cervical spondylotic myelopathy) by appropriate investigations. The pathological hallmarks comprise loss of motor neurons with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurons and TDP-43 immunoreactive inclusions in degenerating lower motor neurons. Signs of upper motor neuron and lower motor neuron damage not explained by any other disease process are suggestive of ALS.\nManagement and treatment\nThe management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Nigel LEIGH  - Dr Lokesh WIJESEKERA"}
{"Disease Name": "Anal fistula", "Disease Definition": "A rare intestinal condition characterized by an abnormal communication between the lower rectum and the perianal skin, which usually develops after an acute perianal abscess. A fistulous traject may be established on either side of the anus (never in the midline) and mucous or fecal discharge can appear. The skin around the external orifice can be irritated. Males are more often affected than females.", "ORPHA ID": 228113, "Summary": ""}
{"Disease Name": "Anaplastic astrocytoma", "Disease Definition": "A rare, high-grade, malignant glial tumor, histologically characterized by abundance of pleomorphic astrocytes and multiple mitotic figures, often associated with diffuse infiltration of the surrounding tissue, considerable edema and mass effect and involvement of the contralateral brain. Depending on the primary localization of the tumor, patients can present with signs of raised intracranial pressure (headache, vomiting, papilledema), seizures, progressive neurological deficits, and/or behavioral changes. The tumor is most commonly localized in the frontal and temporal lobes, brain stem and spinal cord.", "ORPHA ID": 251589, "Summary": ""}
{"Disease Name": "Anaplastic ependymoma", "Disease Definition": "A rare, malignant type of ependymoma that most often arises in the supratentorial region of the brain of children and young adults and that manifests with variable symptoms including headaches, nausea, vision impairment, memory loss and difficulty walking.", "ORPHA ID": 251646, "Summary": ""}
{"Disease Name": "Anaplastic ganglioglioma", "Disease Definition": "A rare mixed neuronal-glial tumor characterized by a mostly supratentorial space-occupying lesion often involving the temporal lobe, although it may occur anywhere in the central nervous system. The tumor shows anaplastic features in its glial component and is considered WHO grade III, which may, albeit inconsistently, indicate more aggressive behavior and less favorable prognosis. Clinical symptoms vary according to the location, the most common manifestation being seizures.", "ORPHA ID": 251957, "Summary": ""}
{"Disease Name": "Anaplastic large cell lymphoma", "Disease Definition": "A rare and aggressive peripheral T-cell non-Hodgkin lymphoma, belonging to the group of CD30-positive lymphoproliferative disorders, which affects lymph nodes and extranodal sites. It is comprised of two sub-types, based on the expression of a protein called anaplastic lymphoma kinase (ALK): ALK positive and ALK negative ALCL.", "ORPHA ID": 98841, "Summary": "Epidemiology\nALCL accounts for approximately 3% of adult non-Hodgkin lymphomas and 10% to 20% of childhood lymphomas. Its prevalence is unknown. The ALK positive subtype usually affects children and young adults. The ALK negative subtype is more commonly found in older patients over the age of 40.\nClinical description\nALCL is characterized by peripheral, mediastinal, or abdominal lymph node involvement. It manifests with the development of painless and enlarged lymph nodes, especially in the neck or armpit (axillary lymph nodes). General symptoms include loss of appetite and fatigue as well as fever, weight loss, and night sweats (B symptoms). Mediastinal involvement manifests as cough, dypsnea and/or edema. ALCL can also extend to extranodal sites such as the bones, bone marrow, subcutaneous tissue, lungs, spleen and liver.\nEtiology\nEtiology is unknown. In the ALK positive sub-type, the anaplastic lymphoma receptor tyrosine kinase ALK gene (2p23) is overexpressed due to a t(2;5)(p23;q35) translocation.\nDiagnostic methods\nDiagnosis is based on physical examination, medical history and is confirmed by histopathological and immunohistochemical evaluation of a lymph node biopsy. The biopsy shows a cohesive growth pattern, usually with lymph node-sinus involvement, with anaplastic cytology (atypical large cells with abundant cytoplasm, prominent nucleoli, and horseshoe-like or reniform nuclei), constant membrane expression of the CD30 antigen, EMA (epithelial membrane antigen) expression in the majority of cases, and CD3, CD5 or CD2 expression (mostly in ALK negative cases). ALK protein is detected by immunohistochemistry in the ALK positive sub-type. Additional tests include blood and bone marrow analysis, as well as imagery (X rays, computed tomography, PET scans and MRI) for bone disease.\nDifferential diagnosis\nDifferential diagnosis includes Hodgkin lymphoma and peripheral T cell lymphomas (see these terms), which may express CD30.\nManagement and treatment\nAnthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like regimens, constitutes the first-line of treatment. It may only be combined with radiotherapy in stage I/II disease. Pediatric patients have distinct protocols similar to protocols used for B-cell lymphomas, with other drugs such methotrexate, etoposide, and cytarabine being used. High-dose chemotherapy followed by autologous stem cell transplantation can also be performed, usually in cases of relapse or as first line treatment in cases with an adverse prognosis. Antibody-drug conjugate therapy (brentuximab velotin) may be given when at least one chemotherapy regimen is unsuccesful.\nPrognosis\nWith treatment, ALK-positive patients (5-year survival of 70-80%) have a better prognosis than ALK-negative patients (5-year survival of 33-49%). Relapse confers a poorer prognosis.\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Pauline BRICE"}
{"Disease Name": "Anaplastic oligoastrocytoma", "Disease Definition": "A rare and aggressive glial tumor of the central nervous system, that usually presents in adults with seizures, is most often located in the cerebral hemispheres and that is associated with a very poor prognosis.", "ORPHA ID": 251663, "Summary": ""}
{"Disease Name": "Anaplastic oligodendroglioma", "Disease Definition": "A rare glial tumor characterized by a grade III oligodendroglial tumour with focal or diffuse anaplastic features. It typically occurs in the supratentorial white matter. Histologically, the cells are enlarged and epithelioid with pleomorphic and increased size nuclei, a vesicular chromatin pattern and prominent nucleoli. Most patients present with seizures.", "ORPHA ID": 251630, "Summary": ""}
{"Disease Name": "Anaplastic thyroid carcinoma", "Disease Definition": "A disorder that represents the ultimate dedifferentiation step of thyroid tumorigenesis and is one of the most severe cancers in humans.", "ORPHA ID": 142, "Summary": "Epidemiology\nIt accounts for less than 2% of thyroid cancers and affects older patients in their sixth to eighth decade.\nClinical description\nUsual clinical presentation is a rapidly growing thyroid mass invading surrounding structures with compressive symptoms. Cervical lymph nodes enlargement and distant metastases occur frequently.\nDiagnostic methods\nThough cytological results obtained by fine needle aspiration may be suggestive of diagnosis, tissue biopsy for immunohistochemichal study can be necessary to exclude lymphoma and to validate aggressive therapies.\nManagement and treatment\nPatients developing anaplastic thyroid cancer must be referred urgently in cancer centers to plan multimodality therapeutic approach depending on their performance status. The treatment regimen combines surgery when feasible, hyperfractionated and accelerated external beam radiotherapy and doxorubicin based chemotherapy. Such treatment can provide control of locoregional disease but does not impact on overall survival in patients with distant metastases. Therapeutic research is investigating redifferenciation strategies and targeted therapies to inhibit EGF receptors and neoplastic angiogenesis. Primary prevention of this lethal disease may consist of adequate treatment of differentiated thyroid cancers and goiters in the elderly.\nPrognosis\nThe prognosis is dismal with a mean survival of four to nine months after diagnosis. Long survivors are patients with emerging disease presenting a resectable tumor and receiving adjuvant radiotherapy and/or chemotherapy.\n\n                            Last update: \n                            April 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Christine DO CAO  - Pr Jean-Louis WEMEAU"}
{"Disease Name": "Anaplastic/large cell medulloblastoma", "Disease Definition": "A histological variant of medulloblastoma, an embryonic malignancy, associated with extremely low survival rates and a high risk of metastatic disease and manifesting with symptoms of increased intracranial pressure such as vomiting, headache, listlessness, papilledema and diplopia.", "ORPHA ID": 251855, "Summary": ""}
{"Disease Name": "Anauxetic dysplasia", "Disease Definition": "A rare spondyloepimetaphyseal dysplasia characterized by severe short-limb short stature beginning prenatally, joint hypermobility, dental abnormalities, dysmorphic facial features (including hypertelorism, midface hypoplasia, macroglossia, and prognathism), and other skeletal anomalies (such as atlantoaxial subluxation causing compression of the spinal cord, kyphoscoliosis, hip dislocation, or rocker-bottom feet). Mild intellectual disability may also be present.", "ORPHA ID": 93347, "Summary": ""}
{"Disease Name": "Andersen-Tawil syndrome", "Disease Definition": "A rare disorder characterized by periodic muscle paralysis, prolongation of the QT interval with a variety of ventricular arrhythmias (leading to predisposition to sudden cardiac death) and characteristic physical features: short stature, scoliosis, low-set ears, hypertelorism, broad nasal root, micrognathia, clinodactyly, brachydactyly and syndactyly.", "ORPHA ID": 37553, "Summary": ""}
{"Disease Name": "Androgen insensitivity syndrome", "Disease Definition": "A rare difference of sex development (DSD) characterized by the presence of female external genitalia, ambiguous genitalia or variable defects in virilization in a 46,XY individual with absent or partial responsiveness to age-appropriate levels of androgens. It comprises two clinical subgroups: complete AIS (CAIS) and partial AIS (PAIS).", "ORPHA ID": 754, "Summary": ""}
{"Disease Name": "ANE syndrome", "Disease Definition": "A rare, genetic, neuro-endocrino-cutaneous disorder characterized by highly variable degrees of alopecia, moderate to severe intellectual disability, progressive, late-onset motor deterioration and combined anterior pituitary hormone deficiency, manifesting with central hypogonadotropic hypogonadism, delayed or absent puberty, growth hormone deficiency (resulting in short stature), progressive central adrenal insufficiency and a hypoplastic anterior pituitary gland. Additional features include hypodontia, flexural reticulate hyperpigmentation, gynecomastia, microcephaly and kyphoscoliosis.", "ORPHA ID": 157954, "Summary": ""}
{"Disease Name": "Aneurysm of sinus of Valsalva", "Disease Definition": "A rare congenital heart malformation of one or more of the aortic sinuses, consisting of a dilation that when unruptured is usually asymptomatic but when ruptured presents with progressive exertional dyspnea, fatigue, chest pain and that can lead to congestive heart failure if left untreated.", "ORPHA ID": 1054, "Summary": ""}
{"Disease Name": "Aneurysm-osteoarthritis syndrome", "Disease Definition": "A rare, genetic, systemic disease characterized by the presence of arterial aneurysms, tortuosity and dissection throughout the arterial tree, associated with early-onset osteoarthritis (predominantly affecting the spine, hands and/or wrists, and knees) and mild craniofacial dysmorphism (incl. long face, high forehead, flat supraorbital ridges, hypertelorism, malar hypoplasia and, anomalies of the palate and uvula), as well as mild skeletal and cutaneous anomalies. Joint abnormalities, such as osteochondritis dissecans and intervertebral disc degeneration, are frequently associated. Additional cardiovascular anomalies may include mitral valve defects, congenital heart malformations, ventricular hypertrophy and atrial fibrillation.", "ORPHA ID": 284984, "Summary": ""}
{"Disease Name": "Aneurysmal bone cyst", "Disease Definition": "A rare bone tumor characterized by a benign, cystic lesion consisting of blood-filled cavities divided by fibrous septa containing fibroblasts, multinucleated osteoclast-type giant cells, and reactive woven bone. The tumor may arise de novo or secondarily, complicating other benign or malignant bone tumors. It most commonly arises during the first two decades of life and often affects the epiphyses of long bones and posterior elements of vertebral bodies. Patients typically present with pain and swelling, or neurological symptoms due to compression of nerve roots or the spinal cord by vertebral tumors.", "ORPHA ID": 480553, "Summary": ""}
{"Disease Name": "Angel-shaped phalango-epiphyseal dysplasia", "Disease Definition": "A form of acromelic dysplasia characterized by the distinctive radiological sign of angel-shaped middle phalanges, a typical metacarpophalangeal pattern profile (mainly affecting first metacarpals and middle phalanges of second, third and fifth digits, which all appear short), epiphyseal changes in the hips and, in some, abnormal dentition and delayed bone age.", "ORPHA ID": 63442, "Summary": "Epidemiology\nThe prevalence is unknown. ASPED is a rare disease with less than 20 cases reported in the literature to date, however, it is likely underdiagnosed.\nClinical description\nClinical manifestations in ASPED are not only restricted to the hands, and the original description reported various combinations of angel-shaped middle phalanges, hip dysplasia and dental anomalies (hypodontia). Patient stature ranges from short to normal. Hip dysplasia gives rise to premature or severe osteoarthritis causing severe intermittent hip pain. Non-specific brachydactyly and hyperextensible interphalangeal joints have been reported, as well as delayed bone age. Delayed dentition, abnormally placed teeth, premature loss of teeth, abnormal enamel, and malocclusion have also been described in some.\nEtiology\nASPED is caused by mutations in the growth differentiation factor 5 (GDF5) gene, located on chromosome 20q11.2, encoding CDMP1 (cartilage derived morphogenetic protein). CDMP1 belongs to the TGF beta super family and plays a role in bone growth and joint morphogenesis.\nDiagnostic methods\nDiagnostic methods include skeletal x-rays, showing the typical radiological features of ASPED, along with GDF5  molecular analysis, which confirms diagnosis. Angel-shaped middle phalanges are usually an isolated bone anomaly, and are shaped like ''Christmas tree angels'', with the wings formed by the diaphyseal cuff of bone surrounding the phalanx, the skirt by a cone-shaped epiphysis, and the head by the distal pseudoepiphysis. Angel-shaped phalanges can be difficult to find in adults. However, they can be associated with dental anomalies, hip dysplasia and short stature.\nDifferential diagnosis\nThe main clinical differential diagnosis is Brachydactyly type C (see this term), which is also associated with a GDF5 mutation, suggesting that both syndromes may be part of the same clinical spectrum.\nAntenatal diagnosis\nAs ASPED is not a serious condition, prenatal diagnosis is not offered.\nGenetic counseling\nASPED is transmitted as an autosomal dominant condition and genetic counseling is possible. Clinical variability and low penetrance have been reported.\nManagement and treatment\nTreatment may involve orthopedic management (i.e. hip arthroplasty), and plastic surgery (when thumb involvement is very severe or if syndactyly is associated). In patients with severe hip involvement, walking aids may be required. Dental anomalies may require orthodontic management.\nPrognosis\nASPED does not affect life-expectancy and the prognosis is good. Quality of life is reduced in those with untreated and severe coxarthrosis.\n\n                            Last update: \n                            December 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Muriel HOLDER-ESPINASSE"}
{"Disease Name": "Angelman syndrome", "Disease Definition": "A neurogenetic disorder characterized by severe intellectual deficit and distinct facial dysmorphic features.", "ORPHA ID": 72, "Summary": "Epidemiology\nPrevalence of AS is estimated to be 1/10,000 to 1/20,000 worldwide.\nClinical description\nPatients with AS appear normal at birth. In the first 6 months of the neonatal period, feeding difficulties and hypotonia may occur, followed by developmental delay between 6 months and 2 years of age. Generally from 1 year of age, the typical features of AS develop: severe intellectual deficit, absent speech, outbursts of laughter with hand flapping, microcephaly, macrostomia, maxillary hypoplasia, prognathia and neurological problems with a puppet-like gait, ataxia and epileptic seizures with specific electroencephalogram (EEG) abnormalities (triphasic delta activity with a maximum over the frontal regions). Other signs that have been described include a happy demeanor, hyperactivity without aggression, short attention span, excitability and sleeping problems with decreased need to sleep, increased sensitivity to heat, attraction to and fascination with water. With advancing age, the typical features of the disease become less marked because of facial coarsening, thoracic scoliosis and mobility problems. Thoracic scoliosis is reported in 40% of AS patients (mostly females). Seizures remain present in adult patients, but hyperactivity, short attention span and sleeping problems improve. In patients with deletion of the 15q11 region, iris and choroidal hypopigmentation are common.\nEtiology\nDifferent genetic mechanisms may cause Angelman syndrome, such as deletion of the 15q11.2-q13 critical region (60-75%), paternal uniparental disomy (2-5%), imprinting defect (2-5%) and mutation in the UBE3A gene (10%). In a group representing 5-26% of patients, the genetic defect remains unidentified.\nDiagnostic methods\nDiagnosis is based on clinical and EEG findings, and can be confirmed in most cases by cytogenetic and molecular testing. The typical EEG pattern can be helpful for diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes hypsarrhythmia in West syndrome or the petit mal variant pattern in Lennox-Gastaut syndrome (see these terms). Other differential diagnoses include Rett syndrome, Mowat-Wilson syndrome, X-linked alpha-thalassemia-intellectual deficit syndrome (ATR-X), and 22q13 deletion syndrome (see these terms).\nGenetic counseling\nGenetic counseling is advised as the recurrence risk varies between 0 and 50%, depending on the underlying genetic mechanism.\nManagement and treatment\nManagement includes physical, occupational and speech therapy including nonverbal methods of communication. As patients commonly develop seizures at a very young age, anticonvulsant medication is required. Sedative medication can be given in patients with severe sleep disorders. Visual function should also be monitored.\nPrognosis\nIn adulthood, patients become less active and have a tendency towards obesity. Mobility decreases with joint contractures leading to difficulties in walking and some patients become wheelchair bound. Life expectancy appears to be normal although autonomy is never reached.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Griet VAN BUGGENHOUT"}
{"Disease Name": "Angiocentric glioma", "Disease Definition": "An extremely rare slow-growing glial neoplasm of the central nervous system, usually arising in a superficial location in the cerebrum, affecting all ages and both sexes, and characterized by intractable seizures and headaches, with most cases being cured by surgical incision alone and therefore having a good prognosis.", "ORPHA ID": 251671, "Summary": ""}
{"Disease Name": "Angioimmunoblastic T-cell lymphoma", "Disease Definition": "A rare T-cell non-Hodgkin lymphoma characterized by infiltration of lymph nodes by neoplastic cells of T follicular helper cell origin with a polymorphous inflammatory background including markedly increased follicular dendritic cells and EBV-positive B-cells, as well as prominent proliferation of high endothelial venules. The spleen, liver, skin, and bone marrow are also frequently involved. Patients typically present with generalized lymphadenopathy, hepatosplenomegaly, systemic symptoms, and polyclonal hypergammaglobulinemia. Pruritic skin rash, arthritis, pleural effusion, and ascites may also be observed. The condition is aggressive with generally poor prognosis.", "ORPHA ID": 86886, "Summary": ""}
{"Disease Name": "Angioma serpiginosum", "Disease Definition": "A benign congenital skin disease characterised by progressive dilation of the subepidermal skin vessels manifesting as purple punctate lesions usually appearing on the lower limbs and buttocks and following the lines of Blaschko.", "ORPHA ID": 95429, "Summary": "Epidemiology\nThe disease occurs almost exclusively in females.\nEtiology\nA mutation in the Xp11.3-Xq12 region has been identified in one of the reported families. However, in this family the AS was associated with oesophageal papillomatosis leading to the suggestion that this case of familial AS represents a mild form of focal dermal hypoplasia (see this term).\nGenetic counseling\nThe majority of cases are sporadic. Only a few familial cases have been reported in the literature so far and transmission may be autosomal dominant or X-linked.\n\n                            Last update: \n                            October 2008"}
{"Disease Name": "Angiomatoid fibrous histiocytoma", "Disease Definition": "A rare soft tissue tumor characterized by a slow-growing, usually painless, subcutaneous nodule, predominantly located in the extremities, less frequently the trunk or head and neck region. Histopathologically, the lesion is well-circumscribed, lobulated, and composed of epitheloid, ovoid, or spindle cells arranged in a nodular and often syncytial pattern, with pseudoangiomatoid spaces and a peripheral fibrous pseudocapsule with a prominent lymphoplasmacytic cuff. The tumor is most common in the first two decades of life and usually follows an indolent course, although local recurrence may occur, while metastasis is rare.", "ORPHA ID": 569164, "Summary": ""}
{"Disease Name": "Angioosteohypertrophic syndrome", "Disease Definition": "A congenital vascular bone syndrome (CVBS) characterized by the presence of a vascular malformation in a limb, mainly of the arteriovenous type, which results in overgrowth of the affected limb.", "ORPHA ID": 2346, "Summary": ""}
{"Disease Name": "Angioosteohypotrophic syndrome", "Disease Definition": "A rare, congenital, vascular anomaly syndrome characterized by venous or, on occasion, arterial malformations which lead to soft tissue hypertrophy and bone hypoplasia. Affected limb is generally shortened, highly deformed, painful and edematous and associates bone and muscle hypotrophy. Single parts, or multiple small parts, of limbs are typically affected but more extensive involvement, including complete extremity, shoulder girdle and axilla, has been reported.", "ORPHA ID": 75508, "Summary": ""}
{"Disease Name": "Angiosarcoma", "Disease Definition": "A rare vascular tumor characterized by a malignant space-occupying lesion composed of cells variably recapitulating features of normal endothelium. It mostly develops as a cutaneous tumor and is much less frequently located in the deep soft tissue. Clinical presentation is an enlarging mass, sometimes with symptoms like coagulopathy, anemia, persistent hematoma, or bruisability. Some tumors are associated with pre-existing conditions, e. g. Klippel-Trenaunay syndrome, Maffucci syndrome, or following radiation, among others. Older age, retroperitoneal location, large size, and high mitotic activity are predictors for poor outcome.", "ORPHA ID": 263413, "Summary": ""}
{"Disease Name": "Angiostrongyliasis", "Disease Definition": "A foodborne zoonotic disease, endemic to Southeast Asia and the Pacific Islands, caused by the rat lungworm Angiostrongylus cantonensis and that is acquired by the ingestion of the infective larvae on vegetables or in raw or undercooked snails, slugs, land crabs, freshwater shrimps, frogs and lizards. The main feature is eosinophilic meningitis, with clinical manifestations including fever, headache, malaise, fatigue, vomiting, rhinorrhea, blurred vision, diplopia, cough, stiff neck, enteritis, constipation and paraesthesia due to the movement of the worms from the intestines to the lungs, central nervous system and eyes. In severe cases without treatment, coma and death can occur.", "ORPHA ID": 74, "Summary": ""}
{"Disease Name": "Angora hair nevus", "Disease Definition": "A rare nevus disorder characterized by the presence of epidermal nevi consisting of depigmented hypertrichosis manifesting with long, soft, white hair which grows from dilated follicles and follows Blaschko's lines, typically located on the scalp, neck, face, trunk and/or limbs. Association with hyperpigmented, hyperkeratotic linear epidermal nevi, macrocephaly, body asymmetry, sacral pit and koilonychia, as well as skeletal, ocular, and neurological abnormalities, has also been reported.", "ORPHA ID": 370039, "Summary": ""}
{"Disease Name": "Anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome", "Disease Definition": "This syndrome is characterized by severe immunodeficiency, osteopetrosis, lymphedema and anhidrotic ectodermal dysplasia.", "ORPHA ID": 69088, "Summary": "Epidemiology\nIt has been described in a few unrelated male patients born to mothers with mild incontinentia pigmenti.\nClinical description\nThe first two reported children died before three years of age from multiple infections with Gram-positive cocci, Gram-negative bacilli, mycobacteria, and fungi.\nEtiology\nThe syndrome is classified as a X-linked osteopetrosis and is caused by mutations in the IKBKG (NEMO) gene (Xq28).\n\n                            Last update: \n                            March 2009"}
{"Disease Name": "Aniridia-absent patella syndrome", "Disease Definition": "A rare syndrome described in three members of a family (a boy, his father, and his paternal grandmother) that is characterized by the association of aniridia with patella aplasia or hypoplasia. The grandmother also had bilateral cataracts and glaucoma. There have been no further descriptions in the literature since 1975.", "ORPHA ID": 1069, "Summary": ""}
{"Disease Name": "Aniridia-cerebellar ataxia-intellectual disability syndrome", "Disease Definition": "A rare, congenital, neurological disorder characterized by the association of partial bilateral aniridia with non-progressive cerebellar ataxia, and intellectual disability.", "ORPHA ID": 1065, "Summary": "Epidemiology\nTo date, less than 30 patients have been reported in the literature.\nClinical description\nAniridia is visible at birth as fixed dilated pupils and is associated with photobia. It can be accompanied with additional ocular findings such as foveal, patchy iris and/or optic nerve hypoplasia, retinal hypopigmentation, and/or pigmentary macular changes leading to reduced visual acuity. Cataract and corneal opacities are never observed. Non-progressive cerebellar ataxia is associated with delayed developmental milestones and hypotonia (visible from the first year of life), gait and balance disorders with incoordination, intention tremor, and scanning speech. Intellectual disability is variable. Mild facial dysmorphic features may be observed such as high forehead, hypertelorism, epicanthic folds, depressed nasal bridge with anteverted nostrils, and thin upper lip. The cases referred to as atypical Gillespie syndrome correspond to those showing a more complex phenotype, associating additional ocular findings and a mild dysmorphic face.\nEtiology\nThe etiology is unknown. Some atypical cases have been linked to mutations in the PAX6 gene (11p13), encoding a transcriptional regulator expressed in ocular, cerebral, olfactory, and pancreatic tissues. One case has also been reported to be due to a de novo translocation of chromosome X and 11 t(X;11) (p22.32;p12), but with no involvement of the PAX6 gene.\nDiagnostic methods\nA presumptive diagnosis can be made in the first months of life: on slit lamp examination, the pupil border of the iris typically shows a scalloped, 'festooned' edge with iris strands extending onto the anterior lens surface at regular intervals. In many cases, neuroimaging studies (CT scan, MRI) show cerebellar hypoplasia or atrophy, especially of the vermis, with occasional white matter changes, and diffuse atrophy of the cerebral hemispheres, brainstem and frontal cortex.\nDifferential diagnosis\nDifferential diagnosis includes Marinesco-Sjögren syndrome (see this term) in which congenital cataract is present, as well as cerebellar ataxia, intellectual disability, and aniridia (see this term).\nGenetic counseling\nSporadic and familial cases have been observed. Although some reported families are compatible with autosomal dominant inheritance, Gillespie syndrome is more likely to be an autosomal recessive condition.\nManagement and treatment\nManagement includes regular ophthalmologic evaluation with prescription of optical aids, physical, speech and occupational therapy for muscular re-education.\nPrognosis\nThere are no reports on the natural history of the disease. Prognosis depends on the proper management and anticipation of ocular and mental symptoms and disabilities.\n\n                            Last update: \n                            December 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Francesc PALAU"}
{"Disease Name": "Aniridia-intellectual disability syndrome", "Disease Definition": "An extremely rare autosomal dominant developmental defect of the eye described in several members of one family that is characterized by the association of moderate intellectual disability with aniridia, lens dislocation, optic nerve hypoplasia and cataracts. There have been no further descriptions in the literature since 1974.", "ORPHA ID": 1068, "Summary": ""}
{"Disease Name": "Aniridia-ptosis-intellectual disability-familial obesity syndrome", "Disease Definition": "An extremely rare syndrome described in three members of a family (a mother and her two children) that is characterized by the association of various ocular abnormalities (partial or complete aniridia, ptosis, pendular nystagmus, corneal pannus, , persistent pupillary membrane, lenticular opacities, foveal hypoplasia, and low visual acuity) with various systemic anomalies including intellectual disability and obesity in the two children, and alopecia, cardiac abnormalities, and frequent spontaneous abortion in the mother. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 1067, "Summary": ""}
{"Disease Name": "Aniridia-renal agenesis-psychomotor retardation syndrome", "Disease Definition": "An extremely rare syndrome reported in two siblings of non consanguineous parents that is characterized by the association of ocular abnormalities (partial aniridia, congenital glaucoma, telecanthus) with frontal bossing, hypertelorism, unilateral renal agenesis and mild psychomotor delay. There have been no further descriptions in the literature since 1974.", "ORPHA ID": 1064, "Summary": ""}
{"Disease Name": "Anisakiasis", "Disease Definition": "A fish-borne zoonosis caused by the ingestion of third stage larvae of nematodes belonging to the genus Anisakis, present in fish or cephalopods. Following its penetration in the human gastrointestinal tract, the parasite can cause gastrointestinal classified as acute (manifesting as abdominal pain, diarrhea, nausea and vomiting), chronic, or ectopic reactions or allergic manifestations (urticaria, angioedema, anaphylactic shock).", "ORPHA ID": 1070, "Summary": "Epidemiology\nTo date, more than 20,000 cases of anisakiasis have been reported worldwide, over 90% from Japan (2,000-3,000 cases reported annually), and the rest from the five continents: Asia (Korea), Europe (the Netherlands, Germany, France, United Kingdom, Spain, Italy), America (the United States, Canada, and South American countries), and New Zealand.\nClinical description\nAnisakiasis can take a number of forms, depending on the location and lesions caused by the larvae. In the luminal anisakiasis, larvae remain in the gastrointestinal tract without penetrating the tissues, causing an asymptomatic infection that may be discovered when the worms are expelled (1 day-2 weeks after ingestion) by coughing, vomiting or defecating. In invasive anisakiasis, larvae penetrate the gastrointestinal mucosa (more rarely the throat). The acute gastric form is characterized by nausea, vomiting, abdominal pain, and diarrhea, within 1-7 hours of the ingestion of contaminated food. If misdiagnosed, it can become chronic, with intermittent abdominal pain, nausea and vomiting lasting from weeks to several years. Symptoms of the acute intestinal form are analogous to those of the gastric one, and manifest 5-7 days after consumption. The chronic intestinal symptoms include weight loss, mild cramping, abdominal pain, and diarrhea, lasting for months or years. The migration of the larvae to the peritoneal cavity or to solid or hollow organs (larva migrans) may cause symptoms related to the involved tissue. In some cases anisakiasis is accompanied by an allergic response, such as urticaria, angioedema and anaphylactic shock. Asthma, conjunctivitis and dermatitis may also be observed as occupational exposure of fish processing employees to Anisakis allergens.\nEtiology\nAnisakiasis is caused by the ingestion of third stage larvae of Anisakid nematodes of the genus Anisakis, present in viscera or muscle of fish or cephalopods which are eaten raw, insufficiently cooked, smoked or marinated. Commonly reported species are Anisakis simplex  (sensu stricto) and Anisakis pegreffii, although the first has a higher rate of penetration in the fish muscle than the second one. Humans are accidental hosts in the life cycle, and the parasites almost never develop further within the human gastrointestinal tract. Some cases of human infection have been reported with worms from a number of species within the Anisakidae (Contracaecum, Pseudoterranova) or Raphidascarididae (Hysterothylacium, negligible) families.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Paolo MERELLA"}
{"Disease Name": "ANK3-related intellectual disability-sleep disturbance syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder characterized by variable degrees of intellectual disability, behavioral problems (including attention deficit and hyperactivity disorder, autism spectrum disorder, and aggressiveness), an altered sleeping pattern, and delayed speech and language development associated with disruption of ankyrin-3 (ANK3 gene). Additional features observed may include muscular hypotonia and spasticity. Epilepsy, chronic hunger, and dysmorphic facial features have been reported.", "ORPHA ID": 356996, "Summary": ""}
{"Disease Name": "Ankyloblepharon filiforme adnatum-cleft palate syndrome", "Disease Definition": "A rare, syndromic, developmental defect of the eye malformation characterized by unilateral or bilateral, single or multiple, filiforme bands of elastic tissue which connect the eyelid margins at the grey line, associated with cleft lip and palate. Eye examination is otherwise normal.", "ORPHA ID": 1072, "Summary": ""}
{"Disease Name": "Ankyloblepharon filiforme adnatum-imperforate anus syndrome", "Disease Definition": "A rare developmental defect during embryogenesis malformation syndrome characterized by bands of extensile tissue connecting the margins of the upper and lower eyelids, in association with anal atresia. Patients may additionally present cleft palate, hydrocephalus and meningomyelocele. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 1074, "Summary": ""}
{"Disease Name": "Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome", "Disease Definition": "An ectodermal dysplasia syndrome with defining features of ankyloblepharon filiforme adnatum (AFA), ectodermal abnormalities and a cleft lip and/or palate.", "ORPHA ID": 1071, "Summary": "Epidemiology\nAnkyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC syndrome) prevalence is unknown.\nClinical description\nA history of skin erosions, especially of the scalp neonatally is typical. Congenital erythroderma occurs in 78%. Skin erosions often persist intermittently for many years, evolving into alopecia and cutaneous scarring of the skin. Wound healing appears to be delayed. Other prevalent skin manifestations include hyperpigmentation and/or hypopigmentation, often reticulated, and palmar and plantar changes with effaced dermatoglyphics. Nail changes are universal and variable and include hyperconvexity, pseudoptyergium and frayed distal margin with nail plate resorption. Hypotrichosis is common and hair is thin, brittle, wiry and uncombable. Mild hypohidrosis is always present. Nearly all cases have clefting abnormalities, ranging from submusous cleft palate, to soft and/or hard cleft palate, cleft lip or a combination. Other oroauditory findings include recurrent otitis media, canal stenosis and over 90% have a conductive hearing loss associated with a delay of speech development. AFA affects most neonates (70%) but is not always evident as these may autolyse or be lysed by a healthcare provider applying ophthalmic antibiotic ointment at birth. Eyes often are deficient of lacrimal puncta. In childhood, other facial features become more apparent and include broad nasal root, hypoplastic alae nasi, short philtrum, thin vermillion border, maxillary hypoplasia and small mandible. Over time, cone-shaped teeth and hypodontia become evident. Other anomalies are limb changes with syndactyly of fingers and toes most common, hypospadias (males 78%) and trismus (less frequently described). Failure to thrive, growth delay and gastrointestinal issues are also common.\nEtiology\nAEC is an autosomal dominant condition caused by pathogenic (usually missense) changes in the Tumor suppressor gene TP63. Over 4/5th of the reported pathogenic variants occur in the sterile alpha motif (SAM) domain, and about 1/5th occur in the transactivation inhibitory (TI) domain of TP63.\nDiagnostic methods\nClinical features can be diagnostic. Light or scanning microscopy of the hair in combination with genetic testing may ascertain diagnosis.\nDifferential diagnosis\nDifferential diagnosis may include epidermolysis bullosa simplex, disorders of cornification, CHAND syndrome and hypohidrotic ectodermal dysplasia. Allelic disorders include Acro-dermal-ungual-lacrimal-tooth (ADULT) syndrome, ectrodactyly-ectodermal dysplasia clefting (EEC) syndrome, limb-mammary syndrome and split hand/foot malformation type 4. AEC is generally distinguished from these other disorders by clinical features (particularly scalp erosions) as well as the location of the TP63 change. The Rapp-Hodgkin syndrome is not a separate disease entity, but is now considered part of the disease spectrum of AEC syndrome.\nAntenatal diagnosis\nIn case of family history, prenatal diagnosis is possible by genetic testing of amniocentesis or chorionic villus sampling.\nGenetic counseling\nAEC syndrome follows an autosomal dominant inheritance pattern. About 70% of cases are caused by a de novo change in TP63. In case of family history, genetic counseling is recommended. Genetic counseling should be proposed to individuals having the pathogenic variants, informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nAFA and cleft palate may require surgical intervention, as well as dental abnormalities requiring prosthetics. Efforts to prevent secondary infections in skin erosions comprise gentle wound care and dilute bleach soaks. Secondary infections should be cultured and treated appropriately. Extra care should be taken to avoid complications in infants with severe skin erosions. Extensive grafting procedures are not recommended. Hearing loss, growth and gastrointestinal problems should be monitored regularly. Gastrostomy is common. Psychological consequences of ectodermal defects should be addressed.\nPrognosis\nOverall prognosis is good with most having normal life expectancy. Unfortunately infants with extensive skin erosions are at risk of premature death due to complications including sepsis and fluid/electrolyte abnormalities. Quality of life and psychosocial functioning is often mildly but variably impacted.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr V. Reid SUTTON"}
{"Disease Name": "Ankylosing vertebral hyperostosis with tylosis", "Disease Definition": "A rare dysostosis with predominant vertebral involvement characterized by paraspinal ligament ossification (most pronounced in the lower thoracic region), osteophytosis, marginal sacroiliac joint sclerosis, and punctate hyperkeratosis on the soles and palms. Patients may be asymptomatic or present mild to moderate back pain. There have been no further descriptions in the literature since 1969.", "ORPHA ID": 2206, "Summary": ""}
{"Disease Name": "Ankylostomiasis", "Disease Definition": "A hookworm infection caused primarily by the species Ancylostoma duodenale  or Necator americanus, usually acquired through penetration of the skin, (often asymptomatic but that can also manifest with an allergic reaction at the site of skin penetration), followed by the migration of larva through the bloodstream to the lungs (causing asymptomatic pneumonitis, eosinophilia) and finally reaching and colonizing the small intestines where they cause blood extravasation leading to diarrhea, abdominal pain, and when untreated, melena, iron-deficiency anemia and protein malnutrition.", "ORPHA ID": 78, "Summary": ""}
{"Disease Name": "Annular atrophic lichen planus", "Disease Definition": "A rare variant of cutaneous lichen planus characterized by both annular and atrophic LP features in the same lesion.", "ORPHA ID": 254411, "Summary": "Epidemiology\nFewer than ten cases have been reported in the literature.\nClinical description\nSmall violaceous papules develop on the trunk and extremities and are characterized by an atrophic centre and a raised hyperpigmented border. Patients are generally middle-aged and have no past history of cutaneous lesions. Histopathologically, the peripheral border has the typical features of lichen planus, while the centre of the lesion shows loss of rete ridges. There is loss of elastic fibres within the papillary dermis, both centrally and peripherally.\nEtiology\nEtiology is unknown.\n\n                            Last update: \n                            May 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Stephanie ARNOLD  - Dr Susan COOPER"}
{"Disease Name": "Annular epidermolytic ichthyosis", "Disease Definition": "A rare clinical variant of epidermolytic ichthyosis (EI) characterized by the presence of a blistering phenotype at birth and the development from early infancy of annular polycyclic erythematous scales on the trunk and extremities.", "ORPHA ID": 281139, "Summary": "Epidemiology\nIt has been reported in less than 10 families.\nClinical description\nAt birth, clinical features are similar to those of classical EI with erythroderma, blistering and superficial skin erosions at sites of minor trauma. In contrast to EI, an improvement of clinical symptoms occurs during early infancy after which patients develop outbursts of annular polycyclic erythematous scales on the trunk and extremities. Skin is normal between the outbursts. These skin abnormalities persist for several weeks to several months with only benign localized disease observed in adulthood. Patients also present palmoplantar hyperkeratosis.\nEtiology\nThe disease is caused by mutations in the KRT1 (12q11-q13) and KRT10 (17q21-q23) genes, encoding keratins 1 and 10 respectively. These mutations impair keratin filament formation and weaken the structural stability of the keratinocyte cytoskeleton.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER"}
{"Disease Name": "Annular lichen planus", "Disease Definition": "A rare variant of cutaneous lichen planus characterized by the development of annular lesions.", "ORPHA ID": 254424, "Summary": "Epidemiology\nThe exact prevalence is unknown.\nClinical description\nAnnular lesions occur in 10% of all cases of lichen planus, they usually occur in association with more classic lesions. Annular LP is characterized by the development of annular violaceous or hyperpigmented plaques, with no central atrophy and slightly raised, non-scaly borders. Genital and oral lesions have been reported, along with lesions affecting the axillae, trunk, and extremities.\nEtiology\nEtiology is unknown.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Stephanie ARNOLD  - Dr Susan COOPER"}
{"Disease Name": "Annular pancreas", "Disease Definition": "A distinct form of duodenal atresia in which the head of the pancreas forms a ring around the second portion of the duodenum.", "ORPHA ID": 675, "Summary": "Epidemiology\nThe annual incidence is estimated at around 1/50,000 births, representing 10% of all cases of duodenal stenosis.\nClinical description\nDuring the neonatal period, the clinical picture is dominated by epigastric distension with vomiting, which is nonbilious as the obstruction is usually supra-vaterian (above the junction of the biliary ducts). As in other forms of duodenal atresia, malformations of the cranial intestine are also frequently present in patients with annular pancreas. Cardiac anomalies may also be present and are more frequent in the context of notochord induction anomalies or deficiency. Chromosomal abnormalities are present in one-third of cases of annular pancreas, with trisomy 21 (followed by trisomy 18 and 13; see these terms) being the most frequently detected anomaly.\nEtiology\nAnnular pancreas is an embryopathy resulting from an anomaly occurring early (towards the fourth week) in development. It is a distinct form of duodenal atresia, rather than a pancreatic anomaly, and should not be confused with other congenital malformations of the pancreas or pancreaticobiliary ducts (such as anomalies of the pancreaticobiliary junction) for which the diagnosis cannot be made until childhood or adulthood.\nDiagnostic methods\nDiagnosis of annular pancreas is often made before birth through ultrasound findings showing duodenal dilation and through difficulties in observing peri-duodenal pancreatic development. In cases where the diagnosis is not made prenatally, it is made in the neonatal period on the basis of the clinical picture and imagining studies (abdominal radiography and ultrasound).\nDifferential diagnosis\nThe differential diagnosis should include other forms of duodenal stenosis.\nAntenatal diagnosis\nPrenatal diagnosis allows management to be planned in a specialized center immediately after birth.\nManagement and treatment\nInvestigations using a gastric tube allow drainage of the digestive tract prior to the site of obstruction. Treatment is surgical and is performed in the neonatal period.\nPrognosis\nThe prognosis for annular pancreas is very favorable, but the overall prognosis depends on the presence of associated malformations.\n\n                            Last update: \n                            January 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Frédéric BARGY"}
{"Disease Name": "Anoctamin-5-related limb-girdle muscular dystrophy R12", "Disease Definition": "A form of limb-girdle muscular dystrophy most often characterized by an adult onset (but ranging from 11 to 51 years) of mainly proximal lower limb weakness, with difficulties standing on tiptoes being one of the initial signs. Proximal upper limb and distal lower limb weakness is also common, as well as atrophy of the quadriceps (most commonly), biceps brachii, and lower leg muscles. Calf hypertrophy has also been reported in some cases. LGMD2L progresses slowly, with most patients remaining ambulatory until late adulthood.", "ORPHA ID": 206549, "Summary": ""}
{"Disease Name": "Anodontia", "Disease Definition": "An extreme developmental dental anomaly characterized by the complete absence of all teeth.", "ORPHA ID": 99797, "Summary": "Epidemiology\nThe prevalence is unknown but it is extremely rare and usually only occurs as part of an associated syndrome such as X-linked hypohidrotic ectodermal dysplasia (X-linked HED; see this term).\nEtiology\nGenes found to be responsible for HED include EDA and EDAR and EDARADD.\nDiagnostic methods\nClinical examination along with a panoramic radiograph (and intra-oral X-rays if needed) is performed when teeth eruption is delayed and teeth are then thought to be missing. In normal conditions all primary teeth and crypts of permanent first molars are visible on radiography at birth and permanent teeth crowns (except third molars) at 6 years of age. A diagnosis of anodontia is given when all teeth are missing.\nManagement and treatment\nTreatment involves full fixed dentures or, in suitable candidates, dental implants. Early mandibular implants therapy is indicated in these severe phenotypes of anodontia. A marked alveolar bone hypotrophy is generally associated with anodontia and requires CT exams of the mandible and 3D reconstructions for implants surgical planning. Maxillary rehabilitation based on osteointegrated implants and prosthodontics is indicated at the end of the skeletal growth. Bone grafts such as onlay autogenous grafts and maxillary sinus floor augmentation procedures are often necessary. Before completion of growth a removable maxillary denture should be used.\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN  - Dr François CLAUSS"}
{"Disease Name": "Anomalous aortic origin of coronary artery", "Disease Definition": "A rare group of coronary artery congenital malformation disorders characterized by an anomalous origin and course of the left or right coronary artery, which originates from the contralateral aortic sinus of Valsalva and has an anomalous trajectory which may be: pre-pulmonary (with no hemodynamic consequences), retroaortic (with a course posterior to the aortic root and no hemodynamic consequences), interarterial (located between the aorta and the pulmonary artery and associated with a poorer prognosis), subpulmonary (with an intraconal or intraseptal course), or retrocardiac (located in the posterior atrioventricular sulcus). Clinical manifestations depend on the specific anomalous origin and course which is present, with patients being frequently asymptomatic, although nonspecific chest pain, palpitations, dizziness, dyspnea or syncope, usually following physical exertion, may be associated. Sudden death, due to compression/occlusion of the coronary artery and usually associated with, or immediately following, vigorous physical exercise, may be occasionally observed.", "ORPHA ID": 541478, "Summary": ""}
{"Disease Name": "Anomalous aortic origin of the left coronary artery", "Disease Definition": "A rare coronary artery congenital malformation characterized by an anomalous origin and course of the left coronary artery, which originates from the right aortic sinus of Valsalva and has an abnormal proximal course, which may be intramural, prepulmonic, subpulmonic, retroaortic, retrocardiac or wrapped around the apex. Patients are frequently asymptomatic, although chest pain, dyspnea, palpitations, dizziness, syncope, and sudden cardiac arrest/death (typically following intense physical exertion) may be observed. This malformation is associated with a high risk of sudden cardiac death so surgical revascularization is recommended even in cases with no associated evidence of myocardial ischemia.", "ORPHA ID": 541443, "Summary": ""}
{"Disease Name": "Anomalous aortic origin of the right coronary artery", "Disease Definition": "A rare coronary artery congenital malformation characterized by an anomalous origin and course of the right coronary artery, which originates from the left aortic sinus of Valsalva and has an abnormal proximal course, which may be intramural, prepulmonic, subpulmonic, retroaortic, retrocardiac or wrapped around the apex. Patients are frequently asymptomatic, although chest pain, dyspnea, palpitations, dizziness, syncope, and sudden cardiac arrest/death (typically following intense physical exertion) may be observed. This malformation is associated with a lower risk of sudden cardiac death therefore surgical revascularization is recommended only when signs and/or symptoms of ischemia are present.", "ORPHA ID": 541454, "Summary": ""}
{"Disease Name": "Anomalous origin of coronary artery from the pulmonary artery", "Disease Definition": "A rare coronary artery congenital malformation characterized by an anomalous origin of the left (ALCAPA) or right (ARCAPA) coronary artery from the pulmonary artery, with variable clinical presentation, ranging from asymptomatic to early heart failure and death depending on the degree of development of collateral circulation between the left and right coronary artery systems, as well as the pressure level of the pulmonary artery. Infants typically present with feeding difficulties, failure to thrive, dyspnea, irritability, hyperhidrosis, heart murmurs, tachypnea, tachycardia and/or chest pain while adults usually associate dyspnea, chest pain, syncope, and intolerance to physical exercise. Sudden death may occur due to congestive heart failure, myocardial infarction, valvular insufficiencies or ventricular arrhythmias. The majority of cases reported are of an ALCAPA, while ARCAPA is rarely observed.", "ORPHA ID": 541507, "Summary": ""}
{"Disease Name": "Anomaly of the coronary ostia", "Disease Definition": "A group of rare congenital coronary artery malformations comprising abnormal number of coronary ostia, malposition of a coronary ostium, and stenosis or atresia of a coronary ostium. Patients may remain asymptomatic or present with variable signs and symptoms, depending on the nature and severity of the malformation, including failure to thrive, dyspnea, syncope, angina pectoris, ventricular tachycardia, and myocardial ischemia.", "ORPHA ID": 542822, "Summary": ""}
{"Disease Name": "Anomaly of the mitral subvalvular apparatus", "Disease Definition": "A group of rare congenital mitral malformations characterized by anomalies of the chordae tendineae and papillary muscles. This comprises anomalous mitral arcade or hammock valve (due to thickened and extremely short chordae tendineae), straddling valve (abnormal attachment of the chordae tendineae to both ventricles), and parachute valve (unifocal attachment of the chordae tendineae to a single or fused papillary muscle), resulting in an incompetent valve with regurgitation and/or stenosis and impaired left ventricular inflow, potentially leading to heart failure. In most cases, other cardiac anomalies are found in association.", "ORPHA ID": 101932, "Summary": ""}
{"Disease Name": "Anomaly of the tricuspid subvalvular apparatus", "Disease Definition": "A group of rare congenital tricuspid malformations characterized by anomalies of the chordae tendineae and papillary muscles, including aberrant chordae tendineae, straddling valve (abnormal attachment of the chordae tendineae to both ventricles), and parachute valve (unifocal attachment of the chordae tendineae to a single or fused papillary muscle), resulting in an incompetent valve with regurgitation and/or stenosis and impaired right ventricular inflow, potentially leading to heart failure. In most cases, other cardiac anomalies are found in association.", "ORPHA ID": 95463, "Summary": ""}
{"Disease Name": "Anonychia with flexural pigmentation", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by anonychia congenita totalis or rudimentary nails, macular hyper- and/or hypopigmentation (particularly affecting groins, axillae and breasts), coarse scalp hair (that becomes markedly thinned in early adult life), dry palmoplantar skin with distorted epidermal ridges and sore, cracked soles, and hypohidrosis. There have been no further descriptions in the literature since 1975.", "ORPHA ID": 69125, "Summary": ""}
{"Disease Name": "Anonychia-microcephaly syndrome", "Disease Definition": "A multiple congenital anomaly disorder characterized by anonychia congenita totalis and microcephaly, and normal intelligence along with some minor anomalies including single transverse palmar creases, fifth-finger clinodactyly and widely-spaced teeth.", "ORPHA ID": 1094, "Summary": ""}
{"Disease Name": "Anophthalmia plus syndrome", "Disease Definition": "A very rare multiple congenital anomaly syndrome characterized by the presence of anophthalmia or severe microphthalmia, cleft lip/palate, facial cleft and sacral neural tube defects, along with various additional anomalies including congenital glaucoma, iris coloboma, primary hyperplastic vitreous, hypertelorism, low-set ears, clinodactyly, choanal atresia/stenosis, dysgenesis of sacrum, tethering of spinal cord, syringomyelia, hypoplasia of corpus callosum, cerebral ventriculomegaly and endocrine abnormalities. An autosomal recessive inheritance has been suggested.", "ORPHA ID": 1104, "Summary": ""}
{"Disease Name": "Anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome, reported in the offsprings of a consanguineous couple and characterized by multiple congenital skeletal (dolichocephaly, skull asymmetry, camptodactyly, clubfoot), muscular (muscle hypoplasia), ocular (anophthalmia, buphthalmos, retinal detachment, aniridia (see this term)) and cardiac (prolapse of tricuspid valves, mitral and tricuspid insufficiency) abnormalities. An autosomal recessive inheritance with variable expressivity was suspected. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 1101, "Summary": ""}
{"Disease Name": "Anophthalmia/microphthalmia-esophageal atresia syndrome", "Disease Definition": "A syndrome that belongs to the group of syndromic microphthalmias and is characterized by the association of uni- or bilateral anophthalmia or microphthalmia, and esophageal atresia with or without trachoesophageal fistula.", "ORPHA ID": 77298, "Summary": "Epidemiology\nPrevalence is unknown but less than 30 cases (male and female) have been described in the literature so far.\nClinical description\nGenital anomalies (hypospadias, micropenis, and/or cryptorchidism) were reported in most of the male patients. Several other associated anomalies have been described including developmental anomalies of the central nervous system, cardiac defects, vertebral anomalies, growth failure, sensorineural hearing loss, anterior pituitary hypoplasia and hypogonadotropic hypogonadism. Intellectual development was normal in some cases, but mild to significant psychomotor delay has also been reported.\nEtiology\nInheritance is autosomal dominant and the syndrome is caused by heterozygous mutations or deletions in the SOX2 gene (3q26.3-q27).\n\n                            Last update: \n                            February 2010"}
{"Disease Name": "Anotia", "Disease Definition": "A congenital malformation of the external ear and the most extreme form of microtia characterized by the complete absence of the external ear and auditory canal, conductive hearing loss, attention deficit disorders and delayed language development.", "ORPHA ID": 93976, "Summary": ""}
{"Disease Name": "Antecubital pterygium syndrome", "Disease Definition": "A rare, genetic, dermis disorder characterized by bilateral, fairly symmetrical, antecubital webbing extending from distal third of humerus to proximal third of forearm, associated with musculoskeletal abnormalities (i.e. absent long head of triceps, bilateral posterior dislocation of the radial head and hypoplasia of the olecranon processes) and absent skin creases over the terminal interphalangeal joints of fingers, clinically manifesting with moderate to severe elbow extension and supination limitation.", "ORPHA ID": 2987, "Summary": ""}
{"Disease Name": "Anterior cutaneous nerve entrapment syndrome", "Disease Definition": "A chronic neuropathic pain syndrome of the abdominal wall caused by entrapment of anterior cutaneous branches of 7 to 12th intercostal nerves along the lateral border of the anterior rectus abdominis fascia causing severe pain and tenderness of the involved dermatome.", "ORPHA ID": 51890, "Summary": "Epidemiology\nAround 20% of patients with chronic abdominal pain have abdominal wall pain, which is often caused by ACNES. The prevalence in patients alleged to have functional abdominal pain is estimated to be 3-4%. One out of 50 patients consulting an emergency department for abdominal pain suffers from ACNES. The incidence in general population is probably 1: 4000 to 5000. ACNES, hence may be not so rare as is thought.\nClinical description\nACNES most commonly affects young women (75%) but can occur at any age, also in children. History of trauma, pregnancy and delivery or abdominal surgery is sometimes present. Patients present with sharp stabbing pain emanating from the anterior abdominal wall. Presentation can be acute or chronic. Patients can usually localize the source of pain to the spot where the nerve is entrapped (lateral margin of rectus abdominis muscle), palpation of which triggers a lancinating pain along the distribution of the involved nerve. The most frequent involved pain location is in the right lower quadrant (50%), however, all other quadrants can be involved. Pain is always in the same area and is aggravated by exercise. Most patients also have concomitant various pseudo-visceral complains, anorexia, nausea, bloating, altered defecation, (pseudo visceral complaints). Asking the patient to tense his/her abdominal wall will elicit the pain (positive Carnett's test).\nEtiology\nACNES is caused by the entrapment of the cutaneous end branches of the intercostal nerve in the muscular foramen as they pass through the rectus abdominis, which probably leads to ischemic neuropathy. Etiology is unclear, but there seems to be a causative relation with any kind of abdominal surgery, pregnancy and sometimes trauma. However, in more than half of the patients there is a sudden onset of pain, without any specific event.\nDiagnostic methods\nImaging and laboratory tests are indicated to rule out potential visceral causes of abdominal pain. The diagnosis is clinical. Physical examination reveals altered skin sensibility in the painful area with one specific painful spot and reproducibility of pain by pinching the affected skin area. Subfascial injection of local anesthetic around the entrapped nerve (the trigger point) serves as both diagnostic and can be therapeutic in about 30% of patients.\nDifferential diagnosis\nDifferential diagnoses include hernias, tumors, tears and endometriosis of abdominal wall, radiculopathy (diabetic, traumatic, herpetic), herniated vertebral disc, rib and vertebral column abnormalities.\nManagement and treatment\nMost pain killers have no effect on this type of neuropathic pain. Treatment is by injection of the anterior cutaneous nerve with a local anesthetic at the point at which it pierces the fascia by free hand or under ultrasound guidance. Neuropathic pain killers like pregabaline or amitryptilline may be helpful. In patients in whom pain persists after several injections, surgical exploration and neurectomy is indicated. This strategy of injections followed by neurectomy is curative in 80% of patients.\nPrognosis\nDiagnostic delay is common; untreated ACNES can lead to functional disability and reduced quality of life resulting in high medical health care costs, highlighting the importance of the awareness of ACNES among medical professionals.\n\n                            Last update: \n                            June 2015\n\n\n                            - Expert reviewer(s): \n                            Dr R.M.H. [Rudi] ROUMEN"}
{"Disease Name": "Anterior maxillary protrusion-strabismus-intellectual disability syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of severe intellectual disability, strabismus, and anterior maxillary protrusion with vertical maxillary excess, open bite, and prominent crowded teeth. Mild cochlear hearing loss has been reported in addition.", "ORPHA ID": 562559, "Summary": ""}
{"Disease Name": "Anterior urethral valve", "Disease Definition": "A rare, congenital, fetal lower urinary tract obstruction (LUTO) anomaly occurring in males and characterized by a posteriorly directed semilunar fold arising from the floor of the anterior urethra and causing urethral obstruction during micturition. The valves may be located anywhere distal to the membranous urethra. Clinical presentation is highly variable, depending on age and degree of urinary obstruction, and includes urinary incontinence, urinary retention, weak urinary stream, post-micturitional dribbling, bulging on the ventral penis, urinary tract infection, and urosepsis.", "ORPHA ID": 435372, "Summary": "Epidemiology\nThe exact prevalence is unknown, although it occurs less frequently than posterior urethral valves. This disease affects males only.\nClinical description\nAnterior urethral valve (AUV) can be located anywhere distal to the membranous urethra, occurring either in the bulbar urethra (40%), penoscrotal junction (30%), or in the penile urethra (30%), and are occasionally associated with urethral diverticulum. Clinical presentation is highly variable and may occur prenatally with hydronephrosis or a distended bladder, or between birth and adolescence with urinary tract infections or weak urinary stream. Other clinical manifestations include lower urinary tract obstruction, palpable distended bladder, urinary incontinence, renal insufficiency, renal dysplasia, a thickened, trabeculated bladder, and vesicoureteral reflux. After valve ablation, patients typically void spontaneously; however, over 20% of patients have abnormal renal function after treatment, which can range from stable azotemia to end stage renal disease. Complications from surgery include bleeding, incomplete valve resection, urethral stricture or damage to the external sphincter.\nEtiology\nA genetic cause has not been identified. AUV is postulated to arise either from a tissue growth imbalance during urethral development, incomplete hypospadias, an abortive process during urethral duplication, or faulty union between glandular and urethral tissue.\nDiagnostic methods\nDiagnosis is with voiding cystourethrogram (VCUG), which typically demonstrates a urethra dilated proximal to the valve and narrowing distal to it. Other findings may include a trabeculated bladder, bladder diverticulum, and urethral diverticulum. On ultrasonography, patients may demonstrate bladder distension and bilateral hydroureteronephrosis.\nDifferential diagnosis\nDifferential diagnosis includes posterior urethral valve, prune belly, and urethral atresia.\nAntenatal diagnosis\nPrenatal ultrasound may identify hydronephrosis, a distended bladder, or periurethral cystic mass which is indicative of the malformation.\nManagement and treatment\nInitial management involves decompression and drainage of the genitourinary system with an indwelling urethral or suprapubic catheter. Definitive surgical treatment is typically with transurethral valve ablation, either with laser, electrocautery or cold knife urethrotomy. However, this may be deferred in favor of a primary vesicostomy in premature infants, or infants with low birth weight and high creatine levels. Due to the risk of developing renal insufficiency and other complications, all patients should be followed up with serial renal and bladder ultrasound. In severe cases with large urethral diverticulum, formal urethral reconstruction is needed, with excision of diverticulum and tubularization of urethra around a catheter.\nPrognosis\nDelayed treatment can lead to renal insufficiency and is potentially life threatening. Typically, valve ablation results in a good functional outcome, although there is a risk of complications and continued renal or bladder dysfunction.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Yazan RAWASHDEH | EUROGEN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Anti-glomerular basement membrane disease", "Disease Definition": "A rare, fulminant small vessel vasculitis that affects the capillary beds of the kidneys and lungs and characterized by the presence of anti-glomerular basement membrane (GBM) and, in its full-blown form, anti-alveolar basement membrane (ABM) antibodies. Consequently, it may manifest as a rapidly progressive, isolated glomerulonephritis (anti-GBM nephritis) or as a pulmonary-renal syndrome with severe lung hemorrhage.", "ORPHA ID": 375, "Summary": "Epidemiology\nThe incidence of the disease is estimated to be approximately 0.6-1.8 cases per million per year in both Asian and European Caucasian (more frequently affected) populations. Men and women seem equally affected. The disorder is responsible for 1-5% of all cases of glomerulonephritis and is the cause in up to 10-15% of patients with rapidly progressive crescentic glomerulonephritis.\nClinical description\nAnti-GBM disease onset is bimodal, occurring mainly in the third and the seventh decades of life. The majority of patients (80-90%) will present with features of rapidly progressive glomerulonephritis. 40 to 60% will have concurrent lung hemorrhage, and a small minority of patients may present with isolated pulmonary disease. Features of lung involvement may include cough, shortness of breath, hemoptysis, chest pain and hypoxia. Anemia is often encountered and fatal respiratory failure may occur in more severe cases. Nephritis mainly presents with a rapidly progressive course. Rarely, renal function may be preserved for several months, despite severe pulmonary hemorrhage. Systemic features (i.e. malaise, fatigue, mild fever, pallor, weight loss) have been reported.\nEtiology\nAnti-GBM disease is considered to be a vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with deposition of anti-basement membrane antibodies against the non-collagenous domain 1 of the alpha 3 chain of type IV collagen (alpha3(IV)NC1). The production of anti-GBM autoantibodies usually precedes the development of clinical manifestations by months. About one-third of the patients will also develop anti-neutrophilic cytoplasmic antibodies (ANCA). Autoreactive T cells may play a role in its pathogenesis and a strong correlation between the condition and HLA-DRB1*1501 and DRB1*1502 has been reported in Caucasian populations.\nDiagnostic methods\nDiagnosis is based on the detection of anti-GBM antibodies either in serum or deposited in tissue, along with pathologic features of crescentic GN, with or without evidence of alveolar hemorrhage. Histologic examination on biopsy may show extensive formation of crescents (extra-capillary cell proliferation), GBM destruction, interstitial inflammation and tissue necrosis.\nDifferential diagnosis\nDifferential diagnosis includes systemic vasculitis (e.g. Wegener's granulomatosis (GPA), microscopic polyarteritis (MPA), systemic lupus erythematosus, Churg-Strauss syndrome (EGPA)) and other vasculitides (e.g. Behçets disease, cryoglobulinemia). Idiopathic progressive glomerulonephritis, severe pneumonia, pulmonary edema with acute renal failure, and renal vein thrombosis with pulmonary embolism should also be considered.\nManagement and treatment\nStandard therapy consists in plasma exchange combined with high doses of glucocorticoids and cyclophosphamide. Recently, several reports of rituximab use have been reported, either as an adjuvant to standard therapy or as a substitute for cyclophosphamide. Dialysis may be required in severe cases, as well as medications that regulate fluid and electrolyte balance and blood pressure. Renal transplantation is not recommended as long as circulating autoantibodies are detected. Sustained remission in the absence of clinical signs of recurrence should be confirmed every 6 months.\nPrognosis\nIf untreated, anti-GBM disease prognosis is poor. Alveolar hemorrhage is the main cause of early death in the disorder. The severity and prognosis of renal disease are correlated with levels of circulating anti-GBM. Relapses are rare.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Dario ROCCATELLO | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Anti-p200 pemphigoid", "Disease Definition": "A rare, acquired, subepidermal autoimmune bullous disease characterized by polymorphic cutaneous lesions (blisters, urticarial lesions or scars/milia) associated with imunoglubulin G deposition in the basement membrane zone. Lesions are frequently localized on extremities, trunk, palmoplantar and cephalic areas as well as mucous membranes.", "ORPHA ID": 454710, "Summary": "Epidemiology\nApproximately 115 cases been reported in the literature to date. A male predominant of about 2:1 is observed.\nClinical description\nThe disease predominantly affects elderly people (mean age 66 years, range 28-91). Cutaneous lesions are polymorphic, but typically include itchy erythematous lesions and tense blisters, vesicles, and erosions on trunk and extremities, with possibly predominant palmoplantar involvement. In some cases, patients can have annularly arranged lesions. Usually, lesions heal without scarring, and milia formation has only been reported in few cases. About half of the patients have mucosal involvement affecting either oral or anogenital mucosa, or both. In Japanese patients, coexisting (mostly preexisting) psoriasis may be present (30% of cases).\nEtiology\nThe exact etiology is unknown, but may be related to laminin gamma-1, consistent with the identified characteristics of the p200 protein (an acidic non-collagenous N-linked glycoprotein localized within the lower lamina lucida outside of hemidesmosomes).\nDiagnostic methods\nDiagnosis is based on the combination of the clinical features and direct immunofluorescence microscopy showing linear deposits of IgG and/or C3 at the dermal-epidermal junction in an n-serrated pattern and is confirmed by detection of a 200-kDa band by immunoblotting of patients' serum on human dermal extracts. About 90% of patients' sera are positive for anti-laminin-gamma 1 reactivity on ELISA or immunoblotting.\nDifferential diagnosis\nDifferential diagnosis includes bullous pemphigoid, epidermolysis bullosa acquisita, mucous membrane pemphigoid, IgA linear bullous dermatosis, pemphigus herpetiform, and pemphigus.\nManagement and treatment\nThe treatment may follow that of bullous pemphigoid. Super-potent topical corticosteroids may be applied on the whole-body surface or tapering doses of prednisolone 0.5 mg/kg/day, frequently associated with dapsone. Doxycycline, azathioprine and ciclosporine can also be used.\nPrognosis\nPrognosis is variable. Most patients achieve complete remission on therapy. The use of systemic corticosteroid treatment may contribute to higher mortality rate in the older patients.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Marion CASTEL | ERN-Skin* - Pr Pascal JOLY | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Antiphospholipid syndrome", "Disease Definition": "A rare systemic autoimmune disease characterized by hypercoagulability with vascular thrombosis and, in women, pregnancy morbidity (miscarriages, severe pre-eclampsia, placental insufficiency) in the presence of serum antiphospholipid antibodies, such as lupus anticoagulant, anticardiolipin antibodies, and anti-beta2-glycoprotein 1 antibodies.", "ORPHA ID": 80, "Summary": ""}
{"Disease Name": "Antisynthetase syndrome", "Disease Definition": "A rare idiopathic inflammatory myopathy (IIM) characterized principally by myositis, generally symmetrical arthritis and interstitial lung disease (ILD) in association with serum autoantibodies to aminoacyl-transfer RNA synthetases (anti-ARS). More variable features include arthralgia, Raynaud phenomenon, heliotrophic rash, distal esophageal dysmotility and mechanic's hands.", "ORPHA ID": 81, "Summary": "Epidemiology\nAbout a quarter of all IIM patients may have antisynthetase syndrome (ASyS), providing a prevalence estimate of 1/25,000-33,000 worldwide. The disorder affects females twice as often as males.\nClinical description\nThe age of onset is highly variable with a mean of 50 years (range 19 to 82). Myositis, arthritis, ILD are key features of the disease. ILD is one of the clinical hallmarks. Respiratory symptoms (shortness of breath, coughing, dysphagia) are found in 40-60% of patients at disease onset. Respiratory insufficiency may be acute or develop gradually. Some patients develop clinically overt myositis while others have hypomyopathic or even amyopathic forms of the disorder. At onset, 20-70% of patients have muscle weakness of the proximal and axial muscles, and many have myalgia and muscle stiffness, similar to the milder presentations of other idiopathic inflammatory myopathies. Non-specific symptoms of fever, loss of appetite, or weight loss may occur. Rarely reported manifestations include Shawl and V signs (erythema over the back and shoulders or over the anterior neck and chest in a V), and periungual erythema. Pulmonary arterial hypertension is possible but rare. The incidence of malignancies appears to be fairly low.\nEtiology\nThe exact pathophysiology is not known. It is currently thought that the disease starts in the lungs triggered by environmental factors (tobacco exposure, airborne contaminants) and infections, and favored by a genetic predisposition. The non-specific tissue damage activates the innate immune system, leading to release of immunogenic neo-antigens. This, in turn, induces the activation of the adaptive immune system with the production of anti-ARS antibodies, and the spreading of the immune response to targeted tissues (muscle, joint, skin).\nDiagnostic methods\nThe diagnosis is based on the clinical features and is confirmed in the presence of positive serologic testing for anti-ARS antibodies (anti-Jo-1, anti-PL-12, anti-PL-7, anti-OJ, anti-KS, anti- YRS, anti-Zo). ILD is diagnosed by high resolution computed tomography (HRCT) of the lungs. The most frequent patterns are non-specific interstitial pneumonia (70% of the patients) and organizing pneumonia (20% of the patients). Creatine kinase (CK) levels are often significantly elevated. Absence of myositis or ILD does not exclude the diagnosis of ASyS. Diagnosis is considered probable in patients with ILD and/or inflammatory myopathy in the presence of anti-ARS. The features on the muscle biopsy include necrosis and regenerative myofibers, C5b-9 depositions on sarcolemma of non-necrotic myofibers, and sarcolemmal MHC class I overexpression with inflammatory cells infiltrates. These features occur mainly in the perifascicular area.\nDifferential diagnosis\nDifferential diagnoses include other inflammatory myopathies and idiopathic isolated ILD such as usual interstitial pneumonia. Joint involvement may also mimic or even overlap with rheumatoid arthritis.\nManagement and treatment\nWhilst there is no consensus on treatment regimens, oral corticosteroids (prednisone) and immunosuppressive agents are the mainstay of treatment. The presence and the severity of ILD is a key point to consider. Depending on the presentation and severity, drug therapy regimens may include azathioprine, methotrexate, cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, polyvalent immunoglobulins or rituximab. Dermatological symptoms have been treated effectively with hydroxychloroquine. ILD generally responds well to immunosuppressive treatment. Exercise is recommended to improve muscle strength. Response to therapy should be assessed clinically on muscle strength and CK levels. Pulmonary function tests and HRCT imaging are important for ILD follow-up.\nPrognosis\nThe disease is chronic, requiring long-term treatment. Prognosis is guarded in severe cases but may stabilize or improve in other cases. Progression of ILD is the main prognostic factor (with aggravation in 20% of cases despite treatment) and is more likely in patients with non-anti-JO-1 antibodies.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE"}
{"Disease Name": "Antley-Bixler syndrome", "Disease Definition": "A rare syndromic craniosynostosis characterized by craniosynostosis with midface hypoplasia, radiohumeral synostosis, femoral bowing and joint contractures.", "ORPHA ID": 83, "Summary": "Epidemiology\nAntley-Bixler syndrome (ABS) has been described in more than 100 patients. The relative prevalence of the two main etiologies is unknown but cases due to FGFR2 variants seem rarer than those due to POR variants.\nClinical description\nChildren present with characteristic facial features, including a large domed forehead, flat nose, and midface hypoplasia with proptosis and dysplastic ears. The types of craniosynostosis may include trigonocephaly (due to early metopic synostosis) or brachycephhaly but also severe pansynostosis with cloverleaf skull. Characteristic skeletal features include the radio-humeral synostosis, femora bowing (with possible fractures). Arachnodactyly and/or camptodactyly, choanal atresia and cleft palate have also been reported. A diverse range of malformations (cardiac, renal, anal or vertebral) are often associated. Urogenital anomalies with sexual ambiguity due to impaired steroidogenesis can occur. Intellectual development is variable.\nEtiology\nTwo genetically distinct forms are observed: type 1 Antley-Bixler syndrome is associated with heterozygous mutations in the FGFR2 gene (10q26) without impairment of steroidogenesis, whereas type 2 Antley-Bixler is associated with homozygous mutations in the POR gene (7q11.2), encoding cytochrome P450 oxidoreductase (POR), which plays a direct role in steroidogenesis. Type 2 Antley-Bixler can thus be accompanied by sexual ambiguity, but this is not a compulsory finding.\nDiagnostic methods\nThe diagnosis is usually suspected by imaging features and confirmed by molecular screening: next generation sequencing panels, whole exome sequencing and whole genome sequencing.\nDifferential diagnosis\nA similar clinical picture is observed due to in utero environmental exposure to 1) fluconazole, a lanosterol 14 alpha-demethylase inhibitor and 2) methotrexate. A similar phenotype has been reported associated with biallelic CYP26B1 variants.\nAntenatal diagnosis\nABS may be evoked in case of syndromic craniosynostosis including radio-humeral synostosis, femora bowing, choanal atresia and other visceral malformations.\nGenetic counseling\nInheritance depends on the gene involved. ABS due to FGFR2 is autosomal dominant, and most cases are de novo. Affected families should be informed that it is associated with a low recurrence risk (the residual risk is due to germinal mosaicism risk, estimated to approximately 1%). ABS due to POR variants is an autosomal recessive disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment is symptomatic, and includes early neurosurgical as well as pulmonary and orthopedic management. This disorder is associated with a high risk of pediatric complications.\nPrognosis\nThe prognosis is poor with the majority of reported patients dying during infancy due to respiratory and medullary complications.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Geneviève BAUJAT | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Aortic arch anomaly-facial dysmorphism-intellectual disability syndrome", "Disease Definition": "A developmental anomaly characterized at birth by the presence of right-sided aortic arch, craniofacial dysmorphism (microcephaly, asymmetric, facial bones, broad forehead, borderline hypertelorism, nasal septum deviation, large nasal cavity, large, posteriorly rotated ears, and microstomia with downturned corners), and intellectual disability. These features were observed in 4 members of one family, involving 2 successive generations, suggesting an autosomal dominant mode of transmission. There have been no further descriptions in the literature since 1968.", "ORPHA ID": 1110, "Summary": ""}
{"Disease Name": "Aortic arch interruption", "Disease Definition": "A rare heart defect characterized by complete lack of anatomical continuity between the transverse aortic arch and the descending thoracic aorta. AAI should be distinguished anatomically from atresia of the aortic arch where continuity between these segments is achieved by an imperforate fibrous strand of various lengths.", "ORPHA ID": 2299, "Summary": ""}
{"Disease Name": "Aorto-ventricular tunnel", "Disease Definition": "A congenital, extracardiac channel which connects the ascending aorta above the sinotubular junction to the cavity of the left, or (less commonly) right ventricle.", "ORPHA ID": 3400, "Summary": "Epidemiology\nThe exact incidence is unknown, estimates ranging from 0.5% of fetal cardiac malformations to less than 0.1% of congenitally malformed hearts in clinico-pathological series. Approximately 130 cases have been reported in the literature, about twice as many cases in males as in females.\nClinical description\nAssociated defects, usually involving the proximal coronary arteries, or the aortic or pulmonary valves, are present in nearly half the cases. Occasional patients present with an asymptomatic heart murmur and cardiac enlargement, but most suffer heart failure in the first year of life.\nEtiology\nThe etiology of aorto-ventricular tunnel is uncertain. It appears to result from a combination of maldevelopment of the cushions which give rise to the pulmonary and aortic roots, and abnormal separation of these structures.\nDiagnostic methods\nEchocardiography is the diagnostic investigation of choice. Antenatal diagnosis by fetal echocardiography is reliable after 18 weeks gestation.\nDifferential diagnosis\nAorto-ventricular tunnel must be distinguished from other lesions which cause rapid run-off of blood from the aorta and produce cardiac failure.\nManagement and treatment\nOptimal management of symptomatic aorto-ventricular tunnel consists of diagnosis by echocardiography, complimented with cardiac catheterization as needed to elucidate coronary arterial origins or associated defects, and prompt surgical repair. Observation of the exceedingly rare, asymptomatic patient with a small tunnel may be justified by occasional spontaneous closure. All patients require life-long follow-up for recurrence of the tunnel, aortic valve incompetence, left ventricular function, and aneurysmal enlargement of the ascending aorta.\n\n                            Last update: \n                            October 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Roxane MCKAY"}
{"Disease Name": "Apert syndrome", "Disease Definition": "A frequent form of acrocephalosyndactyly, a group of inherited congenital malformation disorders, characterized by craniosynostosis, midface hypoplasia, and finger and toe anomalies and/or syndactyly.", "ORPHA ID": 87, "Summary": "Epidemiology\nThe estimated incidence of Apert syndrome is reported to be 1/100,000 to 1/160,000 live births.\nClinical description\nPatients generally have extensive structural and functional impairments related to cranial and limb deformities. Craniosynostosis can lead to acrobrachycephaly or turribrachycephaly with delayed closure of fontanels and a possible impact on brain growth and neurological development. Macrocephaly is also found. Limb malformations mainly consist of soft tissue and bony syndactyly of fingers and toes (involving variable numbers of digits), occasional rhizomelic shortening, and elbow ankylosis, with functional impairments and restriction of mobility. Facial findings include midface hypoplasia that is generally moderate to severe with hypoplasia of the maxilla, shallow orbits, strabismus, hypertelorism, down-slanting palpebral fissures, and proptosis, as well as depressed nasal bridge and deviated nasal septum. Dental findings include delayed eruption, impaction, crowding, thick gingival swelling, and missing teeth, along with a high risk of caries. Unilateral and bilateral posterior crossbites are frequent. Common associated complications include chronic otitis media, hearing loss, and increased ocular pressure that can cause blindness. Moderate to severe intellectual disability and variable developmental delay are also common in AS (more than 50% of cases). Some patients are also reported to have agenesis of the corpus callosum, ventriculomegaly, hydrocephalus, fused cervical vertebrae (usually C5-C6), and occasionally, cardiac and gastrointestinal defects, radiohumeral synostosis, or cleft velum (see this term).\nEtiology\nA mutation in the FGFR2 gene (10q25.3-10q26) involved in cell signaling during embryonic development is causative in Apert syndrome. Advanced paternal age has been associated with de novo mutations, which are found in most cases.\nDiagnostic methods\nDiagnosis is based on the clinical findings at birth. Some cases may be identified prenatally. The diagnosis can be confirmed by molecular genetic testing.\nDifferential diagnosis\nThe differential diagnosis includes other syndromic craniosynostosis syndromes, such as Pfeiffer, Crouzon, Saethre-Chotzen, Muenke, and Jackson-Weiss syndromes (see these terms).\nAntenatal diagnosis\nPrenatal MRI or molecular genetic testing can be used to diagnose suspected cases.\nGenetic counseling\nA mutation in the FGFR2 gene (10q25.3-10q26) involved in cell signaling during embryonic development is causative in Apert syndrome. Advanced paternal age has been associated with de novo mutations, which are found in most cases.\nManagement and treatment\nA multidisciplinary approach to care is necessary with life-long monitoring. Treatment primarily involves craniosynostosis release, followed by surgical advancement or distraction for midface hypoplasia, and reparative or cosmetic treatment of other malformations. Successful treatment can improve aesthetics and functional performance (breathing, mastication, oral and ocular health). In patients with mitten-glove syndactyly, surgical separation of the digits generally provides little functional improvement. The psychosocial aspects of the syndrome should also be taken into account.\nPrognosis\nThe prognosis is guarded. Many individuals have life-threatening complications, including airway and central nervous system compromise. Others can do relatively well with proper medical and surgical management, but intellectual limitations are still very common. Life expectancy varies among patients with AS due to variable clinical severity and treatment success.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Austin HAMM  - Dr Nathaniel ROBIN"}
{"Disease Name": "Aphalangy-hemivertebrae-urogenital-intestinal dysgenesis syndrome", "Disease Definition": "An extremely rare congenital limb malformation syndrome, described in only 3 patients to date,characterized by the association of hypoplasia or aplasia of the hand and foot phalanges, hemivertebrae and various urogenital and/or intestinal abnormalities (i.e. dysgenesis of the urogenital tract and rectum). There have been no further descriptions in the literature since 1991.", "ORPHA ID": 1112, "Summary": ""}
{"Disease Name": "Aphalangy-syndactyly-microcephaly syndrome", "Disease Definition": "An extremely rare malformation syndrome characterized by the association of partial distal aphalangia with syndactyly, duplication of metatarsal IV, microcephaly, and mild intellectual disability.", "ORPHA ID": 1113, "Summary": ""}
{"Disease Name": "Aphonia-deafness-retinal dystrophy-bifid halluces-intellectual disability syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by moderate to severe intellectual disability, congenital aphonia, hearing loss, optic atrophy, retinal dystrophy, broad thumbs and duplicated halluces. Facial dysmorphism (incl. thick eyebrows, ptosis, long, downslanting palpebral fissures, microstomia, low-set, posteriorly rotated ears) and genital abnormalities are also associated.", "ORPHA ID": 324540, "Summary": ""}
{"Disease Name": "Aplasia cutis congenita-intestinal lymphangiectasia syndrome", "Disease Definition": "An extremely rare association syndrome, described in only two brothers to date (one of which died at 2 months of age), characterized by aplasia cutis congenita of the vertex and generalized edema (as well as hypoproteinemia and lymphopenia) due to intestinal lymphangiectasia. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 1116, "Summary": ""}
{"Disease Name": "Aplasia cutis congenita", "Disease Definition": "A rare skin disorder characterized by localized absence of skin that is usually located on the scalp but can occur anywhere on the body including the face, trunk and extremities. Aplasia cutis congenita (ACC) may occasionally be associated with other anomalies.", "ORPHA ID": 1114, "Summary": "Epidemiology\nWorldwide ACC prevalence is approximately 1/10,000 live births.\nClinical description\nACC is noticed immediately at birth and usually presents as a solitary lesion on or near the vertex. There may also be multiple lesions occurring on the scalp or elsewhere. The individual lesion can vary from a superficial, circular or oval, well-demarcated defect or atrophic scar with alopecia to a weeping or granulating ulcer extending to the bone (non-membranous ACC). The lesions can range from few millimeters to more than 10 cm in diameter. Some defects can have a membranous covering that can be filled with fluid, giving it a bullous appearance (membranous ACC). A tuft of long, dark colored hair (hair collar sign) may be present around the membranous lesion suggesting cranial dysraphism. Membranous ACC is not associated with non-neuroectodermal anomalies. The common Frieden classification subdivides ACC into 9 groups based on cause, localization and associated malformations.\nEtiology\nEtiology is manifold; genetic factors (including causal mutations in the genes BMS1 (10q11.21) and DLL4 (15q15.1), identified in a few families), teratogens, amniotic adhesion, vascular anomalies, pharmacological agents (e.g. thyreostatics as methimazole, valproic acid, benzodiazepines, heparin) and drugs (cocaine), intrauterine trauma and herpes virus infections have all been implicated. Membranous ACC of the scalp has been proposed to be due to incomplete closure of ectodermal fusion lines whereas non-membranous ACC rather appears to have vascular causes.\nDiagnostic methods\nNewborns with ACC have to be thoroughly examined for associated anomalies. Extensive cases of ACC necessitate immediate MRI to evaluate any accompanying bone and intracranial malformations. Histologic examination of healed ACC lesions shows scar-like tissue devoid of skin appendages and elastic fibres. Membranous ACC may reveal heterotopic brain tissue.\nDifferential diagnosis\nDifferential diagnoses include traumatic lesions, localized scalp infections, dermoid cyst (facial, cervical, nasal or involving the central nervous system), isolated encephalocele, meningocele and nodular neuronal heterotopia. As the child grows and scarring occurs, sebaceous nevus, nevus psiloliparus, localized scleroderma and other types of cicatricial alopecia should be considered. Hypertrophic scars can be mistaken for scalp tumors. ACC can occur in association with inherited epidermolysis bullosa and with epidermal and organoid nevi (didymosis aplasticosebacea). It may also form part of numerous syndromes including: chromosomal abnormalities (mainly trisomy 13), Adams-Oliver syndromes, Johanson-Blizzard, SCALP syndrome, focal facial dermal dysplasia, oculocerebrocutaneous syndrome, scalp-ear-nipple syndrome, Toriello-Lacassie-Droste syndrome, aplasia cutis congenita-intestinal lymphangiectasia syndrome, aplasia cutis-myopia syndrome, cutis verticis gyrata-thyroid aplasia-intellectual disability syndrome, and others.\nAntenatal diagnosis\nPrenatal diagnosis is limited to ACC types with transmittable genetic origin.\nGenetic counseling\nMost reported cases of nonsyndromic ACC are sporadic, but autosomal dominant inheritance has been reported in familial cases (including the BSM1 and DLL4 pathogenic variants).\nManagement and treatment\nBiopsy, drainage or excision of lesions should not be undertaken without prior imaging. Treatment of ACC usually involves a conservative approach (gentle cleansing, topical antiseptics, hydrocolloidal dressings) allowing the lesions to heal by secondary intention when possible. Repair using skin flaps and grafts is only recommended for larger defects, such as those extending down to the dura mater, to prevent hemorrhage and infection.\nPrognosis\nLess severe cases usually resolve within weeks to months, but alopecia persists. Underlying or associated defects may significantly affect mortality and morbidity.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Henning HAMM"}
{"Disease Name": "Aplasia cutis-myopia syndrome", "Disease Definition": "A rare disorder characterised by the association of aplasia cutis congenita with high myopia, congenital nystagmus and cone-rod dysfunction. It has been described in two siblings (brother and sister). Transmission is autosomal dominant.", "ORPHA ID": 1117, "Summary": ""}
{"Disease Name": "Aplasia of lacrimal and salivary glands", "Disease Definition": "A rare autosomal dominant disorder characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary glands leading to varying features since infancy such as recurrent eye infections, irritable eyes, epiphora, xerostomia, dental caries, dental erosion and oral inflammation.", "ORPHA ID": 86815, "Summary": ""}
{"Disease Name": "Apnea of prematurity", "Disease Definition": "A developmental disorder affecting premature infants, likely secondary to an immaturity of respiratory control resulting in idiopathic pauses in breathing often associated with reduced heart rate and arterial blood oxygen levels. It may be exacerbated by concurrent neonatal diseases.", "ORPHA ID": 99981, "Summary": ""}
{"Disease Name": "Apolipoprotein A-I deficiency", "Disease Definition": "A rare lipoprotein metabolism disorder characterized biochemically by complete absence of apolipoprotein AI and extremely low plasma high density lipoprotein (HDL) cholesterol, and clinically by corneal opacities and xanthomas complicated with premature coronary heart disease (CHD).", "ORPHA ID": 425, "Summary": "Epidemiology\nPrevalence of Apo A-I deficiency is unknown. The disease has been described in about 30 families.\nClinical description\nAlthough extremely low plasma HDL cholesterol may be detected in any patient fortuitously from birth, the age of symptom onset and the clinical presentation varies greatly. While some patients remain asymptomatic until advanced adulthood, others may present from adolescence with a combination of the following symptoms: blurred vision due to corneal opacities or cataract, tubero-eruptive, tendinous, palmar and/or planar xanthomas, xanthelasmas, and premature CHD (e.g. myocardial infarction) and carotid atherosclerosis. Less often, Apo A-I deficiency may manifest with neurosensory signs (e.g. cerebellar ataxia, neurosensory hearing loss, proliferative retinopathy) or other multi-organ manifestations of secondary amyloidosis (e.g. hepatomegaly, nephropathy, cardiomyopathy), all potentially progressing into end-stage organ failure (liver, renal or cardiac failure).\nEtiology\nThe disease is due to various deletions and mutations of the APOA1 gene (11q23-q24), encoding the apo A-I protein, a major constituent of HDL, that lead to decreased apo A-I production, impaired function or increased apo A-I catabolism. The clinical picture depends on the type of mutation. Mutations severely impairing Apo A-I expression (i.e. nonsense or frameshift point mutations, genomic rearrangements), result in premature CHD. Missense mutations associated with detectable plasma apoA-I and very low HDL cholesterol, result in milder cardiovascular symptoms and, occasionally, in systemic or neurological amyloidosis, or are associated with healthy patients with no signs of atherosclerosis.\nDiagnostic methods\nDiagnosis is based on biochemical analysis of plasma Apo A-I and HDL cholesterol levels showing extremely low HDL cholesterol levels and very low to undetectable Apo A-I (inferior to 5 mg/dL). Low HDL cholesterol levels are associated with normal VLDL and LDL cholesterol levels, and normal or decreased triglyceride levels. Histological examination of skin lesions reveals numerous foam cells. Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nThe differential diagnosis includes Tangier disease, LCAT deficiency (see these terms) and secondary causes of extremely low HDL cholesterol levels that include medications (androgenic steroids, paradoxical response to fibrates) and malignancies.\nAntenatal diagnosis\nAntenatal diagnosis is usually not performed, but is possible in families with severe systemic or neurological amyloidosis.\nGenetic counseling\nTransmission is autosomal dominant. Genetic counseling should be offered to the affected families informing them of the 50% risk the offspring has of inheriting the disease-causing mutation and therefore being affected with the disorder.\nManagement and treatment\nTo date, there is no curative therapy. In case of carotid atherosclerosis or cardiovascular complications, a low-fat diet balanced in anti-oxidants (e.g. Mediterranean type) may be combined with statins (HMGCoA reductase inhibitors) that lower LDL cholesterol levels below 70 mg/dL. Oral anti-oxidants, or infused synthetic HDL-mimetics or reconstituted HDL, are being investigated as potential anti-atherosclerotic therapies. Regular cardiovascular monitoring should be offered to Apo AI deficient patients with extremely low HDL cholesterol (<20 mg/dL) because of the increased risk (Odds Ratio x2-3) of coronary artery disease. In cases exhibiting signs of amyloidosis, long-term follow-up of target organ function should be proposed.\nPrognosis\nPrognosis depends on the occurrence of premature CHD and end-stage organ failure in cases with signs of amyloidosis.\n\n                            Last update: \n                            December 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Pascale BENLIAN"}
{"Disease Name": "Apparent mineralocorticoid excess", "Disease Definition": "A rare form of pseudohyperaldosteronism characterized by very early-onset and severe hypertension, associated with low renin levels and hypoaldosteronism.", "ORPHA ID": 320, "Summary": "Epidemiology\nPrevalence is difficult to estimate and likely varies between populations depending on the level of consanguinity. Less than 100 cases have been reported in the literature so far.\nClinical description\nAME is usually diagnosed within the first years of life and is characterized by polyuria and polydipsia, failure to thrive, severe hypertension with low renin and aldosterone levels, profound hypokalemia with metabolic alkalosis, and most often nephrocalcinosis. Stroke has been observed before the age of 10 years in untreated children.\nEtiology\nAME is caused by homozygous or compound heterozygous loss-of-function mutations or deletions in the HSD11B2 gene (16q22). In all cases, these mutations lead to abolition or a marked decrease in the activity of 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2), an enzyme involved in the conversion of cortisol to cortisone.\nDiagnostic methods\nDiagnosis should be suspected on the basis of the clinical and biochemical characteristics. Detection of a marked increase (10 to 100-fold) in the ratio of cortisol/cortisone (F/E) or of the tetrahydroxylated metabolites (THF+alloTHF/THE) in plasma and urine is a strong indication for diagnosis. However, a milder form of AME (AME2, also caused by mutations in the HSD11B2 gene) has been described with less marked hypertension and only mild abnormalities of cortisol metabolism. The diagnosis can be confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnoses include pseudohyperaldosteronism (particularly Liddle syndrome; see this term), as well as other forms of early-onset childhood hypertension (particularly renal hypertension). Natural licorice consumption can result in a clinical picture that mimics AME, but this phenomenon is only rarely observed in children as it requires either a sustained and chronic, or a high and acute, exposure to cause adverse effects.\nAntenatal diagnosis\nFor families in which the disease-causing mutation has already been identified, prenatal diagnosis may be considered in case of a life-threatening case in a previous child.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nEarly diagnosis and treatment is important to prevent end-organ damage (central nervous system, kidney, heart and retina). Two main strategies can be used to treat AME. The first is the blockade of the mineralocorticoid receptor by spironolactone (2-10 mg/kg/day), combined with thiazides to help to normalize blood pressure and reduce hypercalciuria and nephrocalcinosis. The second and complementary strategy, is the administration of exogenous corticoids to block ACTH and suppress the endogenous secretion of cortisol. This strategy has proven efficacy on blood pressure, renin and aldosterone levels but has little effect on urinary cortisol, cortisone and corticosterone concentrations. As the hypertension is severe, nonspecific antihypertensive agents (e.g. calcium antagonists) are also often required.\nPrognosis\nIn the absence of treatment, the prognosis for AME is severe with malignant hypertension, stroke, cardiac and renal insufficiency. However, the prognosis for patients with appropriate treatment appears to be good.\n\n                            Last update: \n                            February 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Xavier JEUNEMAITRE"}
{"Disease Name": "Aprosencephaly cerebellar dysgenesis", "Disease Definition": "A rare genetic non-syndromic central nervous system malformation characterized by absence of the telencephalon and absent or abnormal diencephalic structures, combined with severe abnormalities of the mesencephalon and cerebellum. Further malformations, for example of the hands and feet, have been described in addition.", "ORPHA ID": 1126, "Summary": ""}
{"Disease Name": "Aprosencephaly/atelencephaly spectrum", "Disease Definition": "A group of rare central nervous system malformations characterized by varying degrees of absence or dysplasia of the derivatives of the prosencephalon (i. e. telencephalon and diencephalon), with an intact cranial vault. The spectrum comprises atelencephaly, the less severe form, in which only the telencephalon is affected, and aprosencephaly, where the diencephalon is also involved. The malformations may occur in an isolated form or in association with other anomalies.", "ORPHA ID": 566847, "Summary": ""}
{"Disease Name": "Aquagenic palmoplantar keratoderma", "Disease Definition": "A rare skin disease characterized by transient wrinkling of the skin, edema, formation of whitish papules, pruritus, burning sensation, or pain, on the palms and/or soles in response to contact with water. Duration of exposure and water temperature affect the rate of development and intensity of the lesions. The condition is more common in females than in males and frequently occurs in patients with cystic fibrosis.", "ORPHA ID": 498359, "Summary": ""}
{"Disease Name": "Arachnodactyly-abnormal ossification-intellectual disability syndrome", "Disease Definition": "A multiple congenital developmental anomalies syndrome characterized by arachnodactyly of fingers and toes associated with craniofacial dysmorphism (including abnormal cranial ossification, frontal bossing, flat calvaria, shallow deformed orbits resulting in exophtalmos, midface hypoplasia and micrognathia), feeding difficulties in infancy, infantile muscular hypotonia, and developmental delay leading to intellectual disability.", "ORPHA ID": 1129, "Summary": ""}
{"Disease Name": "Arachnodactyly-intellectual disability-dysmorphism syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by facial dysmorphism (brachycephaly, long, narrow, triangular face, prominent forehead, hypertelorism, flat philtrum, microstomia, thin lips, hypoplastic maxilla), marfanoid habitus with arachnodactyly, and moderate to severe intellectual disability. Additional features may include clinodactyly, triphalangeal thumbs, hammer-shaped toes, hyperextensible joints, hypotonia, hyperreflexia and underdeveloped musculature. Delayed external genitalia development, as well as seizures and mitral regurgitation have been reported in some cases. There have been no further descriptions in the literature since 1995.", "ORPHA ID": 1130, "Summary": ""}
{"Disease Name": "Arachnoid cyst", "Disease Definition": "A disorder with extraparenchymal cysts, intra-arachnoidal collections of fluid, the composition of which is close to that of cerebrospinal fluid. They are often asymptomatic.", "ORPHA ID": 2356, "Summary": "Epidemiology\nStudies carried out since the advent of MRI and CT suggest that the prevalence is higher than previously thought, perhaps as high as 1 per 5000. In neurosurgery case series, cysts are more commonly located in the temporo-sylvian fossae. Temporal cysts are significantly more frequent in males than in females (4:1), while cysts in other locations do not show preponderance for a specific gender. A significant predominance of left-sided temporal cysts is found in males (2:1).\nClinical description\nArachnoid cysts may evolve during postnatal life. This malformation may be primitive or may be due to a disturbed flow of cerebrospinal fluid, generated by agenesis of veins.\nEtiology\nDifferent mechanisms may explain the increase in volume of the cysts: fluid secretion by cells of the cyst wall, unidirectional valvula or fluid movements secondary to movements of vein walls.\nGenetic counseling\nAlthough most diagnosed cases are sporadic, identical arachnoid cysts have been reported in at least three sets of sibs, the parents not being related. In one family, sibs also had microcephaly and intellectual deficit. If mendelian, arachnoid cysts may be an autosomal recessive condition.\n\n                            Last update: \n                            April 2005"}
{"Disease Name": "Arachnoiditis", "Disease Definition": "A chronic inflammation of the arachnoid layer of the meninges, of which adhesive arachnoiditis is the most severe form, characterized by debilitating, intractable neurogenic back and limb pain and a range of other neurological problems.", "ORPHA ID": 137817, "Summary": "Epidemiology\nThe prevalence is unknown. About 25,000 cases of arachnoiditis occur each year, mostly in North and South America, Asia and Europe, where spinal operations are more prevalent.\nClinical description\nPatients present with chronic, persistent deafferentiation pain in the lower back, limbs and trunk that is increased by activity, hyporeflexia, loss of temperature sensation, numbness, and often widespread allodynia, dysesthesia and hyperpathia. Patients may also experience proprioception alterations (including loss of balance, tinnitus and reduced hearing and vision), motor weakness, muscle cramps, fasciculation, anhidrosis, and bladder, bowel and sexual dysfunction. Arachnoiditis may, in a minority of cases, involve the brain as well as the spinal cord, possibly causing communicating hydrocephalus.\nEtiology\nArachnoiditis can be mechanically (localized) or chemically (diffuse) induced, and is often associated with spinal operations (60% of cases), neuroaxial (spinal and epidural) anesthesia (22%), spinal taps (7%), myelography (3%), pain relief procedures and secondary infections. It can also be caused by bacterial and viral spinal infections (7%) and repeated subarachnoid injections of anticancer drugs or antimetabolites. Syringomyelia, cauda equina syndrome, pseudomeningoceles, intrathecal cysts or tethering of the spinal cord and nerve roots (NR) may complicate lumbosacral arachnoiditis. Arachnoiditis occurs as a progression of inflammatory changes. In the early (inflammatory) phase NR are edematous (enhanced), while in the late proliferation stage (adhesive arachnoiditis) NR are clumped and asymmetric. The flow of cerebrospinal fluid from the distal dural sac to the brain is impeded, intrathecal pressure increases and this causes back pain and postural headache. In some cases the scar tissue calcifies (arachnoiditis ossificans).\nDiagnostic methods\nDiagnosis is based on patient history, clinical presentation and a causative event, and can be confirmed by MRI with contrast. When MRI is not possible, myelogram followed by CT scan is indicated. The adhesions generally occur on the dorsal segments, are arranged peripherally, and have been described as looking `like the bark of a tree' when viewed by myelography.\nDifferential diagnosis\nDifferential diagnoses include intra-spinal hematoma or dislodged disc fragment if the condition presents immediately after surgery, and Failed Back Surgery Syndrome (FBSS). Some patients are diagnosed with fibromyalgia (see this term), but these symptoms are likely to occur as a secondary feature due to the altered spinal dynamics.\nManagement and treatment\nIn the early phase, treatment includes large doses of IV methylprednisolone for five days, preferably within three months of the causative injury, followed by a protocol directed to control neuropathic pain using a multimodal approach that includes an anti-inflammatory, an anticonvulsant and an antidepressant. Large doses of opiates, that can cause hyperalgesia, hypersensitivity and tachyphylaxis, and lead to dependence, should be discouraged. If necessary, to treat exacerbation ``flare-ups'', IV infusions of NMDA receptors antagonists (including lidocaine, MgSO4, ketamine) can be given.\nPrognosis\nOnce the proliferative stage has begun, arachnoiditis will be permanent and is complicated by the aging process of the spine. Operations, injections or any other invasions of the spine may exacerbate the disease significantly.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Antonio ALDRETE"}
{"Disease Name": "AREDYLD syndrome", "Disease Definition": "A rare genetic disease characterized by lipoatrophic diabetes, mild craniofacial dysmorphism (such as pronounced antitragal incisura and mandibular prognathism), ectodermal dysplasia (generalized hypotrichosis and dental and nail abnormalities), hypoplasia or aplasia of the breasts, and urogenital/renal anomalies. Additional reported manifestations include skeletal abnormalities and hepatosplenomegaly.", "ORPHA ID": 1133, "Summary": ""}
{"Disease Name": "Argentine hemorrhagic fever", "Disease Definition": "A disorder that caused by the Junin virus (JUNV), is an acute viral hemorrhagic disease characterized by initial fever and malaise followed by gastrointestinal symptoms and in some cases hemorrhagic and neurological manifestations.", "ORPHA ID": 319223, "Summary": ""}
{"Disease Name": "Arginine vasopressin deficiency", "Disease Definition": "Central diabetes insipidus (CDI) is a hypothalamus-pituitary disease characterized by polyuria and polydipsia due to a vasopressin (AVP) deficiency. It can be inherited or acquired (hereditary CDI and acquired CDI; see these terms).", "ORPHA ID": 178029, "Summary": "Epidemiology\nCDI is a rare disease with a reported prevalence of 1/25,000.\nClinical description\nIdiopathic CDI onset can occur at any age but most often in 10-20 year olds. In the familial form, disease onset can be as early as the neonatal period. The symptoms characteristic of CDI are polyuria and polydipsia, usually associated with weight loss. Nocturia is common and in children often presents as enuresis. Polyuria is characterized by a urine volume in excess of 150 ml/kg/24h at birth, 100-110 ml/kg/24h until the age of 2 years, and 40-50 ml/kg/24h in older children and adults. Water deprivation leads to rapid dehydration. In children, additional symptoms of CDI can include lethargy, irritability, growth retardation, weight loss, fever, vomiting or diarrhea. In secondary CDI, further manifestations may be present resulting from the secondary cause.\nEtiology\nAcquired CDI, especially in children and young adults, is caused by destruction or degeneration of the neurons that originate in the supraoptic and paraventricular nuclei of the hypothalamus. The known causes of these lesions include germinoma, craniopharyngioma, Langerhans cell histiocytosis, sarcoidosis (see these terms), local inflammatory, autoimmune or vascular diseases and trauma from surgery or accident. Midline cerebral and cranial malformations are another possible cause of CDI. Between 20 and 50 % of cases are considered idiopathic. Autoimmunity may play a role in the pathogenesis of CDI. Genetic defects in AVP synthesis inherited as autosomal dominant, autosomal recessive or X-linked recessive traits are the underlying cause in less than 10% of CDI.\nDiagnostic methods\nDiagnosis of CDI is based on the demonstration of plasma hyperosmolality (> 300 mosm/l) associated with urine hypoosmolality (< 300 mosm/l or urine/plasma osmolality ratio < 1) and polyuria. A water deprivation test and blood test is needed to differentiate CDI from nephrogenic diabetes insipidus (NDI; see this term). The administration of desmopressin will help to make a differential diagnosis between CDI and NDI. Once the diagnosis of CDI has been established, other investigations are mandatory, including tumor markers, skeletal survey and especially brain neuroimaging.\nDifferential diagnosis\nThe main differential diagnosis is NDI as the disorders share the same manifestations. Recently, the dosage of aquaporin 2 (AQP2) has been used in the differential diagnosis of CDI as the failure to increase AQP2 excretion after desmopressin administration indicates a nephrogenic form of diabetes insipidus. Wolfram syndrome (see this term) is another differential diagnosis.\nGenetic counseling\nGenetic counseling is required in the very rare cases of familial CDI.\nManagement and treatment\nImmediate water intake and drug therapy is the course of treatment for CDI to correct water and electrolyte levels. Desmopressin is the most commonly used antidiuretic drug and can be given parenterally, orally or intranasally. Daily requirements are 100-1200 micrograms in 3 divided doses given orally, approximately 2-40 micrograms intranasally or 0.1-1 micrograms parenterally with maximum plasma concentrations being reached in 40-55 minutes. Follow-up is necessary to monitor electrolyte levels and determine the success of a chosen treatment. In early infancy, fluids alone can be a management strategy. Acquired CDI can be transient if the underlying causes of CDI are removed and the pituitary stalk is intact.\nPrognosis\nThere is no cure for idiopathic CDI but it is a manageable disease with no effect on life expectancy. In cases of secondary CDI, inadequate treatment of the underlying disease can lead to death.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Stefano GHIRARDELLO"}
{"Disease Name": "Arginine vasopressin resistance-intracranial calcification-short stature-facial dysmorphism syndrome", "Disease Definition": "A rare, genetic, renal tubular disease characterised by nephrogenic diabetes insipidus, intracerebral calcifications, intellectual disability, short stature and facial dysmorphism. There have been no further descriptions in the literature since 1990.", "ORPHA ID": 3145, "Summary": ""}
{"Disease Name": "Arginine vasopressin resistance", "Disease Definition": "A rare, genetic renal tubular disease that is characterized by polyuria with polydipsia, recurrent bouts of fever, constipation, and acute hypernatremic dehydration after birth that may cause neurological sequelae.", "ORPHA ID": 223, "Summary": "Epidemiology\nTo date, over 350 families have been reported with genetic mutations, for which over 90% involve the gene AVPR2.\nClinical description\nThe disease typically presents in the first year of life. Typical features of NDI are failure to thrive associated with, feeding difficulties, vomiting, constipation, fever, and irritability. Hypernatremia occurs where management is lacking for urinary water losses. Acquired NDI is more common in adulthood, presenting with polyuria/polydipsia. Affected adults typically drink and void between 10-12 litres per day. Polyuria may exceed 10 liters in children.\nEtiology\nThe disease results from the failure of the renal tubules to respond to antidiuretic hormone. In most cases, the disease is caused by mutations in the gene located on Xq28 coding for the V2 receptor of antidiuretic hormone. In cases of autosomal recessive or dominant transmission, NDI is caused by mutations in the AQP2 gene (12q13) that codes for aquaporin-2. Aquaporin-2 is involved in the transportation of water in the renal tubules. Acquired NDI is mainly caused by drugs with lithium therapy used in psychiatric diseases such as bipolar disorder.\nDiagnostic methods\nA diagnosis of diabetes insipidus (DI) is easily established by the presence of inappropriately dilute urine in the context of hypernatraemic dehydration. If DI is suspected based on history, yet plasma sodium concentration and osmolality are normal, a water deprivation test can help confirm the diagnosis. Once the diagnosis of DI is established, a desmopressin test (DDAVP) can distinguish between central and nephrogenic DI. In congenital NDI, the diagnosis can be confirmed by genetic testing.\nDifferential diagnosis\nThe main differential diagnosis is central diabetes insipidus. There are also forms of secondary inherited forms of NDI, associated with other inherited diseases, such as Bartter syndrome, cystinosis and distal Renal Tubular Acidosis (dRTA). These patients have a clinical phenotype of NDI, but associated with other features of the underlying disorder, such as hypokalaemic alkalosis (Bartter syndrome) or acidosis (cystinosis, dRTA).\nAntenatal diagnosis\nMutation analysis of amniotic cells or chorionic villi is possible in families with a known genetic cause of NDI, but is associated with a small risk of fetal injury or loss. As the osmotic load of breast milk or formulas is low, most cases of NDI present during the weaning period and genetic testing on a blood sample obtained from the umbilical cord at birth is usually sufficient to establish an early diagnosis and thus prevent dehydration episodes.\nGenetic counseling\nIn most cases, the disease is X-linked recessive, but it can also be autosomal recessive or dominant. Genetic counseling should be offered to affected families.\nManagement and treatment\nAbnormal urine concentration does not respond to antidiuretic hormone treatment. Treatment is prophylactic with prevention of hypernatremic dehydration events by minimizing urinary losses. Patients should receive a low salt diet with limited potassium and protein intake. Thiazide diuretics (e.g. hydrochlorothiazide) and prostaglandin synthesis inhibitors (e.g. indomethacin, ibuprofen or celecoxib) can further help reduce urine output. Careful dietetic counselling is recommended to ensure adequate caloric and protein intake, as well as normal growth in children.\nPrognosis\nMental impairment associated with intracranial calcifications has been previously reported, but is no longer seen in patients with adequate medical treatment. One report highlights an increased prevalence of attention deficit/hyperactivity disorder in patients with NDI, but it is unclear if this reflects an intrinsic aspect of the disorder, or the constant craving for water and the frequent need for voiding. Dilation of the urinary tract has been reported in patients with NDI, especially in those with voiding abnormalities and can lead to serious bladder and/or kidney function impairment.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Detlef BÖCKENHAUER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Argininemia", "Disease Definition": "A rare autosomal recessive amino acid metabolism disorder characterized clinically by variable degrees of hyperammonemia, developing from about 3 years of age, and leading to progressive loss of developmental milestones and spasticity in the absence of treatment.", "ORPHA ID": 90, "Summary": ""}
{"Disease Name": "Argininosuccinic aciduria", "Disease Definition": "A rare, genetic disorder of urea cycle metabolism typically characterized by either a severe, neonatal-onset form that manifests with hyperammonemia accompanied with vomiting, hypothermia, lethargy and poor feeding in the first few days of life, or late-onset forms that manifest with stress- or infection-induced episodic hyperammonemia or, in some, behavioral abnormalities and/or learning disabilities, or chronic liver disease. Patients often manifest liver dysfunction.", "ORPHA ID": 23, "Summary": "Epidemiology\nThe prevalence at birth of argininosuccinic aciduria (ASA) ranges between 1/70,000-218,000 worldwide.\nClinical description\nASA can have a variable clinical picture with either a neonatal-onset or a late-onset (at any age outside the newborn period). Neonates with severe neonatal-onset ASA usually appear normal during the first 24-48 hours after birth but within a few days present with severe hyperammonemia manifesting with lethargy, somnolence, refusal to feed, vomiting, tachypnea and respiratory alkalosis. If untreated, worsening lethargy, seizures, coma and death may occur. Late-onset ASA is usually triggered by an acute infection, stress or after high protein intake. A presentation of late-onset cognitive impairment or learning disabilities in the absence of hyperammonemic episodes has also been reported. Some patients can be clinically asymptomatic despite showing clear biochemical signs of the disease. Long-term complications associated with both forms of ASA include chronic hepatomegaly, liver dysfunction (fibrosis or cirrhosis), neurocognitive deficits (i.e. cognitive impairment, seizures, and developmental delay), brittle hair (i.e. trichorrhexis nodosa), hypokalemia and arterial hypertension.\nEtiology\nASA is caused by mutations in the ASL gene (7q11.21) that encodes the enzyme argininosuccinate lyase. This enzyme catalyzes the conversion of argininosuccinic acid into arginine and fumarate during the fourth step of the urea cycle. Defects in this step of the urea cycle lead to an accumulation of plasma ammonia, argininosuccinic acid, citrulline, and urinary orotic acid, and to a plasma arginine deficiency.\nDiagnostic methods\nDiagnosis is based mainly on clinical findings and laboratory test results. Plasma concentrations of ammonia (>150 µmol/L) and citrulline (200-300 µmol/L) are elevated. Elevated levels of argininosuccinic acid (5-110 µmol/L) in the plasma or urine are diagnostic. Molecular genetic testing confirms diagnosis. Newborn screening for ASA is available in the U.S. and parts of Australia, and is considered in several European countries.\nDifferential diagnosis\nDifferential diagnoses include other urea cycle disorders such as carbamoyl-phosphate synthetase 1 deficiency, ornithine transcarbamylase deficiency, citrullinemia type I and arginase deficiency, although neither of these exhibits the classical marker argininosuccinic acid.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease causing mutation on both alleles.\nGenetic counseling\nASA is inherited in an autosomal recessive manner; where both parents are unaffected carriers, the risk of disease transmission is 25%.\nManagement and treatment\nDuring an acute hyperammonemic episode, oral proteins must be avoided (for 24-48 hours' maximum) and intravenous (I.V.) lipids, glucose and insulin (if needed) should be given to promote anabolism. I.V. nitrogen scavenging therapy (with sodium benzoate and/or sodium phenylacetate/phenylbutyrate) should normalize ammonia levels, but if unsuccessful or in case of severe hyperammonemic encephalopathy, hemodialysis is recommended. Long-term management involves dietary protein restriction as well as arginine supplementation; in those with frequent episodes of metabolic decompensation or with hyperammonemia even when following a protein-restricted diet, daily oral nitrogen scavenging therapy (sodium benzoate and/or sodium or glycerol phenylbutyrate) may be successful. Orthotopic liver transplantation offers long-term relief of hyperammonemia but does not seem to sufficiently correct neurological complications. Arterial hypertension can be treated by restoring nitric oxide deficiency.\nPrognosis\nWith early diagnosis and treatment, hyperammonemic episodes can be avoided but long-term complications (neurocognitive impairment, hepatic disease and arterial hypertension) are frequent and have a negative effect on life-expectancy and quality of life.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Johannes HÄBERLE"}
{"Disease Name": "Argyria", "Disease Definition": "A rare dermatosis, which can be either localized or generalized, that occurs after prolonged contact and absorption of silver containing compounds over a period of years and that is characterized by irreversible blue-gray to gray-black staining of skin, fingernails and/or mucous membranes, most evident on sun exposed areas of the skin. Silver exposure is usually occupational but may also occur through dental amalgams, the ingestion of colloidal silver, acupuncture needles, orthopedic implants and topical medications (such as silver sulfadiazine).", "ORPHA ID": 60014, "Summary": ""}
{"Disease Name": "Arnold-Chiari malformation type I", "Disease Definition": "A central nervous system malformation characterized by caudal displacement of the cerebellar tonsils exceeding 5mm below the foramen magnum with or without syringomyelia. Symptoms vary in onset and severity and include suboccipital headache, neck pain, vertigo, tinnitus, ocular symptoms (diplopia, blurred vision, photofobia, nystagmus), lower cranial nerve signs, cerebellar ataxia, and spasticity. Some affected individuals can be asymptomatic.", "ORPHA ID": 268882, "Summary": ""}
{"Disease Name": "Aromatase deficiency", "Disease Definition": "A rare disorder that disrupts the synthesis of estradiol, resulting in hirsutism of mothers during gestation of an affected child; pseudohermaphroditism and virilization in women; and tall stature, osteoporosis and obesity in men.", "ORPHA ID": 91, "Summary": "Epidemiology\nFewer than 20 cases have been reported to date.\nClinical description\nAffected female newborns present with different degrees of ambiguous genitalia, virilization and non-palpable gonads, in one case female genitalia were present. Female internal genitalia differentiation is unaffected. Ovarian cystic follicles may appear in childhood, even at birth, or adolescence when patients manifest primary amenorrhea and no pubertal growth spurt. Breasts remain hypoplastic after initial development during puberty, while pubic hairs develop in a normal fashion. Males may present with cryptorchidism, but are generally asymptomatic until after puberty when patients present with bone pain and tall stature. The pubertal growth spurt is absent, but linear growth continues due to incomplete epiphyseal closure and progressive genu valgum, eunuchoid proportion of the skeleton and osteoporosis manifest. For these reasons the diagnosis is often overlooked in men. Metabolic co-morbidities may manifest as obesity, steatohepatitis, insulin resistance with acanthosis nigricans and dyslipidemia. Fertility is partially or completely disrupted in male patients.\nEtiology\nAromatase (CYP19A1, 15q21.1), or cytochrome P450, synthesizes estradiol from androgens. Several null mutations have been identified, placental expression of aromatase converts androgens to estradiol; excess androgens affect both the mother and fetal development. One reported case of a promoter region mutation exclusively inhibited placental expression.\nDiagnostic methods\nFemales are generally diagnosed at birth. Male patients are usually diagnosed during adulthood due to continuing linear growth in height and unfused epiphyses are revealed by hand radiographs. Measurement of serum estradiol, testosterone and luteinizing hormone may be followed by genetic testing.\nDifferential diagnosis\nIn female patients, differential diagnosis includes congenital adrenal hyperplasia; in male patients, estrogen resistance syndrome 46,XY difference of sex development due to isolated 17, 20 lyase deficiency, congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency and congenital hypogonadotropic hypogonadism.\nAntenatal diagnosis\nDuring the third trimester of gestation, mothers exhibit severe acne, deep voice and in some cases clitoral enlargement and hirsutism, symptoms resolve spontaneously post-partum. Genetic testing is recommended in these cases.\nGenetic counseling\nGenetic testing is recommended for families who have had one affected child, transmission is autosomal recessive.\nManagement and treatment\nFemale patients are candidates for surgical modification of genitalia depending on the degree of ambiguity and must be monitored for ovarian cysts. Upon puberty, daily treatment with estrogen must be administered (0.625 mg/twice weekly increasing to daily) and may be supplemented with progesterone-like hormone and monthly treatments of gonadotrophin-releasing hormone antagonists. Adult men should be treated immediately upon diagnosis: daily transdermal administration of up to 50 µg of estradiol (serum estradiol at 40 pg/ml) for 6-9 months to complete skeletal maturation. Upon epiphyseal closure, estradiol replacement may be reduced to 25 µg daily. Hypocaloric diet should be complemented with calcium, vitamin D and physical activity. Dyslipidemia, glucose intolerance or insulin resistance must be treated symptomatically.\nPrognosis\nLifetime hormone replacement therapy is obligatory. In male patients with late diagnosis, skeletal defects remain even after successful hormonal treatment and may require surgical correction. Furthermore, adiposity and fertility defects are not alleviated by estradiol treatment.\n\n                            Last update: \n                            April 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Cesare CARANI  - Dr Vincenzo ROCHIRA"}
{"Disease Name": "Aromatase excess syndrome", "Disease Definition": "A rare, genetic endocrine disease characterized by increased levels of estrogen due to elevated extraglandular aromatase activity. Males present with heterosexual precocious puberty which manifests with pre- or peripubertal onset of gynecomastia, premature growth spurt, accelerated bone maturation resulting in decreased adult stature, and may present mild hypogonadotropic hypogonadism. Female patients may have isosexual precocious puberty or not have any manifestations at all.", "ORPHA ID": 178345, "Summary": ""}
{"Disease Name": "Aromatic L-amino acid decarboxylase deficiency", "Disease Definition": "A rare, severe, genetic neurometabolic disorder associated with clinical manifestations related to impaired synthesis of dopamine, noradrenaline, adrenaline and serotonin. Clinical manifestations are typically characterized by early-onset muscular hypotonia, movement disorders (oculogyric crisis, dystonia), developmental delay, ptosis and non-motor symptoms (sleep disturbance, irritability, excessive sweating, and nasal congestion).", "ORPHA ID": 35708, "Summary": "Epidemiology\nThe global incidence of aromatic L-amino acid decarboxylase deficiency (AADC) deficiency is unknown. Since the initial description more than 150 patients have been described in the medical literature.\nClinical description\nAADC deficiency typically presents in infancy with muscular hypotonia, oculogyric crises, and developmental delay. Thermoregulation disturbances, autonomic dysfunction, sleep disorders, dystonia, nasal congestion, feeding problems and intellectual disability are additional disease features. Age of onset of initial symptoms ranges from neonatal period to 12 months (mean 2-3 months). The majority of published patients have severe phenotype with profound motor developmental impairment while some present mild to moderate phenotype with ability to walk independently and having functional independence in daily activities. It has been suggested that symptoms can evolve with age.\nEtiology\nAromatic L-amino acid decarboxylase (AADC), coded by the DDC gene (7p12.2-p12.1), is the final enzyme in the biosynthesis of the monoamine neurotransmitters serotonin and dopamine; dopamine is the precursor for norepinephrine and epinephrine. Subsequently, AADC enzyme deficiency results in a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine.\nDiagnostic methods\nThe diagnosis is established by determination of biogenic amines in cerebrospinal fluid (CSF), enzyme activity essay in plasma and mutational analysis. Additionally, measurement of 3-O-methyldopa (3-OMD) in dried blood spot in new born screening programs is proposed and already implemented in some programs.\nDifferential diagnosis\nAADC deficiency can show clinical symptoms overlapping with other primary disorders of biogenic amines or tetrahydrobiopterin (BH4) metabolism that should be differentiated via biochemical investigation of the CSF in the first step. PNPO (pyridoxamine 5'-phosphate oxidase) deficiency can show a similar biochemical pattern in CSF but presents with a different clinical picture.\nAntenatal diagnosis\nA biochemical prenatal diagnosis of AADC deficiency might be possible by measuring 3-OMD, 5-HTP and L-Dopa in amniotic fluid or fetal plasma but if both disease-causing genetic variants are known, the most reliable method of prenatal diagnostic approach is genetic analysis of chorionic villi or amniotic fluid cells. This option should be offered to carriers of mutations of AADC deficiency, especially in case of a known index patient.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive; where both parents are unaffected carriers, there is a 25% risk of transmitting the disease to offspring. Genetic counseling about inheritance, risk of reoccurrence and disease is very important for affected families.\nManagement and treatment\nThe treatment of AADC deficiency is challenging since symptoms are refractory particularly in severe cases. A complex treatment regimen including dopamine agonists, monoamine oxidase inhibitors, pyridoxine phosphate, anticholinergic and antiepileptic drugs are required. Various supportive therapeutic approaches (physiotherapy, speech therapy) are recommended. In clinical trials, gene therapy has demonstrated clinical improvement (reduced frequency of oculogyric crises, weight recovery, and improvement in the ability to sit, walk, and talk over a five-year period). The treatment is pending approval in Europe.\nPrognosis\nThe prognosis mainly depends on the disease severity. There is no clear genotype-phenotype correlation but some mutations are associated with severe phenotype. It has been described that there is a significant childhood mortality risk for patients with severe disease course.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Oya KUSEYRI HÜBSCHMANN  - Pr Thomas OPLADEN"}
{"Disease Name": "Arrhinia-choanal atresia-microphthalmia syndrome", "Disease Definition": "A malformation disorder characterized by complete or incomplete absence of nose (arrhinia), choanal atresia, microphthalmia, anophthalmia and cleft or high palate.", "ORPHA ID": 1135, "Summary": ""}
{"Disease Name": "Arterial dissection-lentiginosis syndrome", "Disease Definition": "A rare association syndrome, reported in several members of two families to date, characterized by arterial dissection, occurring at an early age and presenting with a range of manifestations depending on the vascular territory involved (ex. headache, dysphasia, hemiparesis), in association with cystic medial necrosis and multiple lentigines (brown and black in color and mainly affecting the skin of the trunk and extremities).", "ORPHA ID": 1682, "Summary": ""}
{"Disease Name": "Arterial thoracic outlet syndrome", "Disease Definition": "A form of thoracic outlet syndrome that presents as unilateral upper extremity ischemia.", "ORPHA ID": 357107, "Summary": "Epidemiology\nDetermination of incidence is difficult due to the lack of a confirmatory test for TOS. ATOS accounts for less than 1% of all cases of TOS.\nClinical description\nATOS occurs spontaneously in patients of all ages and presents with upper extremity ischemia (pain, pallor, anesthesia, coldness, claudication). Rarely subclavian thrombi embolize retrograde causing stroke.\nEtiology\nSymptoms of ATOS are caused by subclavian artery compression (often by a cervical rib), or emboli. Subclavian artery compression in the neck results in poststenotic dilation, aneurysm formation, turbulent flow and thrombus formation.\nDiagnostic methods\nDiagnosis is based on a history of upper extremity ischemia and diminished distal pulses or decreased systolic blood pressure in the affected limb. A cervical rib or long cervical transverse process is identified in over 90% of patients. Subclavian stenosis, occlusion or aneurysm on dynamic ultrasonography, magnetic resonance angiography or arteriography supports the diagnosis. Provocative physical exam maneuvers such as the Roos (test is positive when patient is unable to maintain the position of opening and closing hands while arms are in an elevated position for 3 minutes) and Adson's (test is positif if radial pulse disappears while turning the head with extended neck following deep inspiration) tests can also be helpful.\nDifferential diagnosis\nDifferential diagnoses include venous and neurogenic TOS (see these terms), peripheral artery disease and other disorders leading to arterial compromise, such as external compression by a tumor. Venous TOS can be ruled out with venous ultrasound or magnetic resonance venography. True neurogenic TOS presents as a lower trunk brachial plexopathy. Patients with PAD have atherosclerotic risk factors. Other external causes of compression can be ruled out with the appropriate cross sectional imaging.\nManagement and treatment\nAcute arterial ischemia is treated with thrombolysis or embolectomy. Surgical decompression is indicated in symptomatic patients. Arterial reconstruction may be necessary. Physical therapy is generally not helpful.\nPrognosis\nArterial occlusion is limb threatening, but most patients recover full function when treated appropriately. In 91% of cases, ATOS decompression results in complete resolution of symptoms.\n\n                            Last update: \n                            May 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Joseph FEINBERG  - Dr Paul SCHOLTEN"}
{"Disease Name": "Arterial tortuosity syndrome", "Disease Definition": "A rare autosomal recessive connective tissue disorder characterized by tortuosity and elongation of the large and medium-sized arteries and a propensity towards aneurysm formation, vascular dissection, and stenosis of the pulmonary arteries.", "ORPHA ID": 3342, "Summary": "Epidemiology\nApproximately 100 patients have been described in the literature so far. The male to female ratio is 1:1.\nClinical description\nThe clinical manifestations are variable, depending on the arteries affected. Onset usually occurs in infancy or early childhood. The cardiovascular anomalies may lead to right ventricular hypertension, acute respiratory symptoms, ventricular hypertrophy and cardiac failure. Patients are prone to aneurysm formation, dissection and ischemic events. Other typical manifestations include facial dysmorphism (features variably include an long face, hypertelorism, downslanting palpebral fissures, beaked nose, sagging cheeks, a high palate, and micrognathia), soft and hyperextensible skin, cutis laxa, hernias (inguinal, diaphragmatic, or hiatal), skeletal abnormalities, joint hypermobility, congenital contractures, keratoconus and generalized hypotonia.\nEtiology\nThe disease is caused by loss-of-function mutations in the SLC2A10 gene (20q13.12), encoding the glucose/dehydroascorbic acid transporter 10 (GLUT10). So far, 35 SLC2A10 pathogenic variants have been reported in approximately 80 families. The exact role of GLUT10 in the pathogenesis of the disorder remains to be fully clarified. Previous evidences revealed that the deficiency of GLUT10 perturbs the canonical transforming growth factor beta (TGFbeta) pathway, activates a non-canonical alphavbeta3 integrin-TGF beta receptor II signaling and causes the disorganization of different extracellular matrix proteins (i.e. collagens, elastin, fibronectin, decorin), which are essential for the structural integrity of several connective tissues including blood vessels wall. Moreover, as GLUT10 acts as an intracellular transporter of dehydroascorbic acid, the shortage of ascorbate might impair collagen and elastin crosslinking in the endoplasmic reticulum, redox homeostasis in the mitochondria and global and gene-specific methylation/hydroxymethylation affecting the epigenetic regulation in the nucleus.\nDiagnostic methods\nDiagnosis requires further examination by echocardiography (ECG), angiography, and magnetic resonance angiography (MRA) and/or CT scan. Histology shows disruption of elastic fibers of the medial layer of the arterial wall. Detection of mutations in the SLC2A10 gene allows confirmation of the clinical diagnosis, and allows adapted genetic counseling and prognostic information to be provided to the patients.\nDifferential diagnosis\nThe differential diagnosis should include Loeys-Dietz syndrome, Ehlers-Danlos syndromes (particularly the vascular-like classical Ehlers-Danlos syndrome), Marfan syndrome, occipital horn syndrome, and autosomal recessive cutis laxa (particularly the EFEMP2-, FBLN5-, and LTBP4-related Cutis laxa.\nAntenatal diagnosis\nPrenatal diagnosis may be suspected by echocardiography and ultrasonography, and can be confirmed by prenatal molecular diagnosis performed on chorionic villi or amniocytes. Pregnancy requires intensive monitoring of both mother and fetus, cesarean delivery, and multidisciplinary postpartum care.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. The risk of inheriting the disease is 25% where both parents are unaffected carriers.\nManagement and treatment\nAll patients require regular follow-up (periodic EGC, and MRA and/or CT scan) and may benefit from surgical interventions (aortic root replacement for aortic aneurysms and pulmonary artery reconstruction).\nPrognosis\nThe prognosis can be severe and the first few years of life, usually before 5 years of age, might be critical for potentially life-threatening events. The main causes of premature death are respiratory insufficiency due to pulmonary artery stenosis, and heart failure due to either right ventricular hypertension and hypertrophy, myocarditis, and organ failure due to ischemic events.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Marina COLOMBI"}
{"Disease Name": "Arthrochalasia Ehlers-Danlos syndrome", "Disease Definition": "A form of Ehlers-Danlos syndrome (EDS) characterized by congenital bilateral hip dislocation, severe generalized joint hypermobility with recurrent joint dislocations and subluxations, hyperextensible and/or fragile skin.", "ORPHA ID": 1899, "Summary": "Epidemiology\nThe exact prevalence is unknown. It is one of the rare types of EDS.\nClinical description\nPatients affected by arthrochalasia Ehlers-Danlos syndrome (aEDS) present at birth with severe hypermobility of both small and large joints with easy dislocation on manipulation, in combination with muscular hypotonia. Congenital bilateral hip dislocation is present in virtually all cases, and congenital foot deformities (clubfoot, flat foot and skew foot) and other congenital joint subluxations/luxations are common. Skin is hyperextensible and described as hyperelastic/redundant, leading sometimes to a criss-cross crease patterning of the palms and soles. Easy bruising and atrophic scarring may also be present, but are not severe. Hypotonia improves with age but, in combination with foot deformities and instable knees, leads to a delay in acquisition of gross motor milestones. Craniofacial dysmorphism is usually mild and may include large fontanelle, frontal bossing, hypertelorism, blue sclera, depressed nasal bridge, midface hypoplasia, and micrognathia. Throughout life, patients suffer recurrent partial or total joint dislocations of upper and lower limb joints and develop persistent foot, hand and spinal deformities. Some patients may also display bone fragility, manifested with fractures, Wormian bones on cranial radiographs, and osteopenia. Dentinogenesis imperfecta has been reported only in few individuals.\nEtiology\naEDS is caused by heterozygous mutations that lead to partial or total loss of exon 6 in the COL1A1 (17q21.33) or COL1A2 (7q21.3) genes. The mutations lead to the partial or complete loss of the N-telopeptide of the procollagen type I alpha1 and alpha2 chains, respectively, and result in accumulation of abnormally processed type I collagen, the principal component of ligaments, tendons, dermis, bone and dentin.\nDiagnostic methods\nClinical diagnosis is confirmed by the biochemical study of collagen I produced in vitro by cultured skin fibroblasts, or by molecular analysis revealing pathogenic variants in the COL1A1 or COL1A2 genes.\nDifferential diagnosis\nDifferential diagnosis includes Larsen syndrome, classical EDS (cEDS), dermatosparaxis EDS (dEDS), kyphoscoliotic EDS (kEDS) and musculocontractural EDS (mcEDS), Loeys-Dietz syndrome and autosomal recessive cutis laxa type 2B.\nAntenatal diagnosis\nPrenatal testing by molecular or biochemical analyses of a chorionic villus biopsy is possible if a pathogenic mutation has been identified in the family or, if parental mosaicism is suspected. Joint dislocations can be observed on prenatal ultrasound examination (in the third trimester of pregnancy).\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. Genetic counseling can inform parents of an affected child of the 50% risk of disease recurrence among future offspring. Clinically mild or unrecognized parental mosaicism has to be taken into account. Specific heterozygous mutations in COL1A1, c.472-1G>A and c.472-2A>T, have been associated with dentinogenesis imperfecta.\nManagement and treatment\nManagement of orthopedic problems is the center of care for patients with aEDS, with the goal being to achieve stable ambulation. A complete skeletal survey is recommended at diagnosis. Open reductions with an iliac osteotomy, with or without femoral osteotomy, are favorable to treat congenital hip dislocations. Orthotic management and early intervention are recommended to assist standing, walking and activities of daily living.\nPrognosis\nExtensive management seems to be effective, since only few patients described in the literature, mainly those with mutations in COL1A1, are wheelchair bound or unable to walk independently. aEDS patients are at increased risk of premature osteoarthritis.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Cecilia GIUNTA  - Pr Beat STEINMANN"}
{"Disease Name": "Arthrogryposis multiplex congenita-whistling face syndrome", "Disease Definition": "An extremely rare type of arthrogryposis multiplex congenita characterized by the combination of multiple joint contractures with movement limitation, microstomia with a whistling appearance of the mouth that may cause feeding, swallowing, and speech difficulties, a distinctive expressionless facies, severe developmental delay, central and autonomous nervous system dysfunction (excessive salivation, temperature instability, myoclonic epileptic fits, bradycardia), occasionally Pierre-Robin sequence, and lethality generally occurring during the first months of life. Arthrogryposis multiplex congenita-whistling face syndrome has been suggested to be a fetal akinesia deformation sequence.", "ORPHA ID": 1150, "Summary": ""}
{"Disease Name": "Arthrogryposis multiplex congenita", "Disease Definition": "A group of disorders characterized by congenital limb contractures manifesting as limitation of movement of multiple limb joints at birth that is usually non-progressive and may include muscle weakness and fibrosis. This disorder is always associated with decreased intrauterine fetal movement which leads secondarily to the contractures.", "ORPHA ID": 1037, "Summary": ""}
{"Disease Name": "Arthrogryposis-anterior horn cell disease syndrome", "Disease Definition": "A rare arthrogryposis syndrome characterized by the association of arthrogryposis multiplex congenita and a severe form of motor neuron disease with loss of anterior horn cells in the spinal cord. Patients present with fetal akinesia deformation sequence with multiple contractures and facial anomalies, such as low-set ears, hypoplastic jaw, and short neck, as well as hypotonia and respiratory insufficiency. Some patients may survive into childhood and show developmental delay, markedly decreased muscle bulk, dystonic and involuntary movements, ataxia, and poor speech.", "ORPHA ID": 53696, "Summary": ""}
{"Disease Name": "Arthrogryposis-ectodermal dysplasia syndrome", "Disease Definition": "A rare, genetic developmental defect during embryogenesis syndrome characterized by camptodactyly, joint contractures with amyotrophy, and ectodermal anomalies (oligodontia, enamel abnormalities, longitudinally broken nails, hypohidrotic skin with tendency to excessive bruising and scarring after injuries and scratching), as well as growth retardation, kyphoscoliosis, mild facial dysmorphism, and microcephaly. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 3200, "Summary": ""}
{"Disease Name": "Arthrogryposis-hyperkeratosis syndrome, lethal form", "Disease Definition": "A rare arthrogryposis syndrome characterized by the association of multiple congenital joint contractures (of the large joints, fingers and toes) and hyperkeratosis (i.e. thick, scaling and fissured skin), with death occurring in early infancy. There have been no further reports in the literature since 1993.", "ORPHA ID": 1485, "Summary": ""}
{"Disease Name": "Arthrogryposis-like hand anomaly-sensorineural deafness syndrome", "Disease Definition": "A rare syndrome characterized by an arthrogryposis-like hand anomaly and sensorineural deafness. It has been described in only one family. Male-to-male transmission was observed.", "ORPHA ID": 1144, "Summary": ""}
{"Disease Name": "Arthrogryposis-oculomotor limitation-electroretinal anomalies syndrome", "Disease Definition": "An inherited developmental defect syndrome characterized by multiple congenital contractures of limbs, without primary neurologic and/or muscle disease that affects limb function, and ocular anomalies (ptosis, external ophtalmoplegia and/or strabismus). Intelligence is normal.", "ORPHA ID": 1154, "Summary": ""}
{"Disease Name": "Arthrogryposis-renal dysfunction-cholestasis syndrome", "Disease Definition": "A rare, multisystem disorder, characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with low serum gamma-glutamyl transferase activity.", "ORPHA ID": 2697, "Summary": "Epidemiology\nThe prevalence is unknown but less than 100 patients have been reported in the literature so far.\nClinical description\nThe phenotype is variable, even within the same family and cases may go undiagnosed as not all the patients present with the three cardinal features. Renal tubular dysfunction ranges from isolated renal tubular acidosis to complete Fanconi syndrome (polyuria, aminoaciduria, glycosuria, phosphaturia and bicarbonate wasting). Hepatic anomalies include variable combinations of cholestasis, intrahepatic biliary duct hypoplasia and lipofuscin deposition. Additional features include severe failure to thrive, platelet dysfunction (which may be responsible for severe bleeding), facial dysmorphism (low set ears, lax skin, a high arched palate, beaked nose and small anterior fontanelle), diarrhea, recurrent febrile illness, cerebral malformations and sensorineural deafness.\nEtiology\nMutations in the VPS33B gene (15q26.1), involved in intracellular protein trafficking and membrane fusion, have been found in 75% of ARC families, as well as mutations in the VIPAR gene (C14ORF133), encoding a protein that complexes with VPS33B.\nDifferential diagnosis\nThe differential diagnosis should include progressive familial intrahepatic cholestasis disorders, other forms of arthrogryposis multiplex congenita and congenital ichthyosiform dermatoses (see these terms).\nGenetic counseling\nThe syndrome is generally considered to be transmitted as an autosomal recessive trait.\nManagement and treatment\nThere is no specific treatment for the disease.\nPrognosis\nMost patients die within the first year of life despite supportive care for metabolic acidosis and cholestasis and those surviving longer show cirrhosis and severe developmental delay.\n\n                            Last update: \n                            June 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Arthrogryposis-severe scoliosis syndrome", "Disease Definition": "Distal arthrogryposis type 4 is an inherited developmental defect syndrome characterized by multiple congenital contractures of limbs, without primary neurologic and/or muscle disease that affects limb function, and a mild to severe scoliosis. Intelligence is normal.", "ORPHA ID": 65720, "Summary": ""}
{"Disease Name": "Asbestos intoxication", "Disease Definition": "A rare pneumoconiosis caused by exposure to asbestos particles. Symptoms may appear many years after exposure and include progressive dyspnea on exertion, dry cough, chest pain, tightness, inspiratory crackles, clubbing of the fingers. Later complications include mesothelioma and lung cancers.", "ORPHA ID": 2302, "Summary": ""}
{"Disease Name": "Ascher syndrome", "Disease Definition": "A very rare syndrome characterized by a combination of blepharochalasis, double lip, and non-toxic thyroid enlargement (seen in 10-50% of cases), although the occurrence of all three signs at presentation is uncommon. Hypertrophy of the mucosal zone of the lip with persistence of the horizontal sulcus between cutaneous and mucosal zones gives an appearance of double lip, with the upper lip being frequently involved. Blepharochalasis, or episodic edema of eyelid, appears around puberty, is present in 80% of cases, is usually bilateral, and can rarely lead to vision impairment and other ocular complications. Most cases are sporadic, but familial cases (with a possible autosomal dominant inheritance) have also been reported.", "ORPHA ID": 1253, "Summary": ""}
{"Disease Name": "Aseptic abscess syndrome", "Disease Definition": "A rare autoinflammatory disorder characterized by recurrent attacks of fever and sterile abscesses.", "ORPHA ID": 54251, "Summary": "Epidemiology\nIt is a rare disease with approximately 150 patients documented to date, among which 85 cases are in the French aseptic abscess syndrome register.\nClinical description\nIt affects mainly young adults and is characterized by recurrent attacks of fever and abscess-like collections, most frequently localized in the abdomen. Blood markers of inflammation and polymorphonuclear neutrophil levels are elevated. Aseptic abscesses may be either isolated or associated with an underlying condition (60% of patients) such as inflammatory bowel disease or relapsing polychondritis. The abscesses usually precede the diagnosis of inflammatory bowel disease, possibly by several years. A neutrophilic dermatosis, like pyoderma gangrenosum, may also be observed.\nEtiology\nThe etiology is unknown: all searches for a pathogen, including those using PCR with universal and specific probes, remain negative.\nDiagnostic methods\nOn pathologic examination, aseptic abscesses consist of a core of altered polymorphonuclear leukocytes surrounded by palisading histiocytes and sometimes giant cells.\nDifferential diagnosis\nAseptic abscess syndrome is a diagnosis of exclusion. The non-exhaustive list of etiologies to be considered and ruled out includes infectious abscesses (primarily pyogenic, as well as Chlamydia, Bartonella, and Tropheryma whipplei), mycobacterial infection, neoplasia (particularly lymphoma), chronic septic granulomatosis, splenic infarction, and inflammatory conditions (such as sarcoidosis, Wegener's disease, or rheumatoid nodules).\nManagement and treatment\nAntibiotics fail to cure the patients, but dramatic improvements are seen with corticosteroids and immunosuppressive drugs, including biologics.\nPrognosis\nIn the short term, once the diagnosis is established, patients undergo a significant transformation following the initiation of treatment, marked by a rapid resolution of fever. In the longer term, aseptic abscess syndrome is characterized by a high frequency of relapses (60% of patients), with the possibility of multiple relapses. Clinicians have at their disposal numerous treatment options, including biologics. Colchicine, typically used in combination with other treatments, has been described as a protective factor against relapse. There has been no recorded death directly related to aseptic abscess syndrome to date.\n\n                            Last update: \n                            October 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Marc ANDRÉ  - Pr Olivier AUMAITRE  - Dr Ludovic TREFOND"}
{"Disease Name": "Asherman syndrome", "Disease Definition": "A rare, acquired uterine disease characterized by intrauterine adhesions associated with a history of curettage or intrauterine surgery and gynecological symptoms (secondary amenorrhea, hypomenorrhea, pelvic pain, infertility or pregnancy loss).", "ORPHA ID": 137686, "Summary": "Epidemiology\nThe prevalence in the general population is unknown. In infertile populations the prevalence varies from 2.8% to 46% depending on the subpopulation. The greatest risk factor for the disease is iatrogenic trauma to the endometrium.\nClinical description\nThe severity of intrauterine adhesions (IUA) in Asherman's syndrome can vary between complete obliteration of the cavity to minimal, marginal adhesions. Frequently, the uterine cavity is decreased in size. The adhesions are composed of fibromuscular connective tissue bands, with or without surrounding superficial epithelium or glandular tissue. Adhesions vary markedly in their density and size and can be accompanied by areas of endometrial sclerosis. The gravid uterus appears highly predisposed to adhesions, but IUA may develop in non-gravid uterus following intrauterine trauma. Clinical manifestations include infertility, menstrual irregularities, and recurrent pregnancy losses. Amenorrhea or hypomenorrhea are the most frequent symptoms and may be accompanied by dysmenorrhea during the anticipated menstrual period; some patients continue to have normal periods. When the adhesions are exclusively located in the lower uterine tract and functioning endometrium persists, this syndrome can cause severe pelvic pain and retrograde menstruation. Recurrence of UIA post-surgery is high.\nEtiology\nThe intrauterine adhesions result from uterine trauma including curettage, hysteroscopic myomectomy or endometrial ablation. Adhesions may also be diagnosed in women with genital tuberculosis.\nDiagnostic methods\nA history of uterine trauma (typically curettage) associated with menstrual abnormalities/inability to conceive are suggestive of Asherman's syndrome. Hysteroscopy provides definitive diagnosis, and can characterize the site and extent of adhesions as well as assess the endometrium. Magnetic resonance imaging (MRI) can be helpful as a supplementary diagnostic tool, especially when the adhesions involve the endocervix. IUAs are visualized as low signal intensity on T2 weighed-image inside the uterus. Transvaginal ultrasound and hysterosalpingography may be used but have lower diagnostic accuracy.\nDifferential diagnosis\nDifferential diagnosis on unenhanced ultrasound is normal intrauterine longitudinal folds, on hysterosalpingography or saline infusion ultrasonography it includes polyps and minor fibroids.\nManagement and treatment\nFor prevention of intrauterine adherences, a gentle emptying of the uterine cavity after delivery or abortion is mandatory preferably under ultrasound guidance. Intrauterine adhesions are ideally treated with hysteroscopy. Filmy adhesions may be separated by the tip of the hysteroscope. Dense adhesions are treated with hysteroscopic adhesiolysis with either mechanical, electrical or thermal energy techniques. Treatment in severe cases is difficult, and counselling should be offered regarding the lower rate of success and the higher risk of complications. Prevention of re-adhesion is important, and good results have been achieved with intrauterine devices, uterine balloon stent, Foley's catheter, and anti-adhesion barriers. In severe cases, several approaches may be required. Hormonal treatment (oestradiol, combined oestradiol/progesterone) is used to restore the normal endometrium; however, there is no consensus on timing of the administration or the type of regimen. Patients should be assessed one-two months post-operatively as complete resolution of the adhesions is not always possible with a single procedure. Ultrasound, HSG and hysteroscopy are the most common follow-up methods.\nPrognosis\nWhilst some women achieve pregnancy, the burden of infertility post-treatment is significant. The prognosis is worse for patients with a sclerotic, atrophic endometrium.\n\n                            Last update: \n                            May 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Eva DREISLER"}
{"Disease Name": "Aspartylglucosaminuria", "Disease Definition": "A rare oligosaccharidosis characterized by facial dysmorphism, progressive intellectual disability and psychomotor deterioration due to accumulation of glycoasparagines in tissues and body fluids.", "ORPHA ID": 93, "Summary": "Epidemiology\nAspartylglucosaminuria (AGU) is mainly found in Finland; the major pathogenic variants are approximately 50 times more frequent in Finns than non-Finnish Europeans. Outside of Finland, sporadic cases are observed, with > 50 known cases.\nClinical description\nClinical signs of AGU include slowly progressing neurodevelopmental disorder, beginning with clumsiness, delayed speech, and hyperkinesia. Patients also present with mild facial dysmorphism, and slight kyphoscoliosis. Hepatosplenomegaly is rare and has only been reported in non-Finnish cases.\nEtiology\nAGU is caused by pathogenic variants of the AGA gene located on 4q34.3. In Finland, two major mutations have been described (AGU-fin major and AGU-fin minor) and account for more than 98% of disease alleles; systematic screening for heterozygous individuals would thus be possible. Outside of Finland, the disease-causing variants are heterogeneous and often family-specific. The pathogenic variants lead to a deficiency of aspartylglucosaminidase (AGA), an enzyme that cleaves the N-acetylglucosamine-asparagine bond found in N-glycosyled proteins. AGA deficiency causes excess accumulation of glycoasparagines in the tissues and body fluids, with an increased excretion in urine.\nDiagnostic methods\nMost cases are detected by genetic analysis of the AGA gene or by exome sequencing. Biochemically, AGU is characterized by measuring the increased urinary excretion of aspartylglucosamine by liquid chromatography/mass spectrometry. A low activity of AGA enzyme can be measured in the serum, lymphocytes, fibroblasts, amniocytes or trophoblasts.\nDifferential diagnosis\nAs glycoasparagines can also be sporadically detected in the urine of patients with NGLY1 deficiency, genetic analysis and AGA activity measurement should be used to verify the diagnosis.\nAntenatal diagnosis\nPrenatal diagnosis by gene/exome sequencing or AGA enzyme activity measurement are possible.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant), informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nOlder patients may become severely handicapped due to cognitive and physical decline and will require special care. Attempts of curative treatment with allogenic bone marrow grafting showed limited results in five Finish patients. In addition, hematopoietic stem cell transplantation in three non-Finnish AGU patients showed that the intervention needs to be performed early in life to slow down cognitive decline. Treatment with a pharmacological chaperone (trimethylglycine) is currently under clinical evaluation.\nPrognosis\nPatients show a profound cognitive and physical decline after the age of 20-25 years. Death usually occurs before the age of 50, but the oldest Finnish patients have survived over 60 years.\n\n                            Last update: \n                            September 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Minna LAINE  - Pr Ritva TIKKANEN"}
{"Disease Name": "Aspergillosis", "Disease Definition": "A rare infectious disease caused by inhalation of the opportunistic fungus aspergillus that can lead to the following manifestations: allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, chronic necrotizing pulmonary aspergillosis (CNPA), and invasive aspergillosis (IA). Aspergilloma occurs in patients with cavitary lung disease and results in a fungal mass with variable clinical presentations from asymptomatic to life-threatening (massive hemoptysis). CNPA manifests as subacute pneumonia in patients with underlying disease. IA is disseminated aspergillosis that eventually invades other organs. Cutaneous aspergillosis is usually the dermatological manifestation of IA that manifests as erythematous-to-violaceous plaques or papules, often characterized by a central necrotic ulcer or eschar.", "ORPHA ID": 1163, "Summary": ""}
{"Disease Name": "Astley-Kendall dysplasia", "Disease Definition": "A rare, lethal skeletal dysplasia characterized by short limbed dwarfism, osteogenesis imperfecta, and punctate calcification within cartilage. It has been described in less than ten cases.", "ORPHA ID": 85175, "Summary": ""}
{"Disease Name": "Astroblastoma", "Disease Definition": "A very rare glial neoplasm of the central nervous system, most often with an intra-axial peripheral supratentorial location in one hemisphere of the frontal or parietal lobes and usually presenting in infants and young adults with symptoms of vomiting, loss of consciousness, epileptic seizures and headaches.", "ORPHA ID": 251679, "Summary": ""}
{"Disease Name": "Astrocytoma", "Disease Definition": "A complex group of benign and malignant cerebral tumors arising at any age.", "ORPHA ID": 94, "Summary": "Epidemiology\nThey are the most frequent cerebral tumors and represent more than half of all primary brain tumors. Incidence is estimated at 1/12,500.\nClinical description\nThe most frequent benign tumors are juvenile pilocytic astrocytomas (grade I) and diffuse low grade or fibrillary astrocytomas (grade II). The most frequent malignant tumors include anaplastic astrocytomas (grade III), glioblastomas (grade IV, the most severe form of astrocytoma; see this term), giant cell glioblastomas and gliosarcomas. Pleomorphic xanthoastrocytomas can be malignant or benign. These tumors occur at all ages although glioblastomas are more frequent in adults and in elderly people, while pilocytic astrocytomas are more frequent in children and adolescents. Age at diagnosis may influence tumor biology and evolution; the outcome generally being better in children. Speed of tumor growth is related to tumor grade. Symptom duration of less than three months is usually seen with malignant tumors.\nEtiology\nApart from cranial irradiation, which may itself induce glioblastomas, the underlying causes of these tumors are not known. The principal genetic predisposing syndromes are: neurofibromatosis type 1, Turcot syndrome and Li-Fraumeni syndrome (see these terms). Familial cases of isolated astrocytomas are very rare.\nDiagnostic methods\nDiagnosis is made after MRI, which reveals an intraparenchymal lesion associated with a mass effect and compression of the normal structures.\nManagement and treatment\nTreatment first consists of surgery, which aims at removing as much of the tumor as possible. If complete, surgical resection may be the only treatment required for benign astrocytomas. Adjuvant treatment is required for malignant tumors, whatever the quality of the resection. In case of incomplete resection of a benign tumor, adjuvant treatment may also be discussed. Radiation therapy is usually used in adults and in children over 10 years of age. Chemotherapy is preferred for younger children and may even be discussed for adults. The most chemosensitive tumors are pilocytic astrocytomas and anaplastic astrocytomas. Pilocytic tumors are highly curable, while malignant tumors are often fatal. The neurologic and intellectual sequelae of these tumors and their treatment may be severe, especially in young children, elderly people and patients requiring extended irradiation. Patient management requires multidisciplinary teams with expertise in the field of brain neoplasms. The relative rarity of these tumors calls for the management of patients in prospective trials aimed at improving prognosis and quality of survival.\nPrognosis\nPrognosis depends on tumor histology (benign or malignant) and location (operable or not).\n\n                            Last update: \n                            November 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Jacques GRILL"}
{"Disease Name": "Ataxia with vitamin E deficiency", "Disease Definition": "A neurodegenerative disease belonging to the inherited cerebellar ataxias mainly characterized by progressive spino-cerebellar ataxia, loss of proprioception, areflexia, and is associated with a marked deficiency in vitamin E.", "ORPHA ID": 96, "Summary": "Epidemiology\nGlobal prevalence is not known but population-based studies have been performed and prevalence can be extrapolated at approximately 1/300,000. AVED is the second most frequently inherited cerebellar ataxia in North Africa. As vitamin E deficiency might bring protection against malaria (see this term), it could explain a higher prevalence of AVED in Plasmodium infested areas.\nClinical description\nAVED presents generally between ages 5 and 20 years with variable phenotype and severity. Progressive spino-cerebellar ataxia, areflexia and loss of proprioception, mainly in distal joint position and of vibration sense, induce a noticeable clumsiness and imbalance. Patients may have a characteristic head titubation. Tendon reflexes are dramatically reduced and extensor plantar reflexes are frequent. Cerebellar impairment frequently manifests as dysmetria, dysdiadochokinesia and dysarthria. Decreased visual acuity with retinitis pigmentosa may be seen. In some cases, disease onset is late (> 30 years) and the course is milder. On the contrary, in early-onset cases, the course is more severe, with an increased risk of cardiomyopathy. Overall, the clinical picture of AVED is close to that of Friedreich's ataxia (see this term).\nEtiology\nAVED is caused by mutations in the tocopherol (alpha) transfer protein gene (TTPA; 8q13). This protein binds alpha-tocopherol (a vitamin E isomer) and very-low-density lipoproteins (VLDLs) in the liver. When mutated, TTPA prevents vitamin E linking to VLDLs, preventing it to pass into general circulation. Many mutations have been identified, but p.His101Gln and c.744delA are respectively responsible for the late-onset/mild and early-onset/severe forms of the disease.\nDiagnostic methods\nDiagnosis is based on physical examination, on vitamin E plasma dosage and on exclusion of known causes of malabsorption. Laboratory findings reveal a very marked deficiency of vitamin E in plasma but normal levels of lipid and lipoprotein profiles. Neuroimaging does not show an obvious cerebellar atrophy in the first stages of the disease. Electromyography usually reveals a pure sensory neuronopathy (ganglionopathy). Molecular analysis confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis mainly includes Friedreich ataxia, sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) and abetalipoproteinemia (see these terms). Other autosomal recessive cerebellar ataxias may be considered as well (Refsum disease, ataxia telangiectasia, Charcot-Marie-Tooth disease 1A and ataxia with oculomotor apraxia types 1 and 2 (see these terms)).\nAntenatal diagnosis\nAntenatal diagnosis is feasible via molecular genetic testing when the mutation has been identified in the family.\nGenetic counseling\nThe disease has an autosomal recessive mode of inheritance, with a subsequent recurrence risk of 25%.\nManagement and treatment\nTreatment is based on a lifelong high-dose vitamin E supplementation, which should be taken every day. When treated early, some symptoms could be reversible; in older patients disease progression can be slowed. It remains unknown whether in families of index cases vitamin E preventive treatment can be administered in presymptomatic individuals to prevent development of AVED.\nPrognosis\nEven if treated, patients frequently have a poor prognosis and become wheelchair bound within 8 and 20 years of age.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Mathieu ANHEIM"}
{"Disease Name": "Ataxia-deafness-intellectual disability syndrome", "Disease Definition": "A rare genetic syndromic intellectual disability characterized by global developmental delay, intellectual disability, infantile or childhood onset of progressive ataxia, and bilateral sensorineural hearing impairment. Variable features include signs of upper and lower motor neuron disease, peripheral neuropathy, myopathic facies, lower limb muscle wasting, and heel contractures. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 1188, "Summary": ""}
{"Disease Name": "Ataxia-hypogonadism-choroidal dystrophy syndrome", "Disease Definition": "A very rare autosomal recessive, slowly progressive neurodegenerative disorder characterized by the triad of cerebellar ataxia (that generally manifests at adolescence or early adulthood), chorioretinal dystrophy, which may have a later onset (up to the fifth-sixth decade) leading to variable degrees of visual impairment, and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics). Ataxia-hypogonadism-choroidal dystrophy syndrome belongs to a clinical continuum of neurodegenerative disorders along with the clinically overlapping cerebellar ataxia-hypogonadism syndrome (see this term).", "ORPHA ID": 1180, "Summary": ""}
{"Disease Name": "Ataxia-intellectual disability-oculomotor apraxia-cerebellar cysts syndrome", "Disease Definition": "A rare neuro-ophthalmological disease characterized by nonprogressive cerebellar ataxia, delayed motor and language development and intellectual disability, in addition to ophthalmological abnormalities (e.g. oculomotor apraxia, strabismus, amblyopia, retinal dystrophy and myopia). Cerebellar cysts, cerebellar dysplasia and cerebellar vermis hypoplasia, seen on magnetic resonance imaging, are also characteristic of the disease.", "ORPHA ID": 370022, "Summary": ""}
{"Disease Name": "Ataxia-oculomotor apraxia type 1", "Disease Definition": "A rare autosomal recessive cerebellar ataxia, characterized by progressive cerebellar ataxia associated with oculomotor apraxia, severe neuropathy, and hypoalbuminemia.", "ORPHA ID": 1168, "Summary": "Epidemiology\nAtaxia-oculomotor apraxia type 1 (AOA1) represents 3.6% of all autosomal recessive cerebellar ataxia (ARCA) in Portugal; in Japan, AOA1 seems to be the most frequent cause of ARCA. In a cohort of 227 patients mostly of French origin with progressive cerebellar ataxia selected after exclusion of Friedreich ataxia, the relative frequency of AOA1 was of 5%.\nClinical description\nCerebellar ataxia is the first manifestation of AOA1 with a mean age of onset of 4.3 years (2-10 years) and is characterized by progressive gait imbalance followed by dysarthria, and limb dysmetria. Later, peripheral axonal motor neuropathy dominates the clinical picture. Oculomotor apraxia (OMA; inability to coordinate eyes ± head movements: when the head turns toward a lateral target; the head reaches the target before the eyes) is present in almost all individuals with AOA1. Chorea is present at onset in 80% of patients and upper limb dystonia (see this term) occurs in about 50% of individuals. Additional features include square wave jerks, saccadic pursuit and gaze-evoked nystagmus, areflexia followed by severe peripheral neuropathy. Variable intellectual disability is observed.\nEtiology\nAOA1 results from mutations in APTX gene (9p13.3) encoding aprataxin which plays a role in DNA-single-strand break repair. Most mutations identified so far are localized in exons 5, 6 and 7. Some correlations between genotype and phenotype have been established: for example severe and persistent choreic phenotype is associated with mutations A198V; truncating mutations are associated with earlier onset and deletions with more severe phenotype and intellectual disability.\nDiagnostic methods\nDiagnosis of AOA1 is based on the clinical features, the progressive evolution, the absence of extraneurologic findings and family history. Electromyography findings reveal severe axonal sensory-motor neuropathy. Oculographic recordings demonstrate normal latencies, hypometric saccades, decrease mean gain in amplitude and broken saccades into multiple successive saccades. Cerebral magnetic resonance imagery displays cerebellar atrophy. Hypoalbuminemia and hypercholesterolemia are usual (disease duration is positively correlated with cholesterol and negatively correlated with albumin levels). Diagnosis is confirmed by molecular analysis of APTX gene.\nDifferential diagnosis\nDifferential diagnosis includes Friedreich ataxia, ataxia with vitamin E deficiency, AOA2, ataxia-telangiectasia, ataxia-telangiectasia-like disorder, autosomal recessive spastic ataxia of Charlevoix-Saguenay (see these terms).\nAntenatal diagnosis\nCarrier testing for at-risk family members and prenatal testing are possible if both disease-causing alleles in a family are known.\nGenetic counseling\nTransmission of AOA1 is autosomal recessive. Genetic counseling is recommended as each sib of an affected individual has 25% risk of being affected, 50% risk of being an asymptomatic carrier, and 25% risk of being neither affected nor a carrier.\nManagement and treatment\nNo specific treatment exists for AOA1 and management is mainly supportive. It includes physical therapy for cerebellar ataxia and disabilities resulting from peripheral neuropathy; educational support for reading and writing difficulties, speech therapy for dysarthria and cognitive impairment. Low-cholesterol diet and hypolipemiant treatment are recommended. Routine follow-up with a neurologist or neurogenetician is suggested. Some therapeutic trials are on the way such as the evaluation of efficacy of Coenzyme Q10 in evolution of the disease.\nPrognosis\nAOA1 is a progressive neurodegenerative disorder and most patients usually become wheelchair bound from seven to ten years after onset of the disease.\n\n                            Last update: \n                            May 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Perrine CHARLES"}
{"Disease Name": "Ataxia-oculomotor apraxia type 4", "Disease Definition": "A rare autosomal recessive cerebellar ataxia characterized by onset of dystonia and other extrapyramidal signs, ataxia, oculomotor apraxia, and progressive sensorimotor polyneuropathy in the first decade of life. Patients present distal muscle weakness and atrophy, decreased vibratory sensation, and areflexia, and usually become wheelchair-bound by the third decade. Variable cognitive impairment may also be seen.", "ORPHA ID": 459033, "Summary": ""}
{"Disease Name": "Ataxia-pancytopenia syndrome", "Disease Definition": "A rare genetic disease characterized by cerebellar ataxia, cytopenias and predisposition to bone marrow failure and myeloid leukaemia. Neurologic features variably include slowly progressive cerebellar ataxia or balance impairment with cerebellar atrophy and periventricular white matter T2 hyperintensities in brain MRI, horizontal and vertical nystagmus, dysmetria, dysarthria, pyramidal tract signs and reduced nerve conduction velocity. Hematological abnormalities are variable and may be intermittent and include cytopenias of all cell lineages, immunodeficiency, myelodysplasia and acute myeloid leukemia.", "ORPHA ID": 2585, "Summary": ""}
{"Disease Name": "Ataxia-photosensitivity-short stature syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by cerebellar-like ataxia, photosensitivity (mainly of the face and trunk), short stature and intellectual disability. Additonal features include clinodactyly, single palmar transverse crease, high-arched palate, pseudohypertrophy of the calves and aortic valve lesions. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 1184, "Summary": ""}
{"Disease Name": "Ataxia-tapetoretinal degeneration syndrome", "Disease Definition": "A rare hereditary ataxia characterized by simultaneous onset and development of cerebellar ataxia and chorioretinal degeneration (including macular degeneration, advancing choroidal sclerosis, punctata albescens, and retinitis pigmentosa). There have been no further descriptions in the literature since 1963.", "ORPHA ID": 1178, "Summary": ""}
{"Disease Name": "Ataxia-telangiectasia variant", "Disease Definition": "A rare, genetic, persistent combined dystonia characterized by clinical signs similar to ataxia-telangiectasia but with a later (usually adulthood) onset and slower progression. Patients typically present extrapyramidal signs, such as resting tremor, choreathetosis, and dystonia, as the initial symptoms and later often develop mild cerebellar ataxia (with gait usually preserved). Telangiectasia and immunodeficiency may be absent but secondary features of ataxia-telangiectasia, such as risk of malignancy, dysarthria and peripheral neuropathy, are frequently present.", "ORPHA ID": 370109, "Summary": ""}
{"Disease Name": "Ataxia-telangiectasia-like disorder", "Disease Definition": "A rare genetic disease characterized by slowly progressive cerebellar degeneration resulting in ataxia, oculomotor apraxia, and other cerebellar symptoms. There is an increased frequency of spontaneous chromosomal aberrations, as well as hypersensitivity to ionizing radiation, while telangiectasia is absent.", "ORPHA ID": 251347, "Summary": ""}
{"Disease Name": "Ataxia-telangiectasia", "Disease Definition": "A rare autosomal recessive cerebellar ataxia due to a DNA repair defect characterized by progressive neurological impairment with cerebellar syndrome, oculocutaneous telangiectasia, defects in B and T cell-mediated immunity, and increased susceptibility to malignancies (mainly lymphoid neoplasms). High sensitivity to ionizing radiation limits patient treatments.", "ORPHA ID": 100, "Summary": "Epidemiology\nPrevalence is estimated to be 1/100,000 live births.\nClinical description\nThe first manifestations usually occur at 1-2 years of age with progressive walking difficulties, balance disorders followed by slurred speech, drooling and oculomotor apraxia. Choreoathetosis may appear around 9-10 years of age and worsen progressively. Intelligence is normal although slurred speech and drooling may be interpreted as intellectual deficiency. Cutaneo-mucosal telangiectasias (especially of the conjunctivae) usually appear around 3-6 years of age, or later. Immunodeficiency causes recurrent airway infections (otitis, sinusitis, bronchitis, pneumonia) which can lead to bronchiectasis and autoimmune/inflammatory features such as granulomas (mostly of the skin but also other organs); its severity varies widely between patients, from severe lymphopenia (including severe combined immune deficiency and/or severe hypogammaglobulinemia) to no overt biological abnormality. There is a high risk of malignancy, particularly of lymphoma and leukemia (in childhood and adolescence mostly), and carcinomas (in adulthood). Patients are highly sensitive to ionizing radiation, that are forbidden. X-rays imaging must be avoided. Other features include growth delay, infertility, glucose intolerance, non-alcoholic steatohepatitis.\nEtiology\nAtaxia-telangiectasia (A-T) is caused by loss of function biallelic (homozygous or compound heterozygous) pathogenic variants (PVs) of the ATM gene (11q22.3) which encodes a protein kinase involved in double-strand-break DNA repair, notably in the Purkinje cells of the cerebellum and cutaneous and conjunctival endothelial cells. PVs induce stop codons or directly inactivate the kinase domain; some are hypomorphic and lead to an attenuated disease with late onset symptoms and dystonia.\nDiagnostic methods\nEarly diagnosis is difficult. Quasi-constant very high serum level of alpha-fetoprotein is a useful clinical sign. Cytogenetic analysis may help confirm the diagnosis (7;14 translocations) but few laboratories still perform it. Molecular analysis of the ATM gene confirms the diagnosis. Multigene panels for ataxias or immune deficiencies have now greatly facilitated A-T diagnosis and other differential diagnoses.\nDifferential diagnosis\nThe differential diagnosis includes ataxia-telangiectasia-like disorder and ataxia-oculomotor apraxia types 1 and 2.\nAntenatal diagnosis\nAntenatal and preimplantation genetic diagnosis are possible when pathogenic variants have been identified in a family.\nGenetic counseling\nGenetic counseling should be discussed due to the severity and incurability of the disease. Siblings of an affected individual have a 25% chance of being affected. The risk for couples with one PV carrier to have an affected child is estimated at 1/600-800. PV carriers are estimated to represent 1/150-200 of the general population. Genetic testing of the spouse may be discussed.\nManagement and treatment\nThere is no curative therapy. Management is symptomatic and involves physiotherapy, speech therapy and treatment of the infection and pulmonary complications (chronic antibiotic prophylaxis and/or human polyvalent normal Immunoglobulin long-term replacement therapy). The cells of A-T patients show increased susceptibility to ionizing radiation; X-rays, radiotherapy, and some forms of chemotherapy should be used with caution or avoided. Affected children with classical A-T are often wheelchair bound by 10-11 years old. Beta-blockers may reduce trembling and improve fine movements performance. Nicotinamide riboside brings minor improvements of some neurological symptoms. Dexamethasone administration through autologous erythrocytes has shown promising results on neurologic features in clinical trials. Gene therapy using antisense oligonucleotides is currently under trial.\nPrognosis\nThe prognosis is severe due to the occurrence of respiratory infections, neurodegeneration, accelerated cutaneo-mucosal ageing and an increased risk of cancer (35% of patients develop cancer by the age of 20).\n\n                            Last update: \n                            October 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Jessica LE GALL  - Dr Nizar MAHLAOUI | RITA* - Pr Dominique STOPPA-LYONNET \n\n\n                                * European Reference Network"}
{"Disease Name": "Atelosteogenesis type I", "Disease Definition": "A Pierre Robin syndrome associated with bone disease characterized by severe short-limbed dwarfism, joint dislocations, club feet along with distinctive facies and radiographic findings.", "ORPHA ID": 1190, "Summary": "Epidemiology\nAtelosteogenesis I (AOI) is a very rare infrequently described disorder.\nClinical description\nAffected neonates are stillborn or die rapidly after birth and present clinically with severe short-limbed dwarfism, dislocated hip, knee and elbow joints, club feet and if born alive have cardiorespiratory failure. Craniofacial dysmorphism describes a prominent forehead, hypertelorism, a depressed nasal bridge with a grooved tip, micrognathia and frequently a cleft palate. There is a continuum with overlapping clinical findings between atelosteogenesis I, atelosteogenesis III and boomerang dysplasia.\nEtiology\nAtelosteogenesis I results from heterozygous mutations in exons 2-5 and 27-33 of the gene encoding filamin B (FLNB) located to 3p14.\nDiagnostic methods\nDiagnosis can be confirmed from skeletal radiographs, chondro-osseous histopathology and genetic testing. Distinctive radiographic findings comprise severe platyspondyly, distally tapered; shortened, incomplete or absent humeri and femurs; shortened or bowed radii, ulnas, and tibias; hypoplastic pelvis and fibulas; and deficient ossification of the metacarpals, middle and proximal phalanges.\nDifferential diagnosis\nDifferential diagnosis comprises other skeletal dysplasias with severe short-limbed dwarfism such as campomelic dysplasia, Ellis-van Creveld syndrome, achondroplasia, metatropic dysplasia, Roberts syndrome, short rib-polydactyly syndrome, and thanatophoric dysplasia. Other, differential diagnosis includes achondrogenesis, hypophosphatasia, and osteogenesis imperfecta.\nAntenatal diagnosis\nPrenatal ultrasound can detect bone dysplasia and other manifestation and plays an important role in early detection and diagnosis. Prenatal ultrasound findings for AOI may include severe limb shortening and deficient ossification of the long bones, shortened flaring or absent humeri and femurs from 18 weeks onwards. Other skeletal abnormalities as well as some facial dysmorphic features may be detectable.\nGenetic counseling\nAll cases have been autosomal dominant and sporadic resulting from de novo mutations in FLNB.\nManagement and treatment\nPalliative care is offered to newborns suffering from AOI.\nPrognosis\nPrognosis is poor. Death is often due to a combination of pulmonary hypoplasia and tracheobronchomalacia early in life.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Stephen ROBERTSON  - Dr Emma WADE"}
{"Disease Name": "Atelosteogenesis type II", "Disease Definition": "A rare, lethal perinatal bone dysplasia characterized by limb shortening, normal sized skull with cleft palate, hitchhiker thumbs, distinctive facial dysmorphism and radiographic skeletal features, caused by mutations in the diastrophic dysplasia sulfate transporter gene.", "ORPHA ID": 56304, "Summary": ""}
{"Disease Name": "Atelosteogenesis type III", "Disease Definition": "A rare skeletal dysplasia characterized by short limbs dysmorphic facies and diagnostic radiographic findings.", "ORPHA ID": 56305, "Summary": "Epidemiology\nThe prevalence of AOIII is unknown. Less than 25 affected patients have been reported.\nClinical description\nAOII, like AOI, is characterized by rhizomelic limb shortness, dislocated hip, knee and elbow joints, broad hands and feet with broad digits, club feet, facial dysmorphism (midface hypoplasia, micrognathia, cleft palate). Feeding problems and cardiorespiratory insufficiency are often seen in newborns. Clinical manifestations due to secondary complications past early infancy include learning and language problems and a gross motor developmental delay.\nEtiology\nAtelosteogenesis III results from missense mutations or small in-frame deletions in the FLNB gene reported in exons 2-5, 13 and 27-33 resulting in the translation of filamin B protein with altered biochemical properties.\nDiagnostic methods\nThe diagnosis is established after a full skeletal x-ray survey and confirmed with genetic testing. AOIII demonstrates less delay of normal ossification compared to AOI.\nAntenatal diagnosis\nPrenatal diagnosis is possible by ultrasound from 20 weeks onward and by prenatal genetic testing in case of family history.\nGenetic counseling\nMost cases of AOIII are sporadic, but AOIII may be transmitted in an autosomal dominant manner. Affected individuals of which one of the parents presents with a milder phenotype (like Larsen syndrome) (see this term) have been reported. This is likely to be related to a somatic mosaicism in the parents for a mutation that is germline in the offspring.\n\n                            Last update: \n                            July 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Stephen ROBERTSON"}
{"Disease Name": "Athabaskan brainstem dysgenesis syndrome", "Disease Definition": "A rare, genetic, neurological disorder characterized by horizontal gaze palsy, sensorineural deafness, central hypoventilation, developmental delay, and intellectual disability, described in persons of Athabascan American Indian heritage. Swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, internal carotid artery, and cardiac outflow tract anomalies may be additionally observed. No dysmorphic facial features are associated.", "ORPHA ID": 69739, "Summary": ""}
{"Disease Name": "Atherosclerosis-deafness-diabetes-epilepsy-nephropathy syndrome", "Disease Definition": "A rare, severe, circulatory system disease characterized by premature, diffuse, severe atherosclerosis (including the aorta and renal, coronary, and cerebral arteries), sensorineural deafness, diabetes mellitus, progressive neurological deterioration with cerebellar symptoms and photomyoclonic seizures, and progressive nephropathy. Partial deficiency of mitochondrial complexes III and IV in the kidney and fibroblasts (but not in muscle) may be associated. There have been no further descriptions in the literature since 1994.", "ORPHA ID": 1192, "Summary": ""}
{"Disease Name": "Athyreosis", "Disease Definition": "A rare form of thyroid dysgenesis characterized by complete absence of thyroid tissue that results in primary congenital hypothyroidism, a permanent thyroid deficiency that is present from birth.", "ORPHA ID": 95713, "Summary": "Epidemiology\nPrevalence is estimated at around 1/28,000. Athyreosis and thyroid hypoplasia (see this term) combined account for one-third of cases of thyroid dysgenesis.\nClinical description\nClinical manifestations of athyreosis are often subtle or not present at birth, probably as a result of trans-placental passage of some maternal thyroid hormone. More specific symptoms and signs do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age.\nEtiology\nAround 2% of cases have been shown to be familial and may be caused by mutations in the FOXE1,  NKX2-1, NKX2-5 or PAX8 genes (9q22, 14q13, 5q34 and 2q12-q14). Mutations that result in complete inactivation of the TSHR gene (14q31) can present with athyreosis.\nDiagnostic methods\nImaging studies are required to confirm the diagnosis of athyreosis.\nGenetic counseling\nAthyreosis is generally thought to be sporadic. However, recent evidence points to the possibility of a genetic component.\nPrognosis\nWithout treatment athyreosis results in severe intellectual deficit and short stature.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Atkin-Flaitz syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by variable intellectual deficit, macrocephaly, short stature, and facial dysmorphism (such as prominent forehead, prominent supraorbital ridges, hypertelorism, downslanting palpebral fissures, broad nasal tip, anteverted nostrils, thick lower lip, and localized microdontia). Additional reported features include seizures, post-pubertal macroorchidism, obesity, and short, broad hands with tapered fingers.", "ORPHA ID": 1193, "Summary": ""}
{"Disease Name": "Atopic keratoconjunctivitis", "Disease Definition": "A rare, chronic allergic disease of the cornea and conjunctiva occurring in all age groups, characterized by severe itching and burning sensation, conjunctival injection, photophobia and edema with serious cases leading to ulceration of the cornea which can result in blindness. It is often associated with atopic dermatitis.", "ORPHA ID": 163934, "Summary": ""}
{"Disease Name": "Atresia of urethra", "Disease Definition": "A rare fetal lower urinary tract obstruction (LUTO) characterized by closure or failure to develop an opening in the urethra and resulting in obstructive uropathy presenting in utero as megacystis, oligohydramnios or anhydramnios, and potter sequence.", "ORPHA ID": 105, "Summary": "Epidemiology\nPrevalence is unknown, but is higher in males than females.\nClinical description\nAtresia of urethra often presents on routine antenatal ultrasound with megacystis, oligohydramnios or anhydramnios and sometimes urinary ascites. It may cause fetal death. In cases that survive to birth, additional symptoms include respiratory insufficiency due to pulmonary hypoplasia, megaureter, hydronephrosis and enlarged often cystic and functionally impaired/non-functional dysplastic kidneys as well as abdominal distention. Furthermore, a Potter sequence can be found due to oligo- or anhydramnios. Patients may present with patent urachus or vesicocutaneous fistula.\nEtiology\nThe etiology of atresia of the urethra is unknown. Common clinical features arise from the inability of urine to pass out of the body of the fetus, resulting in oligohydramnios which in turn affects the development of the lungs and causes features of Potter sequence. Congenital obstruction of the urinary tract at a critical time in organogenesis has a profound and lifelong effect on kidney, ureteral and bladder function. In rare cases, there is an abnormal opening between the bladder and the rectum which may allow the urine to drain.\nDiagnostic methods\nAntenatal diagnosis is based on ultrasound. By then it is not possible to clearly distinguish between different forms of LUTO. If megacystis occurs in early pregnancy (around 17 weeks of gestation) atresia of the urethra is more likely to be a possible underlying cause then in later gestation. Postnatally, micturating cysto- urethrography and/or cystoscopy can be used for final diagnosis and differentiation between atresia of the urethra and other forms of LUTO as differential diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other causes of megacystis including posterior urethral valve, anterior urethral valve, urethral stenosis, urethral agenesis, double urethra, cloacal malformation and, in rare and severe cases, different forms of voiding dysfunction or megacystis megaureter syndrome. Atresia of urethra can occur in combination with several other conditions including caudal dysplasia, cloacal extrophy, DiGeorge syndrome, prune belly syndrome, Fraser syndrome, cryptophtalmus, Johnson-Munson, Meckel-Gruber, Sirenomelia, and Townes-Brocks syndrome.\nAntenatal diagnosis\nAntenatal diagnosis is based on ultrasound evidence of megacystis and oligohydramnios. Fetal MRI can be used to attempt confirmation of the diagnosis.\nGenetic counseling\nIf atresia of the urethra occurs together with other birth defects, genetic counselling should be considered. For isolated atresia of the urethra no genetic causes are known so far.\nManagement and treatment\nAntenatal treatment involves urinary decompression with a vesico-amniotic shunt. If the antenatal period is survived, postnatal treatment depends on the pulmonary and renal function. All cases with remaining renal function require a suprapubic urine drainage until reconstructive surgery. Successful treatment of severe cases (obstructive uropathy, kidney failure and pulmonary hypoplasia) with extra corporal membrane oxygenation (ECMO) therapy and hemofiltration/peritoneal dialyses has been described.\nPrognosis\nThe malformation usually results in fetal death without surgical intervention. Prenatal decompression allows survival and may even lead to normal bladder and renal function. Nevertheless, progression into kidney failure is common. Extensive surgical reconstruction is to be expected.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Alina HILGER"}
{"Disease Name": "Atrial septal aneurysm", "Disease Definition": "A rare congenital non-syndromic heart malformation characterized by an abnormal protrusion of the interatrial septum into the right or left atrium, or both, during the cardiorespiratory cycle. The defect may be limited to the fossa ovalis or involve the entire septum. It can present as an isolated finding but is more often associated with interatrial shunts, in particular patent foramen ovale. Clinically it increases the risk of peripheral arterial embolism and stroke.", "ORPHA ID": 99107, "Summary": ""}
{"Disease Name": "Atrial septal defect-atrioventricular conduction defects syndrome", "Disease Definition": "An extremely rare genetic congenital heart disease characterized by the presence of atrial septal defect, mostly of the ostium secundum type, associated with conduction anomalies like atrioventricular block, atrial fibrillation or right bundle branch block.", "ORPHA ID": 1479, "Summary": ""}
{"Disease Name": "Atrial standstill", "Disease Definition": "A rare cardiac rhythm disease characterized by a transient or permanent absence of electrical and mechanical atrial activity. Electrocardiographic findings include bradycardia, ectopic supraventricular rhythms, lack of atrial excitability and absent P waves.", "ORPHA ID": 1344, "Summary": ""}
{"Disease Name": "Atrichia with papular lesions", "Disease Definition": "A rare inherited form of alopecia characterized by irreversible hair loss during the neonatal period on all hear-bearing areas of the body, later associated with the development of papular lesions all over the body and preferentially on the face and extensor surfaces of the extremities.", "ORPHA ID": 86819, "Summary": ""}
{"Disease Name": "Atrioventricular defect-blepharophimosis-radial and anal defect syndrome", "Disease Definition": "A rare, genetic multiple congenital anomalies syndrome characterized by atrioventricular septal defects and blepharophimosis, in addition to radial (e.g. aplastic radius, shortened ulna, fifth finger clinodactyly, absent first metacarpal and thumb) and anal (e.g. imperforate or anteriorly place anus, rectovaginal fistula) defects.", "ORPHA ID": 1352, "Summary": ""}
{"Disease Name": "Atrophic lichen planus", "Disease Definition": "A rare variant of cutaneous lichen planus characterized by the development of pale papules or plaques with an atrophic center.", "ORPHA ID": 254449, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nLesions develop on the trunk or lower extremities on skin areas previously affected by classic lichen planus.\nEtiology\nEtiology is unknown.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Stephanie ARNOLD  - Dr Susan COOPER"}
{"Disease Name": "Atrophoderma vermiculata", "Disease Definition": "A rare genetic skin disease characterized by childhood onset of follicular keratotic papules slowly progressing to characteristic ''honeycomb'' atrophy on the cheeks, preauricular area, and forehead. Less frequently, the condition may affect also the upper lip, ears, or limbs. Additional features include facial erythema, milia, and follicular plugs.", "ORPHA ID": 79100, "Summary": ""}
{"Disease Name": "Attenuated Chédiak-Higashi syndrome", "Disease Definition": "A very rare and atypical form of Chédiak-Higashi syndrome (CHS), a genetic disorder characterized by partial oculocutaneous albinism, severe immunodeficiency, mild bleeding, neurological dysfunction and lymphoproliferative disorder.", "ORPHA ID": 352723, "Summary": "Epidemiology\nFewer than 100 cases have been reported to date but the disorder is likely underdiagnosed. The atypical form may account for 10-15% of CHS patients who do not develop the accelerated phase.\nClinical description\nMild adolescent- or adult-onset attenuated CHS is characterized by subtle or absent oculocutaneous albinism, a characteristic feature of classic CHS, as well as minor to severe infections during childhood but a lower frequency of infections in adolescence and adulthood, mild bleeding manifestations, and progressive neurological findings including intellectual deficit, peripheral neuropathy, parkinsonism, balance abnormalities, and tremor.\nEtiology\nMissense mutations in the LYST lysosomal trafficking regulator gene (1q42.1-q42.2) appear to cause this form of CHS.\nGenetic counseling\nAttenuated Chédiak-Higashi syndrome is inherited in an autosomal recessive manner.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Wendy INTRONE"}
{"Disease Name": "Attenuated familial adenomatous polyposis", "Disease Definition": "A mild form of familial adenomatous polyposis characterized by the presence of fewer than 100 adenomatous colonic polyps, a more proximal colonic location, a delayed age of colorectal cancer onset and a more limited expression of the extracolonic features.", "ORPHA ID": 220460, "Summary": ""}
{"Disease Name": "ATTRV122I amyloidosis", "Disease Definition": "A rare hereditary Transthyretin (TTR)-related systemic amyloidosis (ATTR) with predominant cardiac involvement resulting from myocardial infiltration of abnormal amyloid protein.", "ORPHA ID": 85451, "Summary": "Epidemiology\nGlobal prevalence is unknown. The prevalence of the Val122Ile variant has been estimated to be 3.5% in American population of African descent, corresponding to potentially 1.6 million carriers in the USA. However, the actual penetrance in this population is unknown, with estimates as low as 10%.\nClinical description\nPatients present during late adulthood with restrictive cardiomyopathy (with varying degrees of chronic heart failure and possible brady/tachyarrhythmias). Cardiomyopathy may be accompanied by sensorimotor/autonomic polyneuropathy but in many patients carrying this variant the phenotypic expression may remain exclusively cardiac.\nEtiology\nSeveral specific TTR mutations are associated with predominant cardiac involvement. Among these, V122I is particularly common among African-Americans (3.5% of the population).\nDiagnostic methods\nThe gold standard for diagnosis of amyloidosis is histological analysis and Congo red staining of biopsy specimens. Detection of the specific TTR mutation allows confirmation of the diagnosis. A high level of diagnostic suspicion of cardiac amyloidosis can be generated by characteristic echocardiographic and ECG findings, and confirmed by bone tracer scintigraphy and/or magnetic resonance imaging with late enhancement. A family history of cardiac disease may suggest hereditary ATTR amyloidosis etiology.\nDifferential diagnosis\nThe differential diagnosis should include other infiltrative/storage myocardial diseases, including other types of cardiac amyloidosis, such as AL amyloidosis. Hypertrophic cardiomyopathy should also be included in the differential diagnosis.\nAntenatal diagnosis\nConsidering the late-onset phenotype and the increasing availability of disease-modifying therapies, antenatal diagnosis has a very limited role in this specific condition.\nGenetic counseling\nHereditary ATTR amyloidosis is dominantly transmitted. Genetic counseling is generally highly recommended to at-risk patients' relatives, informing them there is a 50% risk of inheritance in siblings and offspring. For the Val122Ile variant in African-Americans, it is particularly important to discuss the low penetrance and possible gender-related variations, with a higher disease rate observed in males over the age of 70. Factors affecting penetrance are still unknown. In general, pre-symptomatic testing is increasingly offered in hereditary ATTR amyloidosis due to emerging disease-modifying therapies.\nManagement and treatment\nClose monitoring of cardiac function and symptoms by an expert cardiologist is recommended. Supportive therapy plays a major role. Disease modifying therapy is available for hereditary V122I amyloidosis. Patient with exclusive cardiomyopathy can be treated with the TTR stabilizer tafamidis at the dose of 61 mg/day. Patients presenting with a mixed phenotype (cardiomyopathy associated with polyneuropathy) are eligible to a gene-silencing treatment, including the RNAi agent patisiran (or vutrisiran, where already available) and the antisense oligonucleotide inotersen.\nPrognosis\nPrognosis is driven by the severity of cardiomyopathy. A validated prognostic staging system for patients with hereditary ATTRV122I amyloidosis is the NAC staging system, in which survival correlates with NT-proBNP concentration and eGFR at diagnosis.\n\n                            Last update: \n                            May 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Laura OBICI | RITA*\n\n\n                                * European Reference Network"}
{"Disease Name": "ATTRV30M amyloidosis", "Disease Definition": "A rare hereditary ATTR amyloidosis (hATTR) characterized by a progressive, length-dependent sensorimotor axonal polyneuropathy and/or autonomic neuropathy in adulthood. Renal, ocular and cardiac involvement also frequently occurs. Two different phenotypes are associated with this mutation, namely early-onset V30M and late-onset V30M, that differ in terms of age on onset (<50 years or >50 years, respectively), presenting features, histopathological characteristics, rate of disease progression and response to therapy.", "ORPHA ID": 85447, "Summary": "Epidemiology\nATTRV30M is the most common hATTR. The worldwide prevalence is unknown, although data is available for countries like Portugal, Japan and Sweden where the disease is relatively frequent. In Portugal the estimated incidence is 1/115,000 people a year, and the estimated prevalence is 1/4,360 adults.\nClinical description\nEarly-onset V30M manifests usually from the fourth decade of life. Inaugural symptoms are consistent with a small fibre neuropathy and typically include pain and temperature sensation loss in lower limbs. Motor neuropathy occurs later. Autonomic features include postural hypotension, gastrointestinal and genitourinary disorders. Rhythm disturbances, including atrioventricular nodal block requiring pacemaker implantation, are also frequent at disease onset. Proteinuria progressing to nephrotic syndrome may be an early clinical finding as well. In late-onset V30M, small and large nerve fibres are usually affected since the early stages of the disease, manifesting with a rapidly progressing sensory and motor polyneuropathy. Carpal tunnel syndrome may anticipate peripheral neuropathy in lower limbs. Infiltrative cardiomyopathy frequently develops, leading to heart failure.\nEtiology\nThe disease is caused by a methionine for valine substitution at residue 30 of the mature TTR protein, which is encoded by the TTR gene located on chromosome18q12.1. It leads to misfolding and dissociation of the TTR tetramer and monomer aggregation as amyloid in tissues and organs.\nDiagnostic methods\nDetection of V30M TTR variant by genetic testing and tissue biopsy (preferably a non-invasive biopsy like minor labial salivary gland, subcutaneous fat tissue or rectal mucosa) are required for a complete diagnosis. Green birefringence on polarized light microscopy after Congo red staining reveal amyloid deposits. Amyloid deposits are typed by immunohistochemistry or mass spectrometry for definite diagnosis when a patient also presents with a serum and/or urinary monoclonal gammopathy.\nDifferential diagnosis\nThe differential diagnosis includes diabetic neuropathy, chronic inflammatory demyelinating polyneuropathy, AL, AGel and AApoAI amyloidosis.\nAntenatal diagnosis\nPrenatal/pre-implantation diagnosis is possible and should be discussed in the context of genetic counseling. It is more relevant in families with early-onset V30M, depending also on local regulations. The emerging availability of effective disease-modifying therapies is reducing the request for pre-implantation diagnosis. Antenatal diagnosis is usually not an option in late-onset V30M, due to advanced age of onset and reduced penetrance.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. Genetic counselling should be offered to affected individuals and their at-risk relatives, informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement of the disease should be multidisciplinary, involving neurologist, geneticist, cardiologist, nephrologist, ophthalmologist and gastroenterologist. Liver transplantation is no longer a first-line treatment. Presently, patients that are able to walk unassisted (FAP stage 1) can be treated with a gene-silencing agent (RNAi patisiran, vutrisiran or ASO inotersen) or with the TTR stabilizer tafamidis 20 mg/day. Patients that require support for walking (FAP stage 2) can be treated with a gene-silencing agent only.\nPrognosis\nThis neurological disease is progressive and highly disabling if untreated. Severe cardiac, renal and ocular manifestations may develop. Before disease-modifying treatment availability, death occurred within a mean interval of 10.8 years after onset of the inaugural symptoms.\n\n                            Last update: \n                            May 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Laura OBICI | RITA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Atypical autism", "Disease Definition": "A rare, pervasive developmental disorder that does not fit the diagnosis for the other specific autistic spectrum disorders (autism, Asperger syndrome, Rett syndrome or childhood disintegrative disorder) and is characterized by usually milder developmental and social delay and less stereotypical autistic behavior.", "ORPHA ID": 199627, "Summary": ""}
{"Disease Name": "Atypical chronic myeloid leukemia", "Disease Definition": "A rare myelodysplastic/myeloproliferative neoplasm characterized by peripheral blood leukocytosis due to increased numbers of morphologically dysplastic neutrophils and their precursors, hypercellular bone marrow with granulocytic proliferation and dysplasia (with or without dysplasia in the erythroid and megakaryocytic lineages), and prominent dysgranulopoiesis, but no or minimal absolute basophilia or monocytosis. Blasts account for less than 20% of leukocytes in the blood and bone marrow. BCR-ABL1 fusion is absent, as well as PDGFRA, PDGFRB or FGFR1 rearrangement, or PCM1-JAK2. Patients may present with signs and symptoms related to splenomegaly, anemia, or thrombocytopenia. Prognosis is generally poor.", "ORPHA ID": 98824, "Summary": ""}
{"Disease Name": "Atypical dentin dysplasia due to SMOC2 deficiency", "Disease Definition": "A rare, genetic, dentin dysplasia disease characterized by extreme microdontia, oligodontia, and abnormal tooth shape (including globular teeth, incisal notches and double tooth formation). Short roots with a variable pulp phenotype (including taurodontia and flame-shaped pulp), enamel hypoplasia and anterior open bite may also be associated.", "ORPHA ID": 314721, "Summary": ""}
{"Disease Name": "Atypical Fanconi syndrome-neonatal hyperinsulinism syndrome", "Disease Definition": "A rare genetic disease characterized by the association of Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. Patients display a phenotype of proximal tubulopathy characterized by generalized aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricemia, and additional features not normally seen in Fanconi syndrome (apart from nephrocalcinosis), namely renal impairment, hypercalciuria with relative hypocalcemia, and hypermagnesemia.", "ORPHA ID": 544628, "Summary": ""}
{"Disease Name": "Atypical glycine encephalopathy", "Disease Definition": "A rare form of glycine encephalopathy presenting disease onset or clinical manifestations that differ from neonatal or infantile glycine encephalopathy.", "ORPHA ID": 289863, "Summary": "Epidemiology\nThe prevalence of atypical glycine encephalopathy is not known. Approximately 20 cases have been reported to date.\nClinical description\nSymptoms are mostly non-specific and are not similar to the severe neurological symptoms observed in neonatal and infantile GE (see these terms). Some patients have milder disease with onset from late infancy to adulthood, while others have rapidly progressive severe disease often of late onset. It also includes patients with transient hyperglycinemia, whose symptoms in neonatal period resemble those of neonatal form. Manifestations include cognitive decline, behavioral disorders, ataxia, peripheral neuropathy and optic atrophy.\nEtiology\nEtiology of atypical glycine encephalopathy remains largely unknown. It was reported that some patients had mutations in genes encoding GCS components.\nGenetic counseling\nMode of inheritance has not been identified in most of patients with atypical glycine encephalopathy\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                             Shigeo KURE"}
{"Disease Name": "Atypical hemolytic uremic syndrome", "Disease Definition": "A rare, genetic thrombotic microangiopathy due to dysregulation of the alternative complement pathway and characterized by the triad of hemolytic anemia, thrombocytopenia, and acute renal dysfunction.", "ORPHA ID": 2134, "Summary": "Epidemiology\nThe estimated prevalence in Europe is 1/100,000. Atypical hemolytic uremic syndrome (aHUS) accounts for 5-10% of hemolytic uremic syndrome (HUS) cases in children, and most cases in adults.\nClinical description\nDisease onset may occur at any age. Presentation is typically of acute onset, nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The episode is usually preceded by a triggering event such as upper respiratory infection or viral gastroenteritis. In 20% of patients, onset is insidious with relapsing subclinical anemia, thrombocytopenia, decreased or rarely preserved renal function, and nonspecific symptoms (e.g.fatigue, and anorexia). The renal manifestations are variable across patients and can range from acute anuric kidney injury requiring dialysis to chronic kidney disease or chronic proteinuria. Approximately half of the cases progress to end-stage kidney disease. Extra-renal manifestations occur in approximately 20% of patients and include neurological symptoms (10%; e.g. irritability, drowsiness, seizures, diplopia, cortical blindness, hemiparesis or hemiplegia, stupor, or coma), myocardial infarction (3%), pulmonary hemorrhage, ischemic colitis, pancreatitis, hepatocellular injury, and peripheral vascular disease.\nEtiology\nMost of the cases present with uncontrolled complement activation that results in endothelial damage. Pathogenic mutations have been identified in several genes coding proteins and regulators of complement cascade. The most frequent include CFH (1q31.3), CFI (4q25), CD46 (1q32.2), C3 (19p13.3) and CFB (6p21.33). Rearrangements in CFH gene and CFH related genes also cause similar phenotype. An acquired form caused by factor H antibodies exists. Approximately 10% of the aHUS patients have these auto-antibodies identified. There is a possible link to CFHR1 and CFHR3 gene deletions that increase the risk of developing these antibodies in an individual.\nDiagnostic methods\nDiagnosis is suspected on presentation of thrombotic microangiopathy with renal involvement, and the exclusion of the main differential diagnoses. Diagnosis is confirmed by genetic testing (sequencing and multiplex ligation-dependent probe amplification (MLPA), complement cascade proteins functional tests and screening for factor H auto-antibodies. Tests should evaluate C3, C4, Complement factor H, I and B, membrane cofactor protein, as well as copy number variations by MLPA in CFHR genes and their hybrids with CFH.\nDifferential diagnosis\nThe main differential diagnoses includes HUS due to Shiga toxin Escherichia coli, thrombotic thrombocytopenic purpura (both congenital and acquired type) and HUS secondary to immunological or external factors (drugs). Cobalamin C deficiency can present in a similar fashion.\nAntenatal diagnosis\nThere are no specific anatomical prenatal markers. Genetic prenatal diagnosis is theoretically possible when there is a known familial genetic risk.\nGenetic counseling\nApproximately 20-25% of cases are familial, usually with autosomal dominant patterns of predisposition. Autosomal recessive pedigrees can be seen less often. Variable penetrance in autosomal dominant pedigrees is common.\nManagement and treatment\nThe recommended first line targeted therapy is with eculizumab which blocks complement terminal pathway, thus halting endothelial damage and ensuing thrombotic microangiopathy. Eculizumab should be administered within 24 hours of presentation and is recommended as a lifelong treatment, although trials are ongoing regarding the safe discontinuation. Targeted therapy is accompanied by symptomatic support of acute renal injury by renal replacement therapy (dialysis) and red blood cell transfusions. Plasma exchange (or plasma infusion) is less effective. However, it might still have some relevance in countries with limited resources and no access to eculizumab. For anti-CFH antibody-mediated disease, immunosuppressive regimens (steroids, rituximab and cyclophosphamide) targeting auto-antibody production combined with plasma exchange are also utilized, particularly when eculizumab is unavailable. All patients on eculizumab treatment require prophylactic N. meningitits vaccination and antibiotic prophylaxis.\nPrognosis\nPrognosis is significantly improved with eculizumab treatment; however, time-to-treatment is a significant factor in recovery of renal function. Without treatment, there is a significant risk of developing end-stage kidney disease.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Michal MALINA | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Atypical hypotonia-cystinuria syndrome", "Disease Definition": "A form of hypotonia-cystinuria type 1 syndrome characterized by mild to moderate intellectual disability in addition to classic hypotonia-cystinuria syndrome phenotype (cystinuria type 1, generalised hypotonia, poor feeding, growth retardation, and minor facial dysmorphism).", "ORPHA ID": 238523, "Summary": ""}
{"Disease Name": "Atypical juvenile parkinsonism", "Disease Definition": "A complex form of young-onset Parkinson disease that manifests with pyramidal signs, eye movement abnormalities, psychiatric manifestations (depression, anxiety, drug-induced psychosis, and impulse control disorders), intellectual disability, and other neurological symptoms (such as ataxia and epilepsy) along with classical parkinsonian symptoms.", "ORPHA ID": 391411, "Summary": "Epidemiology\nTo date, only six families (from Iran, Italy, The Netherlands, Pakistan, and Turkey) have been reported.\nClinical description\nThe disease has a juvenile onset (usually in the early teens or early twenties) and manifests with pyramidal signs, dystonia, psychiatric (depression, anxiety, drug-induced psychosis, dementia, and impulse control disorders) and other neurological (such as ataxia and epilepsy) symptoms along with classical parkinsonian symptoms (bradykinesia, postural instability, rigidity, involuntary movements, dysarthria, supranuclear gaze, hypomimia, gait impairment, and myoclonic jerks). Intellectual disability is also observed.\nEtiology\nMutations in the genes ATP13A2 (1p36), PLA2G6 (22q13.1), FBXO7 (22q12.3), DNAJC6 (1p31.3), SPG11 (15q13-q15), SPG15 (14q24.1) and SYNJ1 (21q22.2) are associated with Atypical juvenile parkinsonism (AJP).\nGenetic counseling\nAJP usually occurs in an autosomal recessive manner. However, sporadic cases have also been reported and the majority of these cases are born from consanguineous parents.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Coro PAISAN-RUIZ"}
{"Disease Name": "Atypical lichen myxedematosus", "Disease Definition": "An intermediate form of lichen myxedematosus (LM) (a form of mucin dermal deposit) which does not meet the criteria for either scleromyxedema or the localized form. Three clinical subtypes have been described and include scleromyxedema without monoclonal gammopathy; localized forms with monoclonal gammopathy and/or systemic symptoms; localized forms with mixed features of the 5 subtypes of localized LM (discrete form, acral persistent papular mucinosis, self-healing papular mucinosis, papular mucinosis of infancy, and a pure nodular form). The course of atypical LM is unpredictable because only a few cases have been reported.", "ORPHA ID": 86797, "Summary": ""}
{"Disease Name": "Atypical Meigs syndrome", "Disease Definition": "A rare benign ovarian tumor characterized by a benign pelvic mass associated with right-sided pleural effusion, but without ascites. The pleural effusion resolves after resection of the tumor.", "ORPHA ID": 314466, "Summary": ""}
{"Disease Name": "Atypical Norrie disease due to Xp11.3 microdeletion", "Disease Definition": "A rare chromosomal anomaly syndrome, resulting from the partial deletion of the short arm of chromosome X, principally characterized by classical Norrie disease (bilateral, severe retinal malformations and opacity of the lens leading to congenital blindness, on occasion associated with progressive sensorineural deafness and intellectual disability), microcephaly, hypotonia, psychomotor and growth delay, moderate to severe mental handicap and disruptive behaviour. Clinical phenotype is highly variable and immunodeficiency, epilepsy and hypogonadism have also been reported.", "ORPHA ID": 261501, "Summary": ""}
{"Disease Name": "Atypical papilloma of choroid plexus", "Disease Definition": "A very rare type of choroid plexus tumor that, contrary to papilloma of the choroid plexus, has an increased likelihood of progression to carcinoma and of recurrence. It displays brisk mitoses, nuclear pleomorphism, raised cellular density, obscurity of the papillary growth pattern, and cell necrosis.", "ORPHA ID": 251902, "Summary": ""}
{"Disease Name": "Atypical progressive supranuclear palsy syndrome", "Disease Definition": "A form of progressive supranuclear palsy syndrome (PSP), a rare late-onset neurodegenerative disease, characterized by an underlying PSP-tau pathology, that does not conform to the classic presentation of PSP. The clinical phenotype is variable and comprises PSP with predominant Parkinsonism (PSP-P), PSP with progressive gait freezing (PSP-PGF), PSP with predominant corticobasal syndrome (PSP-CBS), PSP with predominant speech/language disorder (PSP-SL), PSP with predominant frontal presentation (PSP-F), PSP with predominant ocular motor dysfunction (PSP-OM), and PSP with predominant postural instability (PSP-PI).", "ORPHA ID": 99750, "Summary": ""}
{"Disease Name": "Atypical Rett syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by the presence of two or more of the main criteria for classic Rett syndrome (loss of acquired purposeful hand skills, loss of acquired spoken language, gait abnormalities, stereotypic hand movements), a period of regression followed by recovery or stabilization, and five out of eleven supportive criteria (breathing difficulties, bruxism, impaired sleep pattern, abnormal muscle tone, peripheral vasomotor disturbances, scoliosis/kyphosis, delayed growth, small cold hands and feet, inappropriate laughter or screaming spells, decreased pain sensation, and intense eye communication). Like classic Rett syndrome, it almost exclusively affects girls, while the disease course may be either milder or more severe.", "ORPHA ID": 3095, "Summary": "Epidemiology\nBased on reports that up to 32% of RTT cases show an atypical phenotype, the prevalence of atypical RTT is estimated at around 1/45,000. Like classic RTT, atypical RTT syndrome predominantly affects girls.\nClinical description\nAtypical forms may present with either a milder or more severe clinical picture than that seen in typical RTT. Several subvariants of atypical RTT have been defined. i) The early-onset seizure type (Hanefeld variant) is characterized by seizures in the first months of life with subsequent development of RTT features. ii) The congenital variant (Rolando variant) is the most severe form of atypical RTT, with onset of classic RTT features during the first three months of life. iii) The 'forme fruste' is a milder variant with onset in early childhood and an incomplete and protracted course. iv) The late childhood regression form is characterized by a normal head circumference and by a more gradual and later onset (late childhood) regression of language and motor skills. v) The preserved speech variant (PSD or Zappella variant) is marked by recovery of some verbal and manual skills.\nEtiology\nThe early-onset seizure type (Hanefeld variant) is frequently caused by mutations in the X-linked CDKL5 gene (Xp22). A translocation involving the NTNG1 gene (1p13.2-p13.1) has also been identified in a patient with early seizures and atypical RTT. The congenital variant (Rolando variant) is generally caused by mutations in the FOXG1 gene (14q11-q13). A microdeletion syndrome involving a 14q12 interstitial deletion has also been described with a similar phenotype but with the additional feature of facial dysmorphism. The preserved speech variant (PSD or Zappella variant) is caused in at least some cases by mutations in the MECP2 (Xq28) gene, which is also responsible for the majority of cases of classic RTT.\nDiagnostic methods\nDiagnosis relies on clinical evaluation using the diagnostic criteria for atypical RTT originally defined by Hagberg in 1994: an atypical case must meet at least three of the six main criteria and at least five of the eleven supportive criteria. Molecular analysis may allow confirmation of the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include Angelman syndrome, autism, cerebral palsy, inborn errors of metabolism and severe intellectual deficit (see these terms).\nGenetic counseling\nGenetic counseling should be proposed and prenatal testing is available for female relatives of an index case, who may asymptomatic due to skewed X-inactivation.\nManagement and treatment\nAt present, there is no specific cure for atypical RTT. Treatment is symptomatic and supportive. Medication may be needed for breathing irregularities, sleep disturbances (melatonin), agitation (risperidone), rigidity (carbidopa, levodopa) and motor difficulties, and antiepileptic drugs may be used to control seizures. Anti-reflux agents may also be required.\nPrognosis\nThe course of atypical Rett syndrome, including the age of onset and the severity of symptoms, varies from child to child. Despite the range of symptoms, most individuals with RTT continue to live well into middle-age and beyond.\n\n                            Last update: \n                            March 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Thierry BIENVENU"}
{"Disease Name": "Atypical teratoid rhabdoid tumor", "Disease Definition": "A rare, highly malignant central nervous system (CNS) rhabdoid tumor (RT) found almost exclusively in children.", "ORPHA ID": 99966, "Summary": "Epidemiology\nThe prevalence of ATRT is estimated to be 1- 2% among all pediatric CNS tumors and 10-20% of CNS tumors in patients less than 3 years. The age-standardized incidence rate is estimated to be 1/72,500 persons/year in Austria.\nClinical description\nOnset of primary ATRT occurs from birth to adulthood, with the highest incidence in the first 2 years of life. Only single cases have been reported in adults. Manifestations of ATRT include macrocephaly, vomiting, irritability, headache, apathy/lethargy, ataxia, neck stiffness, and seizures. ATRT can occur in the posterior fossa, fourth ventricle, cerebellar vermis (with intraventricular extension), cerebellum (alone or in combination with a supratentorial tumor), cerebral hemisphere, pineal region, frontal lobe, brainstem, spinal cord or result from metastases of renal RT. ATRT can involve the cerebellopontine angle (CPA), resulting in acute cranial nerve deficits (such as acute facial nerve palsy) as the presenting sign.\nEtiology\nThe vast majority of ATRT tumors show biallelic somatic inactivation of SMARCB1, a gene suppressor which encodes a core member of the adenosine triphosphate (ATP)-dependent SWI/SNF chromatin remodeling complex and which is a key regulator of cell proliferation and differentiation. In rare cases, mutations in the SMARCA4 gene, which encode another SWI/SNF chromatin-remodeling complex member, are observed.\nDiagnostic methods\nDiagnosis is based on imaging findings (magnetic resonance and computed tomography scan) showing large and hyperdense solid tumors with marked tumor necrosis, intratumoral hemorrhage, patchy pattern of enhancement and association with moderate to marked adjacent parenchymal edema. Intratumoral calcification may be observed. Histological examination of the tumor shows a diffuse growth pattern of predominantly polygonal cells, vesicular nuclei with prominent nucleoli, high mitotic index, multiple necrosis or cystic foci and scattered cells that contain a cytoplasmic hyaline globular inclusion adjacent to the nucleus (rhabdoid cells). ATRT may be composed only of rhabdoid cells or, more commonly, may contain areas of rhabdoid cells juxtaposed to areas of primitive neuroepithelial cells and/or mesenchymal tissue and/or epithelial tissue. Tumor cells are immunopositive for vimentin, epithelial markers (cytokeratin, epithelial membrane antigen), rarely positive for the mesenchymal marker S-100 and immunonegative for desmin, GFAP, synaptophysin and neurofilaments. Diagnosis is confirmed by loss of nuclear staining of SMARCB1 (or SMARCA4) protein by immunohistochemistry.\nDifferential diagnosis\nDifferential diagnosis includes medulloblastoma, ependymoblastoma, primitive neuroectodermal tumor, choroid plexus carcinoma, Ewing sarcoma (see these terms), undifferentiated chordoma, anaplastic meningioma and small cell sarcoma.\nGenetic counseling\nATRT can occur sporadically or as part of a RT predisposition syndrome (familial RT; see this term).\nManagement and treatment\nNo standard of care exists for ATRT. Treatment includes the maximal resection of the tumor mass and postoperatively, chemotherapy with radiotherapy as long as it is compatible with the age of the patient.\nPrognosis\nATRT is highly aggressive and the prognosis is exceedingly dismal compared with other malignant brain tumors. Reported survival times have ranged from 0.5 to 11 months, with a particularly poor outcome for infants.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Franck BOURDEAUT"}
{"Disease Name": "Atypical Werner syndrome", "Disease Definition": "An heterogeneous group of cases that are clinically diagnosed as Werner syndrome (WS) but do not carry WRN gene mutations. Similar to classical WS caused by WRN mutations, patients generally exhibit an aged appearance and common age-related disorders at earlier ages compared to the general population.", "ORPHA ID": 79474, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nAtypical WS shows accelerated aging characterized by short stature, thinning/graying of hair, a ''bird-like'' facial appearance, skin atrophy, lipodystrophy, myopathy along with other age-related disorders such as osteoporosis and atherosclerosis. Compared to WS, it has an earlier age of onset (early 20s or earlier) and a more rapid rate of progression. Cataracts are often not present.\nEtiology\nA subset of atypical WS is caused by the mutation of the LMNA gene, the same causal gene seen in Hutchinson-Gilford progeria syndrome (HGPS; see this term) that codes for the nuclear intermediate filament, lamin A/C. The LMNA type of atypical WS follows an autosomal dominant pattern of inheritance. Additional causes of atypical WS are being discovered, and their inheritance patterns elucidated.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Fuki HISAMA  - Dr George MARTIN  - Dr Junko OSHIMA"}
{"Disease Name": "Audiogenic seizures", "Disease Definition": "A rare neurologic disease characterized by seizures that are triggered by acoustic stimulation, which can be simple (as in startle epilepsy) or complex (e.g. musicogenic seizures, seizures triggered by the voice).", "ORPHA ID": 166415, "Summary": ""}
{"Disease Name": "Auditory neuropathy-optic atrophy syndrome", "Disease Definition": "A rare mitochondrial disease characterized by bilateral auditory neuropathy and optic atrophy. Patients present hearing and visual impairment in the first or second decade of life, while psychomotor development is normal. Bilateral retinitis pigmentosa has been reported in association.", "ORPHA ID": 542585, "Summary": ""}
{"Disease Name": "Auricular abnormalities-cleft lip with or without cleft palate-ocular abnormalities syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of auricular abnormalities (such as external ear abnormalities and postauricular pits) and cleft lip with or without cleft palate. Additional manifestations include myopia, nystagmus, and retinal pigment abnormalities.", "ORPHA ID": 77300, "Summary": ""}
{"Disease Name": "Auriculocondylar syndrome", "Disease Definition": "A rare, genetic dysostosis with predominant craniofacial involvement characterized by bilateral external ear malformations, mandibular condyle hypoplasia, microstomia, micrognathia, microglossia and facial asymmetry. Additional manifestations include hypotonia, ptosis, cleft palate, full cheeks, developmental delay, hearing impairment and respiratory distress. Significant intra- and interfamilial phenotypic variation has been reported.", "ORPHA ID": 137888, "Summary": ""}
{"Disease Name": "Auriculoosteodysplasia", "Disease Definition": "A very rare condition characterized by multiple osseous dysplasia, characteristic ear shape (elongation of the lobe that is attached and accompanied by a small, slightly posterior lobule) and somewhat short stature.", "ORPHA ID": 114, "Summary": "Epidemiology\nThe disorder has been observed in numerous members of two families.\nClinical description\nDysplasia of the radiocapitellar joint was a constant finding in all affected individuals.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            March 2008"}
{"Disease Name": "Autism spectrum disorder due to AUTS2 deficiency", "Disease Definition": "A rare genetic syndromic intellectual disability characterized by global developmental delay and borderline to severe intellectual disability, autism spectrum disorder with obsessive behavior, stereotypies, hyperactivity but frequently friendly and affable personality, feeding difficulties, short stature, muscular hypotonia, microcephaly, characteristic dysmorphic features (hypertelorism, high arched eyebrows, ptosis, deep and/or broad nasal bridge, broad/prominent nasal tip, short and/or upturned philtrum, narrow mouth, and micrognathia), and skeletal anomalies (kyphosis and/or scoliosis, arthrogryposis, slender habitus and extremities). Other clinical features may include hernias, congenital heart defects, cryptorchidism and seizures.", "ORPHA ID": 352490, "Summary": ""}
{"Disease Name": "Autism spectrum disorder-epilepsy-arthrogryposis syndrome", "Disease Definition": "A form of congenital disorders of N-linked glycosylation characterized by distal arthrogryposis (mild flexion contractures of the fingers, deviation of the distal phalanges, swan-neck deformity), retromicrognathia, general muscle hypotonia, delayed psychomotor development, autism spectrum disorder (speech delay, abnormal use of speech, difficulties in initiating, understanding and maintaining social interaction, limited non-verbal communication and repetitive behavior), seizures, microcephaly and mild to moderate intellectual disability that becomes apparent with age.", "ORPHA ID": 370943, "Summary": ""}
{"Disease Name": "Autism-epilepsy syndrome due to branched chain ketoacid dehydrogenase kinase deficiency", "Disease Definition": "A rare disorder of branched-chain amino acid metabolism characterized by childhood-onset epilepsy, autism and intellectual disability with reduced levels of plasma branched chain aminoacids.", "ORPHA ID": 308410, "Summary": ""}
{"Disease Name": "Autoerythrocyte sensitization syndrome", "Disease Definition": "A rare autoimmune disease with skin involvement characterized by recurrent episodes with isolated or multiple painful edematous inflammatory skin lesions progressing to ecchymoses within 24 hours, due to autosensitization to a stromal component of the patient's own erythrocytes. The development of the lesions is usually preceded by emotional or physical stress, followed by a prodromal stage with fatigue or malaise. Lower limbs and trunk are the most frequently involved sites. Accompanying features may include fever, arthralgia, myalgia, headache, gastrointestinal problems, or hematuria and epistaxis, among others. The disease occurs predominantly in women.", "ORPHA ID": 324636, "Summary": ""}
{"Disease Name": "Autoimmune encephalopathy with parasomnia and obstructive sleep apnea", "Disease Definition": "A rare neurologic disorder characterized by a unique non-REM and REM parasomnia with sleep breathing dysfunction, gait instability and repetitive episodes of respiratory insufficiency, as well as autoantibodies against IgLON5. Patients may present stridor, chorea, limb ataxia, abnormal ocular movements, and bulbar symptoms (i.e. dysphagia, dysarthria, episodic central hypoventilation) with normal brain MRI. Excessive day sleepiness and cognitive deterioration have also been reported.", "ORPHA ID": 420789, "Summary": ""}
{"Disease Name": "Autoimmune hemolytic anemia, cold type", "Disease Definition": "Cold autoimmune hemolytic anemia comprises two types of autoimmune hemolytic anemia (AIHA; see this term) defined by the presence of cold autoantibodies (autoantibodies which are active at temperatures below 30°C): cold agglutinin disease (CAD), which is the more common, and paroxysmal cold hemoglobinuria (PCH; see these terms).", "ORPHA ID": 228312, "Summary": "Clinical description\nCAD is more common in people over the age of 55 years, while PCH typically presents in young children.\nEtiology\nCAD is caused by IgM autoantibodies while PCH is caused by an IgG immunoglobulin.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Marc MICHEL"}
{"Disease Name": "Autoimmune hemolytic anemia, warm type", "Disease Definition": "Warm autoimmune hemolytic anemia is the most common form of autoimmune hemolytic anemia (see this term) defined by the presence of warm autoantibodies against red blood cells (autoantibodies that are active at temperatures between 37-40°C).", "ORPHA ID": 90033, "Summary": "Epidemiology\nWarm auto-antibodies are responsible for 60/70% of AIHA, whose annual incidence is estimated to be between 1/35,000-1/80,000 in North America and Western Europe.\nClinical description\nWarm AIHA is more common in women (female to male ratio approximately 2:1 in adults). The disease is characterized by symptoms due to the anemia including fatigue, exertional dyspnea, and, more rarely, jaundice and dark urine in case of severe hemolysis. If the disease is severe, fever, chest pain, syncope or heart failure may occur. Hemolysis occurs mainly in the spleen, so mild splenomegaly is relatively common.\nEtiology\nApproximately half of cases of warm AIHA are primary (idiopathic) while the other half are secondary to an underlying condition, frequently chronic lymphocytic leukemia or an autoimmune systemic disease such as systemic lupus erythematosus (SLE; see this term).\nDiagnostic methods\nDiagnosis is based on clinical and laboratory evidence of hemolytic anemia and the detection of autoantibodies with the direct anti-globulin test (DAT). Typically in warm AIHA, the DAT pattern is IgG alone or IgG with complement C3.\nDifferential diagnosis\nThe differential diagnosis of warm AIHA includes a post-transfusional alloimmune hemolytic anemia and, when the DAT is negative (less than 5% of all warm AIHAs), every other cause of either hereditary or acquired hemolytic anemia.\nManagement and treatment\nThe most common therapy and the cornerstone of treatment for warm AIHA are corticosteroids. If these are ineffective, splenectomy can be considered. Rituximab has become an option in refractory disease and the use of immunosuppressors can be helpful in chronic severe refractory cases.\nPrognosis\nWarm AIHA is often severe but death is usually a rare outcome, except in elderly patients who have a higher risk of cardiovascular manifestations (in cases with severe anemia) and also of severe treatment-induced infections. Prognosis depends on the underlying condition.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Marc MICHEL"}
{"Disease Name": "Autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome due to TPP2 deficiency", "Disease Definition": "A rare genetic immune disease characterized by infantile or childhood onset of combined immunodeficiency with recurrent viral, bacterial, and fungal infections, severe autoimmunity mainly manifesting as antibody-mediated destruction of red blood cells, platelets, and neutrophils, and mild to moderate developmental delay. Laboratory findings include decreased circulating T-, B-, and natural killer cells, and hypergammaglobulinemia.", "ORPHA ID": 444463, "Summary": ""}
{"Disease Name": "Autoimmune hemolytic anemia", "Disease Definition": "A rare, autoimmune disorder in which various types of auto-antibodies are directed against red blood cells causing their survival to be shortened and resulting in hemolytic anemia.", "ORPHA ID": 98375, "Summary": "Epidemiology\nThe annual incidence of AIHA is estimated at 1/35,000-1/80,000 in North America and Western Europe. Warm autoantibodies (active at temperatures between 37-40°C) cause 60-70% of cases, cold autoantibodies (active at temperatures below 30°C) account for 13-15% of cases, mixed type occurs in less than 10% of cases and the annual incidence of drug-induced AIHA is estimated at 1/1,000,000.\nClinical description\nThe disease can appear at any age and there is a slight predominance of cases in females (60%). AIHA is characterized by hemolytic anemia, which is most often revealed by an unusual weakness and fatigue with tachycardia and exertional dyspnea, and also in some cases by jaundice, dark urine and/or splenomegaly.\nEtiology\nAIHA can be primary (idiopathic), secondary to infection or associated with diseases such as B-cell lymphomas, other systemic or organ-specific autoimmune diseases, Hodgkin's disease, hepatitis or primary immunodeficiencies, or, in the case of drug-induced AIHA, caused by a reaction to drugs. The condition may develop gradually or occur suddenly. There are different subtypes of AIHA according to the temperature reactivity of the autoantibody: warm AIHA, cold AIHA (which includes cold agglutinin disease, CAD and paroxysmal cold hemoglobinuria or PCH), mixed-type AIHA and drug-induced AIHA (see these terms). Half of warm AIHA cases are idiopathic whereas almost all cold AIHA are secondary.\nDiagnostic methods\nDiagnosis is based on clinical or laboratory evidence of hemolysis and the detection of autoantibodies by means of the direct anti-globulin test (DAT).\nDifferential diagnosis\nBiological differential diagnoses include other non-autoimmune causes of hemolytic anemia.\nManagement and treatment\nTreatment is dependent on correct diagnosis. Cases of drug-induced AIHA should be investigated to determine if stopping a drug will induce remission. For warm AIHAs, corticosteroids are used, followed by splenectomy if necessary. Some targeted therapies, such as rituximab (anti-CD20 monoclonal antibody), have shown promising results. Other immunosuppressive treatments may be suggested. For cold AIHA, keeping the patient warm may be sufficient, and corticosteroids and splenectomy must be avoided as they are known to be ineffective. Rituximab has been demonstrated as a relatively effective and safe option for treating patients with symptomatic chronic cold agglutinin disease. Transfusion may be necessary in cases with inadequate response to therapy and life-threatening worsening anemia. However, transfusion can be complicated because of the presence of the autoantibodies, which can, in addition, increase destruction of the donor red blood cells.\nPrognosis\nPrognosis depends on the underlying cause of the disease and whether symptoms are managed appropriately and in a timely manner, but death is a rare outcome.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Marc MICHEL"}
{"Disease Name": "Autoimmune hepatitis type 1", "Disease Definition": "A form of autoimmune hepatitis characterized by clinical presentation as cryptogenic hepatitis, interface hepatitis on histological examination, elevated serum aminotransferase levels, hypergammaglobulinemia/elevated immunoglobulin G, and presence of circulating autoantibodies, specifically antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), and/or anti-soluble liver antigen/liver pancreas antigen antibodies (anti-SLA/LP). The disease predominantly develops at a post-pubertal age and most commonly takes a chronic course, although acute or acute severe presentation may also be observed. Typical concurrent autoimmune diseases are autoimmune thyroiditis and rheumatic diseases.", "ORPHA ID": 563576, "Summary": ""}
{"Disease Name": "Autoimmune hepatitis type 2", "Disease Definition": "A form of autoimmune hepatitis characterized by clinical presentation as cryptogenic hepatitis, interface hepatitis on histological examination, elevated serum aminotransferase levels, hypergammaglobulinemia/elevated immunoglobulin G, and presence of circulating autoantibodies, specifically antibodies to liver kidney microsome type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) antibodies. The disease typically manifests in childhood or adolescence with an acute onset, often with acute liver failure. Long-term immunosuppression is usually required. Reported concurrent autoimmune diseases are autoimmune thyroiditis, diabetes mellitus, and vitiligo.", "ORPHA ID": 563581, "Summary": ""}
{"Disease Name": "Autoimmune hepatitis", "Disease Definition": "A rare liver disease characterized by immune-mediated, acute or chronic liver inflammation, clinically presenting as cryptogenic hepatitis, with interface hepatitis on histological examination, elevated serum aminotransferase levels, and hypergammaglobulinemia / elevated immunoglobulin G, in the presence or absence of specific circulating autoantibodies. Patients may be asymptomatic, chronically ill, or present with acute liver failure. Concurrent autoimmune diseases are frequently observed.", "ORPHA ID": 2137, "Summary": "Epidemiology\nThe incidence and prevalence of autoimmune hepatitis (AIH) varies across different age groups, ethnicities and geographical region. In Caucasian Europeans and North Americans, the prevalence is approximately 1/6,000. Although possibly under recognized, a lower occurrence is reported in Asian countries. All ages and both genders may be affected, although there is a clear female preponderance.\nClinical description\nThe disease occurs in both pediatric and adult patients. Presentation is highly variable; approximately 25% of patients present with an acute onset or an acute- on-chronic disease process. A subset has severe disease at presentation and may rapidly progress to liver failure. The most common clinical phenotype (two-thirds of patients) is characterized by an insidious onset either without any apparent symptom or with non-specific symptoms (including fatigue, general ill health, right upper quadrant pain, lethargy, malaise, anorexia, weight loss, nausea, pruritus, fluctuating jaundice and polyarthralgia of the small joints without arthritis). Half of patients have liver fibrosis at diagnosis, and one third have cirrhosis irrespective of the presence of symptoms. AIH subtypes are classed based on presence of auto-antibodies. AIH type 1 accounts for 90% of cases, occurs at any age and is defined by detection of either antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), or anti-soluble liver antigen/liver pancreas antigen antibodies (anti-SLA/LP). AIH type 2 is defined by the presence of anti-liver kidney microsome type 1 (anti-LKM1), anti-liver cytosol (anti-LC1) and, rarely, anti-liver-kidney microsomal antibody type 3 (anti-LKM3), onset is in childhood or young adulthood, and is typically of severe acute disease with frequent failure of treatment and frequent relapses after steroid withdrawal. Antibodies may be absent in up to one third of patients, particularly in severe, acute AIH, and is defined as seronegative AIH. Concurrent autoimmune or immune-mediated diseases in the patient are common.\nEtiology\nEnvironmental factors, genetic susceptibility, and impaired immunoregulatory networks are thought to play a role.\nDiagnostic methods\nAIH should be considered in any patient with acute or chronic liver disease. Diagnosis is very challenging, and is based in diagnostic scores comprised of typical, but mostly non-specific, findings of autoantibodies (for which testing is not currently standardized), hypergammaglobulinemia/elevated IgG, histological pattern of interface hepatitis, exclusion of other liver diseases and, eventually, the treatment response to steroids.\nDifferential diagnosis\nThe differential diagnosis is of other causes of acute or chronic liver failure such as the rare disorder Wilson disease as well as viral hepatitis, hepatotoxic drugs, and excessive alcohol consumption.\nManagement and treatment\nThe standard treatment is with a steroid-based induction and followed by thiopurine-based maintenance regime (typically prednisolone and azathioprine). Immunosuppressive treatment tends to be life-long. The aim of treatment is complete biochemical remission defined as normalized liver enzymes and gammaglobulins / IgG. Some patients require second- or third-line treatment due to intolerance or insufficient response to standard treatment. Repeated liver histology can be used to guide therapy. Therapy withdrawal can be considered where patients have stable biochemical remission for at least 24-36 months; however, relapses are common. Untreated autoimmune hepatitis can lead to cirrhosis, complications of cirrhosis, and eventually to liver failure.\nPrognosis\nMorbidity largely relates to treatment side effects. The risk of mortality is determined by disease progression to liver cirrhosis under insufficient treatment response and by acute severe presentation. Patients with AIH-onset under the age of 18 seem to be more prone to recurrent flares.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Marcial SEBODE | RARE-LIVER*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autoimmune hypoparathyroidism", "Disease Definition": "A rare parathyroid disease and phosphocalcic metabolism anomaly characterized by hypocalcemia, hyperphosphatemia, hypercalciuria, and low serum parathyroid hormone levels, in the presence of autoantibodies against parathyroid tissue. Clinical signs and symptoms are of variable severity and include paresthesia, seizures, laryngospasm, tetany, cardiac dysrhythmias, calcifications of the basal ganglia, and neuropsychological manifestations such as anxiety, depression, confusion, or hallucination. The condition may occur as an isolated disease or in association with other autoimmune diseases.", "ORPHA ID": 36913, "Summary": ""}
{"Disease Name": "Autoimmune interstitial lung disease-arthritis syndrome", "Disease Definition": "A rare genetic systemic or rheumatologic disease characterized by interstitial lung disease (often with pulmonary hemorrhage) and inflammatory arthritis, associated with high-titer autoantibodies (including anti-nuclear and anti-neutrophil cytoplasmic antibodies, and rheumatoid factor). Patients present from infancy to adolescence with tachypnea, cough, hemoptysis, and/or joint pain. Some patients may also develop glomerular disease.", "ORPHA ID": 444092, "Summary": ""}
{"Disease Name": "Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency", "Disease Definition": "A rare, primary immunodeficiency characterized by variable combination of enteropathy, hypogammaglobulinemia, recurrent respiratory infections, granulomatous lymphocytic interstitial lung disease, lymphocytic infiltration of non-lymphoid organs (intestine, lung, brain, bone marrow, kidney), autoimmune thrombocytopenia or neutropenia, autoimmune hemolytic anemia and lymphadenopathy.", "ORPHA ID": 436159, "Summary": ""}
{"Disease Name": "Autoimmune lymphoproliferative syndrome-recurrent viral infections due to CASP8 deficiency", "Disease Definition": "A rare genetic disorder characterized by lymphadenopathy and/or splenomegaly and recurrent infections due to herpes viruses.", "ORPHA ID": 275517, "Summary": "Epidemiology\nPrevalence of this disorder is not known. It is extremely rare with four individuals in one family identified to date.\nClinical description\nDevelopment is reported to be normal in affected patients. Clinical signs include lymphadenopathy and splenomegaly, and development of recurrent sinopulmonary and significant mucocutaneous infections with the Herpes zoster and Herpes simplex viruses. Patients are also poorly responsive to immunization and seem to benefit from IVIG supplementation.\nEtiology\nThe disorder is caused by germline homozygous mutations in the CASP8 gene (2q33-q34) involved in the execution phase of cell apoptosis. Carriers with a normal copy of the gene are asymptomatic.\nDiagnostic methods\nBiologically, autoimmune lymphoproliferative syndrome with recurrent viral infections is characterized by slightly elevated double-negative T cells (DNTs), and defective Fas-mediated apoptosis of B, T, and NK lymphocytes.\nGenetic counseling\nThe pattern of inheritance appears to be autosomal recessive.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Koneti RAO"}
{"Disease Name": "Autoimmune lymphoproliferative syndrome", "Disease Definition": "A rare, inherited disorder characterized by non-malignant lymphoproliferation, multilineage cytopenias, and a lifelong increased risk of Hodgkin's and non-Hodgkin's lymphoma.", "ORPHA ID": 3261, "Summary": "Epidemiology\nThe prevalence of ALPS is unknown. It has been characterized in more than 500 patients to date and has been reported worldwide in various ethnic groups.\nClinical description\nALPS is clinically heterogeneous with the following primary clinical signs: lymphoproliferation, manifesting as lymphadenopathy and hepatosplenomegaly with or without hypersplenism, often improving with age, autoimmune disease, mostly involving blood cells, and an increased risk of lymphoma lifelong. Many patients develop non-malignant lymphoproliferation during the first years of life. Clinical manifestations of autoimmunity in the form of hemolytic anemia, thrombocytopenia, neutropenia, or autoimmune hepatitis are of variable severity but these signs are often absent at the time of diagnosis. Autoimmunity has been reported to potentially affect almost any organ, leading to uveitis, pulmonary fibrosis, gastritis, colitis, nephritis, urticaria, arthritis, or rarely autoimmune neurological complications. The disease course is also variable. Several genetic subtypes based on the causative genes and types of mutations have been proposed and result in often similar clinical presentations and outcomes. These include ALPS-FAS, ALPS-FASLG (FASgene), ALPS-CASP10 (CASP10), and ALPS-U (undetermined genetic defect).\nEtiology\nALPS is caused by defective lymphocyte homeostasis. Germline mutations in the FAS (10q24.1), FASLG (1q23), or CASP10 (2q33-q34) genes are known to be associated with ALPS. 75% of cases are associated with heterozygous mutations in FAS. The second largest group (10%) has somatic mutations in FAS, while CASP10 (2-3%) and FASLG (<1%) mutations are extremely rarely reported. Some patients do not have mutations in any of these genes (ALPS-U). More recently one case of an ALPS-like disorder due to mutation in the PRKCD gene (3p21.31) was reported. This patient however did not have elevated DNT cells and hence does not fit the diagnostic criteria.\nDiagnostic methods\nDiagnosis is based on clinical, laboratory and genetic findings. A definitive diagnosis is established in the presence of both of the required diagnostic criteria, i.e. chronic non-malignant, non-infectious lymphadenopathy and/or splenomegalyand elevated TCR alpha/beta-double-negative T cells (DNTs) with normal or elevated lymphocyte counts, along with one primary accessory criterion, including defective lymphocyte apoptosis, and germline or somatic mutations in FAS, FASLG or CASP10.\nGenetic counseling\nDepending on the specific genetic mutation, inheritance may be autosomal dominant or autosomal recessive.\nManagement and treatment\nSome patients may require chronic immunosuppressive therapies with sirolimus and mycophenolate mofetil.\nPrognosis\nThe prognosis for ALPS patients remains guarded. ALPS-FAS patients have a significantly increased risk of non-Hodgkin's and Hodgkin's lymphoma which can occur at any age and responds to conventional chemotherapy.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Koneti RAO"}
{"Disease Name": "Autoimmune pancreatitis type 1", "Disease Definition": "Type 1 autoimmune pancreatitis is a form of autoimmune pancreatitis seen in elderly males (>60 years) and presenting with abdominal pain, steatorrhea, obstructive jaundice and other organ (bile duct, kidneys and retroperitoneum) involvement. It is thought to be due to an immunoglobulin G4 (IgG4)-associated systemic disease.", "ORPHA ID": 280302, "Summary": ""}
{"Disease Name": "Autoimmune pancreatitis type 2", "Disease Definition": "Type 2 autoimmune pancreatitis is a form of autoimmune pancreatitis (see this term) affecting both sexes and having a younger age of onset (<60 years) and presenting with abdominal pain, steatorrhea and obstructive jaundice.", "ORPHA ID": 280315, "Summary": ""}
{"Disease Name": "Autoimmune pancreatitis", "Disease Definition": "A rare pancreatic disease characterized by chronic non-alcoholic pancreatitis that presents with abdominal pain, steatorrhea, obstructive jaundice and responds well to steroid therapy and is seen in two subforms: type 1, which affects elderly males, involves other organs and has increased immunoglobin G4 (IgG4) levels and type 2, which affects both sexes equally but presents at a younger age and has no other organ involvement or increased IgG4 levels.", "ORPHA ID": 103919, "Summary": ""}
{"Disease Name": "Autoimmune polyendocrinopathy type 1", "Disease Definition": "A rare, genetic, disease that manifests in childhood or early adolescence with a combination of chronic mucocutaneous candidiasis, hypoparathyroidism and autoimmune adrenal failure.", "ORPHA ID": 3453, "Summary": "Epidemiology\nIt is a rare disease that is more common in populations with higher rates of consanguineous marriage and, because of a founder effect, in Finland where the prevalence is estimated at 1/25,000. In the north-west of France the prevalence is estimated at 1/500,000.\nClinical description\nThe first manifestation of the disease (usually candidiasis) occurs in childhood with other manifestations appearing progressively. Candidiasis affects particularly the mucosa of the mouth, nails and, more rarely, the genitals, and rarely causes cutaneous effects. The most common autoimmune endocrine involvement is hypoparathyroidism (79-96% of cases). Adrenal failure most often manifests with concurrent mineralocorticoid and glucocorticoid deficiency (78% of cases). Ovarian failure is possible. Diabetes type 1, autoimmune thyroiditis, and lymphocytic hypophysitis are rarer. Other auto-immune manifestations are common: intestinal malabsorption, atrophic gastritis, autoimmune hepatitis, alopecia, vitiligo, hypoplasia of dental enamel, ungual dystrophy, keratoconjunctivitis, and rheumatologic, bony, muscular, renal, bronchiol and hematologic impairments. Splenic atrophy increases the likelihood for severe infections. There is high phenotypic variability, sometimes within the same family, and the number of manifestations is very variable, ranging from 1 to 10.\nEtiology\nThe disease is caused by mutations of the AIRE gene (21q22.3) coding for the AIRE transcription factor, which is involved in immune tolerance mechanisms and contributes to the negative selection of autoreactive T lymphocytes in the thymus, lymph nodes and spleen.\nDiagnostic methods\nDiagnosis is based on the presence of at least two of the three following pathologies: mucocutaneous candidiasis, hypoparathyroidism and adrenal failure. In cases where one of the patient's siblings is affected, one of the three criteria is sufficient for initial diagnosis, which can then be confirmed by molecular analysis. The presence of a litany of antibodies, specifically organ antibodies (sometimes forewarning of a visceral attack) or more general antibodies (anti-interferon AC) can support the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include IPEX syndrome and, principally, autoimmune polyendocrinopathy type 2 (see these terms).\nGenetic counseling\nTransmission is autosomal recessive. Although prenatal diagnosis is not recommended, genetic counseling should be offered.\nManagement and treatment\nManagement is essentially symptomatic. Hormone replacement is used to treat endocrine disorders. A long course of oral systemic antifungal treatment is effective to treat candidiasis, although some patients remain resistant. Immunosuppressive treatment is recommended for cases with autoimmune hepatitis or with severe malabsorption.\nPrognosis\nThe prognosis is variable. The more early the manifestations appear, the more numerous the organs involved. The prognosis can be threatened by: oral or esophageal squamous cell carcinoma, sepsis, fulminant hepatitis, renal failure due to interstitial nephritis or bronchial involvement. On average patients live into their forties, but this varies considerably between patients depending on the severity of disorders.\n\n                            Last update: \n                            February 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Emmanuelle PROUST-LEMOINE  - Pr Jean-Louis WEMEAU"}
{"Disease Name": "Autoimmune polyendocrinopathy type 2", "Disease Definition": "A rare, endocrine disease characterized by autoimmune Addison disease associated with autoimmune thyroid disease or type I diabetes mellitus, or both, and without chronic candidiasis. Additional endocrine (hypogonadism, hypoparathyroidism) and non-endocrine diseases (vitiligo, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, and myasthenia gravies) may be present.", "ORPHA ID": 3143, "Summary": ""}
{"Disease Name": "Autoimmune polyendocrinopathy type 3", "Disease Definition": "A rare, endocrine disease characterized by autoimmune thyroid disease associated with at least one other autoimmune disease, such as type I diabetes mellitus, chronic atrophic gastritis, pernicious anemia, vitiligo, alopecia, or myasthenia gravis, but excluding Addison disease.", "ORPHA ID": 227982, "Summary": ""}
{"Disease Name": "Autoimmune polyendocrinopathy type 4", "Disease Definition": "A rare autoimmune polyendocrinopathy characterized by autoimmune activity against an endocrine organ in combination with at least one more endocrine or non-endocrine organ. Typical autoimmune diseases occurring in this type include insulin-requiring diabetes, pernicious anemia, alopecia, vitiligo, or myasthenia gravis, but not Addison disease, thyroid disease, or hypoparathyroidism.", "ORPHA ID": 227990, "Summary": ""}
{"Disease Name": "Autoimmune polyendocrinopathy", "Disease Definition": "A group of rare endocrine diseases characterized by autoimmune activity against more than one endocrine organ, with possible additional involvement of non-endocrine organs. Autoimmunity is typically directed against different target antigens in different tissues. The two more common autoimmune polyendocrine syndromes (APS), APS type 1 and type 2, have a strong genetic background and have Addison's disease as a major feature. The group furthermore includes APS type 3 and type 4.", "ORPHA ID": 282196, "Summary": ""}
{"Disease Name": "Autoimmune pulmonary alveolar proteinosis", "Disease Definition": "A rare primary interstitial lung disease characterized by the accumulation of lipids and proteins related to surfactant in the alveoli in association with the presence of antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). The disease leads to a progressive impairment of gas exchange and respiratory insufficiency.", "ORPHA ID": 747, "Summary": "Epidemiology\nThe prevalence of autoimmune pulmonary alveolar proteinosis (aPAP) ranges from 1/38,000 in Japan to 1/150,000 in the United States, although the latter figure is likely an underestimate due to underdiagnosis.\nClinical description\nPatients are usually 20 to 50 years of age at presentation (although earlier presentation is possible) and onset is mostly gradual. Some patients have very mild or even no clinical manifestations of the disease (one third of cases). The clinical course is variable with some patients spontaneously improving, others remaining stable and a subset progressing in severity. Symptoms may include fatigue, malaise, weight loss, progressive and exertional dyspnea, persistent cough (dry or productive), and chest discomfort. Pulmonary hypertension and hemoptysis are rarely reported. The lower and rear lung regions are most commonly affected. The main complication is chronic respiratory insufficiency with cor pulmonale, lung infections, and more rarely pulmonary fibrosis.\nEtiology\nGM-CSF is required to stimulate and maintain alveolar macrophage differentiation and function, particularly to catabolize and remove surfactant from the alveolar space. Dysfunction of GM-CSF signaling mediated by GM-CSF autoantibodies results in abnormal surfactant accumulation, leading to the clinical respiratory manifestations of the disease. Dust and fume inhalation also seem to be associated with the development of aPAP. A large proportion of patients have a history of smoking.\nDiagnostic methods\nThe disease is generally suspected on the basis of the clinical signs and disease history. High resolution computed tomography with crazy-paving pattern is supportive. Bronchoalveolar lavage (BAL) is the primary diagnostic method on suspicion of the disorder. Positive periodic acid-Schiff (PAS) staining on BAL is required for diagnosis. In serum, elevated autoantibody concentrations against GM-CSF confirms diagnosis. Transbronchial lung biopsy shows alveoli filled with non-foamy surfactant. Surgical lung biopsy is rarely required to confirm diagnosis. Chest X-ray is useful as follow-up investigation.\nDifferential diagnosis\nDifferential diagnoses include alveolar filling syndromes, like diffuse alveolar hemorrhage and lung edema, as well as infectious diseases (pneumocystis jrovecii pneumonia) and lung cancer.\nManagement and treatment\nTreatment depends on the severity of the clinical manifestations. Whole-lung lavage to remove lipoproteinaceous material from the lungs is the therapy of choice and generally has a good success rate. Inhaled and systemic GM-CSF has proven to be beneficial in up to two-thirds of patients. B-lymphocyte depletion through rituximab administration also seems to be a valid option for aPAP. In particular, the latter treatment is still experimental. Patients with a severe course and respiratory failure may be candidates for lung transplantation.\nPrognosis\nPrognosis has improved with introduction of whole lung lavage and is now considered excellent in most, but not all cases.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Matthias GRIESE | ERN-LUNG*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation", "Disease Definition": "A rare, mixed autoinflammatory and autoimmune syndrome disorder characterized by recurrent neutrophilic blistering skin lesions, arthralgia, ocular inflammation, inflammatory bowel disease, absence of autoantibodies, and mild immunodeficiency manifested by recurrent sinopulmonary infections and deficiency of circulating antibodies. Inflammatory phenotype is not provoked by cold temperatures.", "ORPHA ID": 324530, "Summary": ""}
{"Disease Name": "Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis", "Disease Definition": "A rare, genetic, mixed autoinflammatory and autoimmune syndrome characterized by chronic systemic autoinflammation (presenting as recurrent fever in the neonatal or infantile period) and combined immunodeficiency (manifesting as recurrent viral and invasive bacterial infections). Muscular amylopectinosis may be subclinical or be complicated by myopathy/cardiomyopathy.", "ORPHA ID": 329173, "Summary": ""}
{"Disease Name": "Autosomal agammaglobulinemia", "Disease Definition": "A rare form of agammaglobulinemia, a primary immunodeficiency disease, and is characterized by variable immune dysfunction with frequent and recurrent bacterial infections and/or chronic diarrhea.", "ORPHA ID": 33110, "Summary": "Epidemiology\nFewer than 100 cases of autosomal inherited agammaglobulinemia have been reported to date.\nClinical description\nPatients with autosomal agammaglobulinemia are not able produce adequate amounts of immunoglobulins (Ig) and are therefore at increased risk of developing infections. They often come to medical attention with a dramatic infection at less than 2 years of age. Sepsis, meningitis, pneumonia with empyema, pyoderma (associated with neutropenia), severe diarrhea and enteroviral infection are common. They are generally healthy between episodes of infection. Age of onset is variable but infections generally develop from six months of age. Common clinical signs include upper respiratory tract infections with otitis and sinusitis, and lower respiratory tract infections with pneumonia and bronchiolitis, as well as gastrointestinal tract infections such as gastroenteritis. Less common manifestations include sepsis, meningitis, septic arthritis, osteomyelitis, and pyoderma. Severe bacterial infections with lung or CNS involvement may cause serious morbidity or be life-threatening. Associated autoimmune disorders and neurological complications are also found in some cases.\nEtiology\nThe disorder is due to mutations in various genes involved in humoral immunity, including: IGHM (14q32.33), BLNK (10q23.2-q23.33), CD79A (19q13.2), CD79B (17q23), IGLL1 (22q11.23), PIK3R1 (5q13.1) and TCF3 (19p13.3) Common causative microorganisms include Streptococcus pneumonia, Haemophilus influenza, Staphylococcus aureus, Salmonella spp and Giardia spp and enterovirus.\nDiagnostic methods\nDiagnosis is suspected on the basis of early susceptibility to severe recurrent or persistent infections. particularly if the parents are consanguineous or belong to an isolated population. Abnormal laboratory parameters include low immunoglobulin levels and low or absent peripheral blood mature B lymphocyte counts. Molecular genetic testing should be performed to determine the genetic defect and to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include X-linked agammaglobulinemia in male patients, myelodysplasia or congenital infections.\nGenetic counseling\nIn patients with this form of agammaglobulinemia, autosomal recessive transmission is more common than autosomal dominant transmission. Genetic counseling should be provided to affected families.\nManagement and treatment\nThere is no curative treatment but good disease control can be achieved through consistent gammaglobulin therapy. This can be given intravenously (400-600 mg/kg every 3 to 4 weeks) or subcutaneously (100 mg/kg every week). Therapy should be started as early as possible. Some immunologists advocate chronic prophylactic antibiotics and treatment of acute infections should be prolonged and at maximal doses of antibiotics.\nPrognosis\nThe prognosis depends on the age at diagnosis, compliance with therapy and the development of complications. Most patients on treatment can lead a normal life.\n\n                            Last update: \n                            December 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Marie Ellen CONLEY"}
{"Disease Name": "Autosomal dominant adult-onset proximal spinal muscular atrophy", "Disease Definition": "A rare, genetic, motor neuron disease characterized by adulthood-onset of slowly progressive, proximal muscular weakness with fasciculations, amyotrophy, cramps, and absent/hypoactive reflexes, without bulbar or pyramidal involvement.", "ORPHA ID": 209335, "Summary": ""}
{"Disease Name": "Autosomal dominant aplasia and myelodysplasia", "Disease Definition": "A rare, genetic, hematologic disorder characterized by bone marrow failure which manifests with aplastic anemia and/or myelodysplasia, associated with hearing/ear abnormalities (such as deafness, labyrinthitis), inherited in an autosomal dominant manner.", "ORPHA ID": 314399, "Summary": ""}
{"Disease Name": "Autosomal dominant brachyolmia", "Disease Definition": "A relatively severe form of brachyolmia, a group of rare genetic skeletal disorders, characterized by short-trunked short stature, platyspondyly and kyphoscoliosis. Degenerative joint disease (osteoarthropathy) in the spine, large joints and interphalangeal joints becomes manifest in adulthood.", "ORPHA ID": 93304, "Summary": "Epidemiology\nThe precise prevalence of this form of brachyolmia is not known. About 30 cases have been reported.\nClinical description\nPatients with Brachyolmia type 3 generally have a normal birth weight and length. Affected individuals present with moderately short trunk/short stature and mildly short limbs in childhood. Kyphoscoliosis is common and sometimes severe. Adult patients develop degenerative joint disease in the spine, large joints and small joints of the hands and feet, which may cause significant musculoskeletal morbidity, such as chronic pain in the extremities and spine, and paresthesia. Final adult height is reported to be 155-168 cm (males) and 136-150 cm (females). The radiographic features include severe platyspondyly particularly in the cervical spine, elongated vertebral bodies (overfaced pedicles), broad ilia, and mild metaphyseal irregularity in the proximal femora. Carpal ossification may be mildly delayed, and mild brachydactyly may exist.\nEtiology\nHeterozygous mutations in the TRPV4 gene (12q24.11) are responsible for autosomal dominant brachyolmia. TRPV4 mutations are associated with other skeletal dysplasias, including lethal and nonlethal metatropic dysplasia, spondyloepiphyseal dysplasia Maroteaux type, and spondylometaphyseal dysplasia Kozlowski type (see these terms). Autosomal dominant brachyolmia falls into the mildest end of the TRPV4-associated skeletal dysplasia group. TRPV4 encodes a Ca-permeable, non-selective cation channel that participates in the regulation of osmotic sensitivity and mechanosensitivity. It remains to be explained how dysregulation of the cation channel causes the skeletal abnormalities.\nGenetic counseling\nGenetic counseling should be provided to affected families, in consideration of the autosomal dominant mode of inheritance.\n\n                            Last update: \n                            March 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Gen NISHIMURA"}
{"Disease Name": "Autosomal dominant centronuclear myopathy", "Disease Definition": "A rare, autosomal dominant congenital myopathy characterized by numerous centrally placed nuclei on muscle biopsy and clinical features of a congenital myopathy (hypotonia, distal/proximal muscle weakness, rib cage deformities (sometimes associated with respiratory insufficiency), ptosis, ophthalmoparesis and weakness of the muscles of facial expression with dysmorphic facial features.", "ORPHA ID": 169189, "Summary": "Epidemiology\nThe exact prevalence remains unknown.\nClinical description\nThe age of onset is typically in adolescence, although earlier (neonatal to childhood) and later presentations have been reported. Muscle weakness of variable severity is the major clinical manifestation. Distal muscle involvement, particularly in the lower limb, may precede more proximal weakness; the latter finding corresponds to a sequential pattern of involvement on muscle magnetic resonance imaging (MRI) with early involvement of the ankle plantarflexors, namely the medial gastrocnemius, followed by signal changes in the posterior and, eventually, anterior compartment of the thighs. Marked ocular involvement including ptosis and ophthalmoparesis are common, whilst contractures other than those affecting the Achilles tendon and/or long finger flexors are rare. Cardiorespiratory function has been reported as normal in most cases. Patients with early onset may improve in terms of muscle strength but may develop restrictive respiratory impairment over time. Neuropathic signs (absence of tendon reflexes on neurological examination and fibrillations or reduction of the compound muscle action potential on electrophysiological examination) may be present.\nEtiology\nThe disorder is most commonly caused by mutations in the DNM2 (19p13.2). A geno-phenotype has been reported with mutations in the PH domain associated with disease onset in infancy and early childhood, and mutations in the middle-domain associated with presentation in late childhood or early adulthood. DNM2 mutations also cause Charcot-Marie-Tooth (CMT) disease Type B and CMT2M. Other rare causative genes identified include BIN1 (2q14.3) and CCDC78 (16p13.3), which causes a centronuclear myopathy-like phenotype.\nDiagnostic methods\nDiagnosis is based on typical histopathological findings in combination with suggestive clinical features, and is confirmed by genetic testing. Histological findings include centrally placed nuclei and type 1 predominance; in addition, hypotrophy oxidative stains may reveal radial distribution of sarcoplasmic strands in fibers with central nuclei. Muscle MRI may aid the diagnosis.\nDifferential diagnosis\nThe main differential diagnoses include other congenital myopathies with predominant distal involvement, myotonic dystrophy and, if facial involvement is prominent, fascio-scapulo-humeral dystrophy.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the mutation has previously been identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. The risk to siblings or offspring of an affected individual inheriting the disease is 50%. Genetic counseling should be offered to all patients and families.\nManagement and treatment\nThere is no curative treatment currently available. Management is supportive and based on a multidisciplinary approach.\nPrognosis\nThe disease has usually a slowly progressive course with potential loss of independent ambulation after the sixth decade.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI  - Dr Adele D'AMICO  - Pr Fabiana FATTORI"}
{"Disease Name": "Autosomal dominant cerebellar ataxia type I", "Disease Definition": "A group of spinocerebellar ataxias (SCAs) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement.", "ORPHA ID": 94145, "Summary": "Epidemiology\nThe overall prevalence of SCAs is 1/33,000-1/50,000. The prevalence of ADCA (all types) is estimated at 1/37,000 worldwide. The most common ADCA type I is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations.\nClinical description\nOnset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations that include spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric disorders, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated.\nEtiology\nTo date, 27 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12- SCA14, SCA15/SCA16, SCA17- SCA23, SCA25, SCA27, SCA28, SCA32, SCA34- SCA37, autosomal dominant cerebellar ataxia, deafness and narcolepsy, and dentatorubral pallidoluysian atrophy (DRPLA) (see these terms). ADCA type I can be further divided based on the proposed pathogenetic mechanism into 3 subclasses. Subclass 1 includes ADCA type I caused by CAG repeat expansions such as in SCA1-SCA3, SCA17 and DRPLA. Subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12, as well as hexanucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA36. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/SCA16, SCA27- SCA28 and SCA35.\nDiagnostic methods\nDiagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases.\nDifferential diagnosis\nDifferential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease causing mutation.\nGenetic counseling\nGiven the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics.\nManagement and treatment\nThere are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential.\nPrognosis\nPrognosis is variable depending on the type of SCA and even among kindreds.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Autosomal dominant cerebellar ataxia type III", "Disease Definition": "A group of neurodegenerative disorders characterized by mostly pure cerebellar syndromes with occasional non-cerebellar signs (e.g. pyramidal signs, peripheral neuropathy, writer's cramp) and includes spinocerebellar ataxia (SCA) type 5 (SCA5), SCA6, SCA11, SCA26, SCA30, and SCA31.", "ORPHA ID": 94148, "Summary": "Epidemiology\nThe prevalence is unknown but varies within populations and between geographical locations. SCA6 is the most common form of this group with an estimated prevalence of less than 1/100,000. SCA31 is the second most common form and is found mainly in Japan while the other forms of ACDA type III are rarer.\nClinical description\nAge of onset for these disorders is variable but is usually in adulthood. This group of disorders is characterized by mainly pure cerebellar signs such as dysarthria and gait and limb ataxia (starting with difficulty walking and loss of balance/coordination and progressing to loss of mobility and dysphagia). A spectrum of oculomotor dysfunction is also present in most patients and can include nystagmus as well as impaired vestibulo-ocular reflex and smooth pursuit. Non-cerebellar signs are less common but can include pyramidal signs (SCA11), peripheral neuropathy (SCA6), and writer's cramp (SCA5). The vast majority of these diseases have a slowly progressive course.\nEtiology\nCausal mutations of ACDA type III have been reported in several genes: CACNA1A (19p13) in SCA6, SPTBN2 (11q13.2) in SCA5, TTBK2 (15q15.2) in SCA11, EEF2 (19p13.3) in SCA26 and BEAN1 (16q21) in SCA31. The causal gene of SCA30 has not yet been discovered.\nDiagnostic methods\nDiagnosis is based on characteristic clinical findings, molecular genetic testing and magnetic resonance imaging (MRI) findings. Cerebellar atrophy with Purkinje cell degeneration is the common finding seen in all types of ACDA type III.\nDifferential diagnosis\nDifferential diagnosis includes other forms of rare hereditary ataxias, in particular other types of autosomal dominant cerebellar ataxia (see this term).\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease causing mutation.\nGenetic counseling\nThis group of diseases is inherited in an autosomal dominant manner and genetic counseling is possible.\nManagement and treatment\nThere is no cure for ADCA type III and treatment is supportive. Physical and occupational therapy is essential for maintaining activity along with the use of walking aids, canes and wheelchairs when necessary. Computer devices can help patients with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. In those with vertigo, vestibular suppressants may be beneficial. Consultation with an ophthalmologist is recommended and prism glasses can help with nystagmus. Annual neurological examinations are recommended to monitor disease progression.\nPrognosis\nThe majority of patients with ACDA type III eventually become disabled and cannot walk unassisted. Life-expectancy is slightly reduced (average age of death being 65 years or older).\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome", "Disease Definition": "A rare polymorphic disorder, subtype of autosomal dominant cerebellar ataxia type 1 (ADCA type 1), characterized by ataxia, sensorineural deafness and narcolepsy with cataplexy and dementia.", "ORPHA ID": 314404, "Summary": "Epidemiology\nAutosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome (ADCA-DN) has been reported in more than 80 patients to date from Sweden, the United States, Italy, Brazil, Belgium, China, New Zealand, UK, Taiwan, Germany, and Canada.\nClinical description\nDisease onset usually occurs in adulthood (from the ages of 30-40). Cases have been reported in adolescents. The clinical features include cerebellar ataxia, narcolepsy with cataplexy, sensorineural deafness and dementia including executive dysfunction and global cognitive impairement. Optic atrophy, cataracts, psychosis, depression, sensory neuropathy, pseudobulbar signs, incontinence and limb lymphedema have also been reported but present later in the disease course. Mild brain atrophy with cerebellum involvement is visible with magnetic resonance imaging (MRI).\nEtiology\nADCA-DN is caused by a mutation in the DNA methyltransferase (DNMT1) gene located on chromosome 19p13.2. It encodes an enzyme essential for the repression of transcriptional activity in numerous postmitotic cells.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical findings and molecular genetic testing, the finding of a mutation in the DNMT1 gene.\nDifferential diagnosis\nDifferential diagnosis includes other types of autosomal dominant cerebellar ataxia (ADCA), and hereditary.\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with a known mutation.\nGenetic counseling\nADCA-DN is inherited autosomal dominantly and genetic counseling is possible. Sporadic cases have also been reported. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for ADCA-DN and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity as well as to avoid falls. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Annual neurological examinations are recommended to monitor disease progression.\nPrognosis\nDisease duration from disease onset to death is estimated to be between 10 to 30 years. Almost all affected individuals survive at least until late 40's.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Autosomal dominant cerebellar ataxia", "Disease Definition": "A clinically and genetically heterogeneous group of neurodegenerative diseases characterized by a slowly progressive ataxia of gait, stance and limbs, dysarthria and/or oculomotor disorder, due to cerebellar degeneration in the absence of coexisting diseases. The degenerative process can be limited to the cerebellum (ADCA type 3) or may additionally involve the retina (ADCA type 2), optic nerve, ponto-medullary systems, basal ganglia, cerebral cortex, spinal tracts or peripheral nerves (ADCA type 1). In ACDA type 4, a cerebellar syndrome is associated with epilepsy.", "ORPHA ID": 99, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2 due to DGAT2 mutation", "Disease Definition": "A rare autosomal dominant hereditary axonal motor and sensory neuropathy characterized by childhood onset of slowly progressive distal muscle weakness and atrophy primarily affecting the lower limbs, associated with sensory impairment and ataxia presenting with an unsteady, broad-based gait and frequent falls. Additional signs include decreased deep tendon reflexes and hand tremor.", "ORPHA ID": 487814, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation", "Disease Definition": "A rare form of axonal peripheral sensorimotor neuropathy characterized by classical CMT2 signs and symptoms (progressive weakness and atrophy of distal limb muscles, mild sensory deficits of position, vibration and pain/temperature, pes cavus, and symmetrically absent or reduced muscle and sensory action potentials with relatively preserved nerve conduction velocities in neurophysiological studies) as well as pyramidal tract involvement (spasticity, hyperreflexia). Spasticity and pain may be the presenting symptoms.", "ORPHA ID": 324611, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation", "Disease Definition": "A rare, axonal hereditary motor and sensory neuropathy characterized by adult onset of slowly progressive distal muscle weakness and atrophy, decreased deep tendon reflexes of lower limbs, and mild distal sensory loss leading to gait difficulties in most patients.", "ORPHA ID": 435819, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2 with giant axons", "Disease Definition": "A rare subtype of axonal hereditary motor and sensory neuropathy characterized by distal muscle weakness and atrophy (principally of peroneal muscles) associated with distal sensory loss (tactile, vibration), pes cavus present since infancy or childhood, and axonal swelling with neurofilament accumulation on nerve biopsy. Other features may include hand muscle involvement, hypo/arreflexia, gait disturbances, muscle cramps, toe abnormalities and mild cardiomyopathy.", "ORPHA ID": 401964, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2A1", "Disease Definition": "A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, presenting with a more prominent muscle weakness in lower than upper limbs and frequent postural tremor.", "ORPHA ID": 99946, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2A2", "Disease Definition": "A subtype of Autosomal dominant Charcot-Marie-Tooth disease type 2 characterized by the childhood onset of distal weakness and areflexia (with earlier and more severe involvement of the lower extremities), reduced sensory modalities (primarily pain and temperature sensation), foot deformities, postural tremor, scoliosis and contractures. Optic atrophy, vocal cord palsy with dysphonia, sensorineural hearing loss, spinal cord abnormalities and hydrocephalus have also been reported.", "ORPHA ID": 99947, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2B", "Disease Definition": "A severe form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, with onset in the 2nd or 3rd decade, characterized by ulcerations and infections of feet. Symmetric and distal weakness develops mostly in the legs together with a severe symmetric distal sensory loss, tendon reflexes are only reduced at ankles and foot deformities, including pes cavus or planus and hammer toes, appear in childhood.", "ORPHA ID": 99936, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2C", "Disease Definition": "A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by the association of vocal cord anomalies, impairment of respiratory muscles and sensorineural hearing loss with the distal hands and feet weakness. Onset is between infancy and the 6th decade.", "ORPHA ID": 99937, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2D", "Disease Definition": "A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by distal weakness primarily and predominantly occurring in the upper limbs and tendon reflexes absent or reduced in the arms and decreased in the legs. Progression is slow.", "ORPHA ID": 99938, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2DD", "Disease Definition": "A rare autosomal dominant hereditary axonal motor and sensory neuropathy characterized by predominantly distal weakness and muscle atrophy, decreased or absent tendon reflexes, and reduced vibratory sensation in the lower and upper extremities. Pes cavus develops in many patients. Additional symptoms like ataxia, tremor, or swallowing difficulties have been reported. Patients usually remain ambulatory even late in the disease. Age of onset ranges from childhood to adulthood, with earlier onset tending to be associated with a more severe disease phenotype.", "ORPHA ID": 521414, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2E", "Disease Definition": "A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, with onset in the first to 6th decade with a gait anomaly and a leg weakness that reaches the arms secondarily. Tendon reflexes are reduced or absent and, after years, all patients have a pes cavus. Other signs may be present, including hearing loss and postural tremor.", "ORPHA ID": 99939, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2F", "Disease Definition": "A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by symmetric weakness primarily occurring in the lower limbs (distal muscles in a majority of cases) and reaching the arms only after 5 to 10 years, occasional and predominantly distal sensory loss and reduced tendon reflexes. It presents with gait anomaly between the 1st and 6th decade and early onset is generally associated to a more severe phenotype which may include foot drop.", "ORPHA ID": 99940, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2G", "Disease Definition": "A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy with onset associated to development of foot deformity and walking difficulties between the 1st and the 8th decades, with a median range in the 2nd one. Weakness and sensory loss involve primarily the legs and ankles tendon reflexes are reduced. This disorder has a slowly progressive course.", "ORPHA ID": 99941, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2I", "Disease Definition": "A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by a late onset with severe sensory loss (paresthesia and hypoesthesia) associated with distal weakness, mainly of the legs, and absent or reduced deep tendon reflexes.", "ORPHA ID": 99942, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2J", "Disease Definition": "A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by a relatively late onset, pupillary abnormalities and deafness, in most patients, associated with distal weakness and muscle atrophy.", "ORPHA ID": 99943, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2K", "Disease Definition": "An axonal Charcot-Marie-Tooth (CMT) peripheral sensorimotor polyneuropathy.", "ORPHA ID": 99944, "Summary": "Epidemiology\nCMT2K is a rare form of CMT with only three families reported in the literature so far.\nClinical description\nIt is characterized by a mild phenotype with onset during the second decade of life and very slow progression. Walking ability is retained (one of the reported patients was still able to walk at 70 years of age).\nEtiology\nCMT2K is caused by mutations in the GDAP1 gene (8q13.3), encoding a protein required for mitochondrial fission. Mutations in the same gene are associated with severe early-onset forms of CMT: CMT4A (an autosomal recessive demyelinating form of CMT4) and CMT4C4 (another autosomal recessive form of CMT4 with an axonal phenotype and an association with vocal cord paralysis; see this term).\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen ESPINÓS  - Pr Francesc PALAU"}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2L", "Disease Definition": "A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy. In the single family reported to date, CMT2L onset is between 15 and 33 years. Patients present with a symmetric distal weakness of legs and occasionally of the hands, absent or reduced tendon reflexes, distal legs sensory loss and frequently a pes cavus. Progression is slow.", "ORPHA ID": 99945, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2M", "Disease Definition": "A form of axonal Charcot-Marie-Tooth disease, a peripheral motor and sensory neuropathy, characterized by congenital pstosis and early cataract associated to a mildly progressive peripheral neuropathy of variable onset from birth to the 6th decade, pes cavus, reduced to absent ankles tendon reflexes and sometimes neutropenia.", "ORPHA ID": 228179, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2N", "Disease Definition": "A mild form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, characterized by distal legs sensory loss and weakness that can be asymmetric. Tendon reflexes are reduced in the knees and absent in ankles. Progression is slow.", "ORPHA ID": 228174, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2O", "Disease Definition": "A rare, genetic, subtype of autosomal dominant Charcot-Marie-Tooth disease type 2 characterized by early childhood-onset of slowly progressive, predominantly distal, lower limb muscle weakness and atrophy, delayed motor development, variable sensory loss, and pes cavus in the presence of normal or near-normal nerve conduction velocities. Additional variable features may include proximal muscle weakness, abnormal gait, arthrogryposis, scoliosis, cognitive impairment, and spasticity.", "ORPHA ID": 284232, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2Q", "Disease Definition": "A rare subtype of autosomal dominant Charcot-Marie-Tooth disease type 2, characterized by adolescent to adulthood-onset of symmetrical, slowly progressive distal muscle weakness and atrophy (with a predominant weakness of the distal lower limbs) associated with reduced or absent deep tendon reflexes, pes cavus and mild to moderated deep sensory impairment.", "ORPHA ID": 329258, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2U", "Disease Definition": "A subtype of autosomal dominant Charcot-Marie-Tooth disease type 2, characterized by late adult-onset (50-60 years of age) of slowly progressive, axonal, peripheral sensorimotor neuropathy resulting in distal upper limb and proximal and distal lower limb muscle weakness and atrophy, in conjunction with distal, panmodal sensory impairment in upper and lower limbs. Tendon reflexes are reduced and nerve conduction velocities range from reduced to absent. Neuropathic pain has also been associated.", "ORPHA ID": 397735, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2V", "Disease Definition": "A rare, axonal hereditary motor and sensory neuropathy characterized by adult onset of recurrent pain in legs with or without cramps, progressive loss of deep tendon reflexes and vibration sense, paresthesias in the feet and later in the hands. Patients often experience sleep disturbances and mild sensory ataxia.", "ORPHA ID": 447964, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2W", "Disease Definition": "A rare predominantly axonal hereditary motor and sensory neuropathy characterized by a broad phenotypic spectrum of slowly progressive signs and symptoms mainly affecting the lower limbs. Most patients present with gait difficulties and distal sensory impairment, while some may lack sensory symptoms altogether. Pes cavus is frequently reported. Age of onset is also highly variable, ranging from childhood to late adulthood.", "ORPHA ID": 488333, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2Y", "Disease Definition": "A rare, axonal hereditary motor and sensory neuropathy characterized by progressive distal muscle weakness and atrophy of variable onset and severity. Patients present with postural instability, gait and running difficulties, decreased deep tendon reflexes, foot deformities, fine motor impairment, and distal sensory impairment. Dysarthria, dysphagia, and mild cognitive and behavioral abnormalities have also been reported.", "ORPHA ID": 435387, "Summary": ""}
{"Disease Name": "Autosomal dominant Charcot-Marie-Tooth disease type 2Z", "Disease Definition": "A rare autosomal dominant hereditary axonal motor and sensory neuropathy characterized by early onset of generalized hypotonia and weakness, or later onset of distal lower limb muscle weakness and atrophy, cramps, and sensory impairment. Weakness and atrophy progress in an asymmetric fashion to involve also the proximal and upper limbs in the course of the disease. Additional features are pyramidal signs like increased muscle tone and extensor plantar reflexes, as well as learning difficulties.", "ORPHA ID": 466768, "Summary": ""}
{"Disease Name": "Autosomal dominant childhood-onset proximal spinal muscular atrophy", "Disease Definition": "A rare genetic neuromuscular disease characterized by early onset muscular weakness with predominant proximal lower limb involvement. The disorder is static or only mildly progressive. The severity of manifestations ranges from lethal, congenital muscular atrophy with arthrogryposis to asymptomatic with subclinical features.", "ORPHA ID": 363447, "Summary": ""}
{"Disease Name": "Autosomal dominant congenital benign spinal muscular atrophy", "Disease Definition": "A rare distal hereditary motor neuropathy, with a variable clinical phenotype, typically characterized by congenital, non-progressive, predominantly distal, lower limb muscle weakness and atrophy and congenital (or early-onset) flexion contractures of the hip, knee and ankle joints. Reduced or absent lower limb deep tendon reflexes, skeletal anomalies (bilateral talipes equinovarus, scoliosis, kyphoscoliosis, lumbar hyperlordisis), late ambulation, waddling gait, joint hyperlaxity and/or bladder and bowel dysfuntion are usually also associated.", "ORPHA ID": 1216, "Summary": ""}
{"Disease Name": "Autosomal dominant cutis laxa", "Disease Definition": "A rare connective tissue disorder characterized by wrinkled, redundant and sagging inelastic skin associated in some cases with internal organ involvement.", "ORPHA ID": 90348, "Summary": "Epidemiology\nThe prevalence of ADCL is unknown but less than 50 cases have been reported in the literature so far.\nClinical description\nPatients are usually diagnosed at birth or in early childhood due to the presence of excessive skin folds and loose, redundant skin. ADCL is considered to be a mild form of cutis laxa with limited systemic involvement although associated features may include hernias, cardiac valve anomalies (redundant mitral and tricuspid valves), cardiovascular manifestations (pulmonary stenosis and aortic and arterial dilatation and tortuosity), gastrointestinal diverticuli and emphysema.\nEtiology\nADCL is genetically heterogeneous: mutations in the elastin gene (ELN; 7q11.1-q21.1) have been reported in some cases, whereas mutations in the gene encoding fibulin-5 (FBLN5; 14q31) have been identified in others. Homozygous mutations in the FBLN5 are associated with the more severe form of CL with extensive systemic involvement, autosomal recessive CL type 1 (ARCL1; see this term).\nDiagnostic methods\nDiagnosis is based on clinical examination, family history and pathognomonic histological findings (sparse, fragmented elastic fibers) on skin biopsies. Molecular testing may allow confirmation of the diagnosis.\nDifferential diagnosis\nThe differential diagnosis may include other forms of CL (ARC1 and ARCL2, and X-linked CL) and related syndromes (gerodermia osteodysplastica, wrinkly skin syndrome and De Barsy syndrome), together with the Ehlers-Danlos syndromes, Cantu syndrome and Costello syndrome (see these terms).\nGenetic counseling\nGenetic counseling should be provided to affected families and prenatal diagnosis may be feasible for families in which the disease-causing mutation has been identified.\nManagement and treatment\nThere is no specific treatment for cutis laxa. Management should include symptomatic treatment of any associated manifestations. ADCL is generally a mild cutaneous disease and internal organ involvement is rare.\nPrognosis\nMost patients have a good prognosis and life expectancy is usually normal.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS"}
{"Disease Name": "Autosomal dominant deafness-onychodystrophy syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by congenital hearing impairment, small or absent nails on the hands and feet, and small or absent terminal phalanges.", "ORPHA ID": 79499, "Summary": "Epidemiology\nThe prevalence is unknown but it has been reported in 22 individuals from ten families to date.\nClinical description\nThe main clinical characteristics of dominant deafness-onychodystrophy (DDOD) syndrome are severe sensorineural hearing loss or deafness and onychodystrophy (small or absent fingernails and toenails, sometimes limited to the nails of the first and fifth digits). Brachydactyly, long, finger-like or tri-phalangeal thumbs as well as conical, hypoplastic teeth or oligodontia have also been reported in several patients. Syndactyly, minor facial dysmorphism (mild hypotelorism, deep set eyes and midface hypoplasia), and epilepsy have been seen in individual cases. Unlike DOORS syndrome, most patients with DDOD follow a normal development and have normal intelligence.\nEtiology\nDDOD syndrome is caused, in some cases, by heterozygous mutations in the ATP6V1B2 gene (8p21.3) encoding a vacuolar ATPase (V-ATPase) involved in protein translocation. It is at present unknown whether there can be genetic heterogeneity or not, as not all known families have been tested.\nDiagnostic methods\nDiagnosis is based on the presence of characteristic clinical findings. X-rays of the hands and feet and a brain stem auditory evoked response (BAER) test for hearing loss should be performed. Molecular genetic testing identifying a ATP6V1B2 mutation may confirm the diagnosis but as it is at present uncertain whether DDOD syndrome is genetically heterogeneous, the absence of a mutation will not mean that a diagnosis of DDOD syndrome is incorrect.\nDifferential diagnosis\nThe main differential diagnosis is DOORS syndrome and Coffin-Siris syndrome. The limb anomalies seen in DDOD syndrome can also be found in several other entities including Zimmermann-Laband syndrome, Adams-Oliver syndrome, Temple-Baraitser syndrome and Fontaine Progeroid Syndrome.\nAntenatal diagnosis\nPrenatal diagnosis of DDOD syndrome has not been performed to date.\nGenetic counseling\nDDOD syndrome is inherited autosomal dominantly so if the clinical diagnosis has been established reliably, genetic counseling is possible. In this case, affected families should be informed that risk of transmission from an affected parent to offspring is 50%.\nManagement and treatment\nTreatment is supportive and involves special education for the hearing impaired as well as regular follow-up. Corrective surgery is in principle possible for those with syndactyly, although generally not necessary.\nPrognosis\nThe disease is not life threatening. The main influence on quality of life is hearing loss.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Philippe CAMPEAU"}
{"Disease Name": "Autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome", "Disease Definition": "A rare genetic neuromuscular disease characterized by length-dependent axonal motor neuropathy predominantly affecting the lower limbs, in combination with a myopathy with morphological features of myofibrillar myopathy with aggregates and rimmed vacuoles. Age of onset is typically in the second to third decade of life. Patients present with slowly progressive muscle weakness and atrophy initially affecting the distal lower limbs and later progressing to involve proximal limbs and also truncal muscles. There is no involvement of respiratory and cardiac muscles.", "ORPHA ID": 476093, "Summary": ""}
{"Disease Name": "Autosomal dominant distal renal tubular acidosis", "Disease Definition": "A rare autosomal dominant form of distal renal tubular acidosis characterized by hyperchloremic metabolic acidosis often but not always associated with hypokalemia. Disease onset is in adolescence or adulthood and initial manifestations can include polyuria, polydipsia, muscle weakness and fatigue. Osteomalacia or osteopenia, hypercalciuria, nephrolithiasis and nephrocalcinosis may also develop. Renal failure has not been described.", "ORPHA ID": 93608, "Summary": ""}
{"Disease Name": "Autosomal dominant dopa-responsive dystonia", "Disease Definition": "A rare neurometabolic disorder characterized by childhood-onset dystonia that shows a dramatic and sustained response to low doses of levodopa (L-dopa) and that may be associated with parkinsonism at an older age.", "ORPHA ID": 98808, "Summary": "Epidemiology\nThe estimated European prevalence of dopa-responsive dystonia (DRD) ranges from 1/1,000,000-1/200,000. DYT5a occurs more frequently than autosomal recessive DRD (DYT5b).\nClinical description\nOnset usually occurs in childhood (average age 6 years), and females are 2-4 times more likely to suffer from this disease than males. At onset, DYT5a is typically characterized by lower limb dystonia, most commonly with flexion-inversion of the foot (equinovarus posture) resulting in gait disturbances (that can result in stumbling and falling) with diurnal fluctuations, with symptoms worsening in the evening and improving after sleep. Physical exercise may also aggravate the symptoms. Rarely, arm dystonia, postural tremor of the hands, slowness of movements (bradykinesia) or cervical dystonia are presenting symptoms. In many patients, brisk deep-tendon reflexes and/or dystonic extension of the big toe (striatal toe) are obvious at examination. The disease usually progresses to generalized dystonia, and some patients, especially those with onset in adolescence or adulthood, also develop parkinsonism (manifesting with bradykinesia, rigidity and mainly postural tremor). There is no effect on cognitive or intellectual functioning. Patients with a later disease onset have a milder phenotype. In rare cases depression, anxiety, sleep disturbances and obsessive-compulsive disorder have been reported. Without treatment, adults may suffer from limb contractures.\nEtiology\nDYT5a is caused by mutations in the GCH1 gene (14q22.1-q22.2), encoding the enzyme GTP cyclohydrolase 1 (GTPCH1). This enzyme is essential in the biosyntheisis of tetrahydrobiopterin (the essential co-factor for tyrosine hydroxylase), which is the rate-limiting enzyme in the biosynthesis of dopamine.\nDiagnostic methods\nDiagnosis is based on the presence of characteristic clinical symptoms and the dramatic and sustained improvement of symptoms with the administration of low doses of oral L-dopa. Reduced levels of both total biopterin and neopterin in cerebrospinal fluid (CSF) are typically found in DYT5a patients. Reduced GTPCH1 activity in blood cells is also noted. Molecular genetic testing can identify a mutation in the GCH1 gene.\nDifferential diagnosis\nDifferential diagnoses include other forms of DRD (e.g. autosomal recessive DRD), early onset torsion dystonia, myoclonic dystonia, hyperphenylalaninemia, hereditary spastic paraplegia, young adult-onset parkinsonism or cerebral palsy.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known GCH1 mutation.\nGenetic counseling\nDYT5a is inherited in an autosomal dominant manner, but due to gender-based incomplete penetrance, not everyone with a mutation will display the disease phenotype. Approximately 30-50% of patients with DRD do not report a family history of dystonia. De novo mutations are also possible.\nManagement and treatment\nThis form of dystonia shows a dramatic and sustained response to L-dopa therapy. The current suggested initial dosage of L-dopa/decarboxylase inhibitor for children is 25 mg or less, once a day, and in adults 50 mg once or twice a day. These dosages can be increased in small increments if needed, with typical optimal or maximum doses of approximately 10-20 mg/kg/day. If dyskinesia appears after administration of L-dopa, dosage should be decreased. Treatment is life-long, and alleviation of symptoms can usually be noted after a few weeks to a few months.\nPrognosis\nThere is no decrease in life expectancy, and typically there is a complete or almost complete resolution of symptoms with the administration of L-dopa.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "Autosomal dominant epidermolytic ichthyosis", "Disease Definition": "A rare keratinopathic ichthyosis (KPI) characterized by a blistering phenotype at birth which progressively becomes hyperkeratotic.", "ORPHA ID": 312, "Summary": "Epidemiology\nThe prevalence range of all types of KPI is estimated at 1/909,000 in France. The exact worldwide prevalence of epidermolytic ichthyosis (EI) is unknown but is in the 1/2,300,000-4,350,000 range in Japanese and Danish population studies.\nClinical description\nInfants present at birth, or shortly after, with erythroderma, mild scaling, severe blistering, and superficial erosions at sites of trauma and flexural areas. Yellow-brown hyperkeratotic plaques, often with mild background erythroderma, develop in the first months of life. The skin has a characteristic dirty looking appearance. Hyperkeratosis has a ridged appearance along skin lines and a cobblestone pattern in the extensor surfaces of joints. It is most often generalized but may be limited to joint flexures, anterior neck, abdominal wall, and infragluteal folds, with relative sparing of the face. Over time, hyperkeratosis worsens and blister formation decreases but may still occur (following skin trauma or during summer). Palmoplantar involvement is seen in some patients and painful blisters tend to develop underneath. Digital contractures and pseudoainhum may occur. Skin is often itchy, smelly, and subject to infections. Other features may include hypohidrosis, scalp scaling, nail dystrophy and abnormal posture. Growth failure may be seen in severe cases. EI persists into adulthood, with hyperkeratosis of variable intensity and extension.\nEtiology\nThe disease is caused by mutations in the genes coding for epidermal suprabasal keratins 1 (KRT1; 12q13.13) and 10 (KRT10; 17q21-q23) that impair keratin intermediate filament formation in the suprabasal keratinocytes. A genotype-phenotype correlation exists, with palmoplantar involvement being generally associated with KRT1, as KRT10 is less expressed in these locations. The position of the mutation may influence the severity of the phenotype\nDiagnostic methods\nDiagnosis is based on the clinical picture and on histological examination showing hyperkeratosis with orthokeratosis, hypergranulosis, and cytolysis in the upper stratum spinosum and granular layers with characteristic intracellular vacuolization (epidermolytic hyperkeratosis). Electron microscopy shows suprabasal keratinocytes with keratin intermediate filaments clumps and perinuclear keratin clumps in the upper epidermis. Genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis at birth includes other blistering diseases: toxic epidermal necrolysis, inherited epidermolysis bullosa, staphylococcal scalded skin syndrome, incontinentia pigmenti or herpetic infection. In later stages, blistering, ridges along skin lines, and histologic features help to differentiate it from other forms of ichthyoses. Superficial EI usually has a milder phenotype, lacks keratoderma, and has areas with characteristic superficial scaling. Annular epidermolytic ichthyosis is distinguished by the polycyclic and intermittent lesions.\nAntenatal diagnosis\nGenetic antenatal diagnosis is available.\nGenetic counseling\nThe disease has an autosomal dominant mode of inheritance. Genetic counseling can be offered to affected families when a causing mutation has been identified.\nManagement and treatment\nTreatment is symptomatic. Emollients are often used but have limited efficacy. Topical keratolytics and mechanical removal of scales can improve hyperkeratotic lesions, but may worsen blistering. Some patient, especially those with KRT10 mutation, may benefit from low dose acitretin. Antiseptic washes reduce the bacterial colonization and body odor. Antibiotic therapy is required in cases of bacterial infection.\nPrognosis\nThe severity of the disease is variable. EI impacts the quality of life and social interactions due to skin aspect, pain, walking difficulties, pruritus, body odor, infections, malnutrition and hand contractures. EI can be life-threatening during the neonatal period due to infections and/or dehydration.\n\n                            Last update: \n                            February 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Eulalia BASELGA TORRES | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal dominant epilepsy with auditory features", "Disease Definition": "A rare, genetic, familial partial epilepsy disease characterized by focal seizures associated with prominent ictal auditory symptoms, and/or receptive aphasia, presenting in two or more family members and having a relatively benign evolution.", "ORPHA ID": 101046, "Summary": "Epidemiology\nThe prevalence of autosomal dominant epilepsy with auditory features (ADEAF) is unknown but likely to be very low. Fewer than 3% of persons with epilepsy have a significant family history of epilepsy and only a fraction of these have clinical features consistent with ADEAF.\nClinical description\nADEAF usually presents in adolescence or early adulthood (but can range from 4-50 years of age) with the onset of focal epilepsy originating predominantly in the lateral temporal lobe. Seizures may be precipitated by specific sounds (i.e. telephone ringing or speech) but in most cases there are no recognizable triggers. Ictal manifestations include auditory symptoms (such as humming, buzzing, ringing and, less frequently, more complex sounds such as voices, songs or volume changes) and receptive aphasia. Rarely, additional ictal manifestations, such as other sensory symptoms (e.g. visual or olfactory), as well as motor, psychic, and autonomic symptoms, have been reported. In many cases, focal seizures are followed by secondarily generalized seizures (e.g. generalized tonic-clonic seizures), which can manifest with loss of consciousness and convulsions (often during sleep). Disease course is usually benign with patients often being seizure free following treatment with anti-seizure medications.\nEtiology\nIn approximately one-third of cases, ADEAF is caused by mutations in the LGI1 gene (10q23.33), encoding leucine-rich glioma-inactivated protein 1 and mutations in the RELN gene (7q22.1), encoding reelin. These proteins are thought to play key regulatory roles in both the developing and adult brain. In 50% of cases, the etiology is unknown.\nDiagnostic methods\nDiagnosis is based on the presence of characteristic clinical manifestations, a family history suggesting autosomal dominant inheritance, and normal brain imaging studies (using magnetic resonance imaging and computer tomography scans). Epileptiform interictal EEG abnormalities can be present in up to 2/3 of cases. Molecular genetic testing, identifying a causative mutation, confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other forms of focal epilepsy, such as autosomal dominant sleep-related hypermotor epilepsy and familial focal epilepsy with variable foci (FFEVF).\nAntenatal diagnosis\nPrenatal diagnosis is possible if a pathogenic variant has been previously identified in a family member. Variable penetrance is observed. In practice prenatal testing is not usually performed.\nGenetic counseling\nADEAF is inherited in an autosomal dominant manner. Genetic counseling should inform parents with a pathogenic variant of the 50% risk of passing it on to their offspring. Due to the reduced and age-dependent penetrance seen in ADEAF, approximately 61% of patients who inherit the pathogenic variant will manifest symptomatology.\nManagement and treatment\nADEAF is treated with antiepileptic drugs that are routinely used in clinical practice (e.g. carbamazepine, phenytoin, valproate), with seizure control attained in the majority of cases. Evaluation of relatives is important in order to identify those who may be at risk and might benefit from early treatment initiation and/or measures to reduce risk in the event of seizure onset.\nPrognosis\nAlthough it is a life-long condition, the prognosis is generally good as ADEAF has a benign course and seizures are usually controlled with medication.\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Ruth OTTMAN"}
{"Disease Name": "Autosomal dominant focal dystonia, DYT25 type", "Disease Definition": "A form of focal dystonia characterized by cervical, laryngeal and hand-forearm dystonia.", "ORPHA ID": 329466, "Summary": ""}
{"Disease Name": "Autosomal dominant focal non-epidermolytic palmoplantar keratoderma with plantar blistering", "Disease Definition": "A rare, genetic, isolated, focal palmoplantar keratoderma disease characterized by focal thickening of the skin of the soles, and often of the palms, associated with minimal or no nail involvement. Patients frequently present non-epidermolytic painful plantar blistering and, occasionally, subtle oral leukokeratosis or plantar hyperhidrosis.", "ORPHA ID": 402003, "Summary": ""}
{"Disease Name": "Autosomal dominant generalized dystrophic epidermolysis bullosa", "Disease Definition": "A rare dystrophic epidermolysis bullosa (DEB) characterized by generalized blistering, milia formation, atrophic scarring, and dystrophic nails.", "ORPHA ID": 231568, "Summary": "Epidemiology\nThe prevalence worldwide is unknown, in the USA prevalence at birth is estimated at 1/5,000,000.\nClinical description\nThe clinical picture of intermediate dominant dystrophic epidermolysis bullosa (DDEB-intermediate) is generally milder than that of the autosomal recessive generalized DEB forms. DDEB-intermediate manifests usually at birth with the development of blisters, primarily affecting the limbs. Blisters heal by developing numerous milia and atrophic scars with an onion-like appearance, particularly visible on the elbows, knees, and hands. Nail dystrophy, always present, can lead to loss of nail plates. Usually, fingers and toes are not affected by major cicatricial retractions. Blisters can develop in the mucosa, mainly in the oral cavity and, less commonly, in the esophagus, where they can cause strictures, often in sharp contrast with the scarce cutaneous involvement. Dental caries are relatively frequent. Corneal and genitourinary tract involvement, anemia, and growth delay are rare.\nEtiology\nDDEB-intermediate is caused by mutations in the collagen VII gene (COL7A1; 3p21.31) that lead to an alteration of function or a reduction in the amount of collagen VII. The molecular defect impairs collagen VII assembly into anchoring fibrils which fix the basement membrane to the underlying dermis, causing reduced skin resistance to minor trauma.\nDiagnostic methods\nDiagnosis is suspected at clinical examination and is confirmed by immunofluorescence antigen mapping and/or transmission electron microscopy on skin samples showing a cleavage plane located below the lamina densa of the cutaneous basement membrane zone. Genetic testing confirms the diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes other forms of EB. In the neonatal period, aplasia cutis congenita, herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, linear IgA bullous dermatosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, bullous impetigo, and staphylococcal scalded skin syndrome may need to be considered.\nAntenatal diagnosis\nAntenatal diagnosis is usually not recommended, but some people who are themselves affected, may request it.\nGenetic counseling\nGenetic counseling should be offered to all the patients and their parents. The disorder is autosomal dominant and therefore, for each pregnancy there is 50% risk of transmitting the pathogenic variant from an affected individual to offspring.\nManagement and treatment\nManagement is preventive: protective padding of the skin and appropriate lifestyle measures reduce blistering, and careful wound care prevents secondary infection and reduces scarring. Oral hygiene is important for the management of caries. When present, esophageal strictures can be treated by balloon dilatation with fluoroscopic guidance. In a minority of patients, a follow-up by a dietitian can be required to evaluate nutritional requirements.\nPrognosis\nLife expectancy is normal.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Michela BRENA | ERN-Skin* - Dr Sophie GUEZ | ERN-Skin* - Dr Gianluca TADINI | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal dominant generalized epidermolysis bullosa simplex, intermediate form", "Disease Definition": "Non-Dowling-Meara generalized epidermolysis bullosa simplex, formerly known as epidermolysis bullosa simplex, Köbner type (EBS-K) is a generalized basal subtype of epidermolysis bullosa simplex (EBS, see this term) characterized by non-herpetiform blisters and erosions arising in particular at sites of friction.", "ORPHA ID": 79399, "Summary": "Epidemiology\nWorldwide prevalence is unknown but in Scotland reported overall prevalence of non-Dowling-Meara generalized EBS and localized EBS is 1/35,000.\nClinical description\nOnset of the disease is usually at birth. Blistering tendency usually worsens in summertime (or in warm weather). The frequency of milia, mild atrophic scarring, focal plantar hyperkeratosis and nail dystrophy is intermediate between that of localized EBS and EBS-DM (see these terms), and extracutaneous findings, other than occasional intraoral blistering, are rare. Given the considerable overlap between non-Dowling-Meara EBS and localized EBS within some kindreds, some experts prefer to group both subtypes together.\nEtiology\nNon-Dowling-Meara EBS is caused by dominant negative mutations within either the KRT5 (12q13.13) or KRT14 (17q12-q21) genes, encoding keratin 5 and keratin 14, respectively.\nGenetic counseling\nTransmission is autosomal dominant and sporadic cases are frequent.\nPrognosis\nAlthough the disease can be severely disabling, life-expectancy is normal.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "Autosomal dominant generalized epidermolysis bullosa simplex, severe form", "Disease Definition": "Epidermolysis bullosa simplex, Dowling-Meara type (EBS-DM) is a basal subtype of epidermolysis bullosa simplex (EBS, see this term) characterized by the presence of generalized vesicles and small blisters in grouped or arcuate configuration.", "ORPHA ID": 79396, "Summary": "Epidemiology\nWorldwide prevalence is unknown but reported prevalence in Scotland is 1/1,700,000.\nClinical description\nOnset is usually at birth with large, frequently hemorrhagic blisters. After the neonatal period, the lesions take the typical herpetiform (or herpes-like) clustering with central healing pattern. Blister formation gradually reduces starting from late childhood. By childhood, most patients begin to develop confluent thickening and hyperkeratosis (keratoderma) of the palms and soles which may partially resolve in some patients during mid- to late-adulthood. Along with blisters, skin findings commonly include mild atrophic scarring and post-inflammatory pigmentation, nail shedding and nail dystrophy, as well as occasional milia formation. Lesions may improve in some patients in case of fever, unlike other forms of EB in which warmer weather exacerbates disease activity. The reason for this is unknown. Extracutaneous complications can occur including oral cavity blistering, constipation and, rarely, tracheolaryngeal compromise.\nEtiology\nEBS-DM is caused by dominant negative mutations within either the KRT5 (12q13.13) or KRT14 (17q12-q21) genes, encoding keratin 5 and keratin 14, respectively.\nGenetic counseling\nTransmission is autosomal dominant and sporadic cases are frequent.\nPrognosis\nEBS-DM is frequently associated with marked morbidity in infancy and early childhood and, in rare cases, may result in death during early infancy. Patients also have a markedly increased risk of basal cell carcinoma by mid-adulthood (cumulative risk of 44% by age 55).\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency", "Disease Definition": "A very rare primary immunodeficiency disorder characterized by the clinical triad of high serum IgE (>2000 IU/ml), recurring staphylococcal skin abscesses, and recurrent pneumonia with formation of pneumatoceles.", "ORPHA ID": 2314, "Summary": "Epidemiology\nAnnual incidence is estimated at around 1/1,000,000. The syndrome affects males and females equally.\nClinical description\nAD-HIES typically first manifests with neonatal rash but it affects the immune system, connective tissue, skeleton, and dental development, with variations in severity. Eczema, recurrent skin abscesses, pneumonia with pneumatocele formation, mucocutaneous candidiasis, elevated serum IgE levels, and eosinophilia are the most common features of immune deficiency/dysregulation. Severe recurrent respiratory infections that may lead to chronic respiratory insufficiency are frequent. A distinctive facial appearance is described (rough skin, facial asymmetry, a prominent forehead, deep-set eyes, broad nasal bridge and a fleshy nasal tip, prognathism), along with midline anomalies. Recurrent pathological fractures occur in about 50% of patients (long bones and ribs). Scoliosis of varying degrees of severity is seen in more than 60%. Anomalies of dentinogenesis are a consistent feature. Reduced resorption of primary tooth roots may lead to prolonged retention of primary teeth, which in turn prevents the appropriate eruption of permanent teeth. Vascular features (coronary and aortic aneurysms, thrombosis of the cerebellar artery and congenital patent ductus venosus) have also been reported. Ocular complications may include xanthelasmas, giant chalasias, eyelid nodules, strabismus, and retinal detachment with complicated cataracts. There is also an increased risk of autoimmune and lymphoproliferative diseases.\nEtiology\nIn 70% of patients, the phenotype is associated with heterozygous mutations of the signal transducer and activator of transcription 3 gene (STAT3; 17q21.31). STAT3 plays a key role in the signal transduction of a broad range of cytokines (control of infections caused by fungi and extracellular bacteria). The etiology in the remaining 30% is unknown.\nDiagnostic methods\nThe diagnostic hallmark is increased serum immunoglobulin E (IgE) levels exceeding 2000 U/ml, often higher than 5000 U/ml. A clinical scoring sheet has been defined to assess the probability of diagnosis. Total IgE concentration > 1000 IU/ml and weighted score of clinical features > 30 indicates AD-HIES due to STAT3 deficiency, and a dominant-negative heterozygous mutation in STAT3 provides a definitive diagnosis.\nDifferential diagnosis\nThe differential diagnosis should include cystic fibrosis and chronic granulomatous disease (see these terms), as well as severe atopic dermatitis and HIV-infection. A clinically distinct autosomal recessive hyper-IgE syndrome has also been described (AR-HIES; see this term).\nAntenatal diagnosis\nPrenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.\nGenetic counseling\nThe majority of AD-HIES cases are caused by de novo mutations and are therefore sporadic but autosomal dominant transmission is characteristic for STAT3 mutations.\nManagement and treatment\nThe therapeutic approach involves prevention and management of infections with long-term administration of systemic antibiotics and antifungals. Lung abscesses may require surgery but possible complications require close attention. The role of hematopoietic stem cell transplantation (HSCT) has to be evaluated further.\nPrognosis\nAlthough HIES is associated with significant morbidity and mortality, adequate care, close monitoring, and patient compliance improve the prognosis and can lead to survival of 50 years of age or over.\n\n                            Last update: \n                            June 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Bodo GRIMBACHER  - Dr Cristina WOELLNER"}
{"Disease Name": "Autosomal dominant hyperinsulinism due to Kir6.2 deficiency", "Disease Definition": "A form of diazoxide-sensitive diffuse hyperinsulinism (DHI) characterized by hypoglycemic epiosodes that are usually mild, escaping detection during infancy, and usually a good clinical response to diazoxide, (but some are diazoxide resistant). Autosomal dominant hyperinsulinism due to Kir6.2 deficiency usually has a milder phenotype when compared to that resulting from recessive K+ (K-ATP) channel mutations (Recessive forms of diazoxide-resistant hyperinsulinism).", "ORPHA ID": 276580, "Summary": ""}
{"Disease Name": "Autosomal dominant hyperinsulinism due to SUR1 deficiency", "Disease Definition": "A form of congenital diazoxide-sensitive diffuse hyperinsulinism due to ABCC8 variants and characterized by hypoglycemic episodes that are usually mild, escaping detection during infancy, and usually have a good clinical response to diazoxide. The autosomal dominant hyperinsulinism usually has a milder phenotype when compared to that resulting from recessive potassium (K-ATP) channel mutations.", "ORPHA ID": 276575, "Summary": ""}
{"Disease Name": "Autosomal dominant hypocalcemia", "Disease Definition": "A rare disorder of calcium homeostasis characterized by variable degrees of hypocalcemia with disproportionately low/normal levels of parathyroid hormone (PTH) and persistent normal or elevated renal calcium excretion.", "ORPHA ID": 428, "Summary": "Epidemiology\nPrevalence is unknown, but the disease is likely to be underdiagnosed as the hypocalcemia may remain asymptomatic.\nClinical description\nClinical expression and age of onset are extremely variable (depending on the degree of hypocalcemia), ranging from completely asymptomatic patients (in whom the diagnosis is made by chance during a routine exam) to patients with limited symptoms (cramps, asthenia, paresthesias) and patients with severe symptoms (i.e. recurrent seizures). In addition to hypocalcemia, hypercalciuria or relative hypercalciuria (hypercalciuria within the normal range, but relatively high in the presence of hypocalcemia) is present. Hyperphosphatemia, hypomagnesemia and hypermagnesuria are also common. Nephrocalcinosis and impaired renal function have been reported and cases of autosomal dominant hypocalcemia (ADH) with classical features of Bartter syndrome (BS) have been described (referred to as BS with hypocalcemia). Serum levels of PTH are normal or low. In addition to regulation by PTH, environmental factors also influence calcium homeostasis and may explain why an initially well-controlled hypocalcemia may become symptomatic at various stages of life.\nEtiology\nADH is caused by activating mutations of the gene CASR (3q21.1), encoding the calcium-sensing receptor (CaSR). CaSR is expressed by cells in several tissues and plays a key role in the regulation of calcium-phosphate metabolism by controlling PTH secretion and renal calcium excretion in response to variations in serum calcium levels. Gain-of-function CASR mutations result in increased sensitivity of parathyroid and renal cells to calcium levels, leading to hypocalcemia being perceived as normal. Activating mutations in GNA11 (19p13.3) have also been described.\nDiagnostic methods\nDiagnosis is made through analysis of serum calcium and PTH levels. Molecular analysis of CASR followed by GNA11 confirms diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes all other causes of hypoparathyroidism as well as BS in patients with renal salt wasting.\nAntenatal diagnosis\nAntenatal diagnosis is possible.\nGenetic counseling\nGenetic counseling may be proposed but patients should be informed about the wide variability in clinical presentation.\nManagement and treatment\nTreatment to normalize calcemia levels should be considered with caution, as any increase in calcium levels (even within the normal range) will be perceived by renal cells as hypercalcemia and lead to increased urinary calcium excretion, with increased risk of nephrocalcinosis and renal failure. Treatment should aim towards finding a balance between the clinical signs of hypocalcemia and (near-)normal serum calcium levels. Urine calcium levels should be monitored in order to avoid hypercalciuria rather than adapting treatment towards hypocalcemia. In asymptomatic and mildly symptomatic patients, treatment may not be necessary. Special care must be given to children as chronic hypocalcemia has deleterious effects on intellectual development. Treatment is based on administration of 1-alpha hydroxylated vitamin D (doses ranging from 0.5 to 1.5 micrograms/day, but higher doses are sometimes required). Careful monitoring of calciuria and regular kidney ultrasound are recommended. In cases where calcium homeostasis is difficult to achieve, exogenous PTH can be attempted.\nPrognosis\nThe prognosis is variable, depending on the severity of the hypocalcemia /hypercalciuria and the possible consequences of treatment. In adults, it is associated with a reduced quality of life.\n\n                            Last update: \n                            March 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Lars REJNMARK | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal dominant hypophosphatemic rickets", "Disease Definition": "A rare hereditary renal phosphate-wasting disorder characterized by hypophosphatemia, rickets and/or osteomalacia.", "ORPHA ID": 89937, "Summary": "Epidemiology\nAutosomal dominant hypophosphatemic rickets (ADHR) is extremely rare, to date approximately 50 cases have been reported in the literature.\nClinical description\nClinical manifestations depend on the age of onset (childhood, adolescence, even adulthood) and on the severity of hypophosphatemia. During childhood, the disease manifests with signs and symptoms of rickets. When the disease manifests during adolescence or adulthood, clinical findings include bone pain, muscle weakness, and pseudo fractures. Some patients are asymptomatic throughout life, some patients alternate between symptomatic and non-symptomatic.\nEtiology\nThe disease is caused by activating mutations in the FGF23 gene (12p13) encoding fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone. These mutations render FGF23 resistant to cleavage and thus cause an increase in circulating levels. Increased FGF23 levels leads to reduced renal phosphate reabsorption and decreased intestinal phosphate and calcium absorption, consequently leading to abnormal bone mineralization.\nDiagnostic methods\nDiagnosis is based on clinical findings, and biochemical and X-ray examination. Biochemical findings can include significant hypophosphatemia, hyperphosphaturia (that can disappear with age), elevated circulating levels of FGF23 associated with normal serum levels of calcium, increased plasma levels of alkaline phosphatase. Radiological findings include typical signs of rickets and/or osteomalacia. Molecular genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemia (ARHP), hereditary hypophosphatemic rickets with hypercalciuria (HHRH), fibrous dysplasia of bones, renal Fanconi syndrome, vitamin D deficiency, and tumor-induced osteomalacia.\nGenetic counseling\nTransmission is autosomal dominant with incomplete penetrance.\nManagement and treatment\nTreatment aims at improving growth, bone or joint pain, enhancing mineralization of bones, and preventing skeletal deformities caused by rickets. It consists of daily oral administration of phosphate and calcitriol and is associated with frequent monitoring of height, calcium, alkaline phosphatase, parathyroid hormone, and phosphate serum concentrations, as well as urinary calcium and creatinine. Corrective surgery of skeletal deformities may be required in some cases. Sometimes, nephrocalcinosis and hyperparathyroidism can be observed as complications of the therapy; frequent follow-up is therefore necessary. The efficacy of burosumab (an anti-FGF23 humanized antibody), a recently developed therapy that lowers circulating FGF-23 levels and thus corrects renal phosphate wasting, has not yet been evaluated in ADHR patients.\nPrognosis\nWith treatment, prognosis is very good: growth is normalized and skeletal deformities can be corrected.\n\n                            Last update: \n                            August 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès LINGLART | Endo-ERN* - Dr Anya ROTHENBUHLER | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome", "Disease Definition": "A rare genetic neurodevelopmental disorder characterized by global developmental delay (DD) and variable degrees of intellectual disability (ID) with delayed or limited/absent speech development associated with neonatal hypotonia, feeding difficulties, cardiac anomalies and dysmorphic facial features, predominantly broad nasal tip and thin, tented upper lip. Microcephaly, frequent infections, gastrointestinal and/or ocular anomalies have also been described.", "ORPHA ID": 457193, "Summary": "Epidemiology\nAbout 76 patients are reported in the scientific and medical literature; however, more than 300 are known to patient organizations.\nClinical description\nMost patients present with neonatal hypotonia and feeding difficulties, often requiring nasogastric intubation. The developmental delay and intellectual disability are of variable severity. All patients reported presented with language delay/deficits (mostly expressive limitations) and some patients are non-verbal into adulthood. About half of the patients are diagnosed with a cardiac abnormality (atrial septal defects, ventricular septal defect, patent foramen ovale and/or persistent ductus arteriosus). Other frequent problems are gastroesophageal reflux, constipation and eye abnormalities (strabismus, amblyopia and less frequently refractory errors). A facial gestalt might be recognized with a broad nasal tip, thin tented upper lip and bi-temporal narrowing. Microcephaly occurs in a minority of the patients. Other less common features are autism spectrum disorders, sleep disturbances, craniosynostosis, seizures, increased susceptibility to infections, haematological and immunological abnormalities and bowel obstruction.\nEtiology\nThe disorder is caused by heterozygous pathogenic variants affecting the KAT6A gene (8p11.21) which encodes for a lysine (K) acetyltransferase 6A that forms part of a histone acetyltransferase complex regulating transcriptional activity and gene expression. Genotype-phenotype correlations suggest that variants affecting the last two exons of the gene (16 and 17) are associated with a more severe phenotype.\nDiagnostic methods\nThe diagnosis is established by whole exome or genome sequencing or multi-gene panel including the KAT6A gene. Cases due to copy number variants might be identified by array-comparative genomic hybridization.\nDifferential diagnosis\nThe syndrome has an extensive differential diagnosis in the context of syndromic DD/ID.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe disorder is autosomal dominant. Most cases are sporadic due to de novo variants, but familial and germinal mosaicism cases have been reported. For the affected individual, the risk of transmission is 50% for each pregnancy.\nManagement and treatment\nManagement is symptom-based and requires a multidisciplinary approach. Early speech and language therapy can improve oro-motor dyspraxia and articulation deficits. Augmentative and alternative communication tools are important aids. All patients require early cardiac evaluation with electrocardiogram and echocardiogram. Tube feeding might be required in infants, and all patients should be monitored for signs and symptoms of gastroesophageal reflux. Older patients might need long term medication with laxatives. Bowel obstruction should be considered in case of abdominal pain, and increased vomiting/reflux. Follow-up should include evaluation of behavioural/social difficulties, complete blood count and immune profile for recurrent infections, and regular assessment of vision. For sleep disorder, study of obstructive apnoea is recommended and melatonin supplementation might be considered.\nPrognosis\nLong term prognosis of the disorder is unknown.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Patricia DIAS | ITHACA* - Dr Mariana NEVES | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal dominant intermediate Charcot-Marie-Tooth disease type A", "Disease Definition": "A rare hereditary motor and sensory neuropathy characterized by intermediate motor median nerve conduction velocities (usually between 25 and 45 m/s) and signs of both demyelination and axonal degeneration in nerve biopsies. It presents with usual clinical features of Charcot-Marie-Tooth disease (progressive muscle weakness and atrophy of the distal extremities, distal sensory loss, reduced or absent deep tendon reflexes, and feet deformities) in the first to second decade of life with steady progression until the fourth decade, severe progression and stabilization afterwards.", "ORPHA ID": 100043, "Summary": ""}
{"Disease Name": "Autosomal dominant intermediate Charcot-Marie-Tooth disease type B", "Disease Definition": "A rare hereditary motor and sensory neuropathy characterized by intermediate motor median nerve conduction velocities (usually between 25 and 45 m/s) and signs of both demyelination and axonal degeneration in nerve biopsies. It presents with mild to moderately severe, slowly progressive usual clinical features of Charcot-Marie-Tooth disease (muscle weakness and atrophy of the distal extremities, distal sensory loss, reduced or absent deep tendon reflexes, and feet deformities). Other findings include asymptomatic neutropenia and early-onset cataracts.", "ORPHA ID": 100044, "Summary": ""}
{"Disease Name": "Autosomal dominant intermediate Charcot-Marie-Tooth disease type C", "Disease Definition": "A rare hereditary motor and sensory neuropathy characterized by intermediate motor median nerve conduction velocities (usually between 25 and 60 m/s). It presents with moderately severe, slowly progressive usual clinical features of Charcot-Marie-Tooth disease (muscle weakness and atrophy of the distal extremities, distal sensory loss, reduced or absent deep tendon reflexes, feet deformities, extensor digitorum brevis atrophy). Findings in nerve biopsies include age-dependent axonal degeneration, reduced number of large myelinated fibres, segmental remyelination, and no onion bulbs.", "ORPHA ID": 100045, "Summary": ""}
{"Disease Name": "Autosomal dominant intermediate Charcot-Marie-Tooth disease type D", "Disease Definition": "A rare hereditary motor and sensory neuropathy characterized by intermediate motor median nerve conduction velocities (usually between 25 and 45 m/s) and signs of both axonal degeneration and demyelination without onion bulbs in nerve biopsies. It presents with usual Charcot-Marie-Tooth disease clinical features of variable severity (progressive muscle weakness and atrophy of the distal extremities, distal sensory loss, reduced or absent deep tendon reflexes, and feet deformities). Other findings in some of the families include debilitating neuropathic pain and mild postural/kinetic upper limb tremor.", "ORPHA ID": 100046, "Summary": ""}
{"Disease Name": "Autosomal dominant intermediate Charcot-Marie-Tooth disease type E", "Disease Definition": "A rare hereditary motor and sensory neuropathy disorder characterized by the typical CMT phenotype (slowly progressive distal muscle weakness and atrophy in upper and lower limbs, distal sensory loss in extremities, reduced or absent deep tendon reflexes and foot deformities) associated with focal segmental glomerulosclerosis (manifesting with proteinuria and progression to end-stage renal disease). Mild or moderate sensorineural hearing loss may also be associated. Nerve biopsy reveals both axonal and demyelinating changes and nerve conduction velocities vary from the demyelinating to axonal range (typically between 25-50m/sec).", "ORPHA ID": 93114, "Summary": ""}
{"Disease Name": "Autosomal dominant intermediate Charcot-Marie-Tooth disease type F", "Disease Definition": "A rare hereditary motor and sensory neuropathy disorder characterized by the typical CMT phenotype (slowly progressive distal muscle atrophy and weakness in upper and lower limbs, distal sensory loss in extremities, reduced or absent deep tendon reflexes and foot deformities) with nerve biopsy demonstrating demyelinating and axonal changes and nerve conduction velocities varying from the demyelinating to axonal range.", "ORPHA ID": 352670, "Summary": ""}
{"Disease Name": "Autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain", "Disease Definition": "A rare subtype of autosomal dominant intermediate Charcot-Marie-Tooth disease characterized by debilitating neuropathic pain associated with mild, distal, symmetrical lower limb sensory loss and mild or absent motor dysfunction. Patients typically manifest with burning, aching, shooting, or throbbing pain and intermittent paraesthesia in toes, heels and ankles.", "ORPHA ID": 324585, "Summary": ""}
{"Disease Name": "Autosomal dominant Kenny-Caffey syndrome", "Disease Definition": "A rare, primary bone dysplasia characterized by severe growth retardation, short stature, cortical thickening and medullary stenosis of long bones, delayed closure of the anterior fontanelle, absent diploic space in the skull bones, prominent forehead, macrocephaly, dental anomalies, eye problems (hypermetropia and pseudopapilledema), and hypocalcemia due to hypoparathyroidism, sometimes resulting in convulsions. Intelligence is normal.", "ORPHA ID": 93325, "Summary": ""}
{"Disease Name": "Autosomal dominant keratitis", "Disease Definition": "A rare genetic inflammatory corneal disorder characterized by anterior stromal corneal opacification and vascularization of the peripheral cornea with potential central progression and subsequent reduction in visual acuity. Variable features include abnormalities of the iris, such as stromal defects and ectropion uveae, as well as foveal hypoplasia.", "ORPHA ID": 2334, "Summary": ""}
{"Disease Name": "Autosomal dominant limb-girdle muscular dystrophy type 1A", "Disease Definition": "A rare subtype of autosomal dominant limb girdle muscular dystrophy characterized by an adult onset of proximal shoulder and hip girdle weakness (that later progresses to include distal weakness), nasal speech and dysarthria. Other frequent findings include tightened heel cords, reduced deep-tendon reflexes and elevated creatine kinase serum levels. Respiratory failure, as well as mild facial weakness and dysphagia, may also be observed.", "ORPHA ID": 266, "Summary": ""}
{"Disease Name": "Autosomal dominant macrothrombocytopenia", "Disease Definition": "A rare isolated constitutional thrombocytopenia characterized by abnormally large platelets.", "ORPHA ID": 140957, "Summary": "Epidemiology\nTo date less than 10 cases are reported.\nClinical description\nAutosomal dominant macrothrombocytopenia is caused by mutations in the integrin, beta 3 ITGB3, tubulin, beta-1TUBB1 and actinin, alpha1 ACTN1 genes. These mutations lead to abnormal proplatelets and thrombocytopenia.\nEtiology\nTransmission is autosomal dominant.\n\n                            Last update: \n                            May 2013"}
{"Disease Name": "Autosomal dominant mendelian susceptibility to mycobacterial diseases due to a partial deficiency", "Disease Definition": "A group of variants of mendelian susceptibility to mycobacterial diseases (MSMD) due to dominantly inherited partial deficiencies in interferon gamma receptor 1 (IFN-gammaR1), IFN-gammaR2, signal transducer and activator of transcription 1 (STAT1) or interferon regulator factor 8 (IRF8).", "ORPHA ID": 319543, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe clinical disease seen in all of these variants is relatively mild. Weakly virulent bacillus Calmette-Guérin (BCG) and Mycobacterium avium complex infections are most commonly seen in patients with these diseases.\nEtiology\nAD MSMD due to a partial deficiency is caused by a mutation in one of the following genes: IFNGR1, IFNGR2, STAT1 or IRF8, depending on the variant. These mutations affect the IFN-gamma pathway and lead to susceptibility to infections with BCG and other environmental mycobacteria.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency", "Disease Definition": "A rare, genetic variant of mendelian susceptibility to mycobacterial diseases (MSMD) characterized by a partial deficiency leading to impaired IFN-gamma immunity and, consequently, recurrent, moderately severe infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).", "ORPHA ID": 319581, "Summary": "Epidemiology\nThe prevalence is unknown. Since it was first reported in 1999, more than 70 patients bearing heterozygous mutations in IFNGR1 gene have been reported.\nClinical description\nPatients present with moderately severe mycobacterial infections at around the age of 13 years. These infections are recurrent but less severe than those seen in MSMD due to complete IFN-gammaR1 and IFN-gammaR2 deficiencies (see these terms). Infections with Mycobacterium bovis BCG or Mycobacterium avium often lead to multifocal or unifocal osteomyelitis in patients with this variant. Salmonellosis has been reported in 5% of cases and infections with other pathogens such as Histoplasma capsulatum and varicella-zoster virus have also been reported in single patients.\nEtiology\nAD MSMD due to partial IFN-gammaR1 deficiency is caused by heterozygous mutations in the IFNGR1 gene on chromosome 6q23-q24 that encodes the IFN-gamma receptor ligand binding chain. Microdeletion 818del4 is by far the most common mutation and it corresponds to the first documented hotspot for a microdeletion in the human genome. It leads to the expression of IFN-gamma receptor on the cell surface with no signal transduction and therefore patients only show a partial response to IFN-gamma.\nDiagnostic methods\nDiagnosis is made by laboratory analysis. Cells of patients show a residual response to IFN-gamma in terms of Stat-1 DNA-binding (GAS-binding activity) and HLA-II induction. Genetic testing reveals mutations in IFNGR1.\nDifferential diagnosis\nOther genetic etiologies of MSMD should be excluded.\nAntenatal diagnosis\nThis immunodeficiency is not severe and antenatal diagnosis is not necessary.\nGenetic counseling\nTransmission is autosomal dominant and genetic counseling is possible.\nManagement and treatment\nBCG vaccination should be avoided in those with a known mutation in the IFNGR1 gene. Patients should be treated with antibiotics and, if necessary, with recombinant IFN-gamma.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency", "Disease Definition": "A rare, genetic variant of mendelian susceptibility to mycobacterial diseases (MSMD) characterized by a partial deficiency in IFN-gammaR2, leading to impaired response to IFN-gamma and, consequently, to recurrent, moderately severe infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).", "ORPHA ID": 319589, "Summary": "Epidemiology\nThe prevalence is unknown. It was recently discovered in two patients.\nClinical description\nThe first reported patient with this deficiency presented with moderate mycobacterial infections secondary to BCG vaccination. She developed no other severe infections. The father of this patient was a heterozygous carrier of the mutation, but remained healthy.\nEtiology\nAD MSMD due to partial IFN-gammaR2 deficiency is caused by a heterozygous mutation in the IFNGR2 gene on chromosome 21q22.1-22.2 that encodes the IFN-gamma receptor ligand binding chain 2. The 186delC mutation corresponds to the first mutation conferring an AD partial IFN-gammaR2 deficiency.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Autosomal dominant mitochondrial myopathy with exercise intolerance", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder due to nuclear DNA anomalies characterized by onset of slowly progressive proximal lower limb weakness and exercise intolerance in the first decade of life, followed by weakness of neck flexor, shoulder, and distal leg muscles. Facial muscles become involved still later in the disease course. Additional manifestations are restrictive pulmonary function and short stature. Laboratory studies reveal lactic acidemia and increased serum creatine kinase.", "ORPHA ID": 457050, "Summary": ""}
{"Disease Name": "Autosomal dominant multiple pterygium syndrome", "Disease Definition": "A rare distal arthrogryposis syndrome characterized by multiple pterygia (typically involving the neck, axilla and popliteal areas), joint contractures, ptosis, camptodactyly of the hands with hypoplastic flexion creases, vertebral fusions, severe scoliosis and short stature.", "ORPHA ID": 65743, "Summary": ""}
{"Disease Name": "Autosomal dominant myoglobinuria", "Disease Definition": "A rare metabolic myopathy characterized by episodic myalgia with myoglobinuria which is induced by fever, viral or bacterial infection, prolonged exercise or alcohol abuse, and could, on occasion, lead to acute renal failure. Between episodes, patients may be asymptomatic or could present elevated creatine kinase levels and mild muscle weakness. There have been no further descriptions in the literature since 1997.", "ORPHA ID": 99846, "Summary": ""}
{"Disease Name": "Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome", "Disease Definition": "A rare primary bone dysplasia characterized by micromelia with rhizomelic shortening, metaphyseal widening of the long bones, brachydactyly, small scapulae, micrognathia and thoracic insufficiency requiring tracheostomy and ventilation, and severe myopia and sensorineural hearing loss. Further dysmorphic craniofacial features include frontal bossing, proptosis, epicanthal folds, short nose, flat nasal bridge, anteverted nares, midfacial retrusion, and cleft palate.", "ORPHA ID": 440354, "Summary": ""}
{"Disease Name": "Autosomal dominant neovascular inflammatory vitreoretinopathy", "Disease Definition": "A rare, genetic, vitreoretinal degeneration characterized by a slowly progressive vitreoretinopathy with onset during the second or third decade of life. The disease initially presents as autoimmune uveitis with reduction in the b-wave on electroretinography, and progresses with development of photoreceptor degeneration, vitreous hemorrhage, cystoid macular edema, retinal neovascularization, intraocular fibrosis, secondary glaucoma, and retinal detachment leading to phthisis and complete blindness.", "ORPHA ID": 329211, "Summary": ""}
{"Disease Name": "Autosomal dominant nocturnal frontal lobe epilepsy", "Disease Definition": "A rare seizure disorder characterized by intermittent dystonia and/or choreoathetoid movements that occur during sleep. The clusters of nocturnal motor seizures are often stereotyped and brief.", "ORPHA ID": 98784, "Summary": "Epidemiology\nOver 100 families have been described in the literature to date. Males and females are affected equally.\nClinical description\nThe age of onset varies between 3 and 47 years (usually < 20 years, with a peak during childhood). Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is defined by different motor events of increasing complexity and duration, arising during non-rapid eye movement sleep (NREM), including short-lasting (2-4 sec) stereotyped movements involving the limbs, axial musculature, and/or the head; paroxysmal arousals characterized by sudden and brief arousals (5-10 sec) sometimes accompanied by stereotyped movements, vocalization, and fear; and major attacks (20-30 sec), featuring asymmetric tonic or dystonic posturing, or complex movements (pelvic thrusting, pedaling, choreoathetoid, and ballistic movements of the limbs). Some patients may show ictal deambulatory behaviors often associated with frightened expression. The frequency is highly variable ranging from 5 attacks per night to 5 times per year. Daytime dyskinesia, generalized seizures and auras may occur. Intellect is usually preserved or mildly reduced and psychiatric comorbidity may occur. Paroxysmal hypnogenic dyskinesia (PHD), which was previously characterized as a form of paroxysmal dyskinesia, is now considered to be ADNFLE.\nEtiology\nADNFLE results from malfunction in the thalamo-cortical loops. The genes involved are CHRNA4 (20q13.33), CHRNB2 (1q21.3), CHRNA2 (8p21), KCNT1 (9q34.3), DEPDC5 (22q12.3), CRH (8q13), and CABP4 (11q13.2).\nDiagnostic methods\nDiagnosis relies principally on clinical history revealing at least one of the following four criteria: motor event duration of less than 2 minutes; unstructured vocalization during the episode; experience of an aura preceding the motor attack; history of tonic-clonic seizures during sleep. Diagnosis is also achieved by recording seizures by nocturnal video polysomnography (V-PSG) and confirmed by genetic screening.\nDifferential diagnosis\nDifferential diagnoses include paroxysmal dyskinesia, familial focal epilepsy with variable foci, restless legs syndrome, periodic limb movement disorders (PLMS), REM sleep behavior disorders (RBD), nocturnal panic attacks, non-REM parasomnias, obstructive sleep apnea syndrome, and arousal disorders.\nGenetic counseling\nTransmission is autosomal dominant with a penetrance ranging from 60 % to 80 %. High intra-familial heterogeneity has been described. Sporadic cases may occur.\nManagement and treatment\nThe treatment of choice for ADNFLE includes use of carbamazepine (200-1,000 mg/day). Carbamazepine abolishes seizures in 20% of cases, and gives significant relief (at least 50 % seizure reduction) in another 48%. Oxcarbamazepine, topiramate and acetazolamide (as add-on therapies) may also be used. Nicotine transdermal patches may be efficient in patients who are refractory to standard antiepileptic drugs. Quinidine, a potassium channel blocker, has been reported as a potential therapeutic agent in only a few patients with KCNT1 mutation implicated in ADNFLE and epilepsy of infancy with migrating focal seizures (EIMFS). Surgical treatment may be indicated for drug-resistant patients, both for seizures and for epilepsy-related sleep disturbances. Neuropsychological testing and psychiatric assessment are advised for ADNFLE affected individuals.\nPrognosis\nADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Shinichi HIROSE  - Dr Hirokazu KURAHASHI"}
{"Disease Name": "Autosomal dominant optic atrophy and cataract", "Disease Definition": "A form of autosomal dominant optic atrophy characterized by an early and bilateral optic atrophy leading to insidious visual loss of variable severity, followed by a late anterior and/or posterior cortical cataract. Additional features include sensorineural hearing loss and neurological signs such as tremor, extrapyramidal rigidity and absence of deep tendon reflexes. It is caused by mutations in the OPA3 gene (19q13.32).", "ORPHA ID": 67036, "Summary": ""}
{"Disease Name": "Autosomal dominant optic atrophy and peripheral neuropathy", "Disease Definition": "A rare form of autosomal dominant optic atrophy (ADOA) characterized by progressive and isolated visual loss in the first decade of life, decreased reflexes in the lower limbs and a mild cerebellar stance.", "ORPHA ID": 250932, "Summary": ""}
{"Disease Name": "Autosomal dominant optic atrophy plus syndrome", "Disease Definition": "A rare neuro-ophthalmological disease associating the typical optic atrophy with other extra-ocular manifestations such as sensorineural deafness, myopathy, chronic progressive external ophthalmoplegia, ataxia and peripheral neuropathy. More rarely, other manifestations have been associated with this condition, such as spastic paraplegia or multiple-sclerosis like illness.", "ORPHA ID": 1215, "Summary": "Epidemiology\nAutosomal dominant optic atrophy plus syndrome (ADOA plus) accounts for approximately 20% of all ADOA cases.\nClinical description\nADOA plus is characterized by bilateral and symmetric progressive visual loss (visual acuity ranging from 20/30 to 20/200) and color vision deficiency, occurring typically during the first decade of life. Sensorineural deafness usually occurs later, during the second or third decade of life, although it may also be diagnosed, in rare instances, prior to the optic neuropathy. From the third decade onwards, other extra-ocular manifestations may appear, such as chronic progressive external ophthalmoplegia, proximal myopathy, ataxia and axonal sensory motor polyneuropathy. Other manifestations have been more rarely associated with ADOA plus, such as multiple sclerosis-like illness, migraine, cardiomyopathy, late-onset diabetes mellitus, and spastic paraplegia.\nEtiology\nADOA plus is caused by mutations in the OPA1 gene (3q29), encoding a dynamin-like GTPase involved in the fusion of the inner mitochondrial membrane, in energetic production and mitochondrial DNA stability.\nDiagnostic methods\nOphthalmological examination is not specific and typically shows a moderate bilateral optic atrophy associated with bilateral central or paracentral scotomas. Diagnosis of ADOA plus relies both on the genetic screening of the OPA1 gene and on skeletal muscle biopsy to measure the enzymatic activity of the respiratory chain complexes, allowing histological examination (Gomori-modified trichrome and double cytochrome C oxidase/succinate dehydrogenase staining) which typically reveals features of mitochondrial myopathy (cytochrome C negative fibers and ragged red fibers). Laboratory findings may reveal hyperlactacidemia. Additional investigations may include an audiological work-up, peripheral nerve conduction studies, electromyography, electroencephalography, brain magnetic resonance imaging, according to the patient's symptoms.\nDifferential diagnosis\nDifferential diagnosis includes several other syndromic hereditary optic neuropathies that may have bilateral manifestations associated with extra ocular features and that presents with a similar phenotype, such as Autosomal dominant Charcot-Marie-Tooth disease type 2A, Leber hereditary optic neuropathy, Wolfram syndrome and Wolfram-like syndrome.\nAntenatal diagnosis\nPrenatal identification of a mutation may be proposed in families with previously known mutations, with the understanding that not all the carriers will manifest the disease.\nGenetic counseling\nTransmission is autosomal dominant with variable penetrance and genetic counselling is recommended.\nManagement and treatment\nThere is currently no efficient treatment for ADOA plus. Low-vision aids may be recommended and cochlear implants have been shown to improve audition in patients with sensorineural deafness. The role of idebenone has been anecdotally reported in ADOA. Physiotherapy for the muscular symptoms programs can be warranted for patients with multiple sensory and motor handicaps. Avoiding tobacco and alcohol intake as well as medications interfering with mitochondrial metabolism (certain antibiotics, antivirals) is recommended.\nPrognosis\nVision seems to be more severely affected in patients with ADOA plus than in patients with no extra ocular involvement. If associated, hearing loss can further impair social communication.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Dan MILEA  - Pr Pascal REYNIER"}
{"Disease Name": "Autosomal dominant optic atrophy, classic form", "Disease Definition": "A rare neuro-ophthalmological disease which is one of the most common forms of hereditary optic neuropathy characterized by progressive bilateral visual loss with an onset during the first decade of life, associated with optic disc pallor, visual acuity loss, visual field deficits and color vision defects.", "ORPHA ID": 98673, "Summary": "Epidemiology\nThe prevalence of Autosomal dominant optic atrophy (ADOA) is variable, commonly varying between 1/10,000 in Denmark (due to a founder effect) to 1/35,000 in the UK and probably worldwide.\nClinical description\nADOA is usually detected during the first decade of life, often by vision screening in school but later onset is possible. Visual impairment is usually moderate (visual acuity ranges from 20/80 to 20/120) but may range from mild to severe. Visual field defect is typically centrocecal, central, or paracentral. Color vision is often affected, usually but not always in the blue-yellow axis (tritanopia). Legal blindness is rare. Patients may also be asymptomatic, albeit bearing the mutation. In about 20% of cases, extra-ocular signs are present, such as sensorineural hearing loss or other severe neurological signs, that occur typically later in life, in young adults, such as myopathy, ataxia, peripheral neuropathy, chronic progressive external ophthalmoplegia (ADOA plus). Rare forms of the disease, similar to Behr syndrome have been reported with biallelic OPA1 mutations (Behr syndrome, OPA1).\nEtiology\nA majority, but not all ADOA patients harbor mutations in the gene OPA1 (3q29) which codes for an inner mitochondrial membrane protein intricately involved in mitochondrial biogenesis, mitochondrial DNA replication and mitochondrial dynamics. Visual impairment is highly variable both within and between families, even when considering the same mutation.\nDiagnostic methods\nADOA is most often suspected in children with unexplained optic neuropathy, especially if associated with a similar family history (which may nevertheless be absent in 50% of cases). Fundus examination typically reveals bilateral and symmetrical pallor of the temporal side of the optic nerve head, pallor of the optic nerve rim and a temporal grey crescent, sometimes associated with abnormal optic disc cupping. Visual evoked potentials (VEP) are usually delayed and pattern electroretinogram shows an abnormal N95:P50 ratio, with reduction in the amplitude of the N95 waveform suggesting alterations of the retinal ganglion cells layer. Optical Coherence Tomography (OCT) discloses a global reduction of the peripapillary retinal nerve fiber layer thickness, mainly in the infero-temporal quadrant. The rest of the retinal is tipically normal. The diagnosis is confirmed by the genetic screening of OPA1.\nDifferential diagnosis\nDifferential diagnosis includes all the common causes of optic neuropathies: compressive, inflammatory, ischemic, toxic and metabolic causes. Other hereditary optic neuropathies such as Leber's hereditary optic neuropathy, Wolfram syndrome have different initial presentations (later onset, associated or not with other neurological or systemic signs), but the final clinical phenotype of optic neuropathy is not specific. Other genes involved in isolated or syndromic forms autosomal dominant optic atrophy are : ACO2, SPG7, AFG3L2, MFN2, OPA3, DRP1, and SSBP1.\nAntenatal diagnosis\nPrenatal identification of a mutation may be proposed in families with previously known mutations, with the understanding that not all the carriers will manifest the disease.\nGenetic counseling\nTransmission is autosomal dominant with a penetrance of 50%.\nManagement and treatment\nThere are currently no efficient treatments in ADOA. Low-vision aids may be recommended in patients with severely decreased visual acuity. Tobacco use, excessive alcohol intake and medications that may have mitochondrial toxicity should be avoided.\nPrognosis\nVisual impairment in ADOA is classically irreversible ; spontaneous recovery has been only exceptionally reported. Visual loss is usually mild, but can at times worsen later during lifetime. ADOA does not affect intellectual development or life span. Patients may have normal familial and social life although vocational integration may at times be problematic.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Dan MILEA  - Pr Pascal REYNIER"}
{"Disease Name": "Autosomal dominant osteopetrosis type 1", "Disease Definition": "A rare sclerosing bone disorder characterized by skeletal densification that predominantly involves the cranial vault.", "ORPHA ID": 2783, "Summary": "Epidemiology\nIt is extremely rare, as only 33 cases have been reported in 3 families.\nClinical description\nThe disease typically has onset in late childhood or adolescence. Clinical signs include chronic bone pain and disorders of the cranial nerves (trigeminal neuralgia, facial palsy, hearing loss). The risk of fracture is not increased and patients show normal or even increased trabecular bone strength. Twenty to forty percent of cases are asymptomatic.\nEtiology\nThe disease is due to a gain-of-function mutation in the LRP5 gene (Low density lipoprotein receptor-related protein 5; 11q12-q13) which results in increased bone formation. Therefore, controversy exists whether Autosomal dominant osteopetrosis type 1 is truly a type of osteopetrosis (which is due to failure of osteoclast development or function) or whether it is more accurately described as a `high bone mass' disease.\nDiagnostic methods\nDiagnosis is based on clinical and radiographic evaluation. Radiographs show diffuse skeletal sclerosis, with marked thickening of the cranial vault, slight sclerosis of the spine with dense vertebral arches, and thickened long bone cortices. Bone mineral density (lumbar spine, femoral neck) has a Z-score ranging from +4 to +8 SD.\nGenetic counseling\nTransmission is autosomal dominant. Each child of an affected individual has a 50% risk of being affected. Autosomal dominant osteopetrosis type 1 is a fully penetrant disease.\nManagement and treatment\nTreatment is symptomatic.\nPrognosis\nLife expectancy is normal.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Ravi SAVARIRAYAN  - Dr Zornitza STARK"}
{"Disease Name": "Autosomal dominant otospondylomegaepiphyseal dysplasia", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by craniofacial dysmorphism (midface hypoplasia, depressed nasal bridge, small nose with upturned tip, cleft palate, Pierre Robin sequence), bilateral, pronounced sensorineural hearing loss, and skeletal/joint anomalies (including spondyloepiphyseal dysplasia, arthralgia/arthropathy), in the absence of ocular abnormalities.", "ORPHA ID": 166100, "Summary": ""}
{"Disease Name": "Autosomal dominant palmoplantar keratoderma and congenital alopecia", "Disease Definition": "A rare genetic skin disorder characterized by absence of scalp and body hair and palmoplantar keratoderma, without other hand complications.", "ORPHA ID": 1010, "Summary": "Epidemiology\nTo date, ten individuals with a clinical diagnosis of autosomal dominant palmoplantar keratoderma and congenital alopecia (PPK-CA) have been reported.\nClinical description\nAutosomal dominant PPK-CA usually presents during infancy. Its very early onset is often characterized by fading of facial, scalp and body hair within the first months of life without subsequent re-growth. Body and facial keratosis pilaris are additional features which appear in the following years. Palmoplantar keratoderma develops during infancy and may have an unusual pattern, affecting the two sides of fingers and palms, but usually sparing the palmar sides. Periungueal involvement is typical, leading to secondary nail dystrophy. Autosomal dominant PPK-CA seems to have a more benign course than autosomal recessive PPK-CA (see this term).\nEtiology\nThe genetic basis of autosomal dominant PPK-CA is unknown. Transmission appears to be autosomal dominant.\nDifferential diagnosis\nPalmoplantar keratoderma and congenital alopecia/hypotrichosis is also found in ectodermal dysplasias and keratinization disorders, including hydrotic ectodermal dysplasia; hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome; KID syndrome; odonto-onycho-dermal dysplasia; Lelis syndrome; mutilating palmoplantar keratoderma with periorificial keratotic plaques; and Schöpf-Schulz-Passarge syndrome.\nGenetic counseling\nTransmission appears to be autosomal dominant.\n\n                            Last update: \n                            July 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Marco CASTORI"}
{"Disease Name": "Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis", "Disease Definition": "A rare contiguous gene syndrome involving a partial deletion of chromosome 16 and characterized by early-onset and severe polycystic kidney disease with various manifestations of tuberous sclerosis (multiple angiomyolipomas, lymphangioleiomyomatosis and periventricular calcifications of the central nervous system).", "ORPHA ID": 88924, "Summary": ""}
{"Disease Name": "Autosomal dominant polycystic kidney disease", "Disease Definition": "A rare, genetic, renal tubular disease characterized by progressive outgrowths of fluid-filled cysts from the renal epithelium, which can manifest with hematuria, urinary tract infections, hypertension, and abdominal or flank pain. The slowly progressive loss of kidney function may evolve to end stage kidney disease (ESKD).", "ORPHA ID": 730, "Summary": "Epidemiology\nAutosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, with estimated prevalence of 1/2,500 in Europe.\nClinical description\nSymptoms typically manifests in adulthood; however, approximately 2-5% of cases present before 15 years of age. The renal phenotype ranges from patients in advanced age with preserved kidney function to rare cases of enlarged kidneys that are detected in utero. Clinical symptoms, including early-onset hypertension, abdominal fullness and pain, hematuria and urinary tract infections (UTIs), are usually observed decades before the onset of renal insufficiency. Renal insufficiency is slowly progressive leading to ESKD by 60 years of age in approximately half of patients. Up to a third of adult patients have nephrolithiasis. Extra-renal features often include polycystic liver disease, cardiovascular abnormalities (including left ventricular hypertrophy, aortic root dilatation, arterial aneurysms, heart valve abnormalities and intracranial aneurysms), bronchiectasis, seminal vesicle cysts, pancreatic cysts, and diverticulosis. Male infertility is also described.\nEtiology\nMutations in PKD1 (16p13.3) and PKD2 (4q22.1) account for approximately 78% and 15% of affected individuals, respectively. The remaining ~7% of cases are genetically unresolved or are due to mutations in other recently identified genes, such as GANAB (11q12.3), DNAJB11 and ALG9, involved in the maturation and trafficking of the polycystins.\nDiagnostic methods\nDiagnosis is established by the presence of age-specific ultrasound criteria and an affected first-degree relative, or by genetic testing. Pre-symptomatic screening of ADPKD is not currently recommended for at-risk children. A positive family history is absent in 10-15% of patients. Where other causes of cystic disease have been excluded, a patient with bilaterally enlarged kidneys and innumerable cysts most likely has ADPKD.\nDifferential diagnosis\nThe differential diagnosis for early onset ADPKD is autosomal recessive polycystic kidney disease, renal cysts and diabetes syndrome (HNF1B), tuberous sclerosis complex (TSC), the TSC2/PKD1 contiguous gene syndrome, von Hippel-Lindau syndrome, medullary sponge kidney, simple renal cysts and acquired cystic kidney disease.\nAntenatal diagnosis\nKidney cysts can be detected by prenatal ultrasound scans. Large hyperechogenic kidneys are also a possible early manifestation. Prenatal genetic testing may be possible in at risk families, where the mutation has been previously identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. The risk of inheriting the disease from an affected individual is 50%. However, penetrance is incomplete and intra-familial phenotypes can vary in progression and severity. PKD1 mutations are associated with more severe disease, larger kidneys, earlier onset and earlier development of ESKD, than PKD2 mutations. GANAB mutations are associated with mild cystic disease, usually without decline in kidney function. Mutations arising de novo are possible.\nManagement and treatment\nEarly treatment and management of symptoms and complications, such as arterial hypertension is important. ACE inhibitors are the first choice for treatment of hypertension. For children with a family history of ADPKD, screening for hypertension from the age of 5 years onward is recommended. Tolvaptan, the vasopressin V2 receptor antagonist, has shown to reduce the rates of growth in total kidney volume and renal function loss in ADPKD patients, but also leads to polyuria because of its aquaretic effect. It is currently recommended for adult ADPKD with a rapid disease progression.\nPrognosis\nPrognosis depends on the age of disease onset and the disease severity. Approximately half of affected individuals develop ESKD by 60 years of age. Presence of proteinuria and arterial hypertension in affected children correlate with much more severe disease progression.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Djalila MEKAHLI | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal dominant popliteal pterygium syndrome", "Disease Definition": "A rare genetic, multiple congenital anomalies syndrome characterized by cleft lip, with or without cleft palate, pits in the lower lip, contractures of the lower extremities, abnormal external genitalia, syndactyly of fingers and/or toes, and a pyramidal skin fold over the hallux nail.", "ORPHA ID": 1300, "Summary": "Epidemiology\nThe prevalence of autosomal-dominant-popliteal pterygium syndrome (AD-PPS) is unknown. However, based on the occurence of cleft lip/palate in the general population, the prevalence at birth of popliteal pterygium syndrome (PPS) has been suggested at 1/300,000 with more than 200 cases of AD-PPS being reported worldwide.\nClinical description\nPresentation may be as early as the first trimester, with detection of cleft lip and/or palate on ultrasound. In addition to facial clefts (91%-97%), patients may have lower lip pits or sinuses (45%), webbing of the skin extending from the ischial tuberosities to the heels (popliteal pterygium with contractures possibly impairing mobility) (58%), bifid scrotum and cryptorchidism in affected males and hypoplasia of the labia majora in females, finger and/or toe syndactyly, and skin abnormalities around the nails. Almost all patients have a pyramidal fold of skin overlying the nail of the hallux. Some may have missing teeth. Other occasional features include filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon), spina bifida occulta, retrognathia, accessory medial meniscus, and talipes. Growth and intellectual development are normal in patients with AD-PPS although there are some reports of delayed language acquisition and learning disabilities.\nEtiology\nAD-PPS is associated with mutations in the IRF6 gene (1q32.2-q32.3), involved in the formation of epithelial tissues, especially the periderm. Almost all affected patients harbor mutations in IRF6.\nDiagnostic methods\nDiagnosis is based on the presence of the characteristic range of clinical findings (cleft lip with or without cleft palate, popliteal pterygium, genital and nail anomalies), and can be confirmed by molecular genetic testing. AD-PPS is highly associated with missense mutations in the DNA Binding Domain of IRF6(encoded in exons 3 and 4) that alter residues that are predicted to interact directly with DNA.\nDifferential diagnosis\nMildly affected AD-PPS patients have significant clinical overlap with Van der Woude syndrome (VWS), a disorder caused by deletions and mutations in the same gene (IRF6). In fact, affected individuals in the same family, having the same mutation in IRF6, have been diagnosed with AD-PPS and with VWS. The cause of this variable expressivity is not known. Bartsocas-Papas syndrome, CHAND syndrome and multiple pterygium syndrome should also be considered.\nAntenatal diagnosis\nIf the disease-causing mutation has been identified in the family, prenatal diagnosis for at-risk pregnancies is possible through molecular analysis following amniocentesis or chorionic villus sampling.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant with a 50% risk of disease transmission to offspring. However, penetrance is incomplete and expressivity is variable. De novo mutations have also been reported. Genetic counseling should be provided to affected families.\nManagement and treatment\nIn infants, nutritional intake and weight gain should be monitored. Cleft lip and/or palate should be treated surgically at an early stage and orthodontically by a specialized multidisciplinary team. Speech therapy as well as audiological and dental assessments should also be provided. Surgery may also be required for lip pits, popliteal pterygium, syndactyly and ankyloblepharon. Rarely, surgical correction of abnormal genitalia may be considered. Management of the other manifestations of AD-PPS is generally supportive and symptomatic.\nPrognosis\nOverall prognosis is good. Growth and intelligence are expected to be normal, and corrective surgeries are available, especially for orofacial clefts. However, the prognosis for physical activity depends on the severity of the pterygium and the success of corrective surgery. Genital anomalies may cause infertility.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Elizabeth LESLIE  - Dr Brian SCHUTTE"}
{"Disease Name": "Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome", "Disease Definition": "A rare genetic syndrome with limb malformations as a major feature characterized by preaxial polydactyly of the hands and feet with variable phenotypic expressivity in combination with hypertrichosis extending from the posterior hairline to the middle of the back. Reported limb malformations include triphalangeal thumbs, duplicated thumbs, preaxial extra ray, and syndactyly between digits I and II in the hands, and large or duplicated hallux and syndactyly between toes I and II in the feet.", "ORPHA ID": 476119, "Summary": ""}
{"Disease Name": "Autosomal dominant primary hypomagnesemia with hypocalciuria", "Disease Definition": "A mild form of familial primary hypomagnesemia (FPH), characterized by extreme weakness, tetany and convulsions. Secondary disturbances in calcium excretion are observed.", "ORPHA ID": 34528, "Summary": "Epidemiology\nTo date, only one large pedigree with 18 affected individuals has been reported in the literature.\nClinical description\nAutosomal dominant primary hypomagnesemia with hypocalciuria (ADPHH) can be detected in childhood or in adult life. Most affected individuals are asymptomatic but patients may suffer from generalized convulsions. In adulthood, chondrocalcinosis may be observed.\nDifferential diagnosis\nDifferential diagnosis includes all causes of renal hypomagnesemia, particularly diseases associated with hypocalciuria such as Gitelman syndrome, EAST syndrome and familial primary hypomagnesemia with normocalciuria and normocalcemia (see these terms).\nGenetic counseling\nTransmission is autosomal dominant. Genetic counseling may be proposed and the recurrence risk is 50%.\nManagement and treatment\nManagement is mainly symptomatic and includes oral magnesium supplements.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Rosa VARGAS-POUSSOU"}
{"Disease Name": "Autosomal dominant primary microcephaly", "Disease Definition": "A rare, genetic, non-syndromic, developmental defect during embryogenesis malformation syndrome characterized by a congenital, non-progressive, occipitofrontal head circumference that is 2 or more standard deviations below the mean for age, gender and ethnicity which is associated with normal brain architecture and uncomplicated by other abnormalities. Borderline to moderate intellectual disability, as well as early psychomotor delay, may or may not be associated.", "ORPHA ID": 2514, "Summary": ""}
{"Disease Name": "Autosomal dominant prognathism", "Disease Definition": "A rare, genetic, developmental defect during embryogenesis disorder characterized by abnormal forward projection of the mandible beyond the standard relation to the cranial base, with lower incisors often overlapping the upper incisors, that is inherited in an autosomal dominant manner. Association with mildly everted lower eyelids, flat malar area, thickened lower lip and craniosynostosis has been reported.", "ORPHA ID": 2964, "Summary": ""}
{"Disease Name": "Autosomal dominant progressive external ophthalmoplegia", "Disease Definition": "A rare genetic, neuro-ophthalmological disease characterized by progressive weakness of the external eye muscles, resulting in bilateral ptosis and diffuse symmetric ophthalmoparesis. Additional signs may include skeletal muscle weakness, cataracts, hearing loss, sensory axonal neuropathy, ataxia, parkinsonism, cardiomyopathy, hypogonadism and depression. It is usually less severe than autosomal recessive form.", "ORPHA ID": 254892, "Summary": ""}
{"Disease Name": "Autosomal dominant progressive nephropathy with hypertension", "Disease Definition": "A rare, genetic hypertension characterized by an adult onset of increased blood pressure associated with nephropathy progressing to end-stage renal disease. Renal biopsy may show interstitial fibrosis, glomerulosclerosis and mild tubular atrophy. Increased serum creatinine and proteinuria have also been reported.", "ORPHA ID": 88659, "Summary": ""}
{"Disease Name": "Autosomal dominant proximal renal tubular acidosis", "Disease Definition": "A rare autosomal dominant form of proximal renal tubular acidosis (pRTA) characterized by an isolated defect in the proximal tubule leading to the decreased reabsorption of bicarbonate and consequently causing urinary bicarbonate wastage. Mild growth retardation and reduced bone density are extra-renal complications. Several fractures and delayed puberty are possible features.", "ORPHA ID": 314889, "Summary": ""}
{"Disease Name": "Autosomal dominant proximal spinal muscular atrophy", "Disease Definition": "A group of rare, genetic, motor neuron disease characterized by childhood or adult onset progressive, predominantly proximal, muscular weakness and wasting. Included diseases are Autosomal dominant adult-onset proximal spinal muscular atrophy, Lower motor neuron syndrome with late-adult onset, and Autosomal dominant childhood-onset proximal spinal muscular atrophy.", "ORPHA ID": 211037, "Summary": ""}
{"Disease Name": "Autosomal dominant rhegmatogenous retinal detachment", "Disease Definition": "A rare, hereditary, non-syndromic form of vitreoretinopathy characterized by retinal tears due to abnormal vitreous, and commonly present refractive errors. No other signs or symptoms of Stickler syndrome is present.", "ORPHA ID": 209867, "Summary": ""}
{"Disease Name": "Autosomal dominant Robinow syndrome", "Disease Definition": "The more common type of Robinow syndrome (RS) characterized by mild to moderate limb shortening and abnormalities of the head, face and external genitalia.", "ORPHA ID": 3107, "Summary": "Epidemiology\nAbout 100 cases of this type have been reported in the literature to date.\nClinical description\nThe clinical signs are generally milder in dominant cases of RS than in the AR form. In the presence of rib fusions, the recessive form of the syndrome should be considered.\nEtiology\nMutations in WNT5A gene (3p14.3) have been reported in some patients (< 10%) with autosomal dominant Robinow syndrome.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Juliana MAZZEU"}
{"Disease Name": "Autosomal dominant secondary polycythemia", "Disease Definition": "A rare, genetic, hematologic disease characterized by increased levels of serum hemoglobin, hematocrit and erythrocyte mass, associated with elevated or inappropriately normal erythropoietin serum levels, occurring in various members of a family and with autosomal dominant inheritance.", "ORPHA ID": 247511, "Summary": ""}
{"Disease Name": "Autosomal dominant severe congenital neutropenia", "Disease Definition": "A rare primary immunodeficiency disorder characterized by autosomal dominant inheritance, absolute neutrophil counts below 0.5x10E9/L in the peripheral blood (on three separate occasions over a six month period), granulopoiesis maturation arrest at the promyelocyte/myelocyte stage and early-onset, severe, recurrent bacterial infections.", "ORPHA ID": 486, "Summary": ""}
{"Disease Name": "Autosomal dominant slowed nerve conduction velocity", "Disease Definition": "A rare hereditary demyelinating motor and sensory neuropathy characterized by slowed nerve conduction velocities, in the absence of clinically apparent neurological deficits, gait abnormalities or muscular atrophy, associated with a germline mutation in the ARGHEF10 gene.", "ORPHA ID": 140481, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic ataxia type 1", "Disease Definition": "A rare, genetic, autosomal dominant spastic ataxia disorder characterized by lower-limb spasticity and ataxia in the form of head jerks, ocular movement abnormalities, dysarthria, dysphagia and gait disturbances.", "ORPHA ID": 251282, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 10", "Disease Definition": "A rare, hereditary spastic paraplegia that can present as either a pure or complex phenotype. The pure form is characterized by lower limb spasticity, hyperreflexia and extensor plantar responses, presenting in childhood or adolescence. The complex form is characterized by the association with additional manifestations including peripheral neuropathy with upper limb muscle atrophy, moderate intellectual disability and parkinsonism. Deafness and retinitis pigmentosa have also been reported.", "ORPHA ID": 100991, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 12", "Disease Definition": "A pure form of hereditary spastic paraplegia characterized by a childhood- to adulthood-onset of slowly progressive lower limb spasticity and hyperreflexia of lower extremities, extensor plantar reflexes, distal sensory impairment, variable urinary dysfunction and pes cavus.", "ORPHA ID": 100993, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 13", "Disease Definition": "A rare, pure or complex form of hereditary spastic paraplegia characterized by progressive spastic paraplegia with pyramidal signs in the upper and lower limbs, and decreased vibration sense.", "ORPHA ID": 100994, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 17", "Disease Definition": "A complex hereditary spastic paraplegia characterized by progressive spastic paraplegia, upper and lower limb muscle atrophy, hyperreflexia, extensor plantar responses, pes cavus and occasionally impaired vibration sense. Association with hand muscles amyotrophy typical.", "ORPHA ID": 100998, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 19", "Disease Definition": "A pure form of hereditary spastic paraplegia characterized by a slowly progressive and relatively benign spastic paraplegia presenting in adulthood with spastic gait, lower limb hyperreflexia, extensor plantar responses, bladder dysfunction (urinary urgency and/or incontinence), and mild sensory and motor peripheral neuropathy.", "ORPHA ID": 100999, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 29", "Disease Definition": "A complex form of hereditary spastic paraplegia characterized by a spastic paraplegia presenting in adolescence, associated with the additional manifestations of sensorial hearing impairment due to auditory neuropathy and persistent vomiting due to a hiatal or paraesophageal hernia.", "ORPHA ID": 101009, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 3", "Disease Definition": "A rare, pure or complex form of hereditary spastic paraplegia, with variable phenotype, typically characterized by childhood-onset of minimally progressive, bilateral, mainly symmetric lower limb spasticity and weakness, associated with pes cavus, scoliosis, sphincter disturbances and/or urinary bladder hyperactivity. Rare additional associated manifestations may include mild intellectual disability, axonal motor neuropathy, and seizures.", "ORPHA ID": 100984, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 31", "Disease Definition": "A rare type of hereditary spastic paraplegia usually characterized by a pure phenotype of proximal weakness of the lower extremities with spastic gait and brisk reflexes, with a bimodal age of onset of either childhood or adulthood (>30 years). In some cases, it can present as a complex phenotype with additional associated manifestations including peripheral neuropathy, bulbar palsy (with dysarthria and dysphagia), distal amyotrophy, and impaired distal vibration sense.", "ORPHA ID": 101011, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 36", "Disease Definition": "A complex form of hereditary spastic paraplegia, characterized by an onset in childhood or adulthood of progressive spastic paraplegia (with spastic gait, spasticity, lower limb weakness, pes cavus and urinary urgency) associated with the additional manifestation of peripheral sensorimotor neuropathy.", "ORPHA ID": 320365, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 37", "Disease Definition": "A pure form of hereditary spastic paraplegia characterized by a childhood- to adulthood-onset of slowly progressive spastic gait, extensor plantar responses, brisk tendon reflexes in arms and legs, decreased vibration sense at ankles and urinary dysfunction. Ankle clonus is also reported in some patients.", "ORPHA ID": 171612, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 38", "Disease Definition": "A complex hereditary spastic paraplegia characterized by mild to severe lower limb spasticity, hyperreflexia, extensor plantar responses, impaired vibration sensation, pes cavus, and significant wasting and weakness of the small hand muscles. Temporal lobe epilepsy and cognitive dysfunction have been also reported.", "ORPHA ID": 171617, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 4", "Disease Definition": "A rare form of hereditary spastic paraplegia with high intrafamilial clinical variability, characterized in most cases as a pure phenotype with an adult onset (mainly the 3rd to 5th decade of life, but that can present at any age) of progressive gait impairment due to bilateral lower-limb spasticity and weakness as well as very mild proximal weakness and urinary urgency. In some cases, a complex phenotype is also reported with additional manifestations including cognitive impairment, cerebellar ataxia, epilepsy and neuropathy. A faster disease progression is noted in patients with a later age of onset.", "ORPHA ID": 100985, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 41", "Disease Definition": "A pure form of hereditary spastic paraplegia characterized by onset in adolescence or early adulthood of slowly progressive spastic paraplegia, proximal muscle weakness of the lower extremities and small hand muscles, hyperreflexia, spastic gait and mild urinary compromise.", "ORPHA ID": 320355, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 42", "Disease Definition": "A pure form of hereditary spastic paraplegia characterized by slowly progressive spastic paraplegia of lower extremities with an age of onset ranging from childhood to adulthood and patients presenting with spastic gait, increased tendon reflexes in lower limbs, extensor plantar response, weakness and atrophy of lower limb muscles and, in rare cases, pes cavus. No abnormalities are noted on magnetic resonance imaging.", "ORPHA ID": 171863, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 6", "Disease Definition": "A rare, pure or complex form of hereditary spastic paraplegia typically characterized by presentation in late adolescence or early adulthood as a pure phenotype of lower limb spasticity with hyperreflexia and extensor plantar responses, as well as mild bladder disturbances and pes cavus. Rarely, it can present as a complex phenotype with additional manifestations including epilepsy, variable peripheral neuropathy and/or memory impairment.", "ORPHA ID": 100988, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 73", "Disease Definition": "A pure form of hereditary spastic paraplegia characterized by adult onset of crural spastic paraparesis, hyperreflexia, extensor plantar responses, proximal muscle weakness, mild muscle atrophy, decreased vibration sensation at ankles, and mild urinary dysfunction. Foot deformities have been reported to eventually occur in some patients. No abnormalities are noted on brain magnetic resonance imaging and peripheral nerve conduction velocity studies.", "ORPHA ID": 444099, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 8", "Disease Definition": "A rare, pure or complex form of hereditary spastic paraplegia characterized by early adulthood onset of slowly progressive lower limb spasticity resulting in gait disturbances, hyperreflexia and extensor plantar responses, urinary urgency and/or incontinence, muscle weakness, decreased vibration sense and mild muscular atrophy in lower extremities. It may be associated with complicating signs, such as sensory neuropathy, ataxia (i.e. mild dysmetria, uncoordinated eye movement) and mild dysphagia.", "ORPHA ID": 100989, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 9A", "Disease Definition": "A rare complex hereditary spastic paraplegia characterized by juvenile to adult onset of slowly progressive spasticity mainly affecting the lower limbs, associated with spastic dysarthria and motor neuropathy. Additional manifestations include congenital bilateral cataract, gastroesophageal reflux, persistent vomiting, mild cerebellar signs, pes cavus, and occasionally short stature, among others.", "ORPHA ID": 447753, "Summary": ""}
{"Disease Name": "Autosomal dominant spastic paraplegia type 9B", "Disease Definition": "A rare predominantly pure hereditary spastic paraplegia characterized by juvenile or adult onset of slowly progressive spastic paraparesis, gait disturbances, and increased tendon reflexes. Additional variable manifestations include pes cavus, dysarthria, sensory impairment, and urinary symptoms. Cognition is normal.", "ORPHA ID": 447757, "Summary": ""}
{"Disease Name": "Autosomal dominant spondylocostal dysostosis", "Disease Definition": "A very rare and mild form of spondylocostal dysostosis characterized by vertebral and costal segmentation defects, often with a reduction in the number of ribs.", "ORPHA ID": 1797, "Summary": ""}
{"Disease Name": "Autosomal dominant striatal neurodegeneration", "Disease Definition": "An adult-onset movement disorder characterized by bradykinesia, dysarthria and muscle rigidity.", "ORPHA ID": 228169, "Summary": "Epidemiology\nTo date, ADSD has been observed in seven individuals in one family.\nClinical description\nOnset of symptoms of ADSD is in the fourth to fifth decade of life with mild progressive dysarthria and hypokinesia. Mild bradykinesia presents predominantly as gait disturbance but also as a general slowing of movement. Dysdiadochokinesia is also present and muscle tone is slightly increased. Additional features include stiffness of the tongue and, in some patients, mild difficulties in swallowing. ADSD is characterized by dysfunction and changes of the striatal part of the basal ganglia, visible on MRI scans.\nEtiology\nIt is caused by mutation in the PDE8B gene (5q13.3-q14.1) and is transmitted in an autosomal dominant manner with complete penetrance in the investigated family.\nDiagnostic methods\nDiagnosis is based on brain MRI which shows distinctive and characteristic symmetric lesions of the striatum that appear earlier than the onset of symptoms. A good correlation has been observed between clinical signs and the degree of MRI abnormalities.\nDifferential diagnosis\nDifferential diagnoses include other degenerative diseases causing hypokinesia (such as Parkinson's disease; see this term). However, unlike for these diseases, in ADSD, tremor is not observed. Differential diagnoses also include neuroferritinopathy (see this term). However, ADSD is characterized by hypokinesia whereas neuroferritinopathy is characterized by hyperkinesia. The characteristic MRI changes of the striatum can be regarded as pathognomonic for ADSD.\nAntenatal diagnosis\nAntenatal diagnosis is currently not available but is probably not necessary because of the mild course of the disease.\nManagement and treatment\nThere is currently no known treatment for ADSD and symptoms do not respond to treatment with levodopa.\nPrognosis\nThe course of the disease is mild and allows affected individuals to lead a virtually normal life. Life expectancy does not appear to be affected.\n\n                            Last update: \n                            May 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Gregor KUHLENBÄUMER"}
{"Disease Name": "Autosomal dominant thrombocytopenia with platelet secretion defect", "Disease Definition": "A rare isolated constitutional thrombocytopenia characterized by reduced platelet count and defective platelet ATP secretion, resulting in increased bleeding tendency. Clinical manifestations are easy bruising, gum bleeding, menorrhagia, spontaneous epistaxis, spontaneous muscle hematoma, and potential postpartum hemorrhage, among others.", "ORPHA ID": 466806, "Summary": ""}
{"Disease Name": "Autosomal dominant tubulointerstitial kidney disease", "Disease Definition": "A rare, genetic renal tubular disease characterized by tubular damage and interstitial fibrosis in absence of glomerular lesions and clinically manifesting with chronic kidney disease (CKD) and slow progression to end-stage kidney disease (ESKD).", "ORPHA ID": 34149, "Summary": "Epidemiology\nAutosomal dominants tubulointerstitial kidney (ADTKD) is estimated to account for approximately 2-5% of monogenic causes of chronic kidney disease. In the Caucasian population, no geographic or sex differences are reported.\nClinical description\nThere are four clinical subtypes, classified due to the genetic mutation involved: UMOD-, MUC1-, REN- and HNF1B-related ADTKD. The typical clinical findings in ADTKD are a progressive loss of kidney function with bland urinary sediment, absent-to-mild proteinuria, urinary concentrating defects with low morning urine osmolality, normal or slightly elevated blood pressure, normal or small kidney size and a family history of CKD that is compatible with an autosomal dominant inheritance pattern. Presentation and age of onset varies according to clinical subtype. For ADTKD-UMOD, presentation may occur in adolescence with gout; hyperuricemia and gout are highly prevalent. CKD is often first diagnosed in the late adolescence or early adulthood. ADTKD-MUC1 typically presents with CKD in the early twenties. ADTKD-REN may present as early as infancy with anemia, hyperkalemia and CKD. ADTKD-HNF1B may present in childhood with genitourinary abnormalities, in the teenage years with gout or diabetes, and in the third decade of life with CKD; extrarenal anomalies are possible. All subtypes lead to progressive ESKD, occurring generally between 25 and 70 years of age. Renal cysts may occur but are not typical.\nEtiology\nPathogenic variants are detected in 50-60% of cases and most commonly involve UMOD (16p12.3) and MUC1 (1q22). More rare variants include REN (1q32.1) and HNF1B (17q12), and different genes may be identified in the future.\nDiagnostic methods\nDiagnosis can be difficult due to the lack of distinct clinical features but should be suspected in individuals with a family history of CKD, gout and/or hyperuricemia, a bland urinary sediment and a renal ultrasound that excludes autosomal dominant polycystic disease (ADPKD). If available, kidney biopsy from the patient or an affected family member showing predominant tubulointerstitial fibrosis are supportive of a diagnosis. Genetic testing for a pathogenic variant in the patient or a family member can also be useful.\nDifferential diagnosis\nThe differential diagnoses include atypical ADPKD (DNAJB11-related), nephronophthisis (NPHP1-related), renal coloboma syndrome, tubulointerstitial nephritis and uveitis syndrome, and Sjögren syndrome. Mutations in SEC61A1 have been reported in a few cases with congenital anemia, neutropenia (in one family) and tubulointerstitial kidney disease; mitochondrial mutations have also been associated with an ADTKD phenotype.\nAntenatal diagnosis\nGenetic prenatal diagnosis may be possible where pathogenic variants have previously been identified in a family member.\nGenetic counseling\nThe disease is autosomal dominant. Genetic counseling should be offered to affected individuals informing them that for each conception there is 50% risk of disease transmission. However, penetrance is incomplete and disease expression may vary between affected family members.\nManagement and treatment\nThere is no specific treatment for ADTKD; affected individuals should be treated according to established CKD guidelines, noting that specific recommendations are based on limited evidence in ADTKD. Children with ADTKD-HNF1B and ADTKD-REN disease are likely to benefit from early management by a pediatric nephrologist. Diuretics should be used with caution as they may aggravate salt loss, volume depletion and hyperuricemia. A low-salt diet is not recommended. NSAIDS are contraindicated in ADTKD patients. In patients with gout, urate-lowering treatment may prevent future attacks. Kidney transplantation is the preferred option for ESKD, and ADTKD does not recur in the renal transplant.\nPrognosis\nThe quality of life in patients with ADTKD largely depends on the severity of CKD the presence of CKD-associated comorbidities and the existence of extrarenal manifestations.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Olivier DEVUYST | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal dominant vitreoretinochoroidopathy", "Disease Definition": "A rare, genetic, vitreous-retinal disease characterized by ocular developmental anomalies such as microcornea, a shallow anterior chamber, glaucoma and cataract. Abnormal chorioretinal pigmentation is present, usually lying between the vortex veins and the ora serrata for 360 degrees.", "ORPHA ID": 3086, "Summary": "Epidemiology\nAt least 3 pedigrees have been reported to have ADVIRC.\nClinical description\nAge of onset is variable, but can occur in childhood. ADVIRC is associated with developmental ocular anomalies including microphthalmos/nanophthalmos, microcornea, hypermetropia/high myopia, shallow anterior chamber, angle closure glaucoma, iris dysgenesis, abnormal pupillary ruff, microspherophakia with mild lens opacities (congenital or early-onset posterior/subcapsular cataract), disc gliosis and optic nerve dysplasia. Some patients may experience vision loss. Color vision is generally normal. Discrete rotatory nystagmus may be present. Retinal edema due to vascular incompetence may also be observed. ADVIRC is characterized by a peripheral retinal circumferential hyperpigmented band, punctuate white retinal opacities, fibrillar condensation of the vitreous, vascular abnormalities and neovascularisation. There are no identifiable systemic or skeletal abnormalities.\nEtiology\nADVIRC is caused by mutations in BEST1 (11q12) (Val86Met, Val235Ala and Tyr236Cys), which encodes bestrophin-1 (expressed specifically in the retinal pigment epithelium (RPE)) forming a calcium activated chloride channel involved in regulation of voltage-dependent calcium channels. These mutations may alter normal splicing of BEST1 and result in in-frame alteration of bestrophin-1. However, functional consequences of such in-frame protein alterations remain undefined.\nDiagnostic methods\nDiagnosis of ADVIRC is based on low normal to non-recordable amplitudes of cones and rods on full-field electroretinogram (generalized rod and cone dysfunction), an abnormal electro-oculogram (EOG) (the light rise of EOG is decreased giving a reduced Arden ratio), and normal macular thickness on optical coherence tomography. Funduscopy typically reveals a concentric band of hyperpigmentation in the extreme periphery of one quadrant, with well-defined posterior demarcation, midperipheral chorioretinal atrophy and optic nerve dysplasia. Fundus autofluorescence imaging may show a normal autofluorescence pattern. Goldmann perimetry is often initially normal; however visual field tends to constrict mildly with age. Diagnosis is confirmed by genetic screening of BEST1.\nDifferential diagnosis\nMRCS syndrome (see this term) is generally more severe than ADVIRC. However, both of these BEST1-related conditions show retinal pigmentary abnormalities, retinal dystrophy, microcornea, and early-onset cataract, conditions that overlap and likely form a continuum. Differential diagnosis also includes Best vitelliform macular dystrophy (BVMD), adult-onset foveomacular vitelliform dystrophy and autosomal recessive bestrophinopathy (see these terms).\nGenetic counseling\nTransmission is autosomal dominant and genetic counseling is possible.\nManagement and treatment\nManagement is mainly symptomatic. When choroidal neovascularization occurs, treatment may require laser photocoagulation or intravitreal delivery of anti-vascular endothelial growth factor agents such as bevacizumab and ranibizumab. Cystoid macular edema can be treated with conventional carbonic anhydrase inhibitors (CAIs) either systemically or topically. If presentation is complicated by glaucoma, conventional treatment may require topical agents to lower intraocular pressure, such as CAIs. Laser iridotomy may be advocated if angle closure glaucoma is a risk. Some cases may require additional surgical intervention.\nPrognosis\nMost patients retain a fairly good visual acuity throughout life, although visual acuity may decrease considerably due to macular edema, chorioretinal atrophy, or rarely, retinal detachment and vitreous hemorrhage.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                             Stephanie CHAN  - Pr Ian MACDONALD"}
{"Disease Name": "Autosomal erythropoietic protoporphyria", "Disease Definition": "A rare hereditary disorder of the heme metabolic pathway characterized by accumulation of protoporphyrin in blood, erythrocytes and tissues, with photosensitive skin manifestations.", "ORPHA ID": 79278, "Summary": "Epidemiology\nErythropoietic protoporphyria (EPP) has been reported worldwide, with prevalence ranging from 1/17,000 to 1/100,000.\nClinical description\nIt usually begins in early childhood, with the first exposure to the sun. EPP manifests as acute painful photosensitivity of the skin with erythema and edema, sometimes petechiae, together with stinging and burning sensations without phlyctens, after exposure to sunlight or illumination in the visible spectrum (particularly in the Soret band [400 - 410 nm]). These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. As protoporphyrin is a lipophilic molecule excreted by the liver, patients with EPP are at risk of cholelithiasis with obstruction of the bile ducts, and chronic liver disease which may progress to acute liver failure.\nEtiology\nIn most cases, EPP is due to a partial deficiency of the last enzyme in the heme biosynthesis pathway, ferrochelatase, encoded by the FECH gene (NM_000140.3). The pattern of inheritance of EPP is autosomal dominant where clinical expression is modulated by the presence of the hypomorphic IVS3-48C FECH allele in trans. Autosomal recessive transmission of two mutated alleles of the FECH gene has also been reported.\nDiagnostic methods\nDiagnosis is established by increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 635 nm. Further analysis is recommended, including a search for liver damage and measurement of ferrochelatase activity levels. Genetic analysis (mutations in the FECH gene, presence of the hypomorphic IVS3-48C FECH allele in trans) and family screening are also recommended.\nDifferential diagnosis\nDifferential diagnosis includes X-linked erythropoietic protoporphyria, phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, and angioedema.\nAntenatal diagnosis\nAntenatal diagnosis is theoretically possible, but is not offered.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. Genetic counseling should be offered to affected individuals informing them that there is a 50 % risk of transmitting the pathogenic variant. Autosomal recessive transmission of two mutated alleles of the FECH gene has also been reported.\nManagement and treatment\nTreatment is based on preventive measures such as sun avoidance, protection against visible light (especially blue light) using a high UVA index sunscreen with a high critical wavelength (>370 nm), the use of protective filters on windows and the yellow filter on scialytics, short sessions of UVB TL01 before summer, reducing protoporphyrins (by reducing erythropoiesis with transfusions or by administration of cholestyramine, a bile acid chelator, or by careful phlebotomy), preventing the progression of liver damage to liver failure. Conventional analgesics and beta-carotene have limited effectiveness in EPP. Since liver disease is the major risk associated with EPP, regular monitoring of liver function is key. Sequential liver and bone marrow transplant should be considered in the treatment of severe cases presenting with liver damage.\nPrognosis\nEPP is a chronic disease, and its prognosis depends on the progression of liver disease. However, photosensitivity can affect patients' quality of life. The latter has been improved by the use of afamelanotide. Two molecules, dersimelagon and bitopertin, are currently under development. Patients with EPP should not be given iron supplements without expert medical advice.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Neila TALBI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal recessive anterior segment dysgenesis", "Disease Definition": "A rare anterior segment developmental anomaly without extraocular manifestations characterized by predominant iris and lens abnormalities, including iris hypoplasia, iris transillumination defects, ectropion uveae, corectopia, iridodonesis with ectopia lentis, and cataracts, with bilateral involvement. Increased intraocular pressure is absent in most patients.", "ORPHA ID": 519388, "Summary": ""}
{"Disease Name": "Autosomal recessive ataxia due to PEX10 deficiency", "Disease Definition": "A rare genetic, peroxisomal disease characterized by childhood onset slowly progressive ataxia and axonal motor neuropathy due to PEX 10 deficieny. Marked cerebellar atrophy and pyramidal signs are evident. Patients may present mild cognitive disability, intentional tremor, decreased vibration sense and diabetes mellitus. Additional features may include nystagmus, mydriasis, hyperreflexia and involuntary head movement.", "ORPHA ID": 247815, "Summary": ""}
{"Disease Name": "Autosomal recessive ataxia due to ubiquinone deficiency", "Disease Definition": "This syndrome is characterised by childhood-onset progressive ataxia and cerebellar atrophy.", "ORPHA ID": 139485, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nExercise intolerance with elevated lactate levels and mild intellectual deficit may also be present.\nEtiology\nThe syndrome is caused by ubiquinone deficiency. Mutations in the ADCK3/CABC1 gene have been detected in affected individuals. This gene is already known to play a role in ubiquinone biosynthesis in yeast.\nGenetic counseling\nThe syndrome is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            May 2008"}
{"Disease Name": "Autosomal recessive ataxia, Beauce type", "Disease Definition": "A rare disorder characterised by a slowly progressive pure cerebellar ataxia associated with dysarthria. It has been described in 53 individuals from 26 families of Canadian origin. The mode of transmission is autosomal recessive. Positional cloning has led to the identification of several  gene mutations.", "ORPHA ID": 88644, "Summary": ""}
{"Disease Name": "Autosomal recessive axonal Charcot-Marie-Tooth disease due to copper metabolism defect", "Disease Definition": "A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by motor-predominant axonal polyneuropathy due to a defect in copper metabolism. Patients become symptomatic in infancy or childhood with subtle motor delay or regression, manifesting with progressive weakness, muscle wasting, and absent reflexes in the lower and upper extremities. In addition, vibratory sensation is mildly diminished. Involvement of the face with weakness and fasciculation of facial muscles has also been described.", "ORPHA ID": 521411, "Summary": ""}
{"Disease Name": "Autosomal recessive axonal neuropathy with neuromyotonia", "Disease Definition": "A rare peripheral neuropathy characterized by slowly progressive axonal, motor greater than sensory, polyneuropathy combined with neuromytonia (including spontaneous muscular activity at rest (myokymia), impaired muscle relaxation (pseudomyotonia), and contractures of hands and feet) and neuromyotonic or myokymic discharges on needle EMG. It presents with distal lower limb weakness with gait impairment, muscle stiffness, fasciculations and cramps in hands and legs worsened by cold, decreased to absent tendon reflexes, intrinsic hand muscle atrophy and, variably, mild distal sensory impairment.", "ORPHA ID": 324442, "Summary": ""}
{"Disease Name": "Autosomal recessive bestrophinopathy", "Disease Definition": "A rare retinal dystrophy, characterized by central visual loss in the first 2 decades of life, associated with an absent electrooculogram (EOG) light rise and a reduced electroretinogram (ERG).", "ORPHA ID": 139455, "Summary": "Epidemiology\nThe prevalence of ARB is still unknown; to date less than 20 cases have been described in the world literature.\nClinical description\nARB generally manifests in the first 2 decades of life, but patients may also first become symptomatic as late as the fifth decade of life. Most affected individuals initially present with central visual loss (visual acuity ranging from 20/200 to 20/25) and are usually mildly to highly hyperopic. Additional ocular findings may include short axial length with angle-closure glaucoma, amblyopia, anterior uveitis, strabismus, and color vision defects. Choroidal neovascularization (CNV) has been described in one case. Leukokoria and esotropia have also been reported.\nEtiology\nARB is caused by compound heterozygous or homozygous mutations in the BEST1 gene (11q12) which encodes the chloride ion channel bestrophin-1 (expressed in the retinal pigment epithelium (RPE)). Mutations in BEST1 reduce or abolish the activity of the channel. It has been proposed that ARB may represent the null phenotype of bestrophin-1 in humans.\nDiagnostic methods\nDiagnosis of ARB relies on ophthalmologic examination, familial history and visual electrophysiology revealing an abnormal full-field ERG (reduced amplitudes and delayed implicit times of the rod and cone ERGs). Absent or severe reduction in EOG light rise (Arden ratio= 1.0) is commonly observed. Irregularity of the RPE throughout the posterior fundus, often with scattered punctate flecks (observed by autofluorescence imaging) is also found. Optical coherence tomography (OCT) imaging shows retinal edema, serous subretinal fluid, subretinal yellowish lesions and scars. Classic vitelliform lesions are not present. Fluorescein angiography reveals widespread patchy areas of hyperfluorescence and signs of mild perivascular leakage in the peripheral retina. Cystoid macular edema may be observed. Diagnosis is confirmed by the genetic screening of BEST1.\nDifferential diagnosis\nDifferential diagnosis includes Stargardt disease, familial drusen, Best vitelliform macular dystrophy, age-related macular degeneration (see these terms), central serous chorioretinopathy and chorioretinitis.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\nManagement and treatment\nManagement of ARB is mainly symptomatic and includes treatment of amblyopia, surgical strabismus correction, prophylactic laser (YAG) peripheral iridotomy to prevent angle closure and treat glaucoma, and intravitreal bevacizumab for the treatment for CNV. Cystoid macular edema may be treated with oral administration of acetazolamide. Gene therapy may offer a possible treatment for ARB in the future. Close monitoring of ARB patients is recommended, including repeated gonioscopy to judge the risk of angle closure.\nPrognosis\nOnset of vision loss in patients has been reported to vary between the ages of 4 to 40, and is coincident with initial presentation.\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                             Stephanie CHAN  - Pr Ian MACDONALD"}
{"Disease Name": "Autosomal recessive brachyolmia", "Disease Definition": "Brachyolmia, recessive type is a form of brachyolmia (see this term), a group of rare genetic skeletal disorders, characterized by short-trunked short stature with platyspondyly and scoliosis. Corneal opacities and precocious calcification of the costal cartilage are rare syndromic components. Premature pubarche may occur.", "ORPHA ID": 448242, "Summary": "Epidemiology\nThe precise prevalence of this form of brachyolmia is not known. About 20 cases have been reported. Cases have been reported in various ethnic groups (Japan, Korea, Turkey), sometimes related to consanguineous unions. However, a majority of cases reported so far were of Turkish origin.\nClinical description\nPatients with Brachyolmia, recessive type generally have a normal birth weight and length. Platyspondyly is present in early childhood but patients usually come to medical attention in late childhood or early puberty as a result of stunted growth and short trunk. The radiographic features include platyspondyly with rectangular vertebral bodies and irregular end plates, broad ilia, short femoral neck, and broad proximal interphalangeal joints. Longitudinal striations in the femoral neck are occasionally seen. Precocious calcifications of the costal cartilage are described. The condition is described as relatively benign with the exception of mild non-specific backache and mild scoliosis beginning in young adulthood. However, reports are limited about the final outcome of musculoskeletal morbidity. Mental status and facies are reported to be normal. Some patients are reported to have peripheral punctuate opacities in the cornea found on slit lamp examination (formerly Toledo type).\nEtiology\nA number of different mutations in the PAPSS2 gene (10q23.2-q23.3) have been reported in affected patients. PAPPS2 encodes PAPS (3'-phosphoadenosine 5'-phosphosulfate) synthase 2. PAPSS2 mutations were also reported to cause two other disorders: spondyloepimetaphyseal dysplasia, PAPSS2 type (see this term), and spondylodysplasia and premature pubarche before the discovery of the molecular basis of brachyolmia, recessive type (Hobaek/Toledo type).\nGenetic counseling\nGenetic counseling should be provided to affected families based on the observed autosomal recessive pattern of inheritance.\n\n                            Last update: \n                            February 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Gen NISHIMURA"}
{"Disease Name": "Autosomal recessive centronuclear myopathy", "Disease Definition": "A rare autosomal recessive congenital myopathy characterized by numerous centrally placed nuclei on muscle biopsy and clinical features of a congenital myopathy including facial weakness, ocular abnormalities (ptosis and external ophthalmoplegia) and predominant proximal muscle weakness of variable severity with possible distal involvement.", "ORPHA ID": 169186, "Summary": "Epidemiology\nThe exact prevalence remains unknown.\nClinical description\nThe age of onset varies from birth to childhood. AR-CNM is characterized by facial weakness including severe involvement of the masticatory muscles, and ocular abnormalities such as ptosis and external ophthalmoplegia. Muscle weakness is observed with variable severity. It is usually prominently proximal, but there may be additional distal weakness and wasting in the lower limbs. Foot abnormalities are frequent and other skeletal deformities (including high arched palate and scoliosis) are common. Respiratory involvement may be severe. An associated cardiomyopathy has been documented in a few, genetically unresolved cases. Urinary incontinence may be an associated feature.\nEtiology\nThe disease is associated with mutations in BIN1 (2q14), encoding Myc box-dependent-interacting protein 1. AR- CNMs can be also related to biallelic mutation in RYR1 (19q13.2) , SPEG (2q35) and TTN (2q31.2) genes.\nDiagnostic methods\nDiagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features. Genetic testing is required to confirm the diagnosis. Muscle MRI may be helpful to distinguish AR-CNM from other forms of CNM.\nDifferential diagnosis\nThe main differential diagnoses include other congenital myopathies, myotonic dystrophy and, if facial involvement is prominent, facioscapulohumeral dystrophy.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the mutation has previously been identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. The risk to siblings of inheriting the disease is 25%. Offspring of affected individuals are obligate carriers. Genetic counseling should be offered to all patients and their families.\nManagement and treatment\nThere is no curative treatment currently available. Management is supportive and based on a multidisciplinary approach.\nPrognosis\nIn the absence of severe cardiorespiratory involvement, the prognosis appears favorable, with mild progressive proximal weakness.\n\n                            Last update: \n                            May 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI  - Dr Adele D'AMICO  - Pr Fabiana FATTORI"}
{"Disease Name": "Autosomal recessive cerebellar ataxia due to CWF19L1 deficiency", "Disease Definition": "A rare autosomal recessive cerebellar ataxia characterized by early onset of slowly progressive cerebellar atrophy, clinically manifesting with extremity and truncal ataxia, global developmental delay, intellectual impairment, nystagmus, dysarthria, intention tremor, and pyramidal signs, among others.", "ORPHA ID": 453521, "Summary": ""}
{"Disease Name": "Autosomal recessive cerebellar ataxia due to STUB1 deficiency", "Disease Definition": "A rare hereditary ataxia characterized by progressive truncal and limb ataxia resulting in gait instability. Dysarthria, dysphagia, nystagmus, spasticity of the lower limbs, mild peripheral sensory neuropathy, cognitive impairment and accelerated ageing have also been associated.", "ORPHA ID": 412057, "Summary": ""}
{"Disease Name": "Autosomal recessive cerebellar ataxia with late-onset spasticity", "Disease Definition": "A rare, genetic neurodegenerative disease characterized by childhood or adolescent-onset of cerebellar ataxia with dysarthria which slowly progresses and associates pyramidal signs, including lower limb spasticity, brisk reflexes, and Babinski and Hoffman signs. Patients typically present cerebellar ataxia with development of increasing asymmetric spasticity in upper and lower limbs, and variable axonal sensory or sensorimotor neuropathy. Additional heterogeneous features, including pes cavus, scoliolis, and abnormalities of the brain (e.g. cerebral atrophy), may also be associated.", "ORPHA ID": 352641, "Summary": ""}
{"Disease Name": "Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to RUBCN deficiency", "Disease Definition": "An extremely rare, autosomal recessive, hereditary cerebellar ataxia disorder characterized by early onset of progressive, mild to moderate gait and limb ataxia, moderate to severe dysarthria, and nystagmus or saccadic pursuit, frequently associated with epilepsy, moderate intellectual disability, delayed speech acquisition, and hyporeflexia in the upper extremities. Hyperreflexia in the lower extremities may also be associated.", "ORPHA ID": 404499, "Summary": ""}
{"Disease Name": "Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency", "Disease Definition": "A rare hereditary ataxia characterized by an early onset symptomatic generalized epilepsy, progressive cerebellar ataxia resulting in significant difficulties to walk or wheelchair dependency, and intellectual disability.", "ORPHA ID": 404493, "Summary": ""}
{"Disease Name": "Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency", "Disease Definition": "A rare autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome characterized by early-childhood onset of cerebellar ataxia associated with generalized tonic-clonic epilepsy and psychomotor development delay, dysarthria, gaze-evoked nystagmus and learning disability. Other features in some patients include upper motor neuron signs with leg spasticity and extensor plantar responses, and mild cerebellar atrophy on brain MRI.", "ORPHA ID": 284282, "Summary": ""}
{"Disease Name": "Autosomal recessive cerebellar ataxia-movement disorder syndrome", "Disease Definition": "A rare hereditary ataxia characterized by a progressive cerebellar ataxia associated with disruption of visual fixation by saccadic intrusions (overshooting horizontal saccades with macrosaccadic oscillations and increased velocity of larger saccades). It presents with progressive gait, trunk and limb ataxia with pyramidal tract signs (increased tendon reflexes and Babinski sign), myoclonic jerks, fasciculations, cerebellar dysarthria, sensorimotor axonal neuropathy with impaired joint position, vibration, temperature, pain sensations, pes cavus, and saccadic intrusions with characteristic overshooting horizontal saccades, macrosaccadic oscillations, and increased velocity of larger saccades, without other eye movement disturbances.", "ORPHA ID": 95434, "Summary": ""}
{"Disease Name": "Autosomal recessive cerebellar ataxia-psychomotor delay syndrome", "Disease Definition": "A rare, hereditary, cerebellar ataxia disorder characterized by late-onset spinocerebellar ataxia, manifesting with slowly progressive gait disturbances, dysarthria, limb and truncal ataxia, and smooth-pursuit eye movement disturbance, associated with a history of psychomotor delay from childhood. Mild atrophy of the cerebellar vermis and hemispheres is observed on brain imaging.", "ORPHA ID": 284271, "Summary": ""}
{"Disease Name": "Autosomal recessive cerebellar ataxia-pyramidal signs-nystagmus-oculomotor apraxia syndrome", "Disease Definition": "A rare, genetic, slowly progressive neurodegenerative disease characterized by delayed psychomotor development beginning in infancy, mild to profound intellectual disability, gait and stance ataxia, pyramidal signs (hyperreflexia, extensor plantar responses), dysarthria, and ocular abnormalities (e.g. nystagmus, oculomotor apraxia, abduction deficits, esotropia, ptosis). Brain imaging reveals progressive, generalized cerebellar atrophy, mild ventriculomegaly and, in some, retrocerebellar cysts.", "ORPHA ID": 363429, "Summary": ""}
{"Disease Name": "Autosomal recessive cerebellar ataxia", "Disease Definition": "A heterogeneous group of rare neurological disorders involving both the central and peripheral nervous system (and in some cases other systems and organs), and characterized by degeneration or abnormal development of the cerebellum and spinal cord and, in most cases, early onset occurring before the age of 20 years.", "ORPHA ID": 1172, "Summary": "Epidemiology\nThis group encompasses a large number of rare diseases, the most frequent in the Caucasian population being Friedreich ataxia (estimated prevalence 2-4/100,000), ataxia-telangiectasia (1-2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common.\nClinical description\nBased on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorders), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features.\nEtiology\nThese diseases are caused by mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, alpha-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2).\nDiagnostic methods\nClinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, computed tomography scanning), electrophysiological examination, and mutation analysis when the causative gene has been identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to the autosomal recessive mode of inheritance, a familial history of affected individuals is unlikely.\nGenetic counseling\nThese diseases are transmitted in an autosomal recessive manner.\nManagement and treatment\nFor most ARCA there is no specific drug treatment, except for coenzyme Q10 deficiency and abetalipoproteinemia.\n\n                            Last update: \n                            November 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen ESPINÓS  - Pr Francesc PALAU"}
{"Disease Name": "Autosomal recessive cerebelloparenchymal disorder type 3", "Disease Definition": "A rare autosomal recessive cerebellar ataxia characterized by early onset of non- or slowly progressive cerebellar signs and symptoms including truncal and gait ataxia, dysarthria, dysmetria, dysdiadochokinesis, tremor, and nystagmus. Delayed psychomotor development and intellectual disability are variable. Additional reported features are spasticity, hypotonia, cataracts, and sensorineural hearing loss, among others. Brain imaging shows cerebellar atrophy.", "ORPHA ID": 1170, "Summary": ""}
{"Disease Name": "Autosomal recessive cerebral atrophy", "Disease Definition": "A rare, genetic, neurodegenerative disorder characterized by ventriculomegaly and progressive, symmetrical atrophy of the cerebral cortex grey and white matter (sparing the midbrain, brainstem, cerebellum and infratentorial segments), manifesting in early infancy with acquired microcephaly, irritability, regression of developmental milestones, feeding difficulties, akathisia, exaggerated startle response, spasticity (fisted hands, stiff arms, leg scissoring), abnormal muscle tone with hypotonic trunk and hypertonic extremities, visual impairment and seizures.", "ORPHA ID": 363969, "Summary": ""}
{"Disease Name": "Autosomal recessive Charcot-Marie-Tooth disease type 2X", "Disease Definition": "A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by childhood to adult onset of slowly progressive, sometimes asymmetric distal muscle weakness and atrophy, as well as sensory impairment, predominantly of the lower limbs. Additional common features include pes cavus, kyphoscoliosis, ankle contractures, tremor, or urogenital dysfunction. Fasciculations and proximal involvement may be seen in some cases. Patients usually remain ambulatory.", "ORPHA ID": 466775, "Summary": ""}
{"Disease Name": "Autosomal recessive Charcot-Marie-Tooth disease with hoarseness", "Disease Definition": "A severe, early-onset form of axonal CMT peripheral sensorimotor polyneuropathy.", "ORPHA ID": 101097, "Summary": "Epidemiology\nARCMT2K was originally described in three Spanish families and has since been described in five additional Spanish kindreds, as well as in families from Morocco, France and Poland.\nClinical description\nOnset occurs in the neonatal period or early infancy with a clinical picture similar to that seen in CMT4A (another autosomal recessive form of CMT4 but with a demyelinating phenotype; see this term) including hypotonia, scoliosis, a hoarse voice, vocal cord paralysis and respiratory insufficiency. However, nerve conduction velocities and pathological findings from sural nerve biopsies in ARCMT2K patients are indicative of a predominantly axonal neuropathy with some demyelinating features.\nEtiology\nARCMT2K is caused by mutations in the GDAP1 gene (8q13.3), encoding a protein required for mitochondrial fission. Mutations in the same gene are associated with CMT4A and with a milder, later-onset autosomal dominant axonal form of CMT, CMT2K (see this term).\nPrognosis\nThe prognosis for ARCMT2K may be severe, with two of the reported patients dying during in the fifth decade of life.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen ESPINÓS  - Pr Francesc PALAU"}
{"Disease Name": "Autosomal recessive chorioretinopathy-microcephaly syndrome", "Disease Definition": "A rare neuro-opthalmological disease characterized by severe microcephaly of prenatal onset (with diminutive anterior fontanelle and sutural ridging), growth retardation, global developmental delay and intellectual disability (ranging from mild to profound), dysmorphic features (sloping forehead, micro/retrognathia, prominent ears) and visual impairments (including microphthalmia to anophtalmia, generalized retinopathy or multiple punched-out retinal lesions, retinal folds with retinal detachment, optic nerve hypoplasia, strabismus, nystagmus). Brain MRI may show reduced cortical size, cerebral hemispheres, corpus callosum, pachygyria, symplified gyral folding or normal pattern. Other associated features include epilepsy and neurological deficits.", "ORPHA ID": 2518, "Summary": ""}
{"Disease Name": "Autosomal recessive complex spastic paraplegia due to Kennedy pathway dysfunction", "Disease Definition": "A rare genetic neurological disorder characterized by progressive spastic paraparesis and delayed gross motor development with an onset in infancy or early childhood. Patients also show variable degrees of intellectual disability, speech delay, and dysarthria. Other reported features include microcephaly, seizures, bifid uvula with or without cleft palate, and ocular anomalies. Brain imaging shows white matter abnormalities in the periventricular and other regions.", "ORPHA ID": 506353, "Summary": ""}
{"Disease Name": "Autosomal recessive congenital cerebellar ataxia due to GRID2 deficiency", "Disease Definition": "A rare, genetic, slowly progressive neurodegenerative disease resulting from GRID2 deficiency characterized by motor, speech and cognitive delay, hypotonia, truncal and appendicular ataxia, and eye movement abnormalities (tonic upgaze, nystagmus, oculomotor apraxia). Intention tremor may also be associated. Brain imaging reveals progressive cerebellar atrophy with cerebellar flocculus particularly affected.", "ORPHA ID": 363432, "Summary": ""}
{"Disease Name": "Autosomal recessive congenital cerebellar ataxia due to MGLUR1 deficiency", "Disease Definition": "A rare, genetic, slowly progressive neurodegenerative disease resulting from MGLUR1 deficiency characterized by global developmental delay (beginning in infancy), mild to severe intellectual deficit with poor or absent speech, moderate to severe stance and gait ataxia, pyramidal signs (e.g. hyperreflexia) and mild dysdiadochokinesia, dysmetria, tremors, and/or dysarthria. Oculomotor signs, such as nystagmus, strabismus, ptosis and hypometric saccades, may also be associated. Brain imaging reveals progressive, generalized, moderate to severe cerebellar atrophy, inferior vermian hypoplasia, and/or constitutionally small brain.", "ORPHA ID": 324262, "Summary": ""}
{"Disease Name": "Autosomal recessive cutis laxa type 1", "Disease Definition": "A generalized connective tissue disorder characterized by the association of wrinkled, redundant and sagging inelastic skin with severe systemic manifestations (lung atelectesias and emphysema, vascular anomalies, and gastrointestinal and genitourinary tract diverticuli).", "ORPHA ID": 90349, "Summary": "Epidemiology\nThe prevalence of ARCL1 is unknown but around 60 cases have been reported in the literature so far.\nClinical description\nThe skin manifestations affect the whole body and are usually recognizable from birth. The excessive lax skin is particularly prominent around the axillae, groins and neck and on the face (giving patients an aged appearance with eyelid ptosis and drooping cheeks). Pulmonary emphysema develops early in life (during the neonatal period or by early childhood), often leading to respiratory failure. Common vascular anomalies include arterial aneurysms, fibromuscular artery dysplasia and stenosis leading to progressive heart failure. Genitourinary tract diverticuli lead to vesicoureteral reflux and recurrent infections. Less frequent findings include late closure of the fontanel, joint laxity, hip dislocation, inguinal hernia, arachnodactyly, bone fragility, vascular tortuosity and aortic aneurysm. Intelligence is normal.\nEtiology\nARCL1 is genetically heterogeneous and, although the etiology remains unknown in the majority of cases, mutations have been identified in some patients in the FBLN5 (14q31) and EFEMP2 (11q13) genes, encoding the extracellular matrix proteins fibulin-5 and EGF-containing fibulin-like extracellular matrix protein 2 (Fibulin-4), respectively. Arachnodactyly, bone fragility, vascular tortuosity and aortic aneurysms are common findings in patients carrying EFEMP2 mutations.\nDiagnostic methods\nDetailed clinical evaluation and histological studies of skin biopsies (revealing a moth-eaten appearance, abnormal elastin fiber branching and lose microfibrils associated with reduced elastin synthesis) are usually diagnostic in ARCL1. Molecular testing, available on a research basis only, may confirm the diagnosis in carriers of FBLN5 and EFEMP2 mutations.\nDifferential diagnosis\nThe differential diagnosis should include other forms of CL (autosomal recessive type 2, autosomal dominant and X-lined CL) and related syndromes (gerodermia osteodysplastica, Cantu syndrome, wrinkly skin syndrome and De Barsy syndrome), together with the Ehlers-Danlos syndromes and Costello syndrome (see these terms).\nGenetic counseling\nGenetic counseling should be provided to affected families and prenatal diagnosis through molecular testing is feasible for families in which the disease-causing mutation has been identified.\nManagement and treatment\nThere are no effective therapeutic strategies available for ARCL1. Care should be multidisciplinary with symptomatic treatment of pulmonary emphysema, prophylactic therapy for infections and hernia repair.\nPrognosis\nThe disease course in ARCL1 is severe, with most patients dying in childhood from cardiac or respiratory failure.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS"}
{"Disease Name": "Autosomal recessive cutis laxa type 2", "Disease Definition": "A spectrum of connective tissue disorders characterized by the association of wrinkled, redundant and sagging inelastic skin with growth and developmental delay, and skeletal anomalies. The spectrum ranges from patients with classic autosomal recessive cutis laxa type 2 (ARCL2, Debré type) to patients with a milder form of the disease, wrinkled skin syndrome (WSS).", "ORPHA ID": 90350, "Summary": "Epidemiology\nAround 40 patients with classic ARCL2 have been reported so far.\nClinical description\nPatients with ARCL2 present with generalized cutis laxa at birth but the skin manifestations become less pronounced and may disappear completely with age. Pre- and postnatal growth delay is common. Patients have a characteristic facial appearance (down-slanting palpebral fissures, a broad flat nasal bridge and short nose with anteverted nostrils, large ears and a small mouth). The most common ocular anomalies are strabismus and myopia. Congenital hip dislocation, increased joint laxity, congenital or progressive microcephaly, delayed closure of large fontanels, osteoporosis and decreased bone density are frequent findings. Developmental delay is observed in the majority of patients (mainly due to muscle hypotonia and joint laxity) but congenital brain anomalies are rare (although developmental anomalies such as cobblestone-like brain dysgenesis have been reported in some patients). Intellectual deficit and seizures have been reported in older patients. The systemic manifestations are mild in ARCL2 and pulmonary emphysema and cardiac anomalies are rare.\nEtiology\nThe underlying etiology in the majority of ARCL2 cases remains unknown. However, a combined disorder of N- and O-linked glycosylation (congenital disorder of glycosylation type II) has been detected in some patients and is associated with mutations in the ATP6V0A2 gene (12q24.31). Mutations in ATP6V0A2 have also been identified in patients with WSS. There are no specific clinical features that distinguish ARCL2 patients with glycosylation defects from those without any metabolic anomalies. Mutations in the PYCR1 gene have recently been identified in patients with ARCL2 and in patients with a phenotype (wrinkly skin, osteopenia and progeroid features) overlapping with classic ARCL2 and WSS, and the closely related syndromes, gerodermia osteodysplastica (GO) and de Barsy syndrome (DBS; see these terms).\nDiagnostic methods\nDiagnosis is made on the basis of physical and developmental examination, skeletal surveys, imaging studies, histological analysis of skin biopsies (decreased amounts of structurally abnormal elastin fibers) and biochemical tests (plasma transferrin and apolipoprotein CIII isoelectric focusing for detection of abnormal glycosylation). Molecular testing is available on a clinical basis for families with ATP6V0A2 mutations.\nDifferential diagnosis\nDifferential diagnoses should include other forms of CL (ARCL type 1, autosomal dominant CL and X-linked CL), as well as the clinically overlapping entities GO and DBS (see these terms).\nGenetic counseling\nGenetic counseling should be proposed and prenatal diagnosis through molecular testing is feasible for families in which the disease-causing mutation has been identified.\nManagement and treatment\nThere are no effective therapeutic strategies available for ARCL2 and care should be multidisciplinary with symptomatic management of the ocular and skeletal manifestations, and supportive and educational care for developmental and learning problems.\nPrognosis\nThe prognosis for patients is variable: life expectancy is generally not reduced. Although the skin manifestations improve with age, cognitive decline has been reported in some older patients.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS"}
{"Disease Name": "Autosomal recessive cutis laxa type 2A", "Disease Definition": "A rare, genetic, dermis elastic tissue disease characterized by redundant, overfolded skin of variable severity, ranging from wrinkly skin to cutis laxa associated with pre- and post-natal growth retardation, hypotonia, mild to moderate developmental delay, late closure of anterior fontanelle, and craniofacial dysmorphism (including microcephaly, hypertelorism, downslanting palpebral fissures, large, prominent nasal root with funnel nose, small, low-set ears, long philtrum, drooping facial skin). Additional manifestations may include seizures, intellectual disability, congenital hip dislocation, inguinal hernia, and cortical and cerebellar malformations. Pretibial pseudo-ecchymotic skin lesions have occasionally been associated.", "ORPHA ID": 357058, "Summary": ""}
{"Disease Name": "Autosomal recessive cutis laxa type 2B", "Disease Definition": "A rare, hereditary, developmental defect with connective tissue involvement characterized by cutis laxa of variable severity, in utero growth restriction, congenital hip dislocation and joint hyperlaxity, wrinkling of the skin, in particular the dorsum of hands and feet, and progeroid facial features. Hypotonia, developmental delay, and intellectual disability are common. In addition, cataracts, corneal clouding, wormian bones, lipodystrophy and osteopenia have been reported.", "ORPHA ID": 357064, "Summary": ""}
{"Disease Name": "Autosomal recessive distal osteolysis syndrome", "Disease Definition": "An early-onset distal osteolysis characterised by severe resorption of the hands and feet and absence of the distal and middle phalanges. It has been described in a son and daughter born to consanguineous parents. Other manifestations include distal muscular hypertrophy, flexion contractures, short stature, mild intellectual deficit and characteristic facies (maxillary hypoplasia, exophthalmos, and a broad nasal tip). It is transmitted as an autosomal recessive trait.", "ORPHA ID": 2776, "Summary": ""}
{"Disease Name": "Autosomal recessive distal renal tubular acidosis", "Disease Definition": "A rare autosomal recessive form of proximal renal tubular acidosis (pRTA) characterized by an isolated defect in the proximal tubule leading to the decreased reabsorption of bicarbonate and consequently causing urinary bicarbonate wastage. Mild growth retardation and reduced bone density are extra-renal complications. Several fractures and delayed puberty are possible features.", "ORPHA ID": 402041, "Summary": ""}
{"Disease Name": "Autosomal recessive dopa-responsive dystonia", "Disease Definition": "A very rare neurometabolic disorder characterized by a spectrum of symptoms ranging from those seen in dopa-responsive dystonia (DRD) to progressive infantile encephalopathy.", "ORPHA ID": 101150, "Summary": "Epidemiology\nThe estimated European prevalence of DRD ranges from 1/1,000,000-1/200,000. DYT5b is much less frequent than autosomal dominant DRD (DYT5a); fewer than 50 patients have been described worldwide to date.\nClinical description\nDisease presents in infancy (most frequently in the first year of life) with a progressive hypokinetic-rigid syndrome with generalized dystonia, involuntary jerky movements, postural tremor, or gait disturbances that may fluctuate during the day and show good or excellent responsiveness to levodopa (L-dopa) in most cases (>80%). Eye-rolling movements and/or mild, non-progressive intellectual deficit may be present in some cases. Less frequently, a more severe phenotype of complex encephalopathy can present before the age of 6 months, with marked hypokinesia and progressive truncal hypotonia, combined with focal or generalized dystonia, sometimes with dystonic crises over several days and (often excessive) jerky movements like myoclonus and tremor without diurnal fluctuations. Autonomic disturbances are frequent, such as excessive salivation and sweating, lethargy, constipation, poor feeding and ''pyrexia of unknown origin''. Intellectual deficit, developmental motor delay, bilateral ptosis and oculogyric crises are also frequent.\nEtiology\nDYT5b is caused by mutations in the tyrosine hydroxylase TH gene (11p15.5) encoding tyrosine hydroxylase, an enzyme responsible for catalyzing the conversion of L-tyrosine to L-dopa, the precursor of dopamine. For the two most common missense mutations (c.698G>A and c.707T>C) and for heterozygous truncating mutations, no genotype-phenotype correlation has been observed, but mutations in the promoter region are apparently associated with a milder phenotype.\nDiagnostic methods\nDiagnosis is based on clinical findings and the improvement of symptoms with the administration of oral L-dopa. The finding of homozygous TH mutations confirms diagnosis. Low levels of the dopamine metabolite homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) are found in the cerebrospinal fluid (CSF) of patients with DYT5b. HVA concentrations and the HVA/5-HIAA ratio in CSF appear to correlate with the age of onset and the severity of the phenotype.\nDifferential diagnosis\nDifferential diagnoses include different forms of DRD (e.g. autosomal dominant DRD), early onset torsion dystonia, myoclonic dystonia and other types of early-onset parkinsonism. It can also be mistaken for cerebral palsy or spastic paraplegia. Differential diagnoses that need to be considered for the more severe, encephalopathy-like phenotype include febrile infection-related epilepsy syndrome, neonatal hypoxic and ischemic brain injury, other tetrahydrobiopterin (BH4)-related enzyme deficiencies and mitochondrial disorders.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known TH  mutation.\nGenetic counseling\nDYT5b is inherited in an autosomal recessive manner. Genetic counseling is possible and recommended.\nManagement and treatment\nL-dopa, usually in combination with carbodopa, is the treatment of choice. The less severe phenotype typically shows a significant positive and quick response, but patients with the more severe phenotype frequently show hypersensitivity to L-dopa, with only moderate or no benefit, even after prolonged treatment and careful dosage adjustment, and are more prone to side effects. Dosage should be monitored for side effects and adjusted as necessary. Inhibitors of dopamine degradation like selegiline may be considered alternatively or in addition to L-dopa, but are rarely used in clinical practice.\nPrognosis\nPrognosis depends on the severity of the disease and if/when patients receive treatment.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "Autosomal recessive epidermolytic ichthyosis", "Disease Definition": "A rare, inherited, non-syndromic ichthyosis characterized by congenital, generalized erythroderma with cutaneous blistering and erosions, resembling collodion presentation at birth, replaced by progressive hyperkeratosis later in life without palmoplantar involvement. The ultrastructural pathology consists of sparse keratin filaments and keratin clumps that show a nearly homogeneous, amorphous structure.", "ORPHA ID": 512103, "Summary": ""}
{"Disease Name": "Autosomal recessive extra-oral halitosis", "Disease Definition": "A rare inborn error of metabolism characterized by cabbage-like breath odor with high levels of methanethiol and dimethylsulfide in oral and nasal breath, due to methanethiol oxidase deficiency. Laboratory examination shows elevated levels of dimethylsulfide, dimethylsulfoxide, and dimethylsulfone in blood, cerebrospinal fluid (CSF), and urine.", "ORPHA ID": 562538, "Summary": ""}
{"Disease Name": "Autosomal recessive faciodigitogenital syndrome", "Disease Definition": "A very rare syndrome including short stature, facial dysmorphism, hand abnormalities and shawl scrotum.", "ORPHA ID": 1974, "Summary": "Epidemiology\nIt has been observed in 16 subjects from five distantly related sibships of a large Kuwaiti Bedouin tribe.\nClinical description\nDysmorphic features include triangular or elongated face, hypertelorism, wide palpebral fissures, short, stubby nose with anteverted nostrils, long philtrum and ear anomalies. The hands are small, broad with mild interdigital webbing, 5th finger clinodactyly and lax joints. In one sibship, affected patients had coarse, dry, and hypopigmented hair. The affected patients had no intellectual deficit.\nGenetic counseling\nIn this tribe, the condition is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Autosomal recessive frontotemporal pachygyria", "Disease Definition": "A cerebral malformation characterized by symmetric, bilateral pachygyria with normal head circumference and without polymicrogyria. Clinical manifestations include developmental delay, moderate intellectual disability, normal or slightly decreased muscle tone and deep-tendon reflexes, telecanthus or hypertelorism.", "ORPHA ID": 329329, "Summary": ""}
{"Disease Name": "Autosomal recessive generalized dystrophic epidermolysis bullosa, intermediate form", "Disease Definition": "A rare dystrophic epidermolysis bullosa (DEB) characterized by generalized cutaneous and mucosal blistering that is not associated with severe deformities.", "ORPHA ID": 89842, "Summary": "Epidemiology\nIts exact prevalence is unknown but this sub-type represents the second most common recessive DEB (RDEB), the first one being severe RDEB. The prevalence of all RDEB sub-types, with the exclusion of severe RDEB, has been estimated at 1/2,000,000 in the United States.\nClinical description\nUnder the term intermediate RDEB are grouped a spectrum of phenotypes, showing highly variable severity of the cutaneous and mucosal involvement. The disease manifests at birth or during the neonatal period with generalized blistering. Aplasia cutis congenita (congenital absence of the skin) can also be observed at birth. Healing of blisters results in the development of milia, atrophic scarring (less severe than in severe RDEB), dystrophic nails, and, occasionally, albopapuloid lesions (ivory-white colored, scar-like papules) and scalp abnormalities. In some patients, the scarring phenomena can lead to a certain degree of pseudosyndactyly and loss of nail plates. Extracutaneous involvement is similar but less severe than in severe RDEB with no hand/foot deformities associated with this disease. Oral cavity lesions and excessive dental caries are common. Patients have a lower risk of esophageal strictures and corneal injury than severe RDEB. Growth delay and anemia are rare. Genitourinary tract involvement is rare. The risk of developing squamous cell carcinomas (SCC) is also increased but less common than in severe RDEB and occurs later in adulthood.\nEtiology\nThe disease is caused by mutations within the type VII collagen gene (COL7A1; 3p21.31) that lead to an alteration of function or a reduction in the amounts of collagen VII. This impairs collagen VII assembly into anchoring fibrils, which anchor the basement membrane to the underlying dermis. This in turn causes reduced skin resistance to minor trauma.\nDiagnostic methods\nDiagnosis is suspected at clinical examination and is confirmed by immunofluorescence antigen mapping and/or transmission electron microscopy on skin samples. Genetic testing confirms the diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes other forms of EB. In the neonatal period, aplasia cutis congenita, herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, linear IgA bullous dermatosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, bullous impetigo, and staphylococcal scalded skin syndrome may need to be considered.\nAntenatal diagnosis\nAntenatal diagnosis can be recommended in families with this RDEB subtype, depending on the individual degree of severity.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement is preventive: protective padding of the skin reduces blistering and careful wound care prevents secondary infection and reduces scarring. Oral hygiene is important for management of caries. Nutritional requirements should be evaluated by a dietitian. Esophageal strictures are treated by balloon dilatation with fluoroscopic guidance. A regular follow-up is necessary for the surveillance of SCC. The treatment of SCC is surgical and involves full-thickness excision with wide margins.\nPrognosis\nIn most cases, life expectancy is normal. However, there is an increased risk of development of metastasizing squamous cell carcinomas with a cumulative risk of mortality of 21.5% by age 55.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Carmen SALAVASTRU | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal recessive generalized dystrophic epidermolysis bullosa, severe form", "Disease Definition": "A severe form of dystrophic epidermolysis bullosa (DEB) characterized by generalized cutaneous and mucosal blistering and scarring associated with severe deformities and major extracutaneous involvement.", "ORPHA ID": 79408, "Summary": "Epidemiology\nThe reported prevalence at birth varies between populations, from to 1/333,000 in the United States to 1/77,000 in Europe.\nClinical description\nBlisters develop spontaneously or after the mildest trauma at birth or during the neonatal period and affect all of the body (with predilection for skin over bony prominences) with extensive involvement of the oral and gastrointestinal mucosa. Congenital skin ulceration with extensive denudation of a body area may be present. Lesions heal with retracting scars and milia. Epidermolysis bullosa (EB) nevi may occur. Excessive scarring can lead to adhesion of fingers and toes resulting to pseudosyndactyly, and to joint contractures that further cause disabling hand and foot deformities (''mitten deformities''). Scarring alopecia of the scalp and permanent loss of nail plates are also observed. Eye involvement is frequent and includes blepharitis, loss of eyelashes, ectropion, symblepharon, and corneal blisters that can lead to loss of vision. Chewing and swallowing difficulties are due to ankyloglossia, obliteration of the oral vestibules and progressive microstomia. Dental caries are numerous. Esophageal stricture is frequent and results in severe dysphagia. Anal and perianal erosions cause major pain during defecation and foster constipation. Extensive gastrointestinal involvement in combination with a hypercatabolic state due to permanent wounding, infection and inflammation, induce a state of chronic malnutrition which contributes to growth retardation, delayed puberty, osteopenia and osteoporosis. Urethral strictures may occur. Refractory anemia, iron deficiency and hypoalbuminemia are also observed. Nearly all patients develop at least one aggressive squamous cell carcinoma (SCC), typically during the third-fourth decade of life.\nEtiology\nThe disease is caused by homozygous or compound heterozygous biallelic nonsense mutations in COL7A1 (3p21.31) that usually result in premature termination codons leading to a lack of functional collagen VII, the main constituent of anchoring fibrils that anchor the basement membrane to the dermis.\nDiagnostic methods\nDiagnosis is suspected at clinical examination and is confirmed by immunofluorescence antigen mapping and/or transmission electron microscopy on skin samples showing a cleavage plane located below the lamina densa of the cutaneous basement membrane zone. Genetic testing confirms the diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes other forms of EB. In the neonatal period also herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, and staphylococcal scalded skin syndrome may need to be considered.\nAntenatal diagnosis\nAntenatal diagnosis is always recommended to parents having a child with severe RDEB. The disease-causing pathogenic variants should be disclosed before.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nProtective padding of the skin reduces the blistering and careful wound care helps in preventing secondary infections. Treatment of pain and itch is highly warranted but partly limited in effectiveness. Regular follow-up at an EB-experienced dentist is recommended. Physiotherapy and occupational therapy are necessary to delay gradual loss of mobility and autonomy. Hand and foot deformities can be treated by surgery. Follow-up by a dietitian is essential and gastrostomy feeding may be necessary. Esophageal strictures are treated by balloon dilatation with fluoroscopic guidance. Transfusions, iron supplementation, and erythropoietin administration improve anemia and iron deficiency. Vitamin D supplementation may be indicated to prevent osteoporosis. Regular follow-up is necessary for the surveillance of SCC. Psychological support should be offered.\nPrognosis\nLife expectancy is significantly reduced, mostly due to the development of aggressive SCC with frequent metastases. By the age of 55, the cumulative risk for developing SCC and death is greater than 90% and about 80%, respectively. Other complications that affect prognosis include chronic renal failure, and more rarely, multifactorial cardiomyopathy.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Martin LAIMER | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal recessive generalized epidermolysis bullosa simplex", "Disease Definition": "A rare, inherited, epidermolysis bullosa simplex characterized by neonatal onset of generalized or, less frequently, localized acral blistering. Milia are rare but atrophic scarring and dystrophic nails usually occur, along with focal keratoderma (palms and soles). Severe generalized blistering may cause perinatal death or persist during the entire life. Extracutaneous involvement is common, including anemia, growth retardation, oral cavity abnormalities (blisters and erosions, and caries) and constipation.", "ORPHA ID": 89838, "Summary": ""}
{"Disease Name": "Autosomal recessive hyperinsulinism due to Kir6.2 deficiency", "Disease Definition": "A rare, congenital, isolated hyperinsulinism disorder characterized by neonatal presentation of severe refractory hypoglycemia in the first two days of life, with limited response to medical management, sometimes requiring pancreatic resection. Newborns are often large for gestational age with mild to moderate hepatomegaly and diffuse form of hyperinsulinism due to Kir6.2 deficiency. Persistent hypoglycemia, hyperglycemia and type1 diabetes mellitus may develop later in life. Life-threatening hypoglycemic coma or status epilepticus have also been associated.", "ORPHA ID": 79644, "Summary": ""}
{"Disease Name": "Autosomal recessive hyperinsulinism due to SUR1 deficiency", "Disease Definition": "A rare, congenital, isolated hyperinsulinism disorder characterized by neonatal presentation of severe refractory hypoglycemia in the first two days of life, with limited response to medical management, sometimes requiring pancreatic resection. Newborns are often large for gestational age with mild to moderate hepatomegaly and diffuse form of hyperinsulinism due to SUR1 deficiency. Persistent hypoglycemia, hyperglycemia and type1 diabetes mellitus may develop later in life. Life-threatening hypoglycemic coma or status epilepticus have also been associated.", "ORPHA ID": 79643, "Summary": ""}
{"Disease Name": "Autosomal recessive hypophosphatemic rickets", "Disease Definition": "A rare, autosomal recessive renal phosphate-wasting disorder characterized by childhood-onset hypophosphatemia that clinically manifests with rickets and/or osteomalacia, slow growth/short stature, bone pain and skeletal deformities. Additional findings may include fatigue, muscle weakness and repeated bone fractures.", "ORPHA ID": 289176, "Summary": ""}
{"Disease Name": "Autosomal recessive infantile hypercalcemia", "Disease Definition": "A rare, genetic, phosphocalcic metabolism disorder characterized by early-onset hypercalcemia, hypophosphatemia, hypercalciuria, decreased intact parathyroid hormone serum levels and medullary nephrocalcinosis, typically manifesting with failure to thrive, hypotonia, vomiting, constipation and/or polyuria.", "ORPHA ID": 300547, "Summary": ""}
{"Disease Name": "Autosomal recessive intermediate Charcot-Marie-Tooth disease type A", "Disease Definition": "A subtype of autosomal recessive intermediate Charcot-Marie-Tooth (CMT) disease characterized by severe, early childhood-onset CMT neuropathy with prominent pes equinovarus deformity and impairment of hand muscles. Nerve conduction velocities usually range between 25-35 m/s and both axonal and demyelinating changes are observed on peripheral nerve pathology.", "ORPHA ID": 217055, "Summary": ""}
{"Disease Name": "Autosomal recessive intermediate Charcot-Marie-Tooth disease type B", "Disease Definition": "A rare subtype of autosomal recessive intermediate Charcot-Marie-Tooth (CMT) disease characterized by a CMT neuropathy associated with developmental delay, self-abusive behavior, dysmorphic features and vestibular Schwannoma. Motor nerve conduction velocities demonstrate features of both demyelinating and axonal pathology.", "ORPHA ID": 254334, "Summary": ""}
{"Disease Name": "Autosomal recessive intermediate Charcot-Marie-Tooth disease type C", "Disease Definition": "A rare subtype of autosomal recessive intermediate Charcot-Marie-Tooth (CMT) disease characterized by childhood to adulthood-onset of progressive, moderate to severe, predominantly distal, mostly lower limb muscle weakness and atrophy, foot deformities (including pes cavus and hammer toes), absent deep tendon reflexes and distal sensory loss associated with decreased motor and sensory nerve conduction velocities and features of both demyelinating and axonal neuropathy on sural nerve biopsy.", "ORPHA ID": 369867, "Summary": ""}
{"Disease Name": "Autosomal recessive intermediate Charcot-Marie-Tooth disease type D", "Disease Definition": "Autosomal recessive intermediate Charcot-Marie-Tooth disease type D is a rare hereditary motor and sensory neuropathy characterized by childhood onset of unsteady gait, pes cavus, frequent falls and foot dorsiflexor weakness slowly progressing to distal upper and lower limb muscle weakness and atrophy, distal sensory impairment and reduced tendon reflexes. Additional symptoms may include bilateral sensorineural hearing impairment and neuropathic pain.", "ORPHA ID": 435998, "Summary": ""}
{"Disease Name": "Autosomal recessive isolated optic atrophy", "Disease Definition": "A rare hereditary optic atrophy characterized by an early onset of bilateral optic nerve degeneration without other systemic features. Clinical manifestations include pallor of the optic disks, severe but slowly progressing visual impairment, and in some patients also paracentral scotoma, photophobia and dyschromatopsia.", "ORPHA ID": 98676, "Summary": ""}
{"Disease Name": "Autosomal recessive Kenny-Caffey syndrome", "Disease Definition": "A rare, primary bone dysplasia characterized by prenatal and postnatal growth retardation, short stature, cortical thickening and medullary stenosis of the long bones, absent diploic space in the skull bones, hypocalcemia due to the hypoparathyroidism, small hands and feet, delayed mental and motor development, intellectual disability, dental anomalies, and dysmorphic features, including prominent forehead, small deep-set eyes, beaked nose, and micrognathia.", "ORPHA ID": 93324, "Summary": ""}
{"Disease Name": "Autosomal recessive lethal neonatal axonal sensorimotor polyneuropathy", "Disease Definition": "A rare, genetic, autosomal recessive axonal hereditary motor and sensory neuropathy disease characterized by prenatal onset of a severe sensorimotor axonal polyneuropathy (reflected by reduced fetal movement and polyhydramnios), manifesting, at birth, with respiratory failure requiring mechanical ventilation, profound muscular hypotonia, rapidly progressing distal muscle weakness, and absent deep tendon reflexes, in the absence of contractures, leading to death before 8 months of age. Neuropathological findings show severe loss of large- and medium-sized myelinated fibers without signs of demyelination.", "ORPHA ID": 538096, "Summary": ""}
{"Disease Name": "Autosomal recessive leukoencephalopathy-ischemic stroke-retinitis pigmentosa syndrome", "Disease Definition": "A rare neurologic disease characterized by global developmental delay, intellectual disability, multiple ischemic lesions in brain MRI, behavioral abnormalities, dystonia, choreic movements and pyramidal syndrome, facial dysmorphism (hypertelorism, arched palate, macroglossia), retinitis pigmentosa, scoliosis, seizures.", "ORPHA ID": 314572, "Summary": ""}
{"Disease Name": "Autosomal recessive lower motor neuron disease with childhood onset", "Disease Definition": "A rare, genetic, neuromuscular disease characterized by proximal muscle weakness with an early involvement of foot and hand muscles following normal motor development in early childhood, a rapidly progressive disease course leading to generalized areflexic tetraplegia with contractures, severe scoliosis, hyperlordosis, and progressive respiratory insufficiency leading to assisted ventilation. Cranial nerve functions are normal and tongue wasting and fasciculations are absent. Milder phenotype with a moderate generalized weakness and slower disease progress was reported.", "ORPHA ID": 206580, "Summary": ""}
{"Disease Name": "Autosomal recessive malignant osteopetrosis", "Disease Definition": "A rare congenital disorder of bone resorption characterized by generalized skeletal densification.", "ORPHA ID": 667, "Summary": "Epidemiology\nOsteopetrosis is very rare. The incidence is estimated at 1/250 000 live births. The disease is more frequent in specific geographic regions and ethnic groups where consanguinity is common.\nClinical description\nBone marrow failure, fractures and visual impairment are the classical features of the disease, which begins in early infancy or in fetal life. It results from the failure of osteoclasts to resorb immature bone. This leads to abnormal bone marrow cavity formation and to the clinical signs and symptoms of bone marrow failure. It is accompanied by hepatosplenomegaly due to compensatory extramedullary hematopoiesis. Impaired bone remodeling causes bony narrowing of the cranial nerve foramina, which results in cranial nerve (especially optic nerve) compression. Pathologically, there is a persistence of the primary spongiosa characterized by cores of calcified cartilage within bone. Abnormal remodeling of primary, woven bone to lamellar bone results in 'brittle' bone that is prone to fracture. A rare form of the disease is associated with severe central nervous system dysfunction.\nEtiology\nThe disease is genetically heterogeneous and caused by biallelic mutations. Over 50% of cases are due to mutations in the TCIRG1 gene and another 15% are due to mutations in the CLCN7 gene. A small number of patients with 'pure' recessive osteopetrosis have been described with mutations in OSTM1, and SNX10 gene, whereas mutations in TNFSF11 (RANKL) or TNFRSF11A (RANK) were found in some of the 'osteoclast-poor' forms.\nDiagnostic methods\nThe clinical and radiological features establish the diagnosis. The genetic tests can be performed to confirm the diagnosis and to distinguish the exact form of the disease. Among imaging studies conventional radiography alone can show all the main radiological patterns of osteopetrosis, above all the abnormal increased bone density. Computed Tomography (CT) offers a higher level of detail and a higher spatial resolution than conventional radiography (helpful in a better detection of small associated fractures). MRI of the brain should be performed to assess the presence of cranial nerves involvement, hydrocephalus, and vascular abnormalities. Dual-Energy-X-rays-absorptiometry (DXA) can be used to quantify the increase in bone mass density, even if this tool is unable to predict the fracture risk in patients with osteopetrosis.\nDifferential diagnosis\nInfantile onset osteopetrosis should be distinguished from the much milder autosomal dominant adult disease, the intermediated recessive form of osteopetrosis, and the carbonic anhydrase II deficiency syndrome, which is associated with renal tubular acidosis and less severe osteopetrosis. In doubtful cases a bone biopsy may help in excluding other differential diagnoses.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variants have previously been identified in both parents.\nGenetic counseling\nGenetic analysis is important to recognize classical and atypical forms, being also essential for treatment strategy. Transmission is autosomal recessive. Genetic counseling should be offered to affected individuals, as well as to at-risk couples (both subjects are carriers of a disease-causing mutation) which have a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nPatients may require blood transfusions, treatment for infections and management of their developmental and visual problems. Bone marrow transplant can alleviate many features of the disease but needs to be performed early to minimize optic nerve encroachment. Hematopoietic stem cell transplantation is contraindicated in presence of mutations in OSTM1 or TNFSF11 (RANKL) gene.\nPrognosis\nThe prognosis is variable but improves if bone marrow transplant is performed early.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Elena PEDRINI | ERN BOND* - Dr Paolo SPINNATO \n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal recessive mendelian susceptibility to mycobacterial diseases due to a complete deficiency", "Disease Definition": "A group of genetic variants of mendelian susceptibility to mycobacterial diseases (MSMD) comprised of MSMD due to complete interferon gamma receptor 1 (IFN-gammaR1) deficiency, complete IFN-gammaR2 deficiency, complete interleukin-12 subunit beta (IL12B) deficiency, complete interleukin-12 receptor subunit beta-1 (IL-12RB1) deficiency and complete ISG15 deficiency.", "ORPHA ID": 319535, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nThis group of diseases has extreme clinical variability ranging from relatively mild infections with bacillus Calmette-Guérin (BCG) and salmonellosis (in IL12B and IL-12RB1 deficiencies) to severe and often fatal infections with BCG and other environmental mycobacteria (complete IFN-gammaR1 and IFN-gammaR2 deficiencies).\nEtiology\nAutosomal recessive MSMD due to a complete deficiency is caused by mutations in one of 5 genes: IFNGR1, IFNGR2, IL12B , IL12RB1 and ISG15. Mutations in these genes impair IL-12 dependent IFN-gamma immunity.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Autosomal recessive mendelian susceptibility to mycobacterial diseases due to a partial deficiency", "Disease Definition": "A group of genetic variants of mendelian susceptibility to mycobacterial diseases (MSMD) due to autosomal recessive mutations in the IFNGR1 and IFNGR2 genes which lead to a residual response of IFN-gamma.", "ORPHA ID": 319539, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nInfections in those with autosomal recessive MSMD due to a partial deficiency usually occur after the age of 3 to adulthood. Partial IFN-gammaR1 deficient patients experience infections that are more commonly due to localized non-tuberculosis mycobacterial (NTM) infections. They are also vulnerable to Mycobacterium tuberculosis. Infections in those with a partial IFN-gammaR2 deficiency are due to Mycobacterium bovis BCG and Mycobacterium abscessus. Manifestations include fever, weight loss, lymphadenopathy and hepatosplenomegaly. The infections are usually mild and, with treatment, patients remain in relatively good health.\nEtiology\nAutosomal recessive MSMD due to a partial deficiency is caused by mutations in either the IFNGR1 or IFNGR2 genes. These mutations lead to patients that have only a residual response to IFN-gamma and consequently have selective susceptibility to BCG and non-tuberculosis environmental mycobacteria (EM) infections and in rare cases to tuberculosis infections.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency", "Disease Definition": "A rare primary immunodeficiency characterized by increased susceptibility to infections with candida albicans and weakly pathogenic mycobacteria, such as mycobacterium bovis. Patients present in infancy with chronic mucocutaneous candidiasis of varying severity, disseminated mycobacterial disease, absence of palpable axillary and cervical lymph nodes, reduced thymus size, and variable hepatosplenomegaly. The immunological phenotype comprises mild T-cell lymphopenia, absence of type 1 natural killer T-cells and mucosal-associated invariant T-cells, and low levels of type 3 innate lymphoid cells.", "ORPHA ID": 477857, "Summary": ""}
{"Disease Name": "Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency", "Disease Definition": "A genetic variant of mendelian susceptibility to mycobacterial diseases (MSMD) characterized by a partial deficiency in IFN-gammaR1, leading to a residual response to IFN-gamma and, consequently, to recurrent, moderately severe infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).", "ORPHA ID": 319569, "Summary": "Epidemiology\nThe prevalence is unknown. The same homozygous mutations have been reported in 14 patients in 11 kindreds from Poland, Portugal, Spain and Chile, thus reflecting a founder effect.\nClinical description\nPatients present with moderately severe mycobacterial infections, BCG or EM diseases. These infections are recurrent but less severe than those seen in MSMD due to complete IFN-gammaR1 and IFN-gammaR2 deficiencies (see these terms). Infections with Mycobacterium tuberculosis have also been reported in patients with this disorder.\nEtiology\nAutosomal recessive MSMD due to partial IFN-gammaR1 deficiency is caused by homozygous mutations in the IFNGR1 gene on chromosome 6q23-q24 that encodes the IFN-gamma receptor ligand binding chain. The most common mutation is, by far, I87T. This mutation leads to the expression of IFN-gamma receptors on the cell surface with no signal transduction capacity and they therefore only show a partial response to IFN-gamma.\nDiagnostic methods\nDiagnosis is made by laboratory analysis. Low production of IL12p40 is detected in blood after BCG and BCG+IFN-gamma activation. Cells of patients show a residual response to IFN-gamma in terms of Stat-1 DNA-binding (GAS-binding activity) and HLA-II induction. A mutational analysis will identify a mutation in the IFNGR1 gene. Low levels of IFN-gamma were detected in the serum of the patients.\nDifferential diagnosis\nOther genetic etiologies of MSMD should be excluded.\nAntenatal diagnosis\nThis immunodeficiency is not severe and antenatal diagnosis is not necessary.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling is possible.\nManagement and treatment\nBCG vaccinations should be avoided in those with a known mutation in IFNGR1. Patients should be treated with antibiotics and, if necessary, with recombinant IFN-gamma.\nPrognosis\nPrognosis is usually good.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency", "Disease Definition": "Autosomal recessive mendelian susceptibility to mycobacterial diseases (MSMD) due to partial IFNgammaR2 deficiency is a genetic variant of MSMD (see this term) characterized by a partial deficiency in IFN-gammaR2, leading to a residual response to IFN-gamma and consequently to recurrent, moderately severe infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).", "ORPHA ID": 319574, "Summary": "Epidemiology\nThe prevalence is unknown. Only one patient has been reported with this variant to date.\nClinical description\nThe patient presented with a mild infection caused by BCG and M. abscessus.\nEtiology\nAutosomal recessive MSMD due to partial IFNgammaR2 deficiency is caused by a homozygous mutation (R114C) in IFNGR2 on chromosome 21q22.1-22.2 that encodes the IFN-gamma receptor ligand binding chain. This mutation leads to a residual cellular response to IFN-gamma in terms of IL12p40 production.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling is possible.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial JAK1 deficiency", "Disease Definition": "A rare primary immunodeficiency characterized by recurrent atypical mycobacterial infections, accompanied by relatively minor viral infections, on an immunological background of reduced induction of expression of interferon-regulated genes and dysregulated cytokine production, as revealed by laboratory studies. Global developmental delay and occurrence of non-hematopoietic malignancy at a young age have been reported in association.", "ORPHA ID": 574957, "Summary": ""}
{"Disease Name": "Autosomal recessive multiple pterygium syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital pterygia (webbing) mainly affecting the neck and large joints, arthrogryposis multiplex, short stature, and craniofacial dysmorphism (including ptosis, downslanting palpebral fissures, high-arched palate, and retrognathia). Additional manifestations are decreased movements, facial weakness, respiratory distress, vertebral anomalies, scoliosis, anomalies of the fingers, and cryptorchidism, among others. The disease is a non-lethal variant of multiple pterygium syndrome.", "ORPHA ID": 2990, "Summary": ""}
{"Disease Name": "Autosomal recessive myogenic arthrogryposis multiplex congenita", "Disease Definition": "Autosomal recessive myogenic arthrogryposis multiplex congenita is a rare inherited neuromuscular disease characterized by prenatal presentation (usually in the second trimester) of reduced fetal movements and abnormal positioning resulting in joint abnormalities that may involve both lower and upper extremities and is usually symmetric, severe hypotonia at birth with bilateral club foot, motor development delay, mild facial weakness without opthalmoplegia, absent deep tendon reflexes, normal motor and sensory nerve conduction velocities, no cerebellar or pyramidal involvement, and progressive disease course with loss of ambulation after the first decade of life.", "ORPHA ID": 319332, "Summary": ""}
{"Disease Name": "Autosomal recessive nail dysplasia", "Disease Definition": "A rare, isolated nail anomaly characterized by claw-shaped, thick, hyperplastic, hard and hyperpigmented nails, subungual hyperkeratosis, onycholysis and slow nail growth. Variable degree of disease severity has been reported.", "ORPHA ID": 280654, "Summary": ""}
{"Disease Name": "Autosomal recessive optic atrophy, OPA7 type", "Disease Definition": "A rare, syndromic, hereditary optic neuropathy disorder characterized by early-onset, severe, progressive visual impairment, optic disc pallor and central scotoma, variably associated with dyschromatopsia, auditory neuropathy (e.g. mild progressive sensorineural hearing loss), sensorimotor axonal neuropathy and, occasionally, moderate hypertrophic cardiomyopathy.", "ORPHA ID": 227976, "Summary": ""}
{"Disease Name": "Autosomal recessive palmoplantar keratoderma and congenital alopecia", "Disease Definition": "Autosomal recessive palmoplantar hyperkeratosis and congenital alopecia (PPK-CA) is a rare genetic skin disorder characterized by congenital alopecia and palmoplantar hyperkeratosis. It is usually associated with cataracts, progressive sclerodactyly and pseudo-ainhum.", "ORPHA ID": 1366, "Summary": "Epidemiology\nTo date, autosomal recessive PPK-CA has been reported in two families (seven affected individuals). An additional sporadic patient was likely affected by the same condition.\nClinical description\nSimilarly to the dominant variant, autosomal recessive PPK-CA usually presents during infancy. Its very early onset is often characterized by fading of facial, scalp and body hair within the first months of life without subsequent re-growth. Body and facial keratosis pilaris are additional features which appear in the following years. Skin thickening of palms and soles develops during infancy and may have an unusual pattern affecting the two sides of fingers and palms, but usually sparing the palmar surfaces. Periungueal involvement is typical and leads to secondary nail dystrophy. Autosomal recessive PPK-CA shows a relatively more severe evolution compared to the dominant variant as many patients develop sclerodactyly, small joint contractures and pseudo-ainhum. The original family also had congenital cataract.\nEtiology\nThe genetic basis of autosomal recessive PPK-CA is unknown.\nDifferential diagnosis\nPalmoplantar keratoderma and congenital alopecia/hypotrichosis is also found in ectodermal dysplasias and keratinization disorders, including hydrotic ectodermal dysplasia; hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma yndrome; KID syndrome; odonto-onycho-dermal dysplasia; Lelis syndrome; mutilating palmoplantar keratoderma with periorificial keratotic plaques; and Schöpf-Schulz-Passarge syndrome.\nGenetic counseling\nTransmission appears to be autosomal recessive.\n\n                            Last update: \n                            July 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Marco CASTORI"}
{"Disease Name": "Autosomal recessive polycystic kidney disease", "Disease Definition": "A rare, genetic hepatorenal fibrocystic syndrome characterized by cystic dilatation and ectasia of renal collecting tubules, and a ductal plate malformation of the liver resulting in congenital hepatic fibrosis. Clinical presentation, whilst typically in utero or at birth, is variable and in the most severe cases includes Potter-sequence, oligohydramnios, pulmonary hypoplasia, and massively enlarged echogenic kidneys.", "ORPHA ID": 731, "Summary": "Epidemiology\nPrevalence is estimated at 1/20,000 live births. Male and female children are equally affected.\nClinical description\nThe clinical spectrum is broad and may include variable degrees of renal insufficiency, mild to severe life-threating neonatal respiratory distress/failure due to pulmonary hypoplasia, hyponatremia, hypertension and predisposition to urinary tract infections. Patients can progress to end-stage renal disease (ESRD) at varying ages. Congenital hepatic fibrosis (CHF) is invariably presents at birth, although may be clinically undetectable. The progressive manifestations of CHF typically include portal hypertension (pHTN), gastrointestinal varices and associated bleeding, bile duct disease (Caroli syndrome and cholangitis) and hepatosplenomegaly.\nEtiology\nPKHD1 (6p12.2-3) is the most frequently identified causative gene, and encodes the ciliary protein fibrocystin. Mutations in a cilia-related gene, DZIP1L (3q22.3), encoding a zinc finger protein, has also been identified.\nDiagnostic methods\nThe hepatorenal phenotype and a family history consistent with autosomal-recessive inheritance is suggestive of the disease. Ultrasound typically shows hyperechogenic and enlarged kidneys, with retained contour and microcysts. Liver sonography shows biliary duct ectasia, a heterogeneous liver and possibly signs of pHTN and associated varices. Liver function tests typically remain in the normal ranges but thrombocytopenia and splenomegaly may be signs of pHTN. Genetic testing can confirm the causative mutation.\nDifferential diagnosis\nMain differential diagnoses are other hereditary cystic kidney diseases including autosomal dominant polycystic kidney disease, HNF1beta-associated cystic nephropathies, cystic kidney dysplasia and nephronophthisis, as well as rare metabolic diseases such as glutaric aciduria type II.\nAntenatal diagnosis\nSuspicious prenatal ultrasound findings include bilaterally hyperechogenic, enlarged kidneys with poor cortico-medullary differentiation, with or without oligohydramnios and cysts. Prenatal genetic testing is possible where a mutation has been previously identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. The risk of recurrence in siblings of an affected child is 25%.\nManagement and treatment\nTreatment is supportive with conservative management of chronic kidney disease and hepatic symptoms. In newborns, pulmonary hypoplasia may require mechanical or high frequency ventilation. Hypertension needs aggressive management, often requiring a combination of several drugs, among which angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) are the mainstays. Peritoneal dialysis is recommended as first choice renal replacement treatment (RRT) for children with end-stage renal disease (ESRD). Renal transplantation is the best solution in case of ESRD. Depending on the hepatic phenotype, combined liver and kidney transplantation may be necessary. Regular monitoring of the liver disease is required to identify complications. Liver transplantation may be necessary. Multidisciplinary support should be considered for associated neurocognitive and behavioral problems.\nPrognosis\nThe disease is associated with reduced life expectancy, although survival is improving. In the case of neonatal respiratory distress, mortality has been described as high as 30-40%. For patients surviving the neonatal period, about 50% will develop ESRD within the first decade of life. CHF is an important cause of morbidity and mortality.\n\n                            Last update: \n                            March 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Max Christoph LIEBAU | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity", "Disease Definition": "A rare, genetic primary immunodeficiency characterized by recurrent respiratory and skin viral infections (Epstein-Barr virus, herpes simplex virus, human papillomavirus), deficient spontaneous cytotoxicity of natural killer cells, but preserved antibody-dependent cellular cytotoxicity. No other abnormalities are present on immunologic work-up.", "ORPHA ID": 437552, "Summary": ""}
{"Disease Name": "Autosomal recessive primary microcephaly", "Disease Definition": "Autosomal recessive primary microcephaly (MCPH) is a rare genetically heterogeneous disorder of neurogenic brain development characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.", "ORPHA ID": 2512, "Summary": "Epidemiology\nExact prevalence of non-syndromic microcephaly is not known. MCPH is more common in Asian and Middle Eastern populations than in Caucasians, in whom an annual incidence of 1/1,000,000 is reported. It is more common in specific populations, e.g. northern Pakistanis. Consanguinity appears to play a role in incidence.\nClinical description\nPatients have a reduction in head circumference (HC) at birth of at least 2 standard deviations (SD) below ethnically matched, age- and sex-related mean values. Microcephaly can be observed by week 32 of pregnancy. Subsequent head growth is very slow, and HC worsens during infancy: below -3SD before 6 months, and usually between -4SD and -12SD in adults. Mild to moderate non-progressive intellectual impairment is found, in the absence of any significant neurological deficit. Seizures may be present (10%). Delay in early motor milestones and speech delay are common. Most patients have hyperactive behavior.\nEtiology\nTen subtypes based on the 11 genes have been differentiated. However, patients are basically phenotypically indistinguishable. MCPH is caused by mutations in MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, STIL, CEP63, CEP135 , CASC5  and PHC1. These mutations appear to lead to reduced generation of cerebral cortical neurons during embryonic neurogenesis. Some patients do not harbor these mutations. Some carry mutations in one of the genes of Meier-Gorlin syndrome (see this term), i.e. CDC6, CDT1, ORC1, ORC4, ORC6.\nDiagnostic methods\nDiagnosis is generally based on clinical signs. Reduced occipitofrontal circumference along with mild to moderate cognitive impairment, in the absence of other malformations or dysmorphism, and with normal height to mildly shortened height, are the most common diagnostic criteria. MRI shows grossly normal, proportionately small-sized brain with some degree of gyral simplification, and small normal brainstem and cerebellum. Patients with mutations in WDR62 may show more severe cortical anomalies and may not fulfill the common criteria of MCPH. Molecular genetic testing is available for several genes. The condition can be diagnosed on prenatal ultrasound but absence of microcephaly does not exclude the diagnosis.\nDifferential diagnosis\nMCPH and Seckel syndrome belong to a clinical continuum, as mutations of some genes (CENPJ, CEP152) result in either phenotype. The distinction between MCPH and Seckel relies on a historical distinction between microcephalic patients with normal stature and patients with reduced stature. Normal fundus examination is important to distinguish MCPH from the microcephaly-chorioretinopathy syndromes. MRI is crucial to distinguish MCPH from other disorders with congenital microcephaly, such as lissencephaly, Norman-Roberts type (see this term) or infectious embryofetopathies. Assessment of maternal serum phenylalaninemia is mandatory to exclude maternal phenylketonuria (see this term).\nAntenatal diagnosis\nPrenatal testing and carrier testing are available for families with known gene mutations. When no mutation is identified, fetal MRI could be advised, but normal findings do not exclude the diagnosis.\nGenetic counseling\nInheritance is autosomal recessive. Exact genotype-phenotype correlations have not been established.\nManagement and treatment\nThere is no specific etiologic treatment. Physical and speech therapy may be beneficial. Seizures are usually stabilized with common anticonvulsants. Ritalin may reduce hyperactivity.\nPrognosis\nVital prognosis depends on severity and related manifestations but is generally good.\n\n                            Last update: \n                            March 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES"}
{"Disease Name": "Autosomal recessive progressive external ophthalmoplegia", "Disease Definition": "A rare genetic, neuro-ophthalmological disease characterized by progressive weakness of the external eye muscles, resulting in bilateral ptosis and diffuse, symmetric ophthalmoparesis. Additional signs may include generalized skeletal muscle weakness, muscle atrophy, sensory axonal neuropathy, ataxia, cardiomyopathy, and psychiatric symptoms. It is usually more severe than autosomal dominant form.", "ORPHA ID": 254886, "Summary": ""}
{"Disease Name": "Autosomal recessive proximal renal tubular acidosis", "Disease Definition": "A rare autosomal recessive form of proximal renal tubular acidosis characterized by an isolated defect in the proximal tubule leading to the decreased reabsorption of bicarbonate and consequentially to urinary bicarbonate wastage. Presentation is typically with hyperchloremic acidosis, usually occurring in childhood. Extrarenal manifestations include ocular abnormalities (band keratopathy, glaucoma, and cataracts), intellectual disability and severe growth retardation. Other features like dental enamel defects, basal ganglia calcification and pancreatitis are sometimes present.", "ORPHA ID": 93607, "Summary": ""}
{"Disease Name": "Autosomal recessive Robinow syndrome", "Disease Definition": "Autosomal recessive Robinow syndrome (RRS) is the less common type of Robinow syndrome (RS, see this term) characterized by short-limb dwarfism, costovertebral segmentation defects and abnormalities of the head, face and external genitalia.", "ORPHA ID": 1507, "Summary": "Epidemiology\nFewer than 100 cases of this type have been reported in the literature to date.\nClinical description\nThe disorder is usually recognizable at birth or in early childhood. The clinical signs are generally far more severe in recessive cases of RS than in the dominant form, particularly skeletal abnormalities. All patients with the recessive form of RS suffer from vertebral segmentation abnormalities, resulting in scoliosis and chest deformities. Rib fusions are considered to be characteristic of the autosomal recessive form.\nEtiology\nThe syndrome is caused by mutations in the ROR2 gene (9q22).\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Juliana MAZZEU"}
{"Disease Name": "Autosomal recessive secondary polycythemia not associated with VHL gene", "Disease Definition": "A rare, hereditary, hematologic disease characterized by an increase in hemoglobin, hematocrit and erythrocyte mass resulting in plethora or ruddy complexion, headache, dizziness, tinnitus and exertional dyspnea. In some cases, thrombophlebitis and arthralgia have also been reported.", "ORPHA ID": 247378, "Summary": ""}
{"Disease Name": "Autosomal recessive severe congenital neutropenia due to CSF3R deficiency", "Disease Definition": "A rare, genetic, primary immunodeficiency disorder characterized by predisposition to recurrent, life-threatening bacterial infections associated with decreased peripheral neutrophil granulocytes (absolute neutrophil count less than 500 cells/microliter), resulting from recessively inherited loss-of-function mutations in the CSF3R gene. Full maturation of all three lineages in the bone marrow and refractoriness to in vivo rhG-CSF treatment are associated.", "ORPHA ID": 420702, "Summary": ""}
{"Disease Name": "Autosomal recessive severe congenital neutropenia due to CXCR2 deficiency", "Disease Definition": "A rare, genetic, primary immunodeficiency disorder characterized by recurrent bacterial infections (including septic thrombophlebitis and subacute bacterial endocarditis) and neutropenia without lymphopenia or warts, resulting from recessively inherited mutations in CXCR2.", "ORPHA ID": 420699, "Summary": ""}
{"Disease Name": "Autosomal recessive sideroblastic anemia", "Disease Definition": "Congenital autosomal recessive sideroblastic anemia (ARSA) is a non-syndromic, microcytic/hypochromic sideroblastic anemia, present from early infancy and characterized by severe microcytic anemia, which is not pyridoxine responsive, and increased serum ferritin.", "ORPHA ID": 260305, "Summary": "Epidemiology\nTo date, fewer than 30 unrelated genetically characterized individuals with congenital ARSA have been reported in the northern hemisphere.\nClinical description\nCongenital ARSA presents in early infancy, within the first weeks or months after birth, and is associated with severe microcytic anemia, increased transferrin saturation and increased serum ferritin. Clinical features are those of anemia and iron overload and include pallor, fatigue, weakness, breathlessness, splenomegaly, hyperglycemia, glucose intolerance and skin hyperpigmentation. Complications of iron overload include heart arrhythmias, heart attacks and liver disease (cirrhosis, cancer). Patients need blood transfusions to survive and do not respond to treatment with pyridoxine (vitamin B6).\nEtiology\nARSA is caused by a homozygous or compound heterozygous mutation in the SLC25A38 gene located on chromosome 3p22.1.\nDiagnostic methods\nDiagnosis is based on clinical findings together with full blood examination including blood smear and reticulocyte count, measurement of iron stores and bone marrow aspirate showing ringed sideroblasts. Unresponsiveness to pyridoxine treatment often leads to confirming SLC25A38 gene mutation analysis.\nDifferential diagnosis\nDifferential diagnosis includes other types of sideroblastic anemia and particularly bears resemblance with X-linked sideroblastic anemia (XLSA, see this term).\nAntenatal diagnosis\nIn case of family history, prenatal diagnosis by amniocentesis or chorionic villus sampling and cytogenetic analysis is possible, as early diagnosis in a child may be of great benefit for treatment of anemia and avoidance of iron overload, historically the main cause of early death.\nGenetic counseling\nThe SLC25A38 gene mutation is transmitted as an autosomal recessive trait. Genetic counseling should be offered to affected individuals and their families informing them of the possibilities of carrier testing for at-risk family members and the genetic risk for transmitting it on to their children.\nManagement and treatment\nARSA differs from X-linked sideroblastic anemias because it is usually more severe and is not responsive to treatment with pyridoxine. Treatment is supportive and involves hematological monitoring, the surveillance of iron levels and nearly always comprises chronic blood transfusions. If iron overload has already developed, iron chelation can be used to normalize iron levels. In some cases, bone marrow transplantation is considered as a successful treatment option.\nPrognosis\nPrognosis is variable and depends on the severity of microcytic anemia. Quality of life is affected in the case chronic blood transfusions are needed. In well treated patients life expectancy is thought to be normal.\n\n                            Last update: \n                            July 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Clara CAMASCHELLA"}
{"Disease Name": "Autosomal recessive spastic ataxia of Charlevoix-Saguenay", "Disease Definition": "A rare neurodegenerative disorder characterized by early-onset cerebellar ataxia, a pyramidal syndrome and peripheral neuropathy.", "ORPHA ID": 98, "Summary": "Epidemiology\nIt was initially described in the Charlevoix-Saguenay region of Quebec where incidence of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) at birth has been estimated at 1 in 1,932. The incidence and prevalence worldwide remain unknown but ARSACS is now considered one of the more common recessive ataxias worldwide with cases described in several countries including Turkey, Japan, the Netherlands, Italy, Belgium, France, Spain and more than 20 other countries.\nClinical description\nARSACS is a slowly progressive disease with variable clinical presentation. The age of onset in non-Quebec patients is variable (ranging from late infantile, juvenile to early-adult onset) but in individuals from Quebec, onset occurs between 12 and 18 months of age with gait disturbance and walking difficulties. Other early signs of cerebellar ataxia include upper limbs incoordination, dysarthria and nystagmus. The pyramidal syndrome is characterized by lower limbs spasticity, brisk patellar tendon reflexes and the Babinski sign. Onset of the peripheral neuropathy generally occurs later and leads to absence of the Achilles tendon reflex, distal amyotrophy, pes cavus and deep sensory disturbances (impaired vibration sense). Retinal hypermyelination (without vision loss) is a constant feature in ARSACS patients from Quebec but may be absent in patients from other countries. Cognitive impairments related to cerebellar involvement have been documented. Other manifestations may include spasms, lower limb neuropathic pain and bladder dysfunction.\nEtiology\nARSACS is caused by autosomal recessive mutations in the SACS gene (13q11), which encodes a large protein of partially known function named sacsin.\nDiagnostic methods\nThe diagnosis of ARSACS is established by molecular genetic testing. Clinical diagnosis relies on the results of neurophysiological data (signs of both axonal and demyelinating neuropathy, with nerve conduction studies revealing loss of sensory nerve conduction and reduced motor conduction velocities). MRI brain revealed superior cerebellar vermian atrophy and T2 linear ''striped'' hypointensities in pons. Retinal examination may also be useful for diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other autosomal recessive ataxias, such as Friedreich ataxia, ataxia with vitamin E deficiency (AVED), Abetalipoproteinemia and hereditary forms of spastic paraplegia, in particular spastic paraplegia type 7, spastic paraplegia type 30 and spastic paraplegia type 20 (SPG20-Troyer syndrome).\nAntenatal diagnosis\nAntenatal diagnosis is possible for at-risk couples (both individuals are carriers of a disease-causing mutation) by genetic testing.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment is symptomatic aiming towards improving motor control, decreasing spasticity and should include a rehabilitation team approach that includes physiotherapy, occupational therapy and pharmacotherapy.\nPrognosis\nMost patients become wheelchair-dependent by the fifth decade of life. Death generally occurs during the sixth decade but survival into the seventies has been reported.\n\n                            Last update: \n                            April 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Bernard BRAIS  - Pr Cynthia GAGNON  - Dr Jean MATHIEU"}
{"Disease Name": "Autosomal recessive spastic ataxia with leukoencephalopathy", "Disease Definition": "A rare, genetic, autosomal recessive spastic ataxia disease characterized by cerebellar ataxia, spasticity, cerebellar (and in some cases cerebral) atrophy, dystonia, and leukoencephalopathy.", "ORPHA ID": 314603, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic ataxia-optic atrophy-dysarthria syndrome", "Disease Definition": "A rare, genetic, autosomal recessive spastic ataxia disease characterized by onset in early childhood of spastic paraparesis, cerebellar ataxia, dysarthria and optic atrophy.", "ORPHA ID": 254343, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 11", "Disease Definition": "A complex hereditary spastic paraplegia characterized by progressive lower limbs weakness and spasticity, upper limbs weakness, dysarthria, hypomimia, sphincter disturbances, peripheral neuropathy, learning difficulties, cognitive impairment and dementia. Magnetic resonance imaging shows thin corpus callosum, cerebral atrophy, and periventricular white matter changes.", "ORPHA ID": 2822, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 14", "Disease Definition": "Autosomal recessive spastic paraplegia type 14 is a rare, complex hereditary spastic paraplegia characterized by adulthood-onset of slowly progressive spastic paraplegia of lower limbs presenting with spastic gait, hyperreflexia, and mild lower limb hypertonicity associated with mild intellectual disability, visual agnosia, short and long-term memory deficiency and mild distal motor neuropathy. Bilateral pes cavus and extensor plantar responses are also associated.", "ORPHA ID": 100995, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 15", "Disease Definition": "Autosomal recessive spastic paraplegia type 15 is a complex form of hereditary spastic paraplegia characterized by a childhood to adulthood onset of slowly progressive lower limb spasticity (resulting in gait disturbance, extensor plantar responses and decreased vibration sense) associated with mild intellectual disability, mild cerebellar ataxia, peripheral neuropathy (with distal upper limb amyotrophy) and retinal degeneration. Thin corpus callosum is a common imaging finding.", "ORPHA ID": 100996, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 20", "Disease Definition": "Autosomal recessive spastic paraplegia type 20 (SPG20) is a type of complex hereditary spastic paraplegia characterized by an onset in infancy of progressive spastic paraparesis associated with distal amyotrophy, psuedobulbar palsy, motor and cognitive delays, mild cerebellar signs (dysarthria, dysdiadochokinesia, mild intention tremor), short stature and subtle skeletal abnormalities (pes cavus, mild talipes equinovarus, kyphoscoliosis). SPG20 is due to mutations in the SPG20 gene (13q13.1), which encodes the protein spartin.", "ORPHA ID": 101000, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 21", "Disease Definition": "Autosomal recessive spastic paraplegia type 21 is a complex type of hereditary spastic paraplegia characterized by an onset in adolescence or adulthood of slowly progressive spastic paraparesis associated with the additional manifestations of apraxia, cognitive and speech decline (leading to dementia and akinetic mutism in some cases), personality disturbances and extrapyramidal (e.g. oromandibular dyskinesia, rigidity) and cerebellar (i.e. dysdiadochokinesia and incoordination) signs. Subtle abnormalities (e.g. developmental delays) may be noted earlier in childhood. A thin corpus callosum and white matter abnormalities are equally reported on magnetic resonance imaging.", "ORPHA ID": 101001, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 23", "Disease Definition": "Autosomal recessive spastic paraplegia type 23 (SPG23) is a rare, complex type of hereditary spastic paraplegia that presents in childhood with progressive spastic paraplegia, associated with peripheral neuropathy, skin pigment abnormalities (i.e. vitiligo, hyperpigmentation, diffuse lentigines), premature graying of hair, and characteristic facies (i.e. thin with ''sharp'' features). The SPG23 phenotype has been mapped to a locus on chromosome 1q24-q32.", "ORPHA ID": 101003, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 24", "Disease Definition": "A very rare, pure form of spastic paraplegia characterized by an onset in infancy of lower limb spasticity associated with gait disturbances, scissor gait, tiptoe walking, clonus and increased deep tendon reflexes. Mild upper limb involvement may occasionally also be associated.", "ORPHA ID": 101004, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 25", "Disease Definition": "Autosomal recessive spastic paraplegia type 25 (SPG25) is a rare, complex type of hereditary spastic paraplegia characterized by adult-onset spastic paraplegia associated with spinal pain that radiates to the upper or lower limbs and is related to disk herniation (with minor spondylosis), as well as mild sensorimotor neuropathy. The SPG25 phenotype has been mapped to a locus on chromosome 6q23-q24.1.", "ORPHA ID": 101005, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 26", "Disease Definition": "Autosomal recessive spastic paraplegia type 26 (SPG26) is a rare, complex type of hereditary spastic paraplegia characterized by the onset in childhood/adolescence (ages 2-19) of progressive spastic paraplegia associated mainly with mild to moderate cognitive impairment and developmental delay, cerebellar ataxia, dysarthria, and peripheral neuropathy. Less commonly reported manifestations include skeletal abnormalities (i.e. pes cavus, scoliosis), dyskinesia, dystonia, cataracts, cerebellar signs (i.e. saccadic dysfunction, nystagmus, dysmetria), bladder disturbances, and behavioral problems. SPG26 is caused by mutations in the B4GALNT1 gene (12q13.3), encoding Beta-1, 4 N-acetylgalactosaminyltransferase 1.", "ORPHA ID": 101006, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 27", "Disease Definition": "Autosomal recessive spastic paraplegia type 27 is a rare, pure or complex hereditary spastic paraplegia characterized by a variable onset of slowly progressive lower limb spasticity, hyperreflexia and extensor plantar responses, that may be associated with sensorimotor polyneuropathy, decreased vibration sense, lower limb distal muscle wasting, dysarthria and mild to moderate intellectual disability.", "ORPHA ID": 101007, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 28", "Disease Definition": "Autosomal recessive spastic paraplegia type 28 is a pure form of hereditary spastic paraplegia characterized by a childhood or adolescent onset of slowly progressive, pure crural muscle spastic paraparesis which manifests with mild lower limb weakness, gait difficulties, extensor plantar responses, and hyperreflexia of lower extremities. Less common manifestations include cerebellar oculomotor disturbance with saccadic eye pursuit, pes cavus and scoliosis. Some patients also present pin and vibration sensory loss in distal legs.", "ORPHA ID": 101008, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 32", "Disease Definition": "Autosomal recessive spastic paraplegia type 32 (SPG32) is a rare, complex type of hereditary spastic paraplegia characterized by a slowly progressive spastic paraplegia (with walking difficulties appearing at onset at 6-7 years of age) associated with mild intellectual disability. Brain imaging reveals thin corpus callosum, cortical and cerebellar atrophy, and pontine dysraphia. The SPG32 phenotype has been mapped to a locus on chromosome 14q12-q21.", "ORPHA ID": 171622, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 35", "Disease Definition": "Autosomal recessive spastic paraplegia type 35 is a rare form of hereditary spastic paraplegia characterized by childhood (exceptionally adolescent) onset of a complex phenotype presenting with lower limb (followed by upper limb) spasticity with hyperreflexia and extensor plantar responses, with additional manifestations including progressive dysarthria, dystonia, mild cognitive decline, extrapyramidal features, optic atrophy and seizures. White matter abnormalities and brain iron accumulation have also been observed on brain magnetic resonance imaging.", "ORPHA ID": 171629, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 39", "Disease Definition": "A rare autosomal recessive complex spastic paraplegia characterized by upper motor neuron involvement and peripheral neuropathy with an onset between childhood and early adulthood. Patients present with progressive spasticity, hyperreflexia, and distal upper and lower muscle wasting. Reduced cognitive functioning and cerebellar ataxia have also been reported. MR imaging may reveal cerebellar and/or spinal cord atrophy.", "ORPHA ID": 139480, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 43", "Disease Definition": "Autosomal recessive spastic paraplegia type 43 is a rare, complex hereditary spastic paraplegia characterized by a childhood to adolescent onset of progressive lower limb spasticity, associated with mild to severe gait disturbances, extensor plantar responses, muscle weakness and severe distal atrophy, frequently with upper limb involvement. Additional features may include joint contractures, distal sensory loss and brisk or absent deep tendon reflexes. Other signs, such as depression, memory loss, optic atrophy (with vision loss) and brain iron deposition (revealed by brain imagery), have also been reported.", "ORPHA ID": 320370, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 44", "Disease Definition": "Autosomal recessive spastic paraplegia type 44 (SPG44) is a very rare, complex form of hereditary spastic paraplegia characterized by a late-onset, slowly progressive spastic paraplegia associated with mild ataxia and dysarthria, upper extremity involvement (i.e. loss of finger dexterity, dysmetria), and mild cognitive impairment, without the presence of nystagmus. A hypomyelinating leukodystrophy and thin corpus callosum is observed in all cases and psychomotor development is normal or near normal. SPG44 is caused by mutations in the GJC2 gene (1q41-q42) encoding the gap junction gamma-2 protein.", "ORPHA ID": 320401, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 45", "Disease Definition": "Autosomal recessive spastic paraplegia type 45 is a rare, pure or complex form of hereditary spastic paraplegia characterized by onset in infancy of progressive lower limb spasticity, abnormal gait, increased deep tendon reflexes and extensor plantar responses, that may be associated with intellectual disability. Additional signs, such as contractures in the lower limbs, amyotrophy, clubfoot and optic atrophy, have also been reported.", "ORPHA ID": 320396, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 46", "Disease Definition": "Autosomal recessive spastic paraplegia type 46 (SPG46) is a rare, complex type of hereditary spastic paraplegia characterized by an onset, in infancy or childhood, of the typical signs of spastic paraplegia (i.e. spastic gait and weakness of the lower limbs) associated with a variety of additional manifestations including upper limb spasticity and weakness, pseudobulbar dysarthria, bladder dysfunction, cerebellar ataxia, cataracts, and cognitive impairment that can progress to dementia. Brain imaging may show thinning of the corpus callosum and mild atrophy of the cerebrum and cerebellum. SPG46 is due to mutations in the GBA2 gene (9p13.2) encoding non-lysosomal glucosylceramidase.", "ORPHA ID": 320391, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 48", "Disease Definition": "A rare, pure or complex form of hereditary spastic paraplegia usually characterized by a pure phenotype of a slowly progressive spastic paraplegia associated with urinary incontinence with an onset in mid- to late-adulthood. A complex phenotype, with the additional findings of cognitive impairment, sensorimotor polyneuropathy, ataxia, parkinsonism, and dystonia as well as thin corpus callosum and white matter lesions (seen on brain and spine magnetic resonance imaging), has also been reported.", "ORPHA ID": 306511, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 53", "Disease Definition": "Autosomal recessive spastic paraplegia type 53 (SPG53) is a very rare, complex type of hereditary spastic paraplegia characterized by early-onset spastic paraplegia (with spasticity in the lower extremities that progresses to the upper extremities) associated with developmental and motor delay, mild to moderate cognitive and speech delay, skeletal dysmorphism (e.g. kyphosis and pectus), hypertrichosis and mildly impaired vibration sense. SPG53 is due to mutations in the VPS37A gene (8p22) encoding vacuolar protein sorting-associated protein 37A.", "ORPHA ID": 319199, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 54", "Disease Definition": "Autosomal recessive spastic paraplegia type 54 (SPG54) is a rare, complex form of hereditary spastic paraplegia characterized by the onset in early childhood of progressive spastic paraplegia associated with cerebellar signs, short stature, delayed psychomotor development, intellectual disability and, less commonly, foot contractures, dysarthria, dysphagia, strabismus and optic hypoplasia. SPG54 is caused by mutations in the DDHD2 gene (8p11.23) encoding phospholipase DDHD2.", "ORPHA ID": 320380, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 55", "Disease Definition": "Autosomal recessive spastic paraplegia type 55 (SPG 55) is a rare, complex type of hereditary spastic paraplegia characterized by childhood onset of progressive spastic paraplegia associated with optic atrophy (with reduced visual acuity and central scotoma), ophthalmoplegia, reduced upper-extremity strength and dexterity, muscular atrophy in the lower extremities, and sensorimotor neuropathy. SPG55 is caused by mutations in the C12ORF65 gene (12q24.31) encoding probable peptide chain release factor C12orf65, mitochondrial.", "ORPHA ID": 320375, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 56", "Disease Definition": "A rare form of hereditary spastic paraplegia characterized by delayed walking, toe walking, unsteady and spastic gait, hyperreflexia of the lower limbs, and extensor plantar responses. Upper limbs spasticity and dystonia, subclinical axonal neuropathy, cognitive impairment and intellectual disability have also been associated.", "ORPHA ID": 320411, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 57", "Disease Definition": "Autosomal recessive spastic paraplegia type 57 (SPG57) is an extremely rare, complex type of hereditary spastic paraplegia, characterized by onset in infancy of pronounced leg spasticity (leading to the inability to walk independently), reduced visual acuity due to optic atrophy, and distal wasting of the hands and feet due to an axonal demyelinating sensorimotor neuropathy. SPG57 is caused by mutations in the TFG  gene (3q12.2) encoding protein TFG, which is thought to play a role in ER microtubular architecture and function.", "ORPHA ID": 431329, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 59", "Disease Definition": "A rare, complex hereditary spastic paraplegia characterized by an early onset of progressive lower limb spasticity, tip-toe walking, scissor gait, hyperreflexia and clonus that may be associated with borderline intellectual disability. Nystagmus and pes equinovarus have also been reported.", "ORPHA ID": 401795, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 5A", "Disease Definition": "Autosomal recessive spastic paraplegia type 5A is a form of hereditary spastic paraplegia characterized by either a pure phenotype of slowly progressive spastic paraplegia of the lower extremities with bladder dysfunction and pes cavus or a complex presentation with additional manifestations including cerebellar signs, nystagmus, distal or generalized muscle atrophy and cognitive impairment. Age of onset is highly variable, ranging from early childhood to adulthood. White matter hyperintensity and cerebellar and spinal cord atrophy may be noted, on brain magnetic resonance imaging, in some patients.", "ORPHA ID": 100986, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 60", "Disease Definition": "Autosomal recessive spastic paraplegia type 60 is a rare, complex hereditary spastic paraplegia disorder characterized by infantile onset of progressive lower limb spasticity, inability to walk, hypertonia and impaired vibration sense at ankles, with complicating signs including sensory impairment, nystagmus, motor axonal neuropathy and mild intellectual disability.", "ORPHA ID": 401800, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 61", "Disease Definition": "Autosomal recessive spastic paraplegia type 61 (SPG61) is a rare, complex form of hereditary spastic paraplegia characterized by an onset in infancy of spastic paraplegia (presenting with the inability to walk unsupported and a scissors gait) associated with a motor and sensory polyneuropathy with loss of terminal digits and acropathy. SPG61 is due to a mutation in the ARL6IP1 gene (16p12-p11.2) encoding the ADP-ribosylation factor-like protein 6-interacting protein 1.", "ORPHA ID": 401780, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 62", "Disease Definition": "A pure or complex form of hereditary spastic paraplegia characterized by an onset in the first decade of life of spastic paraperesis (more prominent in lower than upper extremities) and unsteady gait, as well as increased deep tendon reflexes, amyotrophy, cerebellar ataxia, and flexion contractures of the knees, in some.", "ORPHA ID": 401785, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 63", "Disease Definition": "Autosomal recessive spastic paraplegia type 63 (SPG63) is an extremely rare and complex form of hereditary spastic paraplegia characterized by an onset in infancy of spastic paraplegia (presenting with delayed walking and a scissors gait) associated with short stature, and normal cognition. Periventricular deep white matter changes in the corpus callosum are noted on brain imaging. SPG63 is caused by a homozygous mutation in the AMPD2 gene (1p13.3) encoding AMP deaminase 2.", "ORPHA ID": 401805, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 64", "Disease Definition": "Autosomal recessive spastic paraplegia type 64 is an extremely rare and complex form of hereditary spastic paraplegia (see this term), reported in only 4 patients from 2 families to date, characterized by spastic paraplegia (presenting between the ages of 1 to 4 years with abnormal gait) associated with microcephaly, amyotrophy, cerebellar signs (e.g. dysarthria) aggressiveness, delayed puberty and mild to moderate intellectual disability. SPG64 is due to mutations in the ENTPD1 gene (10q24.1), encoding ectonucleoside triphosphate diphosphohydrolase 1.", "ORPHA ID": 401810, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 66", "Disease Definition": "A rare, complex hereditary spastic paraplegia disorder characterized by infantile onset of progressive lower limb spasticity, severe gait disturbances leading to a non-ambulatory state, absent deep tendon reflexes and amyotrophy. Additional signs include severe sensorimotor neuropathy, pes equinovarus and mild intellectual disability. Cerebellar and corpus callosum hypoplasia, as well as colpocephaly, are observed on neuroimaging.", "ORPHA ID": 401815, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 67", "Disease Definition": "Autosomal recessive spastic paraplegia type 67 is an extremely rare, complex hereditary spastic paraplegia characterized by an infancy or childhood onset of global developmental delay and progressive spasticity with tremor in the distal limbs, increased deep tendon reflexes and extensor plantar responses, which may be associated with mild intellectual disability. Additional features include muscle wasting and cerebellar abnormalities.", "ORPHA ID": 401820, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 69", "Disease Definition": "A rare, complex hereditary spastic paraplegia disorder characterized by infantile onset of progressive lower limb spasticity, global developmental delay, hyperreflexia, clonus and extensor plantar reflexes, associated with dysarthria, intellectual disability, cataracts and hearing impairment.", "ORPHA ID": 401830, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 70", "Disease Definition": "Autosomal recessive spastic paraplegia type 70 is a very rare, complex subtype of hereditary spastic paraplegia that presents in infancy with delayed motor development (i.e. crawling, walking) and is characterized by lower limb spasticity, increased deep tendon reflexes, extensor plantar responses, impaired vibratory sensation at ankles, amyotrophy and borderline intellectual disability. Additional signs may include gait disturbances, Achilles tendon contractures, scoliosis and cerebellar abnormalities.", "ORPHA ID": 401835, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 71", "Disease Definition": "A type of autosomal recessive pure hereditary spastic paraplegia characterized by infancy onset of crural spastic paraperesis with scissors gait, extensor plantar response, and increased tendon reflexes. Neuroimaging reveals a thin corpus callosum and electromyography and nerve conduction velocity studies are normal.", "ORPHA ID": 401840, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 74", "Disease Definition": "Autosomal recessive spastic paraplegia type 74 is a rare, genetic, spastic paraplegia-optic atrophy-neuropathy-related (SPOAN-like) disorder characterized by childhood onset of mild to moderate spastic paraparesis which manifests with gait impairment that very slowly progresses into late adulthood, hyperactive patellar reflex and bilateral extensor plantar response, in association with optic atrophy and typical symptoms of peripheral neuropathy, including reduced or absent ankle reflexes, lower limb atrophy and distal sensory impairment. Reduced visual acuity and pes cavus are frequently reported.", "ORPHA ID": 468661, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 75", "Disease Definition": "A rare, complex hereditary spastic paraplegia characterized by an early onset and slow progression of spastic paraplegia associated with cerebellar signs, nystagmus, peripheral neuropathy, extensor plantar responses and borderline to mild intellectual disability. Additional features of hypo- or areflexia, mild upper limb involvement and significant visual impairment (optic atrophy, vision loss, astigmatism) have been reported.", "ORPHA ID": 459056, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 76", "Disease Definition": "Autosomal recessive spastic paraplegia type 76 is a rare, complex hereditary spastic paraplegia characterized by adult onset slowly progressive, mild to moderate lower limb spasticity and hyperreflexia, resulting in gait disturbances, commonly associated with upper limb hyperreflexia and dysarthria. Foot deformities (usually pes cavus) and extensor plantar responses are also frequent. Additional features may include ataxia, lower limb weakness/amyotrophy, abnormal bladder function, distal sensory loss and mild intellectual deterioration.", "ORPHA ID": 488594, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 77", "Disease Definition": "Autosomal recessive spastic paraplegia type 77 is a rare, pure or complex hereditary spastic paraplegia characterized by an infancy to childhood onset of slowly progressive lower limb spasticity, delayed motor milestones, gait disturbances, hyperreflexia and various muscle abnormalities, including weakness, hypotonia, intention tremor and amyotrophy. Ocular abnormalities (e.g. strabismus, ptosis) and other neurological abnormalities, such as dysarthria, seizures and extensor plantar responses, may also be associated.", "ORPHA ID": 466722, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 78", "Disease Definition": "A rare autosomal recessive complex spastic paraplegia characterized by mostly adult-onset progressive spasticity and weakness predominantly affecting the lower limbs, axonal motor and sensory neuropathy, and cerebellar symptoms like ataxia, dysarthria, and oculomotor abnormalities. Variable degrees of cognitive impairment may also be present. Subtle extrapyramidal involvement and supranuclear gaze palsy were reported in some cases. Features on brain imaging include cerebral and cerebellar atrophy and sometimes abnormalities of the corpus callosum or basal ganglia.", "ORPHA ID": 513436, "Summary": ""}
{"Disease Name": "Autosomal recessive spastic paraplegia type 9B", "Disease Definition": "A rare complex hereditary spastic paraplegia characterized by early onset of slowly progressive spastic para- or tetraparesis, increased tendon reflexes, positive Babinski sign, global developmental delay, cognitive impairment, and pseudobulbar palsy. Additional manifestations include dysmorphic facial features, tremor, short stature, and urinary incontinence.", "ORPHA ID": 447760, "Summary": ""}
{"Disease Name": "Autosomal recessive spinocerebellar ataxia-blindness-deafness syndrome", "Disease Definition": "A rare autosomal recessive syndromic cerebellar ataxia characterized by the association of early-onset cerebellar ataxia with hearing loss and blindness. Patients may also present demyelinating peripheral motor neuropathy. Cerebral MRI shows alterations of the cerebellar white matter without cerebellar atrophy.", "ORPHA ID": 95433, "Summary": ""}
{"Disease Name": "Autosomal recessive spondylocostal dysostosis", "Disease Definition": "A rare condition of variable severity associated with vertebral and rib segmentation defects and characterised by a short neck with limited mobility, winged scapulae, a short trunk, and short stature with multiple vertebral anomalies at all levels of the spine.", "ORPHA ID": 2311, "Summary": "Epidemiology\nThe incidence and prevalence are unknown. The disease seems to be more frequent in the Puerto Rican population.\nClinical description\nAutosomal recessive spondylocostal dysostosis (ARSD) is usually diagnosed in the neonatal period. The main skeletal malformations include fusion of the vertebrae, hemivertebrae, and rib fusion with other rib malformations. Deformity of the chest and spine (severe scoliosis, kyphoscoliosis and lordosis) is a natural consequence of these malformations and leads to a dwarf-like appearance. As the thorax is small, infants frequently have respiratory insufficiency and repeated respiratory infections. Anomalies of the central nervous system, genitourinary tract and heart (spina bifida, meningocele, renal and ureteral abnormalities, hypospadias, complex congenital heart disease, atrial septal defect, anomalous pulmonary venous return etc.) have been reported but are not common. Facial dysmorphism and intellectual deficit are occasional features.\nEtiology\nSo far, four genes, all involved in the Notch signalling pathway - DLL3 (19q13.2), MESP2 (15q26.1), LFNG (7p22.3) and HES7 (17p13.1) - have been identified but mutations in these genes do not account for all of the cases.\nDiagnostic methods\nDiagnosis is clinical and may be supported by ultrasonography and spine radiographs.\nAntenatal diagnosis\nPrenatal diagnosis is possible using fetal ultrasound.\nGenetic counseling\nThe disease is inherited as an autosomal recessive trait.\nManagement and treatment\nManagement includes intensive medical care, bone surgery, and orthopedic treatment.\nPrognosis\nARSD may cause respiratory insufficiency that may lead to life-threatening complications in the first year of life.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Autosomal recessive spondylometaphyseal dysplasia, Mégarbané type", "Disease Definition": "A rare, primary bone dysplasia characterized by intrauterine growth retardation, pre- and postnatal disproportionate short stature with short, rhizomelic limbs, facial dysmorphism, a short neck and small thorax. Hypotonia, cardiomegaly and global developmental delay have also been associated. Several radiographic findings have been reported, including ribs with cupped ends, platyspondyly, square iliac bones, horizontal and trident acetabula, hypoplastic ischia, and delayed epiphyseal ossification.", "ORPHA ID": 401979, "Summary": ""}
{"Disease Name": "Autosomal recessive Stickler syndrome", "Disease Definition": "A rare type of Stickler syndrome characterized by moderate to severe sensorineural hearing loss, high myopia, retinal degeneration, vitreous anomalies, and epiphyseal dysplasia. Midface hypoplasia, cleft palate, as well as additional skeletal manifestations (such as platyspondyly, scoliosis, and tibial and femoral bowing at birth) have also been observed.", "ORPHA ID": 250984, "Summary": ""}
{"Disease Name": "Autosomal semi-dominant severe lipodystrophic laminopathy", "Disease Definition": "A rare familial partial lipodystrophy characterized by severe partial lipoatrophy affecting the limbs, trunk, and abdomen, together with faciocervical fat accumulation. Additional manifestations include diabetes, acanthosis nigricans, liver steatosis, and hypertriglyceridemia, as well as low serum leptin and adiponectin levels. Severe cardiac rhythm and conduction disturbances have also been reported.", "ORPHA ID": 280365, "Summary": ""}
{"Disease Name": "Autosomal spastic paraplegia type 18", "Disease Definition": "Autosomal spastic paraplegia type 18 (SPG18) is a rare, complex type of hereditary spastic paraplegia characterized by progressive spastic paraplegia (presenting in early childhood) associated with delayed motor development, severe intellectual disability and joint contractures. A thin corpus callosum is equally noted on brain magnetic resonance imaging. SPG18 is caused by a mutation in the ERLIN2 gene (8p11.2) encoding the protein, Erlin-2.", "ORPHA ID": 209951, "Summary": ""}
{"Disease Name": "Autosomal spastic paraplegia type 30", "Disease Definition": "A rare, pure or complex form of hereditary spastic paraplegia characterized by either a pure spastic paraplegia phenotype, usually presenting in the first or second decade of life, with spastic lower extremities, unsteady spastic gait, hyperreflexia and extensor plantar responses, or as a complicated phenotype with the additional manifestations of distal wasting, saccadic ocular movements, mild cerebellar ataxia and mild, distal, axonal neuropathy.", "ORPHA ID": 101010, "Summary": ""}
{"Disease Name": "Autosomal spastic paraplegia type 58", "Disease Definition": "A rare, complex subtype of hereditary spastic paraplegia characterized by variable onset of slowly progressive lower limb spasticity and weakness and prominent cerebellar ataxia, associated with gait disturbances, dysarthria, increased deep tendon reflexes and extensor plantar responses. Additional features may include involuntary movements (i.e. clonus, tremor, fasciculations, chorea), decreased vibration sense, oculomotor abnormalities (e.g. nystagmus) and distal amyotrophy in the upper and lower limbs.", "ORPHA ID": 397946, "Summary": ""}
{"Disease Name": "Autosomal spastic paraplegia type 72", "Disease Definition": "A rare autosomal dominant pure hereditary spastic paraplegia characterized by early childhood onset of slowly progressive crural spastic paraparesis presenting with spastic gait, mild stiffness at rest, hyperreflexia (in lower limbs), extensor plantar responses and, in some, mild postural tremor, pes cavus, sphincter disturbances and sensory loss at ankles.", "ORPHA ID": 401849, "Summary": ""}
{"Disease Name": "Autosomal systemic lupus erythematosus", "Disease Definition": "A rare, genetic, multisystemic, chronic autoimmune disease characterized by the presence of systemic lupus erythematosus symptoms in two or more members of a single family. Patients present a wide spectrum of clinical manifestations, including cutaneous (malar rash, photosensitivity), ocular (keratoconjunctivitis sicca, retinopathy), gastrointestinal (oral ulceration, abdominal pain), cardiac (atherosclerosis, chest pain), pulmonary (serositis, pleurisy), musculoskeletal (arthralgia, myalgia), renal (nephritis, hematuria), obstetrical (increased spontaneous abortions, neonatal lupus), constitutional (fatigue, loss of appetite) and neuropsychiatric (mood and cognitive disorders) involvement, among others.", "ORPHA ID": 300345, "Summary": ""}
{"Disease Name": "Avian influenza", "Disease Definition": "A rare, infectious disease characterized by variable severity and outcome, ranging from mild upper respiratory tract infection with fever and cough, to influenza-like illness with rapid progression to severe pneumonia, sepsis with shock, acute respiratory distress syndrome and even death. Additional manifestations may include conjunctivitis, nausea, abdominal pain, diarrhea, vomiting, multiple organ dysfunction, and encephalopathy.", "ORPHA ID": 454836, "Summary": ""}
{"Disease Name": "Axenfeld anomaly", "Disease Definition": "A rare, congenital, ocular defect caused by anterior segment dysgenesis and characterized by anteriorly displaced Schwalbe's line and iris bands extending into the cornea. In contrast, Rieger's anomaly includes characteristic iris and pupil anomalies.", "ORPHA ID": 98978, "Summary": ""}
{"Disease Name": "Axenfeld-Rieger syndrome", "Disease Definition": "Axenfeld-Rieger syndrome (ARS) is a generic term used to designate overlapping genetic disorders, in which the major physical condition is anterior segment dysgenesis of the eye. Patients with ARS may also present with multiple variable congenital anomalies.", "ORPHA ID": 782, "Summary": "Epidemiology\nThe syndrome has an estimated prevalence of 1/200,000.\nClinical description\nThe clinical manifestations of ARS are highly variable. Features can be divided into ocular and non-ocular findings. Ocular abnormalities mainly affect the iris: hypoplasia, corectopia or hole formation in the iris mimicking polycoria; cornea: prominent and anteriorly displaced Schwalbe's line (posterior embryotoxon); and the chamber angle: iris strands bridging the iridocorneal angle to the trabecular meshwork. Eye dysgenesis in ARS may cause increased ocular pressure (IOP) leading to glaucoma. Glaucoma can develop in infancy, but usually occurs in adolescence or early adulthood, occasionally after middle age. The most characteristic non-ocular findings are mild craniofacial dysmorphism, dental anomalies and redundant periumblical skin. Mid-face abnormalities include hypertelorism, telecanthus, maxillary hypoplasia with flattening of the mid-face, prominent forehead, and broad, flat nasal bridge. Dental abnormalities may include microdontia or hypodontia. Hypospadias in males, anal stenosis, pituitary abnormalities and growth retardation may also be observed.\nEtiology\nPatients with ARS have been found to have mutations in the transcription factor genes PITX2 (4q25) and FOXC1 (6p25). A large number of different mutations have been identified but there is no clear genotype-phenotype relationship. However, PITX2 mutations are mainly detected in ARS patients with non-ocular changes. The underlying genetic defect is unknown in 60% of cases, and at least two more loci have been associated with ARS.\nDiagnostic methods\nARS is diagnosed by ophthalmologic and clinical examination. Associated systemic findings are supportive of diagnosis. Genetic testing can be used to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include iris hypoplasia (IH), primary congenital glaucoma (PCG) and Peters anomaly (see these terms). Absence of other corneal abnormalities, such as megalocornea, sclerocornea and corneal opacity are useful in distinguishing ARS from other anterior segment disorders.\nAntenatal diagnosis\nIf the disease-causing mutation has been identified in a family, prenatal testing for at-risk pregnancies is possible.\nGenetic counseling\nThe disorders that comprise the ARS spectrum are inherited in an autosomal dominant manner with high penetrance. Genetic counseling can be offered to patients and their families.\nManagement and treatment\nAn annual slit lamp examination should be performed, along with gonioscopy, IOP measurements and funduscopy to assess the retinal nerve fiber layer and optic nerve head involvement due to possible glaucoma. Autoperimetry (automated measurements of the visual fields) is necessary whenever glaucoma is suspected. Should glaucoma develop, drug therapy is recommended before surgery. In case of glaucoma, the goal of treatment is to reach low IOP. Surgery is performed if eye drops are not sufficient in lowering IOP. Medications that decrease aqueous output (beta-blockers, alpha-agonists and carbonic anhydrase inhibitors) are more beneficial than those affecting outflow. However, alpha-agonists should be used with caution in young children because of possible CNS depression. If surgery is necessary, the procedure of choice is trabeculectomy with the adjunctive use of antimetabolites. If photophobia is present in patients with corectopia and polycoria, contact lenses may be used to cover the holes in the iris.\nPrognosis\nPrognosis is good, particularly in the absence of glaucoma.\n\n                            Last update: \n                            July 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Daniella BACH-HOLM  - Pr Zeynep TÜMER"}
{"Disease Name": "Axial mesodermal dysplasia spectrum", "Disease Definition": "Axial mesodermal dysplasia spectrum is a rare developmental defect during embryogenesis syndrome characterized by congenital manifestations of both oculo-auriculo-vertebral spectrum and caudal regression sequence. Phenotype is highly variable but patients typically present facial dysmorphism (incl. asymmetry, hypertelorism), auricular abnormalities (e.g. preauricular tags, microtia, absence of middle ear ossicles), skeletal malformations (hemivertebrae, hip dislocation, sacral agenesis/dysplasia, talipes equinovarus, flexion deformity of lower limbs), cardiac defects (dextrocardia, septal defects), renal and genitourinary anomalies (such as renal agensis/dysplasia, abnormal external genitalia, cryptorchidia), as well as anal anomalies such as anal atresia and rectovesical fistula.", "ORPHA ID": 1834, "Summary": ""}
{"Disease Name": "Axial spondylometaphyseal dysplasia", "Disease Definition": "Axial spondylometaphyseal dysplasia is a rare type of spondylometaphyseal dysplasia characterized by metaphyseal changes of the truncal-juxtatruncal bones associated with retinal dystrophy. Patients typically present progressive postnatal growth failure with rhizomelic shortening of the limbs, a deformed, hypoplastic thorax and retinitis pigmentosa or pigmentary retinal degeneration. Radiographic findings include short ribs with flared, cupped anterior ends, mild platyspondyly, lacy ilia and metaphyseal dysplasia of the proximal femora.", "ORPHA ID": 168549, "Summary": ""}
{"Disease Name": "Axonal polyneuropathy associated with IgG/IgM/IgA monoclonal gammopathy", "Disease Definition": "A rare acquired peripheral neuropathy characterized by symmetric, slowly progressive, predominantly sensory neuropathy, mostly limited to the legs with numbness and paresthesia of the distal leg and mild imbalance. Some patients may experience pain, weakness of foot dorsiflexion, mild proximal leg weakness, and/or upper limb involvement. The majority of patients have IgG monoclonal gammopathy. Systemic illnesses are absent in most cases.", "ORPHA ID": 209004, "Summary": ""}
{"Disease Name": "Aymé-Gripp syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital cataract, sensorineural hearing loss, developmental delay with variable degrees of intellectual disability, seizures, short stature, brachycephaly, and dysmorphic facial features (such as flat facial appearance, ptosis, short nasal tip, long philtrum, low-set and posteriorly rotated ears, and small mouth). Additional reported manifestations are skeletal abnormalities, nail dystrophy, mammary gland hypoplasia, and autism spectrum disorder.", "ORPHA ID": 1272, "Summary": ""}
{"Disease Name": "Azygos continuation of the inferior vena cava", "Disease Definition": "A rare vascular anomaly characterized by absence of the hepatic segment of the inferior vena cava and presence of an enlarged azygos vein (or in rare cases hemiazygos vein, if there is a left-sided inferior vena cava) draining the venous blood from the caudal segments. The post-hepatic segment of the inferior vena cava is present, draining only the hepatic veins into the right atrium. Most patients remain asymptomatic, if the anomaly is isolated. Association with congenital heart disease and asplenia or polysplenia syndromes has been reported.", "ORPHA ID": 99121, "Summary": ""}
{"Disease Name": "B-cell chronic lymphocytic leukemia", "Disease Definition": "B-cell chronic lymphocytic leukemia (B-CLL) is a type of B-cell non-Hodgkin lymphoma (see this term), and the most common form of leukemia in Western countries, affecting elderly adults (mean age of 67 and 72 years) with a slight male predominance (1.7:1), and characterized by a highly variable clinical presentation that can include asymptomatic disease or non-specific B-symptoms such as unintentional weight loss, severe fatigue, fever (without evidence of infection), and night sweats as well as cervical lymphadenopathy, splenomegaly and frequent infections. Some patients can also develop autoimmune complications such as autoimmune hemolytic anemia or immune thrombocytopenia (see these terms). The clinical course is extremely heterogeneous with survival ranging from a few months to several decades.", "ORPHA ID": 67038, "Summary": ""}
{"Disease Name": "B-cell immunodeficiency-limb anomaly-urogenital malformation syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by almost complete lack of B-cells and severe hypogammaglobulinemia, anomalies of the hands and feet, urogenital malformations, and characteristic facial dysmorphism (including microcephaly, highly arched eyebrows, hypoplastic alae nasi, and micrognathia). Most patients are developmentally normal, although moderate mental retardation has also been described.", "ORPHA ID": 567502, "Summary": ""}
{"Disease Name": "B-cell prolymphocytic leukemia", "Disease Definition": "A rare mature B-cell neoplasm characterized by clonal proliferation of B-cell prolymphocytes, with prolymphocytes constituting more than 55% of lymphoid cells in peripheral blood. IG genes are clonally rearranged. Neoplastic cells are present in the bone marrow, peripheral blood, and spleen. Patients usually present with B symptoms, massive splenomegaly but absent or minimal lymphadenopathy, rapidly increasing lymphocyte count, anemia, and thrombocytopenia. Therapy response is poor.", "ORPHA ID": 86852, "Summary": ""}
{"Disease Name": "B3GALT6-related spondylodysplastic Ehlers-Danlos syndrome", "Disease Definition": "A form of spondylodysplastic Ehlers-Danlos syndrome due to variants in B3GALT6 and characterized by short stature, variable degrees of muscle hypotonia, joint hypermobility, especially of the hands, bowing of limbs and congenital or early onset, progressive kyphoscoliosis. Additional features include the typical craniofacial gestalt (prominent forehead, sparse hair, mid-face hypoplasia, blue sclerae, proptosis and abnormal dentition), hyperextensible, soft, thin, translucent and doughy skin, delayed motor and/or cognitive development, characteristic radiographic findings (spondyloepimetaphyseal dysplasia, platyspondyly, anterior beak of vertebral body, short ilia, elbow malalignment and generalized osteoporosis), joint contractures and ascending aortic aneurysm.", "ORPHA ID": 536467, "Summary": "Epidemiology\nTo date, 41 individuals with molecularly diagnosed B3GALT6-related spondylodysplastic EDS, have been reported.\nClinical description\nThe main features are short stature, variable degrees of muscle hypotonia, joint hypermobility, bowing of limbs and congenital or early onset, progressive kyphoscoliosis. Joint hypermobility, especially of the hands and feet, and soft, doughy and hyperextensible skin are some of the most striking characteristics. Facial dysmorphism includes prominent forehead, sparse hair, mid-face hypoplasia, blue sclerae, proptosis and abnormal dentition with discoloration of teeth. Most affected children present from infancy with delayed motor development and hypotonia; half of patients have delayed cognitive development. The majority of patients display severe kyphoscoliosis, which is usually congenital or early onset and progressive. Skeletal anomalies include platyspondyly, short iliac bones and elbow dislocation. Osteopenia has been frequently reported, usually in conjunction with fractures and luxations. Less frequent skeletal anomalies include cervical spine instability, pectus carinatum/excavatum, joint contractures, radioulnar synostosis, limited elbow extension, carpal synostosis, short metacarpals, ulnar deviation of fingers, oligodactyly, hip dysplasia, epiphyseal dysplasia of femoral heads, genu valgus, pes planus, talipes equinovarus, recurrent luxation of the toes and hallux valgus. Approximately one third of the patients have ophthalmological abnormalities, such as myopia, corneal opacity, sclerocornea, blue sclerae, microcornea, glaucoma, optic nerve atrophy and retinal detachment. Cardiovascular anomalies infrequently reported include mitral valve prolapse, aortic valve stenosis and aortic root aneurysm. Other less common features include urinary defects with nephroptosis, bilateral caliceal and ureteral dilatation, laryngeal cleft, tracheomalacia, spontaneous repeated pneumothoraces, chronic respiratory insufficiency, Wilms tumor, cryptorchidism, prominent superficial veins, hypoplastic nails. There are rare reports of sensorineural and conductive hearing loss and cleft palate.\nEtiology\nThe disorder is due to variants of the B3GALT6 gene (1p36.33), encoding for galactosyltransferase II. This gene is responsible for the synthesis of the linker region of proteoglycans, which are essential components of the extracellular matrix of connective tissues.\nDiagnostic methods\nDiagnosis is based on clinical examination, radiological studies and molecular findings.\nDifferential diagnosis\nDifferential diagnosis includes spondyloepimetaphyseal dysplasias (e.g due to KIF22 or EXOC6B), the other forms of spondylodysplastyic EDSs, as well as other genetic syndromes characterized by kyphoscoliosis, joint hypermobility, skin hyperextensibility and short stature.\nAntenatal diagnosis\nPrenatal diagnosis is possible where a known pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement requires a multidisciplinary approach. Musculoskeletal anomalies, in particular kyphoscoliosis, may require a precocious orthopedic intervention. Specific regular follow-up is recommended based on the patient's clinical manifestation. Rehabilitation therapies must be tailored to the patient's characteristics.\nPrognosis\nCurrently, data is limited with regard to life expectancy. Whilst four cases of death in infancy have been described, there are no known reasons to suspect reduced life expectancy. Functional consequences and quality of life depend on disease severity.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Stefano Giuseppe CARAFFI  - Dr Livia GARAVELLI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "B4GALT1-CDG", "Disease Definition": "B4GALT1-CDG is a congenital disorder of glycosylation characterised by macrocephaly due to Dandy-Walker malformation, hydrocephaly, hypotonia, myopathy and coagulation anomalies. To date, only one case has been reported. The syndrome is associated with mutations in the GALT1 gene (localised to region q13 of chromosome 9) leading to a deficiency in the Golgi apparatus enzyme beta-1,4-galactosyl transferase.", "ORPHA ID": 79332, "Summary": ""}
{"Disease Name": "B4GALT7-related spondylodysplastic Ehlers-Danlos syndrome", "Disease Definition": "A form of spondylodysplastic Ehlers-Danlos syndrome due to variants in B4GALT7 and characterized by short stature, variable degrees of muscle hypotonia, joint hypermobility, especially of the hands, and bowing of limbs. Additional features include the typical craniofacial gestalt (mid-face hypoplasia, round, flat face, proptosis and narrow mouth), hyperextensible skin that is soft, thin, translucent and doughy, delayed motor and/or cognitive development, characteristic radiographic findings (such as radio-ulnar synostosis, radial head subluxation or dislocation, metaphyseal flaring and osteopenia) and ocular abnormalities.", "ORPHA ID": 75496, "Summary": "Epidemiology\nTo date, 34 individuals with molecularly diagnosed B4GALT7-related spondylodysplastic Ehlers-Danlos syndrome have been reported.\nClinical description\nThe main features in affected individuals are short stature, bowing of limbs, small joint hypermobility, hyperextensible, soft, doughy skin with delayed wound healing, and radioulnar synostosis. Facial dysmorphism includes short face with midface hypoplasia, proptosis, narrow mouth and loose skin also evident in the face. Most affected children present from infancy with delayed motor development and hypotonia; half of patients have delayed cognitive development. The most frequent skeletal anomalies are contractures or limited elbow movements, radioulnar synostosis, bowing of the ulna and radius, pes planus and osteopenia. Less frequently observed skeletal features include sagittal craniosynostosis, temporomandibular joint dislocation, scoliosis/kyphosis, vertebral coronal cleft, pectus carinatum, clavicular exostoses, patellar dislocation, hip dysplasia, bifid thumb, broad fingertips, ulnar deviation of fingers, equinovarus deformity and hallux valgus. Approximately half of the patients have ophthalmological abnormalities, such as hypermetropia, myopia, strabismus, blue sclerae, ptosis, nystagmus, glaucoma, megalocornea, iris and optic nerve coloboma, small optic nerves and cataracts. Dental anomalies include defective and discoloration of teeth. Less frequently reported features include cardiovascular anomalies (such as aortic/pulmonary stenosis and atrial septal defects) and urinogenetial defects (vesicoureteral reflux, cryptorchidism, hypogonadism, inguinal hernia) as well as hemidiaphragmatic eventration, varicose veins, lymphedema and multiple nevi. Sensorineural/conductive hearing loss and cleft palate are rarely reported.\nEtiology\nThe disorder is due to variants of the B4GALT7 gene (5q35.3), encoding for galactosyltransferase I. This gene is responsible for the synthesis of the linker region of proteoglycans, essential components of the extracellular matrix in connective tissues.\nDiagnostic methods\nDiagnosis is based on clinical examination, radiological studies and molecular findings.\nDifferential diagnosis\nDifferential diagnosis includes other spondylodysplastic Ehlers-Danlos syndromes and genetic conditions with joint hypermobility, skin hyperextensibility and short stature.\nAntenatal diagnosis\nPrenatal diagnosis is possible where a known pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement requires a multi-disciplinary approach. Specific regular follow-up is recommended based on the patient's clinical manifestations. Rehabilitation therapy must be tailored to the patient's characteristics. Musculoskeletal anomalies may require a precocious orthopedic intervention.\nPrognosis\nData is limited with respect to life expectancy; whilst there is only one adult patient reported in the literature, there are currently no known reasons suspect a reduced life expectancy. Functional consequences and quality of life depend on disease severity. The pathology is not progressive.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Gianluca CONTRO  - Dr Livia GARAVELLI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Babesiosis", "Disease Definition": "Babesiosis is an infectious disease caused by protozoa of the genus Babesia and characterized by a febrile illness and hemolytic anemia but with manifestations ranging from an asymptomatic infection to a fulminating illness that can result in death.", "ORPHA ID": 108, "Summary": "Epidemiology\nThe worldwide prevalence is unknown but it is most frequently reported in the U.S. In 2011, 1,124 cases were reported in the U.S. with 92% of those cases occurring in northeastern and upper midwestern states. Sporadic cases have also been reported in Europe, Asia, Africa, Australia and South America.\nClinical description\nMost immunocompetent patients experience mild to moderate illness or are asymptomatic. Symptoms usually begin 1-4 weeks after being bitten by an infected tick, or 1 week to 6 months after a transfusion with contaminated blood. The most common symptoms are fever (that can reach up to 40.9 °C and may be accompanied by splenomegaly), malaise and fatigue. Other common manifestations include chills, sweats, headache, myalgia, arthralgia, nonproductive cough, nausea, and anorexia. Less frequently, some may experience sore throat, photophobia, vomiting, weight loss and depression. Symptoms can last 1-2 weeks but fatigue may persist for several months. In the immunocompomised or the elderly, more severe and prolonged infections with relapses can occur that require hospital admission. B. divergens and B. duncani infections are generally severe and often occur in people who lack a spleen. Complications occur in about half of hospitalized patients and include disseminated intravascular coagulopathy and acute respiratory distress syndrome and less frequently liver, renal or congestive heart failure, coma and death.\nEtiology\nBabesiosis is caused by infections with one of several Babesia species that infect humans, including: B. microti (most common, in the U.S.), B. duncani, B. divergens (most common in Europe), and B. venatorum. Most patients are infected by a bite from an infected nymphal Ixodes scapularis (in the U.S), or Ixodes ricinus (in Europe) tick during early summer to late fall. The parasite can also be transmitted to humans through transfusion of contaminated blood or blood products. A few cases of transplacental transmission have been reported.\nDiagnostic methods\nBabesiosis should be considered in patients with an unexplained febrile illness who reside in or have recently traveled to a Babesia endemic area or who have received a blood transfusion within the previous 6 months. Laboratory tests usually reveal hemolytic anemia, thrombocytopenia and a normal or slightly decreased leukocyte count. Giemsa or Wright stains of blood smears identify the parasites within host erythrocytes that appear round, pear-shaped or oval with a blue cytoplasm with red chromatin. Polymerase chain reaction (PCR) can confirm diagnosis by detecting babesia DNA in a patient's blood. Serological testing can also be useful in confirming the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other infectious diseases such as malaria, Lyme disease, ehrlichiosis, Rocky Mountain spotted fever, typhoid (see these terms) and infectious mononucleosis.\nManagement and treatment\nTreatment for mild to moderate babesiosis consists of the administration of antimicrobial agents, atovaquone and azithromycin, for 7-10 days. Oral quinine and intravenous clindamycin are recommended for those with a severe babesiosis, but patients must be more closely monitored due to higher frequency of adverse effects. Severe disease is treated with partial or complete exchange transfusion. Severely immunocompromised patients may require 6 weeks of antimicrobial therapy if infection persists or recurs. Preventive measures include avoidance of areas where ticks, mice and deer thrive and the use of tick checks, protective clothing and tick repellents.\nPrognosis\nPrognosis depends on the species involved and the health of the patient, but is excellent in most immunocompetent patients.\n\n                            Last update: \n                            October 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Peter KRAUSE"}
{"Disease Name": "Bacterial myositis", "Disease Definition": "A rare acquired skeletal muscle disease characterized by diffuse muscle infection without an intramuscular abscess. Although a wide variety of bacteria can be causative, the majority of cases are due to streptococcal infection. Signs and symptoms depend on the underlying infectious agent and include muscular pain, swelling, weakness, rash, acute rhabdomyolysis, myonecrosis, and gangrene.", "ORPHA ID": 206994, "Summary": ""}
{"Disease Name": "Bacterial susceptibility due to TLR signaling pathway deficiency", "Disease Definition": "Pyogenic bacterial infection due to MyD88 deficiency is a primary immunodeficiency characterized by increased susceptibility to pyogenic bacterial infections, including invasive pneumococcal, invasive staphylococcal and pseudomonas disease.", "ORPHA ID": 183713, "Summary": "Epidemiology\nPrevalence is unknown. Only 24 cases have been reported.\nClinical description\nThe disease presents in childhood with recurrent, life-threatening, pyogenic bacterial infections caused by Streptococcus pneumoniae, Staphylococcus aureus or Pseudomonas aeruginosa. Patients are normally resistant to most other agents. This predisposition to life-threatening infections seems transient and lasts during the first 10 years of life in the cases reported so far. Acute phase responses seen in invasive infections such as elevated temperature and C-reactive protein (CrP) levels may be lower or absent.\nEtiology\nMyD88 deficiency, resulting from mutations in the MYD88 gene (3p22-3p21.3), generally abolishes the cytokine responses of the blood cells.\nDiagnostic methods\nMyD88 deficiency should be suspected in patients with recurrent pyogenic bacterial infections. Diagnosis can be suspected if whole blood cells do not produce inflammatory cytokines upon activation with IL-1beta or Toll-like receptor agonists. Diagnosis can be confirmed by observation of mutations in the MYD88 gene.\nDifferential diagnosis\nDifferential diagnoses include interleukin-1 receptor associated kinase-4 (IRAK4) deficiency (see this term), which can be ruled out by the absence of mutations in the IRAK4 gene, NF-kappaB essential modulator (NEMO) deficiency and inhibitor of NFkappaB essential modulator (IkappaB-alpha) deficiency (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible by trophoblast biopsy when the mutation is identified in the family.\nGenetic counseling\nTransmission is autosomal recessive and the disease has been observed in consanguineous and nonconsanguineous families. Genetic counseling is available.\nManagement and treatment\nTreatment is based on prophylactic antibiotic therapy to prevent infections. Additional IgG substitution may be considered, in particular for patients with impaired antibody responses to polysaccharides. The most important advice for the families and physicians of MyD88-deficient patients is to initiate empiric parenteral antibiotic treatment against Streptococcus pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa, as soon as an infection is suspected or if the patient develops a moderate fever, without taking inflammatory parameters into account, as patients may die from rapid invasive bacterial infection despite appropriate prophylaxis. Secondary adaptation of antibiotic treatment should be done once the causal bacterium has been documented.\nPrognosis\nPrognosis in infancy and early childhood is poor, in particular if the disease is not known to parents and physicians. With appropriate prophylactic antibiotic treatment, the prognosis for most patients improves, with infections becoming less frequent with age.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Laurent CASANOVA  - Pr Capucine PICARD  - Pr Horst VON BERNUTH"}
{"Disease Name": "Bacterial toxic-shock syndrome", "Disease Definition": "Bacterial toxic shock syndrome (TSS) is a potentially fatal, acute disease characterized by a sudden onset of high fever along with nausea, myalgia, vomiting and multisystem organ involvement, potentially leading to shock and death. TSS is mediated by superantigenic toxins, usually caused by an infection with Staphylococcus aureus in staphylococcal TSS (see this term) or Streptococcus pyogenes in streptococcal TSS (see this term).", "ORPHA ID": 36234, "Summary": "Epidemiology\nThe worldwide prevalence is estimated at 1/30, 000.\nClinical description\nThe disease affects mainly young adult women with no previous medical conditions. However, non-menstrual TSS, which can also be observed in men and children, represents up to 50% of Staphylococcal TSS cases. Onset is sudden and includes high fever (>38.9°C), nausea, diarrhea, vomiting, myalgia, abdominal pain and sore throat. Staphylococcal TSS almost always exhibits an erythematous rash and skin peeling as one of its manifestations, whereas it is very rarely seen in streptococcal TSS, which can show signs of soft tissue infection. Serious manifestations include confusion, shock, renal and myocardial dysfunction, acute respiratory distress syndrome (ARDS; see this term) and coma.\nEtiology\nStaphylococcal TSS is due to an infection with Staphylococcus aureus and streptococcal TSS is due to an infection with Streptococcus pyogenes, or rarely, group C or G Streptococcus. Superantigens produced by both bacteria are responsible for the massive and sudden immune reaction seen in TSS. Both forms have been associated with recent traumas (surgery or childbirth) and viral infections, while staphylococcal TSS has also been associated with high absorbency tampon use.\n\n                            Last update: \n                            November 2015\n\n\n                            - Expert reviewer(s): \n                             Claude-Alexandre GUSTAVE  - Pr Gerard LINA  - Dr Anne TRISTAN"}
{"Disease Name": "Bainbridge-Ropers syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder with a variable phenotypic presentation typically characterized by microcephaly, severe feeding difficulties, failure to thrive, severe global development delay that frequently results in absent/poor speech, moderate to severe intellectual disability and hypotonia. Distinctive craniofacial features include prominent forehead, high-arched, thin eyebrows, hypertelorism, downslanting palpebral fissures, long, tubular nose with broad tip and prominent nasal bridge and wide mouth with full, everted lower lip. Joint laxity and ulnar deviation of wrists are also frequently observed.", "ORPHA ID": 352577, "Summary": "Epidemiology\nLess than 100 cases have been reported in literature and databases to date.\nClinical description\nPresentation is usually in the first months of life; however, intrauterine growth retardation has been reported in some cases. Symptoms of global development delay include hypotonia, delay in achieving independent sitting and walking, and marked language delay. Intellectual disability ranges from moderate to severe. Affected individuals may also display autistic features. Feeding difficulties requiring support are frequent. Other frequent gastrointestinal features include gastroesophageal reflux and constipation. Distinct facial features include highly arched or delineated eyebrows and also synophrys, and frequently a highly arched palate. Patients may exhibited skeletal anomalies including scoliotic attitude, joint laxity, pectus excavatum or carinatum and ulnar deviation of wrists.\nEtiology\nThe disorder is due to loss of function mutations in ASXL3 gene (18q12.1).\nDiagnostic methods\nDiagnosis is based on presentation of clinical features, and can be confirmed by genetic testing. Most of the patients described so far had been confirmed by next generation sequencing techniques.\nDifferential diagnosis\nDifferential diagnosis includes other syndromes with moderate-severe intellectual disability and poor language. In some reported cases Cornelia de Lange syndrome was suspected due to feeding difficulties, developmental delay and eyebrow characteristics.\nAntenatal diagnosis\nThere is no definitive antenatal diagnosis available, however ultrasound may show intrauterine growth retardation which should be investigated further. As germline mosaicism has been described, prenatal diagnosis may be considered where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe disorder is autosomal dominant; however, no familial transmission has been observed so far. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that, for each pregnancy, there is 50% risk of passing the mutation to offspring. It is also important to counsel affected families about the possibility of recurrence due to germline mosaicism.\nManagement and treatment\nGiven the multisystemic involvement, multidisciplinary follow-up is needed and should include neurological follow up, developmental assessments, physiotherapy (particularly for joint laxity and musculoskeletal issues), feeding interventions for those with persistent feeding issues, and ophthalmologic follow up for patients with strabismus and/or refractive error.\nPrognosis\nQuality of life and the functional consequences depends on the severity of the developmental delay and intellectual disability.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Irene VALENZUELA PALAFOLL | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Balantidiasis", "Disease Definition": "Balantidiasis is an infectious disease, rare in western countries. It is caused by Balantidium coli, a single celled parasite (ciliate protozoan) that is usually associated with intestinal infection in areas associated with pig rearing. It infects humans occasionally, mostly immunocompromised patients. Some infected people may have no symptoms or only mild diarrhea and abdominal discomfort but others may experience more severe symptoms reminiscent of an acute inflammation of the intestines. Symptoms of Balantidiasis may be similar to those of other infections that cause intestinal inflammation, for example, amoebic dysentery. On very rare occasions this bacterium may invade extra-intestinal organs, mostly the lungs. Metronidazole is the treatment of choice.", "ORPHA ID": 1223, "Summary": ""}
{"Disease Name": "Balint syndrome", "Disease Definition": "Balint syndrome is a rare neurologic disease characterized by the triad of optic ataxia, ocular apraxia and simultanagnosia due to posterior parietal lobe lesions. Patients report ophthalmologic difficulties in the absence of underlying ophthalomologic anomalies and present severe visual and spatial disabilities in locating and reaching objects, initiating voluntary eye movements and perceiving more than one object at a time.", "ORPHA ID": 363746, "Summary": ""}
{"Disease Name": "Baller-Gerold syndrome", "Disease Definition": "Baller-Gerold syndrome is characterized by the association of coronal craniosynostosis with radial ray anomalies (oligodactyly, aplasia or hypoplasia of the thumb, aplasia or hypoplasia of the radius).", "ORPHA ID": 1225, "Summary": "Epidemiology\nAround 30 cases have been reported but the prevalence of the syndrome is unknown.\nClinical description\nCraniosynostosis and radial ray anomalies present at birth and are associated with facial dysmorphism (brachycephaly, ocular exophthalmia, frontal bossing, nasal hypoplasia, small mouth, ogival palate). An inconstant poikiloderma can appear during the first months of life. Delayed growth is nearly always present, usually around -4SD. Patellar aplasia or hypoplasia can be observed during childhood. Intelligence is usually normal. Patients have a predisposition to cancer, in particular osteosarcoma.\nEtiology\nBaller-Gerold syndrome is secondary to mutations of the RECQL4 gene (8q24.3). RECQL4 is a member of the RecQ helicase gene family which cause other diseases predisposing to cancer. The proportion of patients with mutations in this gene has not been determined.\nDiagnostic methods\nDiagnosis of Baller-Gerold syndrome relies on clinical criteria. Given the numerous differential diagnoses, finding a mutation of the RECQL4 gene can help clarify the diagnosis spectrum, genetic counseling and management.\nDifferential diagnosis\nThe principal differential diagnoses include Rothmund-Thomson syndrome (RTS) and RAPADILINO syndrome, also secondary to mutations of the RECQL4 gene (see these terms). A phenotypic continuum between these diseases has been suggested by numerous authors: it is possible that they represent different expressions of the same pathology. Other differential diagnoses include Roberts syndrome and Fanconi anemia, which are frequently associated with radial ray anomalies but rarely with craniosynostosis, and Saethre-Chotzen syndrome which is characterized by coronal craniosynostosis usually without radial ray anomalies (see these terms). The combinationof craniosynostosis and radial ray hypoplasia is also associated with fetal valproic syndrome (see this term). The presence of poikiloderma allows other pathologies to be excluded.\nAntenatal diagnosis\nPrenatal diagnosis by chorionic villus sampling (CVS) is suggested when pathogenic mutations of the RECQL4 gene are found in an index case (homozygous or heterozygous). Ultrasound can be used to identify limb anomalies and an abnormally shaped cranium.\nGenetic counseling\nBaller-Gerold syndrome is inherited in an autosomal recessive manner.\nManagement and treatment\nTreatment consists of surgery of the bilateral craniosynostosis in the first 6 months of life and, if necessary, pollicization of the index finger for thumb reconstruction. When monitoring patients particular clinical attention should be paid to bone pain, limpness or fractures, because of the risk of osteosarcoma. Exposure to the sun should be avoided because of a risk of skin cancer and photosensitivity.\nPrognosis\nThe prognosis for patients with mutations of the RECQL4 gene, homozygous or heterozygous, is related to an increased risk of cancer.\n\n                            Last update: \n                            April 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence OLIVIER-FAIVRE"}
{"Disease Name": "Baló concentric sclerosis", "Disease Definition": "A rare multiple sclerosis variant characterized by discrete concentrically layered, ring-like lesions in the cerebral white matter, consisting of alternating layers of myelinated and demyelinated tissue. Patients most commonly present with symptoms of an intracerebral mass lesion, including headache, cognitive abnormalities, behavioral changes, seizures, aphasia, or hemiparesis, among others, although there may also be classic focal symptoms of multiple sclerosis, such as focal weakness, ataxia, sensory disturbance, or diplopia.", "ORPHA ID": 228165, "Summary": ""}
{"Disease Name": "Bamforth-Lazarus syndrome", "Disease Definition": "A very rare syndrome of congenital hypothyroidism characterized by thyroid dysgenesis (in most cases athyreosis), cleft palate and spiky hair, with or without choanal atresia, and bifid epiglottis. Facial dysmorphism and porencephaly have been reported in isolated cases.", "ORPHA ID": 1226, "Summary": "Epidemiology\nOnly 8 patients from 6 families have been reported to date.\nClinical description\nThe syndrome is typically observed at birth with cleft palate, spiky hair and thyroid dysgenesis (in most cases athyreosis) leading to congenital hypothyroidism that manifests with lethargy, poor feeding, macroglossia, cold or mottled skin, persistent jaundice, and umbilical hernia. Neonatal hyperbilirubinemia is also common. Some may also present with choanal atresia and bifid epiglottis. Facial dysmorphism, consisting of microcephaly, hypertelorism, anteverted nares, narrow nasal bridge, low-set ears, small jaw and retrognathia, has been reported in one case. Porencephaly was also recently described in one case.\nEtiology\nBamforth-Lazarus syndrome is due to homozygous loss-of-function missense mutations located within the forkhead domain of the FOXE1 gene (9q22), encoding thyroid transcription factor 2 (TTF-2). TTF-2 is expressed in the thyroid gland (as well as elsewhere like the tongue, epiglottis and palate) and is thought to play a crucial role in thyroid morphogenesis. Cases reported so far have all been due to homozygous loss-of-function mutations apart from one case described with a novel FOXE1 homozygous mutation causing increased thyroid gene expression.\nDiagnostic methods\nDiagnosis is based on clinical findings of congenital hypothyroidism with cleft palate and spiky hair along with findings of thyroid ultrasonography (USG) and computed tomography examination. Thyroid tissue is either completely absent or non-functional. Serum thyroid stimulation hormone (TSH) levels should be measured (levels will be elevated on newborn screening filter paper test, as is seen in all cases of athyreosis) to determine necessary treatment dosage. Molecular genetic testing can identify a mutation in the FOXE1 gene, confirming diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other forms of syndromic hypothyroidism such as Johanson-Blizzard syndrome.\nAntenatal diagnosis\nWhilst prenatal diagnosis is not performed, a cleft palate and, in some cases, polyhydramnios (resulting from choanal atresia) may be observed during routine antenatal sonography.\nGenetic counseling\nThe disease is inherited autosomal recessively and genetic counseling is possible. Most of the patients reported to date came from consanguineous parents, both being heterozygous for the genetic mutation. Where both parents are heterozygous carriers, there is 25% risk of transmitting the disease to offspring.\nManagement and treatment\nThyroid hormone replacement therapy is the standard treatment for those with Bamforth-Lazarus syndrome and should be started as soon as possible. The dosage of synthetic thyroxine (T4) necessary depends on the patient's age, weight and any other medical conditions. Regular follow up is recommended to monitor any fluctuation in TSH levels and treatment is lifelong. In neonates born with hyperbilirubinemia, phototherapy is often effective. Surgical procedures for cleft palate (maxillo-facial reconstruction and plastic surgery) and choanal atresia (surgery to reopen the nasal passages) should be discussed in a specialized health center. Speech therapy may also be required.\nPrognosis\nWith proper treatment adherence the prognosis is good and children can have normal physical growth, pubertal development, and anterior pituitary function. Quality of life, however, can be affected by cleft palate/choanal atresia as multiple surgeries may be necessary. Intellectual development is normal if treatment for hypothyroidism is not delayed.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Pr John LAZARUS"}
{"Disease Name": "Bangstad syndrome", "Disease Definition": "Bangstad syndrome is a rare endocrine disease characterized by the association of primordial birdheaded nanism, progressive ataxia, goiter, primary gonadal insufficiency and insulin resistant diabetes mellitus. Plasma concentrations of TSH, PTH, LH, FSH, ACTH, glucagon, and insulin are usually elevated. A generalized cell membrane defect was suggested to be the pathophysiological abnormality in these patients. The mode of inheritance was thought to be autosomal recessive. There have been no further descriptions in the literature since 1989.", "ORPHA ID": 1227, "Summary": ""}
{"Disease Name": "Banki syndrome", "Disease Definition": "Banki syndrome is a synostosis syndrome, reported in a single Hungarian family in which members of 3 generations showed lunotriquetral synostosis, clinodactyly, clinometacarpy, brachymetacarpy and leptometacarpy (thin diaphysis). It appeared to be a unique dominant mutation. There have been no further descriptions in the literature since 1965.", "ORPHA ID": 1228, "Summary": ""}
{"Disease Name": "Bannayan-Riley-Ruvalcaba syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by hamartomatous intestinal polyposis, lipomas, macrocephaly and genital lentiginosis.", "ORPHA ID": 109, "Summary": "Epidemiology\nThe prevalence is unknown, but Bannayan-Riley-Ruvalcaba syndrome (BRRS) is generally considered as a rare disease.\nClinical description\nBRRS shares some of the clinical characteristics of Cowden syndrome (CS;) but with differing frequencies. Unlike CS, the classic presentation of BRRS occurs neonatally or shortly thereafter with macrocephaly, Hashimoto struma, lipomatosis, vascular malformations and speckled lentiginosis of the penis or vulva. Developmental delay and gastrointestinal hamartomatous polyposis occur in a subset of BRRS patients. There should be a low threshold to evaluate for autism spectrum disorder in BRRS, especially if a PTEN mutation is found. It is unclear if the case-based signs of myopathic processes in proximal muscles, pectus excavatum, joint hyperextensibility, scoliosis and high birth weight are truly components of BRRS. Although predisposition to cancer was not thought to be a feature of this syndrome, it is now believed that BRRS patients with a germline PTEN mutation share the same risk of cancer development as CS patients.\nEtiology\nBRRS is caused (in 60% of cases) by a mutation in the phosphatase and tensin homolog (PTEN) gene (10q23) that encodes PTEN, a dual-specificity phosphatase. When BRRS is accompanied by germline PTEN mutations, it belongs to the PHTS group. Because the non-PTEN CS-related genes (ex. SDHB-D, AKT1, PIK3CA and KLLN) have not been formally studied in BRRS, it is not clear if they are also etiologic for non-PTEN-related BRRS.\nDiagnostic methods\nThere are no specific criteria for diagnosis of BRRS but it is usually determined by the clinical presentation. The pediatric criteria of the PTEN scoring systemcan be used and are heavily based on the presence or absence of macrocephaly and the presence of one of four sub-criteria (autism spectrum disorder, dermatologic features, vascular malformations and/or gastrointestinal polyposis). A germline PTEN mutation confirms that the BRRS patient belongs to the PHTS group.\nDifferential diagnosis\nDifferential diagnoses include Lhermitte-Duclos syndrome, juvenile polyposis syndrome, Peutz-Jeghers syndrome (PJS), Birt-Hogg-Dube syndrome, Proteus syndrome, Cowden syndrome, Gorlin syndrome, and neurofibromatosis type 1.\nAntenatal diagnosis\nAntenatal diagnosis is possible for at-risk pregnancies if the disease-causing mutation is discovered in an affected family member.\nGenetic counseling\nBRRS is inherited autosomal dominantly. Genetic counseling can be offered to patients with germline PTEN mutations and asymptomatic family members should also be tested for the mutation to identify those that need to be monitored before symptom onset.\nManagement and treatment\nManagement and treatment are multidisciplinary. Monitoring for symptoms of gastrointestinal hamartomatous polyposis is important as they can be more severe than those seen in CS. Once a germline PTEN mutation is identified, the patient should undergo a screening thyroid ultrasound exam, starting at the age of 7, and a low threshold for evaluation for autism spectrum disorder is strongly recommended. In patients over the age of 18, a yearly skin check is recommended. A colonoscopy and biennial renal imaging should begin between the ages of 35-40, unless symptomatic. Women should perform monthly breast self-examinations and yearly breast screenings as well as transvaginal ultrasounds (postmenopausal) or endometrial biopsies beginning at the age of 35. It is also important to pay attention to neurological and vascular malformations as well as GI symptoms.\nPrognosis\nThe prognosis is unknown and is dependent on initial presentation and likely genotype.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Charis ENG"}
{"Disease Name": "BAP1-related tumor predisposition syndrome", "Disease Definition": "BAP1-related tumor predisposition syndrome (TPDS) is an inherited cancer-predisposing syndrome, associated with germline mutations in BAP1 tumor suppressor gene. The most commonly observed cancer types include uveal melanoma, malignant mesothelioma, renal cell carcinoma, lung, ovarian, pancreatic, breast cancer and meningioma, with variable age of onset. Common cutaneous manifestations include malignant melanoma, basal cell carcinoma and benign melanocytic BAP1-mutated atypical intradermal tumors (MBAIT) presenting as multiple skin-coloured to reddish-brown dome-shaped to pedunculated, well-circumscribed papules with an average size of 5 mm, histologically predominantly composed of epithelioid melanocytes with abundant amphophilic cytoplasm, prominent nucleoli and large, vesicular nuclei that vary substantially in size and shape.", "ORPHA ID": 289539, "Summary": ""}
{"Disease Name": "Baraitser-Winter cerebrofrontofacial syndrome", "Disease Definition": "Baraitser-Winter syndrome (BWS) is a malformation syndrome, characterized by facial dysmorphism (hypertelorism with ptosis, broad bulbous nose, ridged metopic suture, arched eyebrows, progressive coarsening of the face), ocular coloboma, pachygyria and/or band heterotopias with antero-posterior gradient, progressive joint stiffening, and intellectual deficit of variable severity, often with severe epilepsy. Pachygyria - epilepsy - intellectual disability - dysmorphism (Fryns-Aftimos syndrome (FA); see this term) corresponds to the appearance of BWS in elderly patients.", "ORPHA ID": 2995, "Summary": "Epidemiology\nBWS and FA were initially considered separate entities. They were reported collectively in approximatively 30 unrelated patients so far.\nClinical description\nThe clinical picture includes striking dysmorphism, hypertelorism, metopic ridging giving a trigonocephalic appearance to the skull, wide palpebral fissures, long downslanted palpebral fissures, congenital ptosis, broad nose with large bulbous or flat tip, prominent nasal root, long philtrum, mild micrognathia and highly arched eyebrows. Facial characteristics get coarser in late infancy and adolescence, with marked nasogenian folds. Cleft lip and palate may be present. Ocular anomalies such as iris and/or retinal coloboma (see these terms) with or without microphthalmos (see this term) are frequent. Most patients present with some degree of cortical dysplasia, pachygyria (often more marked in the frontal area) and subcortical band heterotopias (see this term). In most severe cases, the brain has a lissencephalic aspect, but some patients have a normal MRI. Head circumference tends to evolve to microcephaly during infancy. Growth is mildly delayed, and final stature is below normal. Patients have been reported with hydronephrosis, but, visceral malformations are rare. Intellectual deficiency ranges from mild to profound and correlates with the severity of brain anomalies and the presence of seizures which may be drug-resistant. Limitation of movement in large joints (knee, shoulder, elbow) become apparent in adolescence, and affect walking abilities in adulthood. Kyphoscoliosis may also develop. In infancy, neurological problems are prominent and facial dysmorphism less obvious.\nEtiology\nBWS is a genetically heterogeneous disorder, caused by a heterozygous mutation in one of the 2 genes coding for ubiquitously expressed actins: ACTB, located to 7p22-p12 (BRWS1) and ACTG1 on 17q25.3 (BRWS2). All mutations are missense and probably act by a gain of function mechanism, as deletions of the same genes do not result in BWS phenotype.\nDiagnostic methods\nDiagnosis is confirmed by DNA sequencing of ACTG1 and ACTB.\nDifferential diagnosis\nIn infancy, BWS may resemble Noonan syndrome. Teebi Type Hypertelorism has similar palpebral appearance. CHARGE syndrome, Norman-Roberts type lissencephaly syndrome (see these terms) and other syndromes with lissencephaly/pachygyria as a major feature are partially overlapping.\nAntenatal diagnosis\nAbnormal gyration pattern may be detected prenatally. Recurrence risk is probably < 1%. Antenatal diagnosis is possible, but the low recurrence risk and the risk of induced miscarriage have to be discussed.\nGenetic counseling\nAll molecularly confirmed cases are sporadic, with, in theory, an autosomal dominant transmission, but effective transmission has never been reported.\nManagement and treatment\nDevelopmental delay is managed by appropriate educative measures. Epilepsy management is difficult, as in other forms of pachygyria, some patients are drug resistant, even with polytherapies. Orthopedic monitoring is mandatory, considering progressive joint limitations that could lead to loss of autonomous ambulation.\nPrognosis\nEarly prognosis may be poor in those with severe brain anomalies, but most patients with milder CNS anomalies can reach adulthood, although most patients will never be autonomous.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES"}
{"Disease Name": "Barber-Say syndrome", "Disease Definition": "Barber Say syndrome (BSS) is a rare ectodermal dysplasia with neonatal onset characterized by congenital generalized hypertrichosis, atrophic skin, ectropion and microstomia.", "ORPHA ID": 1231, "Summary": "Epidemiology\nBBS is a rare entity described in eleven patients to date.\nClinical description\nBBS presents with congenital generalized hypertrichosis, facial dysmorphism (typically with bilateral ectropion, absent or sparse eyebrows and lashes, hypertelorism/telecanthus, broad nasal bridge, bulbous nose, anteverted nostrils, macrostomia, thin lips and misshapen ears), hyperlaxity and redundancy of the skin with deep folds, nipple hypoplasia and absence of mammary glands. Teeth are present, but with overgrown gingiva. Dental abnormalities described include taurodontism, shovel-shaped incisors, delayed eruption of deciduous dentition and premature apical closure. Other less frequent findings include cleft palate, hearing loss, mild psychomotor delay and genital abnormalities.\nEtiology\nAutosomal dominant and autosomal recessive transmission, as well as sporadic cases have been reported.\n\n                            Last update: \n                            January 2014"}
{"Disease Name": "Bardet-Biedl syndrome", "Disease Definition": "A rare genetic multisystem disorder characterized by the variable association of retinal dystrophy, obesity, polydactyly, genitourinary and kidney anomalies, learning disability and hypogonadism, with a wide spectrum of other minor manifestations.", "ORPHA ID": 110, "Summary": "Epidemiology\nIn the USA, the prevalence is estimated at 1/100,000. Whilst epidemiological data is limited in Europe, a prevalence of 1/59,000 has been estimated in Denmark and 1/45,000-66,000 in the Reunion Island, France (due to a founder effect).\nClinical description\nThe clinical manifestations are highly variable, even within affected families. Post-axial polydactyly, sometimes associated with brachydactyly and/or syndactyly, is a common congenital feature. Other manifestations develop gradually over the first decade of life. Rapid weight gain is often described in early childhood, with obesity/overweight present in over 90% of individuals after 5 years of age; it is often difficult to treat and is associated with the metabolic syndrome in adults. Rod-cone or choroidal dystrophy causes decreased visual acuity, night blindness, photophobia and loss of central and color vision by late childhood/early adulthood. Other ocular manifestations include strabismus, cataracts, and astigmatism. Kidney and urinary tract abnormalities are common and may lead a progressive decline of kidney function: stage II-V chronic kidney disease (CKD) is described in 30 to over 40% of affected individuals. Developmental delay, cognitive deficit and behavioral disorders (autism, psychosis) are frequent features. Hypogonadism is often reported, especially in males. Minor signs include diabetes mellitus, heart (valvular stenoses, patent ductus arteriosus, cardiomyopathy), gastrointestinal tract (Hirschsprung disease), central nervous system (clumsiness, ataxia), liver (fibrosis, biliary cirrhosis, portal hypertension), and dentition (dental crowding, hypodontia, malocclusion, enamel hypoplasia) abnormalities. Subtle and inconsistent dysmorphic features (brachycephaly, macrocephaly, hypertelorism, midface hypoplasia, retrognathia) have also been reported. Anosmia or hyposmia may also be found as well as bilateral sensorineural hearing loss.\nEtiology\nBardet-Biedl syndrome (BBS) is a ciliopathy associated with abnormalities in proteins involved in the development and function of primary cilia. Pathogenic or likely pathogenic variants in at least 24 different genes have been associated with BBS to date. Depending on the population origin, BBS1 (11q13.2) and BBS10 (12q21.2) are the most frequent genes, respectively accounting for ~23% and 15% of genotyped BBS patients.\nDiagnostic methods\nThe diagnosis of BBS is based on the clinical manifestations (at least four major clinical signs or 3 major and 2 minor clinical signs) and can be confirmed by molecular genetic testing of the causative genes in more than 80% of patients. Visual manifestations are often the first sign leading to diagnosis in patients with no polydactyly; polydactyly and kidney anomalies (hyperechoic or multicystic kidneys) can be antenatal presenting signs.\nDifferential diagnosis\nMain differential diagnoses include Alström syndrome, McKusick-Kaufman syndrome, Joubert syndrome, Jeune syndrome, Sensenbrenner syndrome and Senior-Løken syndrome.\nAntenatal diagnosis\nGenetic prenatal testing for BBS is possible in families with an identified gene mutation.\nGenetic counseling\nBBS is inherited in an autosomal recessive manner. Oligogenic inheritance has also been reported is some affected families. Genetic counseling should be provided to affected families.\nManagement and treatment\nMultidisciplinary management and treatment is required. Most manifestations are treated following standard practice for the general population (obesity, learning disability, kidney anomalies). Setmelanotide was approved for hunger control in genetically confirmed Bardet-Biedl syndrome patients. Genital abnormalities and polydactyly may be treated with surgery.\nPrognosis\nChronic kidney disease is considered the main cause of morbidity and mortality; its severity varies among patients but may potentially lead to end-stage kidney disease requiring dialysis or transplantation. Progressive vision loss due to retinal dystrophy, together with moderate intellectual deficit (when present), behavioral anomalies, hypomimia and obesity will affect the social life of these patients.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Jean MULLER | ERN-EYE* - Pr Miriam ZACCHIA | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Baroreflex failure", "Disease Definition": "A rare autonomic nervous system disorder characterized by diminished or absent buffering capability to prevent blood pressure from rising or falling excessively, due to abnormalities in the vascular baroreceptors, the glossopharyngeal or vagal nerves, or the brain stem. Typical clinical presentations are acute severe sustained hypertension, tachycardia, and headache, or volatile hypertension and tachycardia with headache, diaphoresis, flushing, and emotional instability. Rare cases rather present with hypotension, bradycardia, and dizziness or syncope.", "ORPHA ID": 443084, "Summary": ""}
{"Disease Name": "Barth syndrome", "Disease Definition": "Barth syndrome (BTHS) is an inborn error of phospholipid metabolism characterized by dilated cardiomyopathy (DCM), skeletal myopathy, neutropenia, growth delay and organic aciduria.", "ORPHA ID": 111, "Summary": "Epidemiology\nPrevalence is estimated at 1/454,000 and incidence at 1/140,000 (South-West England, South Wales) to 1/300,000-1/400,000 live births (USA). BTHS affects male patients.\nClinical description\nClinical presentation is highly variable. Most boys will develop DCM during the first decade, generally during the first year of life, which may be accompanied by endocardial fibroelastosis (EFE) and/or left ventricular noncompaction (LVNC). It may start in utero, causing cardiac failure, fetal hydrops and miscarriage or stillbirth during the 2nd/3rd trimester of pregnancy. Ventricular arrhythmia, especially during adolescence, can lead to sudden cardiac death. There is a significant risk of stroke. Skeletal (mostly proximal) myopathy causes delayed motor milestones, hypotonia, severe lethargy or exercise intolerance. There is a tendency to hypoglycemia during the neonatal period. Ninety percent of patients show mild to severe intermittent or persistent neutropenia with a risk of septicemia, severe bacterial sepsis, mouth ulcers and painful gums. Lactic acidosis and mild anemia may occur. Affected boys usually show delayed puberty and growth delay that is observed until the late teens or early 20s, when a substantial growth spurt often occurs. Patients may also present severe difficulties with adequate food intake. Episodic diarrhea is common. Many patients have a similar facial appearance with chubby cheeks, deep-set eyes and prominent ears.\nEtiology\nBTHS is caused by mutations in the TAZ gene (tafazzin; Xq28) which encodes Taz1p acyltransferase involved in the metabolism of cardiolipin, a major phospholipid in inner mitochondrial membranes. Defective Taz1p function results in abnormal remodelling of cardiolipin which ultimately compromises mitochondrial structure or respiratory chain function.\nDiagnostic methods\nDiagnosis was historically based on metabolic screening of urine showing elevated excretion of organic acids (typically 3-methylglutaconic acid (3-MGCA)), followed by TAZ gene sequencing. However, 3-MGC excretion may be normal even in severe cases. Analysis of the ratio of monolysocardiolipin (MLCL) / cardiolipin (CL) on blood, tissue, fibroblasts or stored neonatal bloodspots is therefore the diagnostic test of choice.\nDifferential diagnosis\nDifferential diagnosis includes hereditary, dilated and nutritional cardiomyopathy and idiopathic/cyclic neutropenia (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis (chorionic villus biopsy and/or amniocentesis) is possible in families in which the mutation is known.\nGenetic counseling\nTransmission is X-linked recessive. A son born to a female carrier has a 50% risk of inheriting the mutation and developing the disease, while a daughter has a 50% risk of being a carrier. All daughters of an affected male will be carriers but none of his sons will be affected.\nManagement and treatment\nTreatment is essentially supportive and multidisciplinary. Cardiac failure is treated with conventional drugs or by cardiac transplantation if refractory. The risk of bacterial sepsis in cases of intermittent neutropenia can be reduced by the use of prophylactic antibiotics and/or intermittent use of granulocyte-colony stimulating factor (G-CSF). Difficulties in feeding may necessitate nasogastric or gastrostomy tube feeding.\nPrognosis\nPrognosis has greatly improved with early detection and improvements in treatment and management. Patients are already surviving into their 40s and are expected to live beyond this age.\n\n                            Last update: \n                            June 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Colin STEWARD"}
{"Disease Name": "Bartonella bacilliformis infection", "Disease Definition": "A rare bacterial infectious disease transmitted between humans via bites from infected sand flies in high-altitude valleys of the South American Andes, characterized by two disparate syndromes which can arise independently or sequentially. The first, Oroya fever, occurs about 60 days after the fly bite as a severe hemorrhagic fever with high mortality in untreated individuals. The second, chronic phase, termed verruga peruana, can persist for months or years and manifests with endothelial cell-derived, blood-filled tumors developing on the surface of the skin.", "ORPHA ID": 64692, "Summary": ""}
{"Disease Name": "Bartsocas-Papas syndrome", "Disease Definition": "Bartsocas-Papas syndrome is a rare, inherited, popliteal pterygium syndrome (see this term) characterized by severe popliteal webbing, microcephaly, a typical face with short palpebral fissures, ankyloblepharon, hypoplastic nose, filiform bands between the jaws and facial clefts, oligosyndactyly, genital abnormalities, and additional ectodermal anomalies (i.e. absent hair, eyebrows, lashes, nails). It is often fatal in the neonatal period, but patients living until childhood have been reported.", "ORPHA ID": 1234, "Summary": ""}
{"Disease Name": "Bartter syndrome type 3", "Disease Definition": "A form of Bartter syndrome characterized by a later age at onset than the other types of Bartter syndrome, typically presenting beyond the first year of life with failure to thrive, hypokalemic and hypochloremic metabolic alkalosis, increased levels of plasma renin and aldosterone and low to normal blood pressure.", "ORPHA ID": 93605, "Summary": "Epidemiology\nExact prevalence is not known.\nClinical description\nThe disease is characterized by a milder clinical picture with a wide phenotypic heterogeneity when compared to other types of Bartter syndrome. Only one third of the patients present with maternal polyhydramnios which usually does not lead to prematurity. Patients usually present in the first year of life with failure to thrive, poor weight gain or polyuria with polydipsia. Fatigue, muscle weakness, cramps and carpopedal spasms may occur in some patients. Hypokalemia and hypochloremic metabolic alkalosis are common. Urinary calcium excretion is variable, only a few patients develop medullary nephrocalcinosis. In a subset of patients, the clinical picture and the biochemical abnormalities may resemble Gitelman syndrome, another salt losing tubulopathy caused by mutations in the sodium chloride cotransporter, SLC12A3, of the distal convoluted tubule. Indeed, the biochemical hallmarks of hypomagnesmia with hypocalciuria may also be detected in some patients with this type of Bartter syndrome.\nEtiology\nMutations in the CLCNKB gene (1p36), encoding the basolateral chloride channel ClC-Kb, have been identified as the underlying molecular defect. ClC-Kb is closely related to ClC-Ka, and both channels are expressed in thick ascending limb of the loop of Henle (TAL), ClC-Ka is exclusively expressed in the loop of Henle, whereas ClC-Kb is also expressed in distal convoluted tubule (DCT), thereby explaining the pronounced DCT features (similar to Gitelman syndrome) in some patients with this type of Bartter syndrome.\nDiagnostic methods\nDiagnosis is based on the clinical picture, blood gas analysis, plasma and urine electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, calcium), renin and aldosterone levels. Urinary calcium excretion rates variably range from low to normal or slightly increased. Only genetic testing provides the definite diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes Gitelman syndrome, pseudo-Bartter syndrome (e.g. in cystic fibrosis), HNF1B-nephropathy, and EAST syndrome. From late adolescence, also diuretic abuse, surreptitious vomiting, and surreptitious laxative use need to be ruled out.\nAntenatal diagnosis\nPrenatal diagnosis is technically feasible after genetic counseling and may be considered on an individual basis.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counselling should be offered to any patient with Bartter syndrome and to parents with an affected child. In at-risk couples (both individuals are carriers of a disease-causing mutation) there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment includes oral salt and potassium supplements next to liberal salt and fluid intake. In addition, non-steroidal anti-inflammatory drugs (e.g. indometacin or celecoxib) are helpful in the majority of patients. Potassium-sparing diuretics should only be used with caution. In stressful situations (intercurrent illness, surgical procedures, trauma) blood electrolyte levels may change rapidly, requiring prompt and vigorous treatment.\nPrognosis\nReliable long term outcome data are still lacking. Life expectancy may be reduced in severe cases. Quality of life may be compromised. During follow-up, proteinuria may occur, some patients develop chronic renal failure but rarely need renal replacement therapy.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Martin KONRAD | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Bartter syndrome type 4", "Disease Definition": "A form of Bartter syndrome characterized by maternal polyhydramnios, premature delivery, salt loss, polyuria and sensorineural deafness, associated with hypokalemic and hypochloremic metabolic alkalosis, increased levels of plasma renin and aldosterone, and low to normal blood pressure. Urinary calcium excretion rates are variable, and nephrocalcinosis is typically absent.", "ORPHA ID": 89938, "Summary": "Epidemiology\nIt is the least common of all recessive types of Bartter syndrome.\nClinical description\nA severe type of antenatal Bartter syndrome that typically manifests prenatally with maternal polyhydramnios (due to fetal polyuria) usually evident by the end of second trimester, often leading to preterm labor and prematurity. Postnatally, patients present with polyuria, isosthenuria/hyposthenuria and are at high risk of dehydration, hypovolemic hypotension and shock. Virtually all patients are found to have complete sensorineural deafness. Recurrent vomiting, muscle cramps, spasms and failure to thrive are observed. Progression to renal failure is frequent. Hypokalemic and hypochloremic metabolic alkalosis, and in some cases hypomagnesemia, are noted (hypercalciuria is an inconsistent finding and only transient).\nEtiology\nThe disorder is caused by a defect in chloride reabsorption in the thick ascending limb of the loop of Henle and the early distal convoluted tubule as a consequence of inactivating mutations of the BSND gene (1p32.3), encoding for the protein Barttin (Bartter syndrome type 4A), which is required for the location and proper function of the basolateral chloride channels ClC-Ka and ClC-Kb. Alternatively, the disorder may be caused by digenic mutations in CLCNKA (1p36.13) and CLCNKB (1p36.13) which inactivates the 4 alleles of the 2 genes (Bartter syndrome type 4B). ClC-Ka is highly expressed in the inner ear and contributes to maintaining the high potassium ion concentration in the endolymph necessary for normal hearing, and for which functional disruption leads to nerve deafness.\nDiagnostic methods\nDiagnosis is based on the clinical picture, blood gas analysis, plasma and urine electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, calcium), renin and aldosterone levels. Urinary calcium excretion rates are variably ranging from low to normal or slightly increased. Objective hearing assessment is mandatory to identify sensorineural hearing loss. Only genetic testing provides the definite diagnosis.\nDifferential diagnosis\nThe most important differential diagnoses include congenital chloride diarrhea, pseudohypoaldosteronism type 1, and pseudo-Bartter syndrome (e.g. in cystic fibrosis).\nAntenatal diagnosis\nPrenatal diagnosis is technically feasible after genetic couseling and may be considered on an individual basis.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to any patient with Bartter syndrome and to parents with an affected child. In at-risk couples (both individuals are carriers of a disease-causing mutation) there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nEspecially in the perinatal period, treatment includes vigorous salt and fluid replacement therapy. Non-steroidal anti-inflammatory drugs (e.g. indomethacin or celecoxib) are the second mainstay of therapy. Beyond the neonatal period, next to liberal salt intake, long-term enteral salt and potassium supplements are necessary in most patients. In stressful situations (intercurrent illness with fever, gastroenteritis) blood electrolyte levels may change rapidly, requiring prompt and vigorous intravenous treatment. With respect to deafness, timely intervention ensuring that the child has access to developing receptive and expressive language is of paramount importance.\nPrognosis\nThe perinatal course is critical because of the complications of severe prematurity. Life expectancy may be reduced in severe cases and chronic renal failure may develop in a subset of children. Reliable long term outcome data are still lacking.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Martin KONRAD | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Bartter syndrome type 5", "Disease Definition": "A form of antenatal Bartter syndrome characterized by early maternal polyhydramnios, excessive renal salt loss with secondary metabolic alkalosis in the neonatal period that completely disappears within the first months of life.", "ORPHA ID": 570371, "Summary": ""}
{"Disease Name": "Bartter syndrome", "Disease Definition": "Bartter syndrome is a group of rare renal tubular disease characterized by impaired salt reabsorption in the thick ascending limb of Henle's loop and clinically by the association of hypokalemic alkalosis, hypercalciuria/nephrocalcinosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II.", "ORPHA ID": 112, "Summary": "Epidemiology\nAnnual incidence is estimated at 1/1000,000 in Europe.\nClinical description\nFive distinct genotypes have been described, with four distinct clinical variants: an antenatal/infantile Bartter syndrome (most patients with genotypes I and II; see this term), characterized by polyhydramnios, premature delivery, polyuria, dehydration, hypercalciuria and nephrocalcinosis; an infantile Bartter syndrome with deafness (genotype IV, see this term), with congenital sensorineural deafness; classic Bartter syndrome (mostly patients with genotype III, but also some patients with genotype I and II; see this term), manifesting as polyuria-polydipsia in infancy-childhood through adulthood, dehydration and a variable delay in the height-weight growth curve; and autosomal dominant hypocalcemia with Bartter syndrome (patients with genotype V, see this term), associating chronic hypocalcemia and tubular salt wasting, hypokalemia and alkalosis.\nEtiology\nBartter syndrome results from a defect in sodium, potassium and chloride reabsorption at the level of Henle's loop. They are caused by homozygous or compound heterozygous mutations in four genes encoding proteins involved in tubular fluid reabsorption in the thick ascending part of Henle's loop: SLC12A1 gene (15q15-21), encoding the sodium-potassium-chloride cotransporter NKCC2 in type I Bartter syndrome; KCNJ1 gene (11q24) encoding the potassium channel ROMK in type II; CLCNKB gene (1p36), encoding a basolateral chloride channel, in type III; and BSND gene (1p32.3), encoding barttin, the beta-subunit for the basolateral chloride channels, CLCNKA and CLCNKB in type IV. A final variant (type V) is associated with heterozygous activating mutations of the CASR gene (3q21.1), encoding the calcium sensing receptor.\nDiagnostic methods\nDiagnosis is based on the clinical picture, as well as in plasma and urine electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, calcium), renin and aldosterone levels. Calcium levels in the urine may be normal to markedly increased. Hypocalcemia is observed in Bartter syndrome type V. Genetic testing provides the definite diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes pseudo-Bartter syndrome (diuretic abuse, surreptitious vomiting), Gitelman syndrome, cystic fibrosis and celiac disease (see these terms).\nAntenatal diagnosis\nDiagnostic testing of amniocytes might be indicated for mothers of affected children, or potential heterozygous carriers (close relatives of affected individuals).\nGenetic counseling\nFour of the genetic variants (types I,II,III,IV) of Bartter syndrome are transmitted following an autosomal recessive pattern whereas variant (type V) is transmitted as an autosomal dominant trait.\nManagement and treatment\nTreatment includes oral potassium supplements, non-steroidal anti-inflammatory drugs (e.g. indomethacin) and possibly potassium-sparing diuretics. In stressful situations (intecurrent diseases, surgical procedures, trauma) blood electrolyte levels may change rapidly, requiring prompt and vigorous intravenous treatment.\nPrognosis\nLife expectancy may be reduced in severe cases but renal failure is rare. Quality of life may be poor, growth rate reduced, and hospitalization rate high.\n\n                            Last update: \n                            September 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Giacomo COLUSSI"}
{"Disease Name": "Basel-Vanagaite-Smirin-Yosef syndrome", "Disease Definition": "A rare, genetic intellectual disability syndrome characterized by severe global developmental delay with intellectual disability, microcephaly, growth retardation, ocular defects such as congenital cataract, and nevus flammeus simplex on the forehead. Cardiac, urogenital, and skeletal abnormalities, as well as seizures are present in most patients. Dysmorphic craniofacial features include sparse hair, downslanting palpebral fissures, hypertelorism, broad and overhanging nasal tip and short philtrum, among others.", "ORPHA ID": 464738, "Summary": "Epidemiology\nTo date, 22 patients have been described with common clinical features and biallelic variants in MED25.\nClinical description\nPatients present with some common clinical features. From infancy, almost all have severe global developmental delay with inability to walk and speech, and is followed by intellectual disability (ID). Dysmorphic craniofacial features include sparse hair, high forehead, high frontal hairline, sparse eyebrows, epicanthus, hypertelorism, broad and overhanging nasal tip, short philtrum, exaggerated cupid's bow, retrognathia/micrognathia and nevus flammeus simplex of the forehead. Microcephaly, short stature and feeding difficulties are also reported in some patients, and mandibular prognathia has been reported in various adult individuals from the same family. Other common features that have been described and include 2-3 toe syndactyly, congenital heart diseases (septal defects), urogenital and ocular anomalies (cataract, microcornea, microphthalmia), hypotonia and seizures. Cleft palate, hearing loss, hypospadias, kyphosis / scoliosis, camptodactyly, adducted thumb, tapered fingers with ulnar deviation, overlapping fingers / toes and hyperconvex nails have been described more rarely. Brain imaging abnormalities such as thin corpus callosum, ventriculomegaly and cerebral atrophy are common. Polymicrogyria has recently been reported as a distinctive neuro-radiological finding.\nEtiology\nThe syndrome is caused by homozygous variants in the MED25 gene (19q13.33), coding for a component of the mediator complex. This complex is required for transcription of most RNA polymerase II-dependent genes.\nDiagnostic methods\nDiagnosis is based on clinical examination, brain imaging, cytogenetic and molecular studies.\nDifferential diagnosis\nDifferential diagnosis include other genetic syndromes characterized by intellectual disability accompanied by eye and brain abnormalities.\nAntenatal diagnosis\nPrenatal diagnosis is possible where a known pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement requires a lifelong multidisciplinary approach and includes physical, occupational and speech therapy, in particular non-verbal methods of communication. Treatment is symptomatic and supportive. Antiepileptic drugs may be used to control seizures. Particular attention should be paid to monitoring feeding and growth, particularly as feeding problems tend to occur early on.\nPrognosis\nSome adult patients are reported; however, current data is limited with regard to life expectancy. Prognosis depends on disease severity.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Benedetta CAVIRANI | ITHACA* - Dr Livia GARAVELLI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Bathing suit ichthyosis", "Disease Definition": "Bathing suit ichthyosis (BSI) is a rare variant of autosomal recessive congenital ichthyosis (ARCI; see this term) characterized by the presence of large dark scales in specific areas of the body.", "ORPHA ID": 100976, "Summary": "Epidemiology\nLess than 20 patients are reported in the literature.\nClinical description\nThis particular skin aspect appears after the sheading of a collodion membrane observed at birth. Contrarily to other forms of ARCI, the members (in exception of the folds) and the face are not affected by ichthyosis. Scales are present on warmer skin areas such as the trunk, the scalp, and the axillary region. On affected areas, the patient present with large dark scales similar to those observed in lamellar ichthyosis (LI).\nEtiology\nBSI is caused by specific thermo-sensitive mutations in the TGM1 gene (encoding transglutaminase 1, involved in the cornification of the stratum corneum). Affected skin areas (warmer areas), show a clearly reduced enzyme activity in contrast to healthy skin areas that demonstrate an almost normal enzyme activity. Transmission is autosomal recessive.\n\n                            Last update: \n                            January 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Juliette MAZEREEUW-HAUTIER"}
{"Disease Name": "Bazex syndrome", "Disease Definition": "A rare paraneoplastic syndrome characterized by acral psoriasiform lesions typically involving the ears, nose, fingers and nails of the hands and feet, but may also extend to cheeks, elbows, knees and trunk, with occasional pruritus. In a majority of cases the cutaneous lesions precede the symptoms/diagnosis of malignancy (generally involving the upper aerodigestive tract, but also other squamous cell malignancies).", "ORPHA ID": 166113, "Summary": "Epidemiology\nTo date, approximately 150 cases have been described in the literature. The syndrome most commonly affects males over 40 years of age (mean age of onset: 61 years), and < 10% of cases affect women.\nClinical description\nPatients present with symmetrical, acral, erythemato-squamous psoriasiform eruptions. The most common sites of involvement are the ears, nails, nose, fingers, hands, and feet. Isolated involvement of the helices of the ears, or involvement of the tip of the nose, the distal fingertips, or nails (usually the first sign of the disease), is typical in the early stages of the disease. Lesions may extend to the cheeks, elbows, knees and trunk as the disease progresses. The lesions can be asymptomatic but pain and pruritus can occur in about 20% of cases. Histological findings are not specific and include psoriasiform epidermal hyperplasia, hyperkeratosis with parakeratosis, and perivascular lymphocytic infiltrates in the dermis. In 70% of the cases, the cutaneous lesions precede the symptoms or diagnosis of the malignancy, which is most often a squamous cell carcinoma involving the upper aerodigestive tract.\nEtiology\nThe pathogenesis of Bazex syndrome remains unclear. It may be caused by the production of epidermal growth factor by tumor cells or by cross-reactivity between epidermal and tumor antigens.\nDiagnostic methods\nDiagnosis is based on clinical and histological findings. Complete evaluation of the upper aerodigestive tract should be performed to identify the underlying malignancy.\nDifferential diagnosis\nDifferential diagnoses include psoriasis, allergic contact dermatitis, photosensitivity, dermatomyositis, drug eruption, cutaneous lupus erythematosus and mycosis.\nManagement and treatment\nThe dermatosis may respond to acitretin alone or to a combination of acitretin and UVA phototherapy. Oral and topical steroids have also been reported as effective for the treatment of lesions. Cutaneous lesions regress with the treatment of the underlying malignancy, whereas nail lesions may persist. Recurrence of skin lesions in a successfully treated patient implies a recurrence of the malignancy.\nPrognosis\nPrognosis is related to the underlying neoplasm.\n\n                            Last update: \n                            April 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Arda ISIK"}
{"Disease Name": "Bazex-Dupré-Christol syndrome", "Disease Definition": "Bazex-Dupré-Christol syndrome is a rare genodermatosis with a predisposition to early-onset basal cell carcinomas.", "ORPHA ID": 113, "Summary": "Epidemiology\nSo far, 143 cases have been reported, mostly from France and Belgium.\nClinical description\nThe disease manifests during the neonatal period or during infancy. It is characterized by hypotrichosis, hypohidrosis, milia and basal cell carcinomas of early onset. Follicular atrophoderma is frequent and most common on the dorsum of the hands and feet, the extensor surfaces of the elbows and knees, and the face. Hypotrichosis affects the scalp and sometimes the eyebrows. The milia papules and basal cell carcinomas are located predominantly on the face. Basal cell carcinomas develop in 40% of patients, usually during the 2nd or 3rd decade of life. Additional common features include basal cell hamartomas, trichoepitheliomas and, in very rare cases, atopy, keratosis pilaris, ichthyosis, arachnodactyly with joint hyperlaxity, osteochondritis, deafness and learning difficulties.\nEtiology\nThe gene has been mapped to the long arm of the X chromosome, within the Xq24-q27.1 region. UBE2A (Xq24), encoding a protein involved in repair of UV-damaged DNA, has been proposed as a candidate gene.\nDifferential diagnosis\nThe differential diagnosis should include Gorlin syndrome, which also leads to multiple basal cell carcinomas of early onset, and X-linked dominant chondrodysplasia punctata (see these terms) in which follicular atrophoderma may also be observed. Rombo syndrome and generalized basaloid follicular hamartoma syndrome (see these terms) should also be included in the differential diagnosis.\nGenetic counseling\nTransmission is X-linked dominant.\nManagement and treatment\nManagement involves photoprotection and early detection of basal cell carcinomas. Surgical intervention, and sometimes cryosurgery or topical imiquimod, are indicated for basal cell carcinomas. Radiotherapy is contraindicated.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Jean-Noël DAUENDORFFER  - Pr Philippe SAIAG"}
{"Disease Name": "Becker muscular dystrophy", "Disease Definition": "A rare, genetic muscular dystrophy characterized by progressive muscle wasting and weakness due to degeneration of skeletal, smooth and cardiac muscle.", "ORPHA ID": 98895, "Summary": "Epidemiology\nBecker muscular dystrophy (BMD) primarily affects males; in Europe the estimated prevalence ranges between 1:16,700-1:18,500 male births.\nClinical description\nOnset is usually in childhood, typically after 7 years of age, but can be later. Presenting features in children include toe walking gait and or exercise-related cramps with or without myoglobinuria. Some patients may present following anesthetic induced acute rhabdomyolysis. In older patients, cardiomyopathy may be the presenting feature. As the condition progresses, muscle weakness leads to functional difficulties (difficulty climbing stairs or rising from a chair). Rarely, cardiomyopathy may be the presenting feature. Clinical examination reveals muscle pseudohypertrophy of the calf muscles and there may be atrophy of more proximal muscles such as the quadriceps. There is symmetrical and proximal muscle weakness, with the lower limbs being more severely affected than the upper limbs. There may be joint contractures, especially of the tendo- Achilles. The facial, ophthalmic and bulbar muscles are not involved. The condition is slowly progressive and about 40% of affected patients will eventually become wheelchair-dependent. In wheelchair dependent patients, restrictive respiratory insufficiency occurs due to weakness of the intercostal muscles and diaphragm. Cardiac involvement leads to dilated cardiomyopathy, which can be disproportionate to skeletal muscle involvement.\nEtiology\nBMD is caused by dystrophin deficiency due to in-frame deletions, mutations or duplications in the DMD gene (Xp21.2).\nDiagnostic methods\nDiagnosis is suspected on the basis of the clinical picture, family history and laboratory findings (raised serum creatine kinase to 10-100 times the normal level). The diagnosis is confirmed with DNA testing for variants in the DMD gene. Muscle biopsy shows a dystrophic picture with reduced dystrophin staining.\nDifferential diagnosis\nDifferential diagnosis includes the limb girdle muscular dystrophies, Duchenne muscular dystrophy, malignant hyperthermia and metabolic muscle diseases. In some cases the distinction between a mild variant of BMD and X-linked dilated cardiomyopathy can be difficult.\nAntenatal diagnosis\nIf the diagnosis has been confirmed by genetic testing of carriers, then antenatal, genetic diagnosis is possible.\nGenetic counseling\nBMD is an X-linked recessive disease and genetic counseling is recommended. Male siblings of a proband have a 50% risk of being affected; female siblings have a 50% risk of being carriers. Whilst carriers are typically asymptomatic, a small percentage manifest milder forms of the disease (symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers). Male offspring of an affected male do not inherit the disease, female offspring are obligate carriers.\nManagement and treatment\nManagement includes multidisciplinary care with physiotherapy to reduce joint contractures and prolong walking. Night time ankle-foot orthoses are prescribed for children to reduce tendo- achilles contractures. Cardiac surveillance and monitoring of respiratory function are very important to improve outcome. Early treatment of cardiomyopathy with ACE (angiotensin-converting enzyme) inhibitors and or beta-blockers is recommended, and referral for cardiac transplantation is appropriate for severely affected patients. Patients with respiratory insufficiency should have pneumococcal and flu vaccines. Respiratory insufficiency should be treated with nocturnal BiPAP (bilevel positive airway pressure) and cough augmentation.\nPrognosis\nBMD is slowly progressive with wide phenotypic variability. Despite childhood onset, independent walking is never lost before 16 years of age. Life-expectancy for patients can be normal but may be significantly shortened by dilated cardiomyopathy or respiratory failure.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shpresa PULA  - Pr Rosaline QUINLIVAN"}
{"Disease Name": "Becker nevus syndrome", "Disease Definition": "A rare, syndromic, benign, epidermal nevus syndrome characterized by the association of a Becker nevus (i.e. circumscribed, unilateral, irregularly shaped, hyperpigmented macules, with or without hypertrichosis and/or acneiform lesions, occuring predominantly on the anterior upper trunk or scapular region) with ipsilateral breast hypoplasia or other, typically hypoplastic, skeletal, cutaneous, and/or muscular defects, such as pectoralis major hypoplasia, supernumerary nipples, vertebral defects, scoliosis, limb asymmetry, odontomaxillary hypoplasia and lipoatrophy.", "ORPHA ID": 64755, "Summary": ""}
{"Disease Name": "Beckwith-Wiedemann syndrome", "Disease Definition": "Beckwith-Wiedemann syndrome (BWS) is a genetic disorder characterized by overgrowth, tumor predisposition and congenital malformations.", "ORPHA ID": 116, "Summary": "Clinical description\nPatients tend to grow at an increased rate during the 2nd half of pregnancy and in the first few years of life; adult heights are typically in the normal range. Abnormal growth may also manifest as hemihyperplasia and/or macroglossia (leading to difficulties in feeding, speech and infrequently, sleep apnea). Hypoglycemia is reported in 30-50% of neonates. A recognizable facial gestalt is common and often normalizes by adulthood. In addition to macrosomia, macroglossia, hemihyperplasia and hypoglycemia, characteristic findings may include omphalocele/umbilical hernia/diastasis recti, embryonal tumor, anterior earlobe crease(s) and posterior helical pit(s), nevus flammeus or other vascular malformations, visceromegaly involving abdominal organs, fetal adrenocortical cytomegaly (pathognomonic), renal abnormalities, positive family history, and rarely cleft palate. Cardiac malformations are found in 9-34% of cases and about half of these have spontaneously-resolving cardiomegaly. Cardiomyopathy is rare. Patients are highly predisposed to embryonal malignancies primarily in the first 8 years of life with a risk estimate of 7.5% (range of 4 - 21%).\nEtiology\nBWS is caused by various epigenetic and/or genetic alterations that dysregulate imprinted genes on chromosome 11p15.5. Molecular subgroups are associated with different recurrence risks and different clinical findings (e.g. tumor risks).\nDiagnostic methods\nGenerally, diagnosis is supported by the presence of at least three characteristic clinical findings, however embryonal tumor development may occur with 'milder' presentations. Positive molecular tests may confirm the diagnosis; however a negative result does not rule out BWS.\nDifferential diagnosis\nDifferential diagnoses include Simpson-Golabi-Behmel, Costello, Perlman, and Sotos syndromes, and mucopolysaccharidosis type VI (see these terms).\nAntenatal diagnosis\nPrenatal testing by chorionic villus sampling or amniocentesis can be offered, especially if a cytogenetic or genomic abnormality has been identified; methylation alterations are more reliably detected via amniocentesis at present. Amniocentesis may also be indicated for BWS-associated findings detected on fetal ultrasound (e.g. fetal omphalocele). In the absence of a known molecular defect, screening can be undertaken by measurement of maternal serum alpha-fetoprotein and targeted ultrasound screening.\nGenetic counseling\nThe disease occurs sporadically (85%), but familial transmission is reported (15%). Genetic counseling is recommended and recurrence risk estimation and cascade genetic testing should take into account family history and the molecular subgroup of the affected family member.\nManagement and treatment\nManagement typically involves standard supportive medical and surgical strategies. Tumor surveillance should be initiated if BWS is suspected/diagnosed and in a clinically unaffected monozygotic twin of a patient, but should not be guided by genotype/phenotype correlations at this time. Screening for hypoglycemia should be undertaken in the neonatal period if there are suggestive or diagnostic prenatal findings, and even for clinically unaffected newborns at increased risk based on family history.\nPrognosis\nAt the severe end of the spectrum, patients are at risk of early death due to complications arising from hypoglycemia, prematurity, cardiomyopathy, macroglossia, or tumors. In patients who survive childhood, prognosis is generally good.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Chéryl SHUMAN  - Pr Rosanna WEKSBERG"}
{"Disease Name": "Beemer-Ertbruggen syndrome", "Disease Definition": "Beemer-Ertbruggen syndrome is a lethal malformation syndrome reported in 2 brothers of first-cousin parents that is characterized by hydrocephalus, cardiac malformation, dense bones, and unusual facies with down-slanting palpebral fissures, bulbous nose, broad nasal bridge, micrognathia and a long upper lip. There have been no further descriptions in the literature since 1984.", "ORPHA ID": 1237, "Summary": ""}
{"Disease Name": "Behavioral variant of frontotemporal dementia", "Disease Definition": "Behavioral variant of frontotemporal dementia (bv-FTD) is a form of frontotemporal dementia (FTD; see this term), characterized by progressive behavioral impairment and a decline in executive function with frontal lobe-predominant atrophy.", "ORPHA ID": 275864, "Summary": ""}
{"Disease Name": "Behçet disease", "Disease Definition": "A rare, chronic, relapsing, multisystemic vasculitis characterized by mucocutaneous lesions, as well as articular, vascular, ocular and central nervous system manifestations.", "ORPHA ID": 117, "Summary": "Epidemiology\nBehçet disease (BD) is most often reported in populations along the Silk Road, with highest prevalence reported in Turkey at >1/1,000, versus 1/10,000 in Japan. European cases are more often described in Mediterranean countries.\nClinical description\nOnset most commonly occurs in adults (mean 30 years of age), but pediatric cases have been reported. Relapsing episodes of round oral aphthae with sharp erythematous and elevated borders (1-3 cm diameter) may be accompanied by genital aphthae (>50% of cases); cutaneous features may include pseudo-folliculitis and erythema nodosum. Ocular disorders (posterior uveitis, retinal vasculitis) occur in over 50% of BD patients. Arthralgia and/or non-erosive, asymmetric, arthritis affecting mainly large articulation (knees, ankles ect.) are frequent (45%) and can occur as an initial symptom. Vasculitis in BD is more frequent in the venous system where thromboses in femoro-iliac, superior and inferior vena cava and cerebral territories may occur. Rarer arterial thromboses and aneurysms primarily affect the pulmonary and aorta vessels. Neurological manifestations (neuro-BD) are frequent (>20%), and may include headache, fever, pyramidal signs with hemiparesis, cranial nerve damage, meningitis, behavioral changes and sphincter dysfunction. Aphthoid and/or ulcerative lesions may affect the whole digestive tract but mainly the ileo-caecum and ascending colon, potentially leading to hemorrhages and perforations.\nEtiology\nOf unknown origin, genetic predisposition in BD may allow certain infectious (in particular Streptococcus sanguis) and/or environmental insults to trigger symptoms involving sporadic inflammatory attacks reminiscent of auto-inflammatory disorders due to cross reactions with oral mucosa antigens. HLAB5101 antigen is associated to BD in 50-60% of patients. NF-kB activation and aberrant cytokine levels (eg- IL-6, TNF-a, IL-8, IL-12, IL-17 and IL-21) have been implicated in the pathogenesis of BD. A familial, autosomal dominant form of BD, A20 haploinsufficiency, is linked to mutations in TNFAIP3(6q23.3).\nDiagnostic methods\nThe diagnosis of BD is essentially clinical and is based on the international classification criteria, which are sensitive and specific. The presence of recurrent oral ulceration (at least 3 times over 12 months; 2 points), genital ulceration (2 points), uveitis (2 points), skin lesions (1 point), cardiovascular (1 point), neurologic (1 point) and/or pathergy reaction (1 point). Behçet disease is retained with 4 or more points. Other elements may contribute to the diagnosis. Isolated severe visceral involvement (e.g. vena cava, cerebral and/or subhepatic vein thrombosis, pulmonary aneurysms, neurological involvement and/or retinal vasculitis) can be inaugural and should evoke BD; therefore, systematic request of an expert opinion is recommended. A family history of BD also increases the probability of diagnosis. Searching for the HLA-B51 haplotype is not a strong diagnostic element, but can be useful in situations of diagnostic uncertainty.\nDifferential diagnosis\nDifferential diagnosis depends on upon the manifestations, herpes ulcerations, spondylo-arthropathies, infectious uveitis, relapsing polychondritis, sarcoidosis, antiphospholipid syndrome, Takayasu arteritis, Crohn's disease, infectious meningo-encephalitis or multiple sclerosis may be considered.\nManagement and treatment\nAnti-inflammatory steroids are the basis of treatment; however, corticodependance and relapses may occur upon discontinuation. Concurrent administration of immunosuppresive drugs (e.g. azathioprine, cyclophosphamide, methotrexate or mycophenolate mofetil), are also prescribed but their action is delayed. Anti-TNF and alpha-interferon (2a or 2b) are efficient, particularly in severe uveitis, and antiplatelet or anticoagulation treatments are discussed in case of vascular thrombosis. Colchicine relieves mucocutaneous symptoms. Apremilast has been recently approved in refractory oral ulceration of BD. Efficacy is dependent upon rapid initiation and patient compliance.\nPrognosis\nIn the absence of treatment, the prognosis is severe due to ocular involvement leading potentially to blindness, the risk of lethal arterial rupture, large vessel thrombosis and neurological symptoms potentially causing encephalopathy or cerebral hypertension that may lead to a loss of autonomy. Intensive care coupled with close multidisciplinary follow-up, and adapted immunosuppressive treatment has been shown to reduce morbidity and mortality.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Pr David SAADOUN"}
{"Disease Name": "Bencze syndrome", "Disease Definition": "Bencze syndrome or hemifacial hyperplasia with strabismus is a malformation syndrome involving the abnormal growth of the facial skeleton as well as its soft tissue structure and organs, and is characterized by mild facial asymmetry with unaffected neurocranium and eyeballs, as well as by esotropia, amblyopia and/or convergent strabismus, and occasionally submucous cleft palate. Transmission is autosomal dominant. There have been no further descriptions in the literature since 1979.", "ORPHA ID": 1241, "Summary": ""}
{"Disease Name": "Benign adult familial myoclonic epilepsy", "Disease Definition": "Benign adult familial myoclonic epilepsy (BAFME) is an inherited epileptic syndrome characterized by cortical hand tremors, myoclonic jerks and occasional generalized or focal seizures with a non-progressive or very slowly progressive disease course, and no signs of early dementia or cerebellar ataxia.", "ORPHA ID": 86814, "Summary": "Epidemiology\nWorldwide prevalence is unknown but an estimated prevalence of 1/35,000 was reported in Japan.\nClinical description\nBAFME usually presents in the second decade of life (but age of onset can range from age 11-50) with a minor cortical hand tremor. The tremor consists of continuous, arrhythmic fine twitching in the hands that is exacerbated by fatigue or emotional stress. There is no progression of severity in these tremors until after the age of 70. Myoclonus usually appears around the same age as the cortical tremor and consists of erratic, arrhythmic, segmental jerks of the upper limbs heightened by posture and action. Rare tonic-clonic seizures are also a manifestation of BAFME (peak age of onset being 30), occurring after the appearance of tremors and myoclonus and often precipitated by photic stimulation, emotional stress and sleep deprivation. Some patients from families mapped on chromosome 2p11.1-q12.2 present with drug-resistant complex partial seizures and focal EEG abnormalities. At an advanced age, a worsening of the myoclonus is possible as well as difficulty walking and mild ataxia.\nEtiology\nBAFME has been mapped to at least 4 different chromosomal loci. The identified chromosomal loci linked to BAFME are: 8q23.3-q24.11 in Japanese families (BAFME type 1), 2p11.1-q12.2 in Italian families (BAFME type 2), 5p15.31-p15.1 in a French family (BAFME type 3) and 3q26.32-q28 in a Thai family (BAFME type 4). In addition, a consanguineous Egyptian family with focal epilepsy, neuropsychiatric features, borderline cognitive level, and myoclonus, resembling BAFME but inherited in an autosomal recessive manner was recently described. A homozygous deletion in the CNTN2 (1q32.1) gene encoding contactin 2 was found to be responsible.\nDiagnostic methods\nDiagnosis is based on clinical and electrophysiological findings. Electroencephalographic (EEG) findings include a photomyoclonic response along with abnormality of polyspikes and waves. Patients also display extremely enlarged cortical components of somatosensory evoked potentials and an enhanced C-reflex. Jerk-locked average analysis reveals positive-negative, biphasic spikes preceding myoclonus.\nDifferential diagnosis\nBAFME must be differentiated from epilepsy syndromes with prominent myoclonus features. Patients may easily be misdiagnosed as having juvenile myoclonic epilepsy (JME; see this term) due to the occurence of myoclonic jerks and generalized tonic-clonic seizures. However, JME differs clinically from BAFME by the absence of cortical tremor, the mainly proximal myoclonic jerks, and seizures typically occurring at awakening. The absence of ataxia and dementia, the adult onset, and the usually benign outcome of epilepsy differentiates BAFME from progressive myoclonic epilepsies.\nGenetic counseling\nBAFME is transmitted autosomal dominantly and penetrance is high. Genetic counseling is possible when a family member has the disease and presymptomatic diagnosis may be done in young patients from families mapped on any of the 3 loci, based on electrophysiological findings.\nManagement and treatment\nCortical tremor (unlike essential tremor) usually has a poor response to beta blockers but improves with antiepileptic drugs. As alcohol aggravates these tremors, it should be avoided. Valproate, levetiracetam, and benzodiazepines are most beneficial in the treatment of cortical tremors and myoclonus due to their combined antiepileptic and antimyoclonic effects. In some cases, epilepsy may be difficult to treat.\nPrognosis\nBAFME has no effect on life expectancy. With successful treatment, patients are often relieved from their symptoms.\n\n                            Last update: \n                            February 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Pasquale STRIANO"}
{"Disease Name": "Benign cephalic histiocytosis", "Disease Definition": "A rare non-Langerhans cell histiocytosis characterized by multiple small yellowish-red or brown papules initially erupting predominantly in the head and neck region. The histopathological hallmark of these eventually self-healing lesions is a dermal proliferation of histiocytes with intracytoplasmic comma-shaped bodies, coated vesicles, and desmosome-like structures. Birbeck granules are absent. The disease typically occurs in young children.", "ORPHA ID": 157997, "Summary": ""}
{"Disease Name": "Benign concentric annular macular dystrophy", "Disease Definition": "Benign concentric annular macular dystrophy (BCAMD) is a progressive autosomal dominant macular dystrophy characterized by parafoveal hypopigmentation followed by a retinitis pigmentosa-like phenotype (nyctalopia and peripheral vision loss) with a bull’s eye configuration.", "ORPHA ID": 251287, "Summary": ""}
{"Disease Name": "Benign epithelial tumor of salivary glands", "Disease Definition": "Benign epithelial tumor of salivary glands is a rare neoplastic disease characterized by the presence of a tumor located in the parotid, sublingual, submandibular and/or minor salivary glands, which presents with a wide spectrum of clinical features depending on the location, size and type of salivary gland involved, usually manifesting as a slow-growing, painless, commonly solitary mass, rarely associated with facial nerve palsy or nasal/airway obstruction.", "ORPHA ID": 276148, "Summary": ""}
{"Disease Name": "Benign familial mesial temporal lobe epilepsy", "Disease Definition": "Benign familial mesial temporal lobe epilepsy is a rare epilepsy characterized by seizures with viscerosensory or experential auras, onset in adolescence or early adulthood and good prognosis. It is defined as at least 24 months of seizure freedom with or without antiepileptic medication.", "ORPHA ID": 163717, "Summary": ""}
{"Disease Name": "Benign focal seizures of adolescence", "Disease Definition": "A rare epilepsy typically characterized by isolated focal motor and somatosensory seizures. Less frequently other focal seizure types, with or without secondary generalization, have been described. The seizures usually happen when the patient is awake and take a benign course. The condition is transitory, interictal examinations are normal, and there is usually no family history of epilepsy.", "ORPHA ID": 1544, "Summary": ""}
{"Disease Name": "Benign hereditary chorea", "Disease Definition": "A rare, genetic, movement disorder characterized by early-onset, very slowly progressive choreiform movements that may involve variable parts of the body, typically aggravated by stress or anxiety, in various members of a family. Additional variable manifestations include hypotonia, often resulting in psychomotor delay (including gait disturbances) and dysarthria, as well as myoclonus, dystonia, behavioral symptoms (ADHD, obsessive-compulsive disorder), learning difficulties (particularly in writing) and spasticity with hyperreflexia and/or flexor/extensor plantar reflexes.", "ORPHA ID": 1429, "Summary": ""}
{"Disease Name": "Benign idiopathic neonatal seizures", "Disease Definition": "A rare neonatal epilepsy syndrome characterized by seizures without specific underlying etiology, occurring during the first days of life in infants with an otherwise normal neurological state and no family history of neonatal convulsions. The most commonly partial and clonic seizures usually last for one to three minutes. Repeated seizures may lead to status epilepticus lasting up to 20 hours. Overall, remission rates are high and neurological outcome is favorable.", "ORPHA ID": 64545, "Summary": ""}
{"Disease Name": "Benign infantile focal epilepsy with midline spikes and waves during sleep", "Disease Definition": "Benign infantile focal epilepsy with midline spikes and waves during sleep is a rare infantile epilepsy syndrome characterized by age of onset between 4 and 30 months, partial sporadic seizures presenting with motion arrest, staring, cyanosis and, less common, automatisms and lateralizing signs, and characteristic interictal sleep EEG changes consisting of a spike followed by a bell-shaped slow wave in the midline region.", "ORPHA ID": 166308, "Summary": ""}
{"Disease Name": "Benign infantile seizures associated with mild gastroenteritis", "Disease Definition": "Benign infantile seizures associated with mild gastroenteritis is a rare infantile epilepsy syndrome characterized by benign afebrile seizures in previously healthy infants and children (age range 1 month to 6 years) with mild acute gastroenteritis without any central nervous system infection, severe dehydration, or electrolyte imbalances. In most cases the seizures are tonic-clonic with focal origin on EEG, occur between day 1 and 6 following onset of acute gastroenteritis, cease within 24 hours and do not persist after the illness.", "ORPHA ID": 166305, "Summary": ""}
{"Disease Name": "Benign metanephric tumor", "Disease Definition": "A rare renal tumor characterized by a benign epithelial (metanephric adenoma), biphasic (metanephric adenofibroma) or renal stromal (metanephric stromal tumor) neoplasm. Metanephric adenoma mostly occurs in the fifth to sixth decade of life with distinct female predominance. It may be asymptomatic or present with abdominal pain, hematuria, and/or polycythemia. Metanephric adenofibroma has been described from infancy to young adulthood, potentially causing polycythemia or hematuria. Metanephric stromal tumor typically presents in infancy or childhood as an abdominal mass, sometimes manifestations of extrarenal vasculopathy such as hypertension or hemorrhage.", "ORPHA ID": 464359, "Summary": ""}
{"Disease Name": "Benign nocturnal alternating hemiplegia of childhood", "Disease Definition": "Benign nocturnal alternating hemiplegia of childhood is a rare neurologic disease characterized by recurrent attacks of nocturnal screaming or crying followed or accompanied by unilateral or sometimes bilateral hemiplegia. Disorder is not associated with neurological or developmental impairments but may be associated with mild behavioral abnormalities.", "ORPHA ID": 209973, "Summary": ""}
{"Disease Name": "Benign paroxysmal tonic upgaze of childhood with ataxia", "Disease Definition": "Benign paroxysmal tonic upgaze of childhood with ataxia is a rare paroxysmal movement disorder characterized by episodes of sustained, conjugate, upward deviation of the eyes and down beating saccades in attempted downgaze (with preserved horizontal eye movements) which is accompanied by ataxic symptomatology (unsteady gait, lack of balance and movement coordination disturbances) in an otherwise healthy individual. Bilateral vertical nystagmus is associated. Symptoms generally disappear spontaneously within 1-2 years after onset.", "ORPHA ID": 1179, "Summary": ""}
{"Disease Name": "Benign paroxysmal torticollis of infancy", "Disease Definition": "A rare, transient paroxysmal dystonia characterized by onset of recurrent episodes of torticollic posturing of the head between infancy and early-childhood.", "ORPHA ID": 71518, "Summary": "Epidemiology\nTo date, more than 150 cases have been described in the literature; however, the disease is likely under reported. The condition appears to be slightly more frequent in females.\nClinical description\nOnset typically occurring between 2 and 8 months of age but may occur anywhere between birth and early childhood with episodes occurring between every few weeks and every few months. The duration of the torticollis varies between patients, but usually lasts from a few hours to a few days (although persistence for over one week has been reported). The torticollic episodes (in particular those of shorter duration) may by associated with other symptoms including vomiting, pallor, sweating, apathy or irritability, an unsteady gait, an upwardly-diverted gaze, abnormal truncal posture (tortipelvis) and contraction of the posterior neck muscles (retrocollis). The frequency and duration of the torticollic episodes decreases with age and episodes usually stop completely by 5 years of age.\nEtiology\nThere is some clinical and genetic evidence pointing to benign paroxysmal torticollis as one of the infantile migraine precursors. In some cases disease-causing mutations have been identified in the CACNA1A (19p13.13). In one case, a mutation in PRRT2  (16p11.2) has been identified. Both CACNA1A and PRRT2 have been linked to other diseases such as familial hemiplegic migraine.\nDiagnostic methods\nDiagnostic criteria include i) recurrent attacks in infants and small children ii) head tilt to either side that remits spontaneously after minutes to days iii) one of the following symptoms: pallor, irritability, malaise, vomiting and ataxia which may coexist during attacks iv) normal neurological examination between attacks v) not attributed to another disorder. As the disorder is benign and transient, extensive investigations should be avoided, although some diagnostic tests (brain ultrasound, computerized tomography, magnetic resonance imaging, studies of toxics or drugs and otorhinolaryngological examination), all giving normal results, may be required mainly in the first episode to exclude other causes of torticollis.\nDifferential diagnosis\nThe differential diagnosis (mainly in the first episode) should include intoxication, undesirable secondary effects of drugs, craniocervical junction abnormalities such as atlanto-axial instability, Arnold-Chiari malformation, epilepsy, vertigo, Sandifer's syndrome and posterior fossa tumors in cases with associated symptoms.\nGenetic counseling\nThe disorder usually occurs sporadically; however, a few families with autosomal dominant inheritance have been reported.\nManagement and treatment\nAs the disease is self-limiting and resolves spontaneously by mid-childhood, no treatment is usually required. There is no approved medication for this disease.\nPrognosis\nPrognosis is excellent.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Emilio FERNANDEZ-ALVAREZ  - Dr Esther VAZQUEZ-LOPEZ"}
{"Disease Name": "Benign partial epilepsy of infancy with complex partial seizures", "Disease Definition": "Benign partial epilepsy of infancy with complex partial seizures is a rare infantile epilepsy syndrome characterized by complex partial seizures presenting with motion arrest, decreased responsiveness, staring, automatisms and mild clonic movements, with or without apneas, normal interictal EEG and focal, mostly temporal discharges in ictal EEG. Most often, seizures occur in clusters and have a good response to treatment. Psychomotor development is normal.", "ORPHA ID": 166299, "Summary": ""}
{"Disease Name": "Benign partial epilepsy with secondarily generalized seizures in infancy", "Disease Definition": "Benign partial epilepsy with secondarily generalized seizures in infancy is a rare infantile epilepsy syndrome characterized by seizures presenting with motion arrest and staring. They are followed by generalized tonic-clonic convulsions with normal interictal EEG and focal paroxysmal discharges, followed by generalization in ictal EEG. Seizures usually occur in clusters and are responsive to treatment. Psychomotor development is normal.", "ORPHA ID": 166302, "Summary": ""}
{"Disease Name": "Benign recurrent intrahepatic cholestasis", "Disease Definition": "Benign recurrent intrahepatic cholestasis (BRIC) is a hereditary liver disorder characterized by intermittent episodes of intrahepatic cholestasis, generally without progression to chronic liver damage. BRIC is now believed to belong to a clinical spectrum of intrahepatic cholestatic disorders that ranges from the mild intermittent attacks in BRIC to the severe, chronic and progressive cholestasis seen in progressive familial intrahepatic cholestasis (PFIC; see this term).", "ORPHA ID": 65682, "Summary": "Epidemiology\nThe prevalence of BRIC is unknown.\nClinical description\nThe first cholestatic episode can occur at any age but onset within the first two decades of life is most common. Patients present with bouts of intense pruritus and jaundice that may last for several weeks or months before resolving spontaneously. Associated manifestations include fatigue, loss of appetite, dark urine and pale stools. Hepatomegaly is also a common finding. Between episodes patients show no symptoms and the interval between attacks varies from months to years. The factors triggering the onset of the cholestasis remain unclear but viral infections, pregnancy and oral contraceptives have all been implicated. Two forms of BRIC have been described (BRIC1 and BRIC2) (see these terms). Clinically, these forms are very similar; however, patients with BRIC1 can display extrahepatic features such as hearing loss, pancreatitis and diarrhea, whereas cholelithiasis is a common manifestation of BRIC2. Patients with BRIC2 also have an increased risk for hepatobiliary malignancy.\nEtiology\nBRIC1 is allelic to PFIC1 (see this term) and is caused by mutations in the ATP8B1 gene (18q21) encoding a P-type ATPase expressed at the canalicular membrane of hepatocytes as well as in other epithelia. BRIC2 is allelic to PFIC2 (see this term) and is caused by mutations in the ABCB11 gene (2q24) encoding the liver-specific bile salt export pump (BSEP). The disease-causing mutations in BRIC are generally missense mutations.\nDiagnostic methods\nDiagnosis is based on the clinical history (at least 2-3 episodes of cholestasis), serum biochemistry (low to normal serum gamma GT activity and cholesterol, elevated serum total bile acids and high levels of conjugated bilirubin during episodes), cholangiography (showing normal intra- and extrahepatic bile ducts), liver histology (revealing intrahepatic cholestasis with normal liver structure) and immunohistochemical analysis (absent or reduced BSEP staining in majority of BRIC2 patients). Molecular genetic testing confirms the diagnosis and discriminates between subtypes.\nDifferential diagnosis\nDifferential diagnoses include drug-induced cholestatic disease as well as intrahepatic cholestasis of pregnancy, primary biliary cirrhosis and primary sclerosing cholangitis (see these terms). BRIC can be differentiated from PFIC on the basis of the disease course and liver histology.\nAntenatal diagnosis\nPrenatal testing is available for families in which the disease-causing mutations have already been identified.\nGenetic counseling\nBoth BRIC1 and BRIC2 are inherited in an autosomal recessive manner, although a BRIC family with seemingly autosomal dominant inheritance has been reported.\nManagement and treatment\nManagement is mainly symptomatic: rifampicin and cholestyramine can be used to reduce pruritus and to induce remission of a cholestatic episode in some patients. Plasmapheresis/MARS (Molecular Adsorbents Recirculation System) has also been shown to be of benefit in some cases. For individuals that are unresponsive to medical therapy, endoscopic nasobiliary drainage is generally effective. Partial external biliary diversion is also used to improve quality of life and prevent disease progression. Liver transplantation may eventually be indicated for patients with frequent and severe episodes.\nPrognosis\nThe prognosis is generally good with a tendency for a reduction in the frequency of attacks with age. However, progression from BRIC to PFIC and cirrhosis has been reported in the literature, indicative of a clinical continuum.\n\n                            Last update: \n                            May 2013\n\n\n                            - Expert reviewer(s): \n                            Pr R.H.J. [Roderick] HOUWEN  -  W.L. [Wendy] VAN DER WOERD"}
{"Disease Name": "Benign Samaritan congenital myopathy", "Disease Definition": "Benign Samaritan congenital myopathy is a rare, genetic, skeletal muscle disease characterized by severe neonatal hypotonia with respiratory insufficiency, delay in motor milestones, and dysmorphic features including bitemporal narrowing, epicanthal folds and hypertelorism. Affected individuals show gradual improvement in hypotonia and muscle weakness within the first two years of life resulting in minimal clinical manifestations in adulthood.", "ORPHA ID": 324581, "Summary": ""}
{"Disease Name": "Benign schwannoma", "Disease Definition": "A rare benign peripheral nerve sheath tumor characterized by a usually encapsulated space-occupying lesion composed of differentiated neoplastic Schwann cells. It most commonly arises from peripheral nerves in the head and neck region and extensor aspects of the extremities, but also from spinal and cranial nerves, especially the vestibular nerve. The tumor may be asymptomatic or cause symptoms related to a mass effect. It grows slowly and only rarely undergoes malignant transformation.", "ORPHA ID": 252164, "Summary": ""}
{"Disease Name": "Benign tumor of fallopian tubes", "Disease Definition": "A group of rare uterine adnexal tumors comprising non-metastasizing neoplasms arising from the fallopian tube. This includes epithelial tumors (benign serous tumors such as serous adenofibroma and papilloma) and mature teratomas. Patients may be asymptomatic or present with tubal obstruction.", "ORPHA ID": 180237, "Summary": ""}
{"Disease Name": "BENTA disease", "Disease Definition": "A rare primary immunodeficiency characterized by infantile onset of generalized lymphadenopathy, splenomegaly, and lymphocytosis, with excessive polyclonal expansion of B-cells. Patients present recurrent infections and impaired T-cell and antibody responses, while overt autoimmune manifestations are usually absent. Occurrence of B-cell malignancy later in life has been reported.", "ORPHA ID": 464336, "Summary": ""}
{"Disease Name": "Bernard-Soulier syndrome", "Disease Definition": "A rare, inherited platelet disorder characterized by mild to severe bleeding tendency , macrothrombocytopenia and absent ristocetin-induced platelet agglutination.", "ORPHA ID": 274, "Summary": ""}
{"Disease Name": "Best vitelliform macular dystrophy", "Disease Definition": "Best vitelliform macular dystrophy (BVMD) is a genetic macular dystrophy characterized by loss of central visual acuity, metamorphopsia and a decrease in the Arden ratio secondary to an egg yolk-like lesion located in the foveal or parafoveal region.", "ORPHA ID": 1243, "Summary": "Epidemiology\nThe prevalence is estimated to be between 1/5,000 and 1/67,000 in northern Sweden and Denmark respectively. Males are more affected than females (3:1).\nClinical description\nOnset of BVMD is in childhood and sometimes in later teenage years (5-13 years). Affected individuals have normal vision at birth. BVMD then progresses through distinct stages that include an asymptomatic previtelliform phase (stage 1) followed by the formation of a yellow, egg yolk-like (vitelliform) lesion in the macula (stage 2). The contents become less homogenous and develop a \"scrambled-egg\" appearance (stage 2a). The lesion eventually develops a fluid, yellow-colored vitelline substance (pseudohypopyon or stage 3) and finally breaks down, leaving a scar that causes central visual acuity deterioration (20/200). This may be complicated by a subfoveal choroidal neovascular (CNV) membrane (rare in children). Anomalous color discrimination (mainly the protan axis) and metamorphopsia may be observed but patients retain normal peripheral vision and dark adaptation. Some affected individuals remain asymptomatic.\nEtiology\nBVMD is characterized by atrophy of the retinal pigment epithelium (RPE) affecting photoreceptors with impaired central visual function. In most cases, BVMD is caused by mutations in BEST1 (11q12), encoding for bestrophin-1, a chloride channel expressed in RPE. A defect in this protein leads to accumulation of lipofuscin secondary to abnormal ion exchange.\nDiagnostic methods\nThe clinical diagnosis is based on family history, visual-acuity testing and funduscopy (showing yellow, round deposits of lipofuscin at the center of the macula). Full-field electroretinogram (ERG) is normal. Electro-oculography (EOG) measures standing potential of the eye by recording the Arden ratio (AR; ratio of light peak/dark trough; normal value ≥1.8). AR is usually decreased in BVMD (1.0-1.3). High-resolution optical coherence tomography may identify abnormal accumulation of lipofuscin between photoreceptors and RPE. Diagnosis is confirmed by genetic screening of BEST1.\nDifferential diagnosis\nDifferential diagnosis of BVMD includes adult-onset foveomacular vitelliform dystrophy, age-related macular degeneration, autosomal recessive bestrophinopathy, autosomal dominant vitreoretinochoroidopathy, retinitis pigmentosa (see these terms) and Bull's-eye maculopathy.\nAntenatal diagnosis\nPrenatal diagnosis and preimplantation genetic diagnosis is possible for families in which the disease-causing mutation is known.\nGenetic counseling\nBVMD is inherited in an autosomal dominant manner with complete penetrance. Age of onset and severity of vision loss show inter- and intrafamilial variability.\nManagement and treatment\nManagement is symptomatic and includes use of low vision aids for individuals with significant deterioration in visual acuity. Annual ophthalmologic examination for persons of all ages is recommended. Smoking should be avoided as it increases the risk of neovascular macular degeneration. Photodynamic therapy using verteporfin, direct laser photocoagulation or anti-VEGF agents (bevacizumab) may be options for treating CNV. Transcorneal electrical retinal stimulation may be used to treat BVMD.\nPrognosis\nBVMD may progress to geographic atrophy and in some cases is complicated by development of CNV. 7-9% of patients never experience vision loss, but have an aberrant EOG with normal ERG.\n\n                            Last update: \n                            December 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Ian MACDONALD"}
{"Disease Name": "Beta-ketothiolase deficiency", "Disease Definition": "A rare, genetic organic aciduria affecting ketone body metabolism and the catabolism of isoleucine and characterized by intermittent ketoacidotic episodes associated with vomiting, dyspnea, tachypnoea, hypotonia, lethargy and coma, with an onset during infancy and usually ceasing by adolescence.", "ORPHA ID": 134, "Summary": "Epidemiology\nThe estimated birth prevalence ranges between 1/100,000 to 230,000 worldwide.\nClinical description\nChildren often appear normal at birth with disease presentation typically between the ages of 5 months to 2 years; however, presentation may occur anywhere between birth and childhood. The onset of symptoms usually occurs in the form of a ketoacidotic crisis, most often brought on by stress, fasting, acute illness and/or infections (i.e. gastroenteritis), and rarely by increased dietary protein intake. An acetone or fruity odor on the breath often signals ketoacidosis. These episodes are associated with vomiting, dyspnea, lethargy and unconsciousness, and can lead to coma and death if not treated. Neurological sequelae (such as developmental delay) following severe episodes are common. Rarely, patients present with signs of metabolic encephalopathy (hypotonia, dysarthria, chorea, developmental delay). The occurrence of developmental delay or neurological manifestations before a first ketoacidotic crisis, however, is rare. The frequency of episodes decreases with age, eventually stopping before adolescence. In between episodes, patients are often asymptomatic.\nEtiology\nThis disease is caused by mutations (over 100 described) in the gene, ACAT1 (11q22.3). This gene encodes the enzyme acetyl-CoA acetyltransferase which, when its activity is reduced or absent, impairs the breakdown of isoleucine and acetoacetyl- CoA, hampering the utilization of ketone bodies and leading to toxic accumulations of isoleucine derived acyl-CoA esters in the body.\nDiagnostic methods\nMost patients are diagnosed by demonstrating metabolic acidosis and ketosis, by urinary organic acid analysis (2-methyl-3-hydroxybutyrate (the most reliable marker), 2- methylacetoacetate and tiglylglycine), or by acylcarnitine analysis during metabolic decompensation. Diagnosis can be confirmed by cultured fibroblast enzyme assays (reduced potassium-dependent acetoacetyl-CoA thiolase activity) and molecular genetic testing. Computed tomography of the brain may reveal basal ganglia lesions that have been reported in some patients. Newborn screening programs are available in certain countries including the U.S. and Australia.\nDifferential diagnosis\nThe differential diagnosis includes sepsis, other organic acidurias, HSD10 disease and succinyl-CoA:3-ketoacid CoA transferase deficiency, and other conditions that cause ketoacidosis in childhood.\nAntenatal diagnosis\nIn families with a known disease causing mutation, prenatal testing is possible by molecular genetic testing or enzyme activity assays using cultured amniocytes.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. The risk of inheriting the disease is 25% where both parents are unaffected carriers.\nManagement and treatment\nDuring a ketoacidotic crisis, intravenous fluids with glucose and electrolytes should be administered immediately. Bicarbonate (initially as 1mmol/kg over 10 minutes followed by continuous infusion) should be given to treat acidosis. Carnitine supplementation may be helpful. Dialysis is effective but usually not necessary. Unconscious patients and those with severe dyspnea may require mechanical ventilation. Long-term management involves avoidance of fasting (and intravenous glucose in cases of fever or vomiting) and, in children, a mildly restricted protein intake (1.5-2g/kg/day), avoidance of fat-rich (ketogenic) diet, and L-carnitine therapy in those with low carnitine levels. Avoidance of isoleucine overload might prevent neurological complications, but currently there is no evidence to support this.\nPrognosis\nThe prognosis is often good if detected early and treated properly so as to prevent ketoacidotic attacks.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Toshiyuki FUKAO  - Dr Hideo SASAI"}
{"Disease Name": "Beta-mannosidosis", "Disease Definition": "Beta-mannosidosis is a very rare lysosomal storage disease characterized by developmental delay of varying severity and hearing loss, but that can manifest a wide phenotypic heterogeneity.", "ORPHA ID": 118, "Summary": ""}
{"Disease Name": "Beta-mercaptolactate cysteine disulfiduria", "Disease Definition": "An extremely rare disorder of methionine cycle and sulfur amino acid metabolism characterized by increased urine excretion of beta-mercaptolactate-cysteine disulfide (due to deficiency of mercaptopyruvate sulfurtransferase activity in erythrocytes), leading to a positive cyanide nitroprusside test. Association with intellectual disability, congenital lens dislocation, and behavioral abnormalities has been reported, however the causal link remains to be established. There have been no further descriptions in the literature since 1981.", "ORPHA ID": 1035, "Summary": ""}
{"Disease Name": "Beta-propeller protein-associated neurodegeneration", "Disease Definition": "Beta-propeller protein-associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood, is a rare form of neurodegeneration with brain iron accumulation (NBIA) characterized by early-onset developmental delay and further neurological deterioration in early adulthood.", "ORPHA ID": 329284, "Summary": ""}
{"Disease Name": "Beta-sarcoglycan-related limb-girdle muscular dystrophy R4", "Disease Definition": "A subtype of autosomal recessive limb girdle muscular dystrophy characterized by a childhood to adolescent onset of progressive pelvic- and shoulder-girdle muscle weakness, particularly affecting the pelvic girdle (adductors and flexors of hip). Usually the knees are the earliest and most affected muscles. In advanced stages, involvement of the shoulder girdle (resulting in scapular winging) and the distal muscle groups are observed. Calf hypertrophy, cardiomyopathy, respiratory impairment, tendon contractures, scoliosis, and exercise-induced myoglobinuria may be observed.", "ORPHA ID": 119, "Summary": ""}
{"Disease Name": "Beta-thalassemia associated with another hemoglobin anomaly", "Disease Definition": "Beta-thalassemias associated with hemoglobin (Hb) anomalies result in a variable clinical spectrum, ranging from asymptomatic to severe, depending on the severity of the thalassemia mutation and on the type of the Hb anomaly [hereditary persistence of fetal Hb, delta-beta-thalassemia, Hb C - beta-thalassemia, Hb E - beta-thalassemia and Hb S - beta-thalassemia (see these terms)].", "ORPHA ID": 231230, "Summary": ""}
{"Disease Name": "Beta-thalassemia intermedia", "Disease Definition": "Beta-thalassemia (BT) intermedia is a form of BT (see this term) characterized by mild to moderate anemia which does not or only occasionally requires transfusion.", "ORPHA ID": 231222, "Summary": "Epidemiology\nBT is prevalent in Mediterranean countries, the Middle East, Central Asia, India, Southern China, North Africa and South America. The overall annual incidence of symptomatic cases of beta-thalassemia is estimated at 1/100,000 worldwide and 1/10,000 in the EU. Annual incidence of BT intermedia is not known.\nClinical description\nBT intermedia encompasses a wide clinical spectrum with more severe cases presenting between 2 and 6 years of age with anemia, spleen and sometimes liver enlargement, as well as delayed growth and development. In other cases, patients are completely asymptomatic until adult life with only mild anemia. Hypertrophy of erythroid marrow, with the possibility of extramedullary erythropoiesis, is common and leads to characteristic deformities of the bone and face, osteoporosis with pathologic fractures of long bones and formation of erythropoietic masses primarily affecting the spleen, liver, lymph nodes, chest and spine. Less commonly, erythroid marrow hypertrophy may cause neurological problems (spinal cord compression with paraplegia). Patients may also develop leg ulcers and gallstones. An increased predisposition to thrombosis versus BT major has been reported, especially after splenectomy. Although patients are at risk of iron overload, hypogonadism, hypothyroidism and diabetes are not common. Cardiac involvement may also occur as a result of a high-output state and pulmonary hypertension, while systolic left ventricle function is usually preserved.\nEtiology\nBT intermedia is caused by minor and/or silent mutations in the HBB gene (11p15.5) encoding the beta-chains of hemoglobin (Hb), in the homozygous or compound heterozygous state.\nDiagnostic methods\nDiagnosis is based on clinical findings, hematological tests (Hb level between 7 and 10 g/dl, mean corpuscular volume (MCV) between 50 and 80 fl and mean corpuscular Hb (MCH)between 16 and 24 pg), hemoglobin analysis and molecular genetic testing.\nDifferential diagnosis\nDifferential diagnosis is usually simple but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as myelomonocytic leukemia and aplastic anemia; see these terms).\nGenetic counseling\nTransmission is commonly autosomal recessive and autosomal dominant forms have rarely been reported (dominant beta-thalassemia; see this term). Genetic counseling provides information for patients and at-risk couples (i.e. both carriers) regarding the mode of inheritance, transmission and clinical phenotype. However, there are not always exact genotype-phenotype correlations and prenatal diagnosis is performed in selected cases.\nManagement and treatment\nTreatment is symptomatic. Supplementary folic acid can be prescribed to prevent deficiency from hyperactive bone marrow. Treatment of extramedullary erythropoietic masses is based on radiotherapy, transfusions, or hydroxycarbamide. Main indications for splenectomy are symptoms of splenic enlargement, worsening of anemia (not explained by transient factors such as infection) sometimes associated with leukopenia and/or thrombocytopenia, delayed growth, and heart disease. Iron overload is controlled with chelation therapy. Suitable anticoagulation therapy must be administered before surgery to prevent thrombosis. Pregnant patients need a multidisciplinary approach including specialists in thalassemia care.\nPrognosis\nPrognosis is usually good with appropriate monitoring and treatment. Patients do not usually have severe hemosiderosis and are less prone to iron overload-related cardiac problems. Pulmonary hypertension, thromboembolic complications, overwhelming postsplenectomy sepsis, and the development of hepatocarcinoma may however reduce survival.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA"}
{"Disease Name": "Beta-thalassemia major", "Disease Definition": "Beta-thalassemia (BT) major is a severe early-onset form of BT (see this term) characterized by severe anemia requiring regular red blood cell transfusions.", "ORPHA ID": 231214, "Summary": "Epidemiology\nThe annual incidence of symptomatic cases is estimated at 1/100,000 worldwide and 1/10,000 in the EU. The prevalence of this form is not known.\nClinical description\nOnset is during infancy with severe anemia, failure to thrive and progressive pallor. Feeding problems, diarrhea, irritability, recurrent bouts of fever, and progressive enlargement of the abdomen caused by splenomegaly and hepatomegaly may occur. Untreated or poorly transfused patients show growth retardation, pallor, jaundice, poor musculature, genu valgum, leg ulcers, formation of masses due to extramedullary hematopoiesis, and skeletal changes including deformities in the long bones of the legs and typical craniofacial changes such as bossing of the skull, prominent malar eminence, depression of the bridge of the nose, tendency to a mongoloid slant of the eye, and maxillae hypertrophy, which tends to expose upper teeth. In regularly transfused patients, growth and development tend to be normal but complications related to iron overload may develop, including growth retardation and failure or delay of sexual maturation. Later-onset iron overload complications include dilated myocardiopathy, arrhythmias, liver fibrosis and cirrhosis, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands. Other complications are hypersplenism, venous thrombosis and osteoporosis.\nEtiology\nBT is caused by point mutations or, more rarely, deletions in the HBB gene (11p15.5), leading to reduced (beta+) or absent (beta0) synthesis of the beta-chains of hemoglobin (Hb). Mutations causing BT major are homozygous or compound heterozygous.\nDiagnostic methods\nDiagnosis is suspected in infants younger than 2 years of age with severe microcytic anemia, mild jaundice and hepatosplenomegaly. Blood analysis shows reduced Hb levels (< 7 g/dl), mean corpuscular volume (MCV) > 50 < 70 fl, and mean corpuscular Hb (MCH) > 12 < 20 pg, anisopoikilocytosis and presence of erythroblasts in the peripheral blood smear. Hb analysis and molecular genetic analysis provide diagnostic confirmation.\nDifferential diagnosis\nDifferential diagnosis is usually simple but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as juvenile myelomonocytic leukemia and aplastic anemias; see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible by amniocentesis. Both disease-causing alleles must be identified before prenatal testing can be performed.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling provides information for patients and at-risk couples (i.e. both carriers) regarding the mode of inheritance and transmission. Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified.\nManagement and treatment\nTreatment is based on lifelong transfusions to correct anemia, suppress erythropoiesis, and inhibition of gastrointestinal iron absorption, which occurs in non-transfused patients due to increased, although ineffective, erythropoiesis. Iron chelation should be started once patients have had 10-15 transfusions or when ferritin levels are above 1000 ng/ml. Management should also include treatment of iron overload-related complications (growth deficiency, delayed puberty, hypogonadism, hypopara- and hypothyroidism, diabetes, and osteoporosis). Splenectomy may be required. Bone marrow transplantation (BMT) is at present the only available definitive cure. Recently a first patient was successfully treated with gene therapy.\nPrognosis\nPatients who do not receive regular transfusions and iron chelation usually die before the 2nd or 3rd decade whereas survival is higher in regularly transfused and chelated patients. Cardiac complications are still the major cause of death.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA"}
{"Disease Name": "Beta-thalassemia with other manifestations", "Disease Definition": "Beta-thalassemias with other manifestations are a group of beta-thalassemias (see this term) associated with another disorder.", "ORPHA ID": 231386, "Summary": "Etiology\nThese forms of beta-thalassemia are not related to defects in the beta-globin gene cluster but to mutations either in the gene encoding the transcription factor TFIIH (beta-thalassemia - trichothiodystrophy) or in the X-linked transcription factor GATA-1 (beta-thalassemia - X-linked thrombocytopenia; see these terms).\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA"}
{"Disease Name": "Beta-thalassemia-X-linked thrombocytopenia syndrome", "Disease Definition": "Beta-thalassemia - X-linked thrombocytopenia is a form of beta-thalassemia (see this term) characterized by splenomegaly and petechiae, moderate thrombocytopenia, prolonged bleeding time due to platelet dysfunction, reticulocytosis and mild beta-thalassemia.", "ORPHA ID": 231393, "Summary": "Epidemiology\nPrevalence of this form is not known.\nEtiology\nThe disorder is not associated with mutations in the HBB gene (11p15.5), but with mutations in the gene encoding GATA-binding protein-1 (GATA1; Xp11.23) that result in reduced expression of the beta-globin genes.\nGenetic counseling\nTransmission is X-linked.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA"}
{"Disease Name": "Beta-thalassemia", "Disease Definition": "Beta-thalassemia (BT) is characterized by deficiency (Beta+) or absence (Beta0) of synthesis of the beta globin chains of hemoglobin (Hb).", "ORPHA ID": 848, "Summary": "Epidemiology\nExact prevalence is unknown but annual incidence at birth of symptomatic BT is estimated at 1/100,000 worldwide. The disease was initially described in the Mediterranean basin but severe forms of BT frequently occur throughout the Middle East, South East Asia, India and China. Population migrations have lead to global distribution of the disease.\nClinical description\nThree main types of BT have been described (minor, intermedia and major; see these terms). 1) Thalassemia minor (BT-minor, BT trait) is the heterozygous form and is usually asymptomatic. 2) Thalassemia major (Cooley anemia; BT-major) is the homozygous form and associates splenomegaly and microcytic and hypochromic anemia resulting from dyserythropoiesis and hemolysis. Onset generally occurs from 6-24 months of age. The severe anemia requires systematic transfusions to maintain Hb levels above the range of 90-100 g/L and to allow normal activity. Long-term transfusion of red cell concentrates results in iron overload which hampers the vital prognosis (mainly due to cardiac involvement) and causes significant morbidity (due to endocrinal and hepatic iron deposition). 3) Thalassemia intermedia (BTI) in which the anemia is less severe and diagnosed later in life compared to BT-major. Patients with BTI may or may not require occasional transfusions. Hypersplenism, cholelithiasis, extramedullary hematopoiesis, thrombotic complications and progressive iron overload are the main clinical features that may complicate the course of BTI. Other forms include BT associated with Hb anomalies (HbE - beta-thalassemia resulting in BTI or less frequently BT-major, HbC - beta-thalassemia, delta-beta-thalassemia and hereditary persistence of fetal Hb with BT resulting in inconstant manifestations of BTI; see these terms). Rare autosomal dominant forms have also been described (dominant beta-thalassemia; see this term). In rare instances, BT trait is associated with trichothiodystrophy or X-linked thrombocytopenia (see these terms).\nDiagnostic methods\nDiagnosis of BT anemia relies on analysis of Hb by electrophoresis or HPLC. In BT-major, HbA is absent or greatly reduced and HbF predominates. In BT-minor, the levels of HbA2 are increased and the levels Hb are usually normal to low with microcytosis and hypochromia.\nGenetic counseling\nTransmission is autosomal recessive and around 200 mutations (B0 or B+) have been identified. Genetic counseling is recommended to permit couples who are at risk an informed choice among available options including prenatal diagnosis.\nManagement and treatment\nThere are two major treatment options for BT. 1) A combination of regular transfusions and iron chelation therapy with early and regular parenteral deferoxamine administration has led to increased survival during the last 40 years. Availability of new oral iron chelators and monitoring of cardiac iron overload by MRI result in further clinical improvement and current evaluation is ongoing to determine their impact on morbidity and mortality. In 2006, deferasirox, a once-daily orally administered iron chelator, obtained EU marketing authorization as an Orphan drug for first-line treatment of BT-related iron overload. The marketing authorization for deferiprone, another orally active iron chelator, particularly effective in removing heart iron, is restricted to cases in which treatment with deferoxamine fails or is contraindicated. 2) Hematopoietic stem cell transplant is the curative treatment for BT major: results are very favorable for children displaying an HLA-identical familial donor. Recently, a first patient was successfully treated with gene therapy.\nPrognosis\nPrognosis depends on the severity of the condition but is generally good, particularly if appropriate treatment is provided.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Isabelle THURET"}
{"Disease Name": "Beta-ureidopropionase deficiency", "Disease Definition": "Beta-ureidopropionase deficiency is a very rare pyrimidine metabolism disorder described in fewer than 10 patients to date with an extremely wide clinical picture ranging from asymptomatic cases to neurological (epilepsy, autism) and developmental disorders (urogenital, colorectal).", "ORPHA ID": 65287, "Summary": ""}
{"Disease Name": "Bethlem muscular dystrophy", "Disease Definition": "A form of congenital muscular dystrophy characterized by a congenital to childhood onset of progressive proximal muscle weakness, joint contractures, and potential respiratory insufficiency in adulthood.", "ORPHA ID": 610, "Summary": "Epidemiology\nA Northern England study of genetic muscle disease reported an estimated prevalence of Bethlem muscular dystrophy of 1/129,870 people.\nClinical description\nPatients present with hypotonia and delayed motor milestones in early childhood; mild hypotonia and muscle weakness may be present at birth and slowly progresses during the patient's lifetime. Proximal muscle weakness and joint contractures of the elbows, Achilles tendons, and long finger flexors are evident by adulthood. More than 2/3rd of the patients aged >50 years require mobility aids outdoors. Respiratory involvement in some patients can result in respiratory insufficiency in aduldhood, necessitating nocturnal non-invasive ventilation (NIV).\nEtiology\nThe disease is caused by mutations in the genes coding for the alpha chains of the extracellular matrix protein collagen VI (COL6A1, COL6A2, and COL6A3) and can be inherited in an autosomal dominant or autosomal recessive manner.\nDiagnostic methods\nThe diagnosis of Bethlem myopathy is established in a proband with characteristic clinical, muscle imaging, and muscle immunohistochemical features and the identification of a heterozygous or biallelic pathogenic variants (PVs) in COL6A1, COL6A2 or COL6A3 by molecular genetic testing. Muscle biopsy shows degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue. Collagen VI immunolabeling of muscle ranges from absent collagen VI to mislocalized collagen VI. Muscle MRI can be an excellent diagnostic tool to identify characteristic patterns of abnormal muscle signaling.\nDifferential diagnosis\nThe differential diagnosis includes intermediate COL6-related dystrophy (COL6-RD), Ehlers-Danlos/myopathy overlap syndrome (including COL12A1-related myopathy), limb-girdle muscular dystrophies (LGMDs) including calpainopathy (also called LGMDR1 and LGMD2A) due to PVs in CAPN, Emery-Dreifuss muscular dystrophy due to PVs in EMD, FHL1, or LMNA, FHL1-related myopathy, LAMA2-related dystropy (the partial merosin deficiency subtype), and TTN-related myopathy (the «contractural» phenotype).\nAntenatal diagnosis\nOnce PVs have been identified in an affected family member, prenatal diagnosis and preimplantation genetic testing are possible.\nGenetic counseling\nBethlem muscular dystrophy is usually inherited by an autosomal dominant PV in COL6A1, COL6A2 or COL6A3; in these cases, each child of an affected individual has a 50% chance of inheriting a PV. Less commonly, Bethlem muscular dystrophy can be inherited in an autosomal recessive manner; if both parents are carriers of a disease-causing mutation, they should be informed that there is a 25% risk of having an affected child with each pregnancy. Parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in COL6-RDs and should be considered, given the implications for recurrence risk assessment.\nManagement and treatment\nCurrently, there is no curative treatment; however, careful pulmonary surveillance and proactive care improve the quality of life of affected individuals. Non-invasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) may be necessary to support nocturnal ventilation during adulthood. Use of a mechanical insufflator-exsufflator promotes airway clearance. Physical therapy and occupational therapy are important for providing recommendations for joint stretching, swimming, and aquatherapy. Achilles tendon contractures should be managed with splints and/or tendon release surgery.\nPrognosis\nProximal weakness and joint contractures develop by adulthood. The disease progression is slow with more than 2/3rd of patients aged >50 years old requiring mobility aids (crutches, canes, wheelchair) outdoors. In some patients, respiratory muscle weakness, particularly of the diaphragm, can result in respiratory insufficiency in aduldhood.\n\n                            Last update: \n                            October 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Carsten G. BONNEMANN  - Dr A. Reghan FOLEY"}
{"Disease Name": "Bickerstaff brainstem encephalitis", "Disease Definition": "A rare autoimmune encephalitis/neuropathy characterized by disturbances of consciousness, ophthalmoplegia, ataxia, and hyperreflexia. It has common clinical features with Miller Fisher syndrome.", "ORPHA ID": 79138, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nPatients usually present with onset of diplopia and gait disturbance (gait ataxia) followed by disturbances of consciousness and hyperreflexia, typically following upper respiratory or gastrointestinal tract infections. The symptoms are progressive (within 4 weeks of onset). Flaccid symmetrical tetraparesis may also be observed in 60% of the patients, together with deep or superficial sensory impairment, facial weakness, bulbar palsy, internal ophthalmoplegia, blepharoptosis and nystagmus. In the acute phase of disease, BBE may be so severe that there is coma and complete ophthalmoplegia. Brain MRI studies are usually unremarkable.\nEtiology\nBBE has been reported to occur following upper respiratory or gastrointestinal tract infections. Although the exact pathological mechanism is not fully understood, BBE is associated with the presence of the antiganglioside antibody, anti-GQ1b.\nDiagnostic methods\nDiagnosis is based on the clinical findings, patient history, cerebrospinal fluid (CSF) analysis (revealing raised protein levels), detection of serum anti-GQ1b IgG antibodies (not present in all patients). MRI studies are usually unremarkable. Electroencephalogram and electromyography are indicative of central nervous system and predominantly in the brainstem.\nDifferential diagnosis\nBBE shows clinical overlap with Miller-Fisher syndrome (MFS), a cranial nerve variant of Guillain-Barré syndrome (GBS), as well as with the axonal forms of GBS (acute motor axonal neuropathy and acute motor-sensory axonal neuropathy) in patients with limb weakness, leading several authors to suggest that BBE, MFS and GBS represent variable manifestations of the same clinical spectrum. The differential diagnosis in patients with BBE should also include acute disseminated encephalomyelitis (ADEM), as well as rare post-infectious neurological disorders.\nManagement and treatment\nManagement is based on immunotherapy with intravenous immunoglobulin (IVIg) or plasma exchange.\nPrognosis\nAlthough the clinical picture is severe, the disease course is generally monophasic with complete remission of symptoms within 6 months in over half of the patients. Other patients may have mild to severe residual findings.\n\n                            Last update: \n                            November 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Satoshi KUWABARA"}
{"Disease Name": "Biemond syndrome type 2", "Disease Definition": "Biemond syndrome type 2 (BS2) is a rare genetic neurological and developmental disorder reported in a very small number of patients with a poorly defined phenotype which includes iris coloboma, short stature, obesity, hypogonadism, postaxial polydactyly, and intellectual disability. Hydrocephalus and facial dysostosis were also reported. BS2 shares features with Bardet-Biedl syndrome. There have been no further descriptions in the literature since 1997.", "ORPHA ID": 141333, "Summary": ""}
{"Disease Name": "Bietti crystalline dystrophy", "Disease Definition": "A rare progressive autosomal recessive tapetoretinal degeneration disease, occurring in the third decade of life, characterized by small sparkling crystalline deposits in the posterior retina and corneal limbus in addition to sclerosis of the choroidal vessels and manifesting as nightblindness, decreased vision, paracentral scotoma, and, in the end stages of the disease, legal blindness.", "ORPHA ID": 41751, "Summary": ""}
{"Disease Name": "Bifid nose", "Disease Definition": "A rare congenital nose and cavum anomaly characterized by clefting of the nose ranging from a minimally noticeable groove in the columella to complete clefting of the underlying bones and cartilage (resulting in two half noses) with a usually adequate airway. Bifid nose may be seen in frontonasal dysplasia; other malformations such as hypertelorbitism and midline clefts of the lip may also be associated.", "ORPHA ID": 2695, "Summary": ""}
{"Disease Name": "Bifid uvula", "Disease Definition": "Bifid uvula is a fissure type embryopathy affecting the uvula at the back of the soft palate.", "ORPHA ID": 99771, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nThe cleft in the uvula is median. The clinical forms range from a simple posterior notch to the complete duplication of the uvula. Bifid uvula has no clinical repercussions.\nEtiology\nThis embryopathy appears in the 7th to 12th week of pregnancy following an error in the fusion of the palatine process, which usually involves a fusion that occurs from the front to back of the hard palate, the soft palate and then the uvula. Genetic, environmental and toxic factors are all possible causes.\nDiagnostic methods\nAlthough bifid uvula is usually isolated, it can also been seen in syndromic forms. Usually discovered by chance, it is important to eliminate any association with a submucous cleft velum. A submucous cleft velum is a specific form of cleft palate where a cleft in the muscular tissue is covered by the oral and nasal mucosa.\nManagement and treatment\nWhen bifid uvula is isolated, there are no clinical repercussions and it can be considered as a familial genetic trait. In the isolated forms, once an associated submucous cleft has been ruled out, there is no therapeutic management necessary in the absence of clinical manifestations.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Bifunctional enzyme deficiency", "Disease Definition": "A rare peroxisomal beta-oxidation disorder characterized by deficiency of peroxisomal D-bifunctional protein, type 1 being caused by deficiency of both dehydrogenase and hydratase activities of the enzyme, and types 2 and 3 by hydratase or dehydrogenase deficiency alone, while type 4 is due to compound heterozygous mutations affecting both units and represents a clinically milder phenotype. Types 1-3 are typically fatal in infancy. Patients present with early onset of generalized hypotonia, seizures, severe global developmental delay, craniofacial dysmorphism (large fontanel, high forehead, hypertelorism, epicanthal folds) and elevated plasma very long chain fatty acids. Variable features include hepatomegaly, polymicrogyria, and cerebral white matter abnormalities, among others.", "ORPHA ID": 300, "Summary": ""}
{"Disease Name": "Bilateral acute depigmentation of the iris", "Disease Definition": "Bilateral acute depigmentation of the iris (BADI) is characterized by acute onset of bilateral iris depigmentation, pigment dispersion in the anterior chamber, and heavy pigment deposition in the anterior chamber angle. Patients typically present with acute and usually severe photophobia, blurred vision, red eye, and ocular discomfort or pain with a usually self-limiting clinical course. Cases often occur after a flu-like illness, upper respiratory tract infection, and after the use of oral moxifloxacin. When associated with iris epithelial depigmentation, iris transillumination defects and atonic/mydriatic pupil, the condition is referred to as bilateral acute iris transillumination (BAIT) which has an increased risk of severe intractable rise in intraocular pressure.", "ORPHA ID": 69736, "Summary": ""}
{"Disease Name": "Bilateral frontoparietal polymicrogyria", "Disease Definition": "Bilateral frontoparietal polymicrogyria (BFPP) is a sub-type of polymicrogyria (PMG; see this term), a cerebral cortical malformation characterized by excessive cortical folding and abnormal cortical layering, that involves the frontoparietal region of the brain and that presents with hypotonia, developmental delay, moderate to severe intellectual disability, pyramidal signs, epileptic seizures, non progressive cerebellar ataxia, dysconjugate gaze and/or strabismus.", "ORPHA ID": 101070, "Summary": ""}
{"Disease Name": "Bilateral microtia-deafness-cleft palate syndrome", "Disease Definition": "A rare genetic, orofacial clefting syndrome characterized by the association of bilateral microtia with severe to profound hearing impairment, and cleft palate.", "ORPHA ID": 140963, "Summary": ""}
{"Disease Name": "Bilateral multicystic dysplastic kidney", "Disease Definition": "A rare lethal form of multicystic dysplastic kidney (MCDK), a congenital anomaly of the kidney and urinary tract (CAKUT), in which both kidneys are large, distended by non-communicating multiple cysts and non-functional.", "ORPHA ID": 97364, "Summary": "Epidemiology\nThe prevalence and incidence of bilateral MCDK are unknown.\nClinical description\nBilateral MCDK may be suspected antenatally at routine ultrasound scans, with the majority detected around the 20th week of gestation. It is considered a lethal entity, and most pregnancies are terminated. When born, such infants present with features of the Potter sequence (constellation of signs resulting from prolonged in utero oligohydramnios) including severe pulmonary hypoplasia and severe renal failure, limb anomalies and facial dysmorphic features, and generally die shortly after birth.\nEtiology\nMCDK results from disrupted nephrogenesis but the exact pathogenic mechanism is still unknown. Disturbed formation of nephrons could result from impaired fetal urine flow early in development. Mutations in the HNF1B gene (17q12), coding for hepatocyte nuclear transcription factor 1beta, are known to cause unilateral MCDK and have only rarely been reported for bilateral cases. MCDK is also linked to gestational diabetes and to the use of some medications during pregnancy, such as anti-epileptic drugs.\nDiagnostic methods\nDiagnosis is mainly based on prenatal ultrasound showing large hypoechogenic, non-communicating cysts within an irregularly outlined kidney with no visible renal pelvis. A tiny remnant kidney can be observed if the cysts have involuted. In addition, oligo/anhydramnios is present as a sign of poor functional renal development.\nDifferential diagnosis\nDifferential diagnoses include bilateral pelviureteric junction obstruction, in which the largely dilated calices may appear to be cysts. Posterior urethral valves may result in oligo/anhydramnios, and the megaureter may be mistaken for renal cysts.\nAntenatal diagnosis\nUltrasonographic screening can detect MCDKs from midway through gestation.\nGenetic counseling\nBoth sporadic and familial cases have been observed. In familial cases, transmission is autosomal dominant with a recurrence risk of 50%.\nManagement and treatment\nAs the absence of functional renal tissue results in anhydramnios with pulmonary hypoplasia (Potter sequence), which is generally lethal shortly after birth, most pregnancies with bilateral MCDK will be terminated. When children with bilateral MCDK survive the early postnatal period, renal replacement therapy will be needed.\nPrognosis\nBilateral MCDK is considered a lethal entity.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr M.F. [Michiel] SCHREUDER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Bilateral polymicrogyria", "Disease Definition": "Bilateral polymicrogyria is a rare cerebral malformation due to abnormal neuronal migration defined as a cerebral cortex with many excessively small convolutions. It presents with developmental delay, intellectual disability, seizures and various neurological impairments and may be isolated or comprise a clinical feature of many genetic syndromes. It may also be associated with perinatal cytomegalovirus infection.", "ORPHA ID": 268940, "Summary": ""}
{"Disease Name": "Bilateral striopallidodentate calcinosis", "Disease Definition": "Bilateral striopallidodentate calcinosis (BSPDC, also erroneously called Fahr disease) is characterized by the accumulation of calcium deposits in different brain regions, particularly the basal ganglia and dentate nucleus, and is often associated with neurodegeneration.", "ORPHA ID": 1980, "Summary": "Epidemiology\nThe prevalence of BSPDC is not known, however it is very rare and fewer than 200 cases have been reported. BSPDC is more common in men (male:female ratio 2:1).\nClinical description\nBSPCD can be asymptomatic. Symptomatic forms usually manifest in the fourth decade of life, whereas calcification may be found in the second decade. Patients present with progressive movement disorders, including parkinsonism, chorea, tremor, dystonia, athetosis and orofacial dyskinesia, ataxia and neuropsychiatric disorders including difficultly with concentration and memory, personality and/or behavior changes, and dementia. The first manifestations often include clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements or muscle cramping. Seizures occur frequently. Urinary incontinence may occur.\nEtiology\nThe causative gene or genes are not known. Linkage to chromosome 14q has been established in one family. Calcium is the major element deposited on the basal ganglia and accounts for the radiologic appearance of the disease. It is thought that the calcifications observed are a marker of the disease rather than a cause of the clinical symptoms.\nDiagnostic methods\nSingle proton emission computed tomography (SPECT) reveals markedly decreased perfusion to the basal ganglia bilaterally with decreased perfusion to the cerebral cortices. Diagnosis is based on CT or MRI evidence of bilateral, almost symmetric, calcifications of one or more of the following areas: basal ganglia, dentate nuclei, thalamus and cerebral white matter. Diagnosis is further based on normal childhood growth and development and the absence of parathyroid or other known neurologic disorders. Electroencephalogram, nerve conduction studies, and pattern shift visual-evoked potentials studies are usually normal and brainstem auditory-evoked potentials may vary from normal to minor abnormalities.\nDifferential diagnosis\nDifferential diagnoses include hypoparathyroidism and pseudohypoparathyroidism, which can usually be excluded by normal serum levels of parathyroid hormone, Kenny-Caffey syndrome type 1, neurodegeneration with iron accumulation, Cockayne syndrome and Aicardi-Goutières syndrome (see these terms).\nAntenatal diagnosis\nGenetic counseling may be offered.However, there is currently no possibility of antenatal diagnosis.\nGenetic counseling\nIt can be familial or sporadic. Over 30 families with the familial form have been reported. The familial form of idiopathic basal ganglia calcification is inherited in an autosomal dominant manner.\nManagement and treatment\nThere is no specific treatment available. Treatment based on amelioration of manifestations, including pharmacologic treatment for anxiety, depression, obsessive-compulsive behaviors and dystonia, may be attempted.\nPrognosis\nPrognosis is not fully understood due to a lack of longitudinal studies. However, while asymptomatic cases have been observed in individuals younger than 25 years old, it is possible that symptoms may appear with increasing age.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Bala MANYAM"}
{"Disease Name": "Bile acid CoA ligase deficiency and defective amidation", "Disease Definition": "Bile acid CoA ligase deficiency and defective amidation is an anomaly of bile acid synthesis (see this term) characterized by fat malabsorption, neonatal cholestasis and growth failure.", "ORPHA ID": 276066, "Summary": "Epidemiology\nPrevalence is unknown. Only 8 cases have been reported.\nClinical description\nPatients present with a history of neonatal cholestasis, fat and fat-soluble vitamin malabsorption (rickets or bleeding secondary to hypoprothrombinemia) and growth failure.\nEtiology\nSeveral mutations in the bile acid-CoA ligase gene have been found in most patients with this defect.\nGenetic counseling\nThe mode of transmission of these mutations is not known.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr James HEUBI"}
{"Disease Name": "Biliary atresia with splenic malformation syndrome", "Disease Definition": "Biliary atresia with splenic malformation syndrome (BASM) designates the association of biliary atresia (see this term) and splenic abnormalities (mainly polysplenia and less frequently asplenia, double spleen). Cardiac defect, situs inversus and a preduodenal portal vein can also be present. It represents the embryonal or syndromic form of biliary atresia. It affects newborns or infants and is characterized by jaundice, pale stools, dark urine, failure to thrive, hepatomegaly, coagulopathy, anemia and often palpable spleen.", "ORPHA ID": 244283, "Summary": ""}
{"Disease Name": "Biotin-thiamine-responsive basal ganglia disease", "Disease Definition": "A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness. Imaging may reveal bilateral lesions in the basal ganglia. The disease usually becomes symptomatic in childhood and is life-threatening if left untreated, but symptoms can be reversed and progression prevented by treatment with high doses of biotin and thiamine.", "ORPHA ID": 65284, "Summary": ""}
{"Disease Name": "Biotinidase deficiency", "Disease Definition": "A late-onset form of multiple carboxylase deficiency, an inborn error of biotin metabolism that, if untreated, is characterized by seizures, breathing difficulties, hypotonia, skin rash, alopecia, hearing loss and delayed development.", "ORPHA ID": 79241, "Summary": "Epidemiology\nPrevalence of clinical biotinidase deficiency (BD) is estimated to be 1/61,000. Carrier frequency in the general population is approximately 1/120.\nClinical description\nSymptoms of BD deficiency typically appear within the first few months of life, but later onset has also been reported. Individuals with untreated profound deficiency (less than 10 % of mean normal serum biotinidase activity) have variable clinical findings including seizures, hypotonia, eczematoid rash, alopecia, ataxia, hearing loss, fungal infections, and developmental delay. Metabolically, untreated children can exhibit ketolactic acidosis, organic acidemia (-uria) and mild hyperammonemia. Individuals with untreated partial BD (10% to 30% of mean normal biotinidase activity) may be asymptomatic, but during periods of stress, such as illness, fever or fasting, may develop symptoms similar to those of individuals with profound BD. Multiple adults with optic neuropathy and/or peripheral neuropathy, that is often mistakenly diagnosed as multiple sclerosis, have been shown to have profound biotinidase deficiency.\nEtiology\nBD deficiency is caused by mutations in the BTD gene (3p25) resulting in reduced or absent biotinidase activity. This enzyme recycles free, non-protein bound, biotin which is required for multiple biotin-dependent metabolic processes. There are more than 150 known mutations of the BTD gene that cause BD.\nDiagnostic methods\nThe disorder is detected through newborn screening when available. Other cases are diagnosed by clinical signs and symptoms and confirmed by demonstration of deficient serum biotinidase activity. Molecular mutation analysis of the BTD gene is also possible.\nDifferential diagnosis\nThe symptoms of BD overlap with those of other metabolic diseases, including holocarboxylase synthetase deficiency, isolated carboxylase deficiency, nutritional biotin deficiency, zinc deficiency and essential fatty acid deficiency. Testing for biotinidase deficiency should be considered in all individuals thought to have multiple sclerosis.\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies is possible and can be performed by enzymatic analysis or by mutation analysis when the mutation is known. However, because of the treatability of the disorder, prenatal testing is not considered by most families.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child for each pregnancy. Siblings of patients with BD should be tested for the deficiency even if they do not exhibit symptoms.\nManagement and treatment\nSupplementation with oral biotin in the free, non-protein bound, form is the primary treatment and improves symptoms in symptomatic patients, and prevents symptoms in those identified by newborn screening or before symptoms have developed. Once some features, such as optic atrophy, hearing loss, or developmental delay develop, they may not be reversible with biotin treatment. Treatment with biotin should be maintained lifelong. There are no known, serious adverse effects of biotin therapy. Patients and their families should be warned about the importance of treatment compliance. Periodic ophthalmological, neurological and metabolic evaluations are recommended. Raw eggs should be avoided because of their avidin content (biotin-binding substance), but cooking inactivates the binding effect of avidin.\nPrognosis\nThe prognosis for individuals diagnosed with BD is very good, provided they are treated before symptoms occur and are compliant with biotin therapy. In adult patients presenting with optic neuropathy and/or peripheral neuropathy, improvement in symptoms is likely with early intervention. However, if such individuals remain symptomatic for too long a period, their symptoms may be irreversible.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Barry WOLF"}
{"Disease Name": "Bipartite talus", "Disease Definition": "A rare, genetic bone disorder characterized by the presence of two non-fused talar bone fragments, with the posterior fragment located at the level of the posterior talar process. Patients may present with foot and/or ankle pain (exercise-induced or not), repetitive ankle sprains, chronic ankle ligamentous laxity, restricted ankle motion (i.e. plantar flexion, eversion, and inversion), and mild swelling.", "ORPHA ID": 364198, "Summary": ""}
{"Disease Name": "Birdshot chorioretinopathy", "Disease Definition": "Birdshot chorioretinopathy is a posterior uveitis characterized by multiple cream-colored, hypopigmented choroidal lesions in the fundus and a strong association with HLA-A29 and clinically presenting with blurred vision, floaters, photopsia, scotoma and nyctalopia.", "ORPHA ID": 179, "Summary": "Epidemiology\nThe disease is more common in North European descents with a female preponderance. It accounts for 6%-8% of cases of posterior uveitis. Prevalence in North Carolina is estimated to be 1/700,000.\nClinical description\nThe age of onset is usually the fifth or sixth decade of life. Patients often present with gradual deterioration of vision, floaters, photopsia, scotoma, nyctalopia, metamorphopsia and poor color and contrast sensitivity. Decreased visual acuity in early disease is attributed to macular edema. Persistent inflammation and optic disc edema can lead to optic atrophy and subsequent permanent visual loss. In majority of the patients, the disease is chronic and progressive while 20% of patients develop a limited disease with spontaneous remission. A systemic involvement including essential hypertension, cerebrovascular accidents, hearing loss, vitiligo (see this term) and psoriasis is rarely observed.\nEtiology\nEtiology is unknown but an organ -specific T-cell - driven autoimmune process is implicated, with both choroid and retina being independent targets and sites of inflammation. The Th17 system has also been implicated but this remains unconfirmed. A strong association with HLA-A29 is noted.\nDiagnostic methods\nThe diagnosis is based on clinical findings, supportive flourescein angiography and HLA testing (<50% positive predictive value, as 8% of general population are HLA-A29+), The visual fields may show blind spot enlargement, central/ paracentral scotomas or constriction of the peripheral vision. Fundoscopy reveals characteristic multifocal, hypopigmented, ovoid, cream-colored lesions (50-1500 µm) at the level of the choroid and retinal pigment epithelium in the postequatorial fundus displaying a nasal and radial distribution. Angiography (Indocyanine green (ICG), flourescin) reveals multiple hypofluorescent spots (birdshot lesions), vascular leakage, macular edema, disc edema, optic atrophy and neovascularization (in later stages).\nDifferential diagnosis\nThe differential diagnoses are those diseases that produce white dots in choroid and retina; they include white dot syndromes, vogt-Koyanagi-Harada disease, infectious etiologies (Lyme disease, tuberculosis, toxoplasmosis) and primary intraocular lymphoma (masquerade syndromes) (see these terms).\nGenetic counseling\nMore than 95 percent of patients with birdshot chorioretinopathy are HLA-A29 positive. However, the disease is not considered heritable.\nManagement and treatment\nElectroretinography, flourescin angiography and perimetry are important in the follow-up of patients with Birdshot retinopathy. While periocular, ocular, intravitreal and systemic corticosteroids may be effective in the short-term management of vitritis and macular edema, they are of inconsistent efficacy in the long run. Early introduction of corticosteroid-sparing immune modulatory treatment (cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, tacrolimus, human immunoglobulin G) is advocated, as extended treatment is anticipated in most patients. For refractory cases, daclizumab and infliximab has been helpful.\nPrognosis\nPreservation of central vision until late in the disease and induction of long-term remission are possible with treatment, however the long-term visual prognosis of this disorder remains guarded.\n\n                            Last update: \n                            May 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Simon TAYLOR"}
{"Disease Name": "Birt-Hogg-Dubé syndrome", "Disease Definition": "A rare inherited cancer-predisposing syndrome characterized by skin lesions, benign and malignant kidney tumors, and pulmonary cysts that may be associated with pneumothorax.", "ORPHA ID": 122, "Summary": "Epidemiology\nThe prevalence of Birt-Hogg-Dubé syndrome (BHD) is estimated at 1/200,000 but the exact incidence is unknown. More than 500 families affected by BHD have been reported so far.\nClinical description\nNumerous pleural and subpleural cysts are present in more than 80% of adult BHD patients. They can cause single or recurrent spontaneous pneumothorax, mainly between 20-40 years old. The estimated prevalence of pneumothorax is about 22-38%. The lifetime risk for malignant renal cell carcinoma is estimated to be 20%, with a mean age at diagnosis around 50 years old. The kidney tumors in BHD patients can be multifocal and bilateral and range from benign oncocytomas to malignant renal cell carcinomas including chromophobe, clear cell or papillary subtypes. Chromophobe/oncocytoma hybrid renal cell cancer tumors are characteristic for BHD. Possible associations of BHD with additional tumor types, including colon cancer, thyroid cancer, parotic gland tumors and malignant melanoma, have been reported. The typical skin lesions are fibrofolliculomas that often start to appear between 20-40 years of age and tend to increase in number. Fibrofolliculomas are typically located on the face (especially paranasal and on the forehead) and in the retroauricular regions and on the neck / upper trunk and present as multiple small (2-5 mm) whitish papules. Histopathologically, they are characterized by sharply demarcated intradermal tumors due to a proliferation of collagen and epithelial strands from the upper part of the follicle epithelium protruding into surrounding thickened, basophil, fibro-mucinous stroma. Patients also might develop trichodiscomas and acrochordons.\nEtiology\nBHD syndrome is transmitted in an autosomal dominant fashion. The causative gene, FLCN, is located on chromosome 17p11.2. The FLCN gene encodes folliculin, a protein involved in different important cell functions, including autophagy, regulation of transcription factors, amino acid sensing and lysosomal signaling.\nDiagnostic methods\nClinical diagnosis relies on recognition of typical combinations of clinical manifestations, such as multiple lung cysts, fibrofolliculomas and/or chromophobe/oncocytoma hybrid renal cell cancer tumors. The diagnosis can be confirmed by detection of pathogenic variants in the FLCN gene.\nDifferential diagnosis\nSporadic pulmonary lymphangioleiomyomatosis (LAM) also can present with multiple lung cysts.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe disorder is autosomal dominant, genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nSo far there are no consensus recommendations for clinical surveillance. Provisional recommendations: BHD patients should receive abdominal/pelvic MRI to screen for renal tumor(s) every 1-2 years, starting at 20 years of age. Pneumothoraces are treated as usual; regular screening of the lung by CT is not recommended. Fibrofolliculomas are benign lesions but can be a cosmetic concern for the patients. The definitive treatment for solitary or very prominent lesions is surgical removal. Ablative laser treatment or dermabrasion are treatment options for more extensive areas, but lesions may recur and patients must be aware that scarring can be a possible side effect. Patients with BHD should be screened and pulmonary, renal, and gastrointestinal findings should be managed. Coloscopy every three years, starting at age 40 years and annual ultrasound screening of thyroid and parotid glands should be considered.\nPrognosis\nThe prognosis for patients with BHD depends mainly on early detection and treatment of renal cell cancer. Recurrent pneumothoraxes might affect quality of life and multiple fibrofolliculomas might be perceived disfiguring by the patient.\n\n                            Last update: \n                            November 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Elke SATTLER  - Pr Ortrud STEINLEIN"}
{"Disease Name": "Björnstad syndrome", "Disease Definition": "Björnstad syndrome is characterized by congenital sensorineural hearing loss and pili torti.", "ORPHA ID": 123, "Summary": "Epidemiology\nLess than fifty cases have been reported so far.\nClinical description\nThe hearing loss usually becomes evident very early in life, often in the first year. Pili torti, a condition in which the hair shaft is flattened and twisted, makes the hair very brittle and patients develop hair loss in the first two years of life.\nEtiology\nBjörnstad syndrome is caused by mutations in the BCS1L gene. Mutations in this gene also cause GRACILE syndrome (see this term).\nGenetic counseling\nBjörnstad syndrome is transmitted as an autosomal recessive condition.\n\n                            Last update: \n                            September 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Pascal REYGAGNE"}
{"Disease Name": "Bladder exstrophy", "Disease Definition": "A congenital genitourinary malformation belonging to the spectrum of the exstrophy-epispadias complex (EEC) and is characterized by an evaginated bladder plate, epispadias and an anterior defect of the pelvis, pelvic floor and abdominal wall.", "ORPHA ID": 93930, "Summary": "Epidemiology\nThe prevalence at birth for the EEC is reported at 1/10,000. As epispadias (E), classic bladder exstrophy (CEB) and cloacal exstrophy (EC) are now recognized clinical variants of the same spectrum, accurate epidemiological data on E/EC/CEB are no longer available. However, CEB appears to be more frequent in the white population. Most studies report a male-to-female ratio of around 2.4:1, but ratios as high as 6:1 have also been reported.\nClinical description\nCEB is evident from birth, with the reddish bladder mucosa being visible in the lower abdomen and mucosal polyps sometimes present on the surface. Urine drips from the ureteric orifices on the bladder surface. Other findings include pubic diastasis of various degrees with divergent rectus muscles and inguinal hernias. In males, the penis is short and broad with dorsal chordee. The urethral plate covers the whole dorsum of the penis from the open bladder to the glandular grove. Both corpora cavernosa are located beneath the urethral plate and the colliculus seminalis and the ductus ejaculatorii are visible as tiny openings in the area where the prostate is presumably dorsally located. Females present with a bifid clitoris next to the open urethral plate. The vaginal opening appears narrow and the perineum is shortened due to the anterior displacement of the vagina and anus. Women with CEB have a predisposition for vaginal or uterine prolapse. Spinal anomalies occur in about 7% of cases but gastrointestinal anomalies are rare in CEB.\nEtiology\nCEB results from early abnormal development of the intra-abdominal wall and bladder during rupture of the cloacal membrane. Though the underlying cause remains still unknown, a developmental field defect with both genetic and environmental factors is likely to play a role.\nDiagnostic methods\nDiagnosis is clinical. However, during follow-up, laboratory and imagining studies (such as ultrasound of the urogenital system, pelvic MRI or X-ray, voiding cystography and urodynamics) are useful to determine renal function and assess bladder capacity and detrusor function.\nManagement and treatment\nManagement is primarily surgical, with the main aims of obtaining secure abdominal wall closure, achieving urinary continence with preservation of renal function, and, finally, adequate cosmetic and functional genital reconstruction. Currently, several methods for bladder reconstruction with creation of an outlet resistance and epispadias repair (either as a staged or a one-stage approach) during the newborn period are favored worldwide. Removal of the bladder template with complete urinary diversion to a rectal reservoir can be an alternative.\nPrognosis\nAfter reconstructive surgery of the bladder, continence rates of about 80% are expected during childhood. Though spontaneous voiding is the main issue, additional surgery might be needed to optimize bladder storage and emptying function. In cases of definite reconstruction failure, urinary diversion should be undertaken. In puberty, genital and reproductive function constitute increasingly important issues for both sexes. Psychosocial and psychosexual outcome reflect the importance of long-term care (from birth into adulthood) from a multidisciplinary team of experts for parents and children with EEC to facilitate an adequate quality of life.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Anne-Karoline EBERT  - Dr Michaël LUDWIG  - Pr Heiko REUTTER  - Pr Wolfgang RÖSCH"}
{"Disease Name": "Blake pouch cyst", "Disease Definition": "Blake pouch cyst is a non-syndromic, usually benign, cystic malformation of the posterior fossa characterized by a midline outpouching of the superior medullary velum into the cisterna magna that results from failure of the rudimental fourth ventricular tela choroidea to regress during embryogenesis. Patients can be asymptomatic or present in childhood or adulthood with clinical manifestations of hydrocephalus, such as headache, hypotonia, vertigo, syncope, vomiting, blurred or double vision, nystagmus, papilledema, and delayed gait development.", "ORPHA ID": 98922, "Summary": ""}
{"Disease Name": "Blastic plasmacytoid dendritic cell neoplasm", "Disease Definition": "A rare and highly aggressive myeloid malignancy characterized by predominant cutaneous involvement with concomitant or subsequent bone marrow, lymph node and visceral involvement, as well as central nervous system (CNS) disease. It derives from the precursors of plasmacytoid dendritic cells (pDC).", "ORPHA ID": 86870, "Summary": "Epidemiology\nUS incidence ranges from 500 to 1000 cases per year; global point prevalence is estimated at 12/100,000. Incidence is higher in patients aged ≥ 60 years and in males; ~10% of cases occur in children.\nClinical description\nBPDCN affects patients of all ages but is most common in the elderly. Median age at onset is 60-70 years. It is characterized by skin and bone marrow involvement, but may involve lymph nodes, peripheral blood, liver, spleen and the CNS. The most common clinical presentation is asymptomatic solitary or multiple skin lesions (either isolated purplish nodules, isolated bruise-like papules, or disseminated purplish nodules/macules/papules). Some patients may present with leukemia.\nEtiology\nBPDCN derives from the precursors of pDC. There is no single cytogenetic or molecular change characteristic of BPDCN.\nDiagnostic methods\nDiagnosis requires biopsy of the affected area(s) with morphologic assessment and immunophenotyping. Skin biopsy shows a diffuse, monomorphous infiltrate of medium-sized blast cells resembling lymphoblasts or myeloblasts with massive dermis. Immunohistochemical diagnostic criteria are expression of CD123 (in all cases), CD4 and/or CD56, or one other pDC marker; or expression of any three pDC markers (CD123, TCF4, TCL1, CD303, CD304, CD4, CD56) and no expression of CD3, CD14, CD19, CD34, lysozyme, and myeloperoxidase.\nDifferential diagnosis\nThe differential diagnosis includes acute myeloid leukemia (AML), chronic myelomonocytic leukemia, nasal-type extranodal NK/T cell lymphoma, subcutaneous panniculitis-like T cell lymphoma, and cutaneous T cell lymphoma.\nManagement and treatment\nTagraxofusp, a CD123-directed therapy, is the only drug approved for patients aged ≥2 years with newly diagnosed and relapsed/refractory BPDCN in the USA, or for adults with newly diagnosed BPDCN in Europe. Tagraxofusp, typical chemotherapy regimens for acute myeloid leukemia and acute lymphocytic leukemia, or lymphoma induction chemotherapies, are recommended as first-line treatment by the NCCN AML guideline. However, the chemotherapy regimens are associated with more toxicities, as well as lower survival rates and are not FDA/EMA-approved. Intrathecal chemotherapy should be considered for patients with documented CNS disease at diagnosis. Management strategies should vary according to patients' age and fitness. Off protocol approaches and participation in clinical trials can be considered in young/fit patients. Hematopoietic stem cell transplantation (HSCT) offers the best chance of long-term disease-free survival and should be considered in first remission for all eligible patients.\nPrognosis\nHistorically, prognosis is poor. Median overall survival (OS) ranges from 8 to 12 months following chemotherapy and is 15.7 months following tagraxofusp. Median OS is longer in patients who were bridged to HSCT.\n\n                            Last update: \n                            March 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Naveen PEMMARAJU"}
{"Disease Name": "Blau syndrome", "Disease Definition": "Blau syndrome (BS) is a rare systemic inflammatory disease characterized by early onset granulomatous arthritis, uveitis and skin rash. BS now refers to both the familial and sporadic (formerly early-onset sarcoidosis) form of the same disease. The proposed term pediatric granulomatous arthritis is currently questioned since it fails to represent the systemic nature of the disease.", "ORPHA ID": 90340, "Summary": "Epidemiology\nExact prevalence is unknown. From a Danish registry, the annual incidence was estimated to be 1/1,670,000/ year for children <5 years of age.\nClinical description\nSkin rash (of tiny red/tan dots) is usually the first manifestation and appears as early as the age of 1 month on the face and then spreads to the trunk. Patients can have intermittent episodes of skin lesions that resolve without treatment. Joint manifestations usually begin before the age of 10 with painless cyst-like swellings on the back of feet and wrists. Symmetric arthritis (with boggy inflammatory synovitis and tenosynovitis) of the wrists, ankles, knees and sometimes elbows follows. Camptodactyly due to hypertrophic tenosynovitis is often described as the disease progresses. Severe handicap is not usually experienced until the age of 40-50. An insidious granulomatous iridocyclitis and posterior uveitis (see this term) can evolve into a severe destructive panuveitis. Over time, characteristic iris nodules, focal synechiae, cataract, increased intraocular pressure and characteristic clumpy keratic precipitates at the limbus ensue. Posterior involvement includes vitritis, multifocal choroiditis, retinal vasculopathy and optic nerve edema. Significant visual loss is observed in 20-30% of the affected individuals. The spectrum of clinical manifestations includes fever, malignant systemic and pulmonary hypertension, granulomatous large-vessel vasculitis and granulomatous inflammation of the liver, kidneys and lung.\nEtiology\nBS is due to an inherited or de novo mutation in the NOD2 gene (16q12), responsible for alterations in the innate immune response, inflammation and cell death. From transfection studies, it has been proposed that NOD2 mutations cause activation of nuclear factor kappa B which is in turn an up-regulator of pro-inflammatory cytokine transcription.\nDiagnostic methods\nDiagnosis relies greatly on the demonstration of noncaseating granulomatous inflammation with epithelioid cells and multinucleated giant cells on a skin, synovial or conjunctival biopsy, and genetic testing for mutations in the NOD2 gene.\nDifferential diagnosis\nDifferential diagnoses include polyarthritis and systemic juvenile idiopathic arthritis (JIA; see this term), granulomatous inflammation associated with primary immunodeficiencies, and systemic granulomatous vasculitis. In patients with granulomatous inflammation, chronic infections especially with mycobacteria and fungi must be excluded.\nAntenatal diagnosis\nAntenatal diagnosis and prenatal genetic testing is rarely performed.\nGenetic counseling\nBS is an autosomal dominant disorder in the familial form and genetic counseling is advised.\nManagement and treatment\nThere is no evidence-based data on the optimal treatment of BS. Moderate to low-dose daily corticosteroid therapy is effective in controlling uveitis and joint disease but the side effects of prolonged use may become unacceptable. Methotrexate at a dosage of 10-15 mg/m2 once weekly is effective in suppressing disease activity and allowing corticosteroid tapering. The introduction of anti-TNF monoclonal antibody agents (infliximab and adalimumab) may constitute a major therapeutic advance in the treatment of BS; however, the effect on uveitis activity may be less convincing.\nPrognosis\nBS is a chronic and progressive disease with a variable and often unpredictable spectrum of severity. In cases with expanded manifestations, life expectancy may be reduced. Uveitis has a poor prognosis.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Carlos ROSE  - Pr Carine WOUTERS"}
{"Disease Name": "Bleeding diathesis due to a collagen receptor defect", "Disease Definition": "A rare, genetic coagulation disorder characterized by a mild to moderate bleeding tendency due to impaired platelet activation and aggregation in response to collagen, or impaired platelet-vessel wall interaction, resulting from a collagen receptor defect. Patients manifest with ecchymoses, epistaxis, menorrhagia, and/or post-traumatic and post-surgery bleeding complications. Laboratory analysis reveals prolonged bleeding time and, occasionally, mild thrombocytopenia.", "ORPHA ID": 73271, "Summary": ""}
{"Disease Name": "Bleeding diathesis due to thromboxane synthesis deficiency", "Disease Definition": "A rare, genetic, isolated constitutional thrombocytopenia disease characterized by impaired platelet aggregation resulting from a defect in thromboxane synthesis or signaling, manifesting with mild to moderate mucocutaneous, gastrointestinal or surgical bleeding (e.g. easy bruising, prolonged epistaxis, excessive bleeding after a tooth extraction).", "ORPHA ID": 220443, "Summary": ""}
{"Disease Name": "Bleeding disorder due to CalDAG-GEFI deficiency", "Disease Definition": "Bleeding disorder due to CalDAG-GEFI deficiency is a rare hematologic disease due to defective platelet function and characterized by mucocutaneous bleeding starting in infancy (around 18 months of age), presenting with prolonged and severe epistaxis, hematomas and bleeding after tooth extraction. Massive menorrhagia and chronic anemia have also been reported.", "ORPHA ID": 420566, "Summary": ""}
{"Disease Name": "Bleeding disorder due to P2Y12 defect", "Disease Definition": "P2Y12 defect is a rare hemorrhagic disorder characterized by mild to moderate bleeding diathesis with easy bruising, mucosal bleedings, and excessive post-operative hemorrhage due to defect of the platelet P2Y12 receptor resulting in selective impairment of platelet responses to adenosine diphosphate.", "ORPHA ID": 36355, "Summary": "Epidemiology\nTo date, 14 patients have been described in the world literature.\nClinical description\nP2Y12 defect is a congenital disorder that manifests by mildly to severely prolonged bleeding time, easy bruising, mucosal bleeding (epistaxis, gastric mucosa bleeding, gum bleeding, etc.), menorrhagia, and bleeding complications after trauma and minor or major surgery.\nEtiology\nP2Y12 defect is caused by mutations in the  P2RY12 gene (3q24-q25) which result in the premature truncation of the P2Y12 receptor or in the synthesis of a dysfunctional P2Y12 receptor. ADP activates platelets through its interaction with two G protein-coupled receptors, P2Y1 and P2Y12. The P2Y1 receptor mediates mobilization of ionized calcium and is responsible for ADP-induced shape change andweak and transient aggregation, while the P2Y12 receptor is responsible for the completion and amplification of the response to ADP and to all platelet agonists including thromboxane A2, thrombin, and collagen. P2Y12 receptor thus plays a central role in the formation and stabilization of a thrombus.\nGenetic counseling\nTransmission of P2Y12 deficiency is autosomal recessive. Genetic counseling should be offered to at-risk couples (where both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Marco CATTANEO"}
{"Disease Name": "Bleeding disorder in hemophilia A carriers", "Disease Definition": "A rare bleeding disorder in association with carrier mutations in the F8 gene (Xq28) encoding coagulation factor VIII (FVIII), with a biological activity of FVIII ≥40 IU/dL and characterized clinically by abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction. Spontaneous hemorrhages may occur occasionally. Heavy menstrual bleeding is the most frequent type of bleed in the carriers.", "ORPHA ID": 177926, "Summary": ""}
{"Disease Name": "Bleeding disorder in hemophilia B carriers", "Disease Definition": "A rare bleeding disorder in association with carrier mutations in the F9 gene (Xq27.1) encoding coagulation factor IX (FIX), with a biological activity of FIX ≥40 IU/dL and characterized clinically by abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction. Spontaneous hemorrhages may occur occasionally. Heavy menstrual bleeding is the most frequent type of bleed in the carriers.", "ORPHA ID": 177929, "Summary": ""}
{"Disease Name": "Blepharo-cheilo-odontic syndrome", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by the association of lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and conical teeth.", "ORPHA ID": 1997, "Summary": "Epidemiology\nOver 50 cases have been described in literature to date.\nClinical description\nBlepharocheilodontic syndrome (BCD) syndrome is characterized by eyelid malformations, cleft lip with or without cleft palate (CLP), and dental anomalies. CLP is usually bilateral and eyelid malformations are typical (ectropion of the lower eyelids, euryblepharon, and lagophthalmia). Patients harbor variable expression of ectodermal dysplasia, with constant dental anomalies corresponding to conical teeth and tooth agenesis. Additional variable features have been reported, including congenital hypothyroidism due to thyroid gland hypoplasia or aplasia, imperforate anus, neural tube defect, and syndactyly. Patients have normal intellectual development. Significant interindividual and intrafamilial variability have been reported, as well as incomplete penetrance. Diffuse gastric cancer and lobular breast cancer have been reported in two families so far. To date, the risk of cancer in BCD syndrome is not precisely known, since cancers were not reported in the other reported families.\nEtiology\nBCD syndrome is due to either heterozygous CDH1 or CTNND1 variants. CDH1 encodes the E-cadherin, a transmembrane glycoprotein. CTNND1 encodes the Delta-Catenin, a protein linked to the cytoplasmic domain of E-cadherin. Both proteins are involved in a cell-cell adhesion complex, critical for establishing and maintaining polarized and differentiated epithelia during development. Recurrent missense CDH1 variants have been identified in BCD syndrome, probably impairing ion calcium binding. Variations in CTNND1 correspond predominantly to truncating variants, but missense variants have also been reported. BCD-related to CDH1 and CTNND1 variants are clinically indistinguishable, although the latter usually shows a milder phenotype. CDH1 variants also cause hereditary diffuse gastric cancer (HDGC), and diffuse gastric cancer and lobular breast cancer have been reported in two BCD families with CDH1 variants. Since cancers have not been reported in other reported families to date, the risk of cancer development is not precisely known. No HDGC-related cancer has been reported in patients with CTNND1 variants.\nDiagnostic methods\nThe syndrome is suspected on the association of CLP, typical eyelid malformations and ectodermal dysplasia features. Molecular genetic testing approaches include targeted sequencing of the entire CDH1 and CTNND1 coding regions.\nDifferential diagnosis\nBSD presents with a unique constellation of features and there are no relevant differential diagnoses.\nAntenatal diagnosis\nPrenatal testing is possible if the pathogenic variant has been identified in an affected family member. However if the pathogenic variant is identified in the fetus, the severity of the condition is not predictable.\nGenetic counseling\nBCD syndrome is usually sporadic, but large families have been described. The disorder is autosomal dominant and patients harboring BCD syndrome features and carrying a CDH1 variant or a CTNND1 variant have 50% risk to transmit the pathogenic variant to their offspring. Due to intrafamilial variability and incomplete penetrance, prediction of the severity is difficult.\nManagement and treatment\nManagement of BCD syndrome is supportive and symptomatic. CLP management is surgical, dental, and orthodontic. Early orthodontic follow-up should be proposed. Blepharoplasty is required for ankyloblepharon and for severe eyelid anomalies. Lagophthalmos can lead to corneal abrasion. Ophthalmologic evaluation is recommended to assess eye movement and possible tearing reduction. Congenital hypothyroidism is usually diagnosed through neonatal screening and treated with thyroid replacement therapy. Assessment of risk of cancer is challenging. Currently, there are no clear guidelines for surveillance or prophylactic total gastrectomy.\nPrognosis\nThe prognosis and functional consequences are variable and dependent on the associated anomalies. In families carrying a CDH1 variant and with a positive familial history of CDH1-related cancers, or fitting criteria for hereditary diffuse gastric cancer (HDGC), prognosis can be worsened by the occurrence of cancer.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Jamal GHOUMID | ITHACA* - Pr Florence PETIT | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Blepharonasofacial malformation syndrome", "Disease Definition": "Blepharonasofacial syndrome is a rare otorhinolaryngological malformation syndrome characterized by a distinctive mask-like facial dysmorphism, lacrimal duct obstruction, extrapyramidal features, digital malformations and intellectual disability.", "ORPHA ID": 1252, "Summary": "Epidemiology\nBlepharonasofacial syndrome has been reported in 3 families to date.\nClinical description\nThe facies has a mask-like appearance due to weakness of facial muscles, and lacrimal duct obstruction is characteristic. Clinical features also include telecanthus (with temporal displacement of lacrimal puncta), bulky nose, broad nasal bridge, sometimes a hypoplastic midface, longitudinal cheek furrows, trapezoidal upper lip and malformation of the ears. Intellectual disability, cutaneous syndactyly, torsion dystonia, increased deep tendon reflexes, Babinski sign, poor coordination, and joint laxity are also observed.\nEtiology\nInheritance is thought to be either autosomal or X-linked dominant.\n\n                            Last update: \n                            January 2014"}
{"Disease Name": "Blepharophimosis-intellectual disability syndrome, MKB type", "Disease Definition": "A rare, X-linked, syndromic, intellectual disability disorder affecting only boys and characterized by global development delay with little or no speech, urogenital abnormalities, including scrotal hypoplasia, micro penis, and cryptorchidism, autistic behavior, and facial dysmorphism. Most typical facial features are ptosis, blepharophimosis, a bulbous nasal tip, a long philtrum, and maxillar hypoplasia with full cheeks. Other variable features include microcephaly, hearing loss, dental anomalies, and hyperextensible joints.", "ORPHA ID": 293707, "Summary": ""}
{"Disease Name": "Blepharophimosis-intellectual disability syndrome, Ohdo type", "Disease Definition": "A multiple congenital malformation syndrome characterized by blepharophimosis, ptosis, dental hypoplasia, hearing impairment and intellectual disability.", "ORPHA ID": 2728, "Summary": "Epidemiology\nSo far, less than 30 patients have been reported worldwide.\nClinical description\nAbnormal ears, microcephaly, and growth retardation have been reported occasionally. Male patients may show cryptorchidism and scrotal hypoplasia.\nGenetic counseling\nMost reported cases are sporadic, except the original cases of Ohdo who described two affected sisters and a first cousin, favoring autosomal recessive inheritance. Autosomal dominant, X-linked- and mitochondrial inheritance have also been suggested.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "Blepharophimosis-intellectual disability syndrome, SBBYS type", "Disease Definition": "A rare, genetic, multiple congenital anomalies syndrome characterized by the association of a typical facial phenotype with microcephaly associated with congenital hypothyroidism, skeletal involvement (polydactyly, long thumb(s) and long first toe(s), and patellar hypoplasia/agenesis), and some degree of global developmental delay, hypotonia and intellectual disability. Facial features include an immobile mask-like face, severe blepharophimosis and ptosis, tear duct abnormalities, a broad nasal bridge, bulbous nasal tip, small mouth, thin upper lip, hypoplastic teeth and small, low set ears. Renal and genital anomalies, usually cryptorchidism, are often present in affected males. Congenital heart defects and growth delay are variably present.", "ORPHA ID": 3047, "Summary": "Epidemiology\nAlthough the prevalence of the disorder is unknown, it is thought to be less than 1/1,000,000. To date, 122 individuals with molecularly diagnosed blepharophimosis-intellectual disability syndrome, SBBYS type (SBBYS), have been reported.\nClinical description\nClinical diagnosis is typically based on the striking facial gestalt associated with microcephaly. Skeletal anomalies include long thumbs and great toes, patellar hypoplasia/agenesis, polydactyly (both pre and postaxial), camptodactyly, clinodactyly, brachydactyly, syndactyly, club feet , flexion contractures of the knees and/or hips, and anomalies of the spine, and/or ribs. Individuals generally have developmental delay/intellectual disability, which can be mild. Language disorder, autism spectrum features, anxiety, aggressiveness, attention problems, agenesis or hypoplasia of the corpus callosum, optic nerve hypoplasia and other brain abnormalities have also been reported. Congenital heart malformations (50% of cases), ocular anomalies and bilateral mixed hearing loss are also often present. Renal anomalies (e.g. hydronephrosis or multiple renal cysts), anal and genital anomalies including cryptorchidism, hypospadias, clitoromegaly and/or hypoplasia of the labia minora or majora, are reported in more than 40% of cases. In a minority of cases, thyroid agenesis/hypoplasia, hypothyroidism, intestinal malrotation, dental anomalies, feeding and respiratory difficulties, gastroesophageal reflux, poor growth, short stature, cleft palate, and Pierre Robin sequence are observed. SBBYS is allelic with genitopatellar syndrome and an intermediate phenotype has been described; thus, the disorder may present as part of a spectrum.\nEtiology\nThe syndrome is caused by heterozygous variants in KAT6B (10q22) encoding a highly conserved acetyltransferase that is part of the MYST family, and regulates the expression of multiple genes.\nDiagnostic methods\nDiagnosis is based on clinical examination, brain imaging and molecular studies (specific gene testing if the specific clinical suspicion has been raised, otherwise broader genomic tests).\nDifferential diagnosis\nDifferential diagnosis include other genetic syndromes that associates intellectual disability with one or more of the key features of this disorder.\nAntenatal diagnosis\nPolyhydramnios, increased nuchal translucency and/or cystic hygroma, renal anomalies can be observed during pregnancy but are non-specific. Genetic diagnosis can be proposed to families in which the pathogenic variant has already been identified in an affected relative.\nGenetic counseling\nTransmission is autosomal dominant. Most of the cases described are de novo, so the empirical risk of recurrence is low, 1-2%. Three families have been described in which the pathogenic variant has been inherited from a parent with a mild phenotype. The recurrence risk in these cases is 50%. To date, no cases of germinal mosaicism have been reported but this cannot be excluded.\nManagement and treatment\nManagement requires a lifelong multidisciplinary approach with specific regular follow-up based on the patient's clinical manifestations (pediatric, neuropsychiatric, cardiological, ophthalmological, audiometric, orpthopedic, and genetic examinations). Occupational, physical, speech (in particular non-verbal methods of communication), feeding and educational therapies must be tailored to the patient's needs. Bowel malrotation is a potentially dangerous medical complication. Particular attention should be paid to monitoring feeding and growth, as feeding problems tend to occur early.\nPrognosis\nWhilst there is limited data regarding life expectancy, adult patients are reported and there are no known reasons to suspect reduced life expectancy. Autonomy depends on the degree of involvement and the severity of the psychomotor developmental delay.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Livia GARAVELLI | ITHACA* - Dr Gabriele TRIMARCHI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Blepharophimosis-intellectual disability syndrome, Verloes type", "Disease Definition": "A rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital microcephaly, severe epilepsy with hypsarrhythmia, adducted thumbs, abnormal genitalia, and normal thyroid function. Hypotonia, moderate to severe psychomotor delay, and characteristic facial dysmorphism (including round face with prominent cheeks, blepharophimosis, large, bulbous nose with wide alae nasi, posteriorly rotated ears with dysplastic conchae, narrow mouth, cleft palate, and mild micrognathia) are additional characteristic features.", "ORPHA ID": 293725, "Summary": ""}
{"Disease Name": "Blepharophimosis-intellectual disability syndrome/genitopatellar overlap syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by the presence of major features of both blepharophimosis-intellectual disability syndrome and genitopatellar syndrome. These major features may include blepharophimosis, ptosis, hypomimia, skeletal features like patellar a/hypoplasia and renal and/or genital malformations.", "ORPHA ID": 597746, "Summary": ""}
{"Disease Name": "Blepharophimosis-ptosis-epicanthus inversus syndrome plus", "Disease Definition": "A rare disorder of the ocular adnexa characterized by an extended phenotype of blepharophimosis, ptosis, epicanthus inversus and telechantus syndrome (BPES). When BPES is caused by a microdeletion encompassing other genes in addition to the causative gene FOXL2, the patient has additional features including intellectual disability, external genital anomaly, spastic diplegia, and speech delay. Acquired microcephaly can also be observed.", "ORPHA ID": 572333, "Summary": ""}
{"Disease Name": "Blepharophimosis-ptosis-epicanthus inversus syndrome", "Disease Definition": "A rare ophthalmic disorder characterized by blepharophimosis, ptosis, epicanthus inversus, and telecanthus, that can appear associated with (type 1) or without primary ovarian insufficiency (POI; type 2).", "ORPHA ID": 126, "Summary": "Epidemiology\nThe worldwide prevalence is unknown.\nClinical description\nA congenital disorder characterized by a complex bilateral eyelid malformation including blepharophimosis, ptosis, epicanthus inversus and telecanthus. Other ophthalmic manifestations that are usually associated include lacrimal duct anomalies, amblyopia, strabismus, refractive errors and a lateral displacement of the inferior lacrimal puncta. Additional features include a broad nasal bridge, low-set ears, and a short philtrum. Affected females may develop POI, and are thus considered to have BPES type 1. Females without POI are classed as BPES type 2.\nEtiology\nThe disorder is caused by an intragenic mutation (80%), gene deletion (10-12%), deletions of regulatory elements outside of the FOXL2 gene (3q23)(<5%), and translocations involving the FOXL2 region. FOXL2 encodes a forkhead transcription factor that contains a typical DNA-binding forkhead domain and a polyalanine tract of 14 residues strictly conserved in mammals. FOXL2 is expressed in peri-ocular tissues as well as in the fetal and adult ovaries.\nDiagnostic methods\nDiagnosis is based on presence at birth of the 4 major eyelids features with or without POI (amenorrhea for greater than 6 months, less than age 40 years and follicle stimulating hormone concentration greater than 40 IU/L). The clinical diagnosis is confirmed by the identification of a genetic defect in the FOXL2 gene or its regulatory region.\nDifferential diagnosis\nThe differential diagnoses includes those conditions in which ptosis or blepharophimosis are major features. However, this disorder can be relatively easily distinguished from most of these conditions as its facial appearance is very typical.\nAntenatal diagnosis\nGenetic prenatal testing may be possible where the pathogenic variant has been previously identified in an affected family member.\nGenetic counseling\nWhilst the disorder can occur sporadically (de novo), the pattern of inheritance is typically autosomal dominant and genetic counseling for affected families should be offered. Penetrance for the eyelid phenotype is complete and presence of POI varies between families. Germline mosaicism has been described as well as a recessive mutation (one family) involving a polyalanine expansion of intermediate length.\nManagement and treatment\nThe surgical management is traditionally performed in two stages and involves a medial canthoplasty for correction of the blepharophimosis, epicanthus inversus, and telecanthus at ages 3 to 5 years, followed about a year later by ptosis correction. However, when ptosis is severe, surgical repair is recommended before age 3 years. Ophthalmologic follow-up is important for management of the oculoplastic surgery. All female patients should be assessed and followed up for POI. Management of POI is multidisciplinary ( requiring a geneticist, endocrinologist, gynaecologist) should include counseling of the patient and relatives. Egg donation may be considered as a reproductive option. In the case of a detectable ovarian reserve, therapeutic counseling can lead to fertility preservation.\nPrognosis\nPrognosis is good and patients have a normal lifespan.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Elfride DE BAERE  - Dr Hannah VERDIN"}
{"Disease Name": "Blepharophimosis-ptosis-esotropia-syndactyly-short stature syndrome", "Disease Definition": "A rare syndrome characterised by the association of blepharophimosis and ptosis, V-esotropia, and weakness of extraocular and frontal muscles with syndactyly of the toes, short stature, prognathism, and hypertrophy and fusion of the eyebrows.", "ORPHA ID": 2057, "Summary": ""}
{"Disease Name": "Blepharoptosis-myopia-ectopia lentis syndrome", "Disease Definition": "A rare, genetic, lens position anomaly disease characterized by bilateral congenital blepharoptosis, ectopia lentis and high grade myopia. Additional reported manifestations include abnormally long eye globes and signs of levator aponeurosis disinsertion. There have been no further descriptions in the literature since 1982.", "ORPHA ID": 1259, "Summary": ""}
{"Disease Name": "Blepharospasm-oromandibular dystonia syndrome", "Disease Definition": "A focal dystonia involving symmetrical benign essential blepharospasm (BEB) and oromandibular dystonia.", "ORPHA ID": 93964, "Summary": ""}
{"Disease Name": "Blindness-scoliosis-arachnodactyly syndrome", "Disease Definition": "This syndrome associates progressive visual loss with scoliosis or kyphoscoliosis and arachnodactyly of the fingers and toes.", "ORPHA ID": 171844, "Summary": "Epidemiology\nThe syndrome has been described in four patients (three males and one female) from the same family.\nClinical description\nThe male patients presented with the complete phenotype while the female patient suffered only from blindness.\nEtiology\nNo mutations were found in the FBN1, TGFBR1 and TGFBR2 genes which are associated with other syndromes presenting similar clinical findings (i.e. Marfan syndrome; see this term).\nGenetic counseling\nTransmission seems autosomal dominant.\n\n                            Last update: \n                            October 2009"}
{"Disease Name": "Blomstrand lethal chondrodysplasia", "Disease Definition": "Blomstrand lethal chondrodysplasia (BLC) is a neonatal osteosclerotic dysplasia characterized by advanced endochondral bone maturation, very short limbs, dwarfism and prenatal lethality.", "ORPHA ID": 50945, "Summary": "Epidemiology\nTo date, less than 10 cases have been described in the literature.\nClinical description\nBLC is a congenital disorder characterized by a low birth weight, facial dysmorphism (widely spaced and protruding eyes (which typically show cataract), depressed nasal bridge, short columella, long philtrum, macroglossia, protruding tongue, severe micrognathia), short trunk, narrow thorax and severe rhizo-meso-acromelic shortness of the limbs. Other anomalies also observed include tooth and mammary gland development defects, hypoplastic lungs, aorta coarctation, and bowel malrotation. Two forms of BCL, have been described: type I which is the severe, classical form and type II which has less severe features (such as absence of short trunk or, severely shortened arms but moderately shortened legs).\nEtiology\nBLC is caused by inactivating homozygous or compound heterozygous mutations in PTH1R (3p22-p21.1) which encodes the parathyroid hormone (PTH)/parathyroid-hormone-related peptide (PTHrP) receptor (PTH1R). These mutations result in the decrease in binding or response to PTH and PTHrP.\nDiagnostic methods\nDiagnosis is based on the clinical and radiological characteristics which show generalized increase in bone density with advanced ossification, severe shortness of the long bones with wide metaphyses and club-shaped distal ends, long narrow thorax, calcified hyoid bone and laryngeal cartilage and underdeveloped viscerocranium. Histopathological examination shows an important acceleration of the endochondral ossification in tubular bones, narrow cartilages of the epiphyses and large epiphyseal ossification centers. Diagnosis is confirmed by the genetic screening of PTH1R.\nDifferential diagnosis\nDifferential diagnosis includes primary failure of tooth eruption (see this term) and other lethal short limbed dwarfisms.\nAntenatal diagnosis\nPrenatal diagnosis is achieved by sonographic examination showing polyhydramnios, hydrops fetalis and a fetus with very short limbs, nuchal edema, macroglossia, a protuberant abdomen, internal anomalies and markedly advanced endochondral bone formation.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\nPrognosis\nBoth forms of BLC are lethal either prenatally or shortly after birth.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Harald JÜPPNER  - Dr Caroline SILVE"}
{"Disease Name": "Bloom syndrome", "Disease Definition": "Bloom syndrome is a rare disorder associated with pre- and postnatal growth deficiency, a telangiectatic erythematous rash of the face and other sun-exposed areas, insulin resistance and predisposition to early onset and recurrent cancer of multiple organ systems.", "ORPHA ID": 125, "Summary": "Epidemiology\nBloom syndrome (BSyn) overall prevalence is unknown, but in the Ashkenazi Jewish population it is estimated at approximately 1/ 48,000 births. A founder mutation, known as BLMash is present in approximately 1 in 100 persons of Ashkenazi Jewish background. There are also founder mutations in the Slavic and Hispanic populations.\nClinical description\nIndividuals with BSyn show proportionate growth deficiency of prenatal onset (average birth weight 1757 g) and continuing throughout life (average adult height of 149 cm for men and 138 cm for women). Dolichocephaly, narrow face, prominent nose and ears, and malar and mandibular hypoplasia can be observed. Subcutaneous adipose tissue is sparse. Telangiectatic erythema appears during the first 1-2 years of life on the face (in particular the cheek), dorsum of the hands and other sun-exposed areas. Café-au-lait macules and hypopigmented skin lesions are common. Children with BSyn characteristically feed slowly, have a decreased appetite and eat a limited variety of foods. Despite nutritional interventions, weight gain is modest and children are rarely in the normal range for growth. One major feature of Bsyn is a greatly increased predisposition to cancers in a distribution corresponding to the general population but occurring at a much younger age. Survivors of a first cancer may have multiple cancers in their lifetime. Most men with BSyn have azoospermia or severe oligospermia, while women are often fertile but may begin menopause prematurely.\nEtiology\nBloom syndrome is inherited as an autosomal recessive trait. The BLM gene codes for a RecQ helicase that forms a complex with two other proteins, DNA topoisomerase IIIα and RMI.BLM heterozygotes are healthy and without any clinical features of the disorder.\nDiagnostic methods\nThe diagnosis of BSyn is suspected clinically by identification of characteristic features and is confirmed by identification of biallelic pathogenic variants of the BLM gene on molecular genetic testing.\nDifferential diagnosis\nThe differential diagnosis of Bloom syndrome includes Fanconi anemia, Silver-Russell syndrome, Rothmund-Thomson syndrome, ataxia-telangiectasia, and Nijmegen breakage syndrome. Three other disorders also may be of interest in a differential diagnosis. RECQ-mediated genome instability 1, RECQ-mediated genome instability 2, Microcephaly, growth restriction, & increased sister-chromatid exchange 2.\nAntenatal diagnosis\nPrenatal diagnosis of at-risk pregnancies is possible by cytogenetic (SCE) or molecular genetic testing (BLM sequencing and deletion/duplication) of fetal cells obtained by amniocentesis or chorionic villus sampling. Molecular genetic testing is preferred.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement is symptomatic. Increased calorie density formulas and foods may promote weight gain and increased growth. Although growth hormone treatment may improve linear growth, many clinicians caution against its use because of reports of early onset of cancer in some treated children. Standard antibiotic regimens are used to treat infections. If the serum levels of immunoglobulins are low and the patient is experiencing repeated infections, some have been treated with intravenous or subcutaneous immunoglobulins. Skin protection, including covering exposed skin and use of a broad-spectrum sunscreen with at least 30 SPF is crucial to reduce the sun-sensitive skin rash. Health supervision recommendations for persons with Bloom syndrome have been published, including recommendations for cancer surveillance. Due to hypersensitivity of patients to chemotherapy, reduced dosage and/or duration of therapy is recommended, usually beginning with 50% of the weight-based dosage. Caution should be exercised with use of ionizing radiation or alkylating agents, particularly busulfan, cyclophosphamide or melphalan.\nPrognosis\nThe high occurrence of cancer reduces life expectancy. The median overall life expectancy is approximately 30 years, with cancer and related complications as the leading cause of death.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Christopher CUNNIFF  -  Maeve FLANAGAN"}
{"Disease Name": "Blount disease", "Disease Definition": "Blount disease is characterized by disturbed growth of the inner portion of the upper tibial extremity, progressively leading to bowlegged deformity with bone angulation just below the knee (tibia varus). In 60% of cases, the condition affects both legs.", "ORPHA ID": 2768, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nClinically, patients with Blount disease present with bowing and length discrepancy in the lower limbs and a medial prominence of the proximal tibia. Obesity and early walking are predisposing factors for the development of the disorder.\nEtiology\nThe underlying causes are controversial: it seems to be a multifactorial disease, but the contribution of genetic factors is unknown.\nDiagnostic methods\nBlount disease can only be diagnosed in children over 2 years of age, as tibia varus can occur physiologically.\nManagement and treatment\nA severe untreated deformity can lead to early degenerative arthritis of the knee. Management must be adapted to each child: an orthopaedic therapeutic program is often the first management option, but in more severe cases associated with pain, surgery may be indicated to correct the deformity.\n\n                            Last update: \n                            October 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Blue cone monochromatism", "Disease Definition": "Blue cone monochromatism (BCM) is a recessive X-linked disease characterized by severely impaired color discrimination, low visual acuity, nystagmus, and photophobia, due to dysfunction of the red (L) and green (M) cone photoreceptors. BCM is as an incomplete form of achromatopsia (see this term).", "ORPHA ID": 16, "Summary": "Epidemiology\nThe prevalence is estimated to be 1/100,000 worldwide.\nClinical description\nBCM manifests in early infancy and predominantly affects males, with severely impaired color vision and low visual acuity (only rod and blue cone function is preserved). Additionally, photophobia, myopia, and pendular nystagmus are commonly observed. Nystagmus may wane with time.\nEtiology\nThe disorder is caused by mutations in the red and green opsin gene cluster OPN1LW and OPN1MW (Xq28) and thus affect the corresponding cones. These mutations include deletions of the locus control region that is critical for expression of both genes. These deletions may also extend to parts of or the whole opsin gene cluster. Genomic rearrangements (unequal crossing-over) can result in single red and/or red/green hybrid genes carrying deleterious point mutations. The c.607T>C p.C203R missense mutation is commonly observed, but other missense and nonsense mutations have also been reported.\nDiagnostic methods\nThe diagnosis of BCM is achieved by clinical ophthalmological examination, electrophysiological (i.e. electroretinography/ ERG) and psychophysical testing (i.e. color vision, dark adaptometry), where BCM patients show no response to red and green light but normal response to blue light. Mutation screening can confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes achromatopsia, Leber congenital amaurosis, various types of cone dystrophies (see these terms) and cerebral achromatopsia.\nAntenatal diagnosis\nPrenatal diagnosis may be offered by specialized laboratories for at-risk couples. The use of prenatal diagnostic testing in BCM will vary depending on national customs and ethics.\nGenetic counseling\nBCM is inherited in an X-linked manner. Genetic counseling is mandatory. A carrier female has a 50% risk of transmitting the mutated allele to her offspring. Penetrance is complete with little variability in disease expression.\nManagement and treatment\nThere is no specific therapy available. Management is symptomatic and includes regular ophthalmological follow-up examinations. Patients should be informed about the possibility of using filtering glasses or contact lenses (red tinted or brown) to reduce photophobia and to improve contrast sensitivity. Low-vision aids include high-powered magnifiers for reading.\nPrognosis\nBCM is usually a stationary disease, yet in rare cases, macular degeneration can occur in older patients.\n\n                            Last update: \n                            August 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Susanne KOHL"}
{"Disease Name": "Blue diaper syndrome", "Disease Definition": "A rare inborn error of metabolism characterized by early-onset diarrhea, fever, recurrent hypoglycemia, hypercalcemia with nephrocalcinosis, metabolic acidosis, and indicanuria due to bacterial degradation of malabsorbed tryptophan with excessive indole production which, upon oxidation to indigo blue, causes bluish discoloration of urine spots in the diaper of the affected infant.", "ORPHA ID": 94086, "Summary": ""}
{"Disease Name": "Blue rubber bleb nevus", "Disease Definition": "A rare vascular malformation disorder with cutaneous and visceral lesions frequently associated with serious, potentially fatal bleeding and anemia.", "ORPHA ID": 1059, "Summary": "Epidemiology\nMore than 200 cases have been published so far, but prevalence is unknown.\nClinical description\nMultifocal venous malformations most commonly involve the skin and gastrointestinal tract (GIT), but can also affect the brain, kidneys, lungs, eyes, bones and other organs. Hemostatic abnormalities due to consumption coagulopathy and thrombocythemia have also been described. The lesions are generally present in childhood but can develop later in life. They are usually blue colored and easily compressible with light palpation. The main clinical manifestation is acute or chronic bleeding from the multiple GIT vascular malformations, with the small intestine usually being involved. The acute bleeding presents as hematemesis, melena, or rectal bleeding. Unless treated radically, patients with BRBN develop anemia from chronic gastrointestinal bleeding and require lifelong treatment with iron and blood transfusions. Malignant transformation of the lesions has not been reported so far. Infrequent complications of the gastrointestinal malformations are volvulus, intussusception and intestinal infarction.\nEtiology\nThe cause of the syndrome is still unknown. Although most cases show no apparent hereditary pattern, autosomal dominant expression has been reported in several families. A gene mutation has been mapped to the short arm of chromosome 9 and might be involved in these familial cases.\nDiagnostic methods\nDiagnostic methods include: blood counts, endoscopy, ultrasound, CT, MRI, and histopathology.\nDifferential diagnosis\nDifferential diagnoses include vascular tumors, either benign (hemangiomas) or malignant (Kaposi's sarcoma, angiosarcoma); vascular anomalies associated with congenital or systemic diseases (Klippel-Trenaunay-Weber, Ehlers-Danlos, the CREST variant of scleroderma, and Osler-Weber-Rendu syndrome) and acquired and sporadic lesions (angiodysplasias, gastric antral vascular ectasia, radiation-induced vascular ectasias, and Dieulafoy's lesions) (see these terms).\nManagement and treatment\nCutaneous lesions do not usually bleed: surgery, sclerotherapy or embolization provide a good cosmetic result. In the absence of massive GIT bleeding, a conservative treatment is sufficient (iron supplementation and/or blood transfusions). Corticosteroids, antifibrinolytic agents, high-dose intravenous gamma globulin and interferon alpha are of poor effect. Long-term use of octreotide has been found to reduce blood loss from BRBN and other vascular gastrointestinal lesions. Intra-operative enteroscopy is the accepted ultimate diagnostic and/or therapeutic procedure, allowing immediate resolution of pathological findings by endoscopic coagulation or surgical full-thickness wedge excision. It is recommended to start with capsule wireless endoscopy to specify the indication for the procedure. Capsule endoscopy may also be a useful tool for monitoring the effects of therapy.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Marcela KOPACOVA"}
{"Disease Name": "BNAR syndrome", "Disease Definition": "BNAR syndrome is a very rare multiple congenital anomaly syndrome characterized by a bifid nose (see this term) (with bulbous nasal tip but not associated with hypertelorism) with or without the presence of anal defects (i.e. anteriorly placed anus, rectal stenosis or atresia) and renal dysplasia (unilateral or bilateral renal agenesis, see these terms) and without intellectual disability. BNAR syndrome is phenotypically related to Fraser syndrome and oculotrichoanal syndrome (see these terms).", "ORPHA ID": 217266, "Summary": ""}
{"Disease Name": "Bockenheimer syndrome", "Disease Definition": "A rare vascular anomaly characterized by congenital, progressive, circumscribed venous malformations (phlebectasias) primarily involving the upper and/or lower extremities, either on one side or bilaterally. The malformed vessels are visible beneath the skin. Veins of all sizes are affected. Pain, swelling, muscle wasting, and ulceration may occur.", "ORPHA ID": 217008, "Summary": ""}
{"Disease Name": "Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency", "Disease Definition": "A rare genetic skin disease characterized by severe skin laxity affecting the trunk and limbs.", "ORPHA ID": 91135, "Summary": ""}
{"Disease Name": "Bohring-Opitz syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by intrauterine growth retardation (IUGR), postnatal failure to thrive, severe feeding difficulties, microcephaly/trigonocephaly, facial dysmorphism, a recognizable upper limb posture and severe developmental delay. The upper limb posture consists of internal rotation of the shoulders, flexion of the elbows, ulnar deviation of wrists and/or metacarpophalangeal joints.", "ORPHA ID": 97297, "Summary": "Epidemiology\nTo date 46 cases have been described, less than half of which were molecularly confirmed as carrying a heterozygous pathogenic variation in ASXL1.\nClinical description\nBohring-Opitz syndrome (BOS) is characterized by IUGR, severe neonatal feeding difficulties, and microcephaly/trigonocephaly, cleft lip/palate and hirsutism. Facial dysmorphism is characterized by glabellar/frontal nevus flammeus, synophrys, proptosis, hypertelorism, depressed wide nasal bridge, anteverted nares, full cheeks, and micrognathia. The posture of upper limbs, common in all patients at birth, is characterized by internal rotation of the shoulders, flexion of the elbows, ulnar deviation of wrists and/or metacarpophalangeal joints. Most patients exhibit truncal hypotonia and hypertonic extremities at birth. Seizures and obstructive sleep apnea/sleep disturbances can occur during infancy. Other abnormalities can involve the following organs: brain (corpus callosum defects), eyes (retinal and optic nerve abnormalities, high myopia), heart (bradycardia, septal defect), gastrointestinal tract (cycling emesis, gastroesophageal reflux disease) as well as the joints (contractures, congenital hip/radial head dislocations).\nEtiology\nBOS is due to a heterozygous pathogenic variation in ASXL1 (20q11.21), which acts as a chromatin modulator.\nDiagnostic methods\nClinical diagnosis can be confirmed by sequencing of ASXL1 or by intellectual disability-related next generation sequencing panel including the gene. If sequencing is negative, multiplex ligation-dependent probe amplification may be used.\nDifferential diagnosis\nA BOS-like phenotype related to KLHL7 has been described which has several features in common with BOS (including a similar upper limb posture) but is clinically distinguished by the absence of trigonocephaly, synophrys, high myopia and cycling emesis. Other diseases sharing several features with BOS but lacking the BOS posture include C syndrome, Shashi-Pena syndrome, Bainbridge-Ropers syndrome and Cornelia de Lange syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is possible on chorionic villi or amniotic fluid where the pathogenic variant has been previously identified in the family. Prenatal genetic counseling should therefore be offered to parents of patients with ASXL1 variants to discuss the genetic risks and reproductive options.\nGenetic counseling\nThe disorder is autosomal dominant; however, most cases are de novo. Genetic counseling should be offered to all at-risk couples since germinal mosaicism may occur.\nManagement and treatment\nManagement requires an early multidisciplinary approach. Seizures are drug-responsive. An increased risk of Wilms tumor is reported. An abdominal ultrasound every 3-4 months is suggested in the first 8 years of life.\nPrognosis\nThe rate of infant mortality is high. In patients who survive infancy, feeding difficulties and recurrent infections become less severe. Older patients may have some purposeful limb movements, however, their resting state returns to BOS posture. Intellectual disability ranges from severe to profound.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Stefania BIGONI | ITHACA* - Pr Alessandra FERLINI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Bolivian hemorrhagic fever", "Disease Definition": "Bolivian hemorrhagic fever (BHF), caused by the Machupo virus (MACV), is a severe acute viral hemorrhagic fever characterized by fever, myalgia, and arthralgia followed by hemorrhagic and neurological manifestations.", "ORPHA ID": 319229, "Summary": ""}
{"Disease Name": "Bone dysplasia, lethal Holmgren type", "Disease Definition": "A rare lethal bone dysplasia characterized at birth by low birth weight, a rhizomelic dwarfism, bent femora and short chest producing asphyxia. The initial cases could have been diagnosed as Desbuquois syndrome, or a recessive Larsen syndrome. There has been no further description in the literature since 1988.", "ORPHA ID": 1842, "Summary": ""}
{"Disease Name": "Bonnemann-Meinecke-Reich syndrome", "Disease Definition": "Bonnemann-Meinecke-Reich syndrome is a syndrome of multiple congenital anomalies characterized by an encephalopathy which predominantly occurs in the first year of life and presenting as psychomotor delay. Additional features of the disease include moderate dysmorphia, craniosynostosis, dwarfism (due to growth hormone deficiency), intellectual disability, spasticity, ataxia, retinal degeneration, and adrenal and uterine hypoplasia. The disease has been described in only two families, with each family having two affected siblings. An autosomal recessive inheritance has been suggested. There have been no further descriptions in the literature since 1991.", "ORPHA ID": 1261, "Summary": ""}
{"Disease Name": "Boomerang dysplasia", "Disease Definition": "Boomerang dysplasia (BD) is a rare lethal skeletal dysplasia characterized by severe short-limbed dwarfism, dislocated joints, club feet, distinctive facies and diagnostic x-ray findings of underossified and dysplastic long tubular bones, with a boomerang-like bowing.", "ORPHA ID": 1263, "Summary": "Epidemiology\nThe prevalence of BD is unknown.\nClinical description\nAffected neonates are stillborn or die rapidly after birth and present clinically with severe short-limbed dwarfism, dislocated hip, knee and elbow joints, club feet and proviso born alive have severe cardio respiratory failure. Facial dysmorphism includes midface hypoplasia and cleft palate. Boomerang dysplasia clinically differs from AOI and AOIII because of the boomerang shaped bowing of the femur and occasionally observed encephalocele and omphalocele.\nEtiology\nBD results from missense mutations or small in-frame deletions in the FLNB gene reported in exons 2-5, normally expected to translate full length but biochemically abnormal filamin B protein.\nDiagnostic methods\nDiagnosis can be confirmed from skeletal radiographs, chondro-osseous histopathology and genetic testing. Distinctive radiographic findings are similar to AOI but, BD presents with a more severe deficiency in mineralization, with non-ossification of certain segments of limbs and vertebrates, and a boomerang-like shape of some long tubular bones.\nDifferential diagnosis\nComprises other skeletal dysplasias with severe short-limbed dwarfism such as achondrogenesis, campomelic dysplasia, Ellis-van Creveld syndrome, achondroplasia, metatropic dysplasia, Roberts syndrome, short rib-polydactyly syndrome and thanatophoric dysplasia. Additional differential diagnosis includes diseases associated with impaired ossification such achondrogenesis, hypophosphatasia, and osteogenesis imperfecta (see these terms).\nAntenatal diagnosis\nThe prenatal diagnosis of BD is difficult to ascertain by ultrasound. Ultrasound shows thoracic hypoplasia, limb shortening, delayed ossification of spine and appendicular segments and possibly joint dislocations, similar to AOI and AOIII. Boomerang-shape morphology some long tubular bones may be diagnosed prenatally by 3D-CT scan.\nPrognosis\nPrognosis is poor, as the condition is lethal in utero.\n\n                            Last update: \n                            July 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Stephen ROBERTSON"}
{"Disease Name": "BOR syndrome", "Disease Definition": "A rare otomandibular dysplasia syndrome characterized by branchial arch anomalies (branchial clefts, fistulae, cysts), malformations of the ear associated with hearing impairment (malformations of the auricle with pre-auricular pits, conductive or sensorineural hearing impairment), and renal malformations (urinary tree malformation, renal hypoplasia or agenesis, renal dysplasia, renal cysts).", "ORPHA ID": 107, "Summary": "Epidemiology\nWorldwide, the prevalence of Branchiootorenal (BOR) syndrome in the general population is unknown; however, in the pediatric population it is estimated to be 1/40,000.\nClinical description\nThe expression of the disease varies widely from one family to another and among individuals of the same family. Some individuals do not present with renal abnormalities or a urinary tract malformation.\nEtiology\nThe causative gene, EYA1, is located on the long arm of chromosome 8. Point mutations and deletions in EYA1 have been identified in approximately 40-75% of affected individuals. In a smaller proportion of patients, mutations in the SIX1 and SIX5 genes have been identified, the products of which interact with EYA1 to form transcription factor complexes.\nDiagnostic methods\nThe diagnosis of BOR syndrome might be suspected clinically in an individual with second branchial arch anomalies, auricular malformations, preauricular pits or tags, deafness and/or renal anomalies. Especially if there are other affected family members. By genetic testing, the diagnosis can be validated in around half of the patients.\nDifferential diagnosis\nThe main differential diagnosis is branchio-oculo-facial syndrome (BOFS), caused by TFAP2A variants, which is characterized by branchial defects, highly variable ocular defects and characteristic craniofacial features which can include ear anomalies. Moreover, renal anomalies can occur in patients with BOFS. Other differential diagnosis include hypoparathyroidism-sensorineural deafness-renal disease (HDR) syndrome, due to GATA3 variants, which is distinguished by the presence of hypoparathyroidism in the majority of patients; and otofaciocervical syndrome. Moreover, hearing loss is a common symptom in many genetic disorders.\nAntenatal diagnosis\nPrenatal diagnosis is possible if the pathogenic variant has previously been identified in a family member. Although, the variable expressivity of the syndrome makes it impossible to predict the severity of the disease in the fetus.\nGenetic counseling\nThe disorder is inherited in an autosomal dominant manner; most patients have an affected parent whilst some cases occur sporadically. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. The penetrance is thought to be complete while there is a great intrafamilial and interfamilial variability in the presence, severity and type of anomalies.\nManagement and treatment\nManagement of affected patients includes excision of branchial fistulae or cysts, hearing aids and education programs appropriate for the hearing impaired, and follow-up by a nephrologist. Dialysis or renal transplantation may be required.\nPrognosis\nMost patients with BOR syndrome receiving appropriate treatment are able to lead normal, active lives. The prognosis of BOR syndrome patients primarily depends on the severity of the renal involvement. Pregnancies where the fetus has severe renal impairment can end in a miscarriage. Later in life, the renal disease might progress to end-stage renal disease.\n\n                            Last update: \n                            May 2022\n\n\n                            - Expert reviewer(s): \n                             Ariane SCHMETZ  - Pr Dagmar WIECZOREK | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Borjeson-Forssman-Lehmann syndrome", "Disease Definition": "Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked obesity syndrome characterized by intellectual deficit, truncal obesity, characteristic facial features, hypogonadism, tapered fingers and short toes.", "ORPHA ID": 127, "Summary": "Epidemiology\nThe prevalence is unknown. Approximately 50 patients have been reported, from 24 families and sporadic cases.\nClinical description\nBFLS is found mainly in boys, but several mild to moderately symptomatic females have been reported within known families, and as isolated cases. There is a wide variability in manifestations. At birth, large ears and small genitalia are occasionally evident. The head circumference is variable and hypotonia, leading to poor feeding, is seen in all infants. Developmental delay is often noted before the age of one. In late childhood, truncal obesity is apparent. Fingers are malleable and tapered and feet are usually broad with flexed, short toes. Most have short stature but some are of normal height. In adolescence, gynecomastia develops and genitalia usually remain small. Characteristic coarse facial features also appear in adolescence and include deep-set eyes, narrow forehead, supraorbital ridges, ptosis and large, fleshy earlobes, all of which become more pronounced in adulthood. Intellectual disability can range from mild to severe and is not progressive. Patients are usually sociable and friendly but some experience anxiety, depression and challenging or hypersexual behavior. Less common findings reported include acute precursor T-cell acute lymphoblastic leukemia, Legg-Calvé-Perthes disease (LCPD), cleft lip/palate (see these terms), hypopituitarism, hearing impairment, epilepsy and mild to generalized polyneuropathy. Females are mainly asymptomatic but in rare cases can exhibit learning problems along with some of the physical features seen in males.\nEtiology\nBFLS is caused by mutations in the PHF6 gene, located on Xq26, encoding PHF6, a protein involved in cell growth and proliferation. In general, mutations that result in loss or reduction of PHF6 expression result in more severe clinical symptoms. Loss-of-function mutations and skewed X-inactivation are thought to explain the rare occurrence of symptomatic females. Although most cases are inherited within families, several isolated cases have been reported, where the etiology is unknown.\nDiagnostic methods\nBFLS is suspected on clinical examination when the characteristic symptoms are present. A family history showing X-linked recessive inheritance as well as skewed X-chromosome inactivation in obligate female carriers is a strong additional indicator of BFLS.  PHF6 mutation screening can confirm a diagnosis.\nDifferential diagnosis\nDifferential diagnoses include Coffin-Lowry, Klinefelter, Prader-Willi, Bardet-Biedl, or Wilson-Turner syndromes (see these terms).\nAntenatal diagnosis\nWhen a PHF6 mutation is known to exist in a parent, antenatal diagnosis is possible.\nGenetic counseling\nInheritance is X-linked and genetic counseling is possible to explain X-linkage to families and identify carrier females. Very few patients with BFLS reproduce, but asymptomatic female carriers can pass on the mutation to their children.\nManagement and treatment\nThere is no cure for BFLS. Treatment and management is symptomatic. Special education is started early and followed throughout adolescence and adulthood. A healthy diet is recommended. Adults require variable degrees of supervision which may include institutionalization in severe cases. Testosterone replacement therapy and/or a bilateral mastectomy may be considered for the treatment of gynecomastia. If seizures are present, antiepileptic drugs are prescribed. Symptomatic treatment for LCPD and hearing impairment is available. A social network is important as BFLS patients benefit from strong social relationships.\nPrognosis\nBFLS is not life threatening but due to the intellectual disability encountered, quality of life is limited and life-long supervision is often necessary.\n\n                            Last update: \n                            April 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Mark CORBETT  - Dr Jozef GECZ  - Dr Matt HUNTER"}
{"Disease Name": "Bosley-Salih-Alorainy syndrome", "Disease Definition": "Bosley-Salih-Alorainy syndrome (BSAS) is characterized by variable horizontal gaze dysfunction, profound and bilateral sensorineural deafness associated commonly with severe inner ear maldevelopment, cerebrovascular anomalies (ranging from unilateral internal carotid artery hypoplasia to bilateral agenesis), cardiac malformation, developmental delay and occasionally autism. The syndrome is caused by homozygous mutations in the HOXA1 gene (7p15.2) and is transmitted in an autosomal recessive manner. The syndrome overlaps clinically and genetically with Athabaskan brain dysfunction syndrome (ABDS,). However unlike ABDS, BSAS does not manifest central hypoventilation.", "ORPHA ID": 69737, "Summary": ""}
{"Disease Name": "Bothnia retinal dystrophy", "Disease Definition": "Bothnia retinal dystrophy is a rare form of retinal dystrophy, seen mostly in Northern Sweden, presenting in early childhood with night blindness and progressive maculopathy with a decrease in visual acuity, eventually leading to blindness by adulthood. Retinal degeneration, without obvious bone spicule formation, accompanied by affected visual fields and the typical presence of retinitis punctata albescens (see this term) in the posterior pole are also noted.", "ORPHA ID": 85128, "Summary": ""}
{"Disease Name": "Botulism", "Disease Definition": "Botulism is a rare acquired neuromuscular junction disease, characterized by descending flaccid paralysis caused by botulinum neurotoxins (BoNTs), including four clinical forms with different modes of acquisition.", "ORPHA ID": 1267, "Summary": "Epidemiology\nEstimated global prevalence is less than 1/1,000,000. Annual incidence in Western countries is estimated at 1/2,000,000.\nClinical description\nThe incubation period usually lasts 12 to 36 h, sometimes up to 5-8 days depending on the disease form. The typical clinical picture includes symmetrical cranial nerve palsies followed by symmetrical descending flaccid motor paralysis, with cholinergic dysautonomia. Initial symptoms include blurry vision (accommodation defects, diplopia) with bilateral ptosis, followed by dysautonomic symptoms (dry mouth and eyes, mydriasis, dysphagia, dysarthria, urinary retention and constipation). In the severe forms, paralysis concerns the neck, shoulder, and proximal muscles, followed by involvement of the muscles of the distal upper extremities, the diaphragm and respiratory muscles, which may result in respiratory compromise or arrest. The sensory system and intellectual functions remain unaffected.\nEtiology\nClinical manifestations are common to all forms, whatever the mode of acquisition. Foodborne botulism (see this term) caused by consumption of foods contaminated with BoNTs (homemade or traditional canned-foods, ham, pork products, etc) is the most frequent form of botulism in adults. Intestinal colonization by Clostridium botulinum and in situ toxin production is observed in young infants (infant botulism) and certain adults with risk factors (adult intestinal botulism; see these terms). Wound (or inoculation) botulism, through infection of wounds, is rare and mainly occurs in injection drug users; inhalational botulism and iatrogenic botulism have also been reported (see these terms). Botulism is due to BoNTs produced by C. botulinum and, very rarely, by certain related Clostridia, rod-shaped, strictly anaerobic and sporulating bacteria, i.e neurotoxigenic strains of C. baratii and C. butyricum. There are seven types of BoNTs (A to G) with different antigenic properties. Types A, B, E and, more rarely F, are associated with human botulism. At the site of absorption or adsorption, BoNT diffuses via the blood to the presynaptic membrane of skeletal and autonomic cholinergic nerves. BoNT binds to and enters peripheral cholinergic terminals and causes a block of acetylcholine release, with ensuing flaccid paralysis.\nDiagnostic methods\nDiagnosis is essentially clinical in the first stage; the electromyography (EMG) pattern is characterized by brief, small, abundant potentials (BSAPs). Confirmation is based on BoNT detection in serum, stools, and/or food samples. The detection of BoNT-producing Clostridium in cultures from stools and food or wound samples also supports the diagnosis.\nDifferential diagnosis\nDifferential diagnosis, depending on the disease form, in adults or infants, includes myasthenia, Guillain-Barré syndrome (and Miller Fisher syndrome), Lambert-Eaton syndrome (see these terms), bacterial and chemical food poisoning or chemical intoxication.\nManagement and treatment\nTreatment is symptomatic. Management is based on supportive care and respiratory assistance with recovery in severe cases, in an intensive care unit (ICU). Anti-toxin therapy is effective when it is administrated at the onset of symptoms. In Europe, the formulation currently available for adults is trivalent (anti-A, B, E). A heptavalent (anti-A to G) product is also available. In the USA, bivalent (anti A, B) and monovalent (anti-E) antitoxins are distributed; for infant botulism, a human derived botulinum immune globulin (BIG-IV, anti-A-B) is available.\nPrognosis\nPrognosis varies depending on the different forms of botulism, but is generally correlated with the rapidity of diagnosis and medical assistance. Death resulting from respiratory failure is rare when the patients receive appropriate medical assistance.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Michel POPOFF"}
{"Disease Name": "Boutonneuse fever", "Disease Definition": "A rare spotted fever rickettsiosis caused by infection with the tick-borne bacterium Rickettsia conorii, characterized by the onset of fever after an incubation period of about a week, followed by a centripetally spreading maculopapular rash, which may evolve into a petechial form. Accompanying symptoms are headaches, myalgia and/or arthralgia, among others. The typical ''tache noire'' may be observed at the site of the tick bite for several days. The disease is endemic in Africa, Southern Europe, and India.", "ORPHA ID": 83313, "Summary": ""}
{"Disease Name": "Bowen-Conradi syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by moderate to severe prenatal and postnatal growth retardation, microcephaly, a distinctive facial appearance, profound psychomotor delay, hip and knee contractures and rockerbottom feet.", "ORPHA ID": 1270, "Summary": "Epidemiology\nBowen-Conradi syndrome (BCS) birth prevalence is estimated at 1 per 355 within the Hutterite population living in small farming colonies in the Prairie provinces and Great Plains of North America with a carrier frequency as high as 1/10 in the Hutterite population. Outside this population, BCS is considered very rare and has only been reported clinically in 9 patients worldwide to date. To date, there are no non-Hutterite patients reported with biallelic EMG1 pathogenic variants.\nClinical description\nPrenatally BCS is characterized by intrauterine growth retardation and often a breech presentation. BCS patients fail to thrive, experience severe feeding problems and seldom live past infancy. Distinctive malformations of the head and craniofacial region describe microcephaly at birth, micrognathia and a prominent nose with a noticeable lack of glabellar angle. BCS patients have a severe psychomotor delay, stiff joints, campodactyly or clinodactyly of the little finger and rockerbottom feet. Finger, hip and knee flexion contractures are frequently present. Less common BCS features described include cryptorchidism, seizures, cleft lip with or without cleft palate, congenital heart defect, hypospadias, renal, brain, or other malformations.\nEtiology\nIn the Hutterite population, BCS is over-represented secondary to a founder effect, and is due to a missense mutation in the EMG1 gene located to 12p13.3, leading to disturbances in ribosomal biosynthesis.\nDiagnostic methods\nDiagnosis is typically made postnatally based on clinical manifestations and can then be confirmed with molecular testing. The diagnosis can first be identified on antenatal ultrasound; however the findings (particularly in a non-Hutterite infant) are non-specific and would likely not suggest BCS. In a Hutterite fetus, even in the absence of a positive family history, findings such as microcephaly, contractures, and rocker-bottom feet would be strongly suggestive of BCS.\nDifferential diagnosis\nDifferential diagnosis includes trisomy 18, COFS syndrome and fetal akinesia deformation sequence. Other conditions with microcephaly and severe growth and developmental delay such as chromosome breakage disorders, DNA damage repair disorders, microcephalic primordial dwarfisms and certain forms of carbohydrate deficient glycoprotein syndromes may also show some overlap.\nAntenatal diagnosis\nIn cases with a family history, prenatal diagnosis is available and possible by amniocentesis or chorionic villus sampling and DNA analysis. Targeted mutation analysis of the Hutterite mutation is available prenatally (although rarely pursued) and in some instances carrier testing of both Hutterite parents of a presumed affected pregnancy can strengthen the possibility of diagnosis\nGenetic counseling\nBCS transmission is autosomal recessive. With the discovery of the causative mutation in the Hutterite population, carrier testing is available. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment is merely symptomatic. Feeding is significantly compromised, and most infants require tube feeding. No curative treatment is presently available. The natural history is similar to aneuploidy syndromes such as trisomy 18 and the discussion of palliative care is appropriate.\nPrognosis\nPrognosis is extremely poor. Most children die within the first 2 years of life (range 1 day-9 years). Those who survive beyond 1 year of age show extreme growth failure.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr A.Micheil INNES"}
{"Disease Name": "Brachydactylous dwarfism, Mseleni type", "Disease Definition": "A rare and crippling chondrodysplasia, reported mainly in the Maputaland region in northern Kwazulu Natal, South Africa, characterized by a bilateral and uniform arthropathy of the joints that primarily and most severely affects the hip but that can also affect many other joints (i.e. knees, ankles, wrists, shoulders, elbows), and that manifests with pain and stiffness that progressively limits joint movement, eventually compromising a patient's ability to walk. Severe short staure and brachydactyly have been reported in a few patients with MJD.", "ORPHA ID": 2619, "Summary": ""}
{"Disease Name": "Brachydactyly type A1", "Disease Definition": "A rare, congenital limb malformation characterized by shortened or underdeveloped middle phalanges of all digits, that are sometimes fused with the terminal phalanges. The proximal phalanges of the thumbs and big toes are also shortened. Short stature in adulthood has been reported in association.", "ORPHA ID": 93388, "Summary": ""}
{"Disease Name": "Brachydactyly type A2", "Disease Definition": "A rare, congenital limb malformation characterized by shortening (hypoplasia or aplasia) of the middle phalanges of the index finger and, sometimes, of the fifth finger. On radiographs, the middle phalanx of the index fingers often appear triangular and in severely affected cases, the index finger is curved radially. The lower limb phenotype is generally milder.", "ORPHA ID": 93396, "Summary": ""}
{"Disease Name": "Brachydactyly type A4", "Disease Definition": "A rare congenital limb malformation characterized by short middle phalanges of the 2nd and 5th fingers and absence of the middle phalanges of toes 2 to 5. Occasionally, the 4th digit may be affected and manifests with an abnormally shaped middle phalanx which causes radial deviation of the distal phalanx. Other hand/foot malformations, such as syndactyly, polydactyly, reduction defects and symphalangism, may be associated.", "ORPHA ID": 93394, "Summary": ""}
{"Disease Name": "Brachydactyly type A6", "Disease Definition": "A rare primary bone dysplasia disorder characterized by brachymesophalangy with mesomelic short limbs, and carpal and tarsal bone abnormalities. In general, the affected individuals are of slightly short stature and normal intelligence. The syndrome has been described in a kindred with seven affected members from three generations. Transmission appears to be autosomal dominant.", "ORPHA ID": 93382, "Summary": ""}
{"Disease Name": "Brachydactyly type A7", "Disease Definition": "A rare dysostosis with brachydactyly characterized by variable combinations of features of brachydactyly types A2 (such as delta-shaped middle phalanx of the second finger or toe) and D (short, broad distal phalanx of the thumb) and other types of brachydactyly (symphalangism), as well as unique features (dislocatable thumbs, lateral deviation of second toes with elevation of first toes). There have been no further descriptions in the literature since 1989.", "ORPHA ID": 93397, "Summary": ""}
{"Disease Name": "Brachydactyly type B", "Disease Definition": "A rare congenital limb malformation syndrome characterized by hypoplasia or aplasia of the terminal parts of fingers 2 to 5, with complete absence of the fingernails. The thumbs are always intact but frequently show flattening, splitting or duplication of the distal phalanges. Digits on the radial side of the hand are less severely affected than those on the ulnar side. The feet are similarly affected but less severely. Soft tissue syndactyly, symphalangism, carpal and/or tarsal fusions and shortening of metacarpals and/or metatarsals may be present.", "ORPHA ID": 93383, "Summary": ""}
{"Disease Name": "Brachydactyly type B1", "Disease Definition": "A rare subtype of brachydactyly type B characterized by hypoplasia or aplasia of the distal phalanges of digits 2-5 with or without nail dysplasia, in association with fusion of the middle and distal phalanges, a broad or bifid thumb, and occasionally distal and proximal symphalangism or syndactyly. The feet are less severely affected than the hands.", "ORPHA ID": 572385, "Summary": ""}
{"Disease Name": "Brachydactyly type B2", "Disease Definition": "A clinical subtype of brachydactyly type B characterized by hypoplasia/aplasia of distal and/or middle phalanges in fingers and toes II-V (frequently severe in fingers/toes IV-V, milder in fingers/toes II-III) in association with proximal, and occasionally distal, symphalangism, fusion of carpal/tarsal bones and partial cutaneous syndactyly. Additional reported features include proximal placement of thumbs, sensorineural hearing loss and farsightedness.", "ORPHA ID": 140908, "Summary": ""}
{"Disease Name": "Brachydactyly type C", "Disease Definition": "A rare congenital limb malformation characterized by hypoplastic middle phalanges of fingers 2, 3, and 5, with relative sparing of finger 4, as well as hyperphalangy most commonly affecting fingers 2 and 3, shortening of the first metacarpal with short thumb, and ulnar deviation of fingers 2 and 3. The severity of the malformation is highly variable.", "ORPHA ID": 93384, "Summary": ""}
{"Disease Name": "Brachydactyly type E", "Disease Definition": "Brachydactyly type E (BDE) is a congenital malformation of the digits characterized by variable shortening of the metacarpals with more or less normal length phalanges, although the terminal phalanges are often short.", "ORPHA ID": 93387, "Summary": "Epidemiology\nBDE is very rare.\nClinical description\nOccasionally, the metatarsals are also short. Hyperextensibility of the hand joints is a striking feature. Axial triradius may occur. Affected individuals may be of moderately short stature.\nEtiology\nBDE may be due to mutations in the PTHLH gene (12p12.1-p11.2) or HOXD13 (2q31-q32).\nAntenatal diagnosis\nIt is inherited as an autosomal dominant trait with variable expressivity.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Brachydactyly-arterial hypertension syndrome", "Disease Definition": "A rare genetic brachydactyly syndrome characterized by the association of brachydactyly type E with hypertension (due to vascular or neurovascular anomalies) as well as the additional features of short stature and low birth weight (compared to non-affected family members), stocky build and a round face. The onset of hypertension is often in childhood.", "ORPHA ID": 1276, "Summary": ""}
{"Disease Name": "Brachydactyly-elbow wrist dysplasia syndrome", "Disease Definition": "Brachydactyly-elbow wrist dysplasia syndrome is a rare, genetic bone development disorder characterized by dysplasia of all the bony components of the elbow joint, abnormally shaped carpal bones, wrist joint radial deviation and brachydactyly. Patients typically present with slight flexion at the elbow joints (with impossibilty to perform active extension) and usually associate a limited range of motion of the elbow, wrist and finger articulations. Camptodactyly and syndactyly have also been reported.", "ORPHA ID": 1275, "Summary": ""}
{"Disease Name": "Brachydactyly-long thumb syndrome", "Disease Definition": "A rare autosomal dominant heart-hand syndrome that is characterized by bisymmetric brachydactyly accompanied by long thumbs, joint anomalies (restriction of motion at the shoulder and metacarpophalangeal joints) and cardiac conduction defects. Additional features include small hands and feet, clinodactyly, narrow shoulders with short clavicles, pectus excavatum and mild shortness of the limbs, cardiomegaly and murmur of pulmonic stenosis. There have been no new reports since 1981.", "ORPHA ID": 2946, "Summary": ""}
{"Disease Name": "Brachydactyly-mesomelia-intellectual disability-heart defects syndrome", "Disease Definition": "Brachydactyly-mesomelia-intellectual disability-heart defects syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay, intellectual disability, thin habitus with narrow shoulders, mesomelic shortness of the arms, craniofacial dysmorphism (e.g. long lower face, maxillary hypoplasia, beak nose, short columella, prognathia, high arched palate, obtuse mandibular angle), brachydactyly (mostly involving middle phalanges) and cardiovascular anomalies (i.e. aortic root dilatation, mitral valve prolapse).", "ORPHA ID": 1277, "Summary": ""}
{"Disease Name": "Brachydactyly-nystagmus-cerebellar ataxia syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by brachydactyly, nystagmus, and cerebellar ataxia. Intellectual deficit and strabismus have also been reported. There have been no further descriptions in the literature since 1934.", "ORPHA ID": 1246, "Summary": ""}
{"Disease Name": "Brachydactyly-preaxial hallux varus syndrome", "Disease Definition": "A rare congenital limb malformation characterized the association of hallux varus with short thumbs and first toes (involving the metacarpals, metatarsals, and distal phalanges; the proximal and middle phalanges are of normal length) and abduction of the affected digits. Intellectual deficit was observed in all reported individuals. There have been no further reports since 1994.", "ORPHA ID": 1278, "Summary": ""}
{"Disease Name": "Brachydactyly-short stature-retinitis pigmentosa syndrome", "Disease Definition": "Brachydactyly-short stature-retinitis pigmentosa syndrome is a rare, genetic, congenital limb malformation syndrome characterized by mild to severe short stature, brachydactyly, and retinal degeneration (usually retinitis pigmentosa), associated with variable intellectual disability, developmental delays, and craniofacial anomalies.", "ORPHA ID": 166035, "Summary": ""}
{"Disease Name": "Brachydactyly-syndactyly, Zhao type", "Disease Definition": "Brachydactyly-syndactyly, Zhao type is a recently described syndrome associating a brachydactyly type A4 (short middle phalanges of the 2nd and 5th fingers and absence of middle phalanges of the 2nd to 5th toes) and a syndactyly of the 2nd and 3rd toes. Metacarpals and metatarsals anomalies are common.", "ORPHA ID": 93409, "Summary": "Epidemiology\nThis syndrome has been described in two families.\nEtiology\nIt is caused by HOXD13 mutations in 2q31-q32\nGenetic counseling\nBrachydactyly-syndactyly, Zhao type is inherited as an autosomal dominant trait.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Brachymorphism-onychodysplasia-dysphalangism syndrome", "Disease Definition": "A rare malformation syndrome that is characterized by short stature, hypoplastic fifth digits with tiny dysplastic nails, facial dysmorphism with coarse features including a wide mouth and broad nose, and mild intellectual disability. It has been suggested that Coffin-Siris syndrome and BOD syndrome are perhaps allelic variants.", "ORPHA ID": 1292, "Summary": ""}
{"Disease Name": "Brachyolmia, Maroteaux type", "Disease Definition": "A rare genetic spondylodysplastic dysplasia characterized by short trunk/short stature, generalized platyspondyly with rounding of vertebral bodies. The vertebral bodies show less elongation compared to patients with other types of the disorder. Precocious calcification of the cerebral falx and non-specific minor facial anomalies may be associated. There have been no new reports since 1989.", "ORPHA ID": 93302, "Summary": ""}
{"Disease Name": "Brachyolmia-amelogenesis imperfecta syndrome", "Disease Definition": "An exceedingly rare form of brachyolmia, characterized by mild platyspondyly, broad ilia, elongated femoral necks with coxa valga, scoliosis, and short trunked short stature associated with amelogenesis imperfecta of both primary and permanent dentition.", "ORPHA ID": 2899, "Summary": ""}
{"Disease Name": "Brachyolmia", "Disease Definition": "Brachyolmia is a rare, clinically and genetically heterogeneous group of bone disorders characterized by short trunk, mild short stature, scoliosis and generalized platyspondyly without significant abnormalities in the long bones.", "ORPHA ID": 1293, "Summary": "Epidemiology\nThe prevalence of brachyolmia is not known, but the disorder is probably under-recognized. Fewer than 100 cases have been reported to date. Cases have been reported in various ethnic groups. However, most cases with the Hobaek/Toledo type reported so far were of Turkish origin.\nClinical description\nFour types of brachyolmia have been described: autosomal recessive brachyolmia, Hobaek/Toledo type, autosomal recessive brachyolmia-amelogenesis imperfecta syndrome, autosomal dominant brachyolmia, and autosomal recessive brachyolmia, Maroteaux type (see these terms). The age of onset is generally in childhood with short stature becoming more evident with age. The clinical manifestations are generally mild to moderate, with minor physical functional repercussions. Some patients report non-specific back pain. The disorder is not associated with intellectual disability. AR brachyolmia, Hobaek/Toledo type is characterized by short-trunked short stature with platyspondyly and scoliosis. Corneal opacities and precocious calcification of costal cartilage occur in rare cases. In AR brachyolmia-amelogenesis imperfecta syndrome, short-trunked short stature is associated with platyspondyly and enamel abnormalities. AD brachyolmia is a more severe form with significant short-trunked short stature, platyspondyly and kyphoscoliosis. Lastly, presumably autosomal recessive brachyolmia, Maroteaux type is a vague entity that has not been well characterized but may involve short trunk/short stature, generalized platyspondyly and rounding vertebral bodies.\nEtiology\nMutations in the PAPSS2 gene (10q24) have been found in patients with AR brachyolmia, Hobaek/Toledo type, and in the TRPV4 gene (12q24.1) in patients with AD brachyolmia. Precise pathogenesis is not well understood.\nDiagnostic methods\nClinical and radiological findings are used to diagnose brachyolmia. Molecular genetic testing can also be used to confirm the diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes other genetic skeletal dysplasia syndromes, particularly mild spondyloepiphyseal dysplasia, including mild type 2 collagenopathy and mild Morquio disease (see this term).\nAntenatal diagnosis\nPrenatal diagnosis is available on molecular grounds, when a mutation (or mutations) was ascertained in a familial case.\nGenetic counseling\nBrachyolmia follows either an autosomal recessive or rarely an autosomal dominant pattern of inheritance. Genetic counseling based on the mode of inheritance should be provided to affected families.\nManagement and treatment\nNo specific treatment is currently available for this disease.\nPrognosis\nThe prognosis for patients with brachyolmia is generally very good.\n\n                            Last update: \n                            March 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Gen NISHIMURA"}
{"Disease Name": "Brachytelephalangic chondrodysplasia punctata", "Disease Definition": "Brachytelephalangic chondrodysplasia punctata (BCDP) is a form of non-rhizomelic chondrodysplasia punctata, a primary bone dysplasia, characterized by hypoplasia of the distal phalanges of the fingers, nasal hypoplasia, epiphyseal stippling appearing in the first year of life, as well as mild and non-rhizomelic shortness of the long bones.", "ORPHA ID": 79345, "Summary": "Epidemiology\nThe prevalence of BCDP is not available. A birth prevalence estimate of 1/500,000 newborns has been put forward. The genetic BCDP due to ARSE alterations is pan-ethnic and occurs almost exclusively in males. Another part of BCDP, phenocopies of the genetic ones due to environmental and maternal causes, are also described in both, males and females.\nClinical description\nFirst signs of the disease are often found antenatally by ultrasound imaging, including nasal spine hypoplasia and epiphyseal abnormal calcifications. Stippled epiphyses are usually seen in the tarsus, knee, and distal phalanges, but may be more generalized, including epiphyses of the long bones, vertebrae, hips, hyoid and tracheal cartilage. At birth, the diagnosis is apparent with facial dysmorphism, quite similar to that of maxillonasal dysplasia (or Binder syndrome), i.e. severe nasomaxillary hypoplasia with flattened nasal base, reduced nasal tip protrusion but normal ala of the nose, and short columella. Usually this does not affect birth respiratory function. Typical radiological features of BCDP are hypoplastic pyramidal-shaped distal phalanges with the apices pointing proximally, slightly irregular metaphyses, relatively larger epiphyses, and punctuate calcifications (tracheal, vertebral and tarsal/carpal stippling seen in newborns disappearing in infancy and childhood). Anterior thoracolumbar vertebral body deformities, posterior scalloping and coronal cleft are also sometimes found. Affected individuals do not show asymmetry of the limbs or hypotonia. Relative micromelia without short stature usually develops postnatally and affected adults have a final normal stature. Delay in odontoid ossification may lead to cervical instability in the first months. Less common features include ichthyosis and delayed psychomotor development in cases associated with deletion of ARSE locus. In general, BCDP falls into the mildest end of chondrodysplasia punctata (CDP) spectrum with a good long-term prognosis.\nEtiology\nThe causative gene of BCDP is ARSE (Xp22) encoding the arylsulfatase E protein essential for the correct composition of cartilage and bone matrix during development. ARSE mutations have been identified in only 50% of male patients, and it was proposed that the remainder might represent phenocopies due to maternal-fetal vitamin K deficiency and maternal autoimmune diseases.\nDiagnostic methods\nDiagnosis can be challenging due to the extensive heterogeneity and variability of both phenotypical and genetic features. Radiographs taken shortly after birth may show only a few calcifications of tarsal and long bones epiphysis. Extensive epiphyseal calcifications (usually ankle and distal phalanges), vertebral stippling and distal phalangeal hypoplasia with proximal apices may also been reported. Calcifications can also occur in the larynx, trachea, and main stem bronchi. X-rays may also reveal vertebral abnormalities. Diagnosis can be confirmed in a male patient with identification of a hemizygous pathogenic variant in ARSE.\nDifferential diagnosis\nThe differential diagnosis includes other types of chondrodysplasia punctata, warfarin embryopathy, pseudowarfarin embryopathy, vitamin K malabsorption embryopathy, lupus erythematosus embryopathy, hydantoin embryopathy, Keutel syndrome, and maxillonasal dysplasia.\nAntenatal diagnosis\nPrenatal testing for at-risk pregnancies is possible if the ARSE pathogenic variant has been previously identified in the family.\nGenetic counseling\nThe pattern of inheritance of BCDP is X-linked. Genetic counseling can inform parents that the risk of transmitting the pathogenic variant for a mother is 50% in each pregnancy. Affected males pass the pathogenic variant to all of their daughters and none of their sons.\nManagement and treatment\nTreatment is supportive. All patients with CDP should be explored for clinical signs of spinal cord compression. In rare cases, respiratory difficulty can require in the first weeks monitoring, nasal stents, and feeding tube. Severe maxillary hypoplasia or maxillary retrognathia may require reconstructive surgery in older individuals. Instability of the cervical spine should be screened within the first year, leading to positioning and manipulation prevention measures. Rarely, it may require a cervical collar or spinal fusion.\nPrognosis\nPrognosis is good, as most patients have been reported to have a benign course. However, in some cases cervical canal stenosis with cervical cord compression may lead to serious morbidity and early mortality.\n\n                            Last update: \n                            June 2018\n\n\n                            - Expert reviewer(s): \n                            Dr Geneviève BAUJAT"}
{"Disease Name": "Brachytelephalangy-dysmorphism-Kallmann syndrome", "Disease Definition": "A rare developmental anomaly characterized by brachytelephalangy, distinct craniofacial features (prominent square forehead, telecanthus, small nose, malar hypoplasia, smooth philtrum and thin upper lip) and, relative to other family members, short stature. These features may be associated with anosmia and hypogonadotropic hypogonadism (Kallman syndrome). There have been no further descriptions in the literature since 1986.", "ORPHA ID": 1295, "Summary": ""}
{"Disease Name": "Braddock syndrome", "Disease Definition": "Braddock syndrome is a rare malformation syndrome with multiple congenital abnormalities, described in 2 siblings, that is characterized by VACTERL -like association in combination with pulmonary hypertension, laryngeal webs, blue sclerae, abnormal ears, persistent growth deficiency and normal intellect.", "ORPHA ID": 52047, "Summary": ""}
{"Disease Name": "Bradyopsia", "Disease Definition": "A rare genetic retinal disorder characterized by childhood-onset of markedly delayed visual adaptation to both dark and light conditions, marked difficulties tracking moving objects, and mild photophobia. Visual acuity is variably reduced, while color vision is unaffected.", "ORPHA ID": 75374, "Summary": ""}
{"Disease Name": "Brain calcification, Rajab type", "Disease Definition": "A rare, inherited disorder characterized by widespread calcifications of basal ganglia and cortex, developmental delay, small stature, retinopathy and microcephaly. The absence of progressive deterioration of the neurological functions is characteristic of the disease.", "ORPHA ID": 178506, "Summary": "Epidemiology\nThe syndrome has been described in eight children from two interrelated families.\nEtiology\nBrain calcification, Rajab type is associated with a genetic locus on chromosome 2.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            October 2009"}
{"Disease Name": "Brain dopamine-serotonin vesicular transport disease", "Disease Definition": "A rare infantile-onset neurometabolic disease characterized by dystonia, parkinsonism, nonambulation, autonomic dysfunction, developmental delay and mood disturbances.", "ORPHA ID": 352649, "Summary": "Epidemiology\nThe prevalence is unknown. It has been described in 8 patients from one Saudi Arabian family to date.\nClinical description\nDisease onset presents in infancy with hypotonia, loss of acquired head control and persistent crying and eye deviation. Motor development is delayed and later manifestations include severe parkinsonism, dystonia, ataxia, oculogyric crises, sleep and mood disturbances, temperature instability, excessive diaphoresis, ptosis and postural hypotension. Symptoms show no diurnal variation, do not improve with intake of vitamin B12 or folinic acid and worsened after administration of L-dopa.\nEtiology\nBrain dopamine-serotonin vesicular transport disease is caused by a mutation in the SLC18A2 gene (10q25), encoding the vesicular monoamine transporter 2 (VMAT2) which is responsible for the transport of dopamine and serotonin into synaptic vesicles. Mutations in this gene lead to the impairment of VMAT2 and consequently to problems with motor control, autonomic functioning and mood regulation.\nGenetic counseling\nIt is inherited in an autosomal recessive manner, and genetic counseling is recommended.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "Brain malformation-congenital heart disease-postaxial polydactyly syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by intrauterine growth retardation, multiple congenital malformations (such as brain malformations including ectopic neuropituitary gland, hypoplastic adenopituitary, and hypoplastic cerebellar vermis, cardiac and renal anomalies, and postaxial polydactyly), abnormal hair structure with temporal balding, and dysmorphic facial features with hypoplastic nasal bridge, anteverted nostrils, dysplastic ears, long and smooth philtrum, narrow upper lip, and prominent, asymmetric lower lip. Postnatal growth retardation and severe developmental delay have also been reported.", "ORPHA ID": 75389, "Summary": ""}
{"Disease Name": "Brain malformations-musculoskeletal abnormalities-facial dysmorphism-intellectual disability syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay, intellectual disability and mild to moderate facial dysmorphism in association with variable brain malformations (including abnormal gyration patterns, ventriculomegaly, white matter abnormalities, hypoplasia of the corpus callosum and cerebellar hemispheres), musculoskeletal abnormalities (including hemivertebrae, scoliosis or kyphosis, contractures, and joint laxity), ocular involvement (strabismus, hypermetropia and cortical visual impairment) and hypotonia. Additional clinical manifestations may include seizures, short stature urogenital malformations, heart defects and gastrointestinal malformations.", "ORPHA ID": 500150, "Summary": "Epidemiology\nTo date, approximately 30 patients with this syndrome has been described.\nClinical description\nAll affected individuals have mild to moderate facial dysmorphisms, including facial asymmetry, midface retraction, low-set ears, downslanting palpebral fissures, deep-set eyes, horizontal eyebrows, a broad and/or depressed nasal bridge, and a short philtrum. Developmental delay and intellectual disability are observed in all affected individuals, whilst other manifestations are variably present. Significant brain abnormalities are observed in the majority of individuals scanned and may include abnormal gyration patterns, ventriculomegaly, white matter abnormalities, hypoplasia of the corpus callosum and cerebellar hemispheres. Musculoskeletal involvement is observed in over three-quarters of individuals and may include joint laxity, scoliosis, or kyphosis, hemivertebrae, cubitus valgus, contractures, small hands and feet, and/or abnormal ribs. Eye and/or vision abnormalities are observed in approximately 70% of patients; whilst strabismus is commonly observed, other features may include hyperopia, cortical visual impairment, and optic atrophy. Short stature is observed in half of individuals. Congenital malformations are less frequently present (≤ 30% of individuals) and may include heart defects (ventricular/atrial septal defect and patent ductus arteriosus), urogenital malformations (single kidney, horseshoe kidney, and kidney dysplasia), intestinal atresia, high-arched or cleft palate, and craniosynostosis. Immunoglobulin deficiency and abnormal coagulation has been reported in several patients. Neurological features include hypotonia (75% of individuals) and seizures (55%).\nEtiology\nThe disorder is due to a heterozygous de novo SON mutation (21q22.11), which encodes for a protein required for proper RNA splicing.\nDiagnostic methods\nDiagnosis is with whole exome sequencing.\nDifferential diagnosis\nAs the clinical phenotype is heterogeneous, the differential diagnosis include the whole group of multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay and intellectual disability associated with brain malformations.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nWhilst the disease is autosomal dominant, all reported cases have occurred sporadically.\nManagement and treatment\nA multidisciplinary team approach should be considered, including a pediatrician, clinical geneticist, and psychiatrist. Referral to other specialists (e.g. orthopedic surgeon, ophthalmologist, neurologist) is indicated when specific problems are suspected. Screening of congenital defects (urogenital and heart defects) is recommended after diagnosis. Seizures should be treated according to standard procedures.\nPrognosis\nThe eldest described patient was 34 years of age.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Dr J.M.T. [Jos] DRAAISMA | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Brain-lung-thyroid syndrome", "Disease Definition": "Brain-lung-thyroid syndrome is a rare disorder characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS) and benign hereditary chorea (BHC; see these terms).", "ORPHA ID": 209905, "Summary": "Epidemiology\nPrevalence is unknown but to date about 50 cases have been reported in the literature.\nClinical description\nThe clinical spectrum varies from the complete triad of brain-lung-thyroid syndrome (50%), to brain and thyroid disease (30%), or isolated BHC (13%), which is the mildest expression of the syndrome. In addition, the severity of symptoms varies widely, even in families with the same disease-causing mutation. The thyroid form can present with overt or, more commonly, subclinical hypothyroidism / hyper-thyrotropinemia at birth, in infancy or in early childhood. There is significant correlation between thyroid morphology (55% normal, 35% hemiagenesis or hypoplasia, and 10% athyreosis in 46 published cases) and the commonly mild elevation of thyroid-stimulating hormone (TSH). The lung form presents most commonly as IRDS at term, suggestive for congenital surfactant protein deficiency. In a subgroup of patients, the disease progresses to chronic interstitial lung disease. In other patients, recurrent mild to severe pulmonary infections may be the initial sign of lung disease. The neurological form presents during the first year of life with hypotonia and psychomotor delay, which progresses to BHC between 1 and 5 years of age. Non-progressive BHC after the age of 5 years is the most common and specific sign of the syndrome. Additional non-classical symptoms including hypo- or oligodontia, microcephaly, intellectual deficit, failure to thrive, growth retardation, dysmorphism, hypoparathyroidism and malabsorption have been reported only in patients with large deletions on chromosome 14 including the NKX2-1 gene. Mild intellectual deficit may be present in some patients.\nEtiology\nBrain-lung-thyroid syndrome is caused by mutations in the thyroid transcription factor 1 gene (NKX2-1/TITF1; 14q13.3).\nDiagnostic methods\nDiagnosis is based on neonatal screening rather than clinical presentation of overt hypothyroidism such as feeding difficulty, prolonged jaundice, or large fontanels. Congenital hypothyroidism is screened systematically in many countries and raises suspicion of NKX2-1 defects when found in combination with neurological or respiratory problems. Diagnosis of BHC is based on clinical observation. Cerebral MRI may reveal malformations in about 20% of patients (e.g. dysgenetic basal ganglia, or cerebral atrophy). Diagnosis of brain-lung-thyroid syndrome is confirmed by genetic testing showing mutations in the NKX2-1 gene.\nDifferential diagnosis\nDifferential diagnoses include other forms of congenital hypothyroidism, other causes of infant respiratory distress syndrome, genetic forms of surfactant protein deficiency, and other causes of chorea.\nGenetic counseling\nGenetic counseling of families is essential in the context of autosomal dominant transmission due to life-long morbidity.\nManagement and treatment\nTreatment of congenital hypothyroidism is based on life-long levothyroxin substitution according to international guidelines (starting dose 10-15 mcg/kg/day). Treatment of compensated hypothyroidism / hyperthyrotropinemia should be considered as early as possible. Patients with IRDS at term may require mechanical ventilation for up to several weeks. Treatment options for BHC are not well established.\nPrognosis\nPrognosis varies considerably depending on the severity of symptoms. BHC causes life-long morbidity of varying degrees. Lung disease, if present, can cause mortality in a subgroup of patients.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Gabor SZINNAI"}
{"Disease Name": "Branchio-oculo-facial syndrome", "Disease Definition": "A rare, dominantly inherited multiple congenital anomalies syndrome characterized by highly variable clinical phenotype involving the three main affected systems: branchial (cutaneous) defects, ophthalmic malformations and facial anomalies. Additional features can be present.", "ORPHA ID": 1297, "Summary": "Epidemiology\nThe prevalence of branchio-oculo-facial syndrome (BOFS) is unknown but fewer than 150 individuals with a well-described clinical and/or molecular diagnosis have been reported in the literature so far.\nClinical description\nThe branchial defects include cervical or infra- and/or supra-auricular skin defects that vary in size and shape but are typically characterized as thinned erythematous cutaneous defects. Ocular features are highly variably expressed including microphthalmia, anophthalmia, coloboma, cataract, ptosis, nasolacrimal duct obstruction, strabismus and significant visual impairment. The characteristic craniofacial features include dolichocephaly, hypertelorism, telecanthus, upslanted palpebral fissures, broad nose with full nasal tip, pre-auricular and upper lip pits, external ear anomalies (malformed and prominent pinnae), inner ear and petrous bone anomalies (such as cochlear dysplasia, Mondini dysplasia and enlarged vestibular aqueduct), cleft lip (including lesser forms, such as microform, ''pseudocleft'' or abnormal philtrum) with or without cleft palate, and lower facial nerve and/or muscle hypoplasia (partial 7th cranial nerve weakness). Patients have conductive/sensorineural/mixed hearing loss. Additional findings include ectopic dermal thymus, renal anomalies (dysplastic, multisystem or absent kidneys, vesicoureteral reflux) and ectodermal anomalies (premature hair graying, hypoplastic teeth, dysplastic nails and subcutaneous dermoid-like cysts, often on the scalp). Psychomotor development is typically normal. Autism spectrum disorder, intellectual disability, growth restriction, congenital heart defects and polydactyly are rare.\nEtiology\nBOFS is caused by mutations involving the gene TFAP2A (6p24.3) that encodes the transcription factor AP-2 alpha that regulate gene expression during embryogenesis (of the eye, ear, face, body wall, limbs and neural tube).\nDiagnostic methods\nThe clinical diagnosis of BOFS is established if all three of the main features (branchial, ocular and craniofacial) are present or if two of the three main features are present in addition to either ectopic thymus or a positive family history in a first-degree relative. Diagnosis may be confirmed with molecular testing.\nDifferential diagnosis\nThe most important differential diagnosis of BOFS is the branchio-oto-renal syndrome (BOR syndrome).\nAntenatal diagnosis\nPrenatal diagnosis and preimplantation genetic testing are possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nBOFS has shown almost complete penetrance and a significant inter- and intrafamilial variability. No clear genotype-phenotype correlation exists. Transmission is autosomal dominant and an affected individual has a 50% chance of having an affected child at each pregnancy. About 50-60% of the diagnosed individuals have a de novo pathogenic variant.\nManagement and treatment\nMultidisciplinary care is required, including craniofacial specialists, plastic surgeons, ophthalmologists, otolaryngologists, dentists and genetic counseling for affected families. Renal and cardiac abnormalities should be excluded and when necessary supportive therapies should be considered.\nPrognosis\nPrognosis is generally good but depends on the severity of associated manifestations.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Patricia DIAS | ITHACA* - Dr Mariana NEVES | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Branchiogenic deafness syndrome", "Disease Definition": "Branchiogenic deafness syndrome is a multiple congenital anomalies syndrome, described in one family to date, characterized by branchial cysts or fistulae; ear malformations; congenital hearing loss (conductive, sensorineural, and mixed); internal auditory canal hypoplasia; strabismus; trismus; abnormal fifth fingers; vitiliginous lesions, short stature; and mild learning disability. Renal and uretral abnormalities are absent.", "ORPHA ID": 50815, "Summary": ""}
{"Disease Name": "Branchiootic syndrome", "Disease Definition": "Branchiootic syndrome is a rare, genetic multiple congenital anomalies syndrome characterized by second branchial arch anomalies (branchial cysts and fistulae), malformations of the outer, middle and inner ear associated with sensorineural, mixed or conductive hearing loss, and the absence of renal abnormalities. Typical ear findings consist of malformed auricles (e.g. lop or cupped ears), preauricular pits and/or tags, and middle and/or inner ear dysplasias (inculding cochlear, vestibular and semicircular channel hypoplasia, malformation of the ossicles and of middle ear space).", "ORPHA ID": 52429, "Summary": ""}
{"Disease Name": "Branchioskeletogenital syndrome", "Disease Definition": "Branchioskeletogenital syndrome is a rare multiple congenital anomalies/dysmorphic syndrome characterized by moderate intellectual disability, distinctive craniofacial features (including brachycephaly, facial asymmetry, marked hypertelorism, blepharochalasis, proptosis, a broad nose with concave nasal ridge and bulbous nasal tip, midface hypoplasia, bifid uvula or partial cleft palate, and prognathism), progressive dental anomalies (dentigerous cysts, radicular dentin dysplasia and early tooth loss), vertebral fusions (particularly of C2-C3), and hypospadias. Hearing loss is an additional observed feature.", "ORPHA ID": 1299, "Summary": ""}
{"Disease Name": "Brazilian hemorrhagic fever", "Disease Definition": "Brazilian hemorrhagic fever, caused by the Sabia virus (a newly discovered arenavirus), is a viral hemorrhagic fever, believed to originate from Sao Paulo, Brazil, with only 3 reported cases (2 of which were due to laboratory accidents) to date, characterized by fever, nausea vomiting myalgia tremors, and hemorragic manifestations such as conjunctival petechia and haematemesis, leading potentially to shock, coma and death.", "ORPHA ID": 319239, "Summary": ""}
{"Disease Name": "BRESEK syndrome", "Disease Definition": "A rare genetic, multiple congenital malformation syndrome characterized by brain anomalies (thinning of the corpus callosum with dilatation of ventricles), intellectual disability, ectodermal dysplasia, skeletal deformities (vertebral anomalies, scoliosis, polydactyly), ear/eye anomalies (maldevelopment, small optic nerves, low set and large ears with hearing loss) and kidney dysplasia/hypoplasia. In the case that clinical manifestation is also associated to Hirschsprung disease and cleft palate or cryptorchidism, it is named as BRESHECK syndrome.", "ORPHA ID": 85284, "Summary": ""}
{"Disease Name": "Brittle cornea syndrome", "Disease Definition": "A rare, hereditary connective tissue disease characterized by severe ocular manifestations due to extreme corneal thinning and fragility with rupture in the absence of significant trauma, often leading to irreversible blindness. Extraocular manifestations comprise deafness, developmental hip dysplasia, and joint hypermobility.", "ORPHA ID": 90354, "Summary": ""}
{"Disease Name": "Brody myopathy", "Disease Definition": "A rare genetic skeletal muscle disease characterized by childhood onset of exercise-induced progressive impairment of muscle relaxation, stiffness, cramps, and myalgia, predominantly in the arms, legs, and face (eyelids), and, biochemically, by a reduced sarcoplasmic reticulum Ca(2+)-ATPase activity. Symptoms improve after a few minutes of rest and may be exacerbated by cold. The term Brody syndrome refers to a clinically distinguishable subset of patients without ATP2A1 mutations, with adolescence or adult onset and selective muscular involvement, in which myalgia is more common.", "ORPHA ID": 53347, "Summary": ""}
{"Disease Name": "Bronchial neuroendocrine tumor", "Disease Definition": "A rare neuroendocrine neoplasm characterized by origin from pulmonary neuroendocrine cells and ranging from low-grade typical carcinoid and intermediate-grade atypical carcinoid to high-grade large-cell neuroendocrine carcinoma and small-cell carcinoma. Two thirds of the tumors are located in the major bronchi, with a predilection for the right lung, in particular the middle lobe. Most patients with central bronchial tumors present with hemoptysis, cough, recurrent pulmonary infections, fever, chest discomfort, and unilateral wheezing, while peripheral carcinoids are usually discovered only incidentally. Carcinoid syndrome or Cushing syndrome are very rare. The tumors may be part of multiple endocrine neoplasia type 1.", "ORPHA ID": 97287, "Summary": ""}
{"Disease Name": "Bronchiolitis obliterans", "Disease Definition": "A rare lung disorder that is mainly associated with chronic allograft dysfunction after lung transplantation and that is characterized by inflammation and fibrosis of bronchiolar walls that reduce the diameter of the bronchioles and result in progressive and irreversible airflow obstruction.", "ORPHA ID": 1303, "Summary": ""}
{"Disease Name": "Bronchogenic cyst", "Disease Definition": "Congenital malformations resulting from abnormal budding of the foregut and are most commonly found in the mediastinum.", "ORPHA ID": 2357, "Summary": ""}
{"Disease Name": "Bronchopulmonary dysplasia", "Disease Definition": "Bronchopulmonary dysplasia is a chronic respiratory disease that results from complications related to lung injury during the treatment of infant acute respiratory distress syndrome (see these terms) in low-birth-weight premature infants or from abnormal lung development in older infants. Clinical signs are tachypnea, tachycardia and signs of respiratory distress such as intercostal recession, grunting and nasal flaring.", "ORPHA ID": 70589, "Summary": ""}
{"Disease Name": "Brooke-Spiegler syndrome", "Disease Definition": "A rare genetic disease characterized as an inherited skin tumour predisposition syndrome presenting with skin appendage tumours, namely cylindromas, spiradenomas and trichoepitheliomas", "ORPHA ID": 79493, "Summary": "Epidemiology\nTo date, more than 200 cases of Brooke-Spiegler syndrome (or CYLD Cutaneous Syndrome, CCS) have been reported in the literature. Increased severity in females is recognized.\nClinical description\nCCS typically manifests in adolescence and early adulthood with the appearance of multiple skin tumours including cylindromas, spiradenomas and trichoepitheliomas. Tumour development is progressive and can affect the head and neck as well as torso. Cylindromas present as different sized pink nodules on the scalp which can become confluent (historically called ''turban tumour''). Spiradenomas are painful blue nodules that can measure several centimeters across. Trichoepitheliomas manifest as skin colored papules or firm nodules, bilateral and symmetrically distributed, preferring the central face region, particularly the nose and the surrounding skin. Patients may also develop small milia on the skin of the face. Mosaic presentations are recognised, with risk of genetic transmission to children. A minority of patients can also get major and minor salivary glands neoplasms, usually membranous basal cell adenoma. Malignancies arising in preexisting spiradenoma, cylindroma and spiradenocylindroma have been reported. Malignant tumours may be aggressive carcinomas with local infiltrative growth or metastases. Rarely, skin cylindromas may metastasise to the lung without involvement of lymph nodes (pulmonary cylindromas). Malignant metastases to bone, lung and the liver have been reported.\nEtiology\nCCS is due to germline mutations in the CYLD gene (16q12-q13), a tumour suppressor gene which encodes a protein that plays a key role in negatively regulating several signaling pathways, such as NF-KB, JNK, Wnt, TGFB and TRK.\nDiagnostic methods\nDiagnosis of CCS is based mainly on clinical examination, family history and skin biopsy. Histopathologic findings of cylindromas, spiradenomas and trichoepitheliomas are consistent with CCS. CYLD gene testing is now performed in affected individuals that fit clinical diagnostic criteria.\nDifferential diagnosis\nDifferential clinical diagnosis for multiple skin and/or scalp tumours include Birt-Hogg-Dubé syndrome, neurofibromatosis type 1, Cowden syndrome, tuberous sclerosis complex, Marie-Unna hypotrichosis, basal cell naevus syndrome, pilar cysts, multiple syringomas. These can be usually excluded following clinical examination and skin biopsy of a tumour, followed by dermatopathological assessment.\nGenetic counseling\nCCS is inherited as an autosomal dominant trait with high penetrance and variable expressivity. Prognostication regarding severity, tumour type, or clinical presentation is currently not possible in confirmed CYLD mutation carriers.\nManagement and treatment\nRemoval of cylindroma, spiradenoma, and trichoepithelioma is by conventional surgery. For an optimal outcome, as much normal scalp and skin as possible must remain in place. '' Scalp-sparing'' strategies include early primary excision with direct skin closure, tumour enucleation followed by direct skin closure, and excision followed by secondary intention healing techniques. Hyfrecation for selected small tumours and laser ablation of smaller lesions may be considered. Mohs micrographic surgery for recurrent benign tumours after primary surgical excision may have limited benefit, and lead to unnecessarily large surgical defects. Multidisciplinary skin cancer team management of tumours that have undergone malignant transformation is advised, and such a team may include a dermatologist, plastic surgeon, oncologist, radiologist and pathologist. Radiotherapy should be avoided as this may cause additional new tumours, and may increase risk of maligant transformation. Although malignant transformation is uncommon, patients are advised to report tumours that grow rapidly, or ulcerate and bleed. These features should prompt excision and histological assessment.\nPrognosis\nTumours observed in CCS are usually benign and most patients have a normal life span. The development of malignant tumours may shorten lifespan.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Neil RAJAN"}
{"Disease Name": "Brucellosis", "Disease Definition": "Brucellosis is an anthropozoonotic infection, endemic in the Mediterranean region, the Middle East, Latin America and parts of Asia and Africa, that is caused by gram-negative coccobacilli of the genus Brucella transmitted through consumption of unpasteurized dairy products or through direct contact with infected animals, placentas or aborted fetuses. Brucellosis is characterized by fever, fatigue, malaise, headache, anorexia, weight loss, sweating, osteomuscular pain (joint and lumbar pain), and arthritis.", "ORPHA ID": 1304, "Summary": ""}
{"Disease Name": "Bruck syndrome", "Disease Definition": "Bruck syndrome is characterised by the association of osteogenesis imperfecta and congenital joint contractures.", "ORPHA ID": 2771, "Summary": "Epidemiology\nPrevalence is unknown but less than 40 cases have been reported in the literature so far.\nClinical description\nFeatures include osteoporosis and bone fragility, progressive joint contractures sometimes associated with pterygia, wormian bones, scoliosis due to vertebral deformities and short stature. Mental development is normal.\nEtiology\nThe syndrome is genetically heterogeneous: the locus was mapped to chromosome 17p12 in one family (Bruck syndrome 1) but mutations in the  PLOD2 gene (3q24) encoding telopeptide lysyl hydroxylase (Bruck syndrome 2) have been identified in other affected individuals.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            July 2008"}
{"Disease Name": "Brugada syndrome", "Disease Definition": "A cardiac disorder characterized on electrocardiogram (ECG) by ST segment elevation with a coved aspect on the right precordial leads, and a clinical susceptibility to ventricular tachyarrhythmias and sudden death occurring in the absence of overt myocardial abnormalities.", "ORPHA ID": 130, "Summary": "Epidemiology\nGiven that the ECG pattern diagnostic for Brugada Syndrome is fluctuant, unlike other inherited arrhythmogenic syndromes, the data regarding the prevalence of the disease are controversial. According to a recent metanalysis, the worldwide prevalence of Brugada syndrome is estimated at 1/2,000, but it varies according to region and ethnicity. Brugada syndrome is rare in Hispanic and Caucasian populations and non-rare in Asian populations. By region, the prevalence is estimated at 1/20,000 in North America and 1/10,000 in Europe. Prevalence is higher in Asia and Middle East where estimates range between 1/270-625. The disease is observed more frequently in men than in women (8:1) and it is extremely rare in children.\nClinical description\nSymptoms usually manifest in the third-fourth decade of life. Syncope, typically occurring at rest, is a common presentation. In some cases, tachycardia does not terminate spontaneously and leads to sudden death. Most frequently, the disease occurs in a normal heart, but subtle structural abnormalities of the right ventricle have been described in a subset of patients. Triggers for the onset of arrhythmias may include fever, abundant meals, some drugs (including antiarrhythmics and antidepressants). On ECG, three different patterns may be observed. Type 1, which is the only diagnostic pattern, is defined as a coved-type ST-segment elevation (0.2 mV) followed by a negative T wave. In type 2, ST-segment elevation has a saddleback appearance with a high-takeoff ST-segment elevation (0.2 mV), a trough (0.1mV) displaying ST elevation, and then either a positive or biphasic T wave. Type 3 has either a saddleback appearance or a coved-type ST-segment elevation (maximum 0.1mV). It is important to underline that only Type 1 ECG is diagnostic for the syndrome.\nEtiology\nThe gene SCN5A (3p22.2) is responsible for 30% of cases with a gene variant implicated. Other identified genes include CACNA1C (12p13.33), SCNN1A (12p13), SLMAP (3p14.3), SEMA3A (7q21.11), SCN2B (11q23.3). However, in nearly 70% of affected families the genetic cause is unknown.\nDiagnostic methods\nThe diagnosis is based on clinical examination and detection of type 1 ECG pattern using a 12-lead Holter ECG. In some cases, the ECG manifestations are not obvious or non-diagnostic (type 2, 3 and S ECG patterns). In such instances, a provocative test with the administration of class IC antiarrhythmic drugs (ajmaline, flecainide or procainamide) may be used to confirm/exclude diagnosis. Genetic testing is available after a clinical diagnosis has been established.\nDifferential diagnosis\nDisorders that could present the typical Brugada ECG pattern include isolated right bundle branch block, pectus excavatum, arrhythmogenic right ventricular cardiomyopathy, acute pericarditis, acute myocardial ischemia or infarction, and early repolarization.\nGenetic counseling\nBoth sporadic and familial cases have been reported and pedigree analysis suggests an autosomal dominant pattern of inheritance.\nManagement and treatment\nImplantable cardioverter defibrillator (ICD) is the only therapeutic option of proven efficacy for primary and secondary prophylaxis of cardiac arrest. Thus, correct risk stratification is a major goal for management. Quinidine may be regarded as an adjunctive therapy for patients at higher risk and may reduce the number of cases of ICD shock in patients at risk of recurrence. Recently, epicardial ablation of the right ventricular outflow tract has emerged as a therapeutic option in patients at higher risk.\nPrognosis\nThe majority of patients remain asymptomatic, 20-30% experience syncope and 8-12% experience at least one cardiac arrest (potentially leading to sudden death). Risk factors for cardiac arrest and sudden death are a spontaneously diagnostic ECG pattern and a history of syncope.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Andrea MAZZANTI  - Pr Silvia PRIORI"}
{"Disease Name": "Budd-Chiari syndrome", "Disease Definition": "A rare vascular liver disease characterized by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava.", "ORPHA ID": 131, "Summary": "Epidemiology\nPrevalence of Budd-Chiari syndrome (BCS) remains largely unknown but estimates range between 1/50,000 and 1/100,000.\nClinical description\nThe obstruction leads to hepatic congestion and ischemic necrosis. Severity depends on the speed of onset and extent of the obstruction. Obstructions are generally caused by thrombosis (primary BCS). With time, thrombi reorganize to form a fibrous tissue that leads either to localized stenosis of the thrombotic vein or to diffuse obliteration resulting in its transformation into fibrous cords. Localized stenoses may present as the appearance of a membrane-like structure. Secondary BCS results from tumor invasion into the lumen or compression of the vein by an expansive lesion. BCS presentation and manifestations are extremely diverse, so that the diagnosis must be considered in any patient with acute, acute-on-chronic or chronic liver disease. The principal manifestations of BCS are ascites (which is often massive and intractable) leading to undernutrition and renal insufficiency, gastrointestinal hemorrhage due to portal hypertension, and hepatic insufficiency resulting in encephalopathy and severe infections. However, asymptomatic forms have also been reported.\nEtiology\nPrimary BCS is associated with a combination of factors that lead to a susceptibility for venous thrombosis: primary myeloproliferative neoplasms (present in 50% of cases and manifesting as a 'forme fruste' or atypical forms of the disease, but identified through detection of the JAK2 V617F mutation, CALR mutations or others), Factor V Leiden thrombophilia, protein C deficiency, antiphospholipid syndrome, Behcet disease, paroxysmal nocturnal hemoglobinuria, use of estrogen-progesterone oral contraceptives and systemic inflammatory diseases.\nDiagnostic methods\nDiagnosis can usually be established by non-invasive means through imaging of the hepatic veins and the inferior vena cava (Doppler ultrasound, tomodensitometry and MRI) but requires a radiologist with sufficient experience and with an awareness of the potential diagnosis. Liver biopsy should not be performed to diagnose BCS when vascular imaging demonstrates obstruction of the hepatic venous outflow tract. Hepatic venography or cavography, and liver puncture biopsy are necessary only when BCS of the small hepatic veins is not seen on imaging.\nDifferential diagnosis\nDifferential diagnoses include hepatic veno-occlusive disease / sinusoidal obstruction syndrome (VOD/SOS), cardiac failure, decompensated chronic liver disease, and tumoral invasion of the liver.\nManagement and treatment\nTreatment approaches include correction of the factors leading to an increased risk of thrombosis, long-term anticoagulant therapy, recanalization of the obstructed veins by interventional radiology, TIPS (transjugular intrahepatic portosystemic shunt) and liver transplantation in case of failure of other treatment methods.\nPrognosis\nThe natural course of the disease is very severe (less than 10% of patients survive for more than 3 years without treatment). At present, when the diagnosis is made quickly and treatment is initiated rapidly, the survival rate is 90% at 5 years. The long-term prognosis depends on the associated risk factors for thrombosis.\n\n                            Last update: \n                            November 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Aurélie PLESSIER | RARE-LIVER*\n\n\n                                * European Reference Network"}
{"Disease Name": "Buerger disease", "Disease Definition": "A rare systemic disease characterized by inflammatory, non-necrotizing, non-atherosclerotic, occlusive vascular disease with thrombosis and recanalization affecting small and medium sized arteries and veins of upper and lower extremities.", "ORPHA ID": 36258, "Summary": "Epidemiology\nThe prevalence is estimated at 1/10,000 in Europe but the disease is found worldwide.\nClinical description\nPatients present with clinical manifestations of an occlusive vascular disease characterized by distal arteriopathy of upper limbs: Raynaud's phenomenon at the beginning, rapidly followed by digital ischemia and/or gangrene. In lower limbs vascular disease is characterized at the beginning by plantar claudication then rapidly followed by ischemic distal lesions.\nEtiology\nThe etiology of Buerger disease is unknown, but use or exposure to tobacco is central to the initiation and progression of the disease.\nDiagnostic methods\nThe clinical criteria edited by Olin in 2000 include: age under 45 years; current or recent history of tobacco use; presence of distal-extremity ischemia, indicated by claudication, pain at rest, ischemic ulcers or gangrenes, and documented by non-invasive vascular testing; exclusion of autoimmune diseases, hypercoagulable states and diabetes mellitus; exclusion of a proximal source of emboli by echocardiography or arteriography; consistent arteriographic findings in the clinically involved and non-involved limbs. Vascular Doppler ultrasound is a useful tool which confirms distal arterial lesions (under elbow and knee). Computed tomography (CT-scan) is less useful as vascular lesions are distal. In case of superficial venous thrombosis, Doppler ultrasound will exclude venous insufficiency which is the major risk factor of superficial venous thrombosis. Dynamic oximetry of lower limbs reveals tissue hypoxia contrasting with apparent good clinical condition. Vascular biopsy is never performed because it's an invasive method but it will show specific histological findings: panvasculitis with hypercellular fresh thrombus including many macrophages and polynuclear/multinucleated cells.\nDifferential diagnosis\nThe differential diagnosis includes systemic vasculitis, thrombophilia, diabetes with macrovascular complications, dyslipidemia.\nManagement and treatment\nIf the patient smokes, stopping completely is an essential first step of treatment. The role of other treatments (including vasodilating or anti-clotting drugs, surgical revascularization or sympathectomy) in preventing amputation or treating pain remains unclear.\nPrognosis\nBuerger disease may be associated with functional consequences. Tobacco consumption is associated with a higher risk of limb amputation, either fingers in upper limbs or sub-gonal amputation, in which case, patients may require lower limb prosthesis.\n\n                            Last update: \n                            September 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Marc LAMBERT"}
{"Disease Name": "Bullous diffuse cutaneous mastocytosis", "Disease Definition": "Bullous diffuse cutaneous mastocytosis (BDCM) is a form of diffuse cutaneous mastocytosis (DCM; see this term) characterized by generalized erythroderma and severe blistering associated with the accumulation of mast cells in the skin.", "ORPHA ID": 280785, "Summary": "Epidemiology\nBDCM accounts for the majority of cases of DCM, with round 40 cases described in the literature to date.\nClinical description\nOnset usually occurs during early infancy or during the neonatal period.\nEtiology\nMutations in the KIT gene (4q11-q12) have been detected in patients with BDCM.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Pr A.P. [Arnold] ORANJE"}
{"Disease Name": "Bullous impetigo", "Disease Definition": "A rare, acquired, typically benign, bacterial infectious disease caused by Staphylococcus aureus characterized by large, fragile vesicles and flaccid bullae on an erythematous base, which evolve into moistened erosions with a thin, varnish-like crust, usually localized in intertriginous areas of the trunk and extremities (armpits, groins, between the fingers or toes, beneath the breasts). Although uncommon, systemic symptoms, such as fever, diarrhea, and weakness, may be associated.", "ORPHA ID": 36237, "Summary": ""}
{"Disease Name": "Bullous lichen planus", "Disease Definition": "Bullous lichen planus is a variant of rare lichen planus (see this term) characterized by the development of vesico-bullous lesions.", "ORPHA ID": 33408, "Summary": "Epidemiology\nPrevalence is unknown and only a few cases, both sporadic and familial, have been described in the literature.\nClinical description\nThe disease manifests during childhood or adolescence. Bullous lesions develop on top of preexisting lichen planus papules or on normal skin and generally affect the lower limbs or the lower mucosal lip, and in some rare cases the torso. In this condition, the epithelium separates from the dermis. In the case of oral bullous lichen planus, the vesicles and bullae burst soon after they appear which results in erosions.\nEtiology\nEtiology is unknown.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Susan COOPER"}
{"Disease Name": "Bullous pemphigoid", "Disease Definition": "A rare autoimmune bullous skin disease characterized by acquired, subepidermal tense bullae occurring on normal of inflamed skin and that is typically widespread (occurring in the flexor regions of the proximal arms and legs, in the armpits, groin and the abdomen) and often associated with pruritus. The evolution is typically chronic with spontaneous exacerbations and remission.", "ORPHA ID": 703, "Summary": "Epidemiology\nBullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. It has an estimated prevalence of 1/4,000 in Europe. The incidence is reported to be increasing but currently ranges between 2-22/1,000,000 worldwide.\nClinical description\nBP predominantly affects the elderly with an average age of 80 years and is significantly associated with neurological disorders. Some cases have also been described in children and young adults. The disease is characterized clinically by tight, often large, bullae with a clear content, developing primarily on the edge of erythematous plaques. Intense itching is common. Some patients may have mucosal involvement (10-20% of cases). The rare infantile forms differ from the adult form by its palmo-plantar involvement, especially in children under 1 year of age, and its greater frequency of mucosal involvement.\nEtiology\nBP is immunologically characterized by the production of autoantibodies directed against two structural proteins found in the dermal-epidermal junction and ensuring dermal-epidermal cohesion: BP antigen 1 (BPAG1 or AgBP230), and BP antigen 2 (BPAG2, AgBP180 or collagen XVII). The binding between the autoantibodies and these proteins leads to the separation between the dermis and the epidermis and the formation of blisters. Some drugs are associated with the onset of BP (diuretics, antiarrhythmics, neuroleptics, gliptins, immunotherapies).\nDiagnostic methods\nThe diagnosis is based on clinical features and skin biopsy showing typical light microscopy findings (subepidermal bullae containing eosinophils and/or neutrophils, associated with a dermal infiltrate of eosinophils and /or neutrophils, or a marginalization of eosinophils along the dermal-epidermal junction) and positive direct immunofluorescence microscopy findings (linear deposits of IgG and/or C3 along the dermal-epidermal junction). Blood samples are also needed in order to search for circulating IgG anti-basement membrane autoantibodies by indirect immunofluorescence microscopy studies and anti-BP180 IgG antibodies and anti-BP230 IgG antibodies by ELISA.\nDifferential diagnosis\nThe main differential diagnoses are some forms of acquired bullous epidermolysis and anti-P200 pemphigoid. BP with mucosal involvement may look like mucous membrane pemphigoid even if mucosal involvement is rarely predominant in BP.\nManagement and treatment\nSystemic corticosteroids (CS) (prednisone: 0.5-1 mg/kg/day) is referred as the standard treatment in most countries. The European consensus for first line treatment is with super-potent topical corticosteroids to the whole-body surface sparing the face, or applied to lesions only where the disease is localized/limited, and is followed by a maintenance or tapering schedule as required. In patients with recalcitrant BP and in those with multiple relapses, immunosuppressive drugs (methotrexate, mycophenolate mofetil) are usually used. Doxycycline can be used, especially in patients with contraindications to immunosuppressive drugs or in poor general condition. Recently, new therapeutics have been tested in particular rituximab and omalizumab whose indications remain as yet unclear.\nPrognosis\nBP is a serious disease. In some cases, the prognosis for BP patients is poor.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Marion CASTEL | ERN-Skin* - Pr Pascal JOLY | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Bullous pyoderma gangrenosum", "Disease Definition": "A rare subtype of pyoderma gangrenosum disease characterized by grouped vesicles that rapidly spread and coalesce to form large bullae, which evolve into ulcerations that have an erythematous peripheral halo and central necrosis, mainly affecting the upper limbs and face. Lymphoproliferative diseases are frequently associated, thus prognosis is often compromised.", "ORPHA ID": 538869, "Summary": ""}
{"Disease Name": "Burkitt lymphoma", "Disease Definition": "Burkitt lymphoma is a rare form of malignant mature B-cell non-Hodgkin lymphoma.", "ORPHA ID": 543, "Summary": "Epidemiology\nIn Europe and north America it represents around half of all malignant non-Hodgkin lymphoma in children and around 2% in adults. Two incidence peaks occur: one in childhood/adolescence and the second after the age of 40 years. In Europe the standardized incidence ratio is 1/530,000 for individuals aged between 0 and 14 years and 1/670,000 for individuals aged between 15 and 19 years. Males are affected more than females.\nClinical description\nPatients with HIV in whom antiviral treatment is ineffective are particularly susceptible to Burkitt lymphoma. Two forms of the disease exist: an `endemic' form (sub tropical Africa) linked to the Epstein Barr virus (EBV) that presents classically in the form of a maxillary tumor (an abdominal tumor is often present, particularly in older children), and a `sporadic' form not linked to EBV that develops mainly in the abdomen. Burkitt lymphoma can also develop in the ear, nose and throat and more rarely in other locations (orbit, kidney, bone). The tumor is very proliferative and secondarily invades the bone marrow (in about 35% of cases) and the central nervous system (in about 15% of cases). It has the appearance of tumoral meningitis or paralysis of the cranial nerves. Burkitt leukemia, with the clinical characteristics of other types of leukemia, is possible. The tumors develop from the digestive tract (mainly the intestine) and extend to the peritoneum and sometimes also the liver, pancreas, spleen, kidneys or ovaries. The most frequent clinical signs are abdominal pain, nausea, an alteration of general state and/or the appearance of lymph nodes and tumors.\nEtiology\nIn most cases Burkitt lymphoma is associated with a specific translocation t(8;14)(q24;q32) that juxtaposes the MYC/c-Myc gene (8q24) next to the heavy chain immunoglobulin gene (14q32). In rare cases the translocation affects chromosome 2 (kappa chain in immunoglobulins) or 22 (lambda chain in immunoglobulins). The cells express surface immunoglobulins and B differentiation markers (CD19, CD20). The proliferation index of the tumor is extremely high (Ki67 > 95%). EBV influences the genesis of the endemic form of Burkitt lymphoma but the mechanisms responsible are not well understood.\nDiagnostic methods\nDiagnosis is based on biopsy of a mass, an effusion puncture or bone marrow that reveals the presence of tumor cells. The extent of the tumor can be evaluated using images (mainly ultrasound and scanning).\nDifferential diagnosis\nDifferential diagnoses include other forms of abdominal tumors in children (Wilms tumor and neuroblastomas, although these are retroperitoneal, and desmoplastic tumors; see these terms) and other types of lymphoma and leukemia of B and T precursors in cases with bone marrow involvement.\nManagement and treatment\nManagement should be carried out in a specialist oncology/hematology centers. Treatment is with a few months of intensive chemotherapy. The efficacy of rituximab has not yet been proven but it is the subject of several clinical trials. Burkitt lymphoma constitutes a therapeutic emergency. The key to curing the disease is a combination of rapid and individualized management (particularly adapted to the frequent metabolic problems that occur at the start of treatment) and appropriate anti-tumor treatment.\nPrognosis\nThe current cure rate is in the order of 80-90% thanks to a difficult but relatively short treatment that is without long term sequelae.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Catherine PATTE"}
{"Disease Name": "Burn-McKeown syndrome", "Disease Definition": "A rare multiple congenital anomaly syndrome characterized by bilateral choanal atresia associated with characteristic cranio-facial dysmorphisms (hypertelorism with narrow palpebral fissures, coloboma of inferior eyelid with presence of eyelashes medial to the defect, prominent nasal bridge, thin lips, prominent ears), that can be accompanied by hearing loss, unilateral cleft lip, preauricular tags, cardiac septal defects and anomalies of the kidneys. Affected individuals have normal intelligence.", "ORPHA ID": 1200, "Summary": "Epidemiology\nTo date, approximately 20 families have been reported worldwide.\nClinical description\nAffected individuals present with dysmorphic features from birth onwards. Bilateral choanal stenosis/atresia is potentially life threatening, and may present with respiratory distress at birth. Most patients have lower eyelid defects that can result in corneal exposure and drying. Hearing loss is frequently observed (70% of patients). Cleft lip/palate (approximately 60%) can be uni- or bilateral. Cardiac defects (approximately 30%) include persistent ductus arteriosus (PDA) and patent foramen ovale. Short stature is uncommon but when present is proportionate and mild. Intelligence is typically normal, although intellectual disability has been reported.\nEtiology\nThe disease is usually caused by a loss of function mutation in TXNL4A (18q23) on one allele and a promotor deletion of TXNL4A on the second allele. Only one family has been described with a homozygous promotor deletion. It is still unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. A few patients are associated with mutations in POLR1A (2p11.2).\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and confirmed by sequencing of the promotor and coding region of TXNL4A.\nDifferential diagnosis\nThe features of this syndrome overlaps with those of the CHARGE and Treacher Collins syndromes.\nAntenatal diagnosis\nTheoretically, prenatal diagnosis is possible if there is a positive family history. It is very unlikely that the diagnosis will be prenatally established without a positive family history.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nIntubation is required for neonates presenting with respiratory distress. Surgery is required for choanal atresia. Multidisciplinary referral for evaluation of the possible ophthalmological, audiological, maxillofacial and cardiac anomalies is required. Hearing loss, eye and cardiac defects are managed according to routine procedures. The facial dysmorphism might warrant psychological therapy.\nPrognosis\nQuality of life is reduced due to choanal atresia, hearing loss and facial dysmorphism. Life expectancy is not reduced.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Dagmar WIECZOREK | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Burning mouth syndrome", "Disease Definition": "A rare neurologic disease characterized by an unremitting bilateral symmetrical burning sensation of the oral mucosa without clinical evidence of causative lesions. It most frequently occurs in postmenopausal women and typically affects the tongue, less often the palate, lips, or buccal mucosa. It is often associated with dysgeusia and xerostomia.", "ORPHA ID": 353253, "Summary": ""}
{"Disease Name": "Butterfly-shaped pigment dystrophy", "Disease Definition": "A rare patterned dystrophy of the retinal pigment epithelium characterized by abnormal accumulation of lipofuscin in a butterfly-shaped distribution at the retinal pigment epithelium level. Patients manifest with a slowly progressive loss of vision that often only becomes apparent in old age.", "ORPHA ID": 99001, "Summary": ""}
{"Disease Name": "BVES-related limb-girdle muscular dystrophy", "Disease Definition": "A rare subtype of autosomal recessive limb-girdle muscular dystrophy characterized by atrioventricular block resulting in repeated syncope episodes, elevated creatine kinase serum levels and adult-onset of slowly progressive proximal limb skeletal muscle weakness and atrophy. Muscular dystrophic changes observed in muscle biopsy include diameter variability, increased central nuclei, and presence of necrotic and regenerating fibers.", "ORPHA ID": 476084, "Summary": ""}
{"Disease Name": "Böök syndrome", "Disease Definition": "A rare autosomal dominant ectodermal dysplasia syndrome characterized by premolar aplasia, hyperhidrosis, and premature graying of the hair. Additional features may include a narrow palate, hypoplastic nails, eyebrow anomalies, a unilateral simian crease, and poorly formed dermatoglyphics.", "ORPHA ID": 1262, "Summary": ""}
{"Disease Name": "C syndrome", "Disease Definition": "C syndrome is a rare multiple congenital anomaly/intellectual disability syndrome characterized by trigonocephaly and metopic suture synostosis, dysmorphic facial features, short neck, skeletal anomalies, and variable intellectual disability.", "ORPHA ID": 1308, "Summary": "Epidemiology\nThe prevalence has been estimated to be between 1/800,000 and 1/1,000,000. Less than 60 cases have been reported so far.\nClinical description\nC syndrome is a congenital disorder characterized by trigonocephaly, dysmorphic craniofacial features that include upslanting palpebral fissures, thick epicanthic folds, strabismus, depressed nasal bridge with short/thick nasal septum and columella, flat philtrum, thin vermilion borders, micrognathia, highly arched palate, buccal-gingival frenula, and multiple minor ear anomalies along with frontal midline capillary hemangioma. Cleft palate (see this term) is an occasional finding. The neck is apparently short, but this appears to be related to residual nuchal lymphedema, which may be generalized. Skeletal defects include short rhizo- and acromelic limb segments, hypermobile elbows with crepitus, polydactyly (usually postaxial), syndactyly (see these terms) of toes, sacral dimple and deformed chest. Intellectual disability may be severe, but normal intelligence quotient (IQ) has also been described in a few patients. Seizures and neonatal hypotonia have also been reported. Additional anomalies may include congenital heart malformations (50% of cases, and include interauricular communication, ventricular septal defect, tetralogy of Fallot, Eisenmenger syndrome), hernia (in particular diaphragmatic hernia), renal malformations (unilateral renal agenesis, multicystic dysplastic kidney or horseshoe kidney) (see these terms), genital anomalies (enlarged clitoris, small penis), and anal stenosis. Perinatal mortality rate appears to be around 50%.\nEtiology\nThe etiology of C syndrome is still unknown.\nGenetic counseling\nAlthough most of the reported patients are sporadic, rare cases of familial occurrence have been described. Reports of recurrence in sibs with unaffected parents suggest that familial cases may be caused by germinal mosaicism. As recurrence in siblings has been reported, subsequent pregnancies in affected families should be monitored.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Pr John OPITZ"}
{"Disease Name": "C11ORF73-related autosomal recessive hypomyelinating leukodystrophy", "Disease Definition": "A rare leukodystrophy characterized by infantile onset of lower limb spasticity and severe developmental delay associated with delayed myelination and periventricular white matter abnormalities. Other reported signs and symptoms include microcephaly, optic atrophy, nystagmus, ataxia, or seizures.", "ORPHA ID": 495844, "Summary": ""}
{"Disease Name": "C3 glomerulonephritis", "Disease Definition": "A histological subtype of C3 glomerulopathy characterized by C3 deposition in renal tissue in the absence or near-absence of immunoglobulin deposits, in a patient with the classic clinical features of glomerulonephritis and the electron microscopic findings of predominant subendothelial, occasionally subepithelial (so-called ''humps''), and intramembranous deposits, but without the typical electron-dense deposits of dense deposit disease.", "ORPHA ID": 329931, "Summary": ""}
{"Disease Name": "C3 glomerulopathy", "Disease Definition": "A form of primary membranoproliferative glomerulonephritis characterized by the presence in renal biopsy samples of a glomerulonephritis with sole (or at least dominant) glomerular immunofluorescence staining for C3. Non-specific alterations or proliferative patterns with C3-dominant glomerular staining are also possible. Based upon electron microscopic findings, C3 glomerulopathy (C3G) may be further classified as C3 glomerulonephritis (C3GN) or Dense deposit disease (DDD).", "ORPHA ID": 329918, "Summary": "Epidemiology\nThe estimated incidence of CG3 is 1/300,000-1,000,000. C3G appears to affect both genders equally.\nClinical description\nFeatures of DDD tend to appear earlier than those of C3GN, usually in adolescence. However, the signs and symptoms of either disease may not begin until adulthood. All patients with C3G have proteinuria and/or hematuria; proteinuria is variable and may be nephrotic range. Patients with C3G have variable degrees of azotemia at presentation and variable rate of kidney function decline. Hypertension may be present. Occasionally, rapidly progressive (crescentic) glomerulonephritis develops. Initial clinical manifestations of C3G may be preceded by upper respiratory tract infection. Many patients with DDD, and occasionally patients with C3GN, develop drusen in Bruch's membrane of the retina. Acquired partial lipodystrophy may be noted in DDD. Serum C3 levels are typically low in C3G and other complement abnormalities may be present (e.g. elevated serum levels of sC5b-9). Serum levels of classical pathway components are usually normal, although serum C4 levels may be low in a minority at some point in the disease course. C3 nephritic factor (C3NeF) is found in approximately 80% of patients with DDD and 40% of patients with C3GN.\nEtiology\nWhilst the pathophysiology is not fully elucidated, dysregulation of the alternative complement pathway is well documented: low serum C3 levels associated with C3NeF are observed in most patients and a few carry auto-antibodies against complement factor H (FH) or B (FB), or mutations in complement genes (including Complement Factor H Related genes (CFHR1, 2, 3, 5), CFH and C3). Mutations in combination with common susceptibility variants are also associated with an increased risk of C3G. In patients with underlying defects in the alternative complement pathway, C3G may be triggered by a common infection.\nDiagnostic methods\nThe diagnosis of C3G is made by kidney biopsy in a patient with suspected glomerulonephritis, and is established on histopathology findings of C3 accumulation in renal tissue in the absence, or near-absence of immunoglobulin deposits. Electron microscopy is necessary to further categorized C3G into DDD and C3GN.\nDifferential diagnosis\nThe differential diagnosis includes almost all causes of acute glomerulonephritis and nephrotic syndrome in addition to atheroembolic disease, complement-mediated thrombotic microangiopathy and acute postinfectious glomerulonephritis.\nGenetic counseling\nFamilial cases of C3G with a monogenic cause are rare. In sporadic cases, genetic variants are reported in about 20%, although the pathogenicity of these variants is unknown. When a variant is identified, genetic testing is recommended for family members.\nManagement and treatment\nCurrently, there are limited evidence-based guidelines to inform therapeutic decisions. General measures in all patients with C3G include blood pressure control, minimization of proteinuria with renin-angiotensin system inhibition, and treatment of dyslipidemia. As for those with primary C3G and nephritic-nephrotic phenotype, numerous therapeutic regimens have been tried, including the use of corticosteroids and immunosuppressants, plasmapheresis and plasma exchange. Various different treatment regimens have been reported (MMF and glucocorticoids, rituximab, and eculizumab) but the results are limited. In patients with evidence of alternative pathway of complement dysregulation, particularly if the above approach has not been successful, the use of complement inhibitory agents may be reasonable. Treatment with these agents, particularly with eculizumab, has only proven effective in approximately one-third of patients. Further agents acting upstream, at the C3 convertase level, need to be investigated in clinical trials.\nPrognosis\nProgression to end stage kidney disease occurs within 10 years of diagnosis in ~70% of affected children and 30-50% of affected adults. Disease recurrence in kidney transplants contributes to allograft loss in ~50% of patients within 10 years of transplantation.\n\n                            Last update: \n                            August 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Erica DAINA | ERKNet* - Dr Marina VIVARELLI | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "CACH syndrome", "Disease Definition": "A new leukoencephalopathy, the CACH syndrome (Childhood Ataxia with Central nervous system Hypomyelination) or VWM (Vanishing White Matter) was identified on clinical and MRI criteria. Classically, this disease is characterized by (1) an onset between 2 and 5 years of age, with a cerebello-spastic syndrome exacerbated by episodes of fever or head trauma leading to death after 5 to 10 years of disease evolution, (2) a diffuse involvement of the white matter on cerebral MRI with a CSF-like signal intensity (cavitation), (3) a recessive autosomal mode of inheritance, (4) neuropathologic findings consistent with a cavitating orthochromatic leukodystrophy with increased number of oligodendrocytes with sometimes ``foamy'' aspect.", "ORPHA ID": 135, "Summary": "Epidemiology\nA total of 148 cases have been reported so far. Prevalence of this disease remains unknown.\nClinical description\nClinical symptoms are variable, from fatal infantile forms (Cree leukoencephalopathy) and congenital forms associated with extra-neurological affections, to juvenile and adult forms (ovarioleukodystrophy) characterized by cognitive and behavioural dysfunctions and by a slow progression of the disease, leading to the term of eIF2B-related leukoencephalopathies.\nEtiology\nThis disease is linked to mutations in the five EIF2B genes encoding the five subunits of the eukaryotic initiation factor 2B (eIF2B), involved in the protein synthesis and its regulation under cellular stress. The patho-physiology of the disease would involve a deficiency in astrocytes maturation leading to an increased susceptibility of the white matter to cellular stress.\nDiagnostic methods\nDiagnosis relies on the detection of eIF2B mutations, predominantly affecting the EIF2B5 gene. A decrease in the intrinsic activity of the eIF2B factor (the guanine exchange activity, GEF) in lymphoblasts from patients seems to have a diagnostic value.\nManagement and treatment\nNo specific treatment exists besides the ``prevention'' of cellular stress. Corticosteroids sometimes proved to be useful in acute phases.\nPrognosis\nPrognosis seems to be correlated with the age of onset, the earliest forms being more severe.\n\n                            Last update: \n                            September 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Odile BOESPFLUG-TANGUY  - Dr Anne FOGLI  - Pr Pierre LABAUGE  - Dr Florence NIEL BUETSCHI  - Pr Diana RODRIGUEZ"}
{"Disease Name": "CAD-CDG", "Disease Definition": "A rare congenital disorder of glycosylation caused by mutations in the CAD gene and characterized by epileptic encephalopathy, global developmental delay, normocytic anemia and anisopoikilocytosis. Loss of acquired skills in early childhood is present and natural disease course can be lethal in early childhood.", "ORPHA ID": 448010, "Summary": ""}
{"Disease Name": "CADDS", "Disease Definition": "CADDS is a rare, genetic, neurometabolic disease characterized by severe intrauterine growth retardation, failure to thrive, profound neonatal hypotonia, severe global development delay, elevated very long chain fatty acids in plasma, and neonatal cholestasis leading to hepatic failure and death. Other features include ocular abnormalities (e.g. blindness and cataracts), sensorineural deafness, seizures, and abnormal brain morphology (notably delayed CNS myelination and ventriculomegaly).", "ORPHA ID": 369942, "Summary": ""}
{"Disease Name": "Caffey disease", "Disease Definition": "Caffey disease is an osteosclerotic dysplasia characterized by acute inflammation with massive subperiosteal new bone formation usually involving the diaphyses of the long bones, as well as the ribs, mandible, scapulae, and clavicles. The disease is associated with fever, irritability pain and soft tissue swelling, with onset around the age of 2 months and resolving spontaneously by the age of 2 years. However, prenatal disease onset has also been described.", "ORPHA ID": 1310, "Summary": "Epidemiology\nTo date <100 cases have been described in the literature.\nClinical description\nCaffey disease is characterized by periosteal new bone formation which leads to cortical thickening (hyperostosis) of the affected bone. The bone lesions are often asymmetric with a characteristic involvement of the mandible (70-90% of cases), clavicle, ribs and scapula (20-30%), skull, ilium, long bones. Typically the disease presents with fever and/or pallor, joint swelling (adjacent to involved bones), pain and irritability between birth and age 5 months (average age of onset is 9 weeks). When the mandible is affected, infants may refuse to eat, leading to failure to thrive. The pain may be severe enough to result in pseudo paralysis and individual nerve involvement may result in true localized palsies. The swelling becomes wood hard and fixes to underlying tender bone, but edematous soft tissue remains freely mobile and is never discolored. A prenatal form exists that presents before 35 weeks gestation and is potentially lethal. It is characterized by corticial hyperostosis, bowing or angulation of the long bones and presence of polyhydramnios and fetal lung disease.\nEtiology\nAutosomal dominant Caffey disease is caused by a mutation in the COL1A1 gene (17q21.33). Additional genetic or environmental conditions may be required for the manifestation of the disease. In addition to the autosomal dominant form, several Caffey cases have been described, in which no COL1A1 mutation could be identified.\nDiagnostic methods\nDiagnosis is based on clinical features and radiologic findings of subperiosteal cortical hyperostosis of the diaphyses of the long bones (with sparing of the epiphyses), ribs, scapulae, clavicles, and mandible in a child age 2 months to 5 years. Magnetic resonance imaging of bone can also detect inflammatory signals in adjacent muscle, connective tissue, and in the bone marrow. Laboratory findings include elevated erythrocyte sedimentation and alkaline phosphatase levels along with increased C-reactive protein and immunoglobulin levels. Diagnosis is confirmed by genetic screening.\nDifferential diagnosis\nDifferential diagnosis includes osteogenesis imperfecta, Ehlers-Danlos syndrome, arthrochalasia type, mucopolysaccharidosis type 2 and Hurler syndrome (see these terms), non-accidental childhood injury, hypervitaminosis A, prostaglandin E1 exposure, bone malignancies, osteomyelitis and parotitis.\nAntenatal diagnosis\nPrenatal and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation in the family. On rare occasions, hyperostosis can be detected by ultrasound late in the 3rd trimester of pregnancy, even for the autosomal dominant form.\nGenetic counseling\nCaffey disease either occurs sporadically or is inherited in an autosomal dominant manner with incomplete penetrance. The prenatal form is thought to be inherited in an autosomal recessive manner.\nManagement and treatment\nManagement is mainly supportive and includes use of non-steroidal anti-inflammatory drugs or corticosteroids to improve inflammation and pain, antipyretics, and analgesics in the short term to decrease fever and to relieve pain. Yearly evaluation of linear growth, dental health, joint range of motion re-extensibility, possible hernias and fracture history is recommended.\nPrognosis\nCaffey disease usually has a favorable prognosis as it spontaneously resolves by the age of 2 years. However, the disease sometimes recurs in childhood or adolescence. Moreover, adults who had Caffey disease in childhood may manifest joint laxity, skin hyperextensibility, hernias, and an increased risk for bone fractures and/or deformities.\n\n                            Last update: \n                            April 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Harald JÜPPNER"}
{"Disease Name": "Calcifying aponeurotic fibroma", "Disease Definition": "A rare, superficial fibromatosis characterized by non-malignant, locally invading, fibrosing tumour of differentiated fibroblasts, slowly growing subcutaneously, occurring predominantly distally on the extremities, especially the hands and feet. Histologic examination shows a multinodular pattern with large areas of calcification and fibrosis, and the presence of elongated spindle cells with hyperchromatic plump vesicular nuclei interspersed within fine bands of collagen.", "ORPHA ID": 199260, "Summary": ""}
{"Disease Name": "Calciphylaxis cutis", "Disease Definition": "A rare, life-threatening, non-inflammatory vasculopathy characterized clinically by progressive and painful skin lesions associated with calcification of cutaneous arterial microvessels. Calciphylaxis predominantly affects patients with end-stage kidney disease (ESKD) on dialysis.", "ORPHA ID": 280065, "Summary": ""}
{"Disease Name": "Calciphylaxis", "Disease Definition": "A rare vascular calcification disorder typically characterized by occlusion of microvessels in the cutaneous tissue resulting in painful cutaneous lesions. The disorder is often life-limiting.", "ORPHA ID": 280062, "Summary": "Epidemiology\nCalciphylaxis typically affects patients with end-stage kidney disease (ESKD) treated with dialysis. Incidence amongst patients on hemodialysis varies worldwide, ranging from 0.35 % in the USA to less than 0.03% in Japan. A report suggests an increasing incidence in the USA. The incidence in kidney-transplant recipients and in patients without ESKD, including among those with earlier stages of chronic kidney disease, is unknown. Approximately 60 to 70% of patients with calciphylaxis are women.\nClinical description\nThe average age at the time of diagnosis is reported between 50 to 70 years; very few patients are children. Patients with calciphylaxis typically present with painful skin lesions. The pain is typically severe and there is associated tactile hyperesthesia. The initial manifestations may include skin induration, plaques, nodules, livedo, or purpura. The initial lesions rapidly progress to stellate ulcers with black eschars. Sepsis originating from the resultant wounds is considered the most common cause of death. Rarely, diffuse precipitation of calcium in viscera occurs (mainly in the heart or lungs, but also in the stomach or kidneys) which may lead to fibrosis and thrombosis, and eventually tissue necrosis. Depending on the affected organ, patients may present with dyspnea, cough and respiratory failure or acute heart block and subsequent sudden cardiac death. More than 70% of patients with calciphylaxis require hospitalization for severe ulcers.\nEtiology\nThe exact pathogenesis of calciphylaxis remains unclear. In addition to ESKD, warfarin use has been described as a major risk factor for calciphylaxis.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation. Skin biopsy may facilitate exclusion of conditions that mimic calciphylaxis.\nDifferential diagnosis\nDifferential diagnosis includes warfarin necrosis, peripheral arterial disease, and oxalosis.\nManagement and treatment\nThere is no approved treatment for calciphylaxis. Treatment focuses on pain control, wound management, and mitigation of risk factors. Off label treatments like sodium thiosulfate are frequently used clinically.\nPrognosis\nQuality of life of patients with calciphylaxis is extremely poor. Once calciphylaxis develops then the patients suffer from substantial morbidity related to pain, wounds and limited mobility, and many die within the first year of disease onset.\n\n                            Last update: \n                            October 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Sagar NIGWEKAR"}
{"Disease Name": "Calpain-3-related limb-girdle muscular dystrophy D4", "Disease Definition": "A rare autosomal dominant limb-girdle muscular dystrophy characterized by adult onset of proximal muscle weakness, pain, and wasting predominantly affecting the proximal leg, lumbar paraspinal, and medial gastrocnemius muscles. Upper limb involvement may also be observed in some cases. Serum creatine kinase is often, but not always, elevated, and muscle biopsy shows non-specific myopathic changes. The severity of the disease is variable, although most patients remain ambulatory.", "ORPHA ID": 565909, "Summary": ""}
{"Disease Name": "Calpain-3-related limb-girdle muscular dystrophy R1", "Disease Definition": "A subtype of autosomal recessive limb girdle muscular dystrophy characterized by a variable age of onset of progressive, typically symmetrical and selective weakness and atrophy of proximal shoulder- and pelvic-girdle muscles (gluteus maximus, thigh adductors, and muscles of the posterior compartment of the limbs are most commonly affected) without cardiac or facial involvement. Clinical manifestations include exercise intolerance, a waddling gait, scapular winging and calf pseudo-hypertrophy.", "ORPHA ID": 267, "Summary": ""}
{"Disease Name": "Calvarial doughnut lesions-bone fragility syndrome", "Disease Definition": "A rare primary bone dysplasia with decreased bone density disorder characterized by multiple doughnut-shaped hyperostotic or osteosclerotic calvarial lesions (manifesting with cranial lumps) associated with numerous pathologic fractures, elevated serum alkaline phosphatase levels and osteopenia.", "ORPHA ID": 85192, "Summary": ""}
{"Disease Name": "CAMOS syndrome", "Disease Definition": "A disorder that is characterised by the association of a non-progressive congenital ataxia, severe intellectual deficit, optic atrophy and structural anomalies of the skin vessels. It has been described in five children from a large consanguineous Lebanese family. Short stature and microcephaly were also reported. Transmission is autosomal recessive.", "ORPHA ID": 83472, "Summary": ""}
{"Disease Name": "Campomelia, Cumming type", "Disease Definition": "Campomelia, Cumming type, is characterized by the association of limb defects and multivisceral anomalies.", "ORPHA ID": 1318, "Summary": "Epidemiology\nThe syndrome has been reported in eight infants from four different families.\nClinical description\nSkeletal features include tetramelic campomelia and short long bones. Extraskeletal manifestations may include cervical lymphocele, generalized hydrops, polycystic kidneys, pancreas and liver, fibrotic liver or pancreas, polysplenia, heterotaxia (see this term), lung hypoplastia, short bowel. All newborns reported so far were either stillborn or died shortly after birth.\nGenetic counseling\nIn one of the affected families, three sibs with identical features born to first-cousin parents have been reported, suggestive of autosomal recessive mode of inheritance.\n\n                            Last update: \n                            July 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM"}
{"Disease Name": "Campomelic dysplasia", "Disease Definition": "A rare skeletal dysplasia characterized by peculiar facial anomalies, Pierre Robin sequence, cleft palate, shortening and bowing of long bones. Sexual ambiguity or female external genitalia is possible in individuals with a male karyotype.", "ORPHA ID": 140, "Summary": "Epidemiology\nAlthough epidemiological data is limited, prevalence at birth has been suggested at approximately 1/40,000-80,000.\nClinical description\nThe clinical features include a relatively large head, Pierre Robin sequence with cleft palate, flat face, laryngotracheomalacia, respiratory distress, 11 pairs of ribs, ambiguous genitalia or normal female external genitalia in an individual with a 46,XY karyotype. It also includes dislocated hips, short bowed femura and tibiae (lower limbs more frequently than upper limbs), pretibial skin dimples (bowing of the lower leg is often associated with a skin dimple over the apex of curve) and clubfeet. A few cases of a variant syndrome, referred to as ``acampomelic campomelic dysplasia'' have been described. This variant can be distinguished by the lack of long bone curvature. Many infants die in the neonatal period; additional problems identified in long-term survivors include short stature, cervical spine instability with cord compression, progressive kyphoscoliosis, and hearing impairment. In some cases developmental delay is described.\nEtiology\nThe disorder is autosomal dominant; however, most cases are due to heterozygous de novo mutations in the SOX9 gene (localized to 17q24). In rare individuals the disorder is caused by chromosomal recombination (deletion or translocation) involving the region 17q24.\nDiagnostic methods\nDiagnosis in based on peculiar facial anomalies (flat face, long philtrum, micrognathia), short stature and specific radiological findings (bowed femura and tibiae, dislocated hip, hypoplastic scapulae, hypoplastic and nonmineralized thoracic vertebral pedicles).\nDifferential diagnosis\nIn the prenatal period, differential diagnoses include osteogenesis imperfecta type 2 and 3, hypophosphatasia and thanatophoric dysplasia and Stuve-Wiedemann syndrome; after birth, spondyloepiphyseal dysplasia congenita (SEDC), diastrophic dysplasia and Larsen syndrome may be considered.\nAntenatal diagnosis\nDiagnosis is generally suspected prenatally during the second trimester ultrasound examination, based on the observation of delayed growth associated with bowed femura and tibiae. Prenatal genetic testing can be performed through chorionic villus sampling or amniocentesis when there is a suspicion of the diagnosis or in familial cases where an abnormality of the chromosomal region has already been identified.\nGenetic counseling\nMost cases arise sporadically and in these cases the recurrence risk in siblings of a proband is at estimated 2% (due to germline mosaicism). Approximately 5% of cases are a result of chromosomal recombination involving the region 17q24 and, in rare cases, there may be familial transmission. For this reason, genetic counseling is recommended for couples potentially at risk.\nManagement and treatment\nTreatment is symptomatic and follows standard protocols for cleft palate, clubfeet, hip subluxations, cervical instability and kyphoscoliosis. In individuals with a 46,XY karyotype and undermasculinization of the genitalia, the gonads should be removed due to the increased risk for gonadoblastoma. Hearing aids for those with hearing impairment.\nPrognosis\nNewborns suffering from campomelic dysplasia often die soon after birth as a result of respiratory insufficiency, but about 10 % of individuals survive. Complications (such as kyphoscoliosis, recurrent respiratory infections, hearing loss, light to moderate learning difficulties, small size and hip dislocation) can arise as the patients age.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Maria Francesca BEDESCHI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Camptobrachydactyly", "Disease Definition": "Camptobrachydactyly is an extremely rare brachydactyly syndrome, characterized by short broad hands and feet with brachydactyly associated with congenital flexion contractures of the proximal and/or distal interphalangeal joints of the fingers, as well as syndactyly of feet. Polydactyly, septate vagina and urinary incontinence were also occasionally reported. Camptobrachydactyly has been described in 18 members of 1 family, suggesting an autosomal dominant inheritance. There have been no further descriptions in the literature since 1972.", "ORPHA ID": 1319, "Summary": ""}
{"Disease Name": "Camptodactyly of fingers", "Disease Definition": "Camptodactyly of fingers is a rare, genetic, non-syndromic, congenital limb malformation disorder characterized by a painless, non-traumatic, non-neurogenic, often bilateral, permanent flexion contracture at the proximal interphalangeal joint of a postaxial finger, resulting in permanent volar inclination of the affected digit. The fifth finger is always involved, but additional digits might also be affected.", "ORPHA ID": 295016, "Summary": ""}
{"Disease Name": "Camptodactyly syndrome, Guadalajara type 1", "Disease Definition": "Camptodactyly syndrome, Guadalajara type 1 is a rare syndrome consisting of growth retardation, facial dysmorphism, camptodactyly and skeletal anomalies.", "ORPHA ID": 1327, "Summary": "Epidemiology\nTo date only eight cases have been reported in the literature.\nClinical description\nDysmorphic features include flat face, epicanthic folds, telecanthus, small downturned mouth, small ears with attached lobule and abnormal dental eruption and occlusion. Some patients had psychomotor development delayed.\nGenetic counseling\nThe reported cases suggest the condition is hereditary and is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Camptodactyly syndrome, Guadalajara type 2", "Disease Definition": "Camptodactyly syndrome, Guadalajara type 2 is an extremely rare multiple congenital anomaly syndrome characterized by distinctive intrauterine growth retardation, skeletal dysplasia with multiple malformations including camptodactyly of all fingers, bilateral hallux valgus, short second, fourth and fifth toes, hypoplastic patella, microcephaly, low-set ears, short neck, cuboid-shaped vertebral bodies, pectus excavatum, hip dislocation, and hypoplastic pubic region and genitalia. Camptodactyly syndrome, Guadalajara type 2 has been described in two sisters and is most likely transmitted in an autosomal recessive manner. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 1326, "Summary": ""}
{"Disease Name": "Camptodactyly syndrome, Guadalajara type 3", "Disease Definition": "Camptodactyly syndrome, Guadalajara type 3 is a rare, genetic bone development disorder characterized by hand camptodactyly associated with facial dysmorphism (flat face, hypertelorism, telecanthus, symblepharon, simplified ears, retrognathia) and neck anomalies (short neck with stricking pterygia, muscle sclerosis). Additional features include spinal defects (e.g. cervical and dorso-lumbar spina bifida occulta), congenital shortness of the sternocleidomastoid muscle, flexed wrists and thin hands and feet. Brain structural anomalies, multiple nevi, micropenis and mild intellectual disability are also observed. Imaging reveals increased bone traveculae, cortical thickening of long bones and delayed bone age.", "ORPHA ID": 488434, "Summary": ""}
{"Disease Name": "Camptodactyly-arthropathy-coxa-vara-pericarditis syndrome", "Disease Definition": "A rare, genetic, rheumatologic disease characterized by congenital or early-onset camptodactyly and symmetrical, polyarticular, non-inflammatory, large joint arthropathy with synovial hyperplasia, as well as progressive coxa vara deformity and, occasionally, non-inflammatory pericarditis.", "ORPHA ID": 2848, "Summary": ""}
{"Disease Name": "Camptodactyly-fibrous tissue hyperplasia-skeletal anomalies syndrome", "Disease Definition": "An extremely rare chondrodysplastic malformation syndrome characterized by the combination of arachnodactyly, becoming evident at around the age of 10, camptodactyly, and scoliosis. Additional reported manifestations include a mild intellectual disability and a mild facial dysmorphism including a broad nose and flaring nostrils. There have been no further descriptions in the literature since 1972.", "ORPHA ID": 1321, "Summary": ""}
{"Disease Name": "Camptodactyly-joint contractures-facial skeletal defects syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by the association of camptodactyly, multiple eye defects (fibrosis of the medial rectus muscle, severe myopia, ptosis and exophthalmos), scoliosis, flexion contractures and facial anomalies (arched eyebrows, facial asymmetry with an abnormal skull shape, a prominent nose, small mouth, low-set and dysplastic ears, and a low nuchal hairline).", "ORPHA ID": 1323, "Summary": ""}
{"Disease Name": "Camptodactyly-tall stature-scoliosis-hearing loss syndrome", "Disease Definition": "Camptodactyly-tall stature-scoliosis-hearing loss syndrome is characterised by camptodactyly, tall stature, scoliosis, and hearing loss (CATSHL). It has been described in around 30 individuals from seven generations of the same family. The syndrome is caused by a missense mutation in the FGFR3 gene, leading to a partial loss of function of the encoded protein, which is a negative regulator of bone growth.", "ORPHA ID": 85164, "Summary": ""}
{"Disease Name": "Camptodactyly-taurinuria syndrome", "Disease Definition": "Camptodactyly-taurinuria syndrome is a congenital malformation syndrome characterized by the association of a permanent camptodactyly of the fingers (see this term) with the over excretion of taurine in the urine. Camptodactyly mainly affects the little finger, although any finger may be involved. The disease has been described in 17 affected patients from 4 unrelated families. An autosomal dominant inheritance has been suggested. There have been no further descriptions in the literature since 1966.", "ORPHA ID": 1325, "Summary": ""}
{"Disease Name": "Camurati-Engelmann disease", "Disease Definition": "Camurati-Englemann disease (CED) is a rare, clinically variable bone dysplasia syndrome characterized by hyperostosis of the long bones, skull, spine and pelvis, associated with severe pain in the extremities, a wide-based waddling gait, joint contractures, muscle weakness and easy fatigability. Camurati-Englemann disease (CED) is a rare, clinically variable bone dysplasia syndrome characterized by hyperostosis of the long bones, skull, spine and pelvis, associated with severe pain in the extremities, a wide-based waddling gait, joint contractures, muscle weakness and easy fatigability.", "ORPHA ID": 1328, "Summary": "Epidemiology\nThe prevalence is unknown but more than 300 cases have been reported to date. CED has been described in various ethnic groups, and males and females are affected equally.\nClinical description\nMost of the clinical signs are related to hyperostosis and sclerosis. The age of onset and severity are highly variable, even within the same family. The average age of onset is about 13 years and almost always before 30 years. Patients generally present with pain in the extremities, waddling gait, easy fatigability, and muscle weakness. Pain may be severe, constant and aching and is exacerbated by cold weather and physical activity. Other signs include decreased muscle mass, joint contractures, and sometimes marfanoid body habitus. Later in life, severely affected individuals may present facial abnormalities such as frontal bossing and enlarged mandible, as well as facial paralysis. Other signs of musculoskeletal involvement include lumbar lordosis, kyphosis, scoliosis, coxa valga, genu valgum, and flat feet. Involvement of the orbit may lead to proptosis, papilledema, epiphora, glaucoma, and subluxation of the globe. Conductive and/or sensorineural hearing loss is found in less than 20% of patients. Occasional associated systemic features include anemia, leukocytopenia, and hepatosplenomegaly. Rare signs include sensory loss, slurred speech, dysphagia, cerebellar ataxia, anorexia, decreased subcutaneous tissue, hyperhidrosis of the extremities, delayed dentition, extensive dental caries, delayed puberty, hypogonadism and bladder incontinence.\nEtiology\nIn more than 90% of patients, mutations in the transforming growth factor TGFB1 gene (19q13.1) are detected.\nDiagnostic methods\nDiagnosis of CED is based on the clinical and radiographic signs and can be confirmed by molecular genetic testing. CED should be suspected in patients with proximal muscle weakness and hyperostosis of one or more of the long bones on radiographic imaging. The radiographic hallmark of the disorder is bilateral, sometimes symmetrical, periosteal and endosteal bony sclerosis of the diaphyses of long bones resulting in cortical thickening. Skull, spine and pelvic involvement may be found on radiographic examination.\nDifferential diagnosis\nCamurati-Engelmann disease has characteristic clinical and radiological findings, reducing the need for extensive differential diagnosis. Disorders to consider include craniodiaphyseal dysplasia, autosomal dominant Kenny-Caffey syndrome, juvenile Paget disease, Ghosal hematodiaphyseal dysplasia, Worth type autosomal dominant osteosclerosis, sclerosteosis and hyperostosis corticalis generalisata (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies is possible when the disease-causing mutation has been identified in a family.\nGenetic counseling\nCED is inherited as an autosomal dominant trait with reduced penetrance. The number of cases caused by de novo mutations is not known. Reduced penetrance complicates genetic counseling.\nManagement and treatment\nNo disease-modifying treatment is available. Corticosteroids are reported to relieve the symptoms of CED. Analgesics and non-pharmacological methods can be used to treat pain. NSAIDs and bisphosphonates have been found to be ineffective.\nPrognosis\nCED is a progressive disorder and prognosis is poor. Depending on the severity, quality of life is impaired by pain and reduced mobility.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Wim VAN HUL"}
{"Disease Name": "Canavan disease", "Disease Definition": "Canavan disease (CD) is a neurodegenerative disorder; its spectrum varies between severe forms with leukodystrophy, macrocephaly and severe developmental delay, and a very rare mild/juvenile form characterized by mild developmental delay.", "ORPHA ID": 141, "Summary": "Epidemiology\nThe disease has been reported worldwide, but is more frequent in Ashkenazi Jewish populations. The incidence of severe CD in the non-Jewish population has been estimated at approximately 1:100,000 births. If both parents are of Ashkenazi Jewish descent, the incidence is 1:6,400 to 1:13,500 births. The main form of CD is the severe form.\nClinical description\nTwo forms of CD are clinically distinguishable: severe Canavan disease with onset in the neonatal period or infancy, and mild Canavan disease diagnosed in children (see these terms).In the severe form, patients have severe hypotonia, developmental delay and other neurologic impairments, and a very high N-acetyl-L-aspartic acid (NAA) concentration in urine, blood and cerebrospinal fluid. In mild Canavan disease, there can be mild developmental delay, problems with speech or achievement at school and urine NAA is slightly elevated.\nEtiology\nCD is caused by mutations in the ASPA gene (17p13.3), coding for the aspartoacylase enzyme. Numerous mutations have been identified, and subsequent enzymatic activity is either low or totally absent. In Ashkenazi Jews, two common mutations have been identified. Mild forms of Canavan disease are usually compound heterozygotes with one mild and one severe mutation.\nPrognosis\nPrognosis is variable. In severe Canavan disease, life expectancy is reduced with average survival until 10 years or occasionally longer. In mild Canavan disease, life expectancy is usually normal and the prognosis is good.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Kimberlee MATALON  - Dr Reuben MATALON"}
{"Disease Name": "Cancer-associated retinopathy", "Disease Definition": "A rare paraneoplastic disease of the eye characterized by the presence of extraocular malignancy and circulating autoantibodies against retinal proteins.", "ORPHA ID": 71505, "Summary": "Epidemiology\nCancer-associated retinopathy (CAR) is a rare visual syndrome and its prevalence is still unknown. Females are affected twice as commonly as men. The average age of a CAR patient is about 66 years old.\nClinical description\nThe disease is progressive; visual symptoms and sudden vision loss can manifest before diagnosis of cancer. The disease is highly heterogeneous and patients differ in their clinical presentation and antibody profiles. Different antiretinal antibodies frequently coexist in a single patient, creating antibody-profiles related to the syndrome, with each disease progression stage having its own unique autoantibody signature. Patients typically present with rapidly progressive visual loss, scotomas, dyschromotopsia, nyctalopia, photoaversion, and prolonged dark adaptation. Although the disease is bilateral, initial asymmetry is not uncommon. Deterioration of visual acuity and visual field changes (scotoma, or central constriction) are common, attenuated retinal arteriole, in addition to the presence of serum autoantibodies against retinal proteins, are crucial for diagnosis. The electroretinogram (ERG) typically shows marked reduction or loss of rod and cone-mediated responses. The most common malignancies related to CAR are carcinomas, including breast carcinomas, small cell carcinoma of the lung, non-small cell carcinoma, endometrial, ovarian, cervical, prostate, and colon carcinomas, and cutaneous melanomas.\nEtiology\nThe exact etiology remains unknown but an autoimmune mechanism may contribute to the development of retinal degeneration. No known genetic association has been reported.\nDiagnostic methods\nInitial absence of clinical findings makes the diagnosis challenging. The diagnostic evaluation should include electroretinography (ERG) in patients with unexplained visual glare and subacute visual loss. Optical coherence tomography (OCT) is useful to provide information on the presence of cystoid macular edema (CME) and loss of outer retinal layers, which may include disruption of the ellipsoid zone (EZ). Areas around the macula can show loss of inner and outer segments. The presence of CME is associated to decreased ERG amplitudes and faster EZ loss. Predisposed cancer patients may develop autoantibodies cross-reacting with photoreceptor proteins.\nDifferential diagnosis\nThe main differential diagnosis is non-paraneoplastic autoimmune retinopathy. Other differential diagnoses include white dot syndrome spectrum disorders, retinal degenerative disorders (such as retinitis pigmentosa and cone-rod dystrophy), posterior uveitis, acute zonal occult outer retinopathy (AZOOR) and retinal toxicities from medications such as chemotherapy agents and vitamin deficiencies.\nManagement and treatment\nEarly diagnosis and treatment are critical to lower the risk of irreversible immunological damage to the retinal cells. Treatment involves modulation of the immune system to reduce autoimmune response and systemic antibody levels. Importantly, care for patients with cancer should be consulted with oncologist prior to applying immunosuppressive therapies. Patients with less severe retinal disease or earlier disease can benefit from rituximab monotherapy or with an adjunctive antimetabolite, which may be also added to other immunosuppression like intravenous methylprednisolone, sodium succinate and hydroxyzine as a pretreatment regimen before each rituximab infusion. Response to treatments varies when patients were treated at late stages of retinal disease. Cyclophosphamide or IVIg adjunctive therapies can be applied to patients with more severe or rapidly advancing disease.\nPrognosis\nThe ophthalmological prognosis varies depending on the clinical course of CAR, ranging from progressive visual loss to blindness. The overall prognosis varies depending on the type of cancer present. It is difficult to achieve an improvement in vision in patients who had advanced disease before immunosuppressive treatments were initiated.\n\n                            Last update: \n                            August 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Grazyna ADAMUS"}
{"Disease Name": "CANOMAD syndrome", "Disease Definition": "A rare chronic immune-mediated polyneuropathy characterized by a progressive disabling neuropathy with marked gait disturbance primarily due to sensory ataxia with concurrent cranial neuropathies (internal or external ophthalmoplegia, dysphagia, dysarthria, or facial weakness) and anti-disialosyl IgM antibodies.", "ORPHA ID": 71279, "Summary": "Epidemiology\nThe disease is rare with less than 100 cases reported in the literature. The disease predominantly affects males with a ratio of 3:1 (males:females).\nClinical description\nThe condition appears in adult or elderly age with a median age at onset of 55 years. The clinical picture comprises a chronic neuropathy with marked sensory ataxia and hyporeflexia/areflexia. Patients have relatively preserved motor function in the limbs, although some may develop distal weakness. The clinical manifestations may be fixed, progressive or relapsing-remitting. Electrophysiology and nerve pathology show demyelinating, axonal, or combined demyelinating and axonal features. Nerve ultrasound shows regional nerve enlargement, a finding consistent with acquired demyelination.\nEtiology\nThe etiology remains incompletely characterized. Evidence suggests direct damage to dorsal root ganglia (DRG) and to the nodal axolemma. It is generally accepted that antibodies against gangliosides are pathogenic. The IgM accounting for the anti-ganglioside activity is almost invariably in the form of an IgM paraprotein, which may also have cold agglutinin activity.\nDiagnostic methods\nThe diagnosis is based on the identification of typical clinical and electrodiagnostic features, IgM antibodies to disialosyl antibodies (i.e. GD1b), cold agglutinins and an IgM monoclonal gammopathy.\nDifferential diagnosis\nDifferential diagnosis includes other inflammatory peripheral neuropathies, particularly chronic inflammatory demyelinating polyneuropathy, as well as vascular and demyelinating brainstem lesions.\nManagement and treatment\nRituximab and/or intravenous immunoglobulin (IVIg) are effective in most patients. IVIg may prevent relapses in responsive patients while rituximab may be most effective in halting disease progression. While there is no clear evidence to support a disease-specific dosing regimen for either agent, commonly utilized regimens for other forms of immune-mediated peripheral nervous system disease have been effective.\nPrognosis\nThe functional outcome is generally guarded-to-poor with the majority of patients suffering some degree of permanent disability from the sensory ataxia that defines the illness.\n\n                            Last update: \n                            March 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Robert BUCELLI  - Dr ROCIO GARCIA-SANTIBANEZ"}
{"Disease Name": "Cantú syndrome", "Disease Definition": "Cantu syndrome is a rare disorder characterized by congenital hypertrichosis, osteochondrodysplasia, cardiomegaly, and dysmorphism.", "ORPHA ID": 1517, "Summary": "Epidemiology\nTo date, fewer than 30 cases have been reported.\nClinical description\nDysmorphic features include macrocephaly and a coarse facial appearance with thick eyebrows, prominent supraorbital ridges, broad nasal bridge, anteverted nares, long and large philtrum, prominent mouth with full lips and macroglossia. Affected individuals have hypertrichosis with thick scalp hair extending onto the forehead and generalized increased body hair. Cardiomegaly is found in the majority of patients and pericardial effusions have been present occasionally. Additional findings in most patients included thickened calvarium, broad ribs and metaphyseal widening of long bones with enlarged medullary canals. Mild intellectual deficiency has been described in several patients.\nEtiology\nMost cases appear to be sporadic but a few familial cases, with predominantly autosomal dominant inheritance, have been reported.\n\n                            Last update: \n                            January 2010"}
{"Disease Name": "Cap myopathy", "Disease Definition": "Cap myopathy is a very rare congenital myopathy presenting a weakness of facial and respiratory muscles associated with craniofacial and thoracic deformities, as well as weakness of limb proximal and distal muscles. Onset is at birth or in childhood, weakness progression is slow but may lead to a severe and even fatal prognosis.", "ORPHA ID": 171881, "Summary": ""}
{"Disease Name": "Cap polyposis", "Disease Definition": "A rare colorectal disease characterized by multiple inflammatory polyps that predominantly affect the rectosigmoid area and that manifests primarily as rectal bleeding with abnormal transit, constipation and diarrhea.", "ORPHA ID": 160148, "Summary": "Epidemiology\nTo date, around 67 cases have been described in the world literature. Females seem to be more affected than males.\nClinical description\nThe mean age at presentation is 49 years (range 5-79 years) with clinical manifestations including constipation alternating with periods of mucous and bloody diarrhea, associated with rectal bleeding, chronic straining with defecation, tenesmus, abdominal pain, fatigue, and loss of appetite and weight. Some patients may also show lower limb edema due to a protein-losing enteropathy.\nEtiology\nThe etiology of Cap polyposis (CP) is still unclear but various causes including lower colonic mucosal prolapse, mucosal ischemia, inflammation, abnormal colonic motility, repeated trauma to the colonic mucosa caused by straining, infections (such as Helicobacter pylori infection), and immune disorders have been proposed.\nDiagnostic methods\nThe diagnosis of CP relies on colonoscopy which reveals multiple polyps with white muco-fibrinoid caps and a normal intervening mucosa. The lesions are mainly located in the rectum and sigmoid colon. Pathological examination shows a polypoid lesion with an ulcerated cap of fibrin and mucus, elongated tortuous crypts filled with mucoid exudate, and possibly smooth muscle fibers in the mucosa. Laboratory findings may reveal hypoproteinemia, hypoalbuminemia, and severe anemia with low hemoglobin concentration. C-reactive protein (CRP) levels or white blood cell counts are mostly within the normal reference range.\nDifferential diagnosis\nDifferential diagnosis includes juvenile polyposis syndrome, Cronkhite-Canada syndrome (see these terms), amoebic dysentery, mucosal prolapse syndrome, and inflammatory bowel disease, primarily ulcerative colitis (with inflammatory polyps).\nManagement and treatment\nCP has been treated empirically using sulfasalazine, 5-aminosalicylic acid, orally or anally administered steroids, metronidazole, quinolone,  Helicobacter pylori  eradication therapy and infliximab. For cases refractory to treatment, polypectomy (for fewer than 10 polyps) or surgical resection (for greater numbers of polyps) may be successful. Patients with predominant straining/constipation symptoms can be treated with laxatives.\nPrognosis\nCP is not a premalignant condition. The clinical course of CP ranges from spontaneous remission to a disease course requiring surgical resection of the affected bowel segments. However, the recurrence rates are high, particularly if numerous polyps are present.\n\n                            Last update: \n                            May 2016\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Alain CHAYVIALLE  - Pr Jean-Christophe SAURIN"}
{"Disease Name": "Capillary malformation-arteriovenous malformation", "Disease Definition": "This syndrome is characterised by the association of multiple capillary malformations (CM) with an arteriovenous malformation (AVM) and arteriovenous fistulas.", "ORPHA ID": 137667, "Summary": "Epidemiology\nSo far, it has been described in multiple members of six families.\nClinical description\nThe CMs are atypical: they are small, round-to-oval in shape and pink-red in colour. AVMs may be cutaneous, subcutaneous, intramuscular, intraosseous or cerebral. The association of CM with arteriovenous fistulas or Parkes-Weber syndrome (see this term) was reported in some cases.\nEtiology\nThe syndrome is caused by heterozygous mutations in the RASA1 gene (5q13.3), encoding RAS p21 protein activator 1.\n\n                            Last update: \n                            April 2008"}
{"Disease Name": "CAR T cell therapy-associated cytokine release syndrome", "Disease Definition": "A rare systemic condition affecting patients undergoing chimeric antigen receptor (CAR) T-cell therapy and characterized by a systemic inflammatory response due to massive activation of leukocytes with subsequent cytokine release. It can present with a variety of signs and symptoms ranging from mild, flu-like symptoms (such as fever, fatigue, headache, rash, arthralgia, and myalgia) to severe life-threatening manifestations including vascular leakage, disseminated intravascular coagulation, shock, and multiple organ failure. Respiratory manifestations are common and range from cough and tachypnea to acute respiratory distress syndrome (ARDS).", "ORPHA ID": 542323, "Summary": ""}
{"Disease Name": "Carbamoyl-phosphate synthetase 1 deficiency", "Disease Definition": "A rare, severe disorder of urea cycle metabolism typically characterized by either a neonatal-onset of severe hyperammonemia that occurs few days after birth and manifests with lethargy, vomiting, hypothermia, seizures, coma and death or a presentation outside the newborn period at any age with (sometimes) milder symptoms of hyperammonemia.", "ORPHA ID": 147, "Summary": "Epidemiology\nThe worldwide prevalence ranges between 1/526,000-1,300,000 live births.\nClinical description\nIn the neonatal-onset form of carbamoyl-phosphate synthetase 1 deficiency (CPS1D), patients are usually healthy at birth but after few days they begin to manifest with lethargy and unwillingness to feed. Severe hyperammonemia continues and manifests with vomiting, hypothermia, hypotonia, seizures, coma, and can lead to death. Outside the newborn period, patients can present at any time in life. Risk factors for manifestation include catabolic stressors such as fasting and intercurrent illness. Manifestations include hyperammonemia with irritability, lethargy, headache, seizures, confusion, avoidance of high-protein meals, axial hypotonia and cognitive disability.\nEtiology\nCPS1D is due to mutations in the CPS1 gene (2p) that encodes carbamoyl-phosphate synthetase I (CPS1), an enzyme located in the mitochondrial matrix of hepatocytes and epithelial cells of intestinal mucosa that controls the first step of the urea cycle where ammonia is converted into carbamoyl-phosphate. Mutations in this gene lead to an interruption in the urea cycle and excess nitrogen is not converted to urea for excretion by the kidneys, leading to hyperammonemia.\nDiagnostic methods\nDiagnosis is based mainly on clinical findings and laboratory test results. Biochemical findings include severe hyperammonemia with very low plasma levels of citrulline and arginine, high plasma levels of glutamine, increased transaminases and low or normal levels of orotic acid in the urine. Molecular genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses mainly include other urea cycle disorders and organic acidurias. Amino acid profiles will distinguish CPS1D from argininosuccinic aciduria, citrullinemia type I and arginase deficiency while orotic acid in urine should help to distinguish from ornithine transcarbamylase deficiency. Another more recent differential diagnosis is hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease causing mutation on both alleles.\nGenetic counseling\nCPS1D is inherited in an autosomal recessive manner; there is a 25% risk of inheriting the disease where both parents are unaffected carriers.\nManagement and treatment\nPatients presenting with a hyperammonemic coma must be treated immediately in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration methods), ammonia scavenger therapy implemented, catabolism reversed (through glucose and lipid infusions) and special care taken to reduce the risk of neurological damage (EEG surveillance and treatment of seizures, if necessary). A life-long diet low in natural protein, supplements of essential amino acids, citrulline and arginine as needed, nitrogen scavenger therapy (sodium benzoate and/or sodium or glycerol phenylbutyrate) and appropriate nutritional support to avoid catabolic stress are recommended. Early liver transplantation for those with neonatal-onset CPS1D can correct metabolic abnormalities but does not reverse any neurological complications. Valproic acid should be avoided.\nPrognosis\nPrognosis depends on disease severity but is considered bleak in patients with early neonatal disease. With early diagnosis and optimal treatment started without any delay, the prognosis improves. Episodes of hyperammonemic coma of long duration are associated with a poor neurological outlook.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Johannes HÄBERLE"}
{"Disease Name": "Carcinofibroma of the corpus uteri", "Disease Definition": "Carcinofibroma of the corpus uteri is an extremely rare subtype of mixed müllerian tumor characterized by the presence of a uterine neoplasm which simuntaneously presents a malignant epithelial component (carcinomatous glands) and a benign mesenchymal component. Clinical presentation typically includes dysfunctional vaginal bleeding, abnormal vaginal discharge and/or lower abdominal pain.", "ORPHA ID": 213605, "Summary": ""}
{"Disease Name": "Carcinoid syndrome", "Disease Definition": "A rare neoplastic disease characterized by the occurrence of a hormonal syndrome resulting from secretion of humoral factors (including polypeptides, vasoactive amines, and prostaglandins) from a functional neuroendocrine tumor (particularly from the midgut), typically manifesting with increased bowel movements and diarrhea, episodic vasoactive flushes (particularly of the face), hypotension, tachycardia, venous telangiectasia, dyspnea, and bronchospasms, as well as long-term fibrotic changes in the mesentery, retroperitoneum, and of the cardiac valves.", "ORPHA ID": 100093, "Summary": ""}
{"Disease Name": "Carcinoma of esophagus, salivary gland type", "Disease Definition": "A rare gastroesophageal tumor characterized by a typically submucosal tumor occurring usually in the middle to distal esophagus and histologically characterized as either mucoepidermoid (intimate mixture of mucus, intermediate, and epidermoid cells) or as adenoid cystic carcinoma (biphasic admixture of duct‐lining epithelial and myoepithelial cells with tubular, cribriform, solid, or basaloid growth patterns). Patients may be asymptomatic or may present with progressive dysphagia, heartburn, retrosternal pain and/or weight loss.", "ORPHA ID": 418945, "Summary": ""}
{"Disease Name": "Carcinoma of esophagus", "Disease Definition": "Esophageal carcinoma (EC) is a tumor arising in the epithelial cells lining the esophagus and can be divided into two subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC).", "ORPHA ID": 70482, "Summary": "Epidemiology\nThe estimated annual incidence of EC in Europe is approximately 1/13,300.\nClinical description\nThe disease usually presents between the ages of 50-70 years. It is often asymptomatic until it has reached an advanced disease stage with the first symptoms usually being difficulty in swallowing (dysphagia), especially present when swallowing dry foods. Unintentional weight loss is also common. Manifestations of back or chest pain, hoarseness of voice, unexplained coughing, protracted hiccups, and severe reflux may be presenting or associated symptoms. More rarely, neck swelling from adenopathies may be the initial manifestation.\nEtiology\nThe etiology is unknown but many risk factors for esophageal cancer have been identified. Alcohol abuse, smoking, lye ingestion, radiation therapy and achalasia are associated with ESCC. EAC is associated with Barrett's esophagus (see this term), which is intestinal metaplasia (replacement of normal esophageal epithelia by intestinal epithelia), associated with chronic gastroesophageal reflux disease. EAC has also been associated with obesity, in particular visceral obesity and metabolic syndromes which are more common in men than in women.\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Claire DONOHOE  - Dr John REYNOLDS"}
{"Disease Name": "Carcinoma of gallbladder and extrahepatic biliary tract", "Disease Definition": "Carcinoma of the gallbladder (GBC) is the most common and aggressive form of biliary tract cancer (BTC; see this term) usually arising in the fundus of the gallbladder, rapidly metastasizing to lymph nodes and distant sites.", "ORPHA ID": 56044, "Summary": "Epidemiology\nAnnual incidence rates vary from 1/100,000 to 1/ 4,350 between different ethnic groups and geographical regions. It is rare in developed Western countries but has a high incidence in Japan (1/19,000), northern India, Chile and certain regions of Eastern Europe.\nClinical description\nGBC is a rare neoplasm occurring more often in females (3-4:1 female to male ratio) with an average age of onset of 65 years. Most patients are asymptomatic until the disease is advanced but presenting symptoms include abdominal pain (usually in the upper right quadrant), nausea, vomiting, jaundice, anorexia and weight loss. Gallstones are often present in patients with GBC. GBC is extremely aggressive and invasion of the lymph nodes, liver and other organs occurs rapidly in many cases.\nEtiology\nThe exact etiology is unknown. Genetic susceptibility elicited by chronic inflammation of the gallbladder leading to dysplasia and malignant change is one possibility. Risk factors associated with GBC include a history of gallstones, cholelithiasis, porcelain gallbladder, bacterial infections, high caloric diet and an anomalous pancreaticobiliary junction. A family history of GBC is also a risk factor supporting the hypothesis that genetic and environmental factors both play a role in disease susceptibility. The APOB gene is the only gene identified so far with a direct link to GBC. Mutations in the genes KRAS, INK4a, p53 and EGFR have all been implicated in the pathogenesis of GBC.\nDiagnostic methods\nDiagnosis is based on laboratory tests and imaging studies. Blood tests measuring liver enzymes and tumor marker levels are conducted. There is often an increase in CEA and CA 19-9 tumor markers, especially at an advanced stage. Ultrasound and computed tomography (CT) scans show any masses or enlargement of the gallbladder. Tumor masses are usually found in the neck and body of the gallbladder. The TNM staging system is used to stage GBC and to determine the treatment and prognosis given. Patients are then given a stage based on the International Union Against Cancer (UICC) staging system. Histopathologically most GBCs are adenocarcinomas with various histopathological subtypes. Less frequently there can be squamous cell carcinoma, sarcoma, lymphoma (see this term) or melanoma.\nDifferential diagnosis\nGBC is often misdiagnosed as other types of adenocarcinoma and other benign gallbladder diseases such as chronic cholecystitis and adenomyomatosis.\nManagement and treatment\nThe only curative treatment is complete surgical resection. If obstructive jaundice is present then biliary drainage with stenting is necessary. For T1 tumors a simple or radical (in T1b tumors) open cholecystectomy is recommended and is usually curative. Unfortunately GBC is rarely discovered at such an early stage. T2 tumors are best managed with an en bloc resection of the liver bed. T3 tumors require a selective radical resection depending on the organs affected. T4 tumors are considered unresectable or associated with high surgical morbidity. Chemotherapy can be given to those with unresectable T3 or T4 tumors or metastatic disease in hopes of improving survival and quality of life. Gemcitabine combined with cisplatin therapy is the standard treatment for unresectable biliary tract cancers. Less toxic molecular-targeted agents are now being tested as possible future treatments.\nPrognosis\nAs GBC is often detected only at an advanced disease stage, the prognosis is poor with 5-year survival rates of approximately 20%.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Junji FURUSE"}
{"Disease Name": "Carcinoma of the ampulla of Vater", "Disease Definition": "Carcinoma of the ampulla of Vater is a rare malignant tumor originating from the ampulla of Vater that can present with symptoms of general fatigue, loss of appetite, weight loss, nausea, vomiting, abdominal pain and, most commonly, painless obstructive jaundice. The tumor is believed to arise from duodenal, biliary or pancreatic epilthelium, resulting in the respective histological types. In general, carcinoma of the ampulla of Vater has a better prognosis (5-year survival rate of 45%) than cancers of the distal bile duct and pancreas.", "ORPHA ID": 300557, "Summary": ""}
{"Disease Name": "Carcinosarcoma of the cervix uteri", "Disease Definition": "Carcinosarcoma of the cervix uteri is a rare, malignant, mixed epithelial and mesenchymal tumor, located in the cervix uteri, composed of an admixture of carcinomatous and sarcomatous elements. It usually presents with abnormal vaginal bleeding and a round, well-defined, grey to yellowish-white, pedunculated polypoid mass protruding through the cervical canal. Association with HPV infection (especially serotype 16) has been frequently reported.", "ORPHA ID": 213787, "Summary": ""}
{"Disease Name": "Carcinosarcoma of the corpus uteri", "Disease Definition": "Carcinosarcoma of the corpus uteri is a rare, malignant, mixed epithelial and mesenchymal tumor of the uterine body composed of high-grade carcinomatous and sarcomatous elements. It may present with vaginal bleeding, abnormal vaginal discharge, abdominal pain and/or pelvic mass, with a polypoid tumor sometimes protruding through the cervical canal. Association with Tamoxifen therapy, long-term unopposed estrogen use and previous pelvic radiotherapy has been reported.", "ORPHA ID": 213610, "Summary": ""}
{"Disease Name": "Cardiac anomalies-heterotaxy syndrome", "Disease Definition": "Cardiac anomalies-heterotaxy syndrome is characterised by non-compaction of the ventricular myocardium, bradycardia, pulmonary valve stenosis, and secundum atrial septal defect. Laterality sequence anomalies are also present. So far, the syndrome has been described in nine members from three generations of the same family. Transmission is autosomal dominant and linkage to chromosome 6p24.3-21.2 was reported.", "ORPHA ID": 137628, "Summary": ""}
{"Disease Name": "Cardiac anomalies-short stature-joint hypermobility-facial dysmorphism syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by the combination of cardiac anomalies (most commonly mitral valve defects and cardiomyopathy), short stature, facial dysmorphism and sometimes mild developmental delay.", "ORPHA ID": 228410, "Summary": "Epidemiology\n70 individuals have been described in literature: 34 individuals with TAB2 variants, 36 individuals with TAB2 deletions.\nClinical description\nAlmost all individuals present with a specific facial appearance including: broad forehead, hypertelorism, up/downslanting palpebral fissures, ptosis, low set ears, broad/short neck, and half of the individuals have a face suggestive for Noonan syndrome. Cardiac disease is seen in most individuals and includes mainly mitral valve defects, sometimes in combination with another valve defect, and (dilated) cardiomyopathy. Cardiomyopathy can be present from birth or develop between infancy and adulthood. Other cardiovascular defects are variably reported, including dysplasia of the tricuspid, aortic and pulmonary valves, atrial and/or ventricular septal defects, coarctation of the aorta and thoracic aneurysms. Short stature is often disproportionate (short limbs). Connective tissue abnormalities can include joint hypermobility, umbilical and inguinal hernias, pes planus, pectus excavatum and other skeletal and/or skin abnormalities. Some individuals have mild developmental delay. More severe developmental delay can be seen in larger deletions (>6.47 Mb) containing TAB2, but was never reported in individuals with TAB2 variants. Hearing loss and vision problems are also reported. Hypotonia is reported in individuals with TAB2 deletions, but rarely in TAB2 variants.\nEtiology\nThis syndrome is caused by heterozygous pathogenic variants in the TAB2 gene, or by chromosome 6 deletions including TAB2 (6q25.1). Both TAB2 variants and deletions including TAB2 lead to a highly comparable phenotype.\nDiagnostic methods\nDiagnosis is based on clinical examination, and cytogenetic and molecular studies.\nDifferential diagnosis\nThe differential diagnosis includes Noonan syndrome/RASopathies, cardiospondylocarpofacial syndrome (MAP3K7 gene), cardiac valvular dysplasia (FLNA gene), connective tissue disorders with cardiac valve involvement such as Loeys Dietz type 3 (SMAD3 gene) or 5 (TGFB3 gene).\nAntenatal diagnosis\nDetection of the TAB2 variant or deletion by chorion villus biopsy or amniocentesis should be discussed with adults carrying the deletion or variant.\nGenetic counseling\nTransmission is autosomal dominant. TAB2 deletions often arise de novo, but are also reported in families (largest known familial deletion: 8.67 Mb) and therefore should be excluded in parents before counselling a low recurrence risk. Genetic counselling should be offered to all individuals with a TAB2 variant or deletion. For patients with a heterozygous TAB2 variant or deletion, each pregnancy carries a 50% risk of transmission to offspring. Sibling recurrence in de novo mutations may occur due to mosaicism, but has not been reported.\nManagement and treatment\nRegular cardiac evaluation and evaluation of overall development, hearing, vision and connective tissue abnormalities is recommended for all affected individuals. Cardiac follow-up is needed as valvular heart disease, thoracic aneurysm and cardiomyopathy may manifest later in life. Surgical intervention for cardiac anomalies may be required. The relevance of growth hormone therapy for short stature in this syndrome is not clear and should be studied further.\nPrognosis\nLife expectancy can be limited due to severe cardiac disease. Three children died due to dilated cardiomyopathy and four adults died between the age of 40-60 from the (late) effects of structural heart disease.\n\n                            Last update: \n                            October 2021\n\n\n                            - Expert reviewer(s): \n                             A. [Aafke] ENGWERDA | ITHACA* - Dr W.S. [Mieke] KERSTJENS-FREDERIKSE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Cardiac diverticulum", "Disease Definition": "Congenital cardiac diverticulum (CCD) is a very rare congenital malformation characterized by a muscular appendix emerging from the left ventricular apex, rarely from the right ventricle or from both chambers, with clinical manifestations ranging from asymptomatic to life-threatening hemodynamic collapse.", "ORPHA ID": 1686, "Summary": "Epidemiology\nCCD is a very rare malformation. Exact prevalence and incidence data are not available. About 0.4% or 1 of 250 cardiac necropsy cases showed this malformation. In the literature, the combined number of aneurysm/diverticle reports is 418 cases. Incidence of 1/2700 on echocardiographic studies (0.04% of the population) has been reported. A very slightly higher incidence has been reported in males compared to females (1.05:1.0).\nClinical description\nCongenital cardiac diverticulum is often associated with other cardiac abnormalities (midline defects) but is mostly an isolated anomaly. It is mostly found in infants and children and occasionally as an incidental finding in adults. The left ventricular apex is the most common location, but right ventricular diverticula are also reported. Two types of CCD are described: fibrous CCD which may be asymptomatic or associated with thromboembolic events, and muscular CCD with normal myocardial contraction which is frequently associated with other congenital anomalies and may cause rupture, aortic insufficiency, endocarditis, heart failure and tachyarrhythmia. Other clinical manifestations may include dyspnea, palpitation, and chest pain. Fetal death has also been described because of intrauterine diverticulum rupture. Congenital aneurysms are composed of collagenous or connective tissue and are associated with akinesis or dyskinesis. Acquired forms of cardiac diverticulum/aneurysm are common, particularly after myocardial infarction.\nEtiology\nThe etiology of congenital cardiac diverticulum is not known. Hemodynamic factors may play a role. In the 4th embryonic life there are outpouchings in the early wall of the left ventricle which later enlarge ventriclular cavity volume. Failure during this process could be responsible for the development of aneurysms.\n\n                            Last update: \n                            March 2015"}
{"Disease Name": "Cardiac-valvular Ehlers-Danlos syndrome", "Disease Definition": "A rare form of Ehlers-Danlos syndrome (EDS) characterized by soft skin, skin hyperextensibility, easy bruisability, atrophic scar formation, joint hypermobility and severe, progressive cardiac valvular defects comprising mitral and/or aortic valve insufficiency.", "ORPHA ID": 230851, "Summary": ""}
{"Disease Name": "Cardiocranial syndrome, Pfeiffer type", "Disease Definition": "A rare, multiple congenital anomalies syndrome with intellectual disability commonly characterized by facial dysmorphism (e.g. sagittal craniosynostosis, hypertelorism, strabismus, low-set dysplastic ears, retrognathia or micrognathia, mandibular ankyloses, cleft palate, aplasia uvulae), congenital heart defects (e.g. atrioventricular septal defect, anomalous venous return), genital anomalies (e.g. cryptorchidism, microphallus), as well as growth delay and intellectual disability. In some cases, tracheobronchial anomalies, large joint contractures, syndactyly, rib anomalies and hypoplastic kidneys are reported. Rarely, no cardiac anomaly may be reported.", "ORPHA ID": 2872, "Summary": ""}
{"Disease Name": "Cardiofaciocutaneous syndrome", "Disease Definition": "A rare, multiple congenital anomalies syndrome characterized by craniofacial dysmorphology, congenital heart disease, dermatological abnormalities (most commonly hyperkeratotic skin and sparse, curly hair), neurological manifestations (hypotonia, seizures), failure to thrive and intellectual disability.", "ORPHA ID": 1340, "Summary": "Epidemiology\nAround 300 cases have been published in the literature to date. Prevalence has been estimated at 1/810,000 people in Japan. However prevalence is believed to be higher.\nClinical description\nCardiofaciocutaneous (CFC) syndrome displays wide phenotypic variability. Polyhydramnios is often reported. Neonates present at birth with relative macrocephaly, short webbed neck and distinctive dysmorphic craniofacial features (i.e. coarse facial appearance, large forehead, low-set ears, ptosis, downslanting of eyes, epicanthal folds, short nose with depressed nasal bridge, prominent philtrum, high arched palate, thick lower lip). Cardiac abnormalities, if present, may not be diagnosed until later, and include valvular pulmonary stenosis, interauricular communication and hypertrophic cardiomyopathy. Feeding difficulties, leading to failure to thrive, gastroesophageal reflux (GER), vomiting and constipation often appear in infancy but improve in childhood. Growth failure leading to short stature is sometimes due to a growth hormone deficiency. Dermatological manifestations include sparse, thin, and curly hair; dry, hyperkeratotic and hyperelastic skin (on arms, legs and face); general hyperpigmentation; progressively forming nevi; ichthyosis; palmoplantar keratoderma; café au lait spots; lymphedema; and hemangiomas. Severe eczematous lesions are frequently seen. Hypertelorism, strabismus, nystagmus, optic nerve hypoplasia and astigmatism can lead to decreased vision and acuity. Recurrent otitis media has also been reported. Neurological abnormalities (hypotonia, learning difficulties and developmental delay (motor and speech, mainly)) are seen in all children. In 50% of cases, seizures can also be present.\nEtiology\nCFC syndrome is considered a RASopathy and is due to mutations in one of the 4 genes: BRAF (7q34) (in 75% of CFC cases), MAP2K1 (15q22.1-q22.33), MAP2K2 (19p13.3), and KRAS (12p12.1), which encode proteins of the sarcoma/mitogen-activated protein kinase (RAS/MAPK) signaling pathway. This signaling pathway participates in the regulation of cell differentiation, proliferation, migration, and apoptosis.\nDiagnostic methods\nClinical diagnosis is based mainly on the presence and frequency of the characteristic clinical traits and the sporadic occurrence of the disease. Molecular genetic testing, preferably multigene panel testing, including all known RASopathy genes, is preferable. If unavailable, sequential gene testing is recommended, starting from BRAF, exons 6, 12 and 11 being the most commonly mutated.\nDifferential diagnosis\nDifferential diagnoses include Costello Syndrome (CS) and Noonan Syndrome, which have overlapping phenotypes with CFC syndrome. CFC syndrome, unlike CS, does not appear to have an increased risk of malignancies.\nAntenatal diagnosis\nPrenatal testing is possible in families with a known mutation.\nGenetic counseling\nAll bona fide cases reported to date are due to de novo dominant mutations. Due to sporadic nature of the disease, the sibling recurrence risk is very small.\nManagement and treatment\nManagement requires a multidisciplinary team. Infants may require nasogastric or gastrostomy feeding or a Nissen fundoplication when severe GER is present. Monitoring by a cardiologist is necessary and heart surgery may be required to repair specific defects. Monitoring by a neurologist is needed for the patients presenting seizures. Regular ophthalmology exams as well as corrective lenses or surgery can improve vision. Standard treatment of skin conditions is recommended. Referral to an endocrinologist may also be needed. Early occupational, physical and/or speech therapy promotes motor and speech development.\nPrognosis\nPrognosis is highly variable and is dependent on clinical manifestations. Life-expectancy can be close to normal or reduced (if severe heart and/or neurological manifestations are present).\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Maria Ines KAVAMURA"}
{"Disease Name": "Cardiogenic shock", "Disease Definition": "A rare, cardiac condition characterized by severely decreased cardiac output, hypoperfusion and end-organ dysfunction, in the presence of adequate intravascular volume. The clinical presentation is variable and may range from subtle hemodynamic alterations to overt cardiovascular collapse. Commonly reported features include dyspnea, crackles, elevated jugular venous pressure, altered mental state, abnormal pulse pressure, oliguria, cold extremities, and increased serum lactate levels.", "ORPHA ID": 97292, "Summary": ""}
{"Disease Name": "Cardiomyopathy-cataract-hip spine disease syndrome", "Disease Definition": "A rare triad of dilated cardiomyopathy, premature cataract, and articular disease of the hips and spine characterized by hip joint degeneration, irregular intervertebral disks, and platyspondyly. The ocular abnormalities are often the first symptoms to arise. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 1345, "Summary": ""}
{"Disease Name": "Cardiomyopathy-hypotonia-lactic acidosis syndrome", "Disease Definition": "Cardiomyopathy-hypotonia-lactic acidosis syndrome is characterised by hypertrophic cardiomyopathy, muscular hypotonia and the presence of lactic acidosis at birth. It has been described in two sisters (both of whom died within the first year of life) from a nonconsanguineous Turkish family. The syndrome is caused by a homozygous point mutation in the exon 3A of the SLC25A3 gene encoding a mitochondrial membrane transporter.", "ORPHA ID": 91130, "Summary": ""}
{"Disease Name": "Cardiospondylocarpofacial syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by growth retardation, short stature, feeding difficulty and failure to thrive, cardiac anomalies (septal defects and/or valve dysplasia), joint laxity, short extremities, brachydactyly, carpal and tarsal fusion, cervical vertebral fusion, inner ear malformation with bilateral conductive hearing loss, and dysmorphic facial features (such as hypertelorism, upslanting palpebral fissures, posteriorly rotated ears, anteverted nares, and long philtrum). Additional variable manifestations include gastroesophageal reflux and genitourinary anomalies, among others.", "ORPHA ID": 3238, "Summary": ""}
{"Disease Name": "Carey-Fineman-Ziter syndrome", "Disease Definition": "Carey-Fineman-Ziter (CFZ) syndrome is a rare condition characterized by the association of hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre-Robin sequence (micrognathia, glossoptosis, and high-arched or cleft palate), unusual face, and growth delay.", "ORPHA ID": 1358, "Summary": "Epidemiology\nLess than 20 cases have been reported the literature, including two pairs of sibs.\nClinical description\nMost patients had non-specific peripheral (myopathy) or central (brain anomaly) causes of hypotonia. Some had a non-specific myopathy, with consequent severe scoliosis. Other features, reported in one or two patients with CFZ, included brain anomalies (ventriculomegaly, reduced white matter, neuronal heterotopias, small foci of necrosis with microcalcifications, small pons and brainstem with enlarged pre-pontine and pontocerebellar cisterns), absence of the pectoralis major muscle with an ulnar deviation of the hand (Poland sequence), laryngostenosis, unexplained intermittent arterial hypertension with facial flushing and sweating, hydronephrosis, glanular hypospadias, and talipes equinovarus. Intelligence may be normal but mental disability has been reported. One patient also presented with a gastrointestinal disturbance with biopsy-proven villous atrophy.\nDiagnostic methods\nDiagnosis can be made on the basis of clinical features, but magnetic resonance imaging (MRI) is necessary to detect the brain anomalies.\nGenetic counseling\nAlthough CFZ syndrome has been reported in two pairs of sibs, suggesting an autosomal recessive mode of inheritance, the recurrence risk does not seem to be as high as 25%.\nManagement and treatment\nScoliosis necessitated rod placement in one patient during adolescence, and in another case induced restrictive lung disease and death from pneumonia at 37 years of age.\n\n                            Last update: \n                            April 2006"}
{"Disease Name": "Caribbean parkinsonism", "Disease Definition": "Parkinsonism with dementia of Guadeloupe is characterised by symmetrical bradykinesia, predominantly axial rigidity, postural instability with early falls and cognitive decline with prominent features of frontal lobe dysfunction.", "ORPHA ID": 97355, "Summary": "Epidemiology\nPrevalence is unknown, but a higher number of cases have been described in the French West Indies.\nEtiology\nThis form of atypical parkinsonism may be related to exposure to tropical plants containing mitochondrial complex I inhibitors.\nDifferential diagnosis\nGuadelupian parkinsonism may actually be a tauopathy identical or closely related to progressive supranuclear palsy (see this term).\nManagement and treatment\nMost patients are L-dopa unresponsive.\n\n                            Last update: \n                            December 2007"}
{"Disease Name": "Carney complex-trismus-pseudocamptodactyly syndrome", "Disease Definition": "Carney complex-trismus-pseudocamptodactyly syndrome is a rare genetic heart-hand syndrome characterized by typical manifestations of the Carney complex (spotty pigmentation of the skin, familial cardiac and cutaneous myxomas and endocrinopathy) associated with trismus and distal arthrogryposis (presenting as involuntary contraction of distal and proximal interphalangeal joints of hands evident only on dorsiflexion of wrist and similar lower-limb contractures producing foot deformities).", "ORPHA ID": 319340, "Summary": ""}
{"Disease Name": "Carney complex", "Disease Definition": "A rare endocrine disease characterized by lentigines with a specific peri-orifical distribution, blue nevus, myxomas, various endocrine tumors including primary pigmented nodular adrenocortical disease (PPNAD), acromegaly, thyroid tumors, and a wide range of other tumors.", "ORPHA ID": 1359, "Summary": "Epidemiology\nCarney complex (CNC) is a rare disease with more than 750 cases reported in the scientific and medical literature.\nClinical description\nLentigines with a specific peri-orifical distribution, blue nevus (particularly epithelioid blue nevus), and cutaneous myxomas, with a classical distribution in the eyelids, nipples, external ear canal or genitalia, are frequent and very suggestive of the diagnosis. The most common endocrine gland manifestations are of Cushing syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD), large cell calcifying Sertoli cell tumors, thyroid tumors, and acromegaly. Myxomas can also be observed in the heart and breast. Cardiac myxomas are diagnosed at a median age of 50 but may occur in early childhood, can develop in any cardiac chamber, and may be multiple and/or recurrent.\nEtiology\nIn more than 70% of cases, CNC is related to mutations of the PRKAR1A gene coding for regulatory subunit R1alpha of protein kinase A. The mutation c.709-7del6 is mostly associated with isolated PPNAD, and the mutation c.491-492del is associated with more frequent cardiac myxomas, lentigines and thyroid tumors. Deleterious PDE11A variants have been described in patients with PRKAR1A mutations, with more frequent PPNAD and testicular tumors. A germline triplication mutation involving PRKACB, the gene encoding the catalytic subunit beta of the protein kinase A, has been described in a young woman with acromegaly, lentigines and myxomas who did not harbor a PRKAR1A mutation.\nDiagnostic methods\nDiagnosis is made if two major features are present (e.g. peri-orifical lentigines, myxomas, PPNAD), or one major feature with a supplementary criterion such as a PRKAR1A mutation or an affected first-degree relative. Patients with CNC, or with a genetic predisposition to CNC, should have regular screening for manifestations of the disease. Clinical work-up for all the manifestations of CNC should be performed at least once a year in all patients and should start in infancy.\nDifferential diagnosis\nThe heterogeneity of the manifestations of CNC implies that differential diagnosis should be discussed for each of its numerous manifestations: i.e. differential diagnosis of PPNAD can be the others causes of adrenal Cushing syndrome; PPNAD can be isolated without others manifestations of CNC and no genetic variant of PRKAR1A, or be part of a classic CNC associated with another main feature like lentiginosis and/or myxoma.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in one of the 2 parents.\nGenetic counseling\nAbout 70% of the cases are familial with an autosomal dominant transmission. Genetic analysis should be proposed to all patients with CNC. In a second step, a genome-wide study may be discussed. Genetic counseling should be proposed in families with a known disease-causing mutation.\nManagement and treatment\nCardiac myxomas require surgical removal. Treatment of the other manifestations of CNC should be discussed and may include follow-up, surgery, or medical treatment depending on the location of the tumor, it's size, existence of hormonal excess or volume-related clinical signs, and the suspicion of malignancy. Bilateral adrenalectomy is the most common treatment for CS due to PPNAD.\nPrognosis\nCardiac myxoma complications and other tumors development can greatly impact the lifespan of CNC patients.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Jérôme BERTHERAT | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Carney triad", "Disease Definition": "A rare non-hereditary condition characterized by gastrointestinal stromal tumors (GIST, intramural mesenchymal tumors of the gastrointestinal tract with neuronal or neural crest cell origin), pulmonary chondromas and extraadrenal paragangliomas.", "ORPHA ID": 139411, "Summary": "Epidemiology\nLess than 100 cases have been reported worldwide. Carney's triad primarily affects young women (mean age of onset 20 years).\nClinical description\nMost patients initially present with two of the three tumors (incomplete Carney's triad). The main symptoms at presentation are gastrointestinal bleeding, epigastric pain, anemia and palpable abdominal mass. These symptoms are related to the GIST, which occur in 99% of cases. Additional features include headaches, fatigue, anorexia, hypertension and tachycardia. Pulmonary chondromas (well-differentiated benign cartilaginous tumors) occur in approximately 80% of cases. They are often asymptomatic and may be unilateral (83%) or bilateral (32%). Secreting paragangliomas (typically extraadrenal and most often mediastinal) occur in approximately 50% of patients.\nEtiology\nThe etiology is not completely understood. Impaired succinate dehydrogenase (SDH) function resulting from chromosomal losses (but not mutations) has been detected in some patients with Carney's triad, while SDHD, SDHB or SDHC germline mutations have been found in some patients with Carney-Stratakis dyad (see this term).\nDiagnostic methods\nGastroscopy, radiography and computing tomography are the main diagnostic methods. SDH genetic testing is available. The absence of a paraganglioma, which usually completes the triad after several years (median: 6 years), does not allow exclusion of the diagnosis of Carney's triad. Iodine 131-metoiodobenzylguanidine scintigraphy and Octrescan® may help to detect paragangliomas.\nDifferential diagnosis\nThe differential diagnosis should include Carney-Stratakis dyad.\nManagement and treatment\nThe treatment of choice for GIST and its metastases (overall rate: 50%) is surgical resection. GIST associated with Carney's triad are mostly indolent. Recurrence after surgery is found in approximately 50% of patients, with a mean interval after the initial presentation of 12 years. Imatinib mesylate, an effective agent in the treatment of GIST, is under investigation as an adjuvant treatment. Paragangliomas require surgical resection; chemotherapy and metabolic radiotherapy may be used in malignant cases (overall rate: 10%). Surgery for pulmonary chondromas is indicated only in case of impaired lung function. Approaches targeting SDH function may potentially be useful in treating patients with Carney's triad who show SDH deficiencies. However, at present, there is no drug that restores SDH function. Life-long follow-up should be offered to all patients with Carney's triad.\n\n                            Last update: \n                            September 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Sebastiano FILETTI"}
{"Disease Name": "Carney-Stratakis syndrome", "Disease Definition": "Carney-Stratakis syndrome is a recently described familial syndrome characterized by gastrointestinal stromal tumors (GIST) and paragangliomas, often at multiple sites.", "ORPHA ID": 97286, "Summary": "Epidemiology\nIt is a very rare syndrome reported in less than 20 unrelated families to date. It presents at a young age (median age: 19 years) with an apparently equal ratio of male and female patients.\nClinical description\nPatients with Carney-Stratakis syndrome have both GIST and paraganglioma. The gastric stromal sarcomas are multifocal and the paragangliomas are multicentric. The clinical spectrum of Carney-Stratakis syndrome varies widely, depending on the localization and the size of the tumors, and may include a palpable mass, dysphagia, abdominal pain, weight loss, hematemesis, melena, obstruction, perforation, cranial nerve palsies, tinnitus and hearing loss. GIST are intramural mesenchymal tumors of the gastrointestinal tract that originate from stem cells with characteristics of the interstitial cells of Cajal (the pacemaker cells which regulate peristalsis in the digestive tract). Paragangliomas are usually benign tumors that occur without clinical evidence of oversecretion and that arise within the sympathetic nervous system from cells of the paraganglia.\nEtiology\nThe vast majority of Carney-Stratakis syndrome cases are due to germline mutations of the succinate dehydrogenase (SDH) subunit genes SDHB, SDHC and SDHD.\nDiagnostic methods\nDiagnosis is made by clinical and radiologic examination, and confirmed immunohistochemically. Genetic testing to determine if SDH defects may be contributing to tumor growth or recurrence should be offered to pediatric GIST patients.\nDifferential diagnosis\nThe main differential diagnosis includes Carney triad.\nGenetic counseling\nPredisposition to developing these tumors is inherited in an autosomal dominant manner with incomplete penetrance.\nManagement and treatment\nTreatment modalities are surgery, embolization and radiotherapy. Chemotherapy with imatinib mesylate may be helpful for some patients with advanced-stage GIST. Targeting SDH function may potentiallybe useful in treating Carney-Stratakis syndrome patients but, at present, there are no drugs that restore SDH function. Life-long follow-up should be offered to patients with Carney-Stratakis syndrome.\n\n                            Last update: \n                            January 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe CHANSON"}
{"Disease Name": "Carnitine palmitoyl transferase 1A deficiency", "Disease Definition": "Carnitine palmitoyltransferase 1A (CPT-1A) deficiency is an inborn error of metabolism that affects mitochondrial oxidation of long chain fatty acids (LCFA) in the liver and kidneys, and is characterized by recurrent attacks of fasting-induced hypoketotic hypoglycemia and risk of liver failure.", "ORPHA ID": 156, "Summary": "Epidemiology\nSince the description of the disease in 1981, less than 50 cases have been reported.\nClinical description\nCPT-1A deficiency manifests between birth and 18 months of age with recurrent attacks of hypoketotic hypoglycemia of varying severity, triggered by fasting or intercurrent illness, that can lead to severe neurological sequelae. CPT-1A-deficient patients can also present with hepatic encephalopathy with loss of consciousness, seizures, coma, or even sudden death. There may be a risk of progression to liver failure. Patients with severe CPT-1A deficiency may also have renal tubular acidosis.\nEtiology\nCPT-1A deficiency is due to mutations in the CPT1A gene that codes for the liver isoform of the CPT1 enzyme located within the external mitochondrial membrane and whose function is to conjugate LCFAs to carnitine. This allows the transfer of LCFAs from the cytosol to mitochondria where they will be oxidized. CPT1 enzyme has three isoforms with tissue-specific expression and encoded by different genes: the 'L' isoform, expressed in the liver and kidney by the CPT1A gene (11q13), the 'M' isoform, synthesized in the skeletal and cardiac muscle by the CPT1B gene (22qter), and the brain type isoform expressed by the CPT1C gene (19q13). No clinical cases of deficiency of the muscle or brain type isoform have been described. A genetic variant of CPT1A (which results in a P479L protein change) that is very common in individuals of Alaskan and Greenland Inuit origin and some Canadian Native Americans has been described. The significance of this variant is not yet established and the risk of severe disease association as a result of the variation is uncertain. A single case of an adult who was homozygous for the P479L variant presented with muscular symptoms (muscle cramps), but an association with the variant seems doubtful.\nDiagnostic methods\nDuring metabolic crisis, blood tests reveal hypoglycemia, elevated levels of plasma carnitine and liver transaminases, and mild hyperammonemia. Urine tests may show unusually low levels of ketones, and medium-chain dicarboxylic aciduria. When well, the total free carnitine level may still be elevated but all other metabolic tests will be normal. Molecular testing and evidence of enzyme deficiency by CPT-1A assay (reduction to 5-20% of normal CPT1 activity) in the liver, lymphocytes or cultured fibroblasts, confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes fatty acid and ketogenesis disorders such as medium-chain acyl-CoA dehydrogenase (MCAD deficiency; see this term), other long-chain fatty acid oxidation disorders such as carnitine palmitoyltransferase (CPT) 2 deficiency and Reye's syndrome (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible by mutational analysis if the mutations in a proband have been identified.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be proposed to parents of an affected individual informing them of the 25% risk the offspring has of inheriting the disease-causing mutations.\nManagement and treatment\nTreatment consists primarily of avoidance of fasting. Additional measures may be considered, including nighttime feeds with uncooked cornstarch during childhood and/or a low-fat diet supplemented with medium chain triglycerides that can be metabolized by mitochondria independently from the carnitine cycle. Regular surveillance of liver enzymes and function is necessary.\nPrognosis\nWith treatment, prognosis is good and neurological damage resulting from recurrent hypoglycemia may be prevented.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Michael BENNETT  - Dr Charles STANLEY"}
{"Disease Name": "Carnitine palmitoyl transferase II deficiency, myopathic form", "Disease Definition": "The myopathic form of carnitine palmitoyltransferase II (CPT II) deficiency, an inherited metabolic disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA), is the most common and the least severe form of CPT II deficiency (see this term).", "ORPHA ID": 228302, "Summary": "Epidemiology\nAbout 300 cases of the myopathic form have been reported in the literature, but this number may under-estimate the disease prevalence.\nClinical description\nThe age of onset varies between 1 and 61 years of age with 70% of cases first presenting in childhood. The disease is more common in men, probably reflecting an ascertainment bias related to exposure to prolonged exercise. The clinical manifestations are characterized by recurrent attacks of rhabdomyolysis, muscle pain, and weakness triggered usually by prolonged physical exercise and sometimes exacerbated by extremes in temperature; episodes may also be provoked or exacerbated by prolonged fasting, such as may occur with intercurrent viral illness. Episodes of rhabdomyolysis may be associated with extreme elevation of serum creatine phosphokinase (CPK) and myoglobinuria (75% of cases) and can lead to renal failure (in 8-25% of cases, but rarely requiring dialysis). Patients are asymptomatic between episodes of rhabdomyolysis.\nEtiology\nSeveral missense mutations in the CPT2 gene result in the myopathic form of CPT II deficiency. In Caucasians, the most frequent mutation (60%) is the p.Ser113Leu mutation, which impairs enzyme stability.\nDiagnostic methods\nThe diagnosis is made by an initial tandem mass spectrometry of serum/plasma acylcarnitines followed by mutation analysis and measurements of CPT2 enzyme activity in fresh circulating lymphocytes, muscle or fibroblasts.\nDifferential diagnosis\nThe differential diagnosis should include McArdle disease, Duchenne muscular dystrophy, cytochrome c oxidase deficiency (see these terms), complex II deficiency, complex III deficiency and rhabdomyolysis due to excessive exercise, infections, autoimmune reactions or drug-related neuroleptic syndrome among others.\nGenetic counseling\nTransmission is autosomal recessive. If the disease-causing mutations are identified in an affected individual, early diagnosis by molecular genetic testing can be offered to at-risk relatives to reduce morbidity and mortality.\nManagement and treatment\nTreatment is based on avoidance of prolonged fasting (>12 hr) and a low-fat and high-carbohydrate diet combined with exercise restriction in order to avoid muscle pain and rhabdomyolysis. L-carnitine administration and anaplerotic diet therapy with triheptanoin have been suggested for treatment of the disease; however benefits have not been proven.\nPrognosis\nThe myopathic form of CPT II has a good prognosis.\n\n                            Last update: \n                            May 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Michael BENNETT  - Dr Charles STANLEY"}
{"Disease Name": "Carnitine palmitoyl transferase II deficiency, neonatal form", "Disease Definition": "The neonatal form of carnitine palmitoyltransferase II (CPT II) deficiency (see this term), an inherited disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA), is the lethal form of the disease which presents with multisystem failure.", "ORPHA ID": 228308, "Summary": "Epidemiology\nIt is a rare form of CPT II deficiency that has been reported in less than 20 families.\nClinical description\nAffected infants experience hypoketotic hypoglycemia, liver and respiratory failure and can present with cardiomyopathy, muscle hypotonia, liver calcification, cystic dysplastic kidneys and malformations of the brain due to a neuronal migration defect. Seizures and coma can occur as well as cardiac arrhythmias that generally lead to cardiac arrest in the perinatal/ early infantile period. Death occurs within days to months.\nEtiology\nThe severe neonatal CPT II deficiency is caused by homozygous or compound heterozygous CPT2 mutations that typically result in complete loss of activity of the CPT II enzyme.\nDiagnostic methods\nThe diagnosis is made by an initial tandem mass spectrometry of serum/plasma acylcarnitines followed by mutation analysis and measurements of CPTII enzyme activity in fresh circulating lymphocytes, muscle or skin fibroblasts.\nDifferential diagnosis\nThe differential diagnosis should include severe forms of carnitine-acylcarnitine translocase deficiency (CACT) and very-long-chain acyl-CoA dehydrogenase deficiency (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is available based on a combination of enzymatic and molecular testing (if mutations have been identified in the proband).\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment is only symptomatic.\nPrognosis\nPrognosis is poor. The neonatal form is almost always lethal during the first months of life.\n\n                            Last update: \n                            May 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Michael BENNETT  - Dr Charles STANLEY"}
{"Disease Name": "Carnitine palmitoyl transferase II deficiency, severe infantile form", "Disease Definition": "The severe infantile form of carnitine palmitoyltransferase II (CPT II) deficiency (see this term), an inherited disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA), is the early-onset form of the disease.", "ORPHA ID": 228305, "Summary": "Epidemiology\nIt has been identified in approximately 30 families.\nClinical description\nPresentation can be in the newborn period but most cases have an age of onset between 6 and 24 months. The disease is characterized by a severe fasting intolerance leading to metabolic derangements of hypoketotic hypoglycemia, resulting in coma and seizures, and hepatic encephalopathy leading to liver failure. There is associated skeletal muscle myopathy and cardiomyopathy which can lead to fatal paroxysmal cardiac arrhythmias.\nEtiology\nMissense mutations in the CPT2 gene result in the infantile form of CPT II deficiency. Contrary to the adult myopathic form (see this term), no S113L mutations have ever been detected in the infantile form.\nDiagnostic methods\nThe diagnosis is made by an initial tandem mass spectrometric analysis of serum/plasma acylcarnitines followed by mutation analysis and measurements of CPT2 enzyme activity in fresh circulating lymphocytes, muscle or skin fibroblasts.\nDifferential diagnosis\nThe differential diagnosis should include carnitine-acylcarnitine translocase deficiency (CACT) and very-long-chain acyl-CoA dehydrogenase deficiency (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is available using both molecular and enzymatic analysis.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment is based on prevention of the fasting intolerance by providing carbohydrate calories during periods of febrile or gastrointestinal illness. When well, a low-fat and high-carbohydrate diet is initiated and for the most severe forms of the disease overnight feeding with a slow release carbohydrate such as corn starch can be implemented. Anaplerotic therapy with triheptanoin has also been suggested as a therapy. Plasma carnitine levels may be low in the disease and L-carnitine administration is also used in the treatment but this approach has not been validated in a controlled study.\nPrognosis\nThe severe infantile form may lead to sudden death during infancy due, in general, to paroxysmal cardiac arrhythmias. This is particularly true for undiagnosed cases. Early diagnosis through newborn screening has identified cases pre-symptomatically and outcomes appear to be improving as a result.\n\n                            Last update: \n                            May 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Michael BENNETT  - Dr Charles STANLEY"}
{"Disease Name": "Carnitine palmitoyltransferase II deficiency", "Disease Definition": "Carnitine palmitoyltransferase II (CPT II) deficiency is an inherited metabolic disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA). Three forms of CPT II deficiency have been described: a myopathic form, a severe infantile form and a neonatal form (see these terms).", "ORPHA ID": 157, "Summary": "Epidemiology\nMore than 300 CPT II cases have been described with the myopathic form being the most common (myopathic form: 86%, severe infantile form: 8%, neonatal form: 6% of cases).\nClinical description\nThe myopathic form is the least severe and is characterized by recurrent attacks of rhabdomyolysis, muscle pain and weakness triggered by prolonged physical exercise, fasting, viral illness or extremes in temperature. The severe infantile form is characterized by a severe fasting intolerance leading to metabolic disorders such as hypoketotic hypoglycemia and hepatic encephalopathy. The lethal neonatal form includes symptoms of the infantile disease as well as dysmorphic features (e.g. cystic dysplastic kidneys).\nEtiology\nMore than 60 mutations in the CPT2 gene, resulting in general in amino acid substitutions or small deletions, cause the CPT II deficiency.\nDiagnostic methods\nThe diagnosis is made by an initial tandem mass spectrometry of serum/plasma acylcarnitines followed by mutation analysis and measurements of CPT2 enzyme activity in fresh circulating lymphocytes, muscle or fibroblasts.\nDifferential diagnosis\nThe differential diagnosis for the myopathic form should include McArdle disease, Duchenne muscular dystrophy, and cytochrome c oxidase deficiency (see these terms) among others, and carnitine-acylcarnitine translocase deficiency (CACT) and very-long-chain acyl-CoA dehydrogenase deficiency (see these terms) for the infantile and neonatal forms\nAntenatal diagnosis\nPrenatal diagnosis is available based on a combination of enzymatic and molecular testing.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment is based on avoidance of prolonged fasting (>12 hr) and a low-fat and high-carbohydrate diet.\nPrognosis\nThe myopathic form of CPT II has a good prognosis. The severe infantile form may lead to sudden death during infancy due, in general, to paroxysmal cardiac arrhythmias. The neonatal form is almost always lethal during the first months of life.\n\n                            Last update: \n                            April 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Michael BENNETT  - Dr Charles STANLEY"}
{"Disease Name": "Carnitine-acylcarnitine translocase deficiency", "Disease Definition": "Carnitine-acylcarnitine translocase (CACT) deficiency is a life-threatening, inherited disorder of fatty acid oxidation which usually presents in the neonatal period with severe hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy and/or arrhythmia, hepatic dysfunction, skeletal muscle weakness, and encephalopathy.", "ORPHA ID": 159, "Summary": "Epidemiology\nThe prevalence is unknown. Less than 60 cases have been reported worldwide to date.\nClinical description\nMost patients with CACT deficiency have a severe phenotype presenting within the first 48 hours of life as hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy and arrhythmias, skeletal muscle damage, liver dysfunction and hypothermia. Neurological involvement with encephalopathy, epilepsy and developmental delay are also noted. Some patients present as a sudden infant death. A rare milder phenotype presenting in infancy/early childhood is also described which manifests with episodes of hypoketotic hypoglycemia and hyperammonemia often precipitated by fasting and/or intercurrent illness.\nEtiology\nMutations in the SLC25A20 gene (3p21.31) are responsible for CACT deficiency. CACT is located in the inner mitochondrial membrane and operates a carnitine/acylcarnitine exchange across this membrane. It is an essential component of the carnitine cycle that regulates the transport of long chain fatty acids into the mitochondria where fatty acid oxidation takes place. The milder phenotype results from significant mutant protein activity.\nDiagnostic methods\nPatients with CACT deficiency present with a non-specific dicarboxylic aciduria. Blood acylcarnitine analysis shows a very high acyl fraction with marked increase in C16, C18, and C18:1 species. Free carnitine is very low. Specific enzyme analysis in cultured fibroblasts or lymphocytes will confirm a diagnosis as will the demonstration of two pathogenic mutations in the  SLC25A20 gene. Newborn screening for CACT deficiency is available in Austria, Czech Republic, Germany, Hungary, Iceland, Portugal and Spain.\nDifferential diagnosis\nThe neonatal and severe infantile forms of carnitine palmitoyl transferase II (CPT II) deficiency (see this term) need to be excluded as they have an identical acylcarnitine profile to CACT. Clinically these two disorders are virtually indistinguishable, although congenital abnormalities are not reported in CACT and only sometimes in CPT II.\nAntenatal diagnosis\nPrenatal diagnosis is possible by mutation analysis of chorionic villus tissue when two pathogenic mutations have been established in a family. Specific enzyme analysis is also available for cultured chorionic villus cells.\nGenetic counseling\nCACT is an autosomal recessive condition and genetic counseling is available.\nManagement and treatment\nStrict avoidance of fasting along with the institution of a low long-chain fat diet and medium chain triglyceride (MCT) supplementation is necessary. However, the MCT formula should be as low as possible in C10 and C12 fatty acids as high dietary intake of these can lead to decompensation. Carnitine supplementation is also recommended. During an acute episode, intravenous glucose is administered in order to inhibit lipolysis.\nPrognosis\nSevere CACT deficiency generally has a poor prognosis, with most patients dying before the age of 3 months, although a few infants treated early on in the neonatal period have had a favorable outcome in the medium term. Patients with a mild phenotype generally have a good prognosis given adherence to the treatment regimen.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Simon OLPIN"}
{"Disease Name": "Carnosinase deficiency", "Disease Definition": "A rare inborn error of metabolism characterized by low serum carnosinase activity, persistent carnosinuria, and carnosinemia. The clinical phenotype is highly variable, with some patients remaining asymptomatic, while others have been reported to show severe developmental delay, intellectual disability, hypotonia, seizures, and other neurological signs and symptoms.", "ORPHA ID": 1361, "Summary": ""}
{"Disease Name": "Caroli disease", "Disease Definition": "Caroli disease (CD) is a rare congenital liver disease characterized by non-obstructive cystic dilatations of the intra-hepatic and rarely extra-hepatic bile ducts.", "ORPHA ID": 53035, "Summary": "Epidemiology\nExact prevalence and annual incidence data are not available for CD, but the disease is known to be very rare. An estimated prevalence of 1/1,000,000 has been suggested. There is a slight female gender bias.\nClinical description\nCaroli disease can present at any age. CD ranges from simple ectasias of the larger intra-hepatic bile ducts (in this less common form the name Caroli disease is used) to a syndromic form (Caroli syndrome) that is more common and includes congenital hepatic fibrosis. Some patients remain asymptomatic throughout the disease course. Some develop intra- or extra-hepatic calculi, leading to recurrent cholangitis (with bacteremia and sepsis), and acute pancreatitis. Manifestations are those of complications, mostly bacterial cholangitis, and include abdominal pain and biliary colic, fever with chills, and jaundice. Hepatomegaly, cirrhosis and portal hypertension (with splenomegaly) are also frequently reported to develop. Besides bacterial cholangitis, complications include liver abscess, biliary infection, and in late stages, cholangiocarcinoma. CS is often associated with recessive polycystic kidney disease (see these terms). The course is largely dependent on the associated disorders.\nEtiology\nCD and CS are strongly related to PKHD1 mutations. Abnormal development of the embryonic bile ducts at the stage of ductal plate has been suggested. Full characterization of genetic anomalies associated with CD or CS beyond PKHD1 has not yet been achieved.\nDiagnostic methods\nThe diagnosis is suspected on clinical grounds and confirmed through detection of cystic dilatation in the biliary tree through imaging studies. The key diagnostic procedure is magnetic resonance cholangiography showing a characteristic aspect of abnormal bile ducts. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) should not be used for diagnosis because they are associated with an increased risk of bacterial cholangitis.\nDifferential diagnosis\nThe differential diagnosis should include primary sclerosing cholangitis, isolated polycystic liver disease, and hepatic cystic hamartoma (see these terms), as well as hepatic and choledochal cysts.\nAntenatal diagnosis\nCases of prenatal diagnosis based on ultrasonographic findings have been reported.\nGenetic counseling\nMost cases of CD are sporadic. Syndromic cases (CS) share with congenital hepatic fibrosis and recessive polycystic kidney disease an autosomal recessive transmission.\nManagement and treatment\nManagement depends on the clinical presentation, localization and stage of the disease. Ursodeoxycholic acid may be used to prevent stone formation. Antibiotics are used for cholangitis. Radiological, endoscopic, and surgical intervention may be required for patients with biliary obstruction, abscess formation and liver or bile duct stones. Patients with severe disease may be candidates for liver transplantation.\nPrognosis\nQuality of life may be significantly affected by recurrent cholangitis. Prognosis depends on the clinical course and the risk of cholangiocarcinoma.\n\n                            Last update: \n                            November 2016\n\n\n                            - Expert reviewer(s): \n                            Pr Dominique VALLA"}
{"Disease Name": "Caroli syndrome", "Disease Definition": "A rare genetic hepatic disease characterized by multiple segmental cystic dilatations of both central and smaller peripheral bile ducts associated with congenital hepatic fibrosis. Age of symptom onset is variable, as is disease progression. Patients present recurrent cholangitis, hepatolithiasis, and cholecystolithiasis. Portal hypertension may appear later in the disease course, and the risk of developing cholangiocarcinoma is increased significantly. The syndrome is often associated with autosomal recessive polycystic kidney disease.", "ORPHA ID": 480520, "Summary": ""}
{"Disease Name": "Carpenter syndrome", "Disease Definition": "A rare syndromic craniosynostosis with variable phenotypic expression characterized by craniosynostosis, intellectual disability, distinctive facies, abnormalities of the fingers and toes (brachydactyly, polydactyly and syndactyly), short stature, congenital heart disease, skeletal defects, obesity, genital abnormalities and umbilical hernia.", "ORPHA ID": 65759, "Summary": "Epidemiology\nOver 70 cases have been described in the literature.\nClinical description\nPresentation at birth is with macrosomia, umbilical hernia and craniosynostosis which ranges from cloverleaf configuration to predominant involvement of the metopic ridge to craniofacial asymmetry. Cranial anomalies may lead to raised intercranial pressure, difficulty in articulation, frequent otitis media and resultant hearing loss. Typical abnormalities of the digits include brachydactyly, cutaneous syndactyly, preaxial polydactyly in the toes and postaxial polydactlyly in the hands with broad thumbs and absent middle phalanges. Characteristic facial features may include flat nasal bridge with epicanthal folds, down-slanting palpebral fissures, corneal anomalies, low-set, posteriorly rotated malformed ears, and an underdeveloped maxilla and mandible. Congenital cardiac malformations are frequent and may include ventricular septal defect, patent ductus arteriosus, pulmonic stenosis, tetralogy of Fallot, and transposition of great vessels. Intellectual disability is common (affecting 63-75% of cases). Males often have genital abnormalities such as hypogonadism and cryptorchidism. Small primary dentition is usual, teeth are short, undersized and widely spaced, appearing as small buds worn to the gingival margins and often there is prolonged retention of primary teeth. Growth is either slightly delayed or normal and many individuals have short stature. Persistent obesity, particularly truncal obesity, beginning in childhood is common. Additional skeletal abnormalities such as deformed hips, kyphoscoliosis, and genu valgum frequently occur. Situs inversus, dextrocardia, and polysplenia has been observed in a few patients.\nEtiology\nThe syndrome is caused by truncating, misssense and loss of function mutations in two different genes RAB23 gene (6p12.1) and less commonly MEGF8 gene (19q13.2). MEGF8 mutations are associated with defective lateralization and less severe craniosynostosis (usually involving only the metopic suture) in comparison with individuals with RAB23 gene mutations.\nDiagnostic methods\nClinical diagnosis is suspected on clinical presentation and confirmed by diagnostic molecular genetic screening firstly of RAB23 and then MEGF8.\nDifferential diagnosis\nDifferential diagnosis includes other acrocephalosyndactyly disorders, as well as Gorlin syndrome, Apert syndrome and Greig cephalopolysyndactyly syndrome. Ciliopathy disorders also have overlapping features including the wide clinical variability and features such as obesity and polydactyly. Summitt syndrome and Goodman syndrome falls within the clinical spectrum of Carpenter syndrome.\nAntenatal diagnosis\nGenetic prenatal diagnosis to screen for the causative familial mutations is possible where the mutation has previously been identified in a family member. Ultrasound may detect abnormal head shape, short and bowed femurs, flattened face, proptosis, heart defect, heterotaxy and digit anomalies.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy. Phenotypic expression varies considerably, even within the same family. Genetic counseling is recommended to affected families.\nManagement and treatment\nMultidisciplinary management and treatment is required. Most patients with this syndrome will undergo early craniofacial reconstruction to improve appearance and prevent intellectual disability. Surgery may be required for congenital heart defects and shunting may be required if there is raised intercranial pressure.\nPrognosis\nThe prognosis is highly variable depending on the severity of the malformations and the degree of intellectual disability; some children grow up to become independent adults and others require more support due to intellectual disability or physical challenges. Life expectancy is shortened, mainly due to heart defects.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Corinne COLLET | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Carpotarsal osteochondromatosis", "Disease Definition": "Carpotarsal osteochondromatosis is a very rare primary bone dysplasia disorder characterized by abnormal bone proliferation and osteochondromas in the upper and lower limbs.", "ORPHA ID": 2767, "Summary": ""}
{"Disease Name": "Cartilage-hair hypoplasia", "Disease Definition": "Cartilage-hair hypoplasia is a disease affecting the bone metaphyses causing small stature from birth.", "ORPHA ID": 175, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe disease is associated with fine, slow growing hair, and sometimes with immune deficiencies. Other symptoms include short hands and possibly short, deformed limbs (varus). X-ray reveals metaphyseal lesions, especially in the knees, and large, round epiphyses during childhood. Short stature is common and has very early onset but immune deficiency is not always present. The disease course is variable.\nEtiology\nMutations in the RMRP (RNA component of mitochondrial RNA-processing endoribonuclease) gene, which maps to the 9p21-p12 locus, are responsible for the disease.\nDiagnostic methods\nThe diagnosis is confirmed by direct sequencing of the RMRP gene.\nDifferential diagnosis\nThe differential diagnosis should include other forms of short-limb dwarfism.\nAntenatal diagnosis\nA recurrence risk of 25% justifies prenatal diagnosis, which is possible through molecular analysis if the causative mutation has already been identified in a proband. Micromelia may be detected early in pregnancy during ultrasound follow up, but is not specific.\nGenetic counseling\nCartilage-hair hypoplasia is inherited in an autosomal recessive manner.\nManagement and treatment\nImmunodeficiency, when severe, may require bone marrow transplantation but this does not have any effect on the growth deficiency.\nPrognosis\nThe prognosis depends on the presence and severity of the immune deficiency and the possible association with Hirschsprung disease (see this term).\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Carvajal syndrome", "Disease Definition": "A rare genetic ectodermal dysplasia syndrome characterized by woolly hair (presenting at birth), palmoplantar keratoderma (developing in the first year of life) and dilated cardiomyopathy with predominant left ventricle involvement (developing in childhood) which can lead to life-threatening heart failure in childhood or adolescence.", "ORPHA ID": 65282, "Summary": ""}
{"Disease Name": "Castleman disease", "Disease Definition": "A rare lymphoid hemopathy characterized by involvement of lymph nodes in any part of the body, most frequently the mediastinum, abdomen, neck, or spleen, and occurring as unicentric, idiopathic multicentric, or KSHV/HHV8-associated multicentric Castleman disease. Depending on the type, patients are most commonly asymptomatic or typically present with systemic symptoms.", "ORPHA ID": 160, "Summary": ""}
{"Disease Name": "Cat-eye syndrome", "Disease Definition": "Cat eye syndrome (CES) is a rare chromosomal disorder with a highly variable clinical presentation. Most patients have multiple malformations affecting the eyes (iris coloboma), ears (preauricular pits and/or tags), anal region (anal atresia), heart and kidneys. Intellectual disability is usually mild or borderline normal.", "ORPHA ID": 195, "Summary": "Epidemiology\nCES has an estimated prevalence of 1/50,000 to 1/150,000 live births. Males and females appear to be affected equally.\nClinical description\nCES covers a very wide clinical spectrum in terms of features and severity, ranging from a normal phenotype to severe multisystemic disease. The 3 main visible characteristics are preauricular anomalies, anal atresia, and iris coloboma but none are found consistently. Preauricular skin tags and/or pits are the most consistent feature. The typical eye anomaly is absent in up to 50% of patients. Eye coloboma may involve the iris, the choroid and/or the retina. Less frequently, unilateral microphtalmia, aniridia, cornea clouding, cataract and/or Duane anomaly are observed. In addition to preauricular tags and/or pits, the external ears may be low-set and severely reduced with possible atresia of the external ear canal. Characteristic facial features are down-slanting palpebral fissures, inner epicanthic folds, hypertelorism, flat nasal bridge, and small mandible. Cleft lip/palate (see this term) is sometimes observed. In some individuals, the anal canal is narrow or absent with a fistula from the rectum into an abnormal location (the bladder, vagina or perineum). The most frequently reported congenital heart defect is congenital total pulmonary venous return anomaly and, less frequently, tetralogy of Fallot (see these terms). Congenital kidney abnormalities include absence of one or both kidneys, hydronephrosis, supernumerary kidneys, and/or renal hypoplasia. Skeletal abnormalities include spinal defects and limb malformations. Possible gastrointestinal malformations are biliary atresia, intestinal malrotation and/or Hirschsprung disease (see this term). Other variable features include hernias, cryptorchidism and hypospadias in males. Rarer malformations may affect almost every organ. Most patients have mild intellectual disability (although some moderate to severe) but a few have normal cognitive development. Short stature with growth hormone deficiency is possible in some cases.\nEtiology\nMost patients harbor a small supernumerary bisatellited marker chromosome (sSMC) that results in partial tetrasomy of 22pter-22q11. In one third of cases, this extra chromosome is present in a mosaic state. Other cytogenetic anomalies have been rarely reported, including partial trisomy of chromosome 22 and intrachromosomal triplication of the 22q11 region.\nDiagnostic methods\nThe diagnosis, suspected on the basis of clinical manifestations, is based on cytogenetic testing showing the presence of extra material derived from chromosome 22q11. Fluorescence in situ hybridization (FISH) with specific probes is needed to detect a low level mosaicism.\nDifferential diagnosis\nDifferential diagnosis includes other chromosomal disorders with overlapping phenotypes such as CHARGE syndrome and VACTERL/VATER association (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible through karyotyping and FISH analysis of prenatal samples.\nGenetic counseling\nThe extra chromosome usually arises de novo.\nManagement and treatment\nMultidisciplinary management is necessary and depends on the specific symptoms that are apparent in each patient. Surgical correction is necessary for anal atresia and severe cardiac malformations. Bacterial infections should be anticipated and treated vigorously. Patients should be screened for visual and hearing impairment. Early intervention with educational support can be beneficial.\nPrognosis\nSome patients die from severe malformations in early infancy. Otherwise, life expectancy is generally not significantly reduced.\n\n                            Last update: \n                            January 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Catherine TURLEAU"}
{"Disease Name": "Cat-scratch disease", "Disease Definition": "Cat-scratch disease is a rare infectious disease, caused by the Gram-negative bacteria Bartonella henselae, that is transmitted to humans via a scratch or bite of an infected cat and that has a variable clinical presentation but that usually manifests with an erythematous papule at the site of inoculation followed by chronic regional lymphadenopathy. Clinical course is usually self-limiting but disseminated illness with high fever, hepatosplenomegaly, granulomatous osteolytic lesions, encephalitis, retinitis, and atypical pneumonia can also occur. Cat-scratch disease can atypically present as parinaud oculoglandular syndrome (unilateral conjunctivitis and preauricular lymphadenopathy).", "ORPHA ID": 50839, "Summary": ""}
{"Disease Name": "Cataract-aberrant oral frenula-growth delay syndrome", "Disease Definition": "Cataract-aberrant oral frenula-growth delay syndrome is characterized by cataracts and short stature associated with variable anomalies, including aberrant oral frenula, a characteristic facial appearance (posteriorly angulated ears, upslanting palpebral fissures, small nose, ptosis and epicanthal folds) cavernous hemangiomas and hernias. It has been described in a mother and her two children. It is transmitted as an autosomal dominant trait.", "ORPHA ID": 1373, "Summary": ""}
{"Disease Name": "Cataract-ataxia-deafness syndrome", "Disease Definition": "A rare genetic disease characterized by mild intellectual deficit, congenital cataract, progressive sensorineural hearing impairment, ataxia, peripheral neuropathy, and short stature. There have been no further descriptions in the literature since 1991.", "ORPHA ID": 1368, "Summary": ""}
{"Disease Name": "Cataract-congenital heart disease-neural tube defect syndrome", "Disease Definition": "Cataract-congenital heart disease-neural tube defect syndrome is a multiple congenital anomaly syndrome characterized by sacral neural tube defects resulting in tethered cord, atrial and/or ventricular septal heart defects (that are detected in infancy), bilateral, symmetrical hyperopia, rapidly progressive early childhood cataracts, bilateral aphakic glaucoma, and abnormal facial features (low frontal hairline, small ears, short philtrum, prominent, widely spaced central incisors, and micrognathia). Hypotonia, growth and developmental delay, seizures, and joint limitation are also reported.", "ORPHA ID": 314993, "Summary": ""}
{"Disease Name": "Cataract-deafness-hypogonadism syndrome", "Disease Definition": "Cataract-deafness-hypogonadism syndrome is an extremely rare multiple congenital abnormality syndrome, described in only three brothers to date, that is characterized by the association of congenital cataract, sensorineural deafness, hypogonadism, mild intellectual deficit, hypertrichosis, and short stature. There have been no further descriptions in the literature since 1995.", "ORPHA ID": 1383, "Summary": ""}
{"Disease Name": "Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome", "Disease Definition": "A rare mitochondrial disease characterized by a highly variable phenotypic spectrum comprising delayed motor development, peripheral neuropathy, cataract, short stature due to growth hormone deficiency, nystagmus, sensorineural hearing loss, dysmorphic facial features, and skeletal abnormalities consistent with spondyloepimetaphyseal dysplasia. Hyperextensible joints, achalasia, and telangiectasia have also been described. Cognition is normal. Atrophy of the pituitary gland has been observed in brain imaging.", "ORPHA ID": 436174, "Summary": ""}
{"Disease Name": "Cataract-hypertrichosis-intellectual disability syndrome", "Disease Definition": "Cataract-hypertrichosis-intellectual disability syndrome is characterized by congenital cataract, generalized hypertrichosis and intellectual deficit. It has been described in two Egyptian sibs born to consanguineous parents. It is transmitted as an autosomal recessive trait.", "ORPHA ID": 1375, "Summary": ""}
{"Disease Name": "Cataract-intellectual disability-anal atresia-urinary defects syndrome", "Disease Definition": "Cataract-intellectual disability-anal atresia-urinary defects syndrome is characterised by congenital cataracts with squint, intellectual deficit, anomalies of the genitourinary tract (rectovesical fistula, micropenis, undescended testis, and hypospadias), imperforate anus and other anomalies.", "ORPHA ID": 1381, "Summary": "Epidemiology\nIt has been described in three siblings born to nonconsanguineous parents.\nGenetic counseling\nIt is likely to be transmitted as an autosomal recessive trait.\nManagement and treatment\nThe patients underwent surgery for imperforate anus and cataract.\n\n                            Last update: \n                            March 2007"}
{"Disease Name": "Cataract-intellectual disability-hypogonadism syndrome", "Disease Definition": "This syndrome is characterized by the association of intellectual deficit, congenital cataract, and hypogonadotropic hypogonadism.", "ORPHA ID": 1387, "Summary": "Epidemiology\nLess than 20 cases have been described in the literature so far.\nClinical description\nBesides the three main features of the syndrome, other anomalies have been reported in some of the affected patients including short stature, minor digital abnormalities, microcephaly, cardiomyopathy, heart failure, and mild facial dysmorphism (micrognathia, maxilla hypoplasia, low posterior hairline and large ears).\nEtiology\nMutations in the RAB3GAP2 gene have been identified in some patients.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "Cataract-microcornea syndrome", "Disease Definition": "A rare syndromic, genetic cataract characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Clinical findings include a decreased corneal diameter (inferior to 10 mm) in both meridians in an otherwise normal eye, and an inherited cataract, which is mostly bilateral posterior polar with opacification in the lens periphery that progresses to form a total cataract after visual maturity has been achieved. Association with other ocular manifestations, including myopia, iris coloboma, sclerocornea and Peters anomaly may be observed.", "ORPHA ID": 1377, "Summary": ""}
{"Disease Name": "Cataract-nephropathy-encephalopathy syndrome", "Disease Definition": "A rare lethal combination of manifestations including short stature, congenital cataracts, encephalopathy with epileptic fits, and postmortem confirmation of nephropathy (renal tubular necrosis). There have been no further descriptions in the literature since 1963.", "ORPHA ID": 1380, "Summary": ""}
{"Disease Name": "Catastrophic antiphospholipid syndrome", "Disease Definition": "A rare systemic autoimmune disease characterized by acute onset of life-threatening thromboses in three or more organs either simultaneously or within less than a week, in the presence of serum antiphospholipid antibodies (such as lupus anticoagulant, anticardiolipin antibodies, and anti-beta2-glycoprotein 1 antibodies), and with histopathological confirmation of small-vessel occlusion in at least one affected organ. The condition is often precipitated by infection, trauma, or surgery.", "ORPHA ID": 464343, "Summary": ""}
{"Disease Name": "Catecholaminergic polymorphic ventricular tachycardia", "Disease Definition": "A rare, severe genetic arrhythmogenic disorder of the structurally normal heart characterized by catecholamine-induced ventricular tachycardia (VT) manifesting as syncope and sudden death in young individuals.", "ORPHA ID": 3286, "Summary": "Epidemiology\nThe prevalence of catecholaminergic polymorphic ventricular tachycardia (CPVT) is estimated to be 1/10,000. Both sexes are equally affected.\nClinical description\nTypical age of onset of CPVT is between 7 and 15 years of age. Exercise- or emotion-induced syncopal spells are frequently the first symptom. In a subset of patients (10-20%), the disease is clinically silent, presenting only in the event of sudden death. Up to one third of CPVT patients experience life-threatening arrhythmic events prior to starting treatment. The typical arrhythmias of CPVT are bidirectional VT, and, less frequently, supraventricular tachycardias.\nEtiology\nThe disorder is genetically heterogeneous; in 70% of cases, the cardiac ryanodine receptor (RYR2, 1q43) gene is implicated with autosomal dominant inheritance. Mutations in the cardiac calsequestrin gene (CASQ2, 1p13.1) cause an autosomal recessive form of CPVT in 2% to 5% of patients, and in rare instances may cause autosomal dominant CPVT. Other, rarer genes causing CPVT include Trans-2,3-enoyl-CoA reductase-like (TECRL, 4q13.1), calmodulin-1 (CALM1, 14q32.11), and cardiac triadin (TRDN, 6q22.31).\nDiagnostic methods\nSubjects with a family history of CPVT, or emotion- or exercise-induced sudden death or syncope should undergo exercise stress test and Holter monitoring. Given the reproducibility of arrhythmias, graded exercise stress test is of utmost diagnostic importance. Holter monitoring is also indicated for the rarer cases where acute emotion represents a more powerful trigger. Resting electrocardiogram is usually unremarkable. Cardiac imaging (echocardiogram and MRI) is unremarkable.\nDifferential diagnosis\nThe principal differential diagnoses are long QT syndrome (LQTS), arrhythmogenic right ventricular cardiomyopathy (ARVC), and Andersen-Tawil syndrome.\nAntenatal diagnosis\nAntenatal diagnosis can be performed in families with high penetrance and a highly lethal mutation.\nGenetic counseling\nScreening for the RYR2 mutation and CASQ2 mutation is indicated in all patients with confirmed or suspected CPVT. Screening forTECRL, CALM1, and TRDN mutations may be considered as a second-line analysis. According to the mutation identified, the appropriate genetic counseling should be offered to affected families.\nManagement and treatment\nLifestyle changes such as limitation of physical activity, avoidance of strong emotion and stressful environments should be recommended to all CPVT patients. Beta blockers (BB; particularly nadolol) are the first treatment option for patients with CPVT and the maximum tolerated dose should be administered to control arrhythmias. Flecainide, a sodium channel blocker, can be considered in patients with BB-resistant arrhythmias. Implantable cardioverter defibrillator (ICD) is recommended in CPVT patients who survived a cardiac arrest, and in those experiencing recurrent syncope or breakthrough arrhythmias despite compliance to an optimal medical treatment.\nPrognosis\nAlthough CPVT is a severe disease with high mortality if untreated, early diagnosis and adequate treatment can greatly increase life expectancy. Lifestyle modifications along with optimal medical therapy and ICD implantation in patients with recurrent symptoms portends a favorable prognosis.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Deni KUKAVICA  - Pr Silvia PRIORI"}
{"Disease Name": "Catel-Manzke syndrome", "Disease Definition": "Catel-Manzke syndrome is a rare bone disease characterized by bilateral hyperphalangy and clinodactyly of the index finger typically in association with Pierre Robin sequence (see this term) comprising micrognathia, cleft palate and glossoptosis.", "ORPHA ID": 1388, "Summary": "Epidemiology\nCatel-Manzke syndrome has been described in more than 33 patients.\nClinical description\nThe key feature of Catel-Manzke syndrome is a bilateral hyperphalangy of the index finger in which there is an accessory ossification center at the metacarpophalangeal joint, resulting in radial deviation of the index finger. In 80% of cases, the digital abnormality is associated with Pierre Robin sequence which combines micrognathia, glossoptosis and cleft palate. Additional frequently reported congenital malformations include cardiac defects such as ventricular septal defect and interatrial communication (see these terms). Less frequent findings include iris coloboma, mild facial dysmorphism (hypertelorism, short palpebral fissures, full cheeks, low-set or posteriorly rotated ears), pectus excavatum, pectus carinatum, scoliosis, bilateral brachydactyly, bilateral fifth finger clinodactyly, knee dislocation, talipes, short halluces, failure to thrive and an intellectual disability, ranging from mild to severe.\nEtiology\nHomozygous and compound heterozygous mutations in TGDS (13q32.1) have been implicated as causal in Catel-Manzke syndrome.\nDiagnostic methods\nThe disease is diagnosed at birth due to the manifestions linked with Pierre Robin sequence and the abnormal index finger. Radiological findings confirm digital abnormalities including a supernumerary deltoid or trapezoid bone located ulnarwards between the slightly shortened second metacarpal and the significantly shortened corresponding proximal phalanx. On its ulnar side, or more unusually on its radial side, the accessory bone has a pin-shaped bone, possibly an epiphysis causing a broadening of the index finger at the level of the metacarpophalangeal joint. The supernumerary bone fuses with the first phalanx in later life which may cause subluxation at the metacarpo-phalangeal joint.\nDifferential diagnosis\nDifferential diagnoses related to the bone abnormalities may include Desbuquois syndrome, Temtamy preaxial brachydactyly syndrome and brachydactyly type C (see these terms).\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling is recommended.\nManagement and treatment\nTreatment for airway distress and/or feeding complications involves prone positioning for breathing and/or feeding and is effective for most neonates. The cleft palate is usually corrected by surgical intervention before the age of nine months. Long-term orthodontic care is required. However, follow-up by a multidisciplinary team (pediatrician, craniofacial surgeon, cardiologist, ear, nose and throat specialist and speech therapist) is recommended. The infant continues to need feeding and speech assessments and breathing capacity needs to be monitored.\nPrognosis\nPrognosis is good with appropriate early treatment and successful management of clinical manifestations during the first year of life.\n\n                            Last update: \n                            December 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Almuth CALIEBE"}
{"Disease Name": "Cathepsin A-related arteriopathy-strokes-leukoencephalopathy", "Disease Definition": "A rare genetic cerebral small vessel disease characterized by an adult-onset primary microangiopathy with severe atherosclerosis of arterioles and secondary leukoencephalopathy. Patients may present with migraine, transient ischemic attacks, stroke with central facial palsy, cognitive dysfunction with impaired concentration, dementia, depression, movement disorder, vertigo, dysphagia, dysarthria, sicca syndrome, impaired REM sleep, and therapy-resistant hypertension, among others. Brain MRI typically shows a leukoencephalopathy that is disproportionately severe and extensive compared to the clinical disease.", "ORPHA ID": 575553, "Summary": ""}
{"Disease Name": "Caudal appendage-deafness syndrome", "Disease Definition": "Caudal appendage-deafness syndrome is characterized by caudal appendage, short terminal phalanges, deafness, cryptorchidism, intellectual deficit, short stature and dysmorphism. It has been described in monozygotic twin boys.", "ORPHA ID": 1123, "Summary": ""}
{"Disease Name": "Caudal duplication", "Disease Definition": "Caudal duplication (CD) is a rare developmental anomaly in which structures derived from the embryonic cloaca and notochord are duplicated to varying extents.", "ORPHA ID": 1756, "Summary": ""}
{"Disease Name": "Caudal regression syndrome", "Disease Definition": "A rare congenital malformation of the lower spinal segments characterized by a high truncated conus with either aplasia or hypoplasia of the sacrum and lumbar spine. Coexisting malformations of gastrointestinal, genitourinary, skeletal, nervous system are commonly described.", "ORPHA ID": 3027, "Summary": "Epidemiology\nWhilst the exact prevalence at birth is unknown, the incidence of caudal regression syndrome (CRS) is estimated between 1/20,000-100,000 pregnancies. Maternal diabetes is a major risk factor for developing CRS, and the disorder is up to 200 fold more frequent in this group of patients than in the general population.\nClinical description\nThe spectrum of anomalies affecting the caudal end of the trunk vary from isolated partial agenesis of the sacrococcygeal spine to more severe deformities. The caudal malformation can result in deformities of the pelvis (typically fusion of the iliac wings), anomalies of the lower extremities (i.e. flexion of the knees, varus position of the feet) and motor and neurological deficits of varying degrees of severity (i.e. spontaneous motor activity and impaired deep tendon reflexes of lower limbs). Additional complications of the genitourinary, gastrointestinal and respiratory systems may occur. Genitourinary anomalies can involve unilateral or bilateral renal agenesis, renal ectopia and fused ureters, and generally lead to urinary obstruction, neurogenic bladder, enuresis, or vesicoureteral reflux. Gastrointestinal anomalies can involve inability to control bowel movements (incontinence, encopresis) and an imperforate anus. Congenital heart anomalies are frequently observed. Cases with Chiari I malformation, holoprosencephaly, chronic hypertension and cleft lip and palate have also been reported.\nEtiology\nThe malformations are believed to result from impaired development of the mesoderm prior to 4 weeks gestation. However, vascular steal or hypoperfusion with fetal hypoxemia is also hypothesized due to a few descriptions of a single umbilical cord. Several etiologic factors have been suggested and include maternal diabetes, hypoperfusion, as well as a genetic predisposition (for example mutation in VANGL1 gene (1p13.1), CELSR1 (22q13.31) and, FUZ gene (19q13.33).\nDiagnostic methods\nDiagnosis is based on antenatal ultrasound examination in the first trimester of pregnancy in the most severe cases. The severity of the disease is determined by examination of the newborn by means of postnatal ultrasonographic and nuclear magnetic resonance imaging (MRI) examination.\nDifferential diagnosis\nThe main differential diagnosis is sirenomelia. CRS has also been associated with the VACTERL syndrome, and Currarino syndrome is a form of caudal regression syndrome characterized by the classic triad of presacral mass, sacral bone defect and anorectal malformation. Due to the similarity between sirenomelia, VACTERL and CRS, the distinction between these defects is debated.\nAntenatal diagnosis\nIn severe forms, diagnosis is easier in the first trimester and more difficult later in pregnancy due to oligohydramnios. Sacrococcygeal dysgenesis, abrupt termination of spinal cord, and other anomalies (cardiac, renal, gastrointestinal, lower limbs) can be diagnosed in the second or third trimester. Fetal MRI can be useful in difficult cases or to better define anomalies.\nGenetic counseling\nThe most severe cases of CRS appear to be sporadic but the milder forms appear to be inherited in an autosomal dominant manner with variable phenotypes.\nManagement and treatment\nTreatment and management is supportive and requires a multidisciplinary approach by neurosurgeons, orthopedics, urologists, nephrologists, physical therapists, and psychologists. Neurogenic bladder is commonly described and clean intermittent catheterization and/or anticholinergic drug administration are generally required to treat urological disorders. Surgical interventions such as vesicoureteral reimplantation, cystostomy, Mitrofanoff are commonly performed in order to improve quality of life, urinary continence, and preserve renal function. Surgical reconstruction (Pena Procedure) can be required for imperforate anus, although colostomy may be required in some cases. Depending on the severity of the syndrome, orthopedic interventions may also be required.\nPrognosis\nPrognosis is poor and is mainly related to urological and cardiac malformations. Early neonatal death in the severe forms occurs from cardiac, renal and respiratory complications. Surviving infants usually have normal cognitive function.\n\n                            Last update: \n                            April 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Giovanni MOSIELLO | EUROGEN* - Dr Emmanuelle SAMSON \n\n\n                                * European Reference Network"}
{"Disease Name": "Caudal regression-sirenomelia spectrum", "Disease Definition": "A group of rare genetic developmental defect during embryogenesis disorders characterized by varying degrees of caudal abdomen, pelvic, renal, anorectal, urogenital and/or lumbosacral spine malformations, with or without lower limb fusion. Phenotype is highly variable ranging from minor forms with isolated coccygeal agenesis to severe forms presenting with a single rudimentary limb. Central nervous system anomalies have also been reported.", "ORPHA ID": 444941, "Summary": ""}
{"Disease Name": "Cavitary myiasis", "Disease Definition": "Cavitary myiasis is a rare parasitic disease characterized by the infestation of natural body cavities (e.g. aural, nasal, oral, urogenital myiasis) and internal organs (e.g. cerebral myiasis, ophthalmomyiasis, intestinal and tracheopulmonary myiasis) with dipteran larvae. Clinical presentation is variable depending on the affected site(s) and degree of infestation and include foreign-body sensation (with or without movement sensation), hemorrhage, pain, edema, sensory loss, malodor, and pruritus, among others. Neurological features (e.g. motor deficits, seizures, reduced mental status, extrapyramidal signs) have been reported in cerebral myiasis.", "ORPHA ID": 165958, "Summary": ""}
{"Disease Name": "CCDC115-CDG", "Disease Definition": "A rare congenital disorder of glycosylation characterized by infantile onset of hepatosplenomegaly, progressive liver failure, hypotonia, and global developmental delay. Mild dysmorphic features and seizures have also been reported. Laboratory abnormalities include elevated liver enzymes, mild hypercholesterolemia, and low serum ceruloplasmin.", "ORPHA ID": 468684, "Summary": ""}
{"Disease Name": "CDKL5-deficiency disorder", "Disease Definition": "A rare genetic neurodevelopmental disorder characterized by early-onset drug-resistant seizures and severe neurodevelopmental impairment with major motor development delay.", "ORPHA ID": 505652, "Summary": "Epidemiology\nCDKL5-related epileptic encephalopathy has an estimated birth prevalence of 1/42,400 in the UK (Scotland). It affects predominantly females with a sex ratio of 12:1\nClinical description\nPresentation is of severe seizures with onset in the first six months of life (often within the first 3 months or even the first few weeks after birth), hypotonia, poor eye contact and poor neurocognitive development. Severe hypotonia can be present before seizure onset, as well as irritability, excessive crying, drowsiness, and poor sucking. Seizures are usually difficult and include epileptic spasms, myoclonic seizures, tonic seizures and tonic-clonic seizures. At the beginning EEG might not reveal significant epileptiform abnormalities, however over time abundant and multifocal epileptiform discharges are evident. During the disease course a seizure free period might be observed, this is also reported as ''honey-moon period''. The neurological outcome is poor as most affected individuals cannot walk and many are confined to a wheelchair. Communication strategies are restricted to elementary non-verbal communication. Patients do not develop autonomy to feed themselves. Subtle dysmorphic facial features include a prominent/broad forehead, deep-set eyes, a well-defined philtrum, and everted lower lip, possibly associated with tapered fingers and hallux valgus. Stereotypies are common. Some may have scoliosis, visual impairment, gastrointestinal difficulties, and sleep problems. Epilepsy is drug-resistant and most of patients continue with active epilepsy.\nEtiology\nThe disorder is caused by mutations or deletions in the cyclin-dependent kinase-like 5 (CDKL5, Xp22.13) gene situated in the X chromosome. CDKL5 is a kinase predominantly expressed in the brain. Deficiency in CDKL5 leads to neurodevelopmental alterations.\nDiagnostic methods\nDiagnosis is suspected in patients with early onset epilepsy with a severe developmental delay and with a poor response to anti-epileptic drugs. Genetic identification of CDKL5 alterations confirms diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes developmental epileptic encephalopathies (DEE) with early onset seizures and West syndrome. Molecular testing of the CDKL5 gene should be considered in cases DEE, West syndrome.\nGenetic counseling\nThe pattern of inheritance is X-linked. The risk of recurrence in affected families is low since the pathogenic mutations occur de novo in most cases; however, some cases of parental mosaicism have been reported.\nManagement and treatment\nThere is no medication currently approved for the specific treatment of this disorder. Management is symptom-based and requires a multidisciplinary approach. Anticonvulsant medications and ketogenic diet is used for the management of seizures. Non-pharmacological management includes physical, occupational, visual and speech therapy.\nPrognosis\nLife expectancy is unknown due to underdiagnosis in adults, but adult patients are known. Prognosis is poor with severe psychomotor deficits and intractable seizures remaining into adulthood. Autonomy is never reached.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Helen CROSS | EpiCARE* - Pr Reetta KÄLVIÄINEN | EpiCARE* - Pr Rima NABBOUT | EpiCARE* - Pr Nicola SPECCHIO | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "CEBPE-associated autoinflammation-immunodeficiency-neutrophil dysfunction syndrome", "Disease Definition": "A rare genetic autoinflammatory syndrome with immune deficiency characterized by a combination of autoinflammation, immunodeficiency, and neutrophil dysfunction, as well as mild bleeding diathesis. Patients present recurrent attacks of abdominal pain, high fever, and systemic inflammation lasting four to five days and occurring every few weeks. Attacks may be accompanied by nailbed, tongue, submandibular, and gluteal abscesses, intra-abdominal granulomas, pyoderma gangrenosum, and buccal ulcerations. Frequent episodes of purulent paronychia, superficial skin and mucosal infections, and purulent upper respiratory tract infections have also been reported.", "ORPHA ID": 566067, "Summary": ""}
{"Disease Name": "CEDNIK syndrome", "Disease Definition": "A rare, genetic, neurocutaneous disease characterized by severe developmental abnormalities of the nervous system and aberrant differentiation of the epidermis. Patients present with a unique constellation of clinical signs described with the acronym CEDNIK: CErebral Dysgenesis, Neuropathy, Ichthyosis, and palmoplantar Keratoderma.", "ORPHA ID": 66631, "Summary": ""}
{"Disease Name": "Celiac artery compression syndrome", "Disease Definition": "A rare disease caused by compression of the celiac axis by an abnormally shaped arcuate ligament (the part of the diaphragm in which both pillars join in the midline around the aorta). Patients have recurrent abdominal pain, anorexia and weight loss. The pain is epigastric, and diarrhea or constipation may be present as well. Onset of pain will usually, although not always, be after food intake, and may be associated with nausea and emesis. Other symptoms may include lassitude, exercise intolerance and vomiting. Occasionally, a patient may show an abdominal murmur upon auscultation.", "ORPHA ID": 293208, "Summary": ""}
{"Disease Name": "Celiac disease-epilepsy-cerebral calcification syndrome", "Disease Definition": "Celiac disease, epilepsy and cerebral calcification syndrome (CEC) is a rare disorder characterized by the combination of auto-immune intestinal disease, epileptic seizures and cerebral calcifications.", "ORPHA ID": 1459, "Summary": "Epidemiology\nCEC was first described in 1992 and fewer than 200 cases have been reported so far.\nClinical description\nCeliac disease (CD, see this term) and epilepsy manifest at a variable age, and CD is frequently diagnosed in late childhood, when specific investigations are performed secondary to observation of epileptic seizures and cerebral calcifications (CC). CD can present in a typical form characterized by onset in the first 2 years of life, chronic diarrhea, weight loss, short stature, anorexia, and, in some cases, irritability and vomiting. CD may also present in silent or latent forms, which are characterized - in the absence of gastrointestinal symptoms - by dermatitis herpetiformis, dental enamel defects or autoimmune thyroiditis. In CEC patients, CD usually evolves into latent, silent or paucisymptomatic forms. Epilepsy onset is between infancy and adulthood; most cases occur in early childhood. Most patients present with occipital epileptic seizures, the course being highly variable, with benign, drug-resistant, or epileptic encephalopathy forms. In the latter, severe mental deterioration and/or learning disorders have been reported while a mild mental deterioration is observed in only one third of all CEC cases. CCs are seen in subcortical parieto-occipital regions. CC size does not change significantly over time, but in several cases, new CCs appeared in other regions. Patients with CCs and CD without epilepsy are considered as having an incomplete form of CEC. Some patients with epilepsy and CC without CD are considered to have a CEC with latent CD.\nEtiology\nEtiology of CEC is unclear. It is not known if epilepsy and/or CC are a consequence of CD. CD is an immune auto-inflammatory reaction occurring in predisposed gluten-intolerant individuals. It originates from the jejunal mucosa and spreads to the lamina propria, leading to the observed histopathological features (crypt hyperplasia, jejunal villous atrophy and inflammatory infiltrate in the lamina propria). CD may induce autoimmune responses outside the gastrointestinal tract. Circulating activated T cells may cross the blood-brain barrier and be toxic to myelin or myelin-producing cells. As for isolated CD, CEC is associated with the HLA-DQ2 and HLA-DQ8 genes.\nDiagnostic methods\nDiagnosis relies on anamnestic investigation and EEG to characterize epileptic seizures. Computed tomography (CT) imaging reveals CC. Laboratory findings (antiendomisium antibodies, antigliadin antibodies, anti-tissue-transglutaminase type 2 antibodies, HLA phenotype), and histopathological analysis of small bowel biopsy (jejunal mucosa villous atrophy) enable identification of silent or latent CD in a patient with epileptic seizures and CC.\nDifferential diagnosis\nDifferential diagnosis of CEC includes Sturge-Weber syndrome (see this term) without nevus flammeus and other conditions such as congenital folate malabsorption or adverse effects of methotrexate, antifolate agents and radiotherapy of leukemic children.\nManagement and treatment\nCD requires life-long observance of a gluten-free diet (GFD), leading to clinical and histopathological resolution of symptoms. A study has revealed that early CD diagnosis and treatment by GFD could prevent or reverse the epileptic disorder.\nPrognosis\nEarly diagnosis and good compliance of GFD greatly improve outcome. On the contrary, if treatment is delayed, epilepsy may be more severe and epileptic encephalopathy may develop.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Giuseppe GOBBI"}
{"Disease Name": "CELSR1-related late-onset primary lymphedema", "Disease Definition": "A rare genetic primary lymphedema characterized by unilateral or bilateral lower limb lymphedema of variable severity. The condition shows almost complete penetrance with onset in childhood or adolescence in females, whereas in males it shows incomplete penetrance with later onset of disease. Lymphoscintigraphy in more severely affected individuals reveals lymphatic abnormalities consistent with lymphangiectasia, valve dysfunction, and thoracic duct reflux.", "ORPHA ID": 569816, "Summary": ""}
{"Disease Name": "Cenani-Lenz syndrome", "Disease Definition": "Cenani-Lenz syndrome (CLS) is a congenital malformation syndrome that associates a complex syndactyly of the hands with malformations of the forearm bones and similar manifestations in the lower limbs.", "ORPHA ID": 3258, "Summary": "Epidemiology\nFewer than 30 cases have been described and the exact incidence has not been evaluated. The majority of cases occurred in related families.\nClinical description\nClassical CLS is characterized by the almost symmetrical presence of a total fusion of fingers and synostosis of the hand bones, giving the hands a mitten-like appearance. A variant of the syndrome, with oligodactyly and partial syndactyly, has been reported. The following features characterize the syndrome: carpal, metacarpal and digital synostoses, disorganization of the carpal bones, numeric reduction of the digital rays and toe syndactyly. Other features are radioulnar synostosis with shortening of the radius and ulna, brachymesomelia, radius head dislocation and metatarsal synostoses. The syndrome affects both the upper and lower limbs but, in general, the latter are less severely affected. Associated malformations (renal hypoplasia and vertebral and hemivertebral anomalies) have occasionally been reported. A few publications associate CLS with other, more frequent, forms of syndactyly. Mild facial dysmorphism (ptosis, high-arched palate, high, broad and prominent forehead, hypertelorism, flat nasal bridge, down slanting palpebral fissures, short nose, short prominent philtrum and malar hypoplasia) has been described in isolated cases.\nEtiology\nThe disease is transmitted as an autosomal recessive trait. Homozygous or compound heterozygous mutations of the LRP4 gene (11p12-p11.2) have been identified. A heterozygous duplication of 1.7 Mb covering the GREM1 and FMN1 genes has also been reported in a CLS-like form of the syndrome.\nDiagnostic methods\nDiagnosis is essentially clinical.\nDifferential diagnosis\nCLS can be distinguished clinically from other limb malformations.\nAntenatal diagnosis\nDiagnosis can be suspected antenatally by ultrasonography.\nGenetic counseling\nAs an autosomal recessive syndrome, recurrence risk for CLS is 25% for a subsequent pregnancy.\nManagement and treatment\nSurgical treatment with reconstruction of an individualized finger is recommended but the functional results of syndactyly release may be unsatisfactory.\nPrognosis\nFunctional prognosis depends on the specific limb anomalies of the patient.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Didier LACOMBE"}
{"Disease Name": "Central areolar choroidal dystrophy", "Disease Definition": "A hereditary macular disorder, usually presenting between the ages of 30-60, characterized by a large area of atrophy in the centre of the macula and the loss or absence of photoreceptors, retinal pigment epithelium and choriocapillaris in this area, resulting in a progressive decrease in visual acuity.", "ORPHA ID": 75377, "Summary": ""}
{"Disease Name": "Central cloudy dystrophy of François", "Disease Definition": "Central cloudy dystrophy of François is a very rare form of stromal corneal dystrophy (see this term) characterized by polygonal or rounded stromal opacities surrounded by clear tissue, and generally no effect on vision.", "ORPHA ID": 98972, "Summary": "Epidemiology\nThe prevalence of this form of corneal dystrophy is unknown.\nClinical description\nLesions generally appear in the first decade of life; subjects with the condition are mostly asymptomatic. The course of the disease is non-progressive.\nEtiology\nEtiology is unknown.\nDifferential diagnosis\nCorneal changes are very similar to Vogt posterior crocodile shagreen, a corneal degenerative disease.\nGenetic counseling\nAutosomal dominant inheritance has been reported.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Central congenital hypothyroidism", "Disease Definition": "Central or secondary congenital hypothyroidism is a type of permanent congenital hypothyroidism (see this term) characterized by permanent thyroid hormone deficiency that is present from birth and secondary to a disorder in the thyroid-stimulating hormone (TSH) - thyrotropin-releasing hormone (TRH) system.", "ORPHA ID": 226298, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe clinical manifestations are often subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment central hypothyroidism results in intellectual deficit and short stature.\nEtiology\nCentral hypothyroidism usually results from defects of TSH production and is often part of a disorder causing congenital hypopituitarism (see this term), in which case the clinical signs may also include septo-optic dysplasia or cleft lip and/or palate as well as other signs of hypopituitarism, or part of a larger genetic syndrome such as pituitary stalk interruption syndrome (see this term). Mutations in genes regulating pituitary gland development including HESX1, LHX3, LHX4, POU1F1 and PROP1 (3p21.2-p21.1, 9q34.3, 1q25, 3p11 and 5q) may also cause central hypothyroidism. Central hypothyroidism may also result from isolated TSH deficiency (see this term), which is transmitted in an autosomal recessive manner and is caused by mutations in the TSHB subunit gene (1p13), or from TRH resistance (see this term) caused by mutations in the TRH receptor gene (TRHR; 8q23).\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Central core disease", "Disease Definition": "Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy.", "ORPHA ID": 597, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nCCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness, pronounced in the hip girdle. Orthopaedic complications are common and malignant hyperthermia susceptibility (MHS) is a frequent complication.\nEtiology\nCCD and MHS are allelic conditions, both caused by (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes in the RyR protein are considered to be the main pathogenetic mechanism(s).\nDiagnostic methods\nThe diagnosis of CCD is based on the presence of suggestive clinical features and central cores on muscle biopsy. Muscle MRI may show a characteristic pattern of selective muscle involvement and aid the diagnosis in cases with equivocal histopathological findings. Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis.\nManagement and treatment\nManagement is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia. Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment.\nPrognosis\nIn the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.\n\n                            Last update: \n                            May 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Heinz JUNGBLUTH"}
{"Disease Name": "Central neurocytoma", "Disease Definition": "Central neurocytoma is a very rare brain tumor of young adults (over 100 cases reported worldwide). It is typically found in the lateral ventricles and occasionally in the third ventricle. Symptoms are those of increased intracranial pressure: headache, nausea and vomiting, drowsiness, vision problems and mental changes. Total removal of the tumor is the therapy of choice. Post-operative prognosis is generally good.", "ORPHA ID": 73256, "Summary": ""}
{"Disease Name": "Central polydactyly", "Disease Definition": "A rare congenital limb malformation characterized by complete or partial duplication of one of the three middle digits in a hand or foot. It most commonly affects the fourth digit. The malformation may be unilateral or bilateral and can occur as an isolated defect or in association with other anomalies.", "ORPHA ID": 295004, "Summary": ""}
{"Disease Name": "Central retinal vein occlusion", "Disease Definition": "A rare retinal vasculopathy characterized by impaired venous return from the retinal circulation due to an occlusion occurring within or posterior to the optic nerve head. The clinical presentation is variable and may range from asymptomatic to an abrupt and profound loss of vision. Complications causing visual loss include macular edema, macular ischemia, optic neuropathy, vitreous hemorrhage, tractional retinal detachment, and in more severe cases extensive capillary non-perfusion with a high risk of neovascular glaucoma.", "ORPHA ID": 411527, "Summary": ""}
{"Disease Name": "Central serous chorioretinopathy", "Disease Definition": "A rare, acquired, choroidal disorder characterized by subretinal detachment in the macular área and leakage of fluid under the retina that accumulates under the central macula. Symptoms tend to include blurred or distorted vision (metamorphopsia), moderate dyschromatopsia, relative central scotoma, hypermetropization, micropsia and reduced contrast sensitivity. A blurred or gray spot in the central visual field is common when the retina is detached.", "ORPHA ID": 443079, "Summary": ""}
{"Disease Name": "Centrifugal lipodystrophy", "Disease Definition": "Centrifugal lipodystrophy is a rare, acquired, localized lipodistrophy characterized by single or, occasionally, multiple, centrifugally progressive, asymptomatic to sometimes mildly tender, hypopigmented, lipoatrophic skin depressions with weakly erymatheous inflammatory borders, typically associated with regional ipsilateral lymph nodes swelling. Lesions typically occur on lower trunk (in particular groin and abdomen region), followed by upper trunk (axilla and neighboring regions) and, rarely, neck and head. It is usually not associated with systemic disease and is typically self-resolving.", "ORPHA ID": 90156, "Summary": ""}
{"Disease Name": "Centronuclear myopathy", "Disease Definition": "A rare group of inherited neuromuscular disorders characterized by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy. The clinical picture and other histologic features varies according to gene involved and mode of inheritance.", "ORPHA ID": 595, "Summary": "Epidemiology\nThe exact prevalence and incidence of this group of diseases are unknown. For the X-linked form (XLMTM1) the incidence is estimated at 1/50,000 male birth.\nClinical description\nThese congenital myopathies are characterized by generalized muscle weakness that can range from mild to severe. Symptoms are often present at birth in the severe forms, but may first develop at any point during life, although onset in adulthood is unusual. In the severe forms the common symptoms include hypotonia, feeding difficulties and respiratory distress. Extraocular muscle involvement is also common in all forms. Other common signs and symptoms include delayed motor milestones, facial weakness and ptosis.\nEtiology\nCentronuclear myopathies (CNMs) are genetically widely heterogeneous and have been attributed mainly to X-linked recessive mutations in MTM1 (Xq28), encoding myotubularin 1 (X-linked centronuclear myopathy), autosomal-dominant mutations in DNM2( 19p13.2), encoding dynamin-2, autosomal dominant or recessive mutations in BIN1 (2q14.3), encoding myc box-dependent-interacting protein 1, and autosomal-recessive mutations in RYR1 (19q13.2), encoding the skeletal muscle ryanodine receptor, and in TTN (2q31.2), encoding titin. More recently, there have also been reports on peculiar CNM phenotypes related to autosomal recessive mutations in SPEG (2q35), encoding the striated muscle preferentially expressed protein kinase, and mutations in CCDC78 (16p13.3), encoding the coiled-coil domain-containing protein-78.\nDiagnostic methods\nDiagnosis is based on typical histological findings of central nuclei, hypotrophy and predominance of type I fibers.\nDifferential diagnosis\nThe main differential diagnoses include other forms of congenital myopathies or other neuromuscular conditions with severe neonatal hypotonia.\nAntenatal diagnosis\nIn familial cases, prenatal diagnosis can be performed if the genetic background is known.\nGenetic counseling\nGenetic counseling should be offered to all patients and families in whom a diagnosis of CNM has been made.\nManagement and treatment\nManagement of CNM requires a multidisciplinary approach. No specific therapy exists yet but different therapeutic strategies are under investigation.\nPrognosis\nThe prognosis of this group of disease is variable. Whereas the XLMTM1 is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with a globally more favourable prognosis.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI  - Dr Adele D'AMICO  - Pr Fabiana FATTORI"}
{"Disease Name": "Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome", "Disease Definition": "A rare slowly progressive autosomal recessive syndromic cerebellar ataxia characterized by late-onset cerebellar dysfunction (including gait and limb ataxia, nystagmus, and dysarthria), bilateral vestibulopathy (abnormal vestibulo-ocular reflex), and axonal sensory neuropathy. Variable features may include chronic cough and autonomic dysfunction. Brain imaging usually shows cerebellar atrophy.", "ORPHA ID": 504476, "Summary": ""}
{"Disease Name": "Cerebellar ataxia, Cayman type", "Disease Definition": "A rare, autosomal recessive, congenital, cerebellar ataxia disorder characterized by hypotonia from birth, marked psychomotor delay and prominent cerebellar dysfunction (manifesting with nystagmus, intention tremor, dysarthria, ataxic gait and truncal ataxia), described in an isolated population of the Grand Cayman Island. Cerebellar hypoplasia, observed on CT scan, may be associated.", "ORPHA ID": 94122, "Summary": ""}
{"Disease Name": "Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome", "Disease Definition": "A rare autosomal dominant neurological disorder characterized by early onset cerebellar ataxia, associated with areflexia, progressive optic atrophy, sensorineural deafness, a pes cavus deformity, and abnormal eye movements.", "ORPHA ID": 1171, "Summary": ""}
{"Disease Name": "Cerebellar ataxia-ectodermal dysplasia syndrome", "Disease Definition": "A rare syndromic cerebellar ataxia characterized by hypodontia and sparse hair in combination with cerebellar ataxia and normal intelligence. Imaging demonstrates a cerebellar atrophy.", "ORPHA ID": 1174, "Summary": ""}
{"Disease Name": "Cerebellar ataxia-hypogonadism syndrome", "Disease Definition": "Cerebellar ataxia-hypogonadism syndrome is a very rare autosomal recessive neurodegenerative disorder characterized by the combination of progressive cerebellar ataxia with onset from early childhood to the fourth decade, and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics). Cerebellar ataxia-hypogonadism syndrome belongs to a clinical continuum of neurodegenerative disorders along with clinically overlapping disorders such as ataxia-hypogonadism-choroidal dystrophy syndrome (see this term).", "ORPHA ID": 1173, "Summary": ""}
{"Disease Name": "Cerebellar hypoplasia-tapetoretinal degeneration syndrome", "Disease Definition": "Cerebellar hypoplasia-tapetoretinal degeneration syndrome is a rare syndrome with a cerebellar malformation as a major feature characterized by cerebellar hypoplasia, bilateral retinal pigmentary changes, intellectual disability that can range from mild to moderate and pronounced language development delay. It presents with early developmental delay, central and peripheral non-progressive visual impairment or asymptomatic retinal changes, hypotonia, non-progressive ataxia and nystagmus.", "ORPHA ID": 2246, "Summary": ""}
{"Disease Name": "Cerebellar liponeurocytoma", "Disease Definition": "Cerebellar liponeurocytoma (cLPN) is a rare slow growing neuronal tumor seen more frequently in females than males, occurring most commonly in the cerebellum but occasionally in the supratentorial compartment or the fourth ventricle and presenting in the 4th to 6th decade of life with symptoms of dizziness, headache and gait instability. It often has a high rate of local recurrence.", "ORPHA ID": 251931, "Summary": ""}
{"Disease Name": "Cerebellar-facial-dental syndrome", "Disease Definition": "A rare, autosomal recessive, multiple congenital anomalies/dysmorphic syndrome characterized mainly by developmental delay, variable intellectual disability, microcephaly, cerebellar hypoplasia, dysmorphic features (central incisors macrodontia and slender fingers), short stature and variable congenital anomalies.", "ORPHA ID": 444072, "Summary": "Epidemiology\nTo date, ten patients carrying biallelic BRF1 variants have been reported in the literature.\nClinical description\nThe clinical features of the syndrome include developmental delay and intellectual disability. Congenital microcephaly is present in all patients with occipital frontal circumference recorded and with progressive deceleration. Postnatal growth retardation occurred in all patients with height last evaluation between -2.5 and -5 SD. The most constant dysmorphic features include central incisors macrodontia and slender fingers. Laryngomalacia, tracheomalacia, congenital heart defect, sensorineural hearing impairment and inner ear malformation have been reported. Brain malformations, as detected on magnetic resonance imaging, may include cerebellar hypoplasia, corpus callosum hypoplasia and, more variably, enlarged cisterna magna and enlarged lateral ventricles.\nEtiology\nThe disorder is due to biallelic variants in the BRF1 (14q32.33) gene; the pathogenic variants reported are missense variants, with only one frameshift mutation identified. All variants affect protein residues located within the cyclin 2 protein domain.\nDiagnostic methods\nAll patients reported had been diagnosed by next generation sequencing.\nDifferential diagnosis\nThe disorder is distinguished from other intellectual disability syndromes mainly by short stature and progressive microcephaly. Prominent upper incisors is a remarkable sign.\nAntenatal diagnosis\nWhere the mutation has been identified previously in a proband, prenatal molecular genetic testing could be offered.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Families with an affected child should be counselled that there is a recurrence risk of 25% for each pregnancy.\nManagement and treatment\nStandard management is indicated for intellectual disability and postnatal growth retardation. Echocardiography, abdominal ultrasound and hearing evaluation is recommended at birth. Surveillance should include frequent monitoring of growth and development. Regular ophthalmological follow up is recommended.\nPrognosis\nPatients reported with poor prognosis are related to complex heart defects.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Irene VALENZUELA PALAFOLL | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Cerebral Amyloid Angiopathy", "Disease Definition": "A rare genetic cerebral small vessel disease characterized by amyloid deposition in the cerebral blood vessels leading to predominantly hemorrhagic strokes, focal neurological deficits, and progressive cognitive decline eventually leading to dementia.", "ORPHA ID": 85458, "Summary": "Epidemiology\nThe prevalence is unknown. HCHWA has been described in several families from all over the world. The estimated number of affected patients is between 300 and 400.\nClinical description\nUnlike sporadic forms of cerebral amyloid angiopathy (CAA), HCHWA usually presents in younger patients (<55 years of age) and has more severe manifestations. Clinical features depend on the HCHWA disease type, with 7 discovered to date: Icelandic, Dutch, Arctic, Piedmont, Iowa, Flemish and Italian (see these terms). In general, patients present with either a stroke (with headache, nausea, vomiting, focal neurological deficits, and alterations in consciousness) or progressive dementia of the Alzheimer type. Transient neurological symptoms lasting a few minutes to a few hours, and seizures can also occur. Microbleeds and hemorrhages can occur throughout the brain, and are caused by involvement of the vessels in the cerebral cortex and the meninges. Hemorrhages tend to recur. Cognitive decline is progressive and can lead to dementia, either in a stepwise fashion or slowly progressive as in Alzheimer's disease.\nEtiology\nMost forms of HCHWA (Dutch, Arctic, Piedmont, Iowa, Flemish and Italian) are due to a point-mutation in the APP gene on chromosome 21q21.2, which encodes the beta-amyloid precursor protein. This mutation causes increased accumulation of amyloid-beta protein in the walls of cerebral arteries and capillaries. This can lead to rupture or narrowing of the blood vessels, leading to hemorrhagic or non-hemorrhagic stroke. Sometimes the affected blood vessels show signs of inflammation (CAA-angiitis). Only one form of HCHWA, Icelandic type, is due to a mutation in the CST3 gene on chromosome 20p11.2, encoding the precursor protein cystatin C.\nDiagnostic methods\nFor a probable diagnosis of HCHWA a detailed family history, and (preferably) a magnetic resonance imaging (MRI) scan should be performed. Typically, the MRI shows multiple lobar (cortical, subcortical) hemorrhages and leukoencephalopathy. In the presence of otherwise unexplained lobar hemorrhages and a typical family history, the finding of a causative mutation is sufficient for a definite diagnosis of HCHWA in vivo. At postmortem examination severe CAA, and cortical, lobar or subcortical hemorrhages are found.\nDifferential diagnosis\nDifferential diagnoses include all other conditions that could cause lobar intracerebral hemorrhage such as coagulopathies, vasculitis, intravascular large B-cell lymphoma (see these terms), CNS neoplasms, cavernous malformations, cerebral vascular malformation and antecedent trauma\nAntenatal diagnosis\nAntenatal diagnosis is possible but is rarely performed.\nGenetic counseling\nThe presently known types of HCHWA are inherited in an autosomal dominant manner. Screening of family members of patients with HCHWA is recommended, because of the possibility of genetic counseling. Presymptomatic genetic testing is offered.\nManagement and treatment\nThere is no known acute or preventive treatment for cerebral hemorrhages in HCHWA. Antihypertensive therapy is recommended, even in cases of mild to moderate hypertension, but its efficacy is not evidence-based. Corticosteroids can ameliorate symptoms caused by CAA-related inflammation. Patients experiencing seizures should be given antiepileptic drugs. Surgical hematoma evacuation is rarely performed for HCHWA because of the poor outcome associated with severe neurological deficits.\nPrognosis\nThe prognosis is often poor.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Joost HAAN  - Pr G.M. [Gisela] TERWINDT"}
{"Disease Name": "Cerebral arteriovenous malformation", "Disease Definition": "Cerebral arteriovenous malformation (AVM) is a congenital malformative communication between the veins and the arteries in the brain in the form of a nidus, an anatomical structure composed of dilated and tangled supplying arterioles and drainage veins with no intervening capillary bed, that can be asymptomatic or cause, depending on the location and the size of the AVM, headaches of varying severity, generalized or focal seizures, focalneurological defects (weakness, numbness, speech difficulties, vision loss) or potentially fatal intracranial hemorrhage in case the AVM ruptures.", "ORPHA ID": 46724, "Summary": ""}
{"Disease Name": "Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy", "Disease Definition": "CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary cerebrovascular disorder characterized by mid-adult onset of recurrent subcortical ischemic stroke and cognitive impairment progressing to dementia in addition to migraines with aura and mood disturbances seen in about a third of patients.", "ORPHA ID": 136, "Summary": "Epidemiology\nIn Europe, the prevalence of CADASIL has been estimated to range between 1/50 000- 1/25 000.\nClinical description\nThe first manifestation of the disease occurs at a mean age of 45-50, usually in the form of ischemic stroke or cognitive decline. The disease onset and course is variable, but more than two thirds of patients suffer from (recurrent) stroke or dementia. Migraine, usually with aura, occurs in about a third of patients and often precedes stroke and dementia symptoms, with a mean age of onset of about 30 years. Psychiatric disorders are also common and include depression, apathy and personality changes. Less common signs include reversible acute encephalopathy (accompanied by headache, confusion, and seizures), epilepsy and subclinical peripheral neuropathy. The most common cause of death is pneumonia, followed by sudden unexpected death and asphyxia.\nEtiology\nCADASIL is caused by mutations in the NOTCH3 gene (>95% of cases), located to 19p13.2-p13.1, which encodes transmembrane receptor NOTCH3, mainly expressed in vascular smooth muscle cells. More than 90% are missense mutations which lead to a numerical cysteine alteration in one of the epidermal growth factor receptor (EGFR) encoding exons of NOTCH3 (exons 2-23). The mutated EGFR contains 5 or 7 cysteine residues, rather than the usual 6. This leads to increased multimerisation of the mutated protein and accumulation of mutated NOTCH3 in the vascular wall.\nDiagnostic methods\nThe diagnosis of CADASIL should be considered in patients with young onset stroke or cognitive decline, ischemic changes on MRI (such as symmetrical white matter hyperintensities, subcortical infarctions, microbleeds) and a positive family history for stroke or dementia. Diagnosis can be confirmed through molecular analysis, by the identification of a typical cysteine altering NOTCH3 mutation. Alternatively, electron microscopy of a skin biopsy can be used to reveal characteristic granular deposits in the vessel wall, or immunohistochemical analysis can show positive NOTCH3 staining of the vessel wall.\nDifferential diagnosis\nDifferential diagnoses include Binswanger disease, primary angiitis of the central nervous system and multiple sclerosis as well as other genetic disorders such as CARASIL, MELAS syndrome, Fabry disease and small-vessel diseases associated with COL4A1 mutations (e.g. familial porencephaly) (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis and pre-implantation genetic diagnosis is possible if a disease-causing mutation in the family is known.\nGenetic counseling\nDue to the autosomal dominant inheritance and the generally severe progression, patients and family members should always be offered genetic counseling.\nManagement and treatment\nThere is no cure for CADASIL. Antiplatelet therapy is often used but it has not yet been proven as an effective treatment. Symptomatic treatment can be offered to patients to treat migraines and potential concomitant vascular risk factors (hypertension, hypercholesterolemia and diabetes). Psychological counseling should be offered to patients and their families in order to give them emotional support. Smoking, angiography, anticoagulants and thrombolytic therapy are all to be avoided by those with CADASIL as they increase the risk of cerebrovascular manifestations.\nPrognosis\nThe prognosis is poor with most patients eventually becoming bed-ridden and dement and requiring constant nursing care. The median age at death is 68 years.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Dr S.A.J. [Saskia] LESNIK OBERSTEIN  - Pr G.M. [Gisela] TERWINDT"}
{"Disease Name": "Cerebral autosomal recessive arteriopathy-subcortical infarcts-leukoencephalopathy", "Disease Definition": "CARASIL is a hereditary cerebral small vessel disease characterized by early-onset gait disturbances, premature scalp alopecia, ischemic stroke, acute mid to lower back pain and progressive cognitive disturbances leading to severe dementia.", "ORPHA ID": 199354, "Summary": "Epidemiology\nThe prevalence is unknown. Less than 10 genetically proven cases have been reported, with most of them occurring in Japan where no founder haplotypes have yet been found, indicating the likely existence of unreported cases. The additional familial cases have been reported from Spain and China.\nClinical description\nCARASIL has a slight male predominance. Onset varies but usually the first signs of the disease are diffuse alopecia (not always present) and gait disturbances that can often present before 30 years of age. Attacks of severe lower and mid back pain usually occur between the ages of 20-45. Some may suffer from disk herniations, nodular thickening, and severe spondylitis deformans with osteoporosis. Several cases have shown lumbago without any radiological abnormalities. Half of patients suffer from a typical lacunar stroke while the other half experiences a stepwise deterioration in brain function. Neurological symptoms include pseudobulbar palsy, hyperreflexia, vestibular symptoms, and ophthalmoplegia. Cognitive deficits begin to appear around the age of 30-40 with the first manifestation being forgetfulness. Other manifestations include emotional incontinence, personality changes (lability and irritability), disorientation to time and eventually apallic syndrome. In advanced stages emotional incontinence, abulia and akinetic mutism develop. Patients are usually bedridden 10 years after disease onset but can live for 20-30 years with the illness.\nEtiology\nCARASIL is caused by a mutation in the HTRA1 gene, encoding the HtrA serine peptidase 1 protein (HTRA1) which represses signaling by transforming growth factor (TGF)-beta family members. Patients with a mutation have reduced or no amounts of HTRA1 which leads to increased signaling by the (TGF)-beta family and consequently to the manifestations seen in CARASIL.\nDiagnostic methods\nDiagnosis is based on the presence of characteristic clinical and brain magnetic resonance (MRI) imaging findings. MRI findings are similar to those seen in CADASIL syndrome (see this term) including symmetrical distribution of white matter hypersensitivities. White matter high-signal intensity lesions and multiple lacunar infarctions are observed and are most often located in the periventricular and deep white matter. Dilation of cerebral sulci and lateral ventricles is noted in some individuals. Pathological findings show arteriosclerosis in the cerebral small arteries. Genetic testing can confirm diagnosis with a mutation in the HTRA1 gene.\nDifferential diagnosis\nDifferential diagnoses include primary angiitis of the central nervous system, Binswanger disease, CADASIL, Nasu-Hakola disease, chronic progressive multiple sclerosis and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (see these terms). As Hutchinson-Gilford progeria syndrome and Werner syndrome (see these terms) also feature premature baldness and arteriosclerosis, they must also be excluded.\nAntenatal diagnosis\nAntenatal diagnosis is possible for at-risk pregnancies, where one parent has a known disease-causing mutation in the family.\nGenetic counseling\nCARASIL is inherited autosomal recessively. Genetic counseling is recommended in families where a mutation in the HTRA1 gene has been identified.\nManagement and treatment\nThere is no cure for CARASIL syndrome. Emotional support and counseling for patients and their families is recommended. Canes or a wheelchair may be needed due to gait problems and medications such as tizanidine and baclofen may relieve spasticity. Anxiolytic medication may be prescribed for character changes. A high-salt diet and smoking should be avoided due to arteriosclerosis.\nPrognosis\nThe prognosis is poor with the average duration of illness lasting 10 years.\n\n                            Last update: \n                            May 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Osamu ONODERA"}
{"Disease Name": "Cerebral sinovenous thrombosis", "Disease Definition": "A rare, potentially life-threatening, circulatory system disease characterized by variable signs and symptoms which may include headache, seizures, altered mental status, intracranial hypertension and cavernous sinus syndrome, among others.", "ORPHA ID": 329217, "Summary": ""}
{"Disease Name": "Cerebral visual impairment", "Disease Definition": "A rare neurologic disease characterized by significant visual dysfunction that cannot be explained by ocular abnormalities alone and is due to damage to post-chiasmatic visual pathways and structures during early perinatal development. Signs and symptoms include decreased visual acuity, visual field defects, and impairments in visual processing and attention.", "ORPHA ID": 447788, "Summary": ""}
{"Disease Name": "Cerebrocostomandibular syndrome", "Disease Definition": "Cerebro-costo-mandibular syndrome (CCMS) is characterized at birth by posterior rib gaps and orofacial anomalies reminiscent of Pierre Robin syndrome (see this term) that include palatal defects (short hard palate, absent soft palate, absent uvula), micrognathia and glossoptosis.", "ORPHA ID": 1393, "Summary": "Epidemiology\nMore than 80 cases have been reported to date; both males and females are equally affected.\nClinical description\nCCMS is characterized by orofacial and costovertebral developmental anomalies. Severity is highly variable. Intrauterine growth retardation and low birth weights are common. Orofacial anomalies may include absent soft palate and a short hard palate with posterior notching, micrognathia and glossoptosis. Characteristic dorsal rib defects are sine qua non of the syndrome and often result in a bell-shaped thorax. Posterior rib gaps and rib defects are revealed by X-ray; there is no apparent continuity between the ossified ribs which are usually divided into two portions. This may lead to ''flail chest,'' a paradoxical movement of a segment of the thoracic wall due to broken ribs, which may further hamper respiration. Respiratory difficulties lead to generalized cyanosis and potential hypoxic brain injuries that may be responsible for intellectual deficit that may be observed later. Associated malformations were described in rare cases: microcephaly, absence of external ear canals and spina bifida. Those patients who survive infancy may suffer from growth retardation, scoliosis, reduced lung capacity, dental anomalies, feeding disturbances, conductive hearing loss and language disturbances. Patients who survive the first year of life are reported to survive to adulthood and to harbor a less severe form. These patients may suffer from growth retardation, scoliosis, reduced lung capacity, dentition anomalies, feeding disturbances, intellectual deficit, conductive hearing loss and language disturbance.\nEtiology\nNo causative gene has been identified to date. It has been proposed, however, that defects in the sonic hedgehog (SHH) signaling cascade may be responsible for these developmental anomalies.\nDiagnostic methods\nClinical presentation, along with typical chest X-ray findings, confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include trisomies 13 and 18, and Pierre Robin syndrome (see these terms).\nAntenatal diagnosis\nAlthough most cases are spontaneous, both autosomal recessive and autosomal dominant patterns of inheritance have been observed in familial cases.\nManagement and treatment\nOrofacial anomalies responsible for breathing and feeding difficulties must be immediately addressed and severe cases must be transferred to intensive care units. Affected infants require feeding assistance and should lie in the prone position to help bring the tongue forward and liberate the trachea. Intubation or placement of a nasopharyngeal airway may be necessary. As tracheal intubation may prove impossible, a neonatal laryngeal mask airway, intermittently replaced by nasal prongs and continuous positive airway pressure, may be required. In these most severe cases, tongue-lip adhesion surgical intervention may provide a long term solution. A Haberman feeder may be of use in infants with cleft palate and nasogastric tube supplementation may be required to provide supplementary caloric intake.\nPrognosis\nPrognosis depends upon the severity of anomalies. The most severe forms are often fatal within the first hours after birth and 25% of all reported cases are fatal during the first month of life. This correlates significantly with greater numbers of missing ribs or gaps.\n\n                            Last update: \n                            May 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Hiroyuki NAGASAWA"}
{"Disease Name": "Cerebrofacial arteriovenous metameric syndrome type 1", "Disease Definition": "A rare subtype of cerebrofacial arteriovenous metameric syndrome characterized by unilateral arteriovenous malformations involving the hypothalamus and nasal region (medial prosencephalic group). The condition manifests in childhood. Common presenting signs and symptoms are progressive neurological deficit, hemorrhage, and cosmetic complaints like facial asymmetry.", "ORPHA ID": 141194, "Summary": ""}
{"Disease Name": "Cerebrofacial arteriovenous metameric syndrome type 3", "Disease Definition": "A rare subtype of cerebrofacial arteriovenous metameric syndrome characterized by unilateral arteriovenous malformations involving the cerebellum, pons, and mandible (lateral rhombencephalic group). The condition manifests in childhood. Common presenting signs and symptoms are progressive neurological deficit, hemorrhage, and cosmetic complaints like facial asymmetry.", "ORPHA ID": 141199, "Summary": ""}
{"Disease Name": "Cerebrofacial arteriovenous metameric syndrome", "Disease Definition": "A group of rare, nonhereditary, complex cerebrofacial vascular malformation characterized by multiple ipsilateral arteriovenous malformations (AVMs) with a metameric distribution, affecting various territories of the face with corresponding areas of the brain. The spectrum is highly variable with three types described according to lesion distribution: CAMS 1 derives from the medial prosencephalon with concurrent involvement of hypothalamus, nose, forehead; CAMS 2 arises from the lateral prosencephalon and involves basal ganglia, optic nerve and retina and maxillo-facial region; CAMS 3 derives from the rhombencephalon and involves cerebellum and mandible.", "ORPHA ID": 141189, "Summary": "Epidemiology\nFewer than 100 cases have been reported in the literature to date. The sex ratio is even.\nClinical description\nCerebrofacial arteriovenous metameric syndrome (CAMS) typically presents before the third decade of life. The spectrum is highly variable and symptoms will depend on the lesion's location. The neurological symptoms vary according to the affected cerebral area (hemiparesis, hemorrhage, visual field defect ...) as the maxilla-facial symptoms vary according to the facial extension (nosebleed, maxilla-facial deformation and AVMs, hemorrhage). Focal distribution of the lesions can be seen in partial spectrum of the disease.\nEtiology\nWhile the etiology and risk factors are unknown, a somatic mutation in the neural crest prior to migration is thought to produce the vascular lesions. Recent data suggest the role of somatic mutation of the RAS-MAPK signaling pathway in the pathogenesis of cerebrofacial AVMs.\nDiagnostic methods\nThe diagnosis is made on clinical and radiological exam; partial manifestations of the syndrome does not exclude diagnosis. Retinal AVMs are usually diagnosed by ophthalmoscopy although fluorescein angiography may be required to demonstrate smaller lesions. Intracranial lesions can be diagnosed with magnetic resonance imaging/angiography (MRI/MRA), computed tomography and digital subtraction angiography.\nDifferential diagnosis\nDifferential diagnosis includes has to be made with other types of cerebrofacial vascular metameric syndromes like Sturge-Weber syndromes that affect the venous circulations in a metameric way without any shunt, or Von Hippel-Lindau disease that corresponds to vascular tumors as hemangioblastoma that can be seen in the retina or central nervous system. Lower metameric distribution compared to CAMS will correspond to spinal arteriovenous metameric syndromes (SAMS 1-31, or Cobb syndrome).\nGenetic counseling\nThe disease is sporadic; no familial cases have been identified.\nManagement and treatment\nManagement depends on clinical presentation and can be conservative for asymptomatic or pauci-symptomatic lesions. Treatment is typically symptomatic and may include surgery, embolization or radiosurgery. Usually, given the lesions extension, complete curative treatment is not achievable. Medical antiangiogenic treatments are under evaluation.\nPrognosis\nPrognosis depends on the location and progression of AVMs, and while some patients may remain asymptomatic others will experience visual and/or neurological problems, as cosmetic sequelae related to the soft tissue AVM.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Julien COULIE  - Dr Georges RODESCH | VASCERN* - Dr Stanislas SMAJDA | VASCERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Cerebrofacioarticular syndrome", "Disease Definition": "Cerebrofacioarticular syndrome is a rare multiple congenital anomalies syndrome characterized by mild to severe intellectual disability, a distinctive facial gestalt (blepharophimosis, maxillary hypoplasia, telecanthus, microtia and atresia of the external auditory meatus) as well as skeletal and articular abnormalities (e.g. camptodactyly of the fingers, cutaneous syndactyly, talipes equinovarus, flexion contractures of the proximal interphalangeal joints, hip or elbow subluxation, joint laxity). Affected individuals also present neonatal hypotonia, variable respiratory manifestations, chronic feeding difficulties and gray matter heterotopia.", "ORPHA ID": 314679, "Summary": ""}
{"Disease Name": "Cerebrofaciothoracic dysplasia", "Disease Definition": "Cerebro-facio-thoracic dysplasia or Pascual-Castroviejo syndrome type 1 is a rare syndrome characterized by facial dysmorphism, intellectual deficit and costovertebral abnormalities.", "ORPHA ID": 1394, "Summary": "Epidemiology\nTo date, 13 cases have been reported in the literature.\nClinical description\nDysmorphic features include brachycephaly, hypertelorism, broad nasal bridge, large philtrum, triangular-shaped mouth and micrognathia. There is often synophris and a low hair line on the back. Costovertebral abnormalities are always present: short, bifid or fused ribs, bony bridges joining the posterior arches in some ribs, hemi vertebrae. Intellectual deficit is constant but the severity varies and patients also have cerebral abnormalities: cortical atrophy, hypoplasia of the corpus callosum and cerebellar vermis.\nEtiology\nIt is most likely that the condition is hereditary, transmitted as an autosomal recessive trait.\nAntenatal diagnosis\nAntenatal diagnosis is possible by ultrasonographic monitoring for cerebral, costal or vertebral malformations.\n\n                            Last update: \n                            January 2010"}
{"Disease Name": "Cerebrooculonasal syndrome", "Disease Definition": "Cerebro-oculo-nasal syndrome is a multisystem malformation syndrome that has been reported in about 10 patients. The clinical features include bilateral anophthalmia, abnormal nares, central nervous system anomalies, and neurodevelopmental delay.", "ORPHA ID": 66625, "Summary": "Clinical description\nAdditional features include brachycephaly (the nose may have a proboscis-like appearance) and other facial anomalies such as large forehead, flat supraorbital ridges, ocular hypertelorism, epicanthic folds, downslanting palpebral fissures, sparse and medially absent eyebrows, sparse eyelashes, malar hypoplasia, large philtrum, high-arched palate possibly associated with atypical cleft lip and a single maxillary central incisor, posteriorly rotated ears with hypoplastic tragus and large conchae. Non facial anomalies have also been reported: postaxial polydactyly, genital hypoplasia.\nAntenatal diagnosis\nNo case of prenatal diagnosis has been reported.\nGenetic counseling\nAll cases reported so far have been sporadic, suggesting that the syndrome may be due to a new dominant mutation.\n\n                            Last update: \n                            March 2006"}
{"Disease Name": "Cerebrotendinous xanthomatosis", "Disease Definition": "Cerebrotendinous xanthomatosis (CTX) is an anomaly of bile acid synthesis (see this term) characterized by neonatal cholestasis, childhood-onset cataract, adolescent to young adult-onset tendon xanthomata, and brain xanthomata with adult-onset neurologic dysfunction.", "ORPHA ID": 909, "Summary": "Epidemiology\nMore than 300 patients have been reported worldwide. Prevalence is estimated to be approximately 1/50,000 among Caucasians.\nClinical description\nThe initial clinical manifestation may be neonatal cholestasis or chronic diarrhea from infancy. In 75% of cases, cataract is the first finding, often appearing in childhood. Infants may present with cholestasis and liver dysfunction. Xanthomata may appear in the 2nd or 3rd decade of life, in the Achilles and other tendons (elbow, hand, patella, neck). Some patients show intellectual impairment from infancy, but most have normal or subnormal intellectual function until puberty. Adult-onset progressive neurologic dysfunction includes dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, seizures, and neuropathy. Dementia occurs in the 20s in over 50% of cases. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicidal tendencies may be prominent. Pyramidal signs and/or cerebellar ataxia are present in the 20s or 30s. Patients may experience extrapyramidal manifestations (dystonia and atypical parkinsonism), and peripheral neuropathy.\nEtiology\nCTX is caused by mutations in the sterol 27-hydroxylase gene (CYP27A1; 2q33-qter). Sterol 27-hydroxylase catalyzes the first step in the oxidation of the side-chain of sterol intermediates in the bile acid synthesis (BAS) pathway. Defective enzymatic function disrupts bile acid synthesis leading to cholesterol and cholestanol deposits, which result in a degenerative process.\nDiagnostic methods\nMass spectrometry analysis of urine enables early diagnosis in children by showing characteristic bile alcohol metabolites. Diagnosis in adults is based on two of the following criteria: intractable diarrhea, presenile cataracts, tendinous xanthomata and neurologic abnormalities, and abnormal amounts of cholestanol in serum and tendons. Plasma cholesterol concentration may be low or normal. MRI shows bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter. Molecular genetic testing in a certified laboratory may be used to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other causes of xanthomata such as sitosterolemia and hyperlipemia (especially type IIa, also known as familial hypercholesterolemia [see these terms]), and for infants presenting with cholestasis, all other causes of neonatal cholestasis.\nAntenatal diagnosis\nAntenatal diagnosis can be established by analysis of embryonic tissue when there has been a previously identified sibling.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to affected families.\nManagement and treatment\nFirst-line treatment is based on chenodeoxycholic acid (CDCA) replacement therapy, which normalizes BAS and cholestanol concentrations, and improves neurological symptoms. Inhibitors of HMG-CoA reductase may also be used alone or in combination with CDCA, although they may induce muscle damage. Cataract extraction is typically required by age 50 years. Cholic acid treatment has also been used. It is not as effective as CDCA in suppressing BAS and the production of cholestanol, but lacks the hepatotoxicity of CDCA.\nPrognosis\nEarly diagnosis and treatment are crucial to prevent progressive accumulation of cholestanol and cholesterol: disease progression may be halted and in some cases reversed. Treated patients may have a normal lifespan. In untreated patients, life expectancy is 50 to 60 years. Some early deaths in infancy have also been reported.\n\n                            Last update: \n                            September 2011\n\n\n                            - Expert reviewer(s): \n                            Pr James HEUBI"}
{"Disease Name": "Cernunnos-XLF deficiency", "Disease Definition": "Cernunnos-XLF deficiency is a rare form of combined immunodeficiency characterized by microcephaly, growth retardation, and T and B cell lymphopenia.", "ORPHA ID": 169079, "Summary": "Epidemiology\nPrevalence is unknown. To date, five cases have been reported.\nClinical description\nPatients present in childhood with growth retardation, microcephaly, uro-genital and bone malformations, dysmorphic features, including ''bird-like'' facial dysmorphism, and features of combined immunodeficiency including recurrent opportunistic, viral and bacterial infections. Some patients may also present with autoimmune cytopenia (anemia and thrombocytopenia). Patients share several clinical features with Nijmegen breakage syndrome and LIG 4 deficiency (see these terms).\nEtiology\nThis disease is caused by mutations in the NHEJ1 (or Cernunos) gene (2q35). The resulting defect of Cernunnos/XLF, a core protein of the non-homologous end-joining (NHEJ) pathway, affects the major mechanism of DNA double-strand break repair.\nDiagnostic methods\nDiagnosis is based on the combination of clinical features with evidence of B and T cell lymphocytopenia with normal levels of natural killer (NK) cells. Fibroblasts also exhibit increased radiosensitivity.\nDifferential diagnosis\nDifferential diagnoses include Nijmegen breakage syndrome and LIG4 syndrome (see these terms).\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment is based on antibiotic treatment of infections, immunoglobulin replacement, antiviral prophylaxis and allogeneic hematopoietic stem-cell transplantation (HSCT). Radiotherapy as part of conditioning regimens should be avoided. Reduced intensity conditioning regimens are favored.\nPrognosis\nWithout treatment, the immunodeficiency may result in severe infection, sepsis and early death.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Cerulean cataract", "Disease Definition": "A type of hereditary congenital cataract, distinguished by bluish and white opacifications in the superficial layers of the fetal lens nucleus and adult lens nucleus, and characterized by reduced visual acuity in childhood, eventually necessitating extraction of the lens.", "ORPHA ID": 98989, "Summary": ""}
{"Disease Name": "Cervical aortic arch", "Disease Definition": "A rare, congenital anomaly of the great arteries characterized by cranially situated aortic arch ascending into the neck above the clavicles. Most patients remain asymptomatic, some present with a murmur and a pulsatile neck mass, stridor, dyspnea, recurrent bronchitis, dysphagia or signs and symptoms of a stenosis/aneurism of the aortic arch. Other congenital heart anomalies are frequently associated, including abnormalities of arch laterality and branching, aortic coarctation or aneurysm.", "ORPHA ID": 99079, "Summary": ""}
{"Disease Name": "Cervical dermoid cyst", "Disease Definition": "Cervical dermoid cyst is a rare, benign cutaneous neoplasm containing keratinized epithelium and dermal derivatives, such as hair follicles, sweat and sebaceous glands, smooth muscle or fibroadipose tissue which usually manifests as a slow-growing, painless mass in the submandibular or sublingual space. Depending on the location, and especially after sudden enlargement, it can cause dyspnea, dysphagia or dysphonia.", "ORPHA ID": 141046, "Summary": ""}
{"Disease Name": "Cervical hypertrichosis-peripheral neuropathy syndrome", "Disease Definition": "A rare genetic syndrome characterized by the association of congenital hypertrichosis in the anterior cervical region with peripheral sensory and motor neuropathy. Associated features may include retinal anomalies, spina bifida, kyphoscoliosis and hallux valgus, and developmental delay (one case). There have been no further descriptions in the literature since 1993.", "ORPHA ID": 2218, "Summary": ""}
{"Disease Name": "Cervicofacial fibrochondroma", "Disease Definition": "A rare extraskeletal chondroma located in the head and neck region, histologically typically characterized by lobules of mature, adult hyaline cartilage with chondrocytic cells identifiable in lacunae, and prominent fibrosis. Malignant transformation has not been described.", "ORPHA ID": 141067, "Summary": ""}
{"Disease Name": "CHAND syndrome", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by the association of sparse, woolly, curly hair, ankyloblepharon, and nail dysplasia. Additional reported features include abnormal oral frenula, bifid tongue, lip pits, adhesions between upper and lower lips, hypertelorism and flat nasal bridge, alveolar synechia, and imperforate vagina.", "ORPHA ID": 1401, "Summary": ""}
{"Disease Name": "Chandler syndrome", "Disease Definition": "A clinical variant of iridocorneal endothelial (ICE) syndrome, characterized by very few iris abnormalities but more severe corneal edema and less severe secondary glaucoma than seen in the other two ICE syndrome variants: Cogan-Reese syndrome and essential iris atrophy.", "ORPHA ID": 98979, "Summary": ""}
{"Disease Name": "Chapare hemorrhagic fever", "Disease Definition": "Chapare hemorrhagic fever, caused by the Chapare virus (a new arenavirus), discovered from a small outbreak in Cochabamba, Bolivia between 2003 and 2004, is an acute viral hemorrhagic fever characterized by fever, myalgia, arthralgia, and multiple hemorrhagic signs. About a third of untreated cases go on to develop more severe symptoms with delirium, coma and convulsions and death (in one case). No other cases have been reported since.", "ORPHA ID": 319244, "Summary": ""}
{"Disease Name": "Char syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by the triad of patent ductus arteriosus (PDA), facial dysmorphism (wide-set eyes, downslanting palpebral fissures, mild ptosis, flat midface, flat nasal bridge and upturned nasal tip, short philtrum with a triangular mouth, and thickened, everted lips) and hand anomalies (aplasia or hypoplasia of the middle phalanges of the fifth fingers).", "ORPHA ID": 46627, "Summary": "Epidemiology\nApproximately 100 individuals from 13 families have been reported in the medical and scientific literature.\nClinical description\nTypical facial features include wide-set eyes, downslanting palpebral fissures, mild ptosis, flat midface, flat nasal bridge, upturned nasal tip, a short philtrum, a triangular mouth, and thickened (patulous) everted lips. Hand abnormalities include aplasia or hypoplasia of the middle phalanges of the fifth fingers but can also be as minimal as fifth finger clinodactyly, which can be a normal finding and overlaps with numerous other syndromes. Less common features associated with Char syndrome include additional heart defects (such as interventricular communication or complex congenital defects), additional hand abnormalities (such as interstitial polydactyly, distal symphalangism of the fifth fingers, fusion of the distal interphalangeal joints), polythelia, foot anomalies (interphalangeal joint fusion, clinodactyly, interstitial polydactyly, or syndactyly), strabismus, mild to moderate developmental delay, prominent occiput, persistence of the deciduous teeth in the absence of permanent dentition, and somnambulism.\nEtiology\nCausal mutations have been identified in the TFAP2B gene (chromosome 6p12.3), encoding a member of the AP-2 family of transcription factors. TFAP2B sequence analysis detects pathogenic variants in approximately 50% of affected individuals. The pathogenic variant p.Pro63Arg is associated with a less severe phenotype with mild facial dysmorphism, PDA and absence of hand anomalies. TFAP2B mutations have also been reported in familial patent arterial duct.\nDiagnostic methods\nThe diagnosis is established by the presence of the key clinical features.\nDifferential diagnosis\nThe associated facial features associated are not often confused with those observed in other disorders. The primary differential diagnosis includes other heart-hand syndromes (including Holt-Oram syndrome, Tabatznik syndrome, and heart-hand type III).\nAntenatal diagnosis\nPrenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the pathogenic variant in the family. In at-risk pregnancies, prenatal ultrasound examination may identify abnormal hands or feet, as well as complex congenital heart defects. PDA is a normal fetal feature and cannot be used as a diagnostic marker in utero.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant but may arise de novo. Where the parent is affected, the sibling recurrence risk is 50%. In sporadic cases, the sibling recurrence risk is very low (<1%) due to the theoretical possibility of gonadal mosaicism in a parent.\nManagement and treatment\nThe major focus for management and treatment is the cardiovascular involvement. Management of PDA after the immediate newborn period is determined by the degree of shunting from the aorta to the pulmonary artery. Surgical ligation or ductal occlusion with catheterization are treatment options. Early special care for the dysmorphia and hand anomalies is not required but plastic surgery may be considered later in life. The outcomes of plastic surgery for the facial features are unknown. Preventive pediatric care should be offered for the associated anomalies (including visual problems and developmental delay).\nPrognosis\nThe prognosis depends on the potential presence of associated heart malformations. Early intervention of the additional anomalies can improve outcomes.\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Bruce GELB"}
{"Disease Name": "Charcot-Marie-Tooth disease type 1", "Disease Definition": "Charcot-Marie-Tooth disease type 1 (CMT1) is a group of autosomal dominant demyelinating peripheral neuropathies characterized by distal weakness and atrophy, sensory loss, foot deformities, and slow nerve conduction velocity.", "ORPHA ID": 65753, "Summary": "Epidemiology\nThe prevalence of CMT1 is estimated to be between 1/7,000 and 1/5,000, with CMT1A representing 70% of cases.\nClinical description\nAge of onset of CMT1 varies widely and ranges from infancy to the fourth or subsequent decades of life. Typically, patients become symptomatic between the first and the second decade of life; however, the full clinical picture may appear later. Clinical severity is variable, ranging from extremely mild disease, which goes unrecognized, to considerable weakness and disability. Affected individuals typically develop distal weakness, symmetric atrophy of muscles (mainly peroneal), and reduced-to-absent tendon reflexes. Sensory deficits of position, vibration, and pain/temperature commonly occur in the feet and later in the hands. Pes cavus (or planus) with hammer toes is often present since childhood. Variable scoliosis may develop during adolescence.\nEtiology\nCMT1A can be caused by 1.4 Mb duplications or by point mutations in the PMP22 gene (17p12). CMT1E is caused by point mutations in the PMP22 gene (17p12). CMT1B is associated with MPZ (1q22) gene mutations. CMT1C, CMT1D and CMT1F (see these terms) are associated with pathogenic variants in LITAF (16p13.3), EGR2 (10q21.1) and NEFL (8p21.2), respectively.\nDiagnostic methods\nDiagnosis of CMT1 is based on progressive peripheral motor and sensory neuropathy; slow nerve conduction velocity (NCV) with motor NCV <38 m/s in upper limbs; and positive family history (however, sporadic presentations may occur, due to de novo mutations). Genetic testing is the gold standard for diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other genetic neuropathies, especially X-linked CMT, autosomal dominant CMT2, CMT4, and hereditary neuropathy with liability to pressure palsies (see these terms). CMT1 identification may be challenging when there is no family history and acquired demyelinating neuropathies must also be taken into account.\nAntenatal diagnosis\nPreimplantation genetic diagnosis may be an option for families in which the pathogenic variant has been identified.\nGenetic counseling\nTransmission is autosomal dominant with complete penetrance and genetic counseling is recommended.\nManagement and treatment\nTreatment is multidisciplinary and includes use of special shoes, inserts and/or ankle foot orthoses; forearm crutches, canes, and wheelchairs for the most severe cases, as needed for mobility; surgery for severe pes cavus, as needed; exercise for muscle strengthening, as tolerated; stretching to prevent Achilles' tendon shortening; and regular foot examination for pressure sores. Occupational therapy focused on strategies/tools to help patients with daily living activities is useful, especially for those with hand weakness.\nPrognosis\nCMT1 is slowly progressive and affected individuals experience long plateau periods without obvious deterioration. Most patients remain ambulatory throughout life and have a normal lifespan.\n\n                            Last update: \n                            March 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Davide PAREYSON  - Dr Chiara PISCIOTTA"}
{"Disease Name": "Charcot-Marie-Tooth disease type 1B", "Disease Definition": "Charcot-Marie-Tooth disease type 1B (CMT1B) is a form of CMT1 (see this term), caused by mutations in the MPZ gene (1q22), that presents with the manifestations of peripheral neuropathy (distal muscle weakness and atrophy, foot deformities and sensory loss). The phenotype is variable depending on the particular mutation. Two distinct presentations have been described: (1) an early infantile onset severe phenotype with delayed walking and motor nerve conduction velocities (MNCV) <10 m/s, often referred to as Dejerine-Sottas syndrome (see this term), or (2) a much later onset phenotype (>age 40), with normal or mildly slowed MNCV and more frequent hearing loss and pupillary abnormalities. CMT1B can also cause the classical CMT phenotype in about 15% of total CMT1B cases.", "ORPHA ID": 101082, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 1C", "Disease Definition": "A rare, autosomal dominant, hereditary, demyelinating motor and sensory neuropathy which may present either as a classic Charcot-Marie-Tooth disease phenotype with distal motor weakness and wasting, gait difficulties, parethesias, decreased vibration and pain sensation, or as a milder, predominantly sensory form with transient paresthesias, decreased sensation and distal pain in upper or lower limbs, without significant motor weakness. Pes cavus is a common feature, and additional symptoms may include hand tremor and decreased or absent deep tendon reflexes.", "ORPHA ID": 101083, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 1D", "Disease Definition": "Charcot-Marie-Tooth disease type 1D (CMT1D) is a form of CMT1 (see this term), caused by mutations in the EGR2 gene (10q21.1), with a variable severity and age of onset (from infancy to adulthood), that usually presents with gait abnormalities, progressive wasting and weakness of distal limb muscles, with possible later involvement of proximal muscles, foot deformity and severe reduction in nerve conduction velocity. Additional features may include scoliosis, cranial nerve deficits such as diplopia, and bilateral vocal cord paresis.", "ORPHA ID": 101084, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 1E", "Disease Definition": "A rare subtype of CMT1 characterized by a variable clinical presentation. Onset within the first two years of life with a delay in walking is not uncommon; however, onset may occur later. CMT1E is caused by point mutations in the PMP22 (17p12) gene. The disease severity depends on the particular PMP22 mutation, with some cases being very mild and even resembling hereditary neuropathy with liability to pressure palsies, while others having an earlier onset with a more severe phenotype (reminiscent of Dejerine-Sottas syndrome) than that seen in CMT1A, caused by gene duplication. These severe cases may also report deafness and much slower motor nerve conduction velocities compared to CMT1A patients.", "ORPHA ID": 90658, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 1F", "Disease Definition": "Charcot-Marie-Tooth disease type 1F (CMT1F) is a form of CMT1, with a variable clinical presentation that can range from severe impairment with onset in childhood to mild impairment appearing during adulthood. CMT1F is characterized by a progressive peripheral motor and sensory neuropathy with distal paresis in the lower limbs that varies from mild weakness to complete paralysis of the distal muscle groups, absent tendon reflexes and reduced nerve conduction. CMT1F represents the ''demyelinating'' form of CMT2E and is caused by mutations in the NEFL gene (8p21.2).", "ORPHA ID": 101085, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 2B1", "Disease Definition": "Charcot-Marie-Tooth disease, type 2B1 (CMT2B1, also referred to as CMT4C1) is an axonal CMT peripheral sensorimotor polyneuropathy.", "ORPHA ID": 98856, "Summary": "Epidemiology\nIt has been described exclusively in families originating from North-Western Africa (northwest Algeria and the east of Morocco).\nClinical description\nOnset occurs in the second decade of life. The disease course and severity are variable, even between affected members of the same family. In general, the disease manifests as distal muscle weakness and atrophy that progress gradually to the proximal muscles. Involvement of the upper and lower limbs has been reported. Sensory impairment may also be present but foot deformities are either moderate or absent. Proximal muscle atrophy of the pelvic and scapular girdle may occur later in the disease course.\nEtiology\nCMT2B1 is caused by a p.R644C missense mutation in the lamin A/C protein (encoded by the LMNA gene, 1q22).\nGenetic counseling\nCMT2B1 is transmitted in an autosomal recessive manner.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen ESPINÓS  - Pr Francesc PALAU"}
{"Disease Name": "Charcot-Marie-Tooth disease type 2B2", "Disease Definition": "Charcot-Marie-Tooth disease, type 2B2 (CMT2B2, also referred to as CMT4C3) is an axonal CMT peripheral sensorimotor polyneuropathy that has been described in a large consanguineous Costa Rican family of Spanish ancestry.", "ORPHA ID": 101101, "Summary": "Clinical description\nOnset occurs in adulthood (between 26 and 42 years of age) with symmetric moderate to severe weakness of the distal muscles, predominantly affecting the lower extremities. Marked sensory deficits were also reported.\nEtiology\nCMT2B2 is transmitted in an autosomal recessive manner and the disease-causing gene was mapped to chromosome 19q13.3 (MED25).\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen ESPINÓS  - Pr Francesc PALAU"}
{"Disease Name": "Charcot-Marie-Tooth disease type 2B5", "Disease Definition": "A rare axonal hereditary motor and sensory neuropathy characterized by infantile onset of slowly progressive distal motor weakness and atrophy (more severe in legs and moderate in arms) with mildly delayed motor development, hypotonia, and distal sensory impairment of all sensory modalities.", "ORPHA ID": 228374, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 2H", "Disease Definition": "Charcot-Marie-Tooth disease, type 2H (CMT2H, also referred to as CMT4C2) is an axonal CMT peripheral sensorimotor polyneuropathy associated with pyramidal involvement.", "ORPHA ID": 101102, "Summary": "Epidemiology\nSo far, it has been described in 13 members of a large Tunisian family.\nClinical description\nOnset occurred during the first decade of life with progressive distal atrophy involving both the upper and lower limbs, associated with a mild pyramidal syndrome (brisk patellar and upper limb reflexes, absent ankle reflexes and unattainable plantar reflexes).\nEtiology\nCMT2H is transmitted in an autosomal recessive manner and the disease-causing locus has been mapped to 8q13-21.1. This region contains the GDAP1 gene, which has been implicated in the demyelinating disease CMT4A, and in the axonal disease CMT4C4 or CMT2K (see these terms).\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen ESPINÓS  - Pr Francesc PALAU"}
{"Disease Name": "Charcot-Marie-Tooth disease type 2P", "Disease Definition": "Charcot-Marie-Tooth disease type 2P is a rare, genetic, axonal hereditary motor and sensory neuropathy disorder characterized by adulthood-onset of slowly progressive, occasionally asymmetrical, distal muscle weakness and atrophy (predominantly in the lower limbs), pan-modal sensory loss, muscle cramping in extremities and/or trunk, pes cavus and absent or reduced deep tendon reflexes. Gait anomalies and variable autonomic disturbances, such as erectile dysfunction and urinary urgency, may be associated.", "ORPHA ID": 300319, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 2R", "Disease Definition": "A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by early-onset axial hypotonia, generalized muscle weakness, absent deep tendon reflexes and decreased muscle mass. Electromyography reveals decreased motor nerve conduction velocities with markedly reduced sensory and motor amplitudes.", "ORPHA ID": 397968, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 2S", "Disease Definition": "A rare subtype of axonal hereditary motor and sensory neuropathy characterized by progressive distal muscle weakness and atrophy of both the lower and upper limbs, absent or reduced deep tendon reflexes, mild sensory loss, foot drop, and pes cavus leading eventually to wheelchair dependance. Some patients present with early hypotonia and delayed motor development. Scoliosis and variable autonomic disturbances may be associated.", "ORPHA ID": 443073, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 2T", "Disease Definition": "A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by adult onset of slowly progressive distal muscle weakness and atrophy, sensory impairment, and decreased or absent deep tendon reflexes predominantly in the lower extremities. Patients present gait disturbances but remain ambulatory. Mild involvement of the upper limbs may be seen.", "ORPHA ID": 495274, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 4", "Disease Definition": "A disorder that belongs to the genetically heterogeneous group of CMT peripheral sensorimotor polyneuropathy diseases.", "ORPHA ID": 64749, "Summary": "Epidemiology\nThe prevalence of all forms of CMT is around 1 in 3,330; however, CMT4 is less common and often limited to certain ethnic groups.\nClinical description\nThe term CMT4 is classically applied to autosomal recessive demyelinating forms of CMT, although current trends point towards a reclassification of CMT4 forms to include autosomal recessive axonal types. CMT4 patients present with the typical CMT phenotype characterized by progressive, distally accentuated weakness and atrophy of muscles innervated by the peroneal nerve in the lower limbs, followed by weakness and atrophy of hands, sensory loss, and characteristic foot abnormalities. CMT4 is usually more severe than other forms of CMT and onset occurs earlier. The disease may arise in early infancy with hypotonia or may manifest in later infancy with toe walking. The most common symptoms are walking difficulties with steppage gait or pes cavus. Hammer toes are frequent and other skeletal deformities, such as scoliosis, are often observed. Sensory signs are usually less prominent than motor signs. The most frequent finding is distal loss of sensation to touch, pain, and vibration in the lower limbs. Deep tendon reflexes are reduced or absent in most patients with demyelinating CMT4. To date, 15 forms of CMT4 have been described, including eleven demyelinating (CMT4 types A, 4B1, 4B2, 4C, 4D, 4E, 4F, 4G, 4H, 4J and CCFDN; see these terms) and four axonal forms (CMT4 types 4C1, 4C2, 4C3 and 4C4; see these terms).\nEtiology\nSo far, fourteen genes and two loci have been described associated with these fifteen CMT variants and the roles and functions of the proteins encoded by these CMT4 genes are diverse.\nDiagnostic methods\nThe diagnostic approach includes clinical examinations (natural history of the disease, and neurological and systemic examinations), together with definition of the inheritance pattern, electrophysiological studies and a nerve biopsy for selected patients. Identification of the disease-causing mutation supports the clinical and electrophysiological diagnosis. Definitive diagnosis is extremely difficult because the phenotype is similar throughout the spectrum of clinical types, both demyelinating and axonal.\nGenetic counseling\nGenetic counseling should be offered to the parents of an affected individual and prenatal diagnosis should be proposed when the disease is well diagnosed and the disease-causing mutation in the family has been identified.\nManagement and treatment\nThere is currently no cure for CMT and treatment is only symptomatic: physical therapy and orthopedic management for musculoskeletal dysfunction; pulmonary evaluation, ventilatory support, and scoliosis correction for respiratory dysfunction; and pain control, antidepressants and anticonvulsants for sensory dysfunction.\nPrognosis\nThe prognosis for the different types of CMT4 varies and depends on the clinical severity. In general CMT is a slowly progressive neuropathy, causing eventual disability but, in the absence of secondary complications, does not generally reduce life expectancy. However, early-onset and severe respiratory complications associated with some forms of CMT4 (notably CMT4C4, CMT4B1, CMT4B2 and CMT4E) may lead to a poorer prognosis with early death in some cases.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen ESPINÓS  - Pr Francesc PALAU"}
{"Disease Name": "Charcot-Marie-Tooth disease type 4A", "Disease Definition": "Charcot-Marie-Tooth disease type 4A (CMT4A) is a subtype of Charcot-Marie-Tooth disease type 4 characterized by early-onset (infancy to early childhood) of severe, rapidly progressing demyelinating, axonal, or intermediate sensorimotor neuropathy usually affecting first, and more severely, the distal lower extremities and later the proximal muscles and upper extremities. Nerve conduction velocities range from very slow to normal. Apart from the typical CMT phenotype (distal muscle weakness and atrophy, sensory loss, frequent pes cavus foot deformity), patients commonly present delayed motor development, vocal cord paresis, mild sensory loss, abolished deep tendon reflexes, and skeletal deformities.", "ORPHA ID": 99948, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 4B1", "Disease Definition": "Charcot-Marie-Tooth disease type 4B1 (CMT4B1) is a subtype of Charcot-Marie-Tooth disease type 4 characterized by an early childhood-onset of severe, demyelinating sensorimotor neuropathy, various degrees of complex myelin outfoldings seen on peripheral nerve biopsy, very slow, and often undetectable, nerve conduction velocities, and the typical CMT phenotype (i.e. distal muscle weakness and atrophy, sensory loss, and frequent pes cavus). Other reported features include facial weakness, vocal cord paresis, respiratory difficulties, and skeletal deformities (e.g. chest deformities, claw hands, pes equinovarus).", "ORPHA ID": 99955, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 4B2", "Disease Definition": "Charcot-Marie-Tooth disease type 4B2 (CMT4B2) is a subtype of Charcot-Marie-Tooth type 4 characterized by a severe, early childhood-onset of demyelinating sensorimotor neuropathy, early-onset glaucoma, focally folded myelin sheaths in the peripheral nerves, severely reduced nerve conduction velocities, and the typical CMT phenotype (i.e. distal muscle weakness and atrophy, sensory loss, and frequent pes cavus). Severe visual impairment leading to visual loss has also been reported.", "ORPHA ID": 99956, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 4B3", "Disease Definition": "Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is a subtype of Charcot-Marie-Tooth type 4 characterized by a childhood onset of slowly progressing, demyelinating sensorimotor neuropathy, focally folded myelin sheaths in nerve biopsy, reduced nerve conduction velocities (less than 38 m/s), and the typical CMT phenotype (i.e. distal muscle weakness and atrophy, and sensory loss).", "ORPHA ID": 363981, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 4C", "Disease Definition": "Charcot-Marie-Tooth disease type 4C (CMT4C) is a subtype of Charcot-Marie-Tooth type 4 characterized by childhood or adolescent-onset of a relatively mild, demyelinating sensorimotor neuropathy that contrasts with a severe, rapidly progressing, early-onset scoliosis, and the typical CMT phenotype (i.e. distal muscle weakness and atrophy, sensory loss, and often foot deformity). A wide spectrum of nerve conduction velocities are observed and cranial nerve involvement and kyphoscoliosis have also been reported.", "ORPHA ID": 99949, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 4D", "Disease Definition": "Charcot-Marie-Tooth disease type 4D (CMT4D) is a subtype of Charcot-Marie-Tooth disease type 4 characterized by a childhood-onset of severe, progressive, demyelinating sensorimotor neuropathy manifesting with distal muscle weakness and atrophy, sensorineural hearing impairment leading to deafness (usually in third decade), severely reduced nerve conduction velocities, and skeletal, especially foot, deformities. Tongue atrophy has also been reported.", "ORPHA ID": 99950, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 4E", "Disease Definition": "Charcot-Marie-Tooth disease type 4E (CMT4E) is a congenital, hypomyelinating subtype of Charcot-Marie-Tooth disease type 4 characterized by a Dejerine-Sottas syndrome-like phenotype (incl. hypotonia and/or delayed motor development in infancy), extremely slow nerve conduction velocities, potential respiratory dysfunction, cranial nerve involvement, and the typical CMT phenotype, i.e. distal muscle weakness and atrophy, sensory loss, and foot deformity.", "ORPHA ID": 99951, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 4F", "Disease Definition": "Charcot-Marie-Tooth disease type 4F (CMT4F) is a severe, demyelinating subtype of Charcot-Marie-Tooth disease type 4 characterized by the childhood onset of a slowly-progressing typical CMT phenotype (i.e. distal muscle weakness and atrophy, as well as pes cavus) that presents severe sensory loss (frequently with sensory ataxia), moderately to severely reduced motor nerve conduction velocities and almost invariable absence of sensory nerve action potentials, and delayed motor milestones.", "ORPHA ID": 99952, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 4G", "Disease Definition": "Charcot-Marie-Tooth disease type 4G (CMT4G) is a subtype of Charcot-Marie-Tooth disease type 4 characterized by early childhood onset of progressive distal muscle weakness and atrophy, delayed motor development, prominent distal sensory impairment, areflexia, moderately reduced nerve conduction velocities, and foot and hand deformities in Balkan (Russe) Gypsies.", "ORPHA ID": 99953, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 4H", "Disease Definition": "Charcot-Marie-Tooth disease type 4H is a subtype of Charcot-Marie-Tooth disease type 4 characterized by onset before two years of age of severe, slowly progressive, demyelinating sensorimotor neuropathy manifesting with delayed motor development (walking), unsteady gait, distal muscle weakness and atrophy (more prominent in the lower limbs), areflexia, mild symmetrical stocking-distribution hypoesthesia, and skeletal malformations (incl. kyphoscoliosis, short neck, pes cavus and pes equinus). Severely reduced nerve conduction velocities are associated.", "ORPHA ID": 99954, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease type 4J", "Disease Definition": "Charcot-Marie-Tooth disease type 4J is a subtype of Charcot-Marie-Tooth disease type 4 characterized by childhood- to adulthood-onset of variably severe, rapidly progressive, axonal and demyelinating sensorimotor neuropathy typically manifesting with delayed motor development, proximal and distal asymmetric muscle weakness and atrophy of the lower and upper extremities, severe motor dysfunction with mildly reduced sensory impairment, and areflexia. Nerve conduction velocities range from very mildly to severely reduced.", "ORPHA ID": 139515, "Summary": ""}
{"Disease Name": "Charcot-Marie-Tooth disease-deafness-intellectual disability syndrome", "Disease Definition": "Charcot-Marie-Tooth disease-deafness-intellectual disability syndrome is a rare demyelinating hereditary motor and sensory neuropathy characterized by early-onset, slowly progressive, distal muscular weakness and atrophy with no sensory impairment, congenital sensorineural deafness and mild intellectual disability (with absence of normal speech development). The absence of large myelinated fibers on sural nerve biopsy is equally characteristic of the disease.", "ORPHA ID": 90103, "Summary": ""}
{"Disease Name": "CHARGE syndrome", "Disease Definition": "CHARGE syndrome is a multiple congenital anomaly syndrome characterized by the variable combination of multiple anomalies, mainly Coloboma; Choanal atresia/stenosis; Cranial nerve dysfunction; Characteristic ear anomalies (known as the major 4 C's).", "ORPHA ID": 138, "Summary": "Epidemiology\nThe incidence is estimated to be 1/12,000 - 15,000 live births.\nClinical description\nThe syndrome shows a variable clinical picture, even within a family, depending on the associated anomalies. It presents in the neonatal period with cyanosis due to choanal atresia (60-70%, bony/membranous, unilateral/bilateral) and/or cyanotic heart disease (75-80%; e.g. conotruncal heart malformations, aortic arch defects; see these terms). Coloboma, more likely retinal, is present in 75-90% and can be in conjunction with microphthalmia and lead to vision loss. Ear anomalies (95-100%) include low-set lop or cup-shaped outer ear with deficient cartilage of the outer pinna and a triangular concha, middle ear ossicle malformations, leading to chronic serous otitis media, and sensorineural hearing loss. Cranial nerve abnormalities are frequent and include abnormalities of the olfactory, facial, auditory, vestibular nerves and those involved in swallowing. Central nervous system (CNS) defects involve cerebral atrophy, corpus callosum agenesis, posterior fossa anomalies and cerebellar hypoplasia. Genital hypoplasia and delayed puberty are observed. Failure to thrive is often related to the severe sucking/swallowing problems. Motor delay (due to balance problems), speech delay and delay in fine motor skills are also noted. Dysmorphic facial features include square face, prominent forehead, prominent nasal bridge and asymmetry from the facial palsy. Upper airway defects (e.g. congenital laryngomalacia, congenital tracheomalacia; see these terms), tracheoesophageal fistula (TEF) and gastroesophageal reflux are common. Endocrine dysfunction (growth hormone deficiency, hypogonadotropic hypogonadism) and immune abnormalities (e.g. severe combined immune deficiencies, isolated T-cell lymphopenia) are also observed. Chest infections are frequent. Patients may manifest an autistic like behavior associated with attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD) and anxiety.\nEtiology\nIn most cases, CHARGE syndrome is due to heterozygous mutations in CHD7 (8q12.2) encoding the chromodomain helicase DNA-binding protein.\nDiagnostic methods\nDiagnosis is initially clinical. Any of the major 4 C's criteria should prompt the physician to screen for additional anomalies. Magnetic resonance imaging of the temporal lobe demonstrates absent or hypoplastic semi-circular canals (most predictive feature of the CHD7 mutation). Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes Abruzzo-Erickson syndrome, Kallmann syndrome, 22q11.2 deletion syndrome, VACTERL/VATER association, Kabuki syndrome, renal coloboma syndrome, Cat-eye syndrome, Joubert syndrome, BOR syndrome, 5q11.2 microdeletion syndrome (see these terms) and other chromosomal microdeletion syndromes.\nAntenatal diagnosis\nPrenatal diagnosis involves detection by ultrasound in the 2nd trimester of polyhydramnios, CNS, heart and genitourinary malformations, ear anomalies. Molecular studies can be performed.\nGenetic counseling\nCHARGE syndrome is either sporadic (97%) or shows an autosomal dominant transmission. There is a 1-2% risk of gonadal mosaicism.\nManagement and treatment\nManagement requires a multi-disciplinary approach (involving dieticians, gastroenterologists, endocrinologists, cardiologists) that associates surgical management, services for persons with vision and hearing loss (deaf/blind services), occupational therapy, physiotherapy, speech/language therapy, cochlear implant, behavior therapy and psychological counseling.\nPrognosis\nMortality is high during the neonatal period often due to the combination of cyanotic heart disease, TEF, choanal atresia, T-cell deficiency and brain anomalies. Mortality and morbidity in the post-neonatal period are often related to post-anesthesia events and feeding problems resulting in aspiration pneumonia.\n\n                            Last update: \n                            March 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Kim BLAKE  - Dr Chitra PRASAD"}
{"Disease Name": "Charlie M syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by the common manifestations found in oromandibular-limb hypogenesis syndromes(OLHS) group such as hypoplasia of the mandible, variable limb anomalies like syndactylyl and ectrodactyly, small mouth, cleft palate and hypodontia, accompanied by other clinical signs such as facial paralysis, facial asymmetry, hypertelorism, hypoglossia/aglossia, absent or conically crowned incisors and, ectromelia. There have been no further descriptions in the literature since 1976.", "ORPHA ID": 1406, "Summary": ""}
{"Disease Name": "CHD3-related developmental delay-speech delay-intellectual disability-abnormalities of vision-facial dysmorphism syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by moderate to severe intellectual disability, developmental delay, macrocephaly, speech delay, and hypotonia. Dysmorphic facial features include a high, broad, and/or prominent forehead, laterally sparse eyebrows, widely spaced and deeply-set eyes, narrow palpebral fissures, low-set ears, full/prominent cheeks, midface hypoplasia, thin upper lip, and a pointed chin. Additional variable manifestations include joint laxity, abnormality of vision (including hypermetropia, strabismus, and cerebral visual impairment), genital abnormalities in males, and inguinal, umbilical, or hiatal hernia.", "ORPHA ID": 599082, "Summary": ""}
{"Disease Name": "Cheilitis glandularis", "Disease Definition": "A rare skin disease of unknown origin characterized by macrocheilia and secretions of thick saliva from swollen labial minor salivary glands.", "ORPHA ID": 1221, "Summary": "Epidemiology\nCheilitis glandularis (CG) prevalence is unknown. Less than a 100 cases have been reported to date, predominantly in adult males, and more rarely in adult females.\nClinical description\nThe clinical picture of CG consists of variable degrees of macrocheilia accompanied by the presence of red, dilated ostia of minor salivary glands on the vermilion area. A thick, mucoid material can be obtained from these ostia by manual expression. This viscous saliva often sticks to the vermilion causing discomfort to the patient. Hardening of superficial and deep tissues, including minor salivary glands, may occur. Rarely they may suppurate and drain a purulent discharge (cheilitis apostematosa profunda). Changes occur more frequently on the lower lip, but the upper lip is occasionally affected. Because of the macrocheilia, the vermilion is more exposed to ultra-violet radiation, which may lead to chronic actinic cheilitis and squamous cell carcinoma of the lower lip in rare cases.\nEtiology\nCheilitis glandularis occurs more frequently in fair skinned adults and albino patients seem particularly prone, suggesting an influence of sunlight exposure. Nonetheless, the actual cause of CG remains unknown. Some consider CG as an inflammatory glandular disease while others think it merely represents a clinical reaction pattern to external trauma (mechanic, actinic) with no relation to salivary involvement as salivary glands have been found to be normal in some patients. Recently, changes in the immunohistochemical expression of water flow channels have been demonstrated in cases of CG.\nDiagnostic methods\nDiagnosis is mostly clinical. Histopathologic findings in the vermilion vary from spongiotic changes to chronic actinic epithelial damage, including superficial squamous cell carcinoma. Changes in minor salivary glands include chronic sialadenitis with dilated acinar lobules and ducts. Excretory ducts are ectatic and ductal metaplasia can be observed.\nDifferential diagnosis\nDifferential diagnosis may include cheilitis granulomatosa, cutaneous lupus erythematosus, angioedema, atopic cheilitis, actinic cheilitis, cheilitis artefacta, exfoliative cheilitis, ointment pseudo-cheilitis and benign and malignant minor salivary gland tumours (e.g. cystadenoma, cystadenocarcinoma and mucoepidermoid carcinoma).\nManagement and treatment\nMild cases do not require specific treatment. A lower lip vermilionectomy followed by careful dissection of the minor labial salivary glands is recommended for symptomatic and/or albino patients and is the only curative treatment for CG. Intralesional corticosteroids and oral antibiotics are ineffective. Long-term follow up is recommended, especially in very fair-skinned or albino patients, as the risk of labial squamous cell carcinoma is higher in these patients.\nPrognosis\nWith proper treatment and surveillance, the prognosis is good.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Marcello NICO"}
{"Disease Name": "Cherubism", "Disease Definition": "Cherubism is a rare, self-limiting, fibro-osseous, genetic disease of childhood and adolescence characterized by varying degrees of progressive bilateral enlargement of the mandible and/or maxilla, with clinical repercussions in severe cases.", "ORPHA ID": 184, "Summary": "Epidemiology\nThe prevalence of cherubism is unknown and is difficult to determine because of the wide clinical spectrum. About 300 cases have been reported in various ethnic groups worldwide. The disorder affects males and females equally.\nClinical description\nPatients are normal at birth and most develop some degree of symmetrical mandibular and maxillary enlargement between two and five years of age. These lesions are considered aggressive, non-aggressive or quiescent depending on their clinical behavior, with each type corresponding to a particular age group (early childhood, adolescence or adulthood). In the early stages of the disease, patients may present with lymph node enlargement. The clinical manifestations are highly variable, from subclinical cases to severe enlargement causing visual, respiratory, speech, mastication, and swallowing complications. In severe cases, the fibro-osseous lesions may invade the orbital walls causing lower lid retraction, displacement of the globe, proptosis or diplopia. Respiratory complications are infrequent but can include obstructive sleep apnea, upper airway obstruction and obliteration of the nasal airway. Dental abnormalities include disrupted arrangement of primary dentition, absent teeth, rudimentary molars, premature exfoliation of primary dentition, and displacement of permanent dentition by the cystic lesions. Malocclusion is commonly found. Other organs and systems are usually not affected. Lesions progress slowly until puberty and then start to stabilize and regress through bone remodeling until the age of about 30. At this age, facial abnormalities are generally no longer visible. Cherubism can also be part of Ramon syndrome, neurofibromatosis 1 and fragile X syndrome (see these terms).\nEtiology\nCherubism is caused by missense mutations in the SH3BP2 gene (4p16.3) in approximately 80% of cases, suggesting genetic heterogeneity. The exact mechanism underlying fibrous expansion has not been elucidated. Experimental data points to possible auto-inflammatory disease.\nDiagnostic methods\nThe diagnosis is based on clinical signs, patient age, family history and radiographic findings, and can be confirmed by molecular genetic testing. Histology shows spindle cells embedded in interstitial collagen fibers and osteoclastic giant-cells.\nDifferential diagnosis\nDifferential diagnosis includes Noonan-like syndrome, hyperparathyroidism-jaw tumor syndrome, fibrous dysplasia of bone (see these terms), brown tumor of hyperparathyroidism, and central giant-cell granuloma.\nAntenatal diagnosis\nPrenatal diagnosis is possible when the disease-causing mutation has been detected in the family.\nGenetic counseling\nAbout 50% of cases are familial and the others appear to be related to de novo mutations. Cherubism is considered to be an autosomal dominant trait but there are reports suggesting autosomal recessive transmission. Genetic counseling is recommended for affected families.\nManagement and treatment\nClinical and radiographic monitoring is recommended during the growth phase of lesions. Since the disorder is usually self-limiting, surgery is not always recommended. However, surgical intervention involving resection, curettage or contouring may be required in patients with functional manifestations or for esthetic reasons and to improve quality of life. Surgery is generally indicated once lesions have become quiescent and does not alter disease progression. Careful attention should be paid to the psychological aspects related to disfigurement during childhood and adolescence.\nPrognosis\nDespite the possible severity of signs and symptoms, the condition is benign and the prognosis very good, with rare reports of residual deformity.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Berivan BASKIN"}
{"Disease Name": "Chikungunya", "Disease Definition": "A rare infectious disease characterized by acute onset of high fever associated with debilitating polyarthralgia and usually accompanied by an erythematous skin rash (that may progress to vesiculobullous lesions in children) caused by the mosquitoe-borne Chikungunya virus. Myalgia, severe headache, and lymphadenopathy are frequently associated. Chronically the disease may cause recurrent, long-term polyarthralgia, arthritis, fatigue, and depression.", "ORPHA ID": 324625, "Summary": ""}
{"Disease Name": "Chilblain lupus", "Disease Definition": "A rare, chronic cutaneous lupus erythematosus disease characterized by red or violaceous, initially pruritic (evolving to painful) papules and plaques located on acral areas (especially dorsal aspects of fingers and toes, while the nose and ear involvement is uncommon), exacerbated by cold and damp conditions, with fissuring and ulceration occasionally observed. Coexistence of discoid lupus erythematosus lesions elsewhere on the body and occasional progression to systemic lupus erythematosus may be associated. Histological examination and direct immunofluorescence studies reveal nonspecific inflammatory lupus erythematosus changes while results of cryoglobulin and cold agglutinin studies are negative.", "ORPHA ID": 90280, "Summary": ""}
{"Disease Name": "CHILD syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by unilateral inflammatory and scaling skin lesions with ipsilateral visceral and limb anomalies.", "ORPHA ID": 139, "Summary": "Epidemiology\nLess than 60 cases have been reported to date, mainly in female patients.\nClinical description\nCHILD syndrome (CS) patients present at birth or shortly thereafter with unilateral yellow ichthyosiform nevi in the form of patches halting abruptly at the midline, with an affinity to skin folds (ptychotropism), generally sparing the face. A claw-like onychodystrophy and periungual hyperkeratosis are common, and ipsilateral bald patches may be present. This is accompanied by ipsilateral limb defects, ranging from shortened metacarpals and phalanges to the absence of an entire limb. Additional malformations may include the absence of ribs, vertebrae and long bones, and scoliosis and joint contractures. During the first months of life, punctate calcification of cartilage (stippled epiphyses) may be noted on X-rays. Ipsilateral renal defects have been reported (unilateral hydronephrosis, renal agenesis). Most patients present with normal intellectual development, although unilateral CNS defects have often been reported including unilateral hypoplasia of cranial nerves and the spinal cord, lissencephaly and cerebellar malformation. The involvement may be right or left-sided, but mild contralateral lesions are often noted. Over two-thirds of cases have presented with right-sided involvement, perhaps due to more severe cardiac involvement causing prenatal death in left-sided cases. Lung hypoplasia has also been reported in several cases. Hearing loss, optic atrophy, absence of some facial muscles, thrombocytosis, congenital bilateral hip dislocation, unilateral hypoplasia of the thyroid gland, adrenal glands, ovaries and fallopian tubes have been reported in single cases.\nEtiology\nNSDHL (Xq28) encodes a protein responsible for cholesterol biosynthesis, mutations are typically lethal in males. X-inactivation creates a mosaic of cells lacking the enzyme in females, disrupting embryonic development and leading to a highly variable spectrum of anomalies.\nDiagnostic methods\nIn most cases, the striking lateralization of all lesions, also noted on X-rays, is a strong diagnostic clue. Skin lesion histology reminiscent of psoriasis reveals hyperkeratosis and parakeratosis with inflammatory infiltrates. Biopsies from papillomatous lesions involving the body folds, however, show highly characteristic verruciform xanthoma in the form of lipid-laden histiocytes in the papillary dermis. Ultrasound of viscera, echocardiogram and full brain MRI are required to complement X-rays and identify all anomalies. Genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include X-linked dominant chondrodysplasia punctata, linear nevus sebaceous syndrome and inflammatory linear verrucous epidermal nevus.\nAntenatal diagnosis\nGenetic testing from chorionic villus samples is available; certain anomalies may be identified during routine sonograms.\nGenetic counseling\nTransmission is X-linked dominant. Sporadic cases have been reported, but extreme X-inactivation may mask the phenotype. Mothers should be examined for the presence of minimal symptoms and tested for a NSDHL mutation. Carriers have a 50% risk of transmission to daughters, but cannot transmit to live-born sons.\nManagement and treatment\nLung and heart anomalies are potentially fatal and may require immediate surgical intervention. Renal anomalies may also require draining or removal of the affected kidney. Orthopedic braces or corrective surgery may be necessary. Contralateral autologous skin grafts have been successfully performed. Skin lesions are best treated by topical application of a lotion or ointment containing lovastatin or simvastatin (in combination with cholesterol).\nPrognosis\nPrognosis is highly variable and based upon skeletal or cardiac anomalies. Cases of minimal involvement carry the risk of a severe disease in offspring.\n\n                            Last update: \n                            February 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Aldona PIETRZAK  - Pr Matthias SCHMUTH | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Childhood absence epilepsy", "Disease Definition": "Childhood absence epilepsy (CAE) is a familial generalized pediatric epilepsy, characterized by very frequent (multiple per day) absence seizures, usually occurring in children between the ages of 4 and 10 years, with, in most cases, a good prognosis.", "ORPHA ID": 64280, "Summary": "Epidemiology\nCAE accounts for 10% to 17% of all cases of epilepsy diagnosed in school-aged children. Incidence has been estimated at 1/50,000-1/12,500 in the United States. Females are usually more affected than males.\nClinical description\nCAE usually occurs in children between the ages of 4 and 10 years, with a peak between 5 and 7 years. The disease is characterized by frequent (multiple per day) absence seizures with an abrupt onset and offset. Photosensitivity is reported in 18% of CAE patients. In rare cases, CAE is also associated with an increased rates of adverse behavioral, psychiatric, language, and subtle cognitive comorbidities (including attention problems, anxiety, depression, social isolation and low self-esteem). These cognitive concerns are frequently complicated by attention deficit hyperactivity disorder (ADHD). Intellectual disability may also be observed. Onset of absence seizures under the age of 4 years is observed in a rare subset of CAE patients, a proportion of whom have encephalopathy due to GLUT1 deficiency (see this term).\nEtiology\nAlthough CAE is genetically determined, the precise mode of inheritance and genes involved remain largely unidentified. Mutations in the genes NIPA2 (15q11.2) which encodes a magnesium transporter; CACNA1H (16p13.3) which encodes a T-type calcium channel are reported to be susceptibility genes in Chinese Han population; GABRA1 (5q34), GABRB3 (15q12), GABRG2 (5q34) which encode gamma-aminobutyric acid (GABA) receptors; JRK (8q24.3) which encodes a putative DNA-binding protein; and SLC2A1 (1p34.2) which encodes a facilitated glucose transporter, may be implicated in CAE. Mutations in CLCN2 (3q27.1) which encodes a chloride channel, may be a susceptibility locus in a subset of CAE.\nDiagnostic methods\nDiagnosis relies on the clinical features and electroencephalographic findings of bilateral, synchronous symmetrical spike waves, usually 3 Hz, on a normal background activity.\nDifferential diagnosis\nDifferential diagnosis includes epilepsy with myoclonic absences, Jeavons syndrome, juvenile absence epilepsy, perioral myoclonia with absences, juvenile myoclonic epilepsy, encephalopathy due to GLUT1 deficiency as well as absences associated with chromosomal anomalies (ring chromosome 20, 15q13.3 microdeletion syndrome) (see these terms).\nManagement and treatment\nTreatment of CAE involves the use of antiepileptic drugs such as ethosuximide, valproate, and lamotrigine. However, lack of response is common. Levetiracetam (alternative choice for patients with CAE and photosensitivity) or topiramate are options for refractory absence seizures but may not be successful.\nPrognosis\nIn 56-65% of affected children, a 5-year remission rate off antiepileptic drugs is observed. Terminal remission generally occurs 3-8 years after the onset of CAE. However, in the remaining 30% of children, seizures persist either as absences alone (10-15%), absences with either generalized tonic-clonic or myoclonic seizure (5-15%), or evolution to juvenile myoclonic epilepsy (5-15%).\n\n                            Last update: \n                            November 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Gabrielle RUDOLF"}
{"Disease Name": "Childhood disintegrative disorder", "Disease Definition": "Childhood disintergrative disorder is a rare pervasive developmental disorder with a disease onset before the age of three and characterized by a dramatic loss of behavioral and developmental functioning after atleast two years of normal development. Manifestations of the disease include loss of speech, incontinence, communication and social interaction problems, stereotypical autistic behaviors and dementia.", "ORPHA ID": 168782, "Summary": ""}
{"Disease Name": "Childhood encephalopathy due to thiamine pyrophosphokinase deficiency", "Disease Definition": "Childhood encephalopathy due to thiamine pyrophosphokinase deficiency is a rare inborn error of metabolism disorder characterized by early-onset, acute, encephalopathic episodes (frequently triggered by viral infections), associated with lactic acidosis and alpha-ketoglutaric aciduria, which typically manifest with variable degrees of ataxia, generalized developmental regression (which deteriorates with each episode) and dystonia. Other manifestations include spasticity, seizures, truncal hypotonia, limb hypertonia, brisk tendon reflexes and reversible coma.", "ORPHA ID": 293955, "Summary": ""}
{"Disease Name": "Childhood occipital visual epilepsy", "Disease Definition": "Benign childhood occipital epilepsy, Gastaut type is a rare, genetic neurological disorder characterized by childhood to mid-adolescence onset of frequent, brief, diurnal simple partial seizures which usually begin with visual hallucinations (e.g. phosphenes) and/or ictal blindness and may associate non visual seizures (such as deviation of the eyes, oculoclonic seizures), forced eyelid closure and blinking and sensory hallucinations. Post-ictal headache is common while impairment of consciousness is rare.", "ORPHA ID": 98816, "Summary": ""}
{"Disease Name": "Childhood-onset autosomal recessive myopathy with external ophthalmoplegia", "Disease Definition": "A rare, genetic, non-dystrophic myopathy disease characterized by childhood-onset severe external ophthalmoplegia, typically without ptosis, associated with mild, very slowly progressive muscular weakness and atrophy, involving the facial, neck flexor and limb (upper > lower, proximal > distal) muscles. Muscle biopsy shows type 1 fiber uniformity, absent, or abnormally small, type 2A fibers, increased variability of fiber size, internalized nuclei and/or fatty infiltration.", "ORPHA ID": 363677, "Summary": ""}
{"Disease Name": "Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia", "Disease Definition": "A rare, genetic, autosomal recessive cerebellar ataxia disease characterized by slowly progressive spinocerebellar ataxia developing during childhood, manifesting with gait and limb ataxia, postural tremor, dysarthria, sensory alterations (e.g. decreased vibration sense), eye movement anomalies (i.e. nystagmus, saccadic pursuit, oculomotor apraxia), upper and lower limb fasciculations, and hyperreflexia with Babinski signs. Brain imaging reveals cerebellar, pontine, vermian and medullar atrophy.", "ORPHA ID": 284324, "Summary": ""}
{"Disease Name": "Childhood-onset basal ganglia degeneration syndrome", "Disease Definition": "A rare genetic neurodegenerative disease characterized by sudden onset of progressive motor deterioration and regression of developmental milestones. Manifestations include dystonia and muscle spasms, dysphagia, dysarthria, and eventually loss of speech and ambulation. Brain MRI shows predominantly striatal abnormalities. The disease is potentially associated with a fatal outcome.", "ORPHA ID": 497906, "Summary": ""}
{"Disease Name": "Childhood-onset benign chorea with striatal involvement", "Disease Definition": "A rare genetic hyperkinetic movement disorder characterized predominantly by chorea of variable severity, associated with bilateral striatal abnormalities on cerebral MRI. The disease is scarcely progressive, and cognitive performance is preserved in the majority of cases, although mild cognitive delay has also been reported.", "ORPHA ID": 494541, "Summary": ""}
{"Disease Name": "Childhood-onset hypophosphatasia", "Disease Definition": "A rare, moderate form of hypophosphatasia (HPP) characterized by onset after six months of age and widely variable clinical features from low bone mineral density for age, to unexplained fractures, skeletal deformities, and rickets with short stature and waddling gait.", "ORPHA ID": 247667, "Summary": "Epidemiology\nThe prevalence is unknown. About 130 cases have been reported to date.\nClinical description\nPatients develop manifestations after six months of age and generally before five years of age. Clinical manifestations cover a wide spectrum. Commonly, patients have rickets leading to short stature, with delay in walking and a waddling gait, and bone and joint pain. Skeletal deformities may include dolichocephalic skull and enlarged joints. Other common features are signs of intracranial hypertension and failure to thrive. Diaphyseal and metaphyseal fractures are common. Some affected children have premature loss of deciduous teeth, starting with incisors and then loss of other teeth with intact roots, before five years of age. The disease may follow an intermittent course with remission and recurrence in later life. There may be some clinical overlap between childhood-onset HPP and moderately severe infantile HPP.\nEtiology\nMutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia.\nDiagnostic methods\nDiagnosis is based on clinical presentation, alkaline phosphatase assay and confirmed by genetic testing.\nDifferential diagnosis\nOsteogenesis imperfecta is the most common differential diagnosis of HPP.\nGenetic counseling\nAutosomal recessive and autosomal dominant patterns of inheritance are reported, potentially explaining clinical variability. Genetic counseling is recommended for affected individuals.\nManagement and treatment\nTreatment has traditionally been supportive rehabilitative strategies to minimize functional limitations, and surgery to manage some fractures. However, there is evidence that enzyme replacement therapy with asfotase alfa, approved for pediatric onset HPP (Europe and USA), improves function in childhood-HPP.\nPrognosis\nAffected individuals may have significant disease, with poor mobility, chronic pain, and short stature. In addition, significant rickets, long bone deformity, and non-traumatic fractures are possible. Fractures may heal poorly and can reoccur.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Severine BACROT  - Dr Etienne MORNET"}
{"Disease Name": "Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder", "Disease Definition": "A rare genetic neurodegenerative disease characterized by childhood onset of slowly progressive motor and cognitive regression, resulting in intellectual disability and loss of language and ambulation, associated with the appearance of dystonia, parkinsonism, chorea, or rigidity. Ataxia, dysarthria, and seizures have also been reported. Head circumference percentiles may decline over time. Brain imaging shows progressive cerebral and cerebellar atrophy, in some patients also thinning of the corpus callosum.", "ORPHA ID": 500180, "Summary": ""}
{"Disease Name": "Childhood-onset nemaline myopathy", "Disease Definition": "Childhood onset nemaline myopathy, or mild nemaline myopathy is a type of nemaline myopathy (NM; see this terms) characterized by distal muscle weakness, and sometimes slowness of muscle contraction.", "ORPHA ID": 171439, "Summary": "Epidemiology\nThe annual incidence of NM has been estimated at 1/50,000 live births.\nClinical description\nChildhood onset NM might represent 10-15% of total cases. Onset is around 10 years of age, with initial presentation of symmetric weakness of ankle dorsiflexion and foot drop, or a general slowness of muscle contraction. All movements at the ankle and more proximal limb muscles may be disturbed. Weakness is slowly progressive. Facial, respiratory and cardiac muscles are generally normal, but patients are unable to jump or run because of muscle weakness or slowness.\nEtiology\nThis form of NM is caused by mutations in the ACTA1 (1q42.13), NEB (2q22), TPM2 (9p13.3) or TPM3 (1q21.2) genes.\nGenetic counseling\nTransmission follows an autosomal dominant pattern.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Monique RYAN"}
{"Disease Name": "Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome", "Disease Definition": "A progressive muscular dystrophy characterized by co-existence of limb-girdle weakness and diffuse joint contractures without cardiomyopathy. Patients present lower limb weakness progressing to involve also upper limbs and axial muscles and eventually leading to permanent loss of ambulation, widespread joint contractures in the limbs and sometimes the spine, and variable respiratory involvement. Morphological changes in muscle biopsies include rimmed vacuoles, increased internal nuclei, cytoplasmic bodies, and a dystrophic pattern.", "ORPHA ID": 466921, "Summary": ""}
{"Disease Name": "Childhood-onset spasticity with hyperglycinemia", "Disease Definition": "Childhood-onset spasticity with hyperglycinemia is a rare neurometabolic disease characterized by a childhood onset of progressive spastic ataxia associated with gait disturbances, hyperreflexia, extensor plantar responses and non-ketotic hyperglycinemia typically revealed by biochemical analysis. Additional signs of upper extremity spasticity, dysarthria, learning difficulties, poor concentration, nystagmus, optic atrophy and reduced visual acuity may also be associated.", "ORPHA ID": 401866, "Summary": ""}
{"Disease Name": "CHIME syndrome", "Disease Definition": "CHIME syndrome is a rare ectodermal dysplasia syndrome characterized by ocular colobomas, cardiac defects, ichthyosiform dermatosis, intellectual disability, conductive hearing loss and epilepsy.", "ORPHA ID": 3474, "Summary": "Epidemiology\nPrevalence is unknown. To date, CHIME syndrome has been described in 8 cases.\nClinical description\nCHIME syndrome is characterized by early-onset migratory ichthyosiform dermatosis, bilateral ocular coloboma, conductive hearing loss, seizures, intellectual disability, and characteristic facial features: brachycephaly, mild upslanting of the palpebral fissures, pale blue irides, hypertelorism, flat midface and philtrum, anteverted nostrils, thin upper lip, and excessive creases around a wide mouth. Ears are low-set with thick overfolded helices. Teeth are widely spaced and square in shape. Less constant findings are cleft palate or a less severe equivalent (bifid uvula and/or submucous cleft), cardiac defects (tetralogy of Fallot or transposition of the great vessels), pectus excavatum and supernumerary nipples.\nEtiology\nCHIME syndrome is caused by mutations in the glycosylphosphatidylinositol gene PIGL located to 17p12-p11.2.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            October 2013"}
{"Disease Name": "Choanal atresia, bilateral", "Disease Definition": "A rare, usually sporadic, congenital nose and cavum anomaly characterized by respiratory distress relieved by crying and rhinorrhea that presents at birth. It is caused by blockade of the nose on both sides by bony or soft tissue formed during embryological development.", "ORPHA ID": 137920, "Summary": ""}
{"Disease Name": "Choanal atresia, unilateral", "Disease Definition": "A rare, usually, sporadic congenital anomaly that is more commonly seen in females than in males (2:1), where the nose is blocked by bony or soft tissue formed during embryologic development on only one side (more commonly on the right side) and which is characterized by nasal obstruction and rhinorrhea, usually presenting at birth but that may go undetected until a respiratory infection aggravates the condition.", "ORPHA ID": 137917, "Summary": ""}
{"Disease Name": "Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by choanal atresia, athelia or hypoplastic nipples, branchial arch abnormalities, external ear malformations, hearing loss, thyroid abnormalities, delayed or absent pubertal development, and short stature. Developmental delay / intellectual disability are variably reported.", "ORPHA ID": 589856, "Summary": ""}
{"Disease Name": "Choanal atresia", "Disease Definition": "Choanal atresia (CA) is a congenital anomaly of the posterior nasal airway characterized by the obstruction of one (unilateral) or both (bilateral) choanal aperture(s), with clinical manifestations ranging from acute respiratory distress to chronic nasal obstruction.", "ORPHA ID": 137914, "Summary": "Epidemiology\nCA has a birth prevalence of approximately 1/11,630 in Europe and it follows a ''2:1'' ratio, namely female to male and unilateral to bilateral CA.\nClinical description\nCA is a congenital disorder that consists of a unilateral or bilateral bony or membranous septum between the nose and nasopharynx. In bilateral CA (see this term), neonates present at birth with acute respiratory distress requiring orotracheal intubation or placement of an oropharyngeal cannula. Nasotracheal intubation is not possible. Neonates with bilateral CA can also present with a history of multiple failed extubation attempts, especially in those with secondary airway issues. Spontaneous survival with a bilateral CA is possible but exceptional. In unilateral CA (see this term), infants can be asymptomatic often until the first respiratory infection. The most common presentation is persistent unilateral nasal obstruction or persistent mucoid rhinorrhea. CA can either occur in an isolated form or associated with other congenital deformities such as in CHARGE syndrome, Crouzon disease, Down syndrome, Treacher-Collins syndrome, 22q11.2 deletion syndrome (see these terms) or polydactyly. Bilateral CA is more common in patients with other congenital anomalies while unilateral CA occurs more frequently in isolated cases.\nEtiology\nThe following hypotheses are thought to result in developmental failure of the nasal cavity to communicate with the nasopharynx: persistence of the buccopharyngeal membrane from the fetal foregut; abnormal persistence of mesoderm forming adhesions in the nasochoanal region; abnormal persistence of the nasobuccal membrane of Hochstetter; or misdirection during neural crest cell migration. Prenatal exposure to maternal hyperthyroidism treated with methimazole may also be associated with CA development.\nDiagnostic methods\nInitial clinical evaluation includes introduction of a 6 or 8 French suction catheter via the nostrils, methylene blue dye test, cotton wisp test, and laryngeal mirror test. Flexible nasal endoscopy after mucous suctioning allows direct visualization of the atretic plate in the choana. Definitive evaluation is achieved with a computerized tomography scan which shows thickening of the medial portion of the pterygoid plates and enlargement of the posterior portion of the vomer, with or without membranous involvement. Tomography may also detect an associated malformation of semi-circular canals as found in CHARGE syndrome.\nDifferential diagnosis\nDifferential diagnoses include isolated pyriform aperture stenosis, nasolacrimal duct cyst (see these terms), turbinate hypertrophy, septal dislocation and deviation, antrochoanal polyp or nasal neoplasm.\nManagement and treatment\nThe goal of initial treatment for infants with bilateral CA is to maintain an adequate airway via the oral route. An oral airway or a feeding nipple with large holes to facilitate air flow can be used. If a patient still fails to maintain an adequate airway, endotracheal intubation must be performed. A tracheostomy may be required in patients with severe comorbidities but it is not necessary in cases of isolated (even bilateral) CA. Definitive surgical correction by nasal endoscopic approach is performed when appropriate and when feasible (weight >2kg). Given the relatively low morbidity of unilateral CA, definitive treatment is delayed until a later age (>18 months of age), when possible, as the chance of successful surgical repair increases with age.\nPrognosis\nCA (mainly the bilateral form) is a life-threatening condition and treatment cannot be delayed. In both unilateral and bilateral cases, restenosis necessitating reoperation is common.\n\n                            Last update: \n                            February 2016\n\n\n                            - Expert reviewer(s): \n                            Pr Nicolas LEBOULANGER"}
{"Disease Name": "Cholangiocarcinoma", "Disease Definition": "Cholangiocarcinoma (CCA) is a biliary tract cancer (BTC, see this term) originating in the epithelium of the biliary tree, either intra or extra hepatic.", "ORPHA ID": 70567, "Summary": "Epidemiology\nThe prevalence is unknown but it accounts for approximately 3% of gastrointestinal tumors and 10-15% of all hepatobiliary malignancies.\nClinical description\nCCA can occur in the intra or extra-hepatic biliary tract. A specific type of extra-hepatic CCA known as a Klatskin tumor (see this term) occurs at the junction where the left and right hepatic bile ducts meet the common bile duct (CBD). It is slightly more prevalent in males than females (1.3:1.0) and usually presents in the fifth to seventh decade of life. Clinical manifestations are not usually noted until an advanced disease stage. Extra-hepatic CCA manifests with signs of cholestasis (jaundice, pale stools, dark urine, pruritus), malaise, weight loss and/or progressive weakness. Intra-hepatic CCA may present with an abdominal mass or with non-specific symptoms of decreased appetite, weight loss, abdominal pain and malaise.\nEtiology\nThe etiology is unknown and most cases of CCA occur sporadically. Risk factors include primary sclerosing cholangitis (see this term), secondary sclerosing cholangitis, chronic typhoid carriage, parasitic infections (Opisthochis viverrini and Clonorchis sinensis), exposure to thorotrast (x-ray contrast medium) and choledochal cysts, all of which cause chronic biliary inflammation.\nDiagnostic methods\nDiagnosis is suspected on clinical and laboratory findings. Serum carbohydrate antigen (CA) 19-9 is the glycoprotein tumor marker most often used in the diagnosis of CCA. It is found to be elevated in 85% of patients. Increased CEA levels are also noted. Extra-hepatic tumors cause increased levels of alkaline phosphate (ALP), conjugated bilirubin and gamma-glutamyl transpeptidase (GGT) while intra-hepatic have only slightly elevated ALP levels. Abdominal imaging, visualization of the biliary tree and biopsies of the lesion are necessary for diagnosis. Magnetic resonance cholangiopancreatography (MRCP) provides information on intrahepatic metastases, biliary anatomy and tumor extension and is used in the staging of CCA. It has been advocated to replace endoscopic retrograde cholangiopancreatography (ERCP), a more invasive method. Visualization of the biliary tree and samples through brush cytology or bile duct biopsies are obtained with ERCP. A needle biopsy is performed in those with a liver mass. Extra-hepatic CCA is further divided into anatomical subtypes according to the Bismuth classification and a disease stage is given. Ultrasound, and contrast enhanced helical computerized computed tomography (CT) can be used in visualizing the extent of disease.\nDifferential diagnosis\nIntra-hepatic CCA is often mistaken for metastatic adenocarcinoma. Carcinoma of the gallbladder (see this term), benign strictures and Mirizzi syndrome should be excluded.\nManagement and treatment\nSurgical resection is the only potentially curative treatment for CCA but recurrences after surgery are frequent. Unfortunately CCA is often diagnosed as unresectable because of local extension and/or metastases. Distal CCA arising from the CBD is often treated by pancreatoduodenectomy. More proximal CCA needs hepatic resection. Palliative management involves biliary drainage by inserting metal stents in the biliary tree to release the blockage. Adjuvant chemotherapy after surgery or palliative chemotherapy for unresectable CCA is indicated. Gemcitabine combined with cisplatin therapy is the standard treatment for unresectable biliary tract cancers, including CCA.\nPrognosis\nAs proximal CCA is usually not diagnosed until a late stage of disease, prognosis is poor with 5-year survival rates of 20-50% after resection and almost 0% in unresectable tumors. Death is often due to biliary sepsis, cancer cachexia, malnutrition and liver failure.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Junji FURUSE"}
{"Disease Name": "Choledochal cyst", "Disease Definition": "A rare biliary tract disease characterized by congenital fusiform or cystic dilatation of intra- and/or extrahepatic bile ducts. Females are much more often affected than males. Clinical signs and symptoms include abdominal pain, jaundice, presence of a palpable abdominal mass, nausea, vomiting, or fever. Depending on the age of the patient, the condition may be complicated by stone formation, hepatomegaly, rupture with subsequent bile peritonitis, cholangitis, cholecystitis, biliary strictures, pancreatitis, or secondary biliary cirrhosis. The risk of malignancy, particularly cholangiocarcinoma, is significantly increased.", "ORPHA ID": 480501, "Summary": ""}
{"Disease Name": "Cholera", "Disease Definition": "Cholera is an infectious disease, caused by intestinal infection with Vibrio cholerae, characterized by massive watery diarrhea and severe dehydration that can lead to shock and death if left untreated.", "ORPHA ID": 173, "Summary": "Epidemiology\nCholera is endemic to over 50 countries (defined as having reported cholera cases for the last 3 years with evidence of local transmission), mainly in Asia and Africa. In addition, outbreaks have occurred throughout Africa, Asia, the Middle East, South and Central America, and the Caribbean. Worldwide, it is estimated that there are 1-4 million cases per year. In Europe, the disease is extremely rare, occurring as isolated, imported cases.\nClinical description\nOnce ingested, the incubation period ranges from 12 hours to 5 days. The majority of infected individuals will be asymptomatic, a smaller percentage will develop mild to moderate symptoms, and only a small proportion will develop severe dehydration. Cholera afflicts children and adults equally during epidemics among immunologically-naive populations but in endemic populations, children are more affected. Onset of severe cholera begins with profuse watery diarrhea with a ''rice water'' appearance, usually accompanied by vomiting. Some may experience abdominal cramping and discomfort but fever is extremely rare. Signs of dehydration and electrolyte imbalance soon occur and include sunken eyes, lethargy, dry mouth, decreased skin turgor, wrinkled hands and feet, and cold clammy skin. Kussmaul breathing and muscle cramping are seen in some. In children, seizures, altered consciousness, and coma can occur due to severe hypoglycemia. If left untreated, cholera can lead to severe dehydration, shock, and death within hours.\nEtiology\nCholera is due to an infection with Vibrio cholerae, a Gram negative rod bacteria that grows best in coastal waters and estuaries and is spread by the fecal-oral route. Over 200 serogroups exist but only 2 cause epidemic cholera: O1 and O139. The O1 serogroup is additionally subdivided into the Ogawa and Inaba serotypes. Once ingested, V. cholerae colonizes the small intestine where it releases cholera toxin that results in secretory diarrhea. The disease is associated with poor sanitation resources and lack of access to adequate water.\nDiagnostic methods\nDiagnosis is based on the sudden onset of severe diarrhea as well as recent exposure to the bacteria.  V. cholerae can be isolated from stool samples on selective media, followed by biochemical tests along with serogrouping and serotyping. The comma-shaped, motile bacteria can also be identified by examining fresh stool under dark field microscopy. Immunoassays that detect cholera toxins or  V. cholerae O1 and O139 lipopolysaccharides in the stool are also available.\nDifferential diagnosis\nMild cases can be confused with other causes of gastroenteritis such as Escherichia coli and rotavirus infections.\nManagement and treatment\nTreatment involves immediate rehydration with oral rehydration solutions (preferred when possible) containing salt and glucose or rice-based rehydration solutions and/or isotonic intravenous (IV) solutions. Individuals with severe cholera require an average of 200 ml/kg of fluids within the first 24 hours (may need >350 ml/kg). The initial fluid deficit should be replaced within 3-4 hours of presentation. Antibiotics such as tetracyclines, fluoroquinolones and macrolides are beneficial in moderate to severe cases and should be chosen based on availability and local resistance patterns. A high energy diet should be established once dehydration has been corrected to prevent malnutrition and complications. Access to safe drinking water and adequate sanitation prevents the spread of cholera. Two oral killed cholera vaccines are available, WC-rBS (whole-cell/recombinant B-subunit oral cholera vaccine; licensed in the EU) and BivWC (bivalent whole-cell oral cholera vaccine; used in endemic settings), which are given as 2 or 3 doses and provide 60-85% protection for 2-3 years. Children less than 5 years old, however, receive less protection from vaccination and for a shorter duration than adults.\nPrognosis\nWith proper treatment, the prognosis is good with a mortality rate of <0.2%. If untreated, the mortality rate can reach 50-70%.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Alaina RITTER"}
{"Disease Name": "Cholestasis-lymphedema syndrome", "Disease Definition": "Cholestasis-lymphedema syndrome is a rare genetic disorder characterized by neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and severe chronic lymphedema which mainly affects the lower limbs. Patients often present with fat malabsorption leading to failure to thrive, fat soluble vitamin deficiency with bleeding, rickets, and neuropathy. In 25% of cases, cirrhosis occurs during childhood or later in life.", "ORPHA ID": 1414, "Summary": ""}
{"Disease Name": "Cholesteryl ester storage disease", "Disease Definition": "A form of lysosomal acid lipase deficiency characterized by progressive cholesterol esters and triglyceride accumulation in tissues and organs typically presenting with hepatosplenomegaly, liver dysfunction and/or dyslipidemia.", "ORPHA ID": 75234, "Summary": ""}
{"Disease Name": "Chondrodysplasia punctata, tibial-metacarpal type", "Disease Definition": "A rare, non-rhizomelic, chondrodysplasia punctata syndrome characterized, radiologically, by stippled calcifications and disproportionate, short metacarpals and tibiae (with characteristic overshoot of the proximal fibula), clinically manifesting with severe short stature, bilateral shortening of upper and lower limbs, flat midface and nose, in the absence of cataracts and cutaneous anomalies. Neonatal tachypnea, hydrocephalus and mild developmental delay have been seldomly associated. Additional radiologic features include bowed long bones, platyspondyly and/or vertebral clefts.", "ORPHA ID": 79346, "Summary": ""}
{"Disease Name": "Chondrodysplasia punctata, Toriello type", "Disease Definition": "Chondrodysplasia punctata, Toriello type is a rare, non-rhizomelic, primary bone dysplasia syndrome characterized by calcific stippling of epiphyses in association with minor facial abnormalities, short stature and ocular colobomata. In addition, patients present chondrodysplasia punctata, brachycephaly, flat facial profile with small nose, flat lower eyelids and low-set ears, developmental delay, brachytelephalangy and deep palmar creases. Complex congenital cardiac disease and central nervous system anomalies (including partial absence of corpus callosum, small vermis, enlargement of the cisterna magna and/or of the anterior horns of the lateral ventricles) have been reported.", "ORPHA ID": 79347, "Summary": ""}
{"Disease Name": "Chondrodysplasia with joint dislocations, gPAPP type", "Disease Definition": "A rare, genetic, primary bone dysplasia characterized by prenatal onset of disproportionate short stature, shortening of the limbs, congenital joint dislocations, micrognathia, posterior cleft palate, brachydactyly, short metacarpals and irregular size of the metacarpal epiphyses, supernumerary carpal ossification centers and dysmorphic facial features. In addition, hearing impairment and mild psychomotor delay have also been reported.", "ORPHA ID": 280586, "Summary": ""}
{"Disease Name": "Chondrodysplasia-difference of sex development syndrome", "Disease Definition": "A rare difference of sex development affecting 46,XY individuals and characterized by complete gonadal dysgenesis (normal external female genitalia, lack of pubertal development, primary amenorrhea, and hypergonadotrophic hypogonadism) in association with severe dwarfism with generalized chondrodysplasia (bell-shaped thorax, micromelia, brachydactyly). Other reported features in the live sibling included eye anomalies (hypoplastic irides, myopia, coloboma of optic discs), dysmorphic features (deep-set eyes, upslanting palpebral fissures, puffy eyelids, large ears and mouth, mild prognathism), muscular hypoplasia, mild intellectual deficiency and severe microcephaly with cerebellar vermis hypoplasia.", "ORPHA ID": 1422, "Summary": ""}
{"Disease Name": "Chondroectodermal dysplasia with night blindness", "Disease Definition": "Chondroectodermal dysplasia with night blindness is a rare genetic bone development disorder characterized by proportionate short stature, nail dysplasia (enlarged, convex, hypertrophic nails), hypodontia and night blindness. Osteopenia, a tendency to present fractures, talipes varus with abnormal gait, ear infections, and watering eyes due to narrow tear ducts are frequently associated. Radiologically patients present delayed bone age on wrist X-rays, platyspondyly, and broad metaphyses of humeri with dense and thickened growth plates.", "ORPHA ID": 319195, "Summary": ""}
{"Disease Name": "Chondromyxoid fibroma", "Disease Definition": "A rare bone tumor characterized by a benign lesion composed of lobules of spindle shaped or stellate cells and an abundant myxoid or chondroid matrix. The tumor may occur in almost any osseous location but is most common in long bones, in particular the proximal tibia and the distal femur. Pain is the most common presenting symptom. Prognosis is excellent even in cases with local recurrence.", "ORPHA ID": 404507, "Summary": ""}
{"Disease Name": "Chondrosarcoma", "Disease Definition": "Chondrosarcoma is a malignant bone tumor arising from cartilaginous tissue, most frequently occuring at the ends of the femur and tibia, the proximal end of the humerus and the pelvis; and presenting with a palpable mass and progressive pain. Chondrosarcoma is usually slow growing at low histological grades and can be well managed by intralesional curettage or en-block wide resection.", "ORPHA ID": 55880, "Summary": ""}
{"Disease Name": "Chordoid glioma", "Disease Definition": "Chordoid glioma is an extremely rare glial neoplasm occurring in the region of the anterior third ventricle or hypothalamus, which is non-infiltrative and well-circumscribed and presents most frequently in middle-aged women with symptoms of memory loss and headaches and, because of its location, has a poor prognosis due to surgical morbidity.", "ORPHA ID": 251674, "Summary": ""}
{"Disease Name": "Chordoma", "Disease Definition": "Chordomas are rare malignant tumors arising from embryonic remnants of the notochord in axial skeleton.", "ORPHA ID": 178, "Summary": "Epidemiology\nThey are predominantly found in adults, and comprise 0.2% of all central nervous system tumors and 2-4% of all primary bone neoplasms, with an estimated prevalence of 1 in 2 million people and a male-to-female ratio of 2:1.\nClinical description\nThe clinical presentation depends entirely on the location of the chordoma. The main possible locations are the sacrum, intracranially at the clivus and along the spinal axis. When the tumor is intracranial, the most common presenting symptoms are diplopia, swallowing problems and headache. Other neurologic signs also occur, primarily as cranial nerve palsies. Tumors in the spine can cause pain in the area of the tumor (neck, back or tailbone), as well as arm or leg pain, weakness or numbness, bladder and intestinal disturbances. Chordomas are characterized by slow growth, with local destruction of the bone and extension into the adjacent soft tissue. They can metastasize to lymph nodes, lungs, liver and bone.\nDiagnostic methods\nDiagnosis is made by radiography, computed tomography or magnetic resonance imaging.\nManagement and treatment\nTreatment should be undertaken by expert neurosurgical and radiation oncology teams. Surgery is the primary mode of treatment but excision often remains incomplete despite repeat operations. Radiation in combination with surgery is then often used. High radiation doses (i.e. with proton beams) are required for local control. The role of chemotherapy or targeted therapies is still under investigation.\nPrognosis\nPrognosis depends on the extent and completeness of the tumor excision. Long-term follow-up is required because of the high rate of recurrence of these tumors.\n\n                            Last update: \n                            November 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Ross PINKERTON"}
{"Disease Name": "Choreoacanthocytosis", "Disease Definition": "Chorea-acanthocytosis (ChAc) is a form of neuroacanthocytosis (see this term) and is characterized clinically by a Huntington disease-like phenotype with progressive neurological symptoms including movement disorders, psychiatric manifestations and cognitive disturbances.", "ORPHA ID": 2388, "Summary": "Epidemiology\nPrevalence and incidence are not known, but it is estimated that there are around 1,000 cases worldwide. ChAc appears to be more prevalent in Japan, possibly due to a founder effect, and clusters have been found elsewhere in geographically isolated communities (e.g. French-Canadian population).\nClinical description\nOnset is in early adulthood and the initial presentation is often subtle cognitive or psychiatric symptoms. However, patients may have developed related psychiatric disorders several years before neurological manifestations. In at least 1/3 of patients, seizures, typically generalized, are the first manifestation. In some cases, seizures may precede the appearance of movement disorders by as much as a decade. During the course, most patients develop a characteristic phenotype including chorea, a very peculiar ''feeding dystonia'' with tongue protrusion, orofacial dyskinesias, limb dystonia, involuntary vocalizations, dysarthria and involuntary tongue- and lip-biting. Gait may have a ''rubber man'' appearance with truncal instability and sudden, violent trunk spasms. Most patients develop generalized chorea and some degree of parkinsonism. Impairment of memory and executive functions is frequent. Psychiatric manifestations are common and may present as schizophrenia-like psychosis or obsessive compulsive disorder (OCD). Myopathy and axonal neuropathy are usually mild. Clinical neuromuscular manifestations include areflexia, sensorimotor neuropathy, and variable weakness and atrophy. ChAc usually progresses slowly over 15-30 years, but sudden death, presumably caused by seizures or autonomic involvement, may occur.\nEtiology\nChAc is caused by various mutations in the VPS13A gene (9q21), coding for chorein. No obvious genotype-phenotype correlations have been observed.\nDiagnostic methods\nDiagnosis may be challenging. Presence of self-mutilating lip and tongue biting, or other self-mutilation is strongly suggestive of ChAc. Determination of acanthocytosis in peripheral blood smears may be negative and does not rule out the disorder. Serum CK is mostly elevated. Patients have absent chorein expression in erythrocytes on Western blot. Confirmatory DNA analysis of the VPS13A gene is difficult due to its size and heterogeneity of mutation sites. Electroneurography may demonstrate sensorimotor axonal neuropathy while electromyography shows neurogenic as well as myopathic changes. Electroencephalographic findings are not specific. Neuroradiologically, there is progressive striatal atrophy affecting especially the head of the caudate nucleus as well as impaired striatal glucose metabolism similar to that seen in HD.\nDifferential diagnosis\nThe differential diagnoses depend on the presenting symptoms and include McLeod neuroacanthocytosis syndrome, Huntington's disease, Huntington-like disorders, juvenile Parkinson's disease and Tourette's syndrome (see these terms).\nAntenatal diagnosis\nRoutine methods for prenatal testing can be applied.\nGenetic counseling\nChAc is an autosomal recessive disorder and genetic counseling is recommended. The risk of a sibling developing ChAc are 1:4. If the causative genetic defect is known, presymptomatic diagnosis in siblings at disease risk may be offered.\nManagement and treatment\nNo curative or disease-modifying treatments are currently available and management is purely symptomatic.\nPrognosis\nThe course is usually relentlessly progressive and overall prognosis is poor. Sudden death may be due to seizures, or possibly autonomic dysfunction. There may be gradual generalized weakness with fatal aspiration pneumonia or systemic infections.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Hans JUNG"}
{"Disease Name": "Choriocarcinoma of the central nervous system", "Disease Definition": "A rare primary germ cell tumor of central nervous system characterized by a lesion typically in the region of the pineal gland and the suprasellar compartment, composed of cytotrophoblastic elements and multinucleated syncytiotrophoblastic giant cells. Ectatic stromal vascular channels, blood lakes, and extensive hemorrhagic necrosis are the rule. The tumor usually arises in the second decade of life and predominantly in males. Clinical presentation depends on location and size and includes signs of increased intracranial pressure, visual disturbances, and endocrine abnormalities. Prognosis is generally poor.", "ORPHA ID": 252015, "Summary": ""}
{"Disease Name": "Choroid plexus carcinoma", "Disease Definition": "Choroid plexus carcinoma is a rare and highly aggressive malignant type of choroid plexus tumor (see this term) occurring almost exclusively in children, presenting with cerebrospinal fluid obstruction in the lateral ventricles (most common), the fourth and third ventricles or in multiple ventricles, leading to hydrocephalus and increased intracranial pressure, and manifesting with nausea, vomiting, abnormal eye movements, gait impairment, seizures and enlarged head circumference.", "ORPHA ID": 251899, "Summary": ""}
{"Disease Name": "Choroidal atrophy-alopecia syndrome", "Disease Definition": "A rare ectodermal dysplasia syndrome, characterized by the association of choroidal atrophy (sometimes regional), together with other ectodermal dysplasia features including fine and sparse hair, absent or decreased lashes and eyebrows, and possibly mild visual loss and dysplastic/thick/grooved nails.", "ORPHA ID": 1433, "Summary": ""}
{"Disease Name": "Choroideremia", "Disease Definition": "Choroideremia (CHM) is an X-linked chorioretinal dystrophy characterized by progressive degeneration of the choroid, retinal pigment epithelium (RPE) and retina.", "ORPHA ID": 180, "Summary": "Epidemiology\nThe prevalence is estimated between 1/50,000-1/100,000.\nClinical description\nAffected males experience nyctalopia in the first or second decade of life followed by peripheral visual field constriction with progression from annular scotomas to concentric visual field loss. Impairment in visual acuity is eventually noticed by mid-adulthood. In parallel, fundus changes are observed that consist initially of pigmentary stippling and focal areas of choroid atrophy in the equatorial fundus. In the final stage, there are extensive degenerative changes of the RPE with only remnants of the choroidal vasculature apparent in the macula, far peripheral retina, and near the optic disc. In the advanced stages, the sclera becomes visible on fundus examination in the areas of total choroidal and RPE atrophy. Female carriers generally show no serious visual impairment, but they can show conspicuous fundus abnormalities such as pigment changes in the periphery closely resembling the fine mottling characteristic of the initial stages of the disease in males.\nEtiology\nCHM is caused by mutations in the X-linked CHM gene encoding a Ras-related GTPase Rab escort protein (REP)-1. REP-1 is essential for the post-translational activation and subcellular localization of Rab GTP-binding proteins that control vesicle trafficking in secretory and endocytic pathways. Mutations in CHM leads to impaired association of Rab proteins with donor membranes, thus leading to cell death.\nDiagnostic methods\nThe clinical diagnosis is based on the characteristic fundus appearance, defective dark adaptation, peripheral visual field loss, an electroretinogram pattern of rod-cone degeneration, and a family history consistent with X-linked inheritance. CHM genetic diagnosis includes mRNA and DNA CHM gene analysis to detect punctual mutations, deletions involving multiple and single exons, and in rare cases genomic rearrangements.\nDifferential diagnosis\nDifferential diagnosis includes retinitis pigmentosa (RP), Usher syndrome type 1, and gyrate atrophy of the choroid and retina (see these terms). X-linked RP is distinguished from CHM by the migration of pigment into the retina. Moreover, choriocapilar and retinal atrophy, leaving areas of bare sclera is only present in CHM. Usher syndrome type 1 is distinguished from CHM by the scalloped areas of significant chorioretinal degeneration that are only typical of CHM. Also, profound deafness and vestibular problems are very rare in CHM cases. Gyrate atrophy is distinguished from CHM by elevated plasma concentration of ornithine.\nAntenatal diagnosis\nCarrier testing for at-risk female relatives and prenatal diagnosis for pregnancies at increased risk are possible if the mutation has been identified in an affected family member.\nGenetic counseling\nCHM is inherited in an X-linked manner, with a carrier female having a 50% risk of transmitting the mutation to her offspring.\nManagement and treatment\nManagement includes periodic ophthalmologic examination to monitor progression of CHM or appearance of cataract, and the use of UV-blocking sunglasses. Treatment is not currently available but a gene therapy trial is ongoing.\nPrognosis\nThe disease has a progressive course that leads to severely reduced visual acuity.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen AYUSO  - Dr M. LOPEZ MARTINEZ  - Dr José María MILLÁN SALVADOR  - Dr M. PERAITA  - Dr Rosa RIVEIRO ALVAREZ  - Dr María José TRUJILLO TIEBAS"}
{"Disease Name": "Christianson syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by intellectual deficit, ataxia, postnatal microcephaly, and hyperkinesis.", "ORPHA ID": 85278, "Summary": "Epidemiology\nChristianson syndrome (CS) prevalence is estimated to affect 1 in 16,000 to 100,000 males worldwide.\nClinical description\nAffected males diagnosed with CS typically present with the following core diagnostic features: nonverbal status, intellectual disability (ID), epilepsy, ataxia, postnatal microcephaly, and hyperkinesis. Seizures typically occur prior to the age of three. Secondary symptoms include behaviors associated with autism, Angelman syndrome features, eye movement problems (e.g. strabismus), hypotonia, gastroesophageal reflux disease (GERD), regressions (especially after the 1st decade of life), low height and/weight (progressing with age), and cerebellar vermal atrophy (particularly after the 1st decade). Females with heterozygous NHE6 mutations may present with a wide ranging phenotype ranging from unaffected to more severe neurologic/psychiatric manifestations.\nEtiology\nChristianson syndrome is caused by loss-of-function mutation of the SLC9A6 gene (Xq26.3), which encodes the endosomal Na+/H+ Exchanger 6 (NHE6) protein.\nDiagnostic methods\nCS diagnosis is confirmed by molecular genetic testing. Core diagnostic symptoms include nonverbal status, ID, epilepsy, ataxia, postnatal microcephaly, and hyperkinesis.\nDifferential diagnosis\nDifferential diagnoses include Angelman syndrome and ID (especially if it appears to follow an X-linked pattern).\nAntenatal diagnosis\nPrenatal genetic testing is possible if the familial mutation is known.\nGenetic counseling\nGenetic counseling is advised. Heterozygous females have a 50% risk of transmitting the pathogenic variant in pregnancy.\nManagement and treatment\nManagement of symptoms associated with seizures, ID/developmental delay, motor deficits, feeding difficulties, and/or eye problems is common. No specific treatment exists.\nPrognosis\nProgressive symptoms appear to progress as males age, especially after the 1st decade of life. These include regressions (e.g. walking, talking, and fine/gross motor skills), cerebellar atrophy, and low height/weight. Despite reports of premature mortality in CS males (i.e. ranging from approximately 20-50 years), life expectancy is currently unknown.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Eric MORROW"}
{"Disease Name": "Chromomycosis", "Disease Definition": "Chromomycosis is a chronic cutaneous and subcutaneous fungal infection, found mainly in subtropical and tropical areas (in soil and plant debris and transmitted by traumatic inoculation), and characterized clinically by slow growing, verrucous nodules, squamous plaques, or chronic limited lesions which are most commonly found on the lower limbs and which are characterized histologically by the presence of muriform cells. It is caused by dematiaceous fungi, with the main etiological agents being Fonsecaea pedrosoi, Phialophora verrucosa and Cladophialophora carrionii. Rarely, it can be caused by Rhinocladiella aquaspersa.", "ORPHA ID": 182, "Summary": ""}
{"Disease Name": "Chromophobe renal cell carcinoma", "Disease Definition": "Chromophobe renal cell carcinoma is a rare subtype of renal cell carcinoma, originating from the intercalating cells of the collecting ducts and macroscopically manifesting as a well-circumscribed, highly lobulated, solid tumor that is usually diagnosed at an early stage. It is frequently asymptomatic, or may present with nonspecific symptoms, such as weight loss, fever or fatigue. The classic presentation observed in renal tumors (hematuria, flank pain and palpable mass) is occasionally observed and usually indicates an advanced stage of the disease. It is most frequently sporadic however, several familial cases, associated with Birt-Hogg Dubé syndrome, have been described.", "ORPHA ID": 319303, "Summary": ""}
{"Disease Name": "Chromosome Y microdeletion", "Disease Definition": "A genetic male infertility characterized by azoospermia or oligozoospermia due to chromosome Y microdeletion.", "ORPHA ID": 1646, "Summary": "Epidemiology\nEstimated prevalence is 1/2500.\nClinical description\nThe diagnosis is usually made in adulthood, in the context of a couple's infertility. The spermogram shows non-obstructive azoospermia or oligozoospermia of variable intensity, usually severe.\nEtiology\n5 to 10% of cases of azoospermia (absent sperm) or severe secretory-type oligospermia (<1 million spermatozoa/mL semen) are associated with microdeletions in the euchromatic portion of the Y-chromosome long arm, at the AZF locus (azoospermia factor). Several subregions are distinguished in the AZF locus. In this region, the structure of the Y-chromosome is rich in repeated palindromes and recombination between two flanking sequences sharing a high degree of homology leads to various deletions: i) AZFa deletions (recombination between the sequences HERV15yq1 and HERV15yq2); the rarest - ii) AZFb or P5/proximal-P1 deletions, iii) AZFb+c deletions, of which two types are distinguished: P5/distal-P1 or P4/distal-P1 and iv) AZFc deletions caused by recombination between palindromes b2 and b4.\nDiagnostic methods\nDiagnosis is made on the basis of azoospermia or oligozoospermia in otherwise healthy males after exclusion of other causes of infertility. Molecular diagnosis is made by PCR amplification of STS type sequences (sequence-tagged sites) from the AZFa, b, and c regions. AZFc deletions are the most frequent; they are associated with azoospermia or oligospermia, usually severe. Complete deletions of AZFa, AZFb+c and AZFb regions are always associated with azoospermia: testicular histology shows either total lack of germline cells (SCOS or Sertoli cell only syndrome) or more or less systematized arrested maturation of cells from the spermatogenetic cell lineage.\nDifferential diagnosis\nThe differential diagnosis includes multiple causes of non-obstructive azoospermia, the most frequent being 47,XXY syndrome, other genetic hypogonadisms like Kallmann syndrome, testis inflammation (orchitis), infectious diseases (i.e. mumps after puberty), treatment (cancer chemotherapy), cryptorchidism, etc. Recent studies have identified numerous variants in multiple genes leading to azoo- or oligozoospermia.\nGenetic counseling\nMost Y chromosome microdeletions are de novo. Transmission is Y-linked. In case of spontaneous or following assisted reproductive techniques, male offsprings will inherit the paternal deletion.\nManagement and treatment\nAll chromosome Y microdeletions do not necessarily lead to infertility: firstly, some deletions (especially some partial deletions) do not result in spermatogenesis defects; secondly, among men with severe oligospermia, some can father children without infertility treatment. Finally, when mature spermatozoa are found in the sperm or in the testicles, the infertility problem can be solved with medically assisted procreation techniques such as TESE (testicular sperm extraction)-ICSI (intracytoplasmic sperm injection). However, there is a risk of transmitting the microdeletion to every male infant.\nPrognosis\nThe condition has no impact on life expectancy. Some patients may be psychologically impacted by learning that their infertility is due to a genetic abnormality.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Florence FELLMANN  - Dr James LESPINASSE"}
{"Disease Name": "Chronic actinic dermatitis", "Disease Definition": "Chronic actinic dermatitis (CAD) is an immunologically mediated photodermatosis usually observed in temperate climates and that typically develops in middle-aged to elderly males. CAD is characterized by eczematous and often lichenified pruritic patches and confluent plaques located predominantly on sun-exposed areas with notable sparing of eyelids, skin folds, and postauricular skin. It is often accompanied by multiple contact allergies and usually occurs in a background of either atopic, contact allergic, or seborrheic dermatitis, although it can occur de novo. Resolution of photosensitivity is reported in up to 50% of individuals after 15 years or more, with contact allergies persisting.", "ORPHA ID": 330064, "Summary": ""}
{"Disease Name": "Chronic atrial and intestinal dysrhythmia syndrome", "Disease Definition": "A rare genetic disease characterized by co-occurrence of sick sinus syndrome (manifesting as sinus bradycardia, often requiring pacemaker implantation) and chronic intestinal pseudo-obstruction (which may be of myogenic or neurogenic origin and usually requires total parenteral nutrition), with an age of onset within the first four decades of life. Other cardiac features, such as atrial flutter or fibrillation and valve anomalies, may also be present.", "ORPHA ID": 435988, "Summary": ""}
{"Disease Name": "Chronic beryllium disease", "Disease Definition": "A pneumoconiosis, characterized by granulomatous inflammation, that occurs in individuals who develop beryllium sensitization (BeS), a cell-mediated immune response to environmental and occupational beryllium exposure. BeS precedes the lung disease that may present with chronic dry cough, fatigue, weight loss, chest pain, and increasing dyspnea.", "ORPHA ID": 133, "Summary": "Epidemiology\nThe number of workers exposed to beryllium has been estimated at 1 million in the US, although no accurate figure exists for the US or globally. The prevalence of BeS in those exposed ranges from 1 - 20%. Chronic beryllium disease (CBD) among those with BeS ranges from 15-100%.\nClinical description\nPatients with CBD can range from those who are asymptomatic to those with severe lung dysfunction. Manifestations occur a few months to many years after exposure to beryllium and include chronic dry cough, dyspnea on exertion, chest pain, fatigue, fever, night sweats and weight loss. Additional extrapulmonary manifestations of dermatitis and skin granulomas have been reported. Progressive pulmonary fibrosis can eventually lead to cor pulmonale and respiratory failure. An increased risk of lung cancer among workers exposed to high levels of beryllium has also been observed.\nEtiology\nCBD is caused by occupational or environmental exposure to beryllium and beryllium-containing alloys (usually by inhalation of dust or fumes but also via contact with skin). Over time, in a subset of individuals, a cell-mediated immune response to beryllium may occur, causing the development of sensitized T cells that accumulate within the lungs and eventually form granulomas which can lead to fibrosis. A genetic variant in the HLA-DPB1 gene (6p21.3) with the presence of a glutamic acid at amino acid position 69 has been associated with the development of BeS and CBD.\nDiagnostic methods\nDiagnosis is based on a history of exposure to beryllium, characteristic clinical findings and laboratory testing. BeS can be detected with the beryllium lymphocyte proliferation test (BeLPT). Chest x-ray, CT scan of the lungs, exercise tolerance testing and pulmonary function tests can also aid in the diagnosis. Sampling of the lung with for example bronchoscopy with biopsy and bronchoalveolar lavage is usually required to demonstrate granulomatous inflammation in the lungs and or sensitization to beryllium\nDifferential diagnosis\nThe main differential diagnoses are sarcoidosis (most common), hypersensitivity pneumonitis and tuberculosis as well as other occupational lung diseases (such as silicosis).\nManagement and treatment\nThere is no cure for CBD. Treatment involves recommendations for cessation of beryllium exposure as medically prudent, and the use of immunosuppressive therapies, such as corticosteroids (prednisone). Early symptomatic disease may be treated with inhaled corticosteroids along with a short acting bronchodilator. Methotrexate and other immunosuppressive therapies can reduce steroid side effects. The efficacy of corticosteroids may be limited and relapses can occur after cessation of therapy or when dose is lowered. Those with advanced disease and major breathing difficulties may require oxygen supplementation. In severe cases, a lung transplant may be suggested. Patients should refrain from smoking. CBD may be prevented by providing exposed workers with respiratory protective devices and protective clothing and by minimizing exposure through use of workplace administration and engineering controls. The BeLPT is used to identify patients early on and to define workplace areas for modification in order to ultimately reduce additional BeS and CBD cases.\nPrognosis\nPrognosis varies, with some patients remaining clinically stable for many years and some experiencing a gradual worsening of symptoms over time. A debilitating course resulting in respiratory failure is also possible but regular monitoring and treatment can slow down the disease process.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Lisa MAIER"}
{"Disease Name": "Chronic bilirubin encephalopathy", "Disease Definition": "A rare neurologic disease characterized by the chronic consequences of bilirubin toxicity in the globus pallidus, sub-thalamic nuclei, and other brain regions, after exposure to high levels of unconjugated bilirubin in the neonatal period. Symptoms begin after the acute phase of bilirubin encephalopathy in the first year of life, evolve slowly over several years, and include mild to severe extrapyramidal disturbances (especially dystonia and athetosis), auditory neuropathy spectrum disorder, and oculomotor and dental abnormalities.", "ORPHA ID": 529808, "Summary": ""}
{"Disease Name": "Chronic cutaneous lupus erythematosus", "Disease Definition": "A form of cutaneous lupus erythematosus (CLE) that includes five different forms: discoid lupus erythematosus (DLE), chilblain lupus, hypertrophic or verrucous lupus erythematosus, lupus erythematosus tumidus, and lupus erythematosus panniculitis.", "ORPHA ID": 163531, "Summary": ""}
{"Disease Name": "Chronic diarrhea due to glucoamylase deficiency", "Disease Definition": "A rare intestinal disease characterized by impaired absorption of starch and short polymers of glucose due to primary small intestinal glucoamylase deficiency. Patients present in infancy or early childhood with chronic diarrhea, abdominal distention, and bloating. Levels of pancreatic amylase are typically normal, and histopathological analysis shows normal morphology of the intestinal mucosa.", "ORPHA ID": 103907, "Summary": ""}
{"Disease Name": "Chronic diarrhea with villous atrophy", "Disease Definition": "Chronic diarrhea with villous atrophy is a rare, genetic gastroenterological disease characterized by the early onset of chronic diarrhea, vomiting, anorexia, lactic acidosis, renal insufficiency and hepatic involvement (mild elevation of liver enzymes, steatosis, hepatomegaly). Partial villous atrophy (with eosinophilic infiltration) is observed on intestinal biopsy. Although diarrhea may resolve, the development of neurologic symptoms (cerebellar ataxia, sensorineural deafness, seizures), retinitis pigmentosa and muscle weakness may complicate disease course and lead to death. There have been no further descriptions in the literature since 1994.", "ORPHA ID": 1670, "Summary": ""}
{"Disease Name": "Chronic enteropathy associated with SLCO2A1 gene", "Disease Definition": "A rare genetic gastroenterological disease characterized by the presence of multiple persistent, intractable ulcers of the small intestine, leading to chronic blood and protein loss. Signs and symptoms include abdominal pain, anemia, fatigue, edema, and diarrhea. Morphologically, the condition manifests with multiple sharply demarcated shallow lesions with irregular circular or linear shape.", "ORPHA ID": 468641, "Summary": ""}
{"Disease Name": "Chronic eosinophilic leukemia", "Disease Definition": "A rare myeloproliferative neoplasm characterized by a clonal proliferation of eosinophilic precursors with persistent increase of eosinophils in peripheral blood and bone marrow, accompanied by increased blasts (<20%) or clonal cytogenetic or molecular genetic abnormalities. Cases with BCR-ABL1, PCM1-JAK2, ETV6-JAK2, or BCR-JAK2 fusion, or rearrangement of PDGFRA, PDGFRB, or FGFR1, are not included in this entity. Infiltration of the liver and spleen, as well as a variety of other organs, is typical. Patients may present with constitutional symptoms and signs and symptoms of organ involvement, such as endomyocardial fibrosis, peripheral neuropathy, central nervous system manifestations, respiratory symptoms, or rheumatological findings. Acute transformation is common.", "ORPHA ID": 168940, "Summary": ""}
{"Disease Name": "Chronic Epstein-Barr virus infection syndrome", "Disease Definition": "Chronic Epstein-Barr virus infection syndrome is a rare infectious disease characterized by familial, primary, chronic Epstein-Barr virus infection which typically manifests with persistent mononucleosis-like signs and symptoms, in the absence of secondary immunodeficiency.", "ORPHA ID": 2566, "Summary": ""}
{"Disease Name": "Chronic granulomatous disease", "Disease Definition": "A rare primary immunodeficiency, mainly affecting phagocytes, which is characterized by an increased susceptibility to severe and recurrent bacterial and fungal infections, along with the development of granulomas.", "ORPHA ID": 379, "Summary": "Epidemiology\nChronic granulomatous disease (CGD) average worldwide birth prevalence is estimated between 1/100,000 and 1/217,000.\nClinical description\nCGD can present at any age but is most commonly diagnosed before the age of 5 years. Manifestations include severe and recurrent infections most often due to a characteristic group of pathogens (including Staphylococcus aureus and Aspergillus spp) as well as granulomatous lesions mainly localized to the lung, lymph nodes, gastrointestinal tract and liver. Up to 50% of patients present with diarrhea, abdominal pain, and failure to thrive. Pneumonia, abscesses, cellulitis, adenitis and osteomyelitis are common. Mycobacterial diseases are usually limited to tuberculosis or regional and disseminated Bacillus Calmette-Guérin (BCG) infections. Invasive fungal infections are frequent. Dysregulated inflammation and granuloma formation can cause chorioretinal lesions, functional gastric outlet obstruction, inflammatory bowel disease (IBD), and wound dehiscence. Most female carriers are asymptomatic (unless >80% of their neutrophils are dysfunctional). Autoimmune disorders such as discoid lupus erythematosus and antiphospholipid syndrome can occur in some.\nEtiology\nCGD is caused by mutations in any one of the 6 genes encoding the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits or a critical stabilizer. A mutation in the CYBB gene (Xp21.1) is seen in 65% of cases in North America and Western Europe. The other 35% of cases are due to mutations in the CYBA (16q24), NCF1 (7q11.23), NCF2 (1q25), NCF4 (22q13.1) and CYBC1(17q25.3) genes. A deficiency in the NADPH oxidase enzyme complex leads to decreased production of reactive oxygen species (used by phagocytes to kill bacteria and fungi). The X-linked form of CGD typically presents with infection or IBD earlier than the NCF1-related form. To date, the NCF4-related form has only been associated with IBD but no severe infections.\nDiagnostic methods\nDiagnosis is suspected on clinical findings and confirmed by laboratory tests. Nitroblue tetrazolium (NBT) or dihydrorhodamine (DHR) oxidation assays measure the neutrophil superoxide production by the NADPH oxidase complex, which is absent or greatly reduced. Molecular genetic testing can be used to confirm the diagnosis and identify the specific subunit affected, but is not necessary unless gene therapy or allogeneic transplantation are anticipated. Immunoblot analysis can confirm the absence of the specific NADPH oxidase complex subunit involved.\nDifferential diagnosis\nDifferential diagnosis includes cystic fibrosis, Crohn disease, hyper-IgE syndrome, allergic bronchopulmonary aspergillosis, glutathione synthetase deficiency, and secondary hemophagocytic lymphohistiocytosis. Myeloperoxidase deficiency must also be excluded, as it gives a false positive for the DHR assay test.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a disease-causing mutation.\nGenetic counseling\nCGD follows an X-linked pattern of inheritance in those with a CYBB mutation. It can also be inherited autosomal recessively (due to CYBA, NCF1, NCF2, NCF4 and CYBC1 mutations). Genetic counseling is possible in families when a disease-causing gene has been identified.\nManagement and treatment\nAntibacterial and antifungal prophylaxis is essential in preventing the infections seen in CGD. Lifelong daily doses of trimethoprim-sulfamethoxazole (antibacterial) and itraconazole (anti-fungal) are recommended. Interferon-gamma, 3 times weekly, is also recommended. Hematopoietic stem cell transplantation may be curative and is increasingly used. Gene therapy has been successful in a few cases and is expanding. In those with severe infections, granulocyte transfusions are sometimes used.\nPrognosis\nThe prognosis has greatly improved with the use of antibacterial and antifungal prophylaxis therapy, with most patients living well into adulthood.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Steven HOLLAND"}
{"Disease Name": "Chronic hiccup", "Disease Definition": "Chronic hiccup is a rare movement disorder characterized by involuntary spasmodic contractions of the inspiratory muscles synchronized with larynx closure lasting for more than 48 hours.", "ORPHA ID": 396, "Summary": "Epidemiology\nThe disorder is thought to affect approximately 1/100,000 individuals. Chronic hiccup affect males more often than females.\nClinical description\nThe involuntary spasmodic contractions of the inspiratory muscles followed by the rapid closure of the vocal cords known as hiccups usually last for no more than a few minutes or at most a few hours with spontaneous resolution, and can affect people of any age. In rare pathological cases, hiccups may last for more than two days (chronic /persistent hiccup). Recurrent episodes over long periods are also called chronic hiccup. Clinical repercussions of these episodes may include dehydration, weight loss and malnutrition due to difficulty eating, sleep disorders, depression and exhaustion.\nEtiology\nThe hiccup is poorly understood. According to experimental data it is probably a coordinated ventilatory movement mixing bronchial ventilation, suction and deglutition components. Chronic hiccup is mainly an esophageal and gastric disorder. Other causes may include fever, brain lesions/tumors, cardiovascular disorders (stroke, myocardial infarction), renal failure, metabolic imbalance, peripheral nerve stimulation, or other injuries, drugs (chemotherapy, benzodiazepines, corticosteroids, barbiturates, morphine, and anesthetics), and alcohol. Other triggers include placement of medical instruments, certain foods and beverages, spices and tobacco. Cases also sometimes develop in a context of surgery (pleural, peritoneal or intracranial).\nDiagnostic methods\nClinical diagnosis is usually straightforward given the nature of the involuntary spasms. Imaging or laboratory tests to identify the underlying cause should focus primarily on the esophagus.\nDifferential diagnosis\nHiccups are extremely specific and can rarely be mistaken for another condition.\nManagement and treatment\nMany anecdotal treatments have been described with varying success. Management should ideally focus on identifying and treating the underlying cause, especially esophageal. No specific treatments have proven efficacy in the absence of controlled studies. Pharmacological approaches that have been attempted in cases where no gastroesophageal treatment works include baclofen, chlorpromazine, carbamazepine, haloperidol, metoclopramide, gabapentin, serotoninergic agonists, prokinetics, lidocaine, nifedipine, carvedilol and marijuana. Alternative therapy includes hypnosis and acupuncture. Phrenic nerve blockade is of little benefit since it yields only partial relief at the expense of respiratory insufficiency. Long-term treatment of the frequent esophageal cause can be very useful.\nPrognosis\nPersistent hiccups can reduce quality of life. Very long intractable disease may be debilitating.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Jean CABANE"}
{"Disease Name": "Chronic infantile diarrhea due to guanylate cyclase 2C overactivity", "Disease Definition": "A rare, genetic, intestinal disease characterized by early-onset, chronic diarrhea and intestinal inflammation due to overactivity of guanylate cyclase 2C. Additional manifestations include meteorism, dehydration, metabolic acidosis and electrolyte disturbances. Intestinal dysmotility, small-bowel obstruction and esophagitis (with or without esophageal hernia), as well as irritable bowel syndrome (without severe abdominal pain) and Crohn's disease, are frequently associated.", "ORPHA ID": 314373, "Summary": ""}
{"Disease Name": "Chronic inflammatory demyelinating polyneuropathy", "Disease Definition": "A chronic monophasic, progressive or relapsing symmetric sensorimotor disorder characterized by progressive muscular weakness with impaired sensation, absent or diminished tendon reflexes and elevated cerebrospinal fluid (CSF) proteins.", "ORPHA ID": 2932, "Summary": "Epidemiology\nPrevalence is about 1/200,000 children and 1-7/100,000 adults, but it is generally accepted that the frequency is underestimated.\nClinical description\nOnset may occur at any age but is more common in the 5th and 6th decades. Main clinical manifestations include progressive symmetrical weakness in both proximal and distal muscles of lower and/or upper limbs with partial or complete recovery between recurrences, associated with impaired sensation and absent/diminished tendon reflexes. Disease course is relapsing in 30% of cases, chronic and progressive in 60%, and monophasic with full generally permanent recovery in 10%. In 5-30% of cases, cranial nerve dysfunction may occur. Neuropathic pain, respiratory muscle and sub-clinical CNS involvement have been reported. Autonomic system dysfunction can occur. Children have a more rapid onset, greater disability at the peak and a more frequent relapsing course. CIDP may be associated with hepatitis C, inflammatory bowel disease, lymphoma, HIV, organ transplant, melanoma, or connective tissue disorders.\nEtiology\nCIDP could be due to an immune reaction, resulting in segmental and multifocal demyelination that may induce axonal loss with time.\nDiagnostic methods\nTo be diagnosed with CIDP, patients have to present a 2 month history of progression of demyelinating neuropathy (DN), some have a history of infection. CIDP may also appear more than 8 weeks after Guillain-Barré syndrome (GBS, so-called ``acute CIDP''; see this term). Diagnosis is based primarily on clinical and electrophysiological findings. The need for CSF examination and nerve biopsy depends on the level of clinical diagnostic certainty. When manifestations are present for at least 2 months, electroneuromyogram (ENMG) confirms the diagnosis if 3 of the following criteria are present on several nerves: partial motor-nerve (M-N) conduction blocks, reduced M-N conduction velocity, prolonged distal M-N and F-wave latencies. MRI may demonstrate gadolinium enhancement and proximal nerve/root enlargement. Elevated CSF proteins, with no cells, and demyelination/remyelination, often with inflammation, in nerve-biopsy specimens can provide additional supportive data. Biopsy is currently only recommended in cases of clinical suspicion of CIDP in which ENMG is not conclusive. CIDP should be suspected in virtually any multifocal or generalized neuropathy of unknown cause.\nDifferential diagnosis\nDifferential diagnoses include chronic acquired polyneuropathies (monoclonal gammopathies, diabetes, toxic neuropathies) or inherited neuropathies (Charcot-Marie-Tooth disease or transthyretin amyloid neuropathy; see these terms).\nManagement and treatment\nThe decision to treat depends on initial disease severity, age, general health status and potential contraindications to the 3 validated treatments: steroids, intravenous immunoglobulins (IVIg) or plasma exchanges. Patients with pure motor CIDP should be treated with IVIg rather than steroids. In milder forms, clinical observation and possibly steroid therapy (depending on ENMG results) are advised. Plasmapheresis or a combination of steroids and IVIg can be started if none of these treatments are effective. Refractory cases can be treated with intensive immunosuppression. The effect of interferon beta-1a and alpha, etanercept or rituximab remains uncertain. Neuropathic pain can be treated with antiepileptic medications or tricyclic antidepressants.\nPrognosis\nQuadriplegia, respiratory failure and death can occur but are rare. Patients may present residual symptoms that can lead to reduced quality of life. However long-term prognosis is usually good.\n\n                            Last update: \n                            December 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Michel VALLAT"}
{"Disease Name": "Chronic intestinal failure", "Disease Definition": "Chronic intestinal failure (CIF) is a chronic type of intestinal failure characterized by a nonfunctioning small bowel (that may be reversible or irreversal) where the body is unable to maintain energy and nutritional needs through absorption of food or nutrients via the intestinal tract (despite being metabolically stable) and which therefore necessitates long-term parenteral feeding. CIF may be the result of congenital digestive diseases (such as gastroschisis, atresia of small intestine), short bowel syndrome, intra-abdominal or pelvic cancer, or progressive and devastating gastrointestinal or systemic benign diseases (such as Crohn disease).", "ORPHA ID": 294422, "Summary": ""}
{"Disease Name": "Chronic intestinal pseudoobstruction", "Disease Definition": "A rare and heterogeneous gastroenterological clinical syndrome characterized by recurrent symptoms of intestinal obstruction with radiological features of dilated small or large intestine in absence of any mechanical occlusive lesion. Permanent alterations in neural, muscular, or mesenchymal structures of the intestinal wall or its extrinsic neural control, chronically impair tonic and propulsive motor functions in one or more segments of the gut.", "ORPHA ID": 2978, "Summary": "Epidemiology\nThe incidence of the pediatric form of CIPO has been estimated ≤ 1/40,000 live births. In Japan, the prevalence of CIPO in children < 15 years of age was 1/270,000 and in adults with onset age > 15 years was 1/100,000 and 1/125,000 and the annual incidence was 1/476,000 and 1/435,000 in males and females, respectively.\nClinical description\nPatients present with chronic abdominal pain and distention; in between, acute episodes of severe abdominal pain and vomiting suggest a mechanical obstruction. Patients have diarrhea due to small bowel bacterial overgrowth or constipation due to delayed transit. Weight loss results from malabsorption and inadequate food intake.\nEtiology\nCIPO is often associated with diseases in which treatment and prognosis are those of the underlying condition. In the remaining ''primary'' cases two subgroups can be recognized: those in whom CIPO is caused by an abnormal autoimmune/inflammatory response against neuromuscular structures of the gut and those in whom an inherited or de novo genetic mutation underlies the impairment of muscle, neural, or interstitial cell function. ACTG2 gene variants account for approximately 50% of the genetic cases. Other genes were reported, most of which in single-cases.\nDiagnostic methods\nAbdominal MRI or CT scan should confirm the chronic dilatation of the small or large intestine and should exclude a mechanical obstruction. Patients should therefore be investigated for the presence of numerous diseases that are associated with CIPO, such as Hirshsprung's disease, mitochondrial or paraneoplastic diseases, for the use of drugs that impair gastrointestinal motility, and for family history of similar symptoms. Esophageal, antroduodenal and anorectal manometry play a supportive role in the diagnosis; low amplitude contractions suggest a myopathic disorder whereas disorganized motor patterns suggest a neuropathic disorder. Full-thickness biopsies are usually not recommended but might be indicated to confirm an ongoing inflammatory visceral neuropathy or myopathy before starting immunotherapies. Genes that should be investigated in the case of CIPO include ACTG2, MYH11 and FLNA. Screening of TYMP and POLG should be considered in case of suspected mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The genetic screening of FLNA (NM_001110556.1) in the context of CIPO could be limited to exon 1, as pathogenic mutations resulting in a visceral phenotype are confined to the longer isoform, which is specifically expressed in intestinal smooth muscle cells.\nDifferential diagnosis\nThe differential diagnosis includes mechanical obstruction, acute colonic pseudoobstruction, enteric dismotility and slow transit constipation.\nAntenatal diagnosis\nAntenatal diagnosis of the ACTG2 mutation can be proposed when fetal bladder dilation is observed. Antenatal diagnosis of other genes is theoretically possible but has not been reported in the literature. Antenatal diagnosis is possible when a pathogenic variant has been identified in a family member with the disease.\nGenetic counseling\nGenetic counseling is recommended when cases of chronic intestinal pseudoobstruction are recurrent within the same family or when the physician suspects a genetic etiology.\nManagement and treatment\nManagement depends on the cause of the disorder, the extent and location of intestine involved, and the severity of symptoms. General measures include low residue diets, oral and/or enteral nutrition to prevent malnutrition, prokinetic agents (prucalopride), neostigmine or pyridostigmine to reduce intestinal dilatation and cycles of antibiotics to control bacterial overgrowth. Autoimmune/inflammatory forms might benefit from immunosuppressive treatments. Surgery should be avoided except in selected cases; ostomies can provide safe and effective detention of segmental bowel distention. Intestinal transplantation has become a therapeutic option in selected cases.\nPrognosis\nCIPO is a clinical syndrome characterized by disabling and potentially life-threatening complications over time. Treatment and long-term outcome is heterogeneous and often unsatisfactory.\n\n                            Last update: \n                            June 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Guido BASILISCO  - Dr Margherita MARCHI"}
{"Disease Name": "Chronic lymphoproliferative disorder of natural killer cells", "Disease Definition": "A rare large granular lymphocyte leukemia characterized by persistent (> 6 months) natural killer cell lymphocytosis in the absence of clinical diagnosis of leukemia/lymphoma, autoimmune disease, or chronic viral infections. The clinical course is variable, but generally indolent. Patients often remain asymptomatic, or may present with clinical manifestations including vasculitic skin lesions, neutropenic infections, musculoskeletal symptoms, peripheral neuropathy, or splenomegaly.", "ORPHA ID": 512017, "Summary": ""}
{"Disease Name": "Chronic mast cell leukemia", "Disease Definition": "A rare form of mast cell leukemia characterized by the presence of at least 20% mast cells in bone marrow aspirate smears but often mature mast cell morphology, low proliferation rate, and absence of organ damage and C findings (cytopenias, hepatomegaly, ascites, portal hypertension, splenomegaly, skeletal lesions, malabsorption). The disease course is less aggressive than in the acute form, although patients may later progress.", "ORPHA ID": 566396, "Summary": ""}
{"Disease Name": "Chronic mucocutaneous candidiasis", "Disease Definition": "A rare primary immunodeficiency characterized by persistent, debilitating and/or recurrent infections of the skin, nails, and mucus membranes, mainly with the fungal pathogen Candida albicans.", "ORPHA ID": 1334, "Summary": ""}
{"Disease Name": "Chronic myeloid leukemia", "Disease Definition": "Chronic myeloid leukaemia (CML) is the most common myeloproliferative disorder accounting for 15-20% of all leukaemia cases.", "ORPHA ID": 521, "Summary": "Epidemiology\nIts annual incidence has been estimated at between 1 and 1.5 cases per 100,000 and its prevalence at around 1 in 17,000.\nClinical description\nThe disease is typically triphasic with a chronic phase (CML-CP), accelerated phase (CML-AP) and blast phase (CML-BP). The majority of patients are diagnosed in the chronic phase and may be either asymptomatic (diagnosed through a routine white blood cell count) or present with fatigue, anaemia, weight loss, night sweats or splenomegaly.\nEtiology\nCML is characterised by the presence of the Philadelphia chromosome, an abnormality resulting from a balanced translocation between chromosomes 9 and 22 (t(9;22)(q34;q11.2)). This translocation generates a BCR/ABL gene fusion encoding a constitutively active tyrosine kinase. CML does not appear to be an inherited disease and the factors leading to predisposition for the disorder remain largely unknown.\nManagement and treatment\nAlthough an allogeneic bone marrow transplant is viewed as the only curative treatment option, the prognosis for patients improved dramatically with the targeted development of imatinib mesylate. Imatinib mesylate is a competitive inhibitor of BCR/ABL tyrosine kinase activity and has held EU marketing authorisation as an Orphan drug for the treatment of CML since 2001.\n\n                            Last update: \n                            May 2007"}
{"Disease Name": "Chronic myelomonocytic leukemia", "Disease Definition": "A rare myelodysplastic/myeloproliferative neoplasm characterized by a spectrum of clinical, hematological, and morphological features, ranging from predominantly myelodysplastic to mainly myeloproliferative in nature, with blood monocytosis (> 1G/L, constituting > 10% of circulating leukocytes). Is it often associated with blood cytopenia and/or ''proliferative features'' (increased leukocyte counts, splenomegaly), with marrow dysplasia and risk of progression to acute myeloid leukemia (AML).", "ORPHA ID": 98823, "Summary": "Epidemiology\nThe global annual incidence is approximately 1/147,000 with an important male predominance. The median age at diagnosis is 70.\nClinical description\nThe clinical symptoms are a consequence of blood cytopenias, mainly anemia (e.g. fatigue, dyspnea, possible angina, etc.), and less often of thrombocytopenia (spontaneous bleeding) or myeloproliferation (splenomegaly, serous effusions, and other nonspecific symptoms). The disease is associated with a 30% risk of transformation into AML.\nEtiology\nThe etiology is unknown in 90% of the cases. It has acquired causes for the remaining 10%, including previous treatment with chemotherapy or radiotherapy, and occupational exposure to benzene derivatives or ionizing radiation. Marrow cell analysis by NGS method shows at least one somatic myeloid-lineage associated mutation in 90% of the cases, especially epigenetic (TET2, ASXL1, IDH), spliceosome (SRSF2) or other genes mutations (RUNX, NRAS or KRAS).\nDiagnostic methods\nThe diagnosis is based on the following features: 1) Blood count reveals persistent monocytosis (>1G/L of circulating monocytes) with monocytes representing >10% of leukocytes (with or without increased leukocytes to >10G/L) and ''myelemia'' (myelocytes, metamylocytes) with or without cytopenias: anemia, aregenerative and often macrocytic, with or without thrombocytopenia. Infiltration of the liver, spleen, lymph nodes, and other organs is common. 2) Bone marrow morphology (from aspirate or biopsy) is generally hypercellular, with dysplasia in one to three myeloid lineages, without (<5%) or with (5-20%) excess blasts, and usually monocytosis. 3) Immunophenotyping of circulating monocytes reveals >94% of classical monocytes (MO1, CD14++/CD16−). 4) Bone marrow cytogenetics reveals acquired clonal abnormality in 30 % of the cases, especially chromosome loss (-7) or gain (+8). 5) NGS analysis reveals somatic mutation(s) in > 90% of the cases, especially TET2, SRSF2, ASXL1, RUNX1, NRAS or KRAS, while TP53 mutations are rare.\nDifferential diagnosis\nThe differential diagnosis mainly includes typical or atypical chronic myeloid leukemia (CML).\nManagement and treatment\nManagement and treatment of patients depends on their risk stratification level (of progression into AML). High risk CMML patients should have allogeneic bone marrow transplantation when possible, and otherwise hypomethylating agent-based treatment (azacytidine, decitabine). Lower risk CMML patients need treatment of their anemia with erythropoietin or derivatives. Myeloproliferation is treated by hydroxyurea, and thrombocytopenia (which often has a peripheral component) by the usual treatments used in peripheral thrombocytopenia.\nPrognosis\nPrognosis depends on the types and importance of cytopenias, the marrow blast percentage, marrow cytogenetic abnormalities, proliferative features (mainly leukocyte count) and somatic mutations, accounted for in a CMML prognostic scoring system (CPSS) which separates patients into low and high risk of progression into AML.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Pierre FENAUX | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Chronic myeloproliferative disease, unclassifiable", "Disease Definition": "A rare hematological neoplasm characterized by clonal proliferation of myeloid precursors in the bone marrow, blood and other tissues (spleen, liver), with clinical, morphological and molecular features ofmyeloproliferative neoplasms (MPN), failing to meet criteria of a specific MPN. The presentation is nonspecific and variable and often includes leukocytosis, thrombocytosis and anemia. Splenomegaly, hepatomegaly as well as fatigue, malaise or weight loss may appear in advanced stages.", "ORPHA ID": 86830, "Summary": ""}
{"Disease Name": "Chronic neutrophilic leukemia", "Disease Definition": "A rare myeloproliferative neoplasm characterized by sustained peripheral blood neutrophilia, bone marrow hypercellularity due to neutrophilic granulocyte proliferation, and hepatosplenomegaly. Other organs may be infiltrated in addition. Microscopically, the bone marrow shows an increase in proportion of myelocytes and mature neutrophils, but no significant dysplasia in any of the cell lineages. Peripheral blood neutrophils are mostly segmented, although band forms may also be substantially increased. Cytogenetic abnormalities are absent in most cases. The disease is slowly progressive with progredient neutrophilia followed by anemia and thrombocytopenia. Transformation to acute myeloid leukemia may occur.", "ORPHA ID": 86829, "Summary": ""}
{"Disease Name": "Chronic nonbacterial osteomyelitis/Chronic recurrent multifocal osteomyelitis", "Disease Definition": "Chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), is a chronic autoinflammatory syndrome that is characterized by multiple foci of painful swelling of bones, mainly in the metaphyses of the long bones, in addition to the pelvis, the shoulder girdle and the spine.", "ORPHA ID": 324964, "Summary": "Epidemiology\nDepending on the studies, prevalence of CNO/CRMO has been grossly estimated at between 1/ 160,000 to 1/ 2,000,000 and incidence at between 1/ 250,000 to 1/ 1,000,000. The disease affects predominantly females.\nClinical description\nCNO/CRMO occurs mainly in children and adolescents with an average age of onset of 10 years old. It is characterized by the insidious onset of recurrent episodes of local pain, tenderness, or swelling at the areas of bone inflammation. Inflammation can occur at any site of the skeleton. Metaphyses and epiphyses of the long bones are most frequently affected, in addition to the pelvis, the shoulder girdle and the spine. The neurocranium is almost never affected. Pain occurs predominantly during day hours, but may also be present at night time. The symptoms may induce a limited range of motion, since joints may be affected by arthritis. The severity and time course may vary widely among patients, oscillating between acute exacerbations and spontaneous remission. Systemic manifestations like fever, malaise, weight loss are frequent and the disease may be associated with inflammatory disorders of the skin such as psoriasis vulgaris, palmoplantar pustulosis, acne, pyoderma gangrenosum and rarely Sweet's syndrome, and /or of the intestine, like Crohn's disease, or ulcerative colitis. Adult-onset forms are reported that resemble SAPHO syndrome. It is not clear whether SAPHO syndrome and CNO/CRMO are two separate entities or if they are part of the same disease spectrum with CNO/CRMO being the pediatric equivalent of SAPHO syndrome.\nEtiology\nThe exact pathogenetic mechanism is unknown. An infectious origin is excluded as no apparent infectious agents are detectable at the site of the bone lesion. A genetic component is suspected for CNO/CRMO susceptibility. Immune dysregulation, particularly of the IL-10 and also the IL-1 pathway function, may play a role in the etiology of the disease.\nDiagnostic methods\nDiagnosis is based on a combination of clinical, radiological and histological exams. The classic findings on magnetic resonance imaging (MRI) are initial bone edema, generally followed by osteolytic or sclerotic, then hyperostotic bone lesions, as well as periosteal and soft tissue reaction. Bone lesion biopsies are typically sterile, and along with blood tests and an extensive microbial workup, show nonspecific inflammatory changes.\nDifferential diagnosis\nDifferential diagnosis includes mainly acute or subacute bacterial osteomyelitis, juvenile idiopathic arthritis, hypophosphatasia, Langerhans cell histiocytosis, and malignancies like osteosarcoma, Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, leukemia, and lymphoma. Rare monogenetic syndromes with CNO/CRMO as a component must also be excluded, such as Majeed syndrome, PAPA syndrome and DIRA syndrome (sterile multifocal osteomyelitis with periostitis and pustulosis).\nGenetic counseling\nMost cases are sporadic.\nManagement and treatment\nNon steroid anti-inflammatory drugs (NSAIDs) are the treatment of choice. Oral steroids, bisphosphonates and TNFα blockers can be used as an alternative treatment in cases unresponsive to NSAIDs, or during flares and in order to prevent relapses. The anti-inflammatory action of azithromycin may also contribute to a positive clinical therapeutic effect.\nPrognosis\nThe disease is characterized by alternating periods of remission and relapse, but generally has a ''benign'' course and can eventually resolve. In some cases, bone deformities may occur that can induce long-term disabilities (e.g. vertebra plana, hyperostosis, pain syndrome). Long term evolution towards spondyloarthropathy has been described.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Hermann GIRSCHICK"}
{"Disease Name": "Chronic pneumonitis of infancy", "Disease Definition": "Chronic pneumonitis of infancy is a rare pediatric form of interstitial lung disease (ILD, see this term).", "ORPHA ID": 91359, "Summary": "Epidemiology\nPrevalence of this disease is not known.\nClinical description\nThe clinical and radiologic features are similar to those observed in other forms of ILD (cough, tachypnea, and infiltrative opacities on chest imaging). Specific histological abnormalities include diffuse thickening of alveolar septa, hyperplasia of type 2 alveolar epithelial cells (AEC), and presence of primitive mesenchymal cells within the alveolar septa. In some cases, foci of pulmonary proteinosis-like material have been observed in air spaces.\nPrognosis\nThe prognosis is poor with a high mortality rate.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Annick CLEMENT"}
{"Disease Name": "Chronic primary adrenal insufficiency", "Disease Definition": "Chronic primary adrenal insufficiency (CPAI) is a chronic disorder of the adrenal cortex resulting in the inadequate production of glucocorticoid and mineralocorticoid hormones.", "ORPHA ID": 101959, "Summary": "Epidemiology\nIt is a rare disease with a prevalence of about 1/ 7, 100 and an annual incidence of about 1/ 250, 000 in Western populations.\nClinical description\nDisease onset peaks around 40 but can occur at any age. It presents insidiously with nonspecific symptoms that can be mistaken for other more prevalent conditions. Common manifestations include fatigue, loss of energy, malaise, weight loss, nausea, anorexia (failure to thrive in children), muscle and joint pain. Pigmentation of skin and mucous membranes (darkening of the skin especially in the palmar creases, knuckles, scars, oral mucosa and sites of friction) is a cardinal sign of CPAI. Symptoms of postural hypotension and hypoglycemia are late manifestations. Patients may also crave salt. Vitiligo (see this term) and alopecia areata are often present when an autoimmune disorder is the cause. CPAI also causes dehydroepiandrosterone deficiency causing additional symptoms seen only in women (loss of axillary/pubic hair, absence of pubarch in children, reduced libido and dry skin). Acute adrenal insufficiency (AAI; see this term) can occur if treatment is not followed or during precipitating illnesses and is a life threatening medical emergency.\nEtiology\nThe most common cause of CPAI in the developed world is Addison disease (AD; see this term), also known as autoimmune adrenalitis , seen in 80%-90% of cases. Autoimmune adrenalitis can be isolated or seen as part of an autoimmune disorder (autoimmune polyendocrine syndrome type 1, 2 or 4; see these terms). Infiltrative disorders are another cause of CPAI and include tuberculosis (see this term), fungal infections and AIDS-associated opportunistic infections. Genetic disorders (i.e. congenital adrenal hyperplasia; see this term), tumors, and treatment with certain drugs are other less common causes.\nDiagnostic methods\nBiochemical tests are needed to diagnose CPAI. Early morning serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels are measured. Plasma ACTH is much higher in individuals with CPAI (>22 pmol/L) and morning serum cortisol levels are usually low (<83nmol/L) but can fluctuate. A stimulation test observing the cortisol response to exogenous ACTH is a useful tool in confirming a diagnosis. In healthy subjects serum cortisol concentrations increase (>500 nmol/L) after exogenous ACTH administration but no increase is seen in CPAI patients. Raised plasma ACTH levels confirm adrenal origin of the disease.\nDifferential diagnosis\nSecondary adrenal insufficiency needs to be eliminated. Causes include pituitary tumors (see this term), lymphatic hypophystitis, pituitary tuberculosis and sarcoidosis (see this term), all of which are differential diagnoses.\nManagement and treatment\nManagement is life-long and requires a multidisciplinary team. Glucocorticoid replacement with oral hydrocortisone (10-25 mg daily taken in 2-3 doses) is given to mimic physiological cortisol secretion patterns. Oral fludrocortisone is given to replace mineralocorticoid hormones. Dehydroepiandrosterone replacement is optional. Glucocorticoid levels can be adjusted during times of stress to prevent AAI. The dose of hydrocortisone is maintained on the basis of clinical assessment and responses, taking into account a patient's well-being and presence of signs of over-replacement or under-replacement. An assessment of plasma renin activity is helpful in optimizing the dose of fludrocortisone. Growth and development in children must be monitored. Patients should carry a ready to inject hydrocortisone preparation and wear a medical alert card, in case of adrenal crisis.\nPrognosis\nThere is no cure for CPAI but with proper treatment and care taken to prevent AAI there is no decrease in life expectancy. CPAI is only life threatening when ignored.\n\n                            Last update: \n                            November 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Anne BACHELOT"}
{"Disease Name": "Chronic relapsing inflammatory optic neuritis", "Disease Definition": "A rare inflammatory optic neuropathy characterized by severe and persistent pain followed by subacute visual loss, a relapsing-remitting course, and steroid-dependence. Involvement of both optic nerves is common and is usually sequential. Serum antibodies against aquaporin 4 are absent in most cases. Magnetic resonance imaging shows contrast enhancement of the acutely inflamed optic nerves.", "ORPHA ID": 499085, "Summary": ""}
{"Disease Name": "Chronic respiratory distress with surfactant metabolism deficiency", "Disease Definition": "Chronic respiratory distress with surfactant metabolism deficiency is a rare, genetic, primary interstitial lung disease with a highly variable clinical presentation, ranging from neonatal respiratory distress syndrome to mild to severe interstitial lung disease (typical symptoms include cough, tachypnea, hypoxia, clubbing, crackles, failure to thrive). Lung biopsy reveals diffuse alveolar damage, interstitial thickening with inflammatory infiltrates, fibroblast proliferation, collagen deposition, and multiple foci of fibrosis, alveolar type II cell hyperplasia, abundant foamy alveolar macrophages and granular lipoproteic material in the alveolar lumen. Imaging shows cystic spaces and ground-glass opacities that are typically homogenously diffuse.", "ORPHA ID": 217566, "Summary": ""}
{"Disease Name": "Chronic thromboembolic pulmonary hypertension", "Disease Definition": "A rare complication of acute pulmonary embolism (PE), either symptomatic or not, that is characterized by fibrotic intravascular material occlusion of pulmonary arteries in combination with a secondary microvasculopathy of vessels less than 500 µm. The consequence is an increase in pulmonary vascular resistance (PVR) and progressive right heart failure.", "ORPHA ID": 70591, "Summary": "Epidemiology\nChronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease but the true prevalence is difficult to evaluate since the disease is potentially underdiagnosed. Epidemiological analysis of CTEPH in different countries estimate incidence ranging from 1/20,000-33,000 in the USA and Europe. CTEPH is usually considered as a complication of pulmonary embolism (PE), since 50-75% of patients have a history of PE and from a large meta-analysis, the weighted pooled incidence of CTEPH after an episode of PE is estimated at 0.56-3.2%.\nClinical description\nPatients commonly present with progressive dyspnea on exertion with or without signs of right heart dysfunction. A period between the initial event (acute PE) and the development of clinical signs is common and may last from a few months to many years (median time of 14 months between symptom onset and diagnosis in expert centers).\nEtiology\nThe pathophysiology of CTEPH is assumed to be associated with obstruction of pulmonary arteries by unresolved organized fibrotic clots and a secondary microvasculopathy in pulmonary vessels of less than 500 µm in diameter. The underlying causes of the disease remain unknown.\nDiagnostic methods\nThe diagnosis of CTEPH is suspected when ventilation/perfusion (VQ) lung scan shows mismatched perfusion defects and echocardiography shows high or intermediate probability of pulmonary hypertension (PH). The diagnosis is confirmed by right heart catheterization and pulmonary vascular imaging including CT pulmonary angiography (CTPA) and/or digital subtraction angiography (DSA) which should be performed in expert centres after at least 3 months of effective anticoagulation in order to discriminate this condition from PE. Specific diagnostic signs for CTEPH seen by multidetector CTPA or DSA include ring-like stenoses, webs/slits and chronic total occlusions (pouch lesions or tapered lesions).\nDifferential diagnosis\nDifferential diagnosis includes idiopathic pulmonary artery hypertension, Takayasu arteritis, congenital proximal interruption of a pulmonary artery, tumor thrombus, Von Recklinghausen disease, Osler-Weber-Randu disease or, very rarely, primary sarcoma of the pulmonary artery, and right heart failure with acute pulmonary thromboembolism.\nManagement and treatment\nPatients should be treated with lifelong anticoagulation. In addition, three treatment options have been successfully developed: pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and PH medications. PEA is the treatment of choice for operable patients. Operability is determined by multiple factors including surgical accessibility of the organized thrombi and comorbidities which are assessed during a multidisciplinary meeting in expert centres. Non-operable patients should be treated by PH-targeted therapy with or without BPA. Monotherapy with riociguat is currently the standard-of-care in inoperable CTEPH or persistent/recurrent PH after PEA. More recently, subcutaneous treprostinil, a prostacyclin analogue, has been also approved for the treatment of patients with inoperable CTEPH or persistent/recurrent PH after PEA. Other PH medications or oral combination therapy may be used off-label. Eligibility for BPA depends on the location and type of lesions which are also assessed through a multidisciplinary team approach and many expert centres use PH-targeted therapy prior to BPA to improve its safety by optimizing pre-BPA pulmonary hemodynamics. Multimodality treatment approach needs to be confirmed by further studies and is currently considered in selected patients after multidisciplinary team assessment in expert centers.\nPrognosis\nPrognosis depends on several factors such as operability, hemodynamic impairment and patient's comorbidities. A survival of 89% at 3 years and 72% at 10 years was reported in operated patients. Encouraging observations on improved survival with BPA and PH-targeted therapy in the inoperable CTEPH population have been observed but long-term results are missing.\n\n                            Last update: \n                            October 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Xavier JAIS  - Dr Mitja JEVNIKAR"}
{"Disease Name": "Chronic visceral acid sphingomyelinase deficiency", "Disease Definition": "A rare autosomal recessive, chronic, acid sphingomyelinase deficiency characterized clinically by onset in childhood with hepatosplenomegaly, growth retardation, interstitial lung disease and absence of neurodegenerative disorders.", "ORPHA ID": 77293, "Summary": "Epidemiology\nEpidemiological data is not available specifically for Niemann-Pick disease type B (NPD-B); however, the estimated birth prevalence of acid sphingomyelinase deficiency (both NPD types A and B combined) is between 1/167,000-250,000 in Europe.\nClinical description\nNPD-B is characterized by hepatosplenomegaly with progressive hypersplenism and stable liver dysfunction, gradual deterioration in pulmonary function, osteopenia, and atherogenic lipid profile. Most patients are diagnosed in infancy or childhood. The degree of hepatosplenomegaly ranges from mild to massive. Those with significant organomegaly have hypersplenism with secondary thrombocytopenia. Pulmonary involvement is common in affected individuals of all ages. Most affected individuals have evidence of interstitial lung disease. Abnormal linear growth and delayed skeletal maturation are common in children and adolescents, and can result in significant short stature in adulthood. A proatherogenic lipid profile is seen early in the disease course and some patients develop coronary artery disease. Neurologic manifestations occur infrequently and most of patients had minor and non-progressive findings. Up to one third of individuals with NPD-B have a cherry-red macula.\nEtiology\nNPD-B is caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene (locus 11p15.4), leading to decreased activity of acid sphingomyelinase (ASM), which results in lysosomal accumulation of sphingomyelin (SM) and secondary elevation of cholesterol and other lipids.\nDiagnostic methods\nThe diagnosis of NPD-B is established by detection of biallelic pathogenic variants in SMPD1 and/or residual acid sphingomyelinase enzyme activity (in peripheral blood lymphocytes, cultured skin fibroblasts or dry blood spots (DBS)). The de-acylated form of sphingomyelin (lyso-SPM) is increased in NPD-B and could be measured in plasma and DBS. Histology shows lipid-laden macrophages (foam-cells) in the bone marrow.\nDifferential diagnosis\nDifferential diagnosis includes other lysosomal storage diseases such as Gaucher disease, GM2-gangliosidosis, Niemann-Pick disease type C, lysosomal acid lipase deficiency, hematological malignancy, and primary hepatic disease (e.g., fatty liver, autoimmune, chronic hepatitis B-related, cryptogenic cirrhosis).\nAntenatal diagnosis\nPrenatal diagnosis for pregnancies at increased risk is possible by testing of ASM enzyme activity or by DNA- analysis if both SMPD1 pathogenic variants in the family are known.\nGenetic counseling\nNPD-B is inherited in an autosomal recessive manner. Genetic counseling should be offered to at-risk couples informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nCurrently, only supportive care is available for patients with NPD-B and includes management of coagulopathy and end-stage liver disease manifestations; supplemental oxygen for symptomatic pulmonary disease, and treatment of hyperlipidemia and osteopenia/osteoporosis. Enzyme replacement therapy (ERT) with recombinant human acid sphingomyelinase is in clinical development for the treatment of the non-neurologic manifestations of the disease.\nPrognosis\nPatients with NPD-B may live till late childhood or early adulthood. However, they develop many complications of the disease, significantly affecting the quality of life. The leading cause of death is progressive loss of pulmonary function.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Ekaterina ZAKHAROVA"}
{"Disease Name": "CHST3-related skeletal dysplasia", "Disease Definition": "CHST3-related skeletal dysplasia is a very rare bone disorder characterized clinically by short stature of prenatal onset; dislocation of the knees, hips or elbows; club feet; limitation of range of motion of large joints; progressive kyphosis; and occasional scoliosis. In a few patients, minor heart valve dysplasia has also been described. Intellect, vision and hearing are normal.", "ORPHA ID": 263463, "Summary": ""}
{"Disease Name": "Chudley-McCullough syndrome", "Disease Definition": "Chudley-McCullough syndrome is a rare, genetic, syndromic deafness characterized by severe to profound, bilateral, sensorineural hearing loss (congenital or rapidly progressive in infancy) associated with a complex brain malformation including hydrocephalus, varying degrees of partial corpus callosum agenesis, colpocephaly, cerebral and cerebellar cortical dysplasia (bilateral medial frontal polymicrogyria, bilateral frontal subcortical heteropia) and, in some, arachnoid cysts. Major physical abnormalities or psychomotor delay are usually not associated.", "ORPHA ID": 314597, "Summary": ""}
{"Disease Name": "Chuvash erythrocytosis", "Disease Definition": "Chuvash erythrocytosis is a rare, genetic, congenital secondary polycythemia disorder characterized by increased hemoglobin, hematocrit and erythropoietin serum levels and normal oxygen affinity, which usually manifests with headache, dizziness, dyspnea and/or plethora. Patients present an increased risk of hemorrhage, thrombosis and early death.", "ORPHA ID": 238557, "Summary": ""}
{"Disease Name": "Chylomicron retention disease", "Disease Definition": "Chylomicron retention disease (CRD) is a type of familial hypocholesterolemia characterized by malnutrition, failure to thrive, growth failure, vitamin E deficiency and hepatic, neurologic and ophthalmologic complications.", "ORPHA ID": 71, "Summary": "Epidemiology\nAbout 55 cases have been described to date.\nClinical description\nChylomicron retention disease manifests in infancy or early childhood. Features include an abnormal lipid profile, failure to thrive, chronic malabsorptive diarrhea, vomiting and abdominal distension in early infancy (1-6 months), and vitamin E deficiency. Cardiomyopathy and muscular manifestations have also been described. Essential fatty acid (EFA) deficiency is especially severe early in life. Poor mineralization and delayed bone maturation can occur. Hepatic steatosis is common and hepatomegaly is reported to occur in about 20% of CRD patients. Neurologic complications (areflexia, ataxia, myopathy, sensory neuropathy) and ophthalmologic complications (minor visual abnormalities) are less severe in CRD than in other types of familial hypocholesterolemia.\nEtiology\nThe SAR1B gene has been identified as the cause of CRD. More than 14 different mutations in about 30 patients have been described. This gene encodes the Sar1b protein, which is involved in the transport of chylomicrons (carriers of dietary lipids) from the endoplasmic reticulum to the Golgi apparatus. This mutation results in accumulation of pre-chylomicron transport vesicles in the cytoplasm of enterocytes. Genotyping has revealed that Anderson's disease and CRD are in fact the same condition.\nDiagnostic methods\nDiagnosis is often delayed because symptoms are nonspecific and hypocholesterolemia may be attributed to malnutrition secondary to chronic diarrhea. Diagnosis is based on a history of chronic diarrhea with fat malabsorption and a characteristic abnormal lipid profile: generally a 50% decrease in total cholesterol, LDL-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) in the presence of normal triglycerides. Upper endoscopy and histology reveal fat-laden enterocytes. Elevated creatine kinase (CK) in patients with hypocholesterolemia may be suggestive of CRD. Genotyping makes it possible to identify the SAR1B gene mutations. Parental lipid screening may clarify the diagnosis. An absence of hypocholesterolemia in both parents favors CRD. Consanguinity is frequent in patients with the disorder.\nDifferential diagnosis\nDifferential diagnosis includes abetalipoproteinemia and other genetic hypocholesterolemias characterized by decreased LDL-C, such as homozygous hypobetalipoproteinemia (HBL; see these terms), and acquired disorders associated with low HDL-C.\nGenetic counseling\nThe disease follows an autosomal recessive pattern of inheritance.\nManagement and treatment\nFollow-up should be directed toward monitoring nutrition and growth, and treatment compliance. Management should focus on prevention and early detection of complications (hepatic, neuromuscular, retinal and bone). Control of vitamin E deficiency plays a key role in preventing neurological complications. Treatment includes fat-soluble vitamin supplements and large amounts of vitamin E. Vitamin A, in combination with vitamin E, may help to prevent ophthalmologic complications. Early vitamin D treatment makes it possible to prevent osteopenia. Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet. Dietary counseling is needed not only to monitor fat intake and improve symptoms, but also to maintain sufficient caloric and EFA intake.\nPrognosis\nVery long-term follow-up into adulthood is poorly documented.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Emile LEVY"}
{"Disease Name": "Chylous ascites", "Disease Definition": "Chylous ascites is a rare form of ascites caused by accumulation of lymph in the peritoneal cavity, usually due to intra-abdominal malignancy, liver cirrhosis or abdominal surgery complications, and present with painless but progressive abdominal distension, dyspnea and weight gain.", "ORPHA ID": 1160, "Summary": ""}
{"Disease Name": "Chédiak-Higashi syndrome", "Disease Definition": "Chédiak-Higashi syndrome (CHS) is a rare severe genetic disorder generally characterized by partial oculocutaneous albinism (OCA, see this term), severe immunodeficiency, mild bleeding, neurological dysfunction and lymphoproliferative disorder. A classic, early-onset form and an attenuated, later-onset form (Atypical CHS; see this term) have been described.", "ORPHA ID": 167, "Summary": "Epidemiology\nExact prevalence is difficult to determine; fewer than 500 cases have been reported. Many patients likely remain undiagnosed because of variability in clinical signs. No gender or ethnic predilection has been found.\nClinical description\nPatients with CHS mostly have partial OCA involving the hair, skin, and eyes. Reduced iris pigmentation may be associated with nystagmus, and visual acuity may be impaired. Infections that are predominantly bacterial, but also of viral or fungal origin, begin to occur in infancy and may be severe, affecting primarily the skin and upper respiratory tract. Periodontitis has often been reported. Manifestations of increased bleeding tendency are generally mild and include epistaxis, gum bleeding and easy bruising. Cognitive deficits are often noted in childhood. Most patients develop neurological features by early adulthood as the disease progresses including ataxia, tremor, absent deep-tendon reflexes, and peripheral neuropathy. Some patients have Parkinsonian features with bradykinesia and rigidity. About 85% of CHS patients develop the accelerated phase, a lymphoproliferative disorder which involves fever, anemia, neutropenia, and occasionally thrombocytopenia, as well as lymphadenopathy and hepatosplenomegaly.\nEtiology\nLoss-of-function mutations in the LYST lysosomal trafficking regulator gene (1q42.1-q42.2) are associated with the severe, childhood-onset form of CHS. Missense mutations appear to underlie the atypical form.\nDiagnostic methods\nDiagnosis is suspected in individuals with partial OCA, a history of severe or frequent infections, and minor bleeding tendency. The main criterion is peroxidase-positive giant inclusions in white blood cells identified on the peripheral blood smear. Deficiency of platelet-dense bodies found via whole-mount electron microscopy is also characteristic. Molecular genetic testing supports diagnosis.\nDifferential diagnosis\nDifferential diagnoses include oculocutaneous albinism, Hermansky Pudlak syndrome (specifically HPS-2 caused by mutations in AP3B1), Cross syndrome and Griscelli disease (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis of CHS is available clinically by amniocentesis or chorionic villus sampling and requires prior identification of the genetic mutation in the family.\nGenetic counseling\nCHS follows an autosomal recessive pattern of inheritance. Genetic counseling should be provided to asymptomatic carriers and to affected adults.\nManagement and treatment\nThe hematological and immunological manifestations can be treated by allogenic hematopoietic stem cell transplantation (HSCT) upon diagnosis. HSCT is more successful when performed before the accelerated phase, but does not alter progression of neurological dysfunction. Management of the acceleration phase involves combination therapy with etoposide, dexamethasone, and cyclosporine (the same as for familial hemophagocytic lymphohistiocytosis (HLH); see this term). Infections should be treated promptly with antibiotics or antivirals and exposure to infectious agents avoided. Desmopressin can be used for bleeding prophylaxis. Standard therapeutic measures should be adopted to improve visual acuity and to manage neurological manifestations. Patients should use sunscreen and wear protective UV sunglasses.\nPrognosis\nWithout treatment, prognosis is very poor. Primary causes of mortality in the first 10 years of life are development of the accelerated phase and overwhelming infection. Neurologic manifestations occur in individuals despite bone marrow transplantation.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Wendy INTRONE"}
{"Disease Name": "CIDEC-related familial partial lipodystrophy", "Disease Definition": "A rare, genetic lipodystrophy characterized by abnormal subcutaneous fat distribution, resulting in preservation of visceral, neck and axilliary fat and absence of lower limb and femorogluteal subcutaneous fat. Additional clinical features are acanthosis nigricans, insulin-resistant type II diabetes mellitus, dyslipidemia, and hypertension, leading to pancreatitis, hepatomegaly and hepatic steatosis.", "ORPHA ID": 435651, "Summary": ""}
{"Disease Name": "CINCA syndrome", "Disease Definition": "A rare, genetic, cryopyrin-associated periodic syndrome (CAPS) characterized by neonatal onset of systemic inflammation, urticarial skin rash and arthritis/arthralgia resulting in severe arthropathy and central nervous system involvement (including chronic aseptic meningitis, brain atrophy and sensorineural hearing loss).", "ORPHA ID": 1451, "Summary": "Epidemiology\nWhilst the exact prevalence of chronic infantile neurological, cutaneous, and articular (CINCA) syndrome is unknown, it is estimated that the whole spectrum of CAPS has a prevalence of 1/360,000 in France, CINCA being the less common form. In the Eurofever registry, collecting information on over 250 patients with NLRP3 mutation, about 25% of the patients present the most severe CINCA phenotype.\nClinical description\nDisease onset typically occurs within the first hours/days of life with an urticarial rash, persistent elevation of acute phase reactants, and intermittent fever (which may be low-grade or absent). Typical facial features include frontal bossing and saddle back nose. The rash is typically non-pruritic and changes distribution during the day, without vasculitic alterations. Central nervous system manifestations include chronic aseptic meningitis, which, if left untreated, leads to brain atrophy, severe intellectual disability and sensorineural hearing loss. Typical neurological symptoms include chronic irritability, headache, early morning nausea, vomiting and, rarely, seizures. Ocular manifestations may include conjunctivitis, papilledema, optic nerve atrophy and progressive vision loss. Early degenerative arthropathy frequently involves large joints and causes deformities and contractures.\nEtiology\nMutations (usually de novo ) in the NLRP3 gene (chromosome 1q44) are identified in the majority of patients; however 30-35% of affected individuals lack a detectable mutation. Most of these patients display a somatic mosaicism for NLRP3. The NLRP3 gene plays a key role in innate immunity, encoding a component of the NLRP3-inflammasome, with gain of function mutations leading to overproduction of interleukin 1beta (IL-1beta).\nDiagnostic methods\nThe general consensus is that the clinical picture of CINCA is sufficient for diagnosis. Laboratory analyses document a nonspecific inflammatory syndrome with anemia, granulocyte hyperleukocytosis, elevated erythrocyte sedimentation rate (ESR) and elevated concentrations of C reactive protein. No autoantibodies or immune deficiencies are detected. Skin biopsy shows a neutrophilc dermatosis with massive perivascular neutrophil infiltration without signs of vasculitis. Brain MRI shows evident signs of meningitis with a possible inflammatory involvement of the inner ear. Ophthalmological examination may reveal papilledema. Genetic testing usually detects de-novo NLRP3 mutations but is not obligatory for diagnosis. In the absence of a positive standard genetic test, NLRP3 somatic mosaicism should be investigated\nDifferential diagnosis\nAn infectious disease is often suspected at disease onset. CINCA should be differentiated from similar monogenic or multifactorial autoinflammatory diseases, including, systemic onset juvenile idiopathic arthritis, tumor necrosis factor receptor 1 associated periodic syndrome, and the severe form of mevalonate kinase deficiency, CANDLE syndrome as well as the milder phenotype associated to mutations of NLRP3 (familial cold urticarial and Muckle-Wells syndrome).\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. Affected patients carrying a germinal mutation have a 50% risk of transmitting the disease to each child. In case of somatic mosaicism, risk depends on the possible presence of somatic mutations in reproductive organs of the parents.\nManagement and treatment\nTherapeutic approaches using numerous anti-inflammatory drugs and immunosuppressants have provided disappointing results. Corticosteroids can partially improve the symptoms but at the cost of high toxicity. Anakinra (a receptor antagonist of interleukin-1) and canakinumab (a monoclonal antibody against IL-1beta) have proved to be efficient against inflammatory signs, as well as against intracranial hypertension and hearing loss.\nPrognosis\nWithout adequate and timely treatment, quality of life is often poor. Syndrome severity is wide-ranging and the functional prognosis depends on the degree of neurological manifestations (such as intellectual disability and hearing loss) and the occurrence of tendinous retractions.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Marco GATTORNO"}
{"Disease Name": "Circumscribed palmoplantar hypokeratosis", "Disease Definition": "A rare acquired epidermal dysplasia characterized by annular, well-circumscribed patches of erythematous depressed skin.", "ORPHA ID": 69744, "Summary": "Epidemiology\nSo far, it has been reported in a little over 110 patients, but the condition is likely to be underdiagnosed as it was only recognized in 2002. The majority of reported patients are middle-aged or elderly women in the United States, Japan, and Spain, but cases have also been reported in other European and Asian countries.\nClinical description\nThe lesions are well-circumscribed, usually round and measuring 5-15 mm in diameter, erosion-like plaques that generally occur on the palms or soles and are usually solitary, although a few patients have been reported with two or more lesions. These lesions are asymptomatic but may be mildly pruritic, tender or painful.\nEtiology\nThe etiology is unknown; the lesions may result from a disordered epidermal differentiation or desquamation process. Exceptional congenital cases have been reported.\nDiagnostic methods\nAccurate diagnosis requires histopathological analysis. The characteristic features are a decrease of the horny layer's thickness with a sharp stair-like boundary separating the affected and normal skin, and a slightly diminished granular cell layer.\nDifferential diagnosis\nThe absence of cornoid lamellation allows exclusion of porokeratosis of Mibelli.\nManagement and treatment\nTreatment is not strictly necessary as the lesions are asymptomatic and, by definition, benign; they may be treated with excision, cryotherapy and application of topical calcipotriol.\nPrognosis\nThe condition is chronic and benign. The lesions enlarge slowly over time, before stabilizing. Rarely, the epidermis may show (pre)neoplastic changes.\n\n                            Last update: \n                            December 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Jean KANITAKIS"}
{"Disease Name": "Cirrhosis-dystonia-polycythemia-hypermanganesemia syndrome", "Disease Definition": "A rare disorder of manganese transport characterized by childhood onset of extrapyramidal movement disorder (including dystonia, tremor, and bradykinesia), liver cirrhosis, polycythemia, and hypermanganesemia. Cases with spastic paraparesis without extrapyramidal dysfunction have also been reported. Cognitive functions are preserved. Brain imaging findings are consistent with deposition of manganese in the basal ganglia, dentate nucleus, brain stem, and anterior pituitary.", "ORPHA ID": 309854, "Summary": ""}
{"Disease Name": "Citrin deficiency", "Disease Definition": "A rare autosomal recessive urea cycle defect characterized clinically by recurring episodes of hyperammonemia and associated neuropsychiatric symptoms in the adult-onset form (citrullinemia type II), and by transient cholestasis and variable hepatic dysfunction in the neonatal form (neonatal intrahepatic cholestasis due to citrin deficiency).", "ORPHA ID": 247582, "Summary": ""}
{"Disease Name": "Citrullinemia type I", "Disease Definition": "Citrullinemia type I is a rare autosomal recessive urea cycle defect characterized biologically by hyperammonemia and clinically by progressive lethargy, poor feeding and vomiting in the neonatal form (Acute neonatal citrullinemia type I, see this term) and by variable hyperammonemia in the later-onset form (Adult-onset citrullinemia type I, see this term).", "ORPHA ID": 247525, "Summary": ""}
{"Disease Name": "Citrullinemia type II", "Disease Definition": "A severe subtype of citrin deficiency characterized clinically by adult onset (20 and 50 years of age), recurrent episodes of hyperammonemia and associated neuropsychiatric symptoms such as nocturnal delirium, confusion, restlessness, disorientation, drowsiness, memory loss, abnormal behavior (aggression, irritability, and hyperactivity), seizures, and coma.", "ORPHA ID": 247585, "Summary": ""}
{"Disease Name": "Citrullinemia", "Disease Definition": "Citrullinemia is an autosomal recessively inherited disorder of urea cycle metabolism and ammonia detoxification (see this term) characterized by elevated concentrations of serum citrulline and ammonia. The disease presents with a large range of manifestations including neonatal hyperammonemic encephalopathy with lethargy, seizures and coma; hepatic dysfunction in all age groups; episodes of hyperammonemia and neuropsychiatric symptoms in children or adults, or, can be asymptomatic in some cases (detected in newborn screening programs). Citrullinemia is divided into two main groups that are encoded by different genes: citrullinemia type I (comprised of acute neonatal citrullinemia type I and adult-onset citrullinemia type I) and citrin deficiency (comprised of adult-onset citrullinemia type II and neonatal intrahepatic cholestasis due to citrin deficiency) (see these terms).", "ORPHA ID": 187, "Summary": ""}
{"Disease Name": "CK syndrome", "Disease Definition": "CK syndrome is a rare, genetic, X-linked syndromic intellectual disability disorder characterized by mild to severe intellectual disability, infancy-onset seizures, post-natal microcephaly, cerebral cortical malformations, dysmorphic facial features (including long, narrow face, almond-shaped palpebral fissures, epicanthic folds, high nasal bridge, malar flattening, posteriorly rotated ears, high arched palate, crowded teeth, micrognathia) and thin body habitus. Long and slim fingers/toes, strabismus, hypotonia, spasticity, optic disc atrophy, and behavioral problems (aggression, attention deficit hyperactivity disorder and irritability) are additional features.", "ORPHA ID": 251383, "Summary": ""}
{"Disease Name": "CLAPO syndrome", "Disease Definition": "A rare, complex, vascular malformation syndrome characterized by capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of face and limbs, and partial or generalized overgrowth involving one or more body segments.", "ORPHA ID": 168984, "Summary": ""}
{"Disease Name": "Clark-Baraitser syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, obesity, macrocephaly, behavioral abnormalities (such as aggressive tantrums and autistic-like behavior), and delayed speech development. Dysmorphic facial features include large, square forehead, prominent supraorbital ridges, broad nasal tip, large ears, prominent lower lip, and minor dental anomalies such as small upper lateral incisors and central incisor gap.", "ORPHA ID": 600731, "Summary": ""}
{"Disease Name": "Class I glucose-6-phosphate dehydrogenase deficiency", "Disease Definition": "A rare constitutional hemolytic anemia due to an enzyme disorder characterized by severe glucose-6-phosphate dehydrogenase deficiency (typically <10% residual enzyme activity) associated with chronic non-spherocytic hemolytic anemia of highly variable severity. Patients are at risk of developing neonatal jaundice (potentially leading to kernicterus), gallstones, and reticulocytosis and splenomegaly. They have an increased susceptibility to oxidizing agents provoking episodes of acute hemolysis. Favism, which describes the occurrence of an acute hemolytic reaction in response to the ingestion of fava beans, is more common in infants and young children.", "ORPHA ID": 466026, "Summary": ""}
{"Disease Name": "Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form", "Disease Definition": "A form of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency characterized by abnormal genital development with variable levels of virilization in females and normal genitalia in males in association with glucocorticoid insufficiency with salt-wasting due to aldosterone deficiency, accelerated growth velocity and bone maturation, premature adrenarche and precocious puberty leading to reduced adult height.", "ORPHA ID": 315306, "Summary": ""}
{"Disease Name": "Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form", "Disease Definition": "A form of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency characterized by abnormal genital development with variable levels of virilization in females, and normal genitalia in males in association with glucocorticoid insufficiency with absence of salt-wasting, accelerated growth velocity and bone maturation, premature adrenarche and precocious puberty leading to reduced adult height. Females have a normal uterus and various degrees of abnormal vaginal development.", "ORPHA ID": 315311, "Summary": ""}
{"Disease Name": "Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency", "Disease Definition": "A form of congenital adrenal hyperplasia (CAH) characterized by simple virilizing or salt wasting forms that can manifest with abnormal genital development with variable levels of virilization in females and with adrenal insufficiency in both sexes, and that presents with dehydration and hypoglycemia (which can be lethal if left untreated) in the neonatal period, as well as hyperandrogenia.", "ORPHA ID": 90794, "Summary": "Epidemiology\nClassic CAH due to 21-hydroxylase deficiency (21-OHD) is the most common form of CAH with a prevalence estimated at 1/14,000.\nClinical description\nClassic 21-OHD CAH can be divided into 2 clinical groups: simple-virilizing or salt wasting. Clinical signs are observed prenatally or at birth. Girls present with abnormal genital development with variable levels of virilization, ranging from a nearly male appearance to minimal clitoromegaly. A normal uterus and various degrees of abnormal vaginal development are seen. The external genitalia in boys are normal. Salt wasting forms lead to symptoms of dehydration and hypotension in the first few weeks of life due to aldosterone deficiency. They can develop failure to thrive, hyponatremia, hyperkalemia, acidosis and hypoglycemia which can be life threatening if not treated immediately. Hyperandrogenia manifests with accelerated growth velocity and accelerated skeletal maturation (leading to reduced adult height), advanced bone age, premature pubarche and precocious puberty during childhood, and acne and hirsutism, menstrual problems, subfertility, obesity, and metabolic and cardiovascular disturbances during adulthood. Males with poor hormonal control may develop small testes and benign testicular adrenal rest tumors (TARTs).\nEtiology\nThe disease is caused by a mutation in the CYP21A2 gene located on chromosome 6p21.3 which controls cortisol and aldosterone production.\nDiagnostic methods\nGirls are usually diagnosed at birth when virilization of external genitalia is present. Signs of adrenal insufficiency present during the second week of life in both sexes. Newborn screening programs in most European countries diagnose cases of CAH at birth through 17-hydroxy-progesterone (17-OHP) analysis.\nDifferential diagnosis\nDifferential diagnoses include other forms of CAH, polycystic ovary syndrome (mainly for non-classical CAH) or any diseases with androgen excess.\nAntenatal diagnosis\nPrenatal diagnosis can be achieved by measuring 17-OHP levels in amniotic fluid during the second trimester of gestation or by genotyping through chorionic villus sampling to obtain fetal DNA as early as gestational week 10-12 in families with known CYP21A2 pathogenic genotypes. Methods involving invasive sampling should only be performed if the results will lead to changes in approach or treatment.\nGenetic counseling\nAs classic 21-OHD CAH follows an autosomal recessive pattern of inheritance, genetic counseling is possible.\nManagement and treatment\nPrenatal treatment with dexamethasone can be administered to female fetuses at risk of developing classic CAH, but this procedure is still controversial due to potential side effects. When administered before the 9th week of gestation, it prevents the excessive androgen production responsible for genital virilization in females. If diagnosed after birth, vaginoplasty surgery is usually performed on girls but the timing of the surgery is still debated. Lifelong hormone replacement therapy is needed to treat adrenal insufficiency and to decrease elevated androgen hormone levels in order to allow for normal health, growth and puberty. Hydrocortisone is usually given to children as glucocorticoid (GC) replacement therapy (10-15mg/m2/day divided into 2 or 3 doses) and 9alpha-fludrocortisone for mineralocorticoid (MC) replacement. Dosage is monitored and should be increased during times of stress or intercurrent disease. There is a risk of developing acute adrenal insufficiency and other complications due to chronic hyperandrogenemia in case of poorly controlled disease. Excessive treatment with GC causes cushingoid features, metabolic and cardiovascular disturbances. Excess MC causes hypertension. Regular follow-up by a multidisciplinary team, including pediatric endocrinologists, surgeons, gynecologists, psychologists, is important.\nPrognosis\nLife expectancy may be reduced as patients with CAH have a risk of acute adrenal insufficiency and higher metabolic and cardiovascular risk. Poor disease control may increase the risk of these conditions, as well as of TARTs, menstrual irregularity and subfertility.\n\n                            Last update: \n                            February 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Juliane LEGER | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Classic galactosemia", "Disease Definition": "A life-threatening metabolic disease with onset in the neonatal period. Infants usually develop feeding difficulties, lethargy, and severe liver disease.", "ORPHA ID": 79239, "Summary": "Epidemiology\nGlobal prevalence is unknown but estimated annual incidence has been reported to be between 1/40,000 and 1/60,000 in Western countries. The disorder appears to be more common in the Caucasian population than in other ethnic groups but figures in other populations may be underestimated. Males and females are equally affected.\nClinical description\nWhen ingesting breast milk or lactose-containing formula, infants develop feeding problems, failure to thrive, and signs of liver damage (jaundice, bleeding tendency, hypoglycemia). In the absence of appropriate treatment (galactose restriction), sepsis (E-coli) and neonatal death may occur. Despite adequate treatment, long-term complications appear including cognitive impairments, motor deficits, ovarian dysfunction with reduced fertility in women and diminished bone density. Male fertility has not yet been thoroughly studied.\nEtiology\nClassic galactosemia is caused by mutations in the GALT (9p13) gene encoding the galactose-1-phosphate uridyltransferase enzyme. Mutations that severely impair enzyme activity result in the classic galactosemia phenotype. The so-called variants are mutations associated with higher residual enzyme activity resulting in milder or no features of galactosemia such as the Duarte variant (GALT gene mutation).\nDiagnostic methods\nIn many countries, infants are routinely screened for galactosemia at birth. When neonatal screening is not performed, diagnosis is based on the clinical picture. Diagnosis can be confirmed by assay of the relevant metabolites, enzyme activity and GALT gene mutational analysis.\nDifferential diagnosis\nDifferential diagnoses include galactose epimerase deficiency and other diseases causing acute liver disease in the neonate.\nAntenatal diagnosis\nPrenatal testing is usually performed via gene mutation analysis by chorionic villus sampling. In at-risk relatives, testing is also possible to search for the mutation when already identified in a family.\nGenetic counseling\nGalactosemia follows an autosomal recessive pattern of inheritance. Parents of an affected child have a 25% risk of having affected children in subsequent pregnancies.\nManagement and treatment\nTreatment is based primarily on galactose restriction in the diet. Infants should be fed with soy formula or other lactose-free formula. Patients are advised to follow a lifelong diet. To prevent a diminished bone mass, calcium, vitamin D and vitamin K supplements are recommended if dietary intake does not meet the recommended daily allowance. Monitoring of cognitive and motor development, gonadal function and bone mass is mandatory. Eye examinations are recommended in case of neonatal cataracts or in case of poor dietary compliance. Despite dietary treatment long-term complications occur.\nPrognosis\nPrognosis is dependent on age of diagnosis, disease severity and compliance with dietary restrictions, which affects the onset and course of secondary complications.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Pr M.E. [Estela] RUBIO-GOZALBO  - Dr I. [Inge] TIMMERS"}
{"Disease Name": "Classic glucose transporter type 1 deficiency syndrome", "Disease Definition": "A rare inborn error of metabolism characterized by encephalopathy due to impaired glucose transport into neural cells. The most frequent clinical manifestations are epilepsy, intellectual disability and movement disorder.", "ORPHA ID": 71277, "Summary": "Epidemiology\nIn retrospective cohorts, the prevalence of GLUT1-DS is estimated between 1/25.000 and 1/80.000. However, it might be underestimated since many patients present a minimal symptom phenotype.\nClinical description\nNew-borns usually have normal head size at birth, but acquired microcephaly may become evident in childhood. A frequent initial sign is paroxysmal eye-head movement, characterized by episodes of multidirectional saccadic movements of the eyes and head, without loss of consciousness. Psychomotor developmental delay is usually observed, evolving into intellectual disability, ranging from mild to severe. Most patients have some degree of speech impairment with dysarthria. The most common symptom in infancy/childhood is epilepsy, frequently early onset absences and/or myoclonic-atonic seizures. Movement disorder usually become more evident later in life. They may be persistent, including gait disorders with variable combinations of ataxia and spasticity, or they may also be paroxysmal. Paroxysmal exercise-induced dyskinesia often triggered by physical and emotional stressors is characteristic. Alternating hemiplegia, migraine, cyclic vomiting, stroke-like episodes, writers' cramp, intermittent ataxia, may be possible combined features.\nEtiology\nGlut1 protein, encoded by SLC2A1 gene, is primarily expressed in blood-brain barrier and astrocytes and facilitates glucose transport into the brain; its defect impairs glucose transport into neural cells resulting in cerebral energy deficiency causing encephalopathy.\nDiagnostic methods\nDiagnosis is suggested by clinical features and confirmed by lumbar puncture showing hypoglycorrhachia in a setting of normoglycemia. Mutations or deletions/duplications in SLC2A1 gene are identified in almost 90% of patients. Molecular diagnosis remains elusive in 10% of patients with typical clinical features and CSF profile.\nDifferential diagnosis\nNeurological disorders with similar symptoms and age of onset are familial epilepsies with autosomal dominant transmission, developmental epileptic encephalopathies, paroxysmal movement disorders, opsoclonus-myoclonus syndrome or other paroxysmal neurologic dysfunctions.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nMutations are mainly de novo autosomal dominant. Familial cases and autosomal recessive inheritance have been reported. Once a parent is diagnosed with a SLC2A1 pathogenic variant, prenatal genetic testing is possible.\nManagement and treatment\nTo establish the extent of disease and needs of a GLUT1-DS patient, the following evaluations are recommended: neurological examination, EEG monitoring, consultation with a clinical geneticist, neuropsychological assessment in order to implement a personalized motor, occupational and speech therapy. Ketogenic dietary therapies (KDTs) are, to date, the gold standard treatment for the syndrome: ketone bodies can cross the blood brain barrier and act as alternative fuel for brain metabolism. KDTs are usually effective in controlling seizures; furthermore, neuropsychological impairment and movement disorders may improve. Patients should start KDT as early as possible and continue in adulthood, as symptoms may return upon discontinuation. Some patients may also receive treatment with anti-seizure medications. Certain molecules, such as methylxanthines, phenobarbital, and valproic acid, should be avoided as they have the potential to inhibit Glut1 transport. Therapies currently under investigation are alpha-lipoic acid, ketone esters, triheptanoin and gene therapy.\nPrognosis\nEpileptic manifestations tend to improve or disappear later in life; however, the movement disorder becomes more prominent. Neuropsychological impairment and language disorder do not worsen, but they could be more evident affecting social functioning in adulthood.\n\n                            Last update: \n                            September 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Alessandra CAMERINI  - Dr Valentina DE GIORGIS | EpiCARE* - Pr Roser PONS \n\n\n                                * European Reference Network"}
{"Disease Name": "Classic hairy cell leukemia", "Disease Definition": "A rare, slowly progressive, chronic leukemia characterized by presence of abnormal B-lymphocytes (medium sized with abundant irregular pale cytoplasm, hair-like cytoplasmic projections/ruffled cytoplasmic border, a round or bean-shaped nucleus and absent nucleoli) in the blood or bone marrow, spleen and peripheral blood pancytopenia, notable monocytopenia, and marked susceptibility to infection. The characteristic immunophenotype is CD11c+, CD25+, CD103+ and CD123+ with a BRAF mutation in most cases.", "ORPHA ID": 58017, "Summary": "Epidemiology\nClassic hairy cell leukemia (HCLc) accounts for 2% of all leukemia cases. Estimates of the annual incidence range between 1/213,000-2,860,000 worldwide. HCLc is observed more commonly in caucasians. Men are predominantly affected with a male:female ratio of 4:1.\nClinical description\nDisease onset is typically in middle-age or older adults with an average age of 55 years. Symptoms of HCLc are related to the disruption of normal blood cell production. Low red cell production leads to anemia, low white cell production to increased infections, and low platelet counts to bleeding or easy bruising. Abdominal discomfort is a common symptom, resulting from hepatosplenomegaly. Splenomegaly is present in most cases, and was originally classed as massive in more than 80% of cases. In recent years, massive splenomegaly is less frequent perhaps related to earlier diagnosis. Hepatomegaly with mild liver dysfunction is found in 20% of cases and lymphadenopathy is found in 10% of cases. Complications include recurrent infections, bleeding, bruising, anemia and abdominal discomfort from splenomegaly. Splenic rupture may occur. Patients with HCLc often have monocytopenia. The patients may have opportunistic infections as a result of being immunocompromised due to intrinsic disease-related immune deficiency as well as immunosuppressive treatment.\nEtiology\nEtiology is unknown. Family history of blood cancers, Ashkenazi Jewish heritage, occupational or environmental exposure to chemicals (e.g. insecticides) are considered as possible risk factors. BRAFV600E mutation, which causes constitutive activation of the MAP kinase pathway, is also found in most patients with HCLc.\nDiagnostic methods\nDiagnosis is based on the results of the physical examination, blood tests, and bone marrow biopsy. Abdominal computer tomography may also identify lymphadenopathy. Immunophenotypic evaluations of peripheral blood or bone marrow are essential for establishing the diagnosis. Characteristic immunophenotypic markers include CD11c, CD25, CD103, CD123 positive. BRAF-V600E mutation is also found in most patients.\nDifferential diagnosis\nDifferential diagnoses includes hairy cell leukemia variant, splenic marginal zone lymphoma, and splenic diffuse red pulp B-cell lymphoma.\nManagement and treatment\nHCLc can be treated with chemotherapy (cladribine or pentostatin) or biological therapy (interferon alpha, rituximab). The purine nucleoside analogs, either cladribine (indication authorized in Europe and the USA) or pentostatin, have a higher rate of complete remission compared to biological therapies. Complete or partial remission with chemotherapy is achieved in about 80 to 90% of patients. In patients with active infection, it is important to attempt to control infection before using cladribine because of potential profound and prolonged myelosuppression. Treating patients with uncontrolled infection is challenging. Vermurafenib has been used as a bridge to effective therapy in some patients with life-threatening, uncontrolled infection and proven BRAF-positive mutation. These patients have had anecdotal improvement in hematologic parameters with control of infection; however, more evidence is required. Off-label usage of vemurafenib has been reported to be effective in hairy cell leukemia, in particular it has helped achieve remission in patients with relapsed or resistant disease. Currently, studies are in progress to examine the use of this agent in combination chemoimmunotherapy. For patients with hairy cell leukemia who have a relapse following a prolonged period of initial remission, they may be successfully re-treated with a purine analog or a combination of the purine analog and an anti-CD20 monoclonal antibody (rituximab). For those patients who have had multiple relapses or disease refractory to standard therapy, the anti-CD22 immunotoxin conjugate, moxetumomab (approved in the USA), may also be considered. Where the disease is mild and slow growing, a small number of patients may not require any immediate treatment and remain stable for many years. However, close follow-up of the hematologic parameters is required to avoid the development of serious pancytopenia.\nPrognosis\nMost patients live 10 years or longer with the disease.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Michael GREVER"}
{"Disease Name": "Classic Hodgkin lymphoma", "Disease Definition": "Classical Hodgkin lymphoma (CHL) is a B-cell lymphoma characterized histologically by the presence of large mononuclear Hodgkin cells and multinucleated Reed-Sternberg (HRS) cells.", "ORPHA ID": 391, "Summary": "Epidemiology\nThe annual incidence of CHL in developed countries is approximately 1/40,000. It accounts for 95% of HL cases.\nClinical description\nOnset most commonly occurs in young adults aged 15-30, followed by adults over the age of 55. In the early stages of the disease many patients are asymptomatic. The most common sign of CHL is the painless enlargement or swelling of upper body lymph nodes (most frequently in the neck, axillae or mediastinum). Itchy skin, fatigue and decreased appetite can also be presenting symptoms. Cellular immune deficiency seen in CHL patients increases susceptibility to bacterial, fungal and viral infections. When lymph nodes inside the chest are affected patients can have trouble breathing or a cough. A group of symptoms known as B-symptoms are sometimes present and include: fever, drenching night sweats and unexplained weight loss. Other organs can be affected such as the liver, lung, spleen, bones or bone marrow.\nEtiology\nThe exact cause of CHL is unknown. Epstein-Barr virus (EBV) may have a role in the pathogenesis of CHL as EBV-encoded RNA is present in HRS cells in 40% of cases. A genetic predisposition could also be involved in CHL pathogenesis as polymorphisms seen in the human leukocyte antigen (HLA) genes are often associated with cases of sporadic and familial CHL. They are potentially responsible for an impaired immune response which is usually found in CHL patients. HIV patients have a 5 to 15 fold increased risk of developing CHL, further suggesting the link between immune deficiency and CHL.\nDiagnostic methods\nA biopsy (usually of a lymph node) is performed in order to diagnose CHL and determine one of the 4 histological subtypes of CHL: nodular sclerosis (most common subtype), mixed cellularity, lymphocyte-rich and lymphocyte-depleted. Staging based on the Cotswold staging system is performed in order to determine the severity and spread of CHL and decide on the best course of therapy. Postero-anterior and lateral radiograph and computed tomography (CT) of the chest, neck, abdomen and pelvis are taken. Bone marrow biopsy should be performed unless peripheral blood counts are normal and B symptoms absent. Positron emission tomography (PET) scans can identify sites of disease more accurately than other imaging techniques. Predominant prognostic factors are age and stage.\nDifferential diagnosis\nInfluenza, infectious mononucleosis, other lymphomas (non-Hodgkin lymphoma), systemic lupus erythematosus (see these terms) and HIV infections should be dismissed.\nManagement and treatment\nRadiotherapy and combination chemotherapy are the methods used to treat CHL. Involved field radiotherapy (IFRT) is much preferred over extended-field radiation therapy (EFRT) which has long-term side effects but is sometimes needed in advanced cases. Two cycles of combination chemotherapy followed by IFRT (20Gy) or chemotherapy alone are acceptable standard treatments for adults with limited stage CHL. Care is taken to minimize the gonadotoxic effects of alkylating agents on male children. When standard treatment does not work (or if CHL recurs) high-dose chemotherapy and hematopoietic stem cell transplant may be a final option. Surgery is not recommended. A new targeted agent, the antibody-drug conjugate brentuximab vedotin, has shown substantial effectiveness against recurrent CHL and is being tested in combination with standard agents.\nPrognosis\nThe prognosis of those with HL has greatly improved, with a 5 year survival rate of 80%-85%. The elderly usually have a poorer prognosis as they have a reduced tolerance for chemotherapy and treatment-related deaths can occur. The cure rates are 90% for early-stage CHL and 70% for advanced stage CHL.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Joseph CONNORS"}
{"Disease Name": "Classic maple syrup urine disease", "Disease Definition": "Classic maple syrup urine disease (classic MSUD) is the most severe and probably common form of MSUD (see this term) characterized by a maple syrup odor in the cerumen at birth, poor feeding, lethargy and focal dystonia, followed by progressive encephalopathy and central respiratory failure if untreated.", "ORPHA ID": 268145, "Summary": "Epidemiology\nBirth prevalence of MSUD is estimated at around 1/150,000. Classic MSUD may account for 50-75% of cases.\nClinical description\nOnset of classic MSUD occurs in the neonatal period (usually 12 hours after birth) with the presence of a maple syrup odor in the cerumen and later in urine, poor feeding and drowsiness. Progressive encephalopathy with lethargy, intermittent apnea, stereotyped movements (described as \"fencing\" and bicycling\") and opisthotonus occur in the first few days of life. Without treatment, coma and central respiratory failure occur by days 7 to 10. Later, catabolic stress, infection or injury may cause acute, potentially fatal, leucine intoxication with vomiting, altered consciousness, ataxia and acute dystonia in toddlers and hallucinations, hyperactivity, focal dystonia, ataxia and choreoathetosis in children and adults.\nEtiology\nMSUD is due to mutations in genes encoding 3 of the 4 subunits of the branched chain 2-ketoacid dehydrogenase (BCKAD) complex. The genes are BCKDHA (19q13.1-q13.2), encoding E1a, BCKDHB (6q14.1), encoding E1b, and DBT (1p31), encoding E2 respectively. Mutations lead to accumulation of branched-chain amino acids (especially leucine) and branched-chain alpha-ketoacids. In classic MSUD, mutations in BCKDHA predominate.\nDiagnostic methods\nClassical MSUD is readily diagnosed by tandem mass-spectrometry population newborn screening. Otherwise, isolated ketosis and encephalopathy or maple syrup odor are suggestive. Plasma leucine is greatly elevated, with a ratio of leucine/valine/isoleucine of approximately 4/2/1. Plasma allo-isolucine >5umol/L is diagnostic. Urine branched chain 2-ketoacids (BCKAs) are elevated on gas chromatopgraphy-mass spectrometry. Molecular genetic testing can identify causal mutations, and perhaps suggest a sub-type.\nDifferential diagnosis\nDifferential diagnoses include other inborn errors of metabolism associated with predominant neurological deterioration such as urea cycle defects, organic acidemias (i.e. propionic or isovaleric acidemias, methylmalonic academia with homocystinuria, multiple carboxylase deficiency), and beta-ketothiolase deficiency (see these terms). In infants, ketosis, with the absence of significant metabolic acidosis, hyperammonaemia and hypoglycaemia, rules out many inborn errors of metabolism. In older children with diabetic ketoacidosis, plasma valine is higher than leucine.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease-causing mutation.\nGenetic counseling\nInheritance is autosomal recessive and genetic counseling is possible.\nManagement and treatment\nClassic MSUD in neonates is a medical emergency. Acute management requires aggressive enhancement of protein anabolism using glucose plus insulin, intravenous lipids, plasma amino acid monitoring, and isoleucine and valine supplements. Hemodialysis is often required. Stabilized infants need high calorie BCAA-free formulas, dietary leucine restriction and close outpatient monitoring at a metabolic clinic. Patients require a strict life-long diet and special monitoring during pregnancy. Orthotopic liver transplantation is also an effective treatment.\nPrognosis\nPrognosis is good for those who are diagnosed early, treated promptly and who follow a strict lifelong diet.\n\n                            Last update: \n                            April 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Bridget WILCKEN"}
{"Disease Name": "Classic medulloblastoma", "Disease Definition": "Classic medulloblastoma is a histological variant of medulloblastoma (see this term) ,an embryonic malignancy, having a midline location, occurring most often in children and manifesting with variable symptoms such as headaches, nausea, vomiting and ataxia.", "ORPHA ID": 251867, "Summary": ""}
{"Disease Name": "Classic mycosis fungoides", "Disease Definition": "Classical mycosis fungoides is the most common type of mycosis fungoides (MF; see this term), a form of cutaneous T-cell lymphoma, and is characterized by slow progression from patches to more infiltrated plaques and eventually to tumors.", "ORPHA ID": 2584, "Summary": "Epidemiology\nThe annual incidence of MF and its variants is estimated at between 1/350,000 and 1/110,000, with classical MF accounting for about 80-90% of MF cases. The male to female ratio is 2:1. Classical MF predominantly affects adults and the elderly (median age at diagnosis: 55-60 years).\nClinical description\nThe disease first manifests by skin lesions consisting of flat patches, preferentially located asymmetrically on the buttocks and other sun-protected areas (lower trunk and thighs, and the breasts in women). Usually, patches are hypo- or hyperpigmented in dark-skinned individuals. Pruritus may be observed. In the later stages of the disease, infiltrated plaques and red-violet, dome-shaped tumors or generalized erythroderma may develop. Lymph nodes are the most frequent site of extracutaneous involvement. Visceral involvement (liver, lung, and bone marrow) may also occur.\nEtiology\nThe etiology remains unknown.\nDiagnostic methods\nThe diagnosis is based on clinical presentation and should be confirmed by a skin biopsy. Histological findings reveal a predominance of small pleomorphic (cerebriform) cells with epidermotropism. In most cases, immunohistology shows a memory T-helper phenotype (CD3+, CD4+, CD45Ro+, CD8- and CD45Ra-). CD30 and/or cytotoxic markers (i.e. TIA-1) may be positive in late stages, particularly in tumors with large cell morphology. In rare cases, cytotoxic markers may also be positive in early lesions. Molecular analyses reveal a clonal rearrangement of the T-cell receptor genes (this finding may be absent in early lesions). Staging investigations, including a computer tomography scan and/or positron emission tomography, should be performed in cases of advanced MF.\nDifferential diagnosis\nDifferential diagnoses include inflammatory dermatoses (i.e. atopic dermatitis) in theearly stages of MF, and other large cell non-Hodgkin lymphomas (see this term) in later stages.\nManagement and treatment\nTreatment strategies during the early phases include mainly PUVA (photochemotherapy), interferon alfa-2a, retinoids (alone or in combination, and including new retinoids such as bexarotene), topical chemotherapy, topical steroids, and narrow-band UV-B (311 nm). Advanced disease can be treated by systemic chemotherapy, extracorporeal photopheresis, and/or radiotherapy (including total body electron beam irradiation). Other treatment modalities include new chemotherapeutic drugs (i.e. gemcitabine, fludarabine and pegylated doxorubicin), denileukin diftitox, alemtuzumab, and allogeneic stem cell transplantation. Many other treatment options have been proposed but have only been used in a limited number of patients.\nPrognosis\nThe disease is slowly progressive (it may evolve over 10 to 30 years after the initial presentation). The prognosis depends on the stage at diagnosis.\n\n                            Last update: \n                            June 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Lorenzo CERRONI"}
{"Disease Name": "Classic neuroendocrine tumor of appendix", "Disease Definition": "A rare endocrine tumor of the appendix, seen twice as frequently in females than in males, and usually presenting before the fifth decade of life. It is usually asymptomatic when located in the tip of the appendix (without obstruction), but acute appendicitis is often associated.", "ORPHA ID": 329977, "Summary": ""}
{"Disease Name": "Classic phenylketonuria", "Disease Definition": "A severe form of phenylketonuria (PKU) due to phenylalanine hydroxylase deficiency, an inborn error of amino acid metabolism, characterized in untreated patients by severe intellectual deficit and neuropsychiatric complications.", "ORPHA ID": 79254, "Summary": "Epidemiology\nExact prevalence is not known but is estimated to be about 1/15,000 births. Significant geographic variability is reported. Caucasians appear to be affected more than other ethnic groups. Males and females are affected equally.\nClinical description\nLate diagnosed patients present mostly with progressive developmental delay associated with severe signs including stunted growth, microcephaly, seizures, tremors, eczema, vomiting, musty odor, and subsequently behavioral (hyperactivity) and motor disorders. Untreated patients develop profound, permanent intellectual impairment and deterioration of cognitive performance and motor skills. Demyelination and decreased dopamine, norepinephrine, and serotonin production have been found in patients who do not pursue dietary restrictions into adulthood. Complications later on include exaggerated deep tendon reflexes, tremor, and paraplegia or hemiplegia. In treated patients, clinical signs vary based on treatment and diet compliance, and may include psychiatric disorders such as attention deficit-hyperactivity disorder and depression.\nEtiology\nClassical PKU is related to a complete or near-complete deficiency of phenylalanine hydroxylase. The disorder is caused by variants in the PAH gene (12q22-q24.2) coding for phenylalanine (Phe) hydroxylase. The resulting deficiency in phenylalanine hydroxylase leads to toxic accumulation of Phe in the blood and brain.\nDiagnostic methods\nClassical PKU is usually diagnosed via neonatal screening programs with detection of hyperphenylalaninemia (HPA). Detection is standard in most industrialized countries. PKU is diagnosed at plasma or blood Phe concentrations higher than 120 micromol/L in the untreated state and elevated Phe/Tyr ratio (>2.0). In the absence of early detection through neonatal screening, suspicion is based on clinical signs and symptoms. Diagnosis is confirmed by determination of plasma or blood Phe levels.\nDifferential diagnosis\nDifferential diagnosis includes other forms of HPA such as tetrahydrobiopterin (BH4) deficiency. Neonates with increased Phe may have BH4 deficiency or PKU. An abnormal pattern of pterins in dried blood spots or urine or reduced dihydropteridine reductase activity in dried blood spots indicate BH4 deficiency. A BH4 loading test should be performed to determine whether patients are BH4-responsive or unresponsive.\nAntenatal diagnosis\nPrenatal testing can be performed by molecular testing of the PAH gene if the disease-causing variants have been identified in an affected family member.\nGenetic counseling\nInheritance is autosomal recessive.\nManagement and treatment\nManagement involves restriction of dietary Phe, i.e. all high-protein foods, to normalize blood levels thus preventing the cognitive dysfunction, along with Phe-free medical formula to provide protein and other essential nutrients. Patients tolerate less than 250-350 mg of dietary Phe per day. Levels of Phe tolerance should be determined individually on a regular basis. Current recommendations call for lifelong maintenance of limited Phe intake. However, monitoring of levels is essential to avoid deficiencies of Phe and tyrosine. Foods containing aspartame should be avoided as aspartame releases Phe when digested. Female patients should be particularly cautious during pregnancy due to the fetotoxic effects of high maternal plasma Phe. When properly managed, the disease course is mostly favorable, but some neuropsychiatric complications may occur. Treatment and dietary compliance are the most important factors affecting outcome and prognosis.\nPrognosis\nThe prognosis is good when diagnosis is made early and compliance is high.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Nenad BLAU"}
{"Disease Name": "Classic progressive supranuclear palsy syndrome", "Disease Definition": "A classical form of progressive supranuclear palsy (PSP), a rare late-onset neurodegenerative disease, characterized by slowing of vertical saccadic eye movements, falls due to postural instability, axial akinetic-rigid syndrome, and cognitive impairment. Difficulties in speech and swallowing may develop.", "ORPHA ID": 240071, "Summary": ""}
{"Disease Name": "Classic pyoderma gangrenosum", "Disease Definition": "A rare subtype of pyoderma gangrenosum disease characterized by rapidly progressive, single or multiple, painful, aseptic ulcers which present overhanging, violaceous and undermined borders, surrounding induration and erythema, and granulation tissue (occasionally necrotic tissue and/or a purulent exudate) at the base, mainly affecting the legs (but other body surfaces may also be involved), leading to chronic ulcerations and often regressing with cribriform mutilating scars. The disease presents a chronic relapsing course and systemic features (e.g. fever, malaise, arthralgia, myalgia) may be associated.", "ORPHA ID": 538863, "Summary": ""}
{"Disease Name": "Classical Ehlers-Danlos syndrome", "Disease Definition": "A rare inherited connective tissue disorder characterized by skin hyperextensibility, widened atrophic scars, and generalized joint hypermobility.", "ORPHA ID": 287, "Summary": "Epidemiology\nWorldwide prevalence is estimated at 1/20,000.\nClinical description\nSkin hyperextensilibity, atrophic scarring, and generalized joint hypermobility are the hallmarks of classical Ehlers-Danlos syndrome (cEDS). However, the clinical picture variably involves multiple organ systems, and clinical presentation may occur anywhere between birth and childhood. In childhood, bruising, skin fragility, and abnormal scarring are common signs. Primary muscular hypotonia may occur and, alongside hypermobility, may delay motor development. Fatigue and muscle cramps are relatively frequent. Atrophic scarring is typically extensive, although a minority are more mildly affected. The skin is smooth and doughy. Other dermatologic features are molluscoid pseudotumors, subcutaneous spheroids, piezogenic papules, and defective wound healing. Inguinal/umbilical hernia, mitral valve prolapse, anal prolapse in childhood, cervical insufficiency, rectal and uterine prolapse are other signs of tissue fragility. Joint hypermobility may lead to joint instability, subluxation, dislocation temporomandibular joint dysfunction, joint effusions, foot deformities, osteoarthritis, and pain. In addition to scars, typical facial characteristics are blepharochalasis and epicanthal folds. Pregnancy bears risk for the newborn (prematurity and breech where the infant is affected) and for the mother (extensive episiotomy, tearing of the perineal skin, and prolapse of the uterus and/or the bladder after delivery). In patients with a COL1A1 mutation, there might be an increased at risk for vascular events (spontaneous dissection or rupture of medium-sized arteries).\nEtiology\nThe disease is typically caused by mutations in COL5A1 or COL5A2 encoding type V collagen. In rare cases, cEDS is caused by p.(Arg312Cys) mutation in COL1A1, encoding type I collagen.\nDiagnostic methods\nThe minimal criteria suggestive of cEDS are skin hyperextensibility plus atrophic scarring together with either generalized joint hypermobility and/or at least three of the following minor criteria: easy bruising, soft/doughy skin, skin fragility, molluscoid pseudotumors, subcutaneous spheroids, hernia, epicanthal folds, complications of joint hypermobility, family history of a first degree relative who meets clinical criteria. Definitive diagnosis is reached by genetic testing that can include single-gene testing or use of a multigene panel.\nDifferential diagnosis\nDifferential diagnosis is extensive but primarily includes other EDS types (i.e., hypermobile, cardiac-valvular, classical-like type 1, classical-like type 2, spondylodysplastic, vascular, arthrocalasia, kyphoscoliotic, dermatosparaxis EDS), Loeys-Dietz syndromes, Marfan syndrome, cutis laxa, and other inherited connective tissue disorders.\nAntenatal diagnosis\nOnce the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant and genetic counseling should be offered to affected families. The risk of disease transmission to offspring from an affected parent is 50%, intrafamilial phenotypic variability is observed.\nManagement and treatment\nTreatment and management is symptomatic and preventative. Prevention includes avoidance of undue trauma and excessive stretching. Wounds should be expertly closed via sutures and patients should be known to their local plastic surgeons. A physiotherapeutic program is important in those with hypotonia and delayed motor development. Anti-inflammatory drugs may help with joint pain. Cardiac assessment including echocardiography to look for aortic root dilation and mitral valve prolapse is recommended. Emotional support and behavioral and psychological therapy may be indicated. Surveillance during pregnancy is warranted.\nPrognosis\nLife expectancy can be shortened due to the possibility of vessel rupture, but is otherwise not affected. Quality of life depends on the range of severity.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Marina COLOMBI"}
{"Disease Name": "Classical-like Ehlers-Danlos syndrome type 1", "Disease Definition": "A form of Ehlers-Danlos syndrome characterized by generalized joint hypermobility, skin hyperextensibility and easy bruising without atrophic scarring. Other common features include foot and hand deformities (piezogenic papules, pes planus, broad forefeet, brachydactyly, fragile and thin hand skin breaks or bruises easily), severe fatigue and neuromuscular symptoms including muscle weakness and myalgia.", "ORPHA ID": 230839, "Summary": ""}
{"Disease Name": "Classical-like Ehlers-Danlos syndrome type 2", "Disease Definition": "A rare systemic disease characterized by generalized joint hypermobility with recurrent joint dislocations, redundant and hyperextensible skin with poor wound healing and abnormal scarring, easy bruising, and osteopenia/osteoporosis. Additional manifestations include hypotonia, delayed motor development, foot deformities, prominent superficial veins in the chest region, vascular complications (like mitral valve prolapse and aortic root dilation), hernias, dental anomalies, scoliosis, and facial dysmorphisms (like high palate, micrognathia, narrow palate). Mode of inheritance is autosomal recessive.", "ORPHA ID": 536532, "Summary": ""}
{"Disease Name": "CLCN4-related X-linked intellectual disability syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by intellectual disability of variable degree, behavioral anomalies (including autism, mood disorders, obsessive-compulsive behavior, and hetero- and auto-aggression), and epilepsy. Progressive neurological symptoms like movement disorders and spasticity, as well as subtle dysmorphic features have also been reported. Heterozygous females may be as severely affected as males.", "ORPHA ID": 485350, "Summary": ""}
{"Disease Name": "Clear cell adenocarcinoma of the ovary", "Disease Definition": "A rare, malignant, epithelilal ovarian neoplasm, composed of clear, eosinophilic and hobnail cells displaying variable degrees of tubulocystic, papillary and solid histological patterns, macroscopically appearing as a typically unilateral mass in the ovary which ranges from solid to cystic. Patients are often diagnosed in early stages and usually present with pelvic pain and pressure, an abdominal mass and/or gastrointestinal problems, such as early satiety or bloating. Association with Lynch syndrome has been reported.", "ORPHA ID": 398971, "Summary": ""}
{"Disease Name": "Clear cell papillary renal cell carcinoma", "Disease Definition": "Clear cell papillary renal cell carcinoma is a rare, indolent subtype of clear cell renal carcinoma, arising from epithelial cells in the renal cortex. It most frequently manifests with a well-circumscribed, well-encapsulated, unicentric, unilateral, small tumor that typically does not metastasize. Clinically it can present with flank or abdominal pain or hematuria, although most patients are usually asymptomatic at the time of diagnosis. Bilateral and/or multifocal presentation should raise the suspicion of von Hippel-Lindau syndrome.", "ORPHA ID": 404511, "Summary": ""}
{"Disease Name": "Clear cell renal carcinoma", "Disease Definition": "A rare renal tumor arising from proximal tubular epithelial cells of the renal cortex, characterized histologically by malignant epithelial cells with typical clear cytoplasm in conventional staining methods due to a high glycogen and lipid content, featuring a nested growth pattern. Clinically it may present with hematuria, flank pain, anemia or, less commonly, a palpable abdominal mass.", "ORPHA ID": 319276, "Summary": ""}
{"Disease Name": "Clear cell sarcoma of kidney", "Disease Definition": "Clear cell sarcoma of kidney is a rare, primary, genetic renal tumor usually characterized by a unilateral, unicentric, morphologically diverse tumor that arises from the renal medulla and has a tendency for vascular invasion. Clinically it presents with a palpable abdominal mass, abdominal or flank pain, hematuria, anemia and/or fatigue. Metastatic spread to lymph nodes, bones, lungs, retroperitoneum, brain and liver is common at time of diagnosis and therefore bone pain, cough or neurological compromise may be associated. Metastasis to unusual sites, such as the scalp, neck, nasopharynx, axilla, orbits and epidural space, have been reported.", "ORPHA ID": 457246, "Summary": ""}
{"Disease Name": "Cleft lip and alveolus", "Disease Definition": "Cleft lip and alveolus is a fissure type embryopathy that involves the upper lip, nasal base and alveolar ridge in variable degrees.", "ORPHA ID": 141291, "Summary": "Epidemiology\nThe annual incidence varies from 1/4,000 to 1/10,000 births with major variation among geographic regions and ethnic groups. Cleft lip/alveolus is twice as common in boys as girls and is seen more frequently on the left side.\nClinical description\nThe cleft is paramedian and is located at the philtrum level for the lip and nasal base and at the level of the upper lateral incisor for the alveolar ridge. It involves a cutaneous, muscular and mucosal interruption in the lip, in addition to nostril and nasal septum deformations and an interruption in the alveolar bone and dental arch. The maxillary lateral incisor, at the site of the alveolar cleft, can present with anomalies in shape, number (duplication or agenesis) and position. There is no correlation seen between temporary (primary) and permanent dentition.\nEtiology\nCleft lip/alveolus is an embropathy that appears in the 5th to 7th week of pregnancy, following an error in fusion of the frontal processes (fronto-nasal process, medial and lateral nasal processes, maxillary process). Cleft lip and alveolus are isolated, non-syndromic anomalies in 70% of cases. The remaining 30% of cases are seen in about 300 syndromes where cleft lip/alveolus is just one of the featured anomalies. Non-syndromic clefts are believed to be caused by a combination of genetic and environmental factors. Factors such as the exposure to teratogenic substances during pregnancy (alcohol, tobacco or drugs) can influence genetic susceptibility.\nDiagnostic methods\nDiagnosis is clinical.\nDifferential diagnosis\nThe presence of associated malformations allows for differentiation between isolated and syndromic forms.\nAntenatal diagnosis\nAntenatal diagnosis is often made during prenatal ultrasound. The case is submitted to a multidisciplinary center for prenatal diagnosis in order to establish if it is an isolated anomaly.\nManagement and treatment\nManagement requires multidisciplinary medical and surgical intervention from birth until the end of development. It involves primary surgery followed by secondary maxilla-facial surgery along with plastic surgery. An initial treatment timeline is established during the neonatal period. Management is adapted to the child and based on morphological and functional problems that may arise during growth and development. Orthodontic management aims to correct the dental alignment problems, sometimes during the early primary teeth stage and then in the mixed and permanent stage. Treatment of the alveolar cleft requires a maxillary bone graft and a dental implant can correct permanent lateral incisor agenesis, if present after growth has stopped. The capacity to chew properly depends on the bucco-facial clinical history of the patient and any dental alignment problems. Breathing difficulties can occur due to the nostril anomaly as well as deviation of the vomer and nasal septum and turbinate hypertrophy. Secondary surgery of the nose can be performed to improve nasal appearance and function if necessary.\nPrognosis\nThe prognosis depends on the quality of initial management and the regular follow-up by an experienced interdisciplinary team until the child is fully grown. Cleft lip/alveolus can have functional (morphological, respiratory), esthetic and psychological consequences that require management in a specialized health center.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Cleft lip and palate-craniofacial dysmorphism-congenital heart defect-hearing loss syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome without intellectual disability characterized by unilateral or bilateral cleft lip and palate and craniofacial dysmorphism (including frontal bossing, hypertelorism, broad flat nasal bridge, cupped ears/thickened helices, and micrognathia). Additional manifestations are variable congenital cardiac anomalies, pectus excavatum, abnormalities of the hands and feet, ocular abnormalities (myopia, cataract, staphyloma), and conductive or sensorineural hearing loss.", "ORPHA ID": 508476, "Summary": ""}
{"Disease Name": "Cleft lip-retinopathy syndrome", "Disease Definition": "An exceedingly rare association characterized by cleft lip and progressive retinopathy.", "ORPHA ID": 1995, "Summary": ""}
{"Disease Name": "Cleft lip/palate-deafness-sacral lipoma syndrome", "Disease Definition": "Cleft lip/palate-deafness-sacral lipoma syndrome is characterised by cleft lip/palate, profound sensorineural deafness, and a sacral lipoma. It has been described in two brothers of Chinese origin born to non consanguineous parents. Additional findings included appendages on the heel and thigh, or anterior sacral meningocele and dislocated hip. The mode of inheritance is probably autosomal or X-linked recessive.", "ORPHA ID": 2003, "Summary": ""}
{"Disease Name": "Cleft lip/palate-ectodermal dysplasia syndrome", "Disease Definition": "Zlotogora-Ogur syndrome is an ectodermal dysplasia syndrome characterized by hair, skin and teeth anomalies, facial dysmophism with cleft lip and palate, cutaneous syndactyly and, in some cases, intellectual disability.", "ORPHA ID": 3253, "Summary": "Epidemiology\nThe prevalence is unknown but to date, less than 50 cases have been described in the literature. The disorder is frequent on Margarita Island due to a founder effect.\nClinical description\nZlotogora-Ogur syndrome is a congenital disorder characterized by sparse and twisted hair (pili torti) and absent or sparse eyebrows, hypohidrosis, dry skin, palmoplantar keratoderma, abnormal teeth (delayed eruption, microdontia/hypodontia, and anodontia in adults), facial dysmophism (protruding and malformed ears, micrognathia, bilateral cleft lip and palate), cutaneous syndactyly (fingers and toes) and transverse crease on the palms. Onychodystrophy may be present. Additional features including intellectual disability, deafness, hypoplastic lacrimal puncta, nipple anomalies, genitourinary abnormalities (hypoplastic scrotum and presence of the testes in the inguinal canal), and lumbar lordosis may be observed. Zlotogora-Ogur syndrome and Margarita Island ectodermal dysplasia are the same entity.\nEtiology\nZlotogora-Ogur syndrome is caused by mutations in the gene PVRL1 (11q23-q24) which encodes nectin-1, the principal receptor used by alpha-herpesviruses to mediate entry into human cells. Although the mechanism underlying the physiopathology of Zlotogora-Ogur syndrome is still unknown, it has been proposed that nectin-1 is a cell-cell adhesion molecule that is preferentially expressed in keratinocytes and that mutations in PVRL1 may abrogate NAP (nectin, afadin, ponsin)-dependent cell-cell adhesion.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Joel ZLOTOGORA"}
{"Disease Name": "Cleft lip/palate-intestinal malrotation-cardiopathy syndrome", "Disease Definition": "A rare multiple congenital anomaly syndrome characterized by flat face, hypertelorism, flat occiput, upward slanting palpebral fissures, cleft palate, micrognathia, short neck, and severe congenital heart defects. Malrotation of the intestine, bilateral clinodactyly, bilobed tongue, short fourth metatarsals and bifid thumbs may be additionally observed.", "ORPHA ID": 2001, "Summary": ""}
{"Disease Name": "Cleft lip/palate", "Disease Definition": "Cleft lip and palate is a fissure type embryopathy extending across the upper lip, nasal base, alveolar ridge and the hard and soft palate.", "ORPHA ID": 199306, "Summary": "Epidemiology\nThe annual incidence ranges from 1/2,000 to 1/5,000 births. Cleft lip and palate is seen twice as commonly in boys.\nClinical description\nThe malformation is the association, in varying degrees, of cleft lip/alveolus and cleft palate (see these terms). The lip and alveolus anomaly is paramedian and is located at the philtrum level for the lip and at the level of the upper lateral incisors for the alveolar ridge. It involves a cutaneous, muscular and mucosal interruption in the lip in addition to a nostril and nasal septum deformity and a gap in the alveolar bone and dental arch. Clinical forms range from a simple midline groove in the lip to a complete cleft lip and palate reaching the incisive foramen with an opening in the base of the nostril. The cleft seen in cleft palate is median. The clinical forms range from a simple bifid uvula (see this term) to a complete cleft palate reaching the incisive foramen. Cleft palate can disrupt sucking-swallowing in newborns. In addition, Eustachian tube malformation can lead to incomplete drainage of the middle ear with recurrent otitis and transmission hypoacousia. The maxillary lateral incisor, at the site of the alveolar cleft, can present with anomalies in shape, number (duplication or agenesis) and position. There is no correlation seen between temporary (primary) and permanent dentition.\nEtiology\nCleft lip and palate is an embryopathy that appears, for the cleft lip, in the 5th and 7th week of pregnancy, following an error in fusion of the frontal processes, and for the cleft palate in the 7th and 12th week of pregnancy following an error in fusion of the palatine process. Cleft lip and palate is an isolated, non-syndromic anomaly in 70% of cases and the remaining 30% of cases are seen in about 300 syndromes. Non-syndromic clefts are believed to be caused by a combination of genetic and environmental factors. Factors such as exposure to teratogenic substances during pregnancy (alcohol, tobacco or drugs) can have an influence on genetic susceptibility.\nDiagnostic methods\nThe diagnosis is clinical.\nDifferential diagnosis\nThe presence  of associated malformations allows for differentiation between isolated and syndromic forms.\nAntenatal diagnosis\nAntenatal diagnosis is often made during prenatal ultrasound. The case is submitted to a multidisciplinary center for prenatal diagnosis in order to establish if it is an isolated anomaly.\nManagement and treatment\nManagement requires multidisciplinary medical and surgical intervention from birth until the end of development. It involves primary followed by secondary surgery (maxilla-facial and plastic). Speech therapy management involves guidance and rehabilitation from an early age as well as a pharyngoplasty before entering primary school, if necessary. In the presence of a hypomaxilly, due to an error in maxillary growth, an intermediate bone and/or orthognatic surgery on the maxillae is necessary. Treatment of an alveolar cleft most often requires a maxillary bone graft and, in the presence of permanent lateral incisor agenesis, a dental implant at the end of growth. ENT management involves the monitoring of sero-mucosal pathologies (otitis), hearing, phonation and breathing. Breathing difficulties can occur due to malformation of the nostril as well as deviation of the vomer and nasal septum and turbinate hypertrophy.\nPrognosis\nThe prognosis depends on the quality of initial management and regular follow-up. Cleft palate can have functional, esthetic and psychological consequences that require management in a specialized health center.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Cleft mitral valve", "Disease Definition": "A rare, congenital, non-syndromic heart malformation characterized by a slit-like hole or defect in one of the mitral valve leaflets, which is usually thickened and distorted. It usually affects the anterior leaflet, but the cleft of posterior leaflet has also been described. Cleft mitral valve can be isolated or associated with other congenital heart anomalies.", "ORPHA ID": 95465, "Summary": ""}
{"Disease Name": "Cleft palate-congenital heart defect-intellectual disability syndrome due to 15q14 microdeletion", "Disease Definition": "15q14 microdeletion syndrome is a recently described syndrome characterized by developmental delay, short stature and facial dysmorphism.", "ORPHA ID": 261190, "Summary": "Epidemiology\nIt has been described in 4 patients so far.\nClinical description\nDysmorphic features include bitemporal narrowing, smooth philtrum, pointed chin and dysmorphic ears. All reported patients had a cleft palate, whereas congenital heart defects or epilepsy are observed in patients with large deletions.\nEtiology\nDeletions are located within chromosome band 15q14, distal to the Prader-Willi/Angelman region. They were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size with the smallest deletion being 1.6 Mb in length.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "Cleft palate-large ears-small head syndrome", "Disease Definition": "Cleft palate-large ears-small head syndrome is a rare, genetic syndrome characterized by cleft palate, large protruding ears, microcephaly and short stature (prenatal onset). Other skeletal abnormalities (delayed bone age, distally tapering fingers, hypoplastic distal phalanges, proximally placed thumbs, fifth finger clinodactyly), Pierre Robin sequence, cystic renal dysplasia, proximal renal tubular acidosis, hypospadias, cerebral anomalies on imaging (enlargement of lateral ventricles, mild cortical atrophy), seizures, hypotonia and developmental delay are also observed.", "ORPHA ID": 2013, "Summary": ""}
{"Disease Name": "Cleft palate-lateral synechia syndrome", "Disease Definition": "Cleft palate-lateral synechia syndrome (CPLS) is a congenital malformation syndrome characterized by the association of cleft palate and intra-oral lateral synechiae connecting the free borders of the palate and the floor of the mouth. CPLS is presumed to be inherited in an autosomal dominant manner.", "ORPHA ID": 2016, "Summary": "Epidemiology\n11 cases have been reported in the worldwide literature.\nClinical description\nPatients present with cleft palate at birth and on examination are found to have multiple cord-like adhesions running from the free internal borders of the palate to the lateral parts of the tongue and floor of the mouth. Babies manifest symptoms of cleft palate such as disrupted sucking and swallowing, recurrent ear infections and speech impairment. Lateral synechiae may be asymptomatic or cause feeding difficulty due to restricted opening of mouth. In some cases the synechiae undergo spontaneous resolution.\nEtiology\nEtiology is unclear but interposition of the tongue between the palatal shelves in the embryo due to genetic, teratogenic or mechanical insults could result in a cleft palate while close contact between the floor of the mouth and the palate could predispose to the formation of intraoral synechiae. This can be either due to failed regression of buccopharyngeal membrane or formation of subglossopalatal membrane during the 7th week of embryonic life. Less than normal movement of the mandible and tongue is presumed to predispose to the formation of this subglossopalatal membrane.\nDiagnostic methods\nDiagnosis is clinical. When necessary, computed tomography can help to detect the presence of any bony fusion.\nDifferential diagnosis\nPhenotypic features of CLPS can occur with other congenital anomalies, particularly the Van der Woude (VDW), orofaciodigital syndrome and popliteal pterygium syndrome (see these terms). In one reported family with CPLS, the monozygotic twin of the index case had classic phenotypic features of Fryns syndrome (see this term) suggesting that CPLS may represent a mild phenotypic expression of this syndrome.\nAntenatal diagnosis\nPrenatal diagnosis of cleft palate can be made by prenatal ultrasonogram.\nGenetic counseling\nAn autosomal dominant inheritance pattern with variable expressivity has been proposed.\nManagement and treatment\nManagement includes excision of synechiae and palatal closure. Immediate excision of the synechiae may be necessary due to breathing or feeding problems; obtaining a safe airway for the release of the bands may be difficult. When immediate release of synechiae is not warranted, excision is done during palatal closure. The synechiae has been used to provide additional tissue for the surgical closure of soft palate.\nPrognosis\nThe prognosis depends on the presence of associated anomalies (especially, congenital syngnathia (see this term)), quality of initial repair and regular follow-up.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Cleft palate-short stature-vertebral anomalies syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies syndrome characterized by the association of cleft palate, peculiar facies (asymmetrical appearance, inner epicanthal folds, short nose, anteverted nostrils, low and back-oriented ears, thin upper lip and micrognathism), short stature, short neck , vertebral anomalies and intellectual disability. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 2015, "Summary": ""}
{"Disease Name": "Cleft palate-stapes fixation-oligodontia syndrome", "Disease Definition": "A rare congenital malformation syndrome characterized by cleft soft palate, severe oligodontia of the deciduous teeth, absence of the permanent dentition, bilateral conductive deafness due to fixation of the footplate of the stapes, short halluces with a wide space between the first and second toes, and fusion of carpal and tarsal bones. There have been no further descriptions in the literature since 1971.", "ORPHA ID": 2010, "Summary": ""}
{"Disease Name": "Cleft palate", "Disease Definition": "A fissure type embryopathy that affects the soft and hard palate to varying degrees.", "ORPHA ID": 2014, "Summary": "Epidemiology\nThe annual incidence varies from 1/3,300 to 1/ 10,000 births. Cleft palate is more frequent in girls.\nClinical description\nThe cleft is median and connects the buccal cavity to the two nasal fossa and the naso-pharynx. The clinical forms range from a cleft velum (see this term) with a notch in the back of the hard palate to a complete cleft palate that extends to the incisive foramen. Submucous cleft palate is a specific form with muscle and bone dehiscence covered by oral and nasal mucosa. In these cases, diagnosis is more difficult but milk reflux occurs from birth and speech problems can occur. Cleft palate can disrupt sucking-swallowing in newborns to varying degrees. In the non-syndromic forms, normal feeding is possible. In the syndromic forms, there is a risk of food aspiration. Cleft velum disrupts the physiology of the Eustachian tube which can induce incomplete drainage of the middle ear with recurrent otitis and transmission hypoacousia. Dental alignment problems are due to an error in maxillary growth.\nEtiology\nThis embryopathy appears in the 7th to 12th week of pregnancy following an error in fusion of the palatine process. Non-syndromic clefts are believed to be caused by a combination of genetic and environmental factors. Factors such as exposure to teratogenic substances during pregnancy (alcohol, tobacco or drugs) can influence genetic susceptibility.\nDiagnostic methods\nDiagnosis is clinical.\nDifferential diagnosis\nThe presence of associated malformations allows for differentiation between isolated and syndromic forms. Differential diagnoses include hereditary syndromic forms (in 20% of cases), such as Pierre-Robin, Stickler, van der Woude and velocardiofacial syndromes (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis with an ultrasound is possible from the 2nd trimester onwards by looking for a mandibular retrognathism, an anomaly associated with abnormal amniotic fluid flow. The case is submitted to a multidisciplinary center for prenatal diagnosis in order to establish if it is an isolated anomaly.\nManagement and treatment\nManagement requires multidisciplinary medical and surgical intervention from birth until the end of development. It involves primary surgery sometimes followed by secondary surgery (maxillo-facial and plastic). An initial treatment timeline is established during the neonatal period. Secondary management is adapted to the child and based on morphological and functional problems that may arise during growth and development. Speech therapy management involves guidance and rehabilitation from an early age as well as a pharyngoplasty before entering primary school, if necessary. Orthodontic treatment manages dental alignment problems. In the presence of hypomaxilly caused by an error in maxillary growth, intermediate bone and/or orthognatic surgery on the maxillae is necessary. ENT management monitors seromucous (otitis), auditory and phonetic manifestations.\nPrognosis\nThe prognosis depends on the quality of initial management and regular follow-up. Cleft palate can have functional consequences (morphological, phonetic, orthodontic, masticatory and auditory) that require management in a specialized health center. The syndromic forms, in particular a 22q11 deletion, have a poorer prognosis with more serious speech problems requiring complementary surgical treatment.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Cleft velum", "Disease Definition": "Cleft velum is a fissure type embryopathy that affects in varying degrees the soft palate.", "ORPHA ID": 99772, "Summary": "Epidemiology\nThe annual incidence varies from 1/3,300 to 1/10,000 births, depending on the geographic origin and ethnic group. It is more frequent in girls.\nClinical description\nCleft velum joins the buccal cavity and the nasopharynx or cavum. The clinical forms range from a partial cleft velum to a complete cleft velum extending to the posterior edge of the hard palate. A submucous cleft palate is a specific form with muscular and bony defects covered by the oral and nasal mucosa. In these cases, diagnosis is more difficult but milk reflux occurs from birth and speech problems can occur. Cleft velum can disrupt sucking-swallowing in newborns to varying degrees. In the non-syndromic forms, normal breastfeeding is possible. In syndromic forms, there is a risk of food aspiration (isolated or syndromic Pierre Robin sequence). Cleft velum can disrupt Eustachian tube physiology that can lead to incomplete drainage of the middle ear with recurrent infections (otitis) and transmission hypoacousia.\nEtiology\nThis embryopathy appears between the 7th and 12th week of pregnancy following an error in fusion of the palatine process. Implicated causes include both genetic and environmental factors. Factors such as exposure to teratogenic substances during pregnancy (alcohol, tobacco or drugs) can have an influence on genetic susceptibility.\nDiagnostic methods\nDiagnosis is clinical.\nDifferential diagnosis\nThe presence of associated malformations allows for differentiation between isolated and syndromic forms. Differential diagnoses include syndromic hereditary forms of cleft velum (Pierre-Robin, Stickler, van der Woude and velocardiofacial syndromes;see these terms).\nAntenatal diagnosis\nStarting from the 2nd trimester, antenatal diagnosis with ultrasounds is possible by looking for a mandibular retrognathism, an anomaly associated with abnormal amniotic fluid flow. The case is submitted to a multidisciplinary center for prenatal diagnosis in order to establish if it is an isolated anomaly.\nManagement and treatment\nManagement requires multidisciplinary medical and surgical intervention from birth until the end of development. It involves primary surgery sometimes followed by secondary surgery (maxillo-facial and plastic). An initial treatment timeline is established during the neonatal period. Secondary management is adapted to the child and based on morphological and functional problems that may arise during growth and development. Speech therapy management involves guidance and rehabilitation from an early age as well as a pharyngoplasty before entering primary school, if necessary. ENT management monitors any seromucous (otitis), auditory or phonological manifestations.\nPrognosis\nThe prognosis depends on the quality of initial management and the regular follow-up by an experienced multidisciplinary team. Cleft velum can have functional consequences (morphological, phonetic, and auditory) that require management in a specialized health center.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Cleidocranial dysplasia", "Disease Definition": "Cleidocranial dysplasia (CCD) is a rare genetic developmental abnormality of bone characterized by hypoplastic or aplastic clavicles, persistence of wide-open fontanels and sutures and multiple dental abnormalities.", "ORPHA ID": 1452, "Summary": "Epidemiology\nThe prevalence of CCD is 1/1,000,000, with higher rates in groups with a founder effect. The disorder is found in many ethnic groups and no sex predilection has been reported. It may be underdiagnosed because of the number of relatively mild cases.\nClinical description\nThere is an extremely wide range of clinical manifestations (even within the same family) from isolated dental anomalies to severe malformations with functional repercussions. The main clinical signs are hypoplasia or aplasia of the clavicles with narrow, sloping shoulders that can be approximated anteriorly, delayed fusion of cranial sutures with large, wide-open fontanels at birth that may persist throughout life, and a wide spectrum of dental anomalies including abnormal dentition, uniform or chaotic supernumerary teeth (hyperdontia) in the primary and secondary dentition resulting in crowding and malocclusion, retention of deciduous teeth, delayed eruption of secondary dentition and failure to shed the primary teeth. The dental manifestations may affect articulation and mastication. Other signs include broad flat forehead, hypertelorism, midface hypoplasia, and a pointed jaw giving a characteristic facial appearance as well as brachydactyly, tapering fingers and short, broad thumbs. Associated skeletal abnormalities include short stature, scoliosis, genu valgum, pes planus, a wide pubic symphysis, dysplastic scapulae, and coxa vara, generally with little clinical significance. Secondary complications include recurrent infections of the upper respiratory tract, sleep apnea, mild motor delay and variable degrees of hearing loss. Cognitive and intellectual functions are normal. The proportion of women with CCD requiring cesarean section is higher than in the general population due to cephalopelvic disproportion.\nEtiology\nCCD is caused by mutations in the RUNX2 gene (6p21) involved in differentiation of osteoblasts and bone formation. A wide range of mutations have been identified, with high penetrance and significant variability. No clear phenotype-genotype correlations have been established.\nDiagnostic methods\nDiagnosis is based on clinical signs and on characteristic radiographic findings (wide-open sutures, patent fontanels, cone-shaped thorax with narrow upper thoracic diameter, hand deformities, abnormal dentition). Molecular genetic testing can be used to confirm the diagnosis in patients with atypical clinical and radiological diagnostic features.\nDifferential diagnosis\nDifferential diagnoses include mandibuloacral dysplasia, Crane-Heise syndrome, Yunis-Varon syndrome, pycnodysostosis, CDAGS syndrome, and hypophosphatasia.\nAntenatal diagnosis\nPrenatal diagnosis for pregnancies at increased risk is possible and requires identification of the disease-causing genetic mutation in the family.\nGenetic counseling\nCleidocranial dysplasia follows an autosomal dominant pattern of inheritance. Genetic counseling should be provided to affected families. The number of cases related to de novo mutations appears to be high.\nManagement and treatment\nManagement of dental anomalies is very important with the aim of achieving optimal function and esthetics. Options include removal of retained deciduous, supernumerary and abnormal permanent teeth. Dental surgery should be considered for unerupted teeth and orthodontics for malocclusion. Speech therapy may be required. Antibiotics are recommended for recurrent infections. Because of the role of RUNX2 in bone maintenance and ossification, bone mineral density should be monitored and preventive treatment for osteoporosis considered.\nPrognosis\nThe malformations and complications of CCD rarely cause significant disability. The prognosis is generally good.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Roberto MENDOZA-LONDONO"}
{"Disease Name": "Cleidorhizomelic syndrome", "Disease Definition": "Cleidorhizomelic syndrome is a rhizo-mesomelic dysplasia characterized by rhizomelic short stature/dwarfism in combination with lateral clavicular defects. Additional manifestations include brachydactyly with bilateral clinodactyly and hypoplastic middle phalanx of the fifth digit. X-ray demonstrated an apparent Y-shaped or bifid distal clavicle. Cleidorhizomelic syndrome has been reported in one family (mother and son) and is suspected to be transmitted in an autosomal dominant manner. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 1453, "Summary": ""}
{"Disease Name": "Climatic droplet keratopathy", "Disease Definition": "A rare superficial corneal dystrophy characterized by progressive opacity of the most anterior corneal layers. Slit-lamp examination reveals typical confluent translucent subepithelial deposits, extending in size and growing into clusters of golden droplets covering the cornea with disease progression. Patients present variably compromised visual acuity, depending on the stage of the disease. In advanced stages, decreased corneal sensation may lead to corneal trophic changes, perforation, and permanent visual loss.", "ORPHA ID": 98958, "Summary": ""}
{"Disease Name": "CLIPPERS", "Disease Definition": "CLIPPERS is a rare neuroinflammatory disorder characterized by brainstem-predominant encephalomyelitis which typically presents with cerebellar and cranial nerve manifestations (gait ataxia, dysarthria, visual disorders, parasthesias), as well as brainstem, myelopathy and cognitive findings, that respond to steroid treatment. Punctate curvilinear post-gadolinium contrast enhancement predominantly in the pons and cerebellum is observed on brain MRI and prominent, perivascular, CD3+ T-cell predominantly lymphocytic inflammation in neuropathology.", "ORPHA ID": 284448, "Summary": ""}
{"Disease Name": "CLN12 disease", "Disease Definition": "A rare neuronal ceroid lipofiscinosis disorder characterized by juvenile-onset of progressive spinocerebellar ataxia, bulbar syndrome (manifesting with dysarthria, dysphagia and dysphonia), pyramidal and extrapyramidal involvement (including myoclonus, amyotrophy, unsteady gait, akinesia, rigidity, dysarthric speech) and intellectual deterioration. Muscle biopsy displays autofluorescent bodies and lipofuscin deposits in brain and, occasionally the retina, upon post mortem.", "ORPHA ID": 314632, "Summary": ""}
{"Disease Name": "Cloacal exstrophy", "Disease Definition": "A major birth defect representing the severe end of the spectrum of the exstrophy-epispadias complex (EEC) characterized by omphalocele, exstrophy, imperforate anus and spinal defects (also referred to as the OEIS complex), often associated with other malformations.", "ORPHA ID": 93929, "Summary": "Epidemiology\nPrevalence at birth for EEC is reported at 1/10,000. Epispadias (E), classic bladder exstrophy (CEB) and EC are recognized clinical variants of the same spectrum, so accurate epidemiological data on E/EC/CEB are no longer available. The male-to-female ratio varies between studies; male or female predominance and a sex ratio close to unity have been described.\nClinical description\nPatients present at birth with two exstrophied hemibladders separated by a foreshortened hindgut (often blind-ending resulting in an imperforate anus) or cecum. Omphalocele is found in 88-100% of patients and gastrointestinal (GI) malrotation/duplication and short bowel syndrome (see this term) are present in 46%, with absorptive dysfunction in some cases. The symphysis pubis is widely separated and the pelvis is often asymmetrically shaped. The genitalia, e.g. the penile or clitoral halves, can be located separately on either side of the bladder plates with the adjacent scrotal or labial part. Duplication of the vagina and uterus, as well as vaginal agenesis, has also been reported. Various urological malformations (ureteropelvic junction obstruction, ectopic pelvic kidney, horseshoe kidney, renal hypo- or agenesis, megaureter, ureteral ectopy and ureterocele) may also be present. Spinal abnormalities ranging from hemivertebra to myelomeningocele occur in all patients and may be accompanied by skeletal and limb anomalies (clubfoot deformities, absence of feet, tibial/fibular deformities, and hip dislocation).\nEtiology\nEC results from an anomaly during early embryologic development associated with rupture of the cloacal membrane before fusion with the urorectal septum. The underlying cause remains unknown: genetic and environmental factors are likely to play a role.\nDiagnostic methods\nDiagnosis is evident at birth but spinal ultrasound and radiographs, MRI and urogenital ultrasound are recommended to determine the nature and extent of the malformations, with laboratory tests to detect electrolyte losses from the terminal ileum.\nAntenatal diagnosis\nPrenatal diagnosis is possible from ultrasound findings (non-visualization of the bladder, anterior wall defects, omphalocele and myelomeningocele are major criteria). Prenatal diagnosis should lead to parental counseling to provide information on the nature of the malformation and the extent of surgical reconstruction required. However, termination of pregnancy should not be automatically indicated.\nManagement and treatment\nPatients require immediate postnatal multidisciplinary care followed by surgical management, usually beginning in the newborn period with immediate closure of the meningocele and omphalocele as well as adaptation of bladder halves. Later, a multistage approach for bladder and bowel reconstruction is used, including a mandatory osteotomy due to severe pelvic asymmetry and the large ventral defect. The main aims of management are secure abdominal wall closure, prevention of short bowel syndrome, urinary and fecal continence, preserved renal function, and adequate cosmetic and functional genital reconstruction. Multiple associated anomalies have to be considered to achieve successful reconstruction.\nPrognosis\nSurgical advances and improved neonatal care have led to a dramatic increase in survival rates and improvements in continence rates and therefore quality of life. However, patients require life-long follow up, including psychosocial and psychosexual aspects, from a multidisciplinary team of experts.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Anne-Karoline EBERT  - Dr Michaël LUDWIG  - Pr Heiko REUTTER  - Pr Wolfgang RÖSCH"}
{"Disease Name": "Cloverleaf skull-asphyxiating thoracic dysplasia syndrome", "Disease Definition": "A rare syndromic craniosynostosis characterized by prenatal presentation with cloverleaf skull, micromelia and asphyxiating thoracic dysplasia. Radiologic features include short ribs, horizontal roof of the acetabulum with a rounded median prominence and lateral spurs, deformed long bones with broad metaphyses, and absent ossification of the terminal phalanges. There have been no further descriptions in the literature since 1987.", "ORPHA ID": 100978, "Summary": ""}
{"Disease Name": "Cloverleaf skull-multiple congenital anomalies syndrome", "Disease Definition": "This newly described syndrome is characterized by cloverleaf skull, limb anomalies, facial dysmorphism and multiple congenital anomalies.", "ORPHA ID": 93267, "Summary": "Epidemiology\nIt has been described in three sibs from one family.\nClinical description\nDysmorphic features include protruding forehead, hypertelorism, broad nasal bridge, wide anterior fontanel, short philtrum, downturning mouth, micrognathia and low-set ears. The limbs show rhizomelic shortening. Additional malformations are not constant: omphalocele, bilateral microphthalmia, cataract, narrow chest, ambiguous genitalia, cardiac ventricular septal defect and agenesis of the corpus callosum\nAntenatal diagnosis\nAntenatal diagnosis is possible by ultrasonographic monitoring.\nGenetic counseling\nThe condition seems to be inherited as an autosomal recessive trait.\nPrognosis\nPrognosis is poor.\n\n                            Last update: \n                            November 2010"}
{"Disease Name": "CLOVES syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by congenital lipomatous overgrowth, complex and progressive combined vascular malformations affecting the trunk, and epidermal nevi.", "ORPHA ID": 140944, "Summary": "Epidemiology\nThe prevalence of CLOVES syndrome is unknown and there is no sex predominance. CLOVES syndrome is the most common overgrowth syndrome associated with a PIK3CA variant, also known as PROS (for PIK3CA-related overgrowth spectrum), affecting over 500 patients in France.\nClinical description\nCLOVES syndrome is defined by its acronym (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies). In most cases, hypertrophy, often asymmetrical, is present at birth. The postnatal progression of lesions is usually moderate, but some patients may present hypertrophy with a more severe course. Hypertrophies can affect different parts of the body, more or less extensive, and involve fatty, muscular, nervous and/or skeletal tissues. Associated vascular anomalies (capillary, venous and/or lymphatic) are present in almost half of patients, and epidermal hamartomas are less frequent. Extremity anomalies (syndactyly, polydactyly) are sometimes observed.\nEtiology\nThe syndrome is due to a heterozygous mosaic variation - also known as postzygotic - in the PIK3CA gene, occurring in early embryogenesis. The PIK3CA gene encodes the catalytic alpha of the phosphatidylinositol-4,5-bisphosphate 3-kinase protein.\nDiagnostic methods\nDiagnosis must be confirmed by identification of a mosaic PIK3CA variation on affected tissue without culture, using high-depth high-throughput sequencing. Samples are usually taken by skin biopsy.\nDifferential diagnosis\nThe differential diagnosis includes: 1) other PROS syndromes (Klippel-Trenaunay syndrome, megalencephaly-capillary malformation-polymicrogyria syndrome), 2) Proteus syndrome, which is due to a mosaic variation in the AKT1 gene, and is characterized by the absence of congenital manifestations, the onset of a pathognomonic cerebriform hamartoma, and a rapidly progressive natural course, 3) PTEN-related overgrowth disorders.\nAntenatal diagnosis\nThe diagnosis may be suspected during pregnancy in the presence of segmental tissue hypertrophy, possibly associated with abnormalities of the extremities. A negative amniocentesis does not exclude the diagnosis.\nGenetic counseling\nThe risk for siblings of a proband with a PIK3CA mosaic variant is the same as in the general population if the parents are not variant carriers. Therefore, prenatal diagnosis is not particularly recommended.\nManagement and treatment\nBecause of the multisystemic involvement, patient management requires multi-disciplinary care by expert teams, with at least one annual physical examination, and further investigations may be needed based on clinical presentation. Screening for Wilms tumor (nephroblastoma) is not needed when the risk is less than 5 %. Therapeutic management of CLOVES syndrome consists of preventing and treating complications: medical management of inflammatory or painful inflammatory flare-ups, thrombo-embolic complications, superficial or non-disabling vascular malformations, correction of lower limb length discrepancy, and of a possibly associated scoliosis. Alpelisb, a specific inhibitor of the PI3K-mTOR pathway, is proposed in therapeutic trials or on a compassionate basis, according to a therapeutic protocol. This treatment improves quality of life, reduces hypertrophy and vascular symptoms, and avoids the need for surgery.\nPrognosis\nThe clinical presentation of the disease can be extremely variable, depending on the type of tissue affected by the variation and its extent. Treatment with alpelisib changes the prognosis of the disease for most of the patients.\n\n                            Last update: \n                            January 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Laurent GUIBAUD | ERN CRANIO* - Pr Laurence OLIVIER-FAIVRE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "CNTNAP2-related developmental and epileptic encephalopathy", "Disease Definition": "A rare, genetic, syndromic neurodevelopmental disorder characterized by moderate to mostly severe intellectual disability, speech impairment with normal or mildly delayed motor development and early-onset seizures often accompanied by developmental regression. Autistic behavior and stereotypic movements are common.", "ORPHA ID": 163681, "Summary": "Epidemiology\nCNTNAP2-related developmental and epileptic encephalopathy is a very rare disease and to date, 28 affected individuals from 15 families are reported in literature worldwide.\nClinical description\nIn all affected individuals, moderate to usually severe intellectual disability with speech impairment and seizures is present. Initial motor and cognitive development may be unaffected or only mildly delayed in few cases. Onset of seizures is usually during infancy or early childhood, typically within the first 3.5 years of life. With seizure onset, developmental regression with loss of verbal skills frequently occurs. Subsequently, speech is absent or very limited with only few words in most of the affected individuals. Ataxic gait, muscular hypo- or hypertonia or hyporeflexia can occur. Moreover, behavioral abnormalities such as stereotypic hand movements, teeth grinding, reduced eye contact, self-harm or aggressivity and autistic features are common. Further clinical aspects may include paroxysmal hyperventilation or breathing abnormalities or, rarely, a large head circumference. Focal cortical dysplasia, cerebellar hypoplasia or vermian atrophy may be detected in cerebral magnetic resonance imaging (MRI), but cerebral MRI might also be normal. Minor, but non-specific facial dysmorphism might be noted in few of the affected individuals.\nEtiology\nThe disorder is caused by bi-allelic intragenic deletions (rarely duplications) or truncating variants in the CNTNAP2 gene (7q35-q36.1). It encodes contactin-associated protein 2 (CASPR2), a transmembrane protein from the neurexin superfamily, which is involved in neural-glia interactions and clustering of potassium channels in myelinated axons.\nDiagnostic methods\nDiagnosis might be achieved by targeted testing upon clinical suspicion, but in most cases, it is made by untargeted approaches such as chromosomal microarray analysis and/or multigene panel or exome sequencing.\nDifferential diagnosis\nThe differential diagnosis includes other developmental and epileptic encephalopathies, such as MEF2C-related neurodevelopmental disorder (5q14.3 microdeletion syndrome), Pitt Hopkins syndrome, Angelman syndrome, Rett syndrome or NRXN1-associated autosomal recessive neurodevelopmental disorder.\nAntenatal diagnosis\nPrenatal diagnosis and preimplantation-diagnostics are possible where the pathogenic variant(s) has/have been identified in a family member and/or where carrier status in the parents has been confirmed.\nGenetic counseling\nInheritance is autosomal recessive. For parents who are both carriers of the variant there is a 25% recurrence risk for each pregnancy. Heterozygous carriers of deletions/variants in CNTNAP2 may have an increased risk for variable neuropsychiatric abnormalities.\nManagement and treatment\nManagement of seizures is required. Ongoing developmental assessments are recommended to tailor educational services to individual needs, e.g. physical, occupational, speech therapies and behavioral management strategies.\nPrognosis\nThere are affected individuals living in their fourth decade. Moderate to severe cognitive impairment is present with dependence on others for help in daily living.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Katalin HETZELT | ITHACA* - Pr André REIS | ITHACA* - Pr Christiane ZWEIER \n\n\n                                * European Reference Network"}
{"Disease Name": "COASY protein-associated neurodegeneration", "Disease Definition": "COASY protein-associated neurodegeneration (CoPAN) is a very rare, slowly progressive form of neurodegeneration with brain iron accumulation (NBIA) characterized by classic NBIA features. The clinical manifestations include early-onset spastic-dystonic paraparesis, oromandibular dystonia, dysarthria, parkinsonism, axonal neuropathy, progressive cognitive impairment, complex motor tics, and obsessive-compulsive disorder.", "ORPHA ID": 397725, "Summary": ""}
{"Disease Name": "Coats disease", "Disease Definition": "Coats disease (CD) is an idiopathic disorder characterized by retinal telangiectasia with deposition of intraretinal or subretinal exudates, potentially leading to retinal detachment and unilateral blindness. CD is classically an isolated and unilateral condition affecting otherwise healthy young children.", "ORPHA ID": 190, "Summary": "Epidemiology\nAnnual incidence is <1/1,000,000 in the UK, approximately 80% of cases occur in males.\nClinical description\nCD onset predominantly occurs in male children between 6 and 8 years old. Early stages of the disease are generally asymptomatic and evolution is variable. As children with unilateral vision loss usually do not complain of symptoms, the diagnosis is often based on an abnormal appearance of the pupillary reflex that can best be seen in photos or on red reflex testing. Other common presentations include the onset of strabismus or failure of a school vision screening examination. Ophthalmoscopy reveals unilateral retinal telangiectasia and aneurysms of the retinal vasculature. This is followed by exudation of fluids producing yellow subretinal deposits. The most advanced stages of CD include total retinal detachment, leukocoria and painful glaucoma secondary to angle closure.\nEtiology\nAn abnormal permeability of capillary endothelial cells in the retina, along with abnormal pericytes, causes the retinal vascular leakage that is the hallmark of CD. CD is not heritable, however, somatic mutations in the Norrie Disease Pseudoglioma, NDP, gene have been hypothesized to play a role in the pathogenesis of CD.\nDiagnostic methods\nDiagnostic methods include indirect ophthalmoscopy, fluorescein angiography, ultrasonography, computerized tomography scanning and magnetic resonance imaging.\nDifferential diagnosis\nRetinoblastoma (see this term) is the most important differential diagnosis. B-scan ultrasound and MRI with gadolinium contrast aid in distinguishing between late stage CD and solid tumors. Others include familial exudative vitreoretinopathy, Von Hippel-Lindau disease, intermediate uveitis and incontinentia pigmenti which are more often bilateral, as well as the more typically unilateral conditions such as ocular toxocariasis and persistent hyperplastic primary vitreous (see these terms).\nManagement and treatment\nTreatment depends on severity of disease. Mild peripheral vascular abnormalities may be followed with serial fundus photography. When exudation is present, ablation of incompetent vessels and avascular retina should be performed using laser or less often, cryotherapy. More advanced cases can require surgical intervention for retinal reattachment, such as scleral buckling, or laser photocoagulation combined with pars plana vitrectomy and removal of the vitreous membrane. Intravitreal corticosteroid as well as anti-VEGF agents have been used as adjuvant therapies.\nPrognosis\nThe majority of cases stabilize with proper therapy, although exudation and macular scarring commonly compromise vision. A retrospective study showed that 16% of patients had a final visual acuity of 20/50 or better and 47% had hand motions to no light perception in the affected eye. Approximately 20% of eyes may require enucleation.\n\n                            Last update: \n                            July 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Baker HUBBARD  - Dr Philip LAIRD"}
{"Disease Name": "Coats plus syndrome", "Disease Definition": "Coats plus syndrome is a pleiotropic multisystem disorder characterized by retinal telangiectasia and exudates, intracranial calcification with leukoencephalopathy and brain cysts, osteopenia with predisposition to fractures, bone marrow suppression, gastrointestinal bleeding and portal hypertension. It is transmitted as an autosomal recessive disease.", "ORPHA ID": 313838, "Summary": ""}
{"Disease Name": "Cobblestone lissencephaly without muscular or ocular involvement", "Disease Definition": "A rare, genetic, cobblestone lissencephaly disease characterized by the presence of a constellation of brain malformations, including cortical gyral and sulcus anomalies, white matter signal abnormalities, cerebellar dysplasia and brainstem hypoplasia, existing alone or in conjunction with minimal muscular and ocular abnormalities, typically manifesting with severe developmental delay, increased head circumference, hydrocephalus and seizures.", "ORPHA ID": 352682, "Summary": ""}
{"Disease Name": "Cobblestone lissencephaly", "Disease Definition": "A rare central nervous system malformation which includes a group of diseases that are characterized by a bumpy (or pebbled) appearance of the cerebral cortex, associated with a thickened cortex, reduction in normal sulcation, ventriculomegaly and reduced, abnormal white matter, as well as brainstem and cerebellum hypoplasia and corpus callosum agenesis. Patients generally present variable degrees of developmental delay, hypotonia and ocular abnomalities, however muscular and ocular involvement may be absent.", "ORPHA ID": 51577, "Summary": ""}
{"Disease Name": "Cocaine embryofetopathy", "Disease Definition": "Cocaine embryofetopathy is a group of clinical signs observed in newborns exposed in utero to cocaine, a short-acting central nervous system stimulant used as a recreational drug through inhalation of the powder or intravenous injection. Cocaine use during pregnancy is associated with intrauterine growth restriction, low birth weight, seizures, respiratory distress (decreased apnea density and periodic breathing), feeding difficulties, irritability and lability of state, decreased behavioral and autonomic regulation, poor alertness and orientation and cognitive impairment (impaired auditory information processing , visual-spatial delay and subtle language delay) in the offspring.", "ORPHA ID": 1911, "Summary": ""}
{"Disease Name": "Cocaine intoxication", "Disease Definition": "A rare disorder due to poisoning characterized by variable combination and dose-dependent severity of clinical manifestations, affecting behavior, central nervous and cardiovascular system. Patients present with euphoria, irritability, agitation, psychosis, hallucinations, paranoia, seizures, decreased responsiveness, mydriasis, tachyarrhythmia, chest pain, and cardiovascular collapse. Sometimes also dyspnea, hypertension, hyperthermia, hypothermia, lack of sleep and serotonin syndrome are present. Severe intoxication may lead to coma and death.", "ORPHA ID": 90068, "Summary": ""}
{"Disease Name": "Coccidioidomycosis", "Disease Definition": "Coccidioidomycosis is a fungal infection caused by Coccidioides immitis and C. posadasii, which is endemic to the Southwestern United States, Central America, South America and Mexico, and is acquired by inhalation of the infective arthroconidia, often found in soil. In most cases it is a benign, self-limiting febrile illness, but in a minority of cases it can become a potentially lethal infection of the lungs and, extremely rarely, spread to other organs (through hematogenous dissemination) with manifestations including meningitis, osteomyelitis, and skin and soft-tissue involvement.", "ORPHA ID": 228123, "Summary": ""}
{"Disease Name": "Cochlear nerve deficiency", "Disease Definition": "A rare otorhinolaryngological malformation characterized by a hypoplastic or absent cochlear nerve, resulting in variable hearing loss or total deafness, depending on the quantity of nerve fibers present. The condition can be unilateral or bilateral, occur as an isolated malformation or in the context of a complex syndrome, and may be associated with a hypoplastic internal auditory or cochlear nerve canal.", "ORPHA ID": 502318, "Summary": ""}
{"Disease Name": "Cochleosaccular degeneration-cataract syndrome", "Disease Definition": "Cochleosaccular degeneration-cataract syndrome is characterised by progressive sensorineural hearing loss due to severe cochleosaccular degeneration and cataract. So far, it has been reported in two families. Transmission is autosomal dominant.", "ORPHA ID": 3233, "Summary": ""}
{"Disease Name": "Cockayne syndrome", "Disease Definition": "Cockayne syndrome (CS) is a multisystem condition characterized by short stature, a characteristic facial appearance, premature aging, photosensitivity, progressive neurological dysfunction, and intellectual deficit.", "ORPHA ID": 191, "Summary": "Epidemiology\nThe annual incidence of CS is close to 1/200,000 in European countries.\nClinical description\nDisease severity and the age of onset are variable. In classical type I CS, the first symptoms usually appear during the first year of life. Early-onset cases with more severe symptoms (type II) and late-onset cases with milder symptoms (type III) have also been described. Common signs of the disease include progressive growth failure, intellectual deficit, cerebellar ataxia, spasticity, peripheral demyelinating neuropathy, pigmentary retinopathy, sensorineural hearing loss and dental anomalies (presence of caries). The typical facial appearance includes microcephaly, large ears, a thin nose, and enophthalmia. Cataracts and cutaneous photosensitivity are observed in some patients. Subcutaneous lipoatrophy is present and can lead to signs of premature aging of the skin. COFS syndrome (see this term) is the extreme prenatal form of the CS clinical spectrum characterized by congenital microphthalmia and arthrogryposis.\nEtiology\nCS belongs to the family of NER (nucleotide excision repair)-related disorders together with xeroderma pigmentosum and trichothiodystrophy (see these terms). CS cells show a specific defect in transcription-coupled DNA repair (TCR), a subpathway of NER involved in the removal of UV-induced DNA lesions in actively transcribed genes. Additional defects in basal transcription or in oxidative repair have also been put forward to account for the noncutaneous symptoms of CS. Mutations have been described in two major genes, ERCC6 (CSB; 10q11) and ERCC8 (CSA; 5q12.1). So far, no correlation was found between the three types of CS and the genes involved.\nDiagnostic methods\nDiagnosis is based on detection of the specific TCR defect that can be identified using a radioactive assay in cultured fibroblasts that measures the recovery of RNA synthesis after UV irradiation. This DNA repair test is a decisive tool for the diagnosis of CS. Brain imaging reveals diffuse hypomyelination of the cerebral white matter, calcifications in the putamen, and vermian atrophy.\nDifferential diagnosis\nThe differential diagnosis mainly includes mitochondrial diseases that may show similar clinical features to those seen in CS.\nAntenatal diagnosis\nPrenatal diagnosis can be performed on amniocytes or chorionic cells (using the same cellular test as that employed in fibroblasts) or by direct molecular sequencing if the causative mutations in the family have already been identified.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nManagement is purely supportive and includes physiotherapy, sun protection, hearing aids and often tube feeding or gastrostomy.\nPrognosis\nIn CS type I, death occurs before the end of the second decade as a result of progressive neurologic degeneration. Patients with type II present with a more severe prognosis, whereas patients with type III live into adulthood.\n\n                            Last update: \n                            May 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Hélène DOLLFUS  - Pr Vincent LAUGEL"}
{"Disease Name": "CODAS syndrome", "Disease Definition": "Codas syndrome is a multiple congenital anomalies syndrome characterized by Cerebral, Ocular, Dental, Auricular and Skeletal anomalies.", "ORPHA ID": 1458, "Summary": "Epidemiology\nTo date, three affected children (an unrelated Canadian girl and boy of Mennonite descent, and a girl from Brazil) have been reported.\nClinical description\nCharacteristic features consist of psychomotor delay, cataracts, abnormally shaped teeth (including enamel projections extending from the tips of the cusps), delayed tooth eruption, malformed ears (overfolded and crumpled ears), sensorineural hearing loss, short stature with marked epiphyseal dysplasia, and an unusual facial phenotype characterized mainly by ptosis, epicanthal folds and a grooved nose.\nEtiology\nEtiology remains unknown but some of the features suggest involvement of a collagen gene defect.\nDiagnostic methods\nX-rays show delayed ossification, delayed bone age and spine and pelvic anomalies.\nDifferential diagnosis\nThe differential diagnosis should include chondrodysplasia punctata (the rhizomelic, Conradi-Hunermann, and X-linked dominant types) and Kabuki syndrome (see these terms).\nGenetic counseling\nThe occurrence of two affected children within the Manitoba Mennonite community (a genetic isolate) suggests autosomal recessive inheritance, but other modes of transmission could not be excluded. Familial recurrence has not been documented.\nManagement and treatment\nManagement requires a multidisciplinary approach by specialists in neurology, ophthalmology, otorhinolaryngology, odontology, orthopedics and genetics.\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES"}
{"Disease Name": "Coffin-Lowry syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by global development delay, postnatal growth retardation leading to short stature, facial dysmorphism, short hands with tapering fingers and progressive skeletal abnormalities including kyphoscoliosis and pectus carinatum/excavatum. Intellectual disability ranges from mild to severe.", "ORPHA ID": 192, "Summary": "Epidemiology\nThe exact prevalence is not known but is estimated to be 1/50,000 to 1/100,000. Male patients are generally moderately to severely affected while most female carriers have mild features.\nClinical description\nSevere clinical presentation was reported in the first male patients described. Following the wide application of molecular genetic testing, the phenotype is now recognized as very variable. Affected newborn males often show hypotonia and hyperlaxity of joints with normal growth parameters. Growth retardation and global developmental delay become visible in the first years of life. The facial dysmorphism visible in late childhood and adulthood include prominent forehead, hypertelorism, down-slanting palpebral fissures, epicanthic folds, prominent ears, wide mouth, thick lips with everted lower vermilion, thick nasal alae, and septum. Oral findings include a high narrow palate, a midline lingual furrow, hypodontia, and peg-shaped incisors. Microcephaly is common. Hands are short, soft, and fleshy with skin/joint laxity and tapering fingers. Full and fleshy forearms can be present in childhood. Skeletal abnormalities appear gradually and may include spinal kyphoscoliosis (often progressive) and pectus carinatum/excavatum. Cognitive impairment is variable in severity. Other neurological findings may include epilepsy, progressive paraplegia and stimulus-induced drop attacks (SIDAs). Brain abnormalities have been reported but without a consistent pattern. A happy personality is common although behavioral abnormalities can be present. Other less frequent manifestations are sensorineural hearing loss and heart anomalies. Final stature is usually below the third percentile.\nEtiology\nCoffin-Lowry syndrome (CLS) is caused by pathogenic variations in the RPS6KA3 gene (Xp22.2-p22.1), which encodes ribosomal protein S6 kinase alpha-3, a growth-factor-regulated protein kinase.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and confirmed by the following genetic tests: sequencing of RPS6KA3 or Intellectual Disability-related Next Generation Sequencing panel that includes this gene. If sequencing results are negative, multiplex ligation-dependent probe amplification analysis should be performed in order to assess deletions or duplications.\nDifferential diagnosis\nDifferential diagnosis includes Alpha-thalassemia-X-linked intellectual disability (ATRX) syndrome, Borjeson-Forssman-Lehmann syndrome, FG syndrome type 1, Williams syndrome and Pitt-Hopkins syndrome.\nAntenatal diagnosis\nPrenatal genetic counseling should be offered to parents of patients who are hemizygotes for the pathogenic variant to discuss genetic risk and reproductive options.\nGenetic counseling\nCoffin-Lowry syndrome is an X-linked dominant disorder. About two-thirds of cases occur de novo. The risk of recurrence for the sibs of a proband depend on the mother's genotype. If the mother is a carrier of the pathogenic variation, the risk of transmitting the variant in subsequent pregnancies is 50%. Male offspring inheriting the mutation are affected, and female carriers can be unaffected or show milder phenotypes (Symptomatic form of Coffin-Lowry syndrome in female carriers). If the mother is not a carrier, the risk of recurrence is very low and linked to the possibility of germinal mosaicism.\nManagement and treatment\nManagement requires an early multidisciplinary approach. Kyphoscoliosis/spinal stenosis and SIDAs should be recognized and treated to avoid secondary complications.\nPrognosis\nPrognosis is poor and depends on the severity of the disease. Life span is reported to be reduced.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Stefania BIGONI | ITHACA* - Pr Alessandra FERLINI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Coffin-Siris syndrome", "Disease Definition": "A rare genetic syndromic intellectual disability of broad phenotypic range characterized by developmental delay and variable clinical features which most commonly, but not consistently, include aplasia or hypoplasia of the distal phalanx or nail of the fifth digit, and coarse facial features.", "ORPHA ID": 1465, "Summary": "Epidemiology\nMore than 150 cases of genetically confirmed Coffin-Siris syndrome (CSS) have been clinically reported to date. Exact prevalence and incidence are not known but the disorder is probably under-recognized.\nClinical description\nCoffin-Siris syndrome is a clinically and genetically heterogeneous disorder. It involves a wide range of major and minor clinical findings. Characteristic major features include mild to severe developmental or cognitive delay (in all patients), fifth finger nail/distal phalanx hypoplasia or aplasia (almost all patients at birth), and coarse facial features (commonly observed over time). Distinctive facial features include thick eyebrows and long eyelashes, broad nasal bridge, wide mouth with thick, everted upper and lower lips, and abnormal ear position or shape. Other major findings include short stature, failure to thrive, feeding difficulties, microcephaly, ophthalmological manifestations (cataracts, ptosis, strabismus), cardiac anomalies (ventricular septal/atrial septal defects, tetralogy of Fallot, patent ductus arteriosus), hypertrichosis (arms, face, back) and sparse scalp hair. Minor findings include neurologic involvement (Dandy-Walker malformation, gyral simplification, agenesis of the corpus callosum, seizures, and hypotonia), hearing loss, joint laxity, genito-urinary and renal malformations and frequent infections. Developmental delay and scoliosis appear in infancy and childhood.\nEtiology\nHeterozygous mutation or genomic rearrangement in the following nine genes have been reported to be causative for CSS (highest to lowest proportion of reported cases): ARID1B (6q25.3), SMARCA4 (19p13.3), SMARCC2 (12q13.2), ARID1A (1p36.11), SOX11 (2p25.2), DPF2 (11q13.1), SMARCB1 (22q11.23),SMARCE1 (17q21.2) , and ARID2 (12q12). These genes encode subunits of the BAF complex, which is involved in regulation of gene expression during development.\nDiagnostic methods\nTo date there have been no consistent clinical criteria to assist in the diagnosis. The diagnosis is generally based on the presence of major and at least one minor clinical sign and can be confirmed by molecular genetic testing of the causative genes. Recent studies revealed that fifth finger nail/distal phalanx hypoplasia or aplasia is not a mandatory finding. Microdeletions including ARID1B have been reported.\nDifferential diagnosis\nDifferential diagnoses include Nicolaides-Baraitser syndrome, brachymorphism-onychodysplasia-dysphalangism, DOOR syndrome, hyperphosphatasia-intellectual deficiency syndrome, Borjeson-Forssman-Lehmann syndrome, Wiedemann-Steiner syndrome, Rubinstein-Taybi syndrome and Cornelia de Lange syndrome. Fetal hydantoin syndrome may mimick Coffin-Siris syndrome.\nAntenatal diagnosis\nAs most mutations are de novo, prenatal diagnosis may be difficult to apply.\nGenetic counseling\nAutosomal dominant transmission has been reported regarding ARID1B-related disorder, but most cases are related to de novo mutations. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nTreatment is essentially supportive and symptomatic. Occupational, physical and speech therapy are recommended. Development and feeding should be monitored closely and patients should undergo regular ophthalmological and audiological testing.\nPrognosis\nThe prognosis is poor in severely affected individuals, with aspiration pneumonia and seizures reported in childhood. Association of tumor development including schwannomatosis has been reported.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Naomichi MATSUMOTO  - Dr Nobuhiko OKAMOTO"}
{"Disease Name": "COFS syndrome", "Disease Definition": "Cerebrooculofacioskeletal (COFS) syndrome is a rare genetic disorder, belonging to a family of diseases of DNA repair, characterized by a severe sensorineural involvement.", "ORPHA ID": 1466, "Summary": "Epidemiology\nThe exact incidence is unknown. To date, fewer than 20 cases have been confirmed, at a cellular or molecular level, as being truly similar to the primary cases described by Lowry, Pena and Shokeir in the indigenous population of Manitoba.\nClinical description\nCOFS syndrome constitutes the prenatal extreme form of Cockayne syndrome (see this term). Clinically, the following criteria are found: congenital microcephaly, congenital cataract and/or microphthalmia, arthrogryposis, severe psychomotor developmental delay, height-weight growth delay (principally postnatal) and facial dysmorphism (prominent metopic suture, micrognathism). The axial hypotonia contrasts with the peripheral hypertonia and is associated with feeding difficulties. Cutaneous photosensitivity, peripheral neuropathy, sensorineural hearing loss and pigmentary retinopathy can be observed.\nEtiology\nThe identified mutations mainly concern the ERCC6/CSB gene. One case has been linked to the ERCC1 gene and particular clinical forms with major photosensitivity have been linked with the ERCC2/XPD and ERCC5/XPG genes. All the genes code for proteins implicated in the same route of DNA repair.\nDiagnostic methods\nDiagnosis is based on the evidence of a defect in DNA repair (by transcription-coupled nucleotide-excision). This anomaly can be demonstrated on fibroblasts culture by ultraviolet irradiation. Early cerebral imagery is not very specific, but it can reveal cerebral and cerebellar atrophy; myelinization anomalies and calcifications of the basal ganglia can appear secondarily.\nDifferential diagnosis\nDifferential diagnoses include infectious fetopathies (cytomegalovirus, rubella, toxoplasmosis; see these terms) and MICRO syndrome (see this term) that can present as clinically similar to COFS syndrome, but with normal DNA repair.\nAntenatal diagnosis\nPrenatal diagnosis can be suspected by the presence of cataract, arthrogryposis and microcephaly. It is confirmed by examination of DNA repair in chorionic villi or amniotic cells and by checking for mutations.\nGenetic counseling\nCOFS syndrome is transmitted in an autosomal recessive manner.\nManagement and treatment\nManagement is symptomatic. Enteric feeding is often necessary.\nPrognosis\nCOFS syndrome is a severe disease leading to death in the first years of live, particularly by respiratory infections.\n\n                            Last update: \n                            February 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Hélène DOLLFUS  - Pr Vincent LAUGEL"}
{"Disease Name": "COG1-CDG", "Disease Definition": "COG1-CDG is an extremely rare form of CDG syndrome (see this term) characterized clinically in the few cases reported to date by variable signs including microcephaly, growth retardation, psychomotor retardation and facial dysmorphism.", "ORPHA ID": 263508, "Summary": ""}
{"Disease Name": "COG2-CDG", "Disease Definition": "A rare, congenital disorder of glycosylation caused by mutations in the COG2 gene and characterized by normal presentation at birth, followed by progressive deterioration with postnatal microcephaly, developmental delay, intellectual disability, seizures, spastic quadriplegia, liver dysfunction, hypocupremia and hypoceruloplasminemia in the first year of life. Diffuse cerebral atrophy and thin corpus callosum may be observed on brain MRI.", "ORPHA ID": 435934, "Summary": ""}
{"Disease Name": "COG4-CDG", "Disease Definition": "COG4-CDG is an extremely rare form of CDG syndrome (see this term) characterized clinically in the single reported case to date by seizures, some dysmorphic features, axial hyponia, slight peripheral hypertonia and hyperreflexia.", "ORPHA ID": 263501, "Summary": ""}
{"Disease Name": "COG5-CDG", "Disease Definition": "COG5-CDG is an extremely rare form of CDG syndrome (see this term) characterized clinically in the single reported case to date by moderate mental retardation with slow and inarticulate speech, truncal ataxia, and mild hypotonia.", "ORPHA ID": 263487, "Summary": ""}
{"Disease Name": "COG6-CGD", "Disease Definition": "A rare congenital disorder of glycosylation characterized by neonatal onset of global developmental delay, hypotonia, failure to thrive, hematological/immunological abnormalities, recurrent infections, liver involvement (with hepatosplenomegaly, cholestasis, fibrosis, or cirrhosis), and enteropathy. Additional reported manifestations include dysmorphic craniofacial features (such as microcephaly, broad palpebral fissures, and retrognathia), hypohidrosis, hyperkeratosis, and cardiac and musculoskeletal anomalies. Brain imaging may show hypoplastic corpus callosum, cerebral and cerebellar atrophy, and enlarged ventricles.", "ORPHA ID": 464443, "Summary": ""}
{"Disease Name": "COG7-CDG", "Disease Definition": "COG7-CDG is a congenital disorder of glycosylation characterised by dysmorphism, skeletal dysplasia, hypotonia, hepatosplenomegaly, jaundice, cardiac insufficiency, recurrent infections and epilepsy. To date, it has been described in two infants, both of whom died within the first three months of life. The syndrome is caused by a mutation in the gene encoding COG-7 (chromosome 16), a subunit of the oligomeric Golgi complex.", "ORPHA ID": 79333, "Summary": ""}
{"Disease Name": "COG8-CDG", "Disease Definition": "The CDG (Congenital Disorders of Glycosylation) syndromes are a group of autosomal recessive disorders affecting glycoprotein synthesis. CDG syndrome type IIh is characterised by severe psychomotor retardation, failure to thrive and intolerance to wheat and dairy products.", "ORPHA ID": 95428, "Summary": "Epidemiology\nSo far, only two cases have been described.\nEtiology\nThe disease is caused by mutations in the COG8 gene, which encodes a subunit of the COG complex. This complex is involved vesicle transport in the Golgi apparatus.\n\n                            Last update: \n                            September 2007"}
{"Disease Name": "Cogan syndrome", "Disease Definition": "A rare inflammatory/autoimmune disorder of unknown origin characterized by interstitial keratitis (IK) and audiovestibular dysfunctions.", "ORPHA ID": 1467, "Summary": "Epidemiology\nCogan syndrome (CS) prevalence is unknown. To date, approximately 300 cases have been reported. The disease is primarily described in causasians patients with no gender predilection.\nClinical description\nCS mainly affects young adults, with a median age at onset between 20 and 30 years, and occasionally affects children. The syndrome shows a large spectrum of clinical features. Non-syphilitic IK and cochleovestibular symptoms with unilateral or bilateral sensorineural hearing loss, vertigo and tinnitus are typical CS manifestations. The interval between the onset of ocular and audio-vestibular involvement is usually less than 2 years. CS presentation is considered atypical in presence of unusual ocular involvement (such as uveitis, chronic or recurrent conjunctivitis, scleritis, optic disc edema, and retinal vasculitis, with or without IK), audiovestibular symptoms that do not resemble Menière disease, or when the latency between the two organ involvement is more than 2 years A systemic disease expression is reported in at least 1/3 of the patients, especially in atypical cases, with general symptoms such as fever, headaches, weight loss, and/or in presence of signs of organ involvement, mostly cardiovascular (aortitis, aortic insufficiency, congestive heart failure, Raynaud's phenomenon), neurological (peripheral neuropathy, meningitis, hemiparesis or hemiplegia due to a cerebral vascular accident and aphasia due to a transient ischaemic event) and gastrointestinal systems (diarrhea, melena and abdominal pains).\nEtiology\nCS is supposed to have an autoimmune etiology, and autoantibodies to inner ear antigens and corneal structures, such as the Cogan peptide are usually present, even if they cannot be considered specific CS serological biomarkers.\nDiagnostic methods\nThe diagnosis is mainly clinical of exclusion of infections (in primis syphilis and Lyme disease) on the good response to corticosteroid treatment. There are no confirmatory diagnostic tests, even if laboratory tests, audiogram, and imaging may be useful for supporting the diagnosis and excluding other potential etiologies.\nDifferential diagnosis\nDifferential diagnoses include syphilis, Menière disease, Lyme disease, sarcoidosis, tuberculosis, polyarteritis nodosa, granulomatosis with polyangiitis and Takayasu arteritis.\nManagement and treatment\nCorticosteroids are the cornerstone of CS therapy. Topical glucocorticoids in association with cycloplegics may be considered for the management of isolated, mild eye involvement, while systemic corticosteroids should be considered for more severe eye involvement, hearing impairment, and systemic manifestations. Treatment with high doses of systemic corticosteroids (1-1.5 mg/kg of prednisone daily) are expected to prevent deafness, with a beneficial response usually within 2-3 weeks. However corticosteroids have proven to be of short-term benefit, and they carry a risk of serious side effects, therefore in patients with refractory or steroid-dependent disease, a second line treatment with immunosuppressants should be considered, although conventional immunosuppressive drugs such as methotrexate, cyclophosphamide, azathioprine, or cyclosporin A seem to have a limited efficacy. There are increasing reports of successful response to Infliximab, a tumor necrosis alpha (TNFalpha) blocker. Infliximab showed cochleovestibular symptoms improvement and allowed corticosteroid tapering, with a significantly difference when compared to patients treated with steroids alone or conventional DMARDs. The early use of infliximab as first line therapy in severe cases seems to be even more effective. Cochlear implantation is a valuable rescue surgical strategy in cases of severe sensorineural hearing loss unresponsive to intensive immunosuppressive regimens.\nPrognosis\nThe prognosis is mainly related to the risk of permanent deafness and cardiovascular complications, especially aortic insufficiency. Severe internal organ involvement and cardiovascular complications-related deaths are rare.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Rolando CIMAZ  - Dr Teresa GIANI"}
{"Disease Name": "Cogan-Reese syndrome", "Disease Definition": "A clinical variant of iridocorneal endothelial (ICE) syndrome, characterized by variable iris atrophy, pigmented and pedunculated nodules on the iris and corneal abonormalities. Secondary glaucoma is also a common complication of the disease.", "ORPHA ID": 98980, "Summary": ""}
{"Disease Name": "Cognitive impairment-coarse facies-heart defects-obesity-pulmonary involvement-short stature-skeletal dysplasia syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, short stature, skeletal abnormalities (such as brachydactyly and vertebral anomalies), obesity, cardiac, respiratory, and genitourinary anomalies, and dysmorphic facial features (including coarse facies, thick eyebrows, synophrys, hypertelorism, short, upturned nose, and long philtrum). Additional reported manifestations are microcephaly, hearing impairment, cataract, and gastroesophageal reflux.", "ORPHA ID": 444077, "Summary": ""}
{"Disease Name": "Cohen syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by microcephaly, characteristic facial features, hypotonia, non-progressive intellectual deficit, myopia and retinal dystrophy, neutropenia and truncal obesity.", "ORPHA ID": 193, "Summary": "Epidemiology\nThe prevalence is unknown. Approximately 200 cases have been reported to date. It is overrepresented in the Finnish population and in certain Amish, Greek/Mediterranean and Irish families.\nClinical description\nClinical manifestations seen between families are variable. At birth newborns appear normal as characteristic facial features are not yet present but neutropenia may be. The first manifestations include feeding difficulties, hypotonia, microcephaly, delayed developmental milestones (rolling over, sitting independently) and joint hypermobility. The majority of patients have a short stature with small or narrow hands and feet (compared to normal) and truncal obesity in the teen years. Characteristic facial features (high-arched or wave-shaped eyelids, thick hair, low hairline, short philtrum as well as long-thick eyelashes, prominent nasal root and upper central incisors) start to appear around the age of 5 and become more evident between the ages of 7-14 and into adulthood. Speech development is delayed. Aphthous ulcers are present in some. Recurrent upper respiratory infections are also seen in certain patients, possibly due to neutropenia. Intellectual deficiency is noted but is not progressive and the learning of new concepts is possible. Patients are often very sociable with a cheerful disposition. In adolescence, myopia and strabismus are present along with signs of retinochoroidal dystrophy in most cases. Nyctalopia and a narrowed visual field develop with time, and vision progressively begins to deteriorate after the age of 30. Patients over 45 suffer from severe retinochoroidal atrophy and posterior subcapsular cataracts. Although visual abnormalities are severe they do not lead to blindness.\nEtiology\nCS is caused by a mutation in the vacuolar protein sorting 13B (VPS13B) gene on locus 8q22-8q23 which is thought to have a role in vesicle mediated sorting and intracellular protein trafficking. More than 100 different null mutations (resulting in the truncation of the final protein) have been identified in the gene.\nDiagnostic methods\nCharacteristic clinical findings along with molecular genetic testing for the presence of mutations in the VPS13B gene are required for a definite diagnosis of CS.\nDifferential diagnosis\nDifferential diagnoses include Bardet-Biedl syndrome, Prader-Willi syndrome, Cri-du-chat syndrome, Alström syndrome, Angelman syndrome, Williams syndrome, MORM syndrome and monosomy 1p36 (see these terms). Mirhosseini-Holmes-Walton syndrome is considered allelic to CS and is clinically indistinguishable.\nAntenatal diagnosis\nAntenatal diagnosis is possible if mutations in family members have been identified.\nGenetic counseling\nCS is transmitted autosomal recessively and genetic counseling is recommended for at-risk individuals.\nManagement and treatment\nSpectacles/eyeglasses are necessary. Intellectual deficiency requires special education and children often attend specialized schools. Speech therapy is important during the preschool years to foster speech development as well as physical therapy for motor delay, hypotonia and motor clumsiness. Respiratory infections should be treated with antibiotics. Granulocyte-colony stimulating factor (G-CSF) has been given to some patients to treat neutropenia. Ophthalmologic evaluation is needed to determine visual acuity. No effective treatment has been developed to halt the progression of the retinal disease. In later years, training for the visually impaired can be offered. Psychosocial support should be offered to patients and their families.\nPrognosis\nThere is no evidence of the decrease in life expectancy but quality of life is reduced due to visual impairment.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Heng WANG"}
{"Disease Name": "COL4A1/2-related familial vascular leukoencephalopathy", "Disease Definition": "A rare genetic neurological disorder characterized by the presence of fragile small-vessel intracerebral vasculature in various members of a single family, manifesting, clinically, with single or recurrent hemorrhagic and/or ischemic stroke and, frequently, ocular and renal involvement. Neuroimaging reveals diffuse, periventricular leukoencephalopathy associated with dilated perivascular spaces, lacunar infarction and microhemorrhages.", "ORPHA ID": 36383, "Summary": ""}
{"Disease Name": "Colchicine poisoning", "Disease Definition": "Colchicine poisoning is a potentially life-threatening poisoning, due to ingestion of the drug or consumption of the plant Colchicum autumnale, that usually begins with gastrointestinal symptoms (e.g. abdominal pain, nausea, vomiting, and diarrhea, that cause severe dehydration) and an initial leukocytosis leading to marrow failure (24 hours after ingestion), followed by potentially fatal multi-organ failure with mental status change, oliguric renal failure, disseminated intravascular coagulation, electrolyte imbalance, acid-base disturbance, cardiac failure/arrest and shock within 1-3 days.", "ORPHA ID": 31824, "Summary": ""}
{"Disease Name": "Cold agglutinin disease", "Disease Definition": "Cold agglutinin disease is a type of autoimmune hemolytic anemia (see this term) defined by the presence of cold autoantibodies (autoantibodies which are active at temperatures below 30°C).", "ORPHA ID": 56425, "Summary": "Epidemiology\nCold agglutinin disease represents an estimated 16-32% of AIHA, whose annual incidence is estimated to be between 1/35,000-1/80,000 in North America and Western Europe.\nClinical description\nIt occurs more frequently after the age of 55. Cold agglutinin disease manifests as acute or chronic hemolytic anemia, with associated pallor and fatigue. Symptoms during hemolytic ``crises'' may include severe pain in the back and legs, headache, vomiting, diarrhea, dark urine and hepatosplenomegaly. A cold environment or a concurrent infection may trigger or exacerbate the condition, and episodes of acute hemolysis with hemoglobinemia and hemoglobinuria are more common in winter. The disease may appear abruptly with anemia and hemoglobinuria, or onset may be more gradual and insidious.\nEtiology\nCold agglutinin disease can be primary (idiopathic) or secondary, caused by an underlying condition, such as infection (Mycoplasma pneumoniae), lymphoproliferative disorders, systemic autoimmunity or neoplasm. The majority of cold agglutinin disease is secondary and is due to the presence of monoclonal IgM (kappa subtype in the majority of the cases), which has the properties of a cold agglutinin and is associated with an underlying low-grade B-cell lymphoma (Waldenström macroglobulinemia or lymphocytic lymphoma; see these terms). Idiopathic and lymphoma-associated cold AIHA tend to be chronic while infections tend to cause an acute disease.\nDiagnostic methods\nIn some cases, the diagnosis is made by chance on a standard complete blood count (CBC) detecting abnormal agglutination of the red blood cells. Diagnosis is based on clinical or laboratory evidence of hemolytic anemia and the detection of autoantibodies, specifically IgM, with the direct anti-globulin test (DAT, C3 positive pattern) with the presence of circulating cold agglutinins inthe serum. In secondary cases, lymphocytosis, with the presence of atypical lymphocytes on the smear, can be found in peripheral blood.\nDifferential diagnosis\nThe differential diagnosis for cold agglutinin disease is mixed AIHA (see this term).\nManagement and treatment\nPatients with few clinical symptoms and mild anemia may not require treatment but only avoidance of cold. Keeping the patient warm may be sufficient treatment. The disease is usually refractory to corticosteroids. Rituximab may be an option for treatment in some cases. In the presence of underlying lymphoma, chlorambucil or oral cyclophosphamide may be helpful.\nPrognosis\nThe disease has a chronic course and the outcome is usually benign, except in patients with recurrent episodes of severe anemia or in whom the underlying B-cell lymphoma has an aggressive course.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Marc MICHEL"}
{"Disease Name": "Cold-induced sweating syndrome", "Disease Definition": "Cold-induced sweating syndrome (CISS) is characterized by profuse sweating (involving the chest, face, arms and trunk) induced by cold ambient temperature.", "ORPHA ID": 157820, "Summary": "Epidemiology\nSo far, six cases have been reported of Norwegian, Israeli and Canadian origin.\nClinical description\nAdditional abnormalities may include kyphoscoliosis, a high-arched palate, a nasal voice, depressed nasal bridge, and impaired peripheral sensitivity to pain and temperature.\nEtiology\nCISS is caused by mutations in the CRLF1 gene on chromosome 19p12 (CISS type 1). In one Australian man with no family history, the syndrome was associated with mutations in the CLCF1 gene on chromosome 11q13.3 (CISS type 2).\nGenetic counseling\nCISS is an autosomal recessive disorder.\n\n                            Last update: \n                            February 2009"}
{"Disease Name": "Cole-Carpenter syndrome", "Disease Definition": "An extremely rare form of bone dysplasia characterized by the features of osteogenesis imperfecta such as bone fragility associated with multiple fractures, bone deformities (metaphyseal irregularities and bowing of the long bones) and blue sclera, in association with growth failure, craniosynostosis, hydrocephalus, ocular proptosis, and distinctive facial features (e.g. frontal bossing, midface hypoplasia, and micrognathia).", "ORPHA ID": 2050, "Summary": ""}
{"Disease Name": "Collagen type III glomerulopathy", "Disease Definition": "A rare non-immune-mediated glomerular disease characterized by abnormal accumulation of type III collagen within the mesangium and subendothelial space of the glomerulus. Clinically it usually manifests with proteinuria (often in the nephrotic range), microscopic hematuria, peripheral edema and/or hypertension. Progression to end-stage kidney failure is possible.", "ORPHA ID": 84087, "Summary": "Epidemiology\nApproximately 100 cases have been reported worldwide. Most have been from Japan, where it was first described, though subsequently cases from China, the Indian subcontinent, Europe, North and South America. No definitive variation in penetrance by sex has been described.\nClinical description\nThe disorder typically presents as an adult onset nephrotic syndrome with hypertension, anemia and microangiopathic hemolytic anemia that may appear to be a hemolytic uremic syndrome (HUS). Presentations in pediatric patients is rare and typically associated with familial occurrence. There is some evidence that it may present as a systemic disease including with partial villous atrophy of the intestine, hepatic perisinusoidal fibrosis and on autopsy accumulation of collagen III in spleen, liver, myocardium, and thyroid gland has been reported.\nEtiology\nThe etiology has not been established.\nDiagnostic methods\nRenal biopsy shows glomerular basement membrane double contours without hypercellularity, expansion of subendothelial space and mesangium that is birefringent on picrosirius red staining and negative on silver and congo red stains, and ultrastructural evidence of type III collagen fibers (40-65 nm). Immunostaining with antibodies for anti-Collagen III shows strong staining. Serum analysis will demonstrate increased procollagen III peptide (PIIIP) levels. There are reports of elevated serum hyaluronan levels (1000x normal). A rare case of full house staining and coincident diabetes in a pediatric patient has been reported. In one case where serial biopsies were available, the collagenofibrotic pattern evolved from more typical focal segmental glomerulosclerosis (FSGS). One patient with Hodkin lymphoma was reported to have co-incident collagenofibrotic glomerulopathy.\nDifferential diagnosis\nDifferential diagnosis includes nail-patella syndrome (an LMX1B-associated nephropathy where the lamina densa is not spared on ultrastructural examination), fibrillar collagen in glomerulosclerosis or in diabetic glomerulopathy (diabetic fibrillosis which is segmental with sparing of subendothelial space), fibronectin glomerulopathy (less fibrilar and not banded), Amyloidosis (straight, small, non-banded fibrils that are Congo red positive).\nGenetic counseling\nGenetic testing of LMX1B to exclude nail-patella syndrome is necessary, though a cases of renal limited LMX1B nephropathy has been identified. Familial occurrence in young patients, including in siblings, suggests autosomal recessive inheritance with adult onset cases more likely to be sporadic. Co-occurrence of an inherited Factor H deficiency has been reported.\nManagement and treatment\nDefinitive treatments, including renal transplantation, have not been established. A report of angiotensin II blocker (telmisartan) with improvement in clinical signs and symptoms, albeit with no significant change in laboratory findings, has been reported.\nPrognosis\nThe disorder can be insidious with variable progression to end stage renal disease within 10 years. While no reports of recurrence following transplantation are reported, there is one case where PIIIP levels were elevated in a patient post-transplantation suggesting a risk for recurrence, and one de novo case occurring following a renal transplant.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Avi ROSENBERG"}
{"Disease Name": "Collecting duct carcinoma", "Disease Definition": "Collecting duct carcinoma is a rare, aggressive subtype of renal cell carcinoma, which originates from the epithelium of the distal collecting ducts, and usually manifests with hematuria, flank pain, palpable abdominal mass or nonspecific symptoms, such as fatigue, weight loss or fever. Patients are often asymptomatic for long periods of time and therefore, disease is often locally advanced or metastatic at the time of diagnosis. In cases with metastatic spread, bone pain, cough, dyspnea, pneumonia or neurological compromise may be associated.", "ORPHA ID": 247203, "Summary": ""}
{"Disease Name": "Coloboma of choroid and retina", "Disease Definition": "Coloboma of choroid and retina is a rare, genetic developmental defect during embryogenesis characterized by the partial absence of retinal pigment epithelium and choroid, most frequently located in the inferonasal quadrant. Patients usually present reduced vision and have an increased risk for retinal detachment. Other ocular anomalies (e.g. coloboma of iris, microcornea, nystagmus, strabismus, microphthalmos) are usually associated, however it may also be isolated.", "ORPHA ID": 98942, "Summary": ""}
{"Disease Name": "Coloboma of eye lens", "Disease Definition": "A rare, genetic, developmental defect of the eye characterized by a uni- or bilateral abnormal lens shape (contraction of the lens with a notch) due to segmentally defective, or absent, development of the zonule and flattening of the equator in the region of the zonular defect, typically manifesting with reduced visual acuity. Other ocular anomalies, such as iris, choroid or optic disc colobomas, as well as cataracts and retinal detachment, may be associated.", "ORPHA ID": 98943, "Summary": ""}
{"Disease Name": "Coloboma of eyelid", "Disease Definition": "A rare, genetic, developmental defect of the eye characterized by a uni- or bilateral, symmetrical or asymmetrical, partial or full thickness defect of the superior or inferior eyelid margin, ranging in size from a small notch to complete absence of the entire lid, typically located on the medial to lateral third of the eyelid, resulting in an unprotected cornea and thus possibly leading to exposure keratopathy and vision impairment. It may occur isolated, be associated with other ocular defects or be part of a craniofacial syndrome, such as Treacher-Collins or Goldenhar syndrome.", "ORPHA ID": 98946, "Summary": ""}
{"Disease Name": "Coloboma of inferior eyelid", "Disease Definition": "Coloboma of inferior eyelid is a rare developmental defect during embryogenesis characterized by a unilateral or bilateral, partial or full-thickness, variably sized defect of the inferior eyelid (ranging from a small notch to complete absence of the entire lid) which is usually triangular in shape (with base at eyelid margin) and located on the lateral third of the lid. It can occur isolated, associated with facial clefting or as part of a syndrome.", "ORPHA ID": 155889, "Summary": ""}
{"Disease Name": "Coloboma of iris", "Disease Definition": "A rare, genetic, developmental defect of the eye characterized by a uni- or bilateral notch, gap, hole or fissure, typically located in the inferonasal quadrant of the eye, involving only the pigment epithelium or the iris stroma (incomplete) or involving both (complete), manifesting with iris shape anomalies (e.g. 'keyhole' or oval pupil) and/or photophobia. Association with colobomata in other parts of the eye (incl. ciliary body, zonule, choroid, retina, optic nerve) and complex malformation syndromes (such as CHARGE syndrome) may be observed.", "ORPHA ID": 98944, "Summary": ""}
{"Disease Name": "Coloboma of macula-brachydactyly type B syndrome", "Disease Definition": "A rare congenital malformation syndrome characterized by the combination of bilateral coloboma of macula with horizontal pendular nystagmus and severe visual loss, and brachydactyly type B. The hand and feet defects comprise of shortening of the middle and terminal phalanges of the second to fifth digits, hypoplastic or absent nails (congenital anonychia), broad or bifid thumbs and halluces, syndactyly and flexion deformities of the joints of some digits.", "ORPHA ID": 1471, "Summary": ""}
{"Disease Name": "Coloboma of macula", "Disease Definition": "Coloboma of macula is a rare, non-syndromic developmental defect of the eye characterized by well-circumscribed, oval or rounded, usually unilateral, atrophic lesions of varying size presenting rudimentary or absent retina, choroid and sclera located at the macula leading to decreased vision and, on occasion, other symptoms (e.g. strabismus). It is usually isolated, but may also be associated with Down syndrome, skeletal or renal disorders.", "ORPHA ID": 98945, "Summary": ""}
{"Disease Name": "Coloboma of optic disc", "Disease Definition": "Coloboma of optic disc is a rare, genetic, developmental defect of the eye characterized by a unilateral or bilateral, sharply demarcated, bowl-shaped, glistening white excavation on the optic disc (typically decentered inferiorly) which usually manifests with varying degrees of reduced visual acuity. It can occur isolated or may associate other ocular (e.g. retinal detachment, retinoschisis-like separation) or systemic anomalies (e.g. renal).", "ORPHA ID": 98947, "Summary": ""}
{"Disease Name": "Coloboma of superior eyelid", "Disease Definition": "Coloboma of superior eyelid is a rare developmental defect during embryogenesis characterized by a typically unilateral, partial or full-thickness, variably sized defect of the superior eyelid, ranging from a small notch to complete absence of the entire lid, which is commonly triangular in shape (with base at eyelid margin) and located on the medial third of the lid. It can occur isolated, associated with other anomalies (e.g. ocular/orbital and facial), or as part of a syndrome.", "ORPHA ID": 155884, "Summary": ""}
{"Disease Name": "Colobomatous macrophthalmia-microcornea syndrome", "Disease Definition": "A rare genetic eye disease characterized by microcornea, coloboma of the iris and the optic disc, axial enlargement of the globe, staphyloma, and severe myopia. Additional manifestations are mild cornea plana, iridocorneal angle abnormalities with elevation of intraocular pressure, and shallow anterior chamber depth. Variable expressivity of the phenotype has been described, including unilateral or bilateral involvement, or variable extent of coloboma, among other features.", "ORPHA ID": 468672, "Summary": ""}
{"Disease Name": "Colobomatous microphthalmia-obesity-hypogenitalism-intellectual disability syndrome", "Disease Definition": "A rare syndromic microphthalmia characterized by bilateral, usually asymmetrical, microphthalmia associated typically with a unilateral coloboma, truncal obesity, borderline to mild intellectual disability, hypogenitalism and, more variably, nystagmus, cataracts and developmental delay.", "ORPHA ID": 363741, "Summary": ""}
{"Disease Name": "Colobomatous microphthalmia-rhizomelic dysplasia syndrome", "Disease Definition": "Colobomatous microphthalmia-rhizomelic dysplasia syndrome is a rare, genetic developmental defect during embryogenesis characterized by a range of developmental eye anomalies (including anophthalmia, microphthalmia, colobomas, microcornea, corectopia, cataract) and symmetric limb rhizomelia with short stature and contractures of large joints. Intellectual disability with autistic features, macrocephaly, dysmorphic features, urogenital anomalies (hypospadia, cryptorchidism), cutaneous syndactyly and precocious puberty may also be present.", "ORPHA ID": 424099, "Summary": ""}
{"Disease Name": "Colobomatous microphthalmia", "Disease Definition": "Colobomatous microphthalmia is a developmental disorder of the eye characterized by unilateral or bilateral microphthalmia associated with ocular coloboma.", "ORPHA ID": 98938, "Summary": ""}
{"Disease Name": "Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome", "Disease Definition": "A rare genetic eye disease characterized by optic disc anomalies (bilateral colobomatous optic discs, retinal vessels arising from the peripheral optic disc) and macular atrophy. Peripapillary chorioretinal atrophy and chorioretinal and iris coloboma have also been described. Patients present with horizontal nystagmus and poor visual acuity.", "ORPHA ID": 435930, "Summary": ""}
{"Disease Name": "Colonic atresia", "Disease Definition": "Colonic atresia is a congenital intestinal malformation resulting in a non-latent segment of the colon and characterized by lower intestinal obstruction manifesting with abdominal distention and failure to pass meconium in newborns.", "ORPHA ID": 1198, "Summary": ""}
{"Disease Name": "Colorado tick fever", "Disease Definition": "An acute arboviral infection caused by a Coltivirus transmitted by an infected tick and characterized by a biphasic fever with headache, myalgias, arthralgias, and fatigue that can last 3 weeks or more. In some cases, macular, maculopapular, or petechial rash and/or stiff neck, nausea, vomiting, abdominal pain, diarrhea, and sore throat may also occur.", "ORPHA ID": 83595, "Summary": ""}
{"Disease Name": "Combined deficiency of factor V and factor VIII", "Disease Definition": "A rare inherited bleeding disorder due to the reduction in activity and antigen levels of both factor V (FV) and factor VIII (FVIII) and characterized by mild-to-moderate bleeding symptoms.", "ORPHA ID": 35909, "Summary": "Epidemiology\nPrevalence is estimated between 1/100,000 and 1/1,000,000. The condition is more prevalent in the Mediterranean area and in areas where consanguineous marriages are common.\nClinical description\nCombined FV and FVIII deficiency can manifest at any age. Epistaxis, easy bruising, post-surgical or post partum bleeding and menorrhagia are the most common symptoms. Hemarthrosis and muscular hematomas may occur. The symptoms are usually mild.\nEtiology\nCombined deficiency of factor V and factor VIII is caused by mutations either in the LMAN1 gene (chromosome 18; 18q21) or in the MCFD2 gene (chromosome 2; 2p21). LMAN1 encodes ERGIC-53, a transmembrane lectin, while MCFD2 is an EF-hand-containing protein. The ERGIC-53/MCFD2 protein complex functions as a cargo receptor that facilitates the transport of coagulation factors V and VIII from the endoplasmic reticulum to the Golgi apparatus. Mutations in LMAN1 account for approximately 70% of cases and include only null mutations. Mutations in MCFD2 account for approximately 30% of cases and include both null and missense mutations.\nDiagnostic methods\nDiagnosis is based on the measurement of factor V and factor VIII levels and on the detection of prolonged activated partial thromboplastin and prothrombin times. Levels of factor V and factor VIII range from as low as 1% to as high as 46%, but generally fall between 5% and 30%.\nDifferential diagnosis\nDifferential diagnosis includes co-inheritance of both FV deficiency (chromosome 1) and FVIII deficiency (chromosome X).\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nManagement aims at controlling the bleeding and includes treatments with fresh frozen plasma, FVIII concentrates and desmopressin administration.\nPrognosis\nThe prognosis is favorable for moderate forms of the disease. Management of patients with more severe forms should be carried out at a specialized center.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND"}
{"Disease Name": "Combined hamartoma of the retina and retinal pigment epithelium", "Disease Definition": "A rare benign eye tumor characterized by the presence of glial cells, vascular tissue, and sheets of pigment epithelial cells lacking the distribution and organization of the normal retina and retinal pigment epithelium. The lesion is most commonly found unilaterally as a slightly elevated mass in a peripapillary location but can also occur in the macula or the retinal periphery. It is sometimes associated with neurofibromatosis type 1 or 2, nevoid basal cell carcinoma syndrome, or branchio-oculo-facial syndrome. Patients may be asymptomatic or present with progressive loss of vision.", "ORPHA ID": 440727, "Summary": ""}
{"Disease Name": "Combined hepatocellular carcinoma and cholangiocarcinoma", "Disease Definition": "A rare hepatic tumor characterized by the presence of both hepatocytic and cholangiocytic differentiation within a primary liver carcinoma. The lesion commonly arises in the context of chronic liver disease (such as hepatitis B or C, or steatohepatitis) or exposure to a variety of exogenous agents. Patients may present with signs and symptoms related to the tumor, as well as to the underlying condition. Typical manifestations include right upper quadrant abdominal pain, weight loss, hepatosplenomegaly, jaundice, and ascites. The entity has been associated with a worse prognosis than hepatocellular carcinoma after resection.", "ORPHA ID": 529852, "Summary": ""}
{"Disease Name": "Combined hyperactive dysfunction syndrome of the cranial nerves", "Disease Definition": "A rare, acquired peripheral neuropathy characterized by symptoms arising from combined overactivity in cranial nerves, without any explanatory structural lesion. The symptoms may be unilateral or bilateral, may occur synchronously or metachronously, and include trigeminal neuralgia, hemifacial spasm and glossopharyngeal neuralgia.", "ORPHA ID": 221078, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to CARD11 deficiency", "Disease Definition": "Severe combined immunodeficiency due to CARD11 deficiency is a rare combined T and B cell immunodeficiency characterized by normal numbers of T and B lymphocytes, increased numbers of transitional B cells and hypo- to agammaglobulinemia, decreased numbers of regulatory T cells and defects in T-cell functions. It presents with severe susceptibility to infections, including opportunistic infections.", "ORPHA ID": 357237, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to CARMIL2 deficiency", "Disease Definition": "A rare immune dysregulation disease with immunodeficiency characterized by infantile or childhood onset of a variable phenotype including recurrent/persistent bacterial, fungal, and viral infections with involvement of the skin, lower respiratory tract, and gastrointestinal tract, eczema, allergies, and inflammatory bowel disease, among others. EBV-related smooth muscle tumors have also been reported. Immunophenotyping shows decreased Treg counts, as well as a deficient CD3/CD28 co-stimulation response in CD4+ and CD8+ T-cells.", "ORPHA ID": 542301, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to CD27 deficiency", "Disease Definition": "A rare autosomal recessive primary immunodeficiency characterized by Epstein-Barr virus (EBV)-triggered lymphoprolipherative disorders such as malignant B-cell proliferation, Hodgkin lymphoma, B-cell lymphoma and EBV-driven hemophagocytic lymphohistiocytosis (HLH). Aplastic anemia and inflammatory disorders such as uveitis and oral ulcers are also observed.", "ORPHA ID": 238505, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to CD3gamma deficiency", "Disease Definition": "A rare autosomal recessive primary immunodeficiency characterized by partial T lymphopenia (in particular cytotoxic CD8+ cells) and decreased expression of the T cell receptor (TCR)/CD3 complex with impaired proliferative response to TCR-dependent stimuli, while the mature memory T cell pool is comparatively well preserved, and B cells, natural killer cells, and immunoglobulins are typically normal. The clinical phenotype is highly heterogeneous, ranging from asymptomatic to infancy-onset of severe recurrent infections, as well as occurrence of autoimmune disease or enteropathy.", "ORPHA ID": 169082, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to CD70 deficiency", "Disease Definition": "A rare autosomal recessive primary immunodeficiency characterized by susceptibility to Epstein-Barr virus (EBV)-related disorders (B-cell lymphoproliferative disorders including Hodgkin lymphoma) as well as dysgammaglobulinemia and recurrent infections. Patients can present with recurrent fever, lymphadenopathy, hepatosplenomegaly, Behçet-like stomatitis, pharyngitis, tonsillitis, adenitis, and viral encephalitis.", "ORPHA ID": 538958, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to CRAC channel dysfunction", "Disease Definition": "Combined immunodeficiency (CID) due to Ca2+ release activated Ca2+(CRAC) channel dysfunction is a form of CID characterized by recurrent infections, autoimmunity, congenital myopathy and ectodermal dysplasia. It comprises two sub-types that are due to mutations in the ORAI1 and STIM1 genes: CID due to ORAI1 deficiency and CID due to STIM1 deficiency.", "ORPHA ID": 169090, "Summary": "Epidemiology\nCID due to CRAC channel dysfunction has been reported in 10 patients from 5 families, 6 patients in 3 families with ORAI1 mutations and 4 patients in two families with STIM1 mutations.\nClinical description\nCID due to CRAC channel dysfunction is characterized by recurrent viral, bacterial, mycobacterial and fungal infections from birth, chronic diarrhea, pneumonia, meningitis, enteritis, gastrointestinal candidiasis, sepsis and otitis media. In addition, patients present at birth with congenital myopathy, which is characterized by non-progressive generalized muscular dysplasia. For cases with ORAI1 mutations this presents as poor head control after birth, delayed ambulation and a positive Gower's sign, while patients with STIM1 mutations present with global muscular hypotonia and partial iris hypoplasia. All patients present with ectodermal dysplasia that is characterized by hypocalcified amelogenesis imperfecta (see this term) and leads to the loss of soft dental enamel. Patients with ORAI1 mutations also have anhydrosis, which is characterized by inability to sweat and recurrent fever episodes associated with impaired thermoregulation. Patients with STIM1 mutations also show signs of lymphoproliferative and autoimmune disease including lymphadenopathy, hepatosplenomegaly, autoimmune thrombocytopenia and autoimmune hemolytic anemia.\nEtiology\nCID due to CRAC channel dysfunction is caused by mutations in the ORAI1 and STIM1 genes (12q24 and 11p15.5).\nDiagnostic methods\nDiagnosis is based on clinical features and testing the function and proliferation of T cells. Patients have normal lymphocyte counts and serum immunoglobulin levels but severely compromised T cell activation.\nDifferential diagnosis\nDifferential diagnoses include combined immunodeficiency (CID) due to ZAP70 deficiency, CID due to CD3gamma deficiency, immunodeficiency due to CD25 deficiency, hypohidrotic ectodermal dysplasia with immunodeficiency and anhidrotic ectodermal dysplasia - immunodeficiency - osteopetrosis - lymphedema syndrome.\nAntenatal diagnosis\nPrenatal diagnosis can be performed where there is a family history and where the genetic mutation has been identified.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment with hematopoietic stem cell transplantation (HSCT) has been successful in some cases.\nPrognosis\nWithout treatment, patients fail to thrive and die in their first year of life.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Combined immunodeficiency due to DOCK2 deficiency", "Disease Definition": "A rare, primary combined T and B cell immunodeficiency characterized by early-onset of recurrent, invasive viral and bacterial infections associated with T and B cell lymphopenia, functional defects in T and B cells, poor antibody response and thrombocytopenia. Depending on the type of infectious agent, variable clinical manifestations commonly include recurrent pneumonia, bronchiolitis, otitis media, meningoencephalitis, colitis, and diarrhea, leading to fatal multiorgan failure in severe cases.", "ORPHA ID": 447737, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to DOCK8 deficiency", "Disease Definition": "Combined immunodeficiency due to dedicator of cytokinesis 8 protein (DOCK8) deficiency is a form of T and B cell immunodeficiency characterized by recurrent cutaneous viral infections, susceptibility to cancer and elevated serum levels of immunoglobulin E (IgE).", "ORPHA ID": 217390, "Summary": "Epidemiology\nPrevalence is unknown. To date, 11 patients in eight families have been reported.\nClinical description\nPatients present in childhood with symptoms including atopic dermatitis, severe food and environmental allergies, asthma, recurrent upper and lower respiratory tract infections including otitis media, recurrent sinusitis, bronchitis and pneumonia, and extensive cutaneous viral and bacterial infections including superficial, often ulcerating herpes simplex virus infections, flat and verrucous warts, molluscom contagiosum infections, S. aureus skin infections or abscesses, mucosal or nail candidiasis and otitis externa. Patients with long-term herpes simplex virus infections, human papillomavirus infections or molluscom contagiosum have developed vulvar, facial and anal squamous cell dysplasia and carcinoma. The neurologic, vasculitic and autoimmune symptoms associated with autosomal dominant hyper IgE syndrome due to mutations in STAT3 (see this term), are not observed.\nEtiology\nCID due to DOCK8 deficiency is caused by homozygous or compound heterozygous deletions and point mutations in the DOCK8 gene (9p24), which leads to an absence of DOCK8 protein in lymphocytes, resulting in low absolute T and B lymphocyte counts, mild-to-moderate eosinophilia and very high levels of serum IgE.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Combined immunodeficiency due to GINS1 deficiency", "Disease Definition": "A rare syndrome with combined immunodeficiency characterized by intrauterine and postnatal growth retardation, chronic neutropenia, and natural killer (NK) cell deficiency due a defect in DNA replication leading to blockade of immune cell differentiation in the bone marrow, particularly affecting NK cells. Other clinical features include recurrent viral and bacterial infections and eczema, as well as mild facial dysmorphism.", "ORPHA ID": 505227, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to IL21R deficiency", "Disease Definition": "A rare, genetic, non-severe combined immunodeficiency disorder characterized by variable B- and T-cell defects (including defective B-cell differentiation and impaired T-cell proliferation to mitogens and bacterial antigens) and natural killer cell dysfunction (ranging from impaired cytotoxicity to lymphopenia) due to IL21R deficiency, manifesting with recurrent respiratory and/or gastrointestinal tract infections and, in some cases, with severe, chronic, progressive cholangitis and liver cirrhosis associated with cryptosporidial infection.", "ORPHA ID": 357329, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to ITK deficiency", "Disease Definition": "A rare autosomal recessive primary immunodeficiency characterized by susceptibility to Epstein-Barr virus (EBV)-associated lymphoproliferative disorders such as malignant B-cell proliferation, Hodgkin lymphoma, B-cell lymphoma, lymphoid granulomatosis, hemophagocytic lymphohistiocytosis, and smooth muscle tumor. Patients present persistent symptoms of infectious mononucleosis including recurrent febrile episodes, lymphadenopathies, and hepatosplenomegaly, accompanied by high EBV viral load in the blood. Additional manifestations are autoimmune diseases like hemolytic anemia or renal disease.", "ORPHA ID": 538963, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to LRBA deficiency", "Disease Definition": "A rare, genetic, primary immunodeficiency characterized by early onset of recurrent respiratory infections and variable combination of autoimmune disorders, including hemolytic anemia, thrombocytopenic purpura, lymphoproliferative disease, inflammatory bowel disease, colitis, diabetes, arthritis, and dermatitis. Failure to thrive, hepatosplenomegaly and endocrine abnormalities have also been associated. Variable immunologic findings include deficiency of CD4+ T regulatory cells, decreased B-cells, and hypogammaglobulinemia.", "ORPHA ID": 445018, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to MALT1 deficiency", "Disease Definition": "Combined immunodeficiency due to MALT1 deficiency is a rare, genetic form of primary immunodeficiency characterized by growth retardation, early recurrent pulmonary infections leading to bronchiectasis, inflammatory gastrointestinal disease, and other symptoms, such as rash, dermatitis, skin infections.", "ORPHA ID": 397964, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to Moesin deficiency", "Disease Definition": "A rare combined T and B cell immunodeficiency characterized by childhood onset of recurrent bacterial and varicella zoster virus infections. Eczema and recurrent molluscum have also been reported. Laboratory studies reveal profound and persistent lymphopenia, hypogammaglobulinemia, poor immune response to vaccine antigens, and fluctuating neutropenia.", "ORPHA ID": 504530, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to ORAI1 deficiency", "Disease Definition": "Combined immunodeficiency (CID) due to ORAI1 deficiency is a form of CID due to Calcium release activated Ca2+ (CRAC) channel dysfunction (see this term) characterized by recurrent infections, congenital myopathy, ectodermal dysplasia and anhydrosis.", "ORPHA ID": 317428, "Summary": "Epidemiology\nTo date, it has been reported in 6 patients in 3 families.\nClinical description\nThe disease is characterized by recurrent viral, bacterial, mycobacterial and fungal infections from birth, chronic diarrhea, pneumonia, meningitis, enteritis, gastrointestinal candidiasis, sepsis and otitis media. In addition, patients present at birth with congenital myopathy (see this term), characterized by non-progressive generalized muscular dysplasia. This presents as poor head control after birth, delayed ambulation and a positive Gower's sign. All patients present with ectodermal dysplasia that is characterized by hypocalcified amelogenesis imperfecta (see this term) and leads to the loss of soft dental enamel. Patients also have anhydrosis, which is characterized by inability to sweat and recurrent fever episodes associated with impaired thermoregulation.\nEtiology\nThe disease is caused by mutations in the ORAI1 gene (12q24.31) which codes for calcium release-activated calcium channel protein 1.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Combined immunodeficiency due to OX40 deficiency", "Disease Definition": "Combined immunodeficiency due to OX40 deficiency is a rare combined T and B cell immunodeficiency characterized by susceptibility to develop an aggressive, childhood-onset, disseminated, cutaneous and systemic Kaposi sarcoma.", "ORPHA ID": 431149, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to partial RAG1 deficiency", "Disease Definition": "Combined immunodeficiency due to partial RAG1 deficiency is a form of combined T and B cell immunodeficiency (CID; see this term) characterized by severe and persistent cytomegalovirus (CMV) infection and autoimmune cytopenia.", "ORPHA ID": 231154, "Summary": "Epidemiology\nPrevalence is unknown. To date, 9 cases have been reported.\nClinical description\nPatients present before the age of one year with severe disseminated CMV infection, which can manifest with fever and splenomegaly, and recurrent and severe co-infections including sepsis and pneumonitis. Autoimmune cytopenia also occurs and can include autoimmune hemolytic anemia (see these terms) or neutropenia.\nEtiology\nSCID due to partial RAG1 deficiency is caused by hypomorphic mutation in the RAG1 gene (11p13). This results in oligoclonal expansion of T cell receptor (TCR) gamma-delta T cells and TCR alpha-beta T cell lymphopenia, although total lymphocyte counts are normal, in combination with CMV infection and autoimmunity.\nDiagnostic methods\nDiagnosis is based on clinical evaluation, immunological investigation, including lymphocyte subset phenotyping, lymphocyte proliferation to mitogen stimulation, immunoglobulin levels and antibody response to vaccine antigens, and genetic confirmation.\nDifferential diagnosis\nDifferential diagnoses include other combined immunodeficiencies.\nAntenatal diagnosis\nPrenatal diagnosis can be performed in families where there is a family history and in which the genetic mutation has been identified.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment involves antiviral treatment and management of recurrent infections. Bone marrow transplant has been attempted but may result in graft versus host disease (GVHD; see this term) associated with reactivation of CMV disease. Patients should be treated in centers with experience of transplanting complex primary immunodeficiencies.\nPrognosis\nThe majority of patients reported to date have died within the first few years of life.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Combined immunodeficiency due to RELA haploinsufficiency", "Disease Definition": "A rare non-severe combined immunodeficiency characterized by TNF-dependent chronic mucocutaneous ulcerations and inflammatory bowel disease presenting during the first years of life. Ulcerations occur primarily in the oral, gastrointestinal, and vaginal mucosa.", "ORPHA ID": 596759, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to STIM1 deficiency", "Disease Definition": "Combined immunodeficiency (CID) due to STIM1 deficiency is a form of CID due to Calcium release activated Ca2+(CRAC) channel dysfunction (see this term) characterized by recurrent infections, autoimmunity, congenital myopathy and ectodermal dysplasia.", "ORPHA ID": 317430, "Summary": "Epidemiology\nTo date, it has been reported in 4 patients from two families.\nClinical description\nCID due to STIM1 deficiency is characterized by recurrent viral, bacterial, mycobacterial and fungal infections from birth, chronic diarrhea, pneumonia, meningitis, enteritis, gastrointestinal candidiasis, sepsis and otitis media. In addition, patients present at birth with congenital myopathy (see this term), characterized by non-progressive generalized muscular dysplasia. This presents as global muscular hypotonia and partial iris hypoplasia. All patients present with ectodermal dysplasia that is characterized by hypocalcified amelogenesis imperfecta (see this term) and leads to the loss of soft dental enamel. Patients also show signs of lymphoproliferative and autoimmune disease including lymphadenopathy, hepatosplenomegaly, autoimmune thrombocytopenia and autoimmune hemolytic anemia (see these terms).\nEtiology\nThe disease is caused by mutations in the STIM1 gene (11p15.5) which codes for stromal interaction molecule 1.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Combined immunodeficiency due to STK4 deficiency", "Disease Definition": "A rare, genetic, combined T and B cell immunodeficiency characterized by T- and B-cell lymphopenia, hypergammaglobulinemia and intermittent neutropenia. It presents with recurrent opportunistic viral, bacterial and fungal infections involving skin (cutaneous papillomatosis, molluscum contagiosum, skin abscesses, mucocutaneous candidiasis), upper and lower respiratory tract or septicemia. Other clinical features include autoimmune manifestations (autoimmune hemolytic anemia) and congenital heart defects (atrial septal defects, patent foramen ovale, mitral, triscupid and pulmonary valve insufficiency).", "ORPHA ID": 314689, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to TFRC deficiency", "Disease Definition": "A rare genetic combined T and B cell immunodeficiency characterized by life-threatening infections due to disrupted transferrin receptor 1 endocytosis, resulting in defective cellular iron transport and impaired T and B cell function. Patients present with early-onset chronic diarrhea, severe recurrent infections, and failure to thrive. Laboratory studies reveal hypo- or agammaglobulinemia, normal lymphocyte counts but decreased numbers of memory B cells, intermittent neutropenia and thrombocytopenia, and mild anemia (resistant to iron supplementation) with low mean corpuscular volume.", "ORPHA ID": 476113, "Summary": ""}
{"Disease Name": "Combined immunodeficiency due to ZAP70 deficiency", "Disease Definition": "A very rare, severe, genetic, combined immunodeficiency disorder characterized by lymphocytosis, decreased peripheral CD8+ T-cells, and presence of normal circulating CD4+ T-cells, leading to immune dysfunction.", "ORPHA ID": 911, "Summary": ""}
{"Disease Name": "Combined immunodeficiency with facio-oculo-skeletal anomalies", "Disease Definition": "A rare combined immunodeficiency disorder characterized by primary immunodeficiency manifesting with repeated bacterial, viral and fungal infections, in association with neurological manifestations (hypotonia, cerebellar ataxia, myoclonic seizures), developmental delay, optic atrophy, facial dysmorphism (high forehead, hypoplastic supraorbital ridges, palpebral edema, hypertelorism, flat nasal bridge, broad nasal root and tip, anteverted nares, thin lower lip overlapped by upper lip, square chin) and skeletal anomalies (short metacarpals/metatarsals with cone-shaped epiphyses, osteopenia).", "ORPHA ID": 221139, "Summary": ""}
{"Disease Name": "Combined immunodeficiency with granulomatosis", "Disease Definition": "A rare, genetic, non-severe combined immunodeficiency disease characterized by immunodeficiency (manifested by recurrent and/or severe bacterial and viral infections), destructive noninfectious granulomas involving skin, mucosa and internal organs, and various autoimmune manifestations (including cytopenias, vitiligo, psoriasis, myasthenia gravis, enteropathy). Immunophenotypically, T-cell and B-cell lymphopenia, hypogammaglobulinemia, abnormal specific antibody production and impaired T-cell function are observed.", "ORPHA ID": 157949, "Summary": ""}
{"Disease Name": "Combined immunodeficiency-enteropathy spectrum", "Disease Definition": "A rare genetic disease characterized by multiple intestinal atresia in association with combined immunodeficiency and inflammatory bowel disease. Clinical features include widespread atresia extending from the stomach to the rectum, homogenous calcifications in the abdominal cavity, hepatic cholestasis, cirrhosis, and chronic liver failure, hypoplastic thymus, and increased susceptibility to mainly bacteria and viruses. The immunological phenotype consists of profound generalized T-cell lymphopenia and milder natural killer cell and B-cell lymphopenia, as well as low serum levels of IgG, IgA, and IgM, with elevated serum IgE. The disease is mostly fatal in infancy or childhood.", "ORPHA ID": 436252, "Summary": ""}
{"Disease Name": "Combined malonic and methylmalonic acidemia", "Disease Definition": "A rare inborn error of metabolism characterized by elevation of malonic acid (MA) and methylmalonic acid (MMA) in body fluids, with higher levels of MMA than MA. CMAMMA presents in childhood with metabolic acidosis, developmental delay, dystonia and failure to thrive or in adulthood with seizures, memory loss and cognitive decline.", "ORPHA ID": 289504, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 11", "Disease Definition": "A rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by a highly variable phenotype which ranges from a fatal neonatal/infantile encephalomyopathy with lactic acidosis, hyporeflexia/areflexia, severe hypotonia and respiratory failure to less severe cases presenting with central hypotonia, global developmental delay, congenital sensorineural hearing loss, and renal disease. Additional, variably observed, clinical features include intellectual disability, seizures, and cardiomyopathy.", "ORPHA ID": 324535, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 13", "Disease Definition": "Combined oxidative phosphorylation defect type 13 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by normal early development followed by the sudden onset in infancy of poor feeding, dysphagia, truncal (followed by global) hypotonia, motor regression, abnormal movements (i.e. severe dystonia of limbs, choreoathetosis, facial dyskinesias) and reduced tendon reflexes. The disease course is severe but nonprogressive.", "ORPHA ID": 319514, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 14", "Disease Definition": "Combined oxidative phosphorylation defect type 14 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by neonatal or infancy-onset of seizures that are refractory to treatment, delayed or absent psychomotor development and lactic acidosis. Additional manifestations reported include poor feeding, failure to thrive, microcephaly, hypotonia, anemia and thrombocytopenia.", "ORPHA ID": 319519, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 15", "Disease Definition": "Combined oxidative phosphorylation defect type 15 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by onset in infancy or early childhood of muscular hypotonia, gait ataxia, mild bilateral pyramidal tract signs, developmental delay (affecting mostly speech and coordination) and subsequent intellectual disability. Short stature, obesity, microcephaly, strabismus, nystagmus, reduced visual acuity, lactic acidosis, and a brain neuropathology consistent with Leigh syndrome are also reported.", "ORPHA ID": 319524, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 17", "Disease Definition": "Combined oxidative phosphorylation defect type 17 is a rare, genetic, mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by infantile-onset of severe hypertrophic cardiomyopathy (that occasionally progresses to dilated cardiomyopathy) associated with failure to thrive, global development delay, muscular hypotonia, elevated serum lactate and complex I deficiency in skeletal muscle biopsy. Intellectual disability, pericardial effusion and a mild cardiac phenotype have been also reported.", "ORPHA ID": 369913, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 2", "Disease Definition": "Combined oxidative phosphorylation defect type 2 is a rare mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by severe intrauterine growth retardation, neonatal limb edema and redundant skin on the neck (hydrops), developmental brain defects (corpus callosum agenesis, ventriculomegaly), brachydactyly, dysmorphic facial features with low set ears, severe intractable neonatal lactic acidosis with lethargy, hypotonia, absent spontaneous movements and fatal outcome. Markedly decreased activity of complex I, II + III and IV in muscle and liver have been determined.", "ORPHA ID": 254920, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 20", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder characterized by variable combination of psychomotor delay, hypotonia, muscle weakness, seizures, microcephaly, cardiomyopathy and mild dysmorphic facial features. Variable types of structural brain anomalies have also been reported. Biochemical studies typically show decreased activity of mitochondrial complexes (mainly complex I).", "ORPHA ID": 420728, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 21", "Disease Definition": "Combined oxidative phosphorylation defect type 21 is a rare mitochondrial disease characterized by axial hypotonia with limb hypertonia, developmental delay, hyperlactatemia, central nervous system anomalies visible on magnetic resonance imaging (e.g. corpus callosum hypoplasia, lesions of the globus pallidus) and multiple deficiency of the mitochondrial respiratory chain complexes in muscle tissue, but not in fibroblasts or liver.", "ORPHA ID": 420733, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 23", "Disease Definition": "A rare mitochondrial disease characterized by early onset of hypertrophic cardiomyopathy and variable neurologic symptoms including global developmental delay, hypotonia, intellectual disability, visual impairment, and seizures. Lactic acidosis is present in all patients. Muscle biopsy usually shows decreased activity of mitochondrial complexes I and IV. Brain imaging may reveal variable abnormal signal intensities in the thalamus, basal ganglia, and/or brain stem.", "ORPHA ID": 444013, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 24", "Disease Definition": "Combined oxidative phosphorylation defect type 24 is a rare mitochondrial oxidative phosphorylation disorder characterized by variable phenotype, including developmental delay with psychomotor regression, intellectual disability, epilepsy, Leigh syndrome, non-syndromic hearing loss, visual impairment and severe myopathy. Decreased activity of mitochondrial respiratory complexes and lactic acidosis are common findings, and diffuse cerebral atrophy may be associated.", "ORPHA ID": 444458, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 25", "Disease Definition": "Combined oxidative phosphorylation defect type 25 is a rare mitochondrial oxidative phosphorylation disorder with decreased respiratory complex I and IV enzyme activities, characterized by hypotonia, global developmental delay, neonatal onset of progressive pectus carinatum without other skeletal abnormalities, poor growth, sensorineural hearing loss, dysmorphic features and brain abnormalities such as cerebral atrophy, quadriventricular dilatation and thin corpus callosum posteriorly.", "ORPHA ID": 447954, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 26", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder characterized by a highly variable phenotype which may present as exercise intolerance with prominent exertional dyspnea, progressive muscle weakness, spasticity, and neuropathy, but without cognitive impairment or cardiac involvement, or as global developmental delay, growth retardation, hypotonia, and spasticity. Hypertrophic cardiomyopathy, optic atrophy, seizures, and dysmorphic facial features have also been reported in the more severe phenotype. Serum lactate may be elevated, and muscle biopsy shows myopathic features and variably decreased activity of mitochondrial respiratory chain complexes.", "ORPHA ID": 477684, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 27", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder characterized by a variable clinical phenotype including infantile onset of epileptic encephalopathy, hypotonia, global developmental delay, failure to thrive, complex movement disorder, and liver involvement, as well as childhood onset of severe myoclonus epilepsy, cognitive decline, progressive hearing and visual impairment, and progressive tetraparesis. Serum lactate may be increased, and brain imaging shows variable atrophy and white matter abnormalities.", "ORPHA ID": 477774, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 29", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder characterized by microcephaly, global developmental delay, spastic-dystonic movement disorder, intractable seizures, optic atrophy, autonomic dysfunction, and peripheral neuropathy. Serum lactate is increased, and muscle biopsy shows decreased activity of mitochondrial respiratory complexes I and III. Brain imaging reveals progressive cerebellar atrophy and delayed myelination.", "ORPHA ID": 478029, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 30", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder characterized by neonatal onset of hypotonia, feeding difficulties, deafness, and early fatal respiratory failure. Cardiac and liver involvement has been reported. Serum lactate is increased, and metabolic studies show decreased activity of mitochondrial respiratory complexes I and IV in skeletal muscle.", "ORPHA ID": 478042, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 39", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder characterized by early onset of severe developmental delay (sometimes with regression of developmental milestones) and intellectual disability, poor or absent speech, and hypotonia. Other features include movement disorder, seizures, or microcephaly, among others. Brain imaging may show features of Leigh syndrome with signal abnormalities in the basal ganglia or mid brain, cerebellar atrophy, or thin corpus callosum.", "ORPHA ID": 565624, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 4", "Disease Definition": "Combined oxidative phosphorylation defect type 4 is a rare mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by a neonatal onset of severe metabolic acidosis and respiratory distress, persistent lactic acidosis with episodes of metabolic crises, developmental regression, microcephaly, abnormal gaze fixation and pursuit, axial hypotonia with limb spasticity and reduced spontaneous movements. Neuroimaging studies reveal polymicrogyria, white matter abnormalities and multiple cystic brain lesions, including basal ganglia, and cerebral atrophy. Decreased activity of complex I and IV have been determined in muscle biopsy.", "ORPHA ID": 254925, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 7", "Disease Definition": "Combined oxidative phosphorylation defect type 7 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by a variable phenotype that includes onset in infancy or early childhood of failure to thrive and psychomotor regression (after initial normal development), as well as ocular manifestations (such as ptosis, nystagmus, optic atrophy, ophthalmoplegia and reduced vision). Additional manifestations include bulbar paresis with facial weakness, hypotonia, difficulty chewing, dysphagia, mild dysarthria, ataxia, global muscle atrophy, and areflexia. It has a relatively slow disease progression with patients often living into the third decade of life.", "ORPHA ID": 254930, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 8", "Disease Definition": "Combined oxidative phosphorylation defect type 8 is a mitochondrial disease due to a defect in mitochondrial protein synthesis resulting in deficiency of respiratory chain complexes I, III and IV in the cardiac and skeletal muscle and brain characterized by severe hypertrophic cardiomyopathy, pulmonary hypoplasia, generalized muscle weakness and neurological involvement.", "ORPHA ID": 319504, "Summary": ""}
{"Disease Name": "Combined oxidative phosphorylation defect type 9", "Disease Definition": "Combined oxidative phosphorylation defect type 9 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by initially normal growth and development followed by the infantile-onset of failure to thrive, psychomotor delay, poor feeding, dyspnea, severe hypertrophic cardiomyopathy and hepatomegaly. Laboratory studies report increased plasma lactate and alanine, abnormal liver enzymes and decreased activity of mitochondrial respiratory chain complexes I, III, IV, and V.", "ORPHA ID": 319509, "Summary": ""}
{"Disease Name": "Combined pancreatic lipase-colipase deficiency", "Disease Definition": "Combined pancreatic lipase-colipase deficiency is a disorder of lipid absorption and transport characterized by steatorrhea with foul-smelling stools from birth, diminished serum carotene and vitamin E and a combined deficiency of the pancreatic enzymes lipase and colipase. Patients are otherwise healthy and develop normally with no apparent pancreatic disease. There have been no further descriptions in the literature since 1990.", "ORPHA ID": 309111, "Summary": ""}
{"Disease Name": "Combined pituitary hormone deficiencies, genetic forms", "Disease Definition": "Congenital hypopituitarism is characterized by multiple pituitary hormone deficiency, including somatotroph, thyrotroph, lactotroph, corticotroph or gonadotroph deficiencies. Congenital hypopituitarism is rare compared with the high incidence of hypopituitarism induced by pituitary adenomas, transsphenoidal surgery or radiotherapy.", "ORPHA ID": 95494, "Summary": ""}
{"Disease Name": "Combined pulmonary fibrosis-emphysema syndrome", "Disease Definition": "A rare interstitial lung disease characterized by the coexistence of emphysema and usual interstitial pneumonia, typically occurring in male smokers. Emphysema is usually encountered in the upper lobes, preceding fibrosis of the lower lobes. Patients present with severe dyspnea and markedly reduced diffusion capacity on functional testing, while spirometric values are relatively preserved. The syndrome is frequently complicated by pulmonary hypertension and acute lung injury.", "ORPHA ID": 300564, "Summary": ""}
{"Disease Name": "Commissural lip fistula", "Disease Definition": "A rare otorhinolaryngological malformation characterized by a unilateral or bilateral fistula located at the corner of the mouth, where the vermillion border of the upper lip meets that of the lower lip. The lesion is lined by labial mucosa. It is potentially susceptible to infection.", "ORPHA ID": 141061, "Summary": ""}
{"Disease Name": "Common arterial trunk", "Disease Definition": "Truncus arteriosus (TA) is a rare congenital cardiovascular anomaly characterized by a single arterial trunk arising from the heart by means of a single semilunar valve (i.e. truncal valve). Pulmonary arteries originate from the common arterial trunk distal to the coronary arteries and proximal to the first brachiocephalic branch of the aortic arch. TA typically overrides a large outlet ventricular septal defect (VSD). The intracardiac anatomy usually displays situs solitus and atrioventricular (AV) concordance.", "ORPHA ID": 3384, "Summary": "Epidemiology\nPrevalence ranges from 0.03 to 0.056 per 1,000 live births. In Europe, the average recorded prevalence is 1/10,000 births (including livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis). No striking difference in frequency is observed between the sexes, although most series contain more males than females.\nClinical description\nNeonates with TA present with clinical features of congestive heart failure depending on the extent of the increase in volume of pulmonary blood flow and the presence or absence of truncal valve insufficiency. Symptoms of failure manifest as falls in pulmonary resistance and increases in pulmonary overcirculation occur. Tachypnea, tachycardia, excessive sweating, poor feeding may be the first signs to appear.\nEtiology\nThe etiology of TA remains unknown. In experimental animal models, TA has been linked to abnormal development of cells from the neural crest that are normally located in the outflow region of the developing heart; this is also thought to be an important etiologic factor in some cases of human TA.\nAntenatal diagnosis\nPrenatal detection of truncus arteriosus by ultrasound is documented.\nManagement and treatment\nIn the last 10 to 15 years there have been clinically significant improvements in treatment with early repair. It is now recommended that TA is repaired in the neonatal period and morbidity and mortality are as low as 5% in selected series. Currently, surgical management consists of complete repair with closure of the VSD.\n\n                            Last update: \n                            March 2005\n\n\n                            - Expert reviewer(s): \n                            Dr Luigi BALLERINI"}
{"Disease Name": "Common cystic lymphatic malformation", "Disease Definition": "A group of rare lymphatic malformation disorders characterized by solitary or multifocal, benign, congenital malformation of the lymphatic vessels in the soft tissues, resulting in painless cystic lesions, which are predominantly found in the head and neck (but may affect any site), and which have varying clinical presentation depending on specific size and location of lesion. Categorization into macrocystic lympathic malformations, microcystic lymphatic malformations or mixed cystic lymphatic malformations is reported based on the size of the cyst(s) contained within the lesion. Functional deficits and compromise of vital functions (including breathing, feeding) may be observed.", "ORPHA ID": 458833, "Summary": ""}
{"Disease Name": "Common variable immunodeficiency", "Disease Definition": "Common variable immunodeficiency (CVID) comprises a heterogeneous group of diseases characterized by a significant hypogammaglobulinemia of unknown cause, failure to produce specific antibodies after immunizations and susceptibility to bacterial infections, predominantly caused by encapsulated bacteria.", "ORPHA ID": 1572, "Summary": "Epidemiology\nPrevalence is estimated at 1/25,000 among Caucasians and CVID affects men and women equally.\nClinical description\nWhile some patients are diagnosed with CVID in early childhood, the major peak of onset lies between the second and third decade of life, frequently with several years delay between onset and diagnosis. Over 98% of patients present with recurrent bronchitis, sinusitis, otitis and pneumonia, and chronic pulmonary damage is the major complication. About 25% of patients develop autoimmune phenomena; immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) are the most common (see these terms). Lymphoproliferative disorders such as generalized lymphadenopathy and/or splenomegaly are present in up to 40% of patients, and there is an increased risk of developing gastrointestinal and lymphoid malignancies, especially non-Hodgkin's lymphoma (see this term). Up to 57% of patients develop bronchiectasis. Patients with TACI-deficiency are more likely to be affected by lymphoproliferation and autoimmunity. There is considerable variation in the clinical presentation in patients with a similar genotype.\nEtiology\nCVID can be due to an intrinsic B cell defect (for example CD19-deficiency caused by mutations in CD19; 16p11.2), an intrinsic T cell defect (for example ICOS-deficiency caused by mutations in ICOS; 2q33), mutations in TNF receptors (such as TACI-deficiency or BAFFR-deficiency caused by mutations in TNFRSF13B and TNFRSF13C respectively; 17p11.2 and 22q13.1-q13.31) or without a known genetic defect. Other monogenic defects reported include MSH5, CD81 and CD20 deficiencies.\nDiagnostic methods\nDiagnosis should be suspected in patients with recurrent sinopulmonary infections exceeding an age-specific frequency, and is based on exclusion of other causes of hypogammaglobulinemia. Analyses of lymphocyte function, including analysis of specific antibody responses after vaccination, and immunophenotyping of T and B cells strengthen the diagnosis and indicate subgroups of CVID. Ultrasound and CT of the abdomen may be necessary to assess additional complications including enlarged abdominal lymph nodes, spleen and liver pathology or granulomas.\nDifferential diagnosis\nDifferential diagnosis include other causes of hypogammaglobulinemia including loss of gammaglobulins via the intestine or urine, hematological malignancies, viral infections or drug-induced loss of B-cell function.\nGenetic counseling\nMost cases are sporadic but about 20% are thought to be familial with either autosomal dominant (80%) or autosomal recessive (20%) inheritance. TACI-deficiency is estimated to occur in approximately 10% of cases; the other defects are very rare.\nManagement and treatment\nThere is no curative therapy. Treatment is based on immunoglobulin replacement therapy, using pooled human immunoglobulin, usually administered intravenously or subcutaneously. To reduce long-term pulmonary sequelae, targeted antibiotic treatment is necessary. Patients with bronchiectasis may benefit from lung physiotherapy. The frequently occurring cytopenias require monitoring, and specific treatment such as splenectomy may be indicated. Concurrent autoimmune disorders or malignant disease require specific treatment.\nPrognosis\nPatients with bacterial infections only have a better prognosis than patients with additional complications and can have nearly normal life expectancy, especially if diagnosis and treatment occurs soon after the onset of symptoms.\n\n                            Last update: \n                            June 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Karin ENGELHARDT  - Pr Bodo GRIMBACHER  -  P HERHOLZ"}
{"Disease Name": "Complement component 3 deficiency", "Disease Definition": "Complement component 3 deficiency is a rare, genetic, primary immunodeficiency characterized by susceptibility to infection (mainly by gram negative bacteria) due to extremely low C3 plasma levels. Patients typically present recurrent episodes of sinusitis, tonsillitis, and/or otitis, as well as upper and lower respiratory tract infections (including pneumonia) and skin infections, such as erythema multiforme. Autoimmune disease resembling systemic lupus erythematosus and mesangiocapillary or membranoproliferative glomerulonephritis may develop, resulting in renal failure.", "ORPHA ID": 280133, "Summary": ""}
{"Disease Name": "Complement hyperactivation-angiopathic thrombosis-protein-losing enteropathy syndrome", "Disease Definition": "A rare genetic disease characterized by CD55 deficiency with complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy with abdominal pain, diarrhea, vomiting, primary intestinal lymphangiectasia, hypoproteinemic edema, and malabsorption, leading to anemia and growth delay. Bowel inflammation and recurrent infections associated with hypogammaglobulinemia may also be observed.", "ORPHA ID": 566175, "Summary": ""}
{"Disease Name": "Complete androgen insensitivity syndrome", "Disease Definition": "Complete androgen insensitivity syndrome (CAIS) is a form of androgen insensitivity syndrome (AIS; see this term), a disorder of sex development (DSD), characterized by the presence of female external genitalia in a 46,XY individual with normal testis development but undescended testes and unresponsiveness to age-appropriate levels of androgens.", "ORPHA ID": 99429, "Summary": "Epidemiology\nThe estimated incidence is between 1/20,000 and 1/99,000 live male births.\nClinical description\nThe typical presentation is primary amenorrhea in an adolescent female. CAIS may also present in infancy or childhood with an inguinal hernia or labial swelling containing a testis. Breast development at puberty is normal, but pubic and axillary hair is absent or scanty. The external genitalia are normal female but internal female genitalia are absent. Adult patients are tall. Other presentations may be serendipitous from a mismatch in prenatal sexing (XY) and birth female phenotype, history of an inguinal hernia repair in an older sister, or development of a pelvic tumor in later adult life.\nEtiology\nThe condition is due to mutations in the androgen receptor (AR) gene which is located on the long arm of the X-chromosome (Xq11-12). The AR is a nuclear transcription factor comprising three functional domains. Mutations are distributed throughout the gene, predominantly in 5 of the 8 exons that code for the ligand binding domain. The CAIS phenotype is associated with an AR mutation that completely disrupts AR function; target cells do not respond to testosterone or dihydrostosterone (DHT). An AR mutation is found in more than 95% of patients with CAIS; 30% are de novo mutations.\nDiagnostic methods\nThe diagnosis is based on clinical and biochemical findings in a female with a 46,XY karyotype. The typical hormone profile is increased basal luteinizing hormone (LH) and testosterone levels in adults, and increased testosterone levels in infants following human chorionic gonadotropin (hCG) stimulation. Serum anti-Müllerian hormone (AMH) levels are normal or increased. Pelvic ultrasound or MRI reveal absent Müllerian structures (uterus, Fallopian tubes and upper vagina), due to the action of testicular anti-Müllerian hormone (AMH). Wolffian duct derivatives (vas deferens, epididymis, seminal vesicle) are absent due to androgen resistance. Mutation analysis of the AR gene confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include 17-beta-hydroxysteroid dehydrogenase deficiency, Leydig cell hypoplasia, XY complete gonadal dysgenesis (Swyer syndrome), 5-alpha-reductase type 2 deficiency and variants of congenital adrenal hyperplasia (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is seldom indicated.\nGenetic counseling\nhe condition is X-linked recessive. Affected families should be offered genetic counseling in order to be informed of the risk of recurrence and to identify other potential carriers in the family.\nManagement and treatment\nManagement includes removal of the testes, either after puberty when feminization is complete or before puberty, followed by estrogen replacement therapy at the age of puberty. Vaginal dilatation may be indicated to avoid dyspareunia. Adults require bone mineral density scans every five years. Psychological support is required for disclosure.\nPrognosis\nPrognosis for patients with CAIS is favorable if support and counseling are appropriate. Adults have normal female gender identity. Patients are infertile and have an increased risk of osteoporosis if hormone replacement is inadequate. The risk of carcinoma in situ (a pre-malignant disorder) and gonadoblastoma is less than 5%.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Ieuan HUGHES"}
{"Disease Name": "Complete atrioventricular septal defect", "Disease Definition": "A rare, congenital cardiac anomaly characterized by a common atrioventricular junction with a common AV valve, an interatrial communication just above the common AV valve (ostium primum defect), a posterior interventricular communication (inlet VSD), that results in shunting at both the atrial and ventricular level. Morphologically, the common atrioventricular valve has 4 or 5 leaflets including superior and inferior bridging leaflets with a single annulus.", "ORPHA ID": 1329, "Summary": "Epidemiology\nPrevalence at birth of complete atrioventricular septal defect (CAVSD) is suggested to be 1/5,000 in Europe. Both sexes are equally affected.\nClinical description\nInfants typically present within the first year of life with symptoms of congestive heart failure which may include feeding difficulties, excessive sweating, tachycardia, tachypnea, mild wheezing, failure to thrive, and poor peripheral blood perfusion. If untreated, affected individuals develop irreversible pulmonary hypertension which improves signs of congestive heart failure but worsens tolerance to effort and results in cyanosis and Eisenmenger syndrome. Recurrent pulmonary infections are common. Morphologically, the ventricles may be equal or nearly equal in size (balanced) or one of the ventricles may be significantly larger than the other (unbalanced). The balanced form is typically observed in Down syndrome. Unbalanced ventricles are associated with varying degrees of malalignment of the common atrioventricular valve over the hypoplastic ventricle and hypoplasia of the arterial valve above. Tetralogy of Fallot (TOF) is observed in 5-10% of CAVSD.\nEtiology\nCAVSD is strongly associated with Down syndrome and heterotaxy. Cilia gene mutations could be involved in isolated AVSD. A small fraction of CAVSD cases have been associated with NR2F2 (15q26.2), GATA4 (8p23.1), GATA6 (18q11.2) and CRELD1 (3p25.3) mutations.\nDiagnostic methods\nEchocardiography is used for postnatal diagnosis. Typical findings include a left and superior QRS axis in the frontal plane and counterclockwise depolarization. Chest X-ray may show ventricular enlargement and a greater anterior position of the left atrioventricular valve due to the inlet septal defect, which gives a ''goose neck'' appearance to le left ventricular outflow tract.\nDifferential diagnosis\nDifferential diagnosis includes other congenital cardiac anomalies that result in early heart failure including partial atrioventricular canal, atrial septal defects and large ventricular septal defects.\nAntenatal diagnosis\nCAVSD can be detected with fetal echocardiography; the detection rate is approximately 67%.\nGenetic counseling\nAtrioventricular septal defects (AVSD) can occur in the offspring of mothers with CAVSD.\nManagement and treatment\nDigoxin, diuretics and angiotensin-converting enzymes may be used to treat congestive heart failure prior to surgery. Surgical repair is advised at 3 months of age and is typically performed between 3 and 6 months of age. The three classical techniques are single patch technique, two patch technique (most frequent), and the modified single patch technique. To avoid surgically induced AV block, the position of the AV node and bundle of His must be considered, with the AV node positioned more posteriorly and inferiorly, the non-branching bundle running slightly on the left side of the septal crest with the branching bundle being exposed. Pulmonary artery banding can be proposed before 3 months in very ill patients despite optimal medical therapy. Combined repair of other cardiac anomalies is often performed with desirable results. In case of associated tetralogy of Fallot, complete repair is usually delayed up until 1 year of age. Lifelong follow-up every 2 to 3 years is recommended.\nPrognosis\nWithout surgery, many of the affected individuals will die in infancy. Prognosis after surgical repair is good; however, patients who weigh less the 3 kg or are less than 2.5 years old have a higher risk of mortality during surgery. Pregnancy increases the risk of developing left AVV regurgitation, arrhythmias, deterioration of heart failure, and is not recommended for women with severe pulmonary hypertension.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Lucile HOUYEL"}
{"Disease Name": "Complete hydatidiform mole", "Disease Definition": "A form of hydatiform mole characterized by abnormal hyperplastic trophoblasts and hydropic villi due to fertilization of an enucleated ovocyte by one or two haploid spermatozoa that can manifest with vaginal bleeding accompanied by nausea and frequent vomiting, hyperemesis gravidarum, risk of spontaneous miscarriage, hyperthyroidism, and has the potential of developing into choriocarcinoma.", "ORPHA ID": 254688, "Summary": ""}
{"Disease Name": "Complete septate uterus", "Disease Definition": "Complete septate uterus is a rare, non-syndromic uterovaginal malformation characterized by a uterus that has a longitudinal septum which elongates from the uterine fundus to the internal or external cervical os. Most often women are asymptomatic, however dysmenorrhea, unilateral obstruction, and endometriosis could be observed. Unlike urinary tract abnormalities, which are very rarely associated, poor reproductive outcome is frequent.", "ORPHA ID": 180126, "Summary": ""}
{"Disease Name": "Complex chromosomal rearrangement", "Disease Definition": "A group of rare chromosomal anomalies characterized by constitutional structural chromosomal rearrangements, including translocations, invertions, duplications and deletions, involving at least three breakpoints on two or more chromosomes. Individuals with such arrangements may display various phenotypes including cognitive impairment, congenital abnormalities and infertility, while some can also be phenotypically normal. Both de novo and familial forms are reported.", "ORPHA ID": 263708, "Summary": ""}
{"Disease Name": "Complex lethal osteochondrodysplasia", "Disease Definition": "A rare, genetic, primary bone dysplasia with decreased bone density characterized by fetal lethality, severe hypomineralization of the entire skeleton, barrel shaped thorax with short ribs, multiple intrauterine fractures of ribs and long bones, ascites, pleural effusion, and ventriculomegaly. Variable congenital developmental anomalies affecting the brain, lungs, and kidneys have also been associated.", "ORPHA ID": 457378, "Summary": ""}
{"Disease Name": "Complex regional pain syndrome type 1", "Disease Definition": "Complex regional pain syndrome type 1 (CRPS1) is a form of complex regional pain syndrome (see this term) in which the pain is disproportionate to any known inciting event and is characterized by continuous pain, allodynia, or hyperalgesia as well as edema, coloration (changes in skin blood flow), or abnormal sudomotor activity in the region of pain. Onset of CRPS1 symptoms may occur within a few days to a month after an injury or trauma to the affected limb.", "ORPHA ID": 99995, "Summary": ""}
{"Disease Name": "Complex regional pain syndrome type 2", "Disease Definition": "Complex regional pain syndrome type 2 (CRPS2), or causalgia is a form of complex regional pain syndrome that develops after damage to a peripheral nerve and is characterized by spontaneous pain, allodynia and hyperalgesia , not necessarily limited to the territory of the injured nerve, as well as at some point, edema, changes in skin blood flow or sudomotor dysfunction in the pain area.", "ORPHA ID": 99994, "Summary": ""}
{"Disease Name": "Complex regional pain syndrome", "Disease Definition": "Complex regional pain syndrome (CRPS) is a rare neurologic disease painful progressive condition that corresponds to a group of disorders characterized by a disproportionate spontaneous or stimulus-induced pain, accompanied by a variably mixed myriad of autonomic and motor disorders including symptoms such as swelling, allodynia, skin blood supply and trophic disturbances. CRPS most often affects one of the arms, legs, hands, or feet and usually occurs after an injury or trauma to that limb.", "ORPHA ID": 83452, "Summary": ""}
{"Disease Name": "Composite hemangioendothelioma", "Disease Definition": "A rare vascular tumor characterized by a poorly circumscribed, infiltrative nodular lesion with vascular differentiation, centered in the dermis and subcutis. The tumor is composed of histologically benign, intermediate, and malignant components. Typical is an admixture of different components which include epithelioid and retiform hemangioendothelioma, spindle cell hemangioma, angiosarcoma-like areas, and benign vascular lesions. Predilection sites are the distal extremities. Many patients have a history of lymphedema. Local recurrence is frequent, while metastasis is rare.", "ORPHA ID": 458758, "Summary": ""}
{"Disease Name": "Composite lymphoma", "Disease Definition": "A rare lymphoma characterized by the concurrent occurrence of two or more histologic types of lymphoma involving the same anatomic site. Composite lymphomas can be combinations of two non-Hodgkin lymphomas or of a non-Hodgkin and a Hodgkin lymphoma. In many cases, the tumors are clonally related. Clinical presentation and treatment are determined by the more aggressive component.", "ORPHA ID": 168966, "Summary": ""}
{"Disease Name": "Conductive deafness-malformed external ear syndrome", "Disease Definition": "A very rare, syndromic genetic deafness characterized by mild to moderate conductive hearing loss, dysmorphic pinnae and lip pits or dimples. The pinnae are usually small, cup-shaped, with helix folded forward, and hearing loss is associated with malformed ossicles and displacement of the external auditory canal.", "ORPHA ID": 3216, "Summary": ""}
{"Disease Name": "Conductive deafness-ptosis-skeletal anomalies syndrome", "Disease Definition": "Conductive deafness-ptosis-skeletal anomalies syndrome is a rare, genetic ectodermal dysplasia syndrome characterized by conductive hearing loss due to atresia of the external auditory canal and the middle ear complicated by chronic infection, ptosis and skeletal anomalies (internal rotation of hips, dislocation of the radial heads and fifth finger clinodactyly). In addition, a thin, pinched nose, delayed hair growth and dysplastic teeth are associated. There have been no further descriptions in the literature since 1978.", "ORPHA ID": 3236, "Summary": ""}
{"Disease Name": "Cone dystrophy with supernormal rod response", "Disease Definition": "Cone dystrophy with supernormal rod response (CDSRR) is an inherited retinopathy, with an onset in the first or second decade of life, characterized by poor visual acuity (due to central scotoma), photophobia, severe dyschromatopsia, and occasionally, nystagmus. Night blindness usually develops later in the course of the disease, but it can also be apparent from childhood. A hallmark of CDSRR is the decreased and delayed dark-adapted response to dim flashes in electroretinographic recordings, which contrasts with the supernormal b-wave response at the highest levels of stimulation.", "ORPHA ID": 209932, "Summary": ""}
{"Disease Name": "Cone rod dystrophy", "Disease Definition": "A rare genetic isolated inherited retinal disorder characterized by primary cone degeneration with significant secondary rod involvement, with a variable fundus appearance. Typical presentation includes decreased visual acuity, central scotoma, photophobia, color vision alteration, followed by night blindness and loss of peripheral visual field.", "ORPHA ID": 1872, "Summary": "Epidemiology\nThe prevalence is estimated at 1 in 40,000 in Europe.\nClinical description\nCone rod dystrophy (CRD) is characterized by primary cone involvement or, occasionally, by concomitant loss of both cones and rods, explaining the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The fundus appearance is varaible ranging from normal in the early stages, with only subtle temporal optic nerve pallor, macular pigment migration and atrophy or a bull's-eye maculopathy, to peripheral retinal pigment epithelium atrophy, intra retinal pigmentation migration, arteriolar attenuation, and optic disc pallor as disease progresses. Cone-rod dystrophy (CRD) should be distinguished from rod-cone dystrophy (RCD), also known as retinitis pigmentosa. Unlike RCD, which typically start with night blindness and progressive visual field constriction while central vision is preserved until late stages, CRD is characterized by a primary decrease in central vision leading to earlier legal blindness. At end stage, however, CRDs do not differ from end stage RCDs. CRDs are most frequently nonsyndromic, however they may also be part of several syndromes, such as Alström syndrome, Bardet-Biedl syndrome and Spinocerebellar Ataxia Type 7.\nEtiology\nNonsyndromic CRDs are genetically heterogeneous (28 genes have been identified). The four most commonly mutated genes are ABCA4 (1p22.1) responsible for 30 to 60% of autosomal recessive CRDs, CRX (19q13.33) and GUCY2D (17p13.1) responsible for many reported cases of autosomal dominant CRDs, and RPGR (Xp11.4) responsible for X-linked CRDs.\nDiagnostic methods\nThe diagnosis of CRD is based on clinical history, fundus examination, autofluorescence imaging, optical coherence tomography and full field electroretinogram. Molecular diagnosis can be made for some genes. Fundus examination can be normal at the early stages with only subtle temporal optic disc pallor or may show macular pigment migrations and atrophy or a bull's-eye maculopathy. Late stage findings include peripheral retinal pigment epithelium atrophy, intraretinal pigment migration, arteriolar attenuation, and optic disc pallor.\nDifferential diagnosis\nDifferential diagnosis includes other hereditary cone disorders (including achromatopsia and allied cone dysfunction syndromes, cone dystrophy and Stargardt disease) and the rod-cone dystrophy, also known asretinitis pigmentosa, which is distinguished by the sequence of photoreceptor involvement (rod photoreceptors followed by cone photoreceptors).\nGenetic counseling\nInheritance patterns depend on the gene involved and can be autosomal dominant, autosomal recessive or X-linked recessive. Genetic counseling is always advised.\nManagement and treatment\nCurrently, there is no therapy that stops evolution of the disease or that restores vision. Management aims at slowing down the degenerative process, treating the complications, visual rehabilitation and helping patients to cope with the social and psychological impact of blindness.\nPrognosis\nVisual prognosis is variable, with early central vision loss and progressive visual dysfunction leading to legal blindness before 40 years of age in most cases.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Isabelle AUDO"}
{"Disease Name": "Confetti-like macular atrophy", "Disease Definition": "A rare, acquired, dermis elastic tissue disorder with decreased elastic tissue characterized by multiple, asymptomatic, well demarcated, flat, hypopigmented atrophic macular skin lesions distributed over upper trunk and proximal upper limbs. Histopathological examination reveals atrophic epidermis with decreased basal pigmentation, perivascular mononuclear infiltration in the upper dermis, and disorganized, hyalinized, coarse collagen bundles, and variable loss of elastic fibers in the dermis.", "ORPHA ID": 221142, "Summary": ""}
{"Disease Name": "Congenital abducens nerve palsy", "Disease Definition": "A rare neuro-ophthalmological disease characterized by dysfunction of the ipsilateral lateral rectus muscle with esotropia in primary position, limited or no abduction of the eyeball, and compensatory horizontal face turn toward the palsied eye. The condition commonly resolves spontaneously.", "ORPHA ID": 440233, "Summary": ""}
{"Disease Name": "Congenital achiasma", "Disease Definition": "Congenital achiasma is a rare, genetic, non-syndromic cranial nerve and nuclear aplasia malformation characterized by the congenital absence of the optic chiasm, resulting from the failure of the optic nerve fibers to cross over and decussate to the contralateral hemisphere, leading to decreased vision, strabismus and congenital nystagmus in infancy.", "ORPHA ID": 324353, "Summary": ""}
{"Disease Name": "Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency", "Disease Definition": "A rare form of classic congenital adrenal hyperplasia (CAH) characterized by glucocorticoid deficiency, hyperandrogenism, hypertension and virilization in females.", "ORPHA ID": 90795, "Summary": "Epidemiology\nIt accounts for approximately 5-8% of CAH cases and has an annual incidence of 1/100,000-200,000 live births.\nClinical description\nSevere virilization is seen in the external genitalia of girls while boys appear normal at birth. If the disorder is not recognized during the neonatal period, both girls and boys undergo rapid postnatal growth with accelerated growth velocity and accelerated skeletal maturation, hypertension, premature adrenarche and precocious puberty leading to reduced adult height. There is also a life-long risk for acute adrenal insufficiency.\nEtiology\nThe disease is caused by a mutation in the CYP11B1 gene that is located on chromosome 8 q21. Steroid 11-beta-hydroxylase deficiency causes decreased cortisol secretion and hypertension due to accumulation of glucocorticoid (GC) and mineralocorticoid precursors.\nDiagnostic methods\nDiagnosis of girls with classic CAH due to 11-beta-hydroxylase deficiency (11beta-OHD) is usually at birth when virilization of external genitalia is present. Signs of adrenal insufficiency present in both sexes during the second week of life. However, salt wasting is very uncommon, which may delay the time of diagnosis compared with CAH due to 21-hydroxylase deficiency (21-OHD), because of continued mineralocorticoid receptor stimulation due to elevated desoxycorticosterone (DOC) secretion. Serum levels of 11-desoxycortisol, DOC, androstenedione, 17-OH pregnenolone and ACTH are elevated. 17-OH progesterone may be slightly elevated. Simultaneous measurement of these steroids by liquid chromatography with tandem mass spectrometry (LC-MS/MS) is the most convenient method for diagnosis of 11beta-OHD. CAH can be diagnosed prenatally by genotyping through chorionic villus sampling to obtain fetal DNA as early as gestational week 10-12 in families with known CYP11B1 pathogenic genotypes. Methods involving invasive sampling should only be performed if the results will lead to changes in approach or treatment. National systematic screening programs may diagnose cases of 11beta-OHD CAH at birth due to slightly elevated 17-OH progesterone.\nDifferential diagnosis\nDifferential diagnosis is CAH due to 21-OHD. 17-OH progesterone may be elevated in the newborn, leading to misdiagnosis of 21-OHD.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member or in case of genital abnormalties diagnosed antenatally in girls.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nPrenatal treatment with dexamethasone can be administered to female fetuses at risk of developing classic CAH, but this procedure is still controversial due to potential side effects. When administered before the 9th week of gestation, it prevents the excessive androgen production responsible for genital virilization in females. If diagnosed after birth, vaginoplasty surgery is usually performed on girls, but the timing of the surgery is still debated. Lifelong GC replacement therapy is needed to treat adrenal insufficiency and to decrease elevated androgen hormone levels in order to allow for normal growth and puberty, and normal health without hypertension. Hydrocortisone is usually given to children as GC replacement therapy (10-15mg/m2/day divided into 2 or 3 doses). Dosage is monitored and should be increased during times of stress or intercurrent disease. There is a risk of developing acute adrenal insufficiency (see this term), hypertension and other complications due to chronic hyperandrogenemia in case of poorly controlled disease. Excessive treatment with GC causes cushingoid features and metabolic and cardiovascular disturbances. In all cases, excess mineralocorticoid causes hypertension. Regular follow-up by a multidisciplinary team, including pediatric endocrinologists, surgeons, gynecologists, and psychologists, is important.\nPrognosis\nLife expectancy may be reduced as patients with CAH have a risk of acute adrenal insufficiency, hypertension and higher metabolic and cardiovascular risk. Poor disease control may increase the risk of acute adrenal insufficiency, hypertension, metabolic and cardiovascular morbidities, testicular adrenal rest tumors (TARTs), menstrual irregularity and subfertility.\n\n                            Last update: \n                            February 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Juliane LEGER | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency", "Disease Definition": "A rare form of congenital adrenal hyperplasia due to 17-alpha-hydroxylase (CYP17A1) deficiency and characterized by glucocorticoid deficiency, mineralocorticoid excess leading to hypokalemic hypertension and sex steroid deficiency (hypergonadotrophic hypogonadism). Undervirilization and even female phenotype in 46,XY males, primary amenorrhea in females and lack of pubertal development in both sexes is common. Residual CYP17A1 activity is associated with the severity of this condition with a large spectrum of variability, from presenting in early infancy, to unusually mild courses with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients.", "ORPHA ID": 90793, "Summary": ""}
{"Disease Name": "Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency", "Disease Definition": "A rare form of congenital adrenal hyperplasia (CAH) due to 3-beta-hydroxysteroid dehydrogenase (HSD3B2) deficiency and characterized by salt-wasting and non-salt wasting CAH with a wide variety of symptoms, including glucocorticoid and mineralocorticoid deficiencies in both sexes. Salt wasting can lead to dehydration and hypotension in the first few weeks of life. Affected males had undervirilization manifesting as a micropenis to severe perineoscrotal hypospadias. Females show normal or mildly virilized external genitalia (mild clitoromegaly, labial fusion) due to dehydroepiandrosterone (DHEA) accumulation and conversion to androgens by the normal HSD3B1.", "ORPHA ID": 90791, "Summary": ""}
{"Disease Name": "Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency", "Disease Definition": "A rare form of congenital adrenal hyperplasia due to P450 oxidoreductase deficiency and characterized by glucocorticoid deficiency, virilization of external genitalia in females, and undervirilization in males. Findings range from severely affected infants with 46,XX and 46,XY disorders/differences of sex development (DSD) and cortisol deficiency to mildly affected women who appear to have polycystic ovary syndrome, or mildly affected men with gonadal insufficiency.", "ORPHA ID": 95699, "Summary": ""}
{"Disease Name": "Congenital adrenal hyperplasia", "Disease Definition": "A group of rare inherited endocrine disorders caused by a steroidogenic enzyme deficiency and characterized by adrenal insufficiency and variable degrees of hyper- or hypoandrogenism manifestations, depending on disease type and severity.", "ORPHA ID": 418, "Summary": "Epidemiology\nThe estimated prevalence is 1/10,000. Annual incidence ranges from 1/5,000 to 1/15,000.\nClinical description\nThe most frequent form of congenital adrenal hyperplasia (CAH) is classical CAH due to 21-hydroxylase deficiency which can further be divided into simple virilizing, salt wasting or non-classical (N) types. Girls present at birth with variable levels of virilization of external genitalia with variable degrees of clitoral enlargement and labial fusion. They have a normal uterus but abnormal vaginal development. The genital appearance of affected 46,XX infants is occasionally indistinguishable from that of male genitals but empty of gonads. Gonadal development is normal with ovarian function potentially normal. The external genitalia in boys are normal. Salt wasting forms of CAH lead to symptoms of dehydration, hypoglycemia and hypotension in the first few weeks of life and can be life threatening. Premature pubarche can be seen in children as well as accelerated growth velocity, accelerated skeletal maturation and precocious puberty (leading to reduced adult height). NCAH is often not diagnosed until adolescence when the first symptoms appear. Manifestations seen in females are hirsutism, acne, anovulation and menstrual irregularities. Males (and some females) are asymptomatic. Hirsutism continues in adulthood and women can suffer from chronic anovulation, fertility problems, and metabolic and cardiovascular disturbances. Other rare forms can present with arterial hypertension, craniofacial malformations and atypical external genitalia in both sexes.\nEtiology\nIn 90-95% of cases, CAH is caused by a mutation in the CYP21A2 gene located on chromosome 6p21.3 which encodes for an enzyme that controls cortisol and aldosterone production. Other genes are less frequently involved and result in the following variants of CAH: CAH due to 17-alpha-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency, 11-beta-hydroxylase deficiency, cytochrome P450 oxidoreductase deficiency and congenital lipoid adrenal hyperplasia.\nDiagnostic methods\nDiagnosis of girls with classical CAH is usually at birth when atypical genitalia are present. Babies can be screened for CAH in order to identify those with the classical forms by measuring 17-hydroxy-progesterone (17-OHP) levels. Genetic screening also confirms a diagnosis of CAH by identifying those with a CAH related gene mutation. In most European countries there are newborn screening programs in place to diagnose CAH at birth.\nDifferential diagnosis\nIn adult females a tumor of the ovaries or adrenal glands can mimic the clinical manifestations of CAH with virilization. Polycystic ovarian syndrome is another differential diagnosis.\nAntenatal diagnosis\nAntenatal diagnosis in families with known pathogenic genotypes is possible by screening for a disease-causing gene by amniocentesis or chorionic villus sampling. Noninvasive prenatal diagnosis has been accomplished by analysis of circulating free fetal DNA in maternal blood in proof-of-concept studies.\nGenetic counseling\nThe disorder is autosomal recessive and genetic counseling can be offered to parents with CAH.\nManagement and treatment\nLifelong hormone replacement therapy is needed to treat adrenal insufficiency and decrease elevated androgen levels, to allow for normal growth and puberty in children. Hydrocortisone regulates menstrual cycles and promotes fertility in adult females. Hydrocortisone is usually given to children as glucocorticoid replacement therapy (dosage is monitored and should be increased during times of stress or intercurrent disease) and 9 alpha-fludrocortisone acetate for mineralocorticoid replacement. Genital reconstructive surgery in affected females is no longer considered as an emergency procedure and the ideal timing remains to be determined. Psychological support is often needed. Methods of hair removal treat hirsutism. Menstrual cycles can sometimes be regulated with oral contraceptives. Dexamethasone can be given to pregnant women at risk of having offspring with the mutation (when fetus is female) in order to prevent virilization in girls. This treatment is still controversial due to potential adverse effects.\nPrognosis\nWith proper treatment patients may have a normal life expectancy. However, uncontrolled CAH may be associated with life-threatening acute adrenal insufficiency and a higher risk for comorbidities (metabolic, cardiovascular, subfertility).\n\n                            Last update: \n                            February 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Juliane LEGER | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital agenesis of the scrotum", "Disease Definition": "A rare urogenital tract malformation characterized by the complete absence of the scrotal rugae in the perineum between the penis and anus, with bilateral testes being present in a cryptorchid or ectopic position. Hemiscrotal agenesis refers to the unilateral absence of scrotal skin with an intact midline raphe and ipsilateral cryptorchidism. Both malformations may be isolated findings, or occur in association with other anomalies.", "ORPHA ID": 495879, "Summary": ""}
{"Disease Name": "Congenital alpha2-antiplasmin deficiency", "Disease Definition": "A rare hemorrhagic disorder caused by congenital deficiency of alpha2 antiplasmin, leading to dysregulated fibrinolysis and is characterized by a hemorrhagic tendency presenting from childhood with prolonged bleeding and ecchymoses following minor trauma and spontaneous bleeding episodes (often in unusual locations like diaphysis of long bones).", "ORPHA ID": 79, "Summary": ""}
{"Disease Name": "Congenital alveolar capillary dysplasia", "Disease Definition": "Congenital alveolar capillary dysplasia (ACD) is a rare and fatal developmental lung disease characterized by respiratory distress in neonates due to refractory hypoxemia and severe pulmonary arterial hypertension.", "ORPHA ID": 210122, "Summary": ""}
{"Disease Name": "Congenital amegakaryocytic thrombocytopenia", "Disease Definition": "An isolated constitutional thrombocytopenia characterized by an isolated and severe decrease in the number of platelets and megakaryocytes during the first years of life that develops into bone marrow failure with pancytopenia later in childhood.", "ORPHA ID": 3319, "Summary": "Epidemiology\nCongenital amegakaryocytic thrombocytopenia (CAMT) prevalence is unknown and less than 100 cases have been reported in the literature. In addition, the incidence may be underestimated due to difficult and inconsistent diagnosis of the disease.\nClinical description\nCAMT manifests since birth, often in the first day or at least within the first month of life, with petechiae, purpura, and gastrointestinal, pulmonary or intracranial hemorrhage due to isolated thrombocytopenia and a near absence of megakaryocytes in the bone marrow. Two types of CAMT have been identified. Type I-CAMT is the severe form of the disease and is characterized by persistently low platelet counts and early progression (usually by the age of 2 years) to bone marrow aplasia associated with pancytopenia. Type II-CAMT is a milder form which presents with transient increase of platelet counts over 50x109/L during the first year of life and late (by the age of 3-6 years) or no development of pancytopenia. Cardiac defects (atrial and ventricular septal defects), abnormalities of the central nervous system (cerebral and cerebellar hypoplasia), and retardation of psychomotor development have occasionally been reported.\nEtiology\nCAMT is due to mutations in the MPL gene (1p34) coding for Thrombopoietin (TPO) receptor (c-MPL), expressed in pluripotent hematopoietic stem cells and cells of the megakaryocyte lineage. The binding of TPO to c-MPL stimulates platelet and megakaryocyte production. Different types of mutations have been associated with different phenotypes. Nonsense mutations predicted to result in a complete loss of function of the TPO receptor lead to type I-CAMT, whereas missense mutations predicted to lead to a residual function of the receptor are associated with type II-CAMT. Cases with no defects in the MPL gene are referred to as type III-CAMT. Recently, a 21q22 deletion resulting in RUNX1 haploinsufficiency has been reported in a case of CAMT associated with various anomalies (growth retardation, hearing deficits, hernias, poor feeding).\nDiagnostic methods\nDiagnosis is based on clinical signs, on the evidence by blood tests of thrombocytopenia (platelet count below 50x109/L) with a normal mean platelet volume and of highly elevated serum levels of TPO, and on the observation in a bone marrow aspirate of absent or very few megakaryocytes. Genetic testing can confirm the diagnosis.\nDifferential diagnosis\nThe initial presentation of CAMT with isolated thrombocytopenia can be misdiagnosed as idiopathic thrombocytopenic purpura (ITP), while the late pancytopenic phase is indistinguishable from aplastic anemia. Fanconi anemia, thrombocytopenia-absent radius (TAR), syndrome and Wiscott-Aldrich syndrome (WAS) should be also ruled out.\nAntenatal diagnosis\nPrenatal diagnosis is possible for families in which the disease-causing mutation has been identified.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement is supportive, mainly consisting of multiple platelet transfusions. At present, hematopoietic stem cell transplantation (HSCT) is the only curative therapy.\nPrognosis\nPrognosis is poor and with supportive therapy, progression to full marrow failure (tri-linear marrow aplasia) occurs during the first years of life. 30% of patients with CAMT die due to bleeding complications before the HSCT and 20% due to the HSCT.\n\n                            Last update: \n                            July 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Joan Lluís VIVES-CORRONS"}
{"Disease Name": "Congenital amyoplasia", "Disease Definition": "A rare sporadic arthrogryposis syndrome characterized by multiple congenital contractures presenting in a very specific pattern. It is typically symmetric, involving all four limbs, with internally rotated shoulders, fully extended and fixed elbows, the wrists fixed in flexion, partially flexed fingers, hips fixed in flexion or extension, adducted or abducted, and sometimes dislocated. The knees may be fixed in extension or flexion, and the feet are usually in severe equinovarus position. The jaw and trunk are relatively spared. Normal limb muscle tissue is replaced by fatty, fibrous tissue.", "ORPHA ID": 488586, "Summary": ""}
{"Disease Name": "Congenital analbuminemia", "Disease Definition": "Congenital analbuminemia (CAA) is characterized by the absence or dramatic reduction of circulating human serum albumin (HSA).", "ORPHA ID": 86816, "Summary": "Epidemiology\nPrevalence has been estimated at approximately 1 case per million population, with less than 50 cases being reported in the literature so far. The disorder occurs with no geographic, sex or ethnic predilection.\nClinical description\nIn the majority of cases, CAA is diagnosed in adulthood. Although albumin is the most abundant plasma protein and has many functions, patients with CAA present with only a few mild clinical signs and biochemical abnormalities: fatigue, low blood pressure, edema, increased concentration of several plasma proteins and a prolonged albumin half-life. HSA is either absent or present at very low levels (<1 g/L) but liver function is normal and there is an absence of conditions leading to significant protein loss. The mildness of the clinical manifestations is attributed to the compensatory increase in hepatic biosynthesis of other plasma proteins, notably a compensatory increase in serum globulin concentrations. However, CAA patients may develop lipodystrophy and hypercholesterolemia, possibly leading to premature atherosclerosis and cardiovascular events. Rarely, CAA may be complicated by hypercoagulability, osteoporosis and respiratory tract infections. The disorder appears to be more severe in the fetus or during early infancy, as intrauterine growth retardation and intrauterine death have been reported.\nEtiology\nThe disorder is caused by homozygous or compound heterozygous mutations in the gene coding for HSA (ALB; 4q13.3). More than ten different causative mutations have been identified to date. The Kayseri mutation (a homozygous AT deletion at nucleotides c.228-229, the 91st and 92nd bases of exon 3) appears to be the most common cause of analbuminemia in humans.\nDiagnostic methods\nDiagnosis is based on laboratory analysis of blood specimens (albumin immunoassays and serum protein electrophoresis). DNA analysis is required for identification of the mutation involved.\nDifferential diagnosis\nThe differential diagnosis should include a wide number of pathological conditions that present with reduction of HSA (glomerulonephritis, nephrosis, ascites, systemic lupus erythematosus, intestinal lymphangiectasia, and protein-losing enteropathies; see these terms).\nGenetic counseling\nCAA is transmitted as an autosomal recessive trait and consanguinity has been shown in all reported cases with available genealogic data.\nManagement and treatment\nCAA is a relatively benign and tolerable condition. Management aims at prophylaxis and treatment of the possible cardiovascular complications related to hypercholesterolemia and atherosclerosis. Drugs that bind to the albumin plasma protein fraction should be used with caution in patients with CAA.\n\n                            Last update: \n                            November 2008"}
{"Disease Name": "Congenital anomaly of the tricuspid valve chordae", "Disease Definition": "A rare, congenital anomaly of the tricuspid subvalvular apparatus characterized by aberrant tendinous chords, which insert at the clear zone of the leaflet instead of its free edge and connect to the endocardium instead of the papillary muscles. Resulting tethering of one or more tricuspid leaflets leads to their impaired mobility and tricuspid regurgitation. Association with other congenital cardiac anomalies has been reported.", "ORPHA ID": 99055, "Summary": ""}
{"Disease Name": "Congenital aortic valve stenosis", "Disease Definition": "A rare aortic malformation of variable severity and clinical presentation. Clinical presentations range from a neonatal severe presentation often associated with sudden cardiac death, to a slowly progressive stenosis that presents later with cardiac murmur, chest pain, dizziness, and loss of consciousness with exercise-induced exacerbations. Echocardiography reveals atresia or dysplasia of the aortic valve most commonly associated with a bicuspid morphology, restricted left ventricular outflow, and left ventricular hypertrophy.", "ORPHA ID": 3093, "Summary": ""}
{"Disease Name": "Congenital aortopulmonary window", "Disease Definition": "A rare congenital non-syndromic heart malformation characterized by a communication between the ascending aorta and the pulmonary trunk in the presence of two normally formed semilunar valves. It may be an isolated finding or occur in association with other anomalies. Severe clinical manifestations, such as congestive heart failure or pulmonary hypertension, typically develop in early life.", "ORPHA ID": 2037, "Summary": ""}
{"Disease Name": "Congenital arteriovenous fistula", "Disease Definition": "A rare simple vascular malformation characterized by a congenital abnormal connection between an artery and a vein, appearing as varicose veins with port wine discoloration, leading to a bypass of the capillary bed. Signs and symptoms include palpable continuous thrill in the dilated vessels, continuous machinery murmur with systolic accentuation, collapsing arterial pulse, Nicoladoni Branham sign, as well as local gigantism and hot ulcers due to hypoxia, among others.", "ORPHA ID": 98731, "Summary": ""}
{"Disease Name": "Congenital atransferrinemia", "Disease Definition": "Congenital atransferrinemia is a very rare hematologic disease caused by a transferrin (TF) deficiency and characterized by microcytic, hypochromic anemia (manifesting with pallor, fatigue and growth retardation) and iron overload, and that can be fatal if left untreated.", "ORPHA ID": 1195, "Summary": "Epidemiology\nThe prevalence is unknown. To date, there have been 16 reported cases from 14 families.\nClinical description\nDisease onset usually occurs in infancy or early childhood. Only one reported patient was diagnosed at the age of 20. The presenting manifestations are those of anemia such as fatigue, anorexia, irritability, tachycardia, systolic murmur and pallor. Growth retardation, hepatomegaly and recurrent infections are other frequent manifestations of the disease. In undiagnosed individuals, iron overload can lead to liver cirrhosis, heart failure and arthropathy. Hypothyroidism and splenomegaly have also been reported separately in two isolated cases. Death can occur due to congestive heart failure or pneumonia.\nEtiology\nCongenital atransferrinemia is due to mutations in the TF gene (3q21) encoding TF, a blood protein necessary for the proper transport of iron to the liver, spleen, and bone marrow. Without the synthesis of TF, there is a reduction of iron delivery to developing erythroid precursors in bone marrow, which results in reduced hemoglobin synthesis and consequently to anemia and iron storage in peripheral tissues (secondary hemochromatosis).\nDiagnostic methods\nDiagnosis is based on laboratory testing indicating anemia as well as a serum TF level of less than 35mg/dl. An enlarged liver, due to hemosiderosis may be noted on clinical examination in some cases. Molecular genetic testing can identify a mutation in the TF gene, confirming the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other conditions that manifest with hypotransferrinemia such as GRACILE syndrome and nephrotic syndromes (see these terms) and, in adults, those suffering from chronic alcoholism.\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.\nGenetic counseling\nCongenital atransferrinemia is inherited in an autosomal recessive manner and genetic counseling is available.\nManagement and treatment\nThere is no cure for congenital atransferrinemia. Treatment usually involves monthly phlebotomies followed by infusions of whole plasma or purified apotransferrin which remove excess iron and replenish TF levels, allowing for the proper formation of hemoglobin. Treatment is life-long and regular follow-up is recommended.\nPrognosis\nWith proper treatment the prognosis is good but due to the small number of patients, long-term complications remain unknown. .\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Mayka SÁNCHEZ FERNÁNDEZ"}
{"Disease Name": "Congenital autosomal recessive small-platelet thrombocytopenia", "Disease Definition": "A rare isolated constitutional thrombocytopenia characterized by neonatal onset of small-platelet thrombocytopenia with significantly increased bleeding tendency. Bleeding symptoms include petechial rash, mucosal bleeding, and heavy menstrual bleeding. Growth and development are normal, and there is no increased susceptibility to infections.", "ORPHA ID": 566192, "Summary": ""}
{"Disease Name": "Congenital axonal neuropathy with encephalopathy", "Disease Definition": "A rare, congenital, autosomal recessive axonal hereditary motor and sensory neuropathy disease characterized by axonal neuropathy, manifesting at birth or shortly thereafter with generalized muscular hypotonia, prominently distal muscular weakness, respiratory/swallowing difficulties and diffuse areflexia, associated with central nervous system involvement, which includes progressive microcephaly, seizures, and global developmental delay. Additional variable manifestations include hearing impairment, ocular lesions, skeletal anomalies (e.g. talipes equinovarus, overriding toes, scoliosis, joint contractures), cryptorchidism, and dysmorphic features (such as coarse facies, hypertelorism, high-arched palate). Outcome is typically poor due to respiratory insufficiency and/or aspiration pneumonia.", "ORPHA ID": 538101, "Summary": ""}
{"Disease Name": "Congenital bilateral absence of vas deferens", "Disease Definition": "A rare non-syndromic urogenital tract malformation characterized by improper development of the vas deferens leading to male infertility.", "ORPHA ID": 48, "Summary": "Epidemiology\nCongenital bilateral absence of vas deferens (CBAVD) affects about 1/1,000 males. It is found in 98% of males with cystic fibrosis and accounts for 6-8% of cases of obstructive azoospermia. In about 50% of cases, the CBAVD is associated with the absence of the seminal vesicles. Unilateral renal agenesis is detected in 5-10% of patients with CBAVD, while is present in 5-40% of congenital unilateral absence of vase deferens (ipsilateral).\nClinical description\nCBAVD is usually diagnosed in adult men, either during systematic assessment of cystic fibrosis (CF) or during assessment of isolated infertility (azoospermia). Infertile patients with CBAVD produce small volumes of acidic sperm (< 1 ml with a pH < 7.0). The latter is non-pathognomonic and more common when the seminal vesicles are also absent. CBAVD frequently coexists with kidney anomalies and other comorbidities.\nEtiology\nIn 1990, mutations in the CFTR gene (the causative gene for cystic fibrosis) were identified in 42% of patients in a population of infertile males with CBAVD, suggesting that CBAVD is a genital form of cystic fibrosis. Since then, an exhaustive analysis of the 27 exons of the CFTR gene has led to the classification of CBAVD patients into four groups: I) patients with two mutations in the CFTR gene (19%), II) patients with one mutation in the CFTR gene and having the IVS8-5T allele in the trans position (33%), III) patients with either a mutation in the CFTR gene or having the IVS8-5T allele (27%) and IV) patients with neither the IVS8-5T allele nor a mutation in the CFTR gene (21%).\nDiagnostic methods\nThe diagnosis of CBAVD is clinical. Traditionally, it was based on the absence of the intrascrotal portion of the vas deferens on palpation. The gold standard for diagnosis is scrotal and transrectal ultrasound, which also allows evaluation of the absence of the seminal vesicles. Abdominal ultrasound should be added to rule out a unilateral renal agenesis. Sperm analysis typically shows azoospermia, hypospermia (<1 ml) and acid pH (<7.0). Genetic testing can confirm the mutation in the CFTR gene.\nDifferential diagnosis\nThe differential diagnosis includes other causes of azoospermia and obstruction of the seminal tract (e.g. injuries, infections, cysts, etc.).\nGenetic counseling\nCBAVD patients with CFTR mutations should be informed of the increased risk to develop related diseases and transmit CF to their child. The risk is higher in patient without a solitary kidney. If an affected couple (the male partner is a carrier for a severe CFTR mutation) wishes to have a child with assisted reproductive technology (ART; i.e. surgical sperm retrieval and in vitro fertilization techniques), both partners should be offered genetic testing. If the female partner is not a carrier of one of the CFTR mutations, the risks of having a child affected by CF is <1/1000 (2.5 times higher than in the general population). If a mutation is detected in both partners, the risk of having a child with CF is 25%, and 50% if the mutation is on both alleles in one parent.\nManagement and treatment\nThe diagnosis of CBAVD often has implications that go beyond the problem of infertility because of its potential association with renal anomalies and other clinical conditions related to CFTR mutations. Some patients with a CFTR mutation may later present mild CF symptoms such as recurrent respiratory tract infections and could benefit from referral to a pneumologist or CF center for management and follow-up. In the case of solitary kidney, the patient should be followed a nephrologist.\nPrognosis\nCBAVD has no impact on life expectancy. Nevertheless, associated conditions (namely CF or other CFTR-related conditions) can potentially affect quality of life. If a solitary kidney is present, but renal function otherwise normal, quality of life is usually not impacted.\n\n                            Last update: \n                            June 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Marco CASTAGNETTI  - Dr Giovanni MOSIELLO | EUROGEN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital bile acid synthesis defect type 1", "Disease Definition": "Congenital bile acid synthesis defect type 1 (BAS defect type 1) is the most common anomaly of bile acid synthesis (see this term) characterized by variable manifestations of progressive cholestatic liver disease, and fat malabsorption.", "ORPHA ID": 79301, "Summary": "Epidemiology\nPrevalence is unknown but may be around 1-9/1,000,000 for overall BAS defects, excluding cerebrotendinous xanthomatosis.\nClinical description\nThe clinical presentation is heterogeneous, however most patients present with features of neonatal cholestasis. Clinical features include hepatomegaly with or without splenomegaly, jaundice, fat and fat-soluble vitamin malabsorption, and mild steatorrhea. In most cases, pruritus is absent. Liver function tests present elevated serum transaminases (AST, ALT), conjugated hyperbilirubinemia, and normal gamma-GT. The liver histology shows inflammation, giant cells, evidence of cholestasis, and variable degrees of liver fibrosis. The clinical course of early-onset disease is heterogeneous with some patients resolving jaundice and being identified later in life, or with more fulminant disease that results in death or requires liver transplantation at an early age. The disorder may also present as late-onset chronic cholestasis. In such patients, liver disease is not always evident and patients may have fat-soluble vitamin malabsorption with rickets, corrected by vitamin supplementation, and/or other complications including bleeding diathesis (hematochezia or intracranial bleeding), neuroaxonal dystrophy and night blindness. Serum liver enzymes are initially often normal but later show increases with progression of liver disease to fibrosis. Children and adolescents may also present with extensive fibrosis and/or cirrhosis.\nEtiology\nThe disease is caused by a mutation in the gene encoding 3-beta-hydroxy-delta-5-C27 steroid oxidoreductase (HSD3B7, 16p12-p11.2). Transmission is autosomal recessive.\nDiagnostic methods\nDiagnosis is based on detection of sulfate and glycosulfate conjugates of 3-beta-hydroxy-delta-5 bile acids, which are the signature metabolites of this bile acid defect, on liquid secondary ionization mass spectrometry (LSIMS) analysis of urine. Gas chromatography - mass spectrometry (GC-MS) or electroscopy and tandem mass spectrometry may also be used.\nDifferential diagnosis\nDifferential diagnoses include progressive familial intrahepatic cholestasis, diseases that present with neonatal cholestasis, which includes alpha-1-antitrypsin deficiency of ZZ phenotype, Alagille syndrome, biliary atresia, cystic fibrosis, and metabolic diseases (tyrosinemia type I, galactosemia, hereditary fructose intolerance) (see these terms), diseases that present with fat and fat soluble vitamin malabsorption, including other liver diseases, and intestinal disease, or diseases that present with growth failure.\nAntenatal diagnosis\nAntenatal diagnosis can be made on embryonic tissue obtained when there has been a previously identified sibling. Urine LSIMS in a suspect infant can confirm the diagnosis in the first neonatal days.\nManagement and treatment\nTreatment is based on oral administration of cholic acid which leads to gradual resolution of biochemical and histologic abnormalities and prevents progression of the disease, even in cases with hepatic fibrosis and cirrhosis. Cholic acid therapy stimulates bile flow and suppresses synthesis of atypical bile acids and production of toxic intermediates via the bile acid pathway linked to the pathogenesis of disease.\nPrognosis\nWith early treatment the long-term prognosis is excellent.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr James HEUBI"}
{"Disease Name": "Congenital bile acid synthesis defect type 2", "Disease Definition": "Congenital bile acid synthesis defect type 2 (BAS defect type 2) is an anomaly of bile acid synthesis (see this term) characterized by severe and rapidly progressive cholestatic liver disease, and malabsorption of fat and fat-soluble vitamins.", "ORPHA ID": 79303, "Summary": "Epidemiology\nPrevalence is unknown. This condition is clearly rare but is the second most common anomaly of BAS on screening infants with cholestasis.\nClinical description\nPatients present with neonatal cholestasis and rapid progression to cirrhosis and death in infancy without intervention. The clinical presentation resembles that of congenital BAS defect type 1 (see this term) with hepatosplenomegaly, jaundice, fat-soluble vitamin malabsorption, and steatorrhea. However, the average age at diagnosis is lower, in infancy, and disease progression is more rapid and severe. Liver function tests present elevated serum transaminases (AST, ALT) and gamma-GT, markedly elevated conjugated bilirubinemia and coagulopathy.\nEtiology\nBAS defect type 2 is caused by a mutation in the delta(4)-3-oxosteroid 5-beta-reductase gene (AKR1D1, 7q32-q33). Transmission is autosomal recessive. Liver injury is thought to be caused by diminished primary bile acid synthesis and hepatotoxicity of accumulated atypical bile acids (delta(4)-3-oxo bile acids).\nDiagnostic methods\nDiagnosis is based on urine analysis using liquid secondary ionization mass spectrometry (LSIMS) and gas chromatography - mass spectrometry (GC-MS). LSIMS urine analysis reveals elevated amounts of delta(4)-3-oxo bile acids including 3-oxo-7alpha-hydroxy-4-cholenoic and 3-oxo-7alpha, 12alpha-dihydroxy-4-cholenoic acids. Increased production of delta4-3-oxo bile acids occurs in infants during the first few weeks of life and in patients with end-stage liver disease of other causes. It is important to perform repeat LSIMS urine analysis as, on rare occasions, a resolution of the liver disease occurs with disappearance of atypical bile acids.\nDifferential diagnosis\nDifferential diagnoses include progressive familial intrahepatic cholestasis, diseases that present with neonatal cholestasis, which includes alpha-1-antitrypsin deficiency (ZZ phenotype), tyrosinemia type 1, biliary atresia, choledochal cyst, cystic fibrosis, Alagille syndrome, galactosemia and hereditary fructose intolerance or diseases that present with growth failure (panhypopituitarism) (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis can be established by analysis of embryonic tissue when there has been a previously identified sibling. Urine LSIMS on siblings of affected patients may be performed in the first neonatal days and therapy begun before serious morbidity develops.\nManagement and treatment\nTreatment is based on oral bile acid therapy, which leads to gradual resolution of biochemical and histologic abnormalities and prevents progression of the disease. Cholic acid therapy creates a pool of bile acids which stimulates bile flow and facilitates fat soluble vitamin absorption and suppresses atypical bile acid synthesis thereby reducing the production of toxic bile acid metabolic intermediates. Ursodeoxycholic acid (UDCA) may be used but is not the therapy of choice because UDCA does not suppress atypical bile acid synthesis and the toxic metabolites that may injure the liver continue to be produced.\nPrognosis\nWith early treatment, the long-term prognosis is excellent. If a patient is identified with advanced liver disease, cholic acid therapy may not be effective and liver transplantation may be required. Without treatment, the condition is generally fatal.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr James HEUBI"}
{"Disease Name": "Congenital bile acid synthesis defect type 3", "Disease Definition": "Congenital bile acid synthesis defect type 3 (BAS defect type 3) is a severe anomaly of bile acid synthesis (see this term) characterized by severe neonatal cholestatic liver disease.", "ORPHA ID": 79302, "Summary": "Epidemiology\nTo date, only 2 cases of this disorder have been reported.\nClinical description\nThe index case was a 10-week-old infant with severe progressive cholestasis, hepatosplenomegaly, coagulopathy, cirrhosis and liver synthetic failure from early infancy. Serum transaminases (AST, ALT) were markedly elevated and gamma-GT was normal. Liver histology showed cholestasis, extensive portal fibrosis, inflammation and giant cell transformation, as well as bile duct proliferation.\nEtiology\nBAS defect type 3 is caused by mutations in the 7-alpha hydroxylase gene (CYP7B1, 8q21.3). The deficiency in oxysterol 7alpha-hydroxylation leads to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. The mode of transmission is presumed to be autosomal recessive.\nDiagnostic methods\nDiagnosis, based on analysis of urine using liquid secondary ionization mass spectrometry (LSIMS) shows sulfate and glycosulfate conjugates of unsaturated monohydroxy-cholenoic acids (3beta-hydroxy-5-cholenoic and 3beta-hydroxy-5-cholestenoic acids) and an absence of primary bile acids.\nManagement and treatment\nThis anomaly of bile acid synthesis is particularly severe and is not treatable by primary bile acid therapy.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr James HEUBI"}
{"Disease Name": "Congenital bile acid synthesis defect type 4", "Disease Definition": "Congenital bile acid synthesis defect type 4 (BAS defect type 4) is an anomaly of bile acid synthesis (see this term) characterized by mild cholestatic liver disease, fat malabsorption and/or neurological disease.", "ORPHA ID": 79095, "Summary": "Epidemiology\nFive cases have been reported to date: two siblings presenting with neonatal cholestasis and three adults with neurological disease.\nClinical description\nThe clinical presentation of this defect varies. Infants present with severe fat and fat-soluble vitamin deficiencies, hematochezia and mild cholestasis, whereas adults present with various neurological disorders. It is possible that the adults had undocumented mild liver disease and fat-soluble vitamin deficiency in earlier life that led to neurological disease.\nEtiology\nBAS defect type 4 is caused by a mutation in the AMACR gene (5p13.2-q11.1).\nDiagnostic methods\nDiagnosis is based on liquid secondary ionization mass spectrometry (LSIMS), gas chromatography-mass spectrometry (GC-MS) and electrospray ionization-tandem mass spectrometry analysis of urine, serum and bile.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment is based on primary bile acid therapy with cholic acid. Dietary restriction of phytanic and pristanic acids is likely to be necessary in the long term to prevent neurotoxicity.\n\n                            Last update: \n                            September 2011\n\n\n                            - Expert reviewer(s): \n                            Pr James HEUBI"}
{"Disease Name": "Congenital brachyesophagus-intrathoracic stomach-vertebral anomalies syndrome", "Disease Definition": "A rare syndromic esophageal malformation characterized by severe congenital brachyesophagus with midline diaphragmatic hernia and secondary intrathoracic stomach, and vertebral anomalies (in particular rachischisis of the cervical/thoracic spine). Additional reported manifestations include intrauterine growth restriction, short neck, intestinal malrotation, herniation of other abdominal organs, and cleft lip, among others. The condition is mostly fatal in the neonatal or early infantile period.", "ORPHA ID": 514352, "Summary": ""}
{"Disease Name": "Congenital brain dysgenesis due to glutamine synthetase deficiency", "Disease Definition": "A rare neurometabolic disease characterized by neonatal onset of severe epileptic encephalopathy with brain malformations (including cerebral and cerebellar atrophy, white matter abnormalities, delayed gyration or complete agyria, and thin corpus callosum), generalized hypotonia, and lack of normal development. Additional features include facial dysmorphism and necrolytic erythema of the skin. Biochemical hallmarks are decreased levels of glutamine in body fluids and chronic hyperammonemia. Death may occur in the early post-natal period due to multiple organ failure.", "ORPHA ID": 71278, "Summary": ""}
{"Disease Name": "Congenital cataract microcornea with corneal opacity", "Disease Definition": "A rare genetic eye disease characterized by congenital cataract, microcornea, and corneal opacity, resulting in severe visual impairment or blindness. Depending on the genetic background, other developmental ocular defects may also be present.", "ORPHA ID": 289499, "Summary": ""}
{"Disease Name": "Congenital cataract-anterior segment dysgenesis syndrome", "Disease Definition": "Cataract-glaucoma syndrome is characterised by the association of total bilateral congenital cataract with the secondary occurrence of glaucoma appearing at ages varying between 10 and 40 years.", "ORPHA ID": 162, "Summary": "Epidemiology\nThis very rare syndrome has only been described in three families, one of which contained a few dozen affected individuals spanning eight generations.\nEtiology\nThe syndrome is caused by dysfunction of the PITX3 gene (localised to 10q25). This gene codes for a transcription factor involved in the development of the lens and anterior segment of the eye.\nGenetic counseling\nThe disorder is transmitted as an autosomal dominant trait.\nManagement and treatment\nThe cataract can be managed by classical surgery. Yearly monitoring of ocular tonus is advised; hypertonia is treated classically when it appears.\nPrognosis\nThe prognosis is good if the disease is correctly treated, but can lead to blindness if diagnosis is delayed.\n\n                            Last update: \n                            July 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Pierre BITOUN"}
{"Disease Name": "Congenital cataract-hearing loss-severe developmental delay syndrome", "Disease Definition": "Congenital cataract-hearing loss-severe developmental delay syndrome is a rare, genetic, lethal, neurometabolic disease characterized by congenital cataracts, sensorineural hearing loss, severe psychomotor developmental delay, severe, generalized muscular hypotonia, and central nervous system abnormalities (incl. cerebellar and cerebral hypoplasia, hypomyelination, wide subarachnoid spaces), in the presence of low serum copper and ceruloplasmin. Nystagmus and seizures have also been reported.", "ORPHA ID": 300313, "Summary": ""}
{"Disease Name": "Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome", "Disease Definition": "Congenital cataract - hypertrophic cardiomyopathy - mitochrondrial myopathy (CCM) is a mitochondrial disease (see this term) characterized by cataracts, hypertrophic cardiomyopathy, muscle weakness and lactic acidosis after exercise.", "ORPHA ID": 1369, "Summary": "Epidemiology\nPrevalence of CCM is unknown; approximately 40 cases have been reported to date in disparate locations throughout the world.\nClinical description\nClinical features include congenital cataract (total or rapidly progressive), hypertrophic cardiomyopathy, muscle weakness and lactic acidosis after exercise. CCM may present in two forms, a neonatal lethal form or a chronic form. Hypertrophic cardiomyopathy is diagnosed at birth in half of the patients in both forms. Approximately half of the patients die within the first year of life due to cardiac failure. Nystagmus, strabismus, hypotonia, hyporeflexia and delayed motor development are occasional features. Marked lactic acidemia occurs with even limited muscular exertion. Patients who survive neonatal period and infancy, manifest the chronic form with stable cardiomyopathy and myopathy and have a normal intellect. Physical mobility is impaired due to muscular weakness in most patients.\nEtiology\nIn the majority of CCM patients mutations (nonsense, frame-shift, start codon or splice site) in the AGK gene have been identified. The AGK gene encodes the mitochondrial acylglycerol kinase which plays a role in the assembly of adenine nucleotide translocator (ANT), an essential component of the oxidative phosphorylation in mitochondria. Two patients with distinct autosomal recessive SLC25A4 mutations have been reported (one of whom had cardiomyopathy but not cataract). The SLC25A4 gene encodes the heart and muscle specific isoform 1 of the mitochondrial ANT. The etiology remains genetically unsolved in the rest of cases of CCM. The milder affected individuals carried either splice site or start codon mutations.\nDiagnostic methods\nDiagnostic procedures include serum and urine analysis for lactic acid, radiology and echocardiogram for findings of cardiomyopathy. Muscle biopsy from cardiac and skeletal muscle reveals storage of lipid and glycogen, mitochondrial abnormalities, ANT deficiency and mild decrease of respiratory chain complexes I and IV. Genetic testing may reveal autosomal recessive mutations in AGK  and SLC25A4 and it should be considered early in diagnostic workup.\nDifferential diagnosis\nDifferential diagnoses include mitochondrial encephalo-cardio-myopathy due to TMEM70 deficiency, isolated ATP synthase deficiency and Barth syndrome (see these terms).\nAntenatal diagnosis\nPrenatal genetic testing may be possible for families with affected children.\nGenetic counseling\nThe reported mutations are transmitted in an autosomal recessive manner.\nManagement and treatment\nCCM patients require cataract surgery during infancy and medical management of cardiomyopathy with standard therapy. Patients may require palliative care and a wheelchair for locomotion.\nPrognosis\nApproximately half of the reported patients die in the first year of life due to cardiac failure. The longest surviving patients are in their fifth decade of life.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Tobias HAACK  - Pr Johannes MAYR  - Dr Holger PROKISCH  - Pr Wolfgang SPERL"}
{"Disease Name": "Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome", "Disease Definition": "A rare, genetic, mitochondrial myopathy characterized by congenital cataract, progressive muscular hypotonia that particularly affects the lower limbs, reduced deep tendon reflexes, sensorineural hearing loss, global development delay and lactic acidosis. Muscle biopsy reveals reduced complex I, II and IV respiratory chain activity.", "ORPHA ID": 330054, "Summary": ""}
{"Disease Name": "Congenital cataract-severe neonatal hepatopathy-global developmental delay syndrome", "Disease Definition": "A rare genetic disease characterized by congenital cataract, neonatal hepatic failure and cholestatic jaundice, and global developmental delay. Neonatal death due to progressive liver failure has been reported.", "ORPHA ID": 521432, "Summary": ""}
{"Disease Name": "Congenital cataracts-facial dysmorphism-neuropathy syndrome", "Disease Definition": "A rare autosomal recessive multiple congenital anomalies/dysmorphic syndrome characterized by abnormalities of the eye; mildly dysmorphic facial features; and a hypo/demyelinating, symmetric, distal peripheral neuropathy.", "ORPHA ID": 48431, "Summary": "Epidemiology\nTo date, congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome has been found to occur exclusively in patients of Roma ethnicity; over 190 patients have been diagnosed.\nClinical description\nDevelopmental abnormalities include congenital cataracts, microcornea, microphthalmia and micropupils, primary hypomyelinating polyneuropathy, impaired physical growth, delayed early motor and intellectual development, mild facial dysmorphism and hypogonadism. Para-infectious rhabdomyolysis is a serious complication reported in an increasing number of patients. During general anesthesia, patients with CCFDN require careful monitoring as they have an elevated risk of complications.\nEtiology\nCCFDN is a genetically homogeneous condition in which all patients are homozygous for the same ancestral mutation in the CTDP1 gene. CTDP1 maps to 18qter and encodes a protein phosphatase whose only known substrate is the phosphorylated serine residues of the carboxy-terminal domain of the largest subunit of RNA polymerase II, indicating that CCFDN affects basic cellular processes of gene expression and developmental regulation. All of the affected are homozygous for the CTDP1 Romani founder variant c.863+389C>T.\nDiagnostic methods\nDiagnosis is clinical and is supported by electrophysiological and brain imaging studies. The definitive diagnosis is molecular, based on homozygosity for the CTDP1 mutation.\nDifferential diagnosis\nThe major differential diagnosis is Marinesco-Sjogren syndrome. Some other disorders should be considered as well: Galactokinase (GALK) deficiency, autosomal recessive cerebellar ataxia with late-onset spasticity, INTS1-related neurodevelopmental disorder.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. Once the CTDP1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for CTDP1-CCFDN are possible.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement includes surgical treatment of the cataracts, and rehabilitation and corrective orthopedic surgery for the peripheral neuropathy.\nPrognosis\nThe most disabling manifestations, though not curable, are manageable, and allow for an acceptable quality of life. Current data indicate that patients survive well into adulthood.\n\n                            Last update: \n                            October 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Teodora CHAMOVA | EURO-NMD* - Pr Ivailo TOURNEV | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital central hypoventilation syndrome", "Disease Definition": "Congenital central hypoventilation syndrome (CCHS) is a rare disease due to a severely impaired central autonomic control of breathing and dysfunction of the autonomous nervous system.", "ORPHA ID": 661, "Summary": "Epidemiology\nThe incidence is estimated to be at 1 of 200 000 livebirths.\nClinical description\nAssociation with a Hirschsprung's disease is observed in 16% of the cases.\nEtiology\nA heterozygous mutation of PHOX-2B gene is found in 90% of the patients.\nPrognosis\nDespite a high mortality rate and a lifelong dependence to mechanical ventilation, the long-term outcome of CCHS should be ultimately improved by multidisciplinary and coordinated follow-up of the patients.\n\n                            Last update: \n                            February 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Ha Thi-Tuyet TRANG"}
{"Disease Name": "Congenital cerebellar ataxia due to RNU12 mutation", "Disease Definition": "A rare hereditary ataxia characterized by delayed motor milestones in early infancy, hypotonia, ataxic gait, intention tremor, nystagmus, dysarthric speech, and variable learning difficulties. Neuroimaging shows a mixed picture of cerebellar hypoplasia and degeneration, with an almost absent inferior lobule and thinning of the folia of the vermis. In addition, cisterna magna and fourth ventricle are enlarged with relative sparing of the brain stem volume.", "ORPHA ID": 512260, "Summary": ""}
{"Disease Name": "Congenital cervical spinal stenosis", "Disease Definition": "Congenital cervical spinal stenosis is a rare neurological disease characterized by a congenital narrowing of the bony anatomy of the cervical spinal canal (saggital diameter <14mm), predisposing the individual to symptomatic neural compression, such as cramps, paresthesias, pain, muscle hypertonia and weakness, myelopathy and sphincter disturbances.", "ORPHA ID": 831, "Summary": ""}
{"Disease Name": "Congenital chloride diarrhea", "Disease Definition": "A rare genetic intestinal disease characterized by persistent, potentially life-threatening, watery diarrhea with excessive levels of chloride in stools, hypochloremia, hyponatremia, hypokalemia, and metabolic alkalosis, resulting in chronic dehydration and failure to thrive. Antenatal ultrasound typically reveals polyhydramnios and significant dilatation of the fetal intestinal loops.", "ORPHA ID": 53689, "Summary": ""}
{"Disease Name": "Congenital chronic diarrhea with protein-losing enteropathy", "Disease Definition": "Congenital chronic diarrhea with protein-losing enteropathy is a rare, genetic, intestinal disease characterized by early-onset, chronic, non-infectious, non-bloody, watery diarrhea associated with protein-losing enteropathy which results in hypoalbuminemia, hypogammaglobulinemia and elevated stool alpha-1-antitrypsin. Patients typically present severe, intractable diarrhea, failure to thrive, recurrent infections and edema.", "ORPHA ID": 329242, "Summary": ""}
{"Disease Name": "Congenital chylothorax", "Disease Definition": "Congenital chylothorax is a rare, potentially life-threatening neonatal condition characterized by the accumulation of chyle within the pleural space leading to respiratory distress, malnutrition and immunological compromise, either immediately after birth or within the first few weeks of life. Congenital chylothorax is the most common cause of pleural effusion in neonates; it can occur primarily due to developmental anomalies of the lymphatic duct or can be associated with chromosomal anomalies (e.g. Noonan syndrome, Turner syndrome and Down syndrome), hydrops fetalis, mediastinal neuroblastoma and other congenital malformations.", "ORPHA ID": 264688, "Summary": ""}
{"Disease Name": "Congenital complete agenesis of pericardium", "Disease Definition": "Congenital complete agenesis of pericardium is a rare, mostly asymptomatic, congenital heart malformation characterized by the complete absence of the entire pericardium, or by the absence of either the right (uncommon) or left pericardium. It is occasionally associated with chest pain (common), dyspnea, dizziness, bradycardia and syncope, while exertional manifestations are rare. The disease is usually incidentally diagnosed during surgery or at autopsy.", "ORPHA ID": 99129, "Summary": ""}
{"Disease Name": "Congenital contractural arachnodactyly", "Disease Definition": "A rare connective tissue disorder characterized by multiple flexion contractures, arachnodactyly, kyphoscoliosis, abnormal pinnae and muscular hypoplasia.", "ORPHA ID": 115, "Summary": "Epidemiology\nThe incidence of congenital contractural arachnodactyly (CCA) is unknown and its prevalence is difficult to estimate due to the overlap in phenotype with MFS. About 70 probands have been described with no geographical predilection.\nClinical description\nCCA often presents at birth with congenital contractures, 'crumpled' ear helices, arachnodactyly, and a lean body habitus. Congenital scoliosis is rare. Over the years, the congenital contractures and ear malformations tend to improve, but usually remain noticeable, as well as a lean body habitus. The external ear in adults often shows a prominent anterior crus of the antihelix resulting in a 'tram tracks' appearance with the helical crus. Individuals with CCA are at risk for developing mitral valve prolapse and aortic root dilatation, but the exact risk for complications is unknown but esteemed low. Ocular complications include keratoconus. Ectopia lentis has not been confirmed in individuals with a molecularly proven diagnosis. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, prominent anterior crus of the antihelix, and/or mild contractures without impairment. At the most severe end congenital heart defects and gastrointestinal malrotation and atresia have been documented, though a clear correlation with the genotype remains to be established.\nEtiology\nCCA is caused by a mutation in the FBN2 gene on chromosome 5q23.\nDiagnostic methods\nDuring pregnancy, ultrasound imaging may be used to demonstrate joint contractures and hypokinesia in suspected cases. A clinical scoring system for CCA has been published and can be used for the diagnosis of probands: arachnodactyly, camptodactyly, large joint contractures are each allotted 3 points, dolichostenomelia and pectus deformity are allotted 2 points, (kypho)scoliosis, muscle hypoplasia, highly arched palate, and micrognathia are allotted 1 point. A score of 7 points or more indicates a likely diagnosis of CCA. Confirmation with molecular analysis is advised.\nDifferential diagnosis\nAlthough the clinical features can be similar to Marfan syndrome (MFS), multiple joint contractures (especially of the elbow, knee, and finger joints), and crumpled ears in the absence of significant aortic root dilatation are characteristic of CCA. Crumpled ears can be present in neonatal MFS, that however additionally shows severe valvular disease and/or aortic dilatation.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal dominant. Genetic counseling should be offered to at risk individuals informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement of children with CCA is symptomatic. Early physiotherapy for contractures and scoliosis can prevent morbidity later in life. Cardiac and ophthalmologic evaluations are recommended.\nPrognosis\nSpontaneous improvement in camptodactyly and contractures is observed but residual camptodactyly usually remains. Ear malformations tend to improve. Joint pain may occur later in life and scoliosis can, rarely, be disabling. The risk for aortic dissection has not been established.\n\n                            Last update: \n                            October 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Bert CALLEWAERT | VASCERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital cornea plana", "Disease Definition": "A rare developmental defect of the eye characterized by usually bilateral absence of the normal protrusion of the cornea from the sclera, the corneal curvature being the same as that of the adjacent sclera. Most patients develop hyperopia, hazy corneal limbus, and arcus lipoides at an early age. The condition may present as an autosomal dominant or an autosomal recessive form, with the latter showing more severe signs and symptoms (such as a round and opaque thickening located centrally in the cornea) and more frequent association with other ocular anomalies.", "ORPHA ID": 53691, "Summary": ""}
{"Disease Name": "Congenital coronary artery aneurysm", "Disease Definition": "Congenital coronary artery aneurysm is a rare congenital coronary artery malformation defined as a more than 1.5 fold the normal size dilatation of a coronary artery segment with no identified underlying inflammatory or connective tissue disease. It may be asymptomatic or may present with angina pectoris, myocardial infarction, sudden cardiac death, fistula formation, pericardial tamponade, compression of surrounding structures, or congestive heart failure.", "ORPHA ID": 95491, "Summary": ""}
{"Disease Name": "Congenital cystic eye", "Disease Definition": "A rare structural developmental eye defect characterized by a persistent cyst replacing the eye due to partial or complete failure of the invagination of the optic vesicle during the fetal period. If the failure of invagination is only partial, dysplastic ocular structures may be present. The wall of the cyst is composed of connective tissue lined by neuroglial material. The defect is usually unilateral and may be an isolated finding or occur in association with intra- or extraocular malformations.", "ORPHA ID": 519384, "Summary": ""}
{"Disease Name": "Congenital deficiency in alpha-fetoprotein", "Disease Definition": "Congenital deficiency in alpha-fetoprotein is a benign genetic condition characterized by a dramatically decreased level of alpha-fetoprotein in fetus or neonate.", "ORPHA ID": 168612, "Summary": ""}
{"Disease Name": "Congenital diaphragmatic hernia", "Disease Definition": "A rare developmental defect during embryogenesis which can be a non-syndromic (70%) or syndromic (30%) diaphragmatic malformation characterized by a posterolateral defect of the diaphragm that allows passage of abdominal viscera into the thorax, leading to respiratory insufficiency and persistent pulmonary hypertension.", "ORPHA ID": 2140, "Summary": "Epidemiology\nCongenital diaphragmatic hernia (CDH) is a rare condition occuring in 1-5/10,000 births.\nClinical description\nNewborns display respiratory distress with hypoxia, excavated abdomen with sternal protrusion and in severe cases low APGAR scores at 1 and 5 minutes. Auscultation may reveal a contralateral cardiac displacement and respiratory bruits are absent or decreased on the affected side. Insufficient gas exchange and persistent pulmonary hypertension are associated with hypoplastic lungs. Pulmonary hypertension may become manifest after a brief period of adaptation to post-natal circulation. The defect and hence herniation of the intestine and/or the liver into the thorax occurs more often on the left side. Malrotation or malfixation of the intestine are frequent. One third of cases present with cardiovascular malformations and lesser proportions with skeletal, neural, genitourinary, gastrointestinal or other defects. CDH may be isolated (non-syndromic) or a component of Fryns, Denys-Drash and Donnai-Barrow syndromes as well as certain chromosomal anomalies.\nEtiology\nThe causes of CDH are largely unknown; abnormal embryogenesis due to retinoid signaling dysfunction is likely involved as are mutations of ZFPM2 and GATA6 in some cases. Persistent pulmonary hypertension is due to arteriolar constriction and closure of the pulmonary arterial bed.\nDiagnostic methods\nThoracic and abdominal X-rays locate herniated viscera. Blood gases and pH status, and other derived indexes, reflect the efficiency of gas exchange. Echocardiography of the heart is necessary to exclude associated malformations, to measure the right-to-left shunt and to estimate the severity of pulmonary hypertension.\nDifferential diagnosis\nCDH should be differentiated from cystic malformation of the lung.\nAntenatal diagnosis\nPrenatal ultrasonography reveals herniation, polyhydramnios may appear. Genetic testing for associated chromosomal aberrations and syndromes may indicate syndromic CDH if other manifestations are present. Small lungs size related to the size of the head indicates lung hypoplasia and can be prognostic.\nGenetic counseling\nMost cases are sporadic and appear to be multifactorial, two thirds are male. Recurrence in siblings is 2%. Genetic counseling should be offered.\nManagement and treatment\nTermination of pregnancy may be offered when chromosomal aberrations and syndromes are present. Fetoscopic endoluminal tracheal occlusion (FETO) with a balloon, particularly for fetuses considered otherwise unviable, has yielded survival rates approaching 50%. Gestation should be prolonged until near term if possible; maternal corticosteroids have also been proposed. In newborns, pre- and post-ductal percutaneous oxygen saturation measurements may assess the pulmonary function. Spontaneous ventilation or high frequency, low pressure ventilation (<20-25 cm H2O), no relaxation, alkalinization and adoption of modest gasometric goals (pre-ductal saturation of 80-95%, PaO2 60 mm Hg, hypercapnia <60 mm Hg) are now the standard. Extra-corporeal membrane oxygenation (ECMO) has also been used. Inotropic drugs (eg: dobutamine, dopamine) may be used to treat cardiac anomalies. Surgical repair of the hernia, undertaken only after cardio-respiratory functions are stable, replaces viscera into the abdomen and closes the diaphragmatic defect; a prosthetic patch may be necessary to repair the defect. Some surgeons perform this operation by video-assisted thoracoscopy.\nPrognosis\nConsidering prenatal and preoperative fatalities, mortality is 50-60%. Post-operative survival rate is 70-80%, up to 90% in certain institutions, particularly in non-syndromic CDH. Right-sided hernias seem to have a worse prognosis and may require more ECMO support. After surgical repair, pleural effusions and chronic respiratory tract disease are frequent, along with gastroesophageal reflux. Neurodevelopmental deficits are a risk following bouts of cerebral hypoxia. Neurosensorial deafness has been reported in a small proportion of patients.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Richard KEIJZER"}
{"Disease Name": "Congenital disorder of glycosylation", "Disease Definition": "A fast growing group of inborn errors of metabolism characterized by defective activity of enzymes that participate in glycosylation (modification of proteins and other macromolecules by adding and processing of oligosaccharide side chains). This group is comprised of phenotypically diverse disorders affecting multiple systems including the central nervous system, muscle function, immunity, endocrine system, and coagulation. The numerous entities in this group are subdivided, based on the synthetic pathway affected, into disorder of protein N-glycosylation, disorder of protein O-glycosylation, disorder of multiple glycosylation, and disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation.", "ORPHA ID": 137, "Summary": ""}
{"Disease Name": "Congenital dyserythropoietic anemia type I", "Disease Definition": "Congenital dyserythropoietic anemiatype I (CDA I) is a hematologic disorder of erythropoiesis characterized by moderate to severe macrocytic anemia occasionally associated with limb or nail deformities and scoliosis.", "ORPHA ID": 98869, "Summary": "Epidemiology\nThe prevalence is unknown. Over a 42 year period (from 1967-2009), 122 CDA I cases were reported in Europe.\nClinical description\nCDA I usually presents in the first decade of life. Manifestations include a moderate macrocytic anemia associated with intermittent jaundice, frequent splenomegaly and occasional hepatomegaly. Approximately 1/3 of CDA I patients may also have congenital malformations of the limbs (supernummary toes, hand or feet syndactyly, absence of nails) or heart (ventricular septal defect), double kidneys, short stature or hip dysplasia. Later, cholelithiasis or gallstones may occur. The main complication is iron overload which can lead to organ damage.\nEtiology\nCDA I etiology is not fully understood, but most cases have been associated with mutations in the CDAN1 gene (15q15.2), coding for a histone chaperone interacting protein. Mutations in a predicted endonulease protein encoded by the C15ORF41 gene (15q14) have recently been described in three CDAN1 mutation-negative patients, making it a second causative gene of CDA I. Since some cases of CDA I have no known mutations in either of these two genes, a third locus may exist.\nDiagnostic methods\nLaboratory findings, characterization of erythrocytes and bone marrow (BM) observation are diagnostic. Hemoglobin and haptoglobin are low, bilirubin and ferritin are high, blood smear shows anisopoikilocytosis and basophilic stippled erythrocytes. BM aspirate or trephine biopsy reveals erythroid hyperplasia (erythropoietic to granulopoietic cells ratio of 3 to 8), megablastoid aberrations of chromatin structure, large polyploidy cells with irregular nuclear shape, some bi-, tri- or tetra-nucleated polychromatic erythroblasts and internuclear chromatin bridges in 1-8% of all erythroblasts. Electon microscopy shows spongy heterochromatin with a ''Swiss cheese'' appearance.\nDifferential diagnosis\nThe diagnosis of CDA should be considered following exclusion of other causes of macrocytosis (B12 deficiency, folic acid deficiency or other megaloblastic anemias such as pernicious anemia or thiamine-responsive megaloblastic anemia syndrome; see this term), acquired dyserythropoiesis (myelodysplastic disorders) and hemolytic anemias. Gilbert syndrome (see this term) and infections should be also excluded.\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.\nGenetic counseling\nGenetic counseling is possible in CDA I. It is inherited in an autosomal recessive manner.\nManagement and treatment\nTreatment focuses on hemoglobin normalization with the administration of interferon (IFN) alpha for patients with CDAN1 mutations. The 3 cases reported with mutations in the C15ORF41 gene were unresponsive to IFN-alpha treatment. Serum ferritin must be thoroughly controlled to monitor iron overload and induce iron depletion when needed. Splenectomy is not recommended and individual decisions have to be made in cases with transfusion dependency and enlarged spleen. Transfusion may be necessary in some cases. In-utero transfusions are required for severe cases of fetal anemia. Cholecystectomy is often indicated. Successful allogenic bone marrow transplantation has been described in a few individuals and should be considered only in those transfusion-dependent persons who are resistant to IFN therapy.\nPrognosis\nPrognosis is usually good even if life expectancy is slightly reduced. Morbidity may be important due to iron overload complications that can be fatal if untreated.\n\n                            Last update: \n                            September 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Mayka SÁNCHEZ FERNÁNDEZ"}
{"Disease Name": "Congenital dyserythropoietic anemia type II", "Disease Definition": "Congenital dyserythropoietic anemia type II (CDA II) is the most common form of CDA (see this term) characterized by anemia, jaundice and splenomegaly and often leading to liver iron overload and gallstones.", "ORPHA ID": 98873, "Summary": "Epidemiology\nThe prevalence is unknown. Over a 42 year period (1967-2009), 367 CDA II cases were reported in Europe.\nClinical description\nThe disease usually presents with jaundice and normocytic anemia (mild to severe) in neonates but in some cases symptoms may be so mild that diagnosis can be delayed until adulthood. Splenomegaly and hepatomegaly are also frequent manifestations. Less commonly, posterior mediastinal or paravertebral masses (that consist of extramedullary hemopoietic tissue) are present. In rare cases, hydrops fetalis (see this term) has been associated with CDA II. Long-term complications include secondary hemochromatosis that, if left untreated, can lead to organ damage.\nEtiology\nMost cases of CDA II are caused by mutations in the SEC23B gene (20p11.23), coding for a coating protein involved in the reticulum-Golgi trafficking.\nDiagnostic methods\nDiagnosis of CDA II is based on the presence of congenital anemia, 10-50% binuclearity of bone marrow erythroblasts and increased ferritin levels. Further diagnostic findings include a positive serum acidification (Ham) test, a SDS-PAGE red blood cell (RBC) membrane electrophoresis that reveals a narrow and fast migrating band 3 and a bone marrow electron microscope that reveals the presence of a double membrane in RBC precursors. Molecular genetic analysis can also be used to identify a SEC23B mutation.\nDifferential diagnosis\nThe diagnosis of CDA should be considered following exclusion of other causes of hemolytic anemias (especially hereditary spherocytosis), acquired dyserythropoiesis (myelodysplastic syndromes, acute erythroid leukemia) and microcytic anemias (thalassemias or iron deficiency anemias) (see these terms). Gilbert syndrome (see this term) and infections should be also excluded.\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.\nGenetic counseling\nCDA II is inherited in an autosomal recessive manner and genetic counseling is possible.\nManagement and treatment\nTreatment chosen depends on disease severity and age of patients. Neonates may require an erythrocyte transfusion and in severe cases may be transfusion-dependent for years to come. This need usually diminishes in adolescence and adulthood except under certain circumstances (pregnancy, aplastic crisis, major operations and infections). Hydrops fetalis-associated anemia can be treated with intrauterine transfusions. Vitamin B12 and folic acid supplements are frequently used, although without any evidence of efficacy. The use of erythropoietin formulations also appears to be ineffective. Allogenic bone marrow transplantation has been successful in a few severe cases. Cholecystectomy is often suggested for treatment of cholethiasis. Transfusions can worsen the problem of iron loading and ferritin levels should be monitored annually. Body iron overload can also be monitored by magnetic resonance imaging. Phlebotomies can decrease ferritin concentrations but as they are not well tolerated by some, they should be accompanied by oral chelating agents.\nPrognosis\nThe prognosis of CDA II is usually good. However, morbidity may be important due to iron overload complications that can be fatal if untreated.\n\n                            Last update: \n                            September 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Mayka SÁNCHEZ FERNÁNDEZ"}
{"Disease Name": "Congenital dyserythropoietic anemia type III", "Disease Definition": "A rare form of congenital dyserythropoietic anemia (CDA) characterized by dyserythropoiesis, with big multinucleated erythroblasts in the bone marrow, and manifesting with mild to moderate anemia.", "ORPHA ID": 98870, "Summary": "Epidemiology\nThe prevalence is unknown. Three families have been reported with autosomal dominant CDA III in Sweden, America and Argentina. Four families have been described for the autosomal recessive CDA IIIb form with Spanish or latinoamerican origin. Other sporadic CDA III-like cases have been described. In total, more than 60 cases have been reported worldwide.\nClinical description\nThe clinical presentation is variable. CDA III can manifest with mild anaemia and jaundice in neonates but it may not be discovered until childhood or adulthood. Intensity of symptoms increases during infections, following trauma, and during pregnancy. The autosomal dominant (AD) CDA IIIa form was associated with monoclonal gammopathies, multiple myeloma and retinal angioid streaks, which can lead to visual impairment. The autosomal recessive CDA IIIb form was associated with macrocytic anaemia with marked dyserythropoiesis, erythroid hyperplasia, giant multinucleated erythroblasts, hepatospenomegaly and skull defects secondary to increased extramedullary hematopoiesis. Other sporadic cases of CDA III have been associated with severe erythroid hyperplasia, skeletal disorders, intellectual deficit, and hepatosplenomegaly.\nEtiology\nMutations in KIF23 gene (15q23) has been identified as the causal mutation for AD CDA IIIa. Recently, mutations in the RACGAP1 gene (12q13) were reported as the cause for the autosomal recessive form of CDAIII (named CDAIIIb). KIF23 encodes mitotic kinesin-like protein (MKLP1), which dimerizes and combines with a homodimer of the RACGAP1 protein (Rac GTPase-activating protein 1), to form the centralspindlin complex, crucial for cytokinesis.\nDiagnostic methods\nDiagnosis is based on laboratory findings. The disorder is characterized by mild anaemia, macrocytosis in the peripheral blood, and giant multinucleated erythroblasts (containing up to 12 nuclei) in the bone marrow. Increased levels of serum thymidine kinase, lactate dehydrogenase and bilirubin and very low or undetectable haptoglobin are also characteristic of this disease. Mutations in the KIF23 gene or the RACGAP1 gene can also determine a diagnosis of CDA III, type a or b, respectively.\nDifferential diagnosis\nThe diagnosis of CDA IIIa/CDAIIIb should be considered following exclusion of other causes of macrocytosis (B12 deficiency, folic acid deficiency or other megaloblastic anemias such as pernicious anemia or thiamine-responsive megaloblastic anemia syndrome), acquired dyserythropoiesis (myelodysplastic syndrome, acute erythroid leukemia), hemolytic anemias (hereditary spherocytosis) or microcytic anemias (thalassemias and iron deficiency anemias). Gilbert syndrome and infections should be also excluded.\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.\nGenetic counseling\nGenetic counseling is possible in CDA IIIa and CDA IIIb. CDA IIIa is inherited in an autosomal dominant mode (50% risk of having an affected child at each pregnancy), while CDA IIIb is inherited in an autosomal recessive mode (25% risk of having an affected child at each pregnancy).\nManagement and treatment\nIn most cases anaemia is mild and treatment is not necessary. Only during times of extreme anaemia (often due to pregnancy or surgery), may a transfusion be needed. Ophthalmological follow-up is recommended in those with eye manifestations in CDA IIIa cases. In some cases, splenectomy could be necessary to manage with splenomegaly. Iron overload was reported in one CDAIIIb patient that was regularly treated with blood transfusions. Chelation treatment is recommended for managing iron overload.\nPrognosis\nIn most cases the prognosis is good and there is no decrease in life expectancy. Quality of life may be affected in those with visual impairment or with iron overload complications.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Mayka SÁNCHEZ FERNÁNDEZ"}
{"Disease Name": "Congenital dyserythropoietic anemia type IV", "Disease Definition": "Congenital dyserythropoietic anemia type IV (CDA IV) is a newly discovered form of CDA (see this term) characterized by ineffective erythropoiesis and hemolysis that leads to severe anemia at birth.", "ORPHA ID": 293825, "Summary": "Epidemiology\nThe prevalence is unknown. Only 4 cases have been reported to date.\nClinical description\nPatients have been described as having severe anemia at birth that requires repeated transfusions. Hepatomegaly, splenomegaly, jaundice, hypertrophic cardiomyopathy, and occasional dysmorphic features (large anterior fontanel, hypertelorism, micropenis, and hypospadias) have also been reported. These cases showed increased levels of fetal hemoglobin, a very large number of nucleated red blood cells in peripheral blood and bone marrow erythroblast morphologic abnormalities.\nEtiology\nCDA IV is due to mutations in the KLF1 gene (19p13.2), encoding an erythroid transcription factor that plays a fundamental role in the expression of globin genes and also additional genes that may be involved in erythropoiesis.\nGenetic counseling\nGenetic counseling is possible for CDA IV. It is inherited in an autosomal dominant manner.\n\n                            Last update: \n                            September 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Mayka SÁNCHEZ FERNÁNDEZ"}
{"Disease Name": "Congenital dyserythropoietic anemia", "Disease Definition": "Congenital dyserythropoietic anemia (CDA) is a heterogenous group of hematological disorders of late erythropoiesis and red cell abnormalities that lead to anemia. Five types of CDA are defined: CDA I, CDA II, CDA III, CDA IV and thrombocytopenia with CDA (see these terms).", "ORPHA ID": 85, "Summary": "Epidemiology\nA global CDA prevalence figure is not precisely known. Over a 42 year period (1967-2009), 122 CDA I and 367 CDA II cases were reported in Europe. About 60 cases of CDA III have been reported worldwide as well as 4 cases of CDA IV to date. Three families have been reported to have thrombocytopenia with CDA.\nClinical description\nOnset of CDA generally occurs in childhood or early adulthood, even if clinical signs can occasionally be observed in the neonatal period. Patients share chronic anemia of variable severity and jaundice, frequently associated with splenomegaly and/or hepatomegaly. Symptoms of anemia include fatigue, failure to thrive in infants, headache, dizziness, leg cramps, tachycardia and insomnia. Erythropoiesis is always dysfunctional, as revealed by cellular anomalies and erythroid hyperplasia. CDA I patients have a moderate macrocytic anemia with frequent splenomegaly and occasional hepatomegaly. Jaundice is intermittent and approximately 1/3 of patients have congenital malformations, mostly involving the limbs, but also the heart, kidneys or hip. The main complication is iron overload which can lead to organ damage. In CDA II, the most frequent type, anemia and/or jaundice is usually detected in children or young adults with splenomegaly. Liver iron overload and gallstones are frequent. CDA III is a very rare subtype characterized by mild hemolytic anemia and a predisposition to retinal angioid streaks, gammopathies and myeloma. CDA IV is characterized by the presence of a very large number of nucleated erythrocytes in the peripheral blood. Thrombocytopenia with CDA is characterized by dysmorphic erythrocytes and paucity of the platelets.\nEtiology\nEtiology of CDA is not fully defined. CDA I is due to mutations in the CDAN1 gene (15q15.2), coding for a histone chaperone interacting protein, or in the C15ORF41 gene (15q14), coding for a predicted endonuclease putatively involved in DNA replication and/or chromatin assembly. Since some cases of CDA I have no known mutations in any of these two genes, a third locus may exist. Most cases of CDA II are caused by mutations in the SEC23B gene (20p11.23), coding for a coating protein involved in reticulum-Golgi trafficking. CDA III is due to mutations in the KIF23 gene (15q23), encoding a conserved mitotic kinesin (MKLP1) crucial for cytokinesis. The last 2 CDA types are caused by mutations in the erythroid transcription factor genes KLF1 (19p13.2) and GATA1 (Xp11.23).\nGenetic counseling\nCDA I and CDA II are inherited autosomal recessively while CDA III and CDA IV are inherited autosomal dominantly. Thrombocytopenia with CDA has an X-linked inheritance pattern. Genetic counseling is possible for all types of CDA with a known mutation.\n\n                            Last update: \n                            September 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Mayka SÁNCHEZ FERNÁNDEZ"}
{"Disease Name": "Congenital ectropion uveae", "Disease Definition": "Congenital ectropion uveae is a rare, genetic, non-syndromic developmental defect of the eye characterized by the presence of iris pigment epithelium on the anterior surface of the iris, anterior insertion of the iris, angle dysgenesis and progressive open-angle glaucoma (the latter may present in infancy or may develop later in life). Patients may manifest with headaches, ocular pain, photophobia, and redness, watering and/or swelling of the eye. It can often be associated with neurofibromatosis and less commonly with other ocular abnormalities.", "ORPHA ID": 91491, "Summary": ""}
{"Disease Name": "Congenital enterocyte heparan sulfate deficiency", "Disease Definition": "A rare, severe, genetic, intestinal disease characterized by congenital absence of heparan sulfate from small intestine epithelium manifesting with secretory diarrhea and massive enteric protein loss. Patients present intolerance to enteral feeds during the first few weeks to months of life. Apart from absence of heparan sulfate from the basolateral surface of small intestine enterocytes, small bowel biopsy is otherwise normal.", "ORPHA ID": 103910, "Summary": ""}
{"Disease Name": "Congenital enteropathy due to enteropeptidase deficiency", "Disease Definition": "Congenital enteropathy due to enteropeptidase deficiency is a rare, genetic, gastroenterological disease characterized by early-onset failure to thrive, edema, hypoproteinemia, diarrhea and fat malabsorption (or steatorrhea) in the presence of very low or absent trypsin activity in duodenal fluid. Celiac disease, or other pancreatic or mucosal disorders, may be associated.", "ORPHA ID": 168601, "Summary": ""}
{"Disease Name": "Congenital enterovirus infection", "Disease Definition": "An infectious embryofetopathy including coxsackie viruses and ECHO viruses that have been reported to cause spontaneous abortion, stillbirth, acute systemic illness in the newborn, and possibly fetal malformations.", "ORPHA ID": 292, "Summary": "Epidemiology\nCongenital enterovirus infection (EV) prevalence is still unknown. EV infections are underdiagnosed in the mother (mainly because of frequent subclinical infections) and hence may be far more frequent than supposed.\nClinical description\nClinical manifestations of congenital EV infection ranges from asymptomatic to benign, febrile to severe illness consisting of variable combinations of sepsis, hepatitis, coagulopathy, myocarditis, pneumonitis and meningoencephalitis. Clinical features are observed in utero or occurring in the first 1-2 days of life, some with viremia detected within hours after delivery. Additional features of congenital EV infection include spontaneous abortion, hydrops fetalis and stillbirths in which multiorgan disease may include myocarditis or pancarditis. Fetal anomalies of the cardiovascular, gastrointestinal and genitourinary system, along with neurodevelopmental delay, bilateral pleural effusion, abdominal ascitis, severe respiratory failure, cortical necrosis (that may lead to severe long-term neurologic sequelae) have also been scarcely reported. Infants may also develop a ''sepsis-like syndrome'' characterized by hypotension, leucopenia or leukocytosis, neutropenia, thrombocytopenia, and disseminated intravascular coagulopathy.\nEtiology\nCoxsackie A, B, ECHO viruses, and numbered EVs are believed to cross the placenta and cause fetal disease. Severity and outcome of perinatally acquired enteroviral infection is influenced by several factors, including term at delivery (premature neonates are more susceptible to severe infections), symptoms in the mother, infection in the 10 first days of life, virus strain, route of transmission (in utero or during delivery), and presence of passively acquired serotype-specific maternal antibody.\nDiagnostic methods\nIn case of ultrasound findings antenatal diagnosis of congenital EV infection is achieved by molecular detection of the virus' RNA in amniotic fluid. Postnatal diagnosis of EV infection (congenital or not) relies on molecular detection of the virus' RNA in plasma (including cord blood at birth), stool, nasopharyngeal swab, and cerebrospinal fluid.\nDifferential diagnosis\nDifferential diagnosis includes congenital infection with Toxoplasma gondii, Rubella, Cytomegalovirus, Herpes simplex virus, Parvovirus B19, Syphilis.\nManagement and treatment\nThere is no specific curative treatment for EV maternal or congenital infection.\nPrognosis\nPrognosis of mild congenital EV infections is quite good if reanimation procedures are available. Prognosis of severe congenital EV infections is poor and the disease has been reported to be fatal.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Christelle VAULOUP-FELLOUS"}
{"Disease Name": "Congenital Epstein-Barr virus infection", "Disease Definition": "A rare infectious disease that causes no clinical manifestations in the majority of infants. Indeed, the occurrence of congenital infection with EBV has never been demonstrated conclusively and must be very rare. One case have been reported to present after birth, multiple congenital anomalies (micrognathia, cryptorchidism, central cataracts), dystrophy, generalized hypotonia, hepatosplenomegaly, diffuse petechiae and hematomas and multiple areas of metaphysitis of the long bones at birth. A low birth weight was also reported. No specific follow-up of the fetus is recommended following maternal EBV primary-infection.", "ORPHA ID": 70596, "Summary": ""}
{"Disease Name": "Congenital epulis", "Disease Definition": "A rare soft tissue tumor characterized by a benign space occupying lesion in neonates, most typically located on the gingival mucosa overlying the anterior alveolar ridge of the maxilla near the canine, although the mandibular region may also be involved. Females are much more frequently affected than males. The tumor mostly presents as a single lesion, potentially interfering with feeding and respiration. Metastasis, malignant transformation, or recurrence after excision have not been reported.", "ORPHA ID": 157826, "Summary": ""}
{"Disease Name": "Congenital erosive and vesicular dermatosis", "Disease Definition": "A rare, idiopathic skin disease characterized by widespread, congenital, superficial erosions and vesicles (often involving more than 75% of the body) which heal leaving scars with a supple, symmetrical, reticulated pattern, frequently resulting in cicatricial alopecia and hyperthermia and/or hypohydrosis. Nail anomalies, neurodevelopmental and ophtalmologic abnormalities, tongue atrophy and preterm birth, with or without history of choriomnionitis, are commonly associated.", "ORPHA ID": 231573, "Summary": ""}
{"Disease Name": "Congenital erythropoietic porphyria", "Disease Definition": "A rare erythropoietic porphyria characterized by a non-photoalgesic, polymorphic, mutilating and very severe photodermatosis.", "ORPHA ID": 79277, "Summary": "Epidemiology\nSince its description in the late 19th century, around 220 cases of congenital erythropoietic porphyria (CEP) have been reported in the literature.\nClinical description\nThe disease most often manifests from birth as extremely severe, mutilating cutaneous photosensitivity, sometimes revealed by phototherapy used for the treatment of neonatal jaundice. The main symptoms include rapidly-erosive bullous skin lesions on photoexposed surfaces (hands, face, feet), which can progress to mutilating lesions and disabling retractive scars. Hypertrichosis is common. Urine is often pink to dark red and stains the diaper of affected infants. In severe forms, patients present more or less intense hemolysis. Significant splenomegaly may appear, linked to hemolytic anemia. Bone involvement is constant, with rarefaction of the architecture and risk of multiple fractures.\nEtiology\nCEP is caused by a deficiency in uroporphyrinogen synthase (UROS, the fourth enzyme in the heme biosynthesis pathway), which leads to a massive accumulation of isomeric type I porphyrins (uro and coproporphyrins) in the bone marrow. The enzyme deficiency is due to mutations of the UROS gene (NM_000375.3), coding for UROS. A certain degree of genotype-phenotype correlation has been demonstrated by the identification of so-called \"severe\" or \"moderate\" mutations. In 50 % of cases, the \"severe\" C73R mutation is present.\nDiagnostic methods\nThe diagnosis is easily made based on the evidence of massive accumulation of isomeric type I porphyrins in urine and blood. Detection of UROS deficiency in red blood cells and identification of causative mutations in the UROS gene confirm the diagnosis. Differential diagnosis The differential diagnosis includes hepatoerythropoietic porphyria, porphyria cutanea tarda, acute hepatic porphyrias with cutaneous expression, and epidermolysis bullosa.\nDifferential diagnosis\nThe differential diagnosis includes hepatoerythropoietic porphyria, porphyria cutanea tarda, acute hepatic porphyrias with cutaneous expression, and epidermolysis bullosa.\nAntenatal diagnosis\nIn families at risk, antenatal diagnosis is possible by amniotic fluid analysis, UROS enzyme activity assay, and/or molecular genetic analysis of amniotic fluid cells.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a heterozygous pathogenic variant) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nIntense preventive photoprotection is necessary to avoid the skin lesions and their aggravation. It incorporates the preventive measures proposed for erythropoietic protoporphyria. The risk of lesion infection is constant, but generally controlled by antibiotic therapy. Hemolytic anemia, splenic sequestration, and thrombocytopenia characterize the severity of the disease, often requiring repeated blood transfusions and associated iron overload, which is often difficult to manage. Splenectomy is often necessary. Induction of iron deficiency in moderate forms of CEP by careful phlebotomy has proved effective in some cases, and could be a lifelong supportive treatment option with varying degrees of acceptance by patients and their families. Allogeneic bone marrow transplantation remains the curative treatment of choice for CEP, with spectacular results including disappearance of hemolytic anemia and healing of skin lesions.\nPrognosis\nIn severe forms, the prognosis is dominated by hemolytic anemia and, above all, thrombocytopenia, which can greatly reduce patients' life expectancy. Multiple fractures often lead to motor disability. For the treatment of CEP, an ex vivo gene therapy project using bone marrow cells is currently under development.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Neila TALBI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital esophageal diverticulum", "Disease Definition": "A rare, non-syndromic, congenital esophageal malformation characterized by a false diverticulum, most often located in the upper, posterior esophagus (pharyngo-esophageal) but may occur anywhere along the esophagus (mid-thoracic or epiphrenic). Many patients are asymptomatic, but bad breath, chronic cough, respiratory distress, food regurgitation, dysphagia, chest pain or discomfort, and aspiration pneumonia are typical presenting manifestations.", "ORPHA ID": 91358, "Summary": ""}
{"Disease Name": "Congenital eyelid retraction", "Disease Definition": "Congenital eyelid retraction is a very rare kinetic eyelid anomaly that can affect the upper or lower eyelid, presents at birth, that in some cases can result in corneal exposure, and that may be associated with accessory levator muscle slips.", "ORPHA ID": 99176, "Summary": ""}
{"Disease Name": "Congenital factor II deficiency", "Disease Definition": "A rare inherited bleeding disorder due to reduced activity of factor II (FII, prothrombin) and characterized by mucocutaneous and soft tissue bleeding symptoms.", "ORPHA ID": 325, "Summary": "Epidemiology\nFactor II deficiency is the most rare coagulation factor deficiency. Prevalence of homozygous forms is estimated at 1/2,000,000. Both sexes are equally affected.\nClinical description\nCongenital FII deficiency can manifest at any age, with severe forms of the disease manifesting early in life. Common clinical signs include epistaxis, menorrhagia, oral cavity bleedings, mucosal bleeding, soft tissue bleeding, hemarthrosis, easy bruising, and prolonged bleeding after tooth extraction, trauma or surgery. Severe forms may present intracranial hemorrhage. The severity of the bleeding manifestations correlates with the FII levels. Thromboembolic manifestations have been described in case of dysprothrombinemia.\nEtiology\nInherited FII deficiency is caused by mutations in the F2 gene (11p11-q12) encoding prothrombin.\nDiagnostic methods\nDiagnosis is based on prolonged prothrombin and activated partial thromboplastin times (PT, aPTT) and on low FII coagulant activity measured using a PT based assay. Molecular testing is available, but is unnecessary for diagnosis.\nDifferential diagnosis\nDifferential diagnoses include deficiencies of factors V, VII, X, VIII, IX, XI, XIII or acquired deficiencies in FII (lupus anticoagulant).\nAntenatal diagnosis\nPrenatal diagnosis is available for the most severe forms.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nProthrombin Complex Concentrates (PCCs) or fresh frozen plasma (if PCCs are not available) are usually used to treat hemorrhagic episodes.\nPrognosis\nPrognosis is good with early diagnosis and adequate treatment.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND"}
{"Disease Name": "Congenital factor V deficiency", "Disease Definition": "Congenital factor V deficiency is an inherited bleeding disorder due to reduced plasma levels of factor V (FV) and characterized by mild to severe bleeding symptoms.", "ORPHA ID": 326, "Summary": "Epidemiology\nPrevalence of homozygous forms is estimated at 1/1,000,000. Both sexes are equally affected.\nClinical description\nCongenital FV deficiency can manifest at any age, with the most severe forms manifesting early in life. Common clinical signs include epistaxis, bruising, mucosal bleeding, soft tissue bleeding, and hemarthrosis. Excessive and prolonged bleeding during or following surgery, delivery or trauma are frequent. Women may present with menorrhagia. In severe forms of the disease, there can be a risk of intracranial, pulmonary or gastrointestinal bleedings. The severity of the bleeding manifestations correlates with the FV levels.\nEtiology\nCongenital FV deficiency is caused by mutations in the F5 gene (1q23) controlling the production of plasma FV.\nDiagnostic methods\nDiagnosis is based on prolonged prothrombin and activated partial thromboplastin times (PT, aPTT) and on low FV levels measured using a PT based assay. The bleeding time (BT) may be prolonged. Molecular testing is available, but unnecessary for diagnosis.\nDifferential diagnosis\nDifferential diagnoses include factor VIII deficiency, and combined deficiency of factor V and factor VIII (see these terms).\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nFresh frozen plasma (FFP) is the only treatment as FV concentrates are not available. In acute cases of severe bleeding, the addition of platelet concentrates may be helpful.\nPrognosis\nPrognosis is good with early diagnosis and adequate treatment.\n\n                            Last update: \n                            October 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND"}
{"Disease Name": "Congenital factor VII deficiency", "Disease Definition": "A rare, genetic, congenital vitamin K-dependant coagulation factor deficiency disorder characterized by decreased levels or absence of coagulation factor VII (FVII), resulting in bleeding diathesis of variable severity.", "ORPHA ID": 327, "Summary": "Epidemiology\nEuropean point prevalence appears to be close to 1/300,000, but may be markedly higher in countries where consanguineous marriage is frequent.\nClinical description\nClinical expression of this disorder is highly variable and no consistent relationship has been found between the severity of the hemorrhagic syndrome and the residual levels of FVII activity. The clinical picture can be very severe, with early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, may be moderate with cutaneous/mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by surgery or trauma. Finally, numerous subjects are completely asymptomatic despite a very low FVII level.\nEtiology\nFVII deficiency is caused by mutations in the F7 gene (13q34) coding for FVII. Typically, only homozygotes or compound heterozygotes develop a hemorrhagic syndrome; heterozygotes are usually asymptomatic. More than 250 mutations and six common variants are known to be associated with increased or decreased FVII plasma levels. Large genomic rearrangements have been reported in the literature and in the different locus-specific databases but they are rare. Genetic rearrangements have also been demonstrated, resulting in total or partial deletion of the F7 gene. The proximity and implication with the F10 gene (13q34) might also be the cause of combined deficits.\nDiagnostic methods\nDiagnosis is suspected with isolated prothrombin time and further confirmed by chronometric assays revealing a FVII activity level below that of pooled normal plasma (with values usually being between 70 and 140%). The deficiency is usually symptomatic only for values below 30%.\nDifferential diagnosis\nDifferential diagnoses include hepatocellular insufficiency, hypoavitaminosis K, acquired FVII deficiency associated with severe sepsis and, more rarely, the presence of autoantibodies against FVII.\nAntenatal diagnosis\nDue to the marked heterogeneity of the phenotypes (including asymptomatic individuals), access to prenatal diagnosis depends on the clinical repercussions of the disease in the family being considered. Only the existence of a first child with the very severe form may lead the medical team to propose prenatal diagnosis at the time of a subsequent pregnancy.\nGenetic counseling\nThe disease is transmitted in an autosomal recessive manner. Due to the wide phenotypic heterogeneity of the disorder, with many asymptomatic patients, genetic counseling tends to differ depending on the clinical features specific to a family.\nManagement and treatment\nAt present, the main treatment consists of recombinant activated FVII (eptacog alfa). Concentrated prothrombinic or plasmatic Factor VII may be used as a second choice and frozen plasma as a last resort. However, indications remain difficult to establish prior to surgery in subjects with few or no symptoms. In 2008, recombinant coagulation factor VIIa (rFVIIa) got an Orphan designation in the USA.\nPrognosis\nCongenital FVII deficiency usually has good prognosis. Nevertheless, disease remains very disabling, or even fatal, in patients who cannot benefit from long-term replacement prophylaxis and which present the most severe forms (intracerebral hemorrhage and repeated hemarthroses).\n\n                            Last update: \n                            February 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Muriel GIANSILY-BLAIZOT"}
{"Disease Name": "Congenital factor X deficiency", "Disease Definition": "A rare inherited bleeding disorder with a decreased antigen and/or activity of factor X (FX) and characterized by mild to severe bleeding symptoms.", "ORPHA ID": 328, "Summary": "Epidemiology\nPrevalence of homozygous forms is estimated at 1/1 000 000. Both sexes are equally affected.\nClinical description\nCongenital FX deficiency manifests at any age but in general, severe forms of the disease manifest early in life. Patients may experience severe umbilical cord stump bleeding, recurrent epistaxis, soft-tissue hemorrhages, menorrhagia, easy bruising, intra cranial hemorrhages, hematuria, hemarthroses and excessive bleeding during or following surgery or delivery or trauma.\nEtiology\nInherited congenital FX deficiency is caused by mutations in the F10 gene (13q34) controlling the production of plasma FX. The severity of the bleeding manifestations correlates with the FX level.\nDiagnostic methods\nDiagnosis is based on prolonged prothrombin, activated partial thromboplastin, and Russell viper venom times (PT, aPTT, RVVT), and on reduced levels of FX. Molecular testing is available, but unnecessary for diagnosis.\nDifferential diagnosis\nDifferential diagnoses include deficiencies of factors II, V, VII, VIII, IX, XI, XIII or acquired deficiencies in FX (amyloidosis).\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy. Heterozygote patients most often remain asymptomatic.\nManagement and treatment\nProthrombin Complex Concentrates (PCCs) or fresh frozen plasma (if PCCs are not available) are usually used to treat hemorrhagic episodes. A plasma-derived FX concentrate is now available.\nPrognosis\nPrognosis is good with early diagnosis and adequate treatment.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND"}
{"Disease Name": "Congenital factor XI deficiency", "Disease Definition": "A rare inherited bleeding disorder characterized by reduced levels and/or activity of factor XI (FXI) resulting in moderate bleeding symptoms, usually occurring after trauma or surgery.", "ORPHA ID": 329, "Summary": "Epidemiology\nPrevalence of homozygous forms is estimated at 1/1,000,000. The disease is more frequent in the Ashkenazy Jewish population where the frequency of partial deficiency is 8%. The disease affects both sexes.\nClinical description\nBleeding may manifest at any age, usually occuring after circumcision, dental extractions, trauma, or surgery (in particular surgery in the otorhinological and urogenital areas). Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate. Undiagnosed and untreated patients can develop significant hematomas after a surgical procedure.\nEtiology\nCongenital FXI deficiency is caused by mutations in the F11 gene (4q35.2) controlling the production of plasma FXI. Unlike in most factor deficiencies, the severity of the bleeding manifestations is poorly correlated with the FXI level.\nDiagnostic methods\nDiagnosis is based on a prolonged activated partial thromboplastin time (aPTT), and on reduced levels of FXI. FXI levels are < 20 IU/dL in severe defects and range between 20 and 60 IU/dL in partial deficiencies. Molecular testing is available, but unnecessary for diagnosis.\nDifferential diagnosis\nDifferential diagnoses include deficiencies of factors II, V, VII, X, VIII, IX, XIII, combined deficiency of factor V and factor VIII, von Willebrand disease and platelet function disorders.\nGenetic counseling\nTransmission is mainly autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected, homozygous child at each pregnancy. Heterozygous patients with bleeding symptoms have also been observed, which suggests an autosomal dominant mode of transmission with variable penetrance.\nManagement and treatment\nPatients may require treatment when dental extraction or surgery is planned. Factor XI concentrates or fresh frozen plasma is usually used. Low doses recombinant factor VIIa have been also used. Antifibrinolytics (aminocaproic acid, tranexamic acid) are also helpful as FXI deficiency leads to a hyperfibrinolytic state.\nPrognosis\nPrognosis is good, as bleeding symptoms are usually moderate.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND"}
{"Disease Name": "Congenital factor XII deficiency", "Disease Definition": "A rare, autosomal recessive systemic dysfunction of the hemostatic pathway, that is due to a defect in the coagulation factor XII (FXII or Hageman factor), and is either asymptomatic or characterized by a prolonged activated partial thromboplastin time and an increased risk for thromboembolism. FXII deficiency is strongly associated with primary recurrent abortions.", "ORPHA ID": 330, "Summary": ""}
{"Disease Name": "Congenital factor XIII deficiency", "Disease Definition": "Congenital factor XIII deficiency is an inherited bleeding disorder due to reduced levels and activity of factor XIII (FXIII) and characterized by hemorrhagic diathesis frequently associated with spontaneous abortions and defective wound healing. Factor XIII deficiency is one of the most rare coagulation factor deficiencies.", "ORPHA ID": 331, "Summary": "Epidemiology\nPrevalence of homozygous forms is estimated at around 1/2,000,000. Both sexes are equally affected.\nClinical description\nCongenital FXIII deficiency can manifest at any age, but diagnosis is often made during infancy. Umbilical stump bleeding manifests in up to 80% of patients. Other common signs include intracranial hemorrhage (25-30%), soft tissue bleeding, bruising, hemarthroses (20%), and recurrent spontaneous abortions. In most cases, hemorrhages are delayed (12-36hr) after trauma or surgery. Patients may have poor wound healing. Acquired forms of the disease have also been reported in association with hepatic failure, inflammatory bowel disease (see this term), and myeloid leukemia.\nEtiology\nCongenital FXIII deficiency is usually caused by mutations in the F13A1 gene (6p24.2-p23) encoding the catalytic A subunit, but mutations have also been found in the F13B gene (1q31-q32.1) encoding the B subunit. Transmission is autosomal recessive. The phenotype is less severe when the F13B gene is mutated.\nDiagnostic methods\nDiagnosis is based on quantitative FXIII activity measurement and antigen assays. Common clotting assays such as activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) are normal and cannot be used for the screening. The clot solubility test may also be used (clot is stable for more than 24 hours in case of FXIII deficiency). Molecular testing is available, but unnecessary for diagnosis.\nDifferential diagnosis\nDifferential diagnoses mainly include the other congenital coagulation factor deficiencies: fibrinogen, factors II, V, VII, X, XI, VIII, IX (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible if the causal mutations have previously been identified in the family.\nManagement and treatment\nFactor XIII concentrates or fresh frozen plasma (when FXIII concentrates are not available) is usually used for the treatment of bleedings. Prophylactic therapy with FXIII concentrate should be indicated to prevent recurrent bleedings such as intracranial hemorrhage.\nPrognosis\nIntracranial hemorrhage can be life threatening, but prognosis is favorable if adequate treatment is provided.\n\n                            Last update: \n                            October 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND"}
{"Disease Name": "Congenital fiber-type disproportion myopathy", "Disease Definition": "A rare genetic, congenital, non-dystrophic myopathy characterized by neonatal or infantile-onset hypotonia and mild to severe generalized muscle weakness.", "ORPHA ID": 2020, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nDisease onset is typically at birth or within the first year of life. Limb weakness may be greatest in the limb girdle and proximal limb muscles, but weakness is never solely distal. Facial weakness is often present, resulting in a long face, high-arched palate, and tented upper lip. Ophthalmoplegia and bulbar weakness can be seen. Tendon reflexes are often decreased or absent. Approximately 30% of patients have mild to severe respiratory involvement and feeding difficulties. Contractures (ankles, fingers, hips, elbows, knees) and spinal deformities (scoliosis, kyphoscoliosis, lordosis) occur in approximately 25% of affected children. Congenital hip dislocation and talipes equinovarus may also be present. In rare cases, cardiac involvement, cognitive impairment and cryptorchidism may occur. Ophthalmoplegia, ptosis, and facial and/or bulbar weakness with severe limb/respiratory weakness predict a poor prognosis. Histologically, there is a characteristic (but not specific) reduction in the caliber of type 1 muscle fibers. Type 1 muscle fibers are predominant compared to type 2 fibers, which are either normal or hypertrophied.\nEtiology\nCausative mutations have been identified more frequently in 4 genes, ACTA1 (1q42.13), RYR1 (19q13.2), TPM3 (1q21.3), and SELENON (1p36.11).\nDiagnostic methods\nDiagnosis is based on a combination of clinical presentation and morphologic features observed on skeletal muscle histology. Molecular testing is clinically available for the causative genes.\nDifferential diagnosis\nDifferential diagnoses include other congenital myopathies (X-linked myotubular myopathy, multiminicore disease, nemaline myopathy) and neuromuscular disorders (congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy).\nAntenatal diagnosis\nOnce the pathogenic variant(s) have been identified in the affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CFTD are possible.\nGenetic counseling\nFor the majority of cases the pattern of inheritance is either autosomal recessive or autosomal dominant. The risk to siblings of inheriting the disease is therefore 50% in autosomal dominant forms and 25% in autosomal recessive forms. X-linked inheritance has been reported in one family, with a 50% risk of male siblings of an affected individual inheriting the disease; variable penetrance is seen in female carriers. The causative gene has not been identified.\nManagement and treatment\nManagement is directed towards treating the muscular weakness and contractures (through physical and occupational therapy, exercise, stretching), respiratory problems (breathing exercises, chest physiotherapy, ventilatory support), feeding difficulties (gavage or gastrostomy feedings). Regular orthopedic monitoring is needed and corrective surgery may be necessary.\nPrognosis\nOver time, the disease becomes static in more than 90% of patients or even shows improvement and, rarely, is slowly progressive.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Luciano MERLINI"}
{"Disease Name": "Congenital fibrinogen deficiency", "Disease Definition": "Rare inherited coagulation disorders characterized by bleeding symptoms ranging from mild to severe resulting from reduced quantity and/or quality of circulating fibrinogen. Afibrinogenemia (complete absence of fibrinogen) and hypofibrinogenemia (reduced plasma fibrinogen concentration) correspond to quantitative anomalies of fibrinogen while dysfibrinogenemia corresponds to a functional anomaly of fibrinogen. Hypo- and dysfibrinogenemia may be frequently combined (hypodysfibrinogenemia).", "ORPHA ID": 335, "Summary": "Epidemiology\nPrevalence of afibrinogenemia is estimated at 1/1,000,000. Hypo- and dysfibrinogenemia are more frequent. Both sexes are equally affected. Fibrinogen deficiency can be discovered at any age but afibrinogenemia usually manifests early in childhood, often in the neonatal period.\nClinical description\nCommon manifestations of afibrinogenemia include umbilical cord bleeding, epistaxis, hemarthrosis, gastrointestinal bleeding, menorrhagia, traumatic and surgical bleeding and, rarely, intracranial hemorrhage. Recurrent spontaneous abortions may occur in women affected with afibrinogenemia. Hypofibrinogenemia is characterized by fewer and milder bleeding episodes following trauma or surgery. Most of patients with dysfibrinogenemia are asymptomatic (60%). The others may have bleeding symptoms (28%) or even thrombosis (20%).\nEtiology\nCongenital deficiencies of fibrinogen are caused by mutations in the FGA, FGB, or FGG genes. Afibrinogenemia is autosomal recessive; hypofibrinogenemia and dysfibrinogenemia are mainly autosomal dominant.\nDiagnostic methods\nDiagnosis is based on prolonged activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin and reptilase times and on fibrinogen levels measured by functional (Clauss) and immunological assays.\nDifferential diagnosis\nDifferential diagnoses include the other congenital clotting factor deficiencies (Factors II, V, VII, X, XI, VIII, IX and XIII; see these terms) and acquired fibrinogen deficiency (consumptive coagulopathy, hepatic failure). In case of thrombosis, differential diagnosis also includes congenital or acquired thrombophilia (antithrombin deficiency, protein C or S deficiency, Factor V Leiden mutation, lupus anticoagulant (see these terms) and FII Leiden mutation).\nAntenatal diagnosis\nAntenatal diagnosis of afibrinogenemia is possible if the causal mutations have already been identified in the family.\nManagement and treatment\nFibrinogen concentrates are usually used for the treatment of hemorrhages. Fresh frozen plasma is used when fibrinogen concentrates are not available. Recurrent spontaneous abortions can be prevented by routine prophylaxis based on administration of fibrinogen concentrates early in pregnancy.\nPrognosis\nAlthough life-threatening intracranial hemorrhage may occur, prognosis of afibrinogenemia is good with early diagnosis and adequate treatment. Prognosis of hypo- or dysfibrinogenemia is usually good.\n\n                            Last update: \n                            October 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND"}
{"Disease Name": "Congenital fibrosis of extraocular muscles", "Disease Definition": "A rare syndromic disorder with strabismus characterized by congenital non-progressive ophthalmoplegia affecting the oculomotor and/or trochlear nucleus/nerve and their innervated muscles. Patients present with abnormal resting position of the eyes (in most cases infraducted and exotropic), limitation of vertical and horizontal gaze, impaired binocular vision, amblyopia, unilateral or bilateral blepharoptosis, and compensatory abnormal head posture. Extraocular manifestations include intellectual disability, peripheral neuropathy, and skeletal abnormalities, among others.", "ORPHA ID": 45358, "Summary": ""}
{"Disease Name": "Congenital generalized hypercontractile muscle stiffness syndrome", "Disease Definition": "A rare defect of tropomyosin characterized by decreased fetal movements and generalized muscle stiffness at birth. Additional features include joint contractures, short stature, kyphosis, dysmorphic features, temperature dysregulation, and variably severe respiratory involvement with hypoxemia. Muscle biopsy shows mild myopathic features.", "ORPHA ID": 476406, "Summary": ""}
{"Disease Name": "Congenital generalized hypertrichosis, Ambras type", "Disease Definition": "Congenital generalized hypertrichosis, Ambras type is an extremely rare type of hypertrichosis lanuginosa congenita, a congenital skin disease, that is characterized by the presence of vellus-type hair on the entire body, especially on the face, ears and shoulders, with the exception of palms, soles, and mucous membranes. Facial and dental anomalies can also be observed, such as triangular, coarse face, bulbous nasal tip, long palpebral fissures, delayed tooth eruption and absence of teeth.", "ORPHA ID": 1023, "Summary": ""}
{"Disease Name": "Congenital generalized lipodystrophy", "Disease Definition": "A rare autosomal recessive form of lipodystrophy characterized by the association of generalized lipoatrophy with acromegaloid features, muscle hypertrophy, insulin resistance, hypertriglyceridemia, and liver steatosis.", "ORPHA ID": 528, "Summary": "Clinical description\nPresentation is typically in the first months of life with failure to thrive, hepatomegaly, generalized lipoatrophy, prominent musculature, umbilical prominence, acromegaloid features of extremities. Hypertriglyceridemia, insulin resistance, hyperglycemia and liver steatosis can be present in infancy, or diagnosed in late childhood, adolescence or adulthood. Accelerated growth in infancy, virilization of female patients and precocious puberty have been reported in some cases. High blood pressure, hypertrophic cardiomyopathy and bone cysts are frequent complications. Mild intellectual disability can be present, mainly in CGL related to BSCL2. Muscular dystrophy and cardiac arrhythmia are reported in CGL related to CAVIN1.\nEtiology\nTwo main causative genes have been identified: AGPAT2 (9q34), encoding a key enzyme in triglyceride biosynthesis (1-acyl-glycerol-3-phosphate-O-acyltransferase-2), BSCL2 (11q13), encoding the reticulum endoplasmic seipin protein. A few cases of CGL are due to biallelic pathogenic variants in CAV1 (7q31.2) and CAVIN1 (17q21.2), encoding respectively caveolin-1 and cavin-1, which are major components of specialized plasma membrane microdomains called caveolae. Generalized lipodystrophy is described in rare patients with biallelic pathogenic variants in the genes PPARG (3p25.2) or LMNA (1q22), for which heterozygous mutations are associated with familial partial lipodystrophy.\nDiagnostic methods\nDiagnosis of CGL is based on recognition of the clinical picture and associated metabolic disturbances including low serum leptin levels. The differential diagnosis of each monogenic form of the disease requires genetic testing.\nDifferential diagnosis\nCGL may occur as a feature in other diseases. Differential diagnoses include acquired generalized lipodystrophy (which occurs mainly in the context of auto-immune diseases), monogenic syndromes of insulin resistance, autoinflammatory diseases, partial forms of lipodystrophy and premature ageing syndromes.\nAntenatal diagnosis\nPrenatal diagnosis can be discussed in families with a known disease causing mutation.\nGenetic counseling\nTransmission is autosomal recessive. Couples in which each member carries at least one pathogenic variant should be informed that the risk of disease transmission to their offspring is 25%. A positive genetic test in an adult patient may lead to test the carriership of his/her partner.\nManagement and treatment\nDiet should be carefully managed, avoiding overfeeding in patients with CGL who are typically hyperphagic due to leptin deficiency. A low glycemic-index and low fat diet, supplemented with medium chain triglycerides in infants/children, is usually needed to manage insulin resistance, diabetes and hypertriglyceridemia. Exercise should be encouraged in the absence of cardiac complications. Insulin sensitizers (mainly metformin) and lipid-lowering drugs (statins, or fibrates in case of major hypertriglyceridemia) are helpful. Diabetes may require other non-specific treatments, along with insulin. The orphan drug metreleptin is authorized in Europe, as a therapeutic option in addition to diet, for the treatment of metabolic complications of generalized lipodystrophy associated with leptin deficiency, in adults and children above the age of 2 years. Regular metabolic, hepatic and cardiac monitoring is recommended. Ethinylestradiol should be avoided in women with CGL.\nPrognosis\nPrognosis depends on the presence of associated complications. Complications of diabetes, liver disease, and hypertrophic cardiomyopathy are significant causes of morbidity and early mortality.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Corinne VIGOUROUX"}
{"Disease Name": "Congenital genu flexum", "Disease Definition": "A rare congenital knee dislocation characterized by permanent knee flexion with limited extension. It can be unilateral or bilateral and may occur as an isolated malformation or be part of a syndrome (especially arthrogryposis multiplex congenita).", "ORPHA ID": 295232, "Summary": ""}
{"Disease Name": "Congenital genu recurvatum", "Disease Definition": "A rare congenital knee dislocation characterized by hyperextension of the knee greater than 0° associated with limited flexion, with prominence of the femoral condyles in the popliteal fossa and increased transverse skin folds over the anterior surface of the knee. It can be unilateral or bilateral and may occur as an isolated malformation, be associated with other orthopedic abnormalities (like developmental dysplasia of the hip or clubfoot) or be part of a syndrome (e. g. Larsen's syndrome).", "ORPHA ID": 295229, "Summary": ""}
{"Disease Name": "Congenital Gerbode defect", "Disease Definition": "A rare, congenital non-syndromic heart malformation characterized by an abnormal shunting between the left ventricle and right atrium. The clinical manifestation varies, depending on the volume of the shunt. Small congenital shunts are usually asymptomatic or associated with dyspnea and fever, whereas larger shunts often present with chest pain, fatigue, weakness, lower extremity edema, and sometimes heart failure and death. Other congenital heart anomalies may be associated.", "ORPHA ID": 99095, "Summary": ""}
{"Disease Name": "Congenital glaucoma", "Disease Definition": "A rare ophthalmic disorder characterized by an elevated intra-ocular pressure. The clinical presentation frequently associates an increase in the size of the eye, as well as corneal edema.", "ORPHA ID": 98976, "Summary": "Epidemiology\nCongenital glaucoma (CG) is the most common glaucoma of infancy. The birth prevalence is estimated at around 1/45,450 live births in Europe. Males are more commonly affected than females and the disease is bilateral in 70 to 80% cases.\nClinical description\nDiagnosis is made in the first year of life in about 80% of cases. The classic triad includes epiphora, blepharospasm and photophobia. Affected children are noted as having red watery eyes, cloudy corneas and ocular enlargement, caused by stretching of the immature eye due to elevated intraocular pressure. Children older than 3 years develop progressive myopia and insidious field loss.\nEtiology\nEtiology is poorly understood but the obstruction to the aqueous outflow seems to occur at the iridocorneal angle and at the level of the trabeculum. Gene mapping of affected families has identified three chromosomal loci, GLC3A in 2p22.2, GLC3B in 1p36 and GLC3C in 14q24.3-q31.1 of which, the CYP1B1 gene (2p22.2) on GLC3A harbors mutations. Mutations in LTBP2 (14q24.3) and MYOC (1q23-q24) genes have also been identified.\nDiagnostic methods\nDiagnosis is made by a complete ophthalmologic examination, which reveals a hazy cornea of increased size and presence of Haab's striae, increased intraocular pressure (IOP) (more than 20 mm Hg or asymmetry of more than 5 mm Hg is of concern), deep anterior chamber, abnormally high insertion of iris, poorly developed scleral spur (with gonioscopy), increased cup to disc ratio of the optic nerve head and refraction testing showing myopia and astigmatism. Examination under anesthesia is done if necessary.\nDifferential diagnosis\nThe differential diagnoses for red watery eyes include nasolacrimal duct obstruction, conjunctivitis, corneal abrasion and uveitis while those for corneal enlargement include high axial myopia and megalocornea. The differential diagnoses for corneal clouding and edema include congenital corneal dystrophies, birth trauma, keratitis, congenital ocular anomalies or storage diseases while those for optic nerve cupping include physiologic cupping, coloboma of optic papilla, genetic optic atrophy and optic nerve hypoplasia.\nAntenatal diagnosis\nPrenatal diagnosis can determine the risk of the disease in families with known mutations.\nGenetic counseling\nMost cases are sporadic, in about 10% of cases autosomal recessive inheritance is seen with variable penetrance. In the case of an autosomal recessive inheritance, genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nCongenital glaucoma is primarily managed surgically, with medical therapy playing only an adjunctive role. At first, it is usually practiced angle surgery (such as goniotomy or trabeculotomy), trabeculectomy or deep sclerectomy The choice depends on the severity of the glaucoma and the surgeon's habits Glaucoma drainage devices and diode laser cyclophotocoagulation are used in refractory cases. Amblyopia, corneal scarring and cataract are late complications. Early visual rehabilitation is important to prevent amblyopia. Patients may need regular life-long follow up to monitor IOP.\nPrognosis\nPrognosis is largely related to the timing of presentation; early diagnosis and prompt surgical treatment significantly influences the visual outcome. Most patients successfully treated in infancy maintain good pressure control with stable optic nerves and fully functional visual fields into adulthood.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Emmanuel MARCIANO"}
{"Disease Name": "Congenital glucokinase-related hyperinsulinism", "Disease Definition": "A form of diffuse hyperinsulinism due to glucokinase hyperactivity and characterized by an excessive/ uncontrolled insulin secretion (inappropriate for the level of glycemia) and recurrent episodes of hypoglycemia induced by fasting and glucose rich meals. The clinical spectrum can range from mild and intermediate cases that respond well to dietary modifications and medical management with diazoxide to severe cases that are unresponsive to diazoxide. The potential development of type 2 diabetes with age is another notable feature.", "ORPHA ID": 79299, "Summary": ""}
{"Disease Name": "Congenital heart block", "Disease Definition": "Congenital heart block (CHB) is a rare disorder of atrioventricular conduction, characterized by absence of conduction of atrial impulses to the ventricles with slower ventricular rhythm (atrioventricular dissociation). CHB can occur in association with immunological evidence of maternal connective disease (autoimmune CHD), fetal structural CHD or can be idiopathic.", "ORPHA ID": 60041, "Summary": ""}
{"Disease Name": "Congenital heart defect-round face-developmental delay syndrome", "Disease Definition": "A very rare syndrome described in three sibs of one Japanese family and characterized by congenital heart disease, round face with depressed nasal bridge, small mouth, short stature, and relatively dark skin and typical dermatoglyphic anomalies, and intellectual deficit.", "ORPHA ID": 1355, "Summary": ""}
{"Disease Name": "Congenital hereditary endothelial dystrophy type II", "Disease Definition": "Congenital hereditary endothelial dystrophy II (CHED II) is a rare subtype of posterior corneal dystrophy (see this term) characterized by a diffuse ground-glass appearance of the corneas and marked corneal thickening from birth with nystagmus, and blurred vision.", "ORPHA ID": 293603, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is unknown. Most cases have been identified in children of consanguineous parents from Saudi Arabia, India, Pakistan, Myanmar (Burma) and Ireland.\nClinical description\nDiffuse ground glass lesions are present from birth and are accompanied by nystagmus. Tearing and photophobia are minimal or absent. The course is relatively stable. Patients also occasionally have sensorineural deafness. The cornea is swollen due to extensive stromal edema.\nEtiology\nMost cases are caused by homozygous mutations in the SLC4A11 gene. A high degree of mutational heterogeneity has been detected and genetic heterogeneity may exist as no mutations in SLC4A11 or in its promoter region have been detected in some affected families. In CHED II, an increased tendency for the abnormal endothelium to synthesize a homogenous, posterior, non-banded Descemet membrane is observed.\nGenetic counseling\nTransmission appears to be autosomal recessive.\nManagement and treatment\nPatients with CHED II usually require a penetrating keratoplasty. Procedures for repairing the posterior surface of the cornea, such as a deep lamellar endothelial keratoplasty (DLEK), Descemet stripping endothelial keratoplasty (DSEK), or Descemet stripping automated endothelial keratoplasty (DSAEK) are technically difficult in young children.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Congenital hereditary facial paralysis-variable hearing loss syndrome", "Disease Definition": "Congenital hereditary facial paralysis-variable hearing loss syndrome is an extremely rare autosomal recessive disorder characterized by bilateral facial palsy with masked facies, sensorineural hearing loss, dysmorphic features (midfacial retrusion, low-set ears), and strabismus.", "ORPHA ID": 306530, "Summary": ""}
{"Disease Name": "Congenital herpes simplex virus infection", "Disease Definition": "Congenital herpes virus infection is a group of anomalies that an infant may present as a result of maternal infection and subsequent foetal infection with herpes virus. This virus causes recurrent cutaneous infections in adults, often involving the lips or the genitalia. Herpes infections in other organs, such as the liver or central nervous system, are less frequent.", "ORPHA ID": 293, "Summary": "Clinical description\nSkin lesions and scars, chorioretinitis, microcephaly, hydrencephaly, and microphthalmia have been described in infants with in utero primary herpes virus infections, but a causal relationship between these manifestations and the infection could not be established. Pregnancy complications including preterm delivery, intrauterine growth retardation, and neonatal infection have been attributed to the herpes virus.\nEtiology\nThere are two types of virus (HSV-1 and HSV-2) and both appear to have the same activity. However, type 1 infections more commonly involve the oral cavity, whereas type 2 infections more commonly involve the genital region. It has been suggested that latent HSV-2 infections occur in as many as 20 to 40% of women. Exposure of the foetus to herpes virus at the time of delivery carries a serious risk of infection for the newborn. This risk may be high during the initial infection of the mother (33 to 50%), but probably does not exceed 3% in cases of reinfection because of the protective effect of maternal antibodies.\nDifferential diagnosis\nIt remains difficult to distinguish between cases with a primary infection and those with a previously undetected recurrent infection that has become symptomatic during pregnancy.\nManagement and treatment\nIn spite of described cases of serious foetal illness, primary infection with herpes virus during pregnancy is not an indication for therapeutic abortion, and the use of antivirals in the treatment of primary herpes infections during gestation has been recommended. Some authors recommend caesarean delivery for women with first-episode genital herpes lesions at the time of delivery.\n\n                            Last update: \n                            March 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Elisabeth ROBERT-GNANSIA"}
{"Disease Name": "Congenital high-molecular-weight kininogen deficiency", "Disease Definition": "A rare genetic hematologic disease characterized by abnormal surface-mediated activation of fibrinolysis due to the deficiency of high-molecular-weight kininogen in plasma. Activated partial thromboplastin time (aPTT) may be prolonged. Clinically, patients are typically asymptomatic and do not show increased bleeding or thrombotic tendency.", "ORPHA ID": 483, "Summary": ""}
{"Disease Name": "Congenital Horner syndrome", "Disease Definition": "Congenital Horner syndrome is a rare neurological disorder characterized by relative pupillary miosis and blepharoptosis, evident at birth, caused by interruption of the oculosympathetic innervation at any point along the neural pathway from the hypothalamus to the orbit. Often additional symptoms, such as enophthalmos, facial anhidrosis, iris heterochromia, conjunctival congestion, transient hypotonia and/or pupillary dilation lag, may be present. Association with birth trauma, neoplasms or vascular malformations has been reported.", "ORPHA ID": 91413, "Summary": ""}
{"Disease Name": "Congenital hydrocephalus", "Disease Definition": "A rare central nervous system malformation characterized by abnormally enlarged cerebral ventricles due to impaired cerebrospinal fluid circulation. It arises in utero and can be either acquired or inherited. The severity of the resulting brain damage depends on the duration and extent of ventriculomegaly.", "ORPHA ID": 2185, "Summary": ""}
{"Disease Name": "Congenital hyperinsulinism due to HNF4A deficiency", "Disease Definition": "A form of diazoxide-sensitive diffuse congenital hyperinsulinism due to HNF4A deficiency and, characterized by macrosomia, transient or persistent hyperinsulinemic hypoglycemia (HH), responsiveness to diazoxide and a propensity to develop maturity-onset diabetes of the young subtype 1 (MODY).", "ORPHA ID": 263455, "Summary": ""}
{"Disease Name": "Congenital hypothyroidism due to developmental anomaly", "Disease Definition": "Thyroid dysgenesis is a type of primary congenital hypothyroidism (see this term), a permanent thyroid hormone deficiency that is present from birth.", "ORPHA ID": 95711, "Summary": "Epidemiology\nPrevalence is estimated at about 1/4,700. Thyroid dysgenesis causes 85% of permanent congenital hypothyroidism (see this term) in iodine-sufficient countries. Thyroid dysgenesis occurs in three major forms: thyroid ectopy, athyreosis and thyroid hypoplasia (see these terms). Thyroid ectopy causes two-thirds of thyroid dysgenesis while athyreosis and thyroid hypoplasia account for the other third. Thyroid ectopy is twice as common in females as in males.\nClinical description\nClinical manifestations of thyroid dysgenesis are often subtle or not present at birth, probably as a result of trans-placental passage of some maternal thyroid hormone or due to some residual infant thyroid hormone production. Goiter is always absent. More specific symptoms and signs do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment thyroid dysgenesis results in severe intellectual deficit and short stature. Thyroid ectopy refers to an ectopic location of the thyroid gland, while thyroid athyreosis refers to the complete absence of thyroid tissue and thyroid hypoplasia refers to underdevelopment of the thyroid. Thyroid dysgenesis may also occur as thyroid hemiagenesis (see this term), where half of the gland is missing. In the majority of cases thyroid hemiagenesis is asymptomatic.\nEtiology\nAround 2% of cases have been shown to be familial and may be caused by mutations in the FOXE1,  NKX2-1, NKX2-5 or PAX8 genes (9q22, 14q13, 5q34 and 2q12-q14). Mutations that result in complete inactivation of the TSHR gene (14q31) can present with athyreosis or thyroid hypoplasia.\nDiagnostic methods\nIn countries with newborn screening programs (with either a primary thyroxine (T4)-follow-up TSH or primary TSH test), infants are diagnosed after detection by screening tests. Diagnosis should be confirmed by elevated serum TSH level and low T4 or free T4 level. The type of thyroid dysgenesis can be determined using thyroid radionuclide uptake and scan and thyroid ultrasonography. Genetic testing can also be used.\nDifferential diagnosis\nDifferential diagnoses include other forms of congenital hypothyroidism (see this term), which can be excluded by evidence on imaging studies of the absence or underdevelopment of the thyroid gland.\nAntenatal diagnosis\nGenetic counseling and antenatal diagnosis can be offered in families where a genetic defect has been identified.\nGenetic counseling\nThyroid dysgenesis is generally thought to be sporadic. However, recent evidence points to the possibility of a genetic component.\nManagement and treatment\nIt is not necessary to know the underlying etiology when initiating hormone treatment. Levothyroxine is the treatment of choice; the recommended starting dose is 10-15mcg/kg/day. The immediate goals of treatment are to raise the serum T4 above 130 nmol/L (10 ug/dL) as rapidly as possible; with these starting doses, serum TSH usually normalizes in 2-4 weeks. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and T4 or free T4 should be measured every 1-2 months in the first 6 months of life, every 3 months between 6 months and 3 years of age, and 4 weeks after any dose change.\nPrognosis\nThe prognosis of infants started on treatment early is excellent, with IQs similar to sibling or classmate controls. Lower neurocognitive outcomes may occur in those infants started after more than 30 days of age, on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Congenital hypothyroidism due to maternal intake of antithyroid drugs", "Disease Definition": "A rare congenital hypothyroidism disorder characterized by transient, primary, fetal or neonatal hypothyroidism resulting from transplacental transfer of antithyroid drugs due to maternal intake. Patients may present fetal or neonatal goiter, hoarse cry, reduced tendon reflexes, feeding difficulty, constipation, prolonged jaundice and/or respiratory distress. Elevated levels of T4 and thyroid stimulating hormone usually normalize without treatment within 3 weeks of birth.", "ORPHA ID": 226313, "Summary": ""}
{"Disease Name": "Congenital hypothyroidism due to transplacental passage of TSH-binding inhibitory antibodies", "Disease Definition": "Congenital hypothyroidism due to transplacental passage of maternal thyroid-stimulating hormone (TSH)-binding inhibitory antibodies is a type of transient congenital hypothyroidism (see this term), a thyroid hormone deficiency that is not permanent.", "ORPHA ID": 95715, "Summary": "Epidemiology\nPrevalence is estimated to be 1/100,000.\nClinical description\nPatients may present with symptoms similar to those of permanent CH (see this term) or they may be asymptomatic.\nEtiology\nIt is caused by the transfer of maternal TSH blocking antibodies, which can block the TSH receptor in the neonatal thyroid resulting in hypothyroidism in the infant. The effect can last up to 3-6 months after birth as maternal antibody levels fall.\nManagement and treatment\nTreatment with l-thyroxine is usually required during this period.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Congenital hypothyroidism", "Disease Definition": "Congenital hypothyroidism (CH) is defined as a thyroid hormone deficiency present from birth.", "ORPHA ID": 442, "Summary": "Epidemiology\nIt occurs in approximately 1/2,000 to 1/4,000 newborns and is more common in Asian, Native American, and Hispanic infants.\nClinical description\nThe clinical manifestations are often subtle or not present at birth, probably as a result of trans-placental passage of some maternal thyroid hormone and the fact that many infants have some thyroid production of their own. More specific symptoms often do not develop until several months of age. Common clinical features include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment CH results in severe intellectual deficit and short stature.\nEtiology\nCH can be divided into permanent (with primary, secondary, or peripheral causes) or transient forms (see these terms). Causes of primary CH include thyroid dysgenesis (85% of cases) and inborn errors of thyroid hormone biosynthesis (dyshormonogenesis, 10-15% of cases) (see these terms). The cause of thyroid dysgenesis remains unknown in the vast majority of cases. Secondary or central CH results from thyroid-stimulating hormone (TSH) deficiency and is usually associated with congenital hypopituitarism. Peripheral CH results from defects in thyroid hormone transport, metabolism, or action as in Allan-Herndon-Dudley syndrome or as a result of peripheral resistance to thyroid hormones (see these terms). CH may also occur as part of a syndrome, for example in the Pendred and Bamforth-Lazarus syndromes (see these terms). Transient CH most commonly occurs in preterm infants born in areas of endemic iodine deficiency. In Western countries, transient hypothyroidism is more likely to be associated with exposure to excess iodine, or with maternal thyroid blocking antibodies.\nDiagnostic methods\nIn countries with newborn screening programs (with either a primary thyroxine (T4)-follow-up TSH or primary TSH test), infants are diagnosed after detection by screening tests finding an elevated serum TSH level and low T4 or free T4 level. Other diagnostic tests (thyroid radionuclide uptake and scan, thyroid sonography, or serum thyroglobulin determination) may help pinpoint the underlying etiology and separate transient from permanent cases.\nGenetic counseling\nIf a familial form of CH is discovered, this will guide genetic counseling. Thyroid dysgenesis is usually a sporadic disorder; thyroid dyshormonogenesis is autosomal recessive, with a recurrence risk of 25%.\nManagement and treatment\nEtiological diagnosis is not necessary when initiating thyroid hormone treatment. Levothyroxine is the treatment of choice; the recommended starting dose is 10-15 mcg/kg/day. The immediate goals of treatment are to raise the serum T4 above 130 nmol/L (10 ug/dL) as rapidly as possible; with these starting doses, serum TSH usually normalizes in 2-4 weeks. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and T4 or free T4 should be measured every 1-2 months in the first 6 months of life, every 3 months between 6 months and 3 years of age, and 4 weeks after any dose change.\nPrognosis\nThe prognosis of infants started on treatment early is excellent, with IQs similar to sibling or classmate controls. Lower neurocognitive outcomes may occur in those infants started after more than 30 days of age, on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Congenital ichthyosiform erythroderma", "Disease Definition": "A rare autosomal recessive congenital ichthyosis (ARCI) characterized by generalised scaling accompanied by a more or less severe erythroderma, without blister formation.", "ORPHA ID": 79394, "Summary": "Epidemiology\nPrevalence ranges between 1/200,000 and 1/1,000,000 individuals.\nClinical description\nCongenital ichthyosiform erythroderma (CIE) is a generalized skin disease in which a more or less pronounced erythroderma predominates. A collodion membrane may sometimes be present at birth and will change into ichthyosiform erythroderma after a few days. In addition to the erythroderma, there is usually a generalized, fine, white or grey scaling. The phenotypic expression is very variable and depends on the patient's affected gene and environment. Patients with CIE are particularly prone to severe itching and intolerance to heat. Additional complications (especially for patients who presented with a collodion membrane at birth), can be observed such as ectropion and associated ocular complications (keratitis, corneal scarring), eclabium, palmoplantar keratoderma, nail dystrophy and alopecia. Failure to thrive and short stature may occur, as well as hearing impairment due to the accumulation of scales in the external ear.\nEtiology\nCIE is a part of the autosomal recessive congenital ichthyosis (ARCI) spectrum of disorders and mostly caused by mutations in known ARCI-related genes (ABCA12, ALOX12B, ALOXE3, CYP4F22, NIPAL4, TGM1, PNPLA1). Pathophysiologically, defects in epidermal lipids and differentiation cause disturbance of the epidermal barrier, resulting in increased transepidermal water loss (TEWL). Erythema and disease severity highly correlate with IL-17 expression in patients with ichthyosis.\nDiagnostic methods\nThe diagnosis is based on the clinical picture and confirmed by genetic testing, mainly using next-generation sequencing (NGS) such as multi-gene panel sequencing or whole-exome sequencing (WES).\nDifferential diagnosis\nDifferential diagnosis includes other forms of neonatal erythroderma, especially syndromic ichthyoses (e.g. Netherton syndrome, KID syndrome), congenital reticular ichthyosiform erythroderma (CRIE) caused by specific mutations in the KRT10 or KRT1 gene, various congenital immunodeficiencies (e.g. hyper-IgE syndrome), and atopic dermatitis.\nAntenatal diagnosis\nA prenatal diagnosis (after amniocentesis or chorionic villus sampling) based on molecular genetic methods is possible if the pathogenic variant in the affected gene has previously been identified in a family member.\nGenetic counseling\nCIE is part of the autosomal recessive congenital ichthyosis (ARCI) spectrum of disorders. At-risk couples (both individuals are carriers of a disease-causing mutation) should be offered genetic counseling informing them that there is a 25% risk of having an affected child with each pregnancy.\nManagement and treatment\nManagement is based on daily applications of emollients. Keratolytics can be used but are often not tolerated. Oral retinoids and vitamin A analogues are indicated for hyperkeratosis rather than erythroderma, and are known to exacerbate skin inflammation and pruritus. In addition, these drugs can only be used in a limited way because of their known side effects (teratogenicity, hypertriglyceridaemia, hyperostosis). Topical anti-inflammatory drugs (i.e. steroids and calcineurin inhibitors) are less effective and have the disadvantage of being systemically absorbed. Recombinant human monoclonal anti-IL-17 (secukinumab), anti-IL-12/IL-23 (ustekinumab), and anti-IL-4/IL-13 (dupilumab) antibodies are undergoing clinical trials and have shown promising results.\nPrognosis\nThe prognosis depends on the underlying genetic defect. There is an increased risk of sepsis during the neonatal period. In some patients, the condition may improve with age. Additional diseases or systemic infections can severely worsen the skin condition. Depending on the severity of the skin phenotype, the quality of life can be severely impacted.\n\n                            Last update: \n                            March 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Judith FISCHER | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome", "Disease Definition": "A rare autosomal ichthyosis syndrome with prominent neurologic signs characterized by the association of congenital ichthyosis with global developmental delay, intellectual disability, infantile-onset seizures, and spastic tetraplegia. Brain imaging may show delayed myelination and cerebral atrophy. Marked intrafamilial variability has been reported.", "ORPHA ID": 352333, "Summary": ""}
{"Disease Name": "Congenital ichthyosis-microcephalus-tetraplegia syndrome", "Disease Definition": "A rare autosomal ichthyosis syndrome with prominent neurologic signs characterized by the association of congenital ichthyosis with severe developmental delay, microcephaly, spastic tetraplegia, sensorineural hearing impairment, athetosis, and myoclonus. Marked epileptic discharges with occurrence of tonic spasms have also been reported. Cerebral MRI shows diffuse cortical atrophy. There have been no further descriptions in the literature since 1995.", "ORPHA ID": 2271, "Summary": ""}
{"Disease Name": "Congenital infiltrating lipomatosis of the face", "Disease Definition": "A rare PIK3CA-related overgrowth syndrome characterized by congenital non-hereditary facial overgrowth due to post-zygotic activating mutations in the PIK3CA gene. It is unilateral and involves hypertrophy of both the soft and hard tissue structures on the affected side of the face, including hypertrophy of the facial bones, macroglossia, and proliferation of the parotid gland. Early eruption of the teeth is common.", "ORPHA ID": 583097, "Summary": ""}
{"Disease Name": "Congenital insensitivity to pain with severe intellectual disability", "Disease Definition": "Congenital insensitivity to pain with severe intellectual disability is a rare autosomal recessive hereditary sensory and autonomic neuropathy characterized by the complete absence of pain perception from birth, an unresponsiveness to soft touch, severe non-progressive cognitive delay, and normal motor movement/behavior and strength. Affected cases retained hot and cold perception.", "ORPHA ID": 453510, "Summary": ""}
{"Disease Name": "Congenital insensitivity to pain-anosmia-neuropathic arthropathy", "Disease Definition": "A rare genetic peripheral neuropathy characterized by complete congenital insensitivity to painful stimuli, commonly associated with neuropathic arthropathy. In addition, patients are typically anosmic.", "ORPHA ID": 88642, "Summary": ""}
{"Disease Name": "Congenital insensitivity to pain-hyperhidrosis-absence of cutaneous sensory innervation", "Disease Definition": "A rare hereditary sensory and autonomic neuropathy characterized by congenital insensitivity to pain, general hypesthesia, diminished temperature sensitivity, and hyperhidrosis. Motor function is preserved. Skin biopsy reveals lack of cutaneous innervation except for sensory and autonomic innervation of blood vessels and sweat glands.", "ORPHA ID": 217399, "Summary": ""}
{"Disease Name": "Congenital intrauterine infection-like syndrome", "Disease Definition": "Congenital intrauterine infection-like syndrome is characterised by the presence of microcephaly and intracranial calcifications at birth accompanied by neurological delay, seizures and a clinical course similar to that seen in patients after intrauterine infection with Toxoplasma gondii, Rubella, Cytomegalovirus, Herpes simplex (so-called TORCH syndrome), or other agents, despite repeated tests revealing the absence of any known infectious agent.", "ORPHA ID": 1229, "Summary": "Epidemiology\nMore than 30 cases have been described in the literature so far.\nClinical description\nThe clinical presentation of the reported cases is rather heterogeneous with variable manifestations including intrauterine growth retardation, hepatosplenomegaly, hyperbilirubinaemia, cerebellar hypoplasia or atrophy, and congenital cataract. Affected individuals with associated thrombocytopaenia have also been reported but it has been suggested that these patients may have a distinct subtype.\nEtiology\nThe cause remains unknown.\nDiagnostic methods\nDiagnosis relies on the clinical picture and requires exclusion of intrauterine infections.\nDifferential diagnosis\nCongenital intrauterine infection-like syndrome shows considerable clinical overlap with Aicardi-Goutieres syndrome (AGS, see this term). The two syndromes were reported to differ by the presence of cerebrospinal fluid anomalies (CSF leucocytosis and elevated IFN-alpha levels) in AGS and hepatic dysfunction, congenital microcephaly and thrombocytopaenia in congenital intrauterine infection-like syndrome. However, as the clinical manifestations of both syndromes show significant variability, it has been suggested that AGS and congenital intrauterine infection-like syndrome represent different presentations of the same disease. The differential diagnosis should also include other syndromes characterised by microcephaly and intracranial calcification such as Cockayne syndrome, COFS syndrome (which is usely considered as the neonatal form of Cockayne syndrome) and Hoyeraal-Hreidarsson syndrome (the neonatal presentation of dyskeratosis congenita syndrome; see these terms), some cases of mitochondrial encephalomyopathy, and pseudohypoarathyroidism. Ancient cases may have been reported as ``Fahr disease'', an outdated, causally heterogeneous clinical entity that encompasses several entities with intracranial calcifications.\nGenetic counseling\nSeveral familial cases, compatible with an autosomal recessive pattern of inheritance, have been described.\nManagement and treatment\nTreatment is symptomatic only.\nPrognosis\nThe prognosis is variable but can be severe with several of the reported patients dying within the first year of life.\n\n                            Last update: \n                            May 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES"}
{"Disease Name": "Congenital intrinsic factor deficiency", "Disease Definition": "Congenital intrinsic factor deficiency (IFD) is a rare disorder of vitamin B12 (cobalamin) absorption that is characterized by megaloblastic anemia and neurological abnormalities.", "ORPHA ID": 332, "Summary": "Epidemiology\nThe incidence and prevalence of IFD are unknown. Fewer than 100 cases have been reported in the literature and fewer than 50 cases have been confirmed molecularly.\nClinical description\nThe disease usually manifests before the age of 5 but patients in their 10th and 30th decade of life have also been reported. It manifests with failure to thrive and symptoms of anemia (e.g. asthenia, weakness, headache, infections). If untreated, neurological damage may occur such as peripheral neuropathy, subacute combined degeneration of the spinal cord and/or ataxia. Neurological symptoms may include muscular weakness and abnormal gait.\nEtiology\nPatients have bi-allelic mutations in the GIF gene on chromosome 11 encoding the gastric Intrinsic Factor (IF), a protein necessary for the absorption of vitamin B12. GIF mutations lead to impaired IF synthesis and thus vitamin B12 (cobalamin) malabsorption and deficiency.\nDiagnostic methods\nDiagnosis depends on blood tests that show low serum levels of cobalamin and megaloblastic anemia (decreased red blood cell count and increased mean corpuscular volume). Nowadays, measurement of transcobalamin-bound cobalamin (holo-transcobalamin) in serum is preferred to measurement of total serum cobalamin. As cobalamin deficiency affects enterocyte function, thereby enhancing cobalamin malabsorption, it is recommended to treat first with cobalamin in order to reestablish proper enterocyte function before performing any diagnostic malabsorption testing. Acid secretion is usually present but patients may show low or absent IF amounts in the gastric juice. Urine tests show increased amounts of methylmalonic acid (MMA) and total homocysteine (tHcy). There are no auto-antibodies directed against the gastric parietal cells antigen H+/K+ ATPase (anti-GPC) and intrinsic factor (anti-IFA). Commercial genetic testing is not yet available.\nDifferential diagnosis\nDifferential diagnosis includes Imerslund-Gräsbeck syndrome, transcobalamin II deficiency, cblF defect, and acquired pernicious anemia (see these terms), which is caused by autoimmunity or Helicobacter infection.\nAntenatal diagnosis\nAntenatal diagnosis is not available.\nGenetic counseling\nBoth sporadic cases and familial cases with autosomal recessive transmission have been reported.\nManagement and treatment\nThe standardized treatment consists of weekly to monthly intramuscular injections of vitamin B12. Hydroxocobalamin injections are preferred over cyanocobalamin as the latter may cause muscular pain and have ophthalmo-neurological side effects. Oral vitamin B12 supplementation may be ineffective and not recommended.\nPrognosis\nPrognosis is good. Without treatment, neurological and hematopoietic complications can occur that can also be fatal.\n\n                            Last update: \n                            September 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Stephan TANNER"}
{"Disease Name": "Congenital isolated ACTH deficiency", "Disease Definition": "A rare endocrine disease characterized by neonatal hypoglycemia, prolonged cholestatic jaundice, and seizures. Typical are low plasma ACTH and cortisol levels in the absence of structural pituitary defects, and sometimes low partial growth hormone deficiency is associated.", "ORPHA ID": 199296, "Summary": ""}
{"Disease Name": "Congenital isolated hyperinsulinism", "Disease Definition": "A rare endocrine disease characterized by an excessive or uncontrolled insulin secretion and recurrent episodes of hypoglycemia that can result in neurological sequelae if left untreated. There are two forms according to the response to first line treatment: diazoxide-sensitive and diazoxide-resistant hyperinsulinism; and three histopathological forms: focal, diffuse and atypical forms. Focal forms are only observed in early-onset cases of diazoxide unresponsive patients.", "ORPHA ID": 657, "Summary": "Epidemiology\nIsolated Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycemia in the neonatal period and early infancy. The average birth prevalence is 1/27,000 worldwide, but it may be as high as 1/2,500 in communities with substantial consanguinity.\nClinical description\nCHI can present from birth through early adulthood according to the severity of hypoglycemia. Neonatal onset is the most frequent; newborns, often macrosomic, present with poor feeding, intolerance to fasting and persistent hypoglycemia. Hypoglycemic episodes range from mild (lethargy, hypotonia and irritability) to severe (apnea, seizures or coma) that lead to neurologic sequelae. Patients who present later have recurrent, typical hypoglycemia (pallor, profuse sweating and tachycardia).\nEtiology\nNine genes are associated to CHI; the most common variants involve ABCC8 (11p15.1) and KCNJ11 (11p15.1), the genes encoding the ATP-sensitive potassium channel in pancreatic beta cell.\nDiagnostic methods\nDetectable serum insulin/C-peptide, low ketone bodies and suppressed fatty acids during hypoglycemic episodes are diagnostic of hyperinsulinemic hypoglycemia. Requirement of continuous glucose above the physiological rate of liver glucose production is pathognomonic of hyperinsulinism (HI). Later onset CHI may require provocative testing. The congenital (genetic) form should be established via family history consistent with HI or monogenic diabetes, abnormal biochemical features (hyperammonemia in association with GDH variants, or high plasma C4-OH and urine 3OH-glutarate with HADH variants), and genetic testing. Lastly, in cases unresponsive to diazoxide urgent genetic testing for ABCC8 / KCNJ11 variants and, when necessary, 18F-DOPA-Positron emission tomography (PET) imaging is indicated in order to differentiate the focal and diffuse forms.\nDifferential diagnosis\nDifferential diagnosis include all the other causes of recurrent hypoglycemia: for HI observed from birth these include transient neonatal HI as well as syndromic CHI (more than 30 syndromes feature HI at birth, the most frequent are Beckwith-Wiedemann, Kabuki and Turner syndrome); later in life, these may include insulinoma, post bariatric surgery HI, drug-induced HI, and auto-immune syndromes (HI due to anti-insulin antibodies) etc.\nAntenatal diagnosis\nAntenatal genetic testing is possible when the molecular etiology has been identified in a proband.\nGenetic counseling\nThe disorder can be autosomal dominant or recessive, and thus genetic counseling will depend on the variants responsible (de novo, germline or somatic mutations). Genetic testing may be offered to affected families when the molecular etiology has been identified in a proband.\nManagement and treatment\nNormoglycemia must be rapidly recovered and maintained to prevent irreversible brain damage, especially in neonates. At birth, severe hypoglycemia might require continuous glucose infusion and glucagon injection. Diazoxide is the first line of medical therapy and octreotide is added as an adjunct in diazoxide unresponsive patients. Partial pancreatic resection is curative for focal HI. For patients with diffuse disease, a conservative treatment is proposed when safely possible; for patients resistant to diet and medical management, near-total pancreatectomy may be necessary.\nPrognosis\nFor neonatal-onset CHI, the main concern is the cognitive outcome, which might be impaired in up to 30 to 50% of patients, especially in those who suffered from prolonged and severe hypoglycemia. The spontaneous evolution of glycemia varies: in children the disease severity reduces with time, and sometimes might even resolve, while in others it persists through adulthood. When resolved, a life-long follow-up is advised due to a risk of diabetes. In cases of subtotal pancreatectomy, glucose intolerance and diabetes mellitus requiring insulin is inevitable, occurring within 15 years after the surgery.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Jean-Baptiste ARNOUX | MetabERN* - Dr Cécile SAINT-MARTIN \n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital knee dislocation", "Disease Definition": "A rare congenital limb malformation characterized by either hyperextension of the knee greater than 0° associated with limited flexion (congenital genu recurvatum) or permanent knee flexion with limited extension (congenital genu flexum). It can be unilateral or bilateral and may occur as an isolated malformation, be associated with other orthopedic abnormalities (like developmental dysplasia of the hip or clubfoot), or be part of a syndrome (e. g. Larsen's syndrome, arthrogryposis multiplex congenita).", "ORPHA ID": 295034, "Summary": ""}
{"Disease Name": "Congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, absent scrotum or labia majora, absent or underdeveloped nipples and a tuft of hair extruding from the lactiferous ducts, bilateral corneal opacities, and dysmorphic craniofacial features (microcephaly, short forehead, and ear abnormalities, among others). Patients also show horizontal nystagmus and ataxic gait. Brain MRI reveals small cerebellar hemispheres and vermis and a small pons.", "ORPHA ID": 495875, "Summary": ""}
{"Disease Name": "Congenital lactase deficiency", "Disease Definition": "Congenital lactase deficiency is a rare severe gastrointestinal disorder in newborns primarily reported in Finland and characterized clinically by watery diarrhea on feeding with breast-milk or lactose-containing formula.", "ORPHA ID": 53690, "Summary": ""}
{"Disease Name": "Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type", "Disease Definition": "A rare degenerative mitochondrial disease characterized by chronic metabolic acidosis, hypotonia, facial dysmorphism and delayed development.", "ORPHA ID": 70472, "Summary": "Epidemiology\nThe French Canadian form of Leigh syndrome was first described in Saguenay-Lac-Saint-Jean (SLSJ) (Quebec, Canada) where its prevalence at birth is estimated to be 1/2,000. The prevalence of the gene mutation underlying the disorder, estimated to be 1/23 inhabitants, is due to a triple founder effect characterizing the settlement pattern of SLSJ. Patients were identified in all Quebec and elsewhere in the world (China, Italia and Great Britain for example).\nClinical description\nFacial dysmorphism is characterized by a prominent forehead, wide nasal bridge, hypertelorism, broad anterior fontanelle, midfacial hypoplasia, broad midline, synophrys, and anarched form of the eyebrows, along with mild hirsutism. There are three forms of the disease corresponding to varying degrees of severity: a neonatal form, a classic form and a so-called \"survivor\" form. The neonatal form is characterized by fulminant acidotic states. The classic form can occur from birth with severe lactic acidosis, or manifest between 14-24 months by ataxic gait. This form is associated with episodes of lactic acidosis that can be triggered by physical exertion, emotional stress, infection or a heavy meal, and/or metabolic crises. Patients who survived several episodes, called \"survivors\", cross a critical threshold and show less severe symptoms: hypotonia, asthenia, developmental delay (language acquisition and walking) and, in older patients, truncal ataxia, and a characteristic wide-based gait.\nEtiology\nThe disease is caused by mutations in the LRPPRC gene (2p21), the most frequent being A354V mutation. In Quebec where the disease is more frequent, only one patient has been identified as a heterozygous carrier of the A354V mutation and the C1277Xdel8 deletion. Other mutations in LRPPRC have been described in different populations (including Italy, Great Britain and Turkey) but with lower frequency. LRPPRC codes for the leucine-rich pentatricopeptide repeat-containing protein and appears to be involved in the transport and stability of mature mitochondrial mRNA. Biochemically, the cytochrome C oxidase enzyme (COX) involved in the respiratory chain was found to be deficient in all patients, but other proteins in the respiratory chain may also be.\nDiagnostic methods\nThe main diagnostic method is identification of a causal mutation. In situations where genetic testing is impossible, clinical diagnosis is based on determination of lactate levels in the blood and cerebrospinal fluid and determination of COX activity in fibroblasts from liver and skin biopsies, which were the strategies employed before the causal mutations were discovered.\nDifferential diagnosis\nDifferential diagnosis includes other forms of Leigh syndrome and other possible causes of metabolic acidosis such as MELAS syndrome, glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate dehydrogenase deficiency, and pyruvate carboxylase deficiency.\nAntenatal diagnosis\nSince the discovery of the underlying mutation, prenatal diagnosis is offered to couples that have had an affected child. A carrier test for future parents, including this disease, has also been implanted for all of Quebec's population. Moreover, private companies are now including single-nucleotide polymorphisms (SNPs) of LRPPRC in their genetic diagnosis panel for metabolic diseases, for which the quarter of these SNPs have unknown biological impact.\nGenetic counseling\nThe disease follows a monogenic autosomal recessive pattern of inheritance. Genetic counseling is proposed to couples at risk through identification of heterozygous carriers.\nManagement and treatment\nThere is no specific treatment for this disease but lifestyle changes can upgrade the quality of life of patients. A diet with a balanced intake of proteins, carbohydrates and lipids, spread evenly over the day, is recommended in order to reduce the high energy demands of digestion. Rest and strict compliance with sleeping needs are also beneficial. It is recommended to prevent infections with adequate vaccination and to visit a doctor promptly if the condition of the patient is deteriorating or in case of an infection. Avoidance of tobacco or vaping products and exposition to cigarette smoke and carbon monoxide (from cars or wood heating) is also recommended.\nPrognosis\nIn the neonatal form, the prognosis is very poor. In other patients, life expectancy was often <5 years due to severe episodes of acidosis. Currently, 80% of the patients with this disease present the so-called ''survivor'' form and exceed the age of 5. Clinical comprehension of the symptoms allowed physicians to state guidelines to include in the lifestyle of the patients. Life expectancy of the less severely affected patients can now exceed 20 years of age. The oldest patient with this disease is now 43 years old.\n\n                            Last update: \n                            January 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Bhérer CLAUDE  - Pr Catherine LAPRISE  - Dr Charles MORIN"}
{"Disease Name": "Congenital laryngeal cyst", "Disease Definition": "Congenital laryngeal cyst is a rare larynx anomaly characterized by a cyst involving the larynx or supraglottis locations, such as the epiglottis and vallecula. Timing and severity of presentation depend on the size of the cyst and its proximity to the glottis and range from severe prenatal airway obstruction leading to polyhydramnios and pulmonary hypoplasia to postnatal inspiratory stridor associated with muffled cry, hoarseness and cyanotic episodes, and to feeding difficulties and failure to thrive. It can be associated with laryngomalacia.", "ORPHA ID": 141124, "Summary": ""}
{"Disease Name": "Congenital laryngeal palsy", "Disease Definition": "Congenital laryngeal palsy is a rare larynx anomaly characterized by unilateral or bilateral paralysis of the vocal cords as a result of dysfunction of the motor nerve supply to the larynx. Patients typically present at birth (or shortly thereafter) with stridor, weak or breathy cry, dysphonia or aphonia, feeding or aspiration difficulties and, occasionally, respiratory compromise. Neurological disease, masses that cause compression and aberrant vessels are often associated. Most cases resolve spontaneously over 6-12 months.", "ORPHA ID": 137932, "Summary": ""}
{"Disease Name": "Congenital laryngomalacia", "Disease Definition": "A rare larynx anomaly characterized by an inward collapse of supraglottic airway during inspiration, which manifests with an inspiratory stridor and might be associated with feeding difficulties, swallowing dysfunction, failure to thrive, and respiratory distress.", "ORPHA ID": 2373, "Summary": ""}
{"Disease Name": "Congenital left ventricular aneurysm", "Disease Definition": "A rare congenital non-syndromic heart malformation characterized by a bulging of the left ventricular wall, connected to the left ventricle by a wide neck (with a ratio of the connection to the body of the anomaly >1). The dimensions of aneurysms have been described as small as 0.5 cm in diameter and as big as 8x9 cm in size. Most frequent locations are the left ventricular apex and the perivalvular area. Aneurysms can be a- or dyskinetic or show almost normal contractility. Patients may remain asymptomatic or present with systemic embolization, congestive heart failure, valvular regurgitation, ventricular wall rupture, ventricular tachycardia, or sudden cardiac death.", "ORPHA ID": 1055, "Summary": ""}
{"Disease Name": "Congenital lethal erythroderma", "Disease Definition": "A rare skin disorder characterized by erythrodermic, peeling skin from birth with no obvious nail or hair-shaft abnormalities and other associated anomalies including diarrhea, failure to thrive and severe hypoalbuminaemia resistant to correction by enteral or intravenous supplementation. An autosomal recessive mode of inheritance is highly probable. The prognosis is poor and infants die in the first months of life. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 1954, "Summary": ""}
{"Disease Name": "Congenital lethal myopathy, Compton-North type", "Disease Definition": "Congenital lethal myopathy, Compton-North type is a rare, genetic, lethal, non-dystrophic congenital myopathy disorder characterized, antenatally, by fetal akinesia, intrauterine growth restriction and polyhydramnios, and, following birth, by severe neonatal hypotonia, severe generalized skeletal, bulbar and respiratory muscle weakness, multiple flexion contractures, and normal creatine kinase serum levels. Ultrastructurally, loss of integrin alpha7, beta2-syntrophin and alpha-dystrobrevin from the muscle sarcolemma and disruption of sarcomeres with disorganization of the Z band are observed.", "ORPHA ID": 210163, "Summary": ""}
{"Disease Name": "Congenital limbs-face contractures-hypotonia-developmental delay syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability characterized by severe congenital contractures of the limbs and face, hypotonia, neonatal respiratory distress, and global developmental delay. Dysmorphic facial features include downslanting palpebral fissures, broad nasal bridge, large nares, long philtrum, and deep nasolabial folds, among others. Limb deformities (camptodactyly, clubfoot), short neck, scoliosis, as well as seizures have also been reported. Brain MRI may show cerebral and cerebellar atrophy in some cases.", "ORPHA ID": 562528, "Summary": ""}
{"Disease Name": "Congenital lipoid adrenal hyperplasia due to STAR deficency", "Disease Definition": "A severe form of congenital adrenal hyperplasia (CAH) characterized by severe adrenal insufficiency and sex reversal in males.", "ORPHA ID": 90790, "Summary": "Epidemiology\nThe prevalence is unknown but it is extremely rare and is more common in people of Japanese, Korean (where the heterozygous carrier frequency is estimated to be about one in 300 leading to an estimated number of affected newborns of one in every 250,000 to 300,000) and Palestinian ancestry.\nClinical description\nIt involves both glucocorticoid and mineralocorticoid deficiencies in the adrenal and androgen deficiency in the testis. Age of onset typically occurs in the antenatal period but congenital anomalies are typically seen in the perinatal period. Boys are not virilized and demonstrate a complete girl phenotype with lack of Müllerian structures. The external genitalia of girls are normal. Hypoglycemic seizures, vomiting or symptoms of dehydration are common manifestations in the first few weeks of life and can be life threatening. Acute adrenal insufficiency is an emergency and can occur in some cases. Non-classic lipoid CAH patients typically have an insidious onset of symptoms of adrenal insufficiency beginning as early as two to four years of age. The 46,XY patients have normal-appearing external genitalia, indicating normal intrauterine Leydig cell function leading to normal male external genital development. However, such patients with non-classic lipoid CAH may also have azoospermia and hypergonadotropic hypogonadism.\nEtiology\nThis disease is due to a mutation in the STAR gene, which encodes for a protein that regulates steroid hormone synthesis by mediating cholesterol transfer across the mitochondrial membrane.\nDiagnostic methods\nAbsence of all glucocorticoids, mineralocorticoids and sex steroids is observed. Diagnosis is usually performed during the neonatal period due to glucocorticoid and mineralocorticoid deficiencies. 46,XY are phenotypically female due to impaired testicular steroidogenesis. Biologically, high basal concentrations of ACTH, elevated plasma renin activity, and hypergonadotropic hypergonadism are seen. Milder ''non-classical'' forms have been reported with intermediate phenotypes. Patients may have minimal disorders of mineralocorticoid secretion, with normal electrolytes and mildly elevated plasma renin activity.\nDifferential diagnosis\nDifferential diagnosis includes familial glucocorticoid deficiency.\nAntenatal diagnosis\nPrenatal diagnosis through chorionic villus sampling is possible in case of a familial form, when the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment includes physiological replacement with glucocorticoids, mineralocorticoids, and in the newborn period, salt. Genetic males have female external genitalia and typically undergo orchidectomy and are raised as females. They require estrogen replacement to induce puberty and long term sex steroid administration.\nPrognosis\nWhen affected 46,XX patients receive appropriate glucocorticoid and mineralocorticoid replacement therapy and reach the usual age of puberty, they undergo spontaneous breast development and experience cyclical vaginal bleeding. Successful pregnancy has been achieved. Affected 46,XY individuals are unfertile. Uncontrolled CAH may be associated with life-threatening acute adrenal insufficiency and a higher risk for metabolic and cardiovascular comorbidities.\n\n                            Last update: \n                            February 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Juliane LEGER | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital lobar emphysema", "Disease Definition": "A respiratory abnormality characterized by respiratory distress due to hyperinflation of one or more affected lobes of the lung.", "ORPHA ID": 1928, "Summary": "Epidemiology\nIt is a rare disease with the birth prevalence being 1/20,000 to 1/30,000.\nClinical description\nMost cases present in the neonatal period or in early infancy. Patients with less severe manifestations may present in early childhood or rarely in adulthood. Clinical picture can range from asymptomatic or mildly symptomatic to severe respiratory impairment requiring immediate intervention. Symptomatic patients present with asymmetric chest wall expansion, respiratory distress, dyspnea, tachycardia, cyanosis, and failure to thrive. The left upper lobe is most commonly affected (41%) followed by the right middle lobe (34%) and the right upper lobe (21%). CLE can occur in association with cardiac malformations in 15 to 20% cases.\nEtiology\nAbout 50% of cases have no identifiable etiology; however an abnormality or absence of cartilaginous rings, intrinsic obstruction caused by redundant mucosa, extrinsic obstruction (vascular or bronchial) or hyperinflation alone might explain the CLE. Polyalveolar lobe has also been reported as a cause of CLE.\nDiagnostic methods\nChest X ray and CT scan are the key imaging modalities used for diagnosis. Chest X ray shows hyperlucent affected lobes with mediastinal shift and collapse of ipsilateral unaffected segments. CT scan provides details of affected lobes and vascular involvement. Echocardiography to detect concomitant heart disease can also be performed.\nDifferential diagnosis\nRespiratory distress and radiolucency in chest X rays can lead to a misdiagnosis of tension pneumothorax. Differential diagnoses also include congenital pulmonary airway malformation, pneumonia, bronchiolitis and foreign body aspiration.\nAntenatal diagnosis\nPrenatal diagnosis can be made with ultrasonography by identifying hyperechoic areas in fetal lung and Magnetic Resonance Imaging identify uniform T2 hyperintensity compared to normal lung.\nManagement and treatment\nLobectomy of affected lobes is the widely accepted form of management with a satisfactory outcome. Asymptomatic or mildly symptomatic cases can be managed conservatively but follow up is necessary. Thoracoscopic resection has been attempted and seems to have better post operative outcomes.\nPrognosis\nAsymptomatic cases may regress spontaneously. Prompt diagnosis and surgical intervention usually provide good long term outcome in symptomatic cases. In some cases, CLE can be lethal.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Daniele CATANEO"}
{"Disease Name": "Congenital macroglossia", "Disease Definition": "A rare developmental defect during embryogenesis characterized by muscular hypertrophy, adenoid hyperplasia, or vascular malformation that results in an enlarged, often protruding, tongue. Complications include difficulty in swallowing, breathing and mastication, drooling, dental and skeletal deformities, such as malocclusion, open bite, asymmetry in maxillary and mandibular arches. It may be isolated or associated with genetic syndromes.", "ORPHA ID": 2430, "Summary": ""}
{"Disease Name": "Congenital megacalycosis", "Disease Definition": "Congenital megacalycosis is a rare renal malformation, characterized by non-obstructive dilation of the renal calyces as well as an increased calyceal number (12-20), with a normal renal pelvis, ureter, and bladder. It may be unilateral or bilateral and is usually asymptomatic unless complicated by nephrolithiasis and urinary tract infection.", "ORPHA ID": 93109, "Summary": ""}
{"Disease Name": "Congenital membranous nephropathy due to fetomaternal anti-neutral endopeptidase alloimmunization", "Disease Definition": "A rare, congenital glomerular disease due to maternal anti-neutral endopeptidase (NEP) alloimmunization characterized by severe renal failure and nephrotic syndrome at birth, which rapidly improves in the first weeks of life.", "ORPHA ID": 69063, "Summary": "Epidemiology\nThe disorder has been described in 15 infants from 5 families originating from Portugal, the Netherlands, Italy, Germany and Morocco.\nClinical description\nPresentation is at birth with nephrotic syndrome, acute renal failure (oligoanuria), or both. Very weak and transient proteinuria is also possible. Respiratory distress and hypertension may also be observed during the first days of life. Some degree of dysmorphism with retrognathism, low set ears and large fontanel may be observed in some cases.\nEtiology\nThe disease is caused by the transplacental transfer of nephritogenic anti-NEP Abs (IgG1, IgG4 subtypes) from mothers with truncating mutations of the MME gene (3q25.2; coding for NEP), resulting in a loss of functional of MME. Absence of NEP induces an alloimmunization process, during pregnancy or following an earlier pregnancy, against the NEP antigen inherited by the fetus from the father. The Abs cross the placenta and bind to the NEP expressed on fetal podocytes, ultimately resulting in glomerular damage and proteinuria.\nDiagnostic methods\nDiagnosis is based on laboratory findings showing an increased serum creatinine concentration as well as the development of nephrotic-range proteinuria and hypoalbuminemia in the infant during the first days of life. Anti-NEP Abs may be detected in the infant's serum during the first couple of weeks after birth but disappear thereafter. Diagnosis of membranous nephropathy relies on the kidney biopsy. In some cases, it shows a severe and unusual form of membranous nephropathy, collapse of a majority of capillary tufts in the glomeruli with thickening of the capillary wall, and distension of Bowman's spaces. Marked tubular atrophy and severe lesions of the interlobular arteries and arterioles may also be observed. Immunofluorescence studies reveal subepithelial deposits of IgG in the glomeruli. Electron microscopy examination shows abundant electron-dense deposits typically containing annular formations on the outer aspect of the glomerular capillary wall and a marked atrophy of the brush border.\nDifferential diagnosis\nThe syndrome should be differentiated from other causes of early-onset membranous nephropathy such as congenital infections like syphilis and toxoplasmosis, and neonatal lupus erythematosus.\nAntenatal diagnosis\nPrenatal diagnosis is suspected from the 34th week of gestation by ultrasonography which may show oligohydramnios and enlarged fetal kidneys. NEP deficiency can be detected in women, using fluorescence-activated cell-sorter analysis, by incubating granulocytes with anti-NEP monoclonal Abs, or Western blotting of the urine with anti-NEP Abs. Dosage of IgG1 and IgG4 subtypes of anti-NEP Abs can be achieved in pregnant women by ELISA.\nGenetic counseling\nTransmission of NEP deficiency is autosomal recessive. Penetrance of the infant's renal disease is variable and depends on the quantity and quality of the mother's immune response (IgG4 (milder clinical symptoms) or IgG1 subclass antibodies). Mothers do not show any renal manifestations until the age of 40 when they develop peripheral demyelinating neuropathy.\nManagement and treatment\nNo cure exists. Management is mainly symptomatic and includes oxygenation ventilation for hypoxemia, administration of calcium-channel blockers and beta-blockers for blood-pressure control, management of nephrosis and renal failure if present. In neonates with severe presentation, i.e. renal failure and/or nephrotic syndrome, an exchange transfusion to eliminate circulating anti-NEP antibodies can be considered. From 4 weeks post-term, if proteinuria is still present, RAAS (renin-angiotensin-aldosterone system) inhibition may be started (usually captopril is the preferred agent, accompanied by gastroprotection). Intravenous polyclonal immunoglobulins and plasma exchanges may be envisaged in NEP-deficient mothers with increasing titers of anti-NEP IgG1 before pregnancy. Anti-CD20 therapy is another option but should be stopped 6 months before pregnancy.\nPrognosis\nInfants usually show a rapid improvement of renal failure and the nephrotic syndrome, although a severe form requiring prolonged dialysis may also be observed. Persistent albuminuria has been reported in some cases and postponed development of severe chronic renal failure may occur, especially in subsequent offspring of a NEP-deficient mother.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Hanna DEBIEC  - Pr Pierre RONCO | ERKNet* - Dr Marina VIVARELLI | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital mesoblastic nephroma", "Disease Definition": "A rare renal tumor characterized by a unilateral, solitary, well demarcated, mesenchymal/myofibroblastic neoplasm occurring in very young children. Histopathologically, three subtypes (classic, cellular, and mixed) can be distinguished. The tumor most commonly involves the renal sinus and is typically discovered as a palpable abdominal mass. Patients may also present with hypertension or hematuria, rarely with hypercalcemia or hyperreninemia. Prenatal presentation, usually with polyhydramnios, is not infrequent. The most important prognostic factor is completeness of surgical resection. Overall, malignant potential is low and clinical outcome favorable.", "ORPHA ID": 2665, "Summary": ""}
{"Disease Name": "Congenital microcephaly-severe encephalopathy-progressive cerebral atrophy syndrome", "Disease Definition": "A rare, genetic, neurometabolic disorder characterized by severe, progressive microcephaly, severe to profound global development delay, intellectual disability, seizures (typically tonic and/or myoclonic and frequently intractable), hyperekplexia, and axial hypotonia with appendicular spasticity, as well as hyperreflexia, dyskinetic quadriplegia, and abnormal brain morphology (cerebral atrophy with variable additional features including ventriculomeglay, pons and/or cerebellar hypoplasia, simplified gyral pattern and delayed myelination). Cortical blindness, feeding difficulties and respiratory insufficiency may also be associated.", "ORPHA ID": 391376, "Summary": ""}
{"Disease Name": "Congenital microcoria", "Disease Definition": "Congenital microcoria is a rare autosomal dominant ophthalmological disease caused by maldevelopment of the dilator muscle of the pupil that is characterized by small pupils (<2 mm in diameter) from birth, peripheral iris hypopigmentation and transillumination defects leading to errors of refraction (myopia, astigmatism) and sometimes juvenile open angle glaucoma.", "ORPHA ID": 566, "Summary": ""}
{"Disease Name": "Congenital microgastria", "Disease Definition": "Congenital microgastria is a rare malformation where the embryological development of the stomach is interrupted, leading to an abnormally small foregut in newborns and characterized by extreme feeding intolerance and malnutrition along with growth retardation and death if untreated. It is usually associated with multiple congenital anomalies.", "ORPHA ID": 199293, "Summary": ""}
{"Disease Name": "Congenital mitral stenosis", "Disease Definition": "Congenital mitral stenosis is a congenital heart malformation comprising a spectrum of morphologically heterogeneous developmental anomalies that result in functional and anatomic obstruction of inflow into the left ventricle. The structure of the mitral valve is affected at the level of the supravalvular ring, annulus, leaflets or subvalvar components and include supra-valvular ring, leaflet fusion (intra-leaflet ring), mitral parachute deformity and papillary muscle abnormalities. It may be isolated or associated with other heart malformations. The clinical presentation depends on the degree of obstruction, the presence of regurgitation, the presence and severity of associated pulmonary hypertension, and the presence of associated heart malformations. It may present with symptoms and signs of low cardiac output and right ventricular failure such as pulmonary infections, failure to thrive, exertional dyspnoea, cough, cyanosis and congestive heart failure.", "ORPHA ID": 99057, "Summary": ""}
{"Disease Name": "Congenital muscular alpha-dystroglycanopathy with brain and eye anomalies", "Disease Definition": "Congenital muscular alpha-dystroglycanopathy with brain and eye anomalies (MDDGA) is a cobblestone lissencephaly characterized by and considered to be pathognomonic of a continuum of recessive autosomal disorders with brain, ocular and muscular involvement. MDDGA includes Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama muscular and cerebral dystrophy and muscle eye brain disease with bilateral multicystic leukodystrophy.", "ORPHA ID": 352687, "Summary": ""}
{"Disease Name": "Congenital muscular dystrophy due to LMNA mutation", "Disease Definition": "A rare congenital muscular dystrophy characterized by prominent axial hypotonia, predominantly proximal muscle weakness in upper limbs and distal in lower limbs, joint contractures (initially distal, later proximal), spinal rigidity, and progressive respiratory insufficiency, in the presence of moderately elevated serum creatine kinase. Cardiac arrhythmias and sudden death have also been reported.", "ORPHA ID": 157973, "Summary": "Epidemiology\nTo date over 100 cases of congenital muscular dystrophy due to LMNA (L-CMD) have been reported in the literature; both genders are equally affected.\nClinical description\nThe expressivity, severity and progression of the disease are variable but all present a predominant axial and scapula-humeral topography of muscle weakness and atrophy. Motor symptoms appear during the first two years of life and show often a rapid course. In the most severe patients, no head or trunk support are achieved. In milder patients, a more characteristic picture is observed, with a striking loss of head support (dropped-head syndrome), associated with arm weakness but relatively preserved hip and thigh strength in the initial stages. Skeletal manifestations include muscle and joint contractures, spine rigidity, scoliosis and thoracic lordosis. A progressive thoracic stiffness is associated to the respiratory insufficiency favoring recurrent respiratory infections. Severe cases might show swallowing difficulties. Cardiac arrhythmias and sudden death are not uncommon in this group of patients after the first decade or life.\nEtiology\nThe disorder is due to mutations in the LMNA gene (1q22), coding for type A/C lamins, two intermediate filaments that form cytoplasmic and nuclear networks and shape the nuclear envelope. Myoblasts from L-CMD patients show altered nuclear structure, defective mechanosensing responses and abnormal cell differentiation. Milder phenotypes, known as Emery-Dreifus muscular dystrophy, are also associated with LMNA mutations.\nDiagnostic methods\nDiagnosis mostly relies on clinical observation, typically of early onset axial muscle weakness with distal progression, muscle and joint contractures, dropped-head syndrome, loss of walking and sitting abilities and cardiac arrhythmias in the first or second decade of life. A moderated elevation of serum creatine kinase levels reflects muscle damages. Genetic screening of mutations in the LMNA gene confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other congenital muscular dystrophies (laminin subunit alpha 2-related CMD, Ullrich CMD due to COL6 gene defects), early onset myopathies that present increased CK levels, joint contractures or spinal stiffness (SEPN1-related myopathies, titinopathies, Pompe disease, mitochondrial myopathy in particular TK2-related), and myasthenic syndromes where loss of head support can also be observed.\nAntenatal diagnosis\nReduced fetal movements observed by prenatal ultrasounds should raise suspicions, but is not specific. In families with a proband, prenatal genetic testing may be advised due to the possibility of germinal mosaicism.\nGenetic counseling\nThe disorder is autosomal dominant. Almost all reported cases arise de novo, although germinal mosaicism is a possibility. Genetic counseling should be offered to affected families.\nManagement and treatment\nThe evaluation and management of respiratory, gastro-intestinal, orthopedic and cardiac troubles associated with L-CMD require a multidisciplinary approach. Annual cardiac monitoring by Holter-ECG and ultrasound is recommended to detect cardiac arrhythmias and signs of heart failure. Implantable cardiac monitoring might be considered in some cases. BNP (brain natriuretic peptide) may help to detect cardiac insufficiency. Diuretic drugs, beta-blockers, aldosterone antagonists and ACE (angiotensin-converting-enzyme) inhibitors might improve cardiac function. Some patients have been reported to show motor improvement on corticoid treatment but prospective studies are required to confirm these results.\nPrognosis\nIn the first decade, respiratory insufficiency is the main cause of death. Thereafter, cardiac dysfunction and arrhythmias, which are very frequent in young adults and may lead to sudden death, determine the vital prognosis. Embolic complications due to conduction disorders and right heart failure may worsen the poor prognosis. Respiratory insufficiency and recurrent pulmonary infections reduce the lifespan or may lead to permanent ventilation or tracheostomy.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Susana QUIJANO-ROY"}
{"Disease Name": "Congenital muscular dystrophy type 1B", "Disease Definition": "Congenital muscular dystrophy type 1B is a rare, genetic neuromuscular disorder characterized by proximal and symmetrical muscle weakness (particularly of neck, sternomastoid, facial and diaphragm muscles), spinal rigidity, joint contractures (Achilles tendon, elbows, hands), generalized muscle hypertrophy and early respiratory failure (usually in the first decade of life). Patients typically present delayed motor milestones and grossly elevated serum creatine kinase levels, and with disease progression, forced expiratory abdominal squeeze and nocturnal hypoventilation.", "ORPHA ID": 98893, "Summary": ""}
{"Disease Name": "Congenital muscular dystrophy with cerebellar involvement", "Disease Definition": "A rare, congenital muscular dystrophy due to dystroglycanopathy characterized by proximal muscle weakness with a tendency for muscle hypertrophy and pseudohypertrophy, variable cognitive impairment, microcephaly, cerebellar hypoplasia with or without cysts, and other structural brain anomalies.", "ORPHA ID": 370959, "Summary": ""}
{"Disease Name": "Congenital muscular dystrophy with hyperlaxity", "Disease Definition": "Congenital muscular dystrophy with hyperlaxity is a rare, genetic neuromuscular disease characterized by congenital hypotonia, generalized, slowly progressive muscular weakness, and proximal joint contractures with distal joint hypermobility and hyperlaxity. Scoliosis or rigidity of the spine and delayed motor milestones are also frequently reported. Other manifestations include a long myopathic face and, in rare cases, respiratory failure, mild to moderate intellectual deficiency and short stature. Ambulation may be impaired with time.", "ORPHA ID": 371007, "Summary": ""}
{"Disease Name": "Congenital muscular dystrophy with integrin alpha-7 deficiency", "Disease Definition": "Congenital muscular dystrophy with integrin alpha-7 deficiency is a rare, genetic, congenital muscular dystrophy due to extracellular matrix protein anomaly characterized by early motor development delay and muscle weakness with mild elevation of serum creatine kinase, that may be followed by progressive disease course with predominantly proximal muscle weakness and atrophy, motor development regress, scoliosis and respiratory insufficiency.", "ORPHA ID": 34520, "Summary": ""}
{"Disease Name": "Congenital muscular dystrophy with intellectual disability and severe epilepsy", "Disease Definition": "A rare, fatal, inborn error of metabolism disorder characterized by respiratory distress and severe hypotonia at birth, severe global developmental delay, early-onset intractable seizures, myopathic facies with craniofacial dysmorphism (trigonocephaly/progressive microcephaly, low anterior hairline, arched eyebrows, hypotelorism, strabismus, small nose, prominent philtrum, thin upper lip, high-arched palate, micrognathia, malocclusion), severe, congenital flexion joint contractures and elevated serum creatine kinase levels. Scoliosis, optic atrophy, mild hepatomegaly, and hypoplastic genitalia may also be associated.", "ORPHA ID": 329178, "Summary": ""}
{"Disease Name": "Congenital muscular dystrophy with intellectual disability", "Disease Definition": "A rare, genetic, congenital muscular dystrophy due to dystroglycanopathy disorder characterized by a wide phenotypic spectrum which includes hypotonia and muscular weakness present at birth or early infancy and delayed or arrested motor development, associated with mild to severe intellectual disability and variable brain abnormalities on neuroimaging studies. Feeding difficulties, joint and spinal deformities, respiratory insufficiency, and ocular anomalies (e.g. strabismus, retinal dystrophy, oculomotor apraxia) may be associated. Decreased or absent alpha-dystroglycan on immunohistochemical muscle staining and elevated serum creatine kinase are observed.", "ORPHA ID": 370968, "Summary": ""}
{"Disease Name": "Congenital muscular dystrophy without intellectual disability", "Disease Definition": "A rare, genetic, congenital muscular dystrophy due to dystroglycanopathy characterized by a wide phenotypic spectrum which includes hypotonia and muscular weakness present at birth or early infancy, delayed or arrested motor development, and normal intellectual abilities with normal (or only mild abnormalities) neuroimaging studies. Feeding difficulties, joint and spinal deformities, and respiratory insufficiency may be associated. Decreased alpha-dystroglycan on immunohistochemical muscle staining and elevated serum creatine kinase are observed.", "ORPHA ID": 370980, "Summary": ""}
{"Disease Name": "Congenital muscular dystrophy, Fukuyama type", "Disease Definition": "A rare congenital progressive muscular dystrophy often characterized by brain malformation (cobblestone lissencephaly), dystrophic changes in skeletal muscle, severe intellectual deficit, epilepsy and motor impairment.", "ORPHA ID": 272, "Summary": "Epidemiology\nThe disease has a high prevalence in the Japanese population due to an ancestral mutation, and is extremely uncommon elsewhere. The prevalence of Fukuyama type muscular dystrophy (FCMD) in Japan is estimated at 1/25,000-50,000 live births.\nClinical description\nDisease onset typically occurs in early infancy. Initial symptoms include a poor suck, weak cry, floppiness and developmental delay. Symmetrical generalized muscle weakness and hypotonia are present. With time, patients develop retractile phenotype and show contractures of the hips, knees and interphalangeal joints. Later features include myopathic facial appearance, pseudohypertrophy of the calves and forearms, and ophthalmologic abnormalities (visual impairment and retinal dysplasia). Progressive cardiac involvement, respiratory failure and swallowing and feeding disturbances (leading to recurrent aspiration pneumonia and death) occur in infants with severe FCMD and in patients over ten years of age. Seizures (generalized tonic-clonic convulsions, complex partial seizures and partial seizures with secondary generalization, infantile spasms, tonic seizures and myoclonic seizures) occur in over 50% of affected individuals (median age of seizure onset 1-3 years of age). All patients with the Japanese ancestral mutation show severe intellectual deficit and the intelligence quotient (IQ) is usually between 30 and 60.\nEtiology\nIt is caused by mutations in the fukutin gene (FKTN; 9q31-q33). Of note, FKTN variants are responsible for a clinical spectrum ranging from CMD without brain involvement to isolated, dilated cardiomyopathy.\nDiagnostic methods\nThe diagnosis is based on the clinical picture, characteristic neuroimaging and electromyography findings, muscle biopsy results, and molecular genetic testing.\nDifferential diagnosis\nDifferential diagnoses include Duchenne and Becker muscular dystrophies, and other muscular dystrophies associating a type II lissencephaly (known as dystroglycanopathies). Brain, cerebellar and ocular abnormalities observed in most FCMD patients are similar to and would be diagnosed out of Japan as MEB syndrome. Therefore, there is an increasing tendency to use the global term MEB/FCMD syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement includes physiotherapy, treatment of orthopedic, respiratory and cardiac complications, respiratory aid, and medical or surgical treatment for nutritional and gastrointestinal problems. Control of seizures requires antiepileptic drugs. Surveillance includes monitoring for respiratory and cardiac function.\nPrognosis\nPrognosis depends on the severity of complications, mainly neurologic, cardiac or respiratory.\n\n                            Last update: \n                            January 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI | EURO-NMD* - Pr Susana QUIJANO-ROY | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital muscular dystrophy-infantile cataract-hypogonadism syndrome", "Disease Definition": "Congenital muscular dystrophy-infantile cataract-hypogonadism syndrome is characterized by congenital muscular dystrophy, infantile cataract and hypogonadism. It has been described in seven individuals from an isolated Norwegian village and in one unrelated individual. Transmission appears to be autosomal recessive.", "ORPHA ID": 1875, "Summary": ""}
{"Disease Name": "Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome", "Disease Definition": "A rare congenital muscular dystrophy characterized by neonatal hypotonia, life-threatening respiratory failure, and feeding difficulties, furthermore by delayed motor development, severe muscle weakness predominantly affecting axial muscles (leading to poor head control, rigid cervical spine, and severe scoliosis), generalized joint laxity with no or mild contractures, as well as dry skin with follicular hyperkeratosis. Serum creatine kinase is normal or slightly elevated. Muscle biopsy shows fiber size variability, rounded fibers with mild increase of endomysial connective tissue and adipose replacement, abundant minicore lesions, increase of centrally located nuclei, angular fibers, and cap lesions.", "ORPHA ID": 486815, "Summary": ""}
{"Disease Name": "Congenital muscular dystrophy", "Disease Definition": "Congenital muscular dystrophy (CMD) is a heterogeneous group of neuromuscular disorders with onset at birth or infancy characterized by hypotonia, muscle wasting, weakness or delayed motor milestones. The group includes myopathies with abnormalities at different cellular levels: the extracellular matrix (MDC1A, UCMD; see these terms), the dystrophin-associated glycoprotein complex (alphadystroglycanopathies, integrinopathies see these terms), the endoplasmic reticulum (rigid spine syndrome [RSMD1], and the nuclear envelope (LMNA-related CMD; [L-CMD] and Nesprin-1-related CMD; see these terms).", "ORPHA ID": 97242, "Summary": "Epidemiology\nThe prevalence of CMDs is not well known but is estimated at about 1-9/100,000 in countries where they are most frequent. Males and females are equally affected.\nClinical description\nOrthopaedic and respiratory complications that may be life-threatening often develop in the course of the disease.\nEtiology\nCMDs have autosomal recessive inheritance with the exception of dominant mutations possible in at least two forms (UCMD may have autosomal dominant or recessive inheritance; L-CMD is due to dominant de novo mutations). At least 15 genes are known to be responsible for this group of disorders.\nDiagnostic methods\nDiagnosis is often difficult due to the wide clinical, immunohistochemical and genetic heterogeneity. The diagnosis is based on clinical findings, immunochemical staining on muscle biopsy, and molecular genetic testing. Increased creatine kinase (CK) levels, presence of intellectual deficiency and type of distribution of different signs or symptoms are useful markers to distinguish different forms. CMDs due to collagen VI disorders are complex and may need additional studies in skin fibroblasts.\nDifferential diagnosis\nDifferential diagnoses include congenital and early onset neuromuscular disorders, mainly congenital myopathies, spinal muscular atrophy and congenital myasthenic syndromes (see these theses terms). Patients with mutations in genes identified in other neighbour muscular disorders such as congenital myopathies may present sometimes as a CMD (including the finding of dystrophic features on muscle biopsy) without specific ultrastructural abnormalities on muscle biopsy.\nAntenatal diagnosis\nAntenatal diagnosis is feasible through molecular analysis of amniocytes and in some forms coupled with immunohistochemical staining of chorionic villus samples (MDC1A).\nManagement and treatment\nCurrently there is no curative therapy, but supportive treatments. Besides global and nutritional management, common restrictive respiratory insufficiency may need mechanical respiratory assistance. Orthopedic complications (joint contractures, spinal deformities) are a main concern and preventive or proactive treatment by regular physical and occupational therapies and trunk and limb orthesis is often useful to reduce the severity and course of the deformities. Surgical interventions in spine (spinal fusion) are used to correct or stabilise the spine if scoliosis develops. Tenotomies are also used to reduce the severity of joint contractures but do not have always a beneficial result. Cardiac and neurological symptoms may be particularly severe in certain forms and require specific treatment. Psychological support is very helpful for patients or families.\nPrognosis\nThe prognosis depends on the type of congenital muscular dystrophy. Respiratory insufficiency and brain pathology are the main causes of mortality.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Susana QUIJANO-ROY"}
{"Disease Name": "Congenital myasthenic syndrome", "Disease Definition": "Congenital myasthenic syndrome (CMS) is a group of genetic disorders of impaired neuromuscular transmission at the motor endplate characterized by fatigable muscle weakness.", "ORPHA ID": 590, "Summary": ""}
{"Disease Name": "Congenital myopathy with excess of thin filaments", "Disease Definition": "A rare, genetic, congenital myopathy disorder characterized by variable degrees of muscular weakness, frequently associated with severe nemaline myopathy-like disease (including neonatal hypotonia, lack of spontaneous movements, feeding and swallowing difficulties, frequent respiratory infections, respiratory insufficiency, early death), and histopathologic findings of large, densely packed, subsarcolemmal accumulations of thin, actin-immunopositive filaments (with or without intranuclear nemaline rods) on muscle biopsy.", "ORPHA ID": 98904, "Summary": ""}
{"Disease Name": "Congenital myopathy with internal nuclei and atypical cores", "Disease Definition": "Congenital myopathy with internal nuclei and atypical cores is a rare genetic skeletal muscle disease characterized by neonatal hypotonia, distal more than proximal muscle weakness, progressive exercise intolerance with prominent myalgias, and mild-to-moderate overall motor impairment with preserved ambulation. Face, extraocular, cardiac, and respiratory muscles are unaffected. Mild cognitive impairment is also noted in most patients.", "ORPHA ID": 319160, "Summary": ""}
{"Disease Name": "Congenital myopathy with myasthenic-like onset", "Disease Definition": "Congenital myopathy with myasthenic-like onset is a rare, genetic, non-dystrophic myopathy characterized by fatigable muscle weakness associated with congenital myopathy. Patients present with axial hypotonia, myopathic facies with fatigable ptosis, feeding difficulties, delayed gross motor development and proximal limb weakness with a RYR1-related typical pattern of muscle involvement (i.e. severe involvement of the soleus muscle and sparring of the rectus femoris, sartorius, gracilis and semitendinous muscles). Scoliosis and frequent respiratory tract infections are additional observed features.", "ORPHA ID": 424107, "Summary": ""}
{"Disease Name": "Congenital myopathy with reduced type 2 muscle fibers", "Disease Definition": "A rare congenital myopathy characterized by neonatal onset of severe muscle weakness with selective atrophy/hypotrophy or absence of type II myofibers. Patients present at birth with hypotonia and respiratory failure, as well as mild facial and severe axial and proximal upper and lower limb weakness with areflexia and mild contractures. Eye movements and cardiac function are normal.", "ORPHA ID": 544602, "Summary": ""}
{"Disease Name": "Congenital myopathy, Paradas type", "Disease Definition": "A rare congenital muscular dystrophy characterized by early onset of hypotonia, delayed motor development, and variably progressive generalized muscle weakness. Predominant involvement of pelvic and neck flexor muscles has been reported, as well as early involvement of hamstrings and medial gastrocnemius visible on muscle MRI. Serum creatine kinase levels are markedly elevated (in some cases already from early childhood). Muscle biopsy shows absence of dysferlin.", "ORPHA ID": 199329, "Summary": ""}
{"Disease Name": "Congenital nephrotic syndrome, Finnish type", "Disease Definition": "A rare congenital nephrotic syndrome characterized by massive protein loss and marked edema manifesting in utero or during the first 3 months of life.", "ORPHA ID": 839, "Summary": "Epidemiology\nThis type of nephrotic syndrome is more frequent in Finland with a prevalence of 1/8,200 births. The disease is observed in various ethnic groups worldwide but the prevalence is unknown.\nClinical description\nAffected children show massive proteinuria and edema starting in utero (fetal hydrops). Children usually have low birth weight and are born prematurely; the weight of the placenta constitutes more than 25% of the birth weight. Severe nephrotic syndrome develops soon after birth; typical features include hypoalbuminemia, hyperlipidemia, hypothyreosis, abdominal distension and edema with associated failure to thrive, increased susceptibility to thromboembolic events and severe infections. Histologically, microcystic dilatations of the tubules are seen whereas glomeruli are only slightly modified initially, with variable mesangial cell hypercellularity and/or endocapillary hypercellularity. Electron microscopy shows glomerular effacement of the podocytes.\nEtiology\nThe disease is caused by recessive mutations in the NPHS1 gene (19q13). NPHS1 encodes for Nephrin, a zipper-like protein, which is essential for the porous structure of the glomerular slit diaphragm. To date more than 200 NPHS1 mutations have been detected but two of them have a particular high frequency in affected Finnish children, one is a two base pair deletion in exon 2 resulting in a truncated protein (Fin-major) and the other is a nonsense mutation in exon 26 (Fin minor). These two mutations are observed in 94% of Finnish patients but are quite rare outside Finland.\nDiagnostic methods\nThe diagnosis is suspected on clinical grounds and confirmed by genetic analysis.\nDifferential diagnosis\nDifferential diagnoses include other forms of early onset nephrotic syndrome, including Denys Drash syndrome, Pierson syndrome, Galloway Mowat syndrome, Schimke immuno-osseous dysplasia and congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization.\nAntenatal diagnosis\nAntenatal proteinuria results in an up to 10-fold increase in alpha-fetoprotein concentrations as early as in the 15th week of gestation, with a parallel but smaller rise in the maternal serum level. However, heterozygous mutations in the NPHS1 gene can also lead to increased levels of alpha-fetoprotein, leading to misdiagnosis. Reliable antenatal diagnosis is achieved by gene analysis on a trophoblastic sample.\nGenetic counseling\nThe pattern of disease transmission is autosomal recessive. The risk of recurrence in siblings of an affected individual is 25%.\nManagement and treatment\nThe nephrotic syndrome does not respond to any immunosuppressive therapy and treatment is largely symptomatic, comprising frequent albumin infusions, protein-rich diet, anti-proteinuric pharmacotherapy with RAS (renin-angiotensin system) inhibitors and indomethacin, anticoagulation, thyroid hormone supplementation and aggressive treatment of infections. In case of failure to thrive despite these measures, uni- or bilateral nephrectomy may be necessary to stop the massive protein loss.\nPrognosis\nWith adequate supportive care, most children survive long-term but develop end-stage kidney disease requiring renal replacement therapy within the first 2-3 years of life. Five-year patient and graft survival after transplantation is around 90%, similar as in infants with other causes of end-stage kidney disease. Post-transplant disease recurrence is limited to patients who are homozygous for the Fin major mutation, who have a 30% risk to develop de novo glomerulonephritis due to circulating anti-nephrin antibodies.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Franz SCHAEFER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital neutropenia-myelofibrosis-nephromegaly syndrome", "Disease Definition": "A rare, genetic, primary immunodeficiency disorder characterized by severe congenital neutropenia, bone marrow fibrosis and neutrophil dysfunction which is refractory to granulocyte colony-stimulating factor, manifesting with life-threatening infections and/or deep-seated abscesses, hepato-/splenomegaly, thrombocytopenia, hypergammaglobulinemia, anemia with reticulocytosis and nephromegaly. Other reported features include osteosclerosis and neurological abnormalities (e.g. developmental delay, cortical blindness, hearing loss, thin corpus callosum or dysrhythmia on EEG).", "ORPHA ID": 369852, "Summary": ""}
{"Disease Name": "Congenital oculomotor nerve palsy", "Disease Definition": "A rare ophthalmic disorder with cranial nerve involvement characterized by partial or complete ptosis and ophthalmoplegia with impaired ability to elevate, depress, or adduct the eyeball, causing strabismus and amblyopia. The pupils can also be dilated. The condition is typically unilateral and may present with or without aberrant regeneration.", "ORPHA ID": 440221, "Summary": ""}
{"Disease Name": "Congenital osteogenesis imperfecta-microcephaly-cataracts syndrome", "Disease Definition": "A rare multiple congenital malformations/dysmorphic syndrome characterized by osteogenesis imperfecta with multiple prenatal bone fractures, joint laxity, severe microcephaly, and bilateral cataracts. Additional reported manifestations include dysmorphic facial features (such as blue sclerae, hypertelorism, and low-set ears), lissencephaly, hydrocephalus, and cardiac and genital anomalies. The syndrome is lethal in utero or shortly after birth. There have been no further descriptions in the literature since 1978.", "ORPHA ID": 2772, "Summary": ""}
{"Disease Name": "Congenital pancreatic cyst", "Disease Definition": "A rare pancreatic disease characterized by a most commonly single, unilocular, thin-walled cystic lesion which may be located anywhere within the pancreas (but is more frequently found in the body and tail) and does not communicate with the pancreatic ductal system. Patients may be asymptomatic or present with signs and symptoms of gastrointestinal or biliary obstruction, or pancreatitis. The condition can be isolated or occur in association with other anomalies (such as von Hippel-Lindau disease or polycystic kidney disease).", "ORPHA ID": 313906, "Summary": ""}
{"Disease Name": "Congenital panfollicular nevus", "Disease Definition": "Congenital panfollicular nevus is a rare, benign, skin tumor disorder characterized by the presence of congenital, large (few centimeters), elevated, well-circumscribed, pink-tan, multinodular, non-ulcerative, bosselated-surface skin lesions located on the neck, scalp or hand and which enlarge with time. Histologically, hamartomatous proliferation containing irregularly arranged, malformed hair follicles in various stages of development, surrounded by fibrous tissue and densely distributed within the dermis is observed.", "ORPHA ID": 139414, "Summary": ""}
{"Disease Name": "Congenital partial agenesis of pericardium", "Disease Definition": "Congenital partial agenesis of pericardium is a rare, mostly asymptomatic, congenital heart malformation mainly characterized by the partial absence of the left pericardium. It is occasionally associated with chest pain or dyspnea and is usually incidentally diagnosed during surgery or at autopsy. Herniation and strangulation of a portion of the heart through the pericardial foramen may occur, resulting in myocardial acute ischemia and possible sudden death. Right side pericardium involvement is rare.", "ORPHA ID": 99130, "Summary": ""}
{"Disease Name": "Congenital partial pulmonary venous return anomaly", "Disease Definition": "A form of congenital pulmonary venous return where one or a few of the pulmonary veins drain into the right atrium or one of its tributaries instead of the left atrium. Some patients can be asymptomatic while others can manifest with non-specific signs such as frequent respiratory infections, fatigue and exertional dyspnea.", "ORPHA ID": 99124, "Summary": ""}
{"Disease Name": "Congenital patella dislocation", "Disease Definition": "A rare congenital limb malformation characterized by permanent and manually irreducible lateral dislocation of the kneecap. It typically presents with flexion contracture of the knee, genu valgus, absent or dysplastic trochlear groove of the femur, external rotation of the tibia, and dysfunction of the extensor mechanism. The defect may be unilateral or bilateral and can occur as an isolated malformation, be associated with other malformations of the lower limb, or be part of a polymalformative syndrome.", "ORPHA ID": 295036, "Summary": ""}
{"Disease Name": "Congenital patent ductus arteriosus aneurysm", "Disease Definition": "A rare, congenital, arterial duct anomaly characterized by a saccular dilatation of the ductus arteriosus. It is often asymptomatic or presents shortly after birth with respiratory distress, stridor, cyanosis and/or weak cry. Complications, such as rupture, thromboembolism, infection, airway erosion and/or compression of the adjacent thoracic structures, can develop. Spontaneous resolution has been reported.", "ORPHA ID": 99072, "Summary": ""}
{"Disease Name": "Congenital pericardium anomaly", "Disease Definition": "Congenital pericardium anomaly comprises a group of rare congenital cardiac malformations characterized by the complete (Congenital complete agenesis of pericardium) or partial absence of the pericardium (Congenital partial agenesis of pericardium), or by the presence of pericardial cysts (Pleuropericardial cyst) (see these terms).", "ORPHA ID": 2846, "Summary": ""}
{"Disease Name": "Congenital plasminogen activator inhibitor type 1 deficiency", "Disease Definition": "A rare hemorrhagic disorder due to a constitutional haemostatic factors defect characterized by premature lysis of hemostatic clots and a moderate bleeding tendency.", "ORPHA ID": 465, "Summary": "Epidemiology\nCongenital plasminogen activator inhibitor type 1 (PAI-1) prevalence and incidence remain unknown. Both partial and total PAI-1 deficiencies are extremely rare disorders. In the Amish community (Indiana, USA), eighteen homozygous patients with clinical symptoms and more than 100 heterozygous patients without bleeding symptoms have been reported to date. Additional cases have been reported from North America, Europe and Asia.\nClinical description\nClinical signs of congenital PAI-1 deficiency may appear in early childhood. Spontaneous bleeding is rarely observed, whereas easy bruising or moderate hemorrhage localized to the joints (knees, elbows), nose and gingiva are usually triggered by mild trauma. Menstrual bleeding may be severe, and prolonged bleeding after surgery is common. Hemorrhage is less frequent and less severe (or absent) in heterozygous individuals (partial deficiency) and clinical manifestations, if any, may appear late in life after a traumatic or surgical event.\nEtiology\nAffected patients carry one (heterozygote) or two (homozygote) alleles with a mutation in the SERPINE1 gene (7q22.1), resulting in partial or total antigenic PAI-1 deficiency. PAI-1 is the physiological inhibitor of tissue-type plasminogen activator (t-PA), the main source of intravascular fibrinolysis. PAI-1 deficiency is a quantitative defect; however, in some patients the protein is present but functionally inactive.\nDiagnostic methods\nThe diagnosis is based on antigenic (ELISA) and functional (plasminogen activator inhibition test) assays of PAI-1. A genotype analysis may be necessary in family studies. Molecular genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes acquired PAI-1 deficiency and alpha2-antiplasmin deficiency.\nGenetic counseling\nHeterozygotes are asymptomatic carriers. Carrier testing must be performed for relatives of affected patients with the SERPINE1 genetic variant.\nManagement and treatment\nPrompt diagnosis is essential since hemorrhages can be safely and efficiently treated with fibrinolysis inhibitors (epsilon amino-caproic acid or tranexamic acid), avoiding the use of blood and derivatives. Menstruation and pregnancy require special consideration with regard to diagnosis and treatment with antifibrinolytics.\nPrognosis\nThe prognosis is generally good as bleeding can be prevented and controlled with antifibrinolytic treatment.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Eduardo ANGLES-CANO  - Pr Aurora DE LA PEÑA"}
{"Disease Name": "Congenital portosystemic shunt", "Disease Definition": "Congenital portosystemic shunt is a rare, congenital anomaly of the great veins characterized by an abnormal communication between one or more veins of the portal and the caval systems, resulting in complete or partial diversion of the portal blood away from the liver to the systemic circulation. Clinical manifestations include liver atrophy, hypergalactosemia without uridine diphosphate enzyme deficiency, hyperammonemia, encephalopathy (resulting in learning disabilities, extreme fatigability and seizures), pulmonary hypertension, hypoxemia from hepatopulmonary syndrome and benign or malignant tumours.", "ORPHA ID": 480531, "Summary": ""}
{"Disease Name": "Congenital prekallikrein deficiency", "Disease Definition": "A rare genetic coagulation disorder characterized by the usually incidental laboratory finding of a prolonged activated partial thromboplastin time (aPTT) but normal prothrombin time, due to a deficiency of normal prekallikrein or the presence of nonfunctional prekallikrein. Most patients remain clinically asymptomatic, although an association with cardiovascular conditions (hypertension, myocardial infarction, other coronary artery diseases, and ischemic strokes) and venous thrombosis, as well as rare cases with increased bleeding tendency have been reported.", "ORPHA ID": 749, "Summary": ""}
{"Disease Name": "Congenital primary aphakia", "Disease Definition": "A rare developmental defect during embryogenesis characterised by an absence of the lens. CPAK can be associated with variable secondary ocular defects.", "ORPHA ID": 83461, "Summary": "Epidemiology\nCongenital primary aphakia (CPAK) prevalance is unknown.\nClinical description\nCPAK is a congenital eye defect presenting at birth with no lens formation, resulting from a failure of lens induction from the surface ectoderm and aborted lens development. CPAK is often associated with other ocular anomalies, including aplasia/dysplasia of the anterior segment of the eye, microphthalmia, glaucoma.\nEtiology\nCPAK is caused by variants in the FOXE3 gene. Most cases are autosomal recessive. It is important to note that both dominant and recessive variants in FOXE3 are associated with a variable mixed phenotype of developmental eye disorders including anterior segment dysgenesis, microphthalmia, Peters anomaly, sclerocornea, early-onset cataract, glaucoma and ocular coloboma.\nDiagnostic methods\nMolecular diagnosis can be made through genetic testing, for example whole exome/genome sequencing and can be validated by bi-directional Sanger sequencing. Clinical diagnosis can be made based on clinical examination and confirmed with ultrasound. Anterior segment ultrasound biomicroscopy may aid detection of co-existent anterior segment dysgenesis. Due to the association of CPAK and the rubella virus, a TORCH complex evalutation is also recommended.\nAntenatal diagnosis\nTransabdominal ultrasound at 23 weeks gestation has detected CPAK.\nGenetic counseling\nGenetic testing for FOXE3 variants will provide a molecular diagnosis. This yields information regarding carrier status and provide choices that would not otherwise be available to facilitate decision making for the patient and their family. Genetic testing is essential for defining inheritance patterns, carrier status and enabling effective genetic counselling with consequent implications for prenatal or pre-implantation genetic diagnosis.\nManagement and treatment\nCPAK should be managed by specialists with expertise in the condition. Supportive measures for those with sight impairment include involvement of social services. Regular follow-up will be required to monitor progression of associated anterior segment dysgenesis and glaucoma with medical and surgical interventions where needed. Intraocular surgery is not advised unless steps are taken to avoid inflammatory membrane formation and subsequent retinal detachment. Regular refraction to reduce/prevent amblyopia. Genetic counselling should be offered to the family.\nPrognosis\nEarly diagnosis will enable prompt supportive treatment.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Mariya MOOSAJEE  -  Hajrah SARKAR"}
{"Disease Name": "Congenital primary lymphedema of Gordon", "Disease Definition": "A rare primary lymphedema characterized by bilateral, painless lower limb swelling present at birth. Prominent veins around the ankles and on the dorsa of the feet, dysplastic and upslanting toenails due to edema of the nailbed, and subtle dysmorphic facial features (such as high forehead, hypertelorism, depressed nasal bridge, mild bilateral ear dysplasia, and short neck) have also been described. The degree of lymphatic impairment is milder than in the otherwise clinically similar Milroy disease, as evidenced by slightly less severe lymphedema and significantly more uptake of tracers on lymphoscintigraphy.", "ORPHA ID": 569821, "Summary": ""}
{"Disease Name": "Congenital primary megaureter", "Disease Definition": "A rare non-syndromic urogenital tract malformation characterized by a dilated ureter and normal bladder and bladder outlet. It may be obstructed, refluxing or unobstructed and not refluxing.", "ORPHA ID": 617, "Summary": "Epidemiology\nPrevalence is unknown, but primary megaureter (PM) is the second most common cause of neonatal hydronephrosis. The male to female ratio is nearly 4:1. The left side is more often affected than right (1.6-4.5 times). The incidence of obstructed megaureter is 1/10,000.\nClinical description\nAbout half of cases are asymptomatic (most of these unobstructed nonrefluxing) and discovered on routine antenatal ultrasound. PM is usually diagnosed in children but may present in adults. Symptomatic PM presents with urinary tract infections (UTI), hydronephrosis, fever and abdominal and flank pain. Microscopic hematuria is frequent, may occur without infection and may indicate calculus formation. Patients rarely present with signs of renal failure. Bilateral PM occurs in ~20% of cases and is more likely in children presenting < 1 year old. In unilateral PM, the contra-lateral kidney is absent or dysplastic in 10-15% of patients. ''Obstructed PM'' is the term used when ureteral dilatation due to restricted urinary outflow will cause progressive renal deterioration if untreated.\nEtiology\nThe cause is unknown. It may be due to high fetal urine outflow, changes in the ureter pre-/postnatal or transient anatomical obstructions that improve with postnatal development, such as ureteral folds. Refluxing PM is due to short or absent intravesical ureter, congenital paraureteric diverticulum or other derangement of the vesico-ureteric junction. Obstructed PM occurs when the aperistaltic juxtavesical segment is unable to transport urine at acceptable rates. The cause may be excessive collagen deposition, hypertrophy of ureter muscle, thick periureteral tissues or a circumferential segment devoid of muscle. PM is not known to be hereditary but families with multiple affected members were described.\nDiagnostic methods\nDiagnosis is based on clinical presentation and confirmed by US. Reflux is diagnosed using voiding cystourethrography. Diuretic renography evaluates urine transport dysfunction. Doppler US, MRI and pressure flow studies have been suggested to determine obstruction.\nDifferential diagnosis\nDifferential diagnoses include causes of secondary megaureter: polyuria (diabetes insipidus), infection, bladder outlet obstruction, neuropathic bladder, infravesical obstruction or extrinsic lesions.\nAntenatal diagnosis\nScanning starts at 16-18 weeks of gestation and is repeated depending on the clinical findings. The 28th week is the most sensitive for UT evaluation. Attention must be paid to laterality and grade of dilatation, bladder volume and dynamic of emptying, sex, other malformations, amount of amniotic fluid and echogenicity of the kidneys.\nGenetic counseling\nAt the moment, there is no evidence of genetic cause. Congenital PM can co-occur with other syndromic malformations for which genetic counseling may be indicated (e.g. prune belly, megacystis, Hirschsprung disease, Down syndrome, etc.).\nManagement and treatment\nAntibiotic prophylaxis is started routinely in prenatally detected cases. For refluxing PM, medical management is appropriate during infancy and is continued depending on grade of vesicoureteral reflux and symptoms (UTI and/or renal scars). Surgery is recommended for persistent high-grade reflux in older children. There is no consensus about timing/type of correction; endoscopic subureteric injections of bulking agents or surgical ureteric reimplantation are possible. Nonrefluxing unobstructed PM usually does not require surgery; regular follow-up with antibiotic prophylaxis results in reduction of UT dilation and no deterioration of renal function in 85% of cases. For obstructed PM, surgery is only indicated in cases of significant impairment to urine flow, persistent pain, pyelonephritis, calculi or a decrease in renal function. Temporary endoscopic stenting (with/without previous balloon dilatation) or surgical reimplantation are the preferred options.\nPrognosis\nPM often resolve spontaneously within the first two years of life, with the maturation of the UT.\n\n                            Last update: \n                            June 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Marco CASTAGNETTI  - Dr Giovanni MOSIELLO | EUROGEN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by early-onset progressive bone marrow failure with anemia, leukopenia, mild thrombopenia, and myelodysplastic features, as well as non-hematologic manifestations, such as developmental delay, cataracts, facial dysmorphism, short stature, and skeletal anomalies. Immunodeficiency primarily affects B-cells and may lead to increased susceptibility to infections. Additional reported features include dry skin and eczema, cardiac anomalies, hearing loss, and reduction of cerebral volume on brain imaging.", "ORPHA ID": 508542, "Summary": ""}
{"Disease Name": "Congenital pseudoarthrosis of the clavicle", "Disease Definition": "A rare dysostosis of genetic origin characterized by a painless mass over the clavicle which is due to the failure of the union process of the ossification nuclei of the clavicle.", "ORPHA ID": 66630, "Summary": "Epidemiology\nCurrently, the reported incidence in UK is 1/17,500 livebirths and over 400 cases are described in literature. The condition is most likely underdiagnosed. No gender prevalence was observed.\nClinical description\nThe condition is a typically monolateral painless bulge in the mid-portion of the clavicle, which involves the right side in over 90% of cases. Association with cervicothoracic abnormalities (e.g. cervical ribs) is uncommon (<5%). Association with dextrocardia, in case of involvement of the left clavicle, is unproven.\nEtiology\nEtiology is unknown. Familial inheritance or syndromic association is sporadic (<3%).\nDiagnostic methods\nDiagnosis is usually made during the first years of life by clinical examination and confirmed by plain radiographs.\nDifferential diagnosis\nDifferential diagnosis includes obstetric fracture, post-traumatic nonunion, cleidocranial dysostosis and neurofibromatosis.\nAntenatal diagnosis\nNo case of prenatal diagnosis is reported.\nGenetic counseling\nGenetic counseling is mainly recommended to rule out other similar conditions (cleidocranial dysostosis or neurofibromatosis).\nManagement and treatment\nSurgical repair is recommended in case of pain and functional impairment; other indications include cosmetic issues. The most used surgical procedure consists of open debridement, refreshing of bone ends, fixation with pin or plate and autologous bone graft from iliac crest. The rate of successful union is close to 90%.\nPrognosis\nThe condition is benign. Patients may remain asymptomatic during their entire life. The shoulder's range of movement is usually unimpaired, with no associated pain. In most cases it represents only an esthetic issue. Nevertheless, symptoms may have an apparent slight increase with age, although sufficient information regarding the natural history of the pathology during the adulthood is lacking, especially in untreated patients.\n\n                            Last update: \n                            December 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Alessandro DEPAOLI  - Dr Giovanni TRISOLINO  - Dr Paola ZARANTONELLO"}
{"Disease Name": "Congenital pseudoarthrosis of the femur", "Disease Definition": "A rare bone development disorder characterized by abnormal bowing and subsequent non-healing fracture of the femur resulting in the formation of a false joint (pseudoarthrosis), which is already present at birth. The affected bone is shortened and angulated at the site of the pseudoarthrosis. Congenital hip dysplasia and absence of the patella have been reported in association.", "ORPHA ID": 295020, "Summary": ""}
{"Disease Name": "Congenital pseudoarthrosis of the fibula", "Disease Definition": "A rare bone development disorder characterized by abnormal bowing of the fibula with subsequent non-healing fractures and formation of a false joint (pseudoarthrosis), and instability and angulation at the pseudoarthrosis site. The defect is typically unilateral and often associated with pseudoarthrosis of the tibia and neurofibromatosis type 1.", "ORPHA ID": 295022, "Summary": ""}
{"Disease Name": "Congenital pseudoarthrosis of the radius", "Disease Definition": "A rare bone development disorder characterized by abnormal bowing of the radius and subsequent non-healing fracture with formation of a false joint (pseudoarthrosis), instability and angulation at the pseudoarthrosis site, and shortening of the forearm. Additional signs and symptoms include radial deviation in the wrist joint and limited pronation and supination of the forearm. Neurofibromatosis type 1, osteofibrous dysplasia, and bowing and pseudoarthrosis of the ulna are frequently associated.", "ORPHA ID": 295024, "Summary": ""}
{"Disease Name": "Congenital pseudoarthrosis of the tibia", "Disease Definition": "A rare bone development disorder characterized by mostly anterolateral bowing of the tibia usually evident at birth, with subsequent non-healing fractures and formation of a false joint (pseudoarthrosis), and instability and angulation at the pseudoarthrosis site. In the vast majority of patients the defect is unilateral, and more than half of the cases are associated with neurofibromatosis type 1.", "ORPHA ID": 295018, "Summary": ""}
{"Disease Name": "Congenital pseudoarthrosis of the ulna", "Disease Definition": "A rare bone development disorder characterized by abnormal bowing of the ulna and subsequent non-healing fracture with formation of a false joint (pseudoarthrosis), instability and angulation at the pseudoarthrosis site, and shortening of the forearm. Additional signs and symptoms include concomitant bowing of the radius, abnormalities of the humeroulnar joint, and limited pronation or supination of the forearm. Neurofibromatosis type 1 and osteofibrous dysplasia are frequently associated.", "ORPHA ID": 295026, "Summary": ""}
{"Disease Name": "Congenital ptosis", "Disease Definition": "Congenital ptosis is characterized by superior eyelid drop present at birth.", "ORPHA ID": 91411, "Summary": "Epidemiology\nPrevalence is unknown.\nEtiology\nIsolated congenital ptosis is unilateral in 75% of the cases.\nGenetic counseling\nTwo patterns of inheritance have been described in familial cases: autosomal dominant and X-linked.\nManagement and treatment\nA medical or surgical treatment can potentially be proposed, depending on the severity of ptosis.\n\n                            Last update: \n                            April 2007"}
{"Disease Name": "Congenital pulmonary airway malformation type 0", "Disease Definition": "A rare subtype of congenital pulmonary airway malformation characterized by global arrest of lung development with small, solid appearing lungs with a diffusely granular surface, histologically featuring bronchus-like structures with smooth muscle, glands, and numerous cartilage plates, embedded in loose, vascular mesenchymal tissue. The condition presents at birth and is incompatible with life.", "ORPHA ID": 280827, "Summary": ""}
{"Disease Name": "Congenital pulmonary airway malformation type 1", "Disease Definition": "A rare subtype of congenital pulmonary airway malformation characterized by a multicystic mass of non-functioning lung tissue with one or more dominant cysts of 2 to 10 cm in diameter, which may be surrounded by smaller cysts. The lesions have intracystic communications, can be connected to the tracheobronchial tree, and are usually unilateral, involving a single lobe. Small lesions may remain asymptomatic, while most cases present with respiratory distress in the neonatal period or in infancy, or with recurrent respiratory infections later in life. Pulmonary hypoplasia and severe fetal hydrops are rare complications. The condition is associated with an increased risk of pulmonary malignancy, such as bronchoalveolar carcinoma.", "ORPHA ID": 280832, "Summary": ""}
{"Disease Name": "Congenital pulmonary airway malformation type 2", "Disease Definition": "A rare subtype of congenital pulmonary airway malformation characterized by a multicystic mass of non-functioning lung tissue, consisting of small cysts of less than 2 cm in diameter. The lesions have intracystic communications, can be connected to the tracheobronchial tree, and are usually unilateral, involving a single lobe. The condition often presents with respiratory distress in the neonatal period or in infancy. It is frequently associated with other severe congenital anomalies, such as renal agenesis or dysgenesis, pulmonary sequestration, or cardiac abnormalities.", "ORPHA ID": 280840, "Summary": ""}
{"Disease Name": "Congenital pulmonary airway malformation type 3", "Disease Definition": "A rare subtype of congenital pulmonary airway malformation characterized by a multicystic mass of non-functioning lung tissue consisting of numerous microcysts of less than 0.5 cm in diameter. The lesions have intracystic communications, can be connected to the tracheobronchial tree, and are usually unilateral, involving an entire lobe. The condition may be associated with polyhydramnios, fetal hydrops, and stillbirth, or present with severe respiratory distress in the neonatal period.", "ORPHA ID": 280847, "Summary": ""}
{"Disease Name": "Congenital pulmonary airway malformation type 4", "Disease Definition": "A rare subtype of congenital pulmonary airway malformation characterized by a multicystic mass of non-functioning lung tissue, with peripheral, large, thin-walled, often multiloculated cysts, which may be 8 cm in diameter. The lesions have intracystic communications, can be connected to the tracheobronchial tree, and are usually unilateral, involving a single lobe. Patients present with respiratory distress or respiratory infections in the neonatal period or in infancy. The condition is often associated with tension pneumothorax, signs of mediastinal shift, and malignant transformation to pleuropulmonary blastoma type 1.", "ORPHA ID": 280854, "Summary": ""}
{"Disease Name": "Congenital pulmonary airway malformation", "Disease Definition": "A rare respiratory malformation characterized by a hamartomatous mass of non-functioning lung tissue of variable extent and with variable degrees of cystic or adenomatoid change. Clinical presentation, prognosis, and presence of associated abnormalities depend on the subtype of the lesion. Based on histopathological findings, five subtypes (types 0 to 4) can be differentiated.", "ORPHA ID": 2444, "Summary": ""}
{"Disease Name": "Congenital pulmonary lymphangiectasia", "Disease Definition": "A rare developmental disorder involving the lung and characterized by pulmonary subpleural, interlobar, perivascular, and peribronchial lymphatic dilatation.", "ORPHA ID": 2414, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nCongenital pulmonary lymphangiectasia (PL) presents at birth with severe respiratory distress, tachypnea and cyanosis, with a very high mortality rate at or within a few hours of birth.\nEtiology\nMost reported cases are sporadic and the etiology is not completely understood. It has been suggested that PL lymphatic channels of the fetal lung do not undergo the normal regression process at 20 weeks of gestation. Secondary PL may be caused by a cardiac lesion.\nDiagnostic methods\nThe diagnostic approach includes obtaining a complete family and obstetric history, conventional radiologic studies, ultrasound and magnetic resonance studies, lymphoscintigraphy, lung functionality tests, lung biopsy, bronchoscopy, and pleural effusion examination.\nDifferential diagnosis\nDuring the prenatal period, all causes leading to hydrops fetalis should be considered in the diagnosis of PL.\nAntenatal diagnosis\nFetal ultrasound evaluation plays a key role in the antenatal diagnosis of PL.\nManagement and treatment\nAt birth, mechanical ventilation and pleural drainage are nearly always necessary to obtain a favorable outcome of respiratory distress. Home supplemental oxygen therapy and symptomatic treatment of recurrent cough and wheeze are often necessary during childhood, sometimes associated with prolonged pleural drainage.\nPrognosis\nRecent advances in intensive neonatal care have changed the previously nearly fatal outcome of PL at birth. Patients affected by PL who survive infancy, present medical problems which are characteristic of chronic lung disease.\n\n                            Last update: \n                            October 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Carlo BELLINI  - Pr Francesco BOCCARDO  - Pr Eugenio BONIOLI  - Pr Corradino CAMPISI"}
{"Disease Name": "Congenital pulmonary sequestration", "Disease Definition": "Congenital pulmonary sequestration is a rare respiratory malformation characterized by a cystic or solid mass of nonfunctioning primitive segmental lung tissue that does not communicate with the tracheobronchial tree and has anomalous systemic blood supply. Intralobar pulmonary sequestration may be asymptomatic or may present with recurrent pulmonary infections, hemoptysis, chest pain, cough and is usually diagnosed in older children and adults. Extralobar pulmonary sequestration present with respiratory distress, cyanosis, difficulty feeding or infection, may be associated with other anomalies and is mostly diagnosed in neonates or infants.", "ORPHA ID": 3161, "Summary": ""}
{"Disease Name": "Congenital pulmonary valvar stenosis", "Disease Definition": "A rare congenital heart malformation characterized by an obstruction to flow through the pulmonary valve with a clinical presentation that may vary from critical stenosis presenting in the neonatal period to asymptomatic mild stenosis. The obstruction at the valvular level can be associated with obstruction at the subpulmonary, or supravalvar levels (valvar, subpulmonary, supravalvar pulmonary stenosis (PS).", "ORPHA ID": 3189, "Summary": "Epidemiology\nThe birth prevalence of isolated pulmonary valvar stenosis is between 1/2,000-10,000 in Europe and, worldwide, accounts for between 5-8% of children born with a congenital heart defect (CHD).\nClinical description\nClinical presentation varies according to age. In neonates, critical pulmonary stenosis is diagnosed on signs of right heart failure associated with cyanosis due to supra-systemic pressures and right-to-left shunt through the oval foramen, with ductal dependency. In severe untreated forms, dyspnea or syncope on exercise can occur. However, most patients are asymptomatic and diagnosed on presentation of a heart murmur during infancy or childhood. Congenital pulmonary valvar stenosis is most often isolated, with usually thin leaflets, dome-shaped with a central narrow opening. In 6% of children it is associated with a genetic syndrome, with usually thick, dysplastic leaflets. The malformation can also be associated with several complex malformations such as double outlet right ventricle, transposition of the great arteries, and Ebstein anomaly of the tricuspid valve.\nEtiology\nThe etiology for isolated forms is unknown. Occasionally the malformation is associated with a genetic syndrome (typically the RASopathies) such as Noonan, LEOPARD or Costello syndromes, harboring mutations of gene PTPN11.\nDiagnostic methods\nEchocardiography is the best diagnostic tool. It establishes the diagnosis, looks for other levels of right ventricular outflow tract obstruction, and usually provides sufficient information to plan the treatment. CT-scan or MRI can be useful to assess the anatomy of the subpulmonary infundibulum and pulmonary branches.\nDifferential diagnosis\nDifferential diagnosis includes primary pulmonary causes of cyanosis in neonates, along with other cyanotic heart lesions, such as transposition of the great vessels and tetralogy of Fallot.\nAntenatal diagnosis\nDiagnosis on prenatal ultrasound screening is possible but is only detected in approximately 40% of cases; the rate of detection could be improved by the use of color flow Doppler through the outflow tracts.\nGenetic counseling\nThe risk of recurrence of isolated valvar pulmonary stenosis is low, ranging from 1.7 to 3.7%. Relative risk of recurrence of right ventricular outflow tract obstruction as a whole is high at 48.6%.\nManagement and treatment\nPercutaneous balloon valvuloplasty is the treatment of choice of isolated valvar pulmonary stenosis. When the valve is dysplastic with thickened leaflets, or when there is an associated subvalvar or supravalvar obstruction, surgical valvulotomy or valvulectomy is indicated.\nPrognosis\nThe prognosis of mild forms of valvar pulmonary stenosis is good, with stability or even spontaneous decrease of the gradient with age. The prognosis after balloon valvuloplasty is usually excellent. In rare cases of residual or recurrent pulmonary stenosis, a second balloon valvuloplasty can be attempted with good success rates. If it fails, surgery is indicated. Severe pulmonary regurgitation at late follow-up is rare and may require pulmonary valvar replacement, percutaneous or surgical.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Lucile HOUYEL"}
{"Disease Name": "Congenital pulmonary veins atresia or stenosis", "Disease Definition": "A rare progressive and life-threatening anomaly of the great vessels characterized by narrowing and obstruction of one or more normally positioned pulmonary vein at their junction with the left atrium. Presentation is typically during early infancy with dyspnea, tachypnea, and repeated pulmonary infections. Eventually, when all pulmonary veins of one lung are affected, the disorder results in pulmonary hypertension (PH) and consecutive pulmonary arterial hypertension (PAH). It may manifest as an isolated lesion or associated with other cardiac defects such as congenital pulmonary venous return anomaly and septal defects.", "ORPHA ID": 3188, "Summary": ""}
{"Disease Name": "Congenital pulmonary venous return anomaly", "Disease Definition": "A rare developmental defect during embryogenesis where some or all of the pulmonary veins drain into the right atrium or the systemic veins, with or without the presence of pulmonary venous obstruction, leading to various manifestations such as fatigue, exertional dyspnea, pulmonary arterial hypertension, cyanosis and progressive congestive heart failure. The two main subtypes are congenital partial pulmonary venous return anomaly (PAPVC; see this term), where one or a few of the pulmonary veins are anomalous, and congenital total pulmonary venous return anomaly (TAPVC, see this term), where all of the pulmonary veins are anomalous.", "ORPHA ID": 3090, "Summary": ""}
{"Disease Name": "Congenital renal artery stenosis", "Disease Definition": "A rare renal disease characterized by congenital unilateral or bilateral narrowing of the renal artery leading to severe arterial hypertension and progressive renal failure in the neonate. Manifestations include hypertensive encephalopathy and/or neurological signs and symptoms due to hyponatremia, polyuria, renal electrolyte loss, proteinuria, and hematuria.", "ORPHA ID": 97598, "Summary": ""}
{"Disease Name": "Congenital respiratory-biliary fistula", "Disease Definition": "Congenital respiratory-biliary fistula (RBF) is a rare developmental defect characterized by an anomalous connection of trachea or bronchus with left hepatic duct presenting with respiratory distress, recurrent respiratory infections and biliary expectoration or vomitus.", "ORPHA ID": 2040, "Summary": ""}
{"Disease Name": "Congenital retinal arteriovenous communication", "Disease Definition": "A rare neurovascular malformation characterized by a unilateral, direct communication between the arterial and venous system in the retina via abnormal, enlarged vessels, but without interposed capillaries. The inferotemporal vasculature is most commonly affected. Patients may be asymptomatic or present with variable degrees of visual loss. Local vascular complications include vascular occlusions or retinal or vitreous hemorrhages. The anomaly may occur in isolation or as part of Wyburn-Mason syndrome, in which intracranial (usually ipsilateral) arteriovenous malformations are present.", "ORPHA ID": 353334, "Summary": ""}
{"Disease Name": "Congenital rubella syndrome", "Disease Definition": "An infectious embryofetopathy that may present in an infant as a result of maternal infection early in pregnancy and subsequent fetal infection with rubella virus. The disorder can lead to deafness, cataract, and variety of other permanent manifestations including cardiac and neurological defects.", "ORPHA ID": 290, "Summary": "Epidemiology\nCongenital rubella syndrome (CRS) has been reported to affect an estimated 100,000 infants each year, mainly in developing countries.\nClinical description\nAcquired during the first 8-12 weeks of gestation, rubella infection may cause multiple fetal defects (up to 90% of cases) including neurological (microcephaly), ophthalmic (cataracts, microphthalmia, glaucoma, pigmentary retinopathy, chorioretinitis), auditory (sensorineural deafness), cardiac (peripheral pulmonary artery stenosis, patent ductus arteriosus or ventricular septal defects, etc) defects and fetal wastage or stillbirth. Infection occurring later in gestation is associated with a decline in the risk of birth defects. Fetal defects are rarely associated with maternal rubella occurring after the 14th week of pregnancy, although sensorineural hearing deficit can occur with infection as late as week 20. Additional findings may include: meningoencephalitis, interstitial pneumonitis hepatitis with jaundice (within 24 hours after birth), hepatosplenomegaly, purpura, squint, congenital glaucoma and developmental delay. Infants with congenitally acquired infection may develop manifestations of late-onset disease in later childhood or as adults. Endocrine organs, eyes, hearing and central nervous system may be affected and autoimmune disorders and/or behavioral problems may occur.\nEtiology\nIn pregnant women the virus infects the placenta and the developing fetus. Infants with CRS may excrete the virus for a year or more in pharyngeal secretions and urine.\nDiagnostic methods\nIn the prenatal period, ultrasound examination may fail to diagnose CRS but molecular analysis performed on amniotic fluid (collected at least 6 weeks after maternal infection and after 21 weeks of gestation) will confirm or infirm congenital infection. World Health Organization has established diagnostic criteria. In the postnatal period, its classic triad of clinical signs may suspect CRS: cataract, heart disease, and deafness and confirmed by positive Rubella specific IgM in the newborn.\nDifferential diagnosis\nDifferential diagnosis of maternal rubella includes all infections responsible of maculo-papular rash (parvovirus B19, measles, streptococcus A, enteroviruses, cytomegalovirus (CMV), Epstein-Barr virus, human immunodeficiency virus) and other rashes from non infectious causes. Differential diagnosis of congenital rubella includes congenital infection with Toxoplasma gondii, enteroviruses, CMV, Herpes simplex virus, Varicella, Syphilis.\nManagement and treatment\nTo date, no treatment for rubella or CRS is available. In order to prevent CRS, vaccination of adolescent girls and women of childbearing age is recommended.\nPrognosis\nPrognosis of rubella congenital infection mainly depends on the term at maternal infection. Infected children surviving the neonatal period may face serious developmental disabilities (for example, visual and hearing impairments) and have an increased risk for developmental delay, including autism, type I diabetes mellitus and thyroiditis. A progressive encephalopathy resembling subacute sclerosing leukoencephalitis has been observed in patients with CRS.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Christelle VAULOUP-FELLOUS"}
{"Disease Name": "Congenital short bowel syndrome", "Disease Definition": "Congenital short bowel syndrome is a rare intestinal disorder of neonates of unknown etiology. Patients are born with a short small bowel (less than 75 cm in length) that compromises proper intestinal absorption and leads chronic diarrhea, vomiting and failure to thrive.", "ORPHA ID": 2301, "Summary": ""}
{"Disease Name": "Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome", "Disease Definition": "A form of constitutional sideroblastic anemia characterized by severe microcytic anemia, B-cell lymphopenia , panhypogammaglobulinemia and variable neurodegeneration. The disease presents in infancy with recurrent febrile illnesses, gastrointestinal disturbances, developmental delay, seizures, ataxia and sensorineural deafness.", "ORPHA ID": 369861, "Summary": ""}
{"Disease Name": "Congenital smooth muscle hamartoma", "Disease Definition": "Congenital smooth muscle hamartoma (CSMH) is a rare cutaneous hamartomatous lesion most often located on the lumbosacral area or proximal limbs (but rarely on atypical areas such as scalp, eyelid or foot) and characterized by a disorganized proliferation of smooth muscle fibres of arrector pili presenting usually as a localized skin-colored or hyperpigmented plaque (up to 10 cm in diameter) with prominent vellus hairs (most common classic form) or less commonly by multiple skin-colored papules that can coalesce to form irregularly shaped plaques. With time, hyperpigmentation and vellus hairs usually diminish and neither malignant transformation nor associated systemic involvement has been reported.", "ORPHA ID": 263435, "Summary": ""}
{"Disease Name": "Congenital sodium diarrhea", "Disease Definition": "A rare, genetic, non-syndromic intestinal transport defect characterized by congenital onset of severe watery diarrhea containing high concentrations of sodium, hyponatremia and metabolic acidosis.", "ORPHA ID": 103908, "Summary": "Epidemiology\nWhilst the prevelence is unknown, less than 50 cases of both the syndromic and non-syndromic form have been reported in the literature.\nClinical description\nPresentation is typically prenatal with polyhydramnios, prominent abdominal distension due to dilated fluid-filled loops of the intestine. A watery diarrhea is present after birth, independent of oral feeding (breast or formula) or nil by mouth. The diarrhea can be described as 'non-stopping', and can be mistaken for urine. There are increased bowel sounds at examination, and passing of meconium is never reported. The infants become irritable and eventually apathetic, and develop moderate to severe dehydration. Rarely, there is no watery diarrhea noticed either due to severe dehydration or intestinal paralysis. This pseudo-obstruction is caused by dilated fluid-filled loops of intestine, which may result in volvulus, and the affected neonate typically undergoes abdominal surgery. Laboratory findings include high stool sodium levels (importantly, this can be normal when the depletion of body sodium has progressed for some time) and low serum sodium levels, metabolic acidosis and alkaline fecal pH, and low urinary sodium excretion. Histological findings include a structurally intact epithelium and brush border with a normal villus-to-crypt ratio.\nEtiology\nThe classical (non-syndromic) form of the disorder is due to loss of function of the intestinal sodium/hydrogen exchanger 3 (NHE3; encoded by SLC9A3, 5p15.33), resulting in abrogated sodium absorption, enhanced fluid secretion and diarrhea. Causal mutations have been identified in both SCL9A3 and GUCY2C, encoding an intestinal receptor guanylate cyclase C (GC-C) and for which activating mutations inhibit NHE3. In 40% of patients a genetic mutation has not yet been identified.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and exclusion of the differential diagnosis. Initial diagnosis might include determination of fecal sodium, chloride and potassium. Separate sampling of watery stool and urine should be performed. Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes the syndromic form of congenital sodium diarrhea (due to SPINT2 mutations) which is typically distinguished by the presence of uni- or bilateral choanal atresia at birth. Other differential diagnoses include anatomical bowel obstruction, congenital chloride diarrhea (distinguished by excessive fecal chloride), glucose-galactose malabsorption (which exhibits a diet-induced dehydrating diarrhea with later onset), microvillus inclusion disease and congenital tufting enteropathy (distinguished by histopathology).\nAntenatal diagnosis\nDiagnosis may be suspected on presentation of polyhydramnios in the third trimester. Early, targeted genetic prenatal testing is possible after identifying disease-causing variants in an index patient; however, general concerns to sampling fetal material and diagnosing genetic conditions late in pregnancy would apply.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive for SLC9A3 mutations and autosomal dominant for GUCY2C mutations. The risk of disease transmission to offspring for autosmal recessive disease is 25% where both parents are unaffected carriers. GUCY2C mutations are most often of de-novo origin; so far, germline mosaicism in unaffected parents of such patients has not been reported, resulting in a very low recurrence risk for sibs of affected patients. If a parent is affected and carrier of the pathogenic GUCY2C mutation, the risk of transmission is 50%. Of note, a number of individuals with GUCY2C and SLC9A3 mutations developed inflammatory bowel disease.\nManagement and treatment\nAfter birth, total parenteral nutrition for treatment of dehydration for at least several months is required. Sodium supplementation should be provided for treatment of severe dehydration and to maintain normal body growth by preventing total body sodium depletion. In certain cases, patients may be weaned off total parenteral nutrition. For monitoring adequate sodium supplementation, the fractional excretion of sodium (FENa) should be calculated (normal range reportedly between 0.5%-1.5%).\nPrognosis\nAffected individuals may continue to have mild watery diarrhea but otherwise tend to lead a normal life. Reported complications include growth delay and hypoaldosteronism.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Andreas JANECKE  - Pr Thomas MÜLLER"}
{"Disease Name": "Congenital stationary night blindness", "Disease Definition": "Congenital stationary night blindness (CSNB) refers to a non-progressive group of retinal disorders characterized by night or dim light vision disturbance or delayed dark adaptation, poor visual acuity (ranging from 20/30 to 20/200), myopia (ranging from low (-0.25 diopters [D] to -4.75 D) to high (≥-10.00 D)), nystagmus, strabismus, normal color vision and fundus abnormalities.", "ORPHA ID": 215, "Summary": ""}
{"Disease Name": "Congenital stenosis of the inferior vena cava", "Disease Definition": "A rare vascular anomaly characterized by congenital narrowing of the inferior vena cava mostly at the diaphragmatic level or hepatic segment, with or without web formation. Patients may present with deep vein thrombosis below the obstructed segment as well as swelling, pain, and varices of the lower extremities, abdominal pain/varices, or hematochezia. Presence of collateral veins between upper and lower segments of the stenosis, as well as venous aneurysms are typical associated findings.", "ORPHA ID": 99122, "Summary": ""}
{"Disease Name": "Congenital stromal corneal dystrophy", "Disease Definition": "Congenital stromal corneal dystrophy (CSCD) is an extremely rare form of stromal corneal dystrophy (see this term) characterized by opaque flaky or feathery clouding of the corneal stroma, and moderate to severe visual loss.", "ORPHA ID": 101068, "Summary": "Epidemiology\nThe exact prevalence of this corneal dystrophy is not known but it is very rare: CSCD has been reported in 4 families to date in Germany, France, Belgium and Norway.\nClinical description\nPatients develop bilateral corneal lesions before birth. The flakes and spots become more numerous with age, progressively increasing the effect on vision. Corneal erosions, photophobia and corneal vascularization are absent. Some patients have strabismus or primary open-angle glaucoma.\nEtiology\nThe etiology of this condition is not known but mutations in the DCN gene (12q23) which codes for decorin have been identified in affected patients. DCN codes for a protein that may affect the rate of fibril formation.\nDiagnostic methods\nThe morphologic abnormalities observed in CSCD include a peculiar arrangement of tightly packed lamellae having highly aligned collagen fibrils of an unusually small diameter.\nGenetic counseling\nTransmission appears to be autosomal dominant.\nManagement and treatment\nA penetrating keratoplasty is the treatment of choice.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Congenital subglottic stenosis", "Disease Definition": "A rare larynx anomaly characterized by a partial or complete narrowing of the upper airway extending from just below the vocal folds to the lower border of the cricoid cartilage. Clinical presentation is variable and includes recurrent, croup-like, upper respiratory infections, stridor, dyspnea, barking cough, and in most severe cases acute airway compromise at delivery. It may be an isolated finding, or associated with other congenital anomalies and syndromes.", "ORPHA ID": 141121, "Summary": ""}
{"Disease Name": "Congenital sucrase-isomaltase deficiency", "Disease Definition": "A rare, genetic, congenital carbohydrate intolerance disorder characterized by lack of endogenous sucrase activity, marked reduction in isomaltase activity, and moderate decrease in maltase activity, and clinically manifesting with diarrhea, abdominal pain and bloating, failure to thrive.", "ORPHA ID": 35122, "Summary": "Epidemiology\nThe prevalence for the classical type in the European population is estimated at 1/5,000 but it is higher among the indigenous populations of Alaska, Greenland and Canada. Many cases are probably undiagnosed, especially in patients with milder phenotypes.\nClinical description\nOnset is usually after weaning from breast milk or lactose-only formula to foods containing sucrose and/or starch. Clinical manifestations include osmotic diarrhea, abdominal bloating and discomfort, flatulence and vomiting. This may result in failure to thrive, dehydration and malnutrition. Mildly affected individuals may present with irritable bowel syndrome and loose/frequent stools. Symptom severity depends on residual sucrase and isomaltase activity, as well as the amount of sugar and starch consumed, and thus onset may be later in life. CSID may coexist with other disaccharidase deficiencies (e.g. lactase, maltase-glucoamylase and/or peptidase deficiencies).\nEtiology\nCSID is caused by mutations in genes encoding the brush-border membrane complex, sucrase-isomaltase (SI), which is required for the breakdown of sucrose and starch into monosaccharides. These can then readily be absorbed in the gut facilitated by specific monosaccharide transporters. Amylase (salivary and pancreatic) facilitates the limited digestion of nutritional starch leading to oligomers but debranching has to be catalyzed by isomaltase. The SI deficiency results in an accumulation of disaccharides and glucose-oligomers in the lumen of the gut, causing the abdominal symptoms.\nDiagnostic methods\nDiagnosis may be suspected after presentation with osmotic diarrhea, bloating, abdominal pain and failure to thrive. Duodenal or jejunal mucosal biopsy and assay of disaccharidases is the 'gold standard' diagnostic technique. Samples must be immediately frozen and transported frozen to the analytical lab as preanalytical errors result in false positive findings. Presumed diagnosis can be made by a flat sucrose tolerance test and development of gastrointestinal symptoms, or via the 13C-sucrose breath hydrogen test, which is neither specific nor sensitive. Genetic testing is both an alternative and a supplement to enzymatic studies.\nDifferential diagnosis\nDifferential diagnosis includes the numerous causes of chronic diarrhea (allergic gastroenteropathy, celiac disease, Crohn's disease, irritable bowel syndrome, infection, severe gastro-enteritis, cystic fibrosis, diverticulitis, lactose intolerance, glucose-galactose intolerance, and fructose intolerance) as well as secondary causes of sucrase-isomaltase deficiency (medication, environmental).\nAntenatal diagnosis\nPrenatal diagnosis is possible when there is an index case. Due to relatively good treatment options and outcome, prenatal diagnosis is rarely indicated.\nGenetic counseling\nCSID is transmitted as an autosomal-recessive or autosomal-dominant trait. Offspring of affected individuals are obligate carriers. Heterozygous carriers may also experience symptoms like irritable bowel syndrome.\nManagement and treatment\nTreatment used to be based on a strict sucrose- and starch-restricted diet. However, this is challenging and mostly still associated with CSID- symptoms. Regular consultation with a dietician is strongly recommended. Adjuvant enzyme replacement therapy (ERT) with sacrosidase is recommended to aid in sucrose digestion. The amount of enzyme given has to be titrated based on the residual sucrose activity and the amount of sucrose in the diet. However, sacrosidase ERT does not correct starch maldigestion, patients under sacrosidase treatment are often not symptom-free and still have to stick to starch restriction. Other tailor-made enzyme preparations distributed by specialized pharmacists contain a combination of sacrosidase, amylase and amyloglucosidases, and facilites the complete digestion of starch to monomers. Vitamin supplementation is typically required in infants and children.\nPrognosis\nDietary restriction typically reduces symptoms, but is not sufficient in most patients. Treatment with sacrosidase is effective but not able to mediate starch digestion, and starch-restriction is still necessary. Improved enzyme replacement therapy limits the need for starch restriction in many patients and, frequently, a normal unrestricted diet is possible.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Anibh Martin DAS"}
{"Disease Name": "Congenital supravalvular mitral ring", "Disease Definition": "Congenital supravalvular mitral ring is a rare, congenital, mitral valve malformation characterized by an abnormal ridge of the connective tissue on the atrial side of the mitral valve, which can present clinically with signs and symptoms of left ventricle inflow obstruction (dyspnea, tachypnea, pulmonary hypertension, right ventricle hypertrophy, pulmonary edema). Association with other mitral valve anomalies, aortic stenosis, ventricular septal defect, patent ductus arteriosus, double-outlet right ventricle, pulmonary hypertension, and Shone complex has been reported.", "ORPHA ID": 99059, "Summary": ""}
{"Disease Name": "Congenital syphilis", "Disease Definition": "A rare teratologic disease caused by vertical transmission of the spirochete Treponema pallidum from an infected mother to the fetus, characterized by early congenital syphilis during the first two years of life (maculopapular rash progressing to desquamation, hepatosplenomegaly, osteochondritis, snuffles, and iritis), followed by late congenital syphilis with the classic Hutchinson's triad of Hutchinson's teeth, interstitial keratitis, and eighth nerve deafness. Additional signs may include saddle nose, saber shins, seizures, and mental retardation. Congenital syphilis can also result in stillbirth, neonatal death, and nonimmune hydrops.", "ORPHA ID": 499009, "Summary": ""}
{"Disease Name": "Congenital systemic arteriovenous fistula", "Disease Definition": "Congenital systemic arteriovenous fistula is a rare, potentially life-threatening, vascular malformation characterized by a direct communication between an artery and a vein, without the interposition of the capillary bed, ocurring in the systemic circulation (mainly the cranium, liver, lungs, extremities, and vessels in or near the thoracic wall). Manifestations are variable depending on size and extent of the fistula, the involved blood vessels and the precise location of the collaterals and may include systolic or continuous murmur over the affected organ, tachycardia, increased stroke volume, cardiomegaly and increased pulmonary vascular markings.", "ORPHA ID": 2039, "Summary": ""}
{"Disease Name": "Congenital temporomandibular joint ankylosis", "Disease Definition": "Congenital temporomandibular joint ankylosis is a rare maxillofacial disorder characterized by significant reduction in mouth opening (i.e. from a few millimeters to a few centimeters) in the absence of acquired factors (e.g. trauma, infection) contributing to the ankylosis. It is associated with variable degrees of facial dysmorphism (i.e. lateral deviation of the mandible and chin, lower facial asymmetry, retrognathia, micrognathia, dental malocclusion) and patients typically present with feeding and breathing difficulties. Developmental delay, hypotonia, seizures, and additional dysmorphic features (e.g. pectus excavatum, low-set ears, hypoplastic alae nasi) have also been reported.", "ORPHA ID": 210576, "Summary": ""}
{"Disease Name": "Congenital thrombotic thrombocytopenic purpura", "Disease Definition": "A hereditary form of thrombotic thrombocytopenic purpura (TTP) characterized by profound peripheral thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and single or multiple organ failure of variable severity.", "ORPHA ID": 93583, "Summary": "Epidemiology\nCongenital TTP is much less common than the immune-mediated form of the disease (immune-mediated TTP), accounting for up to only 5% of all TTP cases. Up until 2017, 123 cases had been reported by the International Hereditary Thrombotic Thrombocytopenic Purpura Registry. The annual incidence is estimated at less than 1/1,000,000.\nClinical description\nThe majority of patients present during the neonatal period or during childhood but the clinical manifestations are highly variable with mild manifestations of isolated thrombocytopenia throughout childhood in some, and severe neonatal hyperbilirubinemia with episodes of thrombocytopenia and MAHA developing soon after birth in others. In addition, onset may also occur during adulthood, particularly in women when the initial episode of overt TTP is triggered by the first pregnancy. Infections and vaccinations are also precipitating factors. The clinical course in congenital TTP is characterized typically by more long term relapses than in the immune-mediated form (iTTP), with around 50% of congenital TTP patients developing chronic, frequently relapsing disease. As in immune-mediated TTP, patients may also develop neurological anomalies, renal manifestations, cardiac dysfunction and gastrointestinal symptoms due to widespread microvascular thrombosis.\nEtiology\nCongenital TTP is caused by a mutation in the ADAMTS13 gene (9q34), encoding ADAMTS13, a metalloprotease involved in the cleavage of ultra-large von Willebrand factor multimers with a penetrance of over 90%. Mutations are mainly compound heterozygous and less commonly homozygous, which explains the varied age of onset and severity/frequency of episodes seen in patients with congenital TTP.\nDiagnostic methods\nA diagnosis of TTP should be considered in all patients with thrombocytopenia and microangiopathic hemolytic anemia. A positive familial history, laboratory studies (revealing schistocytes on peripheral blood smears, high serum lactate dehydrogenase levels, low platelet counts and reticulocytosis) and a severe ADAMTS13 deficiency (< 10% of normal values), in the absence of anti-ADAMTS13 antibodies, suggests a diagnosis of congenital TTP. Diagnosis is confirmed by molecular analysis revealing a double heterozygous or homozygous mutation in the ADAMTS13 gene.\nDifferential diagnosis\nIn pregnant patients, congenital TTP needs to be distinguished from iTTP, atypical hemolytic-uremic syndrome and HELLP syndrome.\nGenetic counseling\nCongenital TTP is transmitted in an autosomal recessive manner. Genetic counseling should be provided to affected families. Women diagnosed with congenital TTP should also receive pregnancy counseling in order to inform them of the major risk of TTP exacerbations and to allow for the timely planning of a management strategy (from conception to post-partum period), which mainly includes a prophylactic plasmatherapy. Screening of siblings for ADAMTS13 activity is also recommended.\nManagement and treatment\nAcute episodes in congenital TTP can be treated by plasma infusion (10-15 ml/kg/day until remission) but exchange transfusion is usually required in newborns. Patients with a chronic relapsing disease course may be considered for prophylactic plasma therapy. Regular plasma infusions to maintain ADAMTS13 activity level around 15% are required during pregnancy, in addition to close clinical and biological monitoring by a reference center. During the third trimester, therapeutic plasma exchanges may be required to prevent fluid overload.\nPrognosis\nIn the absence of treatment, TTP is a rapidly fatal disease (mortality rate > 90%). The introduction of therapeutic plasma exchange and plasma infusion has led to a decrease in the mortality rate to around 15%. Plasmatherapy also prevents long term organ complications due to chronic relapses.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Paul COPPO"}
{"Disease Name": "Congenital total pulmonary venous return anomaly", "Disease Definition": "A form of congenital pulmonary venous return where all of the pulmonary veins drain into the right atrium or one of its tributaries, instead of the left atrium, leading to various manifestations such as fatigue, exertional dyspnea, pulmonary arterial hypertension, cyanosis and progressive congestive heart failure.", "ORPHA ID": 99125, "Summary": ""}
{"Disease Name": "Congenital toxoplasmosis", "Disease Definition": "A rare fetopathy characterized by ocular, visceral or intracranial lesions secondary to maternal primary infection by Toxoplasma gondii (Tg).", "ORPHA ID": 858, "Summary": "Epidemiology\nGiven its infectious origin, incidence of congenital toxoplasmosis (CTX) is variable over time and geographically. Screening policies and methods also influence prevalence calculation. Prevalence at birth is estimated to be 0.5 to 1.6/10 000 in Europe.\nClinical description\nClinical presentation is highly variable. Earlier infection is generally more severe but less frequent. Infections in the first trimester may result in miscarriage or fetal death in utero, whereas later ones may be limited to ocular anomalies. Intracranial calcifications, micro- or macrocephaly, ventricular dilatation and hydrocephalus, hepatomegaly, splenomegaly, cardiomegaly, ascites and intrauterine growth retardation can be observed in infected fetuses. When present, clinical manifestations at birth are maculopapular rash, jaundice, generalized lymphadenopathy, organomegaly, central nervous system anomalies and hyperbilirubinemia, anemia, and thrombocytopenia. The first neurologic manifestations are hypotonia, seizures, nystagmus, and, later, delay of developmental milestone acquisition can be seen. The triad of chorioretinitis, intracranial calcifications and hydrocephalus is present in at least 10% of clinical cases. Ocular involvement involves most frequently chorioretinitis, followed by microphthalmia and strabismus. New lesions of chorioretinitis or relapses may develop after months or years: Visual impairment is highly dependent on the parasite genotype, and probably on prenatal and postnatal treatments.\nEtiology\nCTX is caused by the mother's primary infection by Tg, an intracellular protozoan parasite of the Apicomplexa phylum, and the trans-placental infection of the fetus. Nearly 25% of exposed fetuses are infected. Mother is infected by Tg through ingestion of oocysts present in cat feces and soil, or of cysts present in uncooked meat.\nDiagnostic methods\nDiagnosis of pergravidic maternal infection is based on the detection of 1) a true seroconversion with appearance of IgG in a woman previously known to be uninfected, or if the first serology is already positive of 2) of a significant increase in IgG in the context of high IgM titters. The diagnosis of congenital toxoplasmosis relies on the detection of Tg DNA in amniotic fluid or in other products, or of a neosynthesis of IgG, IgM or IgA in the child after birth. Persistence of anti-Toxoplasma IgG at one year of age is considered as the gold standard for congenital toxoplasmosis diagnosis. RT-PCR targeting repetitive DNA segments should be used for the molecular diagnosis of congenital toxoplasmosis. Diagnosis of maternal and congenital infections should be confirmed by expert laboratories.\nDifferential diagnosis\nDifferential diagnosis includes other congenital infections (rubella, CMV, HSV1 and HSV2, regrouped with Tg infection in the TORCH syndrome) and pseudo-TORCH and Aicardi-Goutières syndromes.\nAntenatal diagnosis\nFetal ultrasonography and/or magnetic resonance imaging (MRI) detect and characterize brain, cardiac or placental anomalies. Diagnosis is confirmed only with serological findings in the mother and with PCR findings of Tg infection the amniotic fluid. Fetal ultrasound examination should be repeated in the context of a proven maternal infection. Amniocentesis for PCR should be performed too, after 18 weeks of gestation, and at least 4 weeks after the mother's seroconversion to avoid false negative results. Ultrasound examinations should be more frequent if PCR on amniotic fluid is found to be positive.\nManagement and treatment\nIn several countries, a systematic serological status follow-up of each pregnant woman is organized in order to reduce the number of severely infected children. Seronegative pregnant women are tested regularly to detect seroconversion, with, if needed, a spiramycin-based treatment, expected to reduce vertical transmission. A pyrimethamine-sulphonamide combination is recommended in case of confirmed fetal infection. It is also used after 14 weeks of gestation to prevent vertical transmission. Neonates who are recognized as infected should also be treated even if they are asymptomatic at birth since complications may occur later. The benefits of prenatal and postnatal treatment remain to be quantified.\nPrognosis\nPrognosis is highly dependent on the parasite virulence, the gestational age at maternal infection and on the timing of prenatal and postnatal treatment.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Martine WALLON"}
{"Disease Name": "Congenital tracheal stenosis", "Disease Definition": "A rare malformation characterized by fixed narrowing of the tracheal lumen primarily due to complete tracheal cartilage rings and an absent membranous trachea, which causes breathing difficulty.", "ORPHA ID": 141127, "Summary": ""}
{"Disease Name": "Congenital tracheomalacia", "Disease Definition": "Congenital tracheomalacia is a rare condition where the trachea is soft and flexible causing the tracheal wall to collapse when exhaling, coughing or crying, that usually presents in infancy, and that is characterized by stridor and noisy breathing or upper respiratory infections. Tracheomalacia improves by the age of 18-24 months.", "ORPHA ID": 95430, "Summary": ""}
{"Disease Name": "Congenital tricuspid stenosis", "Disease Definition": "A rare congenital tricuspid malformation characterized by narrowing of the tricuspid valve orifice due to congenital valve anomalies, such as incompletely developed leaflets, shortened and malformed chordae tendineae, small annulus, and/or abnormal number and size of papillary muscles, resulting in right ventricular inflow obstruction. Clinical presentation depends on the degree of stenosis, as well as the presence or absence of additional cardiac anomalies, and includes easy fatigability, swelling of the lower limbs, and hepatomegaly, among others.", "ORPHA ID": 95459, "Summary": ""}
{"Disease Name": "Congenital tricuspid valve dysplasia", "Disease Definition": "A rare congenital tricuspid malformation characterized by irregular thickening of the leaflet tissue by myxoid connective tissue in a normally delaminated tricuspid valve, without septal leaflet displacement, and without an atrialized right ventricle. The chordae tendineae may be short or absent. The affected valve is stenotic and/or incompetent. Clinically, most patients are asymptomatic and are diagnosed in the context of the evaluation of a murmur.", "ORPHA ID": 555874, "Summary": ""}
{"Disease Name": "Congenital trigeminal anesthesia", "Disease Definition": "Congenital trigeminal anesthesia is a rare neuro-ophtalmological disorder characterized by a congenital sensory deficit involving all or some of the sensory components of the trigeminal nerve. Due to corneal anesthesia, it usually presents with recurrent, painless eye infections, painless corneal opacities and/or poorly healing, ulcerated wounds on the facial skin and mucosa (typically the buccal mucosa and/or nasal septum).", "ORPHA ID": 231013, "Summary": ""}
{"Disease Name": "Congenital trochlear nerve palsy", "Disease Definition": "A rare ophthalmic disorder with cranial nerve involvement characterized by dysfunction of the superior oblique muscle with typical eye motility patterns including elevation in adduction, V-pattern related to reduced abduction force in downgaze with unopposed adduction by the inferior rectus muscle, and excyclotorsion. Patients may present with contralateral head tilt to compensate for vertical binocular misalignment and diplopia.", "ORPHA ID": 98686, "Summary": ""}
{"Disease Name": "Congenital tufting enteropathy", "Disease Definition": "Congenital Tufting Enteropathy is a rare congenital enteropathy presenting with early-onset severe and intractable diarrhea that leads to irreversible intestinal failure.", "ORPHA ID": 92050, "Summary": "Epidemiology\nNo epidemiological data is available, however, the prevalence can be estimated at around 1/200,000 births in Europe. The prevalence is higher in areas with high degrees of consanguinity, but cases have been reported worldwide.\nClinical description\nMost affected patients develop digestive intolerance with vomiting and watery diarrhea within the first few months of life. Diarrhea is severe, chronic and persistent despite bowel rest, resulting in electrolyte imbalance and dehydration. Moreover, an intestinal insufficiency leads to malabsorption, malnutrition, and growth impairment. Although most children present with isolated diarrhea, a small number of congenital tufting enteropathy (CTE) patients present with a syndromic form where diarrhea is associated with non-specific punctuated keratitis, and various malformations such as choanal atresia, esophageal atresia, imperforate anus, dysmorphic features, skeletal dysplasia, and (in one case) Dubowitz syndrome.\nEtiology\nCTE is related to abnormal enterocyte development and differentiation. Mutations in the EPCAM gene (2p21) are seen in 73% of CTE patients and are associated with the isolated intestinal disease. Mutations in the SPINT2 gene (19q13.2) are seen in 21% of CTE cases which are clinically characterized by the syndromic form of the disease. Rarely, CTE patients may present with isolated diarrhea but have no mutations in either EPCAM or SPINT2.\nDiagnostic methods\nDiagnosis is based on the combination of clinical and histological criteria. A congenital chronic diarrhea in the absence of an infectious or an inflammatory process, in association with various degrees of small and large bowel villous atrophy and specific histological abnormalities involving the focal crowding of surface enterocytes resembling ''tufts'', and branching crypts, allow for the diagnosis of CTE. When not all criteria are obvious one can be helped by the association of the non-syndromic form of the disease with negative EpCAM immunostaining on patient's duodenal biopsies; or conversely in case of the syndromic form of the disease with a normal EpCAM immunostaining. To date, SPINT2 immunostaining on duodenal biopsies seems useless for the diagnosis. Molecular genetic testing, identifying a mutation in the EPCAM gene or SPINT2 can confirm diagnosis, however, some CTE patients do not have any identified genetic mutations.\nDifferential diagnosis\nThe differential diagnosis primarily includes other protracted congenital diarrhea disorders such as microvillus inclusion disease, congenital chloride diarrhea, congenital sodium diarrhea, and syndromic diarrhea, as well as glucose-galactose malabsorption.\nAntenatal diagnosis\nPrenatal diagnosis is available but can only be offered to families where a first case has already been described. The rarity of CTE and the absence of prenatal signs do not make it an appropriate candidate for either antenatal or postnatal mass screening.\nGenetic counseling\nCTE is transmitted in an autosomal recessive manner with high prevalence of consanguinity and affected siblings in families.\nManagement and treatment\nTo date there is no known curative treatment for CTE. Oral or enteral feedings worsen the diarrhea, however they should be maintained at the minimum tolerated level. CTE patients require daily, long-term parenteral support in order to maintain an adequate nutritional status. Life threatening complications related to intestinal failure and long-term parenteral nutrition may become an indication for intestinal transplantation, thus timing of referral to an expert center is crucial before the onset of severe complications.\nPrognosis\nCurrently, children with CTE reach adulthood if long-term parenteral nutrition is conducted appropriately in an experienced center, otherwise the long-term prognosis may be reserved due to the complications of this delicate palliative treatment.\n\n                            Last update: \n                            April 2017\n\n\n                            - Expert reviewer(s): \n                            Pr Olivier GOULET  - Dr Julie SALOMON"}
{"Disease Name": "Congenital unguarded mitral orifice", "Disease Definition": "Congenital unguarded mitral orifice is a rare, congenital, mitral valve malformation characterized by complete absence of mitral valve leaflets and tensor apparatus at the mitral annulus, which can present clinically with cyanosis, heart murmur, electrocardiogram abnormalities, mild cardiomegaly, or congestive heart failure. Association with heterotaxy, discordant atrioventricular connections, double-outlet right ventricle, pulmonary atresia or stenosis, thin left ventricular wall, and hypoplastic left heart syndrome has been reported.", "ORPHA ID": 99060, "Summary": ""}
{"Disease Name": "Congenital unilateral hypoplasia of depressor anguli oris", "Disease Definition": "A rare, isolated, congenital, head and neck morphological anomaly characterized by the unilateral hypoplasia/agenesis of the depressor anguli oris muscle, resulting in an asymmetric crying facies in neonatal period/infancy (drooping of one corner of the mouth during crying) while eye closure, nasolabial fold and forehead wrinkling are symmetric. Although isolated in the majority of cases, newborns presenting with this morphological anomaly should be referred for further screening for 22q11.2 deletion syndrome and/or other coexisting cardiovascular, musculoskeletal, cervicofacial, respiratory, genitourinary and endocrine anomalies.", "ORPHA ID": 1166, "Summary": ""}
{"Disease Name": "Congenital urachal anomaly", "Disease Definition": "Congenital urachal anomaly (CUA) describes a group of urachal remnants, found more frequently in males than females, that result from incomplete closure of the urachus (an embryological remnant of the allantois) during prenatal development, and that are usually asymptomatic (and found as an incidental finding on a radiological study) but can also present with umbilical discharge (in patent urachus or urachal sinus), infraumblical mass and pain, or with complications such as obstruction and infection. CUAs include patent urachus, urachal sinus, urachal cyst and urachal diverticulum (see these terms).", "ORPHA ID": 435743, "Summary": ""}
{"Disease Name": "Congenital varicella syndrome", "Disease Definition": "A rare acquired developmental anomaly syndrome characterized by skin, neurological, ocular, limbs and growth defects secondary to maternal Varicella-Zoster Virus (VZV) infection.", "ORPHA ID": 291, "Summary": ""}
{"Disease Name": "Congenital velopharyngeal incompetence", "Disease Definition": "A rare otorhinolaryngologic malformation characterized by the isolated finding of a short and immobile soft palate with anatomical disproportion of the velopharyngeal structures, preventing velopharyngeal closure. Patients present with delayed speech development and hypernasal speech.", "ORPHA ID": 2291, "Summary": ""}
{"Disease Name": "Congenital vertebral-cardiac-renal anomalies syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by vertebral segmentation defects associated with cardiac (patent ductus arteriosus, atrial septal defect, hypoplastic left heart) and renal (hypoplastic kidneys, chronic kidney disease) anomalies. Additional reported features include limb defects, short stature, global developmental delay, intellectual disability, and sensorineural hearing loss, among others.", "ORPHA ID": 521438, "Summary": ""}
{"Disease Name": "Congenital vertical talus", "Disease Definition": "Isolated congenital vertical talus (CVT) is a rare pedal deformity recognizable at birth by a dislocation of the talonavicular joint, resulting in a characteristic radiographic near-vertical orientation of the talus.", "ORPHA ID": 178382, "Summary": "Clinical description\nIt occurs more commonly in males than females. Some patients have vertical talus in one foot and clubfoot in the other.\nEtiology\nThe etiology and epidemiology of this condition are largely unknown. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance and mutations in HOXD10 gene have been detected in two families.\nManagement and treatment\nSerial manipulation and cast immobilization followed by limited surgery provides excellent results.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Congenitally corrected transposition of the great arteries", "Disease Definition": "Congenitally corrected transposition (CCT) of the great vessels is a rare cardiac malformation characterized by the combination of discordant atrioventricular and ventriculo-arterial connections, usually accompanied by other cardiovascular malformations.", "ORPHA ID": 216694, "Summary": "Epidemiology\nPrevalence is unknown. Annual incidence has been reported to be around 1/33,000 live births, accounting for approximately 0.05% of congenital heart malformations.\nClinical description\nAssociated malformations typically include ventricular septal defects, obstructions of the outlet from the morphologically left ventricle, and morphological anomalies of the tricuspid valve, although any anatomically feasible lesion can co-exist. The clinical picture and age of onset depend on the associated malformations, with bradycardia, a single loud second heart sound, and heart murmurs being the most common manifestations. Cyanosis is observed in patients with pulmonary stenosis and a ventricular septal defect, while cardiac failure develops earlier in life if there is a hemodynamically significant ventricular septal defect, evidenced in children by easy fatigability, poor weight gain, and feeding intolerance. In the rare cases where there are no associated malformations, congenitally corrected transposition can lead to progressive atrioventricular valvar regurgitation and failure of the systemic ventricle.\nEtiology\nThe etiology of congenitally corrected transposition is currently unknown.\nDiagnostic methods\nDiagnosis can be made by fetal echocardiography, but is more commonly made postnatally based on clinical signs and echocardiography. The anatomical delineation can be further assessed by magnetic resonance imaging (MRI) and catheterization. Diagnosis can also be made late in life when the patient presents with complete heart block or cardiac failure.\nDifferential diagnosis\nThe differential diagnosis is centered on assessing whether the patient presents isolated malformations, or a spectrum of malformations, and includes double inlet left ventricle (see this term) with left-sided incomplete right ventricle, isomerism of atrial appendages with left-handed ventricular topology.\nAntenatal diagnosis\nPrenatal diagnosis of congenitally corrected transposition can readily be made during fetal life by an experienced sonographer.\nGenetic counseling\nCCT is sporadic. There is, however, a higher incidence in families with previous cases of the condition, with a recurrence risk in siblings of between 2.6% to 5.2%.\nManagement and treatment\nMedical management involves treatment of the failing systemic morphologically right ventricle, with timing depending on the severity of the associated malformations. It involves treatment with diuretics, angiotensin-converting enzyme (ACE) inhibitors, and digoxin. If there are conduction abnormalities, the patient may require implantation of a pacemaker, for example in the setting of advanced 2nd or 3rd degree atrioventricular block, or in the presence of symptoms of ventricular dysfunction. Surgical management consists of repair of the associated malformations, or redirection of the systemic and pulmonary venous return associated with an arterial switch, the so-called double switch approach. Regular follow-up by a pediatric cardiologist or by an adult cardiologist who has had special training and experience caring for patients with congenital heart disease is recommended.\nPrognosis\nPrognosis depends on the associated malformations, and on the type and timing of surgical interventions. Life expectancy depends on the associated malformations and the severity of the individual lesions.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Robert ANDERSON"}
{"Disease Name": "Congenitally short costocoracoid ligament", "Disease Definition": "A rare thoracic malformation characterized by fixation of the scapula to the first rib by a congenitally short costocoracoid ligament, leading to limited rotation or retraction of the scapula, as well as rounding of the shoulders and loss of the anterior clavicular contour. There have been no further descriptions in the literature since 1989.", "ORPHA ID": 2391, "Summary": ""}
{"Disease Name": "Congenitally uncorrected transposition of the great arteries", "Disease Definition": "Congenitally uncorrected transposition of the great arteries (congenitally uncorrected TGA), also referred to as complete transposition, is a congenital cardiac malformation characterized by atrioventricular concordance and ventriculoarterial (VA) discordance.", "ORPHA ID": 860, "Summary": "Epidemiology\nThe incidence is estimated at 1 in 3,500-5,000 live births, with a male-to-female ratio of 1.5 to 3.2:1.\nClinical description\nIn 50% of cases, the VA discordance is an isolated finding. In 10% of cases, TGA is associated with noncardiac malformations. The association with other cardiac malformations such as ventricular septal defect (VSD) and left ventricular outflow tract obstruction is frequent and dictates the timing and clinical presentation, which consists of cyanosis with or without congestive heart failure. The onset and severity depend on anatomical and functional variants that influence the degree of mixing between the two circulatory systems. If no obstructive lesions are present and there is a large VSD, cyanosis may go undetected and only be perceived during episodes of crying or agitation. In these cases, signs of congestive heart failure prevail.\nEtiology\nThe exact etiology remains unknown. Some associated risk factors (gestational diabetes mellitus, maternal exposure to rodenticides and herbicides, and maternal use of antiepileptic drugs) have been proposed. Mutations in the growth differentiation factor-1 gene (GDF1), the mediator complex subunit 13-like gene (MED13L) and the gene encoding the cryptic protein (CFC1) have been shown to be implicated in discordant VA connections, but they account for only a small minority of congenitally uncorrected TGA cases.\nDiagnostic methods\nThe diagnosis is confirmed by echocardiography, which also provides information about the morphological details required for future surgical management.\nDifferential diagnosis\nThe differential diagnosis should include other causes of central neonatal cyanosis.\nAntenatal diagnosis\nPrenatal diagnosis by fetal echocardiography is feasible and useful as it may improve early neonatal management and reduce morbidity and mortality.\nManagement and treatment\nPalliative treatment with prostaglandin E1 and balloon atrial septostomy are usually required soon after birth. Surgical correction is performed at a later stage. Usually, the Jatene arterial switch operation is the procedure of choice. Whenever this operation is not feasible, an adequate alternative surgical approach should be implemented.\nPrognosis\nWith the advent of newer and improved surgical techniques and improved post-operative intensive care, the long-term survival is approximately 90% at 15 years of age. However, exercise performance, cognitive function and quality of life may be impaired.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Eduardo CASTELA  - Dr Paula MARTINS"}
{"Disease Name": "Connective tissue disorder due to lysyl hydroxylase-3 deficiency", "Disease Definition": "Connective tissue disorder due to lysyl hydroxylase-3 deficiency is a rare, genetic disease, caused by lack of lysyl hydrohylase 3 (LH3) activity, characterized by multiple tissue and organ involvement, including skeletal abnormalities (club foot, progressive scoliosis, osteopenia, pathologic fractures), ocular involvement (flat retinae, myopia, cataracts) and hair, nail and skin anomalies (coarse, abnormally distributed hair, skin blistering, reduced palmar creases, hypoplastic nails). Patients also present intrauterine growth retardation, facial dysmorphism (flat facial profile, low-set ears, shallow orbits, short and upturned nose, downturned corners of mouth) and joint flexion contractures. Growth and developmental delay, bilateral sensorineural deafness, friable diaphragm and later-onset spontaneous vascular ruptures are additional reported features.", "ORPHA ID": 300284, "Summary": ""}
{"Disease Name": "Cono-spondylar dysplasia", "Disease Definition": "Cono-spondylar dysplasia is a rare genetic primary bone dysplasia disorder characterized by early-onset severe lumbar kyphosis, marked brachydactyly and irregular, pronounced cone epiphyses of the metacarpals and phalanges. Additional reported features include developmental delay, intellectual disability, hypotonia, epileptic seizures and mild facial dysmorphism (incl. long and thin or square-shaped face, slight mid-face hypoplasia, hypertelorism, epicanthic folds, low-set ears, anteverted nostrils). Radiographic findings also reveal hypoplasia of iliac wings and anterior defect of vertebral bodies.", "ORPHA ID": 420794, "Summary": ""}
{"Disease Name": "Conotruncal heart malformations", "Disease Definition": "A group of congenital cardiac outflow tract anomalies that include such defects as tetralogy of Fallot, pulmonary atresia with ventricular septal defect, double-outlet right ventricle (DORV), double-outlet left ventricle, truncus arteriosus and transposition of the great arteries (TGA), among others. This group of defects is frequently found in patients with 22q11.2 deletion syndrome . A deletion of chromosome 22q11.2 has equally been associated in a subset of patients with various types of isolated non-syndromic conotruncal heart malformations (with the exception of DORV and TGA where this is very uncommon).", "ORPHA ID": 2445, "Summary": ""}
{"Disease Name": "Constitutional mismatch repair deficiency syndrome", "Disease Definition": "Constitutional mismatch repair deficiency syndrome is a rare, inherited cancer-predisposing syndrome characterized by the development of a broad spectrum of malignancies during childhood, including mainly brain, hematological and gastrointestinal cancers, although embryonic and other tumors have also been occasionally reported. Non-neoplastic features, in particular manifestations reminiscent of neurofibromatosis type 1 (e.g., café-au-lait spots, freckling, neurofibromas), as well as premalignant and non-malignant lesions (such as adenomas/polpyps) are frequently present before malignancy development.", "ORPHA ID": 252202, "Summary": ""}
{"Disease Name": "Contractures-developmental delay-Pierre Robin syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of Pierre Robin Sequence (congenital micrognathia and glossoptosis with airway obstruction and a U-shaped cleft of the soft palate) with joint contractures and developmental delay. Additional variable manifestations include talipes equinovarus, arachnodactyly, radioulnar synostosis, severe hip dysplasia, cardiac anomalies, facial dysmorphism such as crumpled ear helices, and ocular abnormalities, among others.", "ORPHA ID": 436003, "Summary": ""}
{"Disease Name": "Contractures-ectodermal dysplasia-cleft lip/palate syndrome", "Disease Definition": "A rare ectodermal dyplasia syndrome characterized by severe arthrogryposis, multiple ectodermal dysplasia features, cleft lip/palate, facial dysmorphism, growth deficiency and a moderate delay of psychomotor development. Ectodermal dysplasia manifestations include sparse, brittle and hypopigmented hair, xerosis, multiple nevi, small conical shaped teeth and hypodontia, and facial dysmorphism with blepharophimosis, deep-set eyes and micrognathia.", "ORPHA ID": 1484, "Summary": ""}
{"Disease Name": "Contractures-webbed neck-micrognathia-hypoplastic nipples syndrome", "Disease Definition": "Contractures-webbed neck-micrognathia-hypoplastic nipples syndrome is an extremely rare, multiple congenital anomalies/dysmorphic syndrome characterized by micrognathia, a short, webbed neck, hypoplastic nipples and joint contractures (which improve over time) of the knees and elbows. In addition, sloping shoulders, mild to moderate hearing loss, mild speech impairment and facies with hypertelorism, short philtrum and tented upper lip may be associated.", "ORPHA ID": 314002, "Summary": ""}
{"Disease Name": "Cooks syndrome", "Disease Definition": "Cooks syndrome is a malformation syndrome affecting the apical structures of digits and presenting with hypo/aplasia of nails and distal phalanges. More than half of digits are usually involved and the thumbs may appear digitalized.", "ORPHA ID": 1487, "Summary": "Epidemiology\nTo date, less than 20 individuals have been described in the world literature.\nClinical description\nCooks syndrome is congenital and presents with hypo/anonychia, small or absent distal phalanges and digitalization of the thumbs. Usually, the nails of digits 1-3 are progressively deformed, with anonychia congenita totalis (see this term) in the digits 4-5 and in all toes. Additional features include hypoplasia of the distal phalanges in digits 2-4 with absence of the distal phalanx of digit 5. In the feet, there is absence of all distal phalanges of digits 2-5 with hypoplasia of the distal phalanx of digit 1. Finger pads at the dorsal aspects of the affected fingers may occasionally be seen. To date, no facial dysmorphism has been associated with Cooks syndrome. Cooks syndrome is considered a clinical form of brachydactyly type B (see this term), distinct from the typical variant with sparing or duplication of the thumbs and caused by mutations in the ROR2 gene (9q22).\nEtiology\nThe exact etiology of Cooks syndrome is still unknown but microduplications on chromosome 17q24.3 and involvement of a non-coding element of the SOX9 gene (17q24.3) have recently been associated in some patients with Cooks syndrome. The SOX9 gene is necessary for chondrocyte differentiation and cartilage formation.\nGenetic counseling\nAn autosomal dominant mode of inheritance has been proposed. Genetic counseling may be proposed and the recurrence risk is of 50%.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Marco CASTORI"}
{"Disease Name": "Cooper-Jabs syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by auditory canal atresia (resulting in moderate conductive hearing loss) associated with intellectual disability, ventricular septal defect, umbilical hernia, anteriorly displaced anus, various skeletal anomalies (such as mild clubfoot, long fifth fingers, proximally placed thumbs), and craniofacial dysmorphism which includes brachycephaly, prominent forehead, flattened occiput, midface hypoplasia, anteverted nares, and low set, posteriorly rotated ears with overlapping superior helix. There have been no further descriptions in the literature since 1987.", "ORPHA ID": 1488, "Summary": ""}
{"Disease Name": "Cor triatriatum dexter", "Disease Definition": "A rare, congenital, non-syndromic, heart malformation characterized by the persistence of the embryonic right valve of the sinus venosus which results in a subdivision of right atrium into two chambers. Clinical manifestations depend on the degree of right atrial septation and the size of sinoatrial orifice and vary from asymptomatic to symptoms of tricuspid valve stenosis, atrial fibrillation, cyanosis, syncope, elevated central venous pressure and right heart failure. The anomaly may be isolated or associated with other congenital heart anomalies.", "ORPHA ID": 99098, "Summary": ""}
{"Disease Name": "Cor triatriatum sinister", "Disease Definition": "A rare, congenital, non-syndromic, heart malformation characterized by the presence of a thin, fibromuscular membrane subdividing the left atrium into an upper and lower chamber. The upper chamber receives blood from the pulmonary veins and the lower chamber is attached to the left atrial appendage. Therefore, the membrane blocks the orifice of the mitral valve and leads to obstruction of the left ventricular inflow. It may be asymptomatic or present in infancy with tachypnea, dyspnea, hemoptysis, chest pain, syncope, pulmonary edema, pulmonary hypertension, or heart failure, depending on the degree of obstruction. The anomaly may be isolated or associated with other congenital heart anomalies.", "ORPHA ID": 99099, "Summary": ""}
{"Disease Name": "Corneal dystrophy-perceptive deafness syndrome", "Disease Definition": "Corneal dystrophy-perceptive deafness (CDPD) or Harboyan syndrome is a degenerative corneal disorder characterized by the association of congenital hereditary endothelial dystrophy (CHED; see this term) with progressive, postlingual sensorineural hearing loss.", "ORPHA ID": 1490, "Summary": "Epidemiology\nTo date, 24 cases from 11 families of various origins (Asian Indian, South American Indian, Sephardi Jewish, Brazilian Portuguese, Dutch, Gypsy, Moroccan and Dominican) have been reported.\nClinical description\nThe ocular manifestations in CDPD include diffuse bilateral corneal edema occurring with severe corneal clouding, blurred vision, visual loss and nystagmus. They are apparent at birth or within the neonatal period and are indistinguishable from the ocular findings characterizing autosomal recessive CHED (CHED2). Hearing deficit in CDPD is slowly progressive and is typically identified in patients between 10 and 25 years of age. There are no reported cases with prelingual deafness, however, significant hearing loss in children as young as 4 years old has been detected by audiometry, suggesting that hearing may be affected early in the disease course, even at birth.\nEtiology\nCDPD is caused by mutations in the SLC4A11 gene located at the CHED2 locus on chromosome 20p13-p12, indicating that CHED2 and CDPD are allelic disorders. A total of 62 different SLC4A11 mutations have been reported in 98 families (92 with CHED2 and six with CDPD).\nDiagnostic methods\nDiagnosis is based on clinical criteria, detailed ophthalmological assessment and audiometry. Molecular confirmation of the clinical diagnosis is feasible.\nDifferential diagnosis\nA variety of genetic, metabolic, developmental and acquired diseases presenting with clouding of the cornea should be considered in the differential diagnosis (Peters anomaly, sclerocornea, limbal dermoids and congenital glaucoma; see these terms). Audiometry must be performed to differentiate CDPD from CHED2. Autosomal recessive types of CHED (CHED2) and CDPD should be carefully distinguished from the less severe autosomal dominant type, CHED1.\nGenetic counseling\nMore than 50% of the reported CDPD cases have been associated with parental consanguinity and all reported cases have been consistent with autosomal recessive transmission.\nManagement and treatment\nThe ocular abnormalities in patients with CDPD may be treated with topical hyperosmolar solutions. However, corneal transplantation (penetrating keratoplasty) represents the definitive treatment. Corneal transplantation results in substantial visual gains and has a relatively good surgical prognosis. Audiometric monitoring should be offered to all patients. Hearing aids may be necessary in adolescence.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Marc ABRAMOWICZ  - Dr Julie DESIR"}
{"Disease Name": "Corneal dystrophy", "Disease Definition": "A heterogeneous group of bilateral, genetically determined, non-inflammatory eye diseases that are usually restricted to the cornea. The designation is imprecise but remains in use because of its clinical value.", "ORPHA ID": 34533, "Summary": "Epidemiology\nPrevalence of the corneal dystrophies is variable but these conditions are rare. An indication of the precise number of each of the specific types of corneal dystrophies is unknown as all cases are not reported or recorded in a registry.\nClinical description\nClinically, the corneal dystrophies can be divided into three groups based on the sole or predominant anatomical location of the abnormalities. Some affect primarily the corneal epithelium and its basement membrane or Bowman layer and the superficial corneal stroma (superficial corneal dystrophy), the corneal stroma (stromal corneal dystrophy), or Descemet membrane and the corneal endothelium (posterior corneal dystrophy) (see these terms). Most corneal dystrophies have no systemic manifestations and present with variable shaped corneal opacities in a clear or cloudy cornea and they affect visual acuity to different degrees.\nEtiology\nDifferent corneal dystrophies are caused by mutations in the CHST6, COL8A2, KRT3, KRT12, PIP5K3, SLC4A11, TACSTD2, TCF4, TGFBI, and UBIAD1 genes. Knowledge about the genetic mutations responsible for these disorders has led to a better understanding of their basic defect and to molecular tests for their precise diagnosis. Genes for other corneal dystrophies have been mapped to specific chromosomal loci, but have not yet been identified.\nDiagnostic methods\nAs clinical manifestations vary widely with the different entities, corneal dystrophies should be suspected when corneal transparency is lost or corneal opacities occur spontaneously, particularly in both corneas, and especially in the presence of a positive family history or in the offspring of consanguineous parents. Clinical diagnosis is based on the age of onset and the clinical appearance of the cornea on slit-lamp biomicroscopy. When corneal tissue is excised, it should be examined by light microscopy and transmission electron microscopy (TEM) as this can establish the precise diagnosis of many corneal dystrophies. In dystrophies for which the genetic mutation has been identified, molecular genetic testing can confirm diagnosis.\nDifferential diagnosis\nMain differential diagnoses include various causes of monoclonal gammopathy, lecithin-cholesterol-acyltransferase deficiency, Fabry disease, cystinosis, tyrosinemia type 2, systemic lysosomal storage diseases (mucopolysaccharidoses, lipidoses, mucolipidoses), and several skin diseases (X-linked ichthyosis, keratosis follicularis spinolosa decalvans) (see these terms).\nAntenatal diagnosis\nA prenatal diagnosis of corneal dystrophies caused by known genetic mutations is theoretically possible but is not justified ethically for these non-life-threatening conditions.\nGenetic counseling\nCorneal dystrophies may have an autosomal dominant, autosomal recessive or X-linked recessive Mendelian mode of inheritance. Since the clinical characteristics and mode of inheritance of each of the well-defined corneal dystrophies are well established, genetic counseling can be offered to patients, particularly to provide genetic counseling on treatments and prognoses.\nManagement and treatment\nThe management of the corneal dystrophies varies with the specific disease. Some are treated medically or with methods that excise or ablate the abnormal corneal tissue, such as deep lamellar endothelial keratoplasty (DLEK) and phototherapeutic keratectomy (PTK). Other less debilitating or asymptomatic dystrophies do not warrant treatment.\nPrognosis\nThe prognosis varies from minimal effect on vision to corneal blindness, with marked phenotypic variability.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Corneal endotheliitis", "Disease Definition": "A rare corneal disorder characterized by inflammation of the corneal endothelium with corneal edema, keratic precipitates, mild to moderate anterior chamber reaction, and subsequent visual disturbances. It is often associated with increased intraocular pressure. Based on the distribution of the lesions, a linear, sectorial, disciform, and diffuse form can be distinguished.", "ORPHA ID": 137602, "Summary": ""}
{"Disease Name": "Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome", "Disease Definition": "A rare opthalmic disorder characterized by corneal opacification and dyskeratosis (which may cause visual impairment), associated with systemic features including palmoplantar hyperkeratosis, laryngeal dyskeratosis, pruritic hyperkeratotic scars, chronic rhintis, dyshidrosis and/or nail thickening.", "ORPHA ID": 352662, "Summary": ""}
{"Disease Name": "Cornelia de Lange syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by facial dysmorphism, hypertrichosis, mild to profound intellectual disability, intrauterine growth restriction (IUGR) and/or postnatal growth restriction, feeding difficulties, abnormalities of the hands and feet (ranging from severe reductional limb abnormalities, oligodactyly, to brachymetacarpia of the first metacarpus). Variable visceral malformations may be present.", "ORPHA ID": 199, "Summary": "Epidemiology\nIn Europe, the prevalence at birth of Cornelia de Lange syndrome (CdLS) is estimated at 1/80,000.\nClinical description\nDistinctive facial features include: well-defined arched eyebrows, synophrys, long eyelashes, short nose, concave nasal ridge, anteverted nares, micrognathia, long smooth philtrum, and downturned corners of the mouth with a thin upper lip. Feeding difficulties and failure to thrive are frequently complicated by gastroesophageal reflux. Global developmental delay, in particular speech delay evolves towards intellectual disability ranging from mild to profound. Various behavioral disorders have been reported (anxiety, autistic traits/autism, shyness, compulsive obsessional disorder, self-injurious behavior, psychiatric disorders). Hearing loss is possible as well as various cardiac, renal, skeletal, gastrointestinal, and genital malformations.\nEtiology\nCausative pathogenic variants in six genes involved in structural or regulatory components of the cohesin complex have been identified. NIPBL variants (5p13.2) are the most common cause (70% of patients). Less frequently involved genes include: SMC1A (Xp11.22-p11.21) associated with an X-linked form of CdLS, SMC3 (10q25) missense variants associated with a non-classical phenotype, RAD21 (8q24.11) mainly non-classical phenotype, HDAC8 (Xq13.1) implicated in an X-linked CdLS with some distinctive features, and BRD4 (19p13.12) recently associated with non-classical or mild CdLS. Genotype-phenotype correlations can be made to a certain extent, severe forms are more frequently associated with NIPBL.\nDiagnostic methods\nDiagnosis is often suspected on clinical presentation and a clinical diagnosis can be confirmed for the classical phenotype if full criteria are met. The diagnosis is confirmed by genetic testing for up to 70% of patients presenting a classical phenotype. Gene panels should at least include the causal genes as wells as genes from differential diagnoses (e.g. ANKRD11). Somatic mosaicism occurs quite frequently in CdLS (15%) and saliva or buccal cell swabs should be considered as preferred sample for genetic testing.\nDifferential diagnosis\nHypertrichosis is common in other syndromes that affect chromatin/transcription regulation genes such as Coffin Siris Syndrome, Wiedemann Steiner Syndrome, Rubinstein Taybi syndrome, CHOPS syndrome, etc. Other differential diagnoses include mucopolysaccharidosis, fetal alcohol syndrome, and Smith Lemli Opitz syndrome among others. There are overlapping features between KBG syndrome and mild or atypical CdLS.\nAntenatal diagnosis\nPrenatal ultrasound examination may show IUGR, organ malformations (diaphragmatic hernia, limb defects), increased nuchal thickness, and abnormal facial profile. Prenatal genetic testing can be proposed when the pathogenic variant has been previously identified in a family member.\nGenetic counseling\nMost cases are sporadic. Occasionally, familial transmission occurs, following an autosomal dominant pattern. Genetic counseling can be difficult in milder forms given some inter-individual variability. Germline mosaicism explains recurrence cases when the pathogenic variant is not detected in parents. X-linked forms (SMC1A, HDAC8) require specific genetic counseling.\nManagement and treatment\nThere is no cure for the disorder but psychoeducational care is necessary. Failure to thrive and gastroesophageal reflux require specific care: tube feeding, gastrotomy and Nissen anti-reflux intervention. Screening for multi-visceral or sensorineural complications helps to improve quality of life.\nPrognosis\nLife expectancy with appropriate care is typically unaltered but follow-up data is lacking. Life expectancy can be reduced in case of severe or untreated organ malformations. Quality of life is mostly altered by severe limb defects, behavioral disorders and psychiatric disorders. Hearing impairment can be difficult to diagnose and has been reported to improve with time in some adults.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Alice GOLDENBERG | ITHACA* - Dr Gabriella VERA | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Corneodermatoosseous syndrome", "Disease Definition": "A rare, genetic, ectodermal dysplasia syndrome characterized by corneal epithelial changes (ranging from roughening to nodular irregularities), diffuse palmoplantar hyperkeratosis with thickened, erythematous, scaly lesions affecting the elbows, knees and knuckles, distal onycholysis, brachydactyly accompanied by a single transverse palmar crease, short stature, premature birth, and increased susceptibility to tooth decay. Ocular symptoms include photophobia, reduced night vision, burning and watery eyes, and varying visual acuity. There have been no further descriptions in the literature since 1984.", "ORPHA ID": 3194, "Summary": ""}
{"Disease Name": "Coronary arterial fistula", "Disease Definition": "Coronary arterial fistulas are a connection between one or more of the coronary arteries and a cardiac chamber or great vessel.", "ORPHA ID": 2041, "Summary": "Epidemiology\nTheir exact incidence is unknown but the defect is rare and usually occurs in isolation.\nClinical description\nThe majority of these fistulas are congenital in origin although they may occasionally be detected after cardiac surgery. They do not usually cause symptoms or complications in the first two decades of life, especially when small. After this age, the frequency of both symptoms and complications increases. Complications include 'steal' from the adjacent myocardium, thrombosis and embolism, cardiac failure, atrial fibrillation, rupture, endocarditis/endarteritis and arrhythmias. Thrombosis within the fistula is rare but may cause acute myocardial infarction, paroxysmal atrial fibrillation and ventricular arrhythmias. Spontaneous rupture of the aneurysmal fistula causing haemopericardium has also been reported.\nDiagnostic methods\nWhilst two-dimensional echocardiography helps to differentiate between the different shunts, coronary angiography is the main diagnostic tool for the delineation of the anatomy.\nDifferential diagnosis\nThe main differential diagnosis is patent arterial duct, although other congenital arteriovenous shunts need to be excluded.\nManagement and treatment\nSurgery was the traditional method of treatment but nowadays catheter closure is recommended using a variety of closure devices, such as coils. With the catheter technique, the results are excellent with infrequent complications.\n\n                            Last update: \n                            December 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Shakeel QURESHI"}
{"Disease Name": "Coronary ostial stenosis or atresia", "Disease Definition": "A rare coronary artery congenital malformation characterized by congenital, partial or total occlusion of the left or right coronary artery orifice, associated with hypoplasia of the proximal segment of the corresponding coronary artery. It may present with failure to thrive, dyspnea, syncope, angina pectoris, ventricular tachycardia, myocardial ischemia and/or sudden death.", "ORPHA ID": 99087, "Summary": ""}
{"Disease Name": "Coronary sinus stenosis", "Disease Definition": "A rare congenital anomaly of the coronary sinus characterized by its stenosis at the ostium, lumen, or origin, typically leading to dilation of the vessel. Symptoms are variable and can include palpitations, tachypnea, dyspnea, chest pain, fatigue, and cyanosis. The malformation may be associated with other cardiac anomalies, such as coronary artery-coronary sinus fistula, unroofed coronary sinus, atrial septal defect, coronary sinus-left atrium fistula, total anomalous pulmonary venous connection, and ventricular septal defect.", "ORPHA ID": 99117, "Summary": ""}
{"Disease Name": "Corpus callosum agenesis-abnormal genitalia syndrome", "Disease Definition": "Corpus callosum agenesis-abnormal genitalia syndrome is a rare, genetic developmental defect during embryogenesis syndrome characterized by agenesis of the corpus callosum, mild to severe neurological manifestations (intellectual disability, developmental delay, epilepsy, dystonia), and urogenital anomalies (hypospadias, cryptorchidism, renal dysplasia, ambiguous genitalia). Additionally, skeletal anomalies (limb contractures, scoliosis), dysmorphic facial features (prominent supraorbital ridges, synophris, large eyes) and optic atrophy have been observed.", "ORPHA ID": 2508, "Summary": ""}
{"Disease Name": "Corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome", "Disease Definition": "Corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome is a developmental anomalies syndrome characterized by coloboma of the iris and optic nerve, facial dysmorphism (high forehead, microretrognathia, low-set ears), intellectual deficit, agenesis of the corpus callosum (ACC), sensorineural hearing loss, skeletal anomalies and short stature.", "ORPHA ID": 52055, "Summary": ""}
{"Disease Name": "Corpus callosum agenesis-macrocephaly-hypertelorism syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by agenesis of the corpus callosum, borderline or mild intellectual disability, macrocephaly, and dysmorphic facial features (broad forehead, widely spaced eyes). Chiari type I malformation has also been reported in association.", "ORPHA ID": 459074, "Summary": ""}
{"Disease Name": "Corpus callosum agenesis-neuronopathy syndrome", "Disease Definition": "A rare neurodegenerative disorder characterized by severe progressive sensorimotor neuropathy beginning in infancy with resulting hypotonia, areflexia, amyotrophy and variable degrees of dysgenesis of the corpus callosum. Additional features include mild-to-severe intellectual and developmental delays, and psychiatric manifestations that include paranoid delusions, depression, hallucinations, and 'autistic-like' features. Affected individuals are usually wheelchair restricted in the second decade of life and die in the third decade of life. The disease is inherited as an autosomal recessive trait.", "ORPHA ID": 1496, "Summary": ""}
{"Disease Name": "Cortical blindness-intellectual disability-polydactyly syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by congenital, total, cortical blindness, intellectual disability, postaxial polydactyly of the hands and feet, pre- and postnatal growth delay, psychomotor developmental retardation, and mild facial dysmorphism (incl. prominent forehead, short nose, long philtrum, high-arched palate, and microretrognathia). Recurrent respiratory and intestinal infections, as well as moderate hypertonia and hyperreflexia, are also associated. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 1389, "Summary": ""}
{"Disease Name": "Cortical dysgenesis with pontocerebellar hypoplasia due to TUBB3 mutation", "Disease Definition": "A rare, genetic, non-syndromic cerebral malformation due to abnormal neuronal migration disease characterized by the association of cortical dysplasia and pontocerebellar hypoplasia, manifesting with global developmental delay, mild to severe intellectual disability, axial hypotonia, strabismus, nystagmus and, occasionally, optic nerve hypoplasia. Brain imaging reveals variable malformations, including frontally predominant microgyria, gyral disorganization and simplification, dysmorphic and hypertrophic basal ganglia, cerebellar vermis dysplasia, brainstem/corpus callosum hypoplasia, and/or olfactory bulbs agenesis.", "ORPHA ID": 300570, "Summary": ""}
{"Disease Name": "Corticobasal syndrome", "Disease Definition": "A rare neurologic disease characterized by multifaceted motor system dysfunctions and cognitive defects such as asymmetric rigidity, bradykinesia, limb apraxia, and visuospatial dysfunction.", "ORPHA ID": 454887, "Summary": "Epidemiology\nThe prevalence of Corticobasal syndrome (CBS) is unknown.\nClinical description\nThe disease shows a wide clinical variability between patients with many developing a relatively pure motor syndrome, and others displaying a combination of motor and cognitive deficits. Disease onset is insidious and usually occurs in the 6th to 7th decade of life with symptoms typically being unilateral at first, and the arm being more commonly affected than the leg. It may begin primarily as a movement disorder with rigidity, bradykinesia and tremor, in association with frontal signs, cortical sensory loss, alien limb phenomenon, stimulus induced myoclonus and progressive limb apraxia, which may become bilateral, though usually asymmetrical, as the disease progresses. Gait disturbance and postural instability are common, whereas dystonia and aphasia (speech apraxia, dysfluency and agraphia) are less commonly reported. Additionally, eye movement abnormalities and behavioral manifestations can also be present. Many patients have dementia in later stages of the disease.\nEtiology\nAround 25% of CBS cases are shown to be due to corticobasal degeneration syndrome (CBD). CBD is a distinct tauopathy with selective aggregation of 4 repeat tau proteins with characteristic antigenic and ultrastructural characteristics. The cause is unknown and there is usually no evidence of inheritance (there has been a suggestion of genetic propensity, but this is currently poorly understood). Other causes of CBS include progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD) due to tau or TAR DNA-binding protein 43 (TDP-43), and Alzheimer disease (AD).\nDiagnostic methods\nThe diagnosis of CBS is a clinical one, based on the recognition of characteristic clinical features. Several diagnostic criteria have been proposed, but none have gained universal acceptance. The pathological diagnosis of CBD is only possible at autopsy and is defined by nerve cell loss, gliosis and atrophy of cortical and subcortical structures such as the posterior frontal and/or parietal lobes and the substantia nigra, as well as widespread deposition of hyperphosphorylated 4-repeat tau in neurons and glia. Furthermore, many cases may have co-pathologies which must be taken into consideration.\nDifferential diagnosis\nThe main differential diagnoses include progressive non-fluent aphasia and, to a lesser extent, behavioral variant of frontotemporal dementia, progressive supranuclear palsy, multiple system atrophy, posterior cortical atrophy, AD (the typical/amnestic form) and idiopathic Parkinson's disease.\nGenetic counseling\nFamilial CBS is extremely rare. Genetic counselling can only be offered in these exceptional cases.\nManagement and treatment\nTreatment is symptomatic and focuses on improving function as well as palliative care. Dystonia may be treated with botulinum toxin. Brief response to levodopa may occur, but sustained response to treatment should prompt a reconsideration of the diagnosis. Physical therapy and surgery are not found to offer any symptom relief. Speech therapy can be offered to those with prominent aphasia.\nPrognosis\nQuality of life is decreased in CBS patients as they gradually lose their ability to function independently. The prognosis is poor with the mean disease duration being 5.4-7.9 years after onset.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr James BURRELL"}
{"Disease Name": "Corticosteroid-binding globulin deficiency", "Disease Definition": "Corticosteroid-binding globulin deficiency is a rare, genetic, adrenal disease characterized by diminished corticosteroid-binding capacity associated with normal or low plasma corticosteroid-binding globulin concentration and reduced total plasma cortisol levels. Patients typically present chronic pain, fatigue and hypo/hypertension.", "ORPHA ID": 199247, "Summary": ""}
{"Disease Name": "Costello syndrome", "Disease Definition": "A rare syndrome with intellectual disability, characterized by failure to thrive, short stature, joint laxity, soft skin, and distinctive facial features. Cardiac and neurological involvement is common and there is an increased lifetime risk of certain tumors. Costello syndrome belongs to the RASopathies, a group of conditions resulting from germline derived point mutations affecting the RAS-mitogen activated protein kinase pathway.", "ORPHA ID": 3071, "Summary": "Epidemiology\nCostello syndrome (CS) estimated number of patients worldwide is 300. Estimated birth prevalence has been reported to be 1/300,000 to 1/1 250 000.\nClinical description\nPatients have above-average birth weight from mild hydrops and usually present with severe postnatal feeding difficulties and failure to thrive. The severe feeding difficulties typically necessitate the placement of a feeding tube. Developmental delay with short stature and mild to moderate intellectual disability are present in most cases. Features include relative macrocephaly, coarse facial features (epicanthal folds, full cheeks, low set and prominent ears, upturned nasal nasal tip, large mouth with prominent lips), curly or sparse, fine hair, loose soft skin with deep palmar and plantar creases, and papillomata (torso, extremities, perinasal and/or perianal region generally during childhood). Musculoskeletal features include joint laxity and ulnar deviation of wrists and fingers, hip dysplasia, and kyphoscoliosis in older individuals. Cardiovascular manifestations include valvular pulmonary stenosis, arrhythmia (ectopic or multifocal atrial tachycardia), hypertrophic cardiomyopathy and rarely aortic dilation. The reported neurological signs are hydrocephalus, seizures, Arnold-Chiari malformation type I, syringomyelia, and tethered spinal cord. In later childhood, patients often develop tight Achilles tendons that may require surgical correction. Puberty is often delayed or disordered. The disorder progresses with age and patients often show signs of premature ageing, osteoporosis and osteopenia. An increased risk of about 10-15% for solid malignant tumors (embryonal rhabdomyosarcoma, neuroblastoma in early childhood and transitional cell carcinoma of the bladder in adolescence) is reported.\nEtiology\nCS is caused by heterozygous germline mutations in the proto-oncogene HRAS (11p15.5) involved in controlling cell growth and division in multiple organ systems. The most common variant results in the p.Gly12Ser amino acid substitution, present in about 80% of patients.\nDiagnostic methods\nDiagnosis is based on the constellation of clinical findings, although no single feature is characteristic of the disorder. Diagnosis can be confirmed by molecular genetic testing.\nDifferential diagnosis\nCostello syndrome shows significant clinical overlap with Noonan syndrome and cardiofaciocutaneous syndrome, which are also RASopathies. Other disorders to consider include Beckwith-Wiedemann, Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome) and Simpson-Golabi-Behmel syndromes.\nAntenatal diagnosis\nPrenatal diagnosis is possible if the disease-causing mutation has been identified in an affected family member, or if the diagnosis of CS is suspected prenatally and HRAS sequence analysis is performed.\nGenetic counseling\nAn autosomal dominant pattern of inheritance may be found, typically due to de novo dominant mutations. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nFailure to thrive and cardiac manifestations should be treated with standard measures. Specific educational and intervention strategies may be required for intellectual development and developmental delay. Facial papillomata may require removal with cryotherapy or electrocoagulation. Abdominal and pelvic ultrasound examinations can be considered to screen for embryonal rhabdomyosarcoma and neuroblastoma until 8-10 years of age. Neoplastic complications are treated with standard approaches. Tethered cord may be screened by imaging. Hip dysplasia should be evaluated by an orthopedist.\nPrognosis\nThe risk of neoplasia and severe hypertrophic cardiomyopathy negatively affects the prognosis. The prognosis varies by the specific missense mutations, with neonatal lethal phenotypes and attenuated phenotypes reported.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Karen GRIPP"}
{"Disease Name": "Cowden syndrome", "Disease Definition": "A genodermatosis characterized by the presence of multiple hamartomas in various tissues and an increased risk for malignancies of the breast, thyroid, endometrium, kidney and colorectum. When CS is accompanied by germline PTEN mutations, it belongs to the PTEN hamartoma tumor syndrome (PHTS) group.", "ORPHA ID": 201, "Summary": "Epidemiology\nThe prevalence of Cowden syndrome is unknown but is estimated at 1/200,000.\nClinical description\nDisease manifestations usually occur between the second and third decades of life but can appear at any age. The most commonly, but not uniformly, reported manifestations are macrocephaly (specifically, megalencephaly), mucocutaneous lesions, thyroid abnormalities, fibrocystic disease and carcinoma of the breast, gastrointestinal hamartomas, multiple early onset uterine leiomyomas, and developmental delay. Macrocephaly and rarely dysmorphic facies, if present, are evident at birth. Malignancies such as breast cancer (with an 85% lifetime risk), epithelial thyroid cancer, renal cancer and endometrial carcinoma often appear later in life. Clinicians should consider other red flags of a CS diagnosis which includes Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma which is pathognomonic of CS), mucocutaneous stigmata such as trichilemmomas and papillomatous papules (believed to exist in 100% of CS patients by age 30), ganglioneuromatous gastrointestinal polyps, glycogenic acanthosis, pediatric differentiated (non-medullary) thyroid cancer and endometrial cancer diagnosed relatively early.\nEtiology\nIt is now believed that 25% of CS and CS-like cases are caused by germline mutations in PTEN (10q23), which encodes a dual-specificity phosphatase. Patients with CS/CS-like phenotypes that do not have PTEN involvement have been found to have germline promoter methylation of KLLN (up to 30%), germline variations in SDHB-D (10%), or germline mutations in AKT1 and PIK3CA (10%). More recently, germline SEC23B and USF3 were identified in PTEN wildtype CS/CS-like patients with differentiated thyroid cancer as a predominant phenotype.\nDiagnostic methods\nThe International Cowden Consortium for CS lists the pathognomonic (mucocutaneous lesions, LDD), major (breast cancer, macrocephaly, thyroid cancer and endometrial cancer), and minor criteria used to diagnose this disease. An operational diagnosis is given if a patient displays the pathognomonic skin lesions, two or more major, one major and 3 or more minor, or 4 or more minor criteria. A quantitative scoring system for adults and a separate pediatric criteria system have now been created to aid clinicians at the point of care. Finding germline mutations in PTEN or other causal genes confirms diagnosis.\nDifferential diagnosis\nJuvenile-polyposis syndrome, Peutz-Jeghers syndrome, Birt-Hogg-Dubé syndrome, Gorlin syndrome and neurofibromatosis type 1.\nAntenatal diagnosis\nAntenatal diagnosis is possible for at-risk pregnancies if the disease-causing mutation is discovered in an affected family member.\nGenetic counseling\nCS is inherited autosomal dominantly. Genetic counseling can be offered to patients with germline PTEN mutations and asymptomatic family members should also be tested so that those with a mutation can be monitored before symptom onset.\nManagement and treatment\nManagement and treatment are multidisciplinary and based on genotype. Once a PTEN germline mutation is identified, surveillance guidelines should be followed. Thyroid ultrasound should begin once a mutation is identified, starting at the age of 7. A colonoscopy and biennial renal imaging should begin between the ages of 35-40, unless symptomatic. Women should perform monthly breast self-examinations and yearly breast screenings as well as transvaginal ultrasounds (postmenopausal) or endometrial biopsies beginning at the age of 35.\nPrognosis\nThe pinpointing of the diagnosis (especially by gene) and instituting organ-specific surveillance at the right time results in a good prognosis. When advanced cancers occur before diagnosis is made, a poor outcome is common.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Charis ENG"}
{"Disease Name": "Coxoauricular syndrome", "Disease Definition": "A rare primary bone defect, described only in a mother and her three daughters to date, characterized by short stature, hip dislocation, minor vertebral and pelvic changes, and microtia with hearing loss. There have been no further descriptions in the literature since 1981.", "ORPHA ID": 1508, "Summary": ""}
{"Disease Name": "Coxopodopatellar syndrome", "Disease Definition": "Small patella syndrome (SPS) is a very rare benign bone dysplasia affecting skeletal structures of the lower limb and the pelvis.", "ORPHA ID": 1509, "Summary": "Epidemiology\nLess that 50 patients have been reported worldwide.\nClinical description\nThe main clinical features include patellar aplasia or hypoplasia, associated with absent, delayed or irregular ossification of the ischiopubic junctions and/or the infra-acetabular axe-cut notches. Additional features found in the majority of reported patients include femur and foot anomalies (a wide gap between the first and second toes, short fourth and fifth rays of the feet, and pes planus). Craniofacial anomalies (micrognathia, cleft palate, flattened nose and prominent forehead) have been reported occasionally. Intrafamilial variability of the patellar, pelvic and foot anomalies has been described. Signs and symptoms vary from pain resulting from gonarthrosis in elderly subjects to recurrent luxations from infancy, knee pain, and inability to run and ride a bicycle. However, some cases are asymptomatic.\nEtiology\nSPS is caused by mutations in the human TBX4 gene (chromosome 17q22). TBX4 mutations account for familial cases with a distinctive facial appearance and those without facial features. At present, there is no evidence for a genotype-phenotype correlation.\nDiagnostic methods\nDiagnosis is clinical and radiographical.\nDifferential diagnosis\nSPS should be recognized and differentiated from disorders with aplastic or hypoplastic patellae, such as isolated familial patella aplasia-hypoplasia (PTLAH) syndrome and the more severe nail-patella syndrome (NPS).\nGenetic counseling\nSPS is inherited in an autosomal dominant manner.\nManagement and treatment\nEarly surgical treatment, pain relief therapy and supportive measures should be offered.\n\n                            Last update: \n                            November 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Didier LACOMBE"}
{"Disease Name": "Cramp-fasciculation syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by adult onset of peripheral nerve hyperexcitability causing painful muscle cramps and fasciculations in the limbs, hyperreflexia, stiffness, and muscle pain. Other hypersensitivity-hyperexcitability symptoms are asthma, gastroesophageal reflux, migraine, tremor, cold hyperalgesia, and cardiac conduction defects. Autonomic signs and symptoms, neuropathic pain, cognitive deficits, and anxiety are also observed.", "ORPHA ID": 581271, "Summary": ""}
{"Disease Name": "Crandall syndrome", "Disease Definition": "Crandall syndrome is characterized by progressive sensorineural deafness, alopecia and hypogonadism with LH and GH deficiencies. It has been described in three brothers. It resembles Björnstad's syndrome (see this term) that combines irregular pili torti and deafness. It is probably inherited as and autosomal recessive disorder.", "ORPHA ID": 202, "Summary": ""}
{"Disease Name": "Crane-Heise syndrome", "Disease Definition": "Crane-Heise syndrome is a very rare syndrome characterized by poorly mineralized calvarium, facial dysmorphism, vertebral abnormalities and absent clavicles.", "ORPHA ID": 1512, "Summary": "Epidemiology\nNine cases have been reported in the literature so far.\nClinical description\nDysmorphic features include micrognathia, cleft palate, hypertelorism and upturned nares. Clavicular aplasia is constant and agenesis of cervical vertebral bodies is frequent. Intra uterine growth retardation is constant.\nEtiology\nIt is most likely that the condition is hereditary, transmitted as an autosomal recessive trait.\nAntenatal diagnosis\nAntenatal diagnosis is possible by ultrasonographic monitoring for cerebral and vertebral malformations.\nPrognosis\nPrognosis is poor; the syndrome is almost always lethal soon after birth.\n\n                            Last update: \n                            January 2010"}
{"Disease Name": "Cranial meningocele", "Disease Definition": "A rare central nervous system malformation characterized by herniation of meninges through a permanent defect in the skull. It is lined by arachnoid and contains cerebrospinal fluid, but no brain tissue. Signs and symptoms depend on the location of the lesion and are related to mass effect, skull deformities, or leaking of cerebrospinal fluid.", "ORPHA ID": 268820, "Summary": ""}
{"Disease Name": "Cranio-cervical dystonia with laryngeal and upper-limb involvement", "Disease Definition": "Cranio-cervical dystonia with laryngeal and upper-limb involvement is a rare genetic, isolated dystonia characterized by a variable combination of cervical dystonia with tremor, blepharospasm, oromandibular and laryngeal dystonia. Dystonia progresses slowly and might spread to become segmental. Arm tremor and myoclonic jerks in the arms or neck have also been reported.", "ORPHA ID": 420485, "Summary": ""}
{"Disease Name": "Cranio-osteoarthropathy", "Disease Definition": "Cranio-osteoarthropathy (COA) is a form of primary hypertrophic osteoarthropathy (see this term) characterized by delayed closure of the cranial sutures and fontanels, digital clubbing, arthropathy, and periostosis.", "ORPHA ID": 1525, "Summary": "Epidemiology\nPrevalence is unknown. To date, about 30 cases have been reported.\nClinical description\nCOA presents in childhood with features of primary hypertrophic osteoarthropathy including digital clubbing and clinodactyly of the fingers, eczematous skin eruption, arthropathy and periosteal new bone formation as well as poor neurocranium ossification with delayed closure of the cranial sutures and fontanels, resulting in wide fontanels, and an increased number of wormian bones. COA may also be associated with congenital heart disease.\nEtiology\nIt is caused by mutations in the HPGD gene (4q33-q34) and is inherited as an autosomal recessive trait; however, heterozygous carriers can have a mild phenotype.\n\n                            Last update: \n                            December 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Hermann GIRSCHICK"}
{"Disease Name": "Craniodiaphyseal dysplasia", "Disease Definition": "Craniodiaphyseal dysplasia is a rare sclerotic bone disorder with a variable phenotypic expression with massive generalized hyperostosis and sclerosis, particularly of the skull and facial bones, that may lead to severe deformity.", "ORPHA ID": 1513, "Summary": ""}
{"Disease Name": "Craniodigital-intellectual disability syndrome", "Disease Definition": "Craniodigital syndrome - intellectual deficit is characterised by syndactyly of the fingers and toes, characteristic facies (`startled' facial expression with a small pointed nose, micrognathia, long dark eyelashes and prominent eyebrows) and intellectual deficit.", "ORPHA ID": 1514, "Summary": "Epidemiology\nLess than 10 cases have been described in the literature so far.\nClinical description\nAbnormal dermatoglyphic patterns, growth retardation and brachycephaly have also been reported.\nGenetic counseling\nTransmission appears to be autosomal or X-linked recessive.\n\n                            Last update: \n                            April 2008"}
{"Disease Name": "Cranioectodermal dysplasia", "Disease Definition": "Cranioectodermal dysplasia (CED) is a rare developmental disorder characterized by congenital skeletal and ectodermal defects associated with dysmorphic features, nephronophthisis, hepatic fibrosis and ocular anomalies (mainly retinitis pigmentosa).", "ORPHA ID": 1515, "Summary": "Epidemiology\nTo date, 20 cases have been reported in the literature.\nClinical description\nCED is primarily characterized by an abnormal development of bones (i.e. craniosynostosis/dolichocephaly, narrow thorax, pectus excavatum, rhizomelic micromelia, brachydactyly, syndactyly, clinodactyly, hyperextensible joints), and ectodermal defects such as dental anomalies (reduced enamel thickness, hypodontia, microdontia, taurodontism, malformations of the cusps), sparse hair, and abnormal finger and toe nails. Dysmorphic features are observed such as epicanthic folds, hypotelorism, anteverted nares, and everted lower lip. Patients frequently develop chronic renal failure due to nephronophthisis, usually between the ages of 2 and 6. Liver involvement (hepatic fibrosis) can also be observed. Recurrent lung infections, heart defects and ocular anomalies (nystagmus, myopia, retinal dystrophy, and particularly retinitis pigmentosa) are also possible in the course of the disease.\nEtiology\nCED is a heterogenous condition belonging to the ciliopathy group of diseases and is due to mutations in the IFT122, IFT43, WDR19 and WDR35 genes involved in intraflagellar transport (IFT). This genetic background explains the pleiotropic phenotype of CED that includes manifestations of several ciliopathies.\nDiagnostic methods\nDiagnosis is based on clinical examination. Imagery (ultrasonography), laboratory findings (urine analysis, serum electrolytes, and lipid profile), histological examination and liver and renal function tests allow detection of potential renal and liver anomalies. Ocular anomalies can be detected by eye fundus and electroretinography.\nDifferential diagnosis\nDifferential diagnosis of CED includes Jeune syndrome (see this term) from which it can be distinguished by the presence of craniosynostosis, and skin and dental dysplasia. CED also overlaps with Ellis van Creveld syndrome (see this term) which also shows ectodermal defects and narrow thorax.\nGenetic counseling\nIn most cases, transmission is autosomal recessive.\nManagement and treatment\nIn many cases, renal function rapidly deteriorates, requiring treatment of metabolic acidosis, oral sodium chloride supplementation, then dialysis or renal transplantation in case of end-stage renal failure.\nPrognosis\nPrognosis depends on renal, heart and lung defects which can be life threatening.\n\n                            Last update: \n                            June 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Valérie CORMIER-DAIRE"}
{"Disease Name": "Craniofacial conodysplasia", "Disease Definition": "Craniofacial conodysplasia is characterised by craniofacial dysplasia, cone-shaped physes of the hands and feet, and neurological manifestations resembling cerebral palsy. It has been described in one family. The syndrome appeared to be transmitted as a dominant trait.", "ORPHA ID": 85168, "Summary": ""}
{"Disease Name": "Craniofacial dysostosis-diaphyseal hyperplasia syndrome", "Disease Definition": "Stanescu type dysostosis is a rare form of osteosclerosis.", "ORPHA ID": 1798, "Summary": "Epidemiology\nSo far it has been described in around 30 patients from three families.\nClinical description\nIt is characterized by craniofacial dysostosis with a small cranium and thin skull bone, depressions over the frontoparietal and occipitoparietal sutures, marked hypoplasia of mandible, exophthalmos, cortical sclerosis of the long bones and normal intelligence. The long bones are short and bent, and thickening of bone cortex occurs during the pubertal and post-pubertal periods and increases with age.\nGenetic counseling\nThe syndrome is inherited in an autosomal dominant manner.\n\n                            Last update: \n                            March 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM"}
{"Disease Name": "Craniofacial dysplasia-short stature-ectodermal anomalies-intellectual disability syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by craniofacial dysmorphism (including an abnormal skull shape, hypertelorism, downslanting palpebral fissures, epicanthal folds, low-set ears, depressed nasal bridge, micrognathia), short stature, ectodermal anomalies (such as sparse eyebrows, eyelashes, and scalp hair, hypolastic toenails), developmental delay, and intellectual disability. Additional features may include cerebral/cerebellar malformations and mild renal involvement.", "ORPHA ID": 459061, "Summary": ""}
{"Disease Name": "Craniofacial-deafness-hand syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by facial dysmorphism (including flat facial profile normal calvarium, hypertelorism, small downslanting palpebral fissures with an antimongoloid slant, hypoplastic nose with button tip and slitlike nares, and small, pursed mouth), profound sensorineural hearing loss/deafness and hand anomalies such as ulnar deviations and contractures of the hand.", "ORPHA ID": 1529, "Summary": ""}
{"Disease Name": "Craniofaciofrontodigital syndrome", "Disease Definition": "Craniofaciofrontodigital syndrome is a rare multiple congenital anomalies syndrome characterized by mild intellectual disability, short stature, cardiac anomalies, mild dysmorphic features (macrocephaly, prominent forehead, hypertelorism, exophthalmos), cutis laxa, joint hyperlaxity, wrinkled palms and soles and skeletal anomalies (sella turcica, wide ribs and small vertebral bodies).", "ORPHA ID": 363705, "Summary": ""}
{"Disease Name": "Craniofrontonasal dysplasia-Poland anomaly syndrome", "Disease Definition": "A polymalformative syndrome characterized by craniosynostosis, Poland anomaly, cranio-fronto-nasal dysplasia, and genital and breast anomalies.", "ORPHA ID": 1521, "Summary": ""}
{"Disease Name": "Craniofrontonasal dysplasia", "Disease Definition": "A rare X-linked malformation syndrome characterized by craniofacial abnormalities such as uni- or bicoronal synostosis, hypertelorism and a bifid nose, grooved or split nails, frizzy hair, abnormalities of the shoulder girdle, hands and feet.", "ORPHA ID": 1520, "Summary": "Epidemiology\nIt occurs in fewer than 1/100,000 newborns. Detailed phenotypic analysis shows that females are more severely affected than males, a highly unusual characteristic for an X-linked disorder.\nClinical description\nFemale patients have hypertelorism, and a broad nose with a vertical groove on the top of the nose or a bifid nose, uni or bicoronal craniosynostosis. The following facial abnormalities may be seen: facial asymmetry, downslanting palpebral fissures, dry, curly and frizzy hair, widow's peak, low posterior hairline, webbed neck, highly arched palate, cleft lip and palate, a narrow and V-shaped maxilla. Ophthalmologic abnormalities, abnormal auditory ossicles, and both conductive and sensorineural deafness can be seen. Skeletal deformities may include sloping shoulders with dysplastic clavicles, broad or duplicated thumbs and halluces, short thumbs, brachydactyly, clinodactyly, gaps between the first and second toes, syndactyly, camptodactyly, scoliosis and hyperextensible joints. Longitudinal splits or grooves in the finger- and toe- nails are frequent and characteristic. Diaphragmatic hernia, pectus excavatum or carinatum, breast hypoplasia, cardiac abnormalities, bicornuate uterus, shawl scrotum, hypospadias and agenesis of the corpus callosum occur occasionally. Mild developmental delay can occur. Variable difficulties with speech and language development can be associated. Most of the male patients are mildly affected with hypertelorism only but can occasionally present with a severe female-like phenotype. The cause for this severe phenotype in males is probably mosaic pathogenic variants in EFNB1.\nEtiology\nThe syndrome is caused by variants in the EFNB1 gene. This gene encodes ephrin-B1 and maps to Xq13.1. Random X-inactivation explains the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of ephrin-B1, generating abnormal tissue boundaries.\nDiagnostic methods\nIn case of a low-level of mosaicism for EFNB1 variants, extensive analysis of several types of tissues might be required to detect variants. Variation in EFNB1 is detected from DNA isolated from blood, fibroblast cell lines, saliva and hair roots by a combination of PCR/Sanger sequencing, or by next-generation sequencing and multiplex ligation-dependent probe amplification (MPLA; for the detection of deletions in females).\nDifferential diagnosis\nIsolated hypertelorism can mimic the mild presentation of craniofrontonasal syndrome. The disease needs to be distinguished from other syndromes associated with hypertelorism such as SPECC1L-related hypertelorism syndrome and Baraitser-Winter cerebrofrontofacial syndrome.\nAntenatal diagnosis\nIn case of an established EFNB1 mutation in a parent, prenatal diagnosis is possible.\nGenetic counseling\nThe risk that an affected female will pass the disease on her daughter or son is 50%. An affected male will pass the disease on to all of his daughters but none of his sons.\nManagement and treatment\nMultistage surgery is the general treatment plan for craniosynostosis. The synostotic sutures of the skull are released in the first year of life. The aim of this surgery is decompression of the brain and remodeling of the skull. Correction of the facial anomalies is usually delayed until the age of 5 or later, depending on the severity of hypertelorism, orbital dystopia and shape of the maxilla. Surgical correction of strabismus can be indicated and timing should be discussed within the craniofacial team. Multidisciplinary treatment is mandatory with the input of plastic surgeons, maxillofacial surgeons, ophthalmologists, orthoptists, otolaryngotologists, speech therapists, psychologists and social workers, and orthodontists.\nPrognosis\nLife expectancy in general is similar to the normal population. Quality of life may be affected because of a different facial appearance and the consequences of other congenital abnormalities.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Irene MATHIJSSEN | ERN CRANIO* - Pr Andrew WILKIE | ERN CRANIO*\n\n\n                                * European Reference Network"}
{"Disease Name": "Craniolenticulosutural dysplasia", "Disease Definition": "Craniolenticulosutural dysplasia (CLSD), also known as Boyadjiev-Jabs syndrome, is characterized by the specific association of large and late-closing fontanels, hypertelorism, early-onset cataract and mild generalized skeletal dysplasia.", "ORPHA ID": 50814, "Summary": "Epidemiology\nIt was originally described in 21 members of a Saudi Arabian family, but six new cases from a consanguineous family and one unrelated individual have recently been reported.\nClinical description\nPatients have abnormal hair, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, macrocephaly, significant hypertelorism, and a broad and prominent nose. In addition, CLSD patients have Y-shaped sutural cataracts diagnosed by 1-2 years of age. All affected individuals have proportionate short stature but intellectual development is normal. They have flat feet, joint hypermobility and abnormal dentition. Skeletal defects include scoliosis, high and narrow iliac wings and vertebral body defects. The anterior fontanel does not completely ossify in adulthood.\nEtiology\nCLSD maps to chromosome 14q13-q21 and causative mutations have been identified in the SEC23A gene.\nDiagnostic methods\nCLSD should be considered in evaluation of patients with late-closing fontanels.\nGenetic counseling\nTransmission is consistent with an autosomal recessive pattern of inheritance but other modes of inheritance can not be excluded.\nManagement and treatment\nTreatment of the disorder is symptomatic.\nPrognosis\nThe prognosis is good.\n\n                            Last update: \n                            June 2008"}
{"Disease Name": "Craniometadiaphyseal dysplasia, wormian bone type", "Disease Definition": "Craniometadiaphyseal dysplasia, wormian bone type is an extremely rare craniotubular bone dysplasia syndrome described in fewer than 10 patients to date. Clinical manifestations include macrocephaly, frontal bossing, malar hypoplasia, prominent mandible and dental hypoplasia. Other skeletal anomalies include abnormal bone modeling in tubular bones, multiple wormian bones and deformities of chest, pelvis and elbows. An increased risk of fractures is noted.", "ORPHA ID": 85184, "Summary": ""}
{"Disease Name": "Craniometaphyseal dysplasia", "Disease Definition": "Craniometaphyseal dysplasia (CMD) is a very rare genetic bone disease characterized by progressive diffuse hyperostosis of cranial bones causing facial dysmorphism and functional repercussions, and metaphyseal widening of long bones.", "ORPHA ID": 1522, "Summary": ""}
{"Disease Name": "Craniomicromelic syndrome", "Disease Definition": "A rare syndromic craniosynostosis malformation syndrome characterized by intrauterine growth retardation, underossification of the skull with large fontanels, short limbs with absent phalanges, and finger and toe syndactyly. Reported dysmorphic features include a narrow face with small palpebral fissures, small pointed nose, microstomia, micrognathia, and low-set and posteriorly rotated ears. A posterior encephalocele and other congenital malformations can also be observed.", "ORPHA ID": 1524, "Summary": ""}
{"Disease Name": "Craniopharyngioma", "Disease Definition": "A rare neoplastic/endocrine disease characterized by benign slow growing tumors of low-grade histological malignancy (WHO grade 1) that are located within the sellar and parasellar regions of the skull base.", "ORPHA ID": 54595, "Summary": "Epidemiology\nThe point prevalence of this tumor is approximately 1/50,000.\nClinical description\nClinical manifestations frequently occur long time before diagnosis with most patients at diagnosis having neurological (headaches, visual disturbances) and endocrine (growth delay, disturbances of pubertal development, central diabetes insipidus) dysfunction.\nEtiology\nCraniopharyngiomas are thought to arise from epithelial remnants of the craniopharyngeal duct or Rathke's pouch (adamantinomatous type tumors) or from metaplasia of squamous epithelial cell rests that are remnants of the part of the stomadeum that contributed to the buccal mucosa (squamous papillary type tumors).\nDiagnostic methods\nThe neuroradiological diagnosis is mainly based on the three components of the tumor (cystic, solid and calcified) in the characteristic sellar/parasellar location. Definitive diagnosis is based on histological examination of a surgical specimen.\nDifferential diagnosis\nThe differential diagnosis includes other tumors occurring in this region (pituitary adenomas, germinoma, low-grade glioma), infectious or inflammatory processes (Langerhans cell histiocytosis), vascular malformations (aneurysms) and congenital anomalies (Rathke's cleft cysts).\nAntenatal diagnosis\nDue to increased sensitivity of antenatal diagnostics (ultrasound), the rate of prenatal craniopharyngioma diagnosis is rising.\nManagement and treatment\nIf there is no hypothalamic involvement, the currently favored treatment strategy is tumor resection preserving the integrity of hypothalamus and visual structures. In the presence of hypothalamic invasion, the current hypothalamus-sparing strategy involves sub-total resection with post-operative radiotherapy. Endocrine disturbances are normally permanent and need careful replacement.\nPrognosis\nThe 5 year overall-survival rate is 80%. However, high survival rates are associated with marked morbidity (hypothalamic syndrome, including morbid severe obesity; altered neuropsychological profile) in case of tumor- and/or treatment-associated hypothalamic damage.\n\n                            Last update: \n                            December 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Hermann MÜLLER | PaedCan-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Craniorachischisis", "Disease Definition": "Craniorachischisis is the most severe form of neural tube defect in which both the brain and spinal cord remain open to varying degrees. It is a very rare congenital malformation of the central nervous system.", "ORPHA ID": 63260, "Summary": "Epidemiology\nThe prevalence is not known.\nClinical description\nCraniorachischisis totalis, the most complete form of craniorachischisis, presents anencephaly and total spina bifida together and is lethal.\nEtiology\nAs with other neural tube defects, craniorachischisis is thought to be of multifactorial origin.\nAntenatal diagnosis\nAntenatal diagnosis is possible by ultrasonographic monitoring.\n\n                            Last update: \n                            January 2010"}
{"Disease Name": "Craniorhiny", "Disease Definition": "A rare frontonasal dysplasia malformation syndrome characterized by an oxycephalic skull with craniosynostosis, wide nose with anteverted nostrils, hirsutism at base of nose, agenesis of the nasolacrimal ducts, and bilateral, symmetrical nasolabial cysts on upper lip. Additional features may include hypertelorism. There have been no further descriptions in the literature since 1991.", "ORPHA ID": 157832, "Summary": ""}
{"Disease Name": "Craniosynostosis, Boston type", "Disease Definition": "Craniosynostosis, Boston type is a form of syndromic craniosynostosis, characterized by a highly variable craniosynostosis with frontal bossing, turribrachycephaly and cloverleaf skull anomaly. Hypoplasia of the supraorbital ridges, cleft palate, extra teeth and limb anomalies (triphalangeal thumb, 3-4 syndactyly of the hands, a short first metatarsal, middle phalangeal agenesis in the feet) have also been described. Associated problems include headache, poor vision, and seizures. Intelligence is normal.", "ORPHA ID": 1541, "Summary": ""}
{"Disease Name": "Craniosynostosis, Herrmann-Opitz type", "Disease Definition": "Craniosynostosis, Herrmann-Opitz type is a rare bone development disorder characterized by intellectual disability, short stature, turribrachycephaly, facial dysmorphism (i.e. severe hypertelorism, hypoplasia of supraorbital ridges, abnormal ears, and micrognathia), bony defects of the occiput, and digital anomalies (incl. syndactyly, oligodactyly, and/or brachydactyly). Urethral atresia has also been reported. There have been no further descriptions in the literature since 1987.", "ORPHA ID": 2145, "Summary": ""}
{"Disease Name": "Craniosynostosis, Philadelphia type", "Disease Definition": "Craniosynostosis, Philadelphia type is a form of syndromic craniosynostosis, characterized by sagittal/dolichocephalic head shape with a relatively normal facial appearance and complete soft tissue syndactyly of hand and foot. Transmission is autosomal dominant with variable expression of the hand findings, and incomplete penetrance of the sagittal craniosynostosis. Craniosynostosis, Philadelphia type has been suggested to share the same etiology as syndactyly type 1A.", "ORPHA ID": 1527, "Summary": ""}
{"Disease Name": "Craniosynostosis-anal anomalies-porokeratosis syndrome", "Disease Definition": "Craniosynostosis - anal anomalies - porokeratosis, or CDAGS, is a very rare condition characterized by craniosynostosis and clavicular hypoplasia, (C), delayed closure of the fontanel (D), anal anomalies (A), genitourinary malformations (G) and skin eruption (S).", "ORPHA ID": 85199, "Summary": "Epidemiology\nIt has been described in seven patients from four unrelated families.\nClinical description\nCranial abnormalities include a coronal synostosis with wide-open anterior and posterior fontanels and large parietal foramina. In some patients the skin eruption has been classified as porokeratosis (a disorder of keratinization). Sensorineural hearing loss and mild to severe developmental delay are common.\nGenetic counseling\nThe condition is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Craniosynostosis-Dandy-Walker malformation-hydrocephalus syndrome", "Disease Definition": "A rare malformation disorder characterized by sagittal craniosynostosis, Dandy-Walker malformation, hydrocephalus, craniofacial dysmorphism (including dolichocephaly, hypertelorism, micrognathia, positional ear deformity) and variable developmental delay.", "ORPHA ID": 1538, "Summary": ""}
{"Disease Name": "Craniosynostosis-dental anomalies", "Disease Definition": "A rare syndromic craniosynostosis characterized by premature fusion of multiple or all calvarial sutures (resulting in variable abnormal shape of the head), midface hypoplasia, delayed and ectopic tooth eruption and supernumerary teeth. Associated facial dysmorphism includes proptosis, hypertelorism, beaked nose, and relative prognathism. Variable digital anomalies (e.g. finger and/or toe syndactyly, clinodactyly), short stature, cognitive and/or motor delay, high palate, ear deformity and conductive hearing loss have also been reported.", "ORPHA ID": 284149, "Summary": ""}
{"Disease Name": "Craniosynostosis-hydrocephalus-Arnold-Chiari malformation type I-radioulnar synostosis syndrome", "Disease Definition": "A rare syndromic craniosynostosis characterized by sagittal craniosynostosis, hydrocephalus, Chiari I malformation and radioulnar synostosis. Other clinical findings include blepharophimosis, small low-set ears, hypoplastic philtrum, kidney malformation, and hypogenitalism.", "ORPHA ID": 171839, "Summary": ""}
{"Disease Name": "Craniosynostosis-intracranial calcifications syndrome", "Disease Definition": "Craniosynostosis-intracranial calcifications syndrome is a form of syndromic craniosynostosis characterized by pancraniosynostosis, head circumference below the mid-parental head circumference, mild facial dysmorphism (prominent supraorbital ridges, mild proptosis and maxillary hypoplasia) and calcification of the basal ganglia. The disease is associated with a favorable neurological outcome, normal intelligence and is inherited in an autosomal recessive manner.", "ORPHA ID": 52054, "Summary": ""}
{"Disease Name": "Craniosynostosis-microretrognathia-severe intellectual disability syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay, moderate to severe intellectual disability, dysmorphic features including craniosynostosis, micro-/retrognathia, cleft palate, and brachydactyly, and short stature. Seizures, skeletal anomalies (such as arthrogryposis, gracile bones, and pathological fractures), and renal abnormalities have also been described. Cerebral MRI may show periventricular white matter changes and ventriculomegaly.", "ORPHA ID": 565858, "Summary": ""}
{"Disease Name": "Craniosynostosis", "Disease Definition": "Craniosynostosis is defined as the premature fusion of one or more cranial sutures leading to secondary distortion of skull shape resulting in skull deformities with a variable presentation. Craniosynostosis may occur in an isolated setting or as part of a syndrome.", "ORPHA ID": 1531, "Summary": ""}
{"Disease Name": "Craniotelencephalic dysplasia", "Disease Definition": "Craniotelencephalic dysplasia is an extremely rare, genetic developmental defect during embryogenesis syndrome characterized by craniosynostosis with frontal encephalocele and various additional brain anomalies (severe hydrocephalus, agenesis of the corpus callosum, lissencephaly and polymicrogyria, parenchymal cysts, septo-optic dysplasia) resulting in marked cerebral dysfunction, seizures and very severe psychomotor delay. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 1528, "Summary": ""}
{"Disease Name": "Creatine deficiency syndrome", "Disease Definition": "Creatine deficiency syndrome (CDS) comprises a group of inborn errors of creatine metabolism, characterized by a global developmental delay, intellectual disability and associated neurological (seizures, movement disorders, myopathy) and behavioral manifestions. CDS includes two creatine biosynthesis disorders; guanidinoacetate methyltransferase deficiency and L- Arginine: glycine amidinotransferase deficiency, as well as X-linked creatine transporter deficiency.", "ORPHA ID": 79172, "Summary": ""}
{"Disease Name": "Creeping myiasis", "Disease Definition": "A rare cutaneous myiasis characterized by infestation of humans by the larvae of horse or cattle bot flies. After penetration of the skin, horse bot fly larvae form tunnels in the lower layers of the epidermis, where they can migrate for up to several months, causing serpentine, erythematous lesions with intense pruritus. Cattle bot fly larvae penetrate deeper into the subcutaneous tissue, producing more painful, erythematous lesions, which usually resolve after several hours or days, when the larvae move on to infest another area.", "ORPHA ID": 504, "Summary": ""}
{"Disease Name": "Crigler-Najjar syndrome type 1", "Disease Definition": "A form of Crigler Najjar syndrome (CNS), a hereditary disorder of hepatic bilirubin conjugation, characterized by severe neonatal unconjugated hyperbilirubinemia due to a complete absence of hepatic UDP-glucuronosyltransferase 1A1. The disorder clinically manifests with neonatal, isolated, severe and permanent jaundice with a permanent risk of bilirubin encephalopathy.", "ORPHA ID": 79234, "Summary": "Epidemiology\nThe prevalence of Crigler-Najjar syndrome type 1 (CNS1) is unknown.\nClinical description\nInfants present with persistent jaundice at or soon after birth. Bilirubin encephalopathy (kernicterus manifesting as hypertonia, deafness, oculomotor palsy and lethargy) due to hyperbilirubinemia is a permanent risk. Neurologic defects (injury to basal ganglia, cerebellar and likely hippocampal structures) can occur, generally associated with intellectual and motor impairment.\nEtiology\nNumerous variants in the gene UGT1A1 gene (2q37), encoding the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), have been linked to CNS1. In the liver, UGT1A1 conjugates bilirubin with glucuronic acid, thereby increasing bilirubin water solubility and thus facilitating its excretion. The UGT1A1 variants result in absent UGT1A1 activity with marked impairment of bilirubin conjugation.\nDiagnostic methods\nDiagnosis is based on findings of total serum bilirubin between 20 and 45 mg/dL and presence of traces of bilirubin glucuronides in bile. Diagnosis is confirmed by genomic DNA analysis (ruling out the need for liver biopsy). When liver biopsy was performed, it showed a total deficiency of hepatic UGT1A1 activity.\nDifferential diagnosis\nDifferential diagnosis includes disorders of excessive bilirubin production (hemolysis, infections). CNS type 2 (CNS2) can be excluded by the lack of response to phenobarbital treatment and by DNA analysis.\nAntenatal diagnosis\nPrenatal diagnosis is possible provided both disease-causing mutations have been identified in the proband.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment relies on phototherapy for 10-12 hours a day (to maintain levels of unconjugated hyperbilirubinemia below the neurotoxic threshold and the bilirubilbumin molar ratio <0.7). Orthotopic liver transplantation may be considered and is more effective when performed before onset of neurologic damage. Bilirubin chelators (calcium salts, cholestyramine) may be used. Treatment with heme oxygenase inhibitors (tin-mesoporphyrin) can decrease plasma bilirubin concentrations but are not advised in the long term, because of their side effects (photosensitization). They may be useful for treating acute and severe hyperbilirubinemia but are not available for daily clinical practice. Gene therapy trials are ongoing. Prompt treatment of neurologic manifestations is required to avoid potentially devastating neurologic sequelae (intensive phototherapy, albumin infusions, and plasma exchanges). Unlike CNS2, patients with CNS1 do not respond to phenobarbital.\nPrognosis\nWithout treatment, CNS1 is lethal as a result of kernicterus. With treatment and management children have a good prognosis and may follow normal schooling, even though the treatment is very restrictive. Adult patients who have not undergone liver transplantation still require phototherapy but may have ''near normal'' social and familial lives. A few adult women have given birth to normal children, provided their pregnancies have been carefully followed up.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe LABRUNE | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Crigler-Najjar syndrome type 2", "Disease Definition": "A form of Crigler Najjar syndrome (CNS), a rare hereditary disorder of bilirubin metabolism, characterized by unconjugated hyperbilirubinemia due to reduced and inducible activity of hepatic UDP-glucuronosyltransferase 1A1. The disorder clinically manifests with neonatal, isolated jaundice with a risk of developing bilirubin encephalopathy later in life due to triggers such as stress or infection.", "ORPHA ID": 79235, "Summary": "Epidemiology\nThe prevalence of Crigler Najjar syndrome type 2 (CNS2) is unknown.\nClinical description\nFirst clinical manifestations usually appear soon after birth. CNS2 patients are less severely jaundiced than CNS type 1 (CNS1) patients, have pigmented bile that contains bilirubin glucuronides, and generally do not present neurologic or intellectual impairment. Bilirubin encephalopathy may develop in later life when patients experience a superimposed infection or stress.\nEtiology\nNumerous variants in the UGT1A1 gene (2q37), encoding the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), have been linked to CNS2. In the liver, UGT1A1 conjugates bilirubin with glucuronic acid, thereby increasing bilirubin water solubility and thus facilitating its excretion. The UGT1A1 variants result in reduced, but inducible bilirubin UGT1A1 activity, with marked impairment of bilirubin conjugation.\nDiagnostic methods\nDiagnosis is based on biochemical findings with total serum bilirubin ranging from 6 to 20 mg/dL and presence of bilirubin glucuronides in bile. Diagnosis is confirmed by genomic DNA analysis (ruling out the need for liver biopsy). It may also help in differentiating between the two types of CNS. Liver biopsy, when it was performed, revealed residual enzymatic activity.\nDifferential diagnosis\nDifferential diagnosis includes disorders of excessive bilirubin production (hemolysis). CNS2 can be differentiated from CNS1 by the response to phenobarbital treatment and from mild hepatic deficiency of UGT1A1 (Gilbert syndrome).\nAntenatal diagnosis\nPrenatal diagnosis is possible provided both disease-causing mutations have been identified in the proband.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment relies on daily phenobarbital administration that can induce the expression of UGT1A1 resulting in a decrease in the serum bilirubin level by approximately 60-70%. Patients and their families must be educated to be very careful during infectious episodes and/or fasting periods that are likely to increase bilirubin production and thus increase hyperbilirubinemia. Should this occur, patients must be examined by their physician and serum bilirubin concentration must be measured.\nPrognosis\nPrognosis is good: this form does not cause cognitive or motor impairment during childhood. Adult patients remain jaundiced and must continue phenobarbital treatment throughout their life. However, all patients have to be educated and informed regarding at-risk-for-increase of bilirubin production (infection, stress and prolonged fasting).\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe LABRUNE | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Crigler-Najjar syndrome", "Disease Definition": "A rare hereditary disorder of bilirubin metabolism characterized by unconjugated hyperbilirubinemia due to a either a complete (type 1) or partial and inducible (type 2) hepatic deficit of UDP-glucuronosyltransferase 1A1 activity. The disorder manifests with neonatal jaundice with a risk of developing bilirubin encephalopathy.", "ORPHA ID": 205, "Summary": "Epidemiology\nWhilst data on prevalence is very limited, Crigler Najjar syndrome (CNS) is estimated to affect less than 1/100,000 people in Europe. Both sexes are equally affected.\nClinical description\nFirst clinical manifestations usually appear soon after birth, presenting with isolated jaundice that is more severe in CNS type 1 (CNS1) than in CNS type 2 (CNS2). In CNS1, it may evolve to bilirubin encephalopathy (kernicterus) with hypertonia, deafness, oculomotor palsy and lethargy when the treatment is delayed or inadequate. In CNS2, the risk of kernicterus is much lower but does exist.\nEtiology\nNumerous variants in the gene UGT1A1 (2q37), encoding the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), have been linked to CNS. In the liver, UGT1A1 conjugates bilirubin with glucuronic acid, thereby increasing bilirubin water solubility and thus facilitating its excretion. The UGT1A1 variants result in absent (CNS1) or reduced (CNS2) UGT1A1 activity, with marked impairment of bilirubin conjugation.\nDiagnostic methods\nThe physical examination shows isolated jaundice and biological analyses detect only severe unconjugated hyperbilirubinemia with normal liver function tests. Abdominal imaging studies (CT scans or ultrasonograms) are normal. Currently, definitive diagnosis relies on genomic DNA analysis (ruling out the need for liver biopsy). In the past, definitive diagnosis was based on demonstration of the enzymatic deficiency in the liver (hepatic biopsy performed after three months of age); however, liver biopsy is no longer performed.\nDifferential diagnosis\nDifferential diagnosis varies depending of the type of CNS and includes disorders of excessive bilirubin production (hemolysis) and mild hepatic deficiency of hepatic UGT1A1 (Gilbert syndrome).\nAntenatal diagnosis\nPrenatal diagnosis is possible provided both disease-causing mutations have been identified in the proband.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment of CNS1 relies on phototherapy (initially at hospital and then at home) for 10-12 hours per day. Bilirubin chelators and ursodeoxycholic acid may also be prescribed in these patients. To date, the only effective treatment for CNS1 is liver transplantation. Treatment of CNS2 consists of daily phenobarbital.\nPrognosis\nChildren with CNS1 may develop neurological complications as a consequence of the neurotoxicity of unconjugated bilirubin whereas prognosis is generally good for patients with CNS2.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe LABRUNE | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Crimean-Congo hemorrhagic fever", "Disease Definition": "Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne zoonotic disease caused by CCHF virus and characterized by initial fever, headache, and malaise followed by gastrointestinal symptoms and, in severe cases, bleeding, shock, and multi-organ system failure.", "ORPHA ID": 99827, "Summary": "Epidemiology\nCCHF is endemic throughout Africa, the Balkans, the Middle East, and western Asia. Cases are usually sporadic, although small nosocomial outbreaks sometimes occur when proper infection control practices are not maintained. Around 500 cases are reported per year worldwide, although systematic surveillance is lacking.\nClinical description\nThe incubation period is typically 3-7 days from animal exposure and 1-3 days from a tick bite. Patients generally present with the abrupt onset of non-specific signs and symptoms including fever, malaise, headache, chest pain, and myalgia/arthralgia followed rapidly by gastrointestinal symptoms (diarrhea, nausea, vomiting) and, in some cases, rash. Severe cases develop bleeding (ecchymoses, sub-conjunctival and gastrointestinal hemorrhage), neurologic involvement (disorientation, convulsions, coma), shock, and multi-organ system failure. Mild-to-moderate leukopenia and thrombocytopenia are often noted at presentation and disseminated intravascular coagulation (DIC) commonly develops, best indicated by the presence of D-dimers.\nEtiology\nOver 25 different viruses cause viral hemorrhagic fever. CCHF virus is a member of the virus family Bunyaviridae, genus Nairovirus. The virus is maintained in nature in a cycle between small mammals and ticks, primarily of the Hyalomma species. Ticks also spread CCHF virus to domestic livestock, who are transiently and asymptomatically viremic. Humans are infected either by tick bites or exposure to contaminated blood or excreta of the reservoir or transiently viremic domestic animals. Farmers, abattoir workers, and veterinarians are at risk. Human-to-human transmission occurs through direct contact with blood or bodily fluids of infected persons.\nDiagnostic methods\nCommon diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA) and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically only performed in a few specialized laboratories.\nDifferential diagnosis\nCCHF is difficult to distinguish from a host of other febrile illnesses, at least early in the course of disease. Malaria, typhoid fever, leptospirosis, rickettsial infection, other viral hemorrhagic fevers (see these terms) and meningococcemia need to be excluded.\nManagement and treatment\nPatients should be isolated and viral hemorrhagic fever precautions (face shields, surgical masks, double gloves, surgical gowns, and aprons) should be used to prevent nosocomial transmission. Although there are few controlled data, the nucleoside analogue drug ribavirin appears to be efficacious for CCHF. Otherwise, treatment generally follows the guidelines for severe septicemia. Anti-malarials and broad spectrum antibiotics should be considered until the diagnosis of CCHF can be confirmed. Persons who have unprotected contact with someone with CCHF should be monitored and post-exposure treatment with oral ribavirin considered.\nPrognosis\nThe case-fatality rate is 15-30%. Shock, bleeding, neurological manifestations, high viremia, aspartate aminotransferase (AST) > 150 IU/L, and pregnancy confer a poor prognosis. Although convalescence may last up to a year, survivors usually have no lasting sequelae.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Daniel BAUSCH  -  Andrew BENNETT"}
{"Disease Name": "Crisponi syndrome", "Disease Definition": "Crisponi syndrome (CS) is a severe disorder characterized by muscular contractions at birth, intermittent hyperthermia, facial abnormalities and camptodactyly.", "ORPHA ID": 1545, "Summary": "Epidemiology\nSince the first description of the disease in 1996, it has been described in less than 30 patients from 13 Italian (mainly Sardinian) families.\nClinical description\nExtensive paroxysmal muscular contractions in the face (resembling neonatal tetanus) develop after minimal stimuli. Frequent contractions of the oropharyngeal muscles associated with absence of the swallowing reflex lead to major feeding and respiratory difficulties. All patients described to date displayed facial anomalies, including a large face, chubby cheeks, a broad nose with anteverted nostrils and long philtrum, and bilateral camptodactyly. Hypertonia is frequent. Early in the neonatal period, CS patients develop continuous hyperthermia (unrelated to infectious agents), dyspnea, spells of apnea, and cyanosis during crying. Abnormal central control of respiration may be present at birth, increasing the risk of sudden death. Febrile episodes disappear after the first year of life, whereas feeding difficulties persist. Paradoxal sweating after exposure to low ambient temperatures has been observed in some adolescents.\nEtiology\nMutations in the CRLF1 gene are causative.\nDifferential diagnosis\nCS belongs to a group of conditions with overlapping features, including cold-induced sweating syndromes and Stüve-Wiedemann syndrome (see these terms).\nGenetic counseling\nThe disease is transmitted as an autosomal recessive trait.\nManagement and treatment\nSurviving patients usually develop severe progressive kyphoscoliosis that requires corset therapy or corrective surgery. Marked feeding difficulties require nasogastric tube feeding.\nPrognosis\nCharacteristic hyperthermic crises frequently lead to death within the first months of life.\n\n                            Last update: \n                            June 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Didier LACOMBE"}
{"Disease Name": "Criss-cross heart", "Disease Definition": "Criss cross heart (CCH) is a cardiac malformation where the inflow streams of the two ventricles cross due to twisting of the heart about its major axis. The clinical features depend on the particular cardiac defects associated, like simple or corrected transposition of the great arteries and ventricular septal defects.", "ORPHA ID": 1461, "Summary": "Epidemiology\nThe birth prevalence of CCH is 1 /125, 000 live births and accounts for <0.1% of all congenital heart defects.\nClinical description\nCCH is a congenital disorder which can manifest by severe dyspnea with nasal flaring, retraction of sternal notch, subcostal and intercostal indrawing, diaphoresis, cyanosis, pallor, feeding difficulty, systolic murmur at the left sternal edge and accentuated P2 heart sound, depending on the associated lesions. The most common associations are ventricular septal defect (VSD), complete or congenitally corrected transposition of the great arteries, double outlet right ventricle, pulmonary branch stenosis, straddling mitral or tricuspid valve, mitral stenosis, and subpulmonary, subaortic or supravalvular aortic stenosis (see these terms).\nEtiology\nCCH is caused by abnormal rotation (clockwise or counterclockwise) of the ventricular mass along its long axis during embryonic development. The developmental mechanisms and causes of CCH are still elusive but some studies in mice have linked mutations in the Gja1  gene to the pathogenesis of CCH.\nDiagnostic methods\nDiagnosis is confirmed by 2-dimensional and color Doppler echocardiography revealing the crossing of the atrioventricular connections, without mixing, at the level of the atrioventricular (AV) valves. Failure to obtain a characteristic 4-chamber view (4CV) is a key diagnostic feature of CCH. Biventricular function is normal but perimembranous ventricular septal defects are usually observed. MRI and angiography may be used for the diagnosis of anomalies of the coronary circulation.\nDifferential diagnosis\nDifferential diagnosis includes straddling mitral or tricuspid valve, severe forms of Ebstein malformation (the tricuspid valve opens to the infundibulum, giving the appearance of crossing the valves) (see these terms), and double atrial outlet (an outlet orifice apparently crosses the other valve).\nAntenatal diagnosis\nPrenatal diagnosis can be achieved with a color Doppler ultrasound, by identifying key features of CCH that include the inability to obtain a 4CV at the standard transverse plane through the fetal chest and visualization of the criss cross arrangement of the inflow tracts into the two ventricles simultaneously in the transverse plane of the fetal chest.\nManagement and treatment\nThe surgical management of CCH consists of the repair of major and limiting malformations, with ventricular rotation itself being excluded as the reason for the correction. The initial management is determined by the presence or absence of pulmonary stenosis, and its severity. Where the pulmonary flow is inadequate, early intervention with prostaglandin E1 is indicated for maintaining the patency of the patent arterial duct. When anatomic correction fails, balance in pulmonary flow can be achieved with the construction of a systemic-pulmonary shunt. The corrective surgery is determined by the potential use of both ventricles. The Fontan correction may be indicated as a palliative repair option. Jatene's surgical technique (the arterial switch operation) may be proposed to patients where CCH is associated with transposition of the great arteries, VSD, atrial septal defect and patent arterial duct (see these terms).\nPrognosis\nThe prognosis is unfavorable without surgical treatment. However, after correction of the main defect, normal physical, psychomotor and cardiovascular development may be achieved.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Vera AIELLO  - Dr Italo DE OLIVEIRA"}
{"Disease Name": "Cronkhite-Canada syndrome", "Disease Definition": "Cronkhite-Canada syndrome (CCS) is a rare gastrointestinal (GI) polyposis syndrome characterized by the association of non-hereditary GI polyposis with the cutaneous triad of alopecia, nail changes and hyperpigmentation.", "ORPHA ID": 2930, "Summary": "Epidemiology\nTo date, there have been more than 500 cases reported worldwide. Individuals of European and Asian descent are most often affected, with most case reports emerging from Japan. A slight male predominance has been reported.\nClinical description\nThe mean age of onset is 59 years, but the age at presentation may vary from 31 to 85 years. Presenting symptoms include watery diarrhea with stool volumes of 4-6 L (steatorrhea and melena may also occur), dysgeusia, dry mouth, partial or total lack of appetite, weight loss (often >10 kg), constant or episodic abdominal pain, and weakness. Diarrhea is usually followed by a variable sequence of onychodystrophy (including onycholysis, thinning of the nail plate, onychoschizia and onychomadesis), alopecia (initially patchy, rapidly leading to complete hair loss), and hyperpigmentation (diffuse light-to-dark brownish macules and plaques, and patchy vitiligo) distributed on the palms and soles, upper extremities, face, and chest. More than 10% of CCS patients develop GI cancer (mostly in the sigmoid colon and rectum). Neurologic symptoms (numbness and tingling in the extremities, dysphagia and convulsions) and autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, scleroderma (see these terms), hypothyroidism and membranous glomerulopathy) have been reported in some patients. The GI lesions are usually generalized. The stomach and colon almost always contain polyps and the small bowel is affected in more than 50% of cases. The esophagus is less frequently involved. Common complications include GI bleeding, malabsorption, malnutrition, and infection.\nEtiology\nThe pathogenesis of CCS is still elusive but an immune-mediated process has been proposed and this hypothesis is supported by the increased systemic levels of immunoglobulin G4 and antinuclear antibody found in CCS patients as well as the higher frequency of autoimmune disorders associated with CCS. The cutaneous manifestations of CCS have been attributed to malabsorption and malnutrition caused by the GI pathology. Dysgeusia and dry mouth might result from mucositis or oral infections secondary to malnutrition but other mechanisms may be involved.\nDiagnostic methods\nDiagnosis relies on clinico-pathological features with the correlating cutaneous, radiological, endoscopic and pathological findings. Endoscopic evaluation may reveal multiple sessile polyps in the stomach, small bowel, colon and rectum. Histopathological examination of biopsies may show different types of polyps (hyperplastic or adenomatous (with malignant potential), juvenile, hamartomatous and inflammatory) in the same patient, necessitating resection and/or surveillance. Laboratory parameters reveal normocytic, normochromic anemia, vitamin deficiency, hypoproteinemia and hypoalbuminemia.\nDifferential diagnosis\nDifferential diagnosis includes familial adenomatous polyposis, hyperplastic polyposis syndrome, cap polyposis, juvenile polyposis syndrome, Peutz-Jeghers syndrome and Cowden syndrome (see these terms), as well as lipomatous polyposis, inflammatory polyposis and lymphomatous polyposis.\nGenetic counseling\nCCS occurs sporadically so there is no risk of intrafamilial transmission.\nManagement and treatment\nCurrent treatments, which can be used individually or in combination, include steroids, nutritional therapy (fluid, electrolyte, protein and vitamin supplementation and, if necessary, an elemental diet or parenteral nutrition), 5-aminosalicylate acid, histamine H2 receptor antagonists, anti-tumor necrosis factor alpha agents, immunomodulators, and eradication of Helicobacter pylori. Regular surveillance for GI malignancy is recommended as development of colorectal or gastric cancer has been reported in 10 to 15% of cases.\nPrognosis\nThe clinical course of CCS is progressive with occasional spontaneous remissions and frequent relapses, and with rare progression to malignancy. The 5-year mortality rate of CCS can be as high as 50 % (mainly due to GI malignancy or portal vein thrombosis, infection and membranous glomerulonephritis), even with treatment.\n\n                            Last update: \n                            May 2016\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Alain CHAYVIALLE  - Pr Jean-Christophe SAURIN"}
{"Disease Name": "Crossed polysyndactyly", "Disease Definition": "A rare, hereditary, congenital limb malformation characterized by polydactyly with crossed involvement of hands and feet with no other associated malformations or anomalies. Patients present with a combination of unilateral or bilateral preaxial polydactyly of hands with postaxial polydactyly of feet or postaxial polydactyly of hands with preaxial polydactyly of feet. Additional manifestations include bilateral cutaneous syndactyly of first, second and third toes and occasionally cutaneous syndactyly of hands.", "ORPHA ID": 2935, "Summary": ""}
{"Disease Name": "Crouzon syndrome-acanthosis nigricans syndrome", "Disease Definition": "Crouzon syndrome with acanthosis nigricans (CAN) is a very rare, clinically heterogeneous form of faciocraniostenosis with Crouzon-like features and premature synostosis of cranial sutures (Crouzon disease, see this term), associated with acanthosis nigricans (AN; see this term).", "ORPHA ID": 93262, "Summary": "Epidemiology\nCAN has an estimated prevalence of 1/1,000,000 newborns. Fewer than 70 cases have been described in the medical literature. A female-to-male sex ratio of 2.4:1 has been reported.\nClinical description\nAll patients have congenital craniofacial abnormalities consistent with classic Crouzon syndrome including craniosynostosis, midface hypoplasia, shallow orbits with exophthalmos, down-slanting palpebral fissures and hypertelorism, maxillary hypoplasia with convex nose and posteriorly angulated ears. The synostosis usually involves the coronal sutures. Cases of cloverleaf skull have also been reported. Patients also develop velvety hyperpigmented skin (AN) within the first decade of life, found primarily in body folds such as the neck, axillae, eyelids, and the perioral, inguinal and perianal areas. The skin disorder is sometimes widespread and develops early compared to classic AN. Craniovertebral junction and vertebral anomalies such as mild alterations of the interpediculate distances of the distal vertebral column are subtle and inconstant. Choanal atresia or stenosis is often present (41%), and is considered highly suggestive of CAN. Other commonly reported signs include hydrocephalus (43%), oral abnormalities such as cleft palate (see this term), dental malocclusion, cementomas of the jaw (34%), and melanocytic nevi (25%). Kidney involvement has also been reported. Some of these specific features are rare in patients with classic Crouzon syndrome. Intellectual disability, hearing loss and speech delay are uncommon. The severity is the same in affected males and females.\nEtiology\nCAN is caused by a specific p.Ala391Glu mutation in the fibroblast growth-factor receptor 3 FGFR3 gene (4p16.3), involved in regulation of cell proliferation, differentiation and apoptosis. AN is associated with inadequate stimulation of various fibroblast growth-factor receptors.\nGenetic counseling\nMost cases are sporadic, associated with paternal aging, although familial cases consistent with autosomal dominant inheritance have been reported.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Corinne COLLET  - Pr Federico DI ROCCO"}
{"Disease Name": "Crouzon syndrome", "Disease Definition": "Crouzon disease is characterized by craniosynostosis and facial hypoplasia.", "ORPHA ID": 207, "Summary": "Epidemiology\nThe estimated prevalence in the general population of Europe is 0.9/100,000 .\nClinical description\nCraniosynostosis is variable but many sutures are usually involved. The facial dysmorphology is characterized by ocular hypertelorism, small beaked nose, proptosis, exophthalmos, hypoplastic maxilla and mandibular prognathism. The synostosis is evolutive and is usually either not visible or only slightly visible at birth. It usually manifests by the age of 2 years and becomes progressively more severe. However, precocious and congenital forms have been reported in which hypoplasia of the upper maxilla is pronounced and leads to respiratory difficulties, and the exophthalmia is severe resulting in palpebral malocclusion. Hydrocephaly, descent of the cerebellar tonsils and anomalies in jugular venous drainage are also frequently observed in Crouzon disease and may pose therapeutic problems. Two thirds of patients with Crouzon disease have intracranial hypertension, which may lead to blindness.\nEtiology\nCrouzon disease is caused by mutations of the fibroblast growth factor receptor FGFR2 (10q25.3-q26) with 80% being located to the immunoglobulin (Ig)-like domain III (IgIII domain) of the extracellular region and an additional 20% of mutations being located in the IgI-IgII domains, transmembrane and tyrosine kinase regions. A distinct form of Crouzon disease associated with acanthosis nigricans has been reported and is caused by a specific mutation (p.Ala391Glu) in the transmembrane domain of another protein from the same family, FGFR3 (Crouzon syndrome - acanthosisnigricans; see this term). Moreover, mutations in ERF (19q13.2) gene encoding the ETS2 repressor, resulting in anosteogenic stimulation, have been associated to a Crouzon-like syndrome.\nGenetic counseling\nThe disease is transmitted in an autosomal dominant manner with variable penetrance.\nManagement and treatment\nSurgical interventions are aimed at preventing cerebral, ophthalmological or respiratory complications and correcting the cranio-facial dysmorphy. The craniofacial surgical approach adopted needs to take into account both the cranial and facial synostosis and should be tailored to each patient.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Eric ARNAUD  - Dr Corinne COLLET  - Pr Federico DI ROCCO"}
{"Disease Name": "Cryoglobulinemic vasculitis", "Disease Definition": "A rare immune complex-mediated vasculitis characterized by the presence of circulating cryoprecipitable immune complexes in the serum, manifesting clinically with the classical triad of purpura, weakness and arthralgia.", "ORPHA ID": 91138, "Summary": "Epidemiology\nIt is considered to be a rare disorder, but its true prevalence remains unknown. The disease is more common in Southern Europe than in Northern Europe or Northern America. The prevalence of ''essential'' mixed cryoglobulinemia (MC) has been reported as approximately 1:100,000 (with a female-to-male ratio of 3:1), but this term is now used to refer to only a minority of MC patients without an overt etiological agent.\nClinical description\nTwo types of MC have been described: type II and type III, based on their immunochemical properties. In type II, the cryoprecipitable immune-complexes are composed of monoclonal Ig M, the autoantibodies , and polyclonal IgGs, the autoantigens ; in type III, the immune-complexes are composed of both oligo-/polyclonal IgMs and polyclonal IgGs. Type I cryoglobulinemia involves monoclonal immunoglobulins of only one isotype and is a distinct disease. MC is characterized by variable organ involvement including skin lesions (orthostatic purpura, ulcers), chronic hepatitis, membranoproliferative glomerulonephritis, peripheral neuropathy, diffuse vasculitis, and, less frequently, interstitial lung involvement and endocrine disorders. Some patients may develop lymphatic and hepatic malignancies, usually as late complications. MC syndrome may be associated with numerous infectious or immunological diseases. When isolated, MC may represent a distinct disease, the so-called ''essential'' MC.\nEtiology\nThe etiopathogenesis of MC is not completely understood. Hepatitis C virus (HCV) infection has been suggested to play a causative role, with the contribution of genetic and/or environmental factors, in the majority of patients. Moreover, MC may be associated with other infectious agents or immunological disorders, such as human immunodeficiency virus (HIV) infection or primary Sjogren syndrome.\nDiagnostic methods\nDiagnosis is based on clinical and laboratory findings. Circulating mixed cryoglobulins, low levels of complement component 4 and orthostatic skin purpura are the hallmarks of the disease. Leukocytoclastic vasculitis involving medium-sized and, more often, small-sized blood vessels is the typical pathological finding, easily detectable by means of skin biopsy of recent vasculitic lesions.\nDifferential diagnosis\nDifferential diagnoses include a wide range of systemic, infectious and neoplastic disorders, mainly autoimmune hepatitis, primary Sjögren syndrome, B-cell lymphomas, and rheumatoid arthritis.\nManagement and treatment\nTreatment should be directed according to the underling etiopathogenesis. The first-line treatment of infection-related MC should with the most appropriate specific anti-infectious therapy (typically antivirals). Patients with an underlying lymphoproliferative or autoimmune disorder should receive appropriate disease-specific therapy. Use of immunomodifiers, immunosuppressors, corticosteroids, and/or plasmapheresis should be tailored to the patient according to the progression and severity of specific clinical manifestations, and may be used alone or in combination/sequence with antivirals. Use of immunomodifiers, immunosuppressor and plasmapheresis may play a major role in HCV-negative MC ('essential' MC syndrome) or in clinically active/relapsed MC that can be observed also after HCV eradication in some patients. Anti-CD20 (rituximab) is increasingly employed as an effective and safe treatment for major MC complications (nephropathy, neuropathy, severe vasculitis, etc.). Long-term monitoring is recommended in all MC patients to assure timely diagnosis and treatment of the life-threatening complications.\nPrognosis\nDisease persistence and relapse is more likely to be prevented when the clinical history of MC is considered along with early treatment and eradication of HCV. Similarly, timely treatment of more severe manifestations of the MC syndrome can prevent progression of organ damage. The overall prognosis is poorer in patients with renal disease, liver failure, lymphoproliferative disease and malignancies. In addition, MC type II (less frequently MC type III), particularly in patients with long-lasting disease, shows higher predisposition for the development of malignant B-cell lymphoma or other malignancies.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Clodoveo FERRI"}
{"Disease Name": "Cryptococcosis", "Disease Definition": "A cosmopolitan fungal infection due to Cryptococcus neoformans.", "ORPHA ID": 1546, "Summary": "Epidemiology\nAnnual incidence has been estimated at between 1/5,000 and 1/50,000 depending on the geographic region. Immunodeficient patients are the main target.\nClinical description\nPrimary pulmonary cryptococcosis is usually asymptomatic, but disseminates throughout the organism, particularly to the central nervous system causing subacute meningoencephalitis. Mucocutaneous infection is frequent.\nEtiology\nC. neoformans is an encapsulated yeast that reproduces by budding. It is abundant in the ground, in fruit, milk, and pigeon droppings. Infection is acquired via the respiratory or digestive route, rarely through the skin, and disseminates in the organism by blood or the lymphatic system. Interhuman transmission does not occur.\nDiagnostic methods\nDiagnosis is made after detection of encapsulated yeast in cerebrospinal fluid or other affected organs, or in cultures.\nDifferential diagnosis\nDifferential diagnoses include the other species of Cryptococcus.\nManagement and treatment\nAmphotericin B and newer antifungal drugs (triazoles) sterilize the lesions. The treatment should be continued for as long as the patient is immunodeficient.\nPrognosis\nThe prognosis is usually good if treatment is well conducted.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Annick DATRY"}
{"Disease Name": "Cryptogenic late-onset epileptic spasms", "Disease Definition": "Cryptogenic late-onset epileptic spasms is a rare epilepsy syndrome characterized by late-onset (after 1 year old) epileptic spasms that ocurr in clusters, associated with tonic seizures, atypical absences and cognitive deterioration. Language difficulties and behavior problems are frequently present. EEG is characterized by a temporal, or temporofrontal, slow wave or spike focus combined with synchronous spike-waves and no hypsarrhythmia or background activity.", "ORPHA ID": 163708, "Summary": ""}
{"Disease Name": "Cryptogenic multifocal ulcerous stenosing enteritis", "Disease Definition": "A rare intestinal disease characterized by chronic or relapsing subileus or ileus resulting from multiple unexplained fibrous structures and multiple shallow (i. e. limited to the mucosa or submucosa) ulcerations of the small intestine (mainly the ileum), in the absence of signs of a systemic inflammatory reaction. Patients may present with chronic iron-deficiency anemia due to chronic intestinal blood loss, chronic recurrent abdominal pain, fatigue, edema, or growth retardation. Extraintestinal manifestations such as Sicca syndrome, polyarthralgia, or Raynaud's phenomenon may also be observed.", "ORPHA ID": 468635, "Summary": ""}
{"Disease Name": "Cryptogenic organizing pneumonia", "Disease Definition": "A rare form of idiopathic interstitial pneumonia characterized pathologically by organizing pneumonia (OP) that presents with nonspecific flu-like symptoms, as well as cough and dyspnea, and where no etiological agent is found.", "ORPHA ID": 1302, "Summary": "Epidemiology\nCryptogenic organizing pneumonia (COP) represents 5-10% of interstitial lung diseases. The annual incidence in Iceland has been estimated at 1/90,900.\nClinical description\nMean age of onset is 50-60 years of age and patients present with nonspecific features of mild fever, non-productive cough, malaise, anorexia, weight loss and progressive but mild-to-moderate dyspnea. At auscultation, focal and sparse crackles are often found over the involved areas with clinical features of consolidation in some. There is no sign of finger clubbing. There is often a delay of 3 months or more between the onset of first symptoms and diagnosis. In rapidly progressive cases, dyspnea can be severe. Rare manifestations include chest pain, night sweats, and hemoptysis. Pneumothorax and pneumomediastinum have been reported. COP usually resolves with treatment but relapses occur in up to half of the cases. Though most diagnosed cases are now treated, spontaneous improvement occurring over 3-6 months has also been reported.\nEtiology\nEtiology is unknown. The stages of COP pathogenesis include the injury phase (permeability edema and fibrin deposits in response to alveolar cell injury), the proliferating phase (formation of fibroinflammatory buds), the mature phase (presence of ''mature'' fibrotic buds in the alveolar space) and the resolution phase (reversibility of lesions).\nDiagnostic methods\nDiagnosis is based on clinical picture, imaging, histopathology of the lung and the exclusion of all causes of secondary OP. High resolution computed tomographic scan reveals 3 main imaging patterns: multiple patchy alveolar opacities that may migrate (in the majority of cases; typical COP), a solitary focal nodule or mass (focal COP), or diffuse infiltrative opacities (infiltrative or progressive fibrotic COP). Video-assisted thoracoscopy is the method of choice in obtaining lung tissue but transbronchial biopsies, core needle biopsies, and recently transbronchial cryobiopsies are alternate methods. Hallmark histological findings of OP are patchy filling of the lung alveoli and respiratory bronchioles by buds of granulation tissue composed of fibroblasts and myofibroblasts (Masson bodies). Fiberoptic bronchoscopy with bronchoalveolar lavage reveals a mixed inflammatory profile with marked increase in lymphocytes and slight increase in neutrophils and eosinophils. Elevated C-reactive protein serum level and peripheral blood neutrophil count are reported.\nDifferential diagnosis\nThe main differential diagnosis is idiopathic chronic eosinophilic pneumonia. Secondary OP must also be excluded by elimination of its possible causes, including primary biliary cirrhosis, ulcerative colitis, Crohn disease, Sweet syndrome, sarcoidosis, Behçet disease, primary pulmonary lymphoma, drugs, inhalation exposure, infections, all connective tissue diseases, especially rheumatoid arthritis and idiopathic inflammatory myopathies, and other specific contexts like solid organ transplantation, bone marrow transplantation, etc.\nManagement and treatment\nStandard therapy for COP is corticosteroids, usually with prednisone doses of 0.75 mg/kg/day for 4 weeks that gradually decreases over a period of 24 weeks. In those with rapidly progressing COP, high-dose intravenous methylprednisolone can be given. Focal COP is often diagnosed by the removal of lesions initially thought to be neoplastic, with further therapy often not needed. Relapses should be treated with a starting dose of 20 mg/day of prednisone then tapered over a period of 12 weeks. Relapses that occur too often or while undergoing corticosteroid therapy should prompt a reappraisal of the diagnosis. Immunosuppressive therapy may rarely be used in severe infiltrative COP.\nPrognosis\nThe prognosis is usually good with most cases resolving after corticosteroid treatment. Morbidity is mostly related to prolonged corticosteroid treatment. However, relapses are seen in 13-58% of patients and can have an effect on quality of life if they are frequent.\n\n                            Last update: \n                            October 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Vincent COTTIN | ERN-LUNG*\n\n\n                                * European Reference Network"}
{"Disease Name": "Cryptomicrotia-brachydactyly-excess fingertip arch syndrome", "Disease Definition": "A rare genetic, congenital malformation syndrome characterized by the combination bilateral cryptomicrotia, brachytelomesophalangy with short middle and distal phalanges of digits 2 through 5, hypoplastic toenails and excess fingertip arch patterns. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 1547, "Summary": ""}
{"Disease Name": "Cryptorchidism-arachnodactyly-intellectual disability syndrome", "Disease Definition": "Cryptorchidism-arachnodactyly-intellectual disability syndrome is a rare, multiple congenital anomalies syndrome characterized by psychomotor delay, severe intellectual deficit, severe muscle hypoplasia (with absence of subcutaneous fatty tissue), generalized contractures, craniofacial dysmorphic features (dolichocephaly, esotropia, ears of unequal size, high palate), chest and spinal deformities (i.e. sternum shifted to side, kyphoscoliosis), pulmonary anomalies (unilateral hypoplastic bronchial system), arachnodactyly, and genital abnormalities (cryptorchidism, hypospadias, testicular agenesis). Repeated respiratory tract infections and atelectasis are also associated. There have been no further descriptions in the literature since 1970.", "ORPHA ID": 1548, "Summary": ""}
{"Disease Name": "CTCF-related neurodevelopmental disorder", "Disease Definition": "A rare, genetic, neurodevelopmental disorder characterized by global developmental delay, borderline to severe intellectual disability, feeding difficulties, behavioral anomalies, vision anomalies and mild facial dysmorphism. Other associated features may include microcephaly, short stature, urogenital or palatal anomalies (e.g. cleft palate), minor cardiac defects, recurrent infections or hearing loss.", "ORPHA ID": 363611, "Summary": "Epidemiology\nUp to date, 47 individuals worldwide are reported in the literature.\nClinical description\nAffected individuals usually present with variable developmental delay or intellectual disability, ranging from learning difficulties with normal intellect to severe cognitive impairment. Developmental delay usually becomes evident in childhood with walking age ranging from 12 months to 3 years and language abilities varying from first words at 12 months to absent speech at 12 years of age. Intrauterine growth retardation during pregnancy or low birth measurements are observed in about one third of the reported cases. Feeding difficulties and failure to thrive are common in infants, sometimes requiring temporary tube feeding. Behavioral anomalies are common and include autistic features, hyperactivity, attention deficit or aggressivity. Further frequent and variable clinical aspects include vision anomalies, sensorineural and/or conductive hearing loss, recurrent infections and minor facial dysmorphism such as a long face with a prominent forehead, long palpebral fissures or a bulbous nasal tip. Microcephaly, cardiac defects and palatal anomalies such as high or cleft palate are present in about 30% of patients. Most of the reported individuals show a body height within the normal range, but short stature and less frequently tall stature has been reported. Febrile seizures or epilepsy occur in few individuals as well as nonspecific MRI and minor skeletal anomalies.\nEtiology\nThe disorder is caused by heterozygous, pathogenic variants (larger deletions, truncating variants or missense variants within the zinc-finger domains) in the CTCF-gene on chromosome 16q22.1, which encodes for an important chromatin organizer.\nDiagnostic methods\nDiagnosis is confirmed by genetic testing, usually by non-targeted approaches such as multigene panel or exome sequencing.\nDifferential diagnosis\nThe differential diagnosis includes 22q11.2 deletion syndrome and a number of other neurodevelopmental disorders associated with feeding difficulties, mild developmental delay and variable anomalies.\nAntenatal diagnosis\nPrenatal diagnosis is possible when the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal dominant. Most cases result from a de novo pathogenic variant. Two inherited cases have been reported, where the variant was transmitted from a mildly affected or presumably healthy parent to the affected child, and genetic counseling should be offered in such cases.\nManagement and treatment\nAffected individuals benefit from early developmental support including occupational therapy and special education where needed. Regular evaluation of growth parameters and for vision and hearing anomalies is recommended. If urogenital, cardiac or other anomalies are present or suspected, patients should be referred to the appropriate specialists.\nPrognosis\nThe prognosis is usually good, but depends on severity of the disease and organ involvement. Affected individuals may require life-long support from their caregivers.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Christiane ZWEIER"}
{"Disease Name": "Curly hair-acral keratoderma-caries syndrome", "Disease Definition": "Curly hair-acral keratoderma-caries syndrome is an extremely rare ectodermal dysplasia syndrome characterized by premature loss of curly, brittle, dry hair, premature loss of teeth due to caries, nail dystrophy with thickening of the finger- and toe-nails, acral keratoderma and hypohidrosis. Additionally, sparse eyebrows and eyelashes, receding frontal hairline and flattened malar region are associated. The severity of features appears to increase with age.", "ORPHA ID": 307766, "Summary": ""}
{"Disease Name": "Currarino syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by the triad of anorectal malformations, presacral mass and sacral anomalies.", "ORPHA ID": 1552, "Summary": "Epidemiology\nEstimated prevalence is 1-9/100,000. Recent data estimates a 1.39:1 female-to-male ratio.\nClinical description\nThe disease typically presents as a triad of features (all 3 occur in 20% of cases) including anorectal, sacral and presacral anomalies, sometimes accompanied by other pelvic malformations. It may be an emergency at birth or found later with milder symptoms. Around 1/3rd of the patients are asymptomatic and identified through an affected relative or coincidentally on scans. Presacral anomalies may present as a mass and include anterior meningocoele, teratomas (which may also be sacrococcygeal), enteric cysts or a combination of those. Local pressure may cause constipation, incontinence, peripheral or central neurological symptoms. There is a 1-2 % risk of malignant transformation with various tumour types reported. Sacral agenesis occurs as anterior sacral defects. The S1 vertebra is typically intact. It may result in sickle-shaped (scimitar) sacrum or complete sacral agenesis below S2. Bifid or pepperpot sacrum are less frequent. Spinal cord anomalies (tethering, lipoma, cysts) can occur. Tethered cord can cause bowel/ bladder control issues if untreated. Spinal canal defects (e.g. enterothecal fistula) can cause seeding of gut microorganisms resulting in meningitis. Uterine or external genital anomalies occur in 15% of cases. Structural renal tract issues include kidney or bladder anomalies. Asymmetry of the lower limbs has been reported.\nEtiology\nMNX1 is the only confirmed causal gene to date. All mutational mechanisms have been observed (rearrangements, deletions and SNVs). Cases resulting from 7q36 deletion may be associated with extrapelvic malformations and/or intellectual delay if other genes are involved. Homozygous cases are rare and often lethal early in life. MNX1 is detectable in 57-65% of patients, most frequently in familial cases. The involvement of other genes of interest is ongoing. There is no direct phenotype-genotype correlation. The pathogenic mechanism is still unknown but likely due to MNX1 haploinsufficiency. A disruptive event is speculated to occur during the development of the notochord at Carnegies stage 12 (but has not been observed in humans to date). If the endodermal & ectodermal layers fail to separate, splitting of the notochord and fistula between the gut and the neural tissue may occur.\nDiagnostic methods\nDiagnosis is based on clinical findings. Plain film X-Ray, CT or MRI are useful. MNX1 gene testing can be offered. No international criteria currently exist.\nDifferential diagnosis\nDifferential diagnosis includes caudal regression syndrome, VACTERL association and sacrococcygeal teratoma.\nAntenatal diagnosis\nFoetal ultrasound can reveal a presacral mass or sacral defects if present. Targeted foetal MRI can be considered. Testing for MNX1 can be considered.\nGenetic counseling\nInheritance is autosomal dominant with reduced penetrance and variable expressivity. Genetic counseling and imaging screening can be offered to relatives. If there is an established MNX1 variant, cascade testing can be offered.\nManagement and treatment\nManagement depends on presenting features. Surgical correction of anorectal malformations may be necessary. Conservative management (e.g. stool softening agents) and monitoring may be offered for milder cases. Monitoring of presacral mass is advised. Surgical management (coordinated by various surgical specialities) of presacral masses may be necessary. Cancer biomarkers for presacral teratomas are not well established. Sacral agenesis is managed clinically. If there is cord dysfunction, neurosurgery may be required. Caution is advised for spinal procedures, including anaesthesia. Spinal cord tethering may require early surgery to avoid complications. Follow up is important as the cord can retether.\nPrognosis\nLong term prognosis is good for the majority of patients. Urinary/bowel dysfunction may impact quality of life. Malignant transformation of presacral mass is rare.\n\n                            Last update: \n                            April 2023\n\n\n                            - Expert reviewer(s): \n                            Dr John COLEMAN  - Pr Sally Ann LYNCH | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Curry-Jones syndrome", "Disease Definition": "Curry-Jones syndrome is a form of syndromic craniosynostosis characterized by unilateral coronal craniosynostosis or multiple suture synostosis associated with complete or partial agenesis of the corpus callosum, preaxial polysyndactyly and syndactyly of hands and/or feet, along with anomalies of the skin (characteristic pearly white areas that become scarred and atrophic, abnormal hair growth around the eyes and/or cheeks, and on the limbs), eyes (iris colobomas, microphthalmia,) and intestine (congenital short gut, malrotation, dysmotility, chronic constipation, bleeding and myofibromas). Developmental delay and variable degrees of intellectual disability may also be observed. Multiple intra-abdominal smooth muscle hamartomas, trichoblastoma of the skin, occipital meningoceles and development of desmoplastic medulloblastoma have been reported.", "ORPHA ID": 1553, "Summary": ""}
{"Disease Name": "Cushing disease", "Disease Definition": "A form of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome, an endogenous Cushing syndrome (CS), characterized by chronic over-secretion of adrenocorticotropic hormone (ACTH) due to a pituitary corticotroph adenoma.", "ORPHA ID": 96253, "Summary": "Epidemiology\nCushing disease (CD) is the most common form of endogenous CS. The incidence is estimated to range between 1 out of 588,235 to 833,333 individuals per year, with an estimated incidence of CS (all causes considered) ranging between 1 out of 12,658 to 17,544 individuals per year. The mean age at diagnosis is 40 years and there is a significant female predominance.\nClinical description\nThe disease manifests with signs of CS (resembling corticosteroid side effects, i.e. faciotruncular fat distribution, hypercatabolic syndrome with thinned skin, proximal muscle weakness, oesteoporosis, metabolic syndrome, ...) as well as skin hyperpigmentation and/or neurological complications in rare cases of corticotropic macro-adenoma.\nEtiology\nMost corticotroph adenomas arise in a sporadic setting, with somatic activating driver variants in USP8 in around half of cases. Somatic variants in other genes such as USP48 and NR3C1 are less frequent. TP53 and ATXR somatic variants may be associated with more aggressive tumors. Germline mutations are rare.\nDiagnostic methods\nThe first diagnostic step is to confirm CS (i.e. hypercortisolemic state) based on recommended tests. The second step of diagnosis is plasma ACTH detection to distinguish ACTH-dependent CS (values greater than 20 pg/mL) (4.4 pmol/L) from adrenal CS (ACTH values lower than 10 pg/mL) (2.2 pmol/L). When in doubt, a corticotropin-releasing hormone (CRH) test or a high-dose dexamethasone suppression test and adrenal gland computed tomography (CT) are recommended. The third step localizes the site of ACTH over-secretion: pituitary (CD) or non-pituitary (ectopic ACTH secretion; or EAS). Diagnosis of CD is based on dynamic hormonal tests (CRH test, desmopressin test, high-dose dexamethasone suppression test) to analyze the corticotropic response that distinguishes CD (with response often partially regulated: \"positive\" tests) from EAS (with response generally unregulated: \"negative\" tests) as well as measures of tumor markers, imaging (pituitary magnetic resonance imaging, thoraco-abdomino-pelvic computed tomography, positron emission tomography/computed tomography with Somatostatin analogue +/- 18-F-DOPA or 18-F-fluorodeoxyglucose), and bilateral inferior petrosal sinus sampling for ACTH assay.\nDifferential diagnosis\nThe differential diagnoses of CD are the other forms of Cushing syndrome, nonneoplastic hypercortisolism, generalized glucocorticoid resistance syndrome and lipodystrophy syndromes.\nAntenatal diagnosis\nAntenatal or preimplantation diagnosis may be proposed in families with identified mutations and severe/incurable diseases.\nGenetic counseling\nSuspicion of a genetic condition warrants a specialized genetic consultation. In second line, in cases presenting < 18 years or familial forms, genome-wide association studies may be discussed. Genetic counseling may be proposed in families with a known disease-causing mutation.\nManagement and treatment\nTranssphenoidal pituitary surgery by an experienced pituitary surgeon is recommended as the first-line therapy. Removal of the tumor may lead to full recovery but there is a 20-30% persistence risk after surgery and a 15-30% long-term recurrence risk among patients in remission after surgery. After successful pituitary surgery, hydrocortisone replacement is often required for a few months or a few years. In patients who underwent a non-curative surgery, who relapsed or for whom surgery was not possible initially, several options should be considered individually such as second or delayed surgery, medical treatment, bilateral adrenalectomy or pituitary radiotherapy.\nPrognosis\nUntreated CD can be life-threatening. After remission of CD, sequelae may persist, such as cardiovascular comorbidities, cognitive impairment and psychological disorders.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Laurence GUIGNAT | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Cushing syndrome due to bilateral macronodular adrenocortical disease", "Disease Definition": "A rare adrenal Cushing syndrome characterized by bilateral benign adrenal macronodules (>1 cm) that potentially produce autonomously variable levels of cortisol excess. Although in most cases are ACTH-independent, non-suppressed ACTH levels have been described.", "ORPHA ID": 189427, "Summary": "Epidemiology\nCushing syndrome due to bilateral macronodular adrenocortical disease (BMAD) is a rare form of endogenous CS, responsible for less than 2% of cases; the actual frequency remains unclear as only some of BMAD patients have an overt CS. Sporadic BMAD predominantly affects women, but the sex ratio is balanced in patients with ARMC5 pathogenic variants while more than 8/10 patients with KDM1A pathogenic variants are women.\nClinical description\nMost BMAD cases are identified incidentally during radiological investigation for unrelated conditions. The adrenal glands can be massively enlarged bilaterally with the presence of numerous macronodules; however diffuse adrenal enlargement without nodules has been described. The clinical presentation depends on the extent of excess cortisol, ranging from asymptomatic forms to severe CS. For symptomatic patients, clinical presentation is typically in the fifth decade of life.\nEtiology\nIn isolated BMAD, variants in the ARMC5 gene accounts for more than 80% of the familial forms and about 20-25% of apparently sporadic cases; variants in the KDM1A gene are responsible for BMAD associated with food-dependent CS. A few cases have been reported in association with mosaic variants of GNAS1, a gene which is also responsible for McCune-Albright syndrome (MAS). Genetic mechanisms still remain to be identified in other cases. Rarely, BMAD can be seen in syndromic diseases such as multiple endocrine neoplasia type 1 (MEN1), familial adenomatous polyposis (FAP), or hereditary leiomyomatosis and renal cell cancer (HLRCC).\nDiagnostic methods\nThe first diagnostic step is to confirm CS (i.e. hypercortisolemic state) based on recommended tests. Diagnosis is often difficult because hypercortisolism usually develops slowly over years, may be cyclical and is often associated with subtle CS. Cortisol secretion may be food-dependent with low fasting cortisol concentrations. Hormonal investigations can demonstrate abnormal stimulation of cortisol secretion by various hormones (e.g. GIP, gonadotropin-releasing hormone, aldosterone or androgen secretion). Usually, in BMAD patients with subclinical or overt CS, ACTH is low or sometimes not detectable; however, non-suppressed ACTH levels have also been described. When in doubt, a corticotropin-releasing hormone (CRH) test or a high-dose dexamethasone suppression test and adrenal gland computed tomography (CT) are recommended. The third step is to show bilateral adrenal nodular enlargement on radiological imaging. Diagnosis can be confirmed by histological examination.\nDifferential diagnosis\nDifferential diagnoses include other causes of adrenal CS, and ACTH-dependent CS including pituitary (Cushing disease) or extra-pituitary tumors (ectopic ACTH secretion), other causes of bilateral adrenal masses with no CS (bilateral pheochromocytoma, primary aldosteronism, congenital adrenal hyperplasia, bilateral metastasis of solid cancer, etc.).\nAntenatal diagnosis\nAntenatal or preimplantation diagnosis may be proposed for those with severe and incurable diseases.\nGenetic counseling\nGenetic consultation to offer genetic analysis should be proposed to all patients with BMAD. In a second step, genome-wide study may be discussed. Genetic counseling may be proposed in families with a known disease-causing mutation.\nManagement and treatment\nA surgical or medical treatment should be considered for patients with overt CS and in cases of ascertained mild autonomous cortisol secretion in the presence of clinical consequences of possibly related to hypercortisolism (i.e. diabetes, hypertension, bone fragility). For patients with no evidence for hypercortisolism at diagnosis, active surveillance should be proposed.\nPrognosis\nUntreated CS due to BMAD can be life-threatening. Prognosis after treatment is good but quality of life may be affected. In cases of moderate hypercortisolism, long-term morbidity is due to the increased cardiovascular and metabolic risk factors associated with mild CS.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Jérôme BERTHERAT | Endo-ERN* - Dr Laurence GUIGNAT | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Cushing syndrome due to ectopic ACTH secretion", "Disease Definition": "A form of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome, an endogenous Cushing syndrome (CS), characterized by the secretion of ACTH by non-pituitary neuroendocrine tumors (NETs) of various locations and various degrees of histological differentiation and aggressiveness.", "ORPHA ID": 99889, "Summary": "Epidemiology\nThe annual incidence of Cushing syndrome (CS) due to ectopic ACTH secretion (EAS), is estimated at about 1/1,250,000. The vast majority cases are sporadic and occur in adulthood, with an equal female-to-male ratio.\nClinical description\nClinical features are quite wide ranging. Patients may present like those with CS (truncal and facial obesity and signs of hypercatabolism) and with skin hyperpigmentation, like in Cushing disease (CD), or with skin pigmentation and severe amyotrophy, with or without facial fullness or weight gain. Severe hypokalemia, life-threatening infections, psychiatric disorders, osteoporosis and fractures are seen more frequently in CS due to EAS than in CD. Specific signs depend on the causative tumor, its site and extension, and may include paroxystic hypertension in pheochromocytoma, flush or diarrhea in medullary thyroid carcinoma, and carcinoid syndrome in metastatic carcinoid tumors.\nEtiology\nThe tumors responsible for an EAS have a variety of locations and histological types. The lung is the primary site of 40% of EAS cases (bronchial carcinoid and small cell lung cancer). Other tumors derive mainly from the foregut (larynx, thymus, stomach, duodenum and pancreas). Rarely, pheochromocytomas and medullary thyroid carcinoma secrete ACTH in addition to catecholamines and calcitonin, respectively. Some exceptional inherited cases are described, with ACTH-secreting thymic neuroendocrine tumors (NETs), in the context of multiple endocrine neoplasia type 1 (MEN1), medullary thyroid cancers in MEN2 and pancreatic NETs in the Von Hippel-Lindau syndrome.\nDiagnostic methods\nThe first diagnostic step is to confirm CS (i.e. hypercortisolemic state) based on recommended tests. The second step of diagnosis is plasma ACTH detection to distinguish ACTH-dependent CS (values greater than 20 pg/mL; 4.4 pmol/L) from adrenal CS (ACTH values lower than 10 pg/mL; 2.2 pmol/L). Cortisol and ACTH levels can be very high in EAS. The third step localizes the site of ACTH over-secretion, pituitary (CD) or non-pituitary (EAS). Diagnosis is based on dynamic hormonal tests to analyze the corticotropic response that distinguishes CD (with response often partially regulated: ''positive'' tests) from EAS (with response generally unregulated: ''negative'' tests) as well as measures of tumor markers, imaging (pituitary magnetic resonance imaging, thoraco-abdomino-pelvic computer tomography, positron emission tomography/computed tomography with Somatostatin analogue +/- 18-F-DOPA or 18-F-fluorodeoxyglucose), and bilateral inferior petrosal sinus sampling for ACTH assay. Rare concomitant secretion of corticotropin-releasing hormone (CRH) and ACTH, and exceptional exclusive CRH secretion have been described.\nDifferential diagnosis\nThe differential diagnosis of CS due to EAS is CD.\nAntenatal diagnosis\nAntenatal or preimplantation diagnosis may be proposed for those with severe and incurable diseases (e.g. MEN2, VHL disease, etc.).\nGenetic counseling\nSuspicion of a genetic disease warrants a specialized genetic consultation. Genetic counseling may be proposed in families with a known disease-causing mutation.\nManagement and treatment\nThe ideal treatment is curative surgery of the underlying tumor. Removal of the tumor may lead to full recovery but the condition may recur. If surgery is not curative or possible, a multidisciplinary approach includes chemotherapy, radiotherapy, hormone analogues and/or radionuclide treatment to control tumor growth and associated symptoms. If the tumor is unresectable, or while waiting for the effectiveness of the treatment of the tumor in cases of severe CS, anticortisolic medication and preventive and curative treatment of comorbidities are recommended. Bilateral adrenalectomy can resolve hypercortisolism in cases of non-operable or non-localized secreting tumors or in cases of poor tolerance and inefficacy of medical treatment.\nPrognosis\nPrognosis depends on tumor histology and staging, and on severity of CS. Untreated CS can be life-threatening.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Laurence GUIGNAT | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Cutaneous collagenous vasculopathy", "Disease Definition": "Cutaneous collagenous vasculopathy (CCV) is a primary microangiopathy confined to the skin, characterized by multiple and widespread telangiectasias.", "ORPHA ID": 280779, "Summary": "Epidemiology\nIt is a rare disorder with less than 20 cases reported in the literature to date.\nClinical description\nMost patients present in adulthood with symmetrical telangiectasias appearing on the lower extremities and later progressing to the trunk and upper extremities.\nEtiology\nThe etiology is unknown but CCV is thought to be associated with collagen abnormalities in the skin microvasculature. It can be distinguished from generalized essential telangiectasia (see this term) by characteristic histopathological features that reveal the presence of thickened vascular walls in CCV.\n\n                            Last update: \n                            April 2013"}
{"Disease Name": "Cutaneous larva migrans", "Disease Definition": "Cutaneous larva migrans is a rare parasitic disease characterized by single or multiple, linear or serpiginous, erythematous, slightly elevated cutaneous tracks caused by the larval migration of various nematode species. Tracks are variable in length, generally a few millimeters wide and are frequently located on the feet (although any area of the body is possible). Patients typically present with severe, intractable pruritus, which, in some cases, may cause impaired concentration, loss of sleep, and mood disturbances.", "ORPHA ID": 423717, "Summary": ""}
{"Disease Name": "Cutaneous mastocytoma", "Disease Definition": "Cutaneous mastocytoma is a form of cutaneous mastocytosis (CM, see this term) generally characterized by the presence of a solitary or multiple hyperpigmented macules, plaques or nodules associated with abnormal accumulation of mast cells in the skin.", "ORPHA ID": 79455, "Summary": "Epidemiology\nPrevalence is unknown but mastocytomas are the second most frequent form of CM in children, accounting for 10-15% of cases.\nClinical description\nPatients generally present during infancy, with most presenting in the first three months of life. However, rare cases of onset in adulthood have been reported. Mastocytomas usually appear as oval lesions with red-brown, pink or yellow pigmentation. The diameter varies from around 1-4 cm and the surface may be smooth or have a ''peau d'orange'' appearance. The trunk, face, neck and extremities are the most common sites of involvement. Patients with multiple mastocytomas (up to 5) have been reported with new lesions appearing at different locations up to two months after emergence of the initial lesion. Other skin manifestations may include blistering (most frequent during infancy), pruritus and urticaria. Stroking of the lesions results in Darier's sign and generalized flushing in some cases. Additional systemic symptoms are rarely associated with cutaneous mastocytomas but a few cases with fever, gastrointestinal disturbances (nausea, colic and diarrhea), headaches and asthma-like symptoms have been reported.\nEtiology\nMutations in the KIT gene (4q11-q12) have been identified in some patients with CM, however, this mutation is rare in the pediatric population and the etiology and pathogenesis of cutaneous mastocytoma remains to be determined.\nDiagnostic methods\nDiagnosis is made on the basis of the clinical appearance of the lesions and the presence of Darier's sign. Histopathological examinations confirm the diagnosis by revealing a dense infiltrate of mast cells in the upper dermis.\nDifferential diagnosis\nThe differential diagnosis generally includes melanocytic nevi, xanthomas and juvenile xanthogranuloma (see this term).\nManagement and treatment\nTreatment is symptomatic and includes oral administration of antihistamines, topical steroids and the use of hydrocolloid dressings to cover the lesions. Trigger factors (such as rubbing of the lesions and use of nonsteroidal anti-inflammatory drugs) should be avoided. Surgical excision provides a definitive cure for patients with alarming symptomatic lesions that do not respond to other forms of treatment and has been recommended as a first-line therapy in some cases.\nPrognosis\nThe prognosis for patients with onset during infancy is good with regression of most lesions during childhood and complete resolution by adolescence. Rare cases of persisting mastocytoma in adulthood have been reported. Spontaneous resolution is less common in patients with adult-onset.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Pr A.P. [Arnold] ORANJE"}
{"Disease Name": "Cutaneous mastocytosis", "Disease Definition": "A rare group of mastocytosis diseases characterized by abnormal accumulation and proliferation of mast cells in the skin and including the three recognised forms: diffuse cutaneous mastocytosis, cutaneous mastocytoma and, the most common form, maculopapular cutaneous mastocytosis. In some cases (most commonly in adults), cutaneous mastocytosis may occur in association with mast cell infiltration of various extracutaneous organs, in which case the disorder is referred to as systemic mastocytosis.", "ORPHA ID": 66646, "Summary": ""}
{"Disease Name": "Cutaneous neuroendocrine carcinoma", "Disease Definition": "A rare aggressive skin cancer characterized by a rapidly growing nodule with both epithelial and neuroendocrine features, driven in 80% of cases by the oncogenic Merkel cell polyomavirus (MCPyV).", "ORPHA ID": 79140, "Summary": "Epidemiology\nCutaneous neuroendocrine carcinoma (or Merkel cell carcinoma; MCC) accounts for less than 1% of skin cancers. The annual incidence rates, ranging from 1 out of 1,000,000 to 1 out of 40,000 inhabitants in western countries, has been increasing over the last two decades.\nClinical description\nMCC usually occurs in fair-skinned, elderly people. Overall, 10% of MCC patients are immunosuppressed (transplant recipients, HIV, hematological malignancies). The primary tumor is mostly located on sun-exposed areas and appears as an asymptomatic, rapidly growing, red/violaceous cutaneous nodule. One third of patients already have nodal or distant metastasis at time of diagnosis. A complete work up is necessary at baseline (ultrasonography of the regional lymph nodes and a whole-body imaging with a positron emission tomography scan), allowing to classify the disease according to the 4 stages of the American Joint Committee on Cancer (AJCC) system. In less than 10% of cases, MCC is diagnosed in metastatic lymph nodes, with no evidence of skin primary (''occult primary'').\nEtiology\nIn 2008, Feng, Chang and Moore discovered that the genome of the Merkel cell polyomavirus (MCPyV) was integrated in the DNA of 80% of MCC samples. Since then, MCPyV has been found to be an ubiquitary resident of skin flora, acquiring oncogenic properties following the occurrence of very rare events (integration of its DNA into the genome of the host cell and mutations of the viral genome). On the other hand, 20% of MCC are related to UV-induced mutations especially on TP53 and pRB oncogenes. In both subsets, the most likely cell of origin is an epithelial cell of the epidermis.\nDiagnostic methods\nThe diagnosis of MCC requires a biopsy. Histologically, MCCs appear as a proliferation of basophilic cells with scant cytoplasm, a 'salt and pepper' chromatin pattern and high mitotic rate. The tumor is located in the dermis, frequently extending to the subcutaneous tissue, lacking connection with the epidermis. Immunohistochemistry reveals positivity for neuroendocrine (synaptophysin, chromogranin) and epithelial markers, the hallmark being the paranuclear dot-like pattern of cytokeratin 20 expressed by more than 90% of MCC.\nDifferential diagnosis\nClinical differential diagnosis includes any disease presenting a skin nodule, ranging from benign cysts or lipomas, to skin malignancies such as carcinomas, lymphomas or skin metastases. On histological sections, the main differential diagnoses include basophilic tumors such as small-cell lung carcinoma, carcinoid tumor, malignant lymphoma, and small-cell melanoma, which can be ruled out by appropriate immunohistochemical panels.\nManagement and treatment\nManagement should be discussed in tumor multidisciplinary boards based on the disease stage and general health status of the patient. Patients with localized disease should have a wide excision of the primary tumor with a sentinel lymph node biopsy in the regional area. In case of regional disease, a complete lymph node dissection is usually indicated. Adjuvant radiation therapy is usually provided on the site of the primary tumor and can be proposed on the regional lymph node area if involved. In patients with advanced disease, first line treatment consists in immunotherapy with a PD-1/PD-L1 inhibitor. Avelumab is approved in several countries worldwide in this setting, retifanlimab is approved in Europe and the USA, while pembrolizumab is only approved in the USA.\nPrognosis\nMCC is an aggressive disease with a high propensity to metastasize. Approximately 40% of patients recur within 3 years after initial management, and the overall survival at 5 years is estimated at 60%. The prognosis of patients with advanced disease has improved with the use of immunotherapy.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Mahtab SAMIMI"}
{"Disease Name": "Cutaneous photosensitivity-lethal colitis syndrome", "Disease Definition": "A rare inflammatory bowel disease characterized by early cutaneous photosensitivity manifesting by sun-induced facial erythematous and vesicular lesions and severe recurent colitis which lead to untreatable diarrhea. There have been no further descriptions in the literature since 1991.", "ORPHA ID": 2881, "Summary": ""}
{"Disease Name": "Cutaneous polyarteritis nodosa", "Disease Definition": "Cutaneous polyarteritis nodosa (CPAN) is a rare limited form of polyarteritis nodosa (PAN, see this term), characterized by cutaneous vasculitis and mild and transient extracutaneous manifestations such as mild arthralgia, arthritis,myalgia, and rarely peripheral neuropathy.", "ORPHA ID": 439729, "Summary": ""}
{"Disease Name": "Cutaneous pseudolymphoma", "Disease Definition": "A rare acquired skin disease characterized by a benign, etiologically variable lymphoproliferative process of the skin mimicking cutaneous lymphoma clinically and/or histologically, while not fulfilling criteria for the diagnosis of a specific disease. Depending on the predominant cell type in the infiltrate, T- and B-cell pseudolymphomas can be distinguished.", "ORPHA ID": 451607, "Summary": ""}
{"Disease Name": "Cutaneous small vessel vasculitis", "Disease Definition": "A small vessel vasculitis characterized by neutrophilic inflammation predominantly limited to the superficial cutaneous postcapillary venules and without systemic vasculitis or glomerulonephritis. Typical presentation is of unifocal or multifocal palpable purpura on the lower extremities.", "ORPHA ID": 889, "Summary": "Epidemiology\nThe annual incidence of leukocytoclastic vasculitis in the United States is estimated at 1/220,000, of which 45% consist of cutaneous small vessel vasculitis.\nClinical description\nThe disease onset can occur at any age, and typically presents with non-blanching, palpable purpura and/or petechiae of the lower extremities with unifocal or multifocal distribution. The lesions may coalesce, ulcerate or be surrounded by hemorrhagic bullae. Urticarial lesion can also be observed. Lesions are usually not painful, although they may cause burning and itching. Histological characteristics are non-specific for the disease and include neutrophilic infiltration of the dermal small blood vessel walls, as well as, fibrinoid necrosis and disruption of the vessel wall, leukocytoclasia, endothelial swelling, and erythrocytes extravasation. As the lesion gets older, neutrophils diminish, and lymphocytes become prominent.\nEtiology\nThe disease may be idiopathic (in up to 50% of cases) or secondary to infections, medications, connective tissue diseases, or malignancy. The disease occurs due to the deposition of immune complexes (IC) on the wall of post-capillary venules, which then activates both complement pathways, leading to degranulation of mast cells and neutrophil chemotaxis.\nDiagnostic methods\nDiagnosis is one of exclusion. In general, skin biopsy samples from lesions between 24-48 hours old, should be examined with light microscopy and direct immunofluorescence. A complete history, review of systems, physical examination, and selected laboratory studies also should be performed to assess for inciting causes or extracutaneous involvement.\nDifferential diagnosis\nThe main differential diagnosis is of systemic small vessel vasculitides with cutaneous presentation and includes antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemic vasculitis, immunoglobulin A vasculitis. Other conditions with similar histopathology include infective endocarditis, macular purpura owing to trauma, skin fragility, pigmented purpuric dermatosis, septic emboli, and livedoid vasculopathy.\nManagement and treatment\nTreatment varies and depends on the chronicity of the disease, the severity of cutaneous involvement, and the presence or absence of both an underlying cause. An isolated episode associated with a known inciting factor may be managed by removal or treatment of the trigger, along with symptomatic measures. First-line systemic treatments for chronic, idiopathic disease include colchicine or dapsone, used singly or in combination. Recurrent, chronic, or severely symptomatic disease that does not respond to the aforementioned therapies may require initiation of an immunosuppressive agent such as azathioprine, mycophenolate mofetil, methotrexate, or rituximab.\nPrognosis\nThe clinical outcome is typically good with 90% resolving in weeks to months of onset, but may be complicated by the occurrence of ulcers (treatment prolongation, infections and scarring). The reported relapse rate is between 8-25%.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Xavier PUECHAL  - Pr Benjamin TERRIER"}
{"Disease Name": "Cutis gyrata-acanthosis nigricans-craniosynostosis syndrome", "Disease Definition": "Cutis gyrata-acanthosis nigricans-craniosynostosis syndrome, also known as Beare-Stevenson syndrome (BSS), is a severe form of syndromic craniosynostosis, characterized by a variable degree of craniosynostosis, with cloverleaf skull reported in over 50% of cases, cutis gyrata, corduroy-like linear striations in the skin, acanthosis nigricans, skin tags, and choanal stenosis or atresia). Additional features include facial features similar to Crouzon disease, ear defects (conductive hearing loss, posteriorly angulated ears, stenotic auditory canals, preauricular furrows, and narrow ear canals), hirsutism, a prominent umbilical stump, and genitorurinary anomalies (anteriorly placed anus, hypoplasic labia, hypospadias). BSS is associated with a poor outcome as patients present an elevated risk for sudden death in their first year of life. Significant developmental delay and intellectual disability are observed in most patients who survive infancy.", "ORPHA ID": 1555, "Summary": ""}
{"Disease Name": "Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies", "Disease Definition": "A rare, genetic, dermis elastic tissue disorder characterized by generalized cutis laxa associated with severe, usually early-onset, pulmonary emphysema, frequent and severe gastrointestinal and genitourinary involvement (i.e. bladder/intestine diverticula and/or tortuosity, gastrointestinal fragility, hydronephrosis), and mild cardiovascular involvement (typically limited to peripheral pulmonary artery stenosis only).", "ORPHA ID": 221145, "Summary": ""}
{"Disease Name": "Cutis laxa-Marfanoid syndrome", "Disease Definition": "A rare, genetic, developmental defect with connective tissue involvement syndrome characterized by neonatal cutis laxa, marfanoid habitus with arachnodactyly, pulmonary emphysema, cardiac anomalies, and diaphragmatic hernia. Mild contractures of the elbows, hips, and knees, with bilateral hip dislocation may also be associated. There have been no further descriptions in the literature since 1991.", "ORPHA ID": 171719, "Summary": ""}
{"Disease Name": "Cutis laxa", "Disease Definition": "Cutis laxa (CL) is an inherited or acquired connective tissue disorder characterized by wrinkled, redundant and sagging inelastic skin associated with skeletal and developmental anomalies and, in some cases, with severe systemic involvement. Several different forms of inherited CL have been described, differentiated on the basis of the mode of inheritance and differences in the extent of internal organ involvement, associated anomalies and disease severity.", "ORPHA ID": 209, "Summary": "Epidemiology\nMost cases of CL are inherited, with prevalence at birth being estimated at around 1/1,000,000 and only around 200 families being reported in the literature so far.\nClinical description\nAutosomal recessive types of CL (ARCL) appear to be the most common forms with two subtypes being described: ARCL1 and ARCL2 (see these terms). ARCL1 is the most severe form of CL with generalized involvement leading to life-threatening complications (lung atelectesias and emphysema, vascular anomalies, and gastrointestinal and genitourinary tract diverticuli). ARCL2 appears to cover a spectrum of disorders ranging in severity from the wrinkly skin syndrome (see this term) to more severe disease associated with growth and developmental delay, and skeletal anomalies (classic ARCL2, Debré type; see this term). De Barsy syndrome and geroderma osteodysplastica (see these terms) also show significant clinical overlap with ARCL2. Occipital horn syndrome (X-linked cutis laxa (XRCL); see this term) is very similar to ARCL2; however, several patients present a more severe phenotype and systemic involvement. Autosomal dominant CL (ADCL) is generally a mild cutaneous disorder but systemic manifestations (hernias, cardiac valve anomalies, cardiovascular manifestations, gastrointestinal diverticuli and emphysema) have been noted in some cases.\nEtiology\nAlthough the underlying etiology remains unknown in many patients with the inherited forms of CL, several genes have been implicated: FBLN5 , EFEMP2 and LTBP4 in ARCL1 (14q32.1, 11q13 and 19q13.1-q13.2) , ATP6V0A2 and PYCR1 in ARCL2 (12q24.3 and 17q25.3), and ELN and FBLN5 in ADCL (7q11.2 and 14q32.1)). Homozygous ELNmutations have also been indentified in four patients with a mild form of ARCL.\nDiagnostic methods\nDiagnosis is often problematic due to the considerable clinical overlap between the hereditary forms. The diagnostic approach should include a detailed physical examination, family history, skeletal survey, developmental assessment, imaging studies, histological analysis, liver function tests and biochemical analysis, kidney ultrasound, and ophthalmological and cardiac evaluation.\nDifferential diagnosis\nThe main differential diagnosis is the Ehlers-Danlos syndromes (see these terms) but similar skin manifestations may also occur in patients with Williams syndrome, pseudoxanthoma elasticum, Hutchinson Gilford syndrome, Barber Say syndrome, Costello syndrome, Cardio-Facio-Cutaneous syndrome and Kabuki syndrome (see these terms). Inherited forms of CL should also be distinguished from acquired CL which is commonly preceded by urticaria, angioedema, local or generalized inflammatory skin disease or drug hypersensitivity reactions.\nAntenatal diagnosis\nPrenatal diagnosis is feasible by molecular testing for families in which the genetic anomaly has been identified.\nGenetic counseling\nCorrect diagnosis of the hereditary forms is essential for providing adapted genetic counseling to affected families.\nManagement and treatment\nThere is no efficient treatment for CL and management is symptomatic. Plastic surgery is not generally indicated for the cutaneous manifestations in inherited forms.\nPrognosis\nPrognosis is variable, ranging from a usually fatal outcome in childhood in ARCL1 to a normal life expectancy in less severe forms.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS"}
{"Disease Name": "Cutis marmorata telangiectatica congenita", "Disease Definition": "Cutis marmorata telangiectatica congenita (CMTC) is a congenital localized or generalized vascular anomaly characterized by a persistent cutis marmorata pattern with a marbled bluish to deep purple appearance, spider nevus-like telangiectasia, phlebectasia and, occasionally, ulceration and atrophy of the affected skin.", "ORPHA ID": 1556, "Summary": "Epidemiology\nAbout 300 cases have been reported so far. Both genders seem equally affected.\nClinical description\nIn 90% of cases, the skin anomalies are observed at birth or shortly after birth, and may become more accentuated in the first few weeks. CMTC manifests with a localized or generalized reticulated, frequently asymmetrical, blue-violet colored vascular network in the skin. Skin changes may range from fine diffuse capillary anomalies without atrophy to atrophic or ulcerated larger purple reticulated bands. The cutaneous lesions most commonly occur on the legs, less commonly on the arms and trunk, and rarely involve the face and scalp. More than 50% of the CMTC patients present with associated cutaneous and/or extracutaneous anomalies (referred to as the macrocephaly-CMTC syndrome; see this term), most frequently body asymmetry (hypotrophy or hypertrophy of an involved extremity) and vascular lesions (capillary malformations). Other associated anomalies include neurological abnormalities (psychomotor retardation, seizures, and hypotonia), ocular anomalies (retinal detachment and congenital glaucoma; see this term), syndactyly, and macrocephaly. CMTC can also be associated with Adams-Oliver syndrome (see this term).\nEtiology\nThe etiology remains unknown.\nDiagnostic methods\nDiagnosis is clinical. If the head is affected, ocular and neurological examination should be performed. Possible associated anomalies should be excluded by a careful clinical examination. Histopathologic findings are often nonspecific or show dilated capillaries and veins in the dermis.\nDifferential diagnosis\nDifferential diagnoses include Klippel-Trénaunay syndrome, Sturge-Weber syndrome, Bockenheimer syndrome, some port-wine stain capillary malformations, and macrocephaly-CMTC (see these terms). Persistence of skin changes with local warming distinguishes CMTC from physiological cutis marmorata.\nGenetic counseling\nCMTC occurs sporadically but a genetic basis has been proposed for some affected families.\nManagement and treatment\nTreatment is usually not required. Laser therapy has been tried in several patients with persistent CMTC and variable outcomes have been reported.\nPrognosis\nPrognosis is generally good, with a tendency for clinical improvement during infancy or even complete resolution.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "Cyanide poisoning", "Disease Definition": "A rare intoxication characterized by onset of toxic manifestations within seconds to hours - depending on the route, duration, dosage, and source of exposure - after inhalation of volatile cyanides (especially from fire smoke), ingestion of cyanide (including use of certain medications) or contact with the skin or mucous membranes. In severe cases following inhalation, signs of hyperventilation appear within seconds or minutes and are followed by loss of consciousness with convulsions and ultimately cardiovascular collapse and/or respiratory arrest. Other clinical signs include dizziness, weakness, palpitations, and anxiety, followed by dyspnea, pulmonary edema, confusion, ataxia, and paralysis.", "ORPHA ID": 466670, "Summary": ""}
{"Disease Name": "Cyanide-induced parkinsonism-dystonia", "Disease Definition": "A rare parkinsonian syndrome due to intoxication which develops in individuals surviving an acute cyanide intoxication episode or due to chronic exposure to small cyanide doses. It presents several weeks after acute exposure with progressive typical clinical features of parkinsonism including bradykinesia, rigidity, dystonia, hypomimia, hypokinetic dysarthria, postural instability and retropulsion but no resting or postural tremor. Brain MRI reveals bilateral lesions in the pallidum, posterior putamen, substantia nigra, subthalamic nucleus, temporal and occipital cortex, and cerebellum.", "ORPHA ID": 306692, "Summary": ""}
{"Disease Name": "Cyclic neutropenia", "Disease Definition": "A rare primary immunodeficiency characterized by regular oscillations in blood neutrophil counts from normal or subnormal levels to severe neutropenia, usually with a cycle length of about 21 days. Symptoms during the neutropenic phase include fever, mouth ulcers, but also pneumonia, and peritonitis, among others. Mode of inheritance is autosomal dominant.", "ORPHA ID": 2686, "Summary": ""}
{"Disease Name": "Cyclosporiasis", "Disease Definition": "Cyclosporosis is a parasitic disease caused by Cyclospora cayetanensis, a recently discovered coccidia that was initially described in Peru and then in most intertropical zones. Infection occurs through ingestion of contaminated food or water and leads to abdominal pain, anorexia and diarrhoea, which may resolve spontaneously in immunocompetent individuals but may persist in a chronic form in immunocompromised subjects, leading to a decline in their general state of health.", "ORPHA ID": 210, "Summary": "Epidemiology\nThe prevalence is unknown.\nDiagnostic methods\nThe diagnosis is made by parasitological examination of the stools.\nManagement and treatment\nTreatment revolves around administration of cotrimoxazole.\n\n                            Last update: \n                            December 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Luc PARIS"}
{"Disease Name": "Cylindrical spirals myopathy", "Disease Definition": "Cylindrical spirals myopathy is a rare form of congenital myopathy characterized by global muscle weakness, hypotonia, myotonia and cramps in the presence of cylindrical, spiral-shaped inclusions (located in the central and/or subsacrolemmal areas of muscle fibers) in skeletal muscle biopsy. Abnormal gait, scoliosis, epileptic encephalopathy and psychomotor delay may be associated.", "ORPHA ID": 171886, "Summary": ""}
{"Disease Name": "Cyprus facial-neuromusculoskeletal syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by a specific facial appearance (consisting of a thickened, ridged, triangular skin fold extending from the glabella to the anterior fontanel, bilateral elevation of the medial portion of the eyebrows, hypertelorism, low-set ears, posteriorly rotated ears, and widow's peak), variable skeletal deformities, and neuromuscular and sensory defects, which can be incapacitating in some individuals. Reported features include limb muscle wasting, congenital kyphoscoliosis, hip dislocation, congenital talipes equinovarus, arthrogryposis, joint stiffness/ankyloses, ptosis, and cataracts. Intelligence is normal. There have been no further reports since 1992.", "ORPHA ID": 2674, "Summary": ""}
{"Disease Name": "Cystadenoma of childhood", "Disease Definition": "A benign epithelial ovarian tumor characterized by a usually unilateral, cystic, unilocular or multilocular lesion with a thin wall or septa and no intracystic solid portion on imaging. It often presents with abdominal pain or an asymptomatic abdominal mass and can be associated with ovarian torsion or malignant transformation.", "ORPHA ID": 206470, "Summary": ""}
{"Disease Name": "Cystathioninuria", "Disease Definition": "A rare inborn error of metabolism characterized by abnormal accumulation of plasma cystathionine and subsequent increased urinary excretion due to cystathionine gamma-lyase deficiency. The condition is considered benign without pathological relevance. Mode of inheritance is autosomal recessive.", "ORPHA ID": 212, "Summary": ""}
{"Disease Name": "Cystic echinococcosis", "Disease Definition": "A rare parasitic disease characterized by slowly enlarging cysts of the liver, lungs and other organs which often go unnoticed for years. They are caused principally by the larval form (also called metacestode) of Echinococcus granulosus sensu lato tapeworm. The adult form of this tapeworm parasitizes the intestine of dogs. Cystic echinococcosis (formerly hydatidosis) generally affects large domestic herbivores and humans are dead-end hosts, infected through contact with herding dogs or through ingestion of food contaminated with canine excrement.", "ORPHA ID": 400, "Summary": "Epidemiology\nThe reported annual incidence of human infection in Europe is around 0.15 per 100 000 population. The disease is much more common worldwide, with overall prevalence ranging from 2.1 per 100 000 in China to 1.7% (with a 95% confidence interval between 1.1-2.6) in African countries.\nClinical description\nAfter ingestion, the larvae develop very slowly, forming cysts that are not diagnosed until 5 to 20 years after contamination. The liver (60% of cases), lungs (20% of cases) and other organs (kidneys, spleen, brain, etc.) are the principle sites of cyst formation. When symptoms exist, they are unspecific and depend on the affected organs. They include abdominal pain, malaise, nausea, vomiting, weight loss. Chronic cough, chest pain and shortness of breath can occur in cases of pulmonary cyst. The disease is often asymptomatic but can become fatal if left untreated for years.\nEtiology\nIt is caused by the larval form (called metacestode) of the tapeworm Echinococcus granulosus.\nDiagnostic methods\nDiagnosis is mainly based on imaging (abdomen, thorax, etc.) and serologic testing. Cyst type (i.e development stage) should be determined using ultrasound and/or MRI: active (CE1, CE2), transitional (CE3a, CE3b) or inactive (CE4, CE5).\nDifferential diagnosis\nThe differential diagnosis includes solitary simple liver cyst, polycystic liver disease and neoplastic liver cyst (cystadenoma and cystadenocarcinoma).\nManagement and treatment\nA stage-specific approach is recommended, based on cyst stage, size, location, presence/absence of complications as well as available medical expertise and equipment. Treatment may involve radical surgery or percutaneous treatments associated with short term antiparasitic treatment with benzimidazoles (BMZ), benzimidazoles alone or watch-and-wait approach (follow-up without treatment, for inactive cysts).\nPrognosis\nThe main risk is fissure or rupture of the cyst, associated with allergic/anaphylactic reaction and dissemination of the parasite. Recurrence after surgical or radiological procedure could also occur. Attributable mortality is low (1-2%) and mainly linked to disseminated and/or atypical forms (in the bone or brain).\n\n                            Last update: \n                            August 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Frédéric GRENOUILLET"}
{"Disease Name": "Cystic fibrosis-gastritis-megaloblastic anemia syndrome", "Disease Definition": "A rare genetic disease characterized by cystic fibrosis, gastritis associated with Helicobacter pylori, folate deficiency megaloblastic anemia, and intellectual disability. There have been no further descriptions in the literature since 1991.", "ORPHA ID": 2575, "Summary": ""}
{"Disease Name": "Cystic fibrosis", "Disease Definition": "A rare, genetic pulmonary disorder characterized by sweat, thick mucus secretions causing multisystem disease, chronic infections of the lungs, bulky diarrhea and short stature.", "ORPHA ID": 586, "Summary": "Epidemiology\nCystic fibrosis (CF) is the most common genetic disorder among Caucasians. In Europe, the average prevalence at birth is 1/5,000; the average prevalence in the general population is 1/9,000. There is wide variation in both rates depending on geographic location.\nClinical description\nCF is chronic and usually progressive. Symptoms often start at birth and involve the lungs and gastrointestinal tract. A common presentation might include thick secretions and chronic infections in the lung, bulky diarrhea and short stature. Abnormal airway secretions, inflammation and infections lead to bronchiectasis and early death. CF-related diabetes (CFRD) occurs at high frequency, rising to nearly 50% of patients surviving to age 50. Male sterility is common. Individuals with mild phenotypes may have mild or absent respiratory symptoms in childhood, but some may have infertility or may develop bronchiectasis or pancreatitis later in life. These individuals are typically diagnosed by newborn screening, but may be diagnosed later in life.\nEtiology\nAbnormal chloride channel function causes high salt content sweat and highly viscous mucus secretions. CF is a monogenic autosomal recessive disease caused by CFTR mutations. Among thousands of mutations, less than 300 cause disease when present in a homozygous or compound heterozygous state. About 70% of patients are homozygous for the delta F508 allele; 30 other mutations account for 20% of cases. Genotype and phenotype correlate poorly, but mutations associated with pancreatic insufficiency lead to more severe phenotypes. Mutations permitting residual CFTR function (e.g. R117H) are associated with the milder phenotype. Many factors influence phenotype.\nDiagnostic methods\nDiagnosis requires a typical clinical syndrome and either laboratory confirmed CFTR protein dysfunction or presence of two disease-causing mutations of CFTR on heteroalleles. Sweat testing confirms protein dysfunction. Newborn screening may presumptively diagnose CF before symptoms.\nDifferential diagnosis\nAny cause of bronchiectasis may mimic CF including primary ciliary dyskinesia, immunodeficiency, autoimmune disease, untreated pneumonia, esophageal reflux, or anatomic limitation to airway clearance such as in scoliosis. Some unusual or rare conditions falsely elevate sweat chloride suggesting CF. Genetic testing helps in these cases.\nAntenatal diagnosis\nIn at risk pregnancies, mutation analysis of chorionic villus samples after gestation week eight is possible for diagnosis.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at risk couples carrying CF mutations (identified by birth of a child with CF, neonatal screening detection of carrier status or family history), informing them that the risk of having an affected child at each pregnancy is 25%.\nManagement and treatment\nTreatment is transitioning from addressing symptoms to correcting biochemical defects. The oldest therapies include bronchial drainage and broad spectrum antibiotics for increasingly resistant pathogens. Pancreatic enzyme replacement with vitamin and calorie supplements improve digestion and nutrition. Insulin replacement for CFRD addresses lack of insulin release not seen in other types of diabetes. New CFTR modulators partly restore chloride channel function in about 90% of patients. However, they do not treat absent, truncated or severely malformed proteins.\nPrognosis\nLung disease is the main driver of morbidity and mortality. However, non-specific treatments improved the expectation of life at birth to more than 35 years, and with the advent of CFTR modulator therapy life expectancy has increased to nearly 50 years. Prognosis for newborns with CF may soon approach that of general populations. However, aging CF patients may be more vulnerable to disease associated with aging than the general population.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Theodore LIOU"}
{"Disease Name": "Cystic hamartoma of lung and kidney", "Disease Definition": "Cystic hamartoma of lung and kidney is a rare developmental malformation reported in 3 patients characterized by the presence of benign hamartomatous cysts in kidney and lung, clinically presenting as abdominal mass. Others associated features include hyperplastic nephromegaly, medullary dysplasia and mesoblastic nephroma. There have been no further descriptions in the literature since 1987.", "ORPHA ID": 2111, "Summary": ""}
{"Disease Name": "Cystic leukoencephalopathy without megalencephaly", "Disease Definition": "Cystic leukoencephalopathy without megalencephaly is characterised by non-progressive leukoencephalopathy, bilateral cysts in the anterior part of the temporal lobe, cerebral white matter anomalies and severe psychomotor impairment. Less than 50 patients have been described in the literature so far. Inheritance is most likely autosomal recessive.", "ORPHA ID": 85136, "Summary": ""}
{"Disease Name": "Cysticercosis", "Disease Definition": "Cysticercosis is a parasitic infectious disease characterized by cyst formation in the target tissue of Taenia solium (tapeworm) parasite larvae ingested via the feces of a human with a tapeworm (human-to-human fecal-oral transmission) leading to variable clinical manifestations in muscle, the brain, spinal cord, and eyes. Infection of muscle tissue is generally asymptomatic. Cyst development in the brain and spinal cord is known as neurocysticercosis (NCC) and may cause seizures and headache. NCC can follow a serious course and may be life-threatening. Severe cases of cysticercosis are treated with albendazole and anti-inflammatory drugs.", "ORPHA ID": 1560, "Summary": ""}
{"Disease Name": "Cystinosis", "Disease Definition": "A rare lysosomal disease characterized by an accumulation of cystine inside the lysosomes, causing damage in different organs and tissues, particularly in the kidneys and eyes. Three clinical forms have been described: nephropathic infantile, nephropathic juvenile and ocular.", "ORPHA ID": 213, "Summary": "Epidemiology\nThe prevalence at birth is estimated at around 1/100,000- 1/200,000.\nClinical description\nIn the infantile form (the most common), the first clinical signs appear between 3 and 6 months of age, with a polyuria-polydipsia syndrome and marked growth delay secondary to a generalized proximal tubular dysfunction with severe fluid-electrolyte balance alterations (renal Fanconi syndrome). Hypophosphatemic rickets causing bone deformities are also observed. Ocular involvement caused by cystine deposits in the cornea is responsible for photophobia which usually appears after 3 years of age. Cystine deposits in various organs progressively lead to hypothyroidism, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension in some patients, and muscle and cerebral involvement. In the absence of specific treatment, the disease progresses to end stage renal failure before the age of 10. The first symptoms of juvenile cystinosis (< 5% of patients), typically appear around 6-8 years of age with a milder form of proximal tubulopathy and/or proteinuria in nephrotic syndrome. Progression to renal failure occurs later than in the infantile form. Finally, the ocular form is observed in adults who are generally asymptomatic and may suffer only from photophobia.\nEtiology\nCystinosis is due to a defect in cystine transport out of lysosomes. The causative gene, CTNS (17p13), encodes cystinosin, a lysosomal membrane protein. Mutations in this gene have been detected for all 3 forms of the disease, with a 57-kb deletion detected in 60%-70% of alleles in patients from Northern Europe. Severe truncating mutations cause a more severe disease (infantile form) while mutations allowing the protein residual function cause milder phenotypes (juvenile or ocular).\nDiagnostic methods\nThe diagnosis is based on blood and urine analysis showing features of renal Fanconi syndrome (metabolic acidosis, hypokalemia, hypophosphatemia, hyperaminoaciduria, glycosuria, low molecular weight proteinuria), detection of cystine crystals in the cornea and determination of elevated cystine levels in leucocytes. It is confirmed by CTNS gene analysis.\nDifferential diagnosis\nDifferential diagnosis includes other diseases causing renal Fanconi syndrome (Lowe syndrome, Dent disease, galactosemia, fructose intolerance, thyrosinemia, mitochondrial nephropathies, Wilson disease, Fanconi-Bickel syndrome, lysinuric protein intolerance, idiopathic Fanconi syndromes, secondary Fanconi syndrome due to drug toxicity or substance abuse, recovery of acute tubulus necrosis), diseases causing phosphaturia and rickets, and proteinuria of unknown etiology.\nAntenatal diagnosis\nA prenatal, genetic diagnosis is possible in families with a previously affected child.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling is recommended for affected families. The risk of disease transmission is 25% where both parents are unaffected carriers; disease severity depends on the mutation.\nManagement and treatment\nTreatment consists of administering electrolytes, alkali, phosphate and vitamin D supplements; indomethacin, which improves the general status and growth; and cysteamine. Cysteamine lowers the cystine content in the lysosomes, thereby slowing or even stopping the progression to renal failure and the development of extra-renal manifestations. The side effects of cysteamine include gastrointestinal symptoms, bad breath, sweat odor and allergic reactions. A delayed-released formulation has been developed and approved in the USA and Europe, which allows patients to receive cysteamine twice a day, thus improving compliance and quality of life. Topical cysteamine eye drops (0.5%) are also needed as systemic cysteamine has no effect on cystine corneal deposits.\nPrognosis\nLife expectancy has significantly improved with therapy. Cysteamine delays the need for renal replacement therapy. The disease does not recur in the graft after renal transplantation but continues to progress in other organs and may cause complications (swallowing dysfunction, neurologic complications, lung disease) that may worsen the prognosis.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Elena LEVTCHENKO | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Cystinuria", "Disease Definition": "A rare disorder of renal tubular amino acid transport characterized by recurrent formation of kidney cystine stones.", "ORPHA ID": 214, "Summary": "Epidemiology\nPrevalence of cystinuria has high ethnogeographic variation, ranging from 1:2,500 in the Libyan Jewish population to 1:100,000 in Sweden. The mean global value is estimated at 1:7,000.\nClinical description\nCystinuria develops in patients of any age but renal colic due to cystine stone appears generally in the first two decades of life, with a median age of onset of 15 years. Male patients tend to present with more aggressive disease, and occurrence of renal stones before the age of 3 is more frequent in males. Urolithiasis is bilateral in more than 75% of cases and recurrence rate is over 60%, with a higher rate in male patients. Renal insufficiency is uncommon.\nEtiology\nCystinuria is due to mutations in SLC3A1 (2p21) and SLC7A9 (19q13.11). Both genes are expressed in the renal proximal tubules and the intestinal tract and code for subunits of trans-epithelial transporters for the dibasic amino acids cystine, ornithine, lysine and arginine. The transporter deficiency leads to accumulation of cystine in the urine and subsequent precipitation of cystine crystals or even stone formation. Classification of patients now relies on genetic criteria: type A and type B cystinuria are respectively associated with mutations in the genes SLC3A1 and SLC7A9. Heterozygotes with mutation in one SLC3A1 allele are unaffected, while those who carry mutation in a single SLC7A9 allele show moderately increased urine output of cystine and dibasic amino acids and have a higher risk of developing renal stones when compared to the general population.\nDiagnostic methods\nDiagnosis relies on physical examination, detection of cystine stones and assay of excreted cystine in urine, which in children and young infants may be normalized for urine creatinine. Analysis reveals urinary cystine excretion over 300 - 400 mg/day. Renal ultrasound imaging is the method of choice for stone detection and follow-up. Molecular genetics may confirm diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes three syndromes in which cystinuria is present: 2p21 deletion syndrome, hypotonia-cystinuria syndrome (HCS) and atypical HCS.\nAntenatal diagnosis\nDetection of a hyperechoic colon at routine ultrasound scan before 36 weeks of gestation may suggest a possible diagnosis of cystinuria with a high positive predictive value (89%). In any case, confirmation of the diagnosis should be made after delivery.\nGenetic counseling\nType A cystinuria has an autosomal recessive mode of inheritance, whereas dominant transmission with incomplete penetrance is typically observed in type B cystinuria.\nManagement and treatment\nTreatment requires several approaches to prevent stone formation or growth: high hydration to reduce urinary cystine osmolality, urinary alkalinization to increase cystine solubility (mainly with potassium citrate), and pharmacological cystine-binding medications (alpha-mercaptopropionylglycine, or tiopronin, and D-Penicillamine) to lower free cystine levels in the urine. Measuring the free fraction of cystine in the urine enables titration of the treatment with cystine binding drugs. Side effects of D-Penicillamine and tiopronin, in particular proteinuria, are not uncommon and require routine monitoring with dipsticks and frequently lead to discontinuation of the treatment; they also require zinc, copper and/or vitamin B6 supplementation. Low protein diet in adults or even adolescents is not very effective. When a cystine stone is still small (under 12 mm), extracorporeal shock wave lithotripsy is feasible, but with low efficiency due to the consistency of cystine stones. Over this size, laser stone fragmentation or even percutaneous nephrolithotomy is necessary.\nPrognosis\nPrognosis is good but low patient compliance and recurrence of stone formation and subsequent interventions can very rarely induce renal insufficiency.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Luca DELLO STROLOGO | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Cystoid macular dystrophy", "Disease Definition": "Cystoid macular dystrophy is an autosomal dominantly inherited cystoid macular edema manifesting with macular atrophy, strabismus and, sometimes, pericentral retinitis pigmentosa (see this term). It is associated with a poor visual prognosis.", "ORPHA ID": 75381, "Summary": ""}
{"Disease Name": "Cytophagic histiocytic panniculitis", "Disease Definition": "Cytophagic histiocytic panniculitis (CHP) is a very rare form of panniculitis manifesting as recurrent multiple subcutaneous nodules (which may progressively become ecchymotic and ulcerated), and histologically characterized by lobular panniculitis with lymphocytic and histiocytic infiltration in the subcutaneous adipose tissue.", "ORPHA ID": 94087, "Summary": "Epidemiology\nThe exact prevalence is unknown, but less than 100 cases have been reported (mostly middle-aged and elderly patients).\nClinical description\nThe histiocytic infiltration often involves lymph nodes, bone marrow and other tissues of the reticuloendothelial system. Severe fever, malaise, pancytopenia, hepatosplenomegaly, and mucosal ulcers are common systemic symptoms.\nEtiology\nThe etiology remains unclear. In more than 50% of cases, the disease occurs in immunocompromised patients (those with immunodeficiency, autoimmune disease or hematological disease) and is triggered by an infection (mainly with a virus from the herpes-virus family).\nDiagnostic methods\nDiagnosis relies on the histological features of fat infiltration.\nDifferential diagnosis\nDifferential diagnosis includes malignant histiocytosis and virus-associated hemophagocytic syndrome, as well as systemic Weber-Christian panniculitis (see these terms). A search for subcutaneous T-cell lymphoma is mandatory.\nManagement and treatment\nManagement involves symptomatic treatment and systemic chemotherapy. Combinations of cytotoxic and immunosuppressive drugs have been reported to be efficient. Chemotherapy followed by stem cell rescue should be considered in severe cases.\nPrognosis\nAlthough remissions have been reported, the disease tends to follow a chronic course often complicated by terminal hemorrhagic diathesis and organ system failure.\n\n                            Last update: \n                            June 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "Cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder", "Disease Definition": "A rare genetic hematologic and intestinal disease characterized by childhood onset of bleeding tendency with epistaxis, gum bleeding, gastrointestinal bleeding, hematuria, and menorrhagia due to impaired platelet aggregation and secretion, as well as recurrent gastrointestinal ulcera. Mildly reduced levels of coagulation factor XI have been reported in addition.", "ORPHA ID": 477787, "Summary": ""}
{"Disease Name": "Czeizel-Losonci syndrome", "Disease Definition": "Czeizel-Losonci syndrome (CLS) is an exceedingly rare, severe, congenital genetic malformation disorder characterized by split hand/split foot, hydronephrosis, and spina bifida. Spinal and skeletal manifestations were thoracolumbar scoliosis, spinabifida (spina bifida occulta or spina bifida cystic), Bochdalek diaphragmatic hernia, and radial defects.There have been no further descriptions in the literature since 1987.", "ORPHA ID": 2437, "Summary": ""}
{"Disease Name": "D,L-2-hydroxyglutaric aciduria", "Disease Definition": "A rare inborn error of metabolism characterized by severe neonatal epileptic encephalopathy, episodes of apnea and respiratory distress, severe global developmental delay or absent psychomotor development, severe muscular hypotonia or absent voluntary movements, feeding difficulties and failure to thrive, absence of visual contact, abnormal brain morphology (including cerebral atrophy, ventriculomegaly and hypoplasia or dysplasia of the corpus callosum), mild dysmorphic features (frontal bossing, hypertelorism, downslanting palpebral fissures, flat nasal bridge), elevated CSF and plasma lactate and urinary Krebs cycle metabolites.", "ORPHA ID": 356978, "Summary": ""}
{"Disease Name": "D-2-hydroxyglutaric aciduria", "Disease Definition": "D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare clinically variable neurological form of 2-hydroxyglutaric aciduria (see this term) characterized biochemically by elevated D-2-hydroxyglutaric acid (D-2-HG) in the urine, plasma and cerebrospinal fluid.", "ORPHA ID": 79315, "Summary": "Epidemiology\nExact prevalence and incidence of this disorder are not known but about 80 cases have been reported to date. No geographical predominance has been found for this disorder.\nClinical description\nD-2-hydroxyglutaric aciduria has extremely variable clinical manifestations. Severe cases are characterized by neonatal or early infantile-onset epileptic encephalopathy. Marked hypotonia, cerebral visual failure, developmental delay, seizures, involuntary movements, and cardiomyopathy are common in these cases. Facial dysmorphic features have been reported frequently and include a flat face with a broad nasal bridge, and external ear anomalies. In mild cases, the clinical picture is more variable. Developmental delay and hypotonia are the most common findings. No correlation between D-2-HG levels and clinical symptoms has been found. Some patients with elevated D-2-HG levels are asymptomatic. In general, D-2-hydroxygluratic aciduria caused by heterozygous IDH2 mutations, has a more severe clinical course than D-2-hydroxygluratic aciduria caused by mutations in the D2HGDH gene.\nEtiology\nMutations in the D2HGDH gene (2p25.3) encoding mitochondrial D-2-hydroxyglutarate dehydrogenase have been identified in approximately 50% of patients with this disorder. Others were found to harbor a pathogenic heterozygous mutation in the IDH2 gene (15q21-qter) encoding mitochondrial isocitrate dehydrogenase.\nDiagnostic methods\nDiagnosis is established on the basis of excess D-2-hydroxyglutaric acid in the urine and MRI findings: subependymal cysts, delayed cerebral maturation, and periventricular white-matter abnormalities in severe cases.\nDifferential diagnosis\nUrinary organic acid screening does not allow differentiation between L-2-hydroxygluratic acid and D-2-hydroxyglutaric acid. Therefore, this differentiation has to be performed subsequently by a specialized laboratory.\nAntenatal diagnosis\nPrenatal diagnosis can be performed by mutational analysis and detection of increased levels of D-2-hydroxyglutaric acid in amniotic fluid.\nGenetic counseling\nD-2-HGA caused by mutations in the D2HGDH gene follows an autosomal recessive pattern of inheritance. Genetic counseling is complicated due to the extremely wide clinical picture and poor understanding of the genetic etiology and underlying mechanisms. In contrast, D-2-HGA caused by a de novo heterozygous mutation in the IDH2 gene, is an autosomal dominant trait, with the exception for one reported family.\nManagement and treatment\nThere is no specific treatment for D-2-hydroxyglutaric aciduria. Management mainly involves control of seizures when they are present.\nPrognosis\nThe prognosis is entirely dependent on the severity of the clinical picture and course of the disease.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Pr G.S. [Gajja] SALOMONS  - Dr E.A. [Eduard] STRUYS"}
{"Disease Name": "D-glyceric aciduria", "Disease Definition": "A rare inborn error of metabolism characterized by abnormal urinary excretion of D-glyceric acid due to D-glycerate kinase deficiency. Reported manifestations are highly variable and include a severe encephalopathic picture, chronic metabolic acidosis, developmental delay, intellectual disability, microcephaly, seizures, behavioral abnormalities, as well as only mild speech delay and apparently normal development.", "ORPHA ID": 941, "Summary": ""}
{"Disease Name": "Dahlberg-Borer-Newcomer syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by the association of congenital hypoparathyroidism, nephropathy, congenital lymphedema, mitral valve prolapse and brachytelephalangy. Additional features include mild facial dysmorphism, hyperthricoses, and nail abnormalities. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 1563, "Summary": ""}
{"Disease Name": "Dandy-Walker malformation-postaxial polydactyly syndrome", "Disease Definition": "A syndromic disorder with, as a major feature, the association between Dandy-Walker malformation and postaxial polydactyly. The Dandy-Walker malformation has a variable expression and is characterized by a posterior fossa cyst communicating with the fourth ventricle, the partial or complete absence of the cerebellar vermis, and facultative hydrocephalus. Postaxial polydactyly includes tetramelic postaxial polydactyly of hands and feet with possible enlargement of the fifth metacarpal and metatarsal bones, as well as bifid fifth metacarpals.", "ORPHA ID": 1566, "Summary": ""}
{"Disease Name": "Danon disease", "Disease Definition": "A rare X-linked genetic condition due to deficiency of the lysosomal-associated membrane protein 2 (LAMP2) characterized by severe cardiomyopathy and variable degrees of muscle weakness, frequently associated with intellectual deficits (in males).", "ORPHA ID": 34587, "Summary": "Epidemiology\nMore than 100 families have been described in the literature so far.\nClinical description\nThe disease classically manifests in males at a median age of 13-14 years. The clinical picture may be severe in both sexes, but onset generally occurs later in females and disease progression tends to be slower in females.\nEtiology\nThe disease is caused by mutations in the LAMP2 gene, localised to Xq24. The LAMP2 protein is an essential component of the lysosomal membrane and appears to play a role in autophagosome-lysosome fusion and the cellular process of autophagy. Originally the condition was classified as a 'glycogen storage disease' reflecting elevated glycogen visible on histological analysis; however, as the condition is not due to a specific defect in glycogen storage, the name Danon disease is currently preferred.\nDiagnostic methods\nThe main diagnostic method is molecular genetic testing for identification of loss-of-function variants in LAMP2. Histological and/or electron microscopy findings of cytoplasmic vacuoles and increased cellular glycogen levels can be suggestive of the diagnosis. Exclusion of Pompe disease should be done if LAMP2 molecular testing is non-conclusive. Staining of LAMP-2 protein revealing reduced or absence in males heart, muscle, lymphocytes, may also be performed for diagnosis, but is not widely available clinically. Identification of a LAMP2 pathogenic variant in a proband allows cascade testing of other at-risk relatives.\nDifferential diagnosis\nThe differential diagnosis should include X-linked myopathy with excessive autophagia (XMEA) and glycogen storage disease type 2.\nAntenatal diagnosis\nAntenatal diagnosis of at-risk pregnancies can be done if a known LAMP2 pathogenic variant has been detected in a parent (typically detected in the mother as males with this disease have reduce reproductive fitness).\nGenetic counseling\nGenetic counseling is recommended for the X-linked inheritance pattern seen in the disease.\nManagement and treatment\nThere is no specific treatment for this disease. Symptomatic treatment is required for the cardiac manifestations and patients may require a heart transplant.\nPrognosis\nPatients are at risk of sudden death due to arrhythmia and/or heart failure during early adulthood. Death or transplant occurs at median ages in males and females of 19-21 years and 34-38 years, respectively.\n\n                            Last update: \n                            January 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Eric ADLER  - Dr Matthew TAYLOR"}
{"Disease Name": "Darier disease", "Disease Definition": "A rare, genetic keratinization disorder which is classically characterized by keratotic papules, acral pits, and acral wart-like lesions that can be associated with a trigger, and may occur anywhere on the body (including mucosal surfaces). Extracutaneous manifestations may include, nail anomalies, blepharitis, dry eye, neuropsychiatric illness and, recurrent parotid gland obstruction and xerostomia.", "ORPHA ID": 218, "Summary": "Epidemiology\nThe prevalence of Darier disease (DD) is estimated at around 1/30,000 in Europe.\nClinical description\nDarier disease is a debilitating and chronic condition, with both cutaneous and extra-cutaneous manifestations, which can have a severe impact on patients' general health and quality of life. The cutaneous and extra-cutaneous manifestations have variable expression within and between families. Exacerbations may be triggered by summer, sweating, exposure to sunlight, mental distress, contact with wool and febrile illness. Classical lesions are characterized by keratotic papules (typically occurring on the trunk), acral pits (occurring on palms and soles) and acral wart-like lesions (typically occurring on the hands, particularly after soaking in water). Non-classical lesions may include acral keratoderma, leukodermic macules, giant comedones, vegetations and acral hemorrhagic blisters, and may co-exist with classical lesions. However, non-classical lesions are rare. Lesions can occur anywhere on the body with no specific location. Nail abnormalities include V-shaped notches at the free edge of nail, longitudinal red and white lines, ridging and splitting. Genital involvement, especially on female genitalia, is more frequent in patients with severe disease. Oral mucosal lesions may be found. Extra-cutaneous manifestations vary within and between families and may include, blepharitis, dry eye, neuropsychiatric illness, epilepsy (often only before age 20), learning disabilities, recurrent parotid gland obstruction and xerostomia. Staph aureus colonization in skin & nares is frequent and corresponds with extent of skin area affected and disease severity.\nEtiology\nDD is caused by mutations in the ATP2A2 gene (12q23-q24.1) encoding the sarco/endoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2), which has a central role in intracellular calcium signaling.\nDiagnostic methods\nThe diagnosis is based on histological examination of skin lesion biopsies revealing hyperkeratosis, focal dyskeratosis and suprabasal acantholysis.\nDifferential diagnosis\nDifferential diagnoses include Hailey-Hailey disease, Grover disease (transient acantholytic dermatosis), seborrheic dermatitis, pemphigus, and warty dyskeratoma.\nAntenatal diagnosis\nThe prenatal diagnostic tests and procedures are available for affected couples where the genetic variant has been identified.\nGenetic counseling\nThe disorder is autosomal-dominant with complete and delayed penetrance, and variable expression. Genetic counselling is advised for affected patients to discuss identification of the mutation, the pattern of inheritance as well as the prenatal diagnostic tests and procedures available.\nManagement and treatment\nManagement and treatment are based on case reports and case series reported in the literature as well as clinical experience. The full extent of the disease should be assessed by a dermatologist and includes assessment of the skin involvement (including staph aureus colonization), the extracutaneous involvement (neuropsychiatric illness etc.), family history and triggering factors. Current treatment is symptomatic and includes topical and systemic therapy as well as minimizing exposure to triggers. For patients prone to secondary skin infections, a diluted bleach bath may be considered. Other therapies reported include injection of botulinum toxin to decrease sweating, surgical excision, electrosurgical excision, dermabrasion, laser ablation, photodynamic therapy and electron beam radiation. Extracutaneous manifestations should be treated according to standard protocols.\nPrognosis\nThe disease is characterized by a chronic cycle with acute exacerbations and does not improve with age. In assessing the prognosis, it is very important to consider the extracutaneous manifestations of the disease. Secondary bacterial and viral infections were reported as causes of morbidity and mortality in a few cases.\n\n                            Last update: \n                            May 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Roni DODIUK-GAD"}
{"Disease Name": "DDOST-CDG", "Disease Definition": "DDOST-CDG is a form of congenital disorders of N-linked glycosylation characterized by failure to thrive, developmental delay, hypotonia, strabismus and hepatic dysfunction. The disease is caused by mutations in the gene  DDOST  (1p36.1).", "ORPHA ID": 300536, "Summary": ""}
{"Disease Name": "DDX41-related hematologic malignancy predisposition syndrome", "Disease Definition": "A rare inherited cancer-predisposing syndrome characterized by adult onset of hematologic malignancies mainly affecting the myeloid lineage (such as myelodysplastic syndrome and/or acute myeloid leukemia), less frequently lymphoid malignancies. Some patients have been reported to develop granulomatous or immune disorders (including sarcoidosis, systemic lupus erythematosus, asthma, eczema, or juvenile arthritis) before or in the absence of hematologic malignancies.", "ORPHA ID": 488647, "Summary": ""}
{"Disease Name": "De Barsy syndrome", "Disease Definition": "De Barsy syndrome (DBS) is characterized by facial dysmorphism (down-slanting palpebral fissures, a broad flat nasal bridge and a small mouth) with a progeroid appearance, large and late-closing fontanel, cutis laxa (CL), joint hyperlaxity, athetoid movements and hyperreflexia, pre- and postnatal growth retardation, intellectual deficit and developmental delay, and corneal clouding and cataract.", "ORPHA ID": 2962, "Summary": "Epidemiology\nPrevalence is unknown but around 30 cases have been described in the literature so far.\nEtiology\nThe etiology remains unknown in most cases, however, mutations in the PYCR1 gene (17q25.3) have recently been identified in patients with overlapping phenotypes (wrinkly skin, osteopenia and progeroid features) of DBS, autosomal recessive CL type 2 (ARCL2), wrinkly skin syndrome (WSS), and geroderma osteodysplastica (GO; see these terms).\nDiagnostic methods\nHistological examination of skin biopsies from DBS patients may reveal characteristic frayed and reduced elastic fibers but patients with normal skin biopsy results have also been reported.\nDifferential diagnosis\nThe eye anomalies, athetoid movements and hyperreflexia are distinguishing features of DBS that usually allow this syndrome to be differentiated from GO, ARCL2 and WSS.\nGenetic counseling\nThe condition is transmitted in an autosomal recessive manner.\nManagement and treatment\nTreatment is symptomatic, including early eye-surgery and physiotherapy to avoid contractures.\nPrognosis\nPatients with DBS have variable outcomes. Some patients die in childhood due to severe neurological dysfunction and intercurrent infections. Many patients diagnosed with PYCR1 mutations show a spontaneous improvement of the progerioid features, and in some children the movement disorder remain non-progressive.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS"}
{"Disease Name": "De novo thrombotic microangiopathy after kidney transplantation", "Disease Definition": "A rare renal disease characterized by thrombotic microangiopathy developing de novo in kidney transplant recipients with no evidence of occurrence of the disease prior to transplantation. Precipitating factors include antibody-mediated rejection, immunosuppressive medication, viral infections, and genetic abnormalities in the complement cascade, among others. The condition most commonly occurs within the first 3-6 months post-transplantation. Clinical presentation is highly variable and ranges from a limited form confined to the kidney with relatively good prognosis to a systemic variant consisting of the classic triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury.", "ORPHA ID": 244275, "Summary": ""}
{"Disease Name": "Deaf blind hypopigmentation syndrome, Yemenite type", "Disease Definition": "Yemenite deaf-blind hypopigmentation syndrome is an exceedingly rare genetic disorder characterized by cutaneous pigmentation anomalies, ocular disorders and hearing loss.", "ORPHA ID": 3214, "Summary": "Epidemiology\nThe syndrome was described in 1990 in two patients from the same Yemenite family.\nClinical description\nA brother and sister were described as having cutaneous patchy hypo- and hyperpigmentation on the trunk and extremities, gray hair, white brows and lashes. Ocular manifestations were microcornea, coloboma, and abnormalities of the anterior chamber of the eye. Both patients had severe hearing loss and dental abnormalities. Intelligence was reported to be normal. Their parents were unaffected and possibly consanguineous.\nEtiology\nThe cause of this syndrome has not been determined.\nGenetic counseling\nThe inheritance pattern appears to be autosomal recessive.\n\n                            Last update: \n                            March 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Véronique PINGAULT"}
{"Disease Name": "Deafness with labyrinthine aplasia, microtia, and microdontia", "Disease Definition": "Deafness with labyrinthine aplasia, microtia, and microdontia (LAMM) is a genetic transmission deafness syndrome.", "ORPHA ID": 90024, "Summary": "Epidemiology\nIt has been described in 6 families to date.\nClinical description\nThe profound congenital deafness is associated with a complete absence of inner ear structures (Michel aplasia); microtia type I with small auricle and narrow external auditory canal; and microdontia with widely spaced teeth.\nEtiology\nLinkage analysis followed by sequencing of candidate genes led to identification of three different homozygous mutations in the FGF3 gene (11q13).\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            November 2010"}
{"Disease Name": "Deafness-craniofacial syndrome", "Disease Definition": "Deafness-craniofacial syndrome is characterised by the association of congenital hearing loss and facial dysmorphism (facial asymmetry, a broad nasal root and small nasal alae). It has been described in two members (father and daughter) of one Jewish family. Temporal alopecia was also noted. Transmission appeared to be autosomal dominant.", "ORPHA ID": 3241, "Summary": ""}
{"Disease Name": "Deafness-ear malformation-facial palsy syndrome", "Disease Definition": "Deafness-ear malformation-facial palsy syndrome is characterized by profound conductive deafness due to stapedial abnormalities associated with variable malformations of the external ears and facial paralysis. It has been described in three sibs and their mother. Inheritance is autosomal dominant.", "ORPHA ID": 3232, "Summary": ""}
{"Disease Name": "Deafness-enamel hypoplasia-nail defects syndrome", "Disease Definition": "A rare genetic disease characterized by sensorineural hearing loss, abnormalities in the secondary dentition (such as enamel hypoplasia, taurodontism, or dental overcrowding), and nail abnormalities (including leukonychia and presence of transverse ridges). Association with macular dystrophy has also been reported.", "ORPHA ID": 3220, "Summary": ""}
{"Disease Name": "Deafness-encephaloneuropathy-obesity-valvulopathy syndrome", "Disease Definition": "Deafness-encephaloneuropathy-obesity-valvulopathy syndrome is a rare mitochondrial disease with marked clinical variability typically characterized by encephalomyopathy, kidney disease (nephrotic syndrome), optic atrophy, early-onset deafness, pancytopenia, obesity, and cardiac disease (valvulopathy). Additionally, macrocephaly, intellectual disability, hyperlactatemia, elevated lactate/pyruvate ratio, insulin-dependent diabetes, livedo reticularis, liver dysfunction and seizures have also been associated.", "ORPHA ID": 254898, "Summary": ""}
{"Disease Name": "Deafness-epiphyseal dysplasia-short stature syndrome", "Disease Definition": "A rare syndromic genetic deafness characterized by profound congenital bilateral sensorineural deafness, developmental delay, moderate intellectual disability, generalized delay in bone maturation, short stature, epiphyseal dysplasia particularly of the capital femoral epiphyses, and mild dysmorphic facial features such as prominent forehead and small, pointed chin. Bilateral obstruction of lacrimal ducts and inguinal and umbilical hernias have also been described.", "ORPHA ID": 3218, "Summary": ""}
{"Disease Name": "Deafness-genital anomalies-metacarpal and metatarsal synostosis syndrome", "Disease Definition": "Deafness-genital anomalies-metacarpal and metatarsal synostosis syndrome is characterised by sensorineural deafness, bilateral synostosis of the 4th and 5th metacarpals and metatarsals, genital anomalies (hypospadias in males), psychomotor delay and abnormal dermatoglyphics. So far, it has been described in two unrelated patients. Facial dysmorphism was noted in both patients (prominent forehead, ear anomalies, facial asymmetry and an open mouth appearance).", "ORPHA ID": 3224, "Summary": ""}
{"Disease Name": "Deafness-hypogonadism syndrome", "Disease Definition": "A rare form of syndromic genetic deafness characterized by the association of congenital mixed hearing loss with perilymphatic gusher (Gusher syndrome or DFN3), hypogonadism and abnormal behavior.", "ORPHA ID": 90646, "Summary": "Epidemiology\nIt has been described in five related males.\nEtiology\nInheritance appeared to be X-linked recessive and a microdeletion, encompassing the POU3F4 gene (DFN3 locus), was detected in one of the patients leading to the suggestion that deafness - hypogonadism is a contiguous gene deletion syndrome.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "Deafness-infertility syndrome", "Disease Definition": "Deafness-infertility syndrome (DIS) is a very rare syndrome associating sensorineural deafness and male infertility.", "ORPHA ID": 94064, "Summary": "Epidemiology\nIt has been reported in fewer than 5 families.\nEtiology\nMale infertility is caused by abnormal spermatozoid morphology and motility. DIS is due to a contiguous gene deletion at chromosome 15q15.3 including 2 genes CATSPER2 and STRC, and is inherited in an autosomal recessive manner: affected males are homozygous for the deletion, parents are asymptomatic carriers and homozygous females are deaf but not infertile.\n\n                            Last update: \n                            September 2011"}
{"Disease Name": "Deafness-intellectual disability syndrome, Martin-Probst type", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by congenital sensorineural hearing loss, varying degrees of intellectual disability, short stature, and dysmorphic facial features (such as telecanthus, epicanthic folds, broad nasal root, malar hypoplasia, low-set ears, dental anomalies, and micrognathia). Additional reported manifestations include microcephaly, renal and genitourinary abnormalities, widely spaced, hypoplastic nipples, and adult onset of progressive pancytopenia.", "ORPHA ID": 85321, "Summary": ""}
{"Disease Name": "Deafness-oligodontia syndrome", "Disease Definition": "Deafness-oligodontia syndrome is characterised by sensorineural hearing loss and oligodontia/hypodontia. It has been described in two pairs of siblings and in one isolated case. Dizziness was reported in one of the pairs of siblings. Transmission appears to be autosomal recessive.", "ORPHA ID": 3230, "Summary": ""}
{"Disease Name": "Deafness-onychodystrophy syndrome", "Disease Definition": "Deafness-onychodystrophy syndrome is a group of rare, genetic, developmental defect during embryogenesis disorders characterized by the association of sensorineural deafness and onychodystrophy (e.g. absent/hypoplastic finger and toenails), as well as brachydactyly and finger-like thumbs. Additional features present in one of the diseases comprising this group include osteodystrophy, intellectual disability, seizures, developmental delay, and distinctive facies.", "ORPHA ID": 3231, "Summary": ""}
{"Disease Name": "Deafness-small bowel diverticulosis-neuropathy syndrome", "Disease Definition": "A rare neurologic disease characterized by progressive sensorineural deafness, progressive sensory neuropathy and gastrointestinal abnormalities, including progressive loss of gastric motility and small bowel diverticulosis and ulcerations, resulting in cachexia. Additonal neurological manifestations may include dysarthria and absent tendon reflexes, as well as ptosis and external ophthalmoplegia. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 3217, "Summary": ""}
{"Disease Name": "Deafness-vitiligo-achalasia syndrome", "Disease Definition": "Deafness-vitiligo-achalasia syndrome is characterized by the association of deafness, short stature, vitiligo, muscle wasting, and achalasia.", "ORPHA ID": 3239, "Summary": "Epidemiology\nIt has been described in a brother and his sister born to first-cousin parents.\nGenetic counseling\nIt is likely to be transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            February 2007"}
{"Disease Name": "Dedifferentiated liposarcoma", "Disease Definition": "Dedifferentiated liposarcoma (DDLS) is a high-grade subtype of liposarcoma (LS; see this term) that progresses from well-differentiated liposarcoma (WDLS; see this term), and most often occurs in the retroperitoneum. It is defined as a region of nonlipogenic sarcoma associated with WDLS. .", "ORPHA ID": 99970, "Summary": "Epidemiology\nThe incidence is approximately 1/ 330, 000 persons/year.\nClinical description\nDDLS is a fast growing tumor with potential for distant metastasis but this occurs in less than 15% of patients. Like WDLS, it is usually a painless mass, though it can cause symptoms of obstruction, decrease in appetite and abdominal distention.\nEtiology\nThe etiology is unknown. Like WDLS, DDLS usually has amplification of the chromosome region 12q and associated amplification and overexpression of the MDM2, HMGA2 and CDK4 genes.\nPrognosis\nThe 5-year disease-specific survival rate for DDLS overall is 44% but this is location dependent with extremity lesions having a 5-year disease-specific survival rate of greater than 90%.\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Samuel SINGER"}
{"Disease Name": "Deep dermatophytosis", "Disease Definition": "A rare mycosis characterized by severe, potentially life-threatening dermal and subcutaneous tissue invasion by dermatophytes. Dissemination to lymph nodes is frequent, but the infection may also occasionally spread to the central nervous system. Cutaneous signs and symptoms include erythema, desquamation, itching, nodules, plaques, or ulceration. The majority of deep dermatophytoses develop in immunocompromised patients.", "ORPHA ID": 397587, "Summary": ""}
{"Disease Name": "Deficiency in anterior pituitary function-variable immunodeficiency syndrome", "Disease Definition": "A rare, genetic endocrine disease characterized by the association of common variable immunodeficiency, manifesting with hypogammaglobulinemia and recurrent or severe childhood-onset sinopulmonary infections, followed, possibly many years later, by symptomatic adrenocorticotropic hormone (ACTH) deficiency resulting from anterior pituitary hormone deficiency.", "ORPHA ID": 293978, "Summary": ""}
{"Disease Name": "Dehydrated hereditary stomatocytosis", "Disease Definition": "Dehydrated hereditary stomatocytosis (DHS) is a rare hemolytic anemia characterized by a decreased red cell osmotic fragility due to a defect in cation permeability, resulting in red cell dehydration and mild to moderate compensated hemolysis. Pseudohyperkalemia (loss of potassium ions from red cells on storage at room temperature) is sometimes observed.", "ORPHA ID": 3202, "Summary": "Epidemiology\nThe prevalence of DHS is unknown but to date, about 20 families with DHS have been described in the literature.\nClinical description\nThe clinical presentation of the disease is very heterogeneous. Onset of DHS may occur during the perinatal period with occurrence of edema and ascites (most often not related to an underlying anemia) that usually resolve spontaneously during the first weeks of life but may rarely lead to hydrops fetalis (see this term). Most adult patients present a mild anemia or a totally compensated hemolysis, with fatigue, icterus, splenomegaly and risks of secondary complications including cholelithiasis. Patients can also be referred for unexplained hemochromatosis, since iron overload is frequently associated with the disease. Thrombotic complications (arterial and venous events, including portal vein thrombosis (see this term) and pulmonary hypertension) have been described at a high rate after splenectomy.\nEtiology\nMost reported DHS cases are caused by gain-of-function mutations in the gene PIEZO1 (16q24.3) which encodes part of a mechanosensitive ion channel. This results in increased red cell membrane permeability for cations that consequently leads to cation depletion, dehydration and shortened red cell survival. Rare atypical forms have been associated with mutations in SLC4A1 (17q21.31), coding for the Band 3 anion transport protein, or KCNN4 (19q13.2) which codes for the putative Gardos channel.\nDiagnostic methods\nDiagnosis relies on laboratory findings. The typical presentation includes normal hemoglobin level or mild anemia, normal mean cell volume (MCV) or mild macrocytosis, normal or elevated mean corpuscular hemoglobin concentration (MCHC), elevated reticulocytosis, and a small number of stomatocytes (<10% of red cells). A diagnosis of DHS must be evoked in patients with unexplained iron overload, even if hemoglobin levels are normal, as well as in patients with unexplained hemolysis (before splenectomy) or those presenting with thrombotic events, if already splenectomized. Osmolar gradient ektacytometry is the best phenotypic diagnosis method, showing a leftward shift of the bell-shaped curve with a normal maximum deformability index and a decreased hypo and hyper-osmotic point, reflecting decreased osmotic fragility and cell dehydration, respectively. In some cases, an increased serum potassium level is observed, which results from in vitro leakage and is clinically irrelevant. Measurement of ferritin level and liver magnetic resonance imaging (MRI) are performed to evaluate iron overload. Genetic screening of the causative genes can be performed after phenotypic investigations.\nDifferential diagnosis\nDifferential diagnoses include other causes of hemolysis, including hereditary spherocytosis, overhydrated hereditary stomatocytosis, hemoglobinopathy or red cell enzyme deficiencies such as hemolytic anemia due to red cell pyruvate kinase deficiency (see these terms).\nGenetic counseling\nTransmission is autosomal dominant and genetic counseling should be offered to affected families.\nManagement and treatment\nTreatment is mainly symptomatic. Occurrence of cholelithiasis should be regularly monitored. Folic acid supplementation should be proposed in case of anemia. Pregnancy should be closely monitored. Iron status should be regularly monitored by serum ferritinemia and liver MRI. Iron depletion, most often by phlebotomy, is proposed when ferritinemia reaches the threshold of 1000 ng/ml or when iron liver overload is present. Splenectomy is contraindicated in DHS due to an elevated risk of life threatening arterial and venous thrombotic events.\nPrognosis\nOverall prognosis is favorable in well managed patients (not splenectomized and with regular monitoring of their iron status). Splenectomized patients are at risk of early or late thrombotic events.\n\n                            Last update: \n                            December 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Loïc GARÇON  - Dr Véronique PICARD"}
{"Disease Name": "Dejerine-Sottas syndrome", "Disease Definition": "A clinical entity that represents a severe phenotype of Charcot-Marie-Tooth disease characterized by onset occurring in infancy, severe motor weakness, delayed motor development, extremely slow nerve conduction (< 10-12 m/s), areflexia and foot deformity. Mutations in the genes PMP22 (17p12), MPZ (1q22), EGR2 (10q21.1) and PRX (19q13.2) have been implicated.", "ORPHA ID": 64748, "Summary": ""}
{"Disease Name": "Delayed encephalopathy due to carbon monoxide poisoning", "Disease Definition": "A rare neurologic disease characterized by delayed onset of encephalopathy typically within a few weeks after acute carbon monoxide poisoning. The most common symptoms are cognitive impairment, personality changes, and movement disorder including parkinsonism, among others. Prognosis is good with a high rate of spontaneous recovery within a year.", "ORPHA ID": 306686, "Summary": ""}
{"Disease Name": "Delayed membranous cranial ossification", "Disease Definition": "Delayed membranous cranial ossification is a rare, genetic primary bone dysplasia characterized by absent ossification of calvarial bones at birth and characteristic facial dysmorphisms (frontal bossing, hypertelorism, downward-slanting palpebral fissures, proptosis, flat nasal bridge, low-set ears, midface retrusion). Patients present a soft skull at birth which, over time, progressively ossifies and in adulthood typically results in a deformed skull (with brachycephaly and prominent occiput). No other skeletal abnormalities are associated and patients have normal cognitive and motor development.", "ORPHA ID": 3034, "Summary": ""}
{"Disease Name": "Delayed speech-facial asymmetry-strabismus-ear lobe creases syndrome", "Disease Definition": "This syndrome is extremely rare and is characterized by delayed speech development, mild facial asymmetry, strabismus and transverse ear lobe creases.", "ORPHA ID": 3038, "Summary": "Epidemiology\nTo date, six cases have been reported in five families.\nClinical description\nDysmorphic features include asymmetrical face, unilateral narrow palpebral fissure, divergent strabismus, long philtrum, high-arched palate, apparently low-set ears and transverse ear lobe creases on both sides. Delayed language development is constant but intellectual development can be normal.\nGenetic counseling\nIn one family, the transmission was compatible with either autosomal dominant or X-linked dominant inheritance.\n\n                            Last update: \n                            June 2010"}
{"Disease Name": "Deletion 5q35", "Disease Definition": "Deletion 5q35 refers to the different congenital malformation syndromes resulting from deletions of variable extent of the terminal part of the long arm of chromosome 5 (5q), spanning the region from 5q35.1 to 5q35.3 . The most significant anomaly is a recurring deletion in 5q35.2 comprising the NSD1 gene that causes Sotos syndrome that is characterized by cardinal features including excessive growth during childhood, macrocephaly, distinctive facial gestalt and various degrees of learning difficulty. Subtelomeric deletions of the terminal 3.5 Mb region on 5q35.3 are very rare, characterized by prenatal lymphedema with increased nuchal translucency, pronounced muscular hypotonia in infancy, borderline intelligence, postnatal short stature due to growth hormone deficiency, and a variety of minor anomalies such as mildly bell-shaped chest, minor congenital heart defects and a distinct facial gestalt. Larger deletions including bands 5q35.1, 5q35.2 and 5q35.3 cause a more severe phenotype that associates severe developmental delay with microcephaly, and significant cardiac defects (e.g. atrial septal defect with/without atrioventricular conduction defects, Ebstein anomaly, tetralogy of Fallot) linked to haploinsufficiency of NKX2.5 (5q35.1). Various combinations of signs may result from deletions of variable extent depending on the genes comprised in the deleted segment.", "ORPHA ID": 1627, "Summary": ""}
{"Disease Name": "Delta-beta-thalassemia", "Disease Definition": "Delta-beta-thalassemia is a form of beta-thalassemia (see this term) characterized by decreased or absent synthesis of the delta- and beta-globin chains with a compensatory increase in expression of fetal gamma-chain synthesis.", "ORPHA ID": 231237, "Summary": "Epidemiology\nPrevalence of this form is not known. The condition is found in many ethnic groups but is most common in Greece and Italy.\nClinical description\nThe heterozygous form of the condition is clinically asymptomatic with mild microcytosis and no elevation of HbA2 whereas the few homozygous patients have a mild clinical presentation. When inherited with heterozygous classical beta-thalassemia, patients usually have the thalassemia intermedia phenotype, but the thalassemia major phenotype has been described in some cases.\nEtiology\nDelta-beta-thalassemia is commonly caused by deletions of the entire delta and beta gene sequences with production of only gamma-globin and formation of HbF. Rarely, non-deletional forms have been reported.\nDiagnostic methods\nDiagnosis is based on hypochromic microcytic red cell indices with significant elevation of HbF, ranging from 5-15% in heterozygotes. HbF is heterogeneously distributed among the erythrocytes. The alpha/beta-globin synthesis ratio is >1.\nDifferential diagnosis\nHereditary persistence of fetal Hb and beta-thalassemia (see this term) is the main differential diagnosis. The distinction between these two conditions cannot always be made from routine hematologic analyses and alpha-beta-globin chain synthesis ratio and DNA analysis may be necessary.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA"}
{"Disease Name": "Delta-sarcoglycan-related limb-girdle muscular dystrophy R6", "Disease Definition": "A subtype of autosomal recessive limb-girdle muscular dystrophy characterized by a variable age of onset of progressive weakness and wasting of the proximal skeletal muscles of the shoulder and pelvic girdles, frequently associated with progressive respiratory muscle impairment and cardiomyopathy. Calf hypertrophy, muscle cramps and elevated serum creatine kinase levels are also observed. Neuropsychomotor development is usually normal.", "ORPHA ID": 219, "Summary": ""}
{"Disease Name": "Dementia pugilistica", "Disease Definition": "A rare neurologic disease characterized by progressive neurodegeneration secondary to repetitive mild traumatic brain injuries. The clinical picture is highly variable and includes behavioral or psychiatric symptoms (such as aggression, depression, delusions, and suicidality), cognitive impairment (including diminished attention, memory deficits, executive functioning deficits, and dementia), and motor deficits (including parkinsonism, ataxia, and dysarthria). Neuropathological hallmark is the accumulation of phosphorylated tau-protein in sulci and perivascular regions.", "ORPHA ID": 97353, "Summary": ""}
{"Disease Name": "Demodicidosis", "Disease Definition": "Demodicidosis is a rare parasitic cutaneous disease due to Demodex mite infestation characterized by variable degrees of spinulosis, erythema, papules, and pustules, usually accompanied by a burning or pruritic sensation. Face (incl. eyelids) is most frequently affected, but ear canal, scalp, neck, back, chest, nipples, buttocks, penis, and extremity (legs and arms) involvement have also been observed. Dermoscopic examination reveals Demodex tails and follicular openings.", "ORPHA ID": 283, "Summary": ""}
{"Disease Name": "DEND syndrome", "Disease Definition": "A rare form of neonatal diabetes mellitus characterized by a triad of Developmental delay, Epilepsy, and Neonatal Diabetes (DEND syndrome), with a generally severe course. This form of neonatal diabetes is not associated with abnormal pancreatic development.", "ORPHA ID": 79134, "Summary": "Epidemiology\nFewer than 60 cases have been reported to date.\nClinical description\nDEND syndrome represents the most severe end of the neonatal diabetes mellitus spectrum. Birth-weight is below the 10th percentile in approximately half of the cases. Patients have hyperglycemia requiring insulin therapy that presents within 12 months of birth. The onset is usually before 6 months of age and before 1 month of age in about 1/3rd of the patients. Remission from the hyperglycemia happens in about half of the patients (median age 39 weeks, but may not occur until 5 years old), however, relapse frequently occurs during puberty. The associated neurologic features range from mild to severe developmental delay (psychomotor and cognitive). Attention deficit or language disorder (dyslexia) is found in 100% of cases. Patients also present with intractable epilepsy and muscle hypotonia. A less severe, intermediate form has been described and is known as intermediate DEND syndrome.\nEtiology\nDEND syndrome is caused in most cases by gain of channel function mutations in the KCNJ11 gene (11p15.1), encoding a subunit of the ATP-sensitive potassium (KATP) channel. Mutations in this gene also cause permanent neonatal diabetes mellitus (PNDM). Only 20% of individuals with mutations in this gene develop DEND or the intermediate DEND form. Rare reports of specific mutations in the ABCC8 gene (11p15.1) have also been associated with DEND.\nDiagnostic methods\nDEND syndrome should be suspected when there is onset of diabetes mellitus before 6 months, or before 1 year of age with no pancreatic involvement or no evidence of autoimmune disorder, or with unusual family history and associated neurological complications. The diagnosis is confirmed by genetic testing which should be performed as soon as possible in order to prescribe the appropriate treatment and follow up. Diagnosis should be established before the onset of complications and should not wait for a potential remission of the hypoglycemia.\nDifferential diagnosis\nThe differential diagnosis includes the less severe intermediate DEND syndrome and other forms of neonatal diabetes mellitus, permanent and/or transient.\nAntenatal diagnosis\nNon-invasive prenatal testing of fetal genotype can be performed for monogenic diabetes and give highly accurate results before the third semester.\nGenetic counseling\nThe mode of inheritance of DEND syndrome is usually dominant (50% of transmitting the disease by an affected couple) and rarely recessive (25% chance of transmitting the disease by an affected couple), however, most diagnosed cases occur from a de novo mutation, in which case chances of recurrence in siblings are close to zero.\nManagement and treatment\nTreatment must begin as soon as the diagnosis is established using hypoglycemic sulfonylureas, which act by binding to the regulator SUR1 subunit of the potassium channel, and provide a better metabolic equilibrium than insulin. The clinician should aim to optimize the treatment to the maximum possible dose without causing hypoglycemia (preprandial target: 70-120 mg/dL - postprandial target: 100-145 mg/dL) in order to optimize the drug's beneficial effect on the central nervous system. Calorie and carbohydrate intake must be carefully balanced (15-18 g/kg/d of carbohydrates) to allow for weight gain while avoiding the risk of future insulin resistance. Restriction below the nutritional recommendations for children with low birth weight isn't recommended. Blood glucose must be monitored with as little amount of blood as possible (0.3 microliter) either with an appropriate blood glucose meter or a continuous glucose monitor.\nPrognosis\nIn the neonatal period, the prognosis of the disease is linked to the severity of the symptoms. Rapid diagnosis and treatment with hypoglycemic sulfonylureas after metabolic control has been restored with insulin are critical to improve the prognosis and reduce neurological complications. Later in life, the prognosis depends on the metabolic control which determines the timing of appearance of the long-standing diabetes complications.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Michel POLAK | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Dendritic cell sarcoma not otherwise specified", "Disease Definition": "A rare dendritic cell tumor characterized by a neoplasm composed of spindled to ovoid cells with phenotypic features similar to those of normal indeterminate cells. The tumor cells consistently express S100 protein and CD1a, while langerin, specific B- and T-cell markers, CD30, the histiocytic marker CD163, and the follicular dendritic cell markers CD21, CD23, and CD35 are negative. Birbeck granules are absent on ultrastructural examination. Patients typically present with multiple papules, nodules, or plaques of the skin. Primary lymph node or splenic involvement is less common. Systemic symptoms are usually absent. The clinical course is highly variable.", "ORPHA ID": 86903, "Summary": ""}
{"Disease Name": "Dengue fever", "Disease Definition": "Dengue fever (DF), caused by dengue virus, is an arboviral disease characterized by an initial non-specific febrile illness that can sometimes progress to more severe forms manifesting capillary leakage and hemorrhage (dengue hemorrhagic fever, or DHF) and shock (dengue shock syndrome, or DSS).", "ORPHA ID": 99828, "Summary": "Epidemiology\nDF is found in the tropics worldwide, especially in Southeast Asia, the Pacific region, and the Americas, with 40% of the global population at risk. An estimated 50 to 100 million cases of DF, 500,000 hospitalizations, and 20,000 deaths occur yearly worldwide.\nClinical description\nThe vast majority of dengue virus infections result in DF, which is characterized by sudden onset of fever, malaise, headache (classically retro-orbital), and myalgia/arthralgia, often followed soon after by a petechial rash, which may be pruritic. In most cases, symptoms will resolve within 7 days without further complications. However, in a small minority of patients, a brief period of deffervescence is followed by worsening abdominal symptoms (pain, nausea, vomiting, diarrhea), thrombocytopenia, hemorrhage (DHF: epistaxis, bleeding gums, gastrointestinal bleeding) and a capillary leak syndrome (DSS: hemoconcentration, hypoalbuminemia, pleural effusion, shock). DHF/DSS are seen most often in children under the age of 15 years. Risk is greater with secondary heterologous infection by one of the four dengue virus serotypes, but severe disease may be seen with first infections.\nEtiology\nOver 25 different viruses cause viral hemorrhagic fever. Dengue virus belongs to the Flaviviridae family, genus Flavivirus. Four distinct serotypes, with significant strain variation, are recognized. Dengue viruses are maintained in humans and transmitted between them by the bite of infected mosquitoes, most commonly Aedes aegypti but also Aedes albopictus). Person-to-person transmission has not been reported.\nDiagnostic methods\nCommon diagnostic modalities include serologic testing by enzyme linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). Virus isolation may also be performed in specialized laboratories. The viremic phase of DF/DHF is usually brief (first 3-5 days of illness), after which time detection of anti-dengue IgM antibodies, which appear as early as 2-4 days after disease onset, is the mainstay. Numerous commercial ELISA assays are available with varying degrees of sensitivity and specificity.\nDifferential diagnosis\nDF is difficult to distinguish from a host of other febrile illnesses such as malaria and typhoid fever (see these terms), especially early in the course of disease before the rash appears. For DHF/DSS, other viral hemorrhagic fevers, leptospirosis, rickettsial infection (see these terms) and meningococcemia need to be excluded.\nManagement and treatment\nAs there is presently no antiviral drug available for DF/DHF, treatment is supportive, following the guidelines for treatment of severe septicemia. Insecticide-treated bed nets, room screens and elimination of larval development sites should be used in open-air settings to prevent further transmission.\nPrognosis\nCase-fatality rates for DF are less than 1% but may rise to as high as 40% in DHF/DSS, largely dependent upon whether access to advanced medical care exists. Children and persons with underlying chronic diseases such as diabetes, heart disease, and asthma are at increased risk. The most severe phase of disease usually lasts only a few days and survivors generally have no lasting sequelae.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Daniel BAUSCH  -  Andrew BENNETT"}
{"Disease Name": "Dense deposit disease", "Disease Definition": "A histological subtype of C3 glomerulopathy characterized by C3 deposition in renal tissue in the absence or near-absence of immunoglobulin deposits, in a patient with the classic clinical features of glomerulonephritis and electron microscopic findings of highly electron-dense intra-membranous, osmiophilic deposits.", "ORPHA ID": 93571, "Summary": ""}
{"Disease Name": "Dent disease type 1", "Disease Definition": "A rare X-linked monogenic renal tubular disease, characterized by manifestations of complex proximal tubule dysfunction with low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. Extra-renal involvement is absent.", "ORPHA ID": 93622, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe disease is generally found in males only, who may have manifestations of the disease from early childhood. It is characterized by proximal tubule (PT) dysfunction and LMW proteinuria (100% of cases), associated with hypercalciuria (90-95%), nephrolithiasis (30-50%), nephrocalcinosis (40-50%), and progressive renal failure. PT dysfunction may be severe, resulting in complete Fanconi syndrome, i.e. aminoaciduria, phosphaturia, glycosuria, uricosuria, kaliuresis, and impaired urinary acidification, and can be complicated by rickets or osteomalacia. If tested, nearly all patients have a urinary concentration defect. Patients may present symptoms related to renal stones (abdominal pain, hematuria), Fanconi syndrome (polyuria, poor growth, rickets), or chronic kidney failure. Patients are also frequently referred after fortuitous discovery of nephrocalcinosis, renal stones, proteinuria or other biological signs of PT dysfunction, or after family screening. Some patients present with LMW proteinuria associated with significant albuminuria and glomerulosclerosis, in the absence of nephrotic syndrome and with mild tubular involvement that may be overlooked. There is considerable inter- and intra-familial variability. Most females carriers have low-degree of LMW proteinuria and may develop mild kidney failure later in life.\nEtiology\nDent disease type 1 is caused by inactivating mutations in the CLCN5 gene (Xp11.22) that encodes a 746 amino acid electrogenic Cl-/H+ exchanger (ClC-5). Close to 250 CLCN5 mutations have been reported. Of these 9% are de novo mutations. Approximately 40% of patients with a phenotype compatible with Dent disease do not have CLCN5 mutations. Of these, approximately half have mutations in the OCRL1 gene and are considered to have Dent disease type 2.\nDiagnostic methods\nThe diagnosis is based on the presence of LMW proteinuria, which is associated in the majority of cases with hypercalciuria and other biological, radiological and clinical symptoms of the disease. Molecular genetics confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other causes of low molecular weight proteinuria and Fanconi syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is X-linked. Genetic counseling should be offered to at-risk couples informing them that there is a 50% risk of having an affected boy or a carrier girl at each pregnancy, if the mother carries the mutation.\nManagement and treatment\nCare is supportive, focusing on the prevention of nephrolithiasis, maintaining appropriate hydration and treatment of chronic kidney disease, if present. Long-term treatment with a high citrate diet or supplementation might delay progression of renal disease, even in the absence of stone formation. Thiazide diuretics have been used to treat hypercalciuria, but can cause significant adverse effects; in addition, their benefit on kidney function has not been demonstrated, and they may aggravate hypovolemia and hypokalemia, if present. Similarly, treatment of rickets with vitamin D must be cautious since it may increase hypercalciuria and aggravate nephrocalcinosis.\nPrognosis\nProgression to end-stage renal failure occurs between the third and fifth decades of life in the majority of affected males. Frequency of kidney failure increases with age: approximately 35-40% in patients between 30-50 years, and 75% in between 50 and 60 years. The disease does not recur in the transplanted kidney.\n\n                            Last update: \n                            August 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Gema ARICETA | ERKNet* - Pr Francesco EMMA | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Dent disease type 2", "Disease Definition": "A rare genetic renal tubular disease, characterized by manifestations of proximal tubule dysfunction with low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. Extra-renal involvement is frequent, but may be mild and not recognized.", "ORPHA ID": 93623, "Summary": "Epidemiology\nThe exact prevalence is unknown. Compared to Dent disease type 1, Dent disease type 2 is approximately 4 times less frequent.\nClinical description\nThe disease is generally found in males only, who may have manifestations of the disease from early childhood. It is characterized by proximal tubule (PT) dysfunction and low-molecular-weight (LMW) proteinuria (100% of cases), associated with hypercalciuria (>95%), nephrolithiasis (20-30%), nephrocalcinosis (10-20%), and progressive renal failure. PT dysfunction may be severe, resulting in complete Fanconi syndrome, i.e. aminoaciduria, phosphaturia, uricosuria, kaliuresis, and impaired urinary acidification, and can be complicated by rickets or osteomalacia. Unlike Dent disease type 1, glycosuria is rarely observed. Patients may present symptoms related to renal stones (abdominal pain, hematuria), Fanconi syndrome (polyuria, poor growth, rickets), or chronic kidney failure. Patients are also frequently referred after fortuitous discovery of nephrocalcinosis, renal stones, proteinuria or other biological signs of PT dysfunction. Extra-renal symptoms include variable degrees of intellectual impairment in approximately one-quarter of patients, partial cataract in approximately 10% of patients, and growth retardation (mean height Z-score: -2.1). Nearly all patients have creatine phosphokinase (CPK) and/or lactate dehydrogenase (LDH) levels above the normal range.\nEtiology\nThe disease is due to variants on the OCRL1 gene (Xq26.1) and is allelic with oculocerebrorenal syndrome of Lowe (Lowe syndrome). Unlike Lowe syndrome, severe pathogenic variants causing Dent disease type 2 (nonsense, frameshift, and splice site mutations) are clustered in exons 4-7; variants that are located in other regions of the OCRL1 gene are nearly always missense mutations.\nDiagnostic methods\nThe diagnosis is based on the presence of LMW proteinuria, which is associated in the majority of cases with hypercalciuria and other biological, radiological and clinical symptoms of the disease. Elevated CPK and LDH help distinguishing Dent disease type 1 from type 2. When present, lens abnormalities and intellectual impairment also favor the diagnosis of Dent disease type 2. Molecular genetics confirms the diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes other causes of low molecular weight proteinuria and Fanconi syndrome. There is a continuum in the clinical manifestations of Dent disease type 2 and Lowe syndrome, which are both caused by OCRL1 pathogenic variants. In some patients, the distinction between these two phenotypes can be difficult.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is X-linked. Genetic counseling should be offered to at-risk couples informing them that there is a 50% risk of having an affected boy or a carrier girl at each pregnancy, if the mother carries the mutation.\nManagement and treatment\nCare is supportive. From the renal perspective, the focus is on the prevention of nephrolithiasis, maintaining appropriate hydration and treatment of chronic kidney disease, if present. Experimental data in Dent 1 disease suggest that long-term treatment with a high citrate diet or supplementation with citrate might delay progression of renal disease, but data are not available for Dent 2 disease. Treatment of rickets with vitamin D must be cautious in patients with hypercalciuria and/or nephrocalcinosis. Patients with intellectual impairment require neuropsychological and educational support.\nPrognosis\nProgression to end-stage renal failure occurs between the second and fifth decades of life in the majority of affected males. The disease does not recur in the transplanted kidney.\n\n                            Last update: \n                            August 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Gema ARICETA | ERKNet* - Pr Francesco EMMA | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Dent disease", "Disease Definition": "A rare X-linked renal tubular diseases characterized by a primary proximal tubule dysfunction with low-molecular-weight proteinuria. Other renal features often include hypercalciuria, nephrolithiasis/nephrocalcinosis, and progressive renal failure, among others. There are two subtypes: Dent disease type 1 characterized by an isolated renal phenotype in association with CLCN5 variants, and Dent disease type 2, often characterized by the addition of extra renal manifestations in association with OCRL1 variants.", "ORPHA ID": 1652, "Summary": ""}
{"Disease Name": "Dental ankylosis", "Disease Definition": "A rare odontologic disorder characterized by the loss of the periodontal ligament space and orthodontic mobility.", "ORPHA ID": 1077, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nIn dental ankyloses, the tooth is in contact with the alveolar bone with obliteration of the periodontal ligament and can lead to submergence. It can affect both primary and permanent teeth and may occur at any time during eruption. Permanent molars are less frequently affected than deciduous molars. Varying numbers of teeth may be affected. After eruption, it halts any adaptive changes. In a growing child, an ankylosed tooth appears to 'submerge' as adjacent unaffected teeth and alveolar bone continue their normal pattern of growth occlusally. The disorder may result in loss of the retained molar and neighboring teeth due to caries and periodontal disease, and, in severe cases, deformation of the facial skeleton (reduction in the height of the lower face, relative mandibular prognathism, posterior open bite). Occasionally, dental ankylosis may be associated with fifth finger clinodactyly. Dental ankylosis exists in isolation or associated with other abnormalities as part of a syndrome.\nEtiology\nEtiology remains uncertain but a genetic predisposition, trauma, inflammation or infection may play a causative role.\nDiagnostic methods\nClinical examination and X-ray are the main diagnostic methods for detecting ankylosis.\nDifferential diagnosis\nDifferential diagnosis includes mechanical obstruction, primary failure of eruption, and malocclusion.\nGenetic counseling\nFamilial occurrence has been shown in several families, with autosomal dominance inheritance suggested.\nManagement and treatment\nThe recommended management includes removing the ankylosed tooth to ensure development and eruption of the permanent teeth, and surgery to expose, protect, or reposition the emerging tooth. Dental composites reestablish occlusion and improves esthetics. Decoronation is recommended in the incisal sector before vertical bone development is complete and the crown reaches a certain degree of infraocclusion. This permits preservation of the alveolar bone for eventual implants after completion of growth. Where primary teeth ankylosed, removal of the affected tooth is recommended to ensure development and eruption of the permanent teeth.\nPrognosis\nAnkylosed teeth have an unfavorable prognosis with risk of progression to replacement resorption.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Marion STRUB"}
{"Disease Name": "Dentatorubral pallidoluysian atrophy", "Disease Definition": "A rare subtype of autosomal dominant cerebellar ataxia type I characterized by involuntary movements, ataxia, epilepsy, mental disorders, cognitive decline and prominent anticipation.", "ORPHA ID": 101, "Summary": "Epidemiology\nWorldwide prevalence is unknown. However, the disease is found most commonly in Japan where the prevalence is estimated to be 1/208,000.\nClinical description\nAge of onset ranges from 1 to 60 years (mean age = 28.8 years). Patients with earlier onset (below 20 years of age) tend to show myoclonus epilepsy and intellectual deficit. Patients with late onset (over 40 years of age) tend to present with cerebellar ataxia, choreoathetosis and dementia. Clinical features and the age of onset are significantly correlated with the size of CAG repeats. Head magnetic resonance imaging (MRI) shows atrophy of cerebellum, brainstem, cerebrum and high signal has been shown in periventricular white matter.\nEtiology\nUnstable expansion of CAG repeats in the ATN1 gene (12p13.31) has been demonstrated.\nPrognosis\nPrognosis is poor. DRPLA progresses rather rapidly. The mean disease duration is about 13 years. Recurrent seizures and dysphagia with frequent fluid and food aspiration lead to bronchopneumonia and subsequent death. However, some patients can reach 60 years of age or more.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Dentin dysplasia type I", "Disease Definition": "Dentin dysplasia type I (DD-I) is a rare form of dentin dysplasia (DD, see this term) characterized by sharp conical short roots or rootless teeth.", "ORPHA ID": 99789, "Summary": "Epidemiology\nPrevalence of DD-I is reported to be 1/100,000.\nClinical description\nThe condition affects both primary and permanent dentition. Signs of the condition are variable. In patients with DD-I, the teeth are generally unremarkable clinically with a normal shape and color. However, the roots appear sharp with conical, apical constrictions on radiography. The teeth are generally mobile, with frequent abscess formation and can be lost prematurely. Aberrant dentin formation can lead to partial or total pulp obliteration.\nEtiology\nDD-I is caused by mutations in the DSPP gene (4q21.3) coding for dentin sialophosphoprotein, a precursor for dentin sialoprotein and dentin phosphoprotein which are involved in dentinogenesis.\nDiagnostic methods\nSince teeth in DD-I appear clinically normal, diagnosis is based on radiographic features (abnormal roots, pulp obliteration, partially obliterated crescent shaped pulp chamber and occasionally pulp stones). Molecular genetic testing can be used to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include conditions that have overlapping clinical or radiographic features with DD such as those leading to early tooth loss: Kostmann syndrome, cyclic neutropenia, Chediak-Hegashi syndrome, Langerhans cell histiocytosis, Papillon-Lefèvre syndrome, hypophosphatasia, and vitamin D-resistant rickets (see these terms).\nGenetic counseling\nDD-I follows an autosomal dominant pattern of inheritance. There is therefore a 50% risk that a child born to an affected parent will have the condition.\nManagement and treatment\nAppropriate care makes it possible to achieve good esthetic appearance and functional performance.\nPrognosis\nPrognosis depends primarily on the age of diagnosis and the quality of management.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN"}
{"Disease Name": "Dentin dysplasia type II", "Disease Definition": "Dentin dysplasia type II (DD-II) is a rare mild form of dentin dysplasia (DD, see this term) characterized by normal tooth roots but abnormal primary dentition.", "ORPHA ID": 99791, "Summary": "Epidemiology\nPrevalence of DD-II is not known.\nClinical description\nIn DD-II, features of primary dentition resemble those observed in dentinogenesis imperfecta type 2 (DGI-2, see this term) and include amber translucent coloration, bulbous crowns, cervical constriction, tooth attrition, and short constricted roots. Pulp obliteration is also observed. The permanent dentition seems either unaffected (normal teeth morphology and color) or mild radiographic abnormalities are found (thistle tube-shaped pulp chambers and multiple pulp calcifications).\nEtiology\nDD-II is caused by mutations in the DSPP gene (4q21.3) coding for dentin sialophosphoprotein, a precursor for dentin sialoprotein and dentin phosphoprotein which are involved in dentinogenesis.\nDiagnostic methods\nDiagnosis is based on history, clinical examination and radiographic features. Molecular genetic testing can be used to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include conditions that have similar clinical or radiographic features to DD such as osteogenesis imperfecta or dentinogenesis imperfecta (see these terms).\nGenetic counseling\nDD-2 follows an autosomal dominant pattern of inheritance. There is therefore a 50% risk that a child born to an affected parent will have the condition.\nManagement and treatment\nIn the primary dentition, preformed stainless steel crowns on molars may be used to prevent tooth wear and maintain the occlusal vertical dimension. Appropriate care makes it possible to achieve good esthetic appearance and functional performance.\nPrognosis\nPrognosis depends primarily on the age of diagnosis and the quality of management.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN"}
{"Disease Name": "Dentin dysplasia-sclerotic bones syndrome", "Disease Definition": "Dentin dysplasia-sclerotic bones syndrome is a rare, genetic odontologic disease characterized by the clinical, radiographic, and histologic features of dentine dysplasia and osteosclerosis of all long bones, with heavy cortical bone and narrowed or occluded marrow spaces. There have been no further descriptions in the literature since 1977.", "ORPHA ID": 99792, "Summary": ""}
{"Disease Name": "Dentin dysplasia", "Disease Definition": "Dentin dysplasia (DD) is a rare disorder belonging to the group of hereditary dentin defects (see this term) and is characterized by abnormal dentin structure and root development resulting in abnormal tooth development. It encompasses two subtypes: DD type I and DD type II (see these terms).", "ORPHA ID": 1653, "Summary": "Epidemiology\nPrevalence of DD type I is 1/100,000, and that of DD type II is unknown.\nClinical description\nThere is significant overlap between different types of DD and dentinogenesis imperfecta (DGI, see this term). Two clinical subtypes of DD have been identified. Dentin dysplasia type I (DD-1, see this term) involves sharp conical short roots or rootless teeth and is associated with premature loss of teeth. Dentin dysplasia type II (DD-2, see this term) involves normal tooth roots but abnormal amber color primary dentition, permanent teeth of normal morphology and color with pulp chamber shape anomalies and multiple intrapulpal calcifications.\nEtiology\nDD is caused by mutations in the DSPP gene (4q21.3) coding for dentin sialophosphoprotein, a precursor for dentin sialoprotein and dentin phosphoprotein.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN"}
{"Disease Name": "Dentinogenesis imperfecta type 2", "Disease Definition": "Dentinogenesis imperfecta type 2 (DGI-2) is a rare, severe form of dentinogenesis imperfecta (DGI, see this term) and is characterized by weakness and discoloration of all teeth.", "ORPHA ID": 166260, "Summary": "Epidemiology\nPrevalence of DGI-2 is reported to be 1/6,000 to 1/8,000.\nClinical description\nThe dental features of DGI-2 are typically bulbous crowns with marked cervical constriction along with amber translucent discoloration and tooth attrition. Roots are generally short and constricted. Both primary and permanent teeth present pulp obliteration. Patients with this form of DGI have no normal teeth. Sensorineural hearing loss has also been found in some patients.\nEtiology\nDGI-2 is caused by mutations in the DSPP gene (4q21.3) coding for dentin sialophosphoprotein, a precursor for dentin sialoprotein and dentin phosphoprotein which are involved in dentinogenesis.\nDiagnostic methods\nDiagnosis is based on history, clinical examination and radiographic features. Molecular genetic testing can be used to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include conditions that may have similar clinical or radiographic features to DGI such as osteogenesis imperfecta and dentin dysplasia (see this term). The clinical symptoms may be mistaken for hypocalcified amelogenesis imperfecta, congenital erythropoietic porphyria, conditions leading to early tooth loss (Kostmann syndrome, cyclic neutropenia, Chediak-Hegashi syndrome, Langerhans cell histiocytosis, Papillon-Lefèvre syndrome), vitamin D-resistant rickets (see these terms), as well as permanent teeth discoloration due to tetracyclines, and vitamin D-dependent rickets. It is important to investigate for a history of bone fractures with minimal trauma, hearing loss and to check for blue sclerae to rule out osteogenesis imperfecta (see this term).\nGenetic counseling\nDGI-2 follows an autosomal dominant pattern of inheritance. There is therefore a 50% risk that a child born to an affected parent will have the condition.\nManagement and treatment\nProtection of primary and then permanent teeth with preformed pediatric crowns, cast occlusal onlays on first permanent molars and eventually premolars, may help to minimize tooth wear and maintain the occlusal vertical dimension. Obliteration of pulp spaces in teeth that develop abscesses makes endodontic treatment extremely difficult if not impossible. Appropriate care makes it possible to achieve good esthetic appearance and functional performance. The replacement of teeth might be considered with dentures or implants.\nPrognosis\nPrognosis depends primarily on the age of diagnosis and the quality of management. Early diagnosis and regular dental care cannot always prevent premature tooth loss.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN"}
{"Disease Name": "Dentinogenesis imperfecta type 3", "Disease Definition": "Dentinogenesis imperfecta type 3 (DGI-3) is a rare, severe form of dentinogenesis imperfecta (DGI, see this term) characterized by opalescent primary and permanent teeth, marked attrition, large pulp chambers, multiple pulp exposure and shell teeth radiographically (i.e. teeth which appear hollow due to dentin hypotrophy).", "ORPHA ID": 166265, "Summary": "Epidemiology\nPrevalence of DGI-3 is not known. The disease was identified in the Brandywine isolate in southern Maryland, USA.\nClinical description\nIn DGI-3, both primary and permanent dentition are affected and teeth are often opalescent. Enamel loss and excessive wear have been reported, as well as marked tooth attrition. DGI-3 is associated with multiple periapical radiolucencies in noncarious teeth.\nEtiology\nThe disorder is caused by mutations in the DSPP gene (4q21.3) coding for dentin sialophosphoprotein, a precursor for dentin sialoprotein and dentin phosphoprotein which are involved in dentinogenesis.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN"}
{"Disease Name": "Dentinogenesis imperfecta-short stature-hearing loss-intellectual disability syndrome", "Disease Definition": "A rare malformative syndrome with dentinogenesis imperfecta, characterized by dentin dysplasia with opalescent discoloration and severe attrition of primary and permanent teeth, and delayed eruption, bulbous crowns, long and tapered roots, and progressive root canal obliteration of the permanent dentition, associated with proportionate short stature, sensorineural hearing loss, mild intellectual disability, and dysmorphic facial features. The latter include a prominent nose with high nasal bridge and short philtrum. Osteoporosis, mild platyspondyly, and cone-shaped epiphyses have also been reported.", "ORPHA ID": 71267, "Summary": ""}
{"Disease Name": "Dentinogenesis imperfecta", "Disease Definition": "Dentinogenesis imperfecta (DGI) is a hereditary dentin defect (see this term) characterized by abnormal dentin structure resulting in abnormal tooth development.", "ORPHA ID": 49042, "Summary": "Epidemiology\nPrevalence of DGI is reported to be 1/6,000 to 1/8,000.\nClinical description\nSigns of the condition are variable and there is significant overlap between different types of dentin dysplasia (DD, see this term) and dentinogenesis imperfecta. Three different types of DGI were originally described in the Shield's classification: DGI type 1, type 2 and type 3. The condition formerly known as DGI-1 is now considered to be a syndromic form of DGI associated with osteogenesis imperfecta types 1b,c, 2, 3, 4b, 9, and 10. In dentinogenesis imperfecta type 2 (DGI-2, see this term), osteogenesis imperfecta is not a feature and the condition is usually characterized by abnormal amber or opalescent dentin, worn teeth, bulbous crowns with cervical constriction, short roots, obliterated pulp chambers and root canals (visible on X-rays). Dentinogenesis imperfecta type 3 (DGI-3, see this term) is characterized by opalescent primary and permanent teeth, marked attrition, and large pulp chambers.\nEtiology\nDGI is a hereditary condition caused by missense and nonsense mutations in the DSPP gene (4q21.3) encoding the major proteins involved in dentin formation.\nGenetic counseling\nDGI follows an autosomal dominant pattern of inheritance.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN"}
{"Disease Name": "Denys-Drash syndrome", "Disease Definition": "A rare genetic, syndromic glomerular disorder characterized by the association of nephropathy presenting as persistent proteinuria or overt nephrotic syndrome, Wilms tumor and genitourinary structural defects. In addition, disorders of testicular development are common in subjects with 46,XY karyotype.", "ORPHA ID": 220, "Summary": "Epidemiology\nThe prevalence is not known. Fewer than 300 cases have been reported in the literature to date.\nClinical description\nPresentation is typically of infantile nephrotic syndrome progressing to end-stage renal disease (ESRD) within 1 to 15 years. Alternatively, initial clinical presentation may be with ambiguous external genitalia (e.g. hypospadias, cryptorchidism) in 46,XY individuals or uni- or bilateral Wilms tumor (WT). Affected individuals with 46,XY karyotype may have a wide range of disorders of testicular development ranging from undervirilized male to complete sex reversal, and carry a risk of developing gonadoblastoma in dysgenic gonads. Congenital anomalies of kidney and urinary tract (CAKUT) including duplex or horseshoe kidney, urogenital sinus and vesico-ureteric reflux, are present in ~10% of individuals. Genotype-phenotype correlations have been described; in particular, missense pathogenic variants affecting DNA-binding are associated with severe nephropathy and progression to ESRD within 1-3 years, and truncating variants are associated with a high risk (>85%) of developing WT and having a CAKUT (25%) while proteinuria is typically diagnosed in the second decade of life .\nEtiology\nConstitutional pathogenic variants in the Wilms tumor predisposing genes, WT1 (11p13), most of which are located in exons 8 and 9, have been described in the majority of individuals. WT1 encodes for a protein that serves as regulatory transcription factor important both for renal and gonadal development.\nDiagnostic methods\nDiagnosis is suspected on infantile presentation of glomerulopathy with either urogenital abnormalities and/or WT. Careful renal ultrasonography (US) for WT should be performed in any subject found to have early onset nephrotic syndrome. Diffuse mesangial sclerosis is the classic finding on renal biopsy, although other types of nephropathy are common. Imaging is used to assess internal genitalia. Identification of WT1 pathogenic variant confirms diagnosis. Karyotype testing is recommended for all individuals with ambiguous genitalia or gonadal dysgenesis.\nDifferential diagnosis\nThe differential diagnosis includes WAGR syndrome, Frasier syndrome, Meacham syndrome, congenital nephrotic syndrome of the Finnish type, idiopathic nephrotic syndrome, and isolated diffuse mesangial sclerosis\nAntenatal diagnosis\nUndervirilized / ambiguous genitalia in 46,XY individuals may sometimes be noted on prenatal US. Prenatal genetic testing is possible if the pathogenic variant has been previously identified in a family.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant with non-full penetrance and variable expressivity. Most of the patients have a de novo mutation. Precise evaluation of the risk of reoccurrence requires genetic testing of the index case and his/her biological parents. Where karyotyping is indicated, pre-test genetic counseling on the possibility of detecting sex reversal is recommended.\nManagement and treatment\nMultidisciplinary management should involve a nephrologist, urologist, endocrinologist, oncologist and surgeons. The nephrotic syndrome is resistant to corticosteroids and immunosuppressive drugs. Chronic renal failure is managed initially with nephroprotective medical therapy, followed by renal replacement therapies or transplantation when ESRD occurs. Patients with ESRD are recommended to undergo bilateral nephrectomy at the time of placement of a peritoneal dialysis catheter or renal transplantation to prevent WT development/relapse. Early gonadectomy should be considered in 46,XY with complete gonadal dysgenesis in order to prevent tumorigenesis. WT is treated by nephrectomy with or without chemotherapy.\nPrognosis\nThe prognosis varies widely with most of the subjects living into adulthood. The primary cause of death is renal failure and disseminated WT but respiratory and heart failure have also been reported. Nephrotic syndrome does not recur after kidney transplantation. 46, XY individuals with complete gonadal dysgenesis are infertile.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Beata LIPSKA-ZIETKIEWICZ | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Dermatitis herpetiformis", "Disease Definition": "A chronic autoimmune subepidermal bullous disease characterized by grouped pruritic lesions such as papules, urticarial plaques, erythema, and herpetiform vesiculae, with a predominantly symmetrical distribution on extensor surfaces of the elbows (90%), knees (30%), shoulders, buttocks, sacral region, and face of children and adults. Erosions, excoriations and hyperpigmentation usually follow. It may also appear as a consequence of gluten intolerance.", "ORPHA ID": 1656, "Summary": ""}
{"Disease Name": "Dermatofibrosarcoma protuberans", "Disease Definition": "Dermatofibrosarcoma protuberans (DFSP) is a rare infiltrating soft tissue sarcoma, generally of low grade malignancy, arising from the dermis of the skin and characteristically associated with a specific chromosomal translocation t(17;22).", "ORPHA ID": 31112, "Summary": "Epidemiology\nPrevalence is estimated at 1 in 10,000 and annual incidence is estimated at around 1 in 200,000.\nClinical description\nDFSP can present at any age, including infancy and childhood, but usually presents in the 2nd to 5th decade of life. Between 85 and 90% of tumors are low grade lesions, with the remainder classified as the high grade fibrosarcomatous (FS) type. The lesions typically present as an indurated pink or violet-red plaque or nodular mass on the trunk, proximal extremities, or head and neck region. Growth tends to be slow with local infiltration into deeper tissues and a propensity for local recurrence after excision. However, metastases are rare. Occurrence is sporadic.\nEtiology\nDFSP is most likely fibroblastic in origin: over 90% of cases are associated with dysregulated platelet-derived growth factor (PDGF) production resulting from chromosomal translocation or a supernumerary ring chromosome derived from t(17;22). The translocation breakpoint most often involves the second exon of the PDGFB gene on chromosome 22 (22q13.1), with fusion to the collagen, type I, alpha 1 gene (COL1A1) on chromosome 17 (17q21.33). This chromosomal translocation results in the upregulation of the PDGFB gene in the form of a fused proto-oncogene COL1A1/PDGFB.\nDiagnostic methods\nDiagnosis may be suspected on the basis of histological findings on biopsy samples showing features of a well-differentiated fibroblastic tumor with the characteristic microscopic appearance of interwoven fascicles of cells forming a swirling pattern and positive staining for CD34. Cytogenetic analysis identifying the characteristic t(17;22) chromosomal translocation or interphase FISH using split-apart probes for chromosome 22 can be used to confirm the diagnosis. Imaging modalities suchas MRI or CT scans are most useful for assessing the depth of tumor invasion or identifying metastatic sites.\nDifferential diagnosis\nThe differential diagnosis should include fibrosarcoma (see this term), dermatofibroma, neurofibroma, and other soft tissue tumors.\nManagement and treatment\nComplete surgical resection with clear margins is the standard treatment for primary and recurrent DFSP. Mohs microscopic surgery (MMS) using sequential horizontal sectioning with immediate microscopic examination may reduce the amount of tissue resected and is associated with a low risk of recurrence. Post-operative radiotherapy can be used when resection is incomplete. Imatinib, an oral PDGF receptor tyrosine kinase inhibitor may be beneficial for patients with an unresectable, locally advanced lesion or with metastatic disease. Cytotoxic therapy is of little proven value.\nPrognosis\nThe prognosis is excellent for low grade lesions but a poorer prognosis is associated with the FS variant due to a higher risk of recurrence and metastases. Overall, the rate of mortality is low (< 3% at 10 years).\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Dr D HANDOLIAS  - Pr Grant MCARTHUR"}
{"Disease Name": "Dermatoleukodystrophy", "Disease Definition": "A rare leukodystrophy characterized by congenital thickened, wrinkled skin showing loss of elasticity, in combination with childhood onset of rapidly progressive generalized cognitive and motor impairment quickly resulting in a vegetative state and early death. Neuropathologic examination reveals neuroaxonal leukodystrophy with numerous neuroaxonal spheroids and diffuse loss of axons and myelin sheaths.", "ORPHA ID": 1659, "Summary": ""}
{"Disease Name": "Dermatomyositis", "Disease Definition": "A rare idiopathic inflammatory myopathy (IIM) characterized by evocative skin lesions, muscle involvement with symmetrical proximal muscle weakness, and specific histological features. The clinical subtypes are defined by the presence of myositis-specific antibodies (anti-Mi2, anti-NXP2, anti-TIF1-γ, anti-MDA5, or anti-SAE antibodies) and are associated with specific clinical phenotypes and prognosis.", "ORPHA ID": 221, "Summary": "Epidemiology\nAnnual incidence is estimated between 1/125,000-1,000,000, and prevalence between 1/10,000-50,000. Dermatomyositis (DM) is more common in women than in men (2:1).\nClinical description\nOnset is generally in adulthood, in some cases earlier (Juvenile DM). The classical skin findings are of periorbital heliotrope rash and Gottron's papules, photodistributed violaceous erythema and poikiloderma, and periungual telangiectasias. Symmetrical proximal muscle weakness subsequently develops over weeks or months, with severity depending on antibody type. Anti-Mi2 DM (5-20% of DM patients) and anti-TIF1-gamma DM (15-25%) present a moderate to severe proximal muscle weakness with classical skin lesions. Anti-NXP2 DM (15-25%) presents specifically subcutaneous edema and calcinosis. Anti- SAE DM (5%) presents classical skin lesions with mild or no muscle involvement. Anti-MDA5 DM (5-20%) present with classical skin lesions, ulcerations, mechanic's hands, arthritis, pulmonary involvement, and no or mild muscle involvement. Pulmonary manifestations ranges from aspiration pneumonia to a severe life-threatening rapidly progressive interstitial lung disease (ILD). DM may involve other systems (cardiac, articular, gastro-intestinal). About one third of DM patients develop malignancy, often within 0 to 3 years before or after disease onset (breast and ovarian cancers in women, and lung and prostate cancer in men).\nEtiology\nAlthough the etiology is not fully understood, it is suggested to be associated with certain HLA regions, genes implicated in other autoimmune diseases, and triggers such as infections or cancer. The interferon (IFN) pathways play a key role in DM physiopathology, especially type I IFNs, and an IFN signature has been detected in blood sample, muscle and skin tissues.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical and laboratory (elevated serum creatine kinase and presence of myositis-specific antibody) findings, as well as myopathic findings on electromyography (EMG). It is generally confirmed by muscle biopsy showing inflammatory infiltrates around blood vessels and perifascicular atrophy.\nDifferential diagnosis\nThe differential diagnoses include other inflammatory myopathies, muscular dystrophies of late onset, as well as adult-onset nemaline myopathy, proximal myotonic myopathies, systemic lupus erythematosus, pityriasis rubra pilaris, lichen planus, and polymorphous light eruption.\nManagement and treatment\nTreatment aims to eliminate inflammation and restore muscle performance. Initial treatment includes high-dose corticosteroids, followed by tapering to an appropriate maintenance dose. Immunosuppressive agents (methotrexate, azathioprine, and mycophenolate mofetil) are frequently used in combination. Intravenous immunoglobulin or intravenous methylprednisolone may be used in severe cases. For patients with rapidly progressive ILD a specific approach must be discussed (cyclophosphamide, calcineurin inhibitors). Physical therapy is also recommended. Topical corticosteroid, tacrolimus, and hydroxychloroquine have been used to treat skin manifestations. Patients should avoid direct UV light and use high-factor sunscreen. There is no validated treatment for calcinosis. Pulmonary involvement should be evaluated with high resolution computed tomography and pulmonary function tests, and suspected cardiac involvement with echocardiography. Skin lesion severity should be evaluated with the CDASI (Cutaneous Dermatomyositis Disease Area and Severity Index). Age-appropriate cancer screening is recommended at diagnosis and in cases of relapse within 3 years or refractory disease.\nPrognosis\nPrognosis is sometimes poor and depends on patient response to treatment, severity of disease manifestations and comorbidities (notably, cancer and pulmonary involvement). Increased cancer risk is associated with age > 50 years, male sex, and presence of specific DM autoantibodies: anti-TIF1-y > anti-NXP2 > anti-Mi2. The anti-MDA5 subgroup is associated with 20% mortality due to rapidly progressive ILD.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE"}
{"Disease Name": "Dermatoosteolysis, Kirghizian type", "Disease Definition": "A rare genetic disease characterized by infantile onset of recurrent skin ulcerations, arthralgias, fever, peri-articular fistulous osteolysis, oligodontia, nail dystrophy, and keratitis. The disease takes a self-limiting course in childhood but results in severe cicatrization, chronic arthroses, pseudoacromegalic appearance of hands and feet, secondary scoliosis, and visual impairment. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 1657, "Summary": ""}
{"Disease Name": "Dermatopathia pigmentosa reticularis", "Disease Definition": "A rare, genetic, ectodermal dysplasia characterized by a widespread, early-onset, reticulate hyperpigmentation that persists throughout life, mild, diffuse non-cicatricial alopecia, and onychodystrophy. There are no dental anomalies. Patients may also present with adermatoglyphia, palmoplantar hyperkeratosis, acral dorsal blistering, and hypohidrosis or hyperhidrosis.", "ORPHA ID": 86920, "Summary": ""}
{"Disease Name": "Dermatosparaxis Ehlers-Danlos syndrome", "Disease Definition": "A form of Ehlers-Danlos syndrome (EDS) characterized by extreme skin fragility and laxity, a prominent facial gestalt, excessive bruising and, sometimes, major complications due to visceral and vascular fragility.", "ORPHA ID": 1901, "Summary": ""}
{"Disease Name": "Dermochondrocorneal dystrophy", "Disease Definition": "Dermochondrocorneal dystrophy is characterised by osteochondrodystrophy of the hands and feet, corneal dystrophy and the presence of skin nodules clustered around the metacarpophalangeal and interphalangeal joints, around the nose and ears and on the posterior surface of the elbow. Gingival lesions may also be present. It has been described in less than 20 patients. Transmission is autosomal recessive.", "ORPHA ID": 79149, "Summary": ""}
{"Disease Name": "Dermoid or epidermoid cyst of the central nervous system", "Disease Definition": "A rare congenital tumor characterized by a benign cyst with epithelial and epidermoid components, originating from embryologic displacement and ectopic growth of ectodermal tissue in the central nervous system. In contrast to epidermoid cysts, dermoid cysts also contain dermis and skin appendages. Most common location is the lumbosacral region, as well as the cerebellopontine angle and parasellar area for intracranial lesions. Clinical presentation depends on the location and size of the tumor and includes pain, muscle weakness, motor and sensory disturbances, and incontinence for intraspinal lesions, and intracranial hypertension, gait disturbances, cranial nerve dysfunction, and visual deficits for intracranial tumors. The cysts may rupture and cause chemical meningitis.", "ORPHA ID": 530033, "Summary": ""}
{"Disease Name": "Dermoodontodysplasia", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by a variably severe clinical picture comprising dry, thin skin, onychodysplasia, trichodysplasia, and dental abnormalities (such as hypodontia, microdontia, and persistence of deciduous teeth). There have been no further descriptions in the literature since 1990.", "ORPHA ID": 1660, "Summary": ""}
{"Disease Name": "Dermotrichic syndrome", "Disease Definition": "A rare, genetic, ectodermal dysplasia syndrome characterized by skin, hair and nail anomalies (i.e. generalized ichthyosis, congenital alopecia universalis, dystrophic, convex nails), associated with hypohidrosis without hyperthermia, intellectual disability, seizures, and skeletal (e.g. proportionate short stature, platyspondyly) and intestinal (e.g. congenital aganglionic megacolon) anomalies. Facial dysmorphism includes frontal bossing, blepharophimosis, large ears, low nasal bridge and small nose. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 99688, "Summary": ""}
{"Disease Name": "Desbuquois syndrome", "Disease Definition": "Desbuquois syndrome (DBQD) is an osteochondrodysplasia characterized by severe micromelic dwarfism, facial dysmorphism, joint laxity with multiple dislocations, vertebral and metaphyseal abnormalities and advanced carpotarsal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. A variant form of DBQD, Kim variant (see these terms), has also been described and is characterized by short stature and articular, minor facial and significant hand anomalies.", "ORPHA ID": 1425, "Summary": "Epidemiology\nTo date, less than 50 cases have been described in the literature.\nClinical description\nDBQD is characterized by severe micromelic dwarfism, facial dysmorphism (round flat face, prominent eyes, midface hypoplasia, short nose, microstomia, long upper lip with flat philtrum, microretrognathia, often resulting in isolated Pierre Robin syndrome (see this term)), thoracic hypoplasia, kyphoscoliosis, severe joint laxity with dislocation, and osteopenia. Additional features include glaucoma, cardiac septal defects, lung hypoplasia, obesity and clubbed feet with rocker bottom appearance. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies (accessory ossification center distal to the second metacarpal, bifid distal phalanx, or thumb with delta-shaped phalanx). A variant form of DBQD, Kim variant, has been described in 7 patients originating from Korea and Japan, and is characterized by short stature, articular and minor facial anomalies, together with significant hand anomalies including short metacarpals and elongated phalanges with advanced carpal bone age.\nEtiology\nDBQD type 1 and Kim variant are caused by mutation in the gene CANT1 (17q25.3). However, the function of CANT1 is still unknown. Mutations in the gene XYLT1 (16p12) has been reported to cause DBQD type 2. XYLT1 encodes xylosyltransferase 1 which is involved in proteoglycan synthesis. However not all DBQD type 2 have XYLT1 mutations supporting the involvement of other disease causing genes.\nDiagnostic methods\n'Diagnosis relies upon recognition of clinical and radiological features which include an advanced carpal and tarsal bone age; broad femoral neck with a spur-like projection and prominent lesser trochanter, producing characteristic ''monkey wrench'' (Swedish key) appearance; narrow thorax; coronal or sagittal clefting of the vertebrae and typical hand changes for DBQD type 1 that consist of small delta-shaped extraphalangeal bone, distal to the second metacarpal, leading to radial deviation of the index fingers (delta phalanx or bifid thumb),and horizontal acetabular roofs with dislocation of femoral heads. Diagnosis is confirmed by the genetic screening of CANT1 in type 1 and XYLT1 in type 2DBQD.'\nDifferential diagnosis\nDifferential diagnosis includes autosomal dominant or recessive Larsen syndrome, Reunion island's Larsen syndrome, Catel-Manzke syndrome, chondrodysplasia with joint dislocations, gPAPP type, CHST3-related skeletal dysplasia, spondyloepiphyseal dysplasia, Omani type, diastrophic dwarfism and humerospinal dysostosis (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is achieved by ultrasound during the second trimester of pregnancy, by the detection of hydramnios, hydrops fetalis (see this term), intrauterine growth retardation, vertebral abnormalities and characteristic dysmorphic features.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling is recommended.\nManagement and treatment\nManagement includes regular orthopedic survey with often a need for multiple surgeries (scoliosis, hip and knee dislocation), and eye and ear follow up.\nPrognosis\nType 1 DBQD displays a high lethality rate of >33% due to respiratory failure. Survivors may have intellectual disability, developmental delay, generalized and progressive joint laxity with dislocated knees. Orthopedic complications often limit the ambulation in DBQD.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Valérie CORMIER-DAIRE"}
{"Disease Name": "Desmin-related myopathy with Mallory body-like inclusions", "Disease Definition": "A rare inclusion myopathy characterized by hypotonia and axial muscle weakness leading to spinal rigidity and development of scoliosis and other deformities which can result in respiratory failure. The symptoms are apparent from birth or early childhood. The muscle weakness is not progressive, and most patients remain ambulatory. Muscle biopsies show variable myopathic changes.", "ORPHA ID": 84132, "Summary": ""}
{"Disease Name": "Desminopathy", "Disease Definition": "A rare genetic skeletal muscle disease characterized by abnormal chimeric aggregates of desmin and other cytoskeletal proteins and granulofilamentous material at the ultrastructural level in muscle biopsies and variable clinical myopathological features, age of disease onset and rate of disease progression. Patients present with bilateral skeletal muscle weakness that starts in distal leg muscles and spreads proximally, sometimes involving trunk, neck flexors and facial muscles and often cardiomyopathy manifested by conduction blocks, arrhythmias, chronic heart failure, and sometimes tachyarrhythmia. Weakness eventually leads to wheelchair dependence. Respiratory insufficiency can be a major cause of disability and death, beginning with nocturnal hypoventilation with oxygen desaturation and progressing to daytime respiratory failure.", "ORPHA ID": 98909, "Summary": ""}
{"Disease Name": "Desmoid tumor", "Disease Definition": "A desmoid tumor (DT) is a benign, locally invasive soft tissue tumor associated with a high recurrence rate but with no metastatic potential.", "ORPHA ID": 873, "Summary": "Epidemiology\nDTs account for < 3% of soft tissue tumors. Their annual incidence is estimated to range between 1/250,000-1/500,000. They predominantly affect women and can occur between the ages of 15-60 years, but frequently during early adolescence and with a peak age of about 30 years.\nClinical description\nIn principle, DTs can occur in any part of the body: extra-abdominally (neck, shoulders, upper limbs, gluteal region), abdominally (originating from muscle fascia or the abdominal/chest wall), and more rarely intra-abdominally in the mesentery or retroperitoneum. Usually, they are firm and smooth palpable masses upon discovery. Depending on the location of the tumor, symptoms may include pain, fever, and functional impairment or loss of function of the organ involved. DTs may appear after surgical resections, typically after caesarian section. Intra-abdominal DTs are often observed in patients with an association of familial adenomatous polyposis (FAP) or Gardner syndrome (see these terms).\nEtiology\nDTs result from the proliferation of well-differentiated myofibroblasts. The exact etiopathogenetic mechanism is still unknown, but they seem to have a multi-factorial origin with hormonal and genetic factors being involved. Somatic mutations in the CTNNB1 gene (3q21) encoding beta-catenin have been found in about 85 % of sporadic cases. In cases with FAP, DTs have been associated with mutations in the tumor suppressor gene APC (5q21-q22) encoding the adenomatous polyposis coli protein.\nDiagnostic methods\nInitial diagnosis is based on imaging techniques (computed tomography and magnetic resonance imaging) revealing the presence of an infiltrative growing mass. Diagnosis is confirmed by tumor biopsy showing abundant collagen surrounding elongated spindle-shaped cells containing small and regular nuclei and pale cytoplasm. Immunohistological examination shows expression of muscle cell markers (e.g. actin, desmin, vimentine) and absence of CD34. Moreover, diagnosis can be confirmed by screening for mutations of CTNNB1.\nDifferential diagnosis\nThe differential diagnosis is broad with fibrosarcomas on the one extreme and myofibroblastic processes such as nodular fasciitis and even hypertrophic scars and keloids on the other. The differential diagnosis of intra-abdominal DTs includes gastrointestinal stromal tumors, solitary fibrous tumors, inflammatory myofibroblastic tumors, sclerosing mesenteritis and retroperitoneal fibrosis (see these terms).\nGenetic counseling\nMost cases are sporadic. Familial cases (5-10 %) are associated with FAP.\nManagement and treatment\nComplete surgical resection remains the therapeutic mainstay of DTs. For unresectable tumors or those not amenable to surgical resection with R0 (microscopic tumor clearance) intent or accompanied by an unacceptable function loss, non-surgical treatments comprise radiotherapy, anti-estrogen therapy, non-steroidal anti-inflammatory agents, chemotherapy (e.g. methotrexate, vinblastine/vinorelbine, pegylated liposomal doxorubicin) and/or tyrosine kinase inhibitors (e.g. imatinib, sorafenib). As DTs have a variable and often unpredictable clinical course, a period of watchful waiting is advisable for asymptomatic patients. As DTs often recur, a surveillance strategy every 3-6 months is essential.\nPrognosis\nLocal recurrence occurs in around 70 % of cases. Prognosis depends on the type of tumor. Life expectancy is normal for abdominal and extra-abdominal tumors. However, it is lower in cases of intra-abdominal DTs due to complications such as intestinal obstruction, hydronephrosis or sepsis. Repeated surgical resections are associated with a greater risk of morbidity.\n\n                            Last update: \n                            September 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Bernd KASPER"}
{"Disease Name": "Desmoplastic infantile astrocytoma/ganglioglioma", "Disease Definition": "Desmoplastic infantile astrocytoma/ganglioglioma are mixed neuronal-glial tumors representing a histological spectrum of the same tumor. They are usually supratentorially located, large, cystic masses with a peripheral solid component, characterized by prominent desmoplastic stroma and pleomorphic populations of neoplastic cells with either astrocytic or ganglionic differentiation and poorly differentiated cells in variable proportions. They usually present in the first 18 months of age with rapid head growth, bulging anterior fontanel and bone structures over the tumor, signs of raised intracranial pressure (headache, vomiting, papilledema), focal neurological signs and sometimes seizures.", "ORPHA ID": 251940, "Summary": ""}
{"Disease Name": "Desmoplastic small round cell tumor", "Disease Definition": "An aggressive soft tissue cancer that typically arises in serous lined surfaces of the abdominal or pelvic peritoneum, and spreads to the omentum, lymph nodes and hematogenously disseminates especially to the liver. Extraserous primary location has been reported in exceptional cases.", "ORPHA ID": 83469, "Summary": "Epidemiology\nDSRCT is extremely rare. Only a few hundred cases have been reported worldwide since the first description in 1989. It usually affects males, during adolescence or young adulthood, with a male-to-female ratio of 4:1.\nClinical description\nClinical signs and symptoms of DSRCT are non-specific. DSRCT presents with abdominal pain, enlarged abdomen, dyspepsia, and/or vomiting and weight loss depending on the stage of the disease. Other signs can be observed such as a palpable abdominal mass, gastrointestinal occlusion, ascites, and hepatomegaly. Sometimes, DSRCT can arise from other primary sites such as the brain, thorax, lung, paratesticular region, ovaries and nasal cavity, without characteristic clinical signs.\nEtiology\nDSRCT seems to originate from the mesothelium. In almost all cases, a specific translocation t(11;22)(p13;q12) is found that juxtaposes the EWSR1 gene to the WT1 tumor suppressor gene. However, the underlying molecular mechanism remains unknown. Several other associated chromosomal translocations have been described (t(5;19), t(X;16) and t(4;10)).\nDiagnostic methods\nThe diagnosis is difficult due to the rarity of the tumor and its similarities with other small round cell tumors. Diagnosis is based on clinical signs, endoscopic examination (laparoscopy) and/or imaging techniques (radiography, chest-abdominal-pelvic computed tomography (CAP-CT)). Biopsy of the mass shows nests of poorly differentiated small round cells with little cytoplasm and hyperchromatic nuclei that are surrounded by desmoplastic stroma. Cells can present an epithelial, mesenchymal, or neuronal differentiation. The diagnosis is confirmed by the presence of a polyphenotypic immunoprofile (tumor cells express several cytokeratins (KL1, AE1/AE3), desmin, and neuron-specific enolase), and by molecular identification (FISH, RT-PCR) of the EWSR1/WT1 translocation.\nDifferential diagnosis\nDifferential diagnoses include all the small round cells tumors: Ewing sarcoma and other peripheral neuroectodermal tumors (PNET), Wilms tumor, rhabdomyosarcoma and undifferentiated carcinoma (see these terms).\nManagement and treatment\nManagement is multidisciplinary and must be discussed by a panel of physicians in a specialized center. Up to 30% of DSRCT cases are misdiagnosed leading to incorrect management. There are currently no validated recommendations on clinical management and no cytotoxic agents have been granted a European Marketing Authorization (MA) in this indication. Some teams have proposed treatment based on aggressive multiagent chemotherapy (off-label use), followed by optimal cytoreductive surgery and abdominal radiotherapy. Prospective studies are underway to evaluate the effect of hyperthermic intraperitoneal chemotherapy (HIPEC), maintenance chemotherapy and targeted therapy.\nPrognosis\nPrognosis is poor. Median overall survival is 17 months and less than 20% of patients live more than 5 years after diagnosis.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Gwenaël FERRON  - Pr François-Noël GILLY"}
{"Disease Name": "Desmoplastic/nodular medulloblastoma", "Disease Definition": "Desmoplastic/nodular medulloblastoma is a histological variant of medulloblastoma (see this term), an embryonic malignancy, often located in one of the cerebellar hemispheres, occurring most frequently in adults and manifesting with symptoms such as vomiting and headache.", "ORPHA ID": 251863, "Summary": ""}
{"Disease Name": "Desmosterolosis", "Disease Definition": "Desmosterolosis is a very rare sterol biosynthesis disorder characterized by multiple congenital anomalies, failure to thrive, and intellectual disability, with elevated levels of desmosterol.", "ORPHA ID": 35107, "Summary": "Epidemiology\nOnly 9 cases have been reported in the literature to date.\nClinical description\nDesmosterolosis presents at birth with growth restriction, spasticity with variable degrees of hand contractures, either microcephaly or relative macrocephaly, and microretrognathia. Transient neonatal seizures, nystagmus, strabismus and failure to thrive are also seen in most cases. Intellectual disability occurs in all patients and is first noted by delayed milestones for speech and adaptive, fine and gross motor development. Less common manifestations reported include hirsutism, facial dysmorphism (downslanting palpebral fissures, bilateral epicanthal folds, submucous cleft palate, and thick alveolar ridges), sensorineural hearing loss, patent arterial duct, ambiguous genitalia, bilateral clubfeet, muscle wasting, and cutis aplasia. Optic atrophy, corpus callosum agenesis and loss of white matter are also noted.\nEtiology\nDesmosterolosis is due to mutations in the DHCR24 gene (1p32.3) encoding 3-beta-hydroxysterol delta-24-reductase. This enzyme catalyzes the conversion of desmosterol (the cholesterol precursor) to cholesterol, which is highly involved in embryonic development and morphogenesis. Reduced enzyme activity leads to the accumulation of desmosterol and a lack of cholesterol, disrupting antenatal and postnatal development.\nGenetic counseling\nDesmosterolosis is inherited in an autosomal recessive manner and genetic counseling is possible.\n\n                            Last update: \n                            December 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Nicola BRUNETTI PIERRI  - Pr Giancarlo PARENTI"}
{"Disease Name": "Desquamative interstitial pneumonia", "Disease Definition": "A rare idiopathic interstitial pneumonia characterized by extensive, diffuse intra-alveolar accumulation of pigment-laden macrophages, most commonly associated with long-term exposure to tobacco smoke. Patients present with slowly progressive shortness of breath on exertion and chronic cough with bilateral crackles. Digital clubbing is also frequently observed. Pulmonary function test reveals a restrictive pattern. Computed tomography typically shows diffuse ground-glass opacities with subpleural and lower zone predominance.", "ORPHA ID": 98852, "Summary": ""}
{"Disease Name": "Developmental and epileptic encephalopathy with spike-wave activation in sleep", "Disease Definition": "Continuous spikes and waves during sleep (CSWS) is a rare epileptic encephalopathy of childhood characterized by seizures, an electroencephalographic (EEG) pattern of electrical status epilepticus in sleep (ESES) and neurocognitive regression in at least 2 domains of development.", "ORPHA ID": 725, "Summary": "Epidemiology\nThe prevalence is unknown. CSWS is a rare condition that affects 0.5-1.5% of children with epilepsy (in some series) and has a 3:2 male to female ratio.\nClinical description\nCSWS is an age-related epileptic encephalopathy in which the clinical features evolve over time. After a normal or only moderately abnormal baseline development, seizures usually present at around 2-4 years of age. They are often unilateral, tonic-clonic or clonic and typically occur out of sleep. Seizures become more frequent, severe, and treatment-resistant with a marked deterioration in seizures, EEG, and developmental aspects (i.e. language, social interactions, global intelligence, motor skills and behavior) at approximately 5-6 years of age. During this acute stage, the seizures (absence seizures, clonic, tonic-clonic and others) and EEG abnormalities are difficult to control. Spontaneous improvement in seizures and EEG features occurs before puberty, but most patients remain with severe developmental delay.\nEtiology\nEarly developmental lesions such as vascular insults, especially affecting the thalamus, or malformations of cortical development have been found in approximately half of all cases. Genetic factors, especially mutations in the GRIN2A gene (16p13.2) have been recently linked to CSWS.\nDiagnostic methods\nDiagnosis is based on characteristic clinical evolution (with seizures and neurocognitive regression in at least 2 domains) and EEG findings. The main EEG feature of CSWS is ESES. ESES is characterized by marked potentiation of epileptiform discharges during the transition from wakefulness to sleep leading to (near-) continuous, bilateral or occasionally lateralized slow spikes and waves that occur during a significant proportion of non-rapid eye movement (REM) sleep. Magnetic resonance imaging (MRI) is performed in order to identify any brain lesions. As of now it is not routine clinical practice to perform genetic tests for GRIN2A in CSWS, but testing is available in certain specialized centers.\nDifferential diagnosis\nDifferential diagnosis includes any epileptic syndrome with sleep potentiation of epileptiform activity such as Landau-Kleffner syndrome, Panayiotopoulos and Gastaut types of benign childhood occipital epilepsy and rolandic epilepsy (see these terms).\nGenetic counseling\nAn autosomal dominant transmission has been proposed in families with a GRIN2A mutation.\nManagement and treatment\nThe main aim of treatment is to control seizures. It is unknown whether improvement of EEG abnormalities improves the long-term developmental outcome. High-dose nocturnal benzodiazepines like diazepam or clobazam are successful in reducing epileptiform activity acutely and subacutely. The antiepileptic drugs most often used include valproate, levetiracetam, lamotrigine, and ethosuximide. Corticosteroids are useful but associated with long-term side effects. Epilepsy surgery is an efficacious therapy in selected cases, even when epileptiform discharges are bilateral.\nPrognosis\nAlthough seizures and EEG abnormalities tend to normalize by adolescence, the developmental prognosis is generally poor as neurocognitive regression is permanent in most cases.\n\n                            Last update: \n                            April 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Tobias LODDENKEMPER  - Dr Iván SÁNCHEZ FERNÁNDEZ"}
{"Disease Name": "Developmental and speech delay due to SOX5 deficiency", "Disease Definition": "Developmental and speech delay due to SOX5 deficiency is a rare genetic syndromic intellectual disability characterized by mild to severe global developmental delay, intellectual disability and behavioral abnormalities, hypotonia, strabismus, optic nerve hypoplasia and mild facial dysmorphic features (down slanting palpebral fissures, frontal bossing, crowded teeth, auricular abnormalities and prominent philtral ridges). Other associated clinical features may include seizures and skeletal anomalies (kyphosis/scoliosis, pectus deformities).", "ORPHA ID": 313892, "Summary": ""}
{"Disease Name": "Developmental delay due to methylmalonate semialdehyde dehydrogenase deficiency", "Disease Definition": "A rare, genetic, inborn error of branched-chain amino acid metabolism disorder, with a highly variable clinical and biochemical phenotype, typically characterized by mild to severe global developmental delay, elevated methylmalonic acid and, occasionally, lactic acid plasma levels, and chronic methylmalonic aciduria, which may be accompanied by elevation of additional organic or amino acids in urine (e.g. beta-alanine, methionine, 3-hydroxypropionic, 3-aminoisobutyric and/or 3-hydroxyisobutyric acid). Microcephaly, mild craniofacial dysmorphism, axial hypotonia, liver failure, and central nervous system abnormalities on MRI have also been reported.", "ORPHA ID": 289307, "Summary": ""}
{"Disease Name": "Developmental delay with autism spectrum disorder and gait instability", "Disease Definition": "Developmental delay with autism spectrum disorder and gait instability is a rare, genetic, neurological disorder characterized by infant hypotonia and feeding difficulties, global development delay, mild to moderated intellectual disability, delayed independent ambulation, broad-based gait with arms upheld and flexed at the elbow with brisk walking or running, and limited language skills. Behavior patterns are highly variable and range from sociable and affectionate to autistic behavior.", "ORPHA ID": 329195, "Summary": ""}
{"Disease Name": "Developmental delay-facial dysmorphism syndrome due to MED13L deficiency", "Disease Definition": "A rare, genetic syndromic intellectual disability characterized by developmental delay, mild to severe intellectual disability, facial features (bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance) and a wide spectrum of other nonspecific variable clinical features.", "ORPHA ID": 369891, "Summary": "Epidemiology\nTo date, more than 70 cases have been reported.\nClinical description\nPatients have a variable degree of intellectual disability, global developmental delay (notably with severe speech and language impairment), muscular hypotonia, and facial features (including broad forehead, bitemporal narrowing, upslanting palpebral fissures, low-set ears, flat nasal bridge, bulbous nose, thin vermillion border and open mouth with tongue protrusion). Highly variable additional features include cardiac defects (persistent foramen ovale, ventricular septal defects or tetralogy of Fallot), cerebellar ataxia, seizures, growth difficulties, microcephaly, ventriculomegaly or myelination defects.\nEtiology\nThe disorder is sporadic caused by either a sequence variation in the mediator complex subunit 13-like gene (MED13L), an intragenic microdeletion within the gene, or by a larger microdeletion encompassing the entire gene. Rare intragenic microduplications within MED13L are also reported.\nDiagnostic methods\nThe syndrome could be suspected on the association of developmental delay, speech impairment, motor delay, and facial features (notably, an open mouth with a protruding tongue, a thin vermillion border, upslanting palpebral fissures and a bulbous nasal tip). Molecular genetic testing approaches include array-comparative genomic hybridization for microdeletion identification, and sequencing of the entire MED13L coding region for sequence variants (gene panel, exome sequencing).\nDifferential diagnosis\nSome patients share some clinical features observed in Kleefstra syndome, Mowat-Wilson syndrome, Kabuki syndrome and 1p36 microdeletion.\nAntenatal diagnosis\nPathogenic variations are de novo. However, very rare cases of parental mosaicism are described and prenatal genetic testing may be possible in such families with a proband. No specific prenatal signs are reported.\nGenetic counseling\nMost cases arise de novo and thus the sibling recurrence risk is low. The disorder is autosomal dominant with 50% risk of transmission from affect individuals to their offspring; however, transmission of the condition has never been reported.\nManagement and treatment\nManagement is mainly supportive and symptomatic. Affected patients should benefit from speech therapy. Development, walking evolution, hearing and vision should be monitored closely.\nPrognosis\nThe prognosis and function consequences are variable and dependent on the associated anomalies and intellectual disability.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Jamal GHOUMID | ITHACA* - Dr Thomas SMOL | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome due to 2q24 microdeletion", "Disease Definition": "2q24 microdeletion syndrome is a chromosomal anomaly consisting of a partial long arm deletion of chromosome 2 and characterized clinically by a wide range of manifestations (depending on the specific region deleted) which can include seizures, microcephaly, dysmorphic features, cleft palate, eye abnormalities (coloboma, cataract and microphthalmia), growth retardation, failure to thrive, heart defects, limb anomalies, developmental delay and autism.", "ORPHA ID": 1617, "Summary": ""}
{"Disease Name": "Developmental malformations-deafness-dystonia syndrome", "Disease Definition": "Developmental malformations-deafness-dystonia syndrome is characterised by the association of midline malformations, sensory hearing loss, and a delayed-onset generalised dystonia syndrome.", "ORPHA ID": 79107, "Summary": "Epidemiology\nIt has been described in two monozygotic twins.\nEtiology\nThe syndrome is caused by a missense point mutation in the gene coding for beta-actin, a nonmuscle actin isoform. Mutations in nonmuscle actin isoforms may be associated with developmental anomalies and neurological disorders such as dystonia.\n\n                            Last update: \n                            June 2006"}
{"Disease Name": "Dextrocardia", "Disease Definition": "A rare, congenital, non-syndromic, developmental defect during embryogenesis characterized by positioning of the heart in the right hemithorax, with the base and apex of the heart pointing caudally and to the right, due to abnormalities of embryologic origin that are intrinsic to the heart itself. Situs inversus or situs solitus may be associated, with extracardiac visceral transposition anomalies usually present in the former case and additional cardiac defects (e.g. septal defects, transposition of the great arteries, double-outlet right ventricle, anomalous pulmonary venous return, tetralogy of Fallot) frequently observed in both cases.", "ORPHA ID": 1666, "Summary": ""}
{"Disease Name": "Diabetic embryopathy", "Disease Definition": "A rare disorder characterized by congenital anomalies or foetal/neonatal complications in an infant that are linked to diabetes in the mother.", "ORPHA ID": 1926, "Summary": "Epidemiology\nSeveral reports show that the birth prevalence of congenital malformations can be cut by a third by using strict preconception glycemia control, but the challenge of implementing this approach remains.\nClinical description\nMacrosomia is also a common problem among infants of women with established insulin-dependent diabetes mellitus. Excess mortality among infants of women with preexisting insulin-dependent diabetes mellitus is predominantly due to congenital malformations. All types of congenital malformations are involved, but some are more common. Notably, the risk of cardiovascular malformations (CVM) is increased, and specific studies show that preconceptional maternal diabetes is strongly associated with CVM of early embryonic origin and with cardiomyopathy (respective odds ratios are 5 and 15). CVM of early embryonic origin are laterality defects (cardiovisceral and atrioventricular discordance), outflow tract anomalies (an association was found between truncus arteriosus and double outlet right ventricle, and other anomalies with normally related great arteries but no association was found with simple transpositions), and anomalies of the endocardial cushion (an association was found with complete but not with partial forms of atrioventricular septal defects). CMV also include hypertrophic cardiomyopathy, which is generally benign and transient, although it may be lethal if associated with hydrops fetalis, especially in case of severe macrosomia. Other anomalies associated with maternal preconceptional diabetes are renal malformations, especially uni- or bilateral kidney agenesis. These ageneses are described as either isolated or of part of multiple malformation syndromes that are more common in individuals with maternal diabetes: caudal regression syndrome (a rare anomaly of the lower body pole that represents a continuum of congenital malformations ranging from isolated sacral agenesis to absence of the lumbosacral spine and major visceral anomalies) and DiGeorge anomaly (velo-cardio-facial syndrome).\nEtiology\nCytogenetic studies of DiGeorge anomaly in individuals with maternal diabetes usually detect no abnormalities (i.e. do not uncover a 22q11 microdeletion).\nGenetic counseling\nIn infants of women with established insulin-dependent diabetes mellitus, the risk of congenital malformations is 10 times higher than that in the general population, and the rate of stillbirths is five times higher than that in the general population.\n\n                            Last update: \n                            February 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Elisabeth ROBERT-GNANSIA"}
{"Disease Name": "Diamond-Blackfan anemia", "Disease Definition": "Blackfan-Diamond anemia (DBA) is a congenital aregenerative and often macrocytic anemia with erythroblastopenia.", "ORPHA ID": 124, "Summary": "Epidemiology\nAnnual incidence in the general population of Europe is estimated at around 1/150,000. Both sexes are equally affected and no ethnic predisposition has been identified.\nClinical description\nThe anemia is discovered early in life, usually within the first 2 years; diagnosis after 4 years of age is very unlikely. Pallor and dyspnea, especially during feeding or while sucking, are the principal warning signs. Pallor is isolated, without organomegaly, signs suggestive of hemolysis or involvement of other hematopoietic cell lines. Over half of all DBA patients present with short stature and congenital anomalies, the most frequent being craniofacial (Pierre-Robin syndrome and cleft palate), thumb and urogenital anomalies. Pregnancies in DBA-affected women are now identified as high-risk, for both mother and child. DBA patients may also be at a higher risk of leukemia and cancer.\nEtiology\nAt present, disease-causing mutations are identified in 40-45% of patients. All involved genes code for ribosomal proteins (RPs) from either the small (RPS7, RPS17, RPS19, RPS24) or the large (RPL5, RPL11, RPL35a) ribosomal subunit. Mutations in RPS19, RPL5 and RPL11 are found in 25%, 9% and 6.5% of patients respectively, whereas the other genes are each involved in only 1 to 3% of cases. The only clear genotype/phenotype correlation made so far is the frequent occurrence of craniofacial abnormalities in RPL5 and RPL11 mutation carriers and the rarity of these anomalies in RPS19 mutation carriers.\nDiagnostic methods\nIn a child with anemia and erythroblastopenia, the diagnosis can be supported by a familial history (10-20% of cases), associated malformations (40% of cases), and elevated erythrocyte adenosine deaminase (EAD), which is a frequent but non-specific sign that may also be elevated in relatives in the absence of other DBA symptoms. Detection of a disease-causing mutation is of diagnostic value.\nDifferential diagnosis\nThe differential diagnosis should include transient erythroblastopenia (see this term), chronic parvovirus B19 infection, and other congenital anemias.\nAntenatal diagnosis\nGenetic counseling and prenatal diagnosis are difficult because of the variability of clinical expression and the fact that only 40-45% of patients have an identified mutation within a RP gene. In familial cases, the risk of recurrence is 50%. Close ultrasound follow-up during the pregnancy is recommended in all cases.\nGenetic counseling\nDBA is inherited as an autosomal dominant trait with variable penetrance.\nManagement and treatment\nThe two main therapeutic approaches are regular transfusions and long-term corticosteroid therapy. Treatment must be adapted to each case and according to the age of the patient. Steroids should not be administered during the first year of life. Short stature, occurring both as part of the syndrome and due to treatment-related complications (steroids, hemochromatosis), is a major issue for these patients. Allogenic bone-marrow transplantation must be discussed in corticoresistant patients when an unaffected and HLA-identical sib is available.\nPrognosis\nThe prognosis is generally good. However, complications of treatment and a higher incidence of cancer may reduce life expectancy. Disease severity depends on the quality and response to treatment. For patients undergoing regular transfusions, quality of life is clearly altered.\n\n                            Last update: \n                            February 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Thierry LEBLANC"}
{"Disease Name": "Dianzani autoimmune lymphoproliferative disease", "Disease Definition": "Dianzani autoimmune lymphoproliferative disease (DALD) is a very rare disorder characterized by autoimmunity, lymphadenopathy and/or splenomegaly.", "ORPHA ID": 275523, "Summary": "Epidemiology\nThe prevalence of DALD is not known. The disorder has been reported in fewer than 30 patients to date.\nClinical description\nAge of onset is highly variable, ranging from childhood to young adulthood. In patients with DALD, signs of autoimmunity include recurrent episodes of thrombocytopenia, neutropenia, and/or autoimmune hemolytic anemia. Lymphoadenopathy and/or splenomegaly are invariably noted. A possible increased risk of cancer has been suggested in these patients.\nEtiology\nThe cause of DALD is not known but it is thought to be hereditary.\nDiagnostic methods\nBiologically, DALD is characterized by normal double-negative T-cells (DNTs) and defective in vitro FAS-mediated apoptosis.\nGenetic counseling\nThe pattern of inheritance of DALD is not known.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Koneti RAO"}
{"Disease Name": "DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome", "Disease Definition": "A rare genetic disease characterized by progressive and severe sensorineural hearing loss with onset in the first decade of life, associated with mild thrombocytopenia, often with enlarged platelets. Most patients do not show significant bleeding tendency.", "ORPHA ID": 494444, "Summary": ""}
{"Disease Name": "Diaphanospondylodysostosis", "Disease Definition": "A rare primary bone dysplasia characterized by costovertebral ossification defects with small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent dysmorphic craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most common extraosseous manifestations are renal abnormalities such as multicystic kidneys. The disease is usually perinatally lethal due to respiratory insufficiency.", "ORPHA ID": 66637, "Summary": ""}
{"Disease Name": "Diaphragmatic defect-limb deficiency-skull defect syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by diaphragmatic hernia, lung hypoplasia, ossification defect of the skull, and severe limb hypoplasia. Other clinicial features may include, syndactyly, clinodactyly, extra spleen, absence of the femur or pelvic bone, partial intestinal malrotation, omphalocele and testicular atrophy.", "ORPHA ID": 2141, "Summary": ""}
{"Disease Name": "Diaphragmatic hernia-short bowel-asplenia syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital diaphragmatic hernia, short bowel, and asplenia. Dysmorphic facial features include long forehead, hypertelorism, upturned nares, and small mandible. Atresia of the duodenum has also been reported.", "ORPHA ID": 527468, "Summary": ""}
{"Disease Name": "Diaphyseal medullary stenosis-bone malignancy syndrome", "Disease Definition": "Diaphyseal medullary stenosis with malignant fibrous histiocytoma is a very rare autosomal dominant bone dysplasia/cancer syndrome characterized clinically by bone infarctions, cortical growth abnormalities, pathological fractures, and development of bone sarcoma (malignant fibrous histiocytoma).", "ORPHA ID": 85182, "Summary": ""}
{"Disease Name": "Diastrophic dysplasia", "Disease Definition": "A rare disorder marked by short stature with short extremities (final adult height is 120cm +/- 10cm), and joint malformations leading to multiple joint contractures (principally involving the shoulders, elbows, interphalangeal joints and hips).", "ORPHA ID": 628, "Summary": "Epidemiology\nPrevalence is estimated at 1-1.3/100,000. The disorder affects both males and females.\nClinical description\nAt birth, infants have bilateral clubfoot, short limb deformation of the wrists and abducted thumbs. Cleft palate and mandible hypoplasia are also common findings. Cysts appear on the external ear within the first months of life. Growth is slow and scoliosis is frequent and develops progressively. Joint deformations are severe and can lead to either limitation of joint movement or hyperlaxity. The severity of the clinical manifestations is variable, ranging from very severe to moderate forms that may be diagnosed very late.\nEtiology\nThe syndrome is caused by mutations in the SLC26A2 (or diastrophic dysplasia sulfate transporter; DTDST) gene (5q31-q34), which encodes a sulfate transporter that is predominantly expressed in the cartilage. Mutations in the same gene have been implicated in a moderate form of epiphyseal dysplasia and in several lethal disorders such as achondrogenesis type 1b and atelosteogenesis type 2 (see these terms).\nDiagnostic methods\nDiagnosis is based on radiological findings: short and thick tubular bones, wide metaphyses, short and oval-shaped first metacarpals, subluxation of the thumb (hitchhiker thumb) and subluxation of the cervical vertebrae.\nAntenatal diagnosis\nPrenatal diagnosis may be suspected on the basis of ultrasound findings (clubfoot and short limbs).\nGenetic counseling\nThe syndrome is transmitted in an autosomal recessive manner.\nManagement and treatment\nManagement should include careful monitoring and eventual correction of the progressive scoliosis, and surgical correction of the joint malformations.\nPrognosis\nIn the absence of severe complications (spinal cord compression) associated with spinal malformations, life expectancy is good but the short stature and deformity are usually severe.\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Diazoxide-resistant diffuse hyperinsulinism", "Disease Definition": "Diazoxide-resistant diffuse hyperinsulism (DRDH) is a form of Diazoxide resistant hyperinsulinism (see this term) characterized by recurrent episodes of profound hypoglycemia caused by an excessive/ uncontrolled insulin secretion (inappropriate for the level of glycemia) due to diffuse involvement of pancreas that is unresponsive to medical treatment with diazoxide, often necessitating near total/total pancreatectomy.", "ORPHA ID": 165988, "Summary": ""}
{"Disease Name": "Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency", "Disease Definition": "A rare, congenital, isolated hyperinsulinism disorder characterized by diazoxide unresponsive recurrent episodes of hyperinsulinemic hypoglycemia resulting from an excessive insulin secretion by the pancreatic bêta-cells due to Kir6.2 deficiency. Hypoglycemia may lead to variable clinical manifestation, ranging from asymptomatic hypoglycemia revealed by routine blood glucose monitoring to macrosomia at birth, mild to moderate hepatomegaly and life-threatening hypoglycemic coma or status epilepticus, further leading to poor neurological outcome.", "ORPHA ID": 276603, "Summary": ""}
{"Disease Name": "Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency", "Disease Definition": "A rare, congenital, isolated hyperinsulinism disorder characterized by diazoxide unresponsive recurrent episodes of hyperinsulinemic hypoglycemia resulting from an excessive insulin secretion by the pancreatic beta-cells due to a mutation in the ABCC8 gene. Pancreatic involvement is focal and can be cured by a selective partial pancreatectomy. Hypoglycemia may lead to variable clinical manifestations, ranging from asymptomatic hypoglycemia revealed by routine blood glucose monitoring to macrosomia at birth, mild to moderate hepatomegaly and life-threatening hypoglycemic coma or status epilepticus, further leading to poor neurological outcome.", "ORPHA ID": 276598, "Summary": ""}
{"Disease Name": "Diazoxide-resistant focal hyperinsulinism", "Disease Definition": "A form of congenital diazoxide-resistant hyperinsulinism characterized by recurrent episodes of profound hypoglycemia caused by an excessive/uncontrolled insulin secretion (inappropriate for the level of glycemia) due to a focal adenomatous hyperplasia of pancreas, that is unresponsive to medical treatment with diazoxide.", "ORPHA ID": 79298, "Summary": ""}
{"Disease Name": "Diazoxide-resistant hyperinsulinism", "Disease Definition": "A form of congenital isolated hyperinsulism characterized by an excessive/ uncontrolled insulin secretion (inappropriate for the level of glycemia), recurrent episodes of profound hypoglycemia and resistance to medical management with diazoxide. Pancreatic involvement can be diffuse or focal.", "ORPHA ID": 276585, "Summary": ""}
{"Disease Name": "Dicarboxylic aminoaciduria", "Disease Definition": "A rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of dicarboxylic amino acids, glutamate and aspartate, that can be associated with kidney stones and neuropsychiatric manifestations.", "ORPHA ID": 2195, "Summary": ""}
{"Disease Name": "Didelphys uterus", "Disease Definition": "A rare non-syndromic uterovaginal malformation characterized by two separate uterine cavities and cervices, due to failure of the Müllerian ducts to fuse. A longitudinal vaginal septum of variable thickness and elasticity is also present. Patients may be asymptomatic or experience dyspareunia or dysmenorrhea. There is increased frequency of endometriosis, as well as fertility and gestational issues with significantly reduced chances of seeing a pregnancy to term. The condition may be associated with renal agenesis.", "ORPHA ID": 180086, "Summary": ""}
{"Disease Name": "Didymosis aplasticosebacea", "Disease Definition": "A rare skin disorder characterized by the co-ocurrence of sebaceous nevi with aplasia cutis congenita located directly adjacent or in close proximity and ocular abnormalities including limbal dermoids and coloboma of the conjunctiva.", "ORPHA ID": 370046, "Summary": ""}
{"Disease Name": "Diencephalic syndrome", "Disease Definition": "Diencephalic syndrome (DS) is a rare condition characterized by profound emaciation and failure to thrive (with normal caloric intake and normal linear growth), hyperalertness, hyperkinesia and euphoria, in the presence of hypothalamic tumors.", "ORPHA ID": 1672, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nDS usually presents in infants or young children (mean age 6 months), but can also occur rarely in older children and adults. DS usually occurs in the presence of low grade astrocytoma/glioma brain tumors of the hypothalamus, which may extend into the optic pathway. These tumors are usually more aggressive and appear at a younger age when associated with DS. Rarely, DS can be secondary to craniopharyngioma, as well as other suprasellar tumors. Manifestations of DS include weight loss, eventually leading to severe emaciation (despite normal caloric intake and linear growth) with an absence of subcutaneous fat, as well as hyperalertness, hyperkinesia, and cheerfulness extending to euphoria in some. Nystagmus, strabismus, decreased visual acuity (and very rarely blindness), optic pallor, hydrocephalus, headache, somnolence, and vomiting have also been reported in some cases. Hypothalamic obesity may occur due to hypothalamic damage. Normal or precocious intellectual development is noted. Rarely, tumors may also be associated with neurofibromatosis type 1.\nEtiology\nA variety of chiasmatic and hypothalamic low-grade gliomas have been reported to be associated with DS, most commonly pilocytic and pilomyxoid astrocytoma, but there are case reports of craniopharyngioma, suprasellar ependymoma, suprasellar germinoma, suprasellar epidermoid cyst, and hypothalamic spongioblastoma. These tumors may lead to hypothalamic dysfunction and/or degeneration of the optic nerve. The pathogenesis of DS is unknown. Recently, it was proposed that leptin may be dysregulated, but further studies are needed.\nDiagnostic methods\nWhen DS is suspected clinically (failure to thrive in children despite normal caloric intake), gadolinium-enhanced magnetic resonance imaging of the cranium, as well as of the spine (due to frequent leptomeningeal seeding) is performed, and cerebrospinal fluid analysis may also be necessary. Ophthalmologic examination should be performed to check for any visual abnormalities. Growth hormone and ghrelin levels are increased and insulin and leptin levels are decreased, but those changes may be secondary to the patient's body mass index.\nDifferential diagnosis\nThe differential diagnosis includes gastrointestinal disorders that lead to severe weight loss such celiac disease.\nManagement and treatment\nTreatment aims at removing or reducing the size of the tumor, by surgical or non-surgical methods. Since complete resection of the tumor is not possible due to its location, tumor resection is usually partial and is generally followed by chemotherapy. Radiotherapy is not commonly used, as the patients are young. Patients also require nutritional supplementation (orally or via nasogastric feeding tube or gastrostomy) for malnutrition while symptomatic. Follow-up after completion of treatment includes regular life-long oncologic, neurologic, ophthalmologic and clinical assessments as precocious puberty and pituitary hormone deficiencies may develop.\nPrognosis\nPrognosis depends on the histological type and grade of tumor but is poorer in patients with DS than in patients with similar tumors who do not present with DS. Frequently, these tumors continue to progress despite treatment. If untreated, patients have an average survival time of less than 12 months after diagnosis, but with proper treatment the long-term survival is greatly improved.\n\n                            Last update: \n                            October 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Laurie E. COHEN"}
{"Disease Name": "Diencephalic-mesencephalic junction dysplasia", "Disease Definition": "Diencephalic-mesencephalic junction dysplasia is a rare, genetic, non-syndromic cerebral malformation characterized by severe intellectual disability, progressive postnatal microcephaly, axial hypotonia, spastic quadriparesis, seizures and facial dysmorphism (bushy eyebrows, hairy forehead, broad nasal root, long flat philtrum, V-shaped upper lip). Additionaly, talipes equinovarus, non-obstructive cardiomyopathy, persistent hyperplastic primary vitreous, obstructive hydrocephalus and autistic features may also be associated. On brain magnetic resonance imaging, the 'butterfly sign' is characterisitcally observed and cortical calcifications, agenesis of the corpus callosum, ventriculomegaly, brainstem dysplasia and cerebellar vermis hypoplasia have also been described.", "ORPHA ID": 319192, "Summary": ""}
{"Disease Name": "Dietary iron overload disease", "Disease Definition": "A rare disorder described in sub-Saharan African populations and characterized by iron overload due to excess dietary iron intake and possibly genetic factors, leading to hepatic portal fibrosis and micronodular cirrhosis.", "ORPHA ID": 139507, "Summary": ""}
{"Disease Name": "Diethylstilbestrol syndrome", "Disease Definition": "A malformation syndrome reported in offspring (children and grandchildren) of women exposed to diethylstilbestrol (DES) during pregnancy and is characterized by reproductive tract malformations, decreased fertility and increased risk of developing clear cell carcinoma of the vagina and cervix in young women. Reproductive malformations reported in DES syndrome include small, T-shaped uteri and other uterotubal anomalies that increase the risk of miscarriages in women and epididymal cysts, microphallus, cryptorchidism, or testicular hypoplasia in men. DES, a synthetic nonsteroidal estrogen was widely prescribed from 1940-1970 to prevent miscarriage.", "ORPHA ID": 1916, "Summary": ""}
{"Disease Name": "Difference of sex development-intellectual disability syndrome", "Disease Definition": "A rare syndrome with 46,XY difference of sex development characterized by variable degrees of intellectual disability, short stature, severe genital anomalies resulting in sexual ambiguity (such as pseudovaginal perineoscrotal hypospadias and persistence of Müllerian structures), and ocular anomalies (microphthalmia, coloboma). Craniofacial peculiarities (coarse features, deep set eyes), spina bifida, imperforate anus, and sensorineural hearing loss were also described. No new cases have been reported since 1994.", "ORPHA ID": 2983, "Summary": ""}
{"Disease Name": "Differentiated thyroid carcinoma", "Disease Definition": "A rare, slow-growing, epithelial thyroid carcinoma typically presenting as an asymptomatic thyroid mass and is classed as either papillary thyroid cancer (PTC), follicular thyroid cancer (FTC) or Hurthle cell thyroid cancer (HCTC).", "ORPHA ID": 146, "Summary": "Epidemiology\nThe annual incidence of differentiated thyroid cancer (DTC) is about 1/10,000, and the incidence appears to be increasing. The female to male ratio is about 3:1.\nClinical description\nPTC, FTC, and HCTC have similar presentations, and constitute about 75, 20, and 5 percent of cases, respectively. About 10 percent of PTC are classified as tall cell variant, the most aggressive form of PTC. HCTC is generally considered slightly more aggressive than PTC and FTC. The age at diagnosis is usually over 30 years. Presentation is typically with an asymptomatic thyroid nodule. Rare but worrisome presentations include hoarseness due to vocal cord paralysis and obstruction of the airway or esophagus, and may suggest an aggressive variant of DTC or anaplastic thyroid carcinoma. DTC grows slowly, and distant metastases are rare at the time of presentation. The most common metastatic site is the cervical lymph nodes. Distant metastasis to lungs or bones is rare (about 5%). Pediatric cases are rare. They are more frequently present with lymph node involvement. Despite this apparently more aggressive presentation, the prognosis is excellent. Pathologically, PTC are usually composed of a mixture of papillae and follicles, frequently with relatively large nuclei containing folds and a clear center. About 50% contain calcium deposits. Different histological PTC subtypes have been described. FTC are characterized by microfollicles and presence of capsular and vascular invasion. HCTC, pathologically similar to FTC, are distinguished by mitochondria-rich, eosinophilic cytoplasm. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a recently described variant; it is currently unclear if it is a pre-malignant lesion or a DTC variant.\nEtiology\nDTC arise from the epithelial cells of the thyroid gland. Most DTCs are sporadic and without known cause. Ionizing radiation predisposes to PTC. Iodine deficiency is associated with an increased risk of FTC. The sporadic molecular pathogenesis of these three malignancies is partially understood. In PTC, the V600E BRAF mutation (7q34) as well as fusion genes involving RET (10q11.2) and NTRK1 (1q23.1) are common. Activating RAS mutations occur in both PTC and FTC as well as in benign thyroid lesions. The PAX8/PPARG fusion gene (2q13) is more frequently observed in FTC. About 5% of PTCs have a familial predisposition although the associated germline alterations are unknown. HCTC has a unique and complex genetic profile that includes somatic mutations (including DAXX, TERT, TP53, NRAS, NF1, CDKN1A, ARHGAP35 and complex I mtDNA) and widespread chromosomal loss.\nDiagnostic methods\nDTC usually presents on physical examination or ultrasound as an asymptomatic nodule within the thyroid gland. Serum concentrations of thyroid hormone are usually normal. Thyroid fine needle aspiration biopsy cytology is frequently used to distinguish between the benign and malignant nodules. Additional diagnostic techniques include ultrasound characteristics and genetic analyses of the fine needle biopsy material. Diagnosis is confirmed on pathology review following surgical resection.\nDifferential diagnosis\nDifferential diagnosis of thyroid nodules includes benign thyroid nodules (nodular goiter, thyroid cyst, follicular adenoma), other thyroid malignancies, as well as Hashimoto's thyroiditis and thyroid lymphoma.\nManagement and treatment\nThe treatment of DTC is prioritized. First, complete surgical resection is essential for cure. Second, thyroid hormone administration to suppress TSH to appropriate concentrations helps prevent recurrence. Third, since most DTCs maintain the ability to take up iodine, 131-iodine therapy is useful in eradicating residual microscopic disease. For those few patients refractory to conventional therapy, external radiation and multikinase inhibitors are effective. Long-term follow-up is essential due to the cumulative risk of recurrence (about 20% at 20 years).\nPrognosis\nPrognosis is generally good in most patients, but about 5% of cases are fatal. Good prognosis is associated with age below 55 years and tumors below 4 cm. Poor prognosis is associated with distant metastatic disease, progression to anaplastic thyroid cancer (occasional), and tumors with a TERT promoter mutation plus either an activating V600E BRAF mutation or activating RAS mutation.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Carl MALCHOFF"}
{"Disease Name": "Diffuse alveolar hemorrhage", "Disease Definition": "A rare clinical situation for which there is a European and/or American orphan designation. Characteristics include diffuse bleeding into the alveolar spaces that originate from the pulmonary microvasculature, including the alveolar capillaries, arterioles and venules. Patients present with cough, dyspnea, chest pain, fever, anemia and hemoptysis.", "ORPHA ID": 90060, "Summary": ""}
{"Disease Name": "Diffuse astrocytoma", "Disease Definition": "A rare low-grade astrocytoma characterized by a high degree of cellular differentiation, slow growth, and diffuse infiltration of adjacent brain structures, and corresponding to WHO grade II. The tumor typically affects young adults and has an intrinsic tendency for progression to high-grade glioma. Histological variants are fibrillary, gemistocytic, and protoplasmic astrocytoma. Patients most commonly present with seizures, but also with other neurological or neuropsychological abnormalities, depending on the location.", "ORPHA ID": 251595, "Summary": ""}
{"Disease Name": "Diffuse cerebral and cerebellar atrophy-intractable seizures-progressive microcephaly syndrome", "Disease Definition": "A rare, genetic, central nervous system malformation syndrome characterized by congenital, progressive microcephaly, neonatal to infancy-onset of severe, intractable seizures, and diffuse cerebral cortex and cerebellar vermis atrophy with mild cerebellar hemisphere atrophy, associated with profound global developmental delay. Hypotonia or hypertonia with brisk reflexes, variable dysmorphic facial features, ophthalmological signs (cortical visual impairment, nystagmus, eye deviation) and episodes of sudden extreme agitation caused by severe illness may also be associated.", "ORPHA ID": 404437, "Summary": ""}
{"Disease Name": "Diffuse cutaneous mastocytosis", "Disease Definition": "Diffuse cutaneous mastocytosis (DCM) is a rare form of cutaneous mastocytosis (CM; see this term) characterized by generalized erythroderma, various degrees of blistering, skin with a ''peau d'orange'' appearance and the accumulation of mast cells in the skin. At least two DCM variants are recognized, one with extreme blistering (Bullous DCM; see this term) and one with infiltrations (Pseudoxanthomatous DCM; see this term).", "ORPHA ID": 79456, "Summary": "Epidemiology\nDCM accounts for around 1-2% of all cases of CM and almost exclusively presents during infancy, mainly in the neonatal period. Less than 30 cases of neonatal onset DCM have been described in the literature so far.\nClinical description\nThe majority of patients present with generalized erythroderma with a reddish to brown-orange discoloration and extensive bullae. The blisters may become hemorrhagic, may be grouped or linear, and are usually located on the trunk, extremities or scalp. The bullous lesions typically resolve by 3-5 years of age. A small number of patients have been reported with yellow-orange infiltrated and xanthogranuloma-like abnormalities as the presenting feature of DCM (Pseudoxanthomatous DCM). Over time, the skin becomes thickened and has a doughy consistency. Other cutaneous manifestations may include pruritus, urticaria, a positive Darier's sign and marked dermographism. Systemic symptoms (including flushing, hypotension, severe anaphylaxis, hepatomegaly, diarrhea and gastrointestinal bleeding) appear to be more common in DCM than in other forms of CM with systemic symptoms.\nEtiology\nDCM generally occurs sporadically but a few familial cases have been reported. Mutations in the KIT gene (4q11-q12) have been identified in patients with some forms of mastocytosis and mutations in this gene have been identified in a few patients with DCM.\nDiagnostic methods\nDiagnosis may be suspected on the basis of the clinical findings and can be confirmed by histological examination using mast cell stains (Giemsa and toluidine blue) or immunohistochemical staining for tryptase or kit. Measurements of serum tryptase and urinary N-methylhistamine levels may also be useful for diagnosis and follow-up.\nDifferential diagnosis\nFor patients presenting with widespread bullous lesions the differential diagnosis should include bullous congenital ichthyosiform erythroderma, early-onset forms of epidermolysis bullosa, Poikiloderma of Kindler (see these terms) and staphylococcal scalded skin syndrome.\nManagement and treatment\nTreatment is symptomatic with administration of antihistamines (H1 and H2 in cases with gastrointestinal symptoms), topical steroids and mast cell membrane stabilizers. Factors that trigger mast cell degradation (non-steroidal anti-inflammatory drugs, physical stimuli, emotional stress, insect venom and certain foods) should be avoided. Oral steroid treatment and photochemotherapy with UVA therapy may be of benefit but should only be used in infancy in severe cases that are refractory to alternative treatment options. Close follow-up is required for early detection and management of systemic symptoms.\nPrognosis\nAlthough spontaneous resolution of the bullous lesions occurs before 5 years of age in most DCM patients, the prognosis is variable: DCM is associated with an increased risk of systemic involvement with life-threatening manifestations (gastrointestinal bleeding, anaphylaxis etc.). The association of DCM with mast cell leukemia has been reported in a few patients and persistence of DCM into adult life with transformation to indolent systemic mastocytosis has been described.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Pr A.P. [Arnold] ORANJE"}
{"Disease Name": "Diffuse cutaneous systemic sclerosis", "Disease Definition": "Diffuse cutaneous systemic sclerosis (dcSSc) is a subtype of Systemic Sclerosis (SSc; see this term) characterized by truncal and acral skin fibrosis with an early and significant incidence of diffuse involvement (interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement).", "ORPHA ID": 220393, "Summary": "Epidemiology\nThe prevalence is estimated at about 1/25,000 adults. Women are predominantly affected (F/M sex ratio around 4:1).\nClinical description\nThe disease usually manifests at between 40 and 50 years of age. Pediatric onset can occur but is extremely rare. Raynaud's phenomenon is often the first sign of the disease. The other signs usually appear a few months later. Skin hardening first occurs on the fingers and face, but rapidly becomes generalized. Telangiectasias are sometimes present on the thorax, face, lips, tongue, and fingers. Tendon friction rubs are observed. Esophageal dysmotility is common and provokes gastroesophageal reflux and sometimes dysphagia. Gastrointestinal malabsorption and dysmotility may also be present and are associated with weight loss, vomiting, diarrhea or occlusion. Dry mouth and dental involvement can occur. Arthralgias and acroosteolysis are frequent. Muscular involvement can lead to muscular pain and weakness, and cramps. Severe life-threatening renal involvement may occur (about 2% of cases). Pulmonary fibrosis is frequently seen (60% of cases). Pulmonary hypertension may also occur (10-15% of cases).\nEtiology\nThe exact cause of diffuse cutaneous SSc is unknown. The disease originates from an autoimmune reaction which leads to overproduction of collagen. In some cases, the condition is associated with exposure to chemicals (including silica, solvents and hydrocarbons).\nDiagnostic methods\nDiagnosis is based on typical clinical manifestations and on evidence of specific microangiopathy with giant loops on nailfold capillaroscopy. Skin biopsy is usually not needed. Blood tests must be performed, and show typical antitopoisomerase autoantibodies in 30-40% of cases. The extent of the disease should be evaluated by computed tomography (CT), electrocardiogram, echocardiography, radiography of the hands and esophageal and gastric fibroscopy if needed.\nDifferential diagnosis\nDifferential diagnoses include Sharp syndrome, systemic lupus erythematosus, antiphospholipid syndrome, polyarteritis nodosa, polymyositis, and rheumatoid arthritis (see these terms).\nManagement and treatment\nManagement is mostly symptomatic. Raynaud's phenomenon can be treated with calcium channel blockers. Proton pomp inhibitors are given for gastric reflux. Surgical resection of severe calcinosis may be required. Low doses of corticosteroids with immunosuppressive agents are needed in cases with recent severe cutaneous involvement or in progressive lung fibrosis. Pulmonary vasodilators are given in case of pulmonary arterial hypertension. Patients require regular clinical follow-up with early pulmonary function tests and echocardiography.\nPrognosis\nThe prognosis is severe (10-year survival rate of 60-80%) because of the high risk of life-threatening complications: renal crisis, severe digestive involvement, severe lung fibrosis, and, sometimes, severe heart involvement and pulmonary arterial hypertension.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Eric HACHULLA"}
{"Disease Name": "Diffuse intrinsic pontine glioma", "Disease Definition": "A rare glial tumor characterized by a highly aggressive, diffusely infiltrative pontine lesion generally occurring in children, affecting local nerve fiber tracts and spreading contiguously to involve adjacent structures, but also metastasizing within the central nervous system. Patients mostly present with a short history of symptoms, typically including the classic triad of multiple cranial neuropathies, long tract signs, and ataxia. Signs and symptoms of increased intracranial pressure may present due to obstructive hydrocephalus. Prognosis is poor and not related to histological grade.", "ORPHA ID": 497188, "Summary": ""}
{"Disease Name": "Diffuse large B-cell lymphoma with chronic inflammation", "Disease Definition": "Diffuse large B-cell lymphoma with chronic inflammation is an Epstein-Barr virus-associated malignant lymphoproliferative disorder, developing in a context of long-standing or slow-growing, chronically inflamed lesions, such as chronic pyothorax, metallic implants in bones and joints, chronic osteomyelitis, chronic venous ulcer, or, rarely granulomatous inflammation. The tumor is usually primarily localized, with no involvement of other organs.", "ORPHA ID": 300888, "Summary": ""}
{"Disease Name": "Diffuse large B-cell lymphoma", "Disease Definition": "Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma (NHL; see this term) in adults characterized by a median age of presentation in the sixth decade of life (but also rarely occurring in adolescents and children) with the initial presentation being single or multiple rapidly growing masses (that may or may not be painful) in nodal or extranodal sites (such as thyroid, skin, breast, gastrointestinal tract, testes, bone, or brain) and that can be accompanied by symptoms of fever, night sweats and weight loss. DLBCL has an aggressive disease course, with the elderly having a poorer prognosis than younger patients, and with relapses being common.", "ORPHA ID": 544, "Summary": ""}
{"Disease Name": "Diffuse leptomeningeal melanocytosis", "Disease Definition": "Diffuse leptomeningeal melanocytosis is a rare tumor of meninges arising from leptomeningeal melanocytes, characterized by diffuse infiltration of the leptomeninges (pia mater and arachnoidea) anywhere in the central nervous system. Clinical features may include stillbirth, intracranial hypertension and hydrocephalus, seizure, ataxia, syringomyelia, cranial nerve palsy, intracranial haemorrhage, sphincter dysfunction and neuropsychiatric symptoms. Transformation into malignant melanoma of the central nervous system was reported. It may be associated with congenital nevi, as a part of neurocutaneous melanosis.", "ORPHA ID": 252031, "Summary": ""}
{"Disease Name": "Diffuse lymphatic malformation", "Disease Definition": "A rare developmental defect during embryogenesis characterized by multifocal dilated lymphatic vessels involving multiple organs and tissues. Patients mostly present in infancy and childhood. Clinical course and prognosis depend on the affected sites and extent of the condition, deterioration of lung function being a major cause of morbidity and mortality.", "ORPHA ID": 141209, "Summary": ""}
{"Disease Name": "Diffuse palmoplantar keratoderma with painful fissures", "Disease Definition": "A rare, genetic, isolated palmoplantar keratoderma characterized by non-epidermolytic, diffuse hyperkeratotic lesions affecting both the palms and the soles, associated with a tendency of painful fissuring. Contrary to the clinical findings, histologic examination reveals findings suggestive of keratosis palmoplantaris striata, with orthohyperkeratosis featuring widening of the intercellular spaces and disadhesion of keratocytes in the upper epidermal layers.", "ORPHA ID": 369999, "Summary": ""}
{"Disease Name": "Diffuse palmoplantar keratoderma, Bothnian type", "Disease Definition": "A rare isolated diffuse palmoplantar keratoderma characterized by diffuse, homogeneous, mild to thick, brown-to-yellowish palmoplantar hyperkeratosis (sometimes spreading over the dorsal aspect of fingers). Skin biopsy shows non-epidermolytic changes. There are no changes in hair, teeth or nails, and no syndromic involvement of other organs.", "ORPHA ID": 2337, "Summary": "Epidemiology\nThe disease was first described in Northern Sweden, and subsequently in Denmark and in the United Kingdom. Both sexes are affected. Precise epidemiologic data are not available. A 1994 publication states a point prevalence of 0.3-0.5% in Sweden. It is possible that the prevalence was underestimated prior to the availability of genetic diagnosis.\nClinical description\nDiffuse palmoplantar keratoderma, Bothnian type, presents in the first few months of life with brown-to-yellow keratoderma with an erythematous margin, and extension to dorsal aspects of hands/feet in some patients (transgrediens). Following exposure to water, the keratoderma takes a white, spongy appearance, exhibiting a margin between affected and normal skin. Hyperhidrosis is usually present. Patients can develop superinfections. Histological analysis reveals orthohyperkeratosis without epidermolysis. Superinfection by dermatophytes can be visualized with periodic acid-Schiff-staining.\nEtiology\nBothnian type is due to heterozygous missense mutations in aquaporin 5 (AQP5), which encodes for a water-channel protein.\nDiagnostic methods\nClinical distinction from keratoderma with associated features or syndromic forms, as well as histologic assessment (absence of epidermolysis, see above), helps to narrow down the differential diagnosis. The clinical diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis is broad for diffuse keratoderma and includes aquagenic palmoplantar keratoderma (seen in patients with cystic fibrosis, but also sporadically), KRT1-related diffuse nonepidermolytic keratoderma, epidermolytic palmoplantar keratoderma, localized forms of keratoderma (of which pachyonychia congenita due to keratin 6 mutations can sometimes present with a rather diffuse keratoderma), diffuse recessive keratoderma such as Nagashima type, mal de Meleda, Gamborg-Nielson type, and syndromes presenting with diffuse keratoderma such as palmoplantar keratoderma-esophageal carcinoma syndrome, tyrosinemia type 2, keratoderma hereditarium mutilans, Huriez syndrome, Papillon-Lefevre syndrome, loricrin keratoderma, etc.\nAntenatal diagnosis\nThe disease is benign. Antenatal diagnosis is therefore not recommended.\nGenetic counseling\nThis autosomal-dominant disease has a 50% risk of transmission. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy\nManagement and treatment\nTopical medication (emollients, keratolytics, retinoids, steroids) and systemic retinoids are used, but only case series are available, and prospective studies are lacking. New targeted treatments, according to the specific mechanisms of the disease, are in development.\nPrognosis\nNo impact on life expectancy has been documented. Disease severity is variable. The phenotype includes mild cases. More severe cases impair finger grip and walking, thus negatively affecting quality of life.\n\n                            Last update: \n                            December 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Aldona PIETRZAK  - Pr Matthias SCHMUTH | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Diffuse palmoplantar keratoderma-acrocyanosis syndrome", "Disease Definition": "Diffuse palmoplantar keratoderma-acrocyanosis syndrome is characterised by the association of diffuse palmoplantar keratoderma and acrocyanosis. It has been described in eight members of one family and in two sporadic cases. The mode of inheritance in the familial cases was autosomal dominant.", "ORPHA ID": 86918, "Summary": ""}
{"Disease Name": "Diffuse panbronchiolitis", "Disease Definition": "Diffuse panbronchiolitis is a rare chronic inflammatory obstructive pulmonary disease primarily affecting the respiratory bronchioles throughout both lungs and inducing sinobronchial infection. Onset occurs in the second to fifth decade of life and manifests by chronic cough, exertional dyspnea, and sputum production. Most patients also have chronic paranasal sinusitis", "ORPHA ID": 171700, "Summary": ""}
{"Disease Name": "Digestive duplication cyst of the tongue", "Disease Definition": "Digestive duplication cyst of the tongue is an extremely rare otorhinolaryngological malformation which occurs during early embryogenesis and is characterized by a single, and on occasion multiple, cystic lesion that is most frequently located in the anterior portion of the tongue, either deeply embedded within it or superficially on it. Depending mostly on size and location of the cyst, patients could be asymptomatic or could present a wide array of symptoms, such as varying degrees of respiratory and feeding difficulties, lingual swelling and protrusion, dysphagia, and more rarely, recurrent bleeding or brownish discharge from a lingual sinus.", "ORPHA ID": 141071, "Summary": ""}
{"Disease Name": "Digital extensor muscle aplasia-polyneuropathy", "Disease Definition": "Digital extensor muscle aplasia-polyneuropathy is a rare, hereditary motor and sensory neuropathy characterized by flexion deformities of the thumb and fingers, sensory deficit in the hand and polyneuropathic electrophysiologic findings in the limbs. Operation on the hands reveals extensor muscles and their tendons to be absent or hypoplastic. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 2926, "Summary": ""}
{"Disease Name": "Digitalis poisoning", "Disease Definition": "A rare, potentially life-threatening poisoning that provokes conduction disturbances, characterized by increased automaticity and decreased conduction. Acute poisoning presents with the common initial manifestations of nausea and vomiting, cardiovascular manifestations (bradycardia, heart block and a variety of dysrhythmias), central nervous system manifestations (lethargy, confusion and weakness) and hyperkalemia. Chronic poisoning is more insidious, manifesting with gastrointestinal symptoms, altered mental status, and visual disturbances.", "ORPHA ID": 31828, "Summary": ""}
{"Disease Name": "Dihydropteridine reductase deficiency", "Disease Definition": "A rare form of hyperphenylalaninemia due to tetrahydropterin (BH4) recycling deficiency, leading to central dopamine and serotonin deficiency, clinically characterized by infantile-onset neurological disease of variable severity ranging from mild forms with minor neurological development to severe forms with hypotonia, developmental delay, complex movement disorder dominated by dystonia or dystonia parkinsonism. Some patients may present refractory neurological symptoms like a degree of developmental delay, epilepsy and brain abnormalities.", "ORPHA ID": 226, "Summary": "Epidemiology\nThe global prevalence of BH4 deficiencies remains unknown and great variance can be found among different countries. European newborn screening programs (NBS) reveal that the mean incidence of all hyperphenylalaninemias (HPA) is approximately 1/10,000, with BH4 deficiencies representing 1-2% of cases dihydropteridine reductase deficiency (DHPRD) is the second most frequent of all HPA-associated BH4 deficiencies, representing approximately one third of cases. It is more frequent in regions around the Mediterranean Sea.\nClinical description\nWhen left untreated, the deficiency leads to neurological symptoms typically starting at 4-5 months of age. Neonatal onset has been described in single cases characterized by hypotonia, poor sucking and decreased spontaneous movements. Very frequent symptoms (occurring in >50% of patients) are developmental delay and axial hypotonia. Frequent symptoms (occurring in 25-50% of patients) are, hypertonia of the extremities, epilepsy, impaired speech development and microcephaly. Brain imaging might show progressive calcifications in basal ganglia, white or grey matter, and a pattern of bilateral parietooccipital, and to a lesser extent, frontal and/or cerebellar changes in arterial watershed areas. There are no consistent reports on genotype-phenotype correlation.\nEtiology\nDHPR deficiency is caused by variants in the QDPR gene, which encodes quinoid dihydropteridine reductase involved in the second step of BH4 regeneration. BH4 is an essential cofactor for phenylalanine hydroxylase (PAH), tyrosine (TH) and tryptophan hydroxylase (TPH). Therefore, the tetrahydrobiopterin deficiency causes not only HPA, but also a central dopamine and serotonin deficiency.\nDiagnostic methods\nDHPRD should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when HPA is moderate. The analysis of pterins in urine or dried blood spot (DBS) in patients and the analysis of dihydropteridine reductase (DHPR) enzyme activity in DBS has to follow in all patients with HPA on NBS. The suspected diagnosis can be further confirmed by genetic evaluation of the QDPR gene and/or the measuring of neurotransmitters 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and pterins in cerebrospinal fluid. Clinical consensus guidelines on the different diagnostic options are available with open access.\nDifferential diagnosis\nThe differential diagnosis includes classical phenylketonuria and hyperphenylalaninemia due to autosomal recessive GTP cyclohydrolase I, pterin-4-alpha-carbinolamine dehydratase, 6-pyruvoyl-tetrahydropterin synthase, and DNAJC12 deficiencies.\nAntenatal diagnosis\nPrenatal diagnosis is possible by molecular analysis where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nDHPR deficiency is an autosomal recessive genetic disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of sapropterin hydrochlorid) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophan). Administration of methylfolate or folinic acid can restore cerebral folate levels. In case of insufficient clinical response or L-dopa-induced hyperkinesia long-acting dopamine agonists (e.g. pramipexole) can be used to stabilize the clinical and biochemical picture. Monoamino oxidase inhibitors (selegiline) are also useful to prolong the action of neurotransmitter precursors.\nPrognosis\nLevodopa/carbidopa supplementation drastically improves motor function. However, long-term prognosis correlates with early diagnosis and treatment initiation. In DHPRD, even with treatment, some patients have a degree of developmental delay, epilepsy and, in some cases, brain abnormalities.\n\n                            Last update: \n                            April 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Oya KUSEYRI HÜBSCHMANN | MetabERN* - Pr Thomas OPLADEN | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Dihydropyrimidine dehydrogenase deficiency", "Disease Definition": "A rare disorder of pyrimidine metabolism characterized by a variable phenotype ranging from absence of symptoms to severe neurological involvement with developmental delay, intellectual disability, and seizures. Additional signs and symptoms may include hypotonia, microcephaly, ocular abnormalities (such as microphthalmia, nystagmus, and strabismus), and autistic behavior, among others. Analysis of urine typically shows high levels of uracil and thymine. Patients are at risk of suffering from severe toxicity after the administration of the anti-neoplastic agent 5-fluorouracil.", "ORPHA ID": 1675, "Summary": ""}
{"Disease Name": "Dihydropyrimidinuria", "Disease Definition": "Dihydropyrimidinase (DPD) deficiency is a very rare pyrimidine metabolism disorder with a variable clinical presentation including gastrointestinal manifestations (feeding problems, cyclic vomiting, gastroesophageal reflux, malabsorption with villous atrophy), hypotonia, intellectual deficit, seizures, and less frequently growth retardation, failure to thrive, microcephaly and autism. Asymptomatic cases are also reported. DPD deficiency increases the risk of 5-FU toxicity.", "ORPHA ID": 38874, "Summary": ""}
{"Disease Name": "Dilated cardiomyopathy with ataxia", "Disease Definition": "Dilated cardiomyopathy with ataxia (DCMA) is characterized by severe early onset (before the age of three years) dilated cardiomyopathy (DCM) with conduction defects (long QT syndrome), non-progressive cerebellar ataxia, testicular dysgenesis, and 3-methylglutaconic aciduria.", "ORPHA ID": 66634, "Summary": "Epidemiology\nTo date, all cases of DCMA reported involve individuals from the Dariusleut Hutterite population, an endogamous population of the Great Plains region of Canada and the northern United States.\nClinical description\nPrenatal or postnatal growth failure, significant motor delay (due to cerebellar syndrome with ataxia) and male genital anomalies (ranging from isolated cryptorchidism to severe perineal hypospadias) are very frequent clinical signs. Additional features include optic atrophy, a mild increase in hepatic enzymes with microvesicular hepatic steatosis, a normochromic microcytic anemia, and mild to borderline non-progressive intellectual deficit.\nEtiology\nDCMA is caused by mutation of the DNAJC19 gene (encoding the DNAJC19 protein localized to the mitochondria in cardiac myocytes).\nDifferential diagnosis\nDCMA syndrome shares some clinical features with the X-linked Barth syndrome and the other 3-methylglutaconic acidurias (types I, III and IV; see these terms).\nGenetic counseling\nDCMA is an autosomal recessive condition.\nPrognosis\nIn a clinical study of 18 DCMA patients, over 70% of patients died from either progressive cardiac failure or sudden cardiac death. Improvement with standard medical treatment or complete resolution of the DCM has been reported in some patients.\n\n                            Last update: \n                            January 2007"}
{"Disease Name": "Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome", "Disease Definition": "This syndrome is characterized by the association of dilated cardiomyopathy and hypergonadotropic hypogonadism (DCM-HH).", "ORPHA ID": 2229, "Summary": "Epidemiology\nPrevalence is unknown but less than 20 affected families have been described in the literature so far.\nClinical description\nOccasional findings include a broad nasal base, blepharoptosis, mild intellectual deficit, mild skeletal anomalies, metabolic abnormalities, thyroid hemiagenesis, collagenoma, diabetes mellitus, and thyroid hemiagenesis.\nEtiology\nMutations in the LMNA gene were recently detected in two sisters with an overlapping clinical phenotype (ovarian failure and progressive dilated cardiomyopathy) but with additional findings that included a narrow chest, sloping shoulders, aged appearance of the hands and feet and facial dysmorphism (beaked nose and severe retrognathia).\nGenetic counseling\nTransmission appears to be autosomal recessive.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "Dimethylglycine dehydrogenase deficiency", "Disease Definition": "Dimethylglycine dehydrogenase deficiency is an extremely rare autosomal recessive glycine metabolism disorder characterized clinically in the single reported case to date by muscle fatigue and a fish-like odor.", "ORPHA ID": 243343, "Summary": ""}
{"Disease Name": "Diphallia", "Disease Definition": "A rare, non-syndromic, urogenital tract malformation characterized by complete or partial penile duplication, ranging from only glans duplication to the presence of two penis shafts with either one (i.e. bifid phallus) or two (i.e. true diphallia) corpora cavernosum in each. Additional anomalies, such as urethra duplication, an abnormal voiding pattern, hypo- or epispadias, bifid/ectopic scrotum, bladder exstrophy or duplication, are frequently associated, but it may also present as an isolated anomaly. In severe cases, pubic symphysis diastasis, imperforate or duplicated anus, colon/ rectosigmoidal duplication, inguinal hernia and vertebral anomalies may be observed.", "ORPHA ID": 227, "Summary": ""}
{"Disease Name": "Diphtheria", "Disease Definition": "A rare bacterial infectious disease characterized by an affliction of the upper respiratory tract mediated by the toxin of Corynebacterium diphtheriae. Symptoms include formation of an inflammatory pseudomembrane, fever, sore throat, headaches, coughing, dysphagia, dyspnea, and prominently swollen cervical lymph nodes. The disease may lead to respiratory failure and severe toxin-mediated damage of internal organs, including the heart and kidneys. A cutaneous form of diphtheria is more common in tropical climates and usually follows an indolent course.", "ORPHA ID": 1679, "Summary": ""}
{"Disease Name": "Diphyllobothriasis", "Disease Definition": "Bothriocephalosis is a mammalian cosmopolitan intestinal parasitosis. In addition to non-specific digestive problems (nausea, abdominal pain, lack of appetite), bothriocephalosis provokes an anaemia caused by vitamin B12 deficiency that resembles Biermer anaemia (anaemia characterised by abnormally large red blood cells).", "ORPHA ID": 128, "Summary": "Epidemiology\nThe prevalence is Europe is unknown but more than 10 cases are reported each year, principally from the Italian, Swiss and French Alps.\nEtiology\nIt is an adult cestodosis caused by the large (more than 10 metres) fish tapeworm Diphyllobothrium latum. The life cycle of the parasite is complex and involves two intermediate hosts: a microscopic crustacean, followed by a freshwater fish. Mammals are contaminated through eating fleshy parts of lightly cooked, smoked or undersalted fish.\nDiagnostic methods\nDiagnosis is made by examination of the stools.\nManagement and treatment\nStandard tapeworm treatments (niclosamide or praziquantel) are effective at treating this parasitosis.\n\n                            Last update: \n                            December 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Luc PARIS"}
{"Disease Name": "Diprosopus", "Disease Definition": "Diprosopus is a rare, life-threatening developmental defect during embryogenesis, and a subtype of conjoined twins, characterized by partial or complete duplication of the facial structures on a single head, neck, trunk and body. It may be associated with congenital anomalies involving the cardiovascular, gastrointestinal, respiratory and central nervous systems. Cleft lip and palate have been reported in rare cases.", "ORPHA ID": 1681, "Summary": ""}
{"Disease Name": "Dirofilariasis", "Disease Definition": "Dirofilariasis is a form of filariasis (see this term), caused by the filarial nematode of the genus Dirofilaria (including Dirofilaria repens, Dirofilaria immitis), which is transmitted by mosquitoes. The disease is characterized by the presence of subcutaneous nodules (or a conjunctival form that develops slowly and that can be painless to tender), edema and erythema at the site of parasite localization, a feeling of 'crawling' under the skin, and the ''Calabar'' swelling (similar to thatin loiasis (see this term). The latter may last a few days and recurrences are possible. Common localizations of dirofilaria are head and neck, most commonly in the periorbital region, the limbs and trunk.", "ORPHA ID": 166291, "Summary": ""}
{"Disease Name": "Discoid lupus erythematosus", "Disease Definition": "A rare form of chronic cutaneous lupus erythematosus characterized by erythematous, scaly papules and plaques preferentially occurring on sun-exposed skin areas (scalp, face, and ears) and exhibiting follicular plugging, pigmentary changes, and central atrophy, scarring, and telangiectasia. Skin biopsy shows a perivascular and periadnexal lymphocytic infiltrate and involvement of the dermoepidermal junction with thickening of the basement membrane and vacuolar degeneration of the basal cells. A small percentage of patients may develop systemic lupus erythematosus.", "ORPHA ID": 90281, "Summary": ""}
{"Disease Name": "Discrete papular lichen myxedematosus", "Disease Definition": "Discrete papular lichen myxedematosus is a rare chronic, slowly progressive form of localized lichen myxedematosus (see this term) characterized by the development of a few to multiple small symmetrical skin-coloured mucinous papules on the limbs and trunk.", "ORPHA ID": 90394, "Summary": ""}
{"Disease Name": "Dislocation of the hip-dysmorphism syndrome", "Disease Definition": "Dislocation of the hip-dysmorphism syndrome is a rare multiple congenital anomalies syndrome characterized by bilateral congenital dislocation of the hip, characteristic facial features (flat mid-face, hypertelorism, epicanthus, puffiness around the eyes, broad nasal bridge, carp-shaped mouth), and joint hyperextensibility. Congenital heart defects, congenital dislocation of the knee, congenital inguinal hernia, and vesicoureteric reflux have also been reported. There have been no further descriptions in the literature since 1995.", "ORPHA ID": 2412, "Summary": ""}
{"Disease Name": "Disorder of bile acid synthesis", "Disease Definition": "A group of sterol metabolism disorders due to enzyme deficiencies of bile acid synthesis (BAS) in infants, children and adults, with variable manifestations that include cholestasis, neurological disease, and fat malabsorption. Nine inborn errors have been described, 7 of which lead to liver cholestasis.", "ORPHA ID": 79168, "Summary": "Epidemiology\nOverall prevalence is unknown but estimated prevalence may be around 1-9/1,000,000 for overall BAS defects, excluding cerebrotendinous xanthomatosis. Inborn errors in BAS probably account for 1-2% of cases of unexplained liver disease in infants, children and adolescents.\nClinical description\nAge at diagnosis is variable. Presentation may be in infancy with liver cholestasis, in childhood with unexplained liver disease or in adulthood with neurologic disease. Infants and children may present with complications secondary to fat malabsorption and fat-soluble vitamin deficiency including rickets, bleeding diathesis, neuroaxonal dystrophy and night blindness.\nEtiology\nThe seven inborn errors of BAS leading to liver cholestasis include: 3-beta-hydroxy-C27-steroid oxidoreductase deficiency (BAS defect type 1) that is the most common, delta4-3-oxosteriod-5-beta reductase deficiency (BAS defect type 2), oxysterol 7alpha-hydroxylase deficiency (BAS defect type 3), 2-methylacyl-CoA racemase deficiency (BAS defect type 4;), trihydroxycholestanoic acid (THCA) CoA oxidase deficiency (see this term), bile acid CoA ligase deficiency and defective amidation (see this term), and cerebrotendinous xanthomatosis (see these terms). Cholesterol 7alpha-hydroxylase deficiency (see this term) leads to hypercholesterolemia without liver cholestasis. A reported defect in side chain oxidation in the alternate 25-hydroxylation pathway needs further confirmation.\nDiagnostic methods\nDiagnosis is based on serum hepatic enzyme and bilirubin profile, and analysis of urine, serum and bile using liquid secondary ionization mass spectrometry (LSIMS) and gas chromatography - mass spectrometry (GC-MS).\nDifferential diagnosis\nThe spectrumof differential diagnoses is large and is that of neonatal cholestasis, unexplained fat-soluble vitamin deficiency in infancy and childhood, unexplained liver disease in infancy, childhood and adolescence and unexplained neurologic disease in adults.\nAntenatal diagnosis\nMost defects can be diagnosed antenatally from embryonic tissue when there has been a previously affected sibling. Urine from suspected cases may be screened by LSIMS in the first neonatal days and therapy initiated before significant morbidity develops.\nManagement and treatment\nTreatment is based on primary bile acid therapy. Cholic acid creates a bile acid pool that stimulates bile flow and fat absorption. It does not appear to be effective for type 3. Ursodeoxycholic acid (UDCA) therapy creates a bile acid pool, but does not suppress production of toxic intermediates and is not very effective at facilitating fat absorption. Glycocholic acid therapy is the treatment of choice for bile acid CoA ligase deficiency and defective amidation, improving fat absorption and growth.\nPrognosis\nPrognosis depends on the type of defect. In all defects that affect the steroid nucleus of the bile acid molecule, if untreated, progressive liver disease may develop or reduced intestinal bile acid concentrations may lead to serious morbidity or mortality. Long-term survival and clinical improvement is possible with early treatment. In those defects that affect the side chain, liver disease is milder and neurological disease may predominate.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr James HEUBI"}
{"Disease Name": "Dissecting cellulitis of the scalp", "Disease Definition": "Dissecting cellulitis of the scalp is a rare chronic suppurative dermatosis of the scalp that mainly affects black men and that is characterized by multiple painful inflammatory follicular and perifollicular nodules, pustules, and abscesses that interconnect via sinus tracts and eventually result in scarring alopecia.", "ORPHA ID": 345, "Summary": ""}
{"Disease Name": "Disseminated peritoneal leiomyomatosis", "Disease Definition": "Disseminated peritoneal leiomyomatosis (DPL) is characterized by the proliferation of multiple benign smooth muscle cell-containing nodules in the peritoneal cavity.", "ORPHA ID": 71274, "Summary": "Epidemiology\nFewer than 150 cases have been reported in the literature to date.\nClinical description\nDPL manifests during adulthood and is predominantly found in women. Most patients are asymptomatic but clinical features such as abdominal and pelvic pain, rectal or vaginal bleeding and, more rarely, gastrointestinal disorders have been reported. Malignant transformation is rare and in a few cases, metastases have been found in the liver and lungs.\nEtiology\nEtiology is unknown but DPL seems to be a multifactorial disease with a genetic or hormonal component (high levels of estrogen and progesterone) leading to metaplasia of peritoneal mesenchymal cells. In some women, DPL seems to originate from proliferation of fragments of uterine leiomyoma in the abdominal cavity after laparoscopic surgery.\nDiagnostic methods\nImaging techniques such as ultrasound examination are required for detection of DPL. Diagnosis is confirmed by biopsy of the nodules which reveals the presence of smooth-muscle cells with no atypia or necrosis, fibroblasts and myofibroblasts.\nDifferential diagnosis\nDifferential diagnosis includes parasitic leiomyoma, intravenous leiomyomatosis and other primitive or secondary peritoneal carcinomatoses.\nManagement and treatment\nDepending on the extent of the disease, first-line treatment for DPL is surgical excision or cytoreductive surgery. Hormone intake (e.g. oral contraceptives) must be discontinued. Systemic chemotherapy (off-label use) has been suggested as a treatment option for the rare cases of unresectable or metastatic tumors.\nPrognosis\nPrognosis is usually good. Death has however been observed in some cases presenting unresectable or metastatic tumors.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Olivier GLEHEN"}
{"Disease Name": "Disseminated superficial actinic porokeratosis", "Disease Definition": "A rare skin disease that is the most common form of porokeratosis characterized by the presence of several small annular plaques with a distinctive keratotic rim found most commonly on sun-exposed areas of the skin, particularly the extremities.", "ORPHA ID": 79152, "Summary": "Epidemiology\nDisseminated superficial actinic porokeratosis (DSAP) prevalence is not precisely known, although DSAP is the most common form of porokeratosis. It is more frequently seen in women, probably because they more readily seek advice for cosmetic concerns.\nClinical description\nThe disease usually starts during the third to fourth decade of life (only rarely during childhood). DSAP is characterized by several small (0.5-1 cm), round, pink-brownish plaques, surrounded by a distinctive keratotic rim, corresponding microscopically to the cornoid lamella. They are painless, but pruritus is reported in one third of patients. The lesions appear on skin that is exposed to sunlight (usually the extremities) but never on the palms or soles. They usually appear in summer and may improve or disappear during winter. DSAP is usually a benign disease, although squamous cell carcinoma can very rarely develop within the lesions.\nEtiology\nMutations in the mevalonate kinase (MVK) gene, located to chromosome 12q24, have been found in up to one third of DSAP cases. MVK encodes an enzyme in the mevalonate pathway, which is thought to be crucial for the biosynthesis of cholesterol and isoprenoid as well as the regulation of calcium-induced keratinocyte differentiation. More recently, pathogenic mutations in the SLC17A9 gene (20q13.33) were also found in DSAP patients. Risk factors for DSAP include exposure to ultraviolet light and immunosuppression.\nDiagnostic methods\nHistopathological examination of a cutaneous biopsy confirms the clinical diagnosis of DSAP. The characteristic feature is the presence of a cornoid lamella, i.e. a vertical stack of parakeratotic corneocytes within the horny layer, seated on a shallow depression of the underlying epidermis that is devoid of a granular layer. Molecular genetic testing for a mutation in the MVK gene can also confirm diagnosis.\nDifferential diagnosis\nDifferential diagnoses include (pre)neoplastic or hyperplastic keratotic skin lesions as well as other forms of porokeratosis, such as porokeratosis of Mibelli or superficial disseminated porokeratosis (similar to DSAP but not triggered by sunlight).\nGenetic counseling\nDSAP often follows an autosomal dominant pattern of inheritance, but sporadic cases have also been reported.\nManagement and treatment\nThere is no standard treatment for DSAP. Topical imiquimod 5% cream, topical 5-fluorouracil (5-FU) and topical vitamin D-analogues (tacalcitol, calcipotriol) have shown to be beneficial in treating the lesions of DSAP in some patients. Cryotherapy, electrodessication, laser ablation and photodynamic therapy have been tested with varying results. DSAP patients should limit their exposure to sun.\nPrognosis\nDSAP has a good prognosis as it very rarely progresses to carcinoma. However the disease may cause cosmetic concern and thereby exerts a negative effect on a patient's quality of life.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jean KANITAKIS"}
{"Disease Name": "Distal 16p11.2 microdeletion syndrome", "Disease Definition": "Distal 16p11.2 microdeletion syndrome is a rare chromosomal anomaly syndrome resulting from the partial deletion of the short arm of chromosome 16 with a highly variable phenotype typically characterized by developmental delay, mild intellectual disability and autism spectrum disorder. Macrocephaly (apparent by 2 years of age), structural brain malformations, epilepsy, vertebral anomalies and obesity are frequently associated.", "ORPHA ID": 261222, "Summary": ""}
{"Disease Name": "Distal 17p13.1 microdeletion syndrome", "Disease Definition": "Distal 17p13.1 microdeletion syndrome is a rare chromosomal anomaly syndrome characterized by mild global developmental delay/intellectual disability with poor to absent speech, dysmorphic features (long midface, retrognathia with overbite, protruding ears), microcephaly, failure to thrive, wide-based gait and a body posture with knee and elbow flexion and hands held in a midline.", "ORPHA ID": 319171, "Summary": ""}
{"Disease Name": "Distal 17p13.3 microdeletion syndrome", "Disease Definition": "Distal 17p13.3 microdeletion syndrome is a rare partial monosomy of the short arm of chromosome 17 with a variable phenotype characterized by prenatal and postnatal growth retardation, developmental delay, mild intellectual disability, macrocephaly, mild facial dysmorphisms including prominent forehead, hypertelorism, thick upper and/or lower lip vermillion, and structural abnormalities of the brain variably including white matter abnormalities, prominent Virchow-Robin spaces, Chiari I malformation, corpus callosum hypoplasia, but no lissencephaly.", "ORPHA ID": 261257, "Summary": ""}
{"Disease Name": "Distal 22q11.2 microdeletion syndrome", "Disease Definition": "A rare chromosomal anomaly syndrome, resulting from the partial deletion of the long arm of chromosome 22, outside the DiGeorge critical region. The phenotype is characterized by prematurity, pre- and post-natal growth retardation, developmental delay (particularly speech), mild intellectual disability, variable cardiac defects, and minor skeletal anomalies (such as clinodactyly). Dysmorphic features present in half of the individuals include microcephaly, arched eyebrows, deep set eyes, narrow upslanting palpebral fissures, ear abnormalities (low-set ears, tags and pits), hypoplastic alae nasi, smooth philtrum, down-turned mouth, thin upper lip, retro/micrognatia and pointed chin. For certain very distal deletions including the SMARCB1 gene, there is a risk of developing malignant rhabdoid tumours. Most deletions are de novo .", "ORPHA ID": 261330, "Summary": ""}
{"Disease Name": "Distal 22q11.2 microduplication syndrome", "Disease Definition": "A rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 22, with a highly variable phenotype principally characterized by developmental delay, intellectual disability, behavioral anomalies, and non-specific craniofacial dysmorphism. Congenital heart malformations, visual and hearing impairment, urogenital abnormalities, and seizures have also been reported. Penetrance is incomplete. In 70% of cases, the duplication is inherited from as asymptomatic parent.", "ORPHA ID": 261337, "Summary": ""}
{"Disease Name": "Distal 7q11.23 microdeletion syndrome", "Disease Definition": "Distal 7q11.23 microdeletion syndrome is a rare chromosomal anomaly characterized by epilepsy, neurodevelopmental disorder variably including developmental delays and intellectual disabilities of variable severity, learning disability and neurobehavioral abnormalities (autism spectrum disorder, hyperactivity, impulsivity, aggression, self-abusive behaviors, depression).", "ORPHA ID": 254351, "Summary": ""}
{"Disease Name": "Distal 7q11.23 microduplication syndrome", "Disease Definition": "Distal 7q11.23 microduplication syndrome is a rare chromosomal anomaly characterized by a predominantly neuropsychiatric phenotype with a few dysmorphic characteristics. Speech delay, learning difficulties, attention deficit hyperactivity disorder, bipolar disorder and aggressiveness have been reported.", "ORPHA ID": 261102, "Summary": ""}
{"Disease Name": "Distal anoctaminopathy", "Disease Definition": "Distal anoctaminopathy is a rare, autosomal recessive distal myopathy characterized by early adult-onset, slowly progressive, often asymmetrical, lower limb muscle weakness initially affecting the calves (with relative anterior muscle sparing) and later proximal muscle involvement, as well as highly elevated creatine kinase (CK) serum levels.", "ORPHA ID": 399096, "Summary": "Epidemiology\nWorldwide prevalence of distal anoctaminopathy is unknown, but it may represent up to 10% of anoctamin-5 related muscle disease. To date, more than 20 cases have been described in the literature with males being predominantly affected.\nClinical description\nAge at onset ranges from 20 to 50 years (with first symptoms as early as late teens) with patients typically presenting hypertrophy of distal lower leg muscles (predominantly the calf muscles (gastrocnemius medialis and soleus muscles)) which evolves into muscle atrophy with disease progression. Muscle weakness and wasting are usually asymmetrical and early symptoms include calf muscle tightness during running, reduced sports performance and difficulty to walk on tiptoes. Uncomfortable burning muscle sensation preceding muscle weakness may also be observed. In advanced stages of the disease, muscle weakness and wasting in the proximal lower and upper limbs (especially in the biceps brachii) appears. Clinical manifestations can be mild, or subjectively nonexistent, in spite of presenting clear changes on muscle imaging. Bulbar or respiratory symptoms have not been reported, however rhabdomyolysis has been observed in some patients. Intrafamilial clinical variability has been observed.\nEtiology\nDistal anoctaminopathy is caused by loss of function mutations in the gene ANO5 (11p14.3) which encodes a protein highly expressed in skeletal and cardiac muscle, as well as bone. ANO5 functions are largely unknown. It has been proposed that ANO5 may participate in membrane repair pathway, possibly at levels different from that of dysferlin.\nDiagnostic methods\nDiagnosis is based on clinical, muscle histology and laboratory examinations. Muscle biopsy shows non-specific myopathic changes, whereas blood biochemistry reveals markedly increased CK levels (typically >10 times the normal). Diagnosis is confirmed by genetic screening of ANO5.\nDifferential diagnosis\nDifferential diagnosis includes other distal myopathies, in particular Miyoshi myopathy (which is differentiated by absence of dysferlin on biopsy).\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\nManagement and treatment\nCurrently no specific treatment exists and management is mainly supportive. To prolong survival and improve quality of life, weight control to avoid obesity, physical therapy and stretching exercises to promote mobility, and use of mechanical aids to help ambulation and mobility are recommended.\nPrognosis\nThe progression of the disease is slow and patients generally maintain the ability to walk, although use of ambulatory aids are usually needed in the later stages of the disease.\n\n                            Last update: \n                            September 2018\n\n\n                            - Expert reviewer(s): \n                            Dr Johanna PALMIO  - Pr Bjarne UDD"}
{"Disease Name": "Distal arthrogryposis type 1", "Disease Definition": "A form of arthrogryposis characterized by contractures of the distal regions of the hands and feet in the absence of a primary neurological and/or muscle disease affecting limb function. Facial involvement is limited to a small mouth and impaired mouth opening. No additional anomalies are reported.", "ORPHA ID": 1146, "Summary": "Epidemiology\nEpidemiological data is limited regarding Distal arthrogryposis type 1 (DA1). The prevalence of arthrogryposis overall is estimated between 1/4,300-5,100 live births and the birth prevalence of distal arthrogryposis (DA) has been suggested at 1/20,000. DA1 is the second most frequent type of DA, after DA2B (Sheldon-Hall syndrome). However, the overlap between the two conditions favors a similar frequency of the two forms.\nClinical description\nIn 25% of cases DA1 is suspected prior to delivery, due to joint contractures (camptodactyly and/or clubfoot) and reduce fetal movements, in particular in familial cases. In the newborn a consistent pattern of hand and foot involvement, limited involvement of proximal joints and variable expressivity can be seen. Camptodactyly and clubfoot are largely present. Hypoplasia and/or absence of some interphalangeal creases is common. The shoulders and hips are less frequently affected. While the pattern of affected joints is consistent, the degree to which the joints are affected is highly variable, with equinovarus deformities ranging from mild to severe and hand involvement ranging from isolated hypoplasia of the distal interphalangeal crease of the fifth digit, to severely clenched fist and ulnar deviation of the wrist. In the mildest form of DA1, affected individuals have only hypoplasia of the gastrocnemius. Short stature, small mouth with limited opening and mild microretrognathia are frequently seen. A linear vertical crease along the anterior tibia, usually bilaterally, is described in some patients. Intelligence is normal.\nEtiology\nDA1 is caused by a heterozygous mutation in a gene encoding sarcomeric components of skeletal muscle fibers (TNNI2, 11p15.5; TNNT3, 11p15.5 ; TPM2, 9p13.3; MYH3, 17p13.1; MYBPC1, 12q23.2). The same genes are also responsible for DA2B. Recently, variants in MYLPF (16p11.2), encoding light chains of skeletal muscle myosin, have been described and appears to be more frequently associated with short stature and proximal joint contractures (ie, elbows, hips, knees).\nDiagnostic methods\nDiagnosis is based on clinical examination and molecular studies. Instrumental investigations generally do not show any significant alterations.\nDifferential diagnosis\nThe principal differential diagnosis includes a different type of DA (in particular DA2B), congenital amyoplasia and situations with limitation of fetal joint mobility (neurological/neuromuscular diseases, metabolic disturbances, skeletal dysplasias/connective tissue abnormalities, maternal illness or exposures, space limitation in utero, and intrauterine vascular compromise).\nAntenatal diagnosis\nSome cases can be detected prenatally by ultrasonography. Detection of a known pathogenic mutation by chorionic villus sampling and amniocentesis should be discussed with couples at risk.\nGenetic counseling\nTransmission is autosomal dominant, with a 50% recurrence risk for the offspring of affected individuals. Reduced penetrance and variable expressivity are reported, and some relatives with the mutation are asymptomatic. Some de novo mutations are reported, with a recurrence risk for sibs of approximately 1%. MYLPF variants can be autosomal dominant (50% recurrence risk) or autosomal recessive (25% recurrence risk).\nManagement and treatment\nLong-term orthopedic management and physiotherapy is required. Physiotherapy soon after birth is helpful in mobilizing joints and preventing disuse atrophy. Sometimes surgical procedures are required.\nPrognosis\nLife expectancy is normal. The course of the disease is non-progressive. Significant improvements are achieved with physical and orthopedic therapy. Autonomy is generally unlimited.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Livia GARAVELLI | ITHACA* - Dr Marzia POLLAZZON | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Distal arthrogryposis type 10", "Disease Definition": "A rare, genetic, distal arthrogryposis syndrome characterized by plantar flexion contractures, typically presenting with toe-walking in infancy, variably associated with milder contractures of the hip, elbow, wrist and finger joints. No ocular or neurological abnormalities are associated and serum creatine phosphokinase levels are normal.", "ORPHA ID": 251515, "Summary": ""}
{"Disease Name": "Distal arthrogryposis type 5D", "Disease Definition": "Distal arthrogryposis type 5D is a rare subtype of distal arthrogryposis syndrome characterized by arthrogryposis multiplex congenita affecting the hands, feet, ankle, shoulders and/or neck, with camptodactyly of the fingers and limited knee and hip extension, associated with asymmetric ptosis and, less frequently, other ocular manifestations (e.g. ophthalmoplegia, strabismus). Affected individuals frequently have a bulbous nose, furrowed tongue, micro/retrognathia, a short neck, congenital hip dislocation, club feet, scoliosis and short stature.", "ORPHA ID": 329457, "Summary": ""}
{"Disease Name": "Distal arthrogryposis", "Disease Definition": "A group of rare arthrogryposis syndromes characterized by congenital contractures of two or more areas of the body, primarily involving the hands and feet, while the proximal joints are largely spared, in the absence of primary neurologic and/or muscle disease affecting limb function. Diagnostic features include camptodactyly or pseudocamptodactyly, hypoplastic or absent flexion creases, overriding fingers, ulnar deviation at the wrist, talipes equinovarus, calcaneovalgus deformities, vertical talus, and/or metatarsus varus.", "ORPHA ID": 97120, "Summary": ""}
{"Disease Name": "Distal deletion 10p", "Disease Definition": "Distal monosomy 10p is a rare chromosomal disorder in which the tip of the short arm (p arm) of chromosome 10 is deleted resulting in a variable phenotype depending on the size of the deletion. The deletion may involve only the terminal 10p15 band, or extend towards the centromere to bands 10p14 or 10p13.", "ORPHA ID": 1580, "Summary": "Epidemiology\nAround 50 cases of pure distal monosomy 10p have been reported.\nClinical description\nDistal monosomy 10p encompassing the 10p13 band is associated with cardiac malformations and immune anomalies that overlap with the anomalies reported in the deletion 22q11 syndrome (DiGeorge syndrome/velocardiofacial syndrome spectrum (DGS/VCFS); see this term) with hypoparathyroidism, hypocalcemia, congenital conotruncal heart defects, thymus hypoplasia leading to T-cell deficiency and intellectual deficit. More than 25 patients have been reported with del(10)(p13). In addition to the anomalies related to the DiGeorge syndrome (e.g. conotruncal malformation with thymic hypoplasia), these patients often show an abnormally shaped skull, microcephaly, a long face, high forehead, broad nasal bridge, downslanting palpebral fissures, anteverted nares, hand and foot abnormalities, genitourinary anomalies, hearing loss and severe psychomotor retardation, resulting in a clinical picture that clearly differs from that of the classic 22q11 deletion syndrome. However, due to the similarities in the malformations observed in the two syndromes, del(10)(p13) is referred to as DGS2. The critical region for DGS2 has been mapped to within a 1cM interval in 10p13 which contains the CUGBP2 gene, a candidate gene for developmental heart defects. Smaller deletions involving the region 10p14-pter have been described in < than 10 patients. Some of these patients exhibited the triad: Hypoparathyroidism, sensorineural Deafness, and Renal anomaly (HDR syndrome; see this term). Haploinsufficiency for the trans-acting T-cell-specific transcription factor GATA-3 (encoded by the  GATA3 gene, and mapped to the 10p14-pter region) is responsible for this phenotype. Pure subtelomeric deletions involving 10p15-ter are very rare (< 6 children reported so far).\nEtiology\nThe phenotype remains unclear: low birth weight, persistent growth delay, mild psychomotor retardation and hypotonia have been reported, together with single reports of ventricular septal defect, hydrocephalus and hypogenitalia. Distal monosomy 10p generally occurs de novo or may be associated with a parental translocation.\nDiagnostic methods\nDiagnosis requires cytogenetic analysis and molecular characterization and should include a search for a translocation because deletion may be the result of transmission of a derivative chromosome.\nDifferential diagnosis\nThe differential diagnosis for patients with distal monosomy 10p should include deletion 22q11 syndrome and other causes of hypoparathyroidism, depending on the phenotype.\nAntenatal diagnosis\nPrenatal diagnosis is feasible and genetic counseling should be proposed and depends on the cytogenetic rearrangement responsible for the deletion (de novo or translocation).\nManagement and treatment\nManagement of 10p monosomy includes a comprehensive evaluation of the major clinical criteria: developmental delay, feeding difficulties, hypocalcemia, deafness, cardiac defects, and recurrent infections. Pediatricians, neurologists, nephrologists and endocrinologists should be involved as appropriate. Developmental assessments with speech, physical and occupational therapists are required.\nPrognosis\nThe prognosis is variable, depending on the malformations associated.\n\n                            Last update: \n                            January 2009"}
{"Disease Name": "Distal deletion 10q", "Disease Definition": "Distal monosomy 10q is a chromosomal anomaly involving terminal deletion of the long arm of chromosome 10 and is characterized by facial dysmorphism, pre- and postnatal growth retardation, cardiac and genital anomalies, and developmental delay.", "ORPHA ID": 96148, "Summary": "Epidemiology\nPrevalence is unknown but around 40 cases have been described in the literature so far.\nClinical description\nThere is no specific clinical feature associated with this chromosome anomaly. Craniofacial features include hypertelorism, strabismus, a prominent or broad nasal bridge, and posteriorly rotated low-set ears. Hypotonia is frequent, and limited joint extensions and early scoliosis have been reported in a few cases. Cardiac defects are not a constant finding and vary to include patent ductus arteriosus, ventricular septal defect, tetralogy of Fallot and truncus arteriosus (see these terms). Genital abnormalities have been mostly reported in males and include undescended testis, micropenis and a posterior urethral valve. Bladder distension due to cervical dysfunction may occur in females and may be evident during the antenatal period. Severe genital abnormalities (ambiguous external genitalia) have been reported in a few cases. Psychomotor retardation (generally described as mild) was present in all reported cases.\nEtiology\nDistal monosomy 10q results from a subterminal 10q deletion with breakpoints in the 10q25 or 10q26 band leading to partial monosomy for the genes located in this area. Most of the reported cases involved de novo terminal deletions resulting from abnormal non-allelic homolog recombination during meiosis.\nDiagnostic methods\nDiagnosis is made by molecular analysis. Comparative genomic hybridization (CGH) microarray or subterminal chromosome multiplex ligation-dependent probe amplification (MLPA) may be necessary since conventional cytogenetic analysis may not be sensitive enough to detect very short subterminal deletions.\nAntenatal diagnosis\nAntenatal molecular testing for the presence of a subterminal 10q deletion may be proposed in case of suspicion of a posterior urethral valve in males (associated or not with genital abnormalities) or in case of bladder distension in female fetuses. The risk of recurrence is low but prenatal screening for chromosomal abnormalities must be proposed, with the use of FISH markers for the 10q subterminal region.\nManagement and treatment\nManagement is symptomatic only. Bladder dysfunction may require transient cystostomy. Special education programs to improve cognitive development are needed in most cases.\nPrognosis\nThe prognosis is unclear as there are no available data concerning long-term follow up, especially up until adult age.\n\n                            Last update: \n                            September 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Bruno LEHEUP"}
{"Disease Name": "Distal deletion 12p", "Disease Definition": "A rare partial autosomal monosomy characterized by language development delay with childhood apraxia of speech, mild intellectual disability, behavourial abnormalities (autistic spectrum disorder, attention deficit hyperactivity disorder, anxiety) and mildly dysmorphic nonspecific features. Additional clinical features may include muscular hypotonia and joint laxity, hernias and microcephaly.", "ORPHA ID": 280325, "Summary": ""}
{"Disease Name": "Distal deletion 12q", "Disease Definition": "A rare partial deletion of the long arm of chromosome 12 characterized by variable combinations of developmental delay, intellectual disability, behavioral abnormalities, variable dysmorphic facial features (including microcephalus, coarse face, synophrys, epicanthal folds, large bulbous nose, small ears, low-set and posteriorly rotated ears, or large tongue, among others), and other anomalies such as malformations of the hands and fingers/feet and toes, skin and nail abnormalities, and genitourinary and cardiac abnormalities, among others.", "ORPHA ID": 96149, "Summary": ""}
{"Disease Name": "Distal deletion 13q", "Disease Definition": "Distal monosomy 13q is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the long arm of chromosome 13, with a highly variable phenotype typically characterized by varying degrees of intellectual disability and developmental delay, as well as CNS malformations (e.g. holoprosencephaly, anencephaly, ventriculomegaly, Dandy-Walker malformation), ocular abnormalities (e.g. hypertelorism, microphthalmia, strabismus, aniridia, retinal dysplasia) and craniofacial dysmorphism (microcephaly, trigonocephaly, large and malformed ears, broad prominent nasal bridge, micrognathia). Cardiac, genitourinary, gastrointestinal and skeletal manifestations have also been reported.", "ORPHA ID": 1590, "Summary": ""}
{"Disease Name": "Distal deletion 14q", "Disease Definition": "Distal monosomy 14q is a rare chromosomal anomaly associated with various phenotypic features depending on the size of the deletion. The clinical features may include global developmental delay, hypotonia, congenital heart defects, dysmorphic features (high forehead, small palpebral fissures, epicanthi, blepharophimosis, broad and flat nasal bridge, broad philtrum, thin upper lip, high arched palate, pointed chin, malformed ears). High-pitched, weak cry, seizures and various dental and oftalmological anomalies were also reported.", "ORPHA ID": 96150, "Summary": ""}
{"Disease Name": "Distal deletion 15q", "Disease Definition": "Distal monosomy 15q is a rare chromosomal anomaly syndrome characterized by pre- and postnatal growth restriction, developmental delay, variable degrees of intellectual disability, hand and foot anomalies (e.g. brachy-/clinodactyly, talipes equinovarus, nail hypoplasia, proximally placed digits) and mild craniofacial dysmorphism (incl. microcephaly, triangular face, broad nasal bridge, micrognathia). Neonatal lymphedema, heart malformations, aplasia cutis congenita, aortic root dilatation, and autistic spectrum disorder have also been reported.", "ORPHA ID": 1596, "Summary": ""}
{"Disease Name": "Distal deletion 17q", "Disease Definition": "A partial deletion of the long arm of chromosome 17 characterized by hypotonia, growth delay, severe global developmental delay, microcephaly, seizures, congenital heart anomalies, hand and foot anomalies (syndactyly, symphalangism) and dysmorphic facial features, including round face, hypertelorism, upslanting palpebral fissures, and micrognathia. Reported deletions involve regions 17q21-q24.", "ORPHA ID": 1597, "Summary": ""}
{"Disease Name": "Distal deletion 19p", "Disease Definition": "Distal monosomy 19p13.3 is a rare chromosomal anomaly associated with a wide range of phenotypic features depending on the size of the deletion. It may present with intrauterine growth retardation, failure to thrive, global developmental delay, dysmorphic features (such as broad forehead, midface retrusion, broad nasal bridge, micrognathia, smooth philtrum, low-set, dysplastic ears), congenital anomalies (such as atrial septal defect, gastrointestinal anomalies, renal and urogenital malformations, agenesis of the corpus callosum) and other clinical features (such as hearing loss, visual impairment and immune dysregulation).", "ORPHA ID": 96129, "Summary": ""}
{"Disease Name": "Distal deletion 1q", "Disease Definition": "A rare chromosomal anomaly characterized by an intellectual deficiency, progressive microcephaly, seizures, growth delay, distinct facial dysmorphic features and various midline defects including cardiac, corpus callosum, gastro-oesophalgeal and urogenital anomalies.", "ORPHA ID": 36367, "Summary": ""}
{"Disease Name": "Distal deletion 3p", "Disease Definition": "Distal monosomy 3p is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the short arm of chromosome 3, with a highly variable phenotype typically characterized by pre- and post-natal growth retardation, intellectual disability, developmental delay and craniofacial dysmorphism (microcephaly, trigonocephaly, downslanting palpebral fissures, telecanthus, ptosis, micrognathia). Postaxial polydactyly, hypotonia, renal anomalies and congenital heart defects (e.g. atrioventricular septal defect) may be associated.", "ORPHA ID": 1620, "Summary": ""}
{"Disease Name": "Distal deletion 4q", "Disease Definition": "A rare partial autosomal monosomy characterized by variable combination of craniofacial, developmental, digital, skeletal, and cardiac features: hypotonia, developmental delay, growth deficiency, cleft palate, cardiovascular malformations, abnormalities of the hands and feet and typical dysmorphic features, such as microcephaly, rounded facies, small eyes, broad nasal bridge, upturned nose, full cheeks, small mouth and chin.", "ORPHA ID": 96145, "Summary": ""}
{"Disease Name": "Distal deletion 6p", "Disease Definition": "Distal monosomy 6p is responsible for a distinct chromosome deletion syndrome with a recognizable clinical picture including intellectual deficit, ocular abnormalities, hearing loss, and facial dysmorphism.", "ORPHA ID": 96125, "Summary": "Epidemiology\nPure deletions have been described in less than 10 patients.\nClinical description\nOcular abnormalities mainly affect the anterior chamber of the eye. Dysmorphic features include hypertelorism, broad forehead, down-slanting palpebral fissures, low-set ears, midface hypoplasia, and micrognathia. Intellectual deficit is variable in severity.\nEtiology\nBreakpoints are within 6p24-pter subtelomeric bands and microdeletions are detected by specific subtelomeric probes or comparative genomic hybridization (array-CGH).\n\n                            Last update: \n                            December 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "Distal deletion 7p", "Disease Definition": "Distal monosomy 7p is a partial autosomal monosomy characterized by developmental delay and intellectual disability, digital anomalies, congenital heart and urogenital anomalies, and specific craniofacial features, commonly including craniosynostosis.", "ORPHA ID": 96126, "Summary": ""}
{"Disease Name": "Distal deletion 9p", "Disease Definition": "Distal monosomy 9p is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the short arm of chromosome 9, with a highly variable phenotype typically characterized by intellectual disability, craniofacial dysmorphism (trigonocephaly, upslanting palpebral fissures, hypoplastic supraorbital ridges), abnormal digits (long middle phalanges with short distal phalanges), as well as frequent association with genitourinary abnormalities (cryptorchidism, hypospadias, ambiguous genitalia, 46,XY testicular dysgenesis). Congenital hypothyroidism and cardiovascular defects have been reported in some cases. Patients present an increased risk for gonadoblastoma.", "ORPHA ID": 1642, "Summary": ""}
{"Disease Name": "Distal duplication 10q", "Disease Definition": "Distal trisomy of the long arm of chromosome 10 (10q) is characterized by pre- and postnatal growth retardation, a pattern of specific facial features, hypotonia, and developmental and psychomotor delay.", "ORPHA ID": 96102, "Summary": "Epidemiology\nTo date, approximately 40 cases of trisomy 10q have been reported.\nClinical description\nMost cases are diagnosed in infancy or in childhood. The range and severity of symptoms and physical findings may vary from case to case, depending upon the exact length and location of the duplicated portion of chromosome 10q. Characteristic craniofacial findings include a flat round face with full cheeks and a large prominent forehead, highly arched eyebrows, short and narrow palpebral fissures (blepharophimosis), widely spaced eyes with telecanthus, a short nose, a bow-shaped mouth with a prominent upper lip, and a small mandible. A few major malformations have also been reported, including renal and cardiac anomalies. Minor defects of the hands and/or feet, bone anomalies and cryptorchidism are frequent signs.\nEtiology\nThe duplicated region almost always includes 10qter, with the most frequent proximal breakpoint at 10q24 (with variation from q22 to q25). Interstitial duplications of 10q have also been reported. Most cases of distal trisomy 10q result from of a parental balanced translocation or pericentric inversion, and may be accompanied by another chromosomal imbalance. Intrachromosomal duplications or de novo translocations are also observed.\nDiagnostic methods\nDiagnosis is suspected on the basis of the clinical features and is confirmed by karyotyping and fluorescence in situ hybridization (FISH) with specific 10q probes.\nAntenatal diagnosis\nPrenatal diagnosis is possible using cytogenetic tools.\nGenetic counseling\nThe risk of recurrence for siblings depends on the parental karyotypes.\nManagement and treatment\nManagement is multidisciplinary and symptomatic only. Early educational (speech, occupational and physical therapy) and rehabilitation programs should be offered to all patients.\nPrognosis\nPrognosis is variable. A number of reported patients died in infancy from respiratory problems.\n\n                            Last update: \n                            February 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Catherine TURLEAU"}
{"Disease Name": "Distal duplication 11q", "Disease Definition": "Distal trisomy 11q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 11, with high phenotypic variability principally characterized by craniofacial dysmorphism (brachycephaly/plagiocephaly, low-set, posteriorly rotated ears, short philtrum, micrognathia) and intellectual disability. Short stature and seizures, as well as cardiac (e.g. atrial septal defect), skeletal (incl. brachy/syndactyly) and genital (e.g. micropenis, cryptorchidism) abnormalities may also be associated. Neurodevelopmental anomalies (pain insensitivity, sensorineural hearing loss, expressive language deficiency) and neuropsychiatric disorders (autistic features, auditory hallucination, self-talking) have also been reported.", "ORPHA ID": 96103, "Summary": ""}
{"Disease Name": "Distal duplication 13q", "Disease Definition": "Distal trisomy 13q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 13, with variable phenotype principally characterized by intellectual disability, psychomotor delay, craniofacial dysmorphism (incl. microcephaly, bushy eyebrows, long curled eyelashes, hypotelorism, low-set ears, prominent nasal bridge, long philtrum, high palate, thin upper lip), short neck, polydactyly, and hemangiomas. Cardiac, urogenital and neural tube defects, as well as umbilical and inguinal hernias, seizures and hypotonia, have also been reported.", "ORPHA ID": 96105, "Summary": ""}
{"Disease Name": "Distal duplication 14q", "Disease Definition": "Distal trisomy 14q is a rare, partial duplication of the long arm of chromosome 14 characterized by variable clinical features, most commonly including growth retardation and low birth weight, hypotonia, developmental delay, intellectual disability, short stature, microcephaly, facial dysmorphism (frontal bossing, hypertelorism, bulbous nose, micrognathia, sparse hair and eyebrows), congenital heart defects, spasticity and hyperreflexia.", "ORPHA ID": 1705, "Summary": ""}
{"Disease Name": "Distal duplication 16q", "Disease Definition": "Distal trisomy 16q is a rare chromosomal anomaly syndrome, resulting from the partial trisomy of the long arm of chromosome 16, with variable phenotype principally characterized by developmental delay, severe intellectual disability, hypotonia, facial dysmorphism (incl. high, prominent forehead, epicanthic folds, dysplastic ears, broad/depressed nasal bridge, malar hypoplasia, narrow and arched palate, thin upper lip vermilion, micrognathia) and hand/feet anomalies (e.g. arachnodactyly, talipes equinovarus). Cardiac defects, genitourinary malformations and vertebral anomalies are also associated. Thrombocytopenia and recurrent infections have also been reported.", "ORPHA ID": 96106, "Summary": ""}
{"Disease Name": "Distal duplication 17q", "Disease Definition": "Distal trisomy 17q is a rare chromosomal anomaly syndrome with variable phenotype principally characterized by intellectual disability, developmental delay, short stature, craniofacial dysmorphism (incl. microcephaly, low posterior hairline, frontal bossing, bitemporal narrowing, low-set and malformed ears, flat nasal bridge, long philtrum, wide mouth with downturned corners, thin upper lip) and a short, webbed neck, as well as skeletal anomalies (e.g. brachyrhizomelia, poly-/syndactyly) and joint hyperlaxity. Cardiac, cerebral, and urogenital anomalies are also frequently associated.", "ORPHA ID": 3379, "Summary": ""}
{"Disease Name": "Distal duplication 18q", "Disease Definition": "A rare, partial autosomal trisomy characterized by a variable phenotype that includes hypotonia, motor delay, mild to severe intellectual disability, seizures, variable cerebral anomalies, finger/toe syndactyly, fifth finger clinodactyly, strabismus, short neck and dysmorphic facial features.", "ORPHA ID": 1716, "Summary": ""}
{"Disease Name": "Distal duplication 19q", "Disease Definition": "Distal trisomy 19q is a rare chromosomal anomaly syndrome characterized by low birth weight, developmental delay, intellectual disability, short stature, craniofacial dysmorphism (incl. microcephaly, midface hypoplasia, hypertelorism, flat nasal bridge, ear anomalies, short philtrum, downturned corners of the mouth, micrognathia) and a short neck with redundant skin folds. Additional features may include hypotonia, skeletal anomalies (e.g. clino/camptodactyly), seizures and congenital cardiac, urogenital and gastrointestinal malformations.", "ORPHA ID": 1717, "Summary": ""}
{"Disease Name": "Distal duplication 1p36", "Disease Definition": "Distal trisomy 1p36 is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 1, characterized by borderline to mild intellectual disability, mild developmental delay, metopic craniosynostosis and mild craniofacial dysmorphism (incl. slopping forehead, bitemporal narrowing, blepharophimosis). Other associated abnormalities may include growth retardation, microcephaly, large hands, syndactyly, supernumerary ribs, rectal stenosis and/or anterior displacement of anus. Congenital heart malformations (e.g. atrial septal defect, patent ductus arteriosus) have also been reported.", "ORPHA ID": 96069, "Summary": ""}
{"Disease Name": "Distal duplication 20q", "Disease Definition": "Distal trisomy 20q is a rare chromosomal anomaly syndrome, resulting from the partial trisomy of the long arm of chromosome 20, with high phenotypic variability mostly characterized by neurodevelopmental delay, cardiac malformations (e.g. ventricular septal defect, coarctation of aorta) and facial dysmorphism (incl. large/high forehead, microphthalmia, upslanting palpebral fissures, epicanthus, large, long, low-set ears, anteverted nares, protruding upper lip, cleft lip/palate, micro/retrognathia, dimpled chin). Skeletal (brachydactyly, scoliosis, pectus excavatum) and cerebral anomalies have also been reported.", "ORPHA ID": 96107, "Summary": ""}
{"Disease Name": "Distal duplication 22q", "Disease Definition": "Distal trisomy 22q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 22, with variable phenotype principally characterized by varying degrees of intellectual disabilty and developmental delay, pre- and postnatal growth deficiency, hypotonia, and craniofacial dysmorphism (incl. microcephaly, hypertelorism, narrow and upslanted palpebral fissures, epicanthic folds, low-set dysplastic ears, broad and depressed nasal bridge, cleft lip an/or palate, long philtrum, retro/micrognathia). Congenital heart defects, as well as cerebral, skeletal, renal and genital anomalies, have also been reported.", "ORPHA ID": 96109, "Summary": ""}
{"Disease Name": "Distal duplication 2p", "Disease Definition": "Distal trisomy 2p is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 2, with a highly variable phenotype principally characterized by pre- and post-natal growth failure, global developmental delay, facial dysmorphism (incl. high forehead/frontal bossing, abnormal ear shape and/or position, hypertelorism/telecanthus, broad/depressed nasal bridge) and ocular anomalies (e.g. exophthalmos, retinal hypopigmentation, optic nerve and foveal hypoplasia). Other reported anomalies include generalized hypotonia, pectus excavatum, long fingers and toes, syndactyly, congenital heart (e.g. ventricular and atrial septal defects) and neural tube defects, seizures, pulmonary hypoplasia, diaphragmatic hernia and urogenital anomalies.", "ORPHA ID": 96070, "Summary": ""}
{"Disease Name": "Distal duplication 2q", "Disease Definition": "Distal trisomy 2q is a rare chromosomal anomaly, resulting from the partial duplication of the long arm of chromosome 2, characterized by moderate psychomotor delay, mild intellectual disability, facial dysmorphism (high hairline, prominent forehead, hypertelorism, upslanting palpebral fissures, large, low-set and/or posteriorly rotated ears, depressed/broad nasal bridge, prominent nasal tip, thin upper lip vermillion), clino-/camptodactyly and normal or increased body measurements. On occasion genital anomalies (hypospadias, cryptorchidism, shawl scrotum) and short stature may be observed.", "ORPHA ID": 96094, "Summary": ""}
{"Disease Name": "Distal duplication 3p", "Disease Definition": "Distal trisomy 3p is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 3, with highly variable phenotype principally characterized by craniofacial dysmorphism (incl. brachy-/microcephaly, square facies, frontal bossing, bitemporal indentation, hypertelorism/telecanthus, low-set and/or dysmorphic ears, short nose with broad, flat nasal bridge, prominent cheeks and philtrum, downturned corners of mouth, micrognathia/retrognathia, short neck) associated with psychomotor delay, moderate to severe intellectual disability, cardiac (e.g. patent ductus arteriosus) and urogenital (e.g. renal hypoplasia, hypogenitalism) abnormalities, as well as seizures and presence of whorls on fingers.", "ORPHA ID": 96071, "Summary": ""}
{"Disease Name": "Distal duplication 4q", "Disease Definition": "Distal trisomy 4q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 4, with highly variable phenotype typically characterized by psychomotor delay, intellectual disability, craniofacial dysmorphism (microcephaly, low-set, prominent ears, downslanting palpebral fissures, hypertelorism, epicanthic folds, broad, prominent nasal bridge, high arched and cleft palate, micro-/retrognathia), seizures, as well as tooth and digital anomalies (clinodactyly, polydactyly). Cardiac malformations, renal anomalies, cryptorchidism, hypotonia and hearing impairment have also been reported.", "ORPHA ID": 96096, "Summary": ""}
{"Disease Name": "Distal duplication 5q", "Disease Definition": "Distal trisomy 5q is a rare chromosomal anomaly syndrome, resulting from a partial duplication of the long arm of chromosome 5, characterized by short stature, moderate intellectual disability, and craniofacial dysmorphism (microcephaly, flat facies, large, low-set dysplastic ears, down-slanted, almond-shaped palpebral fissures, hypertelorism, epicanthal folds, small nose, long philtrum, small mouth with thin upper lip, and micrognathia). Patients also frequently present speech and cognitive delay, cardiac (ventriculomegaly, ventricular septum defect) and skeletal abnormalities (craniosynostosis, radial agenesis, ulnar hypoplasia, brachydactyly) and genital malformations (hypospadias, cryptorchidism).", "ORPHA ID": 96097, "Summary": ""}
{"Disease Name": "Distal duplication 6p", "Disease Definition": "Distal trisomy of the short arm of chromosome 6 is characterized by pre- and postnatal growth retardation, a pattern of specific facial features (mostly of the eyes), microcephaly, and developmental delay.", "ORPHA ID": 1745, "Summary": "Epidemiology\nTo date, approximately 40 cases of trisomy 6p have been reported.\nClinical description\nCharacteristic craniofacial findings include a prominent forehead, small and short palpebral fissures (blepharophimosis), upper lid ptosis, close-set eyes with a prominent nasal bridge, a short bulbous nose, a small mouth with thin lips, a small and pointed chin, and low-set ears with poorly developed lobes. A few major malformations have been reported, including congenital heart defects (atrial septal defect, ventricular septal defect and patent arterial duct; see these terms) and renal abnormalities including hydronephrosis and hypoplastic kidney. Cataracts, microcornea and strabismus may be observed.\nEtiology\nThe duplicated region almost always includes 6pter, with proximal breakpoints ranging from 6p21 to 6p25. Interstitial duplications of 6p have also been reported with different phenotypes depending on their size and location. Most cases of distal trisomy 6p result from missegregation of a familial balanced translocation, or pericentric inversion, and are accompanied by another chromosomal imbalance. Intrachromosomal duplications or de novo translocations are also observed.\nDiagnostic methods\nDiagnosis is based on clinical features and confirmed by karyotyping and fluorescence in situ hybridization (FISH) with specific 6p probes. The risk of recurrence for siblings depends on the parental karyotypes.\nAntenatal diagnosis\nCytogenetic prenatal diagnosis is possible.\nManagement and treatment\nManagement is multi-disciplinary and symptomatic only. Early educational and rehabilitation programs should be offered to all patients.\nPrognosis\nThe prognosis is variable. A number of patients have died in infancy from respiratory or severe feeding problems.\n\n                            Last update: \n                            February 2009"}
{"Disease Name": "Distal duplication 6q", "Disease Definition": "Distal trisomy 6q is a rare chromosomal anomaly syndrome resulting from the partial duplication of the long arm of chromosome 6, with highly variable phenotype, typically characterized by growth and developmental delay, intellectual disability, craniofacial dysmorphism (microcephaly, flat facial profile, frontal bossing, hypertelorism, downward-slanting palpebral fissures, flat nasal bridge, anteverted nares, bow shaped mouth, micrognathia), short webbed neck and joint contractures. Cardiac, urogenital, ophthalmologic and hand and foot anomalies, as well as umbilical hernia, spasticity, and seizures, are other features that have been reported.", "ORPHA ID": 96098, "Summary": ""}
{"Disease Name": "Distal duplication 7p", "Disease Definition": "Distal trisomy 7p is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 7, with highly variable phenotype typically characterized by severe to profound psychomotor delay, intellectual disability, dysmorphic features (incl. dolichocephaly, microbrachycephaly, high and/or broad forehead, large anterior fontanel, hypertelorism, downslanting palpebral fissures, low-set, dysplastic ears, low, broad and prominent nasal bridge, abnormal palate, micro-/retrognathia), and hypotonia. Cardiovascular, gastrointestinal, skeletal and urogenital anomalies have commonly been reported.", "ORPHA ID": 96074, "Summary": ""}
{"Disease Name": "Distal duplication 8q", "Disease Definition": "Distal trisomy 8q is a rare chromosomal anomaly syndrome resulting from the partial duplication of the long arm of chromosome 8, with a highly variable phenotype, typically characterized by growth and developmental delay, intellectual disability, short stature, craniofacial dysmorphism (microcephaly, prominent forehead, hypertelorism, abnormal palpebral fissures, low-set, large ears, anteverted tip of nose, micro/retrognathia), congenital heart defects and skeletal and limb anomalies. Other reported features include ophthalmologic abnormalities (e.g. megalocornea), cryptorchidism, hypertrichosis, and neurologic manifestations (e.g. hypotonia, hearing loss, and seizures).", "ORPHA ID": 96100, "Summary": ""}
{"Disease Name": "Distal duplication 9q", "Disease Definition": "Distal trisomy 9q is a rare chromosomal anomaly, resulting from the partial trisomy of the long arm of chromosome 9, with a variable phenotype mostly characterized by psychomotor and speech delay, intellectual disability, hypotonia, long narrow habitus, craniofacial dysmorphism (incl. micro/dolichocephaly, facial asymmetry, narrow palpebral fissures, deep-set eyes, strabismus, microphthalmia, abnormally shaped ears, microstomia, micro/retrognathia) and hand and feet anomalies (incl. arachnodactyly, camptodactyly, abnormal implantation of digits). Congenital flexion contractures and limited joint movements have also been observed.", "ORPHA ID": 96101, "Summary": ""}
{"Disease Name": "Distal hereditary motor neuropathy type 1", "Disease Definition": "Distal hereditary motor neuropathy type 1 is a rare neuromuscular disease characterized by slowly-progressive lower limb muscular weakness and atrophy, without sensory impairment. Additional clinical features may include pes cavus, hammertoe and increased muscle tone.", "ORPHA ID": 139518, "Summary": ""}
{"Disease Name": "Distal hereditary motor neuropathy type 2", "Disease Definition": "A rare autosomal dominant distal hereditary motor neuropathy characterized by onset of slowly progressive distal limb weakness and atrophy between the second and fifth decades of life. Sensory involvement is typically less pronounced or absent. The severity of the condition is variable, and both lower and upper extremities may be involved.", "ORPHA ID": 139525, "Summary": ""}
{"Disease Name": "Distal hereditary motor neuropathy type 5", "Disease Definition": "A rare autosomal dominant distal hereditary motor neuropathy disease characterized by muscle weakness and wasting predominantly affecting the hands, in particular the thenar and first dorsal interosseus muscles, and/or marked foot deformity and gait disturbance. Sensation is normal, although reduced response to vibration has been described. The disease is slowly progressive with an age of onset within the first few decades of life.", "ORPHA ID": 139536, "Summary": ""}
{"Disease Name": "Distal hereditary motor neuropathy type 7", "Disease Definition": "A rare, slowly progressive genetic peripheral neuropathy characterized by distal atrophy and weakness affecting the upper limbs (with a predilection for the thenar eminence) and subsequently the lower limbs, associated with uni- or bilateral vocal cord paresis leading to hoarse voice and breathing difficulties, and facial weakness.", "ORPHA ID": 139589, "Summary": ""}
{"Disease Name": "Distal hereditary motor neuropathy, Jerash type", "Disease Definition": "A rare, genetic, neuromuscular disease characterized by progressive, symmetrical, moderate to severe, distal muscle weakness and atrophy, without sensory involvement, first affecting the lower limbs (towards the end of the first decade) and then involving (within two years) the upper extremities. Patients typically develop foot drop, pes varus, hammer toes and claw hands. Pyramidal tract signs (such as brisk knee reflexes and positive Babinski sign) with absent ankle reflexes are initially associated but regress as disease stabilizes (~10 years after onset).", "ORPHA ID": 139552, "Summary": ""}
{"Disease Name": "Distal limb deficiencies-micrognathia syndrome", "Disease Definition": "The distal limb deficiencies-micrognathia syndrome is characterized by the combination of symmetric severe distal limb reduction deficiencies affecting all four limbs (oligodactyly), microretrognathia, and microstomia with or without cleft palate.", "ORPHA ID": 1307, "Summary": "Epidemiology\nIt has been reported in four patients; two of them were siblings and had moderate intellectual deficiency.\nClinical description\nTwo non-related subjects also had severe myopia, bilateral conductive hearing loss and a renal change, referred to as oligomeganephronia, or renal hypoplasia.\nEtiology\nUsing high resolution oligoarray-based comparative genomic hybridization (aCGH), a 10q24 duplication or triplication was recently detected in all these patients, similar to the duplication detected in an isolated form of split hand foot malformation (SHFM; see this term).\n\n                            Last update: \n                            June 2010"}
{"Disease Name": "Distal monosomy 7q36", "Disease Definition": "Distal monosomy 7q36 is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the long arm of chromosome 7, with a highly variable phenotype typically characterized by holoprosencephaly, growth restriction, developmental delay, facial dysmorphism (facial clefts, prominent forehead, hypertelorism, low-set ears, flat and broad nasal bridge, large mouth), abnormal fingers and palm or sole creases, ocular abnormalities, and other congenital malformations (incl. genital anomalies and caudal deficiency sequence). Cardiopathies have been occasionally reported.", "ORPHA ID": 1636, "Summary": ""}
{"Disease Name": "Distal myopathy with anterior tibial onset", "Disease Definition": "A rare, genetic neuromuscular disease characterized by a progressive muscle weakness starting in the anterior tibial muscles, later involving lower and upper limb muscles, associated with an increased serum creatine kinase levels and absence of dysferlin on muscle biopsy. Patients become wheelchair dependent.", "ORPHA ID": 178400, "Summary": ""}
{"Disease Name": "Distal myopathy with posterior leg and anterior hand involvement", "Disease Definition": "Distal myopathy with posterior leg and anterior hand involvement, also named distal ABD-filaminopathy, is a neuromuscular disease characterized by a progressive symmetric muscle weakness of anterior upper and posterior lower limbs.", "ORPHA ID": 63273, "Summary": "Epidemiology\nIt has been described in several members of an Australian and an Italian family.\nClinical description\nThe disease usually manifests during the third decade of life with thenar muscle weakness resulting in reduced grip strength. The disease is slowly progressive and generally proceeds with calf muscle weakness appearing during the fourth decade and proximal muscles becoming perceptibly affected in the fifth decade. The tibial anterior muscle is spared, so is respiratory function. Mild cardiomyopathy can sometimes be observed.\nEtiology\nThe disease is due to mutations on the actin-binding domain of the FLNC gene that encodes filamin C, a muscle specific filamin that is also associated with myofibrillar myopathy when mutations affect other parts of the protein. The disease mechanism seems to be linked to an increased actin-binding affinity of filamin C.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Rachael DUFF"}
{"Disease Name": "Distal myopathy, Tateyama type", "Disease Definition": "Distal myopathy, Tateyama type is a rare, genetic, slowly progressive, distal myopathy disorder characterized by muscle atrophy and weakness limited to the small muscles of the hands and feet (in particular, thenar and hypothenar muscle atrophy), increased serum creatine kinase, and severely reduced caveolin-3 expression on muscle biopsy. Some patients may also show calf hypertrophy, pes cavus, and signs of muscle hyperexcitability.", "ORPHA ID": 488650, "Summary": ""}
{"Disease Name": "Distal myopathy, Welander type", "Disease Definition": "A rare distal myopathy characterized by weakness in the distal upper extremities, usually finger and wrist extensors which later progresses to all hand muscles and distal lower extremity, primarily in toe and ankle extensors.", "ORPHA ID": 603, "Summary": "Epidemiology\nDistal myopathy, Welander type (WDM) prevalence is unknown. The condition is mainly restricted to a geographical area around the Baltic Sea especially in Finland and Sweden (mid-eastern region), where the estimated prevalence is 1/10,000. However, some patients have been reported in the United Kingdom.\nClinical description\nWDM is a late adult-onset disorder (onset between 40 and 60 years) characterized by initial weakness of index finger extensors followed by extension weakness in the other fingers. Weakness slowly progresses to all hand and lower leg muscles. In the lower limb, the anterior tibial muscle and toe extensors are typically affected leading to walking difficulties and steppage gait. Proximal limb muscles are only rarely involved. Muscle stretch reflexes are preserved (except ankle reflexes which may be lost later in the disease). Cardiac muscle involvement has not been observed. Rare homozygotes individuals show an earlier onset and proximal muscle involvement with faster progression.\nEtiology\nWDM is caused by a missense change (c.1362G>A; p.E384K) in TIA1 gene (2p13) which encodes nucleolysin TIA1 isoform p40, a key component of stress granules (SGs). Under conditions of cellular stress or metabolic changes, nucleolysin TIA1 isoform p40 promotes messenger ribonucleoprotein (mRNP) complexes to assemble in SGs to repress translation. The mutation leads to reduced dynamics of the SGs and abnormal autophagic processing with rimmed vacuolar pathology. In addition, the WDM phenotype has been reported in patients with a digenic combination of a SQSTM1 mutation and TIA1-N357S variant.\nDiagnostic methods\nDiagnosis relies on molecular genetic testing. Additional examinations include muscle biopsy of distal muscles showing dystrophic features and prominent rimmed vacuoles. Sensory examination is usually normal, although some deficits on quantitative temperature and vibration testing have been described. The serum creatine kinase (CK) level is usually normal or slightly elevated. Needle electromyography (EMG) shows small brief 'myopathic' motor units, although a mixed 'myopathic-neuropathic' pattern may be observed. Fibrillations and complex repetitive discharges are often, but not invariably, present. Muscle magnetic resonance imaging shows considerable involvement of posterior calf muscles besides fatty degenerative changes in the anterior compartment.\nDifferential diagnosis\nDifferential diagnosis includes sporadic inclusion body myositis (sIBM), MATR3 distal myopathy, and muscle filaminopathy.\nGenetic counseling\nWDM is inherited as an autosomal dominant trait. Where one parent is affected, there is a 50% risk of disease transmission to offspring. Penetrance is 100% by age 75 years.\nManagement and treatment\nManagement is mainly symptomatic and includes the help of an occupational and a physical therapists and practical tools for finger and hand weakness. Foot drop and wrist weakness may be helped by orthoses.\nPrognosis\nThe progression is benign and life expectancy is normal although the fine motor hand skills are usually lost. Homozygotes exhibit earlier onset, faster progression, and patients become wheelchair-bound by the age of 50 years.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Bjarne UDD"}
{"Disease Name": "Distal myopathy", "Disease Definition": "Distal myopathy refers to a group of muscle diseases which share the clinical pattern of predominant weakness and atrophy beginning in the feet and/or hands.", "ORPHA ID": 599, "Summary": "Epidemiology\nThe estimated prevalence of distal myopathy in the northern region of England is 1/300,000. Some forms have been identified with greater frequency in certain populations. For example, tibial muscular dystrophy is frequent in Finland with a prevalence of 1/5,000 and Welander distal myopathy occurs with greater frequency in Sweden.\nClinical description\nDistal myopathy is characterized by progressive muscular weakness and atrophy beginning in the distal parts of upper and lower limbs with an extremely variable age of onset. Distal myopathy is a genetically heterogeneous group (currently comprising more than 20 genetic types) which affects different regions of the distal extremities and is classified according to clinical features, inheritance pattern, histopathological criteria, and molecular genetics. The main autosomal dominant forms of distal myopathy are Welander distal myopathy (weakness in the distal upper extremities which later progresses to distal lower extremity), tibial muscular dystrophy (mainly affects the front of the lower leg), distal myotilinopathy (progressive distal muscle weakness and peripheral neuropathy with hyporeflexia), late-onset distal myopathy, Markesbery-Griggs type (ZASP-related myofibrillar myopathy), Laing early-onset distal myopathy, distal myopathy with posterior leg and anterior hand involvement (distal ABD-filaminopathy), and adult-onset distal myopathy due to VCP mutation. The genetically confirmed autosomal recessive forms are distal myopathy, Nonaka type (GNE-myopathy, weakness in the anterior distal legs), Miyoshi myopathy (weakness in the distal lower extremity posterior compartment), nebulin-related early-onset distal myopathy and distal anoctaminopathy. The age at onset is extremely variable and for recessive varieties of distal myopathy, symptoms usually develop in early adult life whereas in the dominant Welander and tibial muscular dystrophy, the onset is usually later. However, in some disorders (i.e. Laing early-onset distal myopathy and nebulin-related early-onset distal myopathy) the onset may be during childhood, and even in infancy.\nEtiology\nDistal myopathy is caused by defect or lack of specific proteins that play an essential role in the proper function and health of muscle cells. 15 causative genes have to date been associated with distal myopathy: ANO5 (11p15.1), CRYAB (11q22.3-q23.1), DES (2q35), DYSF (2p13.3), FLNC (7q32-q35), GNE (9p13.1), KLHL9 (9p22), LDB3 (10q22.3-q23.2), MATR3 (5q31.3), MYH7 (14q11.2-q13),  MYOT (5q31.2),  NEB (2q22), TIA1 (2p13), TTN (2q31) and VCP (9p13.3).\nGenetic counseling\nDistal myopathy can be inherited as an autosomal dominant or as an autosomal recessive trait.\n\n                            Last update: \n                            June 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Johanna PALMIO  - Pr Bjarne UDD"}
{"Disease Name": "Distal myotilinopathy", "Disease Definition": "A rare, late adult-onset myofibrillar myopathy characterized by progressive distal muscle weakness associated with peripheral neuropathy and hyporeflexia. Ambulation may be lost within a few years.", "ORPHA ID": 98911, "Summary": ""}
{"Disease Name": "Distal nebulin myopathy", "Disease Definition": "Distal nebulin myopathy is a rare, slowly progressive, autosomal recessive distal myopathy characterized by early onset of predominantly distal muscle weakness and atrophy affecting lower leg extensor muscles, finger extensors and neck flexors. Muscle histology does not always show nemaline rods.", "ORPHA ID": 399103, "Summary": "Epidemiology\nTo date, the disease has been described in 13 patients from five unrelated Finnish families and four non-Finnish families.\nClinical description\nDistal nebulin myopathy manifests initially, in early childhood or young adulthood, by foot drop, but the first symptoms can be seen as early as one year of age. The most severely affected muscles include the ankle dorsiflexors, the finger extensors and the neck flexors. Patients are usually not able to walk on their heels and later in the disease course, there is a mild proximal muscle involvement. Additional features include early-onset moderate facial weakness and mild respiratory problems, such as shortness of breath on strenuous exercise (although only one patient presenting decreased vital capacity has been reported). Cardiac muscle is usually not affected, however cardiomyopathy has been described in one patient.\nEtiology\nDistal nebulin myopathy is caused by biallelic mutations (with at least one of them being missense mutation) in the gene NEB (2q22) which encodes the protein nebulin. The latter is expressed in the thin filaments of striated muscle and is required for the proper assembly of the thin filaments, for the maintenance of their lengths and for their contractile function.\nDiagnostic methods\nDiagnosis is based on clinical, muscle histology and laboratory examinations. Muscle histology shows a marked fiber size variation, presence of hypertrophic fibers with internal nuclei, and variably abundant nemaline rods. CK levels are normal or slightly increased. Diagnosis is confirmed by genetic screening of NEB.\nDifferential diagnosis\nDifferential diagnosis includes other distal myopathies, especially Laing distal myopathy.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\nManagement and treatment\nCurrently no specific treatment is available. Management is mainly symptomatic and includes the help of an occupational and a physical therapists. Foot drop may be aided by orthoses. Occasional monitoring of respiratory function is recommended.\nPrognosis\nPrognosis is good with patients typically remaining ambulant although proximal weakness may occur at the later stages.\n\n                            Last update: \n                            September 2018\n\n\n                            - Expert reviewer(s): \n                            Dr Johanna PALMIO  - Pr Bjarne UDD"}
{"Disease Name": "Distal renal tubular acidosis with anemia", "Disease Definition": "A rare form of distal renal tubular acidosis characterized by a defect in renal acidification and hereditary hemolytic anemia.", "ORPHA ID": 93610, "Summary": ""}
{"Disease Name": "Distal renal tubular acidosis", "Disease Definition": "A rare genetic or acquired renal tubular disease characterized by hyperchloremic metabolic acidosis. Primary distal renal tubular acidosis (dRTA) is often associated with hypokalemia, other forms with hypokalemia, hyperkalemia or normokalemia.", "ORPHA ID": 18, "Summary": "Epidemiology\nPrevalence is unknown. Hereditary forms are more prevalent in areas of high consanguinity (Arabic peninsula and North Africa) whereas acquired dRTA has been reported more frequently in Western countries.\nClinical description\nDisease onset can occur at any age, depending on cause. Hereditary forms include autosomal dominant (AD) and autosomal recessive (AR) dRTA. AR, less frequently AD, subtypes associated with hemolytic anemia and ovalocytosis, stomatocytosis or spherocytosis have also been described in Southeast Asia. AR forms are frequently diagnosed in infants and young children, AD dRTA mostly in adolescents and young adults. Patients with primary dRTA can be asymptomatic or present with polyuria, polydipsia, weakness, and fatigue (symptoms associated with hypokalemia). Failure to thrive, rickets, stunting of growth (in children) and osteomalacia or osteopenia (in adults) are a result of urinary calcium wastage and loss of calcium salts from the bones. Hypercalciuria, nephrolithiasis and nephrocalcinosis usually occur. Low plasma potassium levels in the classic form can also cause cardiac arrhythmias, paralysis and even death. In AR forms, bilateral sensorineural hearing loss (SNHL) may be present at diagnosis or appear later, following a progressive and irreversible course of highly variable severity.\nEtiology\nAD dRTA, the most common dRTA, is usually due to mutations in the SLC4A1 gene (17q21.31). ATP6V1B1 (2p13) or ATP6V0A4 (7q34) mutations cause AR dRTA with or without SNHL. AR dRTA without or with late onset SNHL has been mainly described in patients with ATP6V0A4 mutations. These 3 genes explain 60-80% of primary dRTA. Other rare genetic causes are FOXI1 mutations causing dRTA associated with early hearing loss, and variants in WDR72, which have been described in milder dRTA. Acquired forms of dRTA are thought to be caused by autoimmune diseases or secondary to other conditions like sickle cell anemia, chronic obstructive uropathy, or post-renal transplantation.\nDiagnostic methods\nThe disease is characterized by hyperchloremic metabolic acidosis. The inability to lower urine pH below 5.5 and a positive urine anion gap during spontaneous metabolic acidosis are indicative of dRTA. Provocative tests for further diagnosis include the NH4Cl acidifying test and the furosemide test. Patients also show renal potassium wasting except in the hyperkalemic type. Extra-renal manifestations may facilitate the diagnosis, which can be confirmed by molecular genetic testing, preferably using a next-generation-sequencing-based panel for all potential causative genes.\nDifferential diagnosis\nMain differential diagnosis is proximal RTA along with other causes of chronic metabolic acidosis. A transient proximal tubular dysfunction associated with severe acidosis resembling incomplete Fanconi syndrome is commonly observed in infants with dRTA at diagnosis. Incomplete dRTA refers to an impaired ability to acidify the urine below 5.5 in the absence of overt metabolic acidosis and is diagnosed predominantly in adults with nephrocalcinosis, recurrent nephrolithiasis, osteopenia or hypocitraturia.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variants have previously been identified in a family member.\nGenetic counseling\nIn families with AR dRTA, genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation), informing them that there is a 25% risk of having an affected child at each pregnancy. In AD dRTA, genetic counseling should be offered to affected individuals, informing them that there is a 50% risk of having an affected child at each pregnancy..\nManagement and treatment\nAlkali therapy, usually with sodium bicarbonate or sodium citrate, is the standard treatment (to achieve normal serum bicarbonate levels). Children require very high doses (4-8 meq/kg/day) as compared to adults (1-2 meq/kg/day). Potassium replacement, usually with potassium citrate, is necessary in hypokalemic patients. Hyperkalemic types require low dietary potassium intake and other therapies.\nPrognosis\nAll forms of dRTA are chronic and may have significant effects on growth and development. With treatment, life expectancy is normal and renal failure uncommon but progressive chronic kidney disease is more often observed than expected in the long term, associated with non-adherence, recurrent kidney stones, and when nephrocalcinosis is very severe.\n\n                            Last update: \n                            March 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Gema ARICETA  - Dr Daniel BATLLE"}
{"Disease Name": "Distal spinal muscular atrophy type 3", "Disease Definition": "Distal spinal muscular atrophy type 3 is a rare neuromuscular disease characterized by progressive muscular weakness and atrophy predominantly affecting distal parts of limbs, later involvement of proximal and trunk muscles with marked hyperlordosis and late diaphragmatic dysfunction.", "ORPHA ID": 139547, "Summary": ""}
{"Disease Name": "Distal Xq28 microduplication syndrome", "Disease Definition": "A rare syndromic X-linked intellectual disability characterized by cognitive impairment, behavioral and psychiatric problems, obesity, recurrent infections, atopic diseases, and distinctive facial features in males. Females are clinically asymptomatic or mildly affected, presenting mild learning difficulties and facial dysmorphism.", "ORPHA ID": 293939, "Summary": ""}
{"Disease Name": "Distomatosis", "Disease Definition": "A rare group of infectious disease characterized by the infection of different organs (liver, lungs, or intestines) by flat worms live in contact with epitheliums. Clinical symptoms vary depending on the infected organ. In liver infection, (often presents with inflammation and obstruction of the biliary ducts) fever, allergic reactions (dermographism), abdominal pain, nausea, diarrhoea, hypereosinophilia and angiocholitis attacks can be observed. In lung infection, tuberculosis-like clinical signs (cough or haemoptysis) are observed without fever, however erratic cases may also exist. In intestine infection, painful diarrhea, abdominal pain, oedema (face, abdomen or legs), vomiting, anorexia, or intestinal obstruction can be observed, some patients can also be asymptomatic.", "ORPHA ID": 1685, "Summary": ""}
{"Disease Name": "DITRA", "Disease Definition": "A rare, genetic, autoinflammatory syndrome with immune deficiency disease characterized by recurrent and severe flares of generalized pustular psoriasis associated with high fever, asthenia, and systemic inflammation, due to IL36R antagonist deficiency. Psoriatic nail changes (e.g. pitting and onychomadesis) and ichthyosis may occasionally be associated.", "ORPHA ID": 404546, "Summary": ""}
{"Disease Name": "DK1-CDG", "Disease Definition": "DK1-CDG is characterised by muscular hypotonia and ichthyosis. It has been described in four children from two consanguineous families. All the affected children died during early infancy, two from dilated cardiomyopathy. The syndrome is caused by a deficiency in dolichol kinase 1 (DK1), an enzyme involved in the de novo biosynthesis of dolichol phosphate. The mutations identified in the DK1 gene led to a 96 to 98% reduction in DK activity.", "ORPHA ID": 91131, "Summary": ""}
{"Disease Name": "DNA2-related mitochondrial DNA deletion syndrome", "Disease Definition": "A rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by either late-onset myopathy with progressive external ophthalmoplegia and muscular weakness (predominantly limb-girdle) or early-onset myopathy presenting with decreased fetal movements, congenital ptosis, progressive external ophthalmoplegia, hypotonia and, variably, joint contractures. Reduced content and multiple deletions of mitochondrial DNA is observed in muscle biopsy.", "ORPHA ID": 352470, "Summary": ""}
{"Disease Name": "DNAJB2-related Charcot-Marie-Tooth disease type 2", "Disease Definition": "A rare autosomal recessive axonal hereditary motor and sensory neuropathy characterized by adolescent or adult onset of slowly progressive muscle weakness and atrophy of the distal lower limbs progressing to involve also the upper limbs and proximal muscles, and sensory impairment. Patients present gait disturbances and loss of reflexes, at later stages loss of ambulation, dysarthria, dysphagia, facial weakness, and impairment of respiratory muscles requiring assisted ventilation.", "ORPHA ID": 443950, "Summary": ""}
{"Disease Name": "DNAJB6-related limb-girdle muscular dystrophy D1", "Disease Definition": "A subtype of autosomal dominant limb-girdle muscular dystrophy characterized by an adult-onset of slowly progressive, proximal pelvic girdle weakness, with none, or only minimal, shoulder girdle involvement, and absence of cardiac and respiratory symptoms. Mild to moderate elevated creatine kinase serum levels and gait abnormalities are frequently observed.", "ORPHA ID": 34516, "Summary": ""}
{"Disease Name": "Dobrow syndrome", "Disease Definition": "A rare multiple congenital defects/dysmorphic syndrome characterized by variable degrees of bony syngnathia associated with variable additional abnormalities, including growth retardation, intellectual disability, microcephaly, iris coloboma, nystagmus, deafness, and vertebral segmentation defects, as well as genital, limb and additional facial malformations, among others.", "ORPHA ID": 3262, "Summary": ""}
{"Disease Name": "Dominant beta-thalassemia", "Disease Definition": "Dominant beta-thalassemia is a form of beta-thalassemia (see this term) resulting in moderate to severe anemia.", "ORPHA ID": 231226, "Summary": "Epidemiology\nPrevalence of this form is not known.\nClinical description\nPatients present with moderate to severe anemia, jaundice and splenomegaly.\nEtiology\nRare mutations in the beta-globin HBB gene result in synthesis of extremely unstable beta-globin variants which precipitate in erythroid precursors causing ineffective erythropoiesis.\nDiagnostic methods\nThe presence of hyper-unstable hemoglobin should be suspected in any individual with beta-thalassemia intermedia (see this term) when both parents are hematologically normal (de novo mutations), or in families with a pattern of autosomal dominant transmission of beta-thalassemia intermedia. Diagnosis is based on beta-globin gene sequencing.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA"}
{"Disease Name": "Dominant hypophosphatemia with nephrolithiasis or osteoporosis", "Disease Definition": "A rare, genetic renal tubular disease characterized by phosphate loss in the proximal tubule, leading to hypercalciuria and recurrent urolithiasis and/or osteoporosis.", "ORPHA ID": 244305, "Summary": "Epidemiology\nMore than 10 cases have been identified to date.\nClinical description\nDisease onset is in adulthood with presentation of nephrolithiasis, renal phosphate wasting and skeletal abnormalities variably including osteopenia, osteoporosis and increased susceptibility to fractures. Cases of spinal deformity have also been described.\nEtiology\nHeterozygous mutations have been identified in two genes SCL34A1 (5q35), and SLC9A3R1 (17q25.1). SCL34A1 encodes the main sodium-phosphate cotransporter, sodium-dependent phosphate transport protein 2A (NPT2a), located in the apical membrane of renal proximal tubular cells.  SLC9A3R1 encodes the Na(+)/H(+) exchange regulatory cofactor (NHERF1), a cytoplasmic protein essential for recruitment of transporter or signaling proteins to the plasma membrane which stabilize NaPi-IIa, the parathyroid hormone (PTH) receptor 1, and phospholipase C at the brush border membrane and creates a platform for PTH signaling to NaPi-IIa . SLC9A3R1 mutations decreases NPT2a expression directly or indirectly via an increase in PTH-responsive downregulation of NaPi-IIa. The decreased serum phosphate levels stimulate 1,25-dihydroxy-Vitamin D synthesis leading to absorptive hypercalciuria, which together with elevated urinary phosphate levels can trigger the formation of calcium-phosphate crystals favoring the development of renal calcifications.\nDiagnostic methods\nDiagnosis is usually based on clinical features, plasma and urine electrolytes showing hypophosphatemia, hyperphosphaturia, hypercalciuria and increased serum 1,25-dihydroxy-Vitamin D in response to phosphate deprivation. A definitive diagnosis can be achieved by genetic testing.\nDifferential diagnosis\nThe differential diagnosis includes other forms of inherited hypophosphatemia such as X-linked hypophosphatemia, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. There is a 50% risk of the disease occurring in a sibling or being transmitted to the offspring of affected individuals.\nManagement and treatment\nSupportive treatment is with phosphate and low‐ dose vitamin D supplementation.\nPrognosis\nThere is no information available on outcomes.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Elena LEVTCHENKO | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Donnai-Barrow syndrome", "Disease Definition": "A multiple congenital malformation syndrome characterized by typical facial dysmorphism, myopia and other ocular findings, hearing loss, agenesis of the corpus callosum, low-molecular-weight proteinuria, and variable intellectual disability. Congenital diaphragmatic hernia (CDH) and/or omphalocele are common.", "ORPHA ID": 2143, "Summary": "Epidemiology\nThe prevalence and incidence of Donnai-Barrow syndrome (DBS) are difficult to estimate. Fewer than 50 individuals from about 20 families have been reported. DBS affects all ethnicities; it is more commonly diagnosed in the offspring of consanguineous unions. Males and females are affected equally.\nClinical description\nAlmost all patients have the following features: agenesis/hypogenesis of the corpus callosum, enlarged anterior fontanelle, marked sensorineural hearing loss and hypertelorism. Characteristic facial features include: down-slanting palpebral fissures, short nose with flat nasal bridge, tall broad forehead, widow's peak in the anterior hairline, and sometimes prominent globes. About 40% of patients have CDH and/or omphalocele. Developmental delay and variable intellectual deficit are frequent. High myopia (> 6 diopters), a distinctive optic nerve head dysgenesis, and an increased risk of retinal detachment may lead to progressive loss of vision. Iris coloboma, Focal segmental glomerulosclerosis and proximal tubule dysfunction (rarely progressing to renal insufficiency) are reported occasionally.\nEtiology\nDBS is an autosomal recessive disorder caused by loss of function variants in the LRP2 low-density lipoprotein receptor-related protein 2 gene (2q31.1) encoding the protein megalin, expressed on multiple absorptive epithelia, notably in the brain, kidney, and eye. Megalin plays an important role in endocytosis of numerous ligands and in various signaling pathways.\nDiagnostic methods\nDiagnosis is suggested by a combination of clinical and neuroimaging features along with a typical pattern of low-molecular-weight proteinuria, increased urinary levels of retinol-binding protein (RBP) and RBP/creatinine ratio. The diagnosis is confirmed by molecular genetic testing.\nDifferential diagnosis\nDBS has a characteristic constellation of clinical features limiting differential diagnoses. However, some overlapping signs are found in tetrasomy 12p, Fryns, Chudley-McCullough, Acrocallosal, and Craniofrontonasal syndromes. The renal phenotype partly resembles Dent disease and Lowe syndrome. The ocular phenotype may be suggestive of Stickler syndrome.\nAntenatal diagnosis\nDetection of hypertelorism, agenesis of the corpus callosum, and either CDH or omphalocele by prenatal imaging should raise suspicion of DBS. Prenatal diagnosis for at-risk pregnancies is possible and requires prior identification of the disease-causing mutation in the family.\nGenetic counseling\nDBS is an autosomal recessive disorder. Genetic counseling should be provided to parents of affected children and to their relatives. Parents of an affected child are obligate carriers for the disease-causing allele. The sole exception reported to date is a patient with DBS due to uniparental disomy (UPD).\nManagement and treatment\nRegular screening of vision, hearing, and renal function should be established. Corrective lenses, preventive treatment for retinal detachment, and hearing aids and/or cochlear implants may be required. CDH and/or omphalocele, when present, necessitate surgical intervention. Specific adapted education for vision, hearing and intellectual disabilities should be provided as is needed for affected children.\nPrognosis\nAffected individuals can achieve useful vision and hearing with correction. Overall health status in patients is generally good in childhood and adolescence. End-stage kidney failure is a rare and life-threatening complication. Pre- or peri-natal presentation with diaphragmatic and abdominal wall defects requires surgical intervention and is associated with elevated morbidity and mortality.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Mauro LONGONI  - Dr Barbara POBER"}
{"Disease Name": "DONSON-related microcephaly-short stature-limb abnormalities spectrum", "Disease Definition": "A rare autosomal recessive microcephalic primordial dwarfism characterized by congenital microcephaly and craniofacial features associated with a spectrum of limb abnormalities ranging from mild to severe. Short stature is frequently observed and often is severe.", "ORPHA ID": 572761, "Summary": "Epidemiology\nThe exact prevalence of DONSON-related microcephaly associated with short stature and limb abnormalities spectrum is unknown; slightly more than 50 patients have been reported to date. The Microcephaly Micromelia syndrome is more frequent in a First Nations population in northern Saskatchewan, Canada.\nClinical description\nPresentation is with intrauterine growth retardation or at birth with low birth weight (- 2.9 SD on average), short birth length (-3.7 SD) and congenital microcephaly (-5.1 SD). Craniofacial features include broad nasal bridge, short palpebral fissures, microstomia, and micrognathia. Congenital limb abnormalities vary in severity and involve both upper and lower limbs, with upper limbs more severely affected. The mildest malformations are clinodactyly, camptodactyly, syndactyly, or brachymesophalangia and are mainly associated with the clinical subtype, microcephaly-short stature-limb abnormalities syndrome. Severe malformations are usually associated with microcephaly-micromelia syndrome. Limbs are short with hypoplasia of the radius, ulna, thumb and/or Vth finger. Lower limbs may be underdeveloped (fibula, patella, I and Vth toes). Feet may be clubbed. Perinatal mortality is very high in the microcephaly-micromelia syndrome due to respiratory failure. Subglottic stenosis, diaphragmatic hernia and choanal atresia have been described in some patients with short stature and milder limb abnormalities. Gyration is usually simplified on brain imaging. Intellectual abilities ranges from normal to moderate intellectual disability.\nEtiology\nThe disorder is due to bi-allelic mutations in the downstream neighbor of SON, DONSON  (21q22.11), a replisome component that stabilizes forks during genome replication.\nDiagnostic methods\nDiagnosis is based on clinical signs. Congenital microcephaly, short stature combined with at least minor, I and Vth finger malformations or even hypoplasia/malformations of the upper and/or the lower limbs. Targeted sequencing and whole exome sequencing identify coding variants responsible for the disease. However pathogenic noncoding variants may only be identified using integrative transcriptomic and genomic sequencing.\nDifferential diagnosis\nThere is considerable clinical overlap with Fanconi anemia (FA), and several patients were originally diagnosed with FA. Additional differential diagnosis includes VACTERL, Meier Gorlin syndrome, and Taiby Linder syndrome.\nAntenatal diagnosis\nThe disorder may be identified prenatally using ultrasound. However, absence of microcephaly and limb malformation does not rule out the diagnosis, especially for the mildest types. Once the molecular diagnosis has been established in a family member, prenatal diagnosis is possible.\nGenetic counseling\nIf both parents are heterozygous for a pathogenic DONSON variant, the risk of having an affected child is 25% for each pregnancy.\nManagement and treatment\nTreatment is symptomatic. Adequate nutritional intake, using naso-gastric tube-feeding if needed, should be ensured during the first years of life. Epilepsy is treated with antiepileptic medication. Physiotherapy and speech therapy may be beneficial.\nPrognosis\nLife expectancy is much reduced in microcephaly-micromelia syndrome; all reported patients died, mostly in the perinatal period. In milder forms, the prognosis and quality of life will depend on the severity of the limb malformations and the intellectual disability.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Sandrine PASSEMARD | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "DOORS syndrome", "Disease Definition": "A rare multiple congenital anomalies-intellectual disability syndrome characterized by sensorineural hearing loss (deafness), onychodystrophy, osteodystrophy, mild to profound intellectual disability, and seizures.", "ORPHA ID": 79500, "Summary": "Epidemiology\nThe prevalence is unknown; about 50 cases have been reported to date.\nClinical description\nDisease onset usually presents shortly after birth, but may present in infancy, with profound sensorineural deafness, small or absent nails, and short distal phalanges of hands and feet. About 1/4 of patients have long, finger-like thumbs. Facial features are highly variable and only a broad nasal bridge is present in 1/2 of all cases. Other facial signs, reported infrequently, include anteverted nares, long philtrum, thin upper vermilion and low set ears. Craniosynostosis has been reported in one patient. Optic atrophy leading to blindness, retinal detachment, strabismus, nystagmus, high myopia and cataracts are sometimes reported. Developmental delay is noted from infancy and can range from mild delays in early motor milestones to generalized and lifelong hypotonia. Seizures (often generalized tonic-clonic) are seen in most cases, usually begin in the first year of life and become more marked with age. Along with learning difficulties, behavioral problems may also be noted. Rare manifestations include dental (hypoplastic enamel, abnormal size of teeth), and internal organ (congenital heart defects, unilateral renal agenesis, cystic kidney, duplicated kidney) malformations. The disease is non-progressive.\nEtiology\nDOORS (deafness-onychodystrophy-osteodystrophy-intellectual disability syndrome) syndrome is caused by mutations in the TBC1D24 gene (16p13.3) encoding a protein involved in the regulation of membrane trafficking. It seems likely that DOORS syndrome will prove to be a genetically heterogeneous disease and other causal genes will be identified in the future.\nDiagnostic methods\nPatients are checked for each of the 5 major characteristics by conducting X-rays of the hands and feet, a brain stem auditory evoked response test for hearing loss, and an electroencephalogram (EEG). Elevated levels of 2-oxoglutaric acid in the urine and plasma have repeatedly been reported mostly in patients with TBC1D24  mutations. If present, DOORS syndrome is suspected, although elevated levels can also occur in other disorders. Molecular genetic testing identifying a TBC1D24 mutation may confirm the diagnosis but absence of the mutation does not mean a diagnosis of DOORS syndrome is incorrect.\nDifferential diagnosis\nDifferential diagnoses include Coffin-Siris syndrome, intellectual disability-sparse hair-brachydactyly syndrome, Zimmermann-Laband syndrome, fetal alcohol syndrome and Temple-Baraitser syndrome, autosomal dominant deafness-onychodystrophy syndrome, and disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease-causing mutation.\nGenetic counseling\nDOORS syndrome is inherited autosomal recessively. If the clinical diagnosis has been established with a high degree of certainty, genetic counseling should be provided accordingly.\nManagement and treatment\nTreatment is supportive. Long-term management involves regular ophthalmologic and hearing tests as well as neurological exams such as EEGs. A feeding tube may be necessary in infants with feeding difficulties. Antiepileptic medication may be used to prevent or decrease the frequency of seizures but is not always effective.\nPrognosis\nLife expectancy is usually normal. Intellectual disability is lifelong but there is no known correlation between clinical manifestations and cognition. The number of known adults with DOORS syndrome is at present too small to predict the long term prognosis. Parkinsonism was reported in an adult.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Philippe CAMPEAU"}
{"Disease Name": "Dopa-responsive dystonia due to sepiapterin reductase deficiency", "Disease Definition": "Dopa-responsive dystonia (DRD) due to sepiapterin reductase deficiency (SRD) is a very rare neurometabolic disorder characterized by dystonia with diurnal fluctuations, axial hypotonia, oculogyric crises, and delays in motor and cognitive development.", "ORPHA ID": 70594, "Summary": "Epidemiology\nThe prevalence is unknown. There have been approximately 43 cases reported to date.\nClinical description\nOnset usually occurs before the first year of life with manifestations of dystonia, motor and language delays, weakness, axial hypotonia (and hypotonia in a tetraplegic distribution) and oculogyric crises that show diurnal fluctuations (worse at night and better in the morning after sleeping). Sleep disturbances and psychological symptoms (anxiety, irritability) are common later in childhood. Intellectual deficits are frequently noted but some may only experience mild to moderate learning disabilities. Less common features include parkinsonism (tremor, bradykinesia, rigidity, masked facies), dysarthria, hyperreflexia, limb hypertonia, and autonomic signs. Frequently, dystonia and obvious diurnal fluctuations only develop during the course of the disease, whereas common presenting symptoms in infancy such as developmental delay and hypotonia are unspecific.\nEtiology\nDRD due to an SRD is due to mutations in the SPR gene (2p14-p12), encoding the enzyme sepiapterin reductase (SR). Various mutations in this gene lead to reduced SR activity and consequently to a reduced production of monoamine neurotransmitters.\nDiagnostic methods\nDistinctive cerebrospinal fluid (CSF) findings include low levels of 5-hydroxyindoleacetic (5-HIAA) and homovanillic acid (HVA), and elevated total biopterin and dihydrobiopterin (BH2). SR activity in fibroblasts is usually reduced or absent. Molecular genetic testing can identify mutations in the SPR gene, confirming the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other forms of DRD such as autosomal recessive DRD and autosomal dominant DRD, infantile dystonia-parkinsonism, infantile-onset spastic paraplegia, some forms of epilepsy and cerebral palsy.\nAntenatal diagnosis\nPrenatal diagnosis is possible in those with a known SPR mutation.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling is possible and recommended.\nManagement and treatment\nLike other forms of DRD, DRD due to an SRD responds dramatically to levodopa (L-dopa) therapy. L-dopa is often combined with a peripheral decarboxylase inhibitor such as carbidopa or benserazide. Treatment should be initiated as early as possible to avoid irreversible neurological damage. The dosage of L-dopa given can range from 0.1 to 16.0 mg/kg/day. Transient dyskinesias frequently occur initially as a result of treatment but are usually resolved by decreasing the dosage. In patients with insufficient improvement of symptoms under L-dopa therapy, 5-hydroxytrytophan (5-HTP) at a dosage of 0.14 to 6 mg/kg/day should be given with carbidopa (to reduce side effects), since combination therapy may result in further improvements of motor and sleep symptoms. Treatment is life-long.\nPrognosis\nPrognosis depends on if treatment is initiated early and on disease severity. Those who receive treatment show significant improvement, but most still experience mild motor and sometimes severe cognitive symptoms if treatment is delayed.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "Dopa-responsive dystonia", "Disease Definition": "Dopa-responsive dystonia (DRD) describes a group of neurometabolic disorders characterized by dystonia that typically shows diurnal fluctuations, that responds excellently to levodopa (L-dopa) and that is comprised of autosomal dominant dopa-responsive dystonia (DYT5a), autosomal recessive dopa-responsive dystonia (DYT5b) and dopa responsive dystonia due to sepiapterin reductase (SR) deficiency.", "ORPHA ID": 255, "Summary": "Epidemiology\nThe estimated European prevalence of DRD ranges from 1/1,000,000-1/200,000.\nClinical description\nDRD usually has a pediatric onset, typically with lower limb dystonia that leads to gait disturbances and that usually worsens during the course of the day and is improved in the morning after sleeping. Parkinsonism can develop at a later age in some patients. Anxiety, depression, sleep disturbances and obsessive-compulsive disorders have also been reported in a few patients with DYT5a. Rarer subtypes which are inherited in an autosomal recessive manner typically show a much more severe phenotype, with onset in the first year of life with additional manifestations of global developmental delay, axial hypotonia, oculogyric crises and encephalopathy. DRD responds dramatically and continuously to L-dopa therapy, and patients usually experience a significant improvement of symptoms once treatment is initiated. If untreated, patients can become wheelchair bound.\nEtiology\nDRD is due to mutations in genes that encode proteins essential for the biosynthesis of dopamine. DYT5a is due to mutations in the GTP cyclohydrolase 1 (GCH1) gene (14q22.1 to q22.2) which encodes an enzyme needed for the biosynthesis of tetrahydrobiopterin, the essential co-factor for tyrosine hydroxylase. DYT5b is caused by mutations in the tyrosine hydroxylase TH gene (11p15.5) encoding tyrosine hydroxylase, the enzyme responsible for catalyzing the conversion of tyrosine to L-dopa, the precursor of dopamine. Finally, DRD due to an SRD is due to mutations in the SPR gene (2p14-p12), encoding the enzyme sepiapterin reductase (SR), which is also required for the biosynthesis of tetrahydrobiopterin.\nGenetic counseling\nDRD can be inherited in an autosomal dominant or autosomal recessive manner, depending on the subtype. It can also occur due to de novo mutations.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "Dopamine beta-hydroxylase deficiency", "Disease Definition": "A very rare primary monoamine neurotransmitter synthesis disorder with norepinephrine and adrenaline deficiency that leads to young-onset severe orthostatic hypotension and eyelid ptosis.", "ORPHA ID": 230, "Summary": "Epidemiology\nThe prevalence of dopamine beta-hydroxylase (DBH) deficiency is unknown. Only 25 patients have been reported to date.\nClinical description\nDBH deficiency is mainly characterized by severe early onset orthostatic hypotension. In the neonatal period hypothermia and hypoglycemia can occur. First symptoms of orthostatic hypotension generally occur in early childhood with reduced exercise intolerance. Orthostatic hypotension is profound and can lead to syncope. Other symptoms and signs of the selective noradrenergic failure of the sympathetic nervous system are eyelid ptosis, nasal congestion, and primary enuresis. Sweating is normal. The central nervous system appears to be largely spared. Reduced kidney function, anemia and hypomagnesemia are common.\nEtiology\nDBH deficiency is caused by mutations in the DBH gene (9q34), encoding the enzyme dopamine beta hydroxylase which converts dopamine to noradrenaline. It results in undetectable levels of noradrenaline and adrenaline, and highly increased levels of dopamine in plasma, urine and cerebrospinal fluid.\nDiagnostic methods\nPlasma measurements of catecholamines shows undetectable levels of noradrenaline and adrenaline and increased levels of dopamine. Diagnosis is confirmed by genetic testing of the DBH gene. Diagnosis can be supported by testing DBH enzyme activity in plasma, however this can be falsely absent due to a common polymorphism in the healthy population.\nDifferential diagnosis\nOrthostatic hypotension due to CYB561 mutations gives a comparable clinical picture but levels of dopamine are normal.\nAntenatal diagnosis\nPrenatal diagnosis is possible when the pathogenic variant has been identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nExcellent and sustained clinical response can be achieved by precursor therapy with L-threo-dihydroxyphenylserine (L-DOPS/ Droxidopa). Oral administration of 100 to 500 mg of L-DOPS, twice or three times a day, reverses the orthostatic intolerance. For children, a starting dose of 2 mg/kg/d in 2-3 doses eventually increasing to 5-10 mg/kg/d in 2-3 doses seems reasonable. Dose should be titrated individually based on clinical response. Blood pressure should be monitored regularly and (nightly) hypertension should be avoided (last dose of medication should be given more than 4 hours before bedtime). Regular follow-up of kidney function, electrolytes and hematological parameters is advised.\nPrognosis\nWith L-DOPS treatment, clinical response is excellent and sustained, with improvement of quality of life and exercise intolerance. Mild ptosis can persist under treatment. Catecholamine profile in plasma does not normalize completely.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Oya KUSEYRI HÜBSCHMANN | MetabERN* - Pr Thomas OPLADEN | MetabERN* - Dr Tessa WASSENBERG | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Double outlet left ventricle", "Disease Definition": "Double-outlet left ventricle (DOLV) is an extremely rare congenital cardiac malformation in which both the aorta and the pulmonary artery arise, either exclusively or predominantly, from the morphologic left ventricle.", "ORPHA ID": 3427, "Summary": "Epidemiology\nPrevalence is unknown. The birth prevalence is estimated at less than 1/ 200,000 live births.\nClinical description\nDOLV usually manifests during the neonatal period with cyanosis, tachypnea, exertional dyspnea, failure to thrive, sweating (especially during feeding), unresponsiveness and/or fatigue. DOLV occurs most commonly in the form of atrial situs solitus with atrioventricular (AV) concordance but is often associated with cardiac anomalies such as a ventricular septal defect (VSD), an atrial septal defect, pulmonary stenosis, right ventricular hypoplasia, patent ductus arteriosus, and tricuspid atresia (see these terms). The clinical manifestations depend largely on the type of the associated cardiac defects, e.g. pulmonary or aortic outflow tract obstruction resulting from pulmonary or aortic valve stenosis respectively. DOLV is classified into two sub-types depending on the location of the VSD and the position of the great arteries: DOLV with normal great arteries (DOLV NGA type) with subpulmonary or doubly committed subarterial VSD and levo-position of the anterior pulmonary artery; and DOLV with transposition of the great arteries (DOLV TGA type) with subaortic or doubly committed subarterial VSD and levoposition of the anterior aorta. The two sub-types are almost clinically indistinguishable, apart from cyanosis being more prominent in TGA type.\nEtiology\nThe etiopathology is not clearly understood. Embryologically, DOLV could result from excessive leftward shift of the embryonic conotruncus, anomalous differential absorption of sub-pulmonic and sub-aortic conus, or anomalous differential conal growth.\nDiagnostic methods\nDiagnosis is based on 2-D echocardiography combined with magnetic resonance imaging (MRI) showing both great arteries arising from the morphologic left ventricle. Chest X-ray and/or cardiac catheterization can also be performed.\nDifferential diagnosis\nDifferential diagnosis includes transposition of the great arteries and double outlet right ventricle (see these terms).\nAntenatal diagnosis\nPrenatal echocardiographic diagnosis is possible but very difficult.\nGenetic counseling\nDOLV is a sporadic disease.\nManagement and treatment\nBiventricular repair is the usual treatment for DOLV and is usually accomplished by an intraventricular baffle procedure, by the Rastelli procedure or by a variant of the Lecompte operation. Pulmonary root translocation from the left to the right ventricle can also be performed and provides excellent anatomic and hemodynamic repair. When other cardiac malformations are present, other techniques can be used such as Fontan-type cavopulmonary derivation in the presence of right ventricular hypoplasia.\nPrognosis\nDOLV is associated with high mortality, generally due to heart failure, myocardial infarction or aortic thrombosis. With surgery, the five-year survival rate is estimated at 70-75%. Most patients will continue to present with residual cardiac anomalies, such as aortic or mitral valve regurgitation, arrhythmias or hypertension.\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Hiromi KUROSAWA"}
{"Disease Name": "Double outlet right ventricle", "Disease Definition": "A rare cono-truncal anomaly in which both the aorta and pulmonary artery originate, either entirely or predominantly, from the morphologic right ventricle.", "ORPHA ID": 3426, "Summary": "Epidemiology\nDouble outlet right ventricle (DORV) accounts for about 2-3% of all congenital heart defects, with a birth prevalence rate of 1/ 10,000.\nClinical description\nThe clinical picture varies widely, depending on the combination of the abnormalities present. Symptoms are generally observed during the first days or weeks of life. Cyanosis is the most frequent sign. Tachypnea or breathlessness, poor feeding and slow weight gain are also common. Tachycardia and/or heart murmur may also be observed. DORV is always associated with a ventricular septal defect (VSD) that allows blood to drain from the left ventricle. DORV is classified into sub-types, based on the relationship of the VSD (subaortic, doubly committed, subpulmonary or non-committed) with the great arteries. Other cardiac anomalies frequently associated with DORV include pulmonary stenosis, various degrees of left and right ventricular hypoplasia, atrioventricular (AV) septal defects, and straddling AV valves. Extracardiac anomalies, such as heterotaxy (polysplenia, asplenia, situs ambiguous) intestinal malrotation and ciliary dysfunction could be associated. It is important to figure out that DORV is not a congenital heart disease per se but a mode of ventriculo-arterial connection. Therefore there are several clinical types of DORV, depending on the presence of a pulmonary stenosis and of associated lesions. The functional classification has identified 5 types of DORV: DORV-VSD type, DORV-Fallot, DORV-Taussig Bing, DORV-non committed VSD, DORV-AVSD-heterotaxy. Each type has a specific clinical presentation and surgical treatment.\nEtiology\nDORV results from a failure in the fetal development of the cono-truncus, which is the primary outlet of the heart during embryonic development. The cono-truncal anomalies result in neural crest and second heart field dysfunction. Cardiac progenitor cells are controlled by various genes, such as GDF1 (19p13.11) and CFC1 (2q21.2), which when mutated can result in DORV. DORV is associated with chromosomal anomalies such as 22q11.2 deletion syndrome, trisomy 13, trisomy 18 and CHARGE syndrome and others.\nDiagnostic methods\nDiagnosis is based on 3D echocardiography showing both great arteries arising from the right ventricle. In complex forms, cardiac catheterization-angiography, magnetic resonance imaging (MRI) and /or computed tomography (CT) scan are required. Recently, 3D printed models have been very useful to plane the surgery.\nDifferential diagnosis\nDifferential diagnosis includes transposition of the great arteries, tetralogy of Fallot, ventricular septal defect, and double outlet left ventricle.\nAntenatal diagnosis\nDORV can be diagnosed by fetal echocardiography with a good degree of accuracy when the two vessels arise entirely from the right ventricle.\nGenetic counseling\nDORV is a sporadic disease. Consanguinity seems to be a risk factor. Genetic counseling is not possible.\nManagement and treatment\nIn the presence of two viable ventricles, biventricular repair is the optimal treatment for DORV and it is quite safely achieved in the simple forms (DORV-VSD type, DORV-Fallot type and DORV-TGA type). In the complex forms (DORV with non-committed VSD, DORV-atrioventricular septal defect-pulmonary stenosis-heterotaxy), univentricular repair (Fontan operation) is often preferred by a number of teams, while biventricular repair is performed in selected cases in advanced pediatric heart surgery centers.\nPrognosis\nWithout treatment, prognosis is poor due to severe cyanosis, congestive heart failure or pulmonary hypertension. With biventricular repair, patients have, on average, a normal life expectancy, with possible risk or re-operation. All patients that have received surgery for a DORV require life-long surveillance by a cardiologist. Univentricular palliation requires a very close follow up.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr François LACOUR-GAYET"}
{"Disease Name": "Double uterus-hemivagina-renal agenesis syndrome", "Disease Definition": "A rare congenital urogenital anomaly characterized by the presence of double uterus (didelphys, bicornuate or septum-complete or partial), unilateral cervico-vaginal obstruction (obstructed hemivagina-communicant, not communicant or septate and unilateral cervical atresia) and ipsilateral renal anomalies (renal agenesis and/or other urinary tract anomalies). Patients are usually diagnosed at puberty after menarche due to recurrent severe dysmenorrhea, chronic pelvic pain, excessive foul smelling mucopurulent discharge, spotting and intermenstrual bleeding (depending on the existence of uterine or vaginal communications). Fever, dyspareunia, and a palpable abdominal, pelvic or vaginal mass (mucocolpos or pyocolpos) may also be present.", "ORPHA ID": 3411, "Summary": ""}
{"Disease Name": "Double-orifice mitral valve", "Disease Definition": "A rare, congenital, non-syndromic heart malformation characterized by a single fibrous annulus with two orifices opening into the left ventricle. Clinical presentation is variable and related to the degree of resulting mitral insufficiency and/or stenosis, and depending on the associated heart disease, most commonly atrioventricular septal defect, obstructive left-sided lesions, and cyanotic heart disease. Rare cases of isolated disease have been reported.", "ORPHA ID": 95474, "Summary": ""}
{"Disease Name": "Dowling-Degos disease", "Disease Definition": "A rare, genetic, hyperpigmentation of the skin disease characterized by adulthood-onset of reticular, reddish-brown to dark-brown, macular and/or comedone-like, hyperkeratotic papules with hypopigmented macules, predominantly affecting flexural areas and, on occasion, progressing to involve trunk and acral regions. Histologically, epidermal acanthosis, thin, branch-like, rete ridges, and a tendency for acantholysis and pigmentary incontinence is observed.", "ORPHA ID": 79145, "Summary": ""}
{"Disease Name": "Down syndrome", "Disease Definition": "A total autosomal trisomy that is caused by the presence of a third (partial or total) copy of chromosome 21 and that is characterized by variable intellectual disability, muscular hypotonia, and joint laxity, often associated with a characteristic facial dysmorphism and various anomalies such as cardiac, gastrointestinal, neurosensorial or endocrine defects.", "ORPHA ID": 870, "Summary": "Epidemiology\nPrevalence at birth of Down syndrome (DS) in a country depends largely on non-medical factors, i.e. public policies regarding prenatal diagnosis and care for disabled people, and view of the population for DS and for abortion. In brief, it varies from 1/400 to 1/3000 live births. The risk of having a baby with Down syndrome (DS) increases with maternal age, identically in every population.\nClinical description\nClinical features include variable (often mild) intellectual disability, almost constant muscular hypotonia and joint laxity, associated with morphological signs, malformations (half of cases) and increased risks of some medical complications all-life-long. Morphological features (upslanting palpebral fissures, epicanthus, flat neck, round face, small nose, bilateral single palmar crease) can be mild and are not pathognomonic of the condition. The main potential malformations and complications include: short stature, congenital cataract, conductive hearing loss, heart defects (atrio-ventricular canal), digestive malformations (duodenal atresia), Hirschsprung disease, seizures, sleep apnea, sensory deficiencies, leukemia, auto-immune and endocrine pathologies (hypothyroidism, celiac disease, diabetes mellitus type 1, alopecia areata, earlier aging and early-onset Alzheimer disease.\nEtiology\nIn 95% of the cases, trisomy 21 is an additional independent chromosome 21 (47,+21): the extra chromosome is due to an accidental non-disjunction during meiosis. 2-3% of those cases are in a mosaic state. In the remaining 5%, the supernumerary chromosome 21 or portion of chromosome 21 is translocated to another chromosome (Robertsonian translocation in most cases).\nDiagnostic methods\nThe diagnosis is based on karyotyping.\nDifferential diagnosis\nDifferential diagnosis includes Zellweger syndrome, 9qter deletion or other chromosomal abnormalities. We can also mention the exceptional Aymé-Gripp syndrome.\nAntenatal diagnosis\nIn 70-75% of fetuses, increased nuchal translucency can be seen on first-trimester ultrasonography. On the second-trimester, malformations (essentially cardiac and digestive) are present in 60% of the cases, and can be associated with minor morphological signs. Prenatal diagnosis can be confirmed by fetal karyotype on amniocentesis or chorionic villous sampling. Non-invasive prenatal screening on maternal blood is now available in several countries in case of an increased risk of DS on prenatal screening.\nGenetic counseling\nFor the parents of a child affected by regular trisomy 21, the recurrence risk is only slightly modified (1% until the age of 40 years, linked to maternal age afterwards). In case of DS caused by translocation, the risk is raised only if one of the parents has a balanced rearrangement. For a person with Down syndrome, the risk of transmitting the disease to the descendants is 1/3 (maybe less for males with DS).\nManagement and treatment\nEarly physiotherapy, psychomotor therapy and speech therapy (including alternative non-verbal communication tools, namely sign language and picture exchange, in order to stimulate early communication and induce oral skills) are essential. A person with DS should be involved as soon as possible in decision-making through self-determination. A well-adapted program, including re-education, schooling and social aspects, should be proposed, aiming at obtaining the best possible integration in society (i.e. more than half of people with DS has capabilities to read and write, even partially). Neuropsychological evaluations are important to recognize the specific difficulties and abilities of each person with DS and thus propose cognitive remediation. An adapted medical follow-up is very important in order to detect and treat as soon as possible medical complications. Guidelines have been published. It can be necessary to maintain some support in the adult age, including re-education. Research in medical treatment to improve cognition in people with Down syndrome is active with ongoing clinical trials.\nPrognosis\nMedian life expectancy is now above the age of 60 years in developed countries.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Renaud TOURAINE"}
{"Disease Name": "DPAGT1-CDG", "Disease Definition": "DPAGT1-CDG is a form of congenital disorders of N-linked glycosylation characterized by hypotonia, intractable seizures, developmental delay, microcephaly and severe fetal hypokinesia. Additional features that may be observed include apnea and respiratory deficiency, cataracts, joint contractures, vermian hypoplasia, dysmorphic features (esotropia, arched palate, micrognathia, finger clinodactyly, single flexion creases) and feeding difficulties. The disease is caused by loss-of-function mutations in the gene DPAGT1  (11q23.3).", "ORPHA ID": 86309, "Summary": ""}
{"Disease Name": "DPM1-CDG", "Disease Definition": "A rare disorder of multiple glycosylation pathways characterized by global developmental delay, motor skills delay, hypotonia, seizures, microcephaly and eye abnormalities (including retinopathy, nystagmus, strabismus) with varying onset and severity. Additional clinical features may include peripheral neuropathy, dysmorphic features (facial and limb abnormalities), ataxia and severe gastrointestinal involvement.", "ORPHA ID": 79322, "Summary": ""}
{"Disease Name": "DPM3-CDG", "Disease Definition": "DPM3-CDG is an extremely rare form of CDG syndrome (see this term) characterized clinically in the single reported case by muscle weakness, waddling gait and dilated cardiomyopathy (see this term).", "ORPHA ID": 263494, "Summary": ""}
{"Disease Name": "Dracunculiasis", "Disease Definition": "Dracunculiasis (Guinea worm disease) is a neglected tropical disease (NTD) characterized by a painful burning skin lesion from which the Dracunculus medinensis parasite emerges approximately 1 year after infection resulting from consumption of unsafe drinking water containing parasite-infected copepods (Cyclops spp., microcrustacea also called water fleas).", "ORPHA ID": 231, "Summary": "Epidemiology\nIn 2012, 542 cases were reported in 4 countries (Chad, Ethiopia, Mali, and South Sudan), a decrease of >99% since 1990. The global dracunculiasis program aims to eradicate the parasite from the last remaining endemic villages located in difficult to reach areas.\nClinical description\nClinical manifestations appear 10-14 months after infection and include constitutional symptoms (such as low-grade fever, itchy rash, nausea, vomiting, diarrhea, dizziness) followed by a localized swelling developing into a painful blister, most often on a lower limb. On contact with water, the adult female worm (70-100 cm) bursts through the blister, depositing her larvae in the water where they are consumed by copepods, starting the cycle anew. Local inflammation and secondary bacterial infection of the lesion are common, potentially causing cellulitis, abscess formation, tetanus (see this term), sepsis, and septic arthritis. If the lesion is near a joint, this may lead to joint contractures and permanent disability. If the worm is not fully removed it can create an intense inflammatory reaction that further exacerbates the pain, swelling, and cellulitis.\nEtiology\nDracunculiasis is caused by the parasitic worm Dracunculus medinensis. Transmission occurs after drinking water contaminated with copepods that act as intermediate hosts to the infective parasite larvae. Copepod digestion in the gastrointestinal tract releases the larvae, which migrate to subcutaneous tissues where they mate and pregnant female worms mature.\nDiagnostic methods\nDracunculiasis diagnosis is based on the typical appearance of a skin lesion with a protruding worm, commonly on a lower limb.\nDifferential diagnosis\nOccasionally, another parasitic worm called Onchocerca volvulus, pieces of connective tissue, or fly larvae are confused with emerging  Dracunculus medinensis worms.\nManagement and treatment\nThere is no effective medication or vaccine for dracunculiasis. Infected persons do not become immune to subsequent infection. Treatment is a long painful process consisting of pulling out the emerging worm by rolling it around a piece of gauze or a small stick, a few centimeters a day, in combination with wound cleaning and dressing with antibiotic ointment to prevent secondary bacterial infection.\nPrognosis\nDracunculiasis is not life threatening itself but, rarely, death due to secondary sepsis has been reported. More commonly, the patient is disabled by pain during worm removal, on average for 8.5 weeks, which often has a great impact on everyday life in endemic areas. Joint contractures and permanent disability can occur in some cases.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                             Mark EBERHARD  -  Sharon ROY"}
{"Disease Name": "Dravet syndrome", "Disease Definition": "A rare, genetic, developmental and epileptic encephalopathy characterized by infantile onset of intractable seizures that are often febrile, and associated with cognitive and motor impairment.", "ORPHA ID": 33069, "Summary": "Epidemiology\nThe average prevalence at birth of Dravet syndrome is 1/30,000 (range 1/15,000-40,000).\nClinical description\nOnset of the first seizure is mainly in the first year of life (usually at 5-8 months) in previously healthy infants. Seizures include clonic seizure, often unilateral that alternates between left and right, and generalized tonic-clonic seizures. Seizures are often febrile and long lasting, presenting as febrile status epilepticus (SE). SE is mainly frequent in the first years. Other seizures types may also occur, such as focal or atypical absence seizures, as well as possible clusters of nocturnal tonic or tonic-clonic seizures between age 4 and 11. Photosensitivity, high temperatures, photic stimulation and exercise may trigger seizures. Developmental delay is often apparent by age 2, followed by cognitive plateauing. Speech impairment, progressive gait deterioration with crouching, and sleeping difficulties may also appear at this stage.\nEtiology\nAround 85% of cases are due to a mutation or deletion in the SCN1A gene (2q24.3), encoding a voltage-gated sodium channel. Most mutations are de novo but might be part of a familial spectrum of genetic epilepsy with febrile seizures-plus (GEFS+) in 5-10%. Mutations in the PCDH19 gene (Xq22.1), might account for about 5% of female cases. In about 10% of cases, the etiology is unknown. Somatic mosaic deletions or mutations in SCN1A are found in about 3% of the patients that are initially negative. Few patients are reported with pathogenic variants in other genes such as GABRG2 (5q34), GABRA1 (5q34), STXBP1 (9q34.11), SCN1B (19q13.12), and SCN2A (2q24.3).\nDiagnostic methods\nDiagnosis is based on clinical and electroencephalographic (EEG) findings. At onset, EEG is usually normal but later spikes or poly spike-waves with a slowing of background and multifocal discharges are recorded. Brain magnetic resonance imaging is usually normal. SCN1A pathogenic variants can confirm the diagnosis in the clinical setting of Dravet syndrome.\nDifferential diagnosis\nDifferential diagnosis includes myoclonic atonic epilepsy.\nGenetic counseling\nIn families with a known SCN1A mutation, inheritance is autosomal dominant and genetic counselling is possible, even though the phenotypic range in families can be wide. In cases with de novo mutations, counselling may helpful.\nManagement and treatment\nThe main aim of treatment is to reduce seizure frequency and prevent SE. Valproate, clobazam, stiripentol and bromide may control the febrile seizures early in the disease. Stiripentol may be effective in reducing the duration and the frequency of seizures in combination with valproate and clobazam. The ketogenic diet, topiramate and levetiracetam may provide substantial efficacy as adjunctive therapy as well as cannabidiol in association with clobazam. Ongoing clinical trials showed substantial efficacy of fenfluramine as an add-on. Vagus nerve stimulation can be also considered. Sodium channel blockers (carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine and phenytoin) should be avoided as they worsen seizures. Benzodiazepines are used to treat acute seizures. Children with prominent seizures with falls need protective head gear. Treatment management should be handled by clinicians with expertise in rare and complex epilepsies.\nPrognosis\nSeizures can decrease in frequency in adulthood but often remain refractory to therapies. Moderate to severe cognitive impairment and intractable epilepsy into adulthood is common. Children present a progressive cognitive decline after early language and visual function impairment. Intellectual deficiency is present in around 86% of patients. Autism spectrum disorder can also appear in 31%. Preventing the occurrence of convulsive SE in children may improve the long-term prognosis.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole CHEMALY | EpiCARE* - Pr Rima NABBOUT | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Drug or radiation exposure-related interstitial lung disease", "Disease Definition": "A rare secondary interstitial lung disease (ILD) characterized by development of the condition after exposure to certain drugs or radiation therapy. Diagnostic criteria include clear temporal association, identification of a characteristic reaction pattern to the respective drug, and exclusion of other causes of the ILD. Clinically, drug-induced ILD (DI-ILD) may occur as acute ILD with respiratory failure, or as subacute/chronic DI-ILD. Radiation injury to the lung can develop during or following radiation therapy and depends on the nature and dose of the ionizing radiation, as well as the direction of the radiation beam.", "ORPHA ID": 264978, "Summary": ""}
{"Disease Name": "Drug reaction with eosinophilia and systemic symptoms", "Disease Definition": "A rare hypersensitivity reaction characterized by a generalized infiltrated skin rash with face edema, fever, enlarged lymph nodes, eosinophilia, lymphocytosis and more or less severe visceral involvement (e.g. hepatitis, nephritis, pneumonitis, myocarditis ect.) and, in some patients, reactivation of human herpes virus 6, Epstein-Barr virus and/or cytomegalovirus. Onset usually occurs 2-8 weeks after administration of the causal medication and is most frequently associated with anticonvulsants, antibacterial sulfonamides and allopurinol but many other medications have also been implicated. Histology is characterized by interface dermatitis, sometimes mixed with eczematous and an acute generalized exanthematous pustulosis-like pattern. Auto-immune sequelae may occur.", "ORPHA ID": 139402, "Summary": ""}
{"Disease Name": "Drug- or toxin-induced pulmonary arterial hypertension", "Disease Definition": "Drug- or toxin-induced pulmonary arterial hypertension (PAH) is a form of pulmonary arterial hypertension (PAH, see this term) secondary to the exposition to drugs. Drug- or toxin-induced PAH is characterized by elevated pulmonary arterial resistance leading to right heart failure. Drug or toxin induced PAH is progressive and potentially fatal.", "ORPHA ID": 275786, "Summary": "Epidemiology\nDrug or toxin -induced PAH represented 9.5% of PAH cases in a French Registry, prevalence is hence estimated to be 1/700,000 adults.\nClinical description\nDrug -or toxin-induced PAH has a clinical course similar to idiopathic pulmonary arterial hypertension (IPAH, see this term). Initial symptoms include dyspnea, fatigue, syncope, chest pain, non-productive cough and hemoptysis. Precordial signs include loud and palpable second heart sound, right ventricular heave, pulmonary ejection click and murmurs of pulmonary and tricuspid regurgitation. In more advanced cases patients present dyspnea at rest. Sudden death has been reported in some cases. 70% of patients present heart failure (classed as New York heart association functional classification (NYHA FC) III or IV). More rarely, clubbing of digits, ascites, pedal edema and Raynaud phenomenon (mostly in females) may be observed.\nEtiology\nDrug or toxin -induced PAH may be directly induced by a wide range of drugs and toxins. Anorexigens (aminorex, fenfluramine derivatives (leading to heart valve disease, potentially causing drug or toxin -induced PAH) and benfluorex have been confirmed to be risk factors for PAH and were withdrawn from the market. PAH induced by anorexigens occurs months to years after treatment. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary arterial smooth muscle cells.Amphetamines, cocaine, phentermine and mazindol are also considered as possible risk factors for PAH. Dasatinib, a dual Src/Abl kinase inhibitor, used in the treatment of chronic myeloid leukaemia (see this term) was associated with cases of severe PAH, in part reversible after its withdrawal. Recently few cases of PAH have been reported with interferon therapy whose supposed mechanism is suspected to be linked to endothelial dysfunction. PAH may be a rare complication of other drugs including: nasal decongestants, (e.g. phenylpropanolamine), dietary supplement - L-Tryptophan, and drugs that could act on 5HT2B receptors (e.gpergolide). Mutations in PAH predisposing genes (mainly in BMPR2 gene (2q33) and also in ACVRL1(12q13), Endoglin(9q34), CAV1 (7q31), KCNK3(2p23), Smad9 (13q12) and TBX4 (17q21) could be identified in drug or toxin -induced PAH. These genes are well known to predispose to PAH as an autosomal dominant trait with incomplete penetrance (heritable PAH, see this term) and drug or toxin exposure could act as a second hit in such patients.\nGenetic counseling\nPatients developing Drug or toxin -induced PAH should be screened for PAH predisposing mutations.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Barbara GIRERD  - Pr David MONTANI"}
{"Disease Name": "Drug-induced autoimmune hemolytic anemia", "Disease Definition": "Drug-induced autoimmune hemolytic anemia is a type of autoimmune hemolytic anemia (AIHA; see this term) that occurs as a reaction to therapeutic drugs, and can be due to various mechanisms.", "ORPHA ID": 90037, "Summary": "Epidemiology\nDrug-induced AIHA is rare; annual incidence is estimated at about 1/1,000,000. It is more common in adults and is very rare in children, although some fatal cases in children have been reported.\nClinical description\nThe disease presents with anemia linked to hemolysis, and physical examination may show an enlarged spleen.\nEtiology\nTo date about 100 drugs have been implicated in drug-induced AIHA, including: cephalosporins (primarily cefotetan and ceftriaxone), levodopa, methyldopa, penicillin and its derivatives, quinidine and some nonsteroidal anti-inflammatory drugs.\nDiagnostic methods\nIt is important to consider drug-induced AIHA when a patient serologically presents as either warm- or cold-type AIHA (see these terms) to avoid erroneous diagnosis.\nManagement and treatment\nStopping the drug that is causing the problem may relieve or control the symptoms. Patients may also be given IV immunoglobulin and prednisone to reduce the immune response. Blood transfusion may be needed in severe cases.\nPrognosis\nThe prognosis is good if the causative drug is identified and the patient stops taking it. Death is a rare outcome, but has been reported particularly in children with AIHA caused by cefotetan and ceftriaxone.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Marc MICHEL"}
{"Disease Name": "Drug-induced localized lipodystrophy", "Disease Definition": "Drug-induced localized lipodystrophy is a rare, acquired, localized lipodystrophy characterized by the appearance of asymptomatic, well-demarcated, variably sized, depressed, lipoatrophic lesions secondary to subcutaneous, intradermic or intramuscular drug injection, including corticosteroids, insulin, human growth hormone and antibiotics. Skin coloration may vary from white or hypopigmented to reddish, pinkish or violaceous. Epidermal atrophy may be also present.", "ORPHA ID": 90157, "Summary": ""}
{"Disease Name": "Drug-induced lupus erythematosus", "Disease Definition": "A rare, systemic disease with skin involvement characterized by the onset of idiopathic lupus erythematosus-like signs and symptoms resulting from continuous drug intake (>1 month), which resolve when treatment is discontinued, in persons with no history of autoimmune disease. Manifestations are variable and may be systemic (e.g. arthralgia, myalgia, fever, fatigue, serositis, pleuritis, pericarditis), subacute cutaneous (incl. photosensitive, non-scarring, annular, polycyclic or papulosquamous lesions, malar erythema, vasculitis, bullous lesions, erythema multiforme-like changes), and/or chronic cutaneous (typically discoid lesions in sun-exposed areas). Procainamide and hydralazine are the drugs most frequently implicated.", "ORPHA ID": 231111, "Summary": ""}
{"Disease Name": "Drug-induced vasculitis", "Disease Definition": "A rare secondary vasculitis characterized by inflammation of blood vessels caused by various drugs, including antibiotics, anti-tumor necrosis factor-alpha agents, immunotherapeutic drugs, and psychoactive agents, among others. The skin is most commonly affected, but other tissues and organs, such as the subcutis, kidneys, or lungs, may also be involved. Systemic disease develops only in a minority of patients, typically when treated with the causative drug over a prolonged period of time. Presenting signs and symptoms include skin rash, myalgia, arthralgia, fever, and malaise.", "ORPHA ID": 251325, "Summary": "Epidemiology\nThe incidence and prevalence of drug-induced vasculitis remains unknown. No population-based study has been performed.\nClinical description\nDrug-induced vasculitis typically presents with a petechial rash, purpura and skin necrosis. Symptoms are usually mild and localized. Rarely, systemic involvement of the lungs, kidneys, central nervous system, and/or liver can occur; this can be severe and potentially life-threating. Clinical features include rash, fever, malaise and myalgia, with a temporal relationship with drug administration.\nEtiology\nThe etiology of drug-induced vasculitis (DIV) is incompletely understood, however, aberrant NETosis, breakdown in immune tolerance and epitope spreading, implicated in the development of autoimmunity, have been identified as potential etiological mechanisms.\nDiagnostic methods\nDrug-induced vasculitis is a diagnosis of exclusion. There is no laboratory diagnostic tool for drug-induced vasculitis. Eosinophil count may be raised; this is seen more frequently in the case of systemic involvement. A comprehensive drug history of prescribed and over-the-counter medicines is paramount. Tissue biopsy can be beneficial in confirming the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes systemic lupus erythematosus, other non-drug-induced ANCA-vasculitis, infections, and malignancies.\nManagement and treatment\nTreatment is focused on stopping administration of the offending agent, and is enough to induce remission in mild cases. In addition, short-course and low-dose steroids therapy can be beneficial. For severe presentations, higher doses of steroids for longer durations may be required. In severe systemic presentations patients can be treated according to ANCA-vasculitis flare protocols. Plasma exchange can also be considered. Relapse is likely upon reintroduction of the offending drug.\nPrognosis\nMost cases are mild and resolve with cessation of the offending drug without any long-term sequelae. However, in cases with severe systemic involvement, drug-induced vasculitis can result in critical illness and death.\n\n                            Last update: \n                            March 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Eithne NIC AN RÍOGH"}
{"Disease Name": "Duane anomaly-myopathy-scoliosis syndrome", "Disease Definition": "A rare genetic disease characterized by bilateral Duane retraction syndrome type 3 (consisting of severe limitation of abduction, restriction of adduction, retraction of the globe, and narrowing of the palpebral fissure) and congenital myopathy manifesting as mild non-progressive hypotonia without muscular weakness, as well as delayed motor milestones, severe early-onset scoliosis, and short stature. Intelligence is normal.", "ORPHA ID": 50817, "Summary": ""}
{"Disease Name": "Duane retraction syndrome with congenital deafness", "Disease Definition": "A rare neurologic disease characterized by the presence of Duane retraction syndrome (i. e. a congenital cranial dysinnervation disorder with unilateral or bilateral limitation of abduction and/or adduction of the eye, as well as globe retraction and palpebral fissure narrowing on attempted adduction) in combination with congenital unilateral or bilateral hearing loss. The sidedness of hearing loss corresponds to the sidedness of the retraction syndrome.", "ORPHA ID": 529574, "Summary": ""}
{"Disease Name": "Duane retraction syndrome", "Disease Definition": "A rare, ocular congenital cranial dysinnervation disorder characterized by limited horizontal eye movement accompanied by globe retraction and palpebral fissure narrowing on attempted adduction.", "ORPHA ID": 233, "Summary": "Epidemiology\nDuane retraction syndrome (DRS) prevalence is estimated at between 1/1000 and 1/10,000 in the general population, representing approximately 1-5% of all strabismus cases. Females are more frequently affected than males.\nClinical description\nDRS is a congenital disorder, characterized by non-progressive horizontal ophthalmoplegia without ptosis. Vertical eye movement abnormalities may be observed, including upshoot or downshoot on adduction. Isolated, simplex DRS is usually unilateral and the left eye is more commonly affected. At birth, affected infants have restricted abduction and/or adduction, though it may not be appreciated immediately. Most individuals with DRS have strabismus in primary gaze but can use a compensatory head position to align the eyes, avoiding diplopia. Development of amblyopia is possible. The majority of DRS cases (70%) are not associated with other anomalies. DRS can be classified based on the extent of abduction and adduction: limited or absent abduction with normal or slightly limited adduction (type I) , normal or mildly restricted abduction with limited or absent adduction (type II), absent or limited abduction and adduction (type III). In all types, there is globe retraction with narrowing of palpebral fissure on attempted adduction.\nEtiology\nDRS results from abnormal development of the pontine abducens nucleus or nerve, unilaterally or bilaterally, leading to failure of the normal innervation of the lateral rectus muscle on the affected side. This results in limited abduction and horizontal gaze palsy. Globe retraction and fissure narrowing are due to co-contraction of the medial and lateral rectus muscles on attempted adduction, which is itself secondary to aberrant innervation of the lateral rectus by the oculomotor nerve. Identified genetic pathogenic variants include CHN1 or MAFB and rarely, SALL4.\nDiagnostic methods\nDiagnosis of DRS is based on clinical features. Magnetic resonance imaging of the brainstem reveals small or absent abducens nerves (CNVI). In individuals with DRS due to CHN1 mutations, the optic (CNII), oculomotor (CNIII) and/or trochlear (CNIV) nerves may also be hypoplastic.\nDifferential diagnosis\nDifferential diagnosis of isolated DRS includes syndromic forms of DRS such as Duane-radial ray syndrome (Okihiro syndrome), Townes-Brocks syndrome, acro-renal-ocular syndrome, Bosley-Salih-Alorainy and Athabaskan brainstem dysgenesis-related disorders, Wildervanck syndrome, and oculo-auriculo-vertebral spectrum. Syndromic DRS can also arise from chromosomal anomalies and copy number variants, primarily on chromosome 8. Differential diagnosis of DRS also includes Moebius syndrome, congenital fibrosis of extraocular muscles, and isolated horizontal gaze palsy without globe retraction with or without progressive scoliosis (HGPPS).\nAntenatal diagnosis\nPrenatal and preimplantation genetic testing for at-risk pregnancies is possible if a pathogenic variant has been identified in a family.\nGenetic counseling\nMost cases are sporadic, but up to 10% of patients have affected relatives. When inherited, isolated DRS most commonly segregates in families as an autosomal dominant trait but autosomal recessive inheritance is also possible. In familial forms, DRS is often bilateral; however, incomplete penetrance and variable expressivity can complicate assessments.\nManagement and treatment\nManagement of DRS is mainly supportive and involves wearing spectacles or contact lenses to correct refractive errors, occlusion or penalization of the better-seeing eye for treatment of amblyopia, or prisms to correct for abnormal head posture. Eye muscle surgery may be indicated to correct abnormal head position, to align the eyes in primary gaze, or to correct for upshoot or downshoot on adduction. However, surgery does not restore full normal eye movements. Surveillance is necessary to detect and prevent amblyopia. Vision therapy is advised for secondary convergence insufficiency.\nPrognosis\nIsolated DRS is a benign disorder that, if managed appropriately, results in excellent long-term prognosis for vision. In some cases, amblyopia or loss of binocular single vision might develop.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                             Brenda BARRY  - Dr Elizabeth ENGLE"}
{"Disease Name": "Dubin-Johnson syndrome", "Disease Definition": "Dubin-Johnson syndrome (DJS) is a benign, inherited liver disorder characterized clinically by chronic, predominantly conjugated, hyperbilirubinemia and histopathologically by black-brown pigment deposition in parenchymal liver cells.", "ORPHA ID": 234, "Summary": "Epidemiology\nPrevalence in the general population is unknown. DJS affects individuals of all ethnic origins but is most common among Iranian or Moroccan Jews, in which, due to founder mutations, it has been reported to occur in up to 1/1,300 individuals.\nClinical description\nPatients usually present during adolescence or young adulthood with mild to moderate, recurrent jaundice without pruritus, often triggered by intercurrent illness, pregnancy, oral contraceptives or drugs. Abdominal pain and fatigue are sometimes observed during outbreaks and hepatosplenomegaly may be present in rare cases. Total serum bilirubin (mainly in the conjugated form: the proportion of conjugated to total serum bilirubin is 50-80%) is elevated, usually between 2 and 5 mg/dl (very rarely up to 20 mg/dl). Liver enzyme activities (i.e. aminotransferases, alkaline phosphatase, gamma-glutamyl transpeptidase), total bile acid concentration, albumin level and prothrombin time are normal. An association with clotting factor VII deficiency (see this term) can be observed, especially in Iranian and Moroccan Jews. Histological studies reveal a typical black-brown granular pigment deposition in the cytosol of hepatocytes, mostly in the centrilobular area, without other histological abnormalities.\nEtiology\nDJS is inherited in an autosomal recessive manner and is caused by homozygous mutations in the ABCC2 gene. ABCC2 encodes an ATP-dependent apical membrane transporter that mediates the efflux of bilirubin-glucuronides and other conjugated organic anions from the hepatocyte into bile.\nDiagnostic methods\nDiagnosis should be suspected in patients exhibiting isolated conjugated hyperbilirubinemia (i.e. without changes in liver enzyme activities) in the absence of any septic condition, ultrasound anomaly of the liver or potentially interfering drug. In this context, the characteristic urinary coproporphyrin excretion pattern (i.e. an elevated proportion of coproporphyrin I (over 80%) with a normal total coproporphyrin level) is usually diagnostic for DJS. 99mTc-HIDA cholescintigraphy, showing delayed or non-visualization of the gallbladder and bile ducts and prolonged visualization of the liver may also be useful. Definitive diagnosis can be obtained through molecular analysis of the ABCC2 gene. Although histological studies also allow a definitive diagnosis, liver biopsy is not systematically performed considering the invasive nature of the procedure together with the benign prognosis of the disease.\nDifferential diagnosis\nThe main differential diagnosis is another form of mainly conjugated hyperbilirubinemia, Rotor syndrome (RT; see this term).\nManagement and treatment\nThere is no curative treatment for DJS, even though short-term administration of phenobarbital has been reported to reduce serum bilirubin level in some cases.\nPrognosis\nDJS is a benign disorder and the prognosis for patients is good, highlighting the need for correct diagnosis to avoid unnecessary diagnostic procedures, treatment and follow-up. Progression to liver failure, cirrhosis or hepatic fibrosis is not observed.\n\n                            Last update: \n                            January 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Véronique BARBU  - Dr Christophe CORPECHOT"}
{"Disease Name": "Dubowitz syndrome", "Disease Definition": "Dubowitz syndrome (DS) is a rare multiple congenital syndrome characterized primarly by growth retardation, microcephaly, distinctive facial dysmorphism, cutaneous eczema, a mild to severe intellectual deficit and genital abnormalities.", "ORPHA ID": 235, "Summary": "Epidemiology\nThe total birth prevalence in Europe has been estimated at 1/500,000. Over 150 cases have been described to date.\nClinical description\nNewborns often have a low birth weight with a small head and body size. Facial appearance is characteristic with narrow or triangular shaped head and high or sloping forehead, flat supraorbital ridge, scanty lateral eyebrows, short palpebral fissures, blepharophimosis, ptosis, abnormally modeled ears, broad and flat nasal bridge, micrognathia and unusual configuration of the mouth. Sumucous cleft palate is common. Other findings include cutaneous ezema, high-pitched or hoarse voice, hypospadias and cryptorchidism. Skeletal abnormalities in DS include sacral dimple, and clinodactyly (5th fingers), with cutaneous syndactyly of toes or fingers. Intellectual deficit is mostly mild to moderate. Furthermore a variety of ocular and dental abnormalities, such as hyperopia, cataracts, tapetoretinal degeneration, strabismus and taurodontia, anodontia/hypodontia or hyperdontia have been reported. Behavioral characteristics may include hyperactivity with short attention span, impulsivity and shyness. The spectrum of manifestations of Dubowitz syndrome may also comprise: hematological (aplastic anemia) and congenital heart defects, frequent infections, chromosomal instability and developement of malignancies (acute lymphoblastic leukemia or neuroblastoma; see these terms).\nEtiology\nThe etiology of Dubowitz syndrome has not been evidently elucidated. Two causal genes have been put forward in separate isolated cases and include NSUN2 and LIG4. However due to the large phenotypic overlap of Dubowitz syndrome with other clinical entities, there remains uncertainty on the etiology.\nDiagnostic methods\nDiagnosis is based on the multiple clinical manifestations and is commonly made in early childhood.\nDifferential diagnosis\nDifferential diagnosis includes fetal alcohol syndrome, Bloom syndrome, LIG4 syndrome and Fanconi anemia (see these terms).\nAntenatal diagnosis\nPrenatal growth retardation may be observed on ultrasound but does not lead to a reliable prenatal diagnosis.\nGenetic counseling\nIn some families, Dubowitz syndrome appears to have an autosomal recessive transmission. However, it has been suggested recently that Dubowitz syndrome is a microdeletion/microduplication syndrome rather than an autosomal disorder.\nManagement and treatment\nGrowth, dental speech, behavioral and intellectual development and a general health status check should be monitored regularly and treated appropriately. Eczema and recurrent infections require conservative treatment. Surgical intervention might be necessary for certain cardiovascular, urogenital, craniofacial or limb anomalies. Surveillance of hematological and malignant disorders is recommended.\nPrognosis\nThe prognosis is very variable depending on the severity and types of congenital anomalies present and the long-term outcome still remains elusive, as no data is available after puberty.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Chantal FARRA"}
{"Disease Name": "Duchenne and Becker muscular dystrophy", "Disease Definition": "A group of rare, genetic, progressive muscular dystrophies, including Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and a symptomatic form in female carriers. The diseases represent a spectrum of severity ranging from progressive skeletal and cardiac muscle wasting and weakness (DMD, BMD) to less severe muscle weakness or isolated cardiomyopathy affecting carrier females.", "ORPHA ID": 262, "Summary": "Epidemiology\nThe prevalence of DMD ranges between 1/3,500-1/ 9,300 male births. The prevalence of BMD varies from 1/16,700 to 1/18,500 male births. The prevalence of symptomatic female carriers is unknown.\nClinical description\nDystrophinopathies present with a spectrum of severity whereby BMD is at the mildest end and DMD the most severe, there is an intermediate phenotype in between. At the mildest end of the spectrum exercise-induced muscle cramps and myoglobinuria may be the only feature while at the severe end, there may be complete loss of muscle function, cardiomyopathy and respiratory failure. DMD presents in early childhood, motor milestones are delayed. Brain involvement leads to cognitive impairment (affecting about a third of patients) and/or pervasive behavioral disorders such as ADHD (attention deficit hyperactivity disorder), autism, anxiety and obsessive compulsive disorder. Muscle hypertrophy is evident, especially in the calf muscles. Progression is rapid, such that by the age of 5 there is likely to be a waddling gait and positive Gowers' sign. In untreated boys, walking is lost by 13 years of age (mean 9.5 years). Following loss of ambulation, scoliosis, respiratory failure and cardiomyopathy develop. BMD presents a broad spectrum of clinical severity, with onset of symptoms occurring from early childhood to as late as the sixth decade. Manifesting carriers of DMD and BMD may present with varying degrees of cardiomyopathy and muscle weakness. X-linked dilated cardiomyopathy (XLDCM), which may be caused by mutations in the dystrophin gene, presents with very severe, rapidly progressive, dilated cardiomyopathy.\nEtiology\nDystrophinopathies are allelic conditions caused by deletions, duplications and mutations in the DMD gene, located on the X chromosome (Xp21.2). DMD genetic variants are frame-shift, while BMD variants are in-frame.\nDiagnostic methods\nThe clinical diagnosis can be confirmed by several methods. Creatine Kinase (CK) is very raised. Molecular genetic analysis by MLPA (multiplex ligation-dependent probe amplification) will show a deletion in 60%; full gene sequencing is necessary to identify small deletions, duplications and nonsense mutations. Muscle biopsy for dystrophin analysis which is absent in DMD and reduced in BMD.\nDifferential diagnosis\nThe differential diagnosis includes LGMD and, in adults, other muscle disorders presenting with a raised CK.\nAntenatal diagnosis\nPrenatal diagnosis requires the most precise molecular diagnosis possible in the index case.\nGenetic counseling\nThe pattern of inheritance is X-linked recessive. Genetic counselling of affected families is recommended and screening of women carriers in the family is important.\nManagement and treatment\nThere is no known cure for this group of dystrophinopathies. In DMD, treatment with corticosteroids stabilizes motor function and delays loss of ambulation and respiratory failure by several years. Physiotherapy and orthotics delay the onset of joint contractures. Non-invasive ventilation (NIV) to treat respiratory failure prolongs life expectancy. Regular cardiac monitoring from diagnosis with early treatment using ACE (angiotensin-converting enzyme) inhibitors and beta blockers stabilizes cardiomyopathy. For XLDCM, cardiac transplantation is the treatment of choice.\nPrognosis\nLife expectancy is shortened by cardiac and respiratory involvement, but can be substantially improved with regular monitoring and pro-active management.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shpresa PULA  - Pr Rosaline QUINLIVAN"}
{"Disease Name": "Duchenne muscular dystrophy", "Disease Definition": "A rare, genetic, muscular dystrophy characterized by rapidly progressive muscle weakness and wasting due to degeneration of skeletal, smooth and cardiac muscle.", "ORPHA ID": 98896, "Summary": "Epidemiology\nDMD primarily affects males with an estimated male birth prevalence of 1/3,500-1/9,300.\nClinical description\nOnset occurs in early childhood, and affected boys may show a delay in walking (after 18 months of age) accompanied with speech and/or global developmental delay. Autism and behavioral problems, such as ADHD (attention deficit hyperactivity disorder), anxiety, obsessive compulsive disorder, are relatively common. Untreated children with DMD rarely achieve the ability to run or jump. The condition progresses rapidly and the child develops a waddling gait and a positive Gowers' sign. Climbing stairs becomes difficult and the child falls frequently. Loss of independent ambulation occurs between the ages of 6 and 13 years, the average being 9.5 years in non-steroid treated patients. Once ambulation is lost, joint contractures and scoliosis develop rapidly. Untreated patients die during late teens to early twenties from respiratory failure and or cardiomyopathy\nEtiology\nMuscle damage is caused by the complete absence of the sarcolemmal protein dystrophin as a result of variants in the DMD gene (Xp21.2).\nDiagnostic methods\nDiagnosis is suspected on the basis of the clinical picture, family history and laboratory findings (serum creatine kinase (CK) is 100-200 times the normal level). Genetic testing is the gold standard and involves multiplex-ligation dependent probe amplification (MLPA) for detection of deletions and duplications of exon (s) and full gene sequencing for detecting small deletions and duplications and non-sense or point mutations. Given the value of information provided by genetic analysis muscle biopsy is now recommended when genetic analysis in inconclusive. Genetic testing is therefore a critical tool in the accurate diagnosis of DMD and helps avoid missing the opportunity for personalized treatment.\nDifferential diagnosis\nDifferential diagnoses include severe Becker muscular dystrophy and limb girdle muscular dystrophy.\nAntenatal diagnosis\nAntenatal diagnosis is possible for families in which the diagnosis has been confirmed by molecular testing.\nGenetic counseling\nDMD is an X-linked recessive disease. Genetic counseling is very important: the risk of recurrence is 50% for male siblings of a proband. Female siblings have a 50% risk of being carriers and are usually asymptomatic but a small percentage manifest milder forms of the disease (symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers).\nManagement and treatment\nInternational standards of care recommend a multidisciplinary approach. Physiotherapy includes passive stretching and night time ankle-foot orthoses (AFO) to reduce tendo-Achilles contractures. Treatment with corticosteroids (prednisolone, prednisone or deflazacort) is the gold standard. Corticosteroids should be introduced early or when the child's motor skills plateau, usually around 4-5 years of age. Complications of corticosteroid therapy must be managed and include: weight management, gastric protection, monitoring and treatment of osteoporosis, ophthalmic assessment for cataracts and glaucoma. Ataluren (authorized in Europe) is the only disease-modifying drug for use in ambulatory patients older than 5 years of age and where DMD is caused by non-sense mutations. Cardiac management includes regular monitoring (echo and/or MRI) and prophylactic treatment with ACE inhibitors and/or beta inhibitors to maintain cardiac function. Respiratory management includes monitoring respiratory function, assessment for sleep hypoventilation and timely introduction of BiPAP (bilevel positive airway pressure). In older patients cough augmentation and pneumococcal and flu vaccines are recommended. Surgery may be required for correction of scoliosis.\nPrognosis\nDMD has a severe prognosis and life expectancy is significantly reduced with death occurring in the third to fifth decades, although this is improving with advancements in management and treatment.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shpresa PULA  - Pr Rosaline QUINLIVAN"}
{"Disease Name": "Duodenal atresia", "Disease Definition": "A rare, non-syndromic intestinal malformation characterized by a complete but short segment obliteration of the duodenal lumen.", "ORPHA ID": 1203, "Summary": "Epidemiology\nThe prevalence at birth of duodenal atresia is estimated at 1/11,000 in Europe, with an approximately equal male to female ratio.\nClinical description\nDuodenal atresia is classified into three types: type I (duodenal diaphragm) is linked to the presence of a mucosal diaphragmatic membrane with an intact muscle wall; type II (complete duodenal atresia) characterized by a short fibrous cord connecting the two ends or pouches of the duodenum; and type III (also complete duodenal atresia) which corresponds to a complete separation of the two ends of the duodenum, sometimes together with annular pancreas. Clinical presentation is similar irrespective of the type of atresia with repeated vomiting after feeding during the first day first or second day of life. The vomit is often without bile stain, as most atresias are located above the papilla of Vater. Weight loss, dehydration, and hypochloremic metabolic alkalosis are the most common accompanying symptoms. In rare cases with a membranous atresia, there may by a small opening in the mucosal membrane and less severe obstructions may manifest several months, or even several years, after birth; intermittent vomiting without abdominal distention may be the only presentation.\nEtiology\nVascular anomalies, abnormalities in neural cell migration and failure of recanalization of the duodenal lumen may play a causative role, although the exact cause remains unknown.\nDiagnostic methods\nThe clinical diagnosis is confirmed by abdominal radiography that shows a characteristic 'double bubble'' appearance with air trapped in the first portion of the duodenum (bulb) and stomach. The membranous type with a small luminal opening is diagnosed by endoscopy.\nDifferential diagnosis\nIn 30-52% of infants it is an isolated anomaly, but it is often associated with other congenital abnormalities. Approximately 20 to 30% of infants with duodenal atresia are carriers of trisomy 21, and about 20 to 25% have cardiac anomalies. Other frequently described associated malformations include duodenal growth failure, annular pancreas, which are particular clinical forms of duodenal atresia, and anomalies of the biliopancreatic tract or choledochal cysts. Other differential diagnoses include late appearing pyloric stenosis in cases of incomplete mucosal diaphragm, and other forms of intestinal atresia, small intestinal volvulus due to malrotation, duodenal duplication and duodenal stenosis.\nAntenatal diagnosis\nThe malformation may be diagnosed at prenatal ultrasound from week 16-20 by the appearance of dilatated stomach and duodenal bulb associated with increased amounts of amniotic fluid.\nGenetic counseling\nGenetic counseling should be offered at prenatal diagnosis with special emphasis on the risk of trisomy 21. Whilst different mutations have been associated with duodenal atresia in a few instances, no specific genetic mapping in association with isolated duodenal atresia has been reported.\nManagement and treatment\nManagement involves neonatal resuscitation and surgical correction in the neonatal period. Post-operative complications are rare, but late complications (megaduodenum, blind loop syndrome, duodenogastric reflux, esophagitis, pancreatitis, cholecystitis and cholelithiasis) occur in very rare cases.\nPrognosis\nThe prognosis with early surgical intervention is excellent.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Niels QVIST | ERNICA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Duplication of the pituitary gland", "Disease Definition": "A rare midline cerebral malformation characterized by duplicated pituitary stalks and/or glands within duplicated sella. Patients may present various degrees of facial dysmorphism and endocrine abnormalities, including precocious puberty, hypogonadism, hypothyroidism and/or hyperprolactinemia, as well as associated congenital anomalies, such as clift lip/palate, bifid nasal bridge/tongue/uvula, hypothalamic enlargement with or without hamartoma, nasopharyngeal tumors, corpus callosum agenesis/hypoplasia, basilar artery duplication, and/or vertebral defects (in particular, duplication of the odontoid process).", "ORPHA ID": 314621, "Summary": ""}
{"Disease Name": "Duplication of urethra", "Disease Definition": "A rare congenital genitourinary anomaly, encompassing a wide spectrum of anatomic variants in which the urethra is partially or totally duplicated, which may be asymptomatic or cause symptoms such as incontinence, recurrent urinary infections and difficulty urinating.", "ORPHA ID": 237, "Summary": ""}
{"Disease Name": "Dural sinus malformation", "Disease Definition": "A rare neurovascular malformation characterized by massive dilation of one or more dural sinuses typically associated with arteriovenous shunts. Anatomic types are the lateral type involving the jugular bulb, which presents with minimal symptoms, and the usually symptomatic midline type involving the confluens sinuum (torcular Herophili) and adjacent posterior sinuses. Complications include sinus thrombosis, venous infarction, and cerebral hemorrhage, as well as cardiac failure, macrocrania, and hydrocephalus. Spontaneous regression of the malformation may occur.", "ORPHA ID": 97339, "Summary": ""}
{"Disease Name": "Dyggve-Melchior-Clausen disease", "Disease Definition": "A rare, genetic primary bone dysplasia of the spondylo-epi-metaphyseal dysplasia (SEMD) group characterized by progressive short-trunked dwarfism, protruding sternum, microcephaly, intellectual disability and pathognomonic radiological findings (generalized platyspondyly with double-humped end plates, irregularly ossified femoral heads, a hypoplastic odontoid, and a lace-like appearance of iliac crests)", "ORPHA ID": 239, "Summary": "Epidemiology\nTo date approximately 100 cases have been reported worldwide.\nClinical description\nClinically, Dyggve-Melchior-Clausen disease (DMC) is characterized by progressive dwarfism with short trunk, protruding sternum, rhizomelic limb shortening, postnatal microcephaly with facial dysmorphism, coarse face and intellectual disability varying from moderate to severe. Physical measurements at birth are typically normal, with patients clinically presenting with short stature within the first two years of life along with progressive appearance of the skeletal deformities of the thorax, spine, pelvis, hands and knees. Orthopedic complications usually occur during childhood almost constantly including bilateral hip subluxation, deformations of the knees, lumbar lordosis, scoliosis and thoracic kyphosis. Radiological features include progressive flattened vertebral bodies (platyspondyly) with a double-humped shape clearly visible by 3-4 years of age, misaligned spine, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small pelvis with thickened and scalloped iliac crests. This specific aspect of iliac crests becomes clearly visible around 4 years of age, broadens through adolescence and persists into adulthood. Hands are generally short and broad with irregular shape of metacarpal bones and phalanges.\nEtiology\nThe disease is caused by mutations of the DYM gene (18q21.1). The large majority of mutations identified in the gene predict a loss of function of its product. DYM is expressed in the majority of tissue and codes for dymeclin, a protein which interacts with membranes of the Golgi apparatus, and has a role in the regulation of Golgi homeostasis and membrane trafficking\nDiagnostic methods\nDiagnosis is based on radiological evidence revealing platyspondyly with double vertebral humps, epiphyseal and metaphyseal dysplasia and scalloped iliac crests.\nDifferential diagnosis\nDifferential diagnoses include Smith-McCort syndrome, which presents with the same clinical and radiological features as DMC but without intellectual deficiency, and mucopolysaccharidosis type 4 which is clinically similar but has specific radiological and enzymatic signs.\nGenetic counseling\nTransmission is autosomal recessive. There is a 25% risk of disease transmission where both parents are unaffected carriers.\nManagement and treatment\nManagement requires both a multidisciplinary approach and a long-term follow-up as the disease is progressive. Preventive or corrective orthopedic surgery may be an option to manage lower limb deformities. However, due to the poor quality of osseous tissue, minimal-invasive surgery such as guided growth may be preferable\nPrognosis\nThe disease often progresses towards orthopedic complications which can include lumbar lordosis, thoracic kyphosis, hip luxation, deformation of the knees and spinal cord compression secondary to instability of the atlas-axis.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Vincent EL GHOUZZI  - Pr Alain VERLOES | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "DYRK1A-related intellectual disability syndrome due to 21q22.13q22.2 microdeletion", "Disease Definition": "A rare, syndromic intellectual disability characterized by global developmental delay including severely delayed or absent speech, moderate to severe intellectual disability, behavioral issues, stereotypic behavior, febrile seizures and epilepsy, abnormal gait, vision defects, and characteristic facial features. Intrauterine growth restriction and feeding difficulties are frequently present.", "ORPHA ID": 268261, "Summary": ""}
{"Disease Name": "DYRK1A-related intellectual disability syndrome", "Disease Definition": "A rare genetic syndromic intellectual disability characterized by microcephaly, global developmental delay, mild to severe intellectual disability, impairment of speech, feeding problems, behavior problems (often autism spectrum disorder) and dysmorphic facial features (such as prominent ears, deep-set eyes, a short nose with a broad nasal tip, and retrognathia with a broad chin). Other, more variable manifestations include seizures, short stature, ocular anomalies, cardiac anomalies, urogenital anomalies and musculoskeletal defects.", "ORPHA ID": 464306, "Summary": "Epidemiology\nDYRK1A-related intellectual disability syndrome (DYRK1A syndrome) accounts for 0.1%-0.5% of individuals with intellectual disability and/or autism.\nClinical description\nDevelopmental delay is observed at a young age and, usually, mild to severe intellectual disability later in life. An apparent speech/language delay is typical with understanding seemingly greater than verbal expression. Neonatal feeding problems (reflux, suck or swallowing problems) may occur and may persist into adulthood, warranting tube feeding in some individuals. Low weight and a slender build are common in later in life. Children have delayed motor development but most children learn to walk, sometimes with a broader gait. The motor skills may be hampered by hypertonia and, later in life the, occurrence of contractures. Many individuals have autism spectrum disorder and other behavior disorders (anxiety, hyperactivity or sleeping problems) are possible. Febrile seizures may develop during infancy and epilepsy may ensue thereafter. Eye abnormalities mainly include strabismus, astigmatism, and hypermetropia; other ocular anomalies have also been reported. More variable anomalies include cardiac defects (septal defects, hypoplastic left heart, valve abnormalities, aortic stenosis, and patent ductus arteriosus), urogenital anomalies (undescended testes, hypoplastic scrotum, shawl scrotum, micropenis, hypospadias, inguinal hernia, frequent urinary infections, vesicoureteral reflux, and unilateral renal agenesis) and, less frequently, dental anomalies. Most children have overlapping physical characteristics such as short stature, microcephaly, prominent ears, deep-set eyes, a short nose with a broad nasal tip, and retrognathia with a broad chin. Brain imaging may be indicative of global cerebral underdevelopment or hypomyelination.\nEtiology\nDYRK1A syndrome can be caused by a single nucleotide variant in the DYRK1A gene (21q22.13) or due to a chromosome 22q22.13 (micro)deletion including the DYRK1A gene.\nDiagnostic methods\nThe disorder may be suspected on clinical presentation and diagnosed with molecular genetic testing. Chromosomal microarray analysis may detect chromosome 21q22.13 deletions including DYRK1A. Pathogenic DYRK1A single nucleotide variants may be detected by sequencing of the DYRK1A gene (most often by a multigene panel using whole exome sequencing or genome sequencing).\nDifferential diagnosis\nThere is a broad differential diagnosis including syndromes with primary microcephaly and absence/delay of speech development.\nAntenatal diagnosis\nSigns and symptoms of DYRK1A syndrome may be visible during the third trimester of pregnancy showing urogenital anomalies, cardiac anomalies and/or microcephaly. However, the absence of ultrasound anomalies does not exclude this disorder. Genetic antenatal testing is not applicable as mutations occur de novo.\nGenetic counseling\nTo date, all reported cases, whose parents have undergone genetic testing, have occurred de novo suggesting a low recurrence risk (<1% due to risk of germline mosaicism). Penetrance is likely to be 100%. The course of the syndrome is similar in males and females.\nManagement and treatment\nRegular follow-up is recommended by a pediatrician or a doctor specialized in the care for people with an intellectual disability, preferably in consultation with other specialties in a multidisciplinary setting. These may include a speech therapist, rehabilitation doctor, physiotherapist, occupational therapist and/or dietician. In case of epilepsy, the referral to a neurologist is required. After diagnosis, cardiac evaluation and periodical ophthalmological check-ups are required. In case of behavioral problems, a (child) psychiatrist can be involved in the treatment.\nPrognosis\nBased on current data, life expectancy is not limited in affected individuals as several adults have been reported. Data on possible progression of behavior abnormalities or neurologic findings are still limited.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr B.M.W. [Bregje] VAN BON | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Dysbetalipoproteinemia", "Disease Definition": "A rare combined hyperlipidemia (HLP type 3) characterized by high levels of cholesterol and triglycerides, transported by intermediate density lipoproteins (IDLs), and a high risk of progressive atherosclerosis and premature cardiovascular disease.", "ORPHA ID": 412, "Summary": "Epidemiology\nDysbetalipoproteinemia prevalence is estimated at 1/10,000 in the general population. Men are predominantly affected (male-female ratio about 2:1). The disease very rarely occurs before adulthood or in premenopausal women.\nClinical description\nMost patients are asymptomatic. Clinical signs that may appear during adulthood are xanthomas of the eyelids (i.e. xanthelasma), transient xanthomas on palms (i.e. planar palmar xanthomas) or tuberous xanthomas over elbows or knees. Sensitive hepatomegaly may be observed. Patients develop highly progressive atherosclerosis that can lead to premature cardiovascular disease (stroke, coronary and peripheral artery disease. Patients expressing major hypertriglyceridemia may also develop acute pancreatitis.\nEtiology\nThe disease results from mutations in the APOE gene (19q13.31) encoding apolipoprotein E, a protein mediating the cellular uptake of triglyceride-rich lipoprotein remnants (i.e., IDLs with roughly equal amounts of cholesterol and triglycerides) with anti-oxidant and anti-inflammatory properties. Dietary, metabolic, hormonal factors may aggravate the disease, as well as chronic inflammation, xenobiotics (e.g. immune suppressants, retinoids, antidepressants) or other genetic cofactors (e.g. APOA5, APOC3, LIPC, LPL variants).\nDiagnostic methods\nDiagnosis is based on the evidence of an abnormal lipoprotein profile with increased fasting serum concentrations of total cholesterol, triglycerides and Apolipoprotein B, and lowered plasma high-density lipoprotein (HDL) cholesterol (<40 mg/dL). Genetic testing confirms the diagnosis. In young adults, signs of silent atherosclerosis may be observed with arterial imaging.\nDifferential diagnosis\nDifferential diagnosis includes all other forms of atherogenic hyperlipidemias such as familial hypercholesterolemia, and familial hypertriglyceridemia.\nGenetic counseling\nIn most cases associated with the APOE ''E2'' genotype, inheritance is semi-dominant or conditionally recessive. Carriers of this genotype exhibit the phenotype of HLP type 3 only when other metabolic, exogenous or genetic factors are present. Some patients however, carry heterozygous or compound heterozygous rare APOE variants that are sufficient for the development of the disease; in these cases, transmission is autosomal dominant or semi-dominant.\nManagement and treatment\nTreatment includes a diet poor in carbohydrates and saturated fat, exercise, and lipid-lowering drugs (e.g. fibrates, statins) and is usually sufficient for complete regression of the disease within a few months. In severe cases with overt cardiovascular and/or pancreatic manifestations, intensive therapies (e.g. proprotein convertase subtilisin kexin type 9 (PCSK9), ApoC3 or microsomal triglyceride transfer protein (MTP) inhibitors, LDL apheresis) may be proposed.\nPrognosis\nWithout treatment, patients have a 5-10 times higher risk of premature and recurrent atherothrombotic events than the general population.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Pascale BENLIAN"}
{"Disease Name": "Dyschromatosis symmetrica hereditaria", "Disease Definition": "A rare genodermatosis characterized by the presence of the mixture of hyperpigmented and hypopigmented macules of approximately 5mm in diameter, principally located on the extremities.", "ORPHA ID": 41, "Summary": "Epidemiology\nDSH has been reported mainly in eastern Asia including Japan, although genetically confirmed DSH cases have also been reported in Thai, Indian, European, and Hispanic populations. The prevalence of DSH in Japan is estimated to be approximately 1/67,000 people. There does not appear to be male or female predominance. Pathogenic ADAR was also observed in the American population based on a genetic mutation database which implies that DSH patients might be found in the United States.\nClinical description\nThe first manifestations of the disease generally appear during early childhood and 70% of patients show eruptions until the age of 7. The eruptions might be exacerbated until the age of 20. Skin manifestations on the hands of DSH patients tend to worsen in summer. Quantitative analysis of seasonal changes in DSH severity revealed that sun exposure is only a transiently aggravating factor.\nEtiology\nThe disease is caused by monoallelic mutations in double-stranded RNA-specific adenosine deaminase 1 (ADAR1) gene. Biallelic ADAR1 mutations may also cause a form of Aicardi-Goutières syndrome (a severe genetic inflammatory disease in childhood that affects the brain and the skin, and mimics viral infection) or bilateral striatal necrosis (affecting the central nervous system).\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and confirmed by genetic testing. Although DSH shows autosomal dominant inheritance with nearly complete penetrance, intrafamilial variation of severity of skin manifestation can be seen. Thus, ultraviolet light examination can be useful to check the slight skin manifestation.\nDifferential diagnosis\nThe differential diagnosis includes xeroderma pigmentosum, dyschromatosis universalis hereditaria, reticulate acropigmentation of Kitamura and Aicardi-Goutières syndrome caused by ADAR1 mutations.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe disorder is autosomal dominant; some cases occur sporadically. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. The genetic penetrance is almost 100%.\nManagement and treatment\nThere is no curative treatment. Topical sunscreen and sun-protective clothing can help to control the skin lesions.\nPrognosis\nDSH patient usually have a normal life expectancy.\n\n                            Last update: \n                            June 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Michihiro KONO"}
{"Disease Name": "Dyschromatosis universalis hereditaria", "Disease Definition": "A rare, genetic, pigmentation anomaly of the skin characterized by generalized, irregularly shaped, asymptomatic, hyper- and hypopigmented macules distributed in a reticular pattern involving the trunk, limbs, and sometimes the face. The palms, soles and mucosa are usually not affected. Systemic abnormalities have been rarely reported.", "ORPHA ID": 241, "Summary": ""}
{"Disease Name": "Dysembryoplastic neuroepithelial tumor", "Disease Definition": "A rare mixed neuronal-glial tumor characterized by a benign, usually supratentorial lesion with predominantly cortical location and multinodular architecture. The tumor typically becomes symptomatic in the second or third decade of life with drug-resistant partial seizures. Histological hallmark is the specific glioneuronal element, columns oriented perpendicularly to the cortical surface, formed by bundles of axons attached to oligodendroglia-like cells, while neurons appear to float in an abundant eosinophilic matrix.", "ORPHA ID": 251946, "Summary": ""}
{"Disease Name": "Dysequilibrium syndrome", "Disease Definition": "Dysequilibrium syndrome (DES) is a non-progressive cerebellar disorder characterized by ataxia associated with an intellectual disability, delayed ambulation and cerebellar hypoplasia.", "ORPHA ID": 1766, "Summary": "Epidemiology\nTo date, more than 50 individuals have been reported in the world literature.\nClinical description\nDES is a congenital disorder characterized by nonprogressive cerebellar ataxia, associated with a moderate to profound intellectual disability and delayed ambulation. Gait can be either bipedal or quadrupedal. Additional features include hypotonia, lack of coordination, delayed motor development, seizures, dysarthria, strabismus, short stature and pes planus.\nEtiology\nEtiological subtypes of DES have been reported and include type 1 (CAMRQ1), 2 (CAMRQ2), 3 (CAMRQ3) and 4 (CAMRQ4) which are attributed to mutations in VLDLR (9p24), CA8 (8q12.1), WDR81 (17p13.3) and ATP8A2 (13q12) genes, respectively. VLDLR encodes the very low density lipoprotein receptor (VLDLR) which is involved in neuronal migration in the cerebral cortex and cerebellum. CA8 encodes a carbonic-anhydrase related protein, whose biological function is not yet fully understood. The function of WDR81 is still unknown. ATP8A2 encodes an ATPase which is mainly expressed in brain tissue, with the highest levels found in the cerebellum, and that may be critical for the developmental processes of the central nervous system.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\n\n                            Last update: \n                            March 2016\n\n\n                            - Expert reviewer(s): \n                            Pr Kym BOYCOTT"}
{"Disease Name": "Dysferlin-related limb-girdle muscular dystrophy R2", "Disease Definition": "A subtype of autosomal recessive limb-girdle muscular dystrophy characterized by an onset in late adolescence or early adulthood of slowly progressive, proximal weakness and atrophy of shoulder and pelvic girdle muscles. Cardiac and respiratory muscles are not involved. Hypertrophy of the calf muscles and highly elevated serum creatine kinase levels are frequently observed.", "ORPHA ID": 268, "Summary": ""}
{"Disease Name": "Dyskeratosis congenita", "Disease Definition": "A rare ectodermal dysplasia syndrome that often presents with the classic triad of nail dysplasia, skin pigmentary changes, and oral leukoplakia associated with a high risk of bone marrow failure (BMF) and cancer.", "ORPHA ID": 1775, "Summary": "Epidemiology\nDyskeratosis congenita (DC) prevalence is unknown. More than 400 families are reported in the world.\nClinical description\nDC has a wide phenotypic spectrum and age onset. It classically manifests during childhood with the triad of dysplastic nails, lacy reticular pigmentation and atrophy of the skin at the level of the neck and upper chest, and oral leukoplakia. Patients are at high risk of progressive BMF and may develop myelodysplastic syndrome or acute myelogenous leukemia at any age (the risk increasing with age). There is also an increased risk for solid tumors, typically squamous cell carcinoma of head and neck or anogenital cancer. Additional clinical findings have been reported and may include: developmental delay, short stature, microcephaly, blepharitis, epiphora, periodontal disease, taurodontism, decreased teeth/root ratio, esophageal stenosis, urethral stenosis, osteoporosis, avascular necrosis of femur and/or humerus, premature hair greying/alopecia, or abnormal eyelashes. Patients with DC may also develop pulmonary fibrosis, pulmonary arteriovenous malformations, gastrointestinal telangiectasias, and liver disease. It is important to note that the clinical features of DC progress over time and that all features, including the mucocutaneous triad, may not be present.\nEtiology\nDC is caused by germline mutations in genes important in telomere biology. De novo cases also occur. X-linked recessive DC is due to mutations in DKC1 (Xq28). The autosomal dominant genes associated with DC are TERC (3q26.2), TERT (5p15.33), TINF2 (14q12), RTEL1 (20q13.3), PARN (16p13.12), and ACD (16q22.1). Autosomal recessive genes include TERT (5p15.33), NHP2 (5q35.3), NOP10 (15q14-q15), RTEL1 (20q13.3), WRAP53 (17p13.1), ACD (16q22.1). Mutations in CTC1 (17p13.1), POT1 (7q31.33) and STN1 (10q24.33) are rare causes of DC.\nDiagnostic methods\nDiagnosis should be considered if at least 2 characteristics of the triad are present or one feature in addition to two other primary clinical findings. Clinical diagnosis may be confirmed by telomere length testing by multicolor flow cytometry fluorescence in situ hybridization (flow-FISH), and genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes palmoplantar keratoderma-spastic paralysis syndrome, nail-patella syndrome, autosomal dominant nail dysplasia, poikiloderma with netropenia, Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond Anemia, idiopathic aplastic anemia, idiopathic pulmonary fibrosis, Coats plus syndrome.\nAntenatal diagnosis\nIn case of family history, prenatal genetic diagnosis by chorionic villus sampling or preimplantation genetic diagnosis may be available.\nGenetic counseling\nThe disorder may be inherited in X-linked recessive (XLR), autosomal dominant (AD), or autosomal recessive (AR) patterns.\nManagement and treatment\nManagement includes regular complete clinical examinations. To date hematopoietic stem cell transplantation (HSCT) is the only cure for BMF. Androgen therapy may be considered first when no related donor is available. Treatment of cancer uses individualized chemotherapy and radiotherapy regimens.\nPrognosis\nLife expectancy ranges from infancy to well into the 7th decade. Up to 40% of patients will have BMF by the age of 40. Major causes of morbidity include BMF, cancer and pulmonary complications.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Sharon SAVAGE"}
{"Disease Name": "Dysmorphism-cleft palate-loose skin syndrome", "Disease Definition": "Dysmorphism-cleft palate-loose skin syndrome is a rare, genetic developmental defect during embryogenesis characterized by severe psychomotor delay, intellectual disability, congenital, symmetrical circumferential skin creases of arms and legs, cleft palate, and facial dysmorphism (incl. elongated face, high forehead, blepharophimosis, short palpebral fissures, microphthalmia, microcornea, epicanthic folds, telecanthus, microtia, posteriorly angulated ears, broad nasal bridge, microstomia and micrognathia). Additional features reported include short stature, microcephaly, hypotonia, pectus excavatum, severe scoliosis, hypoplastic scrotum, and mixed hearing loss.", "ORPHA ID": 1779, "Summary": ""}
{"Disease Name": "Dysmorphism-conductive hearing loss-heart defect syndrome", "Disease Definition": "Dysmorphism-conductive hearing loss-heart defect syndrome is a rare, multiple congenital anomalies syndrome characterized by a distinctive facial appearance (low frontal hairline, bilateral ptosis, prominent eyes, flat midface, broad, flat nares, Cupid's bow upper lip vermilion, and small, low-set, posteriorly rotated ears), in addition to cleft palate, conductive hearing loss, heart defects (atrial or ventricular septal defect) and mild developmental delay/intellectual disability.", "ORPHA ID": 289553, "Summary": ""}
{"Disease Name": "Dysmorphism-pectus carinatum-joint laxity syndrome", "Disease Definition": "Dysmorphism-pectus carinatum-joint laxity syndrome is characterised by joint laxity, pectus carinatum and facial dysmorphism (mild frontal bossing, a beaked nose with a low nasal bridge, malar hypoplasia, chubby cheeks, a striking philtrum and arched upper lips). It has been described in two siblings. The mode of transmission is unknown.", "ORPHA ID": 2104, "Summary": ""}
{"Disease Name": "Dysmorphism-short stature-deafness-difference of sex development syndrome", "Disease Definition": "Dysmorphism-short stature-deafness-disorder of sex development syndrome is characterized by dysmorphism (including facial asymmetry, arched eyebrows, hypertelorism, broad and flat nasal bridge, microtia, small nose with anteverted nostrils, micrognathia), deafness, cleft palate, male pseudohermaphroditism, and growth and psychomotor retardation. It has been described in two siblings. It is transmitted as an autosomal recessive trait.", "ORPHA ID": 2282, "Summary": ""}
{"Disease Name": "Dysosteosclerosis", "Disease Definition": "A rare genetic primary bone dysplasia disease characterized by progressive osteosclerosis and platyspondyly.", "ORPHA ID": 1782, "Summary": "Epidemiology\nLess than 30 cases of Dysosteosclerosis have been reported in the literature to date.\nClinical description\nThe disease is characterized by sclerosis of the skull base, ribs, clavicles, scapulae, mid-diaphyses and increased bone fragility. Patients have a prominent forehead, narrow midface, flattening of the vertebral bodies and dental anomalies. Short stature, optic atrophy, hearing impairment, epilepsy, skin changes, and progressive psychomotor deficit are frequent.\nEtiology\nThe disease is caused by mutations in SLC29A3. This gene encodes a nucleoside transporter. Mutations in this gene may also cause Faisalabad histiocytosis, Rosai-Dorfman disease, H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome. Parental consanguinity has been noted in some cases. Mutations in osteopetrosis genes TNFRSF11A and TCIRG1 can also cause dysosteosclerosis.\nDiagnostic methods\nSequencing combined by deletion and duplication analysis is possible.\nDifferential diagnosis\nOsteopetrosis is more common than dysosteosclerosis and distinguishing features are the presence of sclerotic platyspondyly as well as widened and relatively radiolucent sub-metaphyseal regions of long tubular bones with sclerotic diaphysis. Responsible genes include OSTM1, SNX10, CA2, TCIRG1, TNFSF11, CLCN7, PLEKHM1, TNFRSF11A, and LRP5. In Pyle disease, there is important metaphyseal expansion with cortical thinning of the tubular bones well into the diaphyses. There can be mild platyspondyly and skull sclerosis but not as much as in dysosteosclerosis. Genu valgum is a key clinical feature. The responsible gene is SFRP4. In BANDDOS (Brain abnormalities, neurodegeneration, and dysosteosclerosis), there are bone changes similar to dysosteosclerosis, osteopetrosis or Pyle disease, but there is also neurological disease of neonatal, childhood or adult onset. The responsible gene is CSF1R.\nGenetic counseling\nDysosteosclerosis is inherited in an autosomal recessive manner for SLC29A3, TNFRSF11A and TCIRG1 mutation. An X-linked pedigree has also been reported.\nManagement and treatment\nManagement is mostly supportive, bone marrow transplantation was tried in one individual without success.\nPrognosis\nThe overall prognosis is generally poor, although, as in osteopetrosis, there is a wide spectrum of severity.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Philippe CAMPEAU"}
{"Disease Name": "Dysostosis with brachydactyly", "Disease Definition": "Brachydactyly ('short digits') is a general term that refers to disproportionately short fingers and toes, and forms part of the group of limb malformations characterized by bone dysostosis.", "ORPHA ID": 69028, "Summary": "Epidemiology\nThe various types of isolated brachydactyly are rare, except for types A3 and D.\nClinical description\nBrachydactyly can occur either as an isolated malformation or as part of a complex malformation syndrome. To date, many different forms of brachydactyly have been identified. Some forms also result in short stature. In isolated brachydactyly, subtle changes elsewhere may be present. Brachydactyly may also be accompanied by other hand malformations, such as syndactyly, polydactyly, reduction defects, or symphalangism.\nEtiology\nFor the majority of isolated brachydactylies and some syndromic forms of brachydactyly, the causative gene defect has been identified. In isolated brachydactyly, the inheritance is mostly autosomal dominant with variable expressivity and penetrance.\nDiagnostic methods\nDiagnosis is clinical, anthropometric and radiological.\nAntenatal diagnosis\nPrenatal diagnosis is usually not indicated for isolated forms of brachydactyly, but may be appropriate in syndromic forms. Molecular studies of chorionic villus samples at 11 weeks of gestation and by amniocentesis after the 14th week of gestation can provide antenatal diagnosis if the causative mutation in the family is known.\nGenetic counseling\nThe nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms.\nManagement and treatment\nThere is no specific management or treatment that is applicable to all forms of brachydactyly. Plastic surgery is only indicated if the brachydactyly affects hand function or for cosmetic reasons, but is typically not needed. Physical therapy and ergotherapy may ameliorate hand function.\nPrognosis\nPrognosis for the brachydactylies is strongly dependent on the nature of the brachydactyly, and may vary from excellent to severely influencing hand function. If brachydactyly forms part of a syndromic entity, prognosis often depends on the nature of the associated anomalies.\n\n                            Last update: \n                            June 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Mona AGLAN  - Pr Samia TEMTAMY"}
{"Disease Name": "Dysphagia lusoria", "Disease Definition": "A rare aortic arch defect characterized by variable degrees of dysphagia due to compression of the esophagus from an aberrant right subclavian artery (arteria lusoria), which arises as the fourth branch, distal to the left subclavian artery, from the aortic arch. In most cases, the aberrant vessel then passes posterior to the esophagus, less frequently between the trachea and esophagus, or anterior to the trachea. Children may also present with stridor and recurrent chest infections.", "ORPHA ID": 99082, "Summary": ""}
{"Disease Name": "Dysplasia epiphysealis hemimelica", "Disease Definition": "A rare bone development disorder characterized by localized, asymmetric osteochondral overgrowth affecting single or multiple epiphyses, most commonly the distal femur, proximal tibia, and talus. The lesions are typically restricted to one side of the epiphysis, with the medial side being affected twice as often as the lateral side. The condition is usually diagnosed in children, and three times more often in boys than in girls. Patients present with pain, limitation in range of motion, and deformity or swelling of the affected joint.", "ORPHA ID": 1822, "Summary": ""}
{"Disease Name": "Dysplasia of head of femur, Meyer type", "Disease Definition": "Meyer dysplasia of the femoral head is a mild localized form of skeletal dysplasia characterized by delayed, irregular ossification of femoral capital epiphysis.", "ORPHA ID": 168621, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe condition is often discovered incidentally during early childhood (during the second or third year of life). It is often bilateral, although severity may be asymmetric. Clinical manifestations may include a waddling gait, genu valgum, hip pain and restricted movement, although these manifestations are usually transient and the majority of patients are asymptomatic. Resolution without treatment by six years of age has been reported in some cases, however, permanent deformity (flattening) of the femoral head has also been described and could represent a mild form of multiple epiphyseal dysplasia (see this term).\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Dysplastic cortical hyperostosis, Kozlowski-Tsuruta type", "Disease Definition": "Dysplastic cortical hyperostosis is an extremely rare primary bone dysplasia with increased bone density characterized by lethal neonatal dwarfism with hydrops, narrow chest and short limbs with extensive cortical thickening of all long bones, ribs, clavicles and scapulae, and coronal clefts in vertebral bodies.", "ORPHA ID": 2204, "Summary": ""}
{"Disease Name": "Dysraphism-cleft lip/palate-limb reduction defects syndrome", "Disease Definition": "A rare developmental defect during embryogenesis disorder characterized by spinal dysraphism, cleft lip and palate, limb reduction defects and anencephaly. There have been no further descriptions in the literature since 1994.", "ORPHA ID": 2476, "Summary": ""}
{"Disease Name": "Dyssegmental dysplasia, Silverman-Handmaker type", "Disease Definition": "Dyssegmental dysplasia, Silverman-Handmaker type is a rare, genetic, primary bone dysplasia disorder, and lethal form of neonatal short-limbed dwarfism, characterized by anisospondyly, severe short stature and limb shortening, metaphyseal flaring and distinct dysmorphic features (i.e. flat facial appearance, abnormal ears, short neck, narrow thorax). Additional features may include other skeletal findings (e.g. joint contractures, bowed limbs, talipes equinovarus) and urogenital and cardiovascular abnormalities.", "ORPHA ID": 1865, "Summary": ""}
{"Disease Name": "Dysspondyloenchondromatosis", "Disease Definition": "Dysspondyloenchondromatosis is a rare skeletal dysplasia characterized by anisospondyly and multiple enchondromas in vertebrae and the metaphyseal and diaphyseal parts of long tubular bones, leading to kyphoscoliosis and lower limb asymmetry.", "ORPHA ID": 85198, "Summary": ""}
{"Disease Name": "Dystonia 16", "Disease Definition": "Dystonia 16 (DYT16) is a very rare and newly discovered movement disorder which is characterized by early-onset progressive limb dystonia, laryngeal and oromandibular dystonia, and parkinsonism.", "ORPHA ID": 210571, "Summary": "Epidemiology\nIt has been described in 8 patients from three Brazilian families and one German family to date.\nClinical description\nDisease presents in infancy to late childhood with one of two possible phenotypes: either generalized dystonia or dystonia-parkinsonism not responsive to L-Dopa. Dystonia usually starts in one limb, becomes generalized and mainly affects the trunk, neck and oromandibular muscles. Motor and speech developmental delays were also reported. The phenotypic spectrum of this disease is still being determined. Pharmacological therapy is ineffective.\nEtiology\nDYT16 is caused by mutations in the protein kinase, interferon-inducible double stranded RNA dependent activator (PRKRA) gene, located on chromosome 2q31.2.\nGenetic counseling\nDYT16 is inherited in an autosomal recessive manner, and genetic counseling is possible and recommended.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "Dystonia 28", "Disease Definition": "A rare persistent combined dystonia characterized by childhood onset of progressive dystonia typically beginning in the lower limbs and eventually progressing to generalized dystonia with involvement of the upper limbs, trunk, face, and neck. Variable developmental delay and intellectual disability, as well as mild microcephaly, short stature, abnormal eye movements, and slightly dysmorphic facial features have been reported in association.", "ORPHA ID": 589618, "Summary": ""}
{"Disease Name": "Dystonia-aphonia syndrome", "Disease Definition": "Dystonia-aphonia syndrome is a rare, genetic, persistent combined dystonia disorder characterized by slowly progressive, severe, caudo-rostrally spreading generalized dystonia with prominent facial and oro-mandibular involvement leading to severe anarthria and/or aphonia, swallowing difficulties, and gait disturbances. Additional manifestations include slowed horizontal saccades, subclinical epilepsy, photic myoclonus, oral hypertrophic changes (e.g. gingival or lingual hyperplasia), as well as delayed milestones and cognitive impairment.", "ORPHA ID": 412217, "Summary": ""}
{"Disease Name": "Dystonia-parkinsonism-hypermanganesemia syndrome", "Disease Definition": "A rare disorder of manganese transport characterized by progressive movement disorder and elevated blood manganese levels. Patients present in infancy or early childhood with loss of motor milestones, rapidly progressive dystonia, spasticity, bulbar dysfunction, and parkinsonism, resulting in loss of independent ambulation. Cognition may be impaired but is generally better preserved than motor function. Additional manifestations include abnormal head growth and skull deformities. Brain MRI shows abnormalities of the basal ganglia, variably also of other brain regions.", "ORPHA ID": 521406, "Summary": ""}
{"Disease Name": "Dystrophic epidermolysis bullosa pruriginosa", "Disease Definition": "A rare dystrophic epidermolysis bullosa (DEB) characterized by generalized or localized skin lesions associated with severe, if not intractable, pruritus.", "ORPHA ID": 89843, "Summary": "Epidemiology\nPrevalence is unknown. Approximately 100 families or sporadic cases have been reported to date, but it might be underreported.\nClinical description\nWhile skin fragility and blistering lesions usually manifest in infancy, which heal with atrophic scarring and milia formation, the onset of intense pruritus is frequently delayed until the adolescence or even adulthood. At the onset of pruritus, the clinical picture generally worsens with the development of papules, nodules, lichenoid and hypertrophic lesions in a linear distribution, preferentially on the extensor surfaces of the limbs. Nail dystrophy is usually present.\nEtiology\nDEB pruriginosa is caused by mutations within the type VII collagen gene (COL7A1/i>; 3p21.31). Mutations in this gene lead to an alteration in function or to reduced amounts of collagen VII. This impairs its assembly into anchoring fibrils that anchor the basement membrane to the underlying dermis.\nDiagnostic methods\nTransmission electron microscopy shows blister formation below the lamina densa and reduced number of anchoring fibrils in adjacent non-blistered skin. Immunofluorescence mapping shows dermal cleavage of the skin and reduced immunoreactivity for type VII collagen. The diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes nodular prurigo, lichen simplex, lichen planus, hypertrophic scarring and dermatitis artefacta.\nAntenatal diagnosis\nAntenatal diagnosis is not recommended.\nGenetic counseling\nThe disorder is typically sporadic but autosomal dominant and recessive inheritance has also been reported. Genetic counselling should be offered to affected individuals informing them of risk of transmitting the pathogenic variant to offspring.\nManagement and treatment\nClinical management of DEB pruruginosa is often difficult, although generic measures reduce itching. Nevertheless, there are some reports of helpful interventions which include topical treatments (e.g. tacrolimus), systemic agents (e.g. ciclosporin or thalidomide), and cryotherapy. Recently, dupilumab has proven to be effective.\nPrognosis\nThe condition is therapy resistant, but the overall course of the disease is mild to moderate and life expectancy is normal.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Cristina HAS | ERN-Skin* - Pr Carmen SALAVASTRU | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Dystrophic epidermolysis bullosa", "Disease Definition": "A group of inherited epidermolysis bullosa (EB) characterized by cutaneous and mucosal fragility resulting in blisters and superficial ulcerations that develop below the lamina densa of the cutaneous basement membrane and that heal with significant scarring and milia formation. Dystrophic epidermolysis bullosa (DEB) comprises four major and several rare sub-types with the three most common being intermediate dominant DEB, severe recessive DEB and intermediate recessive DEB.", "ORPHA ID": 303, "Summary": "Epidemiology\nDEB is the second most common form of EB, the first being EB simplex. Based on recent data, the prevalence in Europe ranges between 1/120,000-350,000.\nClinical description\nThe clinical picture varies widely, ranging from mild localized to severe generalized involvement. Onset is usually at birth but a delayed onset in infancy, childhood or adolescence can also be observed in milder subtypes. Skin lesions, forming spontaneously or in response to friction, may show a generalized or a localized distribution, particularly on the hands, feet or pretibial areas. Healing of blisters is associated with atrophic or, more rarely, hypertrophic scarring, albopapuloid lesions, milia formation and dystrophic nails. Excessive scarring can lead to highly disabling hand/foot deformities. Mucosal involvement is common and most frequently manifests with oral cavity lesions and esophageal strictures. The eyes and the genitourinary tract can also be affected. Skin and mucosal involvement can lead to anemia, iron deficiency, osteopenia/osteoporosis, growth delay and, rarely, renal failure. DEB patients are also at a higher risk of occurrence of squamous cell carcinomas (SCC).\nEtiology\nDEB is caused by mutations in the COL7A1 (3p21.31) gene encoding type VII collagen. Mutations are either autosomal dominant (dominant DEB) or recessive (recessive DEB), and alter the function or reduce or disrupt the production of collagen VII. This impairs its assembly into anchoring fibrils that anchor the basement membrane to the underlying dermis, resulting in a cleavage plane below the lamina densa, within the upper papillary dermis. In the case of severe recessive DEB there is no collagen VII production.\nDiagnostic methods\nDiagnosis is suspected at clinical examination. It is confirmed by biopsy of skin samples by immunofluorescence antigen mapping and/or transmission electron microscopy (showing a blister cleavage plane beneath the lamina densa of the cutaneous basement membrane zone), and by COL7A1 mutation screening.\nDifferential diagnosis\nThe differential diagnosis includes other forms of EB. During the neonatal period and infancy, it may also include aplasia cutis congenita, herpes simplex infection, epidermolytic ichthyosis, bullous impetigo, staphylococcal scalded skin syndrome, linear IgA bullous dermatosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis. For rare forms of DEB with a late onset, differential diagnosis includes acquired skin disorders such as lichen planus or autoimmune bullous diseases.\nAntenatal diagnosis\nAntenatal diagnosis should be offered to affect families with recessive severe DEB.\nGenetic counseling\nGenetic counseling should be offered to affect families and depends on the inheritance type and form of DEB.\nManagement and treatment\nManagement is preventive and symptomatic and requires an inter- and multidisciplinary approach. Protective padding of the skin and careful wound care reduces blistering, scarring and prevents secondary infection. Treatment of pain and itching is highly warranted but partly limited in effectiveness. Physiotherapy and occupational therapy are necessary to delay gradual loss of mobility and autonomy. Hand deformities can be treated surgically, but have a high recurrence. Nutritional requirements should be evaluated by a dietitian and gastrostomy feeding may be necessary. Esophageal strictures are treated by balloon dilatation with fluoroscopic guidance. Transfusions, iron supplementation, and erythropoietin administration improve anemia and iron deficiency. A regular follow-up with complete skin checks and biopsies is necessary for the surveillance of SCC development. Psychological support should be offered.\nPrognosis\nPrognosis depends on the subtype. Patients with dominant DEB usually have a normal life expectancy. Patients with severe recessive DEB are at high risk of mortality primarily from metastatic SCC, less frequently from chronic renal failure, sepsis and dilated cardiomyopathy.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Martin LAIMER | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Eales disease", "Disease Definition": "A rare ophthalmic disorder characterized by 3 stages: vasculitis, occlusion, and retinal neovascularization, leading to recurrent vitreous hemorrhages and vision loss.", "ORPHA ID": 40923, "Summary": "Epidemiology\nThe prevalence is unknown. The disorder has been reported worldwide but is more commonly observed in the Indian subcontinent where the estimated annual incidence is 1/135-1/200 ophthalmic patients. Males are predominantly affected. Of late, the disease incidence seems to be reducing.\nClinical description\nThe predominant age of onset is 20-30 years (earlier in Asians). The disorder can appear in adolescence. Eales disease (ED) is characterized by 3 sequential vascular responses that determine the course of the disease: inflammation (peripheral retinal perivasculitis); occlusion (peripheral retinal capillary non-perfusion); and neovascularisation of the retina or disk, which often leads to vitreous hemorrhage. The first 2 stages are generally asymptomatic while vitreous hemorrhage (often sudden and unilateral) is characterized by small specks, floaters, ''cobwebs'' and a decrease in visual acuity (often remission). The fellow eye is affected in 50-90% of cases after a gap of 3-10 years. Recurrences are common. Recurrent bleeds result in tractional retinal detachments, retinal tears, and epimacular membranes. Others may show a mild reduction of vision associated with retinal vasculitis (without vitreous hemorrhage). In addition, headache, variation in peripheral circulation, dyspepsia, chronic constipation, and epistaxis have also been associated with ED. Saxena and Kumar classification is based on visual outcomes and is as follows: Stage 1: periphlebitis of small (1a) and large (1b) calibre vessels with superficial retinal hemorrhages; Stage 2a: capillary non-perfusion, 2b: neovascularization elsewhere/of the disc; Stage 3a: fibrovascular proliferation, 3b: vitreous hemorrhage; Stage 4a: traction/combined rhegmatogenous retinal detachment and 4b: rubeosis iridis, neovascular glaucoma, complicated cataract and optic atrophy.\nEtiology\nThe etiology of ED remains elusive; Several immunological, molecular biological, and biochemical studies have indicated the roles of human leukocyte antigen, retinal S-antigen autoimmunity, Mycobacterium tuberculosis genome, free radical damage, and hyperhomocysteinemia in the pathogenesis of Eales disease. An increase of peptide growth factors like platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, transforming growth factors alpha and bêta, vascular endothelial growth factor, urokinase, metalloprotease enzymes, and a 88 kDa protein has been reported.\nDiagnostic methods\nDiagnosis is based on fundus fluorescein angiography (FFA) findings that may show early changes such as periphlebitis, vascular sheathing or peripheral nonperfusion and neovascularization. Wide field angiography is useful for the detection of peripheral lesions in the retina. Ultrasonography is needed to rule out associated retinal detachment and ocular coherence tomography (OCT) offers high-resolution imaging of the retina.\nDifferential diagnosis\nDifferential diagnosis includes retinopathy of prematurity (ROP) sequelae, familial exudative vitreoretinopathy, sarcoidosis, Behçet disease, sickle cell anemia, Terson syndrome, posttraumatic vitreous hemorrhage, juvenile diabetes and primary branch retinal vein occlusion.\nManagement and treatment\nManagement is symptomatic and depends on the stage of the disease. It includes periodic assessment (in the regressed stage of periphlebitis or fresh vitreous hemorrhage), steroids (periocular injections or systemic) and antitubercular drugs (in the active perivasculitis stage). Laser photocoagulation is used in case of neovascularisation of retina or gross capillary nonperfusion. Vitreous surgery is indicated in non-resolving vitreous hemorrhage (usually > 3 months). Intravitreal anti-VEGF therapy is currently being tested as a definitive therapy for ED.\nPrognosis\nIsolated episodes of vitreous hemorrhage usually settle down without visual deficit. However, some patients may lose vision significantly due to recurrent episodes of vitreous hemorrhage, macular changes, and tractional or combined retinal detachment involving the macula. Blindness due to ED is rare. There is no known mortality associated with the disease.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Pukhraj RISHI"}
{"Disease Name": "Ear-patella-short stature syndrome", "Disease Definition": "A rare microcephalic primordial dwarfism characterized by the association of bilateral microtia (severe hypoplasia of ear pinnae), absent patellae, short stature and characteristic facial features such as high forehead, micrognathism with full lips and small mouth, and accentuated nasolabial folds (smile wrinkles linking the nostrils to the labial commissure).", "ORPHA ID": 2554, "Summary": ""}
{"Disease Name": "Early infantile epileptic encephalopathy", "Disease Definition": "A severe form of age-related epileptic encephalopathies characterized by the onset of tonic spasms within the first 3 months of life that can be generalized or lateralized, independent of the sleep cycle, and that can occur hundreds of times per day, leading to psychomotor impairment and death.", "ORPHA ID": 1934, "Summary": "Epidemiology\nIncidence has been estimated at 1/100 000 births in Japan and 1/50,000 births in the U.K.\nClinical description\nOnset of EIEE occurs within the first 3 months of life but some present within the first few weeks after birth. Neonates have poor suckling reflexes, hypotonia and manifest with generalized and symmetrical tonic spasms that can appear in clusters or singly and can last for up to 10 seconds. The pattern of these spasms remains unchanged during wakefulness and sleep and they can occur hundreds of times per day. Other seizure types, including generalized tonic-clonic seizures, focal motor seizures and hemiconvulsions, are seen in 1/3 of cases. Those who live past the age of 2 years manifest with severe psychomotor deficits. In some, EIEE can transition into West syndrome (between 2-6 months of age) and later into Lennox-Gastaut syndrome (see these terms). Certain genetic variants manifest with additional signs such as dyskinetic movements and an atypical Rett-syndrome phenotype (see this term). Death is often due to pneumonia or other complications of a complex disability.\nEtiology\nEIEE may be the result of different etiologies. Many cases have been associated with structural brain abnormalities. Some cases are due to metabolic disorders (cytochrome C oxidase deficiency, carnitine palmitoyl transferase II deficiency; see these terms) or brain malformations (such as porencephaly, hemimegalencephaly; see these terms) that may or not be genetic in origin. Genetic variants of EIEE have been associated with mutations in certain genes such as ARX (Xp22.13) , CDKL5 (Xp22) , SL25A22 (11p15.5) and STXBP1 (9q34.1), among others. The genetic abnormalities are thought to lead to EIEE as they are related to neuronal dysfunction or brain dysgenesis.\nDiagnostic methods\nDiagnosis is based on clinical and electroencephalographic findings. The characteristic electroencephalogram (EEG) displays a suppression burst pattern (which appears with the onset of spasms) that is comprised of bursts of high amplitude spikes and polyspikes that alternate with periods of low voltage basic rhythm (suppression). This EEG pattern is continuous and remains unchanged during both waking and sleeping states. Structural abnormalities can often be seen on cranial MRI.\nDifferential diagnosis\nDifferential diagnoses include other epileptic encephalopathies such as early myoclonic encephalopathy, West syndrome (see these terms) and other early onset epileptic encephalopathies.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known genetic etiology.\nGenetic counseling\nAutosomal recessive inheritance has been reported, but most cases of EIEE are sporadic (de novo mutations). Genetic counseling is therefore very valuable to inform parents that their risk of having further children with EIEE is low.\nManagement and treatment\nThere is no cure for EIEE and patients require constant supervision and care. Antiepileptic drugs such as benzodiazepines, valproate, levetiracetam, zonisamide and phenobarbital have shown limited success in controlling seizures as has pyridoxine. A ketogenic diet has been reported to show some success in seizure control. In those with associated metabolic disorders, once these conditions have been treated there can be an improvement in the course of EIEE. Similarly, EIEE patients with certain structural abnormalities have benefited from surgical intervention, if unilateral.\nPrognosis\nPrognosis is poor with death usually occurring in infancy (50% before age of 2). Survivors have severe psychomotor impairments with continuing seizures.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Helen CROSS"}
{"Disease Name": "Early myoclonic encephalopathy", "Disease Definition": "A rare disorder characterized clinically by the onset of fragmentary myoclonus appearing in the first month of life, often associated with erratic focal seizures and a suppression-burst EEG pattern.", "ORPHA ID": 1935, "Summary": "Epidemiology\nThe prevalence is unknown but Early myoclonic encephalopathy is a rare disease with only around 30 cases described so far.\nClinical description\nOnset sometimes occurs as early as a few hours after birth, and postnatal movements are sometimes reported by the mother to be of the same type as those felt at the end of pregnancy. Other types of seizures, including partial seizures, massive myoclonia, and tonic spasms can also occur; usually at around 3-4 months of age. Neurological abnormalities are constant: very severe delay in psychomotor acquisitions, marked hypotonia, and disturbed alertness, sometimes with a vegetative state. Signs of peripheral neuropathy may also occur in rare cases.\nEtiology\nAlthough the etiology is mostly unknown, nonketotic hyperglycinemia, pyridoxine or pyridoxal-phosphate dependency, together with congenital deficiency of the mitochondrial glutamate transporter are known to produce a similar clinical picture. Therefore, this condition may result from excess glutamate delivery in the synaptic cleft by the end of pregnancy.\nGenetic counseling\nThere is a high risk of familial recurrence since in most cases the disease appears to be inherited as an autosomal recessive trait.\nManagement and treatment\nThere is no effective treatment.\nPrognosis\nThe prognosis is poor: children with the condition survive in a persistent vegetative state or die within the first or second year of life.\n\n                            Last update: \n                            October 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Olivier DULAC"}
{"Disease Name": "Early onset non-syndromic cataract", "Disease Definition": "A rare, genetic, non-syndromic developmental defect of the eye disorder, with high clinical and genetic heterogeneity, most frequently characterized by bilateral, symmetrical, non-progressive cataracts which present at birth or in early-childhood. Additional ocular manifestations (e.g. anterior segment dysgenesis, colobomas, nystagmus, microcornea, microphthalmia, myopia) may be associated, however other organs/systems are usually not affected.", "ORPHA ID": 91492, "Summary": ""}
{"Disease Name": "Early-onset autosomal dominant Alzheimer disease", "Disease Definition": "Early-onset autosomal dominant Alzheimer disease (EOAD) is a progressive dementia with reduction of cognitive functions. EOAD presents the same phenotype as sporadic Alzheimer disease (AD) but has an early age of onset, usually before 60 years old.", "ORPHA ID": 1020, "Summary": "Epidemiology\nEOAD represents less than 1% of all cases of AD.\nClinical description\nInitial findings of EOAD are mainly disorders of episodic memory or changes in behavior. The patient is often anosognosic and the diagnosis is therefore carried out with the help of a family member. Neurological signs that can be associated with EOAD are spastic paraparesis, intracerebral hemorrhages, seizures, extrapyramidal syndrome and exceptionally cerebellar ataxia.\nEtiology\nEOAD is the consequence of either PSEN1 mutations (69%), APP mutations (13%), or APP duplication (7,5%), and exceptionally of PSEN2 mutations (2%). These mutations result in an incompletely understood cascade of events resulting in neuronal death, synapse loss, and the formation of neurofibrillary tangles and senile plaques.\nDiagnostic methods\nEOAD is diagnosed using the clinical criteria of the NINCDS-ADRDA(McKahnn, 1984). Brain imaging can be normal. Lumbar puncture for measurement of cerebrospinal fluid tau and amyloid may be useful (tau and phosphorylated tau are often elevated and amyloid is usually low). Age of onset before 60 years suggests an EOAD and needs a pedigree.\nDifferential diagnosis\nDifferential diagnosis includes depression and other young dementias such as frontotemporal dementia, Lewy body dementia and Huntington disease (see these terms).\nGenetic counseling\nGenetic counseling should be offered to the families.\nManagement and treatment\nManagement is symptomatic and includes the use of cholinesterase inhibitors and partial N-methyl-D-aspartate antagonists. Psychotrops may also be useful.\nPrognosis\nThe disease is progressive; patients have deterioration in their behavior, cognition, and ability to perform activities of daily living. At an advanced stage, patients are confined to bed.\n\n                            Last update: \n                            December 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Lucie GUYANT-MARECHAL"}
{"Disease Name": "Early-onset calcifying leukoencephalopathy-skeletal dysplasia", "Disease Definition": "A rare genetic neurological disorder characterized by pediatric onset of calcifying leukoencephalopathy and skeletal dysplasia. Reported structural brain abnormalities include agenesis of corpus callosum, ventriculomegaly, congenital hydrocephalus, pontocerebellar hypoplasia, periventricular calcifications, Dandy-Walker malformation and absence of microglia. Characteristic skeletal features include increased bone mineral density (reported in skull, pelvic bone and vertebrae), platyspondyly, and under-modeling of tubular bones with widened/radiolucent metaphysis and constricted/sclerotic diaphysis.", "ORPHA ID": 556985, "Summary": ""}
{"Disease Name": "Early-onset cerebellar ataxia with retained tendon reflexes", "Disease Definition": "Early onset cerebellar ataxia with retained reflexes (EOCARR) or Harding ataxia is a cerebellar ataxia characterized by the progressive association of a cerebellar and pyramidal syndrome with progressive cerebellar ataxia, brisk tendon reflexes, and sometimes profound sensory loss.", "ORPHA ID": 1177, "Summary": "Epidemiology\nThe prevalence of EOCARR ataxia has been estimated to be around 1/100,000, and the birth prevalence at 1/48,000 births in North-western Italy.\nClinical description\nEOCARR is a progressive cerebellar ataxia, with disease onset occurring in childhood or in juveniles (ranging from 3 to 20 years with a mean age of 9 years). EOCARR is characterized by dysarthria, gait ataxia, nystagmus, brisk tendon reflexes in the upper and lower limbs, absent ankle reflexes, and discrete or absent deep sensory loss. The association of brisk jerks and absent ankle reflexes may occur. Oculomotor disturbances, dysphagia, tremor, scoliosis, pes cavus, extensor plantar response, and lower limb wasting and weakness may be observed while amyotrophy is rarely observed. Moreover, spasticity may become progressively severe.\nEtiology\nThe exact etiology of EOCARR is still unknown. However, molecular genetic analysis in a Tunisian family confirmed the genetic heterogeneity of this syndrome and mapped the gene locus to chromosome 13q11-12.\nDiagnostic methods\nDiagnosis relies on physical examination as well as on imaging findings (magnetic resonance imaging (MRI) or computed tomography (CT)) revealing cerebellar atrophy. Peripheral nerve conduction and nerve biopsy findings may show moderate to severe axonal sensory-motor neuropathy with axonal regeneration.\nDifferential diagnosis\nDifferential diagnosis includes Friedreich ataxia (FRDA; in contrast to EOCARR shows cardiomyopathy, diabetes mellitus, scoliosis, skeletal deformities or optic atrophy), autosomal dominant cerebellar ataxia (ADCA), autosomal recessive spastic ataxia of Charlevoix-Saguenay, ataxia with vitamin E deficiency (see these terms), and inherited metabolic disorders that may express ataxia.\nGenetic counseling\nTransmission is autosomal recessive. The parents of an affected child should be informed of the 25% risk of transmitting the disease to future offspring.\nManagement and treatment\nTreatment is symptomatic, aimed towards the control of spasticity, and should include physiotherapy and pharmacotherapy (that may include spasmolytic drugs such as baclofen).\nPrognosis\nThe period of latency before becoming wheelchair-bound is significantly longer in EOCARR than in FRDA, resulting in a better prognosis in patients with EOCARR than in those with FRDA.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Francesc PALAU"}
{"Disease Name": "Early-onset epilepsy-intellectual disability-brain anomalies syndrome", "Disease Definition": "A rare congenital disorder of glycosylation characterized by early onset of hypotonia, severe global developmental delay, intellectual disability, and seizures. Ataxia, mild facial dysmorphism, and autistic behavior have also been reported. Brain MRI findings are variable and include cerebral atrophy, cerebellar hypoplasia/atrophy, and thin corpus callosum.", "ORPHA ID": 488635, "Summary": ""}
{"Disease Name": "Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation", "Disease Definition": "Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation is a rare intellectual disability and epilepsy syndrome characterized by global developmental delay and mild to profound intellectual disability, multiple types of usually intractable focal and generalized seizures with variable abnormal EEG findings, and bilateral progressive parenchymal volume loss and thin corpus callosum on brain MRI.", "ORPHA ID": 289266, "Summary": ""}
{"Disease Name": "Early-onset epileptic encephalopathy-cortical blindness-intellectual disability-facial dysmorphism syndrome", "Disease Definition": "Early-onset epileptic encephalopathy-cortical blindness-intellectual disability-facial dysmorphism syndrome is a rare, syndromic intellectual disability syndrome characterized by cortical blindness, different types of seizures, intellectual disability with limited or absent speech, and dysmorphic facial features. Brain imaging typically shows mild pontine hypoplasia, hypoplasia of the corpus callosum and atrophy in the occipital region.", "ORPHA ID": 411986, "Summary": ""}
{"Disease Name": "Early-onset familial hypoaldosteronism", "Disease Definition": "A rare type of familial hypoaldosteronism characterized by early infantile onset of vomiting, diarrhea, severe dehydration, and failure to thrive. Analysis of plasma electrolytes shows hyponatremia, hyperkalemia, and acidosis. Plasma renin activity is elevated, and aldosterone levels are low.", "ORPHA ID": 556030, "Summary": ""}
{"Disease Name": "Early-onset generalized limb-onset dystonia", "Disease Definition": "A rare movement disorder characterized by involuntary, repetitive, sustained muscle contractions or postures that typically begins in a single limb and, in most individuals, followed by progressive involvement of other limbs and the trunk, typically sparing the cranial and cervical region.", "ORPHA ID": 256, "Summary": "Epidemiology\nThe prevalence varies according to region and ethnic population. In the USA the estimated prevalence in the general population is approximately 1/30,000, whilst in Europe the estimated prevalence ranges from 1/ 200,000-330,000, although precise figures are currently not available. The estimated prevalence in the Ashkenazi Jewish population is much higher at 1/3,000-9,000, due to a founder effect.\nClinical description\nSymptoms typically develop first in an arm or leg with dystonic muscle contractions in middle to late childhood, and may first become apparent with specific actions such as writing or walking. In approximately 60-70% of patients, the disease progresses to other body regions (multifocal or generalized dystonia) within about five years, involving at least one leg and one arm, and often axial muscles. Spread to craniocervical muscles may rarely occur. Distribution and severity of symptoms vary widely between affected individuals and even within the same family. This type of dystonia is not associated with other neurologic or systemic abnormalities.\nEtiology\nThe majority of cases are caused by a heterozygous deletion of three base pairs (GAG) in the /TOR1A gene (chromosome 9q34). This gene encodes the protein torsinA, which is ubiquitously expressed and, as an AAA+ ATPase, appears to play a role in various cellular compartments (cytoskeletal dynamics, vesicle fusion, membrane trafficking, and protein folding). The protein shuttles between the endoplasmic reticulum (ER) and the nuclear envelope, where it plays a role in ER-associated degradation, rendering cells less sensitive to ER stress.\nDiagnostic methods\nThe diagnosis is established in a proband by identification of a heterozygous TOR1A three base-pair deletion, c.907_909delGAG, which is the only definitely pathogenic variant in the TOR1A gene identified to date.\nDifferential diagnosis\nDifferential diagnosis includes other forms of isolated dystonia such as Dopa-responsive dystonia (due to either GCH1, SPR, TH), Primary dystonia, DYT6 type (THAP1), and Autosomal dominant focal dystonia, DYT25 type (GNAL). Whilst presenting symptoms may be similar, DYT25 is frequently distinguished by adult-onset focal dystonia, whereas individuals with DYT6 dystonia frequently have prominent cranio-cervical and laryngeal involvement.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant with low penetrance (approximately 30% of carriers become symptomatic) and variable expressivity with respect to age, site of onset, and progression. Molecular testing and genetic counseling are recommended for individuals with an age of onset below 26 years, and may also be considered in those with onset after 26 years who have a relative with typical early-onset isolated dystonia.\nManagement and treatment\nTreatment options include botulinum toxin injections for focal symptoms and pharmacological therapy such as anticholinergics (most commonly trihexyphenidyl) for generalized dystonia. In severe cases with medically refractory early-onset dystonia, surgical approaches, especially deep brain stimulation (DBS) of the internal globus pallidus (GPi) or, in some cases, intrathecal baclofen application should be considered. In recent years, GPi-DBS has been established as an important treatment option for medically refractory isolated generalized dystonia, with most individuals experiencing good or sometimes even dramatic improvement.\nPrognosis\nAll patients have normal cognitive function, and despite a high rate of generalization of dystonic symptoms, approximately 75% of patients are able to maintain ambulation and independence, and therefore a comparatively good quality of life, with modern treatment modalities. In children and adults with severe, medically refractory dystonia, GPi-DBS should be considered early in the course of the disease, since shorter disease duration has been correlated with improved outcomes.\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "Early-onset Lafora body disease", "Disease Definition": "A rare genetic progressive myoclonic epilepsy characterized by childhood onset of progressive dysarthria, myoclonus, ataxia, seizures, and cognitive decline. The disease takes a protracted course with patients surviving into adulthood, developing signs and symptoms like psychosis with outbursts of prolonged agitation and screaming, spasticity and hyperreflexia, confusion, mutism, and incontinence. There are no visual disturbances. Muscle biopsy shows numerous periodic acid-Schiff-positive inclusions, so-called Lafora bodies.", "ORPHA ID": 324290, "Summary": ""}
{"Disease Name": "Early-onset myopathy with fatal cardiomyopathy", "Disease Definition": "A rare genetic neuromuscular disease characterized by neonatal or infancy onset of delayed motor development, generalized muscle weakness involving also the facial muscles, pseudohypertrophy of lower limb muscles, and joint contractures, associated with childhood onset of rapidly progressive dilated cardiomyopathy with arrhythmias leading to sudden cardiac death. Muscle biopsy in early childhood shows minicore-like lesions and centralized nuclei, with dystrophic features being more conspicuous in the second decade of life.", "ORPHA ID": 289377, "Summary": ""}
{"Disease Name": "Early-onset myopathy-areflexia-respiratory distress-dysphagia syndrome", "Disease Definition": "A rare congenital myopathy characterized by early onset of severe muscular weakness, respiratory distress due to diaphragmatic paralysis, dysphagia and areflexia, joint contractures, and scoliosis. Decreased fetal movements are seen in some individuals. Muscle biopsy may show a combination of dystrophic and myopathic features. The clinical course is variable, with some patients becoming ventilator-dependent and never achieving ambulation.", "ORPHA ID": 439212, "Summary": ""}
{"Disease Name": "Early-onset parkinsonism-intellectual disability syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by infantile-onset non-progressive intellectual deficit (with psychomotor developmental delay, cognitive impairment and macrocephaly) and early-onset parkinsonism (before 45 years of age), in male patients.", "ORPHA ID": 2379, "Summary": ""}
{"Disease Name": "Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome", "Disease Definition": "A rare, severe early-onset neurodegenerative encephalopathy characterized mainly by developmental delay (DD) / developmental regression (DR), epilepsy, cortical atrophy, secondary hypomyelination and thin corpus callosum. Additional features include secondary microcephaly, hypotonia, spasticity, optic atrophy and skeletal anomalies.", "ORPHA ID": 496641, "Summary": "Epidemiology\nThe prevalence is unknown. To date, approximately 39 cases have been reported in the literature.\nClinical description\nPresentation is typically in the first year of life with severe developmental delay or regression and epilepsy, with progressive cerebral atrophy. Other neurologic problems include spasticity, hypotonia, optic atrophy, ataxia, thin corpus callosum, and secondary hypomyelination. Most of the patients also have secondary microcephaly, and postnatal growth retardation. Additional features include behavioral problems (aggressiveness, hyperactivity, and agitation), and skeletal anomalies (scoliosis, hip dislocation and plagiocephaly). There are no typical facial dysmorphisms. More recently, three additional patients with less severe phenotypes (including autism spectrum disorder and occasional generalized tonic-clonic seizures responding well to antiepileptic drugs) were described.\nEtiology\nThis syndrome is caused by biallelic pathogenic variants in TBCD gene (17q25.3), encoding tubulin folding co-factor D (TBCD), one of five co-chaperones required for microtubule assembly dynamics. Pathogenic TBCD variants affect TBCD stability and function, resulting in disturbed microtubule dynamics. Recent studies suggest specific genotype-phenotype correlations, relating phenotypic expression to the level of dysfunction of the residual protein caused by the pathogenic variants.\nDiagnostic methods\nMolecular genetic testing approaches may include single-gene molecular genetic testing (Sanger sequencing) based on clinical findings and neuroimaging findings, as well as Next Generation Sequencing (NGS)-based multigene panel or a more comprehensive genomic testing (whole-exome sequencing or whole-genome sequencing).\nDifferential diagnosis\nDifferential diagnoses include most epileptic encephalopathies, such as Undetermined early-onset epileptic encephalopathy and Lennox-Gastaut syndrome and mitochondrial encephalopathies.\nAntenatal diagnosis\nPrenatal diagnosis can be offered if the disease-causing mutations have been identified.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive, meaning that an affected patient has two mutated alleles of TBCD gene. Genetic counseling should be offered to the parents of affected individuals. Each parent of an affected child is usually an asymptomatic carrier of one pathogenic TBCD variant. At each conception, the parents of an affected individual have a 25% risk of having an affected child, a 50% chance of having a child who is an asymptomatic carrier, and a 25% risk of having a child who is neither affected nor a carrier.\nManagement and treatment\nManagement should be multidisciplinary, usually addressing DD/DR and control of seizures. It can include physical, occupational and speech therapy. Epilepsy should be treated with antiepileptic drugs (such as sodium valproate and clonazepam) and ketogenic diet which, as well as pyridoxine, show limited success in controlling seizures.\nPrognosis\nPrognosis depends on the severity of the disease and the presence of seizures. In general, prognosis is poor, with severe to profound global psychomotor developmental delay and refractory epilepsy. Some patients evolve with respiratory failure and early death.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Marcia RODRIGUES | ITHACA* - Dr Marta P. SOARES | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Early-onset progressive encephalopathy with migrant continuous myoclonus", "Disease Definition": "A rare disorder characterized by early-onset progressive encephalopathy with migrant, continuous myoclonus. Three cases have been reported. The focal continuous myoclonus appeared during the first months of life. Prolonged bilateral myoclonic seizures and generalized tonic-clonic seizures occurred later. Subsequently, a progressive encephalopathy with hypotonia and ataxia appeared. Cortical atrophy was revealed by computed tomography (CT) scan and magnetic resonance imaging (MRI). The aetiology is unknown.", "ORPHA ID": 1943, "Summary": ""}
{"Disease Name": "Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome", "Disease Definition": "A rare, genetic neurological disorder characterized by early-onset severe global developmental delay with regression, congenital or acquired microcephaly, hearing loss, truncal hypotonia, appendicular spasticity, and dystonia and/or myoclonus.", "ORPHA ID": 500144, "Summary": "Epidemiology\nCurrently only five affected individuals from four unrelated families (three consanguineous and one non-consanguineous) have been reported in the literature.\nClinical description\nThe clinical phenotypes of the affected individuals are similar: severe global development delay often with regression, epilepsy, congenital or postnatal microcephaly, hearing loss, dysphagia or reflux, scoliosis, truncal hypotonia, dystonia and/or myoclonus and spasticity. Eye and vision problems, such as optic atrophy and cortical visual impairment, neonatal hypertension, vocal cord paralysis, neurogenic bladder and hip subluxation have been described. In patients with no history of seizures at the time of diagnosis, electroencephalography can show paroxysmal discharges. Regarding neuroradiological features, the characteristic brain imaging findings are the following in various combinations: pons hypoplasia, partial or total agenesis of the corpus callosum, ventriculomegaly/hydrocephaly, marked cortical brain atrophy and simplified frontal gyri; cerebellar atrophy is present in two-thirds of patients. The basal ganglia is relatively spared.\nEtiology\nThe syndrome is caused by homozygous variants or compound-heterozygous variants in the TRAPPC12 gene (2p25.3). TRAPPC12 is a component of the TRAPP multi-subunit tethering complex involved in intracellular vesicle trafficking and has also been reported to play a role in mitosis.\nDiagnostic methods\nDiagnosis is based on clinical examination, neurophysiological analysis, neuroradiological studies and cytogenetic and molecular studies (TRAPPC12 molecular analysis, NGS panel or whole-exome sequencing followed by Sanger sequencing).\nDifferential diagnosis\nThe differential diagnosis includes numerous genetic and metabolic diseases.\nAntenatal diagnosis\nRecurrent abortions and polyhydramnios are common in the mothers of the affected individuals. Prenatal signs are non-specific: agenesis of the corpus callosum, ventriculomegaly/hydrocephaly. Detection of the mutation by chorionic villus biopsy or amniocentesis should be discussed with the parents of an index case during subsequent pregnancies.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement requires a lifelong multidisciplinary approach. Regular follow‐up by a pediatrician, neurologist, psychologist/psychiatrist will be very helpful. Periodical evaluations are required to find the most suitable medical services for the individual patient. Symptomatic medications can be used (antiepileptic and antispasticity drugs).\nPrognosis\nThe course of the disease is progressive. Longitudinal data are insufficient to determine the life expectancy and the real amplitude of the phenotypic spectrum.\n\n                            Last update: \n                            May 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Carlo FUSCO  - Dr Susanna RIZZI"}
{"Disease Name": "Early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome", "Disease Definition": "A rare genetic neurodegenerative disease characterized by neonatal to infantile onset of hypotonia, developmental delay, regression of motor skills with distal amyotrophy, ataxia, and spasticity, absent speech or dysarthria, and moderate to severe cognitive impairment. Optic atrophy may also be associated. Brain imaging shows cerebellar atrophy and thin corpus callosum, as well as brain iron accumulation in the pallidum and substantia nigra beginning during the second decade of life.", "ORPHA ID": 496756, "Summary": ""}
{"Disease Name": "Early-onset progressive leukoencephalopathy-central nervous system calcification-deafness-visual impairment syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by early-onset progressive leukoencephalopathy, severe developmental delay, early-onset or congenital deafness (only few cases reported without hearing loss), and visual impairment. All patients manifest calcifications in brain and spinal cord. Cognitive impairment, seizures, hypotonia, spastic tetraplegia or quadriplegia are observed in the majority of the patients. Variable features may include microcephaly and anemia.", "ORPHA ID": 3240, "Summary": ""}
{"Disease Name": "Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome", "Disease Definition": "A rare, genetic, neurodegenerative disease characterized by normal early development followed by childhood onset optic atrophy with progressive vision loss and eventually blindness, followed by progressive neurological decline that typically includes cerebellar ataxia, nystagmus, dorsal column dysfunction (decreased vibration and position sense), spastic paraplegia and finally tetraparesis.", "ORPHA ID": 352654, "Summary": ""}
{"Disease Name": "Early-onset seizures-distal limb anomalies-facial dysmorphism-global developmental delay syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by variable developmental delay, intellectual disability, early-onset seizures, and facial dysmorphism (including arched eyebrows, long palpebral fissures, prominent nasal bridge, large ears, thin upper lip, and high arched palate). Other reported features are microcephaly, hypotonia, growth retardation, congenital heart defects, and malformations of the fingers and toes, as well as additional neurologic manifestations (such as ataxia or spastic quadriplegia). Brain imaging may show hypoplastic corpus callosum, white matter abnormalities, or cortical atrophy.", "ORPHA ID": 505237, "Summary": ""}
{"Disease Name": "Early-onset spastic ataxia-myoclonic epilepsy-neuropathy syndrome", "Disease Definition": "Early-onset spastic ataxia-myoclonic epilepsy-neuropathy syndrome is a rare hereditary spastic ataxia disorder characterized by childhood onset of slowly progressive lower limb spastic paraparesis and cerebellar ataxia (with dysarthria, swallowing difficulties, motor degeneration), associated with sensorimotor neuropathy (including muscle weakness and distal amyotrophy in lower extremities) and progressive myoclonic epilepsy. Ocular signs (ptosis, oculomotor apraxia), dysmetria, dysdiadochokinesia, dystonic movements and myoclonus may also be associated.", "ORPHA ID": 313772, "Summary": ""}
{"Disease Name": "Early-onset X-linked optic atrophy", "Disease Definition": "Early-onset X-linked optic atrophy is a rare form of hereditary optic atrophy, seen in only 4 families to date, with an onset in early childhood, characterized by progressive loss of visual acuity, significant optic nerve pallor and occasionally additional neurological manifestations, with females being unaffected.", "ORPHA ID": 98890, "Summary": ""}
{"Disease Name": "EAST syndrome", "Disease Definition": "A rare genetic disease characterized by the association of epilepsy, ataxia, sensorineural hearing impairment, and renal tubulopathy. Patients present in infancy with generalized seizures, cerebellar dysfunction (including gait ataxia, intention tremor, and dysdiadochokinesis), and variable developmental delay and sensorineural hearing loss. Laboratory studies show persistent hypokalemic metabolic acidosis with hypomagnesemia. Additional reported neurologic features include brisk deep tendon reflexes, ankle clonus, extensor plantar responses, or nystagmus.", "ORPHA ID": 199343, "Summary": ""}
{"Disease Name": "East Texas bleeding disorder", "Disease Definition": "East Texas bleeding disorder is a rare, genetic, coagulation disorder characterized by easy bruising (without hemarthrosis or spontaneous hematomas), epistaxis, menorrhagia, and excessive bleeding after minor trauma and surgical procedures. Patients present a prolonged prothrombin time and/or activated partial thromboplastin time, normal levels of all coagulation factors, and normal protein C activity.", "ORPHA ID": 391320, "Summary": ""}
{"Disease Name": "Eastern equine encephalitis", "Disease Definition": "An acute arboviral infection caused by an alphavirus of the Togaviridae family transmitted by an infected mosquito, that is characterized by the onset of flulike symptoms including fever, chills, weakness, headache, vomiting, abdominal pain with diarrhea, myalgia, leucocytosis, and hematuria, rapidly progressing to diffuse central nervous system (CNS) involvement with confusion, somnolence, or even coma. Seizures, which may progress to status epilepticus and neurologic sequelae, cranial nerve palsies, and photophobia may occur. EEE is associated with a high rate of morbidity and mortality.", "ORPHA ID": 83594, "Summary": ""}
{"Disease Name": "Eating reflex epilepsy", "Disease Definition": "A rare reflex epilepsy characterized by in most cases complex partial seizures triggered by different components of eating, such as the sight of food, proprioceptive, olfactory or gustatory sensations, chewing, salivation, and gastric distension after food intake. The seizures may be idiopathic or associated with symptomatic localization-related epilepsies.", "ORPHA ID": 166418, "Summary": ""}
{"Disease Name": "Ebola hemorrhagic fever", "Disease Definition": "Ebola hemorrhagic fever (EHF), caused by Ebola virus, is a severe viral hemorrhagic disease characterized by initial fever and malaise followed by gastrointestinal symptoms, bleeding, shock, and multi-organ system failure.", "ORPHA ID": 319218, "Summary": "Epidemiology\nEHF is seen in Central and West Africa. EHF is generally recognized only when there are outbreaks, usually of less than 100 cases, which are almost invariably fueled by nosocomial transmission in hospitals in resource-poor areas where proper infection control practices are not maintained. However, seroprevalence studies suggest unrecognized endemic transmission in some areas of Africa.\nClinical description\nAfter an incubation period of about 8 days (range 3-21 days), patients typically present with the abrupt onset of non-specific signs and symptoms including fever, malaise, headache, chest pain, and myalgia/arthralgia, followed rapidly by gastrointestinal symptoms (vomiting, diarrhea, abdominal pain) and, in some cases, a maculopapular skin rash. Severe cases develop bleeding (sub-conjunctival hemorrhage, epistaxis, bleeding from the mouth and rectum, oozing from venipuncture sites), neurologic involvement (disorientation, convulsions, coma), shock, and multi-organ system failure. Mild-to-moderate leukopenia and thrombocytopenia are often present and disseminated intravascular coagulation (DIC) commonly develops, best indicated by the presence of D-dimers.\nEtiology\nOver 25 different viruses cause viral hemorrhagic fever. Ebola virus is a member of the virus family Filoviridae, along with Marburg virus. Six different species of Ebola virus have been identified to date, although only four are pathogenic to humans, all of which are endemic only in sub-Saharan Africa. Accumulating evidence implicates fruit bats as the Ebola virus reservoir, with primary human infection occurring presumably from unwitting contact with bat excreta or saliva. Infection also occasionally occurs through contact with tissues of other wild primates, especially gorillas and chimpanzees, presumably also infected through bat exposure. Human-to-human transmission occurs through direct contact with blood or bodily fluids of infected persons.\nDiagnostic methods\nCommon diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and RT-PCR. Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories.\nDifferential diagnosis\nEHF is difficult to distinguish from a host of other febrile illnesses, at least early in the course of disease. Other viral hemorrhagic fevers need to be excluded, especially Marburg hemorrhagic fever, as well as malaria, typhoid fever, leptospirosis, rickettsial disease (see these terms) and meningococcemia.\nManagement and treatment\nPatients should be isolated and viral hemorrhagic fever precautions (face shields, surgical masks, double gloves, surgical gowns, and aprons) should be used to prevent nosocomial transmission. As there is presently no antiviral drug available for EHF, treatment is supportive, following the guidelines for treatment of severe septicemia. Persons who had unprotected contact with someone with EHF should be monitored.\nPrognosis\nCase fatality rates vary consistently with the specific infecting virus, ranging from zero to over 80%. Shock, bleeding, neurological manifestations, high viremia, AST > 150 IU/L, and pregnancy confer a poor prognosis. Although convalescence may last up to a year, survivors usually have no lasting sequelae.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Daniel BAUSCH  -  Andrew BENNETT"}
{"Disease Name": "Ebstein malformation of the tricuspid valve", "Disease Definition": "A rare congenital cardiac anomaly characterized by downward (apical) displacement of the functional annulus, due to incomplete delamination of the septal and inferior leaflets of the tricuspid valve such that they are hinged within the right ventricle, rather than as expected at the atrioventricular junction. The anterosuperior leaflet is often abnormal (redundancy, fenestrations, tethering with abnormal subvalvar apparatus). The atrioventricular junction and the ''atrialized'' portion of the right ventricle are dilated, with variable degrees of thinning of the right ventricular wall.", "ORPHA ID": 1880, "Summary": "Epidemiology\nThe prevalence at birth is between 1/20,000-100,000. Ebstein malformation of the tricuspid valve accounts for less than 1% of all congenital heart defects. Both sexes are equally affected.\nClinical description\nClinical presentation is heterogeneous and depends on the severity of the lesion (extent of tethering of the antero-superior leaflet across the normal valvar orifice), and the degree of dysfunction of the right ventricle. Patients with minor forms of the disease remain asymptomatic or may present with an incidental murmur, exertional dyspnea, fatigue, or palpitations. Those with severe forms can present at various ages with arrhythmias, cyanosis, and sometimes cardiac failure. Those with the most severe malformations present as neonates, often with so-called ``wall-to-wall'' hearts. During adulthood, supraventricular tachycardia can also be observed, a proportion of patients also having Wolff-Parkinson-White syndrome. The malformation is often associated with other cardiac lesions, such as atrial or ventricular septal defects, patency of the arterial duct, pulmonary stenosis or atresia, or left ventricular non-compaction.\nEtiology\nEtiology is unknown. In some cases, maternal ingestion of lithium was associated with the disease. The incidence of heterozygous MYH7 (14q11.2) mutations is 6%, and more frequent if left ventricular non-compaction is associated.\nDiagnostic methods\nDiagnosis is based on cross-sectional or 3D echocardiography which also reveals the extent of valvular abnormalities (tethering and thinning) as well as the degree of regurgitation or stenosis. Presence of associated defects should also be assessed. Electrocardiogram can reveal right atrial hypertrophy, right bundle branch block, and supraventricular tachycardia. Radiography shows any cardiomegaly. Cardiac MRI shows the full extent of the valvar abnormalities, quantifies right ventricular volume, function and tricuspid regurgitation, and helps to plan surgery.\nDifferential diagnosis\nThe major differential diagnosis, particularly during fetal life, is dysplasia of the leaflets of the tricuspid valve. Both malformations can lead to severe tricuspid insufficiency. Gross thinning of the walls of the right ventricle should not be confused with Uhl anomaly. Severe forms of Ebstein malformation with an imperforate tricuspid valve must be distinguished from tricuspid atresia.\nAntenatal diagnosis\nDiagnosis is usually antenatal and based on severe tricuspid insufficiency with gross dilatation of the right atrium, which can cause fetal hydrops and fetal demise.\nGenetic counseling\nFamilial cases associated with MYH7 are extremely rare; in these cases autosomal dominant transmission is reported.\nManagement and treatment\nMedical treatment relies on inotropic agents (in case of cardiac failure) and antiarrhythmic drugs (in case of tachyarrhythmia). Definitive treatment is surgical and ideally consists of reconstructive surgery by the cone method. Provided that valvar anatomy is favorable, patients should be considered for surgery when they develop symptoms and/or worsening exercise capacity, cyanosis, paradoxical embolism, progressive right ventricle (RV) dilation or dysfunction, or arrhythmias. If the valve is too malformed, replacement with a bioprosthesis is the only option. Partial cavopulmonary connection can be used when RV function is impaired. Most arrhythmias can be treated percutaneously, and oval foramen can be closed percutaneously when responsible for cyanosis.\nPrognosis\nPatients with asymptomatic and mild forms have a normal life expectancy. However, symptoms usually develop progressively from adulthood onwards. Patients with severe forms of the disease, particularly those presenting during the fetal period or as neonates, have an increased risk of death due to biventricular failure, including at birth or during physical exercise. Supraventricular arrhythmias are frequent, particularly in adults, and can lead to sudden cardiac death.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Lucile HOUYEL"}
{"Disease Name": "Ectasia of the left atrial appendage", "Disease Definition": "Ectasia of the left atrial appendage is a rare cardiac malformation characterized by the enlargement of the left auricle without any other associated cardiac lesions. It can be asymptomatic (discovered fortuitously during routine chest imaging as an unusual cardiac shadow) or present clinically with supraventricular tachyarrhythmia, paroxysmal tachycardia, embolic events, respiratory distress, chest pain, angina pectoris or heart failure.", "ORPHA ID": 99102, "Summary": ""}
{"Disease Name": "Ectasia of the right atrial appendage", "Disease Definition": "Ectasia of the right atrial appendage is a rare cardiac malformation characterized by the enlargement of the right auricle without any other associated cardiac lesions. It can be asymptomatic and diagnosed fortuitously, prenatally or during routine clinical examinations or it can present with heart murmur, palpitation, atrial arrhythmia, fatigue, dyspnea or respiratory distress.", "ORPHA ID": 99101, "Summary": ""}
{"Disease Name": "Ectodermal dysplasia syndrome", "Disease Definition": "The term ''ectodermal dysplasia'' defines a heterogeneous group of heritable disorders of the skin and its appendages characterized by the defective development of two or more ectodermal derivatives, including hair, teeth, nails, sweat glands and their modified structures (i.e. ceruminous, mammary and ciliary glands). The spectrum of clinical manifestations is wide and may include additional manifestations from other ectodermal, mesodermal and endodermal structures.", "ORPHA ID": 79373, "Summary": "Epidemiology\nOverall prevalence of ectodermal dysplasia syndromes is unknown, but appears rare with a presumed cumulative incidence of approximately 1/1,429. More than 120 clinically and/or genetically distinct ectodermal dysplasias have been cataloged.\nClinical description\nIn ectodermal dysplasias, the skin usually appears dry with superficial scaling and proneness to dermatitis. Hair is often sparse (i.e. hypotrichosis) and slow-growing, with a tendency towards congenital or early-onset non-inflammatory alopecia. Teeth are slow-growing and defective in number (i.e. hypo-, oligo- and anodontia; see these terms); they are often dysplastic (i.e. peg shaped) and display enamel dysplasia. Nails manifest a wide range of features, comprising but not limited to dystrophic, thickened, and absent nails. Eccrine glands may be reduced in number or totally absent leading to hypohidrosis and anhidrosis, respectively. Hypoplastic breast and nipples and stenosis or agenesis of the lachrymal ducts are further manifestations of sweat gland involvement. A wide range of additional ectodermal features, such as achantosis nigricans (see this term), hyperkeratosis of the palm and soles, and skin hamartomas/neoplasms may be observed. Although many ectodermal dysplasias are disorders with manifestations limited to the skin, hair, teeth, nails and sweat glands, multiple features of ectodermal dysplasia are accompanying signs of many syndromic conditions with systemic involvement.\nEtiology\nOver 53 genes and 3 chromosome regions are responsible for the majority of ectodermal dysplasias as different phenotypes may result from mutations in a single gene.\nDiagnostic methods\nThe present classification of ectodermal dysplasia syndrome is based on clinical features although a genetic classification, just as significant, has been proposed on the basis of gene function.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Marco CASTORI"}
{"Disease Name": "Ectodermal dysplasia with natal teeth, Turnpenny type", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by neonatal teeth, hypo- or oligodontia of the secondary dentition, flexural acanthosis nigricans, and sparse body and scalp hair (the latter being thin and slow-growing). There have been no further descriptions in the literature since 1995.", "ORPHA ID": 69083, "Summary": ""}
{"Disease Name": "Ectodermal dysplasia, trichoodontoonychial type", "Disease Definition": "Ectodermal dysplasia, trichoodontoonychial type is a form of ectodermal dysplasia with hair, teeth and nail involvement characterized predominantly by hypodontia, hypotrichosis, delayed hair growth and brittle nails. Additionally, focal dermal hypoplasia, irregular hyperpigmentation, hypoplastic or absent nipples, amastia, hearing impairment, congenital hip dislocation and asthma have been associated. There have been no further descriptions in the literature since 1996.", "ORPHA ID": 1818, "Summary": ""}
{"Disease Name": "Ectodermal dysplasia-blindness syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, severe visual impairment due to ocular malformations (microphthalmos and microcornea with sclerocornea), short stature, hypotrichosis, dental anomalies, and dysmorphic facial features (such as a narrow nasal bridge with marked distal flaring and low-set, protruding ears). There have been no further descriptions in the literature since 1992.", "ORPHA ID": 1806, "Summary": ""}
{"Disease Name": "Ectodermal dysplasia-hyperhidrosis-cutaneous syndactyly syndrome", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by hypotrichosis, tooth enamel hypoplasia, hypoplastic nails, palmoplantar keratoderma, hyperhidrosis on hands, face, and scalp, bilateral partial cutaneous syndactyly, and dysmorphic facial features with large prominent ear pinnae, pointed nose, and thin upper lips. Association of cardiomegaly has also been reported.", "ORPHA ID": 247827, "Summary": ""}
{"Disease Name": "Ectodermal dysplasia-intellectual disability-central nervous system malformation syndrome", "Disease Definition": "Ectodermal dysplasia-intellectual disability-central nervous system malformation syndrome is a rare, multiple developmental anomalies syndrome characterized by the triad of ectodermal dysplasia (mostly hypohidrotic with dry skin and reduced sweating and sparse, fair scalp hair, eyebrows and eyelashes), severe intellectual disability and variable central nervous system anomalies (cerebellar hypoplasia, dilatation of ventricles, corpus callosum agenesis, Dandy-Walker malformation). Distinct craniofacial dysmorphism with macrocephaly, frontal bossing, midfacial hypoplasia and high arched or cleft palate, as well as cryptorchidism, feeding difficulties and hypotonia, are associated. There have been no further descriptions in the literature since 1998.", "ORPHA ID": 1812, "Summary": ""}
{"Disease Name": "Ectodermal dysplasia-pili torti-cutaneous syndactyly syndrome", "Disease Definition": "Ectodermal dysplasia-syndactyly syndrome is a rare, genetic ectodermal dysplasia syndrome characterized by sparse to absent scalp hair, eyebrows, and eyelashes (with pili torti when present), widely spaced, conical-shaped teeth with peg-shaped, conical crowns and enamel hypoplasia and palmoplantar hyperkeratosis, associated with partial cutaneous syndactyly in hands and feet.", "ORPHA ID": 247820, "Summary": ""}
{"Disease Name": "Ectodermal dysplasia-sensorineural deafness syndrome", "Disease Definition": "Ectodermal dysplasia-sensorineural deafness syndrome is characterised by hidrotic ectodermal dysplasia, sensorineural hearing loss, and contracture of the fifth fingers. It has been described in brother and sister born to consanguineous parents. The girl also presented with thoracic scoliosis. The mode of inheritance is likely to be autosomal recessive.", "ORPHA ID": 1883, "Summary": ""}
{"Disease Name": "Ectodermal dysplasia-skin fragility syndrome", "Disease Definition": "Epidermolysis bullosa simplex due to plakophilin deficiency (EBS-PD) is a suprabasal subtype of epidermolysis bullosa simplex (EBS, see this term) characterized by generalized superficial erosions and less commonly blistering.", "ORPHA ID": 158668, "Summary": "Epidemiology\nPrevalence is unknown but 11 cases have been reported to date.\nClinical description\nOnset of the disease is usually at birth with skin blistering and generalized erythema which rapidly regresses. Skin erosions and crusting are associated with dystrophic nails, hypotrichosis or alopecia with absent or sparse eyelashes and eyebrows, palmoplantar keratoderma with painful fissuring, chronic cheilitis with perioral cracking. Occasionally hair may be woolly rather than reduced. Other variable cutaneous findings and symptoms include follicular hyperkeratosis, perianal erythema and erosions, inflammatory scaly plaques in the flexures, and pruritus. Extracutaneous involvement is usually present, typically with growth retardation, and, in some cases, with recurrent infections, chronic diarrhea, tongue fissuring, and blepharitis.\nEtiology\nEBS-PD is due to mutations in the PKP1 (1q32) gene encoding plakophilin-1.\nGenetic counseling\nTransmission is autosomal recessive.\nPrognosis\nThe disease is frequently associated with significant morbidity, but life-expectancy does not seem to be affected.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "Ectopia cordis", "Disease Definition": "A rare, life-threatening, congenital non-syndromic heart malformation characterized by complete or partial location of the heart outside the thoracic cavity. The main ectopic positions are thoracic but anterior to the sternum, abdominal, thoracoabdominal, and cervical. Associated abnormalities include sternal, diaphragmatic, pericardial, and abdominal wall defects, as well as intracardiac malformations.", "ORPHA ID": 448270, "Summary": ""}
{"Disease Name": "Ectopia lentis-chorioretinal dystrophy-myopia syndrome", "Disease Definition": "A rare, genetic, ophthalmic disorder characterized by the association of lens (ectopia and cataracts) and retinal (generalized tapetoretinal dystrophy and retinal detachment) anomalies, and variable myopia. Microcephaly and intellectual disability has been reported in some patients.", "ORPHA ID": 1884, "Summary": ""}
{"Disease Name": "Ectopic aldosterone-producing tumor", "Disease Definition": "Ectopic aldosterone-producing tumor is an extremely rare aldosterone-producing neoplasm composed of aberrant adrenocortical tissue located outside the adrenal glands (e.g. in retroperitoneum, perirenal or periaortic fatty tissue, thorax, spinal canal, testes, ovaries) typically characterized by symptoms related to increased aldosterone levels (such as sustained, treatment-resistant hypertension and hypokalemia) or symptoms caused by local tumor enlargement.", "ORPHA ID": 231632, "Summary": ""}
{"Disease Name": "Ectrodactyly-polydactyly syndrome", "Disease Definition": "Ectrodactyly-polydactyly syndrome is a rare, genetic, congenital limb malformation disorder characterized by hypoplasia or absence of central digital rays of the hands and/or feet and the presence of one or more, unilateral or bilateral, supernumerary digits on postaxial rays, ranging from hypoplastic digits devoid of osseous structures to complete duplication of a digit. Cutaneous syndactyly, symphalangism and clinodactyly have also been reported. There have been no further descriptions in the literature since 1982.", "ORPHA ID": 1892, "Summary": ""}
{"Disease Name": "EDICT syndrome", "Disease Definition": "A rare, autosomal dominant, eye disorder representing a constellation of inherited ocular findings, including early-onset or congenital cataracts, corneal stromal thinning, early-onset keratoconus, corneal endothelial dystrophy, and iris hypoplasia.", "ORPHA ID": 293936, "Summary": ""}
{"Disease Name": "Edinburgh malformation syndrome", "Disease Definition": "Edinburgh malformation syndrome is a rare, genetic, lethal, multiple congenital anomalies/dysmorphic syndrome characterized by consistently abnormal facial appearance, true or apparent hydrocephalus, motor and cognitive developmental delay, failure to thrive (feeding difficulties, vomiting, chest infections) and death within a few months of birth. Carp mouth, hairiness of the forehead, neonatal hyperbilirubinemia and advanced bone age may also be associated. There have been no further descriptions in the literature since 1991.", "ORPHA ID": 1895, "Summary": ""}
{"Disease Name": "EEC syndrome", "Disease Definition": "EEC syndrome is a genetic developmental disorder characterized by ectrodactyly, ectodermal dysplasia, and orofacial clefts (cleft lip/palate).", "ORPHA ID": 1896, "Summary": "Epidemiology\nThe exact prevalence is not known. More than 300 cases have been described in the literature.\nClinical description\nThe three cardinal signs of the syndrome are ectrodactyly and syndactyly of the hands and feet, cleft lip with or without cleft palate (that can result in speech defects), and abnormalities in several ectodermal structures including skin (i.e. hypopigmentated and dry skin, hyperkeratosis, skin atrophy), hair (i.e. fine and sparse hair and eyebrows), teeth (small, absent or dysplastic teeth), nails (nail dystrophy) and exocrine glands (reductiobsence of sweat, sebaceous and salivary glands). The syndrome presents a wide intra- and interfamilial clinical variability: the presence of the cardinal signs together is not mandatory and each one of them can be expressed in varying degrees of severity. Other associated clinical features include abnormalities of the genitourinary system (i.e. renal agenesis, urethral atresia, hydronephrosis), conductive or sensorineural hearing loss, choanal atresia, mammary gland/nipple hypoplasia, ophthalmological findings (i.e. lacrimal duct defects, photophobia, corneal ulcerations, keratitis, blepharitis, entropion), gland abnormalities (i.e. hypoplastic thymus, hypopituitarism, growth hormone deficiency), and on exceptional occasions, presence of a white sponge nevus, delayed developmental milestones, and malignant lymphoma. Patients do not have intellectual deficit.\nEtiology\nIn more than 90% of cases, EEC is due to missense mutations in the sequence of the TP63 gene (3q27) encoding the TP63 transcription factor that is essential for ectoderm and limb development. These cases correspond to the classical EEC syndrome (EEC type 3) and seem to present some degree of genotype-phenotype correlation. The other cases correspond to EEC syndrome type 1, which shows associated clinical features such as malformedauricles and middle and inner ear malformations, and was mapped to 7q21. EEC type 2 does not exist anymore. EEC syndrome is an autosomal dominant disorder with incomplete penetrance (between 93 and 98%) and variable expression.\nDiagnostic methods\nThe diagnosis is based on clinical examination, X-rays of the limbs and jaw, and, according to the associated features, kidney ultrasound, ophthalmologic examinations, and skin biopsy. Genetic testing may confirm the diagnosis.\nAntenatal diagnosis\nAntenatal diagnosis is based on ultrasonography during the second trimester of pregnancy which may reveal the structural abnormalities. Molecular analysis by chorionic villi sampling or by amniocentesis helps in confirming the diagnosis for families for which the disease-causing mutation was identified.\nGenetic counseling\nGenetic counseling should be offered to affected families informing them of the 50% risk an affected person has of transmitting the disease-causing mutation. Due to germline mosaicism, unaffected parents of a child with EEC syndrome have a 4% risk of having another affected child.\nManagement and treatment\nManagement is multidisciplinary and requires evaluation by orthopedic, plastic and dental surgeons, ophthalmologists, dermatologists, and speech therapists. Surgery allows correction of orofacial and dental abnormalities and improves the function and appearance of the limbs. Ophthalmologic care (e.g. artificial tears in case of dry eyes) is necessary to avoid complications such as cataract and corneal scarring. Hot temperatures, heavy clothing, and exercise must be avoided in case of hypohidrosis.\nPrognosis\nPrognosis is good with a near to normal life expectancy. Hypohidrosis (reductiobsence of sweat glands) presents the most life-threatening complications, as it can cause seizures, coma and eventually death when not managed correctly.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Didier LACOMBE"}
{"Disease Name": "EEM syndrome", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by the association of ectodermal dysplasia (with hypotrichosis affecting scalp hair, eyebrows, and eyelashes, and partial anodontia), ectrodactyly, and macular dystrophy (appearing as a central geographic atrophy of the retinal pigment epithelium and choriocapillary layer of the macular area with coarse hyperpigmentations and sparing of the larger choroidal vessels). Variable additional limb defects (including absence deformities, polydactyly, syndactyly, or camptodactyly) have also been described, the hands often being more severely affected than the feet.", "ORPHA ID": 1897, "Summary": ""}
{"Disease Name": "Ehlers-Danlos syndrome", "Disease Definition": "A heterogeneous group of diseases characterized by fragility of the soft connective tissues resulting in widespread skin, ligament, joint, blood vessel and/or internal organ manifestations. Clinical spectrum is highly variable, ranging from mild skin and joint hyperlaxity to severe physical disability and life-threatening vascular complications. Overlap with osteogenesis imperfecta may be observed resulting in an EDS/osteogenesis imperfecta overlap phenotype. Diseases in this group include classical Ehlers-Danlos syndrome (EDS), musculocontractural EDS, hypermobile EDS, vascular EDS, arthrochalasia EDS, dermatosparaxis EDS, periodontal EDS, X-linked EDS, brittle cornea syndrome, classical-like EDS type 1 and type 2, cardiac-valvular EDS, spondylodysplastic EDS, myopathic EDS, and kyphoscoliotic EDS.", "ORPHA ID": 98249, "Summary": ""}
{"Disease Name": "Ehlers-Danlos/osteogenesis imperfecta syndrome", "Disease Definition": "A rare systemic disease characterized by the association of the features of Ehlers-Danlos syndrome with those of osteogenesis imperfecta. Predominant clinical manifestations include generalized joint hypermobility and dislocations, skin hyperextensibility and/or translucency, easy bruising, and invariable association with mild signs of osteogenesis imperfecta, including short stature, blue sclera, and osteopenia or fractures.", "ORPHA ID": 230857, "Summary": ""}
{"Disease Name": "Ehrlichiosis", "Disease Definition": "A group of acute febrile tick-borne diseases characterized by an overlapping clinical picture that includes fever, headache, myalgias, arthralgias, skin eruptions, gastrointestinal symptoms and neurological manifestations. Diseases in this group include human monocytotropic ehrlichiosis (HME), human granulocytotropic anaplasmosis (HGA), and human ehrlichiosis ewingii (HEE).", "ORPHA ID": 1902, "Summary": ""}
{"Disease Name": "Eiken syndrome", "Disease Definition": "A rare, genetic, primary bone dysplasia syndrome characterized by multiple epiphyseal dysplasia, severely delayed ossification (mainly of the epiphyses, pubic symphysis, hands and feet), abnormal modeling of the bones in hands and feet, abnormal pelvis cartilage persistence, and mild growth retardation. Calcium, phosphate and vitamin D serum levels are typically within normal range, while parathyroid hormone serum levels are normal to slighly elevated. Oligodontia has been rarely associated.", "ORPHA ID": 79106, "Summary": ""}
{"Disease Name": "Eisenmenger syndrome", "Disease Definition": "A rare respiratory disease associated with unoperated congenital heart disease and characterized by congenital heart malformations with reversed or bi-directional shunting through an intra-cardiac or intervascular (usually aorto-pulmonary) communication with the development of PAH.", "ORPHA ID": 97214, "Summary": "Epidemiology\nThe disease is thought to be rare and affects both males and females equally. The incidence of the syndrome is decreasing in the developed world as the vast majority of causative cardiac lesions are now readily treatable. Incidence may still be higher in the less developed regions of the world as perinatal survival is higher but surgical treatment remains unaffordable for many.\nClinical description\nThe disease generally develops in children before puberty, but may develop in adolescence or early adulthood. Infants born with a large ventricular septal defect, an atrio-ventricular septal defect, or a persistently patent arterial duct are most susceptible. Pulmonary hypertension can also be associated with atrial septal defects but it is more controversial as to whether this is more accurately a form of idiopathic pulmonary hypertension (possibly accelerated by the shunt) than directly due to the atrial shunt. Clinical manifestations include exertional dyspnea, fatigue, lethargy, central cyanosis, chest pain, palpitations, atrial and ventricular arrhythmias. Right heart failure (with hepatomegaly, jugular venous distention and peripheral edema), is a very late complication. Dizziness and syncope due to low cardiac output is much rarer in Eisenmenger's syndrome than in PAH without intracardiac shunts. Clubbing and hemoptysis may occur. Precordial signs of ES are loud (often palpable) second heart sound and right ventricular heave. A pulmonary ejection click may be heard; Murmurs are variable and include those of pulmonary and tricuspid regurgitation. Complications include infective endocarditis, hyperviscosity, iron deficiency, bleeding disorders, hyperuricemia, stroke and cerebral abscess. Patients are at extremely high risk of death or major complications during pregnancy and the puerperium.\nEtiology\nThe disease results from communication between right and left sides of the circulation, permitting oxygenated blood to recirculate at high pressure within the pulmonary vasculature. This increase blood pressure +/- increased flow promotes endothelial dysfunction and proliferation; which leads to vascular remodeling, and pulmonary hypertension. Reversal of shunt and development of cyanosis is regarded as Eisenmenger syndrome.\nDiagnostic methods\nDiagnosis is based on the clinical features, pulse oximetry findings, an abnormal electrocardiogram (right axis deviation, right ventricular hypertrophy and right atrial enlargement), echocardiography (underlying lesion, site of shunt and estimating pulmonary arterial pressure) and imaging (MRI and CT). Right-heart catheterization (saturation, hemodynamics and pulmonary vasoreactivity study if appropriate) is usual to establish the diagnosis and may be clinically useful in planning treatment / assessing efficacy. Routine lab testing (total blood count, liver function test, urea, creatinine, electrolytes, uric acid and iron status) is sought to detect emerging complications.\nDifferential diagnosis\nDifferential diagnoses include idiopathic pulmonary hypertension, tetralogy of Fallot, tricuspid atresia, transposition of the great arteries, persistent newborn pulmonary hypertension, pulmonary infection and respiratory failure.\nManagement and treatment\nThe disease can be avoided if appropriate repair of the underlying heart defect is undertaken prior to the establishment of irreversible changes to the pulmonary vascular bed. Management includes maintaining fluid balance, prophylaxis against infective endocarditis, iron supplementation and avoiding precipitating factors (pregnancy, isometric exercise, high altitude). Targeted pharmacological therapies are recommended for symptomatic patients; prostacyclin analogues (treprostinil), endothelin antagonists (bosentan, macitantan), nitric oxide, phosphodiesterase inhibitor (sildenafil). Heart and lung transplantation (or lung transplantation with intracardiac repair) is an option for patients with a poor prognosis who fail to respond to medical therapy.\nPrognosis\nLife expectancy depends on the type and severity of the underlying defect and right ventricular function, and ranges from 20 to 50 years. In patients with the syndrome the maternal mortality rate exceeds 50%. The chances of preterm delivery and low birth weight are extremely high and the likelihood of livebirth drops dramatically with lower maternal oxygen saturation levels (to below 10% in some series) if maternal resting oxygen saturations are less than 85%.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Frances BU'LOCK"}
{"Disease Name": "Elastoderma", "Disease Definition": "An extremely rare, acquired, dermis elastic tissue disorder characterized by localized increased skin laxity associated with delayed skin recoil, typically occurring on the elbows, knees and/or neck. Histologically, focal abundace of elastic tissue in the dermis with pleomorphic and fragmented elastic fibers, without calcification, is observed.", "ORPHA ID": 228240, "Summary": ""}
{"Disease Name": "Elastofibroma dorsi", "Disease Definition": "Elastofibroma dorsi is a rare, acquired, dermis elastic tissue disorder characterized by a benign, slowly progressive, often bilateral, non-encapsulated lesion, usually presenting as an ill-defined mass under the inferior angle of the scapula (but other locations have been reported), which adheres to the deep layers and presents no local signs of inflammation. It is commonly asymptomatic and discovered inadvertently, but symptoms may include pain and discomfort or stiffness when using the shoulder. The presence of a firm mass masked by the scapula during retropulsion of the shoulder and becoming prominent when the shoulder is displaced toward the front is a frequent sign. Neuromuscular involvement of the upper limb may occur in rare cases.", "ORPHA ID": 228243, "Summary": ""}
{"Disease Name": "Elastoma", "Disease Definition": "A rare, genetic or acquired, dermis elastic tissue disorder characterized by asymptomatic, solitary or multiple, firm, skin-colored to yellowish papules or nodules of variable size that are disseminated or grouped in clusters and typically located on the trunk, buttocks, thighs or face, among others. Histologically, focal increase of thickened, tortuous elastic fibers in the reticular dermis, without signs of degeneration, is reported. Isolated cases, as well as cases associated with osteopoikilosis (Buschke-Ollendorf syndrome), may be observed.", "ORPHA ID": 228254, "Summary": ""}
{"Disease Name": "Elastosis perforans serpiginosa", "Disease Definition": "A rare acquired dermis elastic tissue disorder with increased elastic tissue characterized by focal dermal elastosis and transepidermal elimination of abnormal elastic fibers, presenting as small keratotic papules or plaques arranged in groups in serpiginous or annular patterns on the neck, face, and arms, while other areas are less frequently affected. Although spontaneous regression is possible, the lesions often persist over longer periods of time. The condition typically occurs during childhood or early adulthood and is more frequent in men than in women.", "ORPHA ID": 79148, "Summary": ""}
{"Disease Name": "Ellis Van Creveld syndrome", "Disease Definition": "A rare chondral and ectodermal dysplasia characterized by short ribs, polydactyly, growth retardation, and ectodermal and heart defects.", "ORPHA ID": 289, "Summary": "Epidemiology\nIt is a rare disease with approximately 150 cases reported worldwide. The exact prevalence is unknown, but the syndrome seems more common among the Amish community.\nClinical description\nPrenatal abnormalities (that may be detected by ultrasound examination) include narrow thorax, shortening of long bones, hexadactyly and cardiac defects. After birth, cardinal features are short stature, short ribs, polydactyly, and dysplastic fingernails and teeth. Heart defects, especially abnormalities of atrial septation, occur in about 60% of cases. Cognitive and motor development is normal.\nEtiology\nMutations of the EVC and EVC2 genes, located in a head to head configuration on chromosome 4p16, have been identified as causative.\nDifferential diagnosis\nEVC belongs to the short rib-polydactyly group (SRP) and these SRPs, especially type III (Verma-Naumoff syndrome), are discussed in the prenatal differential diagnosis. Postnatally, the essential differential diagnoses include Jeune dystrophy, McKusick-Kaufman syndrome and Weyers syndrome.\nGenetic counseling\nThis rare condition is inherited as an autosomal recessive trait with variable expression.\nManagement and treatment\nThe management of EVC is multidisciplinary. Management during the neonatal period is mostly symptomatic, involving treatment of the respiratory distress due to narrow chest and heart failure. Orthopedic follow-up is required to manage the bones deformities. Professional dental care should be considered for management of the oral manifestations.\nPrognosis\nPrognosis is linked to the respiratory difficulties in the first months of life due to thoracic narrowness and possible heart defects. Prognosis of the final body height is difficult to predict.\n\n                            Last update: \n                            June 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Geneviève BAUJAT  - Dr Martine LE MERRER"}
{"Disease Name": "Emanuel syndrome", "Disease Definition": "A constitutional genomic disorder due to the presence of a supernumerary derivative 22 chromosome and characterized by severe intellectual disability, characteristic facial dysmorphism (micrognathia, hooded eyelids, upslanting downslanting parebral fissures, deep set eyes, low hanging columnella and long philtrum), congenital heart defects and kidney abnormalities.", "ORPHA ID": 96170, "Summary": ""}
{"Disease Name": "Emery-Dreifuss muscular dystrophy", "Disease Definition": "A neuromuscular disease that is characterized by muscular weakness and atrophy, with early joint contractures and cardiomyopathy.", "ORPHA ID": 261, "Summary": "Epidemiology\nEmery-Dreifuss muscular dystrophy (EDMD) prevalence is estimated at 1 in 400,000.\nClinical description\nThe clinical triad is comprised of joint contractures of the Achilles, elbow and posterior neck tendons (beginning during early childhood and worsening to result in limited joint movement). It presents slowly progressive muscle weakness and atrophy (initially and generally with a humeroperoneal distribution but later becoming more diffuse). Cardiac anomalies (conduction defects, rhythm disturbances and dilated cardiomyopathy) that usually manifest at the turn of the 2nd to the 3rd decade of life and may lead to sudden death (sometimes the presenting feature of the disease) and ischemic accidents due to embolism. Disease course and severity vary between families and between patients from the same family.\nEtiology\nSeveral causative genes have been identified encoding ubiquitous proteins including emerin (EMD; Xq28 and FHL1; Xq26.3) for X-linked EDMD and lamin A/C (LMNA; 1q21.2) for EDMD with autosomal transmission. Exceptionally, variants in LUMA (TMEM43), Nesprine1 (SYNE1) and Nesprine2 (SYNE2) were reported in EDMD-like patients with autosomal transmission. Emerin, lamin A/C, Nesprine1, Nesprine2 and LUMA are nuclear envelope proteins. Around 45% of patients do not carry mutations in these genes suggesting other causative genes that remain to be identified.\nDiagnostic methods\nDiagnosis relies on recognition of the clinical triad (although the cardiac manifestations may be absent at onset). Muscular imagining may reveal isolated involvement of the soleus, suggestive of the initial stages of disease. For X-linked forms linked to the EMD gene, immunodetection of emerin in various tissues reveals an absence or reduction of the protein. The diagnosis can be confirmed by detection of EMD mutations. For autosomal forms and X-linked forms linked to FHL1, direct molecular analysis of LMNA, FHL1 , SYNE1, SYNE2 and TMEM43 genes is the only approach for confirming the diagnosis.\nDifferential diagnosis\nThe main differential diagnoses include other forms of myopathy with joint contractures, with or without cardiac involvement (Bethlem myopathy, SEPN1 and FKRP-related myopathies); the desmin-related myopathies; proximal myotonic myopathy; and certain forms of LGMD with cardiac involvement.\nAntenatal diagnosis\nPrenatal diagnosis is possible when the causative mutation is known.\nGenetic counseling\nSeveral modes of transmission have been reported: X-linked and autosomal dominant or recessive. Genetic counselling depends on the mode of transmission and on whether the mutation has been identified or not.\nManagement and treatment\nManagement should include orthopaedic measures (orthopaedic apparatus, surgery for the Achilles tendon contractures and scoliosis). Treatment of the cardiac disease: anti-arrhythmic agents including beta-blockers, diuretics, ACE inhibitors, cardiac devices (pacemaker, implantable cardiac defibrillator) when required, heart transplantation in case of end-stage heart failure, and treatment of the respiratory complications (intermittent nasal ventilation, tracheostomy).\nPrognosis\nPrognosis depends on the severity of muscle weakness, joint contractures, and of the cardiac and respiratory involvement. Patients with severe forms of the disease may lose the capacity to walk or require intermittent nasal ventilation.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Rabah BEN YAOU  - Dr Gisèle BONNE  - Dr France LETURCQ"}
{"Disease Name": "Emery-Nelson syndrome", "Disease Definition": "A rare congenital limb malformation syndrome characterized by facial dysmorphism (high forehead, depressed nasal bridge, long philtrum, flat malar region, high arched palate), short stature and deformities of the hands and feet (small hands/feet, flexion contractures of the first three metacarpophalangeal joints, extension contractures of the thumbs at the interphalangeal joints, clawed toes, mild pes cavus). Additional features include neonatal hypotonia, thin and shiny skin of the hands/feet, ridged nails, dry and coarse hair, mild weakness of the orbicularis oculi muscles and occasional ventricular extrasystoles. Intellectual disability may be present. There have been no further descriptions in the literature since 1970.", "ORPHA ID": 1927, "Summary": ""}
{"Disease Name": "EMILIN-1-related connective tissue disease", "Disease Definition": "A rare hereditary disease with peripheral neuropathy characterized by distal sensorimotor or motor neuropathy of the lower limbs with muscle weakness and atrophy. Some patients show overt connective tissue disease with signs and symptoms like increased skin elasticity and easy bruising (but no atrophic scarring), decreased clotting, aortic aneurysms, joint hypermobility, and recurrent tendon ruptures.", "ORPHA ID": 485418, "Summary": ""}
{"Disease Name": "Enamel-renal syndrome", "Disease Definition": "A extremely rare, genetic malformation syndrome characterized by hypoplastic amelogenesis imperfecta (hypoplastic dental enamel) and nephrocalcinosis (precipitation of calcium salts in renal tissue). Oral manifestations include yellow and misshaped teeth, delayed tooth eruption, and intrapulpal calcifications. Nephrocalcinosis is often asymptomatic but can progress during late childhood or early adulthood to impaired renal function, recurrent urinary infections, renal tubular acidosis, and rarely to end-stage renal failure.", "ORPHA ID": 1031, "Summary": ""}
{"Disease Name": "Encephalitis lethargica", "Disease Definition": "A rare brain inflammatory disease characterized by acute or subacute encephalitis with involvement of the midbrain and basal ganglia occurring in children as well as adults. Initial symptoms are pharyngitis and fever, followed by progressive lethargy, sleep disturbances, extrapyramidal symptoms (parkinsonism, chorea, dystonia), neuropsychiatric manifestations (obsessive-compulsive behavior, mutism, catatonia), and ocular features (oculogyric crises). Autoantibodies against human basal ganglia are often positive. Survivors may develop post-encephalitic syndromes, most prominently parkinsonism.", "ORPHA ID": 83600, "Summary": ""}
{"Disease Name": "Encephalocraniocutaneous lipomatosis", "Disease Definition": "A rare, genetic skin disease characterized by the ocular, cutaneous, and central nervous system anomalies. Typical clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas, leading sometimes to seizures, spasticity, and intellectual disability. Nevus psiloliparus, focal dermal hypo- or aplasia, eyelid skin tags, colobomas, abnormal intracranial vessels, hemispheric atrophy, porencephalic cyst, and hydrocephalus have also been associated.", "ORPHA ID": 2396, "Summary": ""}
{"Disease Name": "Encephalopathy due to mitochondrial and peroxisomal fission defect", "Disease Definition": "A rare mitochondrial disease characterized by a variable phenotype comprising delayed psychomotor development or neurodevelopmental regression, hypotonia, seizures, microcephaly, optic atrophy, pyramidal signs, and peripheral neuropathy, among others. Age of onset and disease severity are also variable with some cases taking a fatal course in early infancy. Serum lactate levels may be elevated. Reported brain imaging findings include abnormal signals in the basal ganglia, cerebral and/or cerebellar atrophy, and white matter abnormalities.", "ORPHA ID": 527276, "Summary": ""}
{"Disease Name": "Encephalopathy due to prosaposin deficiency", "Disease Definition": "A lysosomal storage disease belonging to the group of sphingolipidoses.", "ORPHA ID": 139406, "Summary": "Epidemiology\nIt is very rare with less than 10 cases reported in the literature so far.\nClinical description\nClinically, it is a severe neurovisceral disease manifesting immediately after birth and following a rapidly progressive fatal course (death between 1 and 4 months in the cases documented so far). The neurological signs and symptoms include hypotonia, massive myoclonic bursts, abnormal ocular movements and dystonia. Grand mal seizures and seizures triggered by tactile stimuli have been described. Patients also develop hepatosplenomegaly. Death usually occurs from respiratory failure following repeated pulmonary infections.\nEtiology\nThe disease is caused by mutations in the PSAP gene (10q21) leading to absence or non-functionality of the prosaposin protein. Prosaposin is the common precursor for proteins required for the in vivo lysosomal degradation of several sphingolipids, and has other important but still poorly understood functions. Under normal conditions, proteolytic processing of prosaposin produces four smaller \"sphingolipid activator proteins'' called saposins (or Sap) A, B C and D. An isolated deficiency of each of these factors leads to rare variant genetic forms of Krabbe disease (Sap A), metachromatic leukodystrophy (Sap B), Gaucher disease (Sap C) and, putatively, Farber disease (Sap D; see these terms). In prosaposin deficiency, there is a combined deficiency of all four factors.\nDiagnostic methods\nThe final diagnosis is established by identification of the PSAP mutation(s), but the study of sphingolipids in urine sediment (showing a massive combined excretion of globotriaosylceramide (Gb3), sulfatides and other sphingolipids) is a good orientation test. Low galactosylceramidase in leukocytes has also been reported. Bone marrow/liver biopsies usually show the presence of Gaucher-like macrophages.\nAntenatal diagnosis\nPrenatal diagnosis is feasible by mutation analysis on uncultured (or cultured) chorionic villi, or amniotic fluid cells.\nGenetic counseling\nThe mode of inheritance is autosomal recessive.\nManagement and treatment\nNo specific treatment is available.\nPrognosis\nEncephalopathy due to prosaposin deficiency is a very severe metabolic disorder with a poor prognosis.\n\n                            Last update: \n                            December 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Marie-Thérèse VANIER"}
{"Disease Name": "Encephalopathy due to sulfite oxidase deficiency", "Disease Definition": "Encephalopathy due to sulfite oxidase deficiency is a rare neurometabolic disorder characterized by seizures, progressive encephalopathy and lens dislocation.", "ORPHA ID": 833, "Summary": "Epidemiology\nThe prevalence is unknown but is very rare. At least 100 patients with sulfite oxidase deficiency have been reported with approximately 75% of cases being related to molybdenum cofactor (MoCo) deficiency.\nClinical description\nSymptoms usually occur within the first week after birth with feeding difficulties, vomiting and seizures which are difficult to control. The majority of patients exhibit facial dysmorphism (prominent forehead, narrow bifrontal diameter, sunken eyes, elongated palpebral fissures, puffy cheeks, small nose and long philtrum and thick lips). The course is progressive, with spasticity, severe intellectual deficit, and microcephaly seen in survivors. Lens dislocation usually occurs late in infancy but has been observed as early as two months of age. A late onset form with a milder phenotype has also been described.\nEtiology\nIsolated sulfite oxidase deficiency is caused by a mutation in the SUOX gene (12q13.13) (see this term). The SUOX gene encodes the enzyme sulfite oxidase which catalyzes sulfite to sulfate, a process essential for the catabolism of sulfur-containing amino acids. MoCo deficiency secondary to mutations in either the MOCS1 (6p21.2) or MOCS2 (5q11) genes also causes sulfite oxidase deficiency (see this term). These genes encode two of the biosynthetic MoCo pathway enzymes. Impaired synthesis of MoCo leads to the combined deficiencies in sulfite oxidase, xanthine dehydrogenase, mitochondrial amidoxime reducing component (mARC) and aldehyde oxidase (the four human molybdoenzymes). The GPHN (14q23.3) gene has also been identified as the cause in one case of MoCo deficiency (see this term).\nDiagnostic methods\nA sulfite test strip in a fresh urine sample is a simple screening test but false positive and negative results can occur. Hypouricemia is seen in the MoCo deficiency form of the disease. A third test involves detection of low levels of plasma homocysteine. Diagnosis is confirmed by a skin fibroblast culture showing the absence of sulphite oxidase and/or MoCo activity in cultured fibroblasts. Magnetic resonance imaging shows diffuse cystic lesions within the white matter, basal ganglia and thalamus along with ulegyric changes in the cerebral cortex and cerebellar hypoplasia.\nDifferential diagnosis\nIsolated sulfite oxidase deficiency is clinically indistinguishable from MoCo deficiency (see these terms). Hypoxic-ischemic encephalopathy (see this term) and neonatal hyperekplexia should be eliminated. Feeding difficulties can mimic amino acid intolerances.\nAntenatal diagnosis\nAntenatal diagnosis is possible by measuring the enzyme activity in chorionic villus samples or s-sulfocysteine levels in amniotic fluid, or by DNA analysis.\nGenetic counseling\nThe disease follows an autosomal recessive pattern of inheritance and genetic counseling is possible.\nManagement and treatment\nThere is no cure for sulfite oxidase deficiency. Antiepileptic drugs in various combinations are used for control of seizures. Administration of diets low in sulfur containing amino acids along with sulfate supplementation have been attempted with positive biochemical responses but with no lasting neurological improvement. MoCo type A defective individuals have benefited from precursor Z (cPMP), a precursor to MoCo. Although it cannot reverse the cerebral injury that has already occurred, seizures are stopped and neurotoxicity and further cerebral damage is prevented. Genetic therapy with a MOCS1 expression cassette being carried by AAV vectors is now being studied as a future treatment.\nPrognosis\nThe prognosis of the disease is poor. For those who survive infancy, new treatments have led to improvement in some patients.\n\n                            Last update: \n                            January 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Parayil Sankaran BINDU"}
{"Disease Name": "Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome", "Disease Definition": "Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome is a rare mitochondrial disease due to a defect in coenzyme Q10 biosynthesis that manifests with a broad spectrum of signs and symptoms which may include: neonatal lactic acidosis, global developmental delay, tonus disorder, seizures, reduced spontaneous movements, ventricular hypertrophy, bradycardia, renal tubular dysfunction with massive lactic acid excretion in urine, severe biochemical defect of respiratory chain complexes II/III when assayed together and deficiency of coenzyme Q10 in skeletal muscle. Cerebral and cerebellar atrophy can be seen on magnetic resonance imaging and multiple choroid plexus cysts and symmetrical hyperechoic signal alterations in basal ganglia have been observed on ultrasound.", "ORPHA ID": 319678, "Summary": ""}
{"Disease Name": "Encircling double aortic arch", "Disease Definition": "Encircling double aortic arch is a very rare congenital anomaly of the great arteries characterized by the presence of two aortic arches (right and left) which encircle and compress the trachea and esophagus, resulting in various respiratory and gastrointestinal symptoms (e.g. harsh breathing, stridor, dyspnea, cyanotic and choking episodes, chronic cough, recurrent respiratory tract infections, dysphagia and reflux). Esophageal atresia and tracheoesophageal fistula have also been reported. It usually occurs isolated, but, on occasion, may be associated with other congenital heart anomalies and chromosomal aberations.", "ORPHA ID": 99075, "Summary": ""}
{"Disease Name": "Endocardial fibroelastosis", "Disease Definition": "A rare cardiac disease characterized by thickening of the endocardium due to deposition of collagen and elastic fibers and leading to dilated cardiomyopathy-like phenotypes more often than to restrictive forms. It predominantly occurs in infants and children and may be observed as an isolated disorder or in association with congenital heart conditions.", "ORPHA ID": 2022, "Summary": ""}
{"Disease Name": "Endocrine-cerebro-osteodysplasia syndrome", "Disease Definition": "Endocrine-cerebro-osteodysplasia (ECO) syndrome is characterized by various anomalies of the endocrine, cerebral, and skeletal systems resulting in neonatal mortality.", "ORPHA ID": 199332, "Summary": "Epidemiology\nTo date, six cases from consanguineous parents have been described.\nClinical description\nEndocrine anomalies include hypoplasia of the adrenal and pituitary glands. Skeletal anomalies include micromelia, syndactyly, brachydactyly and ulnar deviation of hands. Facial anomalies, such as midface hypoplasia, micrognathia, and a flat and wide nasal bridge, are also observed.\nEtiology\nThe disease is caused by mutations in the ICK gene, encoding an intestinal cell kinase.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            October 2009"}
{"Disease Name": "Endometrioid carcinoma of ovary", "Disease Definition": "A rare malignant epithelial tumor of ovary characterized by confluent or cribriform proliferations of round, oval, or tubular glands, typically lined by stratified non-mucin-containing epithelium with well-defined luminal margins. Squamous differentiation, secretory changes, oxyphilic variants, sex cord-stromal type patterns, or sertoliform endometrioid carcinomas may occur. Patients most commonly present in the sixth decade of life, either with a pelvic mass with or without pain, or without any symptoms. The tumor may be bilateral and is frequently associated with endometriosis and/or endometrial carcinoma.", "ORPHA ID": 454723, "Summary": ""}
{"Disease Name": "Endophthalmitis", "Disease Definition": "A rare ophthalmic disorder characterized by inflammation involving the vitreous and/or aqueous humors, usually due to bacterial or fungal infection. It may arise endogenously from hematogenous spread of the infectious agent, or exogenously after direct inoculation, and can take an acute or chronic course. Clinical signs and symptoms include progressive vitritis, hypopyon, reduced or blurred vision, red eye, pain, and lid swelling. The condition may be complicated by panophthalmitis, corneal infiltration and perforation, affection of orbital structures, and phthisis bulbi.", "ORPHA ID": 199323, "Summary": ""}
{"Disease Name": "Endosteal hyperostosis, Worth type", "Disease Definition": "A rare sclerozing bone disorder characterized by generalized skeletal densification, particularly of the cranial vault and tubular long bones, which is not associated to an increased risk of fracture.", "ORPHA ID": 2790, "Summary": "Epidemiology\nThe syndrome has been described in less than 10 families.\nClinical description\nCraniofacial anomalies develop during adolescence and include a prominent forehead, wide and deep mandibles, wide nasal root, taurus palatinus and increased gonial angle.\nEtiology\nThe syndrome is due to a mutation in the LRP5 gene that leads to increased bone formation.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            November 2009"}
{"Disease Name": "Endosteal sclerosis-cerebellar hypoplasia syndrome", "Disease Definition": "Endosteal sclerosis-cerebellar hypoplasia syndrome is characterized by congenital cerebellar hypoplasia, endosteal sclerosis, hypotonia, ataxia, mild to moderate developmental delay, short stature, hip dislocation, and tooth eruption disturbances. It has been described in four patients. Less common manifestations are microcephaly, strabismus, nystagmus, optic atrophy, and dysarthria. It is appears to be transmitted as an autosomal recessive trait.", "ORPHA ID": 85186, "Summary": ""}
{"Disease Name": "Eng-Strom syndrome", "Disease Definition": "A rare disorder characterized by intrauterine growth retardation and intermittent locking of the finger joints. It has been described in two individuals: a mother and her daughter. The mode of transmission is autosomal dominant.", "ORPHA ID": 1937, "Summary": ""}
{"Disease Name": "Enlarged parietal foramina", "Disease Definition": "Enlarged parietal foramina (EPF) is a developmental defect, characterized by variable intramembranous ossification defects of the parietal bones, which is either asymptomatic, symptomatic (headaches, nausea, vomiting, intellectual disability) or associated with other pathologies.", "ORPHA ID": 60015, "Summary": "Epidemiology\nPrevalence is estimated to be 1/15,000-1/50,000.\nClinical description\nEPF is a congenital disorder characterized by symmetrical, paired persistent foramina (openings) in the parietal bones (diameter >5 mm), located close to the intersection of the sagittal and lambdoid sutures. In infants, EPF presents as a persistent enlargement extending forward from the posterior fontanelle, caused by a single large central parietal bone defect, termed cranium bifidum. The latter tends to resolve in early childhood leaving two distinct, large parietal foramina through the ossification of a midline bridge. EPF is usually asymptomatic, but may be associated with headaches, nausea, vomiting, intense local pain and intellectual disability. EPF can also be accompanied by meningeal, cortical, and vascular malformations of the posterior fossa (that may predispose to epilepsy), and Duane retraction syndrome (see this term). Craniofacial anomalies including cleft palate, myelomeningocele and isolated encephalocele are rarely associated (see these terms). Clavicular hypoplasia may lead to confusion with cleidocranial dysplasia (see this term).\nEtiology\nEPF is caused by insufficient ossification around the parietal notch. In most cases this results from heterozygous loss of function mutations in human homeobox genes, MSX2 (5q35.2) and ALX4 (11p11.2), which encode transcription factors involved in skeletal development. A possible third locus on 4q21-q23 has also been reported in a large Chinese pedigree. EPF may also be seen in aminopterin/methotrexate embryofetopathy (see this term), which is caused by exposure to folic acid antagonists during the first trimester of preganancy.\nDiagnostic methods\nDiagnosis of EPF is based on family history and on clinical examination. Radiographically, EPF presents as symmetric radiolucencies. Computed tomography (CT) imaging with 3D reconstructions can delineate the osseous defect and magnetic resonance (MR) imaging may demonstrate associated intracranial changes. If EPF is associated with anomalies of the cerebral vasculature, additional vascular imaging like CT, MR, or digital subtraction angiography may be warranted. Diagnosis is confirmed by screening for the pathogenic mutation.\nDifferential diagnosis\nDifferential diagnosis includes Potocki-Shaffer syndrome; distal monosomy 15q; cleidocranial dysplasia; acromelic frontonasal dysplasia; craniosynostosis-anal anomalies-porokeratosis; and frontonasal dysplasia with alopecia and genital anomaly (see these terms).\nAntenatal diagnosis\nPreimplantation genetic testing, or prenatal diagnosis during pregnancy from 10 weeks gestation, is available for families with a known genetic defect.\nGenetic counseling\nTransmission is autosomal dominant with high but incomplete penetrance.\nManagement and treatment\nTreatment for EPF is generally conservative, since the natural history of the defect is to close progressively with age. Protective helmets can be considered in young, active children with particularly large defects, but surgery is not usually recommended. Imaging to assess for any accompanying venous anomalies is imperative prior to any surgical intervention.\nPrognosis\nThere is no known correlation between the size of the defect and the likelihood of having an associated brain abnormality. A spontaneous closure of the defect with growth of the infant has been observed, but it is frequently incomplete.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Tracy LESTER  - Pr Andrew WILKIE"}
{"Disease Name": "Enteric anendocrinosis", "Disease Definition": "A very rare genetic gastroenterological disease characterized by severe malabsorptive diarrhea (requiring parenteral nutrition and disappearing at fasting) due to a lack of intestinal enteroendocrine cells. It is associated with early-onset (within the first weeks of life) dehydration, metabolic acidosis and diabetes mellitus (that can develop until late childhood). Patient may display various degrees of pancreatic insufficiency that does not explain diarrhea, as it is not reduced with pancreatic enzyme supplementation. Central hypogonadism (developing in the second decade), as well as an association with celiac disease have been reported.", "ORPHA ID": 83620, "Summary": ""}
{"Disease Name": "Enteropathy-associated T-cell lymphoma", "Disease Definition": "A rare T-cell non-Hodgkin lymphoma characterized by a neoplasm of intraepithelial T-cells mostly occurring in the jejunum or ileum in patients with celiac disease. The lesion may be multifocal and form ulcerating nodules, plaques, strictures, or an exophytic mass. The mesentery and mesenteric lymph nodes are commonly involved. Patients typically present with abdominal pain, malabsorption or diarrhea, anorexia, weight loss, fatigue, nausea, vomiting, and sometimes intestinal perforation or hemorrhage. Prognosis is generally poor.", "ORPHA ID": 86880, "Summary": ""}
{"Disease Name": "Enthesitis-related juvenile idiopathic arthritis", "Disease Definition": "A rare inflammatory rheumatic disease in a child younger than 16 years characterized by arthritis and/or enthesitis and/or acute anterior uveitis. The most commonly affected joints at diagnosis are the knees, ankles, and hips. The small joints of the feet and toes are also often involved.", "ORPHA ID": 85438, "Summary": "Epidemiology\nThe incidence of juvenile idiopathic arthritis (JIA) in Caucasians is 8.3/100,000. Enthesitis-related juvenile idiopathic arthritis accounts for 10%-20% of these cases. Males account for approximately 60% of cases.\nClinical description\nJIA describes a clinically heterogeneous group of diseases, characterized by arthritis beginning before the age of 16 years, involving one or more joints, and lasting for at least 6 weeks. The enthesitis-related category describes a clinically heterogeneous group of children including some who have predominately enthesitis, enthesitis and arthritis, or axial involvement (sacro iliac or dorsal or lumbosacral pain), or inflammatory bowel disease-associated arthropathy. Onset typically occurs in late childhood or adolescence with a peak age of onset between 10 and 12 years. In the first 6 months of disease, oligoarticular disease is most common.\nEtiology\nThe etiology is unknown.\nDiagnostic methods\nDiagnosis is established by the presence of enthesitis and arthritis, or by the presence of arthritis and at least two of the following: sacroiliac pain and/or spinal inflammation, acute anterior uveitis, presence of the HLA-B27 antigen, a family history of uveitis, and spondylarthropathy, or sacroiliitis with inflammatory bowel disease in a first-degree relative. Arthritis and enthesitis are typically diagnosed by clinical findings of localized pain, tenderness, and swelling; when clinical findings are difficult to assess, echography or MRI could help. Exclusion criteria include the presence of psoriasis in the patient or a family history of psoriasis in a first-degree relative, detection of Rheumatoid Factor IgM in two tests taken at a 3-month interval, and the presence of systemic arthritis in the patient.\nDifferential diagnosis\nDifferential diagnosis should include other types of juvenile idiopathic arthritis, infectious arthritis, other inflammatory diseases, and hemato-oncologic diseases that may lead to arthritis (in particular connective tissue diseases and acute leukemia).\nManagement and treatment\nTreatment typically revolves around monotherapy or combination therapy of nonsteroidal anti-inflammatory drugs (NSAIDs), and biologic anti-TNF agents such as etanercept and adalimumab. Use of biological DMARDs (disease modifying anti-rheumatic drugs) are only recommended in severe, refractory cases. NSAID monotherapy may be appropriate for children with low disease activity and without features of poor prognosis, although continuation of this approach for longer than 2 months may require routine laboratory studies to monitor for hepatic and renal toxicity. In order to manage pain associated with enthesitis in the foot, padded heel inserts may be recommended.\nPrognosis\nProgression to axial disease can occur in children with enthesitis-related JIA. In the majority of cases, the disease progressively evolves into spondylarthritis. By 5 years after disease onset, 92% of children with spondylarthritis develop sacroiliitis. Tarsitis, and hip arthritis within the first 6 months, are associated with worse prognosis. In comparison with other JIA categories, enthesitis-related JIA is associated with worse function, quality of life, and pain. Disease remission is often obtain with biological DMARDs when NSAIDs are insufficient; without treatment, remission occurs in less than 20% of children 5 years after diagnosis.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Chantal DESLANDRE"}
{"Disease Name": "Eosinophilic angiocentric fibrosis", "Disease Definition": "A rare otorhinolaryngologic disease characterized by an indolent submucosal mass of variable size and extent, most commonly arising in the anterior nasal cavity, involving the nasal septum and lateral nasal wall, and potentially extending into the adjacent sinuses. Occurrence in the larynx and lower respiratory tract or the orbit is rare. Histological examination shows concentric angiocentric stromal fibrosis (onionskin fibrosis) and prominent eosinophils. Increased numbers of IgG4-positive plasma cells in the lesion may also be observed, in addition to elevated serum IgG4. Patients typically present with long-standing obstructive symptoms.", "ORPHA ID": 449566, "Summary": ""}
{"Disease Name": "Eosinophilic colitis", "Disease Definition": "A rare gastroenterologic disease characterized by extensive eosinophilic infiltration of the colon in the absence of any known cause of secondary intestinal eosinophilia. Patients present with abdominal pain, nausea, vomiting, diarrhea, gastrointestinal bleeding, malabsorption, and/or weight loss. Symptoms do not correlate with the extent of the disease, which can be segmental or pancolonic. Blood testing may show peripheral eosinophilia. The condition has a bimodal age distribution, with a first peak in neonates and a second peak in young adulthood.", "ORPHA ID": 402035, "Summary": ""}
{"Disease Name": "Eosinophilic fasciitis", "Disease Definition": "A rare idiopathic inflammatory myopathy that is characterized by inflammation and thickening of the fascia, usually associated with peripheral eosinophilia. It presents during adulthood with symmetrical and painful swelling of mainly the extremities that progressively become indurated. Fatigue, disabling cutaneous fibrosis, myositis and arthritis may also be observed.", "ORPHA ID": 3165, "Summary": ""}
{"Disease Name": "Eosinophilic gastroenteritis", "Disease Definition": "A rare benign gastrointestinal disease characterized by the presence of abnormal and nonspecific gastro-intestinal (GI) manifestations, associated with an eosinophilic infiltration of the GI tract, which can affect several segments and involve several layers within the GI wall.", "ORPHA ID": 2070, "Summary": "Epidemiology\nPrevalence and incidence are unknown. To date, more than 280 cases have been reported, mainly in Caucasians and with a slight male preponderance.\nClinical description\nEGE can occur at any age, but it is most commonly observed between the ages of 30 and 50 years. It can affect any area of the digestive tract, with the stomach and duodenum being the most commonly affected sites. The clinical presentation is variable and depends on the region of the digestive tract involved and the depth of eosinophilic involvement. Three sub-types have been defined according to the digestive tract layer involved. Mucosal EGE (the most common sub-type) is characterized by abdominal pain, diarrhea (with or without hemorrhage), dyspepsia, nausea, vomiting, weight loss and symptoms of protein losing enteropathy (e.g. swelling and edema). In children and adolescents, growth retardation, failure to thrive, and anemia may also be observed. Muscular EGE is often associated with hypertrophy and hyperplasia of the muscular layers, leading to symptoms of intestinal stenosis/obstruction (e.g. vomiting, nausea). Less often, symptoms of intussusception can be observed (severe abdominal pain with cramps). Serosal EGE is characterized by bloating, exudative ascites and peripheral eosinophilia. Other features have also been observed such as cholingitis, pancreatitis, and acute appendicitis.\nEtiology\nThe pathogenesis of EGE is poorly understood but it is thought that EGE is mediated by a hypersensitivity reaction. Various stimuli, including food allergens, drugs (azathioprine, gold salts, trimethoprim-sulphonamide) and immunological disorders, may trigger eosinophilic infiltration of the GI tract, followed by degranulation with cytokine release and cellular damage.\nDiagnostic methods\nLaboratory examinations demonstrate peripheral blood eosinophilia and elevated serum IgE concentrations (20-80% of cases). Other findings include steatorrhea, hypoalbuminemia, iron deficiency anemia, and prolonged prothrombin time. Endoscopy shows erythematous, friable, sometimes nodular and ulcerated mucosa. Histopathological examination of gastric and duodenal biopsies confirms the diagnosis by usually showing eosinophilic infiltrates (> 20-30 eosinophils per high-power field) in the absence of other known causes of eosinophilia. Eosinophilic degranulation or cryptitis are also diagnostic.\nDifferential diagnosis\nDifferential diagnosis includes eosinophilic esophagitis, Crohn disease, periarteritis nodosa, Churg-Strauss syndrome, idiopathic hypereosinophilic syndrome, congenital chronic diarrhea with protein-losing enteropathy, celiac disease, lymphoma (see these terms) and gastric cancer.\nManagement and treatment\nIn some early-onset pediatric cases, EGE has resolved by suppressing milk from diet. Complete resolution has also been achieved in children by exclusive feeding with an amino acid-based elemental formula or by following a hypoallergenic diet. In moderate to severe cases, treatment is based on oral corticotherapy. Low dose maintenance corticotherapy is needed in case of relapse and to keep the disease under control. Mast cell stabilizers and antihistamines have been successfully used in some cases.\nPrognosis\nWith treatment, prognosis is good with full resolution of symptoms in spite of a possible relapsing course. Complications have been reported in rare cases, mainly in the serosal sub-type, such as intestinal obstruction and perforation that may require surgery and may affect the quality of life.\n\n                            Last update: \n                            April 2014"}
{"Disease Name": "Eosinophilic granulomatosis with polyangiitis", "Disease Definition": "A rare systemic vasculitis of small vessels characterized by asthma, blood and tissue eosinophilia and vasculitis manifestations.", "ORPHA ID": 183, "Summary": "Epidemiology\nThe prevalence ranges from 1/70,000-100,000 in Europe.\nClinical description\nOnset of eosinophilic granulomatosis with polyangiitis (EGPA) usually occurs in adulthood but may occur anywhere between 15 and 70 years of age. EGPA may involve multiple organ systems. The onset of EGPA is often associated, in patients with preexisting asthma, with worsening of the asthma. Eosinophilic asthma and angiitis are the two hallmarks of the disease. EGPA has been divided into three distinct phases, which may or may not be sequential. The prodromal phase is characterized by asthma with or without allergic rhinitis. The second phase is marked by peripheral blood eosinophilia and eosinophilic tissue infiltration producing a picture similar to those of simple pulmonary eosinophilia (Loeffler syndrome), chronic eosinophilic pneumonia, or eosinophilic gastroenteritis. The third phase, i.e. vasculitic phase, usually develops within 3 years of onset and may involve any of the following organs: heart (myocarditis, pericarditis, failure), peripheral nervous system (mononeuritis multiplex in 78% of patients), paranasal sinuses, muscles, skin and less frequently kidney. Skin involvement (nodules, utricarial rash) occurs in two thirds of patients. Fever, flu-like symptoms, and weight loss are also observed. Anti-myeloperoxidase (MPO)-anti neutrophil cytoplasmic antibodies (ANCA) are found in 30 to 40% of patients and identify patients with a different clinical phenotype (e.g a higher prevalence of renal disease).\nEtiology\nEtiology of EGPA is unknown.\nDiagnostic methods\nClassification criteria of EGPA include, in the presence of evidence of vasculitis, four of the following six features: asthma, eosinophilia, neuropathy, pulmonary infiltrates, paranasal sinus abnormalities and eosinophilic vasculitis. Eosinophilia above 10% is the hallmark laboratory finding in patients with EGPA and may be as high as 75% of the peripheral blood cell count. Findings in chest X-ray (infiltrates, pneumonitis) are extremely common in EGPA. Tissue biopsies show eosinophilia, necrotizing vasculitis of small to medium vessels and, sometimes, small necrotizing granulomatous inflammation.\nDifferential diagnosis\nDifferential diagnoses of EGPA include granulomatosis with polyangiitis, hypereosinophilic syndrome, microscopic polyangiitis, polyarteritis nodosa, drug reactions, bronchocentric granulomatosis, fungal and parasitic infections, and malignancy.\nManagement and treatment\nThe treatment of patients with mild disease involves glucocorticoids (GC) monotherapy. Other immunosuppressive regimens, such as those using cyclophosphamide (CP), azathioprine or methotrexate, are used for patients with an aggressive disease. Other treatments, including rituximab or interferon-alpha, has been used in patients refractory to GC plus CP. Treatment with the anti-interleukin-5 antibody mepolizumab now represents a very effective treatment of GC-dependent eosinophilic asthma; however, its efficacy to treat vasculitis manifestations remains to be evaluated.\nPrognosis\nCardiac involvement used to be the leading cause of death related to EGPA, followed by cerebral hemorrhage and stroke. GC-related toxicity is also a frequent cause of morbidity and mortality. Despite treatment, neurological sequelae rarely resolve completely.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Xavier PUECHAL  - Pr Benjamin TERRIER"}
{"Disease Name": "Ependymal tumor", "Disease Definition": "A tumor of neurectodermal origin arising from ependymal cells that line the ventricles and central canal of the spinal cord, that can occur in both children and adults, and that is characterized by wide a range of clinical manifestations depending on the location of the tumor, such as intracranial hypertension for tumors originating in the posterior fossa, behavioural changes and pyramidal signs for supratentorial tumors, and dysesthesia for tumors of the spinal cord. They can be classified as myxopapillary ependymoma, subependymoma, ependymoma (low grade tumors) or anaplastic ependymoma (grade III tumors).", "ORPHA ID": 301, "Summary": ""}
{"Disease Name": "Ependymoma", "Disease Definition": "Ependymoma is the most frequent intramedullary tumor in adults (but accounts for only 10-12% of pediatric central nervous system tumors), and can be benign or anaplastic. Ependymoma arise from the ependymal cells of the cerebral ventricles, corticle rests and central canal of the spinal cord, and manifest with variable symptoms such headache, vomiting, seizures, focal neurological signs and loss of vision and can cause obstructive hydrocephalus in some cases.", "ORPHA ID": 251636, "Summary": ""}
{"Disease Name": "EPHB4-related lymphatic-related hydrops fetalis", "Disease Definition": "A rare primary lymphedema characterized by a highly variable lymphatic phenotype ranging from severe lymphatic-related hydrops fetalis, which may cause perinatal demise or fully resolve to become completely asymptomatic, to a mild presentation in older patients with persistent varicose veins, peripheral edema, and impaired lymph drainage in the lower limbs. Atrial septal defect has been described in association and may be the only anomaly in some patients.", "ORPHA ID": 568065, "Summary": ""}
{"Disease Name": "Epiblepharon", "Disease Definition": "A rare eyelid malposition disorder characterized by a horizontal fold consisting of redundant skin and underlying pretarsal orbicularis muscle overriding the eyelid margin and causing inward rotation of the eyelashes with potential irritation of the ocular surface. Patients may be asymptomatic or experience foreign body sensation, constant watering, itching, and redness of the eyes. Complications include repeated infections and corneal erosion. The condition is usually bilateral and more commonly affects the lower eyelids.", "ORPHA ID": 99169, "Summary": ""}
{"Disease Name": "Epibulbar lipodermoid-preauricular appendage-polythelia syndrome", "Disease Definition": "Epibulbar lipodermoid – preauricular appendages – polythelia is a branchial arch syndrome described in seven sibs of one Danish family and characterized by supernumerary nipples (polythelia), preauricular appendages and often binocular epibulbar lipodermoids or unilateral subconjunctival lipodermoids.", "ORPHA ID": 231742, "Summary": ""}
{"Disease Name": "Epidemic typhus", "Disease Definition": "A Rickettsial disease characterized by malaise and vague symptoms before the onset of high fever, headache, severe myalgias and less commonly petechial rash on the trunk and limbs, nausea, vomiting, coughing and pneumonia. Most patients also have some central nervous system disturbances, such as meningeal irritation, confusion, drowsiness, seizures, coma, and hearing loss.", "ORPHA ID": 83314, "Summary": ""}
{"Disease Name": "Epidermal nevus syndrome", "Disease Definition": "Epidermal nevus syndrome (ENS) is a rare congenitally acquired syndrome, characterized by the presence of epidermal nevi in association with various developmental abnormalities of the skin, eyes, nervous, skeletal, cardiovascular and urogenital systems.", "ORPHA ID": 35125, "Summary": "Clinical description\nEpidermal nevi are developmental disorders characterized by hyperplasia of epidermal structures in a circumscribed area of the skin. Most are present at birth, occur sporadically and affect both sexes. All well-defined ENS are lethal gene syndromes, except nevus comedonicus syndrome. About 50% of the patients have neurological abnormalities that include mental retardation and epilepsy, spastic paresis, cerebral vascular malformations, cortical atrophy, lateral ventricle enlargement. About one third of the patients may have ocular abnormalities such as colobomas of the eyelid, iris and retina, conjuctival lipodermoids and choristomas, cortical blindness, micro-, macro- or anophthalmia, corneal opacities and cataracts. Skeletal abnormalities and many other non-cutaneous abnormalities may be present.\nManagement and treatment\nNo ideal medical therapy for the cutaneous lesions of ENS exists. The skin lesions may be amenable to surgery. The inflammatory linear verrucous epidermal nevus (ILVEN) sometimes responds to Erbium-YAG laser or vitamin D analogues. Salicylic acid, topical and systemic retinoids, emollients, shave dermabrasion and cryotherapy have been tried. The concomitant skeletal and ocular defects can be surgically repaired. Epilepsy should be treated appropriately.\n\n                            Last update: \n                            April 2004\n\n\n                            - Expert reviewer(s): \n                            Dr Michael KAKEPIS  - Pr Nikolaos STAVRIANEAS"}
{"Disease Name": "Epidermolysis bullosa acquisita", "Disease Definition": "A rare, chronic, incurable, sub epithelial autoimmune bullous disease characterized by the presence of tissue bound autoantibodies against type VII collagen within the basement membrane zone of the dermal-epidermal junction of stratified squamous epithelia. The patient's serum may also have anti-type VII collagen autoantibodies. The clinical presentation is varied, and may involve the skin, oral mucosa and the upper third of the esophagus. The classical presentation is reminiscent of hereditary dystrophic epidermolysis bullosa (EB) with skin fragility, blisters and erosions and skin scarring. Other non-classical clinical presentations include an inflammatory bullous pemphigoid-like eruption, a mucous membrane pemphigoid-like eruption, and an IgA bullous dermatosis-like disease.", "ORPHA ID": 46487, "Summary": "Epidemiology\nThe prevalence is unknown, but the incidence is estimated at 1/96,200 new cases per year.\nClinical description\nEpidermolysis bullosa acquisita (EBA) is an acquired disease with onset typically in middle-aged adults but can rarely occur in childhood. The disease manifests in several possible ways. The classical presentation is reminiscent of hereditary dystrophic EB with skin fragility, blisters and erosions and skin scarring. There is marked skin fragility with skin blisters and erosions over trauma-prone areas of the skin that results in skin scarring. This form is relatively non-inflammatory. Mucous membrane lesions and nail dystrophy are common. A second possible clinical presentation is an inflammatory bullous eruption reminiscent of the autoimmune bullous disease, bullous pemphigoid. These bullae are on inflammatory plaques and may be flexural rather than over trauma-prone areas. A third possible clinical presentation is mucosal-centered with blisters, erosions and scarring of the conjunctival and oral mucosae, but may also involve the larynx and urethra. A fourth possible presentation is an IgA anti-type VII collagen mediated disease reminiscent of IgA bullous dermatosis and dermatitis herpetiformis. Diseases frequently associated with EBA include inflammatory bowel diseases (Crohn's disease and ulcerative colitis) and systemic lupus erythematosus.\nEtiology\nEBA is caused by IgG autoantibodies generated against type VII collagen in the skin located at the dermal-epidermal junction. Type VII collagen is the major component of anchoring fibril structures located at the dermal-epidermal junction just beneath the lamina densa. These structures hold the epidermal and dermal layers of skin together. The autoantibodies against type VII collagen perturbs the function of anchoring fibrils and the adherence between these two main layers of skin is compromised and prone to blistering.\nDiagnostic methods\nDiagnosis is made by histology and direct immunofluorescence (DIF) of skin biopsies, salt-split skin DIF, indirect immunofluorescence (IIF) of patient's serum, salt-split skin IIF, immunoblotting of patient serum against type VII collagen, detection of anti-type VII collagen autoantibodies by ELISA and/or immune-electron microscopy of a skin biopsy.\nDifferential diagnosis\nThe differential diagnosis should include other subepidermal, autoimmune bullous diseases.\nManagement and treatment\nIn EBA patients without inflammatory bowel disease, oral colchicine is the first-line treatment. Dapsone may be helpful in some patients. Oral cyclosporine A controls the disease, but its nephrotoxic side-effects limit its use. In the classical form of EBA, other types of immunosuppressive therapy (such as systemic steroids, azathioprine, mycophenylate mofetil,) are often ineffective, but may be useful in the inflammatory varieties of EBA. Although further trials are necessary, encouraging results have been obtained with other approaches such as intravenous immunoglobulin therapy, extracorporeal photochemotherapy and, more recently, rituximab therapy.\nPrognosis\nEBA is a chronic, incurable disease that leads to dystrophic scarring and milia. During the disease course, the inflammatory forms may evolve to resemble the classical form and vice-versa. Although not fatal, the progressive scarring and involvement of the oral and ocular mucosae can be functionally disabling.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Pr David WOODLEY"}
{"Disease Name": "Epidermolysis bullosa simplex due to BP230 deficiency", "Disease Definition": "A rare, inherited, epidermolysis bullosa simplex characterized by mild, predominantly acral, trauma-induced skin fragility, resulting in blisters. Blisters mostly affect the feet, including the dorsal side.", "ORPHA ID": 412181, "Summary": ""}
{"Disease Name": "Epidermolysis bullosa simplex due to exophilin 5 deficiency", "Disease Definition": "A rare, inherited, epidermolysis bullosa simplex characterized by mild, generalized trauma-induced scale crusts and intermittent blistering, sometimes combined with erosions, recovering with slight scarring and post-inflammatory hyperpigmentation. Clinical symptoms improve with age.", "ORPHA ID": 412189, "Summary": ""}
{"Disease Name": "Epidermolysis bullosa simplex with anodontia/hypodontia", "Disease Definition": "A rare epidermolysis bullosa simplex characterized by the association of the typical trauma-induced blisters with additional features including hearing impairment, alopecia, hypo- or anodontia, and nail dystrophy. Occurrence of vitiliginous skin areas unrelated to the sites of the blisters has also been described.", "ORPHA ID": 2325, "Summary": ""}
{"Disease Name": "Epidermolysis bullosa simplex with circinate migratory erythema", "Disease Definition": "A rare, inherited, epidermolysis bullosa simplex characterized by belt-like areas of erythema with multiple vesicles and small blisters at the advancing edge of erythema. The lesions occur on the limbs and trunk and heal with brown pigmentation but no scarring. Extracutaneous involvement is absent. Onset of the disease is usually at birth.", "ORPHA ID": 158681, "Summary": ""}
{"Disease Name": "Epidermolysis bullosa simplex with mottled pigmentation", "Disease Definition": "A rare, inherited, epidermolysis bullosa simplex characterized by neonatal or infantile onset of generalized blistering with mottled or reticulate brown pigmentation developing later. Blistering is often accompanied by mild nail dystrophy and focal palmoplantar keratoderma, and rarely by milia and mostly affects the limbs and trunk.", "ORPHA ID": 79397, "Summary": ""}
{"Disease Name": "Epidermolysis bullosa simplex with muscular dystrophy", "Disease Definition": "A form of epidermolysis bullosa simplex (EBS) characterized by generalized blistering associated with muscular dystrophy.", "ORPHA ID": 257, "Summary": "Epidemiology\nPrevalence of epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) is unknown, but more than 40 cases have been reported to date.\nClinical description\nOnset of blistering is usually as early as birth, whereas muscular dystrophy manifests between infancy and adulthood, with a median age of onset of 9.5 years. Blisters are often hemorrhagic and heal with mild atrophic scarring and rare milia formation. Associated findings comprise markedly dystrophic nails, and focal keratoderma of the palms and soles. Extracutaneous involvement is usually present, including enamel hypoplasia with premature tooth decay, blistering in the oral cavity, pharynx and, rarely, larynx and trachea with inspiratory stridor and breathing difficulties requiring tracheotomy. Slowly progressive weakness of the head and limb muscles appears between the first year and the fourth decade of life and may confine the patient to a wheelchair. Additional neurological symptoms (ptosis, oculobulbar muscle weakness and fatigability) indicative of a myasthenic syndrome have been described in some patients. Mucosal involvement including urethral mucosae is common. Cardiomyopathy may be associated and, in rare cases, pyloric atresia.\nEtiology\nEBS-MD is caused by mutations in the PLEC gene (8q24) encoding plectin. Plectin deficiency can be demonstrated in skin and muscle by analysis with specific antibodies.\nDiagnostic methods\nDiagnosis is based on the mode of transmission, histopathological findings, and clinical presentation. Immunofluorescence mapping demonstrates lack of immunoreactivity for plectin and a plane of cleavage deep within the basal pole of the basal keratinocytes. Transmission electron microscopy shows intraepidermal split formation with lamina densa and lucida, and hemidesmosomes on the floor of the blister. Genetic testing demonstrates biallelic loss-of-function pathogenic variants in PLEC coding for plectin.\nDifferential diagnosis\nDifferential diagnosis is of other types of EBS and disorders with congenital skin blistering.\nAntenatal diagnosis\nPrenatal diagnosis should be offered to affected families in which the pathogenic variant/s have been previously diagnosed.\nGenetic counseling\nThe disorder is autosomal recessive and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThere is no specific treatment available, treatment is symptomatic with wound management and general support.\nPrognosis\nFrom a prognostic point of view, immunohistochemical recognition of EBS-MD in infancy is particularly important, since in some patients the associated muscular dystrophy may not become apparent until later in childhood or adulthood. EBS-MD may have a fatal outcome.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Cristina HAS | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Epidermolysis bullosa simplex with pyloric atresia", "Disease Definition": "A rare, inherited, epidermolysis bullosa simplex characterized by generalized severe blistering with widespread congenital absence of skin and pyloric atresia that is usually fatal in infancy. Antenatally, pyloric atresia can manifest with polyhydramnios. If patients survive, they experience life-long skin fragility and nail dystrophy. Additional extracutaneous findings include failure to thrive, anemia, sepsis, intraoral blistering, enamel hypoplasia, urethral stenosis and urologic complications.", "ORPHA ID": 158684, "Summary": ""}
{"Disease Name": "Epidermolysis bullosa simplex", "Disease Definition": "A group of hereditary epidermolysis bullosa (HEB) disorders characterized by skin fragility resulting in intraepidermal blisters and erosions that occur either spontaneously or after physical trauma.", "ORPHA ID": 304, "Summary": "Epidemiology\nReported prevalence of epidermolysis bullosa simplex (EBS) ranges between 1/85,000-500,000 worldwide.\nClinical description\nOnset is usually at or shortly after birth, although blistering in localized EBS may not develop until late childhood or early adulthood. Along with localized or generalized blistering and erosions, sometimes showing characteristic patterns (herpetiform grouping), cutaneous features may include nail shedding and dystrophy, and, rarely, milia formation. Scarring is mostly absent or minimal (mild atrophic wrinkling and dyspigmentation). Other findings may include congenital absence of the skin, and localized or diffuse keratoderma of the palms and soles. The commonest extracutaneous manifestation is blistering of the oral cavity. A variety of additional extracutaneous complications may occur and are age-dependent, with time of onset and cumulative risk of occurrence highly dependent on the EBS subtype (e.g. muscular dystrophy in PLEC-related EBS, cardiomyopathy in KLHL24-related EBS, nephropathy in CD151-related EBS). Blisters occur in the basal layer of the epidermis.\nEtiology\nEBS is a genetically heterogeneous group caused by pathogenic variants in specific genes depending on the subtype.\nDiagnostic methods\nDiagnosis is based on determination of the epidermal level within which blisters develop following minor skin traction. Recommended techniques are immunofluorescence antigen mapping (IFM) and transmission electron microscopy (TEM) performed on a skin biopsy sample. Subtypes are then defined on the basis of the mode of transmission, IFM and TEM, and clinical presentation. Cutaneous findings are not reliable diagnostic markers, in particular in neonates. Genetic testing should always be performed to determine the underlying genetic defect. Because of the genetic heterogeneity, analysis by next generation sequencing EB-gene panel is recommended.\nDifferential diagnosis\nDiagnosis is usually straightforward with little need for extensive differential diagnosis. However, in the neonatal period, in utero herpes simplex infection may be considered, especially if there is no family history of blistering disease or if clinical findings are atypical for epidermolysis bullosa. The differential diagnosis in neonates and small children may include congenital aplasia cutis, neonatal pemphigus, neonatal herpes gestationis, staphylococcal scalded skin syndrome, as well as incontinentia pigmenti, epidermolytic ichthyosis, linear IgA dermatosis, bullous pemphigoid, and bullous impetigo.\nAntenatal diagnosis\nPrenatal diagnosis should be offered to families with severe EBS.\nGenetic counseling\nIn autosomal dominant EBS subtypes, affected individuals have an affected parent from whom they inherited a pathogenic variant, but in a high percentage of cases, pathogenic variants occur de novo. Each child of an individual with EBS has a 50% risk of inheriting the pathogenic variant. In autosomal recessive EBS subtypes, the parents of an affected child are obligate heterozygotes for an EBS-related pathogenic variant. Each sib of an affected individual has a 25% risk of being affected, a 50% risk of being heterozygous , and a 25% risk of being unaffected and not heterozygous. Autosomal recessive EBS is common in countries with high rates of consanguineous marriages.\nManagement and treatment\nManagement is based on the avoidance of blistering by meticulous protective skin padding and appropriate life-style to avoid trauma, and prevention of secondary infection by careful wound care. Air-conditioning may help in preventing disease worsening in warm weather. Patients with EBS subtypes with the highest risk of specific extracutaneous complications need to be monitored closely and appropriate measures implemented to prevent the affected tissues from becoming severely injured. Topical inhibitors of IL-1 have proven some benefit in small clinical trials. No specific treatment is available for the extracutaneous manifestations of EBS.\nPrognosis\nPrognosis is highly dependent on the subtype. Most patients have a normal life expectancy but significant morbidity and even early death may occur in some subtypes.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Cristina HAS | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Epidermolytic nevus", "Disease Definition": "A rare nevus characterized by single or multiple non-inflammatory verrucous skin lesions composed of keratinocytes, often present from birth, and distributed along the lines of Blaschko. Histologically, the lesions show features of epidermolytic hyperkeratosis with perinuclear vacuolization of keratinocytes of the upper epidermis with coarse keratohyaline granules. There is no extra-cutaneous involvement. Affected individuals are at risk of parenting a child with bullous ichthyosiform erythroderma.", "ORPHA ID": 497737, "Summary": ""}
{"Disease Name": "Epidermolytic palmoplantar keratoderma", "Disease Definition": "A rare, non-syndromic, hereditary palmoplantar keratoderma characterized by diffuse, yellowish, thick hyperkeratosis of the palms and soles with a sharp demarcation at the volar border and an erythematous margin, and the epidermolytic pattern of changes on the skin biopsy, including perinuclear vacuolization, granular degeneration of keratinocytes in the spinous and granular layer, and tonofilament aggregates. Painful fissures and hyperhidrosis are frequently associated.", "ORPHA ID": 2199, "Summary": ""}
{"Disease Name": "Epignathus", "Disease Definition": "Epignathus is a very rare and life threatening intraoral teratoma, usually arising from the maxilla, mandible, palate or base of skull and invading the cranium, nasopharynx or oral cavity. Epignathus is more commonly seen in females, and presents with various manifestations (depending on the tumor size) including obstructive polyhydramnios in the prenatal period and dyspnea, cyanosis, cough, difficulty in sucking and swallowing, and rarely vomiting (due to swallowing difficulties) postnatally. When large, they can lead to airway obstruction, asphyxia and death in the neonatal period.", "ORPHA ID": 141077, "Summary": ""}
{"Disease Name": "Epilepsy with eyelid myoclonia", "Disease Definition": "A rare, idiopathic, generalized form of reflex epilepsy characterized by childhood onset, unique seizure manifestations, striking light sensitivity, and possible occurrence of generalized tonic-clonic seizures.", "ORPHA ID": 139431, "Summary": "Epidemiology\nPrevalence is unknown but Jeavons syndrome appears to represent around 7-8% of all idiophatic generalized epilepsies (IGEs). The syndrome is slightly more frequent in females than in males.\nClinical description\nOnset occurs in childhood, with a peak at 6-8 years of age. Eyelid myoclonia is the principle clinical feature and may or may not be associated with brief (less than 6s) absences. Eye closure in the presence of uninterrupted light is the major triggering factor. Eyelid myoclonic status epilepticus is reported in up to one fifth of the patients and self-induction, although rare, has been described. Generalized tonic-clonic seizures occur in most patients, but the frequency of the seizures is low. Mental development is usually normal but mild to moderate intellectual deficit has been reported in some cases.\nEtiology\nThe etiology is unknown but Jeavons syndrome appears to be genetically determined: the majority of reported patients have a family history of IGE and a few cases of affected twins have been reported.\nDiagnostic methods\nEyelid myoclonia is a highly distinctive seizure type and is strongly suggestive of Jeavons syndrome. Video-electroencephalography (video-EEG) is the only procedure required for diagnosis and reveals eye closure-related generalized paroxysmal activity. Thus, in patients with eyelid myoclonia with or without absences, associated with photosensitivity and EEG discharges triggered by eye closure, the diagnosis of Jeavons syndrome is straightforward.\nDifferential diagnosis\nHowever, other forms of idiopathic, cryptogenic, and symptomatic epilepsy featuring eyelid myoclonia or eye closure sensitivity (juvenile myoclonic epilepsy, juvenile absence epilepsy, and idiopathic photosensitive occipital lobe epilepsy; see these terms) may also be considered in the differential diagnosis. Misdiagnosis of eyelid myoclonia as a facial tic has also been reported.\nManagement and treatment\nThe seizures in Jeavons syndrome usually respond well to antiepileptic treatment, with antimyoclonic drugs (valproate, benzodiazepines, levetiracetam, and zonisamide) showing the highest level of efficacy and generally allowing good seizure control. However, polytherapy is often needed and some cases may be drug-resistant.\nPrognosis\nThe overall prognosis is good, although Jeavons syndrome is usually a lifelong condition.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Pasquale STRIANO"}
{"Disease Name": "Epilepsy with myoclonic absences", "Disease Definition": "A rare childhood-onset epilepsy characterized by sudden onset, short lasting absence associated with rhythmical myoclonia of head and shoulders.", "ORPHA ID": 86911, "Summary": "Epidemiology\nExact incidence of this rare epilepsy syndrome is unknown. Both sexes are affected, with a male predominance (70%).\nClinical description\nSeizure onset is between 1 to 12 years of age (peak 7 years) and characterized by absences associated with rhythmical jerks of head/shoulders. Other seizure types (generalized tonic-clonic, atonic seizures and typical absences) occur in the majority of patients. At presentation, approximately half the children are developmentally and neurologically normal; a spectrum of learning disability is eventually seen in 70% of cases.\nEtiology\nCurrently, the etiology is unidentified in the majority of cases. In 30% of cases, a genetic cause can be found with possible polygenic etiologies. SLC2A1 variants (1p34.2), causing GLUT1 deficiency, are one of the most common monogenic etiologies of myoclonic absences. There is one case report of a translocation resulting in a truncation in the SYNGAP1 gene causing epilepsy with myoclonic absences. A family history (usually of generalized seizures) is present in 20% of cases. Rarely, there is a family history of febrile seizures.\nDiagnostic methods\nMicro-array and dedicated epilepsy panels can show pathogenic mutations. On electroencephalogram (EEG), generalized spike-and-wave discharges and polyspike-and-wave discharges may occur. Background is otherwise normal. Ictal EEG: regular 3-Hz generalized spike-and-wave accompanies myoclonic absences. Electromyography recordings from the upper arm show a constant relationship between the bilateral myoclonic jerks and spike-and-waves. High resolution magnetic resonance imaging is required to exclude structural brain abnormality although neuroimaging is usually normal. However, mild non-specific diffuse atrophy is seen in some cases.\nDifferential diagnosis\nDifferential diagnosis includes Lennox-Gastaut syndrome (atypical absences may occur with rhythmic myoclonic jerking but EEG background is typically abnormal), myoclonic seizures due to structural brain abnormality, childhood absence epilepsy with a common EEG pattern but the description of the seizure is different, progressive myoclonic epilepsies, and myoclonic atonic epilepsy.\nAntenatal diagnosis\nNot relevant.\nGenetic counseling\nIn case of a monogenic etiology or a chromosomal anomaly, genetic counseling can be provided.\nManagement and treatment\nSeizures are often difficult to treat and may continue into adulthood. Anti-seizure drugs for absence seizures can be used: sodium valproate, ethosuximide, zonisamide, topiramate, or levetiracetam.\nPrognosis\nSeizures are usually difficult to control. Later on, in adolescence and adulthood, other (generalized) seizures may develop in almost half of patients. Sometimes an evolution towards juvenile myoclonic epilepsy is seen. Cognitive function seems to be preserved in children in whom myoclonic absences are controlled.\n\n                            Last update: \n                            December 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Lieven LAGAE | EpiCARE* - Pr Rima NABBOUT | EpiCARE* - Pr Sylvie NGUYEN | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Epilepsy-microcephaly-skeletal dysplasia syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, hypotonia, seizures, microcephaly, delayed bone maturation, and skeletal abnormalities (such as scoliosis or pectus excavatum, among others). Dysmorphic features include coarse face, hirsutism, thick eyebrows, broad nasal septum, short philtrum, large mouth, and prominent ears. There have been no further descriptions in the literature since 1996.", "ORPHA ID": 1948, "Summary": ""}
{"Disease Name": "Epilepsy-telangiectasia syndrome", "Disease Definition": "A rare, genetic, epilepsy syndrome characterized by epilepsy, palpebral conjunctival telangiectasias, borderline to moderate intellectual disability, diminished serum IgA levels, shortened fifth fingers and dysmorphic facial features (including frontal hirsutism, synophrys, anteverted nostrils, prominent ears, long philtrum, irregular teeth implantation, micrognathia). No new cases have been described in the literature since 1978.", "ORPHA ID": 1951, "Summary": ""}
{"Disease Name": "Epileptic encephalopathy with global cerebral demyelination", "Disease Definition": "Epileptic encephalopathy with global cerebral demyelination is a rare mitochondrial substrate carrier disorder characterized by severe muscular hypotonia, seizures (with or without episodic apnea) beginning in the first year of life, and arrested psychomotor development (affecting mainly motor skills). Severe spasticity with hyperreflexia has also been reported. Global cerebral hypomyelination is a characteristic imaging feature of this disease.", "ORPHA ID": 353217, "Summary": ""}
{"Disease Name": "Epiphyseal dysplasia-hearing loss-dysmorphism syndrome", "Disease Definition": "Epiphyseal dysplasia-hearing loss-dysmorphism syndrome is a rare multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay, intellectual disability, short stature, sensorineural hearing impairment, facial dysmorphism (incl. epicanthus, broad, depressed nasal bridge, broad, fleshy nasal tip, mildly anteverted nares, deep nasolabial folds, broad mouth with thin upper lip) and skeletal anomalies (incl. abnormally placed thumbs, brachydactyly, scoliosis, dysplastic carpal bones). Patients also present severe behavior disturbances (aggression, hyperactivity), as well as hypopigmented skin lesions and hypoplastic digital patterns. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 1825, "Summary": ""}
{"Disease Name": "Epiphyseal stippling-osteoclastic hyperplasia syndrome", "Disease Definition": "A rare primary bone dysplasia characterized by extensive epiphyseal, tarsal, spinal, and sometimes metacarpal and/or phalangeal stippling, severe generalized osteopenia, vertebral clefting, platyspondyly, bowing and shortening of the long bones, and variable periosteal cloaking. Laboratory analysis of lysosomal enzymes reveals normal activity. Histopathology shows numerous giant, multinucleated osteoclasts lining Howship lacunae, consistent with increased bone resorption. The condition manifests prenatally and is presumably lethal in the perinatal period.", "ORPHA ID": 1952, "Summary": ""}
{"Disease Name": "Epiphysiolysis of the hip", "Disease Definition": "Epiphysiolysis of the hip is a rare osteonecrosis disorder characterized by unilateral or bilateral disruption of the capital femoral physis with varying degrees of posterior epiphysis translation and simultaneous anterior metaphysis displacement. Patients typically present in pre-adolescence/adolescence with pain of variable intensity in varying locations (hip, groin, thigh, knee).", "ORPHA ID": 399329, "Summary": ""}
{"Disease Name": "Episodic ataxia type 1", "Disease Definition": "A frequent form of Hereditary episodic ataxia characterized by brief episodes of ataxia, neuromyotonia, and continuous interictal myokymia.", "ORPHA ID": 37612, "Summary": ""}
{"Disease Name": "Episodic ataxia type 3", "Disease Definition": "A rare form of Hereditary episodic ataxia characterized by vestibular ataxia, vertigo, tinnitus, and interictal myokymia.", "ORPHA ID": 79135, "Summary": ""}
{"Disease Name": "Episodic ataxia type 4", "Disease Definition": "A rare form of Hereditary episodic ataxia characterized by late-onset episodic ataxia, recurrent attacks of vertigo, and diplopia.", "ORPHA ID": 79136, "Summary": ""}
{"Disease Name": "Episodic ataxia type 5", "Disease Definition": "Episodic ataxia type 5 (EA5) is an extremely rare form of Hereditary episodic ataxia (see this term) characterized by recurrent episodes of vertigo and ataxia lasting several hours.", "ORPHA ID": 211067, "Summary": ""}
{"Disease Name": "Episodic ataxia type 6", "Disease Definition": "Episodic ataxia type 6 (EA6) is an exceedingly rare form of Hereditary episodic ataxia (see this term) with varying degrees of ataxia and associated findings including slurred speech, headache, confusion and hemiplegia.", "ORPHA ID": 209967, "Summary": ""}
{"Disease Name": "Episodic ataxia type 7", "Disease Definition": "Episodic ataxia type 7 (EA7) is an exceedingly rare form of Hereditary episodic ataxia (see this term) characterized by ataxia with weakness, vertigo, and dysarthria without interictal findings.", "ORPHA ID": 209970, "Summary": ""}
{"Disease Name": "Episodic ataxia with slurred speech", "Disease Definition": "Episodic ataxia with slurred speech is a rare hereditary ataxia characterized by recurrent episodes of ataxia with variable frequency and duration, associated with slurred speech, generalized muscle weakness and balance disturbance. Other symptoms may occur between episodes, including intention tremor, gait ataxia, mild dysarthria, myokymia, migraine and nystagmus.", "ORPHA ID": 401953, "Summary": ""}
{"Disease Name": "Epithelial basement membrane dystrophy", "Disease Definition": "A rare corneal dystrophy characterized by thickened, redundant sheets of basement membrane extending into the corneal epithelium, as well as intraepithelial lacunae filled with cellular debris, together presenting as a pattern of ''maps'', ''dots'', and ''fingerprints'' on slit-lamp examination. Patients may be asymptomatic or present with recurrent episodes of painful corneal erosions with variable visual impairment, typically beginning after the age of thirty. The condition is bilateral and may be inherited in an autosomal dominant manner.", "ORPHA ID": 98956, "Summary": ""}
{"Disease Name": "Epithelial recurrent erosion dystrophy", "Disease Definition": "Epithelial recurrent erosion dystrophy (ERED) is a rare form of superficial corneal dystrophy (see this term) characterized by recurrent episodes of epithelial erosions from childhood in the absence of associated diseases, with occasional impairment of vision.", "ORPHA ID": 293381, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is unknown, but numerous cases have been reported to date.\nClinical description\nThe erosions begin spontaneously or are precipitated by minor trauma, dust or smoke. The condition may become apparent by 6 months of age, but as a rule it only starts at 4 to 6 years of age. Most patients have attacks of redness, photophobia, epiphora, and ocular pain. Some experience a burning sensation and report sensitive eyes for years. Exposure to sunlight or draught, dust and smoke and lack of sleep can precipitate attacks. The intensity and frequency of the recurrent epithelial erosions tend to diminish over time, and usually cease by the end of the fourth decade. Vision is sometimes impaired.\nEtiology\nThe etiology has not been completely elucidated. The gene related to ERED remains to be mapped to a specific chromosomal locus.\nDiagnostic methods\nOn slit-lamp examination, the erosions may be accompanied by a subepithelial haze or blebs, and subepithelial opacities, apparently due to fibrosis, or keloid-like nodules may develop. When present, subepithelial opacities continue to enlarge. Specific morphologic abnormalities have not been identified in ERED.\nDifferential diagnosis\nSuspected cases of ERED should be differentiated from other conditions that are accompanied by recurrent epithelial erosions, particularly when erosions are the initial presenting manifestation, such as epithelial basement membrane dystrophy and other superficial or stromal corneal dystrophies (see these terms).\nGenetic counseling\nAn autosomal dominant pattern of inheritance has been reported.\nManagement and treatment\nERED can be treated medically with the aim of healing the epithelial defect and protecting the loosely adherent epithelium. A topical antibiotic, cycloplegic and pressure patch are valuable. A lubricating ointment is useful at night. Hypertonic saline and bandage contact lens therapy may also be beneficial.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Epithelioid hemangioendothelioma", "Disease Definition": "A rare vascular tumor characterized by a solitary lesion in the superficial or deep soft tissue of the extremities, most often originating from a small vein as a fusiform intravascular mass also infiltrating surrounding tissues. It is composed of epithelioid endothelial cells arranged in short cords and nests in a myxohyaline stroma. Patients present with an often painful nodule which may be associated with edema or thrombophlebitis. In classic epithelioid hemangioendothelioma lacking atypical histological features metastatic rate and mortality are low.", "ORPHA ID": 157791, "Summary": ""}
{"Disease Name": "Epithelioid sarcoma", "Disease Definition": "A rare, soft tissue tumor characterized by high incidence of local recurrence, regional lymph node involvement and distant metastases. It commonly affects the soft tissue under the skin of a finger, hand, forearm, lower leg or foot, less often other areas of the body.", "ORPHA ID": 293202, "Summary": ""}
{"Disease Name": "Epithelioid trophoblastic tumor", "Disease Definition": "A rare gestational trophoblastic neoplasmcharacterized histologically by invasion of the myometrium and/or cervix uteri by regular epithelioid cells of chorion laeve type intermediate trophoblasts which clusters in a hyaline stroma. The disease generally occurs several years after pregnancy and indicative signs are irregular metrorrhagia and moderate increases in chorionic gonadotropin levels.", "ORPHA ID": 254698, "Summary": ""}
{"Disease Name": "Epstein-Barr virus-associated gastric carcinoma", "Disease Definition": "A rare form of gastric carcinoma characterized by a latent EBV infection in gastric carcinoma cells, diffuse-type histology, a proximal location (in the body and cardia of the stomach) and a relatively favorable prognosis.", "ORPHA ID": 313920, "Summary": ""}
{"Disease Name": "Epstein-Barr virus-positive diffuse large B-cell lymphoma", "Disease Definition": "Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly is a rare form of diffuse large B-cell lymphoma occurring most commonly in patients over the age of 50 (usually between 70-75 years of age), without overt immunodeficiency, and presenting with nodal and extranodal involvement (in sites such as the stomach, lung, skin and pancreas) and B symptoms (fever, night sweats, weight loss). The tumor is characterized by an aggressive course and a short survival rate.", "ORPHA ID": 289661, "Summary": ""}
{"Disease Name": "Erdheim-Chester disease", "Disease Definition": "Erdheim-Chester disease (ECD), a non-Langerhans form of histiocytosis, is a multisystemic disease characterized by various manifestations such as skeletal involvement with bone pain, exophthalmos, diabetes insipidus, renal impairment and central nervous system (CNS) and/or cardiovascular involvement.", "ORPHA ID": 35687, "Summary": "Epidemiology\nPrevalence is unknown. More than 500 cases (<15 pediatric) have been reported since 1930.\nClinical description\nECD usually presents in adults aged 40-60 with a 3:1 male to female ratio. Clinical course varies from asymptomatic to multisystemic, life-threatening forms. The pathognomonic feature of ECD is osteosclerosis of the long bones manifesting as bone pain, mainly affecting the distal lowerlimbs (50% of cases). Pituitary gland infiltration leads to diabetes insipidus and rarely hyperprolactinemia and gonadotropin insufficiency. Constitutional symptoms include fever, weakness and weight loss. Infiltrations in other organs can lead to intracranial hypertension, exophthalmos, papilledema, adrenal insufficiency, xanthelasmas and papulonodular skin lesions. CNS involvement can cause cerebellar and pyramidal syndromes, headaches, seizures, cognitive impairment, cranial nerve palsies and sensory disturbances. A frequent cardiovascular involvement is the ''coated aorta''. Renal arteries can also be involved, leading to reno-vascular hypertension. Pericardial involvement may be complicated by a tamponade. Pseudo-tumoral infiltration of the right atrium is also seen. Dyspnea, due to lung infiltration, has been reported. Pseudo retroperitoneal fibrosis is sometimes complicated by bilateral hydronephrosis.\nEtiology\nEtiology is unknown but it is thought to be either a reactive or neoplastic disorder. Elevated levels of interferon-alpha (IFN-alpha), interleukin (IL)-7, IL-12, monocyte chemoattractant protein-1 and decreased levels of IL-4 found in ECD patients support an associated systemic immune Th-1 oriented perturbation. Recent findings of mutations in the BRAF proto-oncogene in > 50% of ECD cases clearly add further complexity to the pathophysiology of ECD.\nDiagnostic methods\nThe hallmark histological finding is the xanthogranulomatous or xanthomatous infiltration of tissues with spumous histiocytes. Immunohistochemical staining of a biopsy sample is CD68-positive and CD1a-negative. Bone x-rays usually display bilateral and symmetric cortical osteosclerosis of the long bones, while technetium 99m bone scintigraphy shows almost constantly evidence of symmetric and abnormally strong labeling of the distal ends of the long bones of the lower limbs (and sometimes the upper limbs). Abdominal CT scan may show a ''hairy kidney'' appearance (in 50%) which can be biopsied.\nDifferential diagnosis\nDifferential diagnosis includes Langerhans' cell histiocytosis, Rosai-Dorfman disease, Takayasu arteritis, Wegener's granulomatosis, primary hypophysitis, chronic recurrent multifocal osteomyelitis (see these terms), malignancies, neurosarcoidosis, mycobacterial infections and metabolic disorders.\nManagement and treatment\nFirst line treatment is the administration of standard or pegylated IFN-alpha for all forms of ECD with higher doses (9 million units, 3 times per week) required on a long-term basis for those with CNS and cardiac localizations (if well tolerated). Bisphosphonates may be given to alleviate bone pain. Cladribine can be given to those with orbital involvement that have been resistant to other forms of treatment. Anakinra can improve symptoms of mild forms of ECD in patients where IFN-alpha was ineffective. Recently, infliximab and vemurafenib have been used with some success, this latter drug seeming very promising for patients with a BRAFV600 mutation. PET scans are recommended for the assessment of disease activity.\nPrognosis\nECD has a variable prognosis but is overall poorer in those with CNS involvement. Before IFN-alpha, the mean survival after diagnosis was 19.2 months. Nowadays, with IFN-alpha treatments, the mortality rate is only 26%, and 5-year survival is 68%.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Julien HAROCHE"}
{"Disease Name": "Ermine phenotype", "Disease Definition": "A rare deafness characterized by the association of bilateral sensorineural hearing loss and white hair with scattered black tufts, as well as skin areas of hyper- and hypopigmentation. Additional reported features include global developmental delay and moderate intellectual disability, growth retardation, microcephaly, hypotonia, mild dysmorphic facial features (deeply set eyes, broad nasal bridge, slight bowing of the upper lip), retinal depigmentation, anomalies of the fingers and toes, and white matter abnormalities on brain imaging.", "ORPHA ID": 999, "Summary": ""}
{"Disease Name": "Erosive pustular dermatosis of the scalp", "Disease Definition": "Erosive pustular dermatosis of the scalp is a rare chronic inflammation of the scalp usually occurring in elderly women (>70 years old) and characterized by the development of painful pustules, shallow erosions, and crusting on atrophic skin that eventually result in cicatricial alopecia.", "ORPHA ID": 222, "Summary": ""}
{"Disease Name": "Erythema elevatum diutinum", "Disease Definition": "Erythema elevatum diutinum (EED) is a distinctive form of chronic cutaneous vasculitis, belonging to the group of the neutrophilic dermatoses.", "ORPHA ID": 90000, "Summary": "Epidemiology\nIt is very rare, although the exact prevalence is unknown.\nClinical description\nThe disease manifests as chronic, red to purple papules, located mainly on the dorsal aspect of the main joints (knees, elbows, hands and feet). Acute lesions may appear bullous, necrotic or hemorrhagic. Older lesions are yellowish or brown.\nEtiology\nEED is not an inherited disease and the exact aetiology remains unknown. EED is a reactive process, which may occur in isolation or in the context of an inflammatory or systemic disease, or in association with blood abnormalities (gammopathies) or infections (including HIV infection).\nDiagnostic methods\nDiagnosis is made on the basis of the clinical presentation and after histological analysis of skin biopsies by a dermatopathologist.\nDifferential diagnosis\nEED should be distinguished from other types of papular or nodular dermatoses, as well as fibrous tumors and xanthomas.\nManagement and treatment\nManagement includes a complete clinical examination by a dermatologist, together with screening for infections, digestive disorders, and gammopathies (serum electrophoresis). Dapsone is the first line of treatment for EED. Treatment must be monitored clinically and by blood examination. In cases were dapsone is inefficient or poorly tolerated, other drugs may provide an effective treatment.\nPrognosis\nAlthough EED is a chronic condition, it is usually sensitive to treatment and the prognosis is good.\n\n                            Last update: \n                            September 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Daniel WALLACH"}
{"Disease Name": "Erythema multiforme major", "Disease Definition": "A rare skin disease characterized most typically by targetoid papules with 3-rings of concentric color variation (dark center, surrounded by lighter pink ring and an outer red ring) symmetrically distributed on the extensor surfaces of the extremities, or more diffuse, accompanied by 2 or more mucosal involvements (erosions of the oral, genital, anal mucosa, conjunctivitis, pseudomembranes). The condition is commonly proceeded by prodromal symptoms of malaise, fever, and myalgias, and is usually self-limiting, resolving within a few weeks; although, there is a risk of recurrence. The disease is mostly triggered by infectious agents (herpes virus, mycoplasma pneumoniae) but a subset of patients have auto-antibodies targeting plakins. Rare cases of severe mucosal sequelae have been described.", "ORPHA ID": 502499, "Summary": ""}
{"Disease Name": "Erythema palmare hereditarium", "Disease Definition": "Erythema palmare hereditarium is a rare, benign, congenital genetic skin disorder characterized by permanent and asymptomatic erythema of the palmar and, less frequently, the solar surfaces. In most cases, it presents with sharply demarcated redness of the thenar and hypothenar eminences, as well as the palmar aspect of the phalanges, with scattered telangiectasia spots that do not cause any discomfort (pain, itching or burning) to the patient.", "ORPHA ID": 231031, "Summary": ""}
{"Disease Name": "Erythroderma desquamativum", "Disease Definition": "A rare immune deficiency with skin involvement characterized by early infantile onset of a clinical tetrad comprising generalized severe seborrheic-like erythroderma, recurrent secondary bacterial or fungal infections (most commonly Staphylococcus aureus, Candida, and gram-negative bacteria), persistent, profuse malabsorptive diarrhea, and failure to thrive or marked wasting. Associated systemic symptoms include fever, anemia, and weight loss. Further critical complications are impaired thermoregulation and severe fluid loss due to extensive exfoliation.", "ORPHA ID": 314, "Summary": ""}
{"Disease Name": "Erythrokeratoderma ''en cocardes''", "Disease Definition": "A rare, genetic, epidermal disorder characterized by intermittent (remitting and recurring), annular, polycyclic, target-like (or 'en cocardes') plaques with concentric rings of scaling erythema occurring on the extremities, flexural areas, and trunk. Concurrent erythrokeratoderma variabilis-like scaly plaques are commonly found in other parts of the body.", "ORPHA ID": 315, "Summary": ""}
{"Disease Name": "Erythrokeratoderma variabilis progressiva", "Disease Definition": "Erythrokeratoderma variabilis progressiva (EKVP) is a type of erythrokeratoderma characterized by the association of hyperkeratosis and erythema in persistent, although sometimes variable, circumscribed lesions. Progressive symmetric erythrokeratoderma (PSEK) and erythrokeratoderma variabilis (EKV) are probably no longer two distinctive diseases but rather the two clinical manifestations of a same disease, now known as EKVP.", "ORPHA ID": 308166, "Summary": "Epidemiology\nErythrokeratoderma is a rare skin disease whose prevalence has recently been estimated at around 1/ 2, 000,000 people. Both sexes are affected equally.\nClinical description\nThe disease usually starts in the early months of life or later in infancy. Erythema at birth has been described. Patients present with well-demarcated, erythematous patches and hyperkeratotic plaques that are arranged symmetrically. The lesions favor the extensor surface of the upper and lower extremities, buttocks and face. The plaques tend to progress during childhood, with lesions stabilizing thereafter. Considerable clinical overlap exists between PSEK and EKV, the main distinguishing feature being the presence of migratory erythema in patients with EKV. The migratory aspects of the lesions may also change over time, according to lifetime periods. The palms and soles are usually normal but some patients may have palmoplantar keratoderma. Minimal pruritus may be noted. Improvement has rarely been reported.\nEtiology\nEKVP is caused by mutations in the connexin genes GJB4 (1p35-p34), coding for connexin-30.3 or GJB3 (1p34), coding for connexin-31. Connexins are proteins that form gap junctions that allow the transport and signaling between neighboring cells in the epidermis. Since other unrelated multiethnic patients were negative for connexin genes, new causal genes are yet to be discovered. De novo mutations in GJA1 (6q22.31) were also reporting as causing EKVP.\nDiagnostic methods\nDiagnosis is based on the presence of characteristic clinical features. The histopathological features are non-specific. Light microscopy, in the case of EKV, reveals orthokeratotic basket-weave hyperkeratosis, moderate to severe acanthosis with prominent granular layer, and papillomatosis; and in the case of PSEK, there is acanthosis of the epidermis with basket-weave and often patchy parakeratotic hyperkeratosis. The granular layer is prominent and sometimes shows intracellular vacuolization. Follicular plugging is not uncommon. Electron microscopy reveals, in the case of EKV, a reduced number of keratinosomes within the stratum granulosum and sometimes clumped tonofilaments; and in the case of PSEK, perinuclear vacuolization and lipid-like vacuoles or laminated inclusions in the stratum corneum, but these features are not diagnostic.\nDifferential diagnosis\nDifferential diagnosis includes other diseases with erythematous and hyperkeratotic lesions such as KID syndrome, keratoderma hereditarium mutilans with ichthyosis, pityriasis rubra pilaris and psoriasis.\nGenetic counseling\nThe majority of cases follow an autosomal dominant mode of inheritance but approximately 40% occur sporadically. Autosomal recessive inheritance has also been described and should be considered when providing genetic counseling, especially in consanguineous families.\nManagement and treatment\nTreatment is symptomatic. Emollients are often used but their efficacy is limited. Topical keratolytics or oral acitretin can reduce the thickness of the lesions. Isotretinoin has been used instead of acitretin in some cases.\nPrognosis\nEKVP is not a life threatening disease, but it may have an impact on the patient's quality of life and cause social handicap due to the skin's appearance. General health is unaffected.\n\n                            Last update: \n                            October 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Juliette MAZEREEUW-HAUTIER  - Dr Emilie TOURNIER"}
{"Disease Name": "Erythrokeratodermia-cardiomyopathy syndrome", "Disease Definition": "Erythrokeratodermia-cardiomyopathy syndrome is a rare, genetic erythrokeratoderma disorder characterized by generalized cutaneous erythema with fine white scales and pruritus refractory to treatment, progressive dilated cardiomyopathy, palmoplantar keratoderma, sparse or absent eyebrows and eyelashes, sparse scalp hair, nail dystrophy, and dental enamel anomalies. Variable features include failure to thrive, developmental delay, and development of corneal opacities. Histology shows psoriasiform acanthosis, hypogranulosis, and compact orthohyperkeratosis.", "ORPHA ID": 476096, "Summary": ""}
{"Disease Name": "Erythropoietic uroporphyria associated with myeloid malignancy", "Disease Definition": "A rare porphyria characterized by a pre-existing myeloid disorder, skin fragility and blistering on the exposed areas, and hemorrhagic bullae typically on the back of the hands. Urine, plasma and fecal porphyrins are increased.", "ORPHA ID": 280379, "Summary": ""}
{"Disease Name": "Esophageal atresia", "Disease Definition": "A rare congenital malformation characterized by an interruption in the continuity of the esophagus, with or without persistent communication with the trachea. The clinical presentation varies according to the anatomy, and can lead to the inability to swallow or, in the most severe cases, respiratory distress.", "ORPHA ID": 1199, "Summary": "Epidemiology\nEsophageal atresia (EA) occurs in approximately 1/5000 live births worldwide. The birth prevalence in Europe is slightly higher at 1/4,000.\nClinical description\nThe Gross classification describes five different types. Type A (1%) without fistula, type B (2%) with a fistula to upper esophageal pouch, type C (86%) with a fistula to distal esophageal pouch, type D (1%) with fistula to upper and distal esophageal pouch, and type E (4%) with an isolated fistula without interruption in the esophageal continuity. A distance between the two pouches corresponding to the height of three vertebra or more is classified as long-gap esophageal atresia. The newborn infants with EA are unable to swallow saliva and are noted to have excessive salivation requiring repeated suctioning in children with Gross type A, B and C. In Gross type D the respiratory distress and coughing will be the prevailing symptom. In the Gross type E (isolated fistula without esophageal interruption) episodes of choking and cyanosis on feeding to subtle symptoms of wheezing and recurrent respiratory infections in neonatal or childhood may be seen.\nEtiology\nThe etiology is largely unknown and is likely to be multifactorial. Genomic analysis have identified de novo variants in protein-coding regions in different gene loci.\nDiagnostic methods\nThe likelihood of an atresia is increased by the presence of polyhydramnios. Inserting a nasogastric tube at birth allows the diagnosis to be confirmed or excluded and should be performed in all infants born to a mother with polyhydramnios, as well as in infants who produce excessive mucus soon after delivery. In EA, the tube will not progress beyond 10 cm from the mouth. Further confirmation is obtained by plain X-ray of the chest and abdomen. In patients with Gross type E the diagnosis may be confirmed by bronchoscopy or esophageal contrast studies.\nDifferential diagnosis\nIn 50% of cases, EA is associated with other anomalies, the majority involving one or more of the VACTERL association anomalies (vertebral, anorectal, cardiac, tracheoesophageal, renal and limb defects).\nAntenatal diagnosis\nThe diagnosis may be suspected prenatally by a small or absent stomach bubble on ultrasound scan at around 18 weeks of gestation. The likelihood of an atresia is increased by the presence of polyhydramnios. Magnetic resonance imaging (MRI) has the highest diagnostic sensitivity and specificity.\nGenetic counseling\nThe vast majority of cases are sporadic and the recurrence risk for siblings is 1%.\nManagement and treatment\nDefinitive management involves disconnection of the tracheooesophageal fistula, closure of the tracheal defect and primary anastomosis of the esophagus during the neonatal period. Delayed primary repair should be attempted when there is a 'long gap' between the ends of the esophagus. Various traction methods have been developed to increase the length of the pouches to facilitate a primary anastomosis. If it fails, organ replacement (stomach, jejunum or colon) may be necessary. In Gross type E, the fistula must be transected and closed. Open surgical or endoscopic (thoracoscopic) procedures may be used. Anastomotic stenosis and leakage are the most common postoperative complications and are usually handled endoscopically.\nPrognosis\nSurvival is directly related to birth weight and to the presence of a major cardiac defect. Infants weighing over 1500 g and having no major cardiac problems have a near 100% survival rate, but the survival rate decreases in the presence of additional risk factors. Dysphagia and gastroesophageal reflux disease are common long-term sequelae.\n\n                            Last update: \n                            May 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Niels QVIST | ERNICA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Esophageal duplication cyst", "Disease Definition": "A rare, congenital, non-syndromic esophageal malformation characterized by tubular or spherical cystic masses that have a double layer of surrounding smooth muscle lined with squamous or enteric epithelium, and are continuous or contiguous to the esophagus. The cyst is typically distally located and may or may not communicate with the esophageal lumen. Most become symptomatic presenting with a wide range of symptoms including dysphagia, non-productive cough, chest pain or failure to thrive. Others like palpitations due cardiac arrhythmia, thoracic back pain, and fever due to mediastinitis, have also been reported.", "ORPHA ID": 100047, "Summary": ""}
{"Disease Name": "Essential fructosuria", "Disease Definition": "Essential fructosuria is a rare autosomal recessive disorder of fructose metabolism (see this term) caused by a deficiency of fructokinaseenzyme activity. It is characterized by elevated fructosemia and presence of fructosuria following ingestion of fructose and related sugars (sucrose, sorbitol). Essential fructosuria is clinically asymptomatic and harmless. Dietary restriction is not indicated.", "ORPHA ID": 2056, "Summary": ""}
{"Disease Name": "Essential iris atrophy", "Disease Definition": "A clinical variant of iridocorneal endothelial (ICE) syndrome, characterized by progressive iris atrophy and holes present on the surface of the iris, corneal edema, corectopia, uveal ectropion and anterior synechiae. Secondary glaucoma is also a common complication of the disease.", "ORPHA ID": 98981, "Summary": ""}
{"Disease Name": "Essential thrombocythemia", "Disease Definition": "Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN, see this term) characterized by a sustained elevation of platelet number (> 450 x 109/L) with a tendency for thrombosis and hemorrhage.", "ORPHA ID": 3318, "Summary": "Epidemiology\nPrevalence is estimated at 1/4,200 in the US and is reported at 1/3,333 in Sweden. Median age at diagnosis is 60-65 years, but the disease may occur at any age, with another peak in incidence in younger women. The female to male ratio is about 2:1.\nClinical description\nThe clinical picture is dominated by a predisposition to vascular occlusive events and hemorrhages. Some patients with ET are asymptomatic, while others may experience microcirculatory disturbances or vasomotor events: headaches, visual disturbances, lightheadedness, atypical chest pain, distal paresthesias, erythromelalgia, and other symptoms of transient neurological ischemia. Less frequently ET is associated with an increased risk of hemorrhage. Main risks for patients include thromboses (arterial and venous), which can induce severe neurological, cardiac or peripheral artery manifestations. Transformation to myelofibrosis (see this term) or acute leukemia is possible in a small proportion of patients on the long term.\nEtiology\nSomatic mutations in the JAK2 gene are the most common genetic alterations found in ET. Mutations in  LNK  gene down regulate JAK2 pathway and can be causative. Mutations in MPL gene has also been found in cases of ET with myeloproliferation. Recently mutations in  CALR  have been identified in many patients who were negative for JAK2  and  MPL. The detailed pathogenic mechanism is unknown. Although ET is usually an acquired (non hereditary) disease, a familial form, primary familial thrombocytosis (see this term) has also been observed.\nDiagnostic methods\nDiagnosis is based on a sustained high level of platelets (over 450x109/L) in the absence of reactive causes (like iron deficiency or inflammation, see below), evidence of a clonal marker (somatic mutation in JAK2, CALR , MPL  or other genes involved in MPN pathogenesis), bone marrow showing increased megakaryocytes with large and mature morphology with no increase in reticulin and an absence of MPN among relatives to rule out primary familial polycythemia (see this term).\nDifferential diagnosis\nDifferential diagnoses include the other myeloproliferative neoplasms (polycythemia vera, primary myelofibrosis, chronic myeloid leukemia; see these terms), myeloid malignancies (myelodysplastic syndrome), causes of secondary thrombocytosis (inflammation, cancer, iron deficiency, asplenia) and primary familial thrombocytosis (see this term).\nManagement and treatment\nManagement is currently based on the risk of thrombosis, and may involve anti-aggregation therapy and/or platelet cytoreduction. Hydroxycarbamide and aspirin are effective in high risk patients. Anagrelide is approved in European Union as platelet lowering agent in patients resistant or intolerant to hydroxycarbamide. Conventional and pegylated recombinant interferon alpha (IFN) are effective in controlling platelet counts, although there is no evidence of efficacy in preventing thrombosis and could be preferred to conventional cytoreductive therapies in younger patients. Risk factors associated with arteriosclerotic disease (hypertension, diabetes, smoking etc) must be actively managed. Conventional cytoreductive therapies are contra-indicated in pregnancy.\nPrognosis\nOverall survival is similar to that of a healthy population matched by age and sex during the first decade after diagnosis and may differ thereafter (due to disease complications such as thrombosis, transformation to myelofibrosis, acute leukemia or myelodysplasia). When properly managed and carefully followed, life expectancy of ET patients can be similar to that of general population.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Jacques KILADJIAN"}
{"Disease Name": "Esthesioneuroblastoma", "Disease Definition": "Esthesioneuroblastoma (ENB) is a rare malignant neoplasm of the sinonasal cavity, arising from the basal layers of olfactory neuroepithelial cells in the superior nasal vault, which usually occurs in the 5th to 6th decades of life and is characterized clinically by non-specific symptoms such as progressive ipsilateral nasal block, sinusitis, facial pain, intermittent headaches, hyposmia/dysosmia, rhinorrhea and epistaxis as well as proptosis, diplopia and excessive lacrimation due to orbital extension. With early treatment and in the absence of distant metastases, ENB appears to have a good prognosis (compared to other superior nasal malignancies), despite a high rate of cervical metastases.", "ORPHA ID": 1957, "Summary": ""}
{"Disease Name": "Estrogen resistance syndrome", "Disease Definition": "Estrogen resistance syndrome is a rare, genetic endocrine disease characterized by estrogen-receptor insensitivity to estrogens and the presence of elevated estrogen and gonadotropin serum levels. Clinical manifestations include absent breast development and primary amenorrhea in association with multicystic ovaries and/or hypoplastic uterus in female patients, normal or abnormal gonadal development in male patients and markedly delayed bone maturation, persistence of open epiphyses, reduced bone mineral density, and variable tall stature in both sexes. Glucose intolerance, hyperinsulinemia and lipid abnormalities may also be present.", "ORPHA ID": 785, "Summary": ""}
{"Disease Name": "Ethylene glycol poisoning", "Disease Definition": "A rare poisoning resulting in elevated anion gap metabolic acidosis, due to the production of glycolic acid, glyoxylic acid, and oxalic acid by alcohol dehydrogenase (ADH) in the liver when ethylene glycol is metabolized, characterized initially by euphoria, slurred speech, encephalopathy, coma and seizures, and followed by late manifestations such as tachycardia, arrhythmias, myocardial depression, hemodynamic imbalance and, finally, acute renal failure.", "ORPHA ID": 31826, "Summary": ""}
{"Disease Name": "Ethylmalonic encephalopathy", "Disease Definition": "A rare, early-onset, progressive neurologic disease characterized by elevated excretion of ethylmalonic acid (EMA) with recurrent petechiae, orthostatic acrocyanosis and chronic diarrhea associated with neurodevelopmental delay, psychomotor regression and hypotonia with brain magnetic resonance imaging (MRI) abnormalities.", "ORPHA ID": 51188, "Summary": "Epidemiology\nMore than 70 cases have been described in the literature so far.\nClinical description\nThe disease manifests at birth or in the first few months of life with neurological, intestinal and vascular manifestations. Neurological symptoms include progressive encephalopathy, developmental delay, hypotonia, seizures and movement disorders. MRI abnormalities include symmetric patchy T2-weighted signals in the basal ganglia, periventricular white matter and dentate nuclei, brain stem, and cerebellar white matter. In some instances, cortical atrophy and diffuse leukoencephalopathy are present. Common gastrointestinal signs are chronic hemorrhagic diarrhea and failure to thrive. Vascular lesions include petechial purpura and orthostatic acrocyanosis. Spastic tetraplegia may be present. In addition to increased excretion of EMA, methylsuccinic acid, thiosulphate and C4-C6-acylglycines (isobutyryl-, isovaleryl-, 2-methylbutyryl-, hexanoylglycine) may also be found in small, but elevated, amounts in the urine. Blood levels of lactic acid and C4-C5-acylcarnitines may be elevated.\nEtiology\nEE is inherited in an autosomal recessive manner and is caused by variants of the ETHE1 gene (chromosome 19q13), encoding a mitochondrial sulfur dioxygenase (SDO) involved in the catabolic oxidation of hydrogen sulfide (H2S) to sulfate.\nDiagnostic methods\nDiagnosis is based on clinical examination, urinalysis, blood test, brain MRI and genetic analysis. As a large number of different disease-causing variants have been identified, DNA sequencing of all seven exons of the ETHE1 gene is necessary for the molecular diagnosis. The diagnosis of EE due to ETHE1 variants is clear if homozygosity (which should be confirmed by genotyping of the parents) or compound heterozygosity are present in the patient.\nDifferential diagnosis\nIn some cases, the urine and blood patterns identified in EE patients may resemble those seen in multiple acyl-CoA dehydrogenase deficiency (MADD or glutaric aciduria type 2) but in others they resemble those seen in short chain acyl-CoA dehydrogenase deficiency (SCADD), where the only abnormalities seen may be elevated EMA in urine with or without blood elevation of butyryl-carnitine. It seems, at least in severe cases, that the clinical picture of recurrent petechiae, orthostatic acrocyanosis and chronic diarrhea is specific for EE. However, more cases need to be identified before it can be determined whether milder cases of EE exist with clinical features like MADD or SCADD. In the absence of any detectable ETHE1 gene variant, molecular analysis should include sequencing of the SCAD gene (for variants which lead to SCADD) and, eventually, of the two-electron transfer flavoprotein (ETFA and ETFB) genes and the ETFDH gene (one of which may carry variants in patients with MADD).\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nAt the moment, no treatment approved by the FDA or EMA exists. Treatment is primarily supportive including antispastic medications, muscle relaxants, and anti-seizure medication. L-carnitine, riboflavin and/or Q10 supplements, as well as other vitamin therapies, may improve energy metabolism and alleviate oxidative stress. N-acetylcysteine (NAC) in combination with metronidazole are the only drugs known to slow disease progression and improve the metabolic abnormalities of EE. NAC, a cell-permeable precursor of glutathione, is the physiologic acceptors of the sulfur atom of hydrogen sulfide (H2S), which has deficient clearance in persons with EE. Metronidazole is an anaerobic bactericide, which can reduce the sulfide-producing bacterial load in the large intestine. Liver transplantation has been proposed and used in few cases with the aim to restore the liver ability to scavenge the most of the circulating H2S from intestinal blood.\nPrognosis\nThe prognosis is generally poor: although milder chronic cases are known, most patients die before the age of 10 years.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Ivano DI MEO  - Dr Valeria TIRANTI | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "Euryblepharon", "Disease Definition": "Euryblepharon is a rare congenital eyelid anomaly of unknown etiology characterized by the bilateral horizontal enlargement of the palpebral fissure with vertically shortened eyelids, lateral canthus malpositioning and lateral ectropion. It may be isolated or associated with other ocular anomalies (e.g. strabismus or telecanthus; see this term) or systemic anomalies (e.g. blepharo-cheilo-odontic syndrome, see this term). In severe cases, it may result in lagophthalmos and exposure keratopathy, requiring surgical treatment.", "ORPHA ID": 99172, "Summary": ""}
{"Disease Name": "Euthyroid dysprealbuminemic hyperthyroxinemia", "Disease Definition": "A rare genetic endocrine disease characterized by increased affinity of a mutated transthyretin for T4. Total and free T4 may be normal or elevated, but affected individuals are clinically euthyroid.", "ORPHA ID": 597939, "Summary": ""}
{"Disease Name": "Euthyroid Graves orbitopathy", "Disease Definition": "A rare ophthalmic disorder characterized by clinical signs of Graves orbitopathy (i. e. unilateral or bilateral lid retraction, exophthalmos, soft tissue involvement, restrictive myopathy, and/or optic neuropathy) with normal thyroid function and without any signs of hyperthyroidism. Laboratory examination typically reveals low serum levels of thyroid-stimulating hormone receptor autoantibodies.", "ORPHA ID": 466682, "Summary": ""}
{"Disease Name": "Evans syndrome", "Disease Definition": "A rare chronic hematologic disorder characterized by the simultaneous or sequential association of autoimmune hemolytic anemia (AIHA; a disorder in which auto-antibodies are directed against red blood cells causing anemia of varying degrees of severity) with immune thrombocytopenic purpura (ITP; a coagulation disorder in which auto-antibodies are directed against platelets causing hemorrhagic episodes) and occasionally autoimmune neutropenia, in the absence of a known underlying etiology.", "ORPHA ID": 1959, "Summary": "Epidemiology\nThe prevalence in Europe is estimated at 1/1,000,000 but there are no robust epidemiological data available.\nClinical description\nThe syndrome can manifest both in childhood or adulthood. Episodes of thrombocytopenia may precede, occur concurrently with (50% of cases), or follow episodes of AIHA. The severity of symptoms and the delay between episodes of AIHA and/or ITP is variable. In non simultaneous cases in adults, the delay between the episodes is on average of 4 years. ITP is often revealed by mucocutaneous hemorrhage with epistaxis, petechiae, purpura, and ecchymoses. In case of severe thrombocytopenia, hematuria, gastrointestinal and/or cerebromeningeal hemorrhage may be observed in rare cases. AIHA manifests as an unusual weakness, pallor, fatigue with tachycardia and exertional dyspnea, and also in some cases jaundice, dark urine and/or splenomegaly.\nEtiology\nEvans syndrome is an autoimmune disorder in which non-cross-reacting autoantibodies are targeted towards different antigenic determinants on red cells, platelets, sometimes neutrophils; however, the exact pathophysiologic mechanism is unknown. Because of the observation of a decrease in T-helper and an increase in T-suppressor lymphocyte population, it is suggested that the cytopenia may be related to T-cell abnormalities. Evans syndrome is frequently associated with other diseases, such as systemic lupus erythematosus, antiphospholipid syndrome, autoimmune lymphoproliferative syndrome, and common variable immunodeficiency (see these terms), which could point to a common cellular and humoral abnormality.\nDiagnostic methods\nDiagnosis is based on a complete blood count showing anemia (hemoglobin level <12g/dL) and thrombocytopenia (platelet count <100,000/microL), associated or not with neutropenia (neutrophil count <1500/microL). A raised lactate dehydrogenase (LDH) and/or direct bilirubin level, and a decreased haptoglobin level indicate hemolysis. A positive direct antiglobulin test (Coombs test) confirms the presence of antibodies targeting red blood cells (RBCs) antigens. The presence of autoantibodies targeting both platelets and neutrophils cans also be observed.\nDifferential diagnosis\nDifferential diagnosis mainly includes microangiopathies such as thrombotic thrombocytopenic purpura, and typical or atypical hemolytic uremic syndrome (see these terms).\nGenetic counseling\nMost of the cases are sporadic. Familial cases have exceptionally been observed, mainly in the setting of an underlying primary immunodeficiency.\nManagement and treatment\nImmunosuppressive therapy combined or not with intravenous immunoglobulin for ITP constitutes the first-line treatment. Administration of corticosteroids (prednisone) is the mainstay of treatment but other drugs can be prescribed for refractory cases such as rituximab, cyclosporine, azathioprine, cyclophosphamide, and danazol. Splenectomy is performed as a third-line treatment; however long-term remission is less frequent and patients show a high risk of sepsis. In severe cases, hematopoietic stem cell transplantation may be required.\nPrognosis\nEvans syndrome is a chronic disease with alternating periods of remission and relapse of AIHA and/or ITP despite treatment, which can be associated with significant morbidity and mortality due to severe hemorrhage and infections in case of severe thrombocytopenia and neutropenia.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Marc MICHEL"}
{"Disease Name": "EVEN-plus syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by epiphyseal and vertebral dysplasia and abnormalities of the external ears (severe microtia or anotia) and the nose (hypoplastic nose with bifid tip, triangular nares, or anteverted nares). Additional variable findings include short stature, localized aplasia cutis, hypodontia, synophrys, agenesis of the corpus callosum, and cardiac, gastrointestinal, and/or urogenital malformations, among others. Psychomotor development may be delayed.", "ORPHA ID": 496751, "Summary": ""}
{"Disease Name": "Exercise-induced hyperinsulinism", "Disease Definition": "A rare form of congenital diazoxide-sensitive diffuse hyperinsulinism characterized by episodes of hypoglycemia induced by exercise due to an inappropriate lactate and pyruvate sensitivity in pancreatic beta-cells. Presentation is of recurring episodes of hypoglycemia associated with elevated insulin levels, within 30 minutes of a short period of anaerobic exercise. The degree of hypoglycemia associated with exercise is variable and is only partially responsive to diazoxide.", "ORPHA ID": 165991, "Summary": ""}
{"Disease Name": "Exercise-induced malignant hyperthermia", "Disease Definition": "A rare disease with malignant hyperthermia characterized by exercise-induced life-threatening hyperthermia with a body temperature over 40°C and signs of encephalopathy ranging from confusion to convulsions or coma. Incidence increases with rising ambient temperature and relative humidity. Manifestations may include rhabdomyolysis (presenting with myalgia, muscle weakness, and myoglobinuria), tachycardia, and in severe cases multiorgan failure.", "ORPHA ID": 466650, "Summary": ""}
{"Disease Name": "Exfoliative ichthyosis", "Disease Definition": "Exfoliative ichthyosis is an inherited, non-syndromic, congenital ichthyosis disorder characterized by the infancy-onset of palmoplantar peeling of the skin (aggravated by exposure to water and by occlusion) associated with dry, scaly skin over most of the body. Pruritus and hypohidrosis may also be associated. Well-demarcated areas of denuded skin appear in moist and traumatized regions and skin biopsies reveal reduced cell-cell adhesion in the basal and suprabasal layers, prominent intercellular edema, numerous aggregates of keratin filaments in basal keratinocytes, attenuated cornified cell envelopes, and epidermal barrier impairment.", "ORPHA ID": 289586, "Summary": ""}
{"Disease Name": "Exostoses-anetodermia-brachydactyly type E syndrome", "Disease Definition": "An association reported in a single kindred characterized by the variable presence of the following features: anetodermia (macular atrophy of the skin), multiple exostoses, and brachydactyly type E. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 1962, "Summary": ""}
{"Disease Name": "Exstrophy-epispadias complex", "Disease Definition": "Exstrophy-Epispadias Complex (EEC) represents a spectrum of genitourinary malformations ranging in severity from epispadias (E) and classical bladder exstrophy (CEB) to exstrophy of the cloaca (EC) as the most severe form (see these terms). Depending on severity, the EEC may involve the urinary system, the musculoskeletal system, the pelvis, the pelvic floor, the abdominal wall, the genitalia and sometimes the spine and the anus.", "ORPHA ID": 322, "Summary": "Epidemiology\nThe prevalence at birth for the whole spectrum is reported at 1/10,000, ranging from 1/30,000 for CEB to 1/200,000 for EC, with an overall greater proportion of affected males.\nClinical description\nEEC is characterized by a visible defect of the lower abdominal wall, either with an evaginated bladder plate (CEB), or with an open urethral plate in males or a cleft in females (E). Urine drips from the ureteric orifices, visible on the bladder surface or per urethram. In the rare cases of CE, two exstrophied hemibladders, as well as omphalocele, an imperforate anus and spinal defects, can be seen after birth. Atypical forms of the EEC (duplicated exstrophy, covered exstrophy and pseudo-exstrophy) have also been described. EEC results from mechanical disruption or enlargement of the cloacal membrane, which prevents the invasion of mesodermal cells along the infraumbilical midline and thereby results in exstrophy. The timing of the rupture determines the severity of the malformation.\nEtiology\nThe underlying cause remains unknown: rare cases of familial occurrence have been reported and both genetic and environmental factors are likely to play a role in the etiology of EEC.\nDiagnostic methods\nDiagnosis at birth is made on the basis of the clinical presentation but EEC may be detected prenatally during careful ultrasound examinations with the index finding of repeated non-visualization of a normally filled fetal bladder.\nGenetic counseling\nExtensive counseling should be provided to parents but due to a generally favorable outcome with appropriate surgical management, termination of the pregnancy should no longer be systematically recommended.\nManagement and treatment\nManagement is primarily surgical, with the main aims of obtaining secure abdominal wall closure, achieving urinary continence with preservation of renal function, and, finally, adequate cosmetic and functional genital reconstruction. Currently, several methods for bladder reconstruction with creation of an outlet resistance (either as a staged or a one-stage approach) during the newborn period are favored worldwide. Removal of the bladder template with complete urinary diversion to a rectal reservoir can be an alternative. After reconstructive surgery of the bladder, continence rates of about 80% are expected during childhood. Though spontaneous voiding is the main issue, additional surgery might be needed to optimize bladder storage and emptying function. In cases of definite reconstruction failure, urinary diversion should be undertaken. In puberty, genital and reproductive functions constitute increasingly important issues for both sexes. Psychosocial and psychosexual outcome reflect the importance of long-term care (from birth into adulthood) from a multidisciplinary team of experts for parents and children with EEC to facilitate an adequate quality of life.\n\n                            Last update: \n                            October 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Anne-Karoline EBERT  - Dr Michaël LUDWIG  - Pr Heiko REUTTER  - Pr Wolfgang RÖSCH"}
{"Disease Name": "Extensive peripapillary myelinated nerve fibers", "Disease Definition": "A rare ophthalmic disorder characterized by visual abnormalities (such as myopia, strabismus, or amblyopia) due to the presence of myelinated retinal nerve fibers, which appear as whitish patches with feathery edges at the level of the retinal nerve fiber layer and may be continuous or discontinuous with the optic nerve head. The defect can be unilateral or bilateral.", "ORPHA ID": 440724, "Summary": ""}
{"Disease Name": "Extensor tendons of finger anomalies", "Disease Definition": "Extensor tendons of finger anomalies is a rare, genetic, congenital limb malformation characterized by bilateral anomalous attachment of the extensor tendons of the four ulnar fingers. Attachment occurrs to the medial and lateral aspects of the middle phalanges leading to constant flexion in the midphalangeal joints and inability to extend the fingers. There have been no further descriptions in the literature since 1980.", "ORPHA ID": 3294, "Summary": ""}
{"Disease Name": "External auditory canal aplasia/hypoplasia", "Disease Definition": "A rare, otorhinolaryngological malformation characterized by failure in development of the external ear canal resulting in variable degree of malformations ranging from complete absence to mild stenosis and malformation of the middle ear. It is typically unilateral, it manifests with hearing loss on the affected side, and might be associated with microtia or hypoplastic pinna, an aberrant facial nerve course, and cholesteatoma.", "ORPHA ID": 141074, "Summary": ""}
{"Disease Name": "External auditory canal atresia-vertical talus-hypertelorism syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by the triad: congenital, bilateral, symmetrical, subtotal, external auditory canal atresia, bilateral vertical talus and increased interocular distance.", "ORPHA ID": 3023, "Summary": ""}
{"Disease Name": "Extracranial carotid artery aneurysm", "Disease Definition": "A rare vascular anomaly characterized by dilation of the internal or the common carotid artery greater than 150% of the diameter of the normal, healthy vessel. Lesions of the carotid bifurcation are typically fusiform, degenerative in nature, and may occur bilaterally, while saccular aneurysms are usually unilateral and mostly located in the middle segment of the internal carotid artery. Symptomatic patients may present with a palpable pulsating mass, local pain, cerebral ischemia, peripheral nerve dysfunction, stridor, or voice changes due to local compression.", "ORPHA ID": 494424, "Summary": ""}
{"Disease Name": "Extracutaneous mastocytoma", "Disease Definition": "A rare neoplastic disease characterized by a localized, unifocal, low-grade tumor composed of mature mast cells, without evidence of systemic mastocytosis or skin lesions. The tumor most commonly arises in the lung and shows a non-destructive growth pattern.", "ORPHA ID": 66662, "Summary": ""}
{"Disease Name": "Extragonadal germinoma", "Disease Definition": "A rare, malignant germ cell tumor that occur in the midline of the body as a result of abnormal germ cell migration during embryogenesis. Clinical manifestations are variable and depend on the location and size of the tumor. Central nervous system tumor might present with headache, visual disturbances, endocrine abnormalities, and signs of increased intracranial pressure. A mediastinal tumor commonly presents with chest pain, dyspnea, cough and fever. Abdominal mass with or without pain, backache and weight loss are common clinical presentations in retroperitoneal tumor.", "ORPHA ID": 182127, "Summary": ""}
{"Disease Name": "Extragonadal teratoma", "Disease Definition": "Extragonadal teratoma is an extremely rare, benign or malignant germ cell tumor characterized, clinically, by a teratoma presenting in an extragonadal location (e.g. retroperitoneum, mediastinum, craniofacial or sacrococcygeal region, intraosseous, solid organs) and, histologically, by displaying well-differentiated structures, as well as immature elements. Presenting symptoms are variable depending on size and location of tumor.", "ORPHA ID": 883, "Summary": ""}
{"Disease Name": "Extramammary Paget disease", "Disease Definition": "A rare skin tumor characterized by predominantly intraepithelial growth of an adenocarcinoma which may either arise primarily in the skin (primary extramammary Paget disease) or result from intraepithelial spread of a visceral carcinoma (secondary extramammary Paget disease). The lesion is typically located in the anogenital region, presenting as a scaly, oozing, pruritic or painful erythematous plaque often resembling eczema. It may exhibit an invasive component with a significant risk of lymph node metastasis.", "ORPHA ID": 2800, "Summary": ""}
{"Disease Name": "Extraneural perineurioma", "Disease Definition": "Extraneural perineurioma is a rare tumor of cranial and spinal nerves arising from peripheral nerve sheet and composed exclusively or predominantly of cells showing perineurial differentiation. It presents as a well-circumscribed, rarely encapsulated mass, not associated with a recognizable nerve, most commonly arising in the dermis and subcutis of the extremities or trunk, or, rarely, in deep soft tissue or skin (e.g., in the stomach, kidney, pancreas, maxillary sinus, mandible, bronchial tree and the face). The clinical presentation depends on the localization.", "ORPHA ID": 100002, "Summary": ""}
{"Disease Name": "Extranodal nasal NK/T cell lymphoma", "Disease Definition": "Extranodal nasal NK/T cell lymphoma (NKTCL) is a rare, malignant neoplasm mainly affecting men in the fifth decade of life, that usually arises in the nose, paranasal sinuses, orbits or upper airway, and that can present with a nasal mass, nasal bleeding, nasal obstruction, palate perforation (i.e. midline perforation of the hard palate), and mid-facial and/or upper airway destructive lesions. In advanced disease stages, which are associated with a poor prognosis, NKTCL may disseminate to other organs. A few cases of NKTCL presenting primarily in the lymph nodes have also been described.", "ORPHA ID": 86879, "Summary": ""}
{"Disease Name": "Extrapelvic endometriosis", "Disease Definition": "A rare, non-malformative gynecologic disease characterized by the presence of functional endometrial glands and stroma in extrapelvic locations, such as lungs, pleura, kidneys, bladder, abdominal wall, umbilicus, and cesarean section scar among others. Clinical manifestations are menstrually-related and depend on the location of the ectopic tissue, but in general include pain, mass/nodule, swelling and/or bleeding in the involved area.", "ORPHA ID": 137820, "Summary": ""}
{"Disease Name": "Extraskeletal Ewing sarcoma", "Disease Definition": "Extraskeletal Ewing sarcoma is a rare, poorly differentiated, highly malignant, soft tissue tumor, derived from neuroectoderm, that is morphologically indistinguishable from skeletal Ewing sarcoma but is located in extraosseous locations, with the most common being: chest wall, paravertebral region, abdominopelvic area (with predilection for the retroperitoneal space), gluteal region and lower extremities. Clinical presentation is highly variable and depends on tumor localization. Local recurrence is common and metastatic disease most frequently involves the bones and lungs.", "ORPHA ID": 370334, "Summary": ""}
{"Disease Name": "Extraskeletal myxoid chondrosarcoma", "Disease Definition": "A rare soft tissue sarcoma characterized by a lesion in the deep soft tissues of the proximal extremities and limb girdles, composed of malignant chondroblast-like cells arranged in cords, clusters, or networks, and an abundant myxoid matrix. The tumor is typically encased by a pseudocapsule and divided into multiple nodules by fibrous septa. Patients present with a soft tissue mass which can be painful and may ulcerate the skin or restrict range of motion if located next to joints. Despite prolonged survival, local recurrence and metastasis are frequent.", "ORPHA ID": 209916, "Summary": ""}
{"Disease Name": "Extrasystoles-short stature-hyperpigmentation-microcephaly syndrome", "Disease Definition": "Extrasystoles-short stature-hyperpigmentation-microcephaly syndrome is a rare, genetic, malformation syndrome with short stature characterized by microcephaly, borderline intellectual disability, hyperpigmentation of the skin, short stature, and ventricular extrasystoles. Cardiac syncope may also be associated. There have been no further descriptions in the literature since 1975.", "ORPHA ID": 1964, "Summary": ""}
{"Disease Name": "Extraventricular neurocytoma", "Disease Definition": "Extraventricular neurocytoma (EVN), a variant of central neurocytoma (see this term), is a rare neuronal neoplasm, composed of round cells with neuronal differentiation, which is located outside of the ventricular system, usually within the spinal cord or cerebral hemispheres and that manifests with headache, nausea, vomiting, complex partial seizures or focal neurological deficits. In some cases it may exhibit atypical features consistent with aggressive clinical behavior.", "ORPHA ID": 251927, "Summary": ""}
{"Disease Name": "Eyebrow duplication-syndactyly syndrome", "Disease Definition": "Eyebrow duplication-syndactyly syndrome is characterised by partial duplication of the eyebrows and syndactyly of the fingers and toes. It has been described in three patients (a brother and sister and an isolated case). Skin hyperelasticity, hypertrichosis and long eyelashes, and abnormal periorbital wrinkling were also reported in some of the patients. Transmission is autosomal recessive.", "ORPHA ID": 3172, "Summary": ""}
{"Disease Name": "F12-related hereditary angioedema with normal C1Inh", "Disease Definition": "A rare hereditary angioedema characterized by normal serum levels and function of C1 inhibitor, normal C1 activity, and, clinically, recurrent subcutaneous edema, abdominal pain attacks, and episodes of potentially life-threatening upper airway obstruction. The disorder occurs almost exclusively in women, and episodes are often precipitated or worsened by high estrogen levels (such as during pregnancy or treatment with oral contraceptives).", "ORPHA ID": 100054, "Summary": ""}
{"Disease Name": "Fabry disease", "Disease Definition": "A rare genetic, multisystemic lysosomal disease characterized by specific cutaneous (angiokeratoma), neurological (pain), renal (proteinuria, chronic kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular manifestations (transient ischemic attacks, strokes). The phenotypic expression depends on age of onset and, in females, the level of X-inactivation.", "ORPHA ID": 324, "Summary": "Epidemiology\nWorldwide, the average prevalence at birth is approximately 1/15,000, but Fabry disease is an underdiagnosed condition and the frequency may be higher.\nClinical description\nThe clinical picture covers a wide spectrum ranging from mild cases in some heterozygous females, to severe cases in classically affected hemizygous males with no residual alpha-galactosidase A activity. The classical form typically has onset in childhood and may have all the characteristic neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and cerebrovascular signs of the disease. Female patients may have very mild to severe symptoms. Pain is a common early symptom (chronic pain characterized by burning and tingling paresthesia and occasional episodic crises) but may wane in adulthood. Anhidrosis or hypohidrosis may occur causing heat and exercise intolerance. Other signs include angiokeratoma, corneal deposits, tinnitus, hearing loss, fatigue, cardiac and cerebrovascular abnormalities (left ventricular hypertrophy, arrhythmia), dyspnea, and chronic kidney disease. The later-onset form starts in adulthood and in such cases cardiac involvement is the prevailing feature.\nEtiology\nFabry disease is a disorder of glycosphingolipid metabolism caused by the functional deficiency of the lysosomal alpha-galactosidase due to pathogenic variants in the GLA gene (Xq21.3-q22). Deficient activity results in accumulation of globotriaosylceramide (Gb3) and its deacylated form, lyso-Gb3, within lysosomes which is then believed to trigger a cascade of cellular events.\nDiagnostic methods\nThe definitive laboratory diagnosis involves demonstration of marked enzyme deficiency in hemizygous males and identification of a pathogenic variant in GLA. Enzyme analysis may occasionally help to detect heterozygotes but is often inconclusive due to X-chromosomal inactivation, making molecular testing (GLA genotyping) of females mandatory.\nDifferential diagnosis\nIn childhood, other possible causes of pain such as rheumatoid arthritis and \"growing pains\" must be ruled out. In adulthood, multiple sclerosis and irritable bowel syndrome (IBS) are occasionally considered.\nAntenatal diagnosis\nPrenatal diagnosis, available by determination of DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses (after non-invasive prenatal testing for fetal sex determination). Pre-implantation genetic diagnosis is possible.\nGenetic counseling\nThe pattern of inheritance is X-linked. The existence of atypical, later-onset, variants and the availability of specific therapies for Fabry disease should be considered when delivering genetic counseling.\nManagement and treatment\nA disease-specific therapeutic option (enzyme replacement therapy using in vitro engineered alpha-galactosidase A) has been available since 2001 and meta-analyses of its long-term efficacy suggest promising outcomes. Enzyme enhancement with a pharmacological chaperone is approved in patients with amenable GLA variants following recent clinical trials. Plant-derived enzyme replacement therapy, substrate reduction therapy (SRT) and gene therapy using adeno-associated viral vectors are currently under investigation in clinical trials. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors or angiotensin receptors blockers), antiarrhythmic agents, pace-maker or implantable cardioverter defibrillator, dialysis, and kidney transplant.\nPrognosis\nWith age, progressive damage to tissues develops, leading to organ failure. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit the life-expectancy of untreated males and females versus the general population.\n\n                            Last update: \n                            March 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Dominique GERMAIN"}
{"Disease Name": "Facial arteriovenous malformation", "Disease Definition": "Facial arteriovenous malformation is a rare vascular anomaly characterized by abnormal communication between arteries and veins, bypassing the capillary bed, located in the facial area. Lesions may be asymptomatic or may manifest with pain, ulceration, pulsation, tinnitus, minor bleeding or potentially life-threatening hemorrhage, blurred vision, impaired hearing, headache, paresthesia, enlargement of facial bones with intraosseous lesions, intraosseous hemangiomas, and speech, breathing and swallowing difficulties, as well as neuropathy.", "ORPHA ID": 156230, "Summary": ""}
{"Disease Name": "Facial dermoid cyst", "Disease Definition": "Facial dermoid cyst is a rare, benign cutaneous neoplasm containing keratinized epithelium and dermal derivatives, such as hair follicles, sweat and sebaceous glands, smooth muscle or fibroadipose tissue, which usually manifests as a firm, nonpulsatile mass, often with a sinus opening or a hair-bearing punctum, most commonly located in the periorbital and nasal area.", "ORPHA ID": 141051, "Summary": ""}
{"Disease Name": "Facial diplegia with paresthesias", "Disease Definition": "A rare localized variant of Guillain-Barré syndrome characterized by rapidly progressive bilateral facial nerve palsy, distal paresthesias, and minimal or no motor weakness. Deep tendon reflexes are usually diminished or absent but can be present or even exaggerated in rare cases. CSF analysis may reveal albuminocytologic dissociation. Nerve conduction velocity studies often show demyelinating type of neuropathy, although axonal polyneuropathy has been also described.", "ORPHA ID": 480701, "Summary": ""}
{"Disease Name": "Facial dysmorphism-anorexia-cachexia-eye and skin anomalies syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by facial dysmorphism (mild eyelid ptosis, xanthelasma, anterverted nostrils, bifid nasal tip, short palate), severe muscle wasting and cachexia, retinitis pigmentosa, numerous lentigines and café-au-lait spots, as well as mild, soft tissue syndactyly. Additional features include nasal speech, chest asymmetry, pectus excavatum, genu varum, pes planus, and thyroid papillary carcinoma and diffuse enlargement. There have been no further description in the literature since 1984.", "ORPHA ID": 1969, "Summary": ""}
{"Disease Name": "Facial dysmorphism-developmental delay-behavioral abnormalities syndrome due to 10p11.21p12.31 microdeletion", "Disease Definition": "A rare, genetic syndromic intellectual disability characterized by developmental delay, hypotonia, speech delay, mild to moderate intellectual disability, abnormal behavior (autistic, aggressive, hyperactive) and dysmorphic facial features, including synophrys or thick eyebrows, deep set eyes, bulbous nasal tip and full cheeks. Congenital heart and brain anomalies, visual and hearing impairment are also common.", "ORPHA ID": 284169, "Summary": ""}
{"Disease Name": "Facial dysmorphism-hypertrichosis-epilepsy-intellectual disability/developmental delay-gingival overgrowth syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by variable intellectual disability and/or developmental delay, epilepsy, generalized hypertrichosis, severe gingival overgrowth and visual impairment in some patients. Common craniofacial features include bitemporal narrowing, bushy and straight eyebrows, long eyelashes, low-set ears, deep/short philtrum, everted upper lip, prominent upper and lower vermilion, wide mouth, micrognathia, and retrognathia.", "ORPHA ID": 598603, "Summary": ""}
{"Disease Name": "Facial dysmorphism-immunodeficiency-livedo-short stature syndrome", "Disease Definition": "Facial dysmorphism-immunodeficiency-livedo-short stature syndrome is a rare genetic disease characterized by facial dysmorphism with malar hypoplasia and high forehead, immunodeficiency resulting in recurrent infections, impaired growth (with normal growth hormone production and response) resulting in short stature, and livedo affecting face and extremities. Immunological analyses show low memory B-cell and naïve T cell counts, decreased T cell proliferation, and reduced IgM, IgG2 and IgG4 titers. Patients do not exhibit increased susceptibility to cancer.", "ORPHA ID": 352712, "Summary": ""}
{"Disease Name": "Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome", "Disease Definition": "Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome is a syndromic developmental defect of the eye characterized by dislocated or subluxated crystalline lenses, anterior segment abnormalities, and distinctive facial features such as flat cheeks and a prominent, beaked nose. Affected individuals may develop nontraumatic conjunctival cysts, also referred to as filtering blebs.", "ORPHA ID": 412022, "Summary": ""}
{"Disease Name": "Facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by severe intellectual deficit, Dandy-Walker malformation, macrocephaly, severe myopia, brachytelephalangy with short and broad fingernails, and dysmorphic facial features (such as thick eyebrows, synophrys, epicanthal folds, low-set ears, short philtrum, and high-arched palate). Additional reported manifestations include seizures and skeletal and genital anomalies, among others. There have been no further descriptions in the literature since 1989.", "ORPHA ID": 1970, "Summary": ""}
{"Disease Name": "Facial dysmorphism-ocular anomalies-osteopenia-intellectual disability-dental anomalies syndrome", "Disease Definition": "A rare, genetic developmental defect during embryogenesis disorder characterized by craniofacial dysmorphism (incl. brachycephaly, prominent forehead, sparse lateral eyebrows, severe hypertelorism, upslanting palpebral fissures, epicanthal folds, protruding ears, broad nasal bridge, pointed nasal tip, flat philtrum, anteverted nostrils, large mouth, thin upper vermilion border, highly arched palate and mild micrognathia) associated with osteopenia leading to repeated long bone fractures, severe myopia, mild to moderate sensorineural or mixed hearing loss, enamel hypoplasia, sloping shoulders and mild intellectual disability.", "ORPHA ID": 314555, "Summary": ""}
{"Disease Name": "Facial dysmorphism-shawl scrotum-joint laxity syndrome", "Disease Definition": "Facial dysmorphism-shawl scrotum-joint laxity syndrome is characterised by facial dysmorphism (hypertelorism, telecanthus, downslanting palpebral fissures, ptosis, malar hypoplasia, broad nasal bridge, thin upper lip, smooth philtrum, and low-set prominent ears) and associated with joint anomalies (genu valgum or cubitus valgus, hyper-extensible joints, etc.). It has been described in two patients (a mother and her son). The boy also had hypoplastic shawl scrotum and cryptorchidism, and the mother had mild intellectual deficit.", "ORPHA ID": 1778, "Summary": ""}
{"Disease Name": "Facial onset sensory and motor neuronopathy", "Disease Definition": "Facial onset sensory and motor neuronopathy is characterised initially by paraesthesia and numbness in the region of the trigeminal nerve distribution, which later progresses to involve the scalp, neck, upper trunk and upper limbs. Onset of motor manifestations occurs later with cramps, fasciculations, dysphagia, dysarthria, muscle weakness and atrophy. This syndrome has been described in four males and appears to be a slowly progressive neurodegenerative disease.", "ORPHA ID": 85162, "Summary": ""}
{"Disease Name": "Faciocardiorenal syndrome", "Disease Definition": "A very rare syndrome characterized by intellectual deficit, horseshoe kidney, and congenital heart defects.", "ORPHA ID": 1973, "Summary": "Epidemiology\nFour cases have been reported in the literature in two unrelated families.\nClinical description\nDysmorphic features include plagiocephaly, malar hypoplasia, broad nasal bridge, poorly developed philtrum and nasal alae, cleft palate and hypodontia. Congenital heart defects were endocardial fibroelastosis in one family and prolapse of the tricuspid valve in the other.\nGenetic counseling\nThe condition is probably hereditary, and transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            February 2010"}
{"Disease Name": "Facioscapulohumeral dystrophy", "Disease Definition": "A rare neuromuscular disease characterized by progressive muscle weakness with focal involvement of the facial, shoulder and limb muscles.", "ORPHA ID": 269, "Summary": "Epidemiology\nFacioscapulohumeral muscular dystrophy (FSHD) is a rare familial disease with an estimated prevalence from 1/8,000 to 1/20,000. It is the third most common form of hereditary myopathy.\nClinical description\nOnset occurs at any age. Disease progression is usually slow but some patients display periods of stability followed by periods of rapid deterioration. Early onset of FSHD is associated with more widespread muscle weakness. The initial manifestation is frequently facial weakness (difficulties whistling, smiling and closing the eyes) but the main complaint could be shoulder involvement (difficulties rising the arms, scapular winging and sloping shoulders). The disease progresses to include forearm weakness and wrist extension weakness. Abdominal and distal lower limb muscle, principally tibialis anterior, may also be affected early in the disease, while proximal lower leg muscles are affected later. Asymmetry of muscle involvement is frequently described. Significant clinical variability exists and atypical presentations have been reported. Sensory, cardiac and neurological signs may be present in rare cases.\nEtiology\nTwo genetic subtypes of FSHD have been identified: the classical form (FSHD1) which is associated with a pathogenic contraction of the D4Z4 repeat on a 4qA chromosome 4 and FSHD2 which is associated with mutations in SMCHD1 (18p11.32). In FSHD1, repeat contractions are associated with local hypomethylation and change in chromatin relaxation on chromosome 4 that increases the likelihood of toxic DUX4 (4q35.2) gene expression in skeletal muscle. In FSHD2, patients harboring mutation in SMCHD1 have a profound hypomethylation of chromosomes 4 and 10, allowing chromosome 4 to express the toxic DUX4 transcript.\nDiagnostic methods\nDiagnosis of FSHD1 is achieved by identification of a D4Z4 pathogenic contraction (D4Z4 repeat number less than 10) on the permissive 4qA allele of chromosome 4. In this situation, the residual number of D4Z4 units inversely correlates with severity. SMCHD1 mutations should be screened when FSHD phenotype is not associated with the D4Z4 pathogenic contraction and in FSHD1 families diagnosed with between 7 to 10 D4Z4 repeats and a severe phenotype.\nDifferential diagnosis\nAtypical cases should be accurately studied to exclude a concomitant pathology. Differential diagnosis mainly includes limb-girdle muscular dystrophy but also neuromuscular diseases presenting with scapular winging such as glycogen storage disease due to acid maltase deficiency, late-onset endocrine myopathy, inclusion body myopathy with Paget disease of bone and frontotemporal dementia, proximal neuropathies or neuronopathies.\nGenetic counseling\nTransmission is autosomal dominant in both FSHD1 and FSHD2. Penetrance in FSHD1 is incomplete and around 30% of carriers do not manifest the disease. Mosaicism may explain the occurrence of severe forms in children born to parents showing no signs of the disease. In some families, digenic inheritance of both FSHD1 and FSHD2 genetic conditions can modify the severity. Genetic counseling and prenatal diagnosis are therefore challenging.\nManagement and treatment\nTreatment is symptomatic, aiming towards prevention of joint stiffness and pain by passive mobilization and administration of antalgics. In severe cases, ventilator support may be required. Surgical treatment involves fixation of the scapula and may lead to an improvement in the range of motion of the arms.\nPrognosis\nPrognosis depends upon the extent of functional capacity loss. Life expectancy is not reduced unless respiratory functions are affected; however, this is a rare occurrence.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Sabrina SACCONI | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "FADD-related immunodeficiency", "Disease Definition": "FADD-related immunodeficiency is a rare genetic immunological disease reported in a single consanguineous Pakistani family with several affected members presenting with severe bacterial and viral infections, recurrent hepatopathy (portal inflammation, fibrosis), and recurrent, stereotypical febrile episodes, sometimes lasting several days, with encephalopathy and difficult-to-control seizures. Variable cardiac malformations were also reported. Although there were autoimmune lymphoproliferative syndrome (ALPS)-like biological features, clinical ALPS was not present. A homozygous missense mutation in the FADD gene (11q13.3) was found in the family and the disease is thought to follow an autosomal recessive pattern of inheritance.", "ORPHA ID": 306550, "Summary": ""}
{"Disease Name": "Fallot complex-intellectual disability-growth delay syndrome", "Disease Definition": "Fallot complex - intellectual deficit - growth delay is a rare disorder characterized by tetralogy of Fallot, minor facial anomalies, and severe intellectual deficiency and growth delay.", "ORPHA ID": 3304, "Summary": "Epidemiology\nTo date, five patients have been reported in two families.\nClinical description\nDysmorphic features include large, protruding, abnormally modeled ears and broad nasal root. Microcephaly and syndactyly of 2nd and 3rd toes have also been recorded. All five patients have severe intellectual deficiency.\nGenetic counseling\nThe condition is probably hereditary, and is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            April 2010"}
{"Disease Name": "Familial acute necrotizing encephalopathy", "Disease Definition": "Familial acute necrotizing encephalopathy or ADANE is a potentially fatal neurological disease characterised by neuropathological lesions principally involving the brainstem, thalamus and putamen.", "ORPHA ID": 88619, "Summary": "Epidemiology\nIt has been described in 11 members of one family.\nClinical description\nOnset occurs during early childhood, typically a few days after a febrile illness. Manifestations include vomiting, seizures, spasticity, language regression, rigidity and abnormal posturing of the head. Residual neurologic impairment (muscle weakness, speech disturbance, intellectual deficit and mood disorders) persists in some patients. The disease is chronic in one out of two cases.\nGenetic counseling\nThe mode of transmission appears to be autosomal dominant with incomplete penetrance.\n\n                            Last update: \n                            September 2007"}
{"Disease Name": "Familial adenomatous polyposis", "Disease Definition": "Familial adenomatous polyposis (FAP) is characterized by the development of hundreds to thousands of adenomas in the rectum and colon during the second decade of life.", "ORPHA ID": 733, "Summary": "Epidemiology\nFAP has a birth incidence of about 1/8,300, manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the EU, prevalence is estimated at 1/11,300-1/37,600.\nClinical description\nMost patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Generally, cancers start to develop a decade after appearance of the polyps. Nonspecific symptoms may include constipation or diarrhea, abdominal pain, palpable abdominal masses and weight loss. FAP may present some extraintestinal manifestations such as osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts and central nervous system). A less aggressive variant of FAP, attenuated FAP (AFAP; see this term), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk. Some lesions (skull and mandible osteomas, dental abnormalities, and fibromas on the scalp, shoulders, arms and back) are indicative of the Gardner syndrome, whereas the association of FAP and medulloblastoma is referred to as the Turcot syndrome (see these terms).\nEtiology\nClassic FAP results from a germline mutation in the APC gene (5q21-q22). Most patients (about 70%) have a family history of colorectal polyps and cancer. In one patient subset, a MUTYH mutation (1p34.1) causes a recessively inherited polyposis condition, MUTYH-related familial adenomatous polyposis (see this term), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract.\nDiagnostic methods\nDiagnosis is based on family history, clinical findings, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnoses include other disorders causing multiple polyps (Peutz-Jeghers syndrome, familial juvenile polyposis or hyperplastic polyposis, hereditary mixed polyposis syndrome, and Lynch syndrome; see these terms).\nAntenatal diagnosis\nPresymptomatic and prenatal (amniocentesis and chorionic villous sampling), and even preimplantation genetic testing, is possible. Referral to a geneticist or genetic counselor is mandatory.\nGenetic counseling\nClassic FAP is inherited in an autosomal dominant manner. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed.\nManagement and treatment\nCancer prevention and maintaining a good quality of life are the main goals of management, and regular and systematic follow-up and supportive care should be offered to all patients. By the late teens or early twenties, colorectal cancer prophylactic surgery is advocated. The recommended alternatives are total proctocolectomy, and ileoanal pouch or ileorectal anastomosis for AFAP. Duodenal cancer and desmoids are the two main causes of mortality after total colectomy. They need to be identified early and treated. Upper endoscopy is necessary for surveillance to reduce the risk of ampullary and duodenal cancer. Patients with progressive tumors and unresectable disease may respond or stabilize with a combination of cytotoxic chemotherapy and surgery. Celecoxib has received marketing authorization by the US Food and Drug Administration (FDA) and the European Medicines Agency to be used as an adjunctive therapy in patients with FAP.\nPrognosis\nPatients with FAP carry a 100% risk of CRC. However, this risk is reduced significantly when patients enter a screening-treatment program.\n\n                            Last update: \n                            October 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Dani BERCOVICH  - Dr Elizabeth HALF  - Pr Paul ROZEN"}
{"Disease Name": "Familial adrenal hypoplasia with absent pituitary luteinizing hormone", "Disease Definition": "A rare endocrine disease characterized by a miniature adult type of congenital adrenal hypoplasia (residual adrenal cortex is composed of a small amount of permanent adult cortex with normal structural organization), selective absence of pituitary luteinizing hormone in otherwise normal brain, and neonatal demise. Patients present with hypogonadotropic hypogonadism, hypoglycemia, seizures, encephalopathy and diabetes insipidus. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 95700, "Summary": ""}
{"Disease Name": "Familial advanced sleep-phase syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by very early sleep onset and offset. Plasma melatonin levels and body core temperature rhythms are also phase-advanced. The sleep-wake cycle is generally shortened. Additional reported features include migraine with or without aura and seasonal affective disorder.", "ORPHA ID": 164736, "Summary": ""}
{"Disease Name": "Familial afibrinogenemia", "Disease Definition": "Familial afibrinogenemia is a coagulation disorder characterized by bleeding symptoms due to a complete absence of circulating fibrinogen.", "ORPHA ID": 98880, "Summary": "Epidemiology\nPrevalence of afibrinogenemia is estimated at 1/1,000,000.\nClinical description\nCommon manifestations of afibrinogenemia include umbilical cord bleeding, epistaxis, hemarthrosis, gastrointestinal bleeding, menorrhagia, traumatic and surgical bleeding and, rarely, intracranial hemorrhage. Recurrent spontaneous abortions may occur.\nEtiology\nThe deficiency is due to various mutations in the FGA, FGB, or FGG genes.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            October 2009"}
{"Disease Name": "Familial Alzheimer-like prion disease", "Disease Definition": "Familial Alzheimer-like prion disease is an exceedingly rare form of prion disease (see this term) characterized by the neuropathological features of Alzheimer disease including memory impairment and depression, related to abnormal prion protein (PrP) caused by a gene mutation in PRNP. Patients present with a prolonged, atypical course (absence of myoclonus or ataxia) unlike other forms of prion disease with severe neurofibrillary tangle pathology and high levels of cerebral amyloidosis.", "ORPHA ID": 280397, "Summary": ""}
{"Disease Name": "Familial anetoderma", "Disease Definition": "Familial anetoderma is an extremely rare genetic skin disease characterized by loss of elastin tissue leading to localized areas of flaccid skin and a family history of the disorder.", "ORPHA ID": 228277, "Summary": ""}
{"Disease Name": "Familial angiolipomatosis", "Disease Definition": "Familial angiolipomatosis is a rare, genetic, subcutaneous tissue disorder characterized by the presence of benign, usually multiple, subcutaneous tumors composed of adipose tissue and blood vessels, typically manifesting as yellow, firm, circumscribed, 1-4 cm in diameter tumors located in the arms, legs and trunk, with deep extension of the lesions between muscles, tendons and joint capsules (without infiltration of these structures), in several members of a single family. Tumors may be tender or mildly painful when palpated and do not regress spontaneously.", "ORPHA ID": 199279, "Summary": ""}
{"Disease Name": "Familial aortic dissection", "Disease Definition": "Familial aortic dissection is the term used to describe rupture of the aortic wall at the level of the media, resulting in the formation of a false channel and deviation of part of the aortic flux. Familial predisposition to thoracic aortic aneurysms and type A dissections (concerning the ascending aorta and/or the aortic arch) has been demonstrated in around 19% of patients presenting with thoracic aortic dissections and several loci have been identified so far (16p12.2-p13.13, 3p24-25). This predisposition is transmitted in an autosomal dominant manner.", "ORPHA ID": 229, "Summary": ""}
{"Disease Name": "Familial articular hypermobility syndrome", "Disease Definition": "A rare genetic disease characterized by generalized joint laxity leading to recurrent dislocation of major joints, such as the hip (often with congenital hip dislocation), shoulder, elbow, or patella. Patients often experience muscle and joint pain (sometimes with effusion) and may develop degenerative joint changes at a relatively early age. Skin abnormalities are absent.", "ORPHA ID": 2295, "Summary": ""}
{"Disease Name": "Familial atrial fibrillation", "Disease Definition": "Familial atrial fibrillation is a rare, genetically heterogenous cardiac disease characterized by erratic activation of the atria with an irregular ventricular response, in various members of a single family. It may be asymptomatic or associated with palpitations, dyspnea and light-headedness. Concomitant rhythm disorders and cardiomyopathies are frequently reported.", "ORPHA ID": 334, "Summary": ""}
{"Disease Name": "Familial atrial myxoma", "Disease Definition": "A rare, genetic cardiac tumor characterized by the presence of a primary, benign, gelatinous mass located in the atria and composed of primitive connective tissue cells and stroma (resembling mesenchyme) in several members of a family. Clinical presentation depends on the size, mobility and location of tumor, ranging from nonspecific and/or constitutional symptoms to sudden cardiac death, and includes dyspnea, hemoptisis, syncope, fatigue, fever, cutaneous rash, increases in venous pressure and/or peripheral edema.", "ORPHA ID": 615, "Summary": ""}
{"Disease Name": "Familial atrial tachyarrhythmia-infra-Hisian cardiac conduction disease", "Disease Definition": "A rare genetic cardiac disease characterized by variably expressed atrial tachyarrhythmia (such as atrial flutter, paroxysmal or chronic atrial fibrillation, ectopic atrial tachycardia, or multifocal atrial tachycardia), infra-Hisian conduction system disease, and vulnerability to dilated cardiomyopathy. Age of onset ranges between childhood and adulthood.", "ORPHA ID": 436242, "Summary": ""}
{"Disease Name": "Familial atypical multiple mole melanoma syndrome", "Disease Definition": "Familial atypical multiple mole melanoma (FAMMM) syndrome is an inherited genodermatosis characterized by the presence of multiple melanocytic nevi (often >50) and a family history of melanoma as well as, in a subset of patients, an increased risk of developing pancreatic cancer (see this term) and other malignancies.", "ORPHA ID": 404560, "Summary": "Epidemiology\nThe prevalence is unknown. An accurate estimate of the prevalence of FAMMM syndrome is difficult to make given the highly variable phenotype displayed both between and within FAMMM syndrome kindreds and the limited data available.\nClinical description\nThe clinical phenotype of FAMMM syndrome shows wide heterogeneity in regards to the presence of nevi and familial predisposition to melanoma and pancreatic cancer (mainly adenocarcinoma). The disease most often presents in children and teenagers but can occur at any age. The presenting feature is usually a high total body nevi count (usually more than 50). The majority will be clinically typical but some may have an atypical appearance (asymmetrical, raised, and/or different shades of tan, brown, black, or red and often of different sizes) resembling early melanoma and most frequently occur on the back, chest, buttocks, breasts, and scalp. Melanomas can arise from atypical moles or de novo and have been reported in some FAMMM syndrome patients as early as the second to third decade of life. Those with CDNK2A mutations have a 90% risk of developing melanoma by the age of 80 and a 20% increased risk of developing pancreatic cancer by the age of 75. These mutations are also associated with a younger age of onset. Other cancers that can be rarely associated with FAMMM syndrome include breast cancer, esophageal cancer and sarcoma.\nEtiology\nFAMMM syndrome has been associated with mutations in the 16p locus of CDKN2A  (9p21), a tumor suppressor gene involved in cell cycle inhibition. However, approximately 60% of patients with FAMMM syndrome do not have a  CDKN2A  mutation.\nDiagnostic methods\nDiagnostic criteria for FAMMM syndrome are as follows: high total body nevi count (usually >50), nevi with certain histologies (i.e. lentiginous pattern, nuclear atypia) and melanomas in 1 or more first or second degree relatives. Nevi are evaluated for melanoma based on the ABCDE characteristics (asymmetry, border irregularity, color variation, diameter >6 mm, and evolution or elevation). Dermatoscopy is also a non-invasive method of identifying melanomas. Molecular genetic testing identifying a CDKN2A mutation confirms diagnosis but the absence of a mutation in this gene does not exclude a diagnosis of FAMMM syndrome.\nDifferential diagnosis\nDifferential diagnoses include cutaneous neurofibromas and pancreatic ductal adenocarcinoma as well as Neurofibromatosis type 1 (see this term).\nGenetic counseling\nFAMMM syndrome is inherited in an autosomal dominant manner with incomplete penetrance. Genetic counseling should be offered to patients and their families.\nManagement and treatment\nScreening for melanoma in FAMMM syndrome kindreds should begin at age 10 and include a total body skin examination with the use of dermoscopy. Follow-up clinical exams or self-exams should then be performed every 6 months to monitor any changes in nevi. In families with a history of pancreatic cancer or a CDKN2A mutation, screening by computed tomography, magnetic resonance imaging, or endoscopic ultrasound can be offered starting at age 40. Melanoma, pancreatic cancer and other cancers should follow standard treatment guidelines.\nPrognosis\nIn those with pancreatic cancer, the prognosis is poor. Early diagnosis and treatment of melanoma tends to lead to a better prognosis.\n\n                            Last update: \n                            February 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Henry LYNCH"}
{"Disease Name": "Familial avascular necrosis of femoral head", "Disease Definition": "Avascular necrosis of femoral head (ANFH) is a severely disabling disease characterised by progressive groin pain, a limping gait, leg length discrepancy, collapse of the subchondral bone, limitation of hip function and eventual degeneration of the hip joint requiring total hip arthroplasty.", "ORPHA ID": 86820, "Summary": "Epidemiology\nThe prevalence of ANFH is unknown but around 15,000 cases are reported in each year in the USA. Familial forms of ANFH appear to be very rare, with only three families identified so far.\nClinical description\nAge of onset in these familial cases ranges from 15-48 years (as opposed to between 3rd to 5th decade of life for other forms of ANFH).\nEtiology\nMost cases are associated with mechanical disruption (hip trauma or surgery), hypofibrinolysis, steroid use, smoking, alcohol intake, haemoglobinopathies and hyperlipidaemia.Transmission in familial cases is autosomal dominant and mutations in the type II collagen gene (COL2A1) have been detected in affected family members.\n\n                            Last update: \n                            May 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Familial benign copper deficiency", "Disease Definition": "Familial benign copper deficiency is a rare disorder of mineral absorption and transport characterized by hypocupremia that manifests as failure to thrive, mild anemia, repeated seizures, hypotonia, and seborrheic skin. Spurring of the femur and tibia are also noted on radiographic imaging. Symptoms are reversible or improve with supplements of oral copper. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 1551, "Summary": ""}
{"Disease Name": "Familial benign flecked retina", "Disease Definition": "Familial benign flecked retina is a rare retinal dystrophy characterized by diffuse bilateral white-yellow fleck-like lessions extending to the far periphery of the retina but sparing the foveal region, with asymptomatic clinical phenotype and absence of electrophysiologic deficits.", "ORPHA ID": 363989, "Summary": ""}
{"Disease Name": "Familial bicuspid aortic valve", "Disease Definition": "Familial bicuspid aortic valve is a rare, genetic, aortic malformation defined as a presence of abnormal two-leaflet aortic valve in at least 2 first-degree relatives. It is frequently asymptomatic or may be associated with progressive aortic valve disease (aortic regurgitation and/or aortic stenosis, typically due to valve calcification) and a concomitant aortopathy (i.e. aortic dilation, aortic aneurysm and/or dissection).", "ORPHA ID": 402075, "Summary": ""}
{"Disease Name": "Familial calcium pyrophosphate deposition", "Disease Definition": "A rare inherited rheumatologic disease which causes calcification of articular fibrocartilage or hyaline cartilage, a process termed chondrocalcinosis (CC). It often associates with acute synovitis and osteoarthritis (OA).", "ORPHA ID": 1416, "Summary": "Epidemiology\nFamilial calcium pyrophosphate deposition (CPPD) prevalence is unknown. It is rare: about 100 affected families have been identified to date.\nClinical description\nFamilial CPPD manifests in early adulthood (20-40 years old) and has a variable clinical phenotype. Generally, it is associated with acute CPP crystal arthritis involving the knees, the wrists, the shoulders, and/or a severe chronic inflammatory arthropathy, mimicking osteoarthritis (OA). In acute CPP crystal arthritis cases, acute episodes of pain, stiffness, swelling and sometimes ankylosis, can be observed in any joint, the knees or the wrist being the most affected. The attacks can last from hours (6-24) to days and can induce a limited range of motion. Chronic inflammatory arthropathy usually affects the knee, wrist, elbow, shoulder and hip, and can induce a severe OA-like arthropathy. Very rarely, familial CPPD can be associated with non rheumatological features, such as recurrent infantile seizures as was the case in a British family with CPPD and polyarticular chondrocalcinosis but without structural arthropathy.\nEtiology\nMutations in the ANKH gene (human homologue of progressive ankylosis; 5p15.2), encoding a protein involved in cellular inorganic pyrophosphate transport, were identified in some cases of familial CPPD. Other familial cases have been linked to mutation in the Tumor Necrosis Factor Receptor Super Family member 11B (TNFRSF11B) gene coding for osteoprotegerin (OPG) Other causative genes are yet to be determined. Mutations in the collagen α-1(II) chain gene (COL2A1; 12q12-13.2), that codes for the major structural protein of cartilage, have been found to cause a particular form of chondrocalcinosis characterized by severe early onset OA, spondylo-epiphysial dysplasia and secondary CPPD.\nDiagnostic methods\nDiagnosis of CPPD is based on the identification of CPP crystals in synovial fluid by compensated polarized light. X-rays show calcium deposits within cartilage and fibro cartilage, mainly in knees, wrists and shoulders. X-ray findings support the diagnosis of CPPD, but the absence of radiographic CC does not exclude it. Ultrasonography allows for the detection of CC in peripheral joints, which typically appears as thin hyperechoic bands within hyaline cartilage and hyperechoic sparkling spots in fibrocartilage. Calcium deposits can be seen as well with Computed Tomography and DECT.\nDifferential diagnosis\nDifferential diagnosis includes other genetic conditions causing secondary CC such as chronic hypomagnesaemia (particularly the Gitelman syndrome), hereditary hemochromatosis and hypophosphatasia. In the large majority of cases, CPPD occur sporadically but it is a separate, much more common entity, with aging being the most important risk factor.\nAntenatal diagnosis\nAntenatal diagnosis could be possible when ANKH mutations in the family have already been found.\nGenetic counseling\nFamilial CPPD has an autosomal dominant mode of inheritance with variable penetrance.\nManagement and treatment\nManagement is mainly symptomatic. To date, there are no effective treatments capable of dissolving calcium deposits. Acute CPP arthritis should be treated by non-steroidal anti-inflammatory drugs (NSAIDs), or corticosteroid injections. For difficult to treat patients, IL-1 blockers could be used Preliminary reports suggested Tocilizumab to be effective. CPPD with OA should be managed as primary OA, by a combination of non-pharmacological and pharmacological treatments (analgesics, NSAIDs).\nPrognosis\nSome forms may be severe and result in considerable pain and disability.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Augustin LATOURTE  - Pr Pascal RICHETTE"}
{"Disease Name": "Familial caudal dysgenesis", "Disease Definition": "A rare, genetic, developmental defect during embryogenesis disorder characterized by varying degrees of caudal dysgenesis, ranging from a single umbilical artery or imperforate anus to full sirenomelia, in several members of the same family. Phenotype includes lumbosacral agenesis, anal atresia or ectopia, genitourinary abnormalities, components of VATER or VACTERL association, and facial dysmorphism (flat facies, abnormal ears, bilateral epicanthic folds, depressed nasal bridge, micrognathia). Additional features reported include cardiovascular (e.g. endocardial cushion defect, hypoplasia of pulmonary artery) and skeletal (kyphosis, hemipelvis) anomalies.", "ORPHA ID": 1768, "Summary": ""}
{"Disease Name": "Familial cavitary optic disc anomaly", "Disease Definition": "A rare genetic eye disease characterized by congenital profound excavation of the optic nerve head with diminished visual field, in the absence of elevated intraocular pressure. Many patients lack a well-formed retinal artery and have multiple radial cilioretinal arteries instead. The condition is mostly bilateral, may worsen progressively, and is often complicated by serous macular detachment with profound visual loss.", "ORPHA ID": 464760, "Summary": ""}
{"Disease Name": "Familial cerebral cavernous malformation", "Disease Definition": "A rare, capillary-venous malformations characterized by closely clustered irregular dilated capillaries that can be asymptomatic or that can cause variable neurological manifestations such as seizures, non-specific headaches, progressive or transient focal neurologic deficits, and/or cerebral hemorrhages.", "ORPHA ID": 221061, "Summary": "Epidemiology\nThe overall prevalence of all CCMs has been estimated at 1/200 to 1/1,000 individuals. Familial cerebral cavernous malformation (FCCM) represents about 20% of all CCM cases with an estimated prevalence of 1/5,000 -1/10,000 and is therefore rare, contrarily to sporadic CCMs which are not. A strong founder effect has been found in Hispanic-American CCM families.\nClinical description\nClose to 60% of FCCM patients are symptomatic. FCCM usually manifests between 20 to 30 years of age, but clinical manifestations can occur at any age. Symptoms include seizures (40-70%), non-specific headaches (10-30%), progressive or transient focal neurologic deficits (35-50%), and/or cerebral hemorrhages (41%). FCCM patients most often present with multiple lesions, ranging from a few millimeters to a few centimeters in size. FCCMs occur predominantly in the brain, but have also been reported in the spinal cord, retina (5% of FCCM patients) and skin.\nEtiology\nTo date, mutations in three genes have been demonstrated to cause familial CCM; KRIT1,  CCM2 and PDCD10, located on chromosome 7q21.2, 7p13, and 3q26.1 respectively, which encode proteins that, among their various functions, modulate junction formation between vascular endothelial cells.\nDiagnostic methods\nCerebral magnetic resonance imaging (MRI) revealing the CCM(s) is the gold standard investigation to diagnose CCM and should include a T2 gradient echo sequence which is highly sensitive for hemosiderin. MRI shows multiple lesions in most FCCM patients in contrast with sporadic cases who harbor only one lesion. The detection of multiple CCM lesions is therefore strongly suggestive of the genetic nature of the disease. Molecular screening of FCCM genes is sometimes useful to ascertain the diagnosis in patients showing atypical MRI lesions; however, in most cases, it is used for genetic counseling.\nDifferential diagnosis\nIn cases presenting with atypical hemorrhagic MRI lesions, the differential diagnosis of FCCM includes multiple hemorrhagic metastases or hereditary cerebral hemorrhage with amyloidosis.\nAntenatal diagnosis\nPrenatal diagnosis is possible. However, in practice, very few prenatal diagnoses are requested in this disease (mostly in families where several patients have been severely affected with CCMs in the basal ganglia or spinal cord or pons).\nGenetic counseling\nFCCM is transmitted as an autosomal dominant trait with incomplete penetrance. Genetic counseling should be offered to the affected families informing them of the 50% risk of inheriting the mutated gene. Other important considerations in evaluating the genetic predisposition of CCMs include the number of lesions on the MRI brain scan, family history of CCM clinical characteristics, and the age of onset.\nManagement and treatment\nRegular check-ups, generally with an MRI once a year, are recommended after the discovery of a CCM, as additional asymptomatic lesions may appear with time. These MRI check-ups can be spaced to once every 5 years in the absence of intercurrent symptoms. Treatment of seizures and headaches is symptomatic. Lesions causing severe disabling seizures and/or focal neurologic deficits and/or cerebral hemorrhages call for surgical removal of lesions whenever possible. Acetylsalicylic acid, heparin and warfarin may increase the risk of hemorrhage.\nPrognosis\nFCCM is an evolving condition with a strong correlation between the patient's age and the number of CCM lesions. The hemorrhagic event rate is estimated at 2-5% per lesion per year. Functional outcome is mostly conditioned by the location of CCM lesions, with brainstem and basal ganglia lesions having a worse prognosis. Available data suggest that in most patients the long-term prognosis is quite favorable with a preserved autonomy in 80% of cases.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Elisabeth TOURNIER-LASSERVE"}
{"Disease Name": "Familial cerebral saccular aneurysm", "Disease Definition": "A rare genetic neurovascular malformation characterized by sac-like bulging of cerebral arteries due to weakening of the endothelial layer. Familial occurrence is suspected when two or more affected first- to third-degree relatives are present in a family. Aneurysms may remain asymptomatic throughout life, or rupture and thereby cause potentially life-threatening subarachnoid hemorrhage. Patients with familial cerebral saccular aneurysm are more likely to develop more than one brain aneurysm, are at greater risk of rupture, and tend to have poorer outcome after rupture than patients with sporadic cerebral aneurysms.", "ORPHA ID": 231160, "Summary": ""}
{"Disease Name": "Familial cervical artery dissection", "Disease Definition": "A rare genetic neurological disorder characterized by dissection of the cervical artery in various members of a single family, presenting with variable manifestations which range from asymptomatic to the triad of ipsilateral pain in the head, neck, and face, Horner syndrome, and cerebral or retinal ischemic symptoms. Headache and cerebral ischemic features are most frequently observed.", "ORPHA ID": 36382, "Summary": ""}
{"Disease Name": "Familial Chilblain lupus", "Disease Definition": "A rare monogenic form of cutaneous lupus erythematosus characterized by infantile or childhood onset of cold-induced erythematous papules or plaques predominantly on the fingers, toes, nose, cheeks, and ears. Recurrent ulceration of the lesions may lead to necrotic tissue destruction and mutilation. Patients may experience ischemia of the affected acral regions. Histological findings include cutaneous perivascular inflammatory infiltrates with deposits of immunoglobulins or complement.", "ORPHA ID": 481662, "Summary": ""}
{"Disease Name": "Familial chylomicronemia syndrome", "Disease Definition": "A rare genetic hyperlipidemia characterized by excessive increase in plasma triglyceride levels due to the accumulation of chylomicrons, which manifests biochemically as severe hypertriglyceridemia. Clinical manifestations include recurrent episodes of acute pancreatitis, abdominal pain, nausea, fatigue, diarrhea, hepatosplenomegaly, eruptive xanthomas, lipemia retinalis and failure to thrive. Children may be asymptomatic with later onset of symptoms. The condition is not associated with severe atherosclerosis.", "ORPHA ID": 444490, "Summary": "Epidemiology\nFamilial chylomicronemia syndrome (FCS) has an estimated prevalence of 1/300,000 (ranging from 1/100,000 to 1/1,000,000 in Europe and North America). Founder effects are seen in Quebec and the Cayman Islands.\nClinical description\nPresentation in infancy includes failure to thrive, abdominal pain, nausea and vomiting progressing to acute pancreatitis. Symptoms and signs include fatigue, irritability, lipemia retinalis, eruptive xanthomas on trunk, back and gluteal region, and hepatosplenomegaly. Lipemic plasma indicates severely elevated plasma triglyceride levels due to pathological presence of chylomicrons (>10 mmol/L or >875 mg/dL).\nEtiology\nMost FCS patients have bi-allelic loss-of-function variants in LPL encoding lipoprotein lipase. Other minor causal genes encoding factors that interact with LPL, including apolipoprotein (apo) A-V (APOA5), apo C-II (APOC2), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) and lipase maturation factor 1 (LMF1).\nDiagnostic methods\nDefinitive diagnosis is made by DNA sequencing. Biochemical methods are non-specific with technical performance challenges.\nDifferential diagnosis\nIn young adults, multifactorial (polygenic) chylomicronemia is 50 to 100 times as common as FCS and is associated with many secondary factors, hepatosteatosis, renal impairment or proteinuria. Patients with autoimmune diseases can develop antibodies against GPIHBP1 and develop chylomicronemia secondarily. Patients with undiagnosed partial lipodystrophy may present with chylomicronemia and pancreatitis.\nAntenatal diagnosis\nAntenatal diagnosis is not commonly offered, since FCS is manageable with dietary intervention.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (i.e. parents of a known FCS child or where both individuals are known carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThe mainstay of treatment is fat restriction, reducing total fat to <10% of calories or <20 grams per day, in combination with weight maintenance, exercise, and avoidance of processed foods, alcohol and smoking. Standard lipid-lowering medications and plasmapheresis are ineffective. Volanesorsen (apo C-III antisense oligonucleotide) is available in the EU but not North America; similar agents are in development.\nPrognosis\nSome patients have lived for six decades after the initial FCS diagnosis with minimal sequelae reportedly by adhering to a strict diet. Chylomicrons are not atherogenic, so atherosclerosis is uncommon in FCS patients, unlike other severe hypertriglyceridemia patients.\n\n                            Last update: \n                            March 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Robert HEGELE"}
{"Disease Name": "Familial clubfoot due to 17q23.1q23.2 microduplication", "Disease Definition": "17q23.1-q23.2 microduplication is a newly described cause of familial isolated clubfoot.", "ORPHA ID": 238578, "Summary": "Epidemiology\nIt has been described in three families.\nClinical description\nAll cases with clubfoot were male and clubfoot was bilateral in all except one case. Clinically, the feet were short, with broad and overlapping toes. Mild nail hypoplasia was present in two affected individuals and mild short stature was common.\nGenetic counseling\nThe microduplication segregated with autosomal-dominant clubfoot in all three families but with incomplete penetrance. This microduplication was identified by array CGH (comparative genomic hybridization).\n\n                            Last update: \n                            October 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "Familial clubfoot with or without associated lower limb anomalies", "Disease Definition": "Familial clubfoot with or without associated lower limb anomalies is a rare congenital limb malformation syndrome characterized by malalignment of the bones and joints of the foot and ankle, with presence of forefoot and midfoot adductus, hindfoot varus, and ankle equinus, presenting as rigid inward turning of the foot towards the midline, in various members of a single family. Hypoplasia of lower leg muscles is a frequently associated finding. Patients may present with other low-limb malformations, such as patellar hypoplasia, oblique talus, tibial hemimelia, and polydactyly.", "ORPHA ID": 199315, "Summary": ""}
{"Disease Name": "Familial cold urticaria", "Disease Definition": "Familial cold urticaria (FCAS) is the mildest form of cryopyrin-associated periodic syndrome (CAPS; see this term) and is characterized by recurrent episodes of urticaria-like skin rash triggered by exposure to cold associated with low-grade fever, general malaise, eye redness and arthralgia/myalgia.", "ORPHA ID": 47045, "Summary": "Epidemiology\nThe exact prevalence of FCAS is unknown. Most cases have been published in the USA, and this CAPS phenotype could be less frequent in Europe in comparison with MWS and CINCA.\nClinical description\nFCAS generally starts in childhood (<10 years, often at birth), but may occasionally start later, and is characterized by recurrent episodes of non-pruritic urticaria-like rash triggered by exposure to cold (5 minutes to 3 hours and not necessarily by touch). Lesions last about 12 hours (range 30 minutes to 72 hours) and are typically associated with a burning sensation. Low-grade, daylong episodes of fever, malaise, conjunctivitis, and abdominal discomfort are also observed. Polyarthralgias involving hands, knees, and ankles are very common and incapacitating. Other joints involved are feet, wrists, and elbows. Profuse sweating, drowsiness, headache, extreme thirst, and nausea are also noticed after cold exposure. Amyloidosis, arthritis are uncommon while deafness, lymphadenopathy, and serositis are absent\nEtiology\nFCAS is caused by gain-of-function point mutations in the NLRP3 gene (1q44), which encodes cryopyrin. Mutations in NLRP3 gene ultimately lead to the increased secretion of the proinflammatory cytokine interleukin (IL)-1 beta and dysregulated inflammation. Mutations in this gene may also cause two additional forms of CAPS which are Muckle-Wells syndrome (MWS) and CINCA syndrome (see these terms), demonstrating that all three disorders are allelic. Some patients with a classical phenotype of FCAS, MWS or CINCA syndrome may not have mutations in NLRP3, suggesting involvement of additional genes. In addition, somatic NLRP3 mosaicism could explain 30-60% of patients with negative conventional genetic testing. Patients carrying identical amino acid substitution may present with distinctly different clinical subtypes, suggesting that additional genetic and/or environmental modifying factors are required to define the clinical phenotype.\nGenetic counseling\nTransmission is autosomal dominant. Genetic counseling may be proposed and the recurrence risk is 50%.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Isabelle KONE-PAUT"}
{"Disease Name": "Familial colorectal cancer Type X", "Disease Definition": "A rare inherited cancer-predisposing syndrome characterized by the fulfilment of the Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC) but without alterations, either somatic or germline, in the DNA mismatch repair (MMR) genes.", "ORPHA ID": 440437, "Summary": "Epidemiology\nCummulative evidence suggests that 40% of families with hereditary non-polyposis colorectal cancer (meeting Amsterdam criteria) do not show defects in the MMR machinery. A US population-based study finds that 2.6% of all colorectal cancer patients diagnosed meet the Amsterdam criteria for HNPCC, placing the estimated incidence of Familial Colorectal Cancer Type X (FCCTX) at approximately 1% of all CRC cases. There is no male or female predominance.\nClinical description\nFCCTX includes a heterogeneous group of patients with familial aggregation of colorectal cancer (CRC), without gastrointestinal polyposis, and without evidence or molecular suspicion of Lynch syndrome. FCCTX is characterized by a strong aggregation of CRC cases in the family (fulfilment of Amsterdam criteria for hereditary nonpolyposis CRC) and absence of MMR deficiency, either germline or somatic. FCCTX tumors have normal expression of MMR proteins and no microsatellite instability, and no germline pathogenic variants in MMR genes are identified. FCCTX tumors are heterogeneous, likely due to their different etiologies. Compared to Lynch syndrome, FCCTX is not associated with extracolonic cancers, has a later mean age at CRC diagnosis (50-60 years vs 40 years), is more likely left-sided, and less likely associated with synchronous or metachronous cancers. FCCTX tumors have a more heterogeneous architecture, a predominant tubular growth pattern, less frequent mucinous histology, and less frequent peritumoral or tumor-infiltrating lymphocytes.\nEtiology\nThe search for FCCTX causal genes has been large unsuccessful. Despite the identification of multiple candidate genes, only RSP20 has been unequivocally linked to the disease, explaining approximatively 0.07% of MMR-proficient familial/early-onset CRC cases.\nDiagnostic methods\nBy definition, the diagnosis of FCCTX is based on the fulfilment of the clinical Amsterdam criteria for hereditary non-polyposis CRC and absence of an MMR defect. Amsterdam criteria include: having at least three relatives affected with histologically confirmed CRC or another HNPCC-associated cancer (endometrial, small bowel, ureter, renal pelvis), with at least one patient being a first-degree relative of the other two; at least two successive generations affected; at least one cancer diagnosed before age 50 (adenomatous polyposis excluded). MMR proficiency is evaluated under these criteria: Absence of microsatellite instability (MSI) in the tumors; normal expression of MLH1, MSH2, MSH6 and PMS2 proteins in the tumors; no germline pathogenic variants in the MMR genes. Multigene panel testing must be considered for CRC patients and/or families suspected of having a hereditary colorectal cancer syndrome and may reveal, although unfrequently, an RPS20 mutation in the case of FCCTX.\nDifferential diagnosis\nDifferential diagnosis includes Lynch syndrome and other forms of MMR-deficient hereditary nonpolyposis colon cancer. In rare cases, nonpolyposis CRC can occur in some forms of intestinal polyposis syndromes, caused by germline pathogenic variants in polyposis genes with a particularly broad polyposis expressivity—e.g. BMPR1A, MUTYH (biallelic), POLE, POLD1, or NTHL1. Other hereditary cancer syndromes may predispose to MMR-proficient CRC (and may be caused by mutations in BRCA1, BRCA2, ATM, CHEK2, or TP53).\nGenetic counseling\nA germline pathogenic variant in a hereditary cancer gene is hardly ever identified in FCCTX cases. Due to the increased risk of CRC, genetic counseling should be offered to family members based on the family history of cancer and ages at diagnosis following country-specific guidelines. RPS20-associated hereditary nonpolyposis CRC is an autosomal dominant disease. There is a 50% risk of transmitting the pathogenic allele at each pregnancy. The scarce data available suggests that this form of CRC occurs in the adulthood and that its penetrance is likely high.\nManagement and treatment\nIn the absence of a pathogenic variant in a cancer predisposition gene, cancer surveillance and clinical management of FCCTX families should be based on the personal and family history of cancer and the ages at cancer onset, as recommended by country-specific guidelines for colorectal cancer.\nPrognosis\nFCCTX cases show an excess of cancer-related mortality compared to Lynch syndrome, and an overall worse prognosis, both in terms of disease-free and overall survival.\n\n                            Last update: \n                            December 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Stefan ARETZ | ERN GENTURIS* - Dr Marta PINEDA RÍU | ERN GENTURIS* - Dr Laura VALLE | ERN GENTURIS*\n\n\n                                * European Reference Network"}
{"Disease Name": "Familial congenital mirror movements", "Disease Definition": "A rare, genetic, movement disorder characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side of the body, which are present in various first-degree members of a family, persist beyond the first decade of life, and have no associated comorbidities.", "ORPHA ID": 238722, "Summary": ""}
{"Disease Name": "Familial congenital nasolacrimal duct obstruction", "Disease Definition": "A rare, genetic, otorhinolaryngological malformation characterized by congenital impatency of the nasolacrimal draingage system in various members of a family. Presentation is not specific and may include a uni- or bilateral medial canthal mass, dacryocystitis, nasal obstruction, periorbital cellulitis, and epiphora. Dacryocystocele and lacrimal puncta agenesis may be associated.", "ORPHA ID": 451612, "Summary": ""}
{"Disease Name": "Familial congenital palsy of trochlear nerve", "Disease Definition": "A rare, genetic, neuro-ophthalmological disease characterized by congenital fourth cranial nerve palsy, manifesting with hypertropia in side gaze, unexplained head tilt, acquired vertical diplopia, and progressive increase in vertical fusional vergence amplitudes with prolonged occlusion. Facial asymmetry (i.e. hemifacial retrusion, upward slanting of mouth on the side of the head tilt, mild enophthalmos of paretic eye) and superior oblique tendon abnormalities (such as absence, redundance, misdirection) are frequently associated. Some asymptomatic cases have been reported.", "ORPHA ID": 91498, "Summary": ""}
{"Disease Name": "Familial cortical myoclonus", "Disease Definition": "Familial cortical myoclonus is a rare, genetic movement disorder characterized by autosomal dominant, adult-onset, slowly progressive, multifocal, cortical myoclonus. Patients present somatosensory-evoked, brief, jerky, involuntary movements in the face, arms and legs, associated in most cases with sustained, multiple, sudden falls without loss of consciousness. Seizures or other neurological deficits, aside from mild cerebellar ataxia late in the course of the illness, are absent.", "ORPHA ID": 319189, "Summary": ""}
{"Disease Name": "Familial cutaneous collagenoma", "Disease Definition": "Familial cutaneous collagenoma is a connective tissue nevus characterized by multiple, flesh-colored asymptomatic nodules distributed symmetrically on the trunk and upper arms (mainly on the upper two-thirds of the back), manifesting around adolescence. The skin biopsy reveals an accumulation of collagen fibers with reduction in the number of elastic fibers. Cardiac anomalies may be observed. Familial cutaneous collagenoma follows an autosomal dominant mode of transmission.", "ORPHA ID": 53296, "Summary": ""}
{"Disease Name": "Familial cutaneous telangiectasia and oropharyngeal cancer predisposition syndrome", "Disease Definition": "A rare, inherited cancer-predisposing syndrome characterized by an early development of cutaneous telangiectasia, mild dental and nail anomalies, patchy alopecia over the affected skin areas and increased lifetime risk for oropharyngeal cancer. Other types of cancer have also been reported.", "ORPHA ID": 313846, "Summary": ""}
{"Disease Name": "Familial developmental dysphasia", "Disease Definition": "Familial developmental dysphasia is a severe form of developmental verbal apraxia characterized by a deficit in spontaneous speech, writing, grammatical judgment and repetition, defective articulation, moderate to severe degree of dyspraxia, a reduced use of consonant clusters, and comprehension delay. Hearing and intelligence are normal.", "ORPHA ID": 1799, "Summary": ""}
{"Disease Name": "Familial digital arthropathy-brachydactyly", "Disease Definition": "Familial digital arthropathy-brachydactyly is characterised by the association of arthropathy of interphalangeal, metacarpophalangeal and metatarsophalangeal joints with brachydactyly of the middle and distal phalanges. It has been described in numerous members from five generations of one large family. Inheritance is autosomal dominant.", "ORPHA ID": 85169, "Summary": ""}
{"Disease Name": "Familial dilated cardiomyopathy with conduction defect due to LMNA mutation", "Disease Definition": "A rare familial cardiomyopathy characterized by left ventricular enlargement and/or reduced systolic function preceded or accompanied by significant conduction system disease and/or arrhythmias including bradyarrhythmias, supraventricular or ventricular arrhythmias. Disease onset is usually in early to mid-adulthood. Sudden cardiac death may occur and may be the presenting symptom. In some cases, it is associated with skeletal myopathy.", "ORPHA ID": 300751, "Summary": ""}
{"Disease Name": "Familial drusen", "Disease Definition": "A rare, genetic macular dystrophy disorder characterized by the presence of small yellow-white accumulations of extracellular material under the retinal pigment epithelium in the ocular posterior pole, and affecting multiple members of a family. The disease has a variable clinical presentation ranging from asymptomatic patients to progressive loss of vision and scotomas, possibly associated with subfoveal choroidal neovascularization, extensive pigmentary changes, geographic atrophy and/or subretinal hemorrhage.", "ORPHA ID": 75376, "Summary": ""}
{"Disease Name": "Familial dysautonomia", "Disease Definition": "A rare hereditary sensory and autonomic neuropathy characterized by decreased pain and temperature perception, absent deep tendon reflexes, proprioceptive ataxia, afferent baroreflex failure and progressive optic neuropathy.", "ORPHA ID": 1764, "Summary": "Epidemiology\nThe disease affects individuals of Ashkenazi Jewish ancestry. The prevalence at birth in the Ashkenazi Jewish population is estimated at 1/10,000 in North America and 1/3,700 in Israel.\nClinical description\nThe disease is present at birth and is progressive. Initial symptoms (from birth to 3 years) include swallowing problems, aspiration pneumonia, hypotonia, temperature and blood pressure instability, and delayed development. Lack of fungiform papilla on the tongue and absence of tears with emotional crying are classic features, but not easily recognized (the tongue appears inconspicuous and lack of overflow tears is normal until about seven months of age). No obvious dysmorphism is present at birth, but a characteristic facial expression develops over time. Pain and temperature perception are decreased, but not absent. Proprioception and vibration sense are markedly decreased. Deep tendon reflexes are absent. Feeding difficulties due to gastrointestinal dysmotility (oropharyngeal incoordination, abnormal esophageal peristalsis, erratic gastric emptying, gastroesophageal reflux) occur early and may persist throughout life. Episodes of protracted vomiting attacks and hypertension termed 'autonomic crises'' can be recurrent. Forty percent of the patients manifest a cyclical crisis pattern that can occur daily, weekly, or monthly with personality changes ranging from irritability and withdrawal to general excitation. Chronic lung disease (secondary to repeated aspirations), restrictive lung disease (imposed by scoliosis), and chemoreceptor dysfunction (resulting in blunted responses to hypoxemia) are frequent. Orthostatic hypotension without compensatory tachycardia is always present, as well as episodic hypertension in response to emotional stress or visceral pain. Chronic renal failure is common. Progressive optic neuropathy and neurotrophic keratopathy result in severe visual loss. There is ample phenotypic variation particularly in cognitive abilities. Severe kyphoscoliosis and short stature are common.\nEtiology\nThe disease is due to a founder mutation in the ELP1 gene (9q31), encoding elongator-1 protein, resulting in a truncated unstable protein. ELP1 is implicated in the migration, survival, and myelination of neurons during development and, in humans, the mutation affects the development of primary sensory and autonomic neurons.\nDiagnostic methods\nDiagnosis is based upon clinical recognition of both sensory and autonomic dysfunction as well as alacrima, absent fungiform papillae, and abnormal histamine test with absent axon flare. Genetic testing provides a definitive diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN). Normal or increased sweating easily distinguishes familial dysautonomia (FD) from HSAN4, also hypertensive crises are unique to FD and not present in other HSANs. Deep tendon reflexes are absent in FD.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families where the pathogenic variant has previously been identified.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of affected individuals are obligate carriers.\nManagement and treatment\nManagement should be tailored for each patient, as the clinical expression varies considerably. It is supportive and mainly directed towards protecting the cornea, and management of gastrointestinal dysfunction, respiratory dysfunction, and blood pressure lability.\nPrognosis\nAverage age of death is in the third decade of life but patients may live into the seventh decade.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Horacio KAUFMANN  - Pr Jose-Alberto PALMA"}
{"Disease Name": "Familial dysfibrinogenemia", "Disease Definition": "Familial dysfibrinogenemia is a coagulation disorder characterized by a bleeding tendency due to a functional anomaly of circulating fibrinogen.", "ORPHA ID": 98881, "Summary": "Epidemiology\nPrevalence is unknown but dysfibrinogenemia is more frequent than afibrinogenemia which has a prevalence of 1/1,000,000.\nClinical description\nMost patients with dysfibrinogenemia are asymptomatic. The others may have mild bleeding symptoms or even thrombosis.\nEtiology\nThe deficiency is due to various mutations in the FGA, FGB, or FGG genes.\nGenetic counseling\nTransmission is mainly autosomal dominant.\n\n                            Last update: \n                            October 2009"}
{"Disease Name": "Familial dyskinesia and facial myokymia", "Disease Definition": "Familial dyskinesia and facial myokymia is a rare paroxysmal movement disorder, with childhood or adolescent onset, characterized by paroxysmal choreiform, dystonic, and myoclonic movements involving the limbs (mostly distal upper limbs), neck and/or face, which can progressively increase in both frequency and severity until they become nearly constant. Patients may also present with delayed motor milestones, perioral and periorbital dyskinesias, dysarthria, hypotonia, and weakness.", "ORPHA ID": 324588, "Summary": ""}
{"Disease Name": "Familial encephalopathy with neuroserpin inclusion bodies", "Disease Definition": "A rare serpinopathy characterized by progressive myoclonus epilepsy and/or pre-senile dementia with prominent frontal-lobe features and relative sparing of recall memory. In addition, other neurological manifestations like cerebellar symptoms and pyramidal signs may be present. Age of onset is variable, the disease having been reported in children as well as elderly patients. Neuropathological examination reveals the typical neuronal inclusions of mutated neuroserpin (Collins bodies).", "ORPHA ID": 85110, "Summary": ""}
{"Disease Name": "Familial episodic pain syndrome with predominantly lower limb involvement", "Disease Definition": "A subtype of familial episodic pain syndrome characterized by intense, episodic and/or cyclic pain mainly localized in the distal lower limbs (occasionally affecting upper limbs as well) which is triggered/exacerbated by fatigue, cold exposure and/or weather changes and alleviated with anti-inflammatory medication, that has a tendancy to diminish in frequency with age. Episodes usually occur late in the day, last 15-30 min and associate sweating and a cold sensation of affected area.", "ORPHA ID": 391392, "Summary": ""}
{"Disease Name": "Familial episodic pain syndrome with predominantly upper body involvement", "Disease Definition": "A subtype of familial episodic pain syndrome characterized by episodes of severe debilitating pain mainly affecting shoulders, thorax and arms (occasionally radiating to the abdomen and legs), triggered by fasting, fatigue, cold temperatures or physical exercise, which last for 60-90 min and respond poorly to conventional analgesia. Intense pain episodes are accompanied by dyspnea, tachycardia, sweating, generalized pallor, peribuccal cyanosis, and stiffness of the abdominal wall and are followed by a period of exhaustion and somnolence.", "ORPHA ID": 391389, "Summary": ""}
{"Disease Name": "Familial episodic pain syndrome", "Disease Definition": "A rare genetic peripheral neuropathy characterized by recurrent, stereotyped, episodic intense pain, ocurring predominantly in either the upper body or lower limbs in several members of a family, which is triggered or exacerbated by fatigue, cold exposure, fasting, weather changes and/or physical stress or exertion and may or may not diminish with age. Sweating and other manifestations, such as tachycardia, breathing difficulties and generalized pallor, may be associated.", "ORPHA ID": 391384, "Summary": ""}
{"Disease Name": "Familial expansile osteolysis", "Disease Definition": "A rare primary bone dysplasia characterized by abnormal bone metabolism with bone pain, deformity, pathological fractures, early conductive hearing loss, and dental abnormalities. Focal bone lesions are typically found in the appendicular skeleton and consist of progressively expanding lytic areas, while generalized disordered bone modeling and altered trabecular pattern are the result of the multifocal, progressive nature of the disease. Age of onset is variable, mode of inheritance is autosomal dominant.", "ORPHA ID": 85195, "Summary": ""}
{"Disease Name": "Familial exudative vitreoretinopathy", "Disease Definition": "Familial exudative vitreoretinopathy (FEVR) is a rare hereditary vitreoretinal disorder characterized by abnormal or incomplete vascularization of the peripheral retina leading to variable clinical manifestations ranging from no effects to minor anomalies, or even retinal detachment with blindness.", "ORPHA ID": 891, "Summary": "Epidemiology\nThe prevalence of FEVR is unknown. It is usually inherited dominantly and many asymptomatic individuals may not come to medical attention as a result of non-penetrance. Males and females appear to be affected equally, except in the X-linked form which only affects males.\nClinical description\nThe clinical manifestations of FEVR are highly variable among patients in the same family and even between the two eyes. In many patients, retinal abnormalities do not affect vision. Most symptomatic individuals with FEVR present at an early age with peripheral vision disturbances, and flashes or floaters. Major objective signs are similar to retinopathy of prematurity (see this term) and include large angle kappa, retinal detachment, stretched posterior retinal vessels, dragged optic disc, and retinal folds. These ocular anomalies are followed by complications, such as retinal neovascularization and exudates, retinal and vitreous bleeding, vitreoretinal traction, ectopia of the macula, and cataracts. Strabismus and leukocoria are also reported. Patients with severe manifestations are often registered as blind in early infancy. Reduced bone mass with a predisposition to fractures has been reported in some patients (LRP5 mutations).\nEtiology\nMutations in the FZD4 (11q14-q21) or LRP5 (11q13.4) genes have been associated with autosomal dominant FEVR as well as ZNF408 (11p11.2). LRP5 has also been associated with recessive cases. X-linked recessive FEVR is associated with mutations in the NDP gene (Xp11.4-p11.3). Some dominant or recessive cases have been reported to be associated with TSPAN12 (7q31.31). In about 50% of cases, the genetic mutations causing FEVR are unknown.\nDiagnostic methods\nEarly diagnosis is very important in order to avoid serious complications that may develop within the first two decades of life. The diagnosis is based on ophthalmic and general history, including gestational age, birth weight and on ophthalmic examination for the presence of an avascular zone in the peripheral retina by slit lamp biomicroscopy and funduscopy of the peripheral retina in full mydriasis and, if possible, fluorescein angiography. A compatible inheritance pattern within the family may suggest the diagnosis, which can be confirmed by molecular genetic testing.\nDifferential diagnosis\nRetinopathy of prematurity (see this term) is the main differential diagnosis and can generally be ruled out based on gestational age, if available. Other similar conditions include Norrie disease, Coats disease, and persistent hyperplastic primary vitreous (see these terms).\nAntenatal diagnosis\nFEVR is genetically and clinically heterogeneous, complicating prenatal diagnosis. Furthermore, requests for prenatal diagnosis of the disease are rare.\nGenetic counseling\nThe disease most commonly shows autosomal dominant inheritance, and more rarely X-linked recessive or autosomal recessive patterns of inheritance. Significant non-penetrance has been reported. Corresponding genetic counseling should be provided to affected families.\nManagement and treatment\nPresymptomatic testing can be offered to families in which the causative mutations have been identified. Standard surgical approaches are used to correct retinal detachment, but results are variable. Prophylactic cryotherapy or argon laser photocoagulation are recommended to reduce new vascularization caused by ischemia. Regular fundus examination is recommended to monitor symptomatic patients. Asymptomatic children and young adults showing avascularity should be monitored annually.\nPrognosis\nThe clinical presentation of FEVR is highly variable. The usual course of the disease has not been well established making the prognosis difficult to ascertain. Progressive loss of vision is reported in severe cases.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Dr F.N. [Nienke] BOONSTRA  - Dr Rob COLLIN"}
{"Disease Name": "Familial focal epilepsy with variable foci", "Disease Definition": "Familial focal epilepsy with variable foci is a rare genetic epilepsy disorder characterized by autosomal dominant lesional and nonlesional focal epilepsy with variable penetrance. Focal seizures emanate from different cortical locations (temporal, frontal, centroparietal, parietal, parietaloccipital, occipital) in different family members, but for each individual a single focus remains constant throughout lifetime. Seizure type (tonic, tonic-clonic or hyperkinetic) and severity varies among family members and tends to decrease (but do not disappear) during adulthood. Many patients have an aura and show automatisms during diurnal seizures whereas others have nocturnal seizures. Most individuals are of normal intelligence but patients with intellectual disability, autistic spectrum disorder and obsessive-compulsive disorder have been described.", "ORPHA ID": 98820, "Summary": ""}
{"Disease Name": "Familial gastric type 1 neuroendocrine tumor", "Disease Definition": "A rare neoplastic disease characterized by occurrence of atypical and aggressive gastric type 1 neuroendocrine tumors (NET) in early adulthood. The tumors often show nodal infiltration requiring total gastrectomy. Synchronous gastric adenocarcinoma has also been reported. Patients present high serum gastrin concentrations and iron-deficiency anemia (rather than megaloblastic anemia, which is a typical feature in patients with sporadic gastric type 1 NET, where the tumor usually arises on the background of autoimmune atrophic gastritis).", "ORPHA ID": 464756, "Summary": ""}
{"Disease Name": "Familial generalized lentiginosis", "Disease Definition": "Familial generalized lentiginosis is a rare, inherited, skin hyperpigmentation disorder characterized by widespread lentigines without associated noncutaneous abnormalities. Patients present multiple brown to dark brown, non-elevated macula of 0.2 to 1 cm in diameter, spread over the entire body, sometimes including palms or soles, but never oral mucosa.", "ORPHA ID": 231040, "Summary": ""}
{"Disease Name": "Familial gestational hyperthyroidism", "Disease Definition": "A rare genetic hyperthyroidism characterized by hyperemesis gravidarum associated with hyperthyroidism due to hypersensitivity of the thyrotropin receptor to chorionic gonadotropin, in the absence of abnormally high serum chorionic gonadotropin levels. Clinical manifestations include severe nausea, vomiting, weight loss, tachycardia, excessive sweating, and hand tremor, but no signs of ophthalmopathy.", "ORPHA ID": 99819, "Summary": ""}
{"Disease Name": "Familial glucocorticoid deficiency", "Disease Definition": "Familial glucocorticoid deficiency (FGD) is a group of primary adrenal insufficiencies characterized clinically by neonatal hyperpigmentation, hypoglycemia, failure to thrive, and recurrent infections, and biochemically by glucocorticoid deficiency without mineralocorticoid deficiency.", "ORPHA ID": 361, "Summary": "Epidemiology\nThe prevalence is unknown. In Ireland there is a prevalence of around 1/200,000, but this is likely to be skewed by a high prevalence in the Irish Traveler sub-population.\nClinical description\nFGD usually presents in infancy or early childhood with hyperpigmentation of the skin and gums (present at birth or that develops over time), hypoglycemic seizures and failure to thrive. Recurrent infections are also a common finding (and may be the presenting sign in older children). Weakness, fatigue, weight loss, anorexia, vomiting, flank or abdominal pain, constipation and diarrhea are additional symptoms seen in some patients due to hypocortisolemia. Hypoglycemic crises resulting in convulsions can lead to coma or death if untreated and recurrent hypolglycemia may lead to neurological sequelae (i.e. learning disabilities, intellectual deficit, and sometimes severe, neuronal damage leading to major sensory and motor defects such as quadriplegia). Tall stature has been reported in some patients with FGD, typically those with MC2R gene defects. MRAP defects have been associated with a more severe disease and an earlier age of onset while a milder phenotype is seen in those with defects in the MCM4 gene (Irish Traveler FGD).\nEtiology\nFGD is due, in most cases, to defects in the adrenocorticotropin (ACTH) receptor, or its signaling pathway, resulting in a failure of the cells of zona fasciculata in the adrenal cortex to respond appropriately to adrenocorticotrophic hormone (ACTH), leading to a glucocorticoid deficiency. These defects are most commonly caused by mutations in MC2R (18p11.2), accounting for 25% of cases, and MRAP (21q22.1), accounting for 20% of cases. Other mutations reported in patients with FGD include MCM4 (8q12-q13), probably uniquely in the Irish Traveler population;  NNT (5p12), accounting for around 15% of cases; and TXNRD2 (22q11.21). Certain partially inactivating mutations of STAR (8p11.2) or CYP11A1 (15q23-q24) can cause a phenotype that masquerades as FGD.\nDiagnostic methods\nDiagnosis is based on clinical and laboratory findings. Patients have high plasma ACTH and low serum morning cortisol levels that do not respond to exogenous ACTH stimulation. Mineralocorticoid function is normal. Molecular genetic testing revealing a mutation in one of the disease causing genes confirms diagnosis of FGD.\nDifferential diagnosis\nThe main differential diagnosis of FGD is Addison's disease (usually of autoimmune origin), in which case a mineralocorticoid deficiency is present. Other differential diagnoses include triple A syndrome, congenital adrenal hyperplasia and other acquired causes of primary adrenal insufficiency (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease causing mutation but is rarely performed.\nGenetic counseling\nFDG is inherited in an autosomal recessive manner. Genetic counseling is possible.\nManagement and treatment\nTreatment consists of a replacement therapy with oral hydrocortisone. A dosage of 10-12 mg/m2/day (usually divided into three doses) normalizes cortisol and reduces, but rarely normalizes, ACTH. Dose modification is necessary during stresses such as surgery or intercurrent illness, and patients should have injectable hydrocortisone available for emergencies and carry a medical alert type bracelet or card. Prompt and adequate treatment of a hypoglycemic crisis is essential. Treatment is life-long.\nPrognosis\nThe prognosis is good for patients who are diagnosed and treated early. Only when left untreated is FGD a disease with high morbidity (neurological sequelae) and mortality.\n\n                            Last update: \n                            April 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Adrian CLARK"}
{"Disease Name": "Familial hemophagocytic lymphohistiocytosis", "Disease Definition": "Familial Hemophagocytic lymphohistiocytosis (FHL) is a rare primary immunodeficiency characterized by a macrophage activation syndrome (see this term) with an onset usually occurring within a few months or less common several years after birth.", "ORPHA ID": 540, "Summary": ""}
{"Disease Name": "Familial hyperaldosteronism type I", "Disease Definition": "A rare heritable, glucocorticoid remediable form of primary aldosteronism (PA) characterized by early-onset hypertension, hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA), and abnormal production of 18-oxocortisol and 18-hydroxycortisol.", "ORPHA ID": 403, "Summary": "Epidemiology\nPA is the most common form of secondary hypertension and is found in up to 10% of hypertensive patients. However, familial forms are rare and represent 6-7% of PA cases. Familial hyperaldosteronism type I (FH-I) is estimated at approximately 1% of all PA cases, but may reach 3% in the hypertensive pediatric population.\nClinical description\nHypertension of varying severity, even among members of the same family, manifests often before the age of 20. It can be accompanied with symptoms of severe hypertension such as headaches and nausea. Exogenous glucocorticoids are effective in reducing hyperaldosteronism and normalizing blood pressure. Cardiovascular complications due to aldosterone excess, such as fibrosis, left ventricular (LV) dysfunction, arrhythmias, and myocardial infarction, can be associated with the disease; abnormal cardiac function may manifest even in young normotensive patients. In adults, FH-I is associated with high risk of hemorrhagic stroke and ruptured intracranial aneurysms occurring at a young age.\nEtiology\nFH-I is due to an unequal crossing over on the long arm of chromosome 8 between the CYP11B2 gene (coding for cytochrome P450 11B2 or aldosterone synthase), normally expressed in the zona glomerulosa (ZG), and the CYP11B1 gene (coding for the cytochrome P450 11B1 or steroid 11-beta-hydroxylase), normally expressed in the zona fasciculata (ZF), resulting in a chimeric gene composed of the adrenocorticotropic hormone (ACTH)-sensitive promoter of the CYP11B1 gene and the coding region of the CYP11B2gene. This leads to an excessive aldosterone synthase production in the zona fasciculata of the adrenal cortex, regulated by ACTH rather than by the renin-angiotensin system. Excessive aldosterone synthesis leads to increased sodium reabsorption, loss of potassium and subsequent increased water reabsorption.\nDiagnostic methods\nThe diagnosis is suggested by the clinical picture and a family history of early-onset hypertension and/or stroke. Blood and urinary tests show biological signs of primary aldosteronism, i.e. increased aldosterone levels and low plasma renin activity (tested after correction of potassium levels) with an abnormal aldosterone/renin ratio, associated or not with low serum potassium levels, and elevated urinary levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. Diagnosis is confirmed by genetic testing providing evidence of the hybrid gene by Southern blot and/or long-range PCR. Many patients are diagnosed during familial genetic screening in case of family history.\nDifferential diagnosis\nThe clinical presentation resembles that of the other familial forms of hyperaldosteronism (FH-II, FH-III). Specific features of FH-I are the presence of hybrid steroids 18-hydroxycortisol and 18-oxocortisol in the urine and the suppression of aldosterone by dexamethasone.\nGenetic counseling\nTransmission is autosomal dominant and genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nOnce the diagnosis is ascertained, small doses of glucocorticoids (dexamethasone at 0.125-0.250 mg/day or prednisone at 2.5 -5 mg/day) are sufficient to correct hypertension and reduce the production of aldosterone. Small doses are essential in order to avoid side effects of glucocorticoid treatment; complete suppression of ACTH-regulated hybrid gene activity is not necessary for controlling hypertension. In severe cases, dexamethasone can be combined with a mineralocorticoid receptor antagonist and other non-specific antihypertensive drugs. Because of the side effects of glucocorticoids, in children eplerenone can be given instead.\nPrognosis\nWith treatment, hypertension can be controlled for many years, and echocardiographic parameters maintained at normal values.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Maria-Christina ZENNARO"}
{"Disease Name": "Familial hyperaldosteronism type II", "Disease Definition": "A heritable form of primary aldosteronism (PA) characterized by hypertension of varying severity, non-glucocorticoid remediable hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA) and increased aldosterone-to-renin ratio.", "ORPHA ID": 404, "Summary": "Epidemiology\nPA is the most common form of secondary hypertension and is found in up to 10% of hypertensive patients. However, familial forms are rare and represent 6-7% of adult PA cases. Familial hyperaldosteronism type II (FH-II) is considered the most common form of familial hyperaldosteronism and it is estimated at around 6% of all PA cases.\nClinical description\nThe clinical and biochemical presentation of FH-II is indistinguishable from sporadic PA, although early onset PA may be observed. Hypertension of varying severity, even within members of the same family, is noted in most patients and occurs at different ages. Fatigue, and muscle weakness are reported. Complications due to hypertension and aldosterone excess (including sodium retention and hypokalemia) may occur. Patients with PA are at increased risk of cardiovascular events, such as coronary artery disease, stroke, non-fatal myocardial infarction, atrial fibrillation and heart failure.\nEtiology\nFH-II is due to heterozygous gain-of-function mutations in the CLCN2 gene (3q27.1) coding for the CLC-2 chloride channel. Mutations are located in different domains of the ClC-2 channel and affect channel function to different degrees, explaining phenotypic heterogeneity. The mutations result in constitutive channel activation, membrane depolarization of the zona glomerulosa cells of the adrenal cortex, opening of voltage-gated calcium channels, and activation of the calcium signaling pathway that triggers aldosterone biosynthesis.\nDiagnostic methods\nFH-II is diagnosed when PA is confirmed in two or more family members and other familial forms are excluded. Patients show a non-specific variable aldosterone response to upright posture or AngII infusion. Early onset PA may be observed associated with specific CLCN2 mutations.\nDifferential diagnosis\nFH-II is clinically and biochemically indistinguishable from sporadic PA, although in some cases, CLCN2 mutations are associated with early onset PA. Differential diagnosis also includes the other forms of FH (FH-I, FH-III and FH-IV).\nGenetic counseling\nFH-II is transmitted in an autosomal dominant mode with variable penetrance. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of transmitting the pathogenic variant at each pregnancy.\nManagement and treatment\nFH-II does not respond to glucocorticoid treatment and no specific treatment has been identified for carriers of CLCN2 mutations. Treatment consists of medical therapy with mineralocorticoid receptor antagonists, associated to additional antihypertensive medication if required.\nPrognosis\nWith treatment prognosis is good.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Maria-Christina ZENNARO"}
{"Disease Name": "Familial hyperaldosteronism type III", "Disease Definition": "A rare heritable form of primary aldosteronism (PA) that is characterized by early-onset severe hypertension, non- glucocorticoid-remediable hyperaldosteronism, overproduction of 18-oxocortisol and 18-hydroxycortisol, and profound hypokalemia.", "ORPHA ID": 251274, "Summary": "Epidemiology\nPA is the most common form of secondary hypertension and is found in up to 10% of hypertensive patients. However, familial forms are rare and represent 6-7% of adult PA cases. The frequency of familial hyperaldosteronism type III (FH-III) is unknown.\nClinical description\nSevere hypertension associated with profound hypokalemia generally manifests during early childhood. It can be accompanied with polydipsia, polyuria, and headaches. Marked bilateral adrenal hyperplasia has been described. In some cases, a mild form of FH-III with normal appearing adrenals and treatable with medical therapy, resembling family hyperaldosteronism type II (FH-II) or type IV (FH-IV), has been reported.\nEtiology\nFH-III is due to heterozygous missense mutations of the KCNJ5 gene (11q24), encoding the G-protein-activated inward rectifier potassium channel GIRK-4. These mutations result in loss of channel selectivity, membrane depolarization of the zona glomerulosa cells of the adrenal cortex, opening of voltage-activated calcium channels, and activation of the calcium signaling pathway that triggers aldosterone biosynthesis. There is a genotype-phenotype correlation, with the mild phenotype observed in patients with the p.G151E and p.Y152C mutations.\nDiagnostic methods\nBlood and urinary tests show profound hypokalemia, increased aldosterone levels not suppressible by dexamethasone, suppressed plasma renin activity, with an abnormal aldosterone/renin ratio and elevated levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nThe severe form of FH-III presents with severe and treatment resistant hypertension and profound hypokalemia. In mild forms, the clinical presentation resembles that of the other familial forms of hyperaldosteronism (FH-II, FH-IV).\nGenetic counseling\nTransmission is autosomal dominant. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of transmitting the pathogenic variant at each pregnancy.\nManagement and treatment\nFH-III does not respond to glucocorticoid treatment. Severe cases require bilateral adrenalectomy to normalize blood pressure and hypokalemia, whereas mild cases are treated with medical therapy with mineralocorticoid receptor antagonists and/or other antihypertensive drugs if required.\nPrognosis\nIn severe cases treated with bilateral adrenalectomy, life-long glucocorticoid and mineralocorticoid replacement therapy is required. In mild cases, prognosis is good with medical treatment.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Maria-Christina ZENNARO"}
{"Disease Name": "Familial hyperaldosteronism", "Disease Definition": "Familial hyperaldosteronism (FH) is the heritable form of primary aldosteronism (PA) which comprises three identified subtypes to date: FH type I (FH-I; see this term) characterized by early-onset hypertension, glucocorticoid remediable adrenocorticotropic hormone (ACTH)-dependent hyperaldosteronism, variable hypokalemia, and overproduction of 18-oxocortisol and 18-hydroxycortisol; FH type II (FH-II; see this term) characterized by hypertension of varying severity and hyperaldosteronism not suppressible by dexamethasone; and FH type III (FH-III; see this term) characterized by profound hypokalemia, early-onset severe hypertension, non glucocorticoid-remediable hyperaldosteronism, and overproduction of 18-oxocortisol and 18-hydroxycortisol.", "ORPHA ID": 235936, "Summary": ""}
{"Disease Name": "Familial hypercholanemia", "Disease Definition": "Familial hypercholanemia is a very rare genetic disorder characterized clinically by elevated serum bile acid concentrations, itching, and fat malabsorption reported in patients of Old Order Amish descent.", "ORPHA ID": 238475, "Summary": ""}
{"Disease Name": "Familial hyperphosphatemic tumoral calcinosis/Hyperphosphatemic hyperostosis syndrome", "Disease Definition": "A rare autosomal recessive disorder characterized by the occurrence of cutaneous and subcutaneous calcified masses, usually adjacent to large joints, such as hips, shoulders and elbows. It can occur in the setting of hyperphosphatemia or normophosphatemia, depending on the type of gene mutation involved.", "ORPHA ID": 306661, "Summary": ""}
{"Disease Name": "Familial hyperprolactinemia", "Disease Definition": "Familial hyperprolactinemia is a rare, genetic endocrine disorder characterized by persistently high prolactin serum levels (not associated with gestation, puerperium, drug intake or pituitary tumor) in multiple members of a family. Clinically it manifests with signs usually observed in hyperprolactinemia, which are: secondary medroxyprogesterone acetate (MPA)-negative amenorrhea and galactorrhea in female patients, and hypogonadism and decreased testosterone level-driven sexual dysfunction in male patients. Oligomenorrhea and primary infertility have also been reported in some female patients.", "ORPHA ID": 397685, "Summary": ""}
{"Disease Name": "Familial hyperthyroidism due to mutations in TSH receptor", "Disease Definition": "A rare hyperthyroidism characterized by mild to severe hyperthyroidism, presence of goiter, absence of features of autoimmunity, frequent relapses while on treatment and a positive family history.", "ORPHA ID": 424, "Summary": ""}
{"Disease Name": "Familial hypoaldosteronism", "Disease Definition": "A rare genetic hypoaldosteronism that typically presents in infancy (earl-onset familial hypoaldosternism) as a life-threatening electrolyte imbalance (failure to thrive, recurrent vomiting, and severe dehydration). A history of fever, diarrhoea, lethargy, poor weight gain, poor feeding since birth may also be present. Older subjects (late-onset familial hypoaldosteronism) are less severely affected or asymptomatic.", "ORPHA ID": 427, "Summary": ""}
{"Disease Name": "Familial hypocalciuric hypercalcemia", "Disease Definition": "Familial hypocalciuric hypercalcemia (FHH) is a generally asymptomatic genetic disorder of phosphocalcic metabolism characterized by lifelong moderate hypercalcemia along with normo- or hypocalciuria and elevated plasma parathyroid hormone (PTH) concentration.", "ORPHA ID": 405, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nFHH is biologically characterized by moderate but significant hypercalcemia associated with levels of PTH and urinary calcium excretion that appear inappropriate in the presence of the hypercalcemia: serum levels of PTH are, in general, normal or slightly increased and calciuria is low. FHH is usually asymptomatic but rarely symptoms of fatigue, weakness, excessive thirst and concentration problems are experienced. Some adults suffer from relapsing pancreatitis, chondrocalcinosis and premature vascular calcification.\nEtiology\nThere are 3 genetic types of FHH based on chromosome location. FHH type 1 accounts for 65% of cases and is due to inactivating mutations in the CASR gene, localized to 3q21.1. This gene encodes the calcium-sensing receptor (CaSR). Loss of CaSR function results in a reduction in the sensitivity of parathyroid and renal cells to calcium levels so hypercalcemia is perceived as normal. The other 35% have either a mutation GNA11 (19p13.3) seen in FHH type 2 or AP2S1 (19q13.2-q13.3) seen in FHH type 3 (see these terms) or in genes not yet discovered. FHH is rarely caused by auto-antibodies against CaSR in those without a mutation.\nDiagnostic methods\nFHH is suspected when mild hypercalcemia is seen along with normal or slightly elevated PTH, relative hypocalciuria, and normal phosphate levels. FHH must be suspected in the presence of persistent hypercalcemia despite surgical removal of a parathyroid adenoma. Family members are screened for serum calcium concentrations and CASR mutation analysis is performed in order to confirm a diagnosis. As de novo mutations are frequently described, the CASR gene must also be sequenced in the presence of typical biological features even in the absence of familial history of hypercalcemia. In FHH type 2, marked hypocalciuria is noted. FHH type 3 exhibits mild hypophosphatemia and elevated plasma PTH concentrations.\nDifferential diagnosis\nPrimary hyperparathyroidism is clinically similar to FHH, apart from the presence of hypercalcemia. Other differential diagnoses include humoral malignant hypercalcemia and sarcoidosis (see this term).\nAntenatal diagnosis\nAs FHH is benign, prenatal testing is not recommended. It can be considered if both parents have FHH type 1, as their offspring have a higher risk of developing neonatal severe primary hyperparathyroidism (NSHPT; see this term), a particular clinical identity which can be life-threatening.\nGenetic counseling\nFHH is inherited as a dominant trait. Genetic counseling can be offered to family members of affected individuals and genetic screening for the CASR familial mutation.\nManagement and treatment\nAs FHH is usually asymptomatic, treatment is not necessary. The hypercalcemia seen in FHH does not respond to diuretics or bisphosphonates. For those with constantly elevated serum calcium concentrations >14mg/dL or in those with NSHPT or relapsing pancreatitis, a total parathyroidectomy can be beneficial. Pregnant women with FHH must be identified, as in the developing fetus a context of marked hypercalcemia leads to the inhibition of endogenous secretion of PTH and a high risk of developing severe hypocalcemia during the first days of life. In newborns of two FHH parents, calcium levels should be monitored for the first days of life as NSHPT can develop.\nPrognosis\nFHH does not lower life expectancy and has a benign, stable course.\n\n                            Last update: \n                            May 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Anne LIENHARDT-ROUSSIE"}
{"Disease Name": "Familial hypofibrinogenemia", "Disease Definition": "Familial hypofibrinogenemia is a coagulation disorder characterized by mild bleeding symptoms following trauma or surgery due to a reduced plasma fibrinogen concentration.", "ORPHA ID": 101041, "Summary": "Epidemiology\nPrevalence is unknown but hypofibrinogenemia is more frequent than afibrinogenemia which has a prevalence of 1/1,000,000.\nEtiology\nThe deficiency is due to various mutations in the FGA, FGB, or FGG genes.\nGenetic counseling\nTransmission is mainly autosomal dominant.\n\n                            Last update: \n                            October 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND"}
{"Disease Name": "Familial idiopathic dilatation of the right atrium", "Disease Definition": "A rare congenital heart malformation of unknown etiology that is characterized by an extremely dilated right atrium, and that is usually asymptomatic and fortuitously discovered by echocardiography or chest radiography, and can be sometimes associated with other anomalies such as atrial arrhythmias (e.g. atrial flutter, atrial fibrillation, supraventricular tachycardia), severe tricuspid regurgitation, or atrial thrombus that could lead to potentially life-threatening thromboembolic complications.", "ORPHA ID": 1677, "Summary": ""}
{"Disease Name": "Familial infantile bilateral striatal necrosis", "Disease Definition": "Familial infantile bilateral striatal necrosis is the familial form of infantile bilateral striatal necrosis (IBSN; see this term), a syndrome of bilateral symmetric spongy degeneration of the caudate nucleaus, putamen and globus pallidus characterized by developmental regression, choreoathetosis and dystonia progressing to spastic quadriparesis.", "ORPHA ID": 225154, "Summary": "Epidemiology\nThe prevalence of familial IBSN has been estimated at less than 1/1,000,000.\nClinical description\nThe age of onset varies between 7 months and 15 months. Clinical features include choreoathetosis, dystonia, rigidity, spasticity, dysphagia, optic atrophy, intellectual deficit, developmental regression of motor and verbal skills, failure to thrive, myoclonus, quadriparesis, cerebellar ataxia and nystagmus. The disease has an insidious onset and a slowly progressive downhill course.\nEtiology\nAutosomal recessive infantile striatonigral degeneration is caused by mutation in the NUP62 gene (19q13.33) and mitochondrial infantile striatonigral degeneration is caused by mutation in the ATP synthase-6 gene (MTATP6).\nDiagnostic methods\nDiagnosis is based on clinical observation of choreoathetoid movements of the face, trunk and extremities and evidence of basal ganglia degeneration on CT and MRI images.\nDifferential diagnosis\nDifferential diagnoses include Wilson's disease, acute disseminated encephalomyelitis, neurodegeneration with brain iron accumulation, Leigh disease, juvenile Huntington chorea, methylmalonic aciduria, guanidinoacetate methyltransferase deficiency, glutaric acidemia I (see these terms), carbon monoxide intoxication, small vessel arteritis and trauma.\nGenetic counseling\nAntenatal diagnosis and genetic counseling is offered to families of affected patients.\nManagement and treatment\nThere is no standard therapy for familial IBSN. Treatment with oral biotin has been observed to slow disease progress initially.\nPrognosis\nPrognosis is usually poor with patients progressing to spastic quadriparesis followed by death, usually due to infection.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Rachel STRAUSSBERG"}
{"Disease Name": "Familial infantile myoclonic epilepsy", "Disease Definition": "A rare, genetic, infantile epilepsy syndrome disease characterized by neonatal- to infancy-onset myoclonic focal seizures occurring in various members of a family, associated in some with mild dysarthria, ataxia and borderline-to-moderate intellectual disability.", "ORPHA ID": 352582, "Summary": ""}
{"Disease Name": "Familial intestinal malrotation", "Disease Definition": "A rare familial intestinal malformation characterized by failure of the rotation of the developing gastrointestinal tract around the superior mesenteric artery during embryonic development, resulting in a spectrum of abnormalities of intestinal position and fixation. Patients most typically present in the neonatal period with midgut volvulus, which can lead to short bowel syndrome or even death. Signs and symptoms include bilious vomiting, feeding intolerance, failure to thrive, constipation, bloody stools, or intermittent apnea. The condition may also manifest later in life with complications like kinking or hernias and a broad range of intestinal symptoms. It can be an isolated finding or occur in association with other anomalies.", "ORPHA ID": 508410, "Summary": ""}
{"Disease Name": "Familial isolated café-au-lait macules", "Disease Definition": "Neurofibromatosis type 6 (NF6), also referred as café-au-lait spots syndrome, is a cutaneous disorder characterized by the presence of several café-au-lait (CAL) macules without any other manifestations of neurofibromatosis or any other systemic disorder.", "ORPHA ID": 2678, "Summary": "Epidemiology\nPrevalence is unknown, but the disease appears to be extremely rare.\nClinical description\nThe macules may appear in infancy, but usually they are detected after 2 years of age. CAL lesions are hyperpigmented with smooth or irregular borders. Their size may vary from a few millimeters to more than 10 cm.\nEtiology\nThe etiology of NF6 remains unknown. Close linkage to the NF1 gene (17q11.2) has been reported in some cases.\nDiagnostic methods\nThe diagnosis is based on the presence of six or more CAL macules.\nDifferential diagnosis\nDifferential diagnoses include neurofibromatosis type 1, McCune-Albright syndrome, and tuberous sclerosis (see these terms).\nGenetic counseling\nTransmission is autosomal dominant.\nManagement and treatment\nIsolated CAL lesions do not require medical care.\nPrognosis\nCAL spots are benign and may resolve with age.\n\n                            Last update: \n                            April 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Pierre WOLKENSTEIN"}
{"Disease Name": "Familial isolated clinodactyly of fingers", "Disease Definition": "Familial isolated clinodactyly of fingers is a rare, genetic, non-syndromic, congenital limb malformation disorder characterized by angulation of a digit in the radio-ulnar (coronal) plane, away from the axis of joint flexion-extension, in several members of a single family with no other associated manifestations. Deviation is usually bilateral and commonly involves the fifth finger. Affected digits present trapezoidal or delta-shaped phalanges on imaging.", "ORPHA ID": 295014, "Summary": ""}
{"Disease Name": "Familial isolated congenital asplenia", "Disease Definition": "Familial isolated congenital asplenia is a rare, non-syndromic, potentially life-threatening visceral malformation characterized by the absence of normal spleen function, resulting in a primary immunodeficiency. Typically, the condition manifests with severe, recurrent, overwhelming infections (especially pneumococcal sepsis) in otherwise apparently healthy infants. In adults with no history of severe sepsis in infancy, thrombocytosis may be the presenting sign. Howell-Jolly bodies on blood smears and an absent spleen on abdominal ultrasound examination are highly suggestive associated findings.", "ORPHA ID": 101351, "Summary": ""}
{"Disease Name": "Familial isolated dilated cardiomyopathy", "Disease Definition": "A rare familial cardiomyopathy characterized by the dilation of left ventricle and progressively impairing of systolic ventricular function, in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment. The disease may cause heart failure or arrhythmia. The disease is isolated when no additional atypical cardiac or extracardiac manifestations are present.", "ORPHA ID": 154, "Summary": "Epidemiology\nThe prevalence and incidence of Familial isolated dilated cardiomyopathy (FDC) is unknown; however, the incidence of dilated cardiomyopathy (DCM) is estimated between 1/12,000-28,000 worldwide; the prevalence of dilated cardiomyopathy is estimated at 1/2500; FDC is reported to make up about 20-30% of DCM case (range 2-65%).\nClinical description\nThe disease is defined by the presence of two major clinical criteria: left ventricular (LV) fractional shortening less than 25% and/or LV ejection fraction less than 45% with LV end diastolic diameter greater than 117% of the predicted value (corrected for age and body surface area based on Henry's formula), in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment. The disease can develop at any age, in either sex. LV mass is often greatly increased in this disorder but LV wall thickness is normal. Symptoms of heart failure may be present as well as arrhythmias. Other presentations include the incidental detection of asymptomatic cardiomegaly and symptoms related to coexisting conduction disturbance or thromboembolic complications. Typically, there is a history of DCM in the family.\nEtiology\nAround 30-40% of FDC has an identified genetic origin attributed to over 50 genes, a number that is constantly increasing as new genes are discovered. Most mutations include titin (TTN; 15-27%), lamins A/C (LMNA; 6%), Beta-myosin heavy chain (MYH7; 4.20%), myopalladin (MYPN; 3.50%) and cardiac troponin T (TNNC1, TNNI3 and  TNNT2; 2.90%).\nDiagnostic methods\nClinical screening of relatives, in particular first degree relatives, of primary DCM cases using electrocardiogram (ECG) and echocardiography allow the identification of familial FDC. Two or more affected relatives with dilated cardiomyopathy meet the above major criteria for the disease. Cardiac catheterization and CT or MRI scan are used also. Genetic screening of the family is also possible.\nDifferential diagnosis\nDifferential diagnosis include the various non-genetic causes of dilated cardiomayopathy, such as cardiac AL amyloidosis or senile amyloidosis, peripartum cardiomyopathy, sarcoidosis, myocarditis, autoimmune cardiomyopathy.\nAntenatal diagnosis\nFetal echocardiography, B and M-mode, is the main diagnostic tool to determine the neonatal outcome. A hemodynamic evaluation can be performed by Doppler mode. Antenatal diagnosis is very rare due to the manifestation of the pathology later on during adult life. Fetal echocardiography is therefore not widely recommended unless there is a family history of neonatal case. Prenatal genetic testing may be considered on a case-by-case basis in the context of a pathogenic variant identified in the family.\nGenetic counseling\nFamilial dilated cardiomyopathy is primarily an autosomal dominant disease, but autosomal recessive, X-linked and mitochondrial forms have also been described. Genetic counseling is therefore possible. The transmission outcome is 50% in an autosomal dominant case and 25% for a recessive transmission.\nManagement and treatment\nThe pathology is treated with a combination of medications, depending on the symptoms. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta-blockers, diuretics, digoxin, blood-thinning medications are used. The management of alimentation is important in affected families, and exercise and healthy habits are essential.\nPrognosis\nThe prognosis of dilated cardiomyopathy is very poor in the absence of therapeutic management but mortality is largely reduced by medical and non-medical treatments. The prognosis may be influenced by the associated mutations.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe CHARRON"}
{"Disease Name": "Familial isolated hyperparathyroidism", "Disease Definition": "A rare, hereditary, familial primary hyperparathyroidism disease characterized by primary hyperparathyroidism due to single or multiple parathyroid tumors in at least two first-degree relatives in the absence of evidence of other endocrine disorders, tumors and/or systemic manifestations.", "ORPHA ID": 99879, "Summary": ""}
{"Disease Name": "Familial isolated hypoparathyroidism due to agenesis of parathyroid gland", "Disease Definition": "A rare genetic endocrine disease characterized by severe hypocalcemia, seizures, hyperphosphatemia, and impaired secretion of the parathyroid hormone (PTH) by the parathyroid glands (not affecting other endocrine glands). Complications include psychomotor and growth delay, delayed dentition, and cataracts.", "ORPHA ID": 2239, "Summary": ""}
{"Disease Name": "Familial isolated hypoparathyroidism due to impaired PTH secretion", "Disease Definition": "A rare genetic endocrine disease characterized by impaired secretion of the parathyroid hormone (PTH) by the parathyroid glands not causing other endocrine or developmental disturbances. Complications include impaired renal function, psychomotor and growth delay, delayed dentition, and cataracts.", "ORPHA ID": 189466, "Summary": ""}
{"Disease Name": "Familial isolated hypoparathyroidism", "Disease Definition": "A rare heterogeneous group of metabolic disorders characterized by abnormal calcium metabolism causing hypocalcemia due to insufficient serum levels of bioactive parathormone (PTH), without other endocrine disorders or developmental defects.", "ORPHA ID": 2238, "Summary": "Epidemiology\nCases have been reported around the world, including in Denmark, the USA, and Korea. There is no apparent gender predominance.\nClinical description\nDisease onset can occur at any age (from the neonatal period to adulthood) but symptoms generally start within the first decade of life. The clinical signs are mainly those of non-surgical hypoparathyroidism with hypocalcemia, causing myopathy, muscular weakness, cramps, tetany, lenticular cataracts, and teeth anomalies.\nEtiology\nPossible mechanisms causing FIH include: 1) an inappropriate low calcium set-point due to variants in the CASR gene, causing autosomal dominant hypocalcemia; 2) recessive loss of function or dominant negative variants in the GCM2 gene (6p24.22), which encodes a transcription factor of importance to development, proliferation and maintenance of the parathyroid cells; 3) dominant or recessive variants in the PTH gene (11p15.3) causing either impaired secretion of PTH, apoptosis of parathyroid cells, or secretion of bioinactive PTH, with either undetectable or elevated serum levels of immunoreactive PTH, 4) variants in the autoimmune regulator (AIRE) gene without signs of other diseases associated with loss of AIRE function.\nDiagnostic methods\nDiagnosis is based on biochemistry showing low serum calcium and PTH levels, and confirmed by genetic testing. If PTH levels are high, the bioactivity of the PTH molecule may have to be evaluated.\nDifferential diagnosis\nThe differential diagnosis includes other non-surgical hypoparathyroidism with hypocalcemia and low PTH levels such as autoimmune hypoparathyroidism, and autoimmune polyendocrinopathy type 1, or syndromes with hypoparathyroidism as a feature like 22q11.2 deletion syndrome. In patients presenting with hypocalcemia with high PTH levels, pseudohypoparathyroidism or secondary hyperparathyroidism should be considered.\nAntenatal diagnosis\nAntenatal diagnosis is possible if the genetic variant is known in the family.\nGenetic counseling\nIsolated hypoparathyroidism may be sporadic or familial, with autosomal dominant or recessive inheritance.\nManagement and treatment\nManagement consists of symptomatic treatment with supplementary calcium and active vitamin D.\nPrognosis\nIf well treated, life expectancy is normal but quality of life may be negatively impacted.\n\n                            Last update: \n                            March 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Lars REJNMARK | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Familial isolated pituitary adenoma", "Disease Definition": "A rare, hereditary endocrine tumor characterized by a benign pituitary adenoma that is either secreting (e.g. prolactin, growth hormone, thyroid stimulating hormone) or non-secreting. Symptoms may occur due to either the hormonal hypersecretion and/or the mass effect of the lesion on local structures in the brain.", "ORPHA ID": 314777, "Summary": "Epidemiology\nFamilial isolated pituitary adenoma (FIPA) prevalence is unknown. However, FIPA represents around 2-5% of pituitary adenoma cases. A female predominance is reported.\nClinical description\nIn FIPA, pituitary adenomas can be of any secretory type (e.g. prolactinoma, acromegaly, Cushing's disease, TSH-secreting) or can be non-secreting. FIPA kindreds usually have 2-4 members affected with pituitary adenomas, while larger numbers of affected patients per family can occur infrequently. In FIPA, pituitary adenomas generally begin at a younger age and are larger than corresponding sporadic non-FIPA cases. Pituitary adenomas in FIPA can cause symptoms due to hormonal hypersecretion and/or due to the mass effect of the pituitary adenoma on local structures in the brain (e.g. visual disturbance). In FIPA families with AIP mutations pituitary adenoma growth characteristics are often aggressive and hormonal hypersecretion may be marked.\nEtiology\nIn up to 80% of FIPA families, the etiology of pituitary adenomas is unknown. However, mutations in the gene AIP (11q13.2 ) account for about 20% of FIPA kindreds. AIP is thought to act as a tumor suppressor gene. Pituitary adenomas due to germline AIP mutations are accompanied by a second hit of the other allele (e.g. deletion or mutation) and this is thought to favor or stimulate tumorigenesis.\nDiagnostic methods\nFIPA kindreds usually have 2-4 members affected with pituitary adenomas. Hormonal testing is used to identify abnormal hormonal secretion in FIPA. Magnetic resonance imaging (MRI) is used to confirm the presence and dimensions of a pituitary adenoma. AIP mutations can lead to pituitary apoplexy in FIPA kindreds, so MRI and hormonal signs of apoplexy may be present in affected family members.\nDifferential diagnosis\nDifferential diagnosis include multiple endocrine neoplasia type 1 and familial infantile gigantism, which may present as FIPA.\nGenetic counseling\nIn children of FIPA cases with AIP mutations, the pattern of inheritance is autosomal dominant and, thus, there is a 50% risk of inheriting the mutation from an affected parent. For families with unidentified gene, an autosomal dominant inheritance pattern has been suggested. Large international studies have shown that only about 20% of AIP mutation carriers eventually develop a pituitary adenoma.\nManagement and treatment\nPituitary adenomas in the setting of FIPA are generally managed according to guideline recommendations for non-FIPA pituitary adenomas. However, in FIPA families with AIP mutations, pituitary adenomas (often growth hormone secreting) can be large and poorly responsive to treatment with surgery and medical therapy.\nPrognosis\nFormal outcome studies for patients with FIPA as compared with sporadic pituitary adenoma patients have not been performed. However, due to larger tumor size, younger age at onset and lower responses to medical therapies (particularly in FIPA families with AIP mutations), hormonal and tumoral effects may be more difficult to control and may require a larger burden of treatment.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Albert BECKERS  - Dr Adrian DALY"}
{"Disease Name": "Familial isolated restrictive cardiomyopathy", "Disease Definition": "A rare genetic cardiac disease characterized by restrictive ventricular filling due to high ventricular stiffness that results in severe diastolic dysfunction in the absence of dilated or hypertrophied ventricles.", "ORPHA ID": 75249, "Summary": "Epidemiology\nThe prevalence is unknown; however, from a European registry the familial form is reported to account for 30% of restrictive cardiomyopathy.\nClinical description\nClinical presentation of restrictive cardiomyopathy (RCM) is heterogeneous, with onset at any age. Dyspnea is the most common symptom, followed by edema, palpitation, fatigue, orthopnea and chest pain. The typical symptoms upon examination include jugular venous distension, elevated systemic and pulmonary venous pressures, systolic murmur, lower-extremity edema, atrial fibrillation, cardiomegaly, and less frequently atrioventricular block. In advance disease, symptoms include pulmonary congestion, hepatomegaly, ascites and edema. Diastolic volumes are normal or reduced, and whilst initial systolic function is normal or near-normal, it may deteriorate with diseases progression. The ejection fraction is typically above 50%. Mild-to-moderate tricuspid and mitral valve regurgitation is common. Bi-atrial dilatation due chronic elevation of atrial pressure usually develops which along with pulmonary venous congestion and pleural effusions can result in moderate to generalized cardiomegaly. Other changes in cardiac morphology, such as ventricular dilatation, septal and ventricular hypertrophy, typically do not occur in RCM. Myocardial biopsy typically demonstrates interstitial fibrosis, and mild to moderated myocyte hypertrophy, without evidence of amyloid deposition, eosinophil infiltration or other systemic infiltration. Death can occur suddenly or as a result of congestive heart failure, cardiac arrhythmias, or other associated complications.\nEtiology\nRCM is due to increased ventricle stiffness resulting in restricted ventricular filling either unilaterally or bilaterally. Most cases of RCM remain idiopathic; however, an increasing number of disease causing mutations have been identified and include the sarcomere subunits, such as troponin T (TNNT2, 1q32.1), troponin I (TNNI3, 19q13.42), alpha-actin (ACTC, 15q14), beta-myosin heavy chain (MYH7, 14q11.2), myopalladin (MYPN, 10q21.3), and filamin C (FLNC, 7q32.1) as well as kinesin-like protein KIF20A (KIF20A, 5q31.2).\nDiagnostic methods\nDiagnosis is made with cardiac echocardiography supported by electrocardiogram, cardiac catheterization, and endomyocardial biopsy. Typical findings on echography include enlargement of atria, normal or reduced left ventricular end diastolic dimension and/or volume, restrictive left ventricular filling pattern, normal or near normal systolic function, and normal ventricular wall thickness. Thorough hemodynamic evaluation with cardiac catheterization may be required to exclude the differential diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes constrictive pericarditis and infiltrative myocardial disease such as cardiac amyloidosis, and other secondary causes of restrictive myopathy such as storage disease.\nGenetic counseling\nFor patients with known mutation, the pattern of inheritance is autosomal dominant and, therefore, there is a 50% risk of disease transmission from an affected parent to offspring. Autosomal recessive inheritance has been observed in one family. Genetic counseling should be offered to affected families, with clinical screening of asymptomatic family members.\nManagement and treatment\nCardiac transplant is the sole effective procedure in treating the disease. Pediatric patients should obtain preference on the waiting list due to the high risk of sudden death and to prevent the need for heart-lung transplantation. No single drug improves prognosis of RCM. Whilst diuretics are commonly used to reduce preload, excessive reduction may decrease ventricular filling. Thus, diuretics should be limited to patients presenting with symptomatic pulmonary venous congestion and/or right heart failure. ACE (angiotensin-converting enzyme) inhibitors and vasodilators are considered detrimental for the treatment of RCM. Anti-dysrhythmic therapy or implantable cardioverter defibrillators (AICD) may be an option for patients presenting with atrial fibrillation or ischemia. Pacemaker is considered in the presence of high degree atrioventricular block. Anti-coagulants reduce the risk of thromboembolic events.\nPrognosis\nPrognosis is usually poor, especially in pediatric patients, with 50 percent of deaths occurring within 2 years of diagnosis. For patients 10 years of age and above, the 5-year survival rate is 64 percent.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe CHARRON"}
{"Disease Name": "Familial isolated retinal arteriolar tortuosity", "Disease Definition": "A rare genetic cerebral small vessel disease characterized by isolated marked tortuosity of second-order and third-order retinal arteries with normal first-order arteries and venous system, typically located in the macular and peripapillary area and developing during childhood or early adulthood. The disease may be asymptomatic, although most patients present variable degrees of transient vision loss due to retinal hemorrhage following physical exertion or minor trauma.", "ORPHA ID": 75326, "Summary": ""}
{"Disease Name": "Familial isolated trichomegaly", "Disease Definition": "Familial isolated trichomegaly is a rare genetic hair anomaly characterized by a prolonged anagen phase of the eyelash hairs, leading to extreme eyelash growth that may result in corneal irritation. Increased growth of hair on other parts of the face (eyebrows, cheeks, forehead) and/or the body (chest, arms, legs) may be associated.", "ORPHA ID": 411788, "Summary": ""}
{"Disease Name": "Familial juvenile hypertrophy of the breast", "Disease Definition": "A rare breast malformation disorder characterized by unilateral or bilateral, symmetrical or asymmetrical, uncontrolled, rapid and massive enlargement of the breast(s) in peripubertal females, occurring in various members of a family. Additional associated manifestations may include skin hyperemia, dilated subcutaneous veins, skin necrosis, kyphosis, lordosis and anonychia. Growth and development are otherwise normal.", "ORPHA ID": 180176, "Summary": ""}
{"Disease Name": "Familial keratoacanthoma", "Disease Definition": "A rare inherited skin cancer syndrome characterized by the coexistence of features typical of both multiple self-healing squamous epithelioma and generalized eruptive keratoacanthoma, such as multiple small miliary-type lesions, larger self-healing lesions, and nodulo-ulcerative lesions. Lesions do not have a predilection for the mucosal surfaces.", "ORPHA ID": 493, "Summary": ""}
{"Disease Name": "Familial LCAT deficiency", "Disease Definition": "Familial LCAT (lecithin-cholesterol acyltransferase) deficiency (FLD) is a form of lecithin-cholesterol acyltransferase deficiency (LCAT; see this term) characterized clinically by corneal opacities, hemolytic anemia, and renal failure, and biochemically by severely decreased HDL cholesterol and complete deficiency of the LCAT enzyme.", "ORPHA ID": 79293, "Summary": "Epidemiology\nPrevalence and incidence of FLD are unknown. The disease is very rare: about 70 cases have been reported to date.\nClinical description\nAge of onset and severity of clinical manifestations are variable. Corneal opacities usually develop in early childhood and are characterized by grayish dots throughout the corneal stroma. Over time, corneal opacities may lead to severe visual impairment requiring corneal transplantation. The degree of hemolytic anemia is variable. Renal insufficiency is often observed from the second or third decade of life and may present with proteinuria. Renal disease may progress to end-stage renal failure requiring hemodialysis and/or kidney transplantation. Signs of atherosclerosis, hepatomegaly, splenomegaly, and lymphadenopathy have been reported in rare cases.\nEtiology\nFLD is caused by mutations in the LCAT gene (16q22.1) encoding the LCAT enzyme which catalyzes the formation of cholesterol esters in lipoproteins, leading to progressive lipid deposition in body tissues. More than 70 different mutations have been identified and appear to result in absence of LCAT production or synthesis of an enzyme with no alpha- or beta-LCAT activity (i.e., the activity of LCAT in esterifying cholesterol within HDL or other lipoproteins, respectively). There is no clear genotype-phenotype correlation since family members with the same mutation have been found to have different clinical and biochemical pictures. Environmental factors or other minor genes may therefore also be involved in the disorder.\nDiagnostic methods\nFamily history of characteristic disease features may be useful in diagnosis of the disorder. Diagnostic suspicion is also based on clinical signs and on laboratory tests showing a severe reduction of plasma HDL cholesterol. Kidney biopsy showing distinctive lipid deposits in the glomeruli on histology may also assist in diagnosis. Definitive diagnosis requires molecular genetic testing of the LCAT gene and functional analysis of the gene product.\nDifferential diagnosis\nDifferential diagnosis includes fish eye disease (FED) and Tangier Disease (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible.\nGenetic counseling\nFLD follows an autosomal recessive pattern of inheritance. Genetic counseling is recommended in affected families.\nManagement and treatment\nKidney function and visual acuity should be monitored in affected patients. Treatment for anemia and renal insufficiency is symptomatic. Hemodialysis or even kidney transplantation may be needed. Severe visual impairment may require corneal transplantation.\nPrognosis\nPrognosis is variable. End-stage renal disease is the most serious outcome.\n\n                            Last update: \n                            March 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Laura CALABRESI  - Pr Guido FRANCESCHINI"}
{"Disease Name": "Familial long QT syndrome", "Disease Definition": "A rare group of genetic, cardiac rhythm diseases characterized by a prolongation of the QT interval at basal electrocardiography (ECG) and by a high risk of life-threatening arrhythmias.", "ORPHA ID": 768, "Summary": "Epidemiology\nThe most prevalent form, Romano-Ward syndrome (RWS), has a prevalence close to 1/2,500 live births. The other forms of familial LQTS are extremely rare.\nClinical description\nThe two cardinal manifestations of LQTS are syncopal episodes, which may lead to cardiac arrest and sudden cardiac death, and electrocardiographic abnormalities: prolongation of the QT interval and T wave abnormalities. Where there are no extracardiac features, the disease is referred to as RWS. RWS related to SCN5A is sometimes associated with 2:1 atrioventricular block and very early occurrence of cardiac arrhythmias, especially in de novo cases. The Jervell and Lange-Nielsen syndrome also has congenital deafness. Timothy syndrome can be associated with syndactyly, facial dysmorphism and neurodevelopmental features. The Andersen-Tawil syndrome is no longer considered part of LQTS.\nEtiology\nAll the LQTS genes identified so far encode cardiac ion channel subunits or proteins involved in modulating ionic currents. Mutations in the genes that encode the cardiac potassium and sodium channels (KCNQ1, 11p15.5-p15.4 ; KCNH2, 7q36.1 ; SCN5A, 3p22.2) mainly cause the disease by prolonging the duration of repolarization and, thus, of the action potential. KCNQ1 is the most common LQTS variant.\nDiagnostic methods\nGiven the characteristic features of LQTS, the typical cases present no diagnostic difficulties for physicians aware of the disease. However, borderline cases are more complex and require the evaluation of various electrocardiographic, clinical, and familial findings, as proposed in the specific diagnostic criteria (the Schwartz score). The molecular screening is now part of the diagnostic process.\nDifferential diagnosis\nDifferential diagnosis must be made with epilepsy, catecholaminergic polymorphic ventricular tachycardia (CPVT), and drug-induced LQTS.\nAntenatal diagnosis\nPrenatal diagnosis should be considered when one of the parents has LQTS.\nGenetic counseling\nInheritance may be autosomal dominant or autosomal recessive and depends on the genes involved and the form of familial LQTS. Genetic counseling should be offered to affected families.\nManagement and treatment\nTreatment should always begin with beta-blockers, unless there are valid contraindications. If the patient has a further syncopal episode despite a full dose beta-blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation. Implantable cardioverter-defibrillator (ICD) therapy should be considered when the degree of protection afforded by beta-blockers and LCSD does not appear sufficient, with the final decision being based on individual patient characteristics (age, sex, clinical history, genetic subgroup including mutation-specific features in some cases, and the presence of ECG signs from 24-hour Holter recordings, indicating high electrical instability).\nPrognosis\nThe prognosis is usually good in patients that are correctly diagnosed and treated. The exceptions are patients with Timothy syndrome, Jervell and Lange-Nielsen syndrome patients carrying KCNQ1 mutations and patients with LQTS related to either Calmodulin, TRDN or SCN5A variants.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Peter SCHWARTZ"}
{"Disease Name": "Familial median cleft of the upper and lower lips", "Disease Definition": "A rare developmental defect during embryogenesis characterized by incomplete median clefts of both the lower lip (limited to the vermilion, with no muscle involvement) and upper lip (with muscle involvement), double labial frenulum and fusion of the upper gingival and upper labial mucosa (resulting in a shallow upper vestibular fold), in addition to poor dental alignment, and increased interdental distance between the lower and upper median incisors.", "ORPHA ID": 401942, "Summary": ""}
{"Disease Name": "Familial Mediterranean fever", "Disease Definition": "Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterized by recurrent short episodes of fever and serositis resulting in pain in the abdomen, chest, joints and muscles.", "ORPHA ID": 342, "Summary": "Epidemiology\nFMF is primarily found in the south-eastern Mediterranean area. Populations having a high prevalence (1/200-1/1000) of the disease are non-Ashkenazi Jews, Turks, Armenians and Arabs. It is not considered rare in Italy, Greece or Spain.\nClinical description\nDisease onset usually occurs before the age of 30 with an earlier onset corresponding to a more severe phenotype. FMF can be divided into 2 types: FMF type 1 and 2. Type 1 is characterized by attacks (as often as once a week or every few years) of fever and serositis lasting 1-4 days and resolving spontaneously. Stress, exposure to cold, fat-rich meals, infections, certain drugs and menstrual cycles are possible attack triggers. Mild symptoms (myalgia, headache, nausea, dyspnea, arthralgia, low back pain, asthenia and anxiety) precede attacks and last about 17 hours. Attacks manifest as fever (38°C-40°C lasting 12-72 hours and not responding to antibiotics), diffuse or localized abdominal pain (often mimicking acute abdomen), constipation (diarrhea in children), arthralgias (in large joints), arthritis (in upper/lower limb/knee joints) and chest pain caused by pleuritis and/or pericarditis (see this term). In 7-40% of patients cutaneous involvement is also present. Amyloidosis type AA (see this term) can be a serious long term complication. FMF type 2 describes a phenotype where amyloidosis occurs as the first and only manifestation of the disease.\nEtiology\nTo date, 218 mutations in the MEFV gene on chromosome 16 encoding the pyrin/marenostrin protein are responsible for the phenotypic variance (M694V homozygous mutations are associated with increased severity) seen in the disease. As not all patients have a mutation in the MEFV gene, other factors may be involved.\nDiagnostic methods\nThe Tel-Hashomer criteria states that 2 major criteria (fever and serositis, amyloidosis AA, effectiveness of colchicine) or 1 major and 2 minor criteria (recurrent attacks of fever, erysipela-like erythema, relatives affected by FMF) must be present for diagnosis. Genetic testing only has a 70-80 % positive predictive value.\nDifferential diagnosis\nDifferential diagnoses include hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), TNF receptor-associated periodic syndrome and periodic fever (TRAPS), Marshall's syndrome with periodic fever, transthyretin-related amyloidosis and Behçet's disease (see these terms).\nAntenatal diagnosis\nAntenatal testing is possible, but not advised.\nGenetic counseling\nFMF follows an autosomal recessive pattern of inheritance. Genetic counseling for parents with an MEFV mutation can inform them of their risk of passing it on to their children.\nManagement and treatment\nColchicine (oral or by I.V.) is the drug used to treat FMF. It reduces or eliminates FMF attacks and prevents the occurrence of amyloidosis type AA (see this term). Dosage ranges up to 0.03mg/kg/body weight/daily, or to a maximum of 3mg/daily, and must be taken regularly on a life-long basis. During an attack a nonsteroidal anti-inflammatory drug can be administered.Patients intolerant to colchicine have no alternative of matching efficacy, but Anakinra, interferon-alpha and selective serotonin reuptake inhibitors (SSRIs) have shown encouraging results in some patients. Annual physical examinations along with regulary monitoring of serum amyloid A protein (SAA) is recommended to prevent amyloidosis; colchicine can enhance B12 malabsorption and in rare cases can causes alopecia (see this term) and bone marrow suppression. Macrolides, diltiazem, grapefruit and cyclosporine should not be taken with colchicine as fatal toxicity can occur. Dialysis and organ transplantation might be necessary for those with renal amyloidosis.\nPrognosis\nAlthough there is no cure for FMF, colchicine treatment improves patient quality of life. Untreated FMF patients and those with renal amyloidosis have a less favorable prognosis.\n\n                            Last update: \n                            January 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Raffaele MANNA"}
{"Disease Name": "Familial medullary thyroid carcinoma", "Disease Definition": "A rare thyroid tumor characterized by a malignant neoplasm derived from the calcitonin-secreting parafollicular C-cells of the thyroid and occurring familially, but not as a component of multiple endocrine neoplasia syndromes. The commonly multifocal, bilateral nodules are typically located at the junction of the upper and middle thirds of the thyroid lobes. Clinically, patients may present with diarrhea, flushing, or weight loss caused by excessive secretion of calcitonin by the tumor. In rare cases, the tumor can also cause Cushing syndrome due to ectopic corticotropin production.", "ORPHA ID": 99361, "Summary": ""}
{"Disease Name": "Familial melanoma", "Disease Definition": "Familial melanoma (FM) is a rare inherited form of melanoma characterized by development of histologically confirmed melanoma in two first degrees relatives or more relatives in an affected family.", "ORPHA ID": 618, "Summary": "Epidemiology\nFM is thought to account for about 10% of all cases of cutaneous melanoma. Melanoma primarily affects populations of European origin. Incidence is higher in geographical regions with greater sun exposure (southern USA, Australia, New Zealand). Incidence was estimated at 1/90,000 in Europe in 2012.\nClinical description\nFamilial melanoma tends to occur earlier than non-familial melanoma. The average age of onset is often between 30 and 40 years, while non-familial melanoma typically occurs in the general population between 50 and 60. Earlier and later onset is nonetheless reported in some families. A higher frequency of multiple primary melanomas is also found. Melanoma generally presents as a pigmented lesion on the skin. It is often asymmetrical with irregular borders and color variegation. The diameter is often greater than 6 mm. The most common sites are the trunk, lower legs and back. All four main clinicopathologic subtypes of primary cutaneous melanoma described (spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma) are observed. A variety of growth patterns are found with progression to a potential for metastasis to other organs. Atypical moles are often found in families with FM.\nEtiology\nThe risk of familial melanoma is closely related to a wide range of genetic alterations in susceptibility genes but also appears to be influenced by phenotypic risk factors, such as pigmentation, freckling and nevi and sun reactions but also exposure to UV radiation. Complex interactions between genetic and environmental factors are therefore thought to underlie FM. The most common high-penetrance susceptibility gene implicated in FM is CDKN2A, accounting for predisposition in approximately 20% of FM. CDK4, another high risk gene, is rarely involved. Mutations of BAP1,POT1, TERF2IP, ACD,and TERT have recently been reported and penetrance remains to be determined. Medium penetrance genes include MITFandMC1R.Some twenty common genetic variants modulate risk for melanoma in low clustering families.\nDiagnostic methods\nFM is suspected in individuals when two or more close relatives have developed melanoma. A new or changing skin mole should be assessed to identify melanoma. Changes include color, border, size, and symmetry.\nDifferential diagnosis\nThe main differential diagnoses are seborrheic keratosis, atypical mole, familial atypical multiple mole melanoma and skin carcinoma.\nGenetic counseling\nIn some affected families, susceptibility is consistent with autosomal dominant inheritance but in most cases, a polygenic mode of inheritance appears likely. Patients should be informed that a family history of melanoma in one close relative is associated with an average 2-fold increased risk. History in more than one relative and relevant personal phenotypic characteristics such as multiple pigmented atypical melanocytic lesions result in a significantly higher risk.\nManagement and treatment\nLong-term screening of individuals at high risk and monitoring in FM families is recommended. This involves a total-body skin examination by a qualified dermatologist every six months. Self-examination of skin should be encouraged. Treatment is similar to sporadic melanoma and is largely based on surgery at initial stages.\nPrognosis\nPrognosis is variable and depends on time of diagnosis, thickness, presence of ulceration, mitotic index, and possible lymph node involvement, and distant metastatic disease. Early diagnosis (with thin Breslow thickness) is associated with a high percentage of cure. Monitoring of melanoma families aims to detect melanoma offering skin surveillance resulting in a favorable prognosis.\n\n                            Last update: \n                            February 2016\n\n\n                            - Expert reviewer(s): \n                            Pr Marie-Françoise AVRIL  - Pr Eve MAUBEC"}
{"Disease Name": "Familial mesial temporal lobe epilepsy with febrile seizures", "Disease Definition": "A rare, genetic, familial partial epilepsy disease characterized by simple partial seizures, complex partial seizures and/or secondarily generalized seizures, originating from the inner aspect of the temporal lobe, associated with an antecedant history of febrile seizures, ocurring in various members of a family. Hippocampal abnormalities (e.g. hippocampal sclerosis) may also be associated.", "ORPHA ID": 165805, "Summary": ""}
{"Disease Name": "Familial mitral valve prolapse", "Disease Definition": "A rare familial congenital mitral malformation characterized by systolic displacement of one or both mitral leaflets >2 mm beyond the annular plane into the left atrium. Typical histological findings include myxomatous degeneration and degradation of collagen and elastin. Patients may remain asymptomatic or develop complications such as severe mitral regurgitation, endocarditis, and heart failure.", "ORPHA ID": 741, "Summary": ""}
{"Disease Name": "Familial monosomy 7 syndrome", "Disease Definition": "A rare neoplastic disease characterized by infantile to childhood onset of evidence of bone marrow insufficiency/failure associated with increased risk for myelodysplastic syndrome or acute myeloid leukemia. Most patients present with petechiae, easy bruising, or anemia. Rapid progression is common, and prognosis is generally poor.", "ORPHA ID": 495930, "Summary": ""}
{"Disease Name": "Familial multinodular goiter", "Disease Definition": "A rare thyroid disease characterized by familial occurrence of thyroid enlargement due to the development of multiple hyperplastic nodules with onset in childhood or adolescence. The condition is commonly associated with the development of other benign or malignant tumors.", "ORPHA ID": 276399, "Summary": ""}
{"Disease Name": "Familial multiple discoid fibromas", "Disease Definition": "A rare, genetic, skin tumor disorder characterized by childhood-onset of multiple, benign, asymptomatic, white to flesh-colored papules predominently located on the face, ears, neck and trunk, not associated with systemic organ involvement, malignancies or FLCN gene locus mutation.", "ORPHA ID": 538756, "Summary": ""}
{"Disease Name": "Familial multiple lipomatosis", "Disease Definition": "Familial multiple lipomatosis is a rare, benign, genetic skin disease characterized by numerous, painless, encapsulated lipomas located in the subcutaneous adipose tissue of the trunk and extremities, with relative sparing of the neck and shoulders. Association with gastroduodenal lipomatosis, brain anomalies or lipomatosis, and refractory epilepsy has been reported.", "ORPHA ID": 199276, "Summary": ""}
{"Disease Name": "Familial multiple meningioma", "Disease Definition": "Familial multiple meningioma is a rare, benign neoplasm of the central nervous system characterized by the development of multiple or, rarely, solitary meningiomas in two or more blood relatives, without other apparent syndromic manifestations. Depending on the localization, growth rate and size of the tumors, patients can present with subtle, gradually worsening or abrupt and severe neurological compromise or can be completely asymptomatic.", "ORPHA ID": 263662, "Summary": ""}
{"Disease Name": "Familial multiple nevi flammei", "Disease Definition": "Familial multiple nevi flammei is a rare, genetic capillary malformation disorder characterized by dark red to purple birthmarks which manifest as flat, sharply circumscribed cutaneous lesions, typically situated in the head and neck region, in various members of a single family. The lesions grow proportionally with the individual, change in color and often thicken with age.", "ORPHA ID": 624, "Summary": ""}
{"Disease Name": "Familial nasal acilia", "Disease Definition": "Familial nasal acilia is a rare genetic otorhinolaryngologic disease characterized by respiratory morbidity due to lack of cilia on the respiratory tract epithelial cells. The disease manifests from birth with respiratory distress, neonatal pneumonia, dyspnea, lobar atelectasis and bronchiectasis. Recurrent infections of the upper and lower respiratory tract, chronic humid coughing, and chronic sinusitis, otitis and rhinitis are typical lifelong presenting conditions.", "ORPHA ID": 922, "Summary": ""}
{"Disease Name": "Familial nonmedullary thyroid carcinoma", "Disease Definition": "A rare non-syndromic form of thyroid cancer characterized by occurrence of thyroid carcinoma (TC) as the primary feature in a familial setting.", "ORPHA ID": 319494, "Summary": ""}
{"Disease Name": "Familial omphalocele syndrome with facial dysmorphism", "Disease Definition": "Familial omphalocele syndrome with facial dysmorphism is a rare genetic developmental defect during embryogenesis characterized by omphalocele associated with facial dysmorphism including flat face, short, upturned nose, long and wide philtrum and flattened maxillary arch and abnormalities of hands.", "ORPHA ID": 280403, "Summary": ""}
{"Disease Name": "Familial or sporadic hemiplegic migraine", "Disease Definition": "A rare variety of migraine with aura characterized by the presence of a motor weakness during the aura. There are two main forms depending on the familial history: patients with at least one first- or second-degree relative who has aura including motor weakness have familial hemiplegic migraine (FHM); patients without such familial history have sporadic hemiplegic migraine (SHM).", "ORPHA ID": 569, "Summary": "Epidemiology\nThe prevalence of hemiplegic migraine (HM) is one in 10,000, with FHM and SHM being equally frequent.\nClinical description\nTypical HM attacks are characterised by motor weakness that is always associated with other aura symptoms, the most frequent being sensory, visual and speech disorders. In addition, basilar-type symptoms occur in up to 70% of patients. Severe attacks may occur in both FHM and SHM with prolonged hemiplegia, confusion, coma, fever and seizures. The clinical spectrum also includes permanent cerebellar signs (nystagmus, ataxia, dysarthria) and less frequently various types of seizures and intellectual deficit.\nEtiology\nThe three causative genes identified so far encode ion-transporters (CACNA1A, ATP1A2 and SCNA1). Molecular diagnosis is now possible through screening of these three genes.\nGenetic counseling\nFHM is transmitted in an autosomal dominant manner.\nManagement and treatment\nTreatment involves the same approaches used for other varieties of migraine with aura, with the exception that triptans are contraindicated in FHM/SHM. Based on new pathophysiological insights, preventive treatments using various antiepileptic agents seem promising.\nPrognosis\nPrognosis is usually good.\n\n                            Last update: \n                            April 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Anne DUCROS"}
{"Disease Name": "Familial ossifying fibroma", "Disease Definition": "A rare genetic bone disease characterized by multifocal, painless, benign fibrocemento-osseous lesions of the jaws which expand progressively and can cause severe facial deformity. It usually manifests at an early age and is often associated with abnormalities of the long bones and pathologic fractures. Radiologically, the lesions are of mixed radiopaque/radiolucent appearance. Incomplete surgical removal may lead to more rapid growth of the residual lesion.", "ORPHA ID": 435329, "Summary": ""}
{"Disease Name": "Familial osteochondritis dissecans", "Disease Definition": "Familial osteochondritis dissecans is a rare genetic skeletal disorder characterized clinically by abnormal chondro-skeletal development, disproportionate short stature and skeletal deformation mainly affecting the knees, hips, ankles and elbows with onset generally in late childhood or adolescence.", "ORPHA ID": 251262, "Summary": ""}
{"Disease Name": "Familial osteodysplasia, Anderson type", "Disease Definition": "Familial osteodysplasia, Anderson type is a rare, genetic dysostosis disorder characterized by craniofacial bone abnormalities (i.e. midface hypoplasia, broad, flat nasal bridge, narrow, thin prognathic mandible with pointed chin, malocclusion, partial dental agenesis) associated with additional osseous anomalies, including scoliosis, calvarial thinning, pointed spinous processes, clinodactyly and abnormal phalanges. Elevated erythrocyte sedimentation rate, hyperuricemia and hypertension have also been reported. There have been no further descriptions in the literature since 1982.", "ORPHA ID": 2769, "Summary": ""}
{"Disease Name": "Familial pancreatic carcinoma", "Disease Definition": "Familial pancreatic carcinoma is defined by the presence of pancreatic cancer (PC) in two or more first-degree relatives.", "ORPHA ID": 1333, "Summary": "Epidemiology\nThe annual incidence has been estimated at approximately 1-10/1,000,000, representing 5-10% of all PC cases.\nClinical description\nIn familial cases, disease onset occurs before 50 years of age, earlier than for the other forms of PC. A high incidence of familial PC has been observed within hereditary syndromes (Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma syndrome, hereditary breast and ovarian cancer syndrome, and hereditary nonpolyposis colorectal cancer; see these terms). Smoking represents a significant risk factor associated with familial PC. PC can arise from the exocrine (95%) or endocrine portions of the pancreas. In 60% of cases it occurs within the head of the pancreas. The main symptoms are non-specific and include pain in the upper abdomen that typically radiates to the back, loss of appetite, significant weight loss and painless jaundice due to bile duct obstruction. As the clinical course is silent, PC often goes undetected until the advanced stages of the disease. In more than 80% of cases, the cancer is either locally advanced or disseminated at the time of diagnosis. A rapid growth pattern, early vascular dissemination, spread to regional lymph nodes, and metastases to distant organs (liver, peritoneum, lungs) are characteristic. PC can also invade the surrounding visceral organs.\nEtiology\nMutations in the KRAS,  CDKN2A, TP53, and SMAD4 genes have been shown to play a role in the etiology of PC. However, they are still not clinically useful for screening or for diagnosing the disease.\nDiagnostic methods\nDiagnostic methods include ultrasound, contrast-enhanced multidetector computed tomography (MDCT); magnetic resonance (MR) imaging, and integrated positron emission tomography (PET)/computed tomography (CT). Invasive diagnostic techniques are endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound. CA 19-9 is a sensitive tumor serum marker but is not specific.\nDifferential diagnosis\nDifferential diagnoses include a wide variety of diseases such as acute and chronic pancreatitis, cholangitis, cholecystitis, cholelithiasis, bile duct tumors and strictures, and gastric cancer and ulcers.\nManagement and treatment\nSurgical resection is the only potentially curative treatment. However, most patients (80%) present with advanced non-resectable tumors. In these cases, chemotherapy (gemcitabine) or radiotherapy, alone or in combination, are alternative treatments, although rather ineffective.\nPrognosis\nPrognosis is poor (with an overall 5-year survival rate of 5%). Even after complete resection of the tumor, recurrence rates remain high. Patients with a family history of PC should be strongly advised to avoid or cease smoking.\n\n                            Last update: \n                            September 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Dominique VALLA"}
{"Disease Name": "Familial papillary or follicular thyroid carcinoma", "Disease Definition": "Familial papillary or follicular thyroid carcinoma is a rare, hereditary nonmedullary thyroid carcinoma characterized by the presence of differentiated thyroid cancer of follicular cell origin in two or more first-degree relatives, in the absence of other familial tumor syndromes or radiation exposure. Frequent capsular invasion is observed. Biopsy reveals multicentric tumors with multiple adenomatous nodules with or without oxyphilia and follicular or papillary carcinoma histology.", "ORPHA ID": 319487, "Summary": ""}
{"Disease Name": "Familial papillary thyroid carcinoma with renal papillary neoplasia", "Disease Definition": "An extremely rare inherited tumor syndrome within the familial nonmedullary thyroid cancer group.", "ORPHA ID": 97290, "Summary": ""}
{"Disease Name": "Familial paroxysmal ataxia", "Disease Definition": "A form of hereditary episodic ataxia (EA) characterized by paroxysmal episodes of ataxia lasting hours, with interictal nystagmus and mildly progressive ataxia.", "ORPHA ID": 97, "Summary": ""}
{"Disease Name": "Familial partial lipodystrophy, Dunnigan type", "Disease Definition": "A rare, genetic lipodystrophy characterized by a loss of subcutaneous adipose tissue from the trunk, buttocks and limbs; fat accumulation in the neck, face, axillary and pelvic regions; muscular hypertrophy; and usually associated with metabolic complications such as insulin resistance, diabetes mellitus, dyslipidemia and liver steatosis.", "ORPHA ID": 2348, "Summary": "Epidemiology\nFamilial partial lipodystrophy, Dunnigan type (FPLD2) is the most frequent form of familial partial lipodystrophy (FPLD) for which the prevalence is estimated at less than 1/100,000 in Europe; although, this is likely an underestimate.\nClinical description\nOnset of lipodystrophy usually occurs at or around puberty, with regional loss of subcutaneous adipose tissue from the limbs, buttocks and trunk, followed by a progressive fat accumulation on the face, neck and axillary regions giving patients a cushingoid appearance. Females often have a more severe phenotype than males. An increased skeletal muscle volume and mass is also noted. Prominent veins (due to lipoatrophy) are noted in the limbs. Metabolic complications appear progressively in adolescence or in adulthood and include insulin resistance, diabetes, hepatic steatosis, acanthosis nigricans, high blood pressure, and premature atherosclerosis with an increased risk of coronary heart disease. Some patients may display the features of polycystic ovary syndrome such as hirsutism, oligomenorrhea, polycystic ovaries and infertility. All patients are typically predisposed to early cardiovascular diseases. Other manifestations may include complications of diabetes, recurrent acute pancreatitis and liver steatohepatitis or cirrhosis.\nEtiology\nFPLD2 is caused by mutations in the LMNA gene (1q22) encoding the nuclear intermediate filaments A-type lamins. Typical forms of FPLD2 are mainly due to heterozygous substitutions at the 482nd codon of the gene (p.R482W/Q or L mutation). Other monoallelic or biallelic LMNA pathogenic variants are rarely found, and are more frequently associated with atypical forms of lipodystrophies, associated or not with other laminopathic phenotypes (muscular and/or cardiac dystrophies, accelerated aging).\nDiagnostic methods\nDiagnosis is made by clinical examination, analysis of fat distribution by imaging (MRI, CT-scan and whole-body dual-energy X-ray absorptiometry) and evaluation of metabolic status (hypertriglyceridemia, low levels of high density lipoprotein (HDL)-cholesterol in the blood, hyperinsulinemia, altered glucose tolerance, low circulating levels of leptin and adiponectin). Body mass index is usually normal. Liver enzyme levels should be measured and ultrasonography of liver should be performed, and with transient elastography if a fatty liver disease is suspected. Cardiovascular investigations are needed to search for rhythm and conduction disturbances, and early atherosclerosis. Molecular genetic testing confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other forms of FPLD as well as Cushing syndrome, type 2 diabetes, metabolic syndrome and acquired lipodystrophy.\nAntenatal diagnosis\nPrenatal diagnosis could be discussed in families with a known disease causing mutation.\nGenetic counseling\nFPLD2 is inherited in an autosomal dominant manner; where there is an affected parent, the risk of disease transmission is 50%.\nManagement and treatment\nTreatment consists of correcting metabolic abnormalities and managing complications. Monitoring diet (reduced intake of dietary fats and carbohydrates) and maintaining daily physical activity can improve the metabolic complications of lipodystrophy. Insulin sensitizers (mainly metformin) and lipid-lowering drugs (statins, or fibrates in case of major hypertriglyceridemia) can also be helpful. Diabetes may require other non-specific treatments, along with insulin. The orphan drug metreleptin is authorized under exceptional circumstances in Europe for the treatment of metabolic complications of partial forms of lipodystrophies, in adults and children above the age of 12 years, where standard treatments have failed. Further studies are required to investigate the benefits and risks of treatment. Regular cardiac monitoring is recommended. Ethinylestradiol should be avoided in women with FPLD2. Plastic surgery can help some patients.\nPrognosis\nPrognosis is linked to the severity of associated comorbidities (diabetes, pancreatitis, cardiovascular diseases).\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Corinne VIGOUROUX"}
{"Disease Name": "Familial partial lipodystrophy, Köbberling type", "Disease Definition": "Familial partial lipodystrophy, Köbberling type, is a very rare form of familial partial lipodystrophy (FPLD; see this term) of unknown etiology characterized by lipoatrophy that is confined to the limbs and a normal or increased fat distribution of the face, neck, and trunk. Arterial hypertension and diabetes have also been associated. Inheritance is thought to be autosomal dominant.", "ORPHA ID": 79084, "Summary": ""}
{"Disease Name": "Familial partial lipodystrophy", "Disease Definition": "A group of rare genetic lipodystrophies characterized, in most cases, by fat loss from the limbs and buttocks, from childhood or early adulthood, and often associated with acanthosis nigricans, insulin resistance, diabetes, hypertriglyceridemia and liver steatosis.", "ORPHA ID": 98306, "Summary": "Epidemiology\nThe prevalence of familial partial lipodystrophy (FPLD) is estimated at less than 1/100,000 in Europe; however, this is likely an underestimate.\nClinical description\nWhilst FPLD is clinically and genetically heterogeneous, each form of FPLD shows a varying degree of lipoatrophy of trunk and/or extremities with sparing subcutaneous fat or even fat accumulation in the cervico-facial and/or truncal region. Patients appear normal at birth and throughout childhood regarding fat distribution but develop clinically apparent changes near puberty. Metabolic complications appear progressively in adolescence or in adulthood and include insulin resistance, diabetes, hepatic steatosis, acanthosis nigricans, high blood pressure, and premature atherosclerosis with an increased risk of coronary heart disease. Some females may display the features of polycystic ovary syndrome such as hirsutism, oligomenorrhea, polycystic ovaries and infertility. Patients are typically predisposed to early cardiovascular diseases. Other manifestations may include complications of diabetes, recurrent acute pancreatitis and liver steatohepatitis or cirrhosis. FPLD3 is frequently associated with severe hypertension.\nEtiology\nFPLD2, the most common form of FPLD, is caused by a mutation in the LMNA gene (1q22) encoding the nuclear intermediate filaments A-type lamins. Other mutations in this gene can lead to atypical lipodystrophies, more frequently associated with other laminopathic phenotypes (muscular and/or cardiac dystrophies, accelerated aging) such as autosomal codominant severe lipodystrophic laminopathy. Other genes associated with rarer genetic variants of FPLD include PPARG (3p25; FPLD3), AKT2 (19q13.1-q13.2), PLIN1 (15q26; FPLD4), CIDEC (3p25; FPLD5) and LIPE (19q13.1-q13.2; FPLD6). FPLD1 is probably of oligogenic or polygenic origin including different etiological subtypes . Many patients with a FPLD phenotype do not display any pathogenic variants in these genes and thus other disease-causing genes are yet to be discovered.\nDiagnostic methods\nDiagnosis is made by clinical examination, analysis of fat distribution by imaging (MRI, CT-scan and whole-body dual-energy X-ray absorptiometry) and evaluation of metabolic status (hypertriglyceridemia, low levels of high density lipoprotein (HDL)-cholesterol in the blood, hyperinsulinemia, altered glucose tolerance, low circulating levels of leptin and adiponectin). Body mass index is usually normal. Liver enzyme levels should be measured and ultrasonography of liver should be performed, and with transient elastography if a fatty liver disease is suspected. Cardiovascular investigations are needed to search for rhythm and conduction disturbances, and early atherosclerosis. Molecular genetic testing confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other forms of FPLD as well as Cushing syndrome, type 2 diabetes, metabolic syndrome and acquired lipodystrophy.\nAntenatal diagnosis\nPrenatal diagnosis could be discussed in families with a known disease causing mutation.\nGenetic counseling\nDepending on the causal mutation involved, FPLD can be inherited in an autosomal dominant or recessive manner. Genetic counseling is possible in families with a known disease-causing mutation.\nManagement and treatment\nTreatment consists of correcting metabolic abnormalities and managing complications. Monitoring diet (reduced intake of dietary fats and carbohydrates) and maintaining daily physical activity can improve the metabolic complications of lipodystrophy. Insulin sensitizers (mainly metformin) and lipid-lowering drugs (statins, or fibrates in case of major hypertriglyceridemia) can also be helpful. Diabetes may require other non-specific treatments, along with insulin. The orphan drug metreleptin is authorized under exceptional circumstances in Europe for the treatment of metabolic complications of partial forms of lipodystrophies, in adults and children above the age of 12 years, where standard treatments have failed. Further studies are required to investigate the benefits and risks of treatment. Regular cardiac monitoring is recommended. Ethinylestradiol should be avoided in women with FPLD and hypertriglyceridemia. Plastic surgery can help some patients.\nPrognosis\nPrognosis is linked to the severity of associated comorbidities (diabetes, pancreatitis, cardiovascular diseases).\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Corinne VIGOUROUX"}
{"Disease Name": "Familial patent arterial duct", "Disease Definition": "Familial patent arterial duct is a rare, genetic, non-syndromic, congenital anomaly of the great arteries characterized by the presence of an isolated patent arterial duct (PDA) (i.e. failure of closure of ductus arteriosis after birth) in several members of the same family. Clinical presentation is similar to the sporadic form and may range from neonatal-onset tachypnea, diaphoresis and failure to thrive to adult-onset atrial arrhythmia, signs and symptoms of heart failure and cyanosis limited to the lower extremities.", "ORPHA ID": 466729, "Summary": ""}
{"Disease Name": "Familial peripheral male-limited precocious puberty", "Disease Definition": "Familial male limited precocious puberty (FMPP) is a gonadotropin-independent familial form of male-limited precocious puberty, generally presenting between 2-5 years of age as accelerated growth, early development of secondary sexual characteristics and reduced adult height.", "ORPHA ID": 3000, "Summary": "Epidemiology\nFMPP is a very rare condition; prevalence is less than 1/1,000,000.\nClinical description\nFMPP presents in boys from 2-5 years of age with precocious signs of puberty including growth acceleration, penile enlargement, acne, pubic hair and facial hair. Spontaneous erection and masturbatory behavior are commonly observed. Testicular volume is moderately increased, in contrast to central precocious puberty (see this term) where testicular volume is markedly enlarged, similar to normal puberty. Presentation is variable, even between siblings, but most untreated patients have been reported to have premature epiphyseal fusion resulting in a compromised adult height. Aggressive behavior and social exclusion may occur. Mild oligospermia has been reported in some adults, but most individuals retain fertility. An increased risk of attention-deficit hyperactivity disorder (ADHD) has been observed.\nEtiology\nFMPP is caused by an activating mutation of the Lutropin-Choriogonadotropic Hormone Receptor gene (LHCGR, 2p21) which leads to increased levels of sex steroids in the context of low luteinizing hormone. This receptor's chronic activation leads to precocious testosterone production by Leydig cells. No effect is observed in female carriers due to the dual luteinizing hormone (LH)/ follicle stimulating hormone (FSH) signal necessary to promote ovarian stimulation.\nDiagnostic methods\nPatients display increased serum testosterone levels (typically 3- 20 nmol/l) and decreased secretion of gonadotropins, even after stimulation with luteinizing hormone-releasing hormone (LHRH). Radiological examination reveals skeletal maturation. Diagnosis is confirmed by genetic testing identifying activating mutations in the LHCGR gene.\nDifferential diagnosis\nDifferential diagnoses include other causes of precocious puberty associated with low levels of gonadotropins such as adrenal tumors, testicular Leydig cell tumors (ruled out by testicular ultrasound since they can be of small size), human chorionic gonadotropin (HCG)-secreting tumors, congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, CAH due to 11-beta-hydroxylase deficiency, central precocious puberty (with detectable LH levels that can be stimulated by gonadotropin-releasing hormone (GnRH) or GnRH agonists) (see these terms), and occult exposure to androgens.\nAntenatal diagnosis\nPrenatal genetic screening is feasible when a proband has been identified.\nGenetic counseling\nTransmission is autosomal dominant. Mothers may act as silent carriers, with each son having a 50% risk of displaying FMPP.\nManagement and treatment\nTreatment consists in reducing hyperandrogenism in children (sexual maturation, stature). Two options have been proposed. The first one consists of administrating the androgen antagonist bicalutamide (12.5-100 mg/d) together with aromatase inhibitors such as anastrozole (1 mg/d) or letrozole (2.5 mg/d) to normalize the growth rates until adult height has been reached. The second option consists of administrating androgen biosynthesis inhibitors such as ketoconazole (15 mg/kg/d) that result in a decrease in testosterone levels. In both cases, the treatments may be supplemented by GnRH therapy if central (gonadotropin-dependent) precocious puberty develops. Psychological counseling is needed to help the patient and family adjust to the stimulative effects of high androgen levels.\nPrognosis\nPrognosis is good; with treatment most patients reach an appropriate adult height. The disease does not seem to have any consequence during adulthood but this is based on limited clinical reports.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Claude CAREL"}
{"Disease Name": "Familial platelet disorder with associated myeloid malignancy", "Disease Definition": "A rare, genetic, constitutional thrombocytopenia disease characterized by mild to moderate thrombocytopenia, abnormal platelet function and a propensity to develop hematological malignancies, mainly of myeloid origin.", "ORPHA ID": 71290, "Summary": "Epidemiology\nThe estimated prevalence at birth is less than 1/ 1 000 000. There are no available data on the incidence of the disease.\nClinical description\nPatients present mild to moderate thrombocytopenia (with normal platelet size) and/or abnormalities of platelet function, in particular defective release of delta granules and/or aggregation defects. However, a clear bleeding history (i.e., severe epistaxis, easy bruising, petechial or prolonged bleeding) is absent in many affected individuals. In the event of severe thrombocytopenia or profound platelet dysfunction, thrombocytopenia is usually recognized during the perinatal or infancy period.\nEtiology\nHeterozygous germline nonsense or missense variants as well as deletions in or of RUNX1 gene (21q22.12) have been identified as the causative alteration of the disease.\nDiagnostic methods\nDiagnosis is suspected in patients who present with mild to moderate thrombocytopenia, thrombocyte aggregation defect and/or a hematological malignancy (mainly MDS/AML, but also T-ALL) and may have a history of the same in various other family members. Genetic testing including sequencing and copy number analyses that identifies a pathogenic variant in RUNX1 confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses for familial platelet disorder with associated myeloid malignancy include several inherited disorders such as congenital amegakaryocytic thrombocytopenia (CAMT), thrombocytopenia with absent radii (TAR), and Wiskott-Aldrich syndrome (WAS).\nAntenatal diagnosis\nPrenatal diagnosis is possible in families in which a causative gene mutation has been previously identified in an affected family member.\nGenetic counseling\nThe disease is inherited as an autosomal dominant trait exhibiting incomplete penetrance and variable expressivity. Genetic counseling informing patients with a causative mutation of the 50% risk of transmission to future offspring and their risk to leukemia should be offered in expert centers.\nManagement and treatment\nCurrently, hematopoietic stem cell transplantation (HSCT) in preleukaemic patients with the disease remains debatable due to transplantation-associated risks and incomplete penetrance of the disease. In patients with a hematologic malignancy, HSCT may be indicated. However, HSCT using cells of HLA-matched relatives carrying the familial gene variant have to be avoided.\nPrognosis\nPrognosis depends on the development of a hematological malignancy and its disease course.\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Tim RIPPERGER"}
{"Disease Name": "Familial primary localized cutaneous amyloidosis", "Disease Definition": "A rare primary cutaneous amyloidosis characterized by familial occurrence of lichen and/or macular amyloidosis due to fibrillary degeneration and apoptosis of basal keratinocytes, followed by conversion of filamentous masses into amyloid material in the papillary dermis. Patients typically present with a pruritic eruption of grouped hyperkeratotic papules, which may coalesce to form hyperkeratotic plaques, with a predilection for the lower limbs (lichen amyloidosis), or with hyperpigmented macules, sometimes with a reticulate pattern, most commonly arising on the back, chest or interscapular areas (macular amyloidosis).", "ORPHA ID": 353220, "Summary": ""}
{"Disease Name": "Familial progressive cardiac conduction defect", "Disease Definition": "A genetic cardiac rhythm disease that may progress to complete atrioventricular (AV) block. The disease is either asymptomatic or manifests as dyspnea, dizziness, syncope, abdominal pain, heart failure or sudden death.", "ORPHA ID": 871, "Summary": "Epidemiology\nTo date more than 50 Familial progressive cardiac conduction defect (PCCD) cases have been described in the literature.\nClinical description\nThe age of disease onset is variable. Familial PCCD is either asymptomatic or manifests as dyspnea, dizziness, syncopal episodes, abdominal pain, heart failure or sudden death when complete heart block develops. Syncope during exertion has been reported and the disease can progress from a normal electrocardiography (ECG) to right or left bundle branch block and from the latter to complete heart block.\nEtiology\nFamilial PCCD is a degenerative process affecting the His-Purkinje pathway. Mutations in three genes have been identified as disease-causing: SCN5A, SCN1B and TRPM4. Mutations in the genes NKX2-5, TBX5, PRKAG2 and LMNA have been identified when familial PCCD is accompanied by congenital heart disease. Isolated PCCD has also been described in families with carriers of a mutation in one of these genes. A candidate gene, GJA5, has been associated with severe, early onset PCCD and has been described in 2 blood relatives.\nDiagnostic methods\nDiagnosis of familial PCCD relies on family history of syncope, pacemaker implantation, and sudden death as well as on echocardiogram (ECG) findings showing a major conduction defect (complete right bundle branch block, complete left bundle branch block, left anterior fascicular block / hemiblock or left posterior hemiblock, prolonged PR interval or complete AV block with broad QRS complexes). In most cases, normal cardiac structure and contractile function are observed, but in some, complete AV block can lead to dilation of the left ventricle and heart failure. Ventricular tachycardia and torsade de pointes may be recorded during the recovery phase of an exercise stress test or during complete AV block. Potential congenital heart disease or cardiomyopathy is investigated by ECG or cardiac MRI. Screening of the genes involved in familial PCCD should be achieved even in cases of isolated PCCD at a young age.\nDifferential diagnosis\nThe differential diagnosis includes Brugada syndrome, idiopathic ventricular fibrillation, long QT syndrome, lupus neonatal, progressive familial heart block type II, and sudden infant death syndrome.\nGenetic counseling\nTransmission is autosomal dominant with incomplete penetrance and variable expressivity. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% of passing the mutation to offspring. Recessive or sporadic forms are rare.\nManagement and treatment\nTreatment of PCCD includes the timely implantation of a permanent pacemaker. Follow-up at 6-month intervals is recommended in patients with any degree of heart block and at least a yearly examination is recommended in members of the affected families with a normal ECG. Medications with conduction-slowing properties should be restricted, and fever, an aggravating trigger in individuals with SCN5A mutations, should be preemptively treated. When a clinical diagnosis of PCCD potentially from genetic origin is established in an index case (i.e; PCCD at early age, several cases of PCCD within the family) clinical investigation of first-degree family members is necessary.\nPrognosis\nThere is no genotype-based risk stratification for patients with PCCD. A high incidence of sudden death is observed in patients with either first-degree AV block in association with bifascicular block or in those with symptomatic advanced AV block. In patients who receive pacemaker implantation, the prognosis is excellent and is very close to that of the general population, except in those with LMNA mutations that can lead to ventricular tachycardia and sudden cardiac death. In this population, ICD implantation is recommended in case of severe cardiac conduction defect. For this reason, rapid genetic evaluation to screen LMNA gene is advise in case of PCCD in patient with clinical evaluation in favor of LMNA mutation (presence of ventricular tachycardia, LGE in the septum on the MRI).\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Vincent PROBST"}
{"Disease Name": "Familial progressive hyper- and hypopigmentation", "Disease Definition": "Familial progressive hyper- and hypopigmentation is a rare, genetic, skin pigmentation anomaly disorder characterized by progressive, diffuse, partly blotchy, hyperpigmented lesions that are intermixed with multiple café-au-lait spots, hypopigmented maculae and lentigines and are located on the face, neck, trunk and limbs, as well as, frequently, the palms, soles and oral mucosa. Dispigmentation pattern can range from well isolated café-au-lait/hypopigmented patches on a background of normal-appearing skin to confetti-like or mottled appearance.", "ORPHA ID": 280628, "Summary": ""}
{"Disease Name": "Familial progressive hyperpigmentation", "Disease Definition": "Familial progressive hyperpigmentation is a rare, genetic, skin pigmentation anomaly disorder characterized by irregular patches of hyperpigmented skin which present at birth or in early infancy and increase in size, number and confluence with age. Affected areas of the body include the face, neck, trunk and limbs, as well as the palms, soles, oral mucosa and conjuctiva. No hypogmentation macules are observed and no systemic diseases are associated.", "ORPHA ID": 79146, "Summary": ""}
{"Disease Name": "Familial progressive retinal dystrophy-iris coloboma-congenital cataract syndrome", "Disease Definition": "A rare, genetic retinal disorder characterized by bilateral iris coloboma, progressive retinal dystrophy and marked loss of vision, with or without congenital cataracts. Iridolenticular adhesions, scattered retinal pigmented epithelia mottling, and mild hypermetropic astigmatism may be associated.", "ORPHA ID": 488197, "Summary": ""}
{"Disease Name": "Familial prostate cancer", "Disease Definition": "Familial prostate cancer (FPC) is a malignant tumor of the prostate with an early onset. FPC is either asymptomatic or causes mictionary symptoms, erectile dysfunction, bone pain, venous compression and infectious or inflammatory syndrome (for the metastatic forms). It is also characterized by familial antecedents.", "ORPHA ID": 1331, "Summary": ""}
{"Disease Name": "Familial pseudohyperkalemia", "Disease Definition": "Familial pseudohyperkalemia (FP) is an inherited, mild, non-hemolytic subtype of hereditary stomatocytosis that is associated with a temperature-dependent anomaly in red cell membrane permeability to potassium that leads to high in vitro potassium levels in samples stored below 37°C. FP is not associated with additional hematological abnormalities, although affected individuals may show some mild abnormalities like macrocytosis.", "ORPHA ID": 90044, "Summary": "Epidemiology\nThe prevalence is unknown. Less than 15 kindreds have been reported in the literature so far (the majority being from the United Kingdom). The Arg723Gln substitution in ABCB6 leading to FP-Cardiff (a temperature-dependent pattern of cation leak previously recognized in a UK family) may affect 1/500 Europeans.\nClinical description\nFP is an asymptomatic condition that presents through blood tests as unexpectedly high plasma potassium levels, after storage at or below room temperature.\nEtiology\nAll families identified so far have mutations in the ABCB6 gene (2q36), leading to an inherited abnormality in the movement of ions across the red cell membrane, such that when the red cells are cooled they lose potassium into the plasma. Mutations in the PIEZO1 gene have been found in a kindred diagnosed as having FP but actually having dehydrated hereditary stomatocytosis (DHS; see this term), a condition that can have a similar presentation as FP due to the low number of stomatocytes.\nDiagnostic methods\nDiagnosis of FP may be suspected in patients with apparent hyperkalemia, but otherwise normal clinical and hematological findings, in whom pseudohyperkalemia due to other causes (cell lysis, extreme leukocytosis or thrombocythemia, or use of EDTA anticoagulant) has been excluded. The presence of red-cell based pseudohyperkalemia can be tested by taking heparinized blood, aliquoting, and storing aliquots at 37, 20 and 0°C over 24 hours. At time points, aliquots are taken and spun and the plasma potassium measured in the sample. In the 'pseudohyperkalemic' sample the plasma potassium will typically be normal at time zero, then rise with time in the samples which are stored at 20 and 0°C. In normal samples there is very little change at any temperature. The affected individuals may show mild abnormalities in the red cells (e.g. macrocytosis).\nDifferential diagnosis\nFP needs to be differentiated from true hyperkalemia associated with reduced renal function, acidosis, the use of certain medications and rare diseases such as Addison's disease and pseudohypoaldosteronism type 2 (see these terms). Pseudohyperkalemia can also be caused by leukemic and thrombocythemic conditions, lysis during venipuncture and by the use of EDTA anticoagulant.\nGenetic counseling\nFP is inherited as an autosomal dominant trait. Genetic counseling may be provided to patients and their families to explain the autosomal dominant and fully penetrant nature of the disorder.\nManagement and treatment\nNo treatment is required. However, correct diagnosis is important so that needless urgent calls to hospital, and occasionally misplaced insulin/glucose and/or fludrocortisone treatment (for supposed true hyperkalemia) can be avoided. Because some FP variants show quite large abnormalities at refrigerator temperatures, affected individuals should not donate blood for transfusion.\nPrognosis\nThe prognosis for patients is excellent. Most patients remain asymptomatic.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Lesley BRUCE  - Pr Gordon STEWART"}
{"Disease Name": "Familial reactive perforating collagenosis", "Disease Definition": "Familial reactive perforating collagenosis is a very rare genetic skin disease characterized by transepidermal elimination of collagen fibers presenting as recurrent spontaneously involuting keratotic papules or nodules.", "ORPHA ID": 79147, "Summary": ""}
{"Disease Name": "Familial recurrent peripheral facial palsy", "Disease Definition": "A rare peripheral neuropathy characterized by an acute onset of unilateral facial muscle weakness with Bell's phenomenon. It is non-progressive, resolves spontaneously, and it might be recurrent with no obvious precipitating factors.", "ORPHA ID": 2809, "Summary": ""}
{"Disease Name": "Familial renal glucosuria", "Disease Definition": "A rare, genetic, glucose transport disorder characterized by the presence of persistent isolated glucosuria in the absence of both proximal tubular dysfunction and hyperglycemia. The disorder is benign in the majority of cases although it may occasionally manifest with polyuria, enuresis, a mild growth and pubertal maturation delay, hypercalciuria, aminoaciduria and, in severe cases, increased incidence of urinary infections and episodic dehydration and ketosis during pregnancy and starvation.", "ORPHA ID": 69076, "Summary": ""}
{"Disease Name": "Familial retinal arterial macroaneurysm", "Disease Definition": "A rare, genetic cardiac disease characterized by an early onset of retinal artery macroaneurysms formation and concomitant supravalvular pulmonic stenosis, often requiring surgical correction.", "ORPHA ID": 284247, "Summary": ""}
{"Disease Name": "Familial scaphocephaly syndrome, McGillivray type", "Disease Definition": "Familial scaphocephaly syndrome, McGillivray type is a rare newly described craniosynostosis (see this term) syndrome characterized by scaphocephaly, macrocephaly, severe maxillary retrusion, and mild intellectual disability.", "ORPHA ID": 168624, "Summary": "Epidemiology\nIt has been reported in 11 patients from a three-generation family.\nClinical description\nThe patients had variable dysmorphic features including high forehead, marked midface hypoplasia with severe maxillary retrusion, relative or absolute prognathism, and malocclusion. More severely affected patients were male and had intellectual disability.\nEtiology\nMolecular analysis revealed a K526E mutation of the fibroblast growth factor receptor 2 gene, FGFR2.\nGenetic counseling\nIn this family, findings are consistent with autosomal dominant inheritance.\n\n                            Last update: \n                            November 2010"}
{"Disease Name": "Familial short QT syndrome", "Disease Definition": "A rare, genetic cardiac rhythm disease characterized by a short QTc interval on the surface electrocardiogram (ECG) with a high risk of syncope or sudden death due to malignant ventricular arrhythmia.", "ORPHA ID": 51083, "Summary": "Epidemiology\nThis extremely rare syndrome affects mainly young adults or infants and has been reported in nearly 80 families. The disease has been predominantly reported in males.\nClinical description\nWhilst the disease may remain asymptomatic, the most common clinical presentation is a cardiac arrest (CA), with approximately 40% of patients suffering an episode of CA between birth and 40 years of age. Other symptoms include syncope and arrhythmias including atrial fibrillation, ventricular fibrillation (VF), supraventricular tachycardia (SVT), and polymorphic ventricular tachycardia. There is a high risk of recurrent arrhythmic events in symptomatic patients. The risk of sudden cardiac death (SDC) is highest in the first year of life and between 20 to 40 years.\nEtiology\nMutations in the genes KCNQ1 (11p15.5), KCNH2 (7q36.1), and KCNJ2 (17q24.3), encoding cardiac ionic potassium channels, and the gene encoding the calcium channel, CACNA2D1 (7q21.11), have been identified in affected patients. 40% of patients do not have a genetic cause identified.\nDiagnostic methods\nAccording to the European Society of Cardiology Guidelines, SQTS is diagnosed by the presence of a corrected QT (QTc) interval less than or equal to 340 ms on resting 12-lead ECG or should be considered in the presence of a QTc less than or equal 360 ms and one or more of the following: a confirmed pathogenic mutation, a family history of SQTS, a family history of sudden death at young age (less than 40 years of age), or history of ventricular tachyarrhythmia/ventricular fibrillation (VT/VF) in the absence of heart disease. When a patient is diagnosed, clinical assessment is recommended in all family members, including an ECG in newborns.\nDifferential diagnosis\nDifferential diagnosis includes other repolarizing disorders such as Brugada syndrome and early repolarization syndrome. Of note, a few rare patients with Brugada syndrome have been reported to have a short QTc.\nGenetic counseling\nTransmission is autosomal dominant. Genetic counseling should be offered to affected families. First-degree relatives of an affected individual have a 50% risk of being affected. Sporadic cases have also been reported.\nManagement and treatment\nCurrently, an automatic implantable cardioverter-defibrillator (ICD) is recommended for patients who have experienced a sustained VT/VF episode or have survived an aborted cardiac arrest. However, ICD is complicated by a high probability of inappropriate ICD shocks, particularly in pediatric patients, and requires appropriate programming to prevent T-wave oversensing. Quinidine prophylaxis may be considered in patients where ICD is contraindicated/refused or in asymptomatic SQTS patients with a family history of SDC. Patients on quinidine should be carefully monitored for QT prolongation and possible pro-arrhythmic events.\nPrognosis\nThe risk of sudden cardiac death is high, and a history of survived cardiac arrest at the initial presentation is a strong predictor of recurrent ventricular arrhythmias over the course of time.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Isabelle DENJOY"}
{"Disease Name": "Familial sick sinus syndrome", "Disease Definition": "A rare cardiac rhythm disease, usually of the elderly, characterized by electrocardiographic findings of sinus bradycardia, atrial fibrillation, atrial tachycardia sinus arrest, or sino-atrial block, and that manifest with symptoms like syncope, dizziness, palpitations, fatigue, or even heart failure. It results from malfunction of the cardiac conduction system, probably secondary to degenerative fibrosis of nodal tissue in the elderly or secondary to cardiac disorders in younger patients.", "ORPHA ID": 166282, "Summary": ""}
{"Disease Name": "Familial spontaneous pneumothorax", "Disease Definition": "Familial spontaneous pneumothorax is a rare, genetic pulmonary disease characterized by the uni- or bilateral accumulation of air in the pleural cavity in persons with a positive family history and no underlying lung disease or previous chest trauma. Patients typically present dyspnea associated with acute onset of sharp and steady pleutiric chest pain of variable severity (which resolves within 24h even though pneumothorax is still present). Reflex tachycardia and/or respiratory or circulatory compromise may be observed. Other syndromes (e.g. Birt-Hogg-Dube, Marfan or Ehlers-Danlos syndromes) may be associated.", "ORPHA ID": 2903, "Summary": ""}
{"Disease Name": "Familial steroid-resistant nephrotic syndrome with adrenal insufficiency", "Disease Definition": "A rare disorder with multisystemic involvement and glomerulopathy characterized by progressive steroid-resistant nephrotic syndrome typically associated with focal segmental glomerulosclerosis, as well as primary adrenal insufficiency with adrenal calcifications. Age of onset and disease course are variable, with some cases presenting as severe fetal hydrops, while most patients present in infancy or early childhood and progress to end-stage renal disease within a few years. Additional features include ichthyosis, primary hypothyroidism, hypogonadism, immunodeficiency, and neurological manifestations (such as cognitive impairment, ataxia, sensorineural hearing loss, or seizures).", "ORPHA ID": 506334, "Summary": ""}
{"Disease Name": "Familial steroid-resistant nephrotic syndrome with sensorineural deafness", "Disease Definition": "A rare, genetic coenzyme Q10 deficiency characterized by sensorineural deafness and severe, progressive nephrotic syndrome not responding to steroid treatment. Clinical manifestations include early onset proteinuria, hypoalbuminemia and edema, leading to end-stage renal disease. The renal biopsy reveals focal segmental glomerulosclerosis and diffuse mesangial sclerosis. Rarely, seizures, ataxia and dysmorphic features have been described.", "ORPHA ID": 280406, "Summary": ""}
{"Disease Name": "Familial supernumerary nipples", "Disease Definition": "Familial supernumerary nipples is a rare breast malformation characterized by the presence, in various members of a single family, of one or more nipple(s) and/or their related tissue, in addition to the normal bilateral chest nipples. The anomaly is usually situated along the embryonic milk line, from axillae to inguinal regions, but other locations are also possible. Association with dental abnormalities, Becker nevus, renal or underlying breast tissue malignancy and genitourinary malformations has been reported.", "ORPHA ID": 2456, "Summary": ""}
{"Disease Name": "Familial temporal lobe epilepsy", "Disease Definition": "A rare, genetic epilepsy characterized by mostly benign simple or complex partial seizures with autonomic or psychic auras. Seizures occur infrequently, are of short duration and are usually well controlled with medication. Development and cognition are normal.", "ORPHA ID": 98819, "Summary": ""}
{"Disease Name": "Familial thoracic aortic aneurysm and aortic dissection", "Disease Definition": "Familial thoracic aortic aneurysm and aortic dissection is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch or descending aorta) in the absence of any other associated disease. Depending on the size, location and progression rate of dilatation/dissection, patients may be asymptomatic or may present dyspnea, cough, jaw, neck, chest or back pain, head, neck or upper limb edema, difficulty swallowing, voice hoarseness, pale skin, faint pulse and/or numbness/tingling in limbs. Patients have increased risk of presenting life threatening aortic rupture.", "ORPHA ID": 91387, "Summary": ""}
{"Disease Name": "Familial thrombocytosis", "Disease Definition": "Familial thrombocytosis is a type of thrombocytosis, a sustained elevation of platelet numbers, which affects the platelet/megakaryocyte lineage and may create a tendency for thrombosis and hemorrhage but does not cause myeloproliferation.", "ORPHA ID": 71493, "Summary": "Epidemiology\nThe prevalence of familial thrombocytosis is not known.\nClinical description\nThe disease usually presents at birth but can be discovered at any time during life and thus can affect all ages. Patients present with thrombocytosis which is often discovered on a routine blood test. The clinical presentation is similar to sporadic essential thrombocythemia (ET; see this term) and may include impaired microcirculation resulting in brief episodes of fainting and dizziness, an increased risk of thrombotic events, hemorrhage, and mild splenomegaly. Patients with mutations in the MPL gene also experience frequent development of bone marrow fibrosis and seem to be free of hemorrhagic complications. The course of the disease is milder than sporadic ET and is devoid of the risk of leukemic transformation or progression toward myelofibrosis with myeloid metaplasia.\nEtiology\nFamilial thrombocytosis is caused by germline mutations in the THPO gene (3q26.3-q27) or in the MPL (MPL S505N) gene (1p34)\nDiagnostic methods\nDiagnosis is based on the observation of elevated levels of platelets (over 450 x 109/L) and the elimination of secondary causes of thrombocythemia. Genetic testing is required to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include causes of thrombocytosis with myeloproliferative neoplasm including chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, sporadic or familial ET and myelodysplasic disorders with thrombocytosis including sideroblastic anemia or 5q- syndrome (see these terms), although these can be excluded by the presence of myeloproliferation. Differential diagnoses also include causes of secondary thrombocytosis including iron deficiency, malignancy, chronic inflammatory disease, splenectomy or aspleny and protracted marrow regeneration.\nGenetic counseling\nTransmission is autosomal dominant with high penetrance.\nManagement and treatment\nTreatment is based on low dose aspirin at diagnosis. There is no consensus for using platelet lowering therapy despite an increased risk of thrombosis. Patients may have an increased risk of thrombotic events and hemorrhage.\nPrognosis\nThe predominant clinical feature is impaired microcirculation resulting in brief episodes of fainting and dizziness responding well to aspirin when the THPO gene is mutated and an increased risk of thrombosis and a frequent development of marrow fibrosis when MPL gene is mutated. All these may affect life expectancy.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Jean BRIERE"}
{"Disease Name": "Familial thrombomodulin anomalies", "Disease Definition": "A rare, life-threatening, genetic coagulation disorder characterized by an increased risk of blood clot formation in several members of a family due to a thrombomodulin gene mutation. Patients may manifest with venous thromboembolic disease, premature myocardial infarction and/or arterial thrombosis.", "ORPHA ID": 3324, "Summary": ""}
{"Disease Name": "Familial thyroglossal duct cyst", "Disease Definition": "A very rare inherited form of TDC characterized by a mass measuring 3 cm in diameter or less in the midline area of the neck.", "ORPHA ID": 93953, "Summary": ""}
{"Disease Name": "Familial thyroid dyshormonogenesis", "Disease Definition": "Familial thyroid dyshormonogenesis is a type of primary congenital hypothyroidism (see this term), a permanent thyroid hormone deficiency that is present from birth, which results from inborn errors of thyroid hormone synthesis.", "ORPHA ID": 95716, "Summary": "Epidemiology\nThyroid dyshormonogenesis accounts for 10-15% of permanent congenital hypothyroidism (see this term).\nClinical description\nClinical manifestations are those of other forms of congenital hypothyroidism (see this term). In addition to features of hypothyroidism, patients with dyshormonogenesis can present with goiter.\nEtiology\nDyshormonogenesis is caused by hereditary defects in the steps of thyroid hormone synthesis and secretion, the majority of which are transmitted in an autosomal recessive manner but at least one condition has autosomal dominant inheritance. The most common defect is that of thyroid peroxidase activity, which leads to total iodide organification defects (TIOD) and can be caused by autosomal dominant mutations in the DUOX2 and DUOX2A genes (15q15.3, 15q15). Less severe defects cause partial iodide organification defects (PIOD) and can include defects in sodium/iodide transport, defective thyroglobulin action or a defect in the enzyme iodotyrosine deiodinase.\nDiagnostic methods\nIn countries with newborn screening programs (with either a primary thyroxine (T4)-follow-up thyroid-stimulating hormone (TSH) or primary TSH test), infants with congenital hypothyroidism are diagnosed after detection by screening tests. However, goiter is rarely seen in babies detected by newborn screening. Diagnosis should be confirmed by elevated serum TSH level and low T4 or free T4 level. TIOD diagnosis is based on high radioactive iodine (RAI) uptake of the thyroid gland followed by more than 90% release after sodium perchlorate administration. Genetic testing can also be used. PIOD is diagnosed with 50-90% release after perchlorate administration (and can be confirmed by genetic testing).\nDifferential diagnosis\nDifferential diagnoses include other forms of congenital hypothyroidism (see this term).\nAntenatal diagnosis\nGenetic counseling and antenatal diagnosis can be offered in families where a genetic defect has been identified.\nManagement and treatment\nLevothyroxine is the treatment of choice (starting dose 10-15mcg/kg/day), with the immediate goal to raise the serum T4 above 130 nmol/L (10 ug/dL) as rapidly as possible; with these doses, serum TSH usually normalizes in 2-4 weeks. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and T4 or free T4 should be measured every 1-2 months in the first 6 months of life, every 3 months between 6 months and 3 years of age, and 4 weeks after any dose change.\nPrognosis\nThe prognosis of infants started on treatment early is excellent, with IQs similar to sibling or classmate controls. Lower neurocognitive outcomes may occur in those infants started at a later age (>30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Familial tumoral calcinosis", "Disease Definition": "A phosphocalcic metabolism anomaly, occuring particularly among younger age groups, characterized by the presence of calcified masses in the juxta-articular regions (hip, elbow, ankle and scapula) without joint involvement. Histologically, lesions display collagen necrobiosis, followed by cyst formation and a foreign-body response with calcification. Two forms have been described: normocalcemic tumoral calcinosis and familial tumoral calcinosis.", "ORPHA ID": 53715, "Summary": ""}
{"Disease Name": "Familial vesicoureteral reflux", "Disease Definition": "Familial vesicoureteral reflux is a rare, non-syndromic urogenital tract malformation characterized by the familial occurrence of retrograde flow of urine from the bladder into the ureter and sometimes the kidneys. Patients may be asymptomatic or may present with recurrent, sometimes febrile, urinary tract infections that, in case of acute pyelonephritis, may lead to serious complications (renal scarring, hypertension, renal failure). Spontaneous resolution of the disorder is possible.", "ORPHA ID": 289365, "Summary": ""}
{"Disease Name": "Familial visceral myopathy", "Disease Definition": "Familial visceral myopathy is a rare hereditary myopathic degeneration of both gastrointestinal and urinary tracts that causes chronic intestinal pseudo-obstruction. It usually presents after the first decade of life with megaduodenum, megacystis and symptoms such as abdominal distension and/or pain, vomiting, constipation, diarrhea, dysphagia, and/or urinary tract infections.n.", "ORPHA ID": 2604, "Summary": ""}
{"Disease Name": "Fanconi anemia", "Disease Definition": "A rare genetic multisystem disorder characterized by progressive pancytopenia with bone marrow failure, variable congenital malformations and predisposition to develop hematological or solid tumors.", "ORPHA ID": 84, "Summary": "Epidemiology\nThe expected prevalence at birth is at least 1/160,000.\nClinical description\nThe first signs of Fanconi anemia (FA) are typically non-hematological features. Limb anomalies typically affect the extremities, are unilateral or (usually asymmetric) bilateral. Minor anomalies can also be present such as low birth length and weight, microcephaly and/or microphthalmia. Skin pigmentation abnormalities (café-au-lait spots) and hypoplastic thenar eminence are frequent. Almost 20% of patients have ear malformations with or without hearing loss. Congenital malformations may involve other organ systems and vary within families. Short stature is syndromic and/or associated to endocrinopathies. Fertility is frequently impaired in males, and is highly disturbed in half of females. When congenital malformations are not prominent, diagnosis may be delayed until the onset of hematological anomalies. Bone marrow failure (BMF) occurs at a median age of 7 years, developing in 90% of patients by 40 years of age. The first manifestations are macrocytosis (very early) and thrombocytopenia. In patients with somatic mosaïcism, blood counts may stay normal until occurrence of hematological malignancy. In general, patients are highly predisposed to solid tumors (most frequently head and neck or anogenital regions).\nEtiology\nFA is genetically heterogeneous and the implicated variants are involved in DNA repair and genomic stability. More than 90% of patients have mutations within FANCA, FANCC, FANCG or FANCD2 genes. Mutations in genes with an upstream role in the FA-core complex are associated with classic FA. Some of ''Downstream'' variants (e.g.BRCA2) are associated with a very high risk of solid tumors in infancy and early childhood.\nDiagnostic methods\nDiagnosis relies on the evaluation of chromosomal breakage induced by diepoxybutane (DEB) or mitomycin C (MMC). This test may be normal in patients with somatic mosaicism; in which case, tests should be performed on fibroblasts.\nDifferential diagnosis\nFA clinical manifestations overlap with many malformation syndromes (Dubowitz, Seckel, Holt-Oram, Baller-Gerold, thrombocytopenia-absent radius, Nijmegen breakage syndromes, VACTERL association, dyskeratosis congenital, Blackfan-Diamond anemia) and diagnosis of FA is often delayed until a patient develops BMF or malignancies. FA should be considered in the differential diagnosis of all young patients with BMF of unknown etiology, and in other cancer predisposition syndromes (Bloom, Rothmund-Thomson or Werner syndromes) or syndromes with either constitutional or acquired BMF.\nAntenatal diagnosis\nPrenatal diagnosis is feasible with a chromosomal breakage assay on fetal blood or, when the mutation is known, by genetic testing.\nGenetic counseling\nThe disorder is usually autosomal recessive. Very rarely, X-linked (FANCB, < 1%) or autosomal dominant (FANCR, <1%) transmission may occur. If the variant is known, medical assisted reproduction should be offered to parents.\nManagement and treatment\nSupportive care includes transfusions of packed red blood cells (RBC) or leucodepleted platelets but if regular transfusion is required, hematopoietic stem cell transplantation (HSCT) should be considered. Currently, the only curative treatment for hematologic manifestations is HSCT. Symptomatic treatment includes oral androgen administration, which improves blood counts in most patients but is associated with severe liver toxicity and does not suppress the leukemic risk. Administration of G-CSF, best after bone marrow aspirate, should be considered in patients with acute severe infections. Regular screening for hematological malignancies is recommended during childhood in non-transplanted patients; with the exception of 1q anomalies, identification of a clonal event should lead to transplantation. Screening for solid tumors should start in adolescence, especially in the post-transplant setting; risk may be higher in patients with chronic GVHD. Any suspect lesion should be biopsied. When malignancies develop, treatment is complicated by the sensitivity to radiation and chemotherapy of FA patients.\nPrognosis\nHSCT efficiently treats BMF. Solid tumors prevention and treatment are the main challenge for transplanted patients.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Thierry LEBLANC | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Fanconi-Bickel syndrome", "Disease Definition": "A rare glycogen storage disease due to a deficiency in solute carrier family 2, facilitated glucose transporter member 2 and characterized by hepatorenal glycogen accumulation leading to severe renal tubular dysfunction and impaired glucose and galactose metabolism.", "ORPHA ID": 2088, "Summary": "Epidemiology\nThe prevalence is unknown but less than 200 cases have been described in the literature to date.\nClinical description\nOnset occurs during the first few months of life with failure to thrive, polyuria, normo/hypokalemic metabolic acidosis, fasting hypoglycemia and post-feeding hyperglycemia. Metabolic acidosis, hypokalemia, hypophosphatemia and rickets are the consequence of severe proximal tubule dysfunction. Growth retardation and hepatosplenomegaly resulting in a protruding abdomen are evident by early childhood. Puberty can be delayed. Generalized osteoporosis can lead to fractures already during childhood. Some patients also display an abnormal fat distribution.\nEtiology\nThe disease is due to homozygous or compound heterozygous mutations in the SLC2A2 gene (3q26.2-q27), encoding the protein, solute carrier family 2, facilitated glucose transporter member 2.\nDiagnostic methods\nDiagnosis may be suspected on the basis of the clinical manifestations, radiological findings revealing rickets, and from characteristic results from laboratory investigations showing proximal renal tubular dysfunction (massive glucosuria, proteinuria, phosphaturia, hypophosphatemia, aminoaciduria and hypouricemia). However, several cases have been detected through neonatal screening of galactose levels. Additional laboratory findings include fasting hypoglycemia, ketonuria and hypercholesterolemia. Elevated serum biotinidase activity is also found in patients and has recently been proposed as a diagnostic marker for this syndrome and other glycogen storage diseases. Analysis of biopsy samples reveals liver steatosis, and glycogen accumulation in the hepatocytes and proximal renal tubular cells. The diagnosis can be confirmed by identification of a mutation in the SLC2A2 gene.\nDifferential diagnosis\nThe principle differential diagnosis is type I glycogen storage disease, which is caused by glucose-6-phosphatase deficiency. The renal phenotype must be differentiated from other forms of genetically determined Fanconi Syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is possible for families in which the SLC2A2 mutation has already been identified.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive and genetic counseling is recommended for affected families. The risk of offspring inheriting the disease is 25% where both parents are unaffected carriers.\nManagement and treatment\nThere is no causal treatment. Therapy consists of replacing water and electrolytes lost through urine excretion as a result of the proximal tubule dysfunction. In addition, Vitamin D replacement is also fundamental for preventing hypophosphatemic rickets. Patients should follow a galactose-restricted diabetic diet with fructose as the main source of carbohydrate. During infancy, night feeding can be necessary in order to avoid hypoglycemia.\nPrognosis\nThe long-term prognosis is unknown. However, the description of the first identified patients reveals that renal function is preserved in adulthood despite renal tubular dysfunction and liver involvement also persisting.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Francesco TREPICCIONE | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Farber disease", "Disease Definition": "A subcutaneous tissue disease characterized by a spectrum of clinical signs ranging from the classical triad of painful and progressively deformed joints, subcutaneous nodules, and progressive hoarseness (due to laryngeal involvement) that presents in infancy, to varying phenotypes with respiratory and neurologic involvement.", "ORPHA ID": 333, "Summary": "Epidemiology\nApproximately 200 cases of Farber disease have been reported worldwide in the literature to date.\nClinical description\nA high clinical variability is seen between patients. The classic phenotype presents at around 3-6 months of age with painful, swollen and stiff joints of the hands and feet, prominent subcutaneous nodules over pressure points, and progressive hoarseness leading to aphonia due to vocal cord infiltration. Patients can also develop cardiac, pulmonary and neurological defects. Progressive neurological deterioration can be marked in some forms with seizures, paraparesis and developmental delay. The most severe neonatal form presents at birth with hydrops fetalis, lethargy, and failure to thrive, as well as hepatosplenomegaly, rapid neurological deterioration, and granulomatous infiltrations to various other organs (i.e. liver, spleen, lungs). Milder forms have also been described with no neurological defects and a longer life-expectancy. In some patients, the disease manifests in childhood as a spinal muscular atrophy associated with progressive myoclonic epilepsy (SMA-PME) in the absence of subcutaneous nodules.\nEtiology\nFarber disease is caused by mutations in the N-acylsphingosine amidohydrolase (ASAH1) gene (8p22) which encodes acid ceramidase, a lysosomal enzyme that hydrolyzes ceramide into sphingosine and free fatty acid. A deficient activity of this enzyme leads to an accumulation of ceramide in most tissues.\nDiagnostic methods\nDiagnosis is based on clinical and laboratory findings by assaying the activity of acid ceramidase in peripheral blood leukocytes, cultured lymphoid cells or cultured skin fibroblasts. Alternatively, diagnosis can be performed by determining ceramide concentration in cultured cells or tissues or by studying lysosomal ceramide catabolism in cultured living cells. Identification of mutations in the ASAH1 gene by molecular genetic testing usually allows for diagnostic confirmation.\nDifferential diagnosis\nDifferential diagnoses include juvenile idiopathic arthritis, stiff skin syndrome and lethal restrictive dermopathy. Encephalopathy due to prosaposin deficiency should also be excluded.\nAntenatal diagnosis\nPrenatal diagnosis by DNA testing is possible in families with a known disease-causing mutation. Alternatively, prenatal diagnosis can be performed by measuring acid ceramidase activity in cultured amniotic fluid cells or chorionic villi.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be proposed to affected families informing them of a 25% risk of transmitting the disease where both parents are unaffected carriers.\nManagement and treatment\nThere is currently no effective specific therapy for Farber disease, and symptomatic treatment is based on analgesics, corticotherapy, and plastic surgery. However, allogeneic hematopoietic stem cell transplantation provides a promising approach for patients with limited neurological involvement.\nPrognosis\nThe prognosis varies, with some patients dying within the first few days of life (severe neonatal form) and others living until adolescence or early adulthood (milder forms).\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Thierry LEVADE"}
{"Disease Name": "Farmer's lung disease", "Disease Definition": "Farmer's lung disease is the main form of occupational hypersensitivity pneumonitis (see this term), caused by chronic inhalation of microorganisms, often thermophilic actinomycetes and less commonly saccharopolyspora rectivirgula, living in mouldy hay, straw, or grain. It is characterized by variable degrees of dyspnea, cough, tiredness, headaches and occasional fever/night sweats, with acute, sub-acute or chronic clinical course", "ORPHA ID": 99906, "Summary": ""}
{"Disease Name": "FASTKD2-related infantile mitochondrial encephalomyopathy", "Disease Definition": "A rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by infantile-onset encephalomyopathy presenting with developmental delay, slowly progressive hemiplegia, intractable epileptic seizures and asymmetrical brain atrophy with dilatation of the ipsilateral ventricle system. Additional features include optic atrophy, mildly increased plasma and/or CSF lactate and decreased cytochrome c oxidase activity in skeletal muscle biopsy.", "ORPHA ID": 166105, "Summary": ""}
{"Disease Name": "Fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease", "Disease Definition": "A rare glycogen storage disease characterized by fetal or neonatal onset of severe cardiomyopathy with non-lysosomal glycogen accumulation and fatal outcome in infancy. Patients present with massive cardiomegaly, severe cardiac and respiratory complications, and failure to thrive. Non-specific facial dysmorphism, bilateral cataracts, macroglossia, hydrocephalus, enlarged kidneys, and skeletal muscle involvement have been reported in some cases.", "ORPHA ID": 439854, "Summary": ""}
{"Disease Name": "Fatal familial insomnia", "Disease Definition": "A rare inherited human prion disease characterized by adult onset of progressive disturbance and loss of circadian rhythms, dysautonomia with increased sympathetic activity, and cognitive impairment with fluctuating vigilance, impaired long-term memory, disorientation, and oneiric states. Motor disturbances include myoclonus, cerebellar ataxia, and pyramidal signs. The disease rapidly leads to a somnolent or comatose state and is typically fatal after 9 or 30 months on average (bimodal course). Neuropathologic examination shows marked neuronal loss and gliosis predominantly in thalamic nuclei and inferior olives, while deposition of abnormal prion protein may be relatively sparse.", "ORPHA ID": 466, "Summary": ""}
{"Disease Name": "Fatal infantile cytochrome C oxidase deficiency", "Disease Definition": "Fatal infantile cytochrome C oxidase deficiency is a very rare mitochondrial disease characterized clinically by cardioencephalomyopathy resulting in death in infancy.", "ORPHA ID": 1561, "Summary": ""}
{"Disease Name": "Fatal infantile hypertonic myofibrillar myopathy", "Disease Definition": "Fatal infantile hypertonic myofibrillar myopathy is a rare, genetic skeletal muscle disease characterized by muscle stiffness and rigidity, hypertonia, weakness, respiratory distress and normal cognition. Patients have persistently elevated creatine kinase and histopathology is typical of myofibrillar myopathy. The manifestation onset follows the short period of normal infantile development and leads to progressive respiratory insufficiency and early death.", "ORPHA ID": 280553, "Summary": ""}
{"Disease Name": "Fatal infantile lactic acidosis with methylmalonic aciduria", "Disease Definition": "Fatal infantile lactic acidosis with methylmalonic aciduria is a rare neurometabolic disease characterized by infantile onset of severe encephalomyopathy, lactic acidosis and elevated methylmalonic acid urinary excretion. Clinically it manifests with severe psychomotor delay, hypotonia, failure to thrive, feeding difficulties and dystonia. Epilepsy and multiple congenital anomalies may be associated.", "ORPHA ID": 17, "Summary": ""}
{"Disease Name": "Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3", "Disease Definition": "Combined oxidative phosphorylation deficiency type 3 is an extremely rare clinically heterogenous disorder described in about 5 patients to date. Clinical signs included hypotonia, lactic acidosis, and hepatic insufficiency, with progressive encephalomyopathy or hypertrophic cardiomyopathy.", "ORPHA ID": 168566, "Summary": ""}
{"Disease Name": "Fatal post-viral neurodegenerative disorder", "Disease Definition": "A rare neuroinflammatory disease characterized by the onset of ataxia, dysarthia and cerebral white matter changes which are triggered by viral infection. Episodic progressive neurodegeneration (manifesting with loss of motor and verbal skills, muscle weakness, further cerebral white matter degeneration and, eventually, death) is observed in the absence of hematopathology, cytokine overproduction, fever, hypertrigliceridemia, hypofibrinogenemia and hyperferritinemia.", "ORPHA ID": 391343, "Summary": ""}
{"Disease Name": "FATCO syndrome", "Disease Definition": "A rare, genetic, congenital limb malformation syndrome characterized by unilateral or bilateral fibular aplasia/hypoplasia, tibial campomelia, and lower limb oligosyndactyly involving the lateral rays. Upper limb oligosyndactyly and cleft lip/palate may also be associated.", "ORPHA ID": 2492, "Summary": ""}
{"Disease Name": "Fatty acid hydroxylase-associated neurodegeneration", "Disease Definition": "Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a very rare, autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA) characterized by childhood-onset focal dystonia, progressive spastic paraplegia that progresses to tetra paresis, ataxia, dysarthria, intellectual decline, and oculomotor disturbances (optic atrophy), accompanied by iron deposition in the globus pallidus.", "ORPHA ID": 329308, "Summary": ""}
{"Disease Name": "Fatty acyl-CoA reductase 1 deficiency", "Disease Definition": "A rare disorder of plasmalogen biosynthesis characterized by syndromic severe intellectual disability with congenital cataracts, early-onset epilepsy, microcephaly, global developmental delay, growth retardation and short stature, and spastic quadriparesis. Dysmorphic facial features may be present, including high-arched eyebrows, flattened nasal root, hypertelorism, and long and smooth philtrum. Rhizomelia is not part of the syndrome. Cerebellar atrophy, white matter abnormalities, and Dandy-Walker malformation have been described on brain imaging.", "ORPHA ID": 438178, "Summary": ""}
{"Disease Name": "FBLN1-related developmental delay-central nervous system anomaly-syndactyly syndrome", "Disease Definition": "FBLN1-related developmental delay-central nervous system anomaly-syndactyly syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by delayed motor development, intellectual disability, dysarthria, pseudobulbar signs, cryptorchidism, and syndactyly associated with a  FLBN1  gene point mutation. Macular degeneration and signs of brain atrophy and spinal cord compression have also been reported.", "ORPHA ID": 404451, "Summary": ""}
{"Disease Name": "Febrile infection-related epilepsy syndrome", "Disease Definition": "A rare, potentially fatal , epileptic encephalopathy characterized by explosive-onset of recurrent multifocal and bilateral tonic-clonic seizures following an unspecific febrile illness. The syndrome develops without a clear acute structural, toxic or metabolic cause, in a patient without previous epilepsy. FIRES is a subgroup of new-onset refractory status epilepticus (NORSE), and requires a preceding febrile infection as a mandatory feature.", "ORPHA ID": 163703, "Summary": "Epidemiology\nBased on a small cohort study, in Germany the prevalence is estimated at 1/100,000 and annual incidence at 1/1,000,000 in children and adolescents. Global epidemiological date is lacking. In pediatric cases there is a male predominance, while females seem to be more frequently affected in adulthood. Familial cases have not been reported.\nClinical description\nFebrile infection-related epilepsy syndrome (FIRES) is most common in school-age children. Typically, a previously healthy individual manifests with a sudden onset of recurrent multifocal and bilateral tonic-clonic seizures, following an unspecific febrile illness. Refractory, and usually superrefractory, status epilepticus develops. The acute phase can last for weeks or months. A chronic phase follows, without a latent period, characterized by refractory focal epilepsy along with, often severe, impairments in memory, cognition and behavior. Motor disability is less common.\nEtiology\nThe etiology is not fully known. Most likely FIRES is an immune-inflammatory-mediated epileptic encephalopathy, with a vicious circle of inflammation and hyperexcitability. Findings in cerebrospinal fluid (CSF), and the poor response to immune therapies, point to the innate immune system and autoinflammatory rather than autoimmune mechanisms. Variants in known epilepsy genes do not seem to predispose to FIRES.\nDiagnostic methods\nAn extensive work-up is needed to exclude treatable conditions. Initial magnetic resonance imaging is normal or shows temporal lobe signal abnormalities. Diffuse brain atrophy and mesial temporal lobe changes are common in the chronic phase. Analysis of CSF shows normal findings or mild pleocytosis but no presence of pathogens and usually no oligoclonal bands or neuronal antibodies. Metabolic investigations are negative. Genetic investigations to exclude genetic epilepsies such as those related to POLG. Continuous electroencephalogram (cEEG) is required to monitor seizures and depth of anesthesia. Beta-delta complexes resembling extreme delta brush is recorded in some patients in the early phase.\nDifferential diagnosis\nDifferential diagnoses include, but are not limited to, infectious or autoimmune encephalitis (e.g. anti-NMDAR encephalitis and other antineuronal antibody-related encephalitides, acute disseminated encephalomyelitis), primary angiitis of the central nervous system, acute necrotizing encephalopathy, other infection-induced encephalopathies, metabolic diseases (e.g. mitochondrial disorders, citrullinemia, thiamin metabolism disorders) and genetic epilepsies (e.g. Dravet syndrome, PCDH19 epilepsy).\nManagement and treatment\nMonitoring in intensive care during the acute phase is mandatory. Anti-seizure medications are often ineffective. High-dose benzodiazepines can have a transient efficacy. Usually, general anesthesia with barbiturates (titrated to burst suppression) are needed to stop seizures, even if prolonged burst-suppression can be associated with a worse cognitive outcome. Recurrence is common on awakening, necessitating repeated anesthesia. Immune therapy is usually disappointing but anakinra or tocilizumab has been highly effective in a few cases. So far, the ketogenic diet has seemed most beneficial, especially if initiated early, but no controlled trials exist. Ketamine, inhalation anesthetics, cannabidiol, hypothermia and neurostimulation have shown transient efficacy in a few cases.\nPrognosis\nFIRES has a poor prognosis with a high risk of chronic drug-resistant epilepsy and significant cognitive impairment, but a few patients have fully recovered. The mortality rate is around 12% in children.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Rima NABBOUT | EpiCARE* - Pr Nicola SPECCHIO | EpiCARE* - Pr Tommy STÖDBERG | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Feingold syndrome type 1", "Disease Definition": "A rare, genetic congenital malformation syndrome characterized by digital anomalies (shortening of the 2nd and 5th middle phalanx of the hand, clinodactyly of the 5th finger, syndactyly of toes 2-3 and/or 4-5, thumb hypoplasia), microcephaly, facial dysmorphism (short palpebral fissures and micrognathia), gastrointestinal atresia (primarily esophageal and/or duodenal), and mild-to-moderate learning disability.", "ORPHA ID": 391641, "Summary": "Epidemiology\nThe exact prevalence is unknown. Feingold syndrome type 1 (FS1) accounts for the vast majority of FS cases. An estimated 120 cases have been reported to date.\nClinical description\nCharacteristic clinical findings of FS1 are present at birth with digital anomalies being the most frequent and including: brachymesophalangy (most commonly affecting the 2nd and 5th fingers), thumb hypoplasia and toe syndactyly. Microcephaly and facial dysmorphism (short palpebral fissures, micrognathia) are also noted in most cases. The most serious manifestations that are noted in approximately half of cases are esophageal and duodenal (rarely jejunal or anal) atresia, with or without tracheo-esophageal fistula. The presence of a fistula can be indicated by signs such as coughing, gagging, vomiting, abdominal distension and, in some cases, respiratory distress. Gastrointestinal atresia must be treated immediately or it can be fatal. Mild learning deficits can become apparent in early childhood but severe intellectual disability is very rarely seen.\nEtiology\nFS1 is caused by a mutation or deletion in the proto-oncogene MYCN (2p24.3). It encodes a protein with a basic helix-loop-helix domain that is expressed at various stages of human embryonic development.\nDiagnostic methods\nDiagnosis is based on characteristic clinical features and imaging studies. Gastrointestinal atresia can be seen with pre-natal or post-natal ultrasound or by MRI. Molecular genetic testing can identify a MYCN mutation, confirming a diagnosis of FS1.\nDifferential diagnosis\nDifferential diagnosis of FS1 includes FS type 2 (FS2), VACTERL association, CHARGE syndrome, brachydactyly type A4 and Fanconi anemia.\nAntenatal diagnosis\nPrenatal testing is possible in FS1 families with a known MYCN mutation or deletion.\nGenetic counseling\nFS1 is inherited autosomal dominantly; however, most cases arise de novo. Genetic counseling is possible.\nManagement and treatment\nExtensive medical examinations are needed to identify possible anomalies of the heart or kidneys. Management of FS1 (and FS2) typically centers on surgical correction of the specific congenital anomalies (certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae. Gastrointestinal atresia requires prompt treatment involving IV fluid administration and surgery. Optimal surgical treatment of infants with esophageal atresia and tracheoesophageal fistula remains controversial and gastroesophageal reflux (GER) is extremely frequent in patients treated for the two conditions. GER is refractory to medical treatment and often requires anti-reflux surgery. Renal and cardiac anomalies should receive the standard treatments and prophylactic antibiotics may be beneficial. Special education is recommended for children and adults with learning deficits. Hearing loss should equally be monitored by an audiologist. Cochlear implants are possible in certain cases.\nPrognosis\nPrognosis depends on congenital malformations (especially cardiac and renal anomalies) present. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Loïc DE PONTUAL | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Feingold syndrome type 2", "Disease Definition": "A rare, genetic congenital malformation syndrome characterized by microcephaly, short stature, digital anomalies (brachymesophalangy, fifth finger clinodactyly, syndactyly of toes and hypoplastic thumbs) and mild intellectual disabilities but that lacks the manifestations of gastrointestinal atresia.", "ORPHA ID": 391646, "Summary": "Epidemiology\nFeingold syndrome type 2 (FS2) is extremely rare with less than 20 patients described in the literature to date.\nClinical description\nFS2 patients present with microcephaly, brachydactyly, brachymesophalangy of the second and fifth fingers, hypoplastic thumbs and toe syndactyly as seen in FS1. Mild intellectual disability is also noted. Unlike FS1, patients with FS2 lack any form of gastrointestinal atresia and they do not display short palpebral fissures.\nEtiology\nFS2 is thought to be caused by a hemizygous deletion in the MIR17HG gene on chromosome 13q31.3. This is the first example of a syndromic development deficit in humans that is caused by a miRNA gene.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and can be confirmed by high-resolution CGH (comparative genomic hybridization) arrays.\nDifferential diagnosis\nDifferential diagnosis of FS2 includes FS type 1 (FS1), VACTERL association, CHARGE syndrome, brachydactyly type A4 and Fanconi anemia.\nAntenatal diagnosis\nPrenatal testing is possible in FS2 families with a known MIR17HG mutation or deletion.\nGenetic counseling\nFS2 is inherited in an autosomal dominant manner; however, most cases arise de novo. Genetic counseling is possible.\nManagement and treatment\nExtensive medical examinations are needed to identify possible anomalies of the heart or kidneys. Management of FS2 typically centers for long-term medical sequelae. Occupational therapy / surgical intervention for finger/toe anomalies may be required. Renal and cardiac anomalies should receive the standard treatments and prophylactic antibiotics may be beneficial. Special education is recommended for children and adults with learning deficits. Hearing loss should equally be monitored by an audiologist. Cochlear implants are possible in certain cases.\nPrognosis\nPrognosis depends on congenital malformations (especially cardiac and renal anomalies) present. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Loïc DE PONTUAL | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Feingold syndrome", "Disease Definition": "A rare genetic, congenital malformation syndrome characterized by microcephaly, short stature and numerous digital anomalies (brachymesophanlangy, fifth finger clinodactyly, syndactyly of toes and hypoplastic thumbs), mild learning deficit and short palpebral fissures. The two subtypes are clinically distinguished by the presence (type 1) or absence (type 2) gastrointestinal atresia.", "ORPHA ID": 1305, "Summary": ""}
{"Disease Name": "Felty syndrome", "Disease Definition": "Felty syndrome (FS), also known as ''super rheumatoid'' disease, is a severe form of rheumatoid arthritis (RA), characterized by a triad of RA, splenomegaly and neutropenia, resulting in susceptibility to bacterial infections.", "ORPHA ID": 47612, "Summary": "Epidemiology\nFS is estimated to occur in about 1- 3% of RA patients after an average of 10 to 15 years of arthritis. FS is uncommon in the African American population.\nClinical description\nFS is about 3 times more common in females during the third through fifth decades of life (earlier in men). Clinically, the disorder is characterized by chronic arthritis with severe joint destruction contrasting with moderate or absent joint inflammation and severe extra-articular disease. The knee, wrist, ankle, metacarpophalangeal and proximal interphalangeal joints are most commonly involved. Involvement of axial joints is less common. Symmetrical joint involvement is the characteristic feature of the disease. Hepato-splenomegaly and lymphadenopathy are commonly seen. Other extra-articular manifestations of FS are episcleritis, vasculitis, pleuritis, pulmonary fibrosis, rheumatoid nodules, neuropathy, leg ulcers, skin hyperpigmentation (usually on extensor surface of the lower leg), anemia and weight loss. The most critical manifestation of FS is neutropenia, resulting in a higher incidence of bacterial infections (affecting most frequently skin, mouth, and upper and lower respiratory tract). Rarely, FS may be revealed by neutropenia in an RA patient. FS can be associated with other autoimmune diseases such as Sjögren syndrome, vasculitis and systemic lupus erythematosus (SLE).\nEtiology\nThe pathophysiology of FS is still not well understood butit has been proposed that an autoimmune response against neutrophil antigens might be the underlying mechanism. An increased incidence of infections may stimulate a neutrophil response that includes histone deimination and the expulsion of chromatin from the cell. Neutrophil extracellular chromatin traps (NETs) containing deiminated histones, in complex with bacterial adjuvants, are the most likely antigenic trigger for the production of autoantibodies to deiminated histones. These autoantibodies or their immune complexes may further stimulate neutrophils, thus completing a self-sustaining cycle that drives the depletion of mature neutrophils. A higher incidence of anti-deiminated histone autoantibodies is found in FS patients. About 95% of FS patients have a MHC class II HLA-DR4 allele. African Americans have a low incidence of this antigen.\nDiagnostic methods\nDiagnosis of FS includes physical examination as well as complete blood count revealing leucopenia, neutropenia, and thrombocytopenia and high serum titers of rheumatoid factor antibodies, antinuclear antibodies, antihistone antibodies and HLA-DR4 positivity. Microscopic analysis of spleen biopsies reveals enlargement of the germinal center in follicles, and infiltration of neutrophils and macrophages. Severe joint destruction may be observed radiologically.\nDifferential diagnosis\nFS differs from RA by more severe arthritis and extra-articular manifestations. Differential diagnosis of FS also includes large granular lymphocyte (LGL) leukemia (when associated with RA, called pseudo Felty), RA, systemic lupus erythematosus (SLE), Still's disease, articular brucellosis, and chronic bacterial endocarditis.\nManagement and treatment\nFS is difficult to treat and the standard of care is directed against underlying RA with an additional goal of treating neutropenia and recurrent infections. This comprises several disease-modifying anti-rheumatic drugs (including sulfasalazine, hydroxychloroquine) and methotrexate. Recombinant granulopoietic growth factors (G-CSF) have also been used to improve neutrophil counts. For treatment-resistant cases with splenomegaly, a splenectomy can be considered. Rituximab (RTX) have been used as second-line therapy in patients with refractory FS.\nPrognosis\nFS has a poor prognosis and recurrent infections may lead to increased mortality.\n\n                            Last update: \n                            September 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Nishant DWIVEDI  - Dr Marko RADIC"}
{"Disease Name": "Female infertility due to oocyte meiotic arrest", "Disease Definition": "A rare genetic female infertility characterized by oocyte maturation arrest during any of the various stages of meiosis I or II. In some patients, first polar body oocytes may be retrieved, but these either show fertilization failure or early embryonic arrest. Affected women have regular menstrual cycles.", "ORPHA ID": 488191, "Summary": ""}
{"Disease Name": "Female infertility due to zona pellucida defect", "Disease Definition": "Female infertility due to zona pellucida defect is a rare, genetic, female infertility disorder characterized by the presence of abnormal oocytes that lack a zona pellucida. Affected individuals are unable to conceive despite having normal menstrual cycles and sex hormone levels, as well as no obstructions in the fallopian tubes or defects of the uterus or adnexa.", "ORPHA ID": 404466, "Summary": ""}
{"Disease Name": "Female restricted epilepsy with intellectual disability", "Disease Definition": "Female restricted epilepsy with intellectual disability is a rare X-linked epilepsy syndrome characterized by febrile or afebrile seizures (mainly tonic-clonic, but also absence, myoclonic, and atonic) starting in the first years of life and, in most cases, developmental delay and intellectual disability of variable severity. Behavioral disturbances (e.g. autistic features, hyperactivity, and aggressiveness) are also frequently associated. This disease affects exclusively females, with male carriers being unaffected, despite an X-linked inheritance.", "ORPHA ID": 101039, "Summary": ""}
{"Disease Name": "Femoral-facial syndrome", "Disease Definition": "Femoral-facial syndrome is characterized by predominant femoral hypoplasia (bilateral or unilateral) and unusual facies.", "ORPHA ID": 1988, "Summary": "Epidemiology\nTo date, 55 cases have been reported in the literature.\nClinical description\nFacial features include upslanting palpebral fissures, short nose with broad tip, long philtrum, thin upper lip, micrognathia and cleft palate. The complete syndrome with cleft palate has been reported only in females. The following associated anomalies may be present: vertebral segmentation defects, preaxial polydactyly, ear defects, genitourinary tract abnormalities, lung hypoplasia, dysplastic kidneys, patent arterial duct (see this term). Intellectual development has been reported normal. In two patients, central nervous system anomalies (corticosubcortical atrophy, colpocephaly, partial agenesis of corpus callosum, hypoplasia of the falx cerebri and absent septum pellucidum) have been described. Many patients show asymmetrical changes.\nEtiology\nMaternal diabetes has been recognized as a causative factor in more than 20% of the reported cases.\nGenetic counseling\nMajority of cases are sporadic. Familial occurrence has been reported in three cases.\n\n                            Last update: \n                            July 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM"}
{"Disease Name": "Femur-fibula-ulna complex", "Disease Definition": "A rare congenital limb malformation syndrome characterized by a highly variable combination of congenital anomalies of the femur, fibula, and/or ulna, which can appear along with finger/toe anomalies at the ulnar/fibular side. Limb defects are asymmetrical, with upper limbs more often affected than lower limbs, and the right side of the body more often affected than the left. Abnormalities of the upper limb include amelia, hypoplasia of the humerus, humero-radial synostosis, and malformation of the ulna and ulnar rays. Abnormalities of the lower limb include absence of the proximal part of the femur and absence of the fibula. Axial skeleton, internal organs and intellectual function are usually normal.", "ORPHA ID": 2019, "Summary": ""}
{"Disease Name": "Ferro-cerebro-cutaneous syndrome", "Disease Definition": "Ferro-cerebro-cutaneous syndrome is a rare, genetic, metabolic liver disease characterized by progressive neurodegeneration, cutaneous abnormalities, including varying degrees of ichthyosis or seborrheic dermatitis, and systemic iron overload. Patients manifest with infantile-onset seizures, encephalopathy, abnormal eye movements, axial hypotonia with peripheral hypertonia, brisk reflexes, cortical blindness and deafness, myoclonus and hepato/splenomegaly, as well as oral manifestations, including microdontia, widely spaced and pointed teeth with delayed eruption, and gingival overgrowth.", "ORPHA ID": 397922, "Summary": ""}
{"Disease Name": "Fetal akinesia deformation sequence", "Disease Definition": "The fetal akinesia/hypokinesia sequence (or Pena-Shokeir syndrome type I) is characterized by multiple joint contractures, facial anomalies and pulmonary hypoplasia. Whatever the cause, the common feature of this sequence is decreased foetal activity.", "ORPHA ID": 994, "Summary": "Epidemiology\nThe syndrome is rare: about 100 cases have been described in the literature. About 30% are stillborn, and the majority of those live-born die of the complications of pulmonary hypoplasia.\nClinical description\nFailure of normal deglutition results in polyhydramnios, and a lack of movement of the diaphragm and intercostal muscles leads to pulmonary hypoplasia. The lack of normal fetal movement also results in a short umbilical cord and multiple joint contractures. Ulnar deviation of the hands, rocker-bottom feet, camptodactyly, sparse dermal ridges and absence of palmar flexion creases are the other components of the fetal akinesia sequence. The face is expressionless, with hypertelorism, telecanthus and poorly folded, small, and posteriorly angulated ears, and the mouth is small with micrognathia and high-arched palate. Cleft palate and cardiac defects may occur occasionally. Many of these babies are born prematurely, and even when born at term their growth is delayed, they have a short neck and cryptorchidism. If they survive, they are likely to develop short-gut syndrome with malabsorption.\nEtiology\nThe Pena-Shokeir syndrome is not a unitary entity but is etiologically heterogeneous. Maternal myasthenia gravis has been diagnosed in some cases, and experiments in animal models show that curarization of the mother induces fetal akinesia. All plausible causes of fetal immobility should be searched for (myogenic, neurogenic, ischemic/anoxic), with biopsies when possible.\nDifferential diagnosis\nThere are similarities between Pena-Shokeir syndrome type I and the trisomy 18 syndrome: both may include multiple ankyloses, camptodactyly, and rocker-bottom feet. Karyotyping permits differential diagnosis.\nAntenatal diagnosis\nPrenatal diagnosis after the birth of an index case relies on ultrasound, which may reveal polyhydramnios, ankyloses, scalp oedema, and decreased chest movements in a fetus with pulmonary hypoplasia.\nGenetic counseling\nAutosomal recessive inheritance (with parental consanguinity and/or recurrence in sibs) has been implied in about 50% of the published cases. The heterogeneity makes accurate recurrence risk counselling difficult. A 0.01 to 25% risk for recurrence seems most appropriate in apparently sporadic cases.\n\n                            Last update: \n                            July 2005"}
{"Disease Name": "Fetal akinesia-cerebral and retinal hemorrhage syndrome", "Disease Definition": "Fetal akinesia-cerebral and retinal hemorrhage syndrome is a rare, lethal, congenital myopathy syndrome characterized by decreased fetal movements and polyhydraminos in utero and the presence of akinesia, severe hypotonia with respiratory insufficiency, absent reflexes, joint contractures, skeletal abnormalities with thin ribs and bones, intracranial and retinal hemorrhages and decreased birth weight in the neonate.", "ORPHA ID": 363409, "Summary": ""}
{"Disease Name": "Fetal alcohol syndrome", "Disease Definition": "Fetal alcohol syndrome (FAS) is a rare malformation syndrome caused by excessive maternal consumption of alcohol during pregnancy. It is characterized by prenatal and/or postnatal growth deficiency (weight and/or height <10th percentile), a unique cluster of minor facial anomalies (short palpebral fissures, flat and smooth philtrum, and thin upper lip) and severe central nervous system (CNS) abnormalities including microcephaly, and cognitive and behavioral impairment (intellectual disability, deficit in general cognition, learning and language, executive function, visual-spatial processing, memory, and attention).", "ORPHA ID": 1915, "Summary": ""}
{"Disease Name": "Fetal and neonatal alloimmune thrombocytopenia", "Disease Definition": "A rare hematological disease characterized by maternal alloimmunisation against fetal platelet antigens that are inherited from the father and different from those present in the mother, and usually presents as a severe isolated thrombocytopenia in otherwise healthy newborns.", "ORPHA ID": 853, "Summary": "Epidemiology\nThe incidence of fetal/neonatal alloimmune thrombocytopaenia (FNAIT) has been estimated between 1/800 to 1/2 000 live births.\nClinical description\nFNAIT has been considered to be the platelet counterpart of Rh Hemolytic Disease of the Newborn (RHD). Unlike RHD, FNAIT can occur during a first pregnancy. The spectrum of the disease may range from sub-clinical moderate thrombocytopenia to life-threatening bleeding in the neonatal period. Mildly affected infants may be asymptomatic. In those with severe thrombocytopenia, the most common presentations are petechiae, purpura or cephalohematoma at birth, associated with a major risk of intracranial hemorrhage (up to 20% of reported cases), which leads to death or neurological sequelae.\nEtiology\nFNAIT results from the transplacental passage of maternal alloantibodies (which are IgG) against fetal platelet antigens which are inherited from the father. In Caucasians, the most frequent platelet antigen (HPA) involved in FNAIT is HPA-1a (anti-HPA-1a alloantibodies), which is located on glycoprotein IIIa (GPIIIa), accounting for 75-80% of cases. The other main antigens involved are HPA-2, HPA-3, HPA-5, and HPA-15. The mechanisms of maternal immunization are only partly understood. Fetal syncytiotrophoblasts express GPIIIa on their cell surface and the spread of their extracellular vesicles in the maternal circulating blood system may possibly be at the origin of immunization, beginning with the first pregnancy.\nDiagnostic methods\nAlloimmune thrombocytopenia is more often unexpected and is usually diagnosed after birth. Once suspected, the diagnosis is confirmed by demonstration of maternal antiplatelet alloantibodies directed against a paternal antigen inherited by the fetus/neonate.\nDifferential diagnosis\nDifferential diagnosis includes sepsis/ infection, perinatal hypoxia, intrauterine growth restriction, prematurity, necrotizing enterocolitis, disseminated intravascular coagulation (DIC), other congenital conditions associated with thrombocytopenia, fetal intracranial hemorrhage without abnormal platelet count.\nAntenatal diagnosis\nTo enable appropriate counseling for subsequent pregnancies, the father's HPA genotype should be determined wherever possible. If he is homozygous and particularly if the mother still has the relevant antiplatelet antibodies, the subsequent fetus is at risk. In the case of paternal heterozygosity for the offending antigen, or when paternity is uncertain, fetal HPA genotyping can be done on chorionic villi or amniotic cells. A noninvasive procedure of HPA genotyping from maternal serum is now available for some HPA.\nGenetic counseling\nInheritance of the paternal HPA is autosomal dominant; genetic counselling should be offered to allo-immunized women, informing them that there is a 50% risk of having an HPA-incompatible fetus when the father is heterozygous for the offending antigen. All fetuses are HPA-incompatible if the father is homozygous for the offending antigen.\nManagement and treatment\nPost-natal management involves transfusion of platelets devoid of this antigen, and should not be delayed by biological confirmation of the diagnosis (once the diagnosis is suspected), especially in case of severe thrombocytopenia. Prompt diagnosis and treatment are essential to reduce the chances of death and disability due to hemorrhage. Due to the high rate of recurrence and increased severity of the fetal thrombocytopenia in successive pregnancies, antenatal therapy should be offered. Fetal blood sampling by cordocentesis remains possible in situations of intermediate risk if there is a question about the indication of medical treatment and where vaginal delivery is requested.\nPrognosis\nThe most feared complication of FNAIT is the occurrence of intracranial hemorrhage, leading to death or neurological sequelae. In addition, miscarriage has also been observed.\n\n                            Last update: \n                            March 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Gérald BERTRAND  - Pr Norbert WINER"}
{"Disease Name": "Fetal carbamazepine syndrome", "Disease Definition": "Fetal carbamazepine syndrome is a drug-related embryofetopathy that can occur when an embryo/fetus is exposed to carbamazepine and that is characterized by facial dysmorphism, with some similarities to that seen in fetal valproate syndrome (see this term), such as epicanthal folds, upward slanting palpebral fissures, short nose, micrognathia and malar hypoplasia, as well as nail dysplasia and major anomalies including cleft lip/palate, neural tube defects and cardiac anomalies. In utero exposure to carbamazepine, in combination with valproate, has been associated with significant developmental delay (particularly affecting verbal intelligence) and a high rate of congenital anomalies.", "ORPHA ID": 370076, "Summary": ""}
{"Disease Name": "Fetal cytomegalovirus syndrome", "Disease Definition": "A fetopathy that is likely to occur when a cytomegalovirus (CMV) infected pregnant woman transmits the virus in utero. Children born with congenital CMV infection may present with hepatomegaly, splenomegaly, jaundice, pneumonitis, fetal growth retardation, petechiae, purpura, and thrombocytopenia. Congenital CMV infection can equally result in major neurological sequelae, including microcephaly, intracranial calcifications, sensorineural hearing loss, chorioretinitis, intellectual and motor disabilities, and seizure disorders. CMV disease sequelae caused by a primary infection are usually more severe than those caused by the reactivation of a latent infection.", "ORPHA ID": 294, "Summary": ""}
{"Disease Name": "Fetal encasement syndrome", "Disease Definition": "Fetal encasement syndrome is a rare, lethal developmental defect during embryogenesis characterized by severe fetal malformations, including craniofacial dysmorphism (abnormal cyst in the cranial region, hypoplastic eyeballs, two orifices in the nasal region separated by a nasal septum, abnormal orifice replacing the mouth), omphalocele and immotile, hypoplastic limbs encased under an abnormal, transparent, membrane-like skin. Additional features include absence of adnexal structures of the skin on the outer aspect of the limbs, as well as underdeveloped skeletal muscles and bones. Association with tetralogy of Fallot, horse-shoe kidneys and diaphragm and lung lobulation defects is reported.", "ORPHA ID": 465824, "Summary": ""}
{"Disease Name": "Fetal Gaucher disease", "Disease Definition": "Fetal Gaucher disease is the perinatal lethal form of Gaucher disease (GD; see this term).", "ORPHA ID": 85212, "Summary": "Epidemiology\nIt is very rare with an incidence of less than 5% of GD cases.\nClinical description\nThis form is particularly severe. The disease manifests in the fetus with a decrease or absence of fetal movements, fetal and placental anasarca, hepatosplenomegaly, ichthyosis, arthrogryposis, facial dysmorphism and fetal thrombocytopenia. Death usually occurs in utero or shortly after birth (<3 months).\nEtiology\nFetal Gaucher disease is a lysosomal storage disease caused by a mutation in the GBA gene (1q21) that encodes for the lysosomal enzyme, glucocerebrosidase. The enzyme deficiency resulting from the mutation leads to accumulation of glucosylceramide (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, spleen and bone marrow (Gaucher cells).\nDiagnostic methods\nDiagnosis is made by demonstrating a deficiency in the enzymatic activity of glucocerebrosidase.\nAntenatal diagnosis\nBiochemical prenatal diagnosis is recommended for couples who have already had a child diagnosed with Fetal Gaucher disease or GD type 2. It can be carried out by measuring the enzyme activity in chorionic villus samples at 10-12 weeks of pregnancy or in amniocytes in culture towards 16 weeks of pregnancy.\nGenetic counseling\nThe transmission is autosomal recessive.\nManagement and treatment\nThere is no treatment for this severe form of the disease.\n\n                            Last update: \n                            February 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN"}
{"Disease Name": "Fetal hydantoin syndrome", "Disease Definition": "A drug-related embryofetopathy that can occur when an embryo/fetus is exposed to the anticonvulsant drug phenytoin, characterized by distinct craniofacial anomalies (hypertelorism and epicanthal folds, short nose and deep nasal bridge, malformed and low set ears, short neck) as well as hypoplastic distal phalanges and underdevelopment of nails of fingers and toes, prenatal and postnatal growth retardation, and neurological impairment (at a 2-3 times higher risk than that of the general population) including cognitive deficits and motor developmental delay. Less commonly, microcephaly, ocular defects, oral clefts, umbilical and inguinal hernias, hypospadias and cardiac anomalies have also been reported.", "ORPHA ID": 1912, "Summary": ""}
{"Disease Name": "Fetal iodine syndrome", "Disease Definition": "Fetal iodine syndrome refers to symptoms and signs that may be observed in a fetus or newborn when the mother was exposed during pregnancy to inappropriate (insufficient or excessive) amounts of iodine. Iodine deficiency is associated with goiter and hypothyroidism. When severe iodine deficiency occurs during pregnancy, it is associated with congenital hypothyroidism that is manifested by increased neonatal morbi-mortality and severe mental dysfunction, hyperactivity, attention disorders and a substantial decrease of IQ of an irreversible nature. Excessive iodine ingestion during the third trimester of pregnancy can result in hypothyroidism and fetal goiter due to a prolonged inhibition of thyroid hormone synthesis, an increase in thyrotropin (TSH).", "ORPHA ID": 1910, "Summary": ""}
{"Disease Name": "Fetal methylmercury syndrome", "Disease Definition": "A toxic embryofetopathy characterized by a group of symptoms with unspecific neurologic involvement that may be observed in a foetus or newborn when the mother was exposed during pregnancy to excessive amounts of methylmercury.", "ORPHA ID": 1917, "Summary": "Epidemiology\nSevere methylmercury poisoning cases were reported in the context of two large epidemics: in the Minamata area, in Japan, and in Iraq, both affecting hundreds of people. The Japanese cases resulted from local seafood consumption and sea mercury pollution by a local industrial installation. Iraqi cases resulted from contaminated flour consumption. Large cohort studies in New-Zealand, the Faroe Islands and the Seychelles have documented a risk of less severe prenatal (and/or postnatal) methylmercury poisoning associated with frequent fish consumption (more than 2 or 3 times a week) in thousands of individuals.\nClinical description\nIn severe cases, the clinical picture of prenatal methylmercury poisoning is one of unspecific infantile cerebral palsy, with ataxic motor disturbances, psychomotor retardation and seizures. In populations with high fish consumption, the only manifestations of methylmercury encephalopathy are impaired psychomotor and cognitive performances. They are associated with increased risks of preterm delivery, lower birth weight, and impaired postnatal growth.\nEtiology\nMethylmercury is absorbed from the intestinal tract, through the skin and by inhalation. Most of the human exposure is through food ingestion. In blood, methylmercury being lipophilic is mostly in red cells. It is transported through the placenta to the fetus and accumulated in fetal brain. In cells, methylmercury is partly demethylated into inorganic mercury which is mostly distributed in the liver and kidneys. Elimination is mainly through the fecal route; about 10 % of the amount excreted is in the urine, in the form of inorganic mercury. Methylmercury is also excreted in milk (where its concentration is about 5 % of the concentration in the maternal blood).\nDiagnostic methods\nThe best biomarkers of methylmercury exposure and internal dose are mercury concentrations in hair and whole-blood. In most individuals from the general population, they are under 2 µg/g and 8 µg/L, respectively.\nDifferential diagnosis\nThe clinical picture in prenatal or postnatal severe methylmercury poisoning is one of unspecific encephalopathy. The responsibility of methylmercury should be considered when a high fish consumption is characterized.\nManagement and treatment\nSince exposure to methylmercury is primarily through fish consumption, it is recommended to consume not more than 2 portions of fish per week, especially for children and women of childbearing age. Fish consumption should be reduced in individuals with hair or whole-blood mercury levels of more than 2.5 µg/g or 10 µg/L, and without delay, when these levels exceed 10 µg/g or 40 µg/L, respectively. Biomonitoring and search for neurodevelopmental disorders are recommended for children with hair or whole-blood mercury levels above 10 µg/g or 40 µg/L, respectively or born from mothers who exceeded these levels during pregnancy. Mercury chelation should be considered only in those cases where severe neurological complications are possible.\nPrognosis\nMethylmercury-induced cognitive and psychomotor impairments are not always completely corrected by the decrease of internal methylmercury dose. However, a correct diet, a careful surveillance of neurodevelopment with attentive learning stimulations, can counterbalance the effects of this neurotoxic substance.\n\n                            Last update: \n                            April 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Robert GARNIER  - Dr Magali LABADIE  - Dr Christine TOURNOUD"}
{"Disease Name": "Fetal minoxidil syndrome", "Disease Definition": "Fetal minoxidil syndrome is characterized by a group of symptoms that may be observed in a fetus or newborn when the mother has taken minoxidil during pregnancy. Minoxidil is used in the treatment of malignant renal hypertension and as a topical solution to induce scalp hair growth. Hypertrichosis that gradually diminishes during the first six postnatal months has been reported. Additional reported features include cardiac (congenital great vessel transposition and pulmonary valve stenosis), neurodevelopmental (caudal regression sequence) (see these terms), gastrointestinal, renal, and limb malformations. Conclusive studies are however not available.", "ORPHA ID": 1918, "Summary": ""}
{"Disease Name": "Fetal parvovirus syndrome", "Disease Definition": "Foetal parvovirus syndrome is a foetopathy likely to occur when a pregnant woman is infected by parvovirus B19. In adults, the virus causes a butterfly erythema infectiosum (also called Fifth Disease; 'slapped cheek disease') and flu-like symptoms with symmetric polyarthralgias, which usually do not warrant prenatal diagnosis.", "ORPHA ID": 295, "Summary": "Etiology\nThe pathogenesis of foetal parvovirus infections lies in the virus affinity for progenitor erythroid cells, with infection resulting in aplastic crisis. Anaemia induces a risk of hydrops and foetal death by cardiac failure in 10 to 20% of cases.\nDiagnostic methods\nDiagnosis is established by evidence of either a severe aregenerative anaemia and virus cells (by electronic microscopy) in foetal blood, or viral DNA in amniotic fluid by PCR analysis.\nAntenatal diagnosis\nIn most cases, prenatal diagnosis of parvovirus infection is performed on the basis of a foetal hydrops.\nManagement and treatment\nManagement of aplastic crisis using foetal transfusions is debated, but experience has prompted the use of intrauterine transfusion for severely affected foetuses at less than 32 weeks of gestation.\nPrognosis\nNo significant sequelae were found in the long-term outcomes of one third of children exposed in utero to maternal parvovirus B19 infection.\n\n                            Last update: \n                            February 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Elisabeth ROBERT-GNANSIA"}
{"Disease Name": "Fetal trimethadione syndrome", "Disease Definition": "A drug-related embryofetopathy that can occur when an embryo/fetus is exposed to trimethadione and that is characterized by pre- and post-natal growth retardation, intellectual deficit, developmental and speech delay, craniofacial anomalies (with some similarities to those seen in fetal valproate syndrome), and less commonly, cleft palate, malformations of the heart, urogenital system and limbs. Trimethadione is an antiepileptic drug that has been removed from the market in Europe and is no longer used much in other countries due to teratogenicity and potential side effects.", "ORPHA ID": 1913, "Summary": ""}
{"Disease Name": "Fetal valproate spectrum disorder", "Disease Definition": "A rare teratogenic disease due to embryo/fetal exposure to valproic acid (VPA) and subsequently characterized by a distinct facial dysmorphism, congenital anomalies and developmental delay (especially in language and communication).", "ORPHA ID": 1906, "Summary": "Epidemiology\nPrevalence of fetal valproate syndrome (FVS) is unknown. An incidence of neural tube defects (NTDs) of 1-2% has been associated with the use of VPA during the first trimester of pregnancy (10-20 times the rate seen in the general population) while the incidence of congenital heart disease, neurodevelopmental delay and autism spectrum disorder (ASD) are estimated to be around 4 to 5 times higher than in the general population.\nClinical description\nThe majority of infants exposed to VPA in utero are born healthy. Intrauterine growth retardation is present in 10% of cases but postnatal growth is usually normal and general health is good. Characteristic facial features of FVS are many of the following: high/broad forehead with bifrontal narrowing, metopic craniosynostosis, epicanthal folds, medial deficiency of eyebrows, infraorbital groove, small/broad upturned nose, long and shallow philtrum, long upper lip with thin vermillion borders, thick lower lip and downturned angles of mouth. Congenital anomalies associated with FVS include neural tube defects (e.g. spina bifida aperta), congenital heart defects (e.g. ventricular septal defect), oral clefts, genital abnormalities (e.g. hypospadias with undescended testicles) and limb defects, and less commonly, inguinal and umbilical hernia, tracheomalacia, supernumerary nipples, bifid ribs and pre-axial defects of the feet. Children exposed to VPA have a higher risk of developmental problems such a decreased cognitive function (especially in verbal intelligence), attention deficit disorder, learning difficulties and often the communication problems of ASD.\nEtiology\nFVS is caused by the exposure during pregnancy to VPA (valproate), a mood stabilizer and broad-spectrum antiepileptic drug (AED. Primarily metabolized in the liver, VPA readily crosses the placenta, where concentrations are higher than in the mother. Embryos and fetuses exposed to VPA during the 1st trimester (especially to doses exceeding 600 mg/day but lower doses may also be teratogenic) have a higher risk of developing FVS, as this is the principal period of structural development.\nDiagnostic methods\nDiagnosis is based on the presence of the well-recognized cluster of clinical findings in infants born to mothers who took VPA during pregnancy.\nDifferential diagnosis\nDifferential diagnoses include other types of AED-related embryofetopathies (e.g. fetal hydantoin syndrome) and possibly fetal alcohol spectrum disorder.\nAntenatal diagnosis\nPrenatal diagnosis is possible by the detection of anomalies such as NTDs, cardiac and other organ anomalies by ultrasonographic examination and estimation of maternal serum alpha-fetoprotein (with a history of antenatal valproate intake).\nManagement and treatment\nVPA should be avoided (if possible) during pregnancy and high dose folic acid (4-5 mg/day) should be started 6 weeks before conception and continued through the first trimester. In pregnant women with no effective alternative, VPA should be administered in slow release form at the lowest possible divided dosage and preferably as a monotherapy along with high dose folic acid. Surveillance of the newborn should include searching for dysmorphic facial features, congenital malformations and withdrawal symptoms at birth. Long-term follow-up of the child should include early diagnosis and management of any potential behavioral or neurodevelopmental effect and educational and psychosocial support, whenever needed. Management of congenital anomalies should follow standard treatment protocols. Children with ASD should receive the regular treatment offered to children with communication disorders.\nPrognosis\nThe prognosis of newborns is highly variable and depends on the clinical and behavioral symptoms, timing of exposure and the dosage of VPA taken by the mother. Life expectancy may be decreased in those with multiple congenital anomalies (in particular of the cardiovascular system and NTD) or with significant intellectual disability.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Koren GIDEON  - Pr Asher ORNOY"}
{"Disease Name": "Fever-associated acute infantile liver failure syndrome", "Disease Definition": "A rare genetic parenchymatous liver disease characterized by infantile or early childhood onset of recurrent episodes of acute liver failure precipitated by a febrile illness. During the life-threatening episodes, patients present with vomiting, lethargy, jaundice, as well as elevated levels of liver enzymes and coagulopathy. There is usually complete recovery between the episodes with conservative treatment.", "ORPHA ID": 464724, "Summary": ""}
{"Disease Name": "FG syndrome type 1", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by developmental delay and intellectual disability, early hypotonia, constipation, feeding problems, imperforate anus, characteristic behavior (affable, eager to please), and dysmorphic craniofacial features (such as relative macrocephaly, prominent forehead with frontal hair upsweep, hypertelorism, downslanting palpebral fissures, and open mouth). Additional manifestations are partial agenesis of the corpus callosum, sensorineural hearing loss, joint laxity, cardiac anomalies, and abnormalities of the fingers and toes, among others.", "ORPHA ID": 93932, "Summary": ""}
{"Disease Name": "FGFR2-related bent bone dysplasia", "Disease Definition": "FGFR2-related bent bone dysplasia is a rare, genetic, lethal, primary bone dysplasia characterized by dysmorphic craniofacial features (low-set, posteriorly rotated ears, hypertelorism, megalophtalmos, flattened and hypoplastic midface, micrognathia), hypomineralization of the calvarium, craniosynostosis, hypoplastic clavicles and pubis, and bent long bones (particularly involving the femora), caused by germline mutations in the FGFR2 gene. Prematurely erupted fetal teeth, osteopenia, hirsutism, clitoromegaly, gingival hyperplasia, and hepatosplenomegaly with extramedullary hematopoiesis may also be associated.", "ORPHA ID": 313855, "Summary": ""}
{"Disease Name": "Fibroblastic rheumatism", "Disease Definition": "A rare rheumatologic disease characterized by sudden onset of symmetric inflammatory distal polyarthritis and multiple firm cutaneous nodules with predilection for the upper and lower extremities. Patients often develop sclerodactyly and joint contractures. Skin biopsy shows fibroblastic proliferation in a matrix of thickened collagen fibers, with loss of elastic fibers and no mucin deposition.", "ORPHA ID": 477650, "Summary": ""}
{"Disease Name": "Fibrochondrogenesis", "Disease Definition": "Fibrochondrogenesis is a rare, neonatally lethal, rhizomelic chondrodysplasia. Eleven cases have been reported. The face is distinctive and characterized by protuberant eyes, flat midface, flat small nose with anteverted nares and a small mouth with long upper lip. Cleft palate, micrognathia and bifid tongue can occur. The limbs show marked shortness of all segments with relatively normal hands and feet. No internal anomalies other than omphalocele have been reported. Transmission is probably autosomal recessive. Recurrence in a consanguineous family (affecting both sexes) and concordance of affected male twins have been reported.", "ORPHA ID": 2021, "Summary": ""}
{"Disease Name": "Fibrodysplasia ossificans progressiva", "Disease Definition": "Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissue characterized by congenital malformations of the great toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites.", "ORPHA ID": 337, "Summary": "Epidemiology\nThe worldwide prevalence is approximately 1/2,000,000. There is no ethnic, racial, gender, or geographic predilection to FOP.\nClinical description\nChildren who have FOP appear normal at birth except for congenital malformations of the great toes (hallux valgus, malformed first metatarsal, and/or monophalangism). During the first decade of life, sporadic episodes of painful soft tissue swellings (flare-ups) occur which are often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls or fatigue. If diagnosis of FOP is suspected, any invasive intervention (such as biopsy), which may lead to flare-ups, is contraindicated. These flare-ups transform skeletal muscles, tendons, ligaments, fascia, and aponeuroses into heterotopic bone, rendering movement impossible. Patients with atypical forms of FOP have been described. They either present with the classic features of FOP plus one or more atypical features (e.g. intercurrent aplastic anemia, craniopharyngioma, childhood glaucoma or growth retardation) (FOP plus), or present major variations in one or both of the two classic defining features of FOP (e.g., normal great toes or severe reduction deficits of digits) (FOP variants).\nEtiology\nClassic FOP is caused by a recurrent activating mutation (617G>A; R206H) in the gene ACVR1 (ALK2) encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor. Atypical FOP patients also have heterozygous ACVR1 missense mutations in conserved amino acids.\nDiagnostic methods\nThe diagnosis of FOP is made by clinical evaluation. Plain radiographs can substantiate more subtle great toe abnormalities and the presence of heterotopic ossification. Confirmatory genetic testing is available.\nDifferential diagnosis\nDifferential diagnosis includes progressive osseous heteroplasia, osteosarcoma, lymphedema, soft tissue sarcoma, desmoid tumors (see these terms), aggressive juvenile fibromatosis, and non-hereditary (acquired) heterotopic ossification.\nAntenatal diagnosis\nPrenatal testing is not yet routinely available.\nGenetic counseling\nAlthough most cases of FOP are sporadic (non-inherited mutations), a small number of inherited FOP cases show germline transmission with an autosomal dominant pattern.\nManagement and treatment\nAt present, there is no definitive treatment, but a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. Preventative management is based on prophylactic measures against falls (e.g. improvement in household safety, use of protective headgear), respiratory decline (e.g., incentive spirometry), and viral infections.\nPrognosis\nThe median lifespan is approximately 40 years of age. Most patients are wheelchair-bound by the end of the second decade of life and commonly die of complications of thoracic insufficiency syndrome.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Kaplan FREDERICK  - Dr Robert PIGNOLO  - Dr Eileen SHORE"}
{"Disease Name": "Fibrohistiocytic inflammatory pseudotumor of the liver", "Disease Definition": "A subtype of inflammatory pseudotumor of the liver characterized by a benign, well-circumscribed tumor with fibrohistiocytic infiltration (including xanthogranulomatous inflammation, multinucleated giant cells, and neutrophilic infiltration), typically localized in the peripheral hepatic parenchyma. Presentation may be of non-specific symptoms (fever, malaise, and abdominal pain) or as an incidental finding.", "ORPHA ID": 555434, "Summary": ""}
{"Disease Name": "Fibrolamellar hepatocellular carcinoma", "Disease Definition": "A rare variant of hepatocellular carcinoma (HCC) presenting in adolescents or young adults with no underlying liver disease. Clinical presentation is non specific, with abdominal mass, abdominal discomfort or pain, fatigue and weight loss. Patients can also be asymptomatic. HCC markers (alpha fetoprotein) are normal. Fibrolamellar HCC presents as a unique, well-delimited mass at imagery and a biopsy confirms the diagnosis, showing well-differentiated tumor cells surrounded by thick collagen bands.", "ORPHA ID": 401920, "Summary": ""}
{"Disease Name": "Fibronectin glomerulopathy", "Disease Definition": "A primary glomerular disease characterized by proteinuria, type IV renal tubular acidosis, microscopic hematuria and hypertension that may lead to end-stage renal failure in the second to sixth decade of life.", "ORPHA ID": 84090, "Summary": "Epidemiology\nFibronectin glomerulopathy exact prevalence is unknown. Only 20 families and 25 sporadic cases have been described in the literature so far.\nClinical description\nFibronectin glomerulopathy may present at different ages, although mostly in adolescence or early adulthood, with typical features of a nephrotic syndrome including hypertension, which can be severe, and edema, which initially develops around the eyes and legs but with time may become generalized. Patients may also present with varying degrees of renal failure that progressively worsen over several years, reaching end stage renal disease in the second to sixth decade of life.\nEtiology\nClustering of the disease within families indicates a genetic origin. In 40% of families, the disease is caused by heterozygous mutations in the FN1 gene (2q34) encoding fibronectin. Whole-genome linkage analysis in a large pedigree showed another disease locus on 1q32, however no specific candidate genes has been identified so far.\nDiagnostic methods\nDiagnosis rests on renal biopsy. Typical findings at light microscopy are enlarged glomeruli with deposits in the mesangium and subendothelial space, usually with scant immunoreactivity for immunoglobulins or complement factors. Electron microscopy reveals deposits mainly located in the subendothelial space but also in the subepithelial and intramembranous spaces. Homogeneous granular deposits dominate in most cases; in some an admixture of fibrils is observed. The most striking finding is the immunoreactivity of the glomerular deposits to fibronectin. Family history is supportive of the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other chronic non-amyloid glomerulopathies with organized deposits including mixed cryoglobulinemia, fibrillary glomerulonephritis, immunotactoid glomerulopathy, collagen type III glomerulopathy, systemic lupus erythematosus, diabetes glomerulopathy and other non-specific collagen deposition diseases. It is difficult to discriminate fibronectin glomerulopathy from membranoproliferative glomerulonephritis at light microscopy examination.\nGenetic counseling\nSegregation with disease appearance in successive generations is consistent with an autosomal dominant pattern of inheritance with age-related penetrance. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no specific treatment for fibronectin glomerulopathy. Treatment of symptoms can include corticosteroids, diuretics and treatment for hypertension. Antiproteinuric and renoprotective treatment with ACE inhibitors or anti-AT1R antagonists could be of help to slow renal disease progression. More advanced cases of renal failure require renal dialysis or transplantation.\nPrognosis\nPrognosis is uncertain, in some cases the disease follows an indolent course and in others it leads to end stage renal disease and chronic renal failure in the second to sixth decade of life.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Marina NORIS | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Fibrous dysplasia of bone", "Disease Definition": "A rare, benign, primary bone dysplasia characterized by progressive replacement of normal bone and marrow with fibrous connective tissue in either one (monostotic) or multiple (polyostotic) bones. Clinical manifestations depend on the anatomic location of the replacement and may include bone pain, deformities, pathological fractures, and cranial nerve deficits.", "ORPHA ID": 249, "Summary": "Epidemiology\nThe prevalence is unknown and is difficult to estimate due to the frequent asymptomatic lesions.\nClinical description\nFD can involve the craniofacial, axial, and/or appendicular skeleton separately or simultaneously, and ranges from isolated asymptomatic monostotic lesions to severely incapacitating polyostotic lesions leading to pain, fracture, deformity or loss of vision and hearing. The monostotic form represents approximately 70% of cases, may present with pain or a pathologic fracture, and is usually diagnosed between 10 to 30 years of age. The polyostotic form represents 20-30% of cases with the majority of patients becoming symptomatic before 10 years of age. The most common sites of involvement include the femur, tibia, skull and facial bones, pelvis, rib, humerus, radius and ulna, lumbar spine, clavicle, and cervical spine. Lesions may be unilateral or, less commonly, bilateral. Initial symptoms are usually pain in the involved limb(s), associated with a limp if the lower extremity is involved, and spontaneous fracture. Weakened structural integrity frequently leads to significant bowing and leg-length discrepancies in patients with limb involvement. Sphenoidal bone involvement is variably associated with cranial nerve deficits, essentially loss of vison (affecting less than 10% of individuals with optic nerve compression). Many patients with polyostotic forms also present with renal phosphate wasting, which accounts for an increased risk of fracture. At the extreme end of the spectrum, a small proportion of patients also have endocrine manifestations, the most common being a peripheral precocious puberty. Hyperthyroidism and growth hormone hypersecretion are also quite frequently observed, while Cushing syndrome is exceptional. These patients also have café-au-lait cutaneous spots. These endocrine or cutaneous features represent the McCune-Albright syndrome. Pancreatic intraductal papillary mucinous neoplasms have been described in patients with extended forms.\nEtiology\nActivating somatic mutations in the GNAS gene (20q13.32), which encodes the alpha-subunit of the Gs protein receptor (Gs alpha) in target cells, is responsible for bone cell alterations as well as for the involvement of other cells/tissues bearing the same molecular defect (melanocytes, endocrine cells).\nDiagnostic methods\nImaging and, when necessary, histology are the cornerstones of diagnosis. The pathognomonic radiological picture includes radiolucency and a ''ground glass'' appearance (with no visible trabecular pattern in affected areas), variable presence of endosteal scalloping of the inner cortex (but with a smooth nonreactive periosteal surface), curvature of the femoral neck and proximal shaft (often causing a coxa vara deformity of the knee), and shepherd's crook deformity.\nDifferential diagnosis\nDifferential diagnoses includes osteofibrous dysplasia, osteochondroma, exostosis, osteosarcoma, chondrosarcoma, osteofibroma, skull meningioma, osteoma\nGenetic counseling\nMutations affect only somatic cells and are therefore not hereditary, thus genetic counseling may provide reassurance but is not strictly necessary.\nManagement and treatment\nThe conventional therapeutic approach is essentially symptomatic (analgesics) and orthopedic (prevention and treatment of bone complications). Treatment is typically with intravenous pamidronate, which rapidly relieves bone pain in most patients, and progressively increases bone mineralization in osteolytic areas in about half of patients. In contrast, placebo controlled randomized trials have shown that oral bisphosphonates are no more efficacious than placebo to reduce bone pain. Tubular phosphate wasting is common and should be treated with phosphate supplementation and calcitriol.\nPrognosis\nPrognosis is generally good in patients with the monostotic form. Polyostotic patients need to be monitored more closely, but as disease has a tendency to stabilize after adolescence, outcomes are often good in adults.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Roland CHAPURLAT"}
{"Disease Name": "Fibular aplasia-complex brachydactyly syndrome", "Disease Definition": "A rare syndrome characterised by severe reduction or absence of the fibula and complex brachydactyly. Less than 30 cases have been described in the literature so far. The syndrome is inherited in an autosomal recessive manner and is caused by mutations in the cartilage-derived morphogenetic protein-1 gene (GDF5).", "ORPHA ID": 2639, "Summary": ""}
{"Disease Name": "Fibular aplasia-ectrodactyly syndrome", "Disease Definition": "A rare, genetic, congenital dysostosis disorder characterized by fibular aplasia (or hypoplasia) associated with ectrodactyly and/or brachydactyly or syndactyly. Additonal variable features include shortening of the femur, as well as tibial, hip, knee, and/or ankle defects.", "ORPHA ID": 1118, "Summary": ""}
{"Disease Name": "Fibular dimelia-diplopodia syndrome", "Disease Definition": "A very rare, genetic, congenital limb malformation syndrome characterized by duplication of the fibula associated with pre-axial mirror polydactyly of the foot, that may occur as an isolated malformation or be assoicated with other anomalies, including ulnar dimelia, facial abnormalities and sacrococcygeal teratoma.", "ORPHA ID": 1757, "Summary": ""}
{"Disease Name": "Fibulo-ulnar hypoplasia-renal anomalies syndrome", "Disease Definition": "Fibulo-ulnar hypoplasia-renal anomalies syndrome is characterized by fibuloulnar dysostosis with renal anomalies. It has been described in two sibs born to nonconsanguinous parents. The syndrome is lethal at birth (respiratory failure). Clinical manifestations include ear and facial anomalies (including micrognathia), symmetrical shortness of long bones, fibular agenesis and hypoplastic ulna, oligosyndactyly, congenital heart defects, and cystic or hypoplastic kidney. It is transmitted as an autosomal recessive trait.", "ORPHA ID": 2256, "Summary": ""}
{"Disease Name": "Filariasis", "Disease Definition": "A parasitic disease caused by tissue-invasive, vector-borne nematodes which can be found anywhere in the human body and that are transmitted to humans through the bite of an infected mosquito or fly or by consumption of unsafe drinking water and which, depending on the subtype can manifest with lymphedema, dermatitis, subcutaneous edema and eye involvement. The disorder is a major public health problem in many tropical and subtropical countries. Six subtypes have been described in the literature: lymphatic filariasis, onchocerciasis, loiasis, mansonelliasis, dirofilariasis and dracunculiasis caused by Wuchereria bancrofti and filarioidea of the genus Brugia; Onchocerca volvulus; Loa loa; Mansonella; Dirofilaria; and Dracunculus medinensis, respectively. Tropical eosinophilia is considered a frequent manifestation.", "ORPHA ID": 2034, "Summary": ""}
{"Disease Name": "Filippi syndrome", "Disease Definition": "Filippi syndrome is characterised by microcephaly, cutaneous syndactyly of the fingers and toes, intellectual deficit, growth retardation and a characteristic facies (high and broad nasal bridge, thin alae nasi, micrognathia and a high frontal hairline). So far, less than 25 cases have been reported. Cryptorchidism, polydactyly, and teeth and hair anomalies may also be present. Transmission is autosomal recessive.", "ORPHA ID": 3255, "Summary": ""}
{"Disease Name": "Finger hyperphalangy-toe anomalies-severe pectus excavatum syndrome", "Disease Definition": "A rare, genetic, congenital limb malformation syndrome characterized by bilateral short broad thumbs, short deviated index fingers, clinodactyly of the fifth fingers, broad, valgus-deviated halluces and laterally-deviated, overlapping second toe, associated with severe pectus excavatum and craniofacial dysmorphism (including brachycephaly, low anterior hairline, flat supraorbital ridges, telecanthus, upslanting palpebral fissures, maxillary hypoplasia, posteriorly rotated ears, microsomia and micrognathia). Radiological findings include thumb, index, and middle finger hyperphalangy, with severe delta phalanxes in affected fingers and halluces.", "ORPHA ID": 369979, "Summary": ""}
{"Disease Name": "Fingerprint body myopathy", "Disease Definition": "Fingerprint body myopathy is a congenital benign muscle disorder characterised by congenital hypotonia and weakness and by the presence of numerous fingerprint bodies located at the periphery of the muscle fibers. Prevalence is unknown. Less than 20 patients have been described. Few sporadic cases have been observed, as well as cases of recessive transmission.", "ORPHA ID": 97232, "Summary": ""}
{"Disease Name": "Finnish upper limb-onset distal myopathy", "Disease Definition": "Finnish upper limb-onset distal myopathy is a rare, genetic distal myopathy characterized by slowly progressive distal to proximal limb muscle weakness and atrophy, with characteristic early involvement of thenar and hypothenar muscles. Patients present with clumsiness of the hands and stumbling in the fourth to fifth decade of life, and later develop steppage gait and contractures of the hands. Progressive fatty degeneration affects intrinsic muscles of the hands, gluteus medium and both anterior and posterior compartment muscles of the distal lower extremities, with later involvement of forearm muscles, triceps, infraspinatus and the proximal lower limb muscles. Asymmetry of muscle involvement is common.", "ORPHA ID": 399086, "Summary": ""}
{"Disease Name": "First branchial cleft anomaly", "Disease Definition": "A rare otorhinolaryngological malformation characterized by recurrent infections, swelling, pain, discharge and abscess formation in the defect area. The anomaly results from incomplete fusion of the ventral part of the first and second branchial arch, presenting as either a fistula, sinus or cyst occurring anywhere between the external auditory canal and the mandibular angle, including parotid gland.", "ORPHA ID": 141013, "Summary": ""}
{"Disease Name": "Fish-eye disease", "Disease Definition": "Fish eye disease (FED) is a form of genetic LCAT (lecithin-cholesterol acyltransferase) deficiency (see this term) characterized clinically by corneal opacifications, and biochemically by significantly reduced HDL cholesterol and partial LCAT enzyme deficiency.", "ORPHA ID": 79292, "Summary": "Epidemiology\nFish eye disease is very rare; about 30 cases have been reported to date. Fish eye disease seems to be less common than familial LCAT deficiency (see this term).\nClinical description\nCorneal opacities are progressive and are observed from an early age (adolescence or young adulthood) and sometimes result in visual impairment. These lesions are generally more severe than in complete LCAT deficiency (familial LCAT deficiency, see this term) and form a mosaic pattern of small dot-like grey-white opacities. Signs of atherosclerosis have only been reported in rare cases although patients have low HDL cholesterol levels. Hepatomegaly, splenomegaly and lymphadenopathy are generally not present.\nEtiology\n18 different mutations in the LCAT gene (16q22.1), encoding the LCAT enzyme which catalyzes the formation of cholesterol esters in lipoproteins, have been identified in FED cases. In patients with this disorder, alpha-LCAT activity (i.e., the activity of LCAT in esterifying cholesterol within HDL) is abolished, but beta-LCAT activity (i.e., the activity of LCAT in esterifying cholesterol within other lipoproteins) is preserved. Impaired enzyme function is thought to result in deposition of lipids in the cornea.\nDiagnostic methods\nInitial diagnosis is suspected on the basis of corneal clouding. Definitive diagnosis requires molecular genetic testing of the LCAT gene and functional analysis of the gene product.\nDifferential diagnosis\nDifferential diagnosis includes Schnyder corneal dystrophy as well as familial LCAT deficiency and Tangier disease (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible.\nGenetic counseling\nFED follows an autosomal recessive pattern of inheritance. Genetic counseling should be offered to affected families.\nManagement and treatment\nTreatment is symptomatic. Severe visual impairment may require corneal transplantation.\nPrognosis\nMorbidity is related to progressive corneal opacification, which may lead to visual impairment.\n\n                            Last update: \n                            March 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Laura CALABRESI  - Pr Guido FRANCESCHINI"}
{"Disease Name": "Fixed drug eruption", "Disease Definition": "A rare hypersensitivity reaction characterized by the appearance of erythematous or violaceous, round, sometimes painful, plaques that may or may not result in long-lasting pigmentation and which recur (usually at the same site) upon re-exposure to the causative medication. The severe form of the disease, generalized bullous fixed drug eruption, occurs typically in the elderly and may be life-threatening. Onset usually occurs 30 minutes to several hours after administration of the causal medication. Many medications, including paracetamol, have been implicated. The disease may rarely be induced by food. Histology is characterized by interface dermatitis or epidermal necrolysis in bullous forms.", "ORPHA ID": 293812, "Summary": ""}
{"Disease Name": "Fixed subaortic stenosis", "Disease Definition": "Fixed subaortic stenosis (FSS) is a rare heart malformation characterized by the obstruction by membranous or fibromuscular tissue of the left ventricular outflow tract (LVOT) below the aortic valve, that occurs as an isolated lesion or in association with additional cardiac malformations (e.g. ventricular septal defect, patent ductus arteriosus, coarctation of the aorta), that presents in childhood with signs of LVOT obstruction (e.g. dyspnea, chest pain, syncope, palpitations) and that can potentially lead to life-threatening complications (e.g. aortic regurgitation, infective endocarditis). It comprises three anatomical subforms: discrete fixed membranous subaortic stenosis (membranous tissue encircling the LVOT), discrete fibromuscular subaortic stenosis (fibromuscular tissue encircling the LVOT) and tunnel subaortic stenosis (fibromuscular diffuse tunnel-like narrowing of the LVOT), the two latter forms being generally more severe than the membranous form.", "ORPHA ID": 3092, "Summary": ""}
{"Disease Name": "FKRP-related limb-girdle muscular dystrophy R9", "Disease Definition": "A form of autosomal recessive limb-girdle muscular dystrophy that presents a highly variable age of onset and phenotypic spectrum typically characterized by slowly progressive proximal weakness of the pelvic and shoulder girdle musculature (predominantly affecting the lower limbs), frequently associated with waddling gait, scapular winging, calf and tongue hypertrophy, exercise-induced myalgia, abdominal muscle weakness, cardiomyopathy, respiratory muscle involvement, and myoglobinuria and/or elevated creatine kinase serum levels.", "ORPHA ID": 34515, "Summary": "Epidemiology\nDue to a founder mutation in Scandinavia (excluding Finland) the prevalence figures for FKRP-related limb-girdle muscular dystrophy R9 (LGMDR9) is much higher than the rest of the world (about 1/50,000). In countries with Scandinavian immigration (Northern Europe and northern states of America) the prevalence is also relatively high.\nClinical description\nThe age of onset is correlated to the genotype and residual expression of fukutin-related protein. Thus, patients homozygous for the common, mild mutation (c.826C>A) usually have an onset in the third decade, while patients compound heterozygous for this mutation have onset before age 10, and loose ambulation around age 20 and need assisted ventilation 5-10 years after that. The manifesting symptoms start in the lower extremities with difficulties raising from a chair, climbing stairs and running. Later proximal weakness starts in the arms with visible scapular winging. Of note, a third of patients may present with myoglobinuria on physical exertion, before weakness is noticed. Patients may develop a cardiomyopathy that requires medical treatment. In rare cases, a cardiac transplant is required. Left ventricular ejection fraction drops on average 0.4% per year. Patients homozygous for the c.826C>A mutation in FKRP loose ambulation around age 60 and may need assisted ventilation at night, but the timing of these losses is highly variable.\nEtiology\nThe loss of glycosylation of alpha-dystroglycan due to pathogenic variants in FKRP (19q13.32) leads to poor linkage of the myocyte to the extracellular matrix, which produces muscle damage.\nDiagnostic methods\nThe diagnosis is directed towards a limb girdle muscular dystrophy based on clinical presentation with proximal wasting and weakness, most pronounced in legs. The primary diagnosis is based on finding of two pathogenic variants in FKRP. Creatine kinase is usually elevated above 1,000 and can reach undetectable levels after strenuous exercise that can also result in myoglobinuria. A muscle biopsy shows dystrophic changes, and staining for glycosylation of alpha-dystroglycan with VIA4 and IIH6 antibodies shows loss of glycosylation.\nDifferential diagnosis\nThe list of other muscle disease which present with proximal weakness is long. First and foremost, the other, numerous, limb girdle dystrophies should be considered. Other differential diagnoses include Becker muscular dystrophy, Bethlem myopathy, mitochondrial myopathy, poly-/dermatomyositis, and muscle glycogenosis (especially Pompe disease and debrancher deficiency). Spinal muscular dystrophy in mild forms and congenital myasthenia patients are also valid differential diagnoses.\nGenetic counseling\nFor parents of an affected child, the risk of having another affected child is 25% at each pregnancy. As this is a recessive rare disease, genetic counselling for affected individuals is rarely needed due to the low carrier frequency in the background population. However, carrier testing of an unaffected spouse is relevant in Scandinavia (excluding Finland) as the carrier frequency is 1/150-200 people.\nManagement and treatment\nCurrently, there are no approved specific drugs for the disease. Supportive therapies with assisted ventilation, medical treatment for heart failure, early retirement if weakness becomes too severe, and assisted devices for ambulation and general mobility (e.g. handles in the toilet) are recommended. Different gene therapies and substrate (ribitol) therapies are being researched and clinical trials are imminent.\nPrognosis\nQuality of life is highly influenced by the loss of motor function and respiratory limitations. Life expectancy is unknown, but usually normal in patients homozygous for the c.826C>A mutation. Patients compound heterozygous for the mutation likely have reduced life expectancy because of invasive ventilation from early age and the subsequent complications.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Pr John VISSING"}
{"Disease Name": "Flat face-microstomia-ear anomaly syndrome", "Disease Definition": "Flat face-microstomia-ear anomaly syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by dysmorphic facial features, including high forehead, elongated and flattened midface, arched and sparse eyebrows, short palpebral fissures, telecanthus, long nose with hypoplastic nostrils, long philtrum, high and narrow palate and microstomia with downturned corners. Ears are characteristically malformed, large, low-set and posteriorly rotated and nasal speech is associated. There have been no further descriptions in the literature since 1994.", "ORPHA ID": 1968, "Summary": ""}
{"Disease Name": "Fleck corneal dystrophy", "Disease Definition": "Fleck corneal dystrophy (FCD) is a rare generally asymptomatic form of stromal corneal dystrophy (see this term) characterized by multiple asymptomatic, non-progressive opacities disseminated throughout the corneal stroma with no effect on visual acuity.", "ORPHA ID": 98970, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is not known. FCD affects males and females equally.\nClinical description\nThe condition may occur throughout life and has been reported in children as young as 2 years of age. Corneal sensation is usually normal. Vision is not affected but mild photophobia may occur.\nEtiology\nFleck corneal dystrophy is caused by a mutation in the  PIKFYVE gene (2q34).\nDiagnostic methods\nLesions are mostly minute and symmetrical. Opacities are sometimes small, oval, round, or semi-circular with distinct borders resembling flecks in the central and peripheral cornea. Opacities may also resemble snowflakes or clouds and consist of small grayish aggregations with ill-defined margins, occurring particularly in the central third of the cornea.\nGenetic counseling\nAn autosomal dominant pattern of inheritance has been reported.\nManagement and treatment\nFleck dystrophy does not require specific treatment.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "FLNA-related X-linked myxomatous valvular dysplasia", "Disease Definition": "A rare genetic cardiac malformation characterized by progressive myxomatous degeneration predominantly of the mitral valve (but not uncommonly with multivalvular involvement), presenting as valve thickening and dysfunction with variable stenosis, prolapse, and/or regurgitation, and potentially resulting in lethal heart failure. Hyperextensible skin and joint hypermobility have been reported in some patients. Hemizygous males display a more severe phenotype than heterozygous females.", "ORPHA ID": 555877, "Summary": ""}
{"Disease Name": "Floating-Harbor syndrome", "Disease Definition": "A multiple congenital anomalies/dysmorphic syndrome-intellectual disability that is characterized by facial dysmorphism, short stature with delayed bone age, and expressive language delay.", "ORPHA ID": 2044, "Summary": "Epidemiology\nFloating-Harbor syndrome prevalence and incidence are unknown. Around 100 cases have been reported in the literature to date.\nClinical description\nFacial features include a triangular-shaped face, a prominent bulbous nose with a broad nasal bridge, a wide columella, deep-set eyes with long eyelashes, a wide mouth with a thin upper lip, low-set ears and sometimes broad thumbs and big toes. The speech defect is marked by impairment of expressive language and is often associated with a peculiar hypernasal voice. Stature is usually reported to be below the third percentile and between 2 and 4 SD below the mean. Bone age is always delayed. Other variable manifestations include celiac disease, pseudoarthrosis of the clavicle, intellectual disability, dental anomalies (malocclusion, microdontia, supernumerary upper teeth), a short neck, brachydactyly, and clinodactyly of the 5th finger. Associated genitourinary and cardiac anomalies have been reported in a few cases.\nEtiology\nThe syndrome is associated with heterozygous mutations in exon 33 or mostly in exon 34 of the SRCAP gene (16p11.2), with two recurrent mutations (Arg2444* and Arg2435*). SRCAP encodes an ATPase which is involved in chromatin remodeling and is the cofactor of CREBBP, the gene responsible for Rubinstein-Taybi syndrome.\nDiagnostic methods\nDiagnosis is based on clinical examination and can be confirmed by genetic testing.\nDifferential diagnosis\nThe differential diagnosis should include other dysmorphic syndromes, in particular Rubinstein-Taybi syndrome.\nAntenatal diagnosis\nPrenatal diagnosis can be considered for families in which the disease-causing mutation has been identified.\nGenetic counseling\nThe majority of reported cases are sporadic, but a few familial cases with autosomal dominant inheritance have been reported.\nManagement and treatment\nManagement is only symptomatic. Patients may benefit from developmental and educational programs and should receive regular orthodontic care. Growth hormone therapy may be of benefit in some patients.\nPrognosis\nDespite the presence of short stature and learning difficulties, in general patients appear to remain in good health and have a good quality of life.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Didier LACOMBE"}
{"Disease Name": "Florid cemento-osseous dysplasia", "Disease Definition": "Florid cemento-osseous dysplasia (FCOD) is a rare fibro-osseous lesion in the jaw that predominantly affects middle-aged women of African descent. It is generally asymptomatic or may manifest with pain and gingival swelling. Radiologically, it is characterized by multiple dense lobulated bone lesions, often symmetrically located in various regions of the jaw.", "ORPHA ID": 83451, "Summary": ""}
{"Disease Name": "FLOTCH syndrome", "Disease Definition": "FLOTCH syndrome is a rare, genetic, cutaneous disorder characterized by leuchonychia and multiple, recurrent pilar cysts, associated or not with ciliar dystrophy and/or koilonychia. Renal calculi have also been reported.", "ORPHA ID": 2045, "Summary": ""}
{"Disease Name": "Flynn-Aird syndrome", "Disease Definition": "A rare genetic disease characterized by childhood onset of bilateral progressive sensorineural hearing loss, ocular anomalies (myopia, cataract, retinitis pigmentosa), central and peripheral nervous system features (dementia, epilepsy, ataxia, peripheral neuropathy), ectodermal features (skin atrophy, alopecia, dental caries), and skeletal anomalies (bone cysts, joint stiffness, scoliosis, kyphosis). Laboratory examination may reveal elevated cerebrospinal fluid protein.", "ORPHA ID": 2047, "Summary": ""}
{"Disease Name": "Focal acral hyperkeratosis", "Disease Definition": "A rare epidermal disease characterized by multiple, usually asymptomatic, yellowish to flesh colored hyperkeratotic papules and plaques on the palms and soles, with a preference for the palmar and plantar margins. Histological examination shows pronounced orthohyperkeratosis overlying a crateriform depression in the epidermis, with hypergranulosis and mild acanthosis, while elastorrhexis is absent. The lesions appear in the second or third decade of life and gradually increase in number over several years. The condition may be sporadic or familial.", "ORPHA ID": 308013, "Summary": ""}
{"Disease Name": "Focal dermal hypoplasia", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by abnormalities in ectodermal- and mesodermal-derived tissues, classically manifesting with skin abnormalities, limb defects, ocular malformations, and mild facial dysmorphism.", "ORPHA ID": 2092, "Summary": "Epidemiology\nThe exact prevalence of focal dermal hypoplasia (FDH) is unknown. To date, around 300 cases have been reported in the literature. Female to male ratio is 9:1, with no racial or ethnic predilection.\nClinical description\nFDH usually manifests in the neonatal period and characteristic skin findings include congenital patchy skin hypoplasia, nodular, subcutaneous fat herniation, hyper/hypo-pigmentation in Blaschko linear distribution, telangiectasia and ridged, dysplastic or hypoplastic nails. Sparse hair/alopecia and later-onset, verrucoid, periorificial, skin and mucous membrane papillomas are also frequently associated. Characteristic limb malformations include ectrodactyly, syndactyly, oligodactyly and marked long bone reduction, as well as occasionally observed costovertebral abnormalities (e.g. fused or bifid ribs, hemi- or butterfly vertebrae), which may lead to kyphosis/kyphoscoliosis. Typical ocular abnormalities include congenital microphtalmia (occasionally anophtalmia), cataracts and iris and chorioretinal colobomas. Dental abnormalities are also frequently observed and include enamel defects, as well as abnormal number and form of the primary and secondary dentition. Craniofacial dysmorphism, including facial asymmetry, notched nasal alae, small, underfolded pinnae and a pointed chin, may be associated. Other system abnormalities, such as genital labial hypoplasia, abdominal wall defects, and, occasionally, malrotation of the gut may be additional features.\nEtiology\nFDH is caused by mutations in the PORCN gene (Xp11.23), which encodes the porcupine O-acyltransferase, involved in the secretion and signaling of WNT proteins, important for embryonic tissue development. Different types of PORCN mutations, including nonsense, missense, and frameshift mutations, as well as partial- or whole-gene deletions, have been described. In familial cases, affected parents usually display a milder form of FDH.\nDiagnostic methods\nDiagnosis is based on the presence of characteristic clinical findings and is confirmed or established, in cases of inconclusive clinical presentation, by molecular genetic testing which reveals a pathogenic variant in the PORCN gene.\nDifferential diagnosis\nDifferential diagnoses should include microphtalmia with linear skin defects (MLS) and incontinentia pigmenti (IP), as well as oculocerebrocutaneous syndrome and Rothmund-Thompson syndrome.\nAntenatal diagnosis\nPrenatal testing for at-risk pregnancies is possible when a mutation has been previously identified in the family.\nGenetic counseling\nFDH follows an X-linked dominant pattern of inheritance and is usually lethal in utero in hemizygous, non-mosaic male fetuses. Approximately 95% of females with FDH have a de novo PORCN pathogenic variant and only 5% inherit it from a parent. Live-born affected males are rare (about 10% of FDH cases) and are nearly always mosaic for a de novo postzygotic mutation. Genetic counseling should be offered to affected females informing them of the 33% risk of giving birth to an affected daughter, an unaffected son, or and unaffected daughter.\nManagement and treatment\nTreatment is symptomatic and involves dermatological, orthopedic, ophthalmologic and dental care. Verrucous papillomas may require surgical intervention.\nPrognosis\nPrognosis is variable depending on severity on manifestations. Individuals with severe forms of the syndrome usually die during infancy, however, a normal life expectancy may be reached in patients with less severe findings.\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Maria Paola LOMBARDI"}
{"Disease Name": "Focal epilepsy-intellectual disability-cerebro-cerebellar malformation", "Disease Definition": "Focal epilepsy-intellectual disability-cerebro-cerebellar malformation is a rare, genetic neurological disorder characterized by early infantile-onset of seizures, borderline to moderate intellectual disability, cerebellar features including dysarthria and ataxia and cerebellar atrophy and cortical thickening observed on MRI imaging. Seizures are typically focal (with prominent eye blinking, facial and limb jerking), precipitated by fever and often commence with an oral sensory aura (anesthetized tongue sensation). When not properly controlled by anti-epileptic medication, weekly frequency and persistance into adult life is observed.", "ORPHA ID": 352587, "Summary": ""}
{"Disease Name": "Focal facial dermal dysplasia type I", "Disease Definition": "Focal facial dermal dysplasia type I (FFDD1), also known as Brauer syndrome, is a focal facial dysplasia (FFDD; see this term) characterized by congenital bitemporal cutis aplasia.", "ORPHA ID": 79133, "Summary": "Epidemiology\nFFDD1 has been reported in over 80 cases including three large multi-generational families (German, English, Australian) and several sporadic cases.\nClinical description\nThe bitemporal, rarely unilateral, hypoplastic scar-like lesions in FFDD, resembling forceps marks, are usually the only manifestations of FFDD1. Other very rarely described and usually mild facial dysmorphic features may comprise a low frontal hairline, sparse hair, sparse lateral eyebrows, distichiasis (upper lashes), flattened nasal tip, bulbous nasal tip, prominent upper lip, skin dimples lateral to lips, horizontal chin furrow, vertical chin cleft, and linear grooves on the forehead. Most patients usually have normal intelligence.\nEtiology\nEtiology is unknown.\nDiagnostic methods\nClinical examination reveals bitemporal scars.\nDifferential diagnosis\nDifferential diagnosis includes focal facial dermal dysplasia type 2 and 3 (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is not available\nGenetic counseling\nFFDD1 is transmitted in an autosomal dominant manner with full penetrance.\nManagement and treatment\nNo specific treatment exists. There is limited experience with plastic surgery for the facial scar-like lesions.\nPrognosis\nAffected individuals have a normal intelligence and life span.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Robert DESNICK  - Dr Beomhee LEE"}
{"Disease Name": "Focal facial dermal dysplasia type II", "Disease Definition": "Focal facial dermal dysplasia type II (FFDD2) is a focal facial dermal dysplasia (FFDD; see this term), characterized by congenital bitemporal scar-like depressions and other facial and organ abnormalities.", "ORPHA ID": 398173, "Summary": "Epidemiology\nTo date, FFDD2 has been reported in over 20 cases from 8 families.\nClinical description\nFFDD2 is characterized by congenital bitemporal hypoplastic scar-like lesions resembling forceps marks with additional facial dysmorphic features. These frequently include low frontal hairline, sparse hair, periorbital puffiness, sparse lateral and upward lifting eyebrows, distichiasis (upper lashes), lack of lower lashes, flattened and/or bulbous nasal tip, and a prominent upper lip (with an inverted ''V'' contour). Occasionally epicanthal folds , linear grooves on forehead, skin dimples lateral to lips and redundant skin are reported. Cardiac and genital or urinary abnormalities have been rarely noted. Developmental delay, severe intellectual disability, behavioral problems, and learning difficulties may be observed.\nEtiology\nThe etiology of FFDD2 is unknown.\nDiagnostic methods\nFFDD2 is diagnosed in patients bearing autosomal dominant bitemporal scar-like lesions and multiple FFDD2 features.\nDifferential diagnosis\nDifferential diagnosis includes focal facial dermal dysplasia type I (FFDD1) and focal facial dermal dysplasia type III (FFDD3; see these terms).\nGenetic counseling\nFFDD2 is transmitted in an autosomal dominant manner with variable expressivity and incomplete penetrance.\nManagement and treatment\nManagement comprises opthalmologic evaluations periodically. There is limited experience with plastic surgery for the facial scar-like lesions.\nPrognosis\nAffected individuals have a normal life span, but involvement of other organ systems may alter the prognosis.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Robert DESNICK  - Dr Beomhee LEE"}
{"Disease Name": "Focal facial dermal dysplasia type III", "Disease Definition": "Focal facial dermal dysplasia type III (FFDD3) is a rare focal facial dermal dysplasia (FFDD; see this term), characterized primarily by congenital bitemporal scar-like depressions and a typical, but variable facial dysmorphism, which may include distichiasis (upper lids) or lacking eyelashes, slanted eyebrows and a flattened and/or bulbous nasal tip and other features such as a low frontal hairline, sparse hair, redundant skin, epicanthal folds, low-set dysplastic ears, blepharitis and conjunctivitis.", "ORPHA ID": 1807, "Summary": "Epidemiology\nFFDD3 is reported in over 20 patients from more than 15 families, but only 4 consanguineous families have had TWIST2 mutations.\nClinical description\nFFDD3 is characterized by congenital bitemporal hypoplastic scar-like lesions resembling forceps marks with typical facial dysmorphic features. In addition, they may have periorbital puffiness (leonine facies), sparse lateral and upward lifting eyebrows, distichiasis (upper lashes), a lack of lower lashes and a prominent upper lip (with an inverted ''V'' contour). Nose abnormalities are very frequent and comprise a flattened and/or bulbous nasal tip with septum extended below the alae nasi. Additional frequent features describe a low frontal hairline, sparse hair, epicanthal folds, blepharitis, conjunctivitis, low-set dysplastic ears, and redundant skin. Other eye abnormalities less often reported include short and/or slanting palpebral fissures, as well as impaired vision, nystagmus, exotropia, hypertelorism and absent meibomian glands. Skin dimples lateral to lips, vertical chin clefts, horizontal chin furrows and linear grooves on forehead occur occasionally. Other features such as a pectum deformities and cardiac and genitorurinary abnormalities are rare. Patients generally have normal growth and development. Heterozygous family members may present with minor manifestations, such as partial absence of lower eyelashes and distichiasis of upper lashes. Developmental delay, severe intellectual disability, behavioral problems, and learning difficulties may be observed.\nEtiology\nFFDD3 is caused by homozygous mutations in the TWIST2 gene, which encodes a bHLH transcription factor involved in dermal facial development in mammals. To date two nonsense mutations, c.324C>T (p. Q65X) and c.486C>T (p.Q119X), and two small deletions that caused frameshift mutations, c.168delC (p.S57AfsX45) and c.91delC (p.R31GfsX71), have been reported. However, the majority of unrelated FFDD3 patients evaluated have had normal TWIST2 sequences, indicating the molecular genetic heterogeneity of the disorder. Studies are under way to interrogate whole exome or genome sequencing in these patients and their parents to determine the causative defects.\nDiagnostic methods\nFFDD3 is diagnosed in patients bearing autosomal recessive bitemporal scar-like lesions and typical FFDD3 facial features, and is confirmed by genetic testing of TWIST2. However, many patients with typical FFDD3 features have normal TWIST2 sequences (~80%). Thus, diagnosis is clinically based for most patients on the characteristic bitemporal lesions and facial dysmorphism regardless of inheritance. Also, the facial phenotype may be milder in patients without TWIST2 mutations.\nDifferential diagnosis\nDifferential diagnosis includes FFDD1 and FFDD2 (see these terms).\nGenetic counseling\nMany cases are sporadic. Inheritance is autosomal recessive for patients with TWIST2 mutations. Heterozygous parents will have a 1 in 4 risk of an affected child with each pregnancy. For other patients, the inheritance is unclear.\nManagement and treatment\nPursed lips and eye abnormalities may be surgically corrected, but there is limited experience with plastic surgery.\nPrognosis\nIn patients with normal intelligence, normal life span is expected. Patients with developmental delay may have other organ system involvement which may affect health and longevity.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Robert DESNICK  - Dr Beomhee LEE"}
{"Disease Name": "Focal facial dermal dysplasia type IV", "Disease Definition": "Focal facial dermal dysplasia type IV (FFDD4) is a rare focal facial dysplasia (FFDD; see this term), characterized by congenital isolated preauricular and/or cheek blister scar-like lesions.", "ORPHA ID": 398189, "Summary": "Epidemiology\nTo date, FFDD4 is reported in over 20 patients.\nClinical description\nFFDD4 is characterized by isolated congenital bilateral hypoplastic atrophic skin lesions distributed in a distinctive, curvilinear manner between the maxillary and manibular prominences in the preauricular region and/or cheek. Affected FFDD4 patients typically do not present with extra-cutaneous manifestations, although in a small number of cases, a hair collar sign (circumscription of the cutaneous lesion with terminal hairs), polyps on the buccal mucosa with a similar distribution pattern, and developmental delay have been reported.\nEtiology\nFFDD4 is caused in a subset of affected cases (four out of five unrelated families) by a 7 base pair duplication, c.844_851dupCCATGCA (p. p.Glu284fsX128) or a missense mutation, c.1433G>A (p.Arg478His) in the CYP26C1 gene, which is involved in retinoic acid metabolism and important in the formation of the mandibular and maxillary prominences. The short duplication occurs in 0.3% of the healthy control population, suggesting that heterozygosity for the alteration does not result in phenotypic manifestations.\nDiagnostic methods\nFFDD4 is diagnosed in patients with isolated preauricular scar-like lesions, typically in the absence of other manifestations. These patients were homozygous for the seven base pair duplication or were heteroallelic for the seven base pair duplication and the missense mutation in the CYP26C1 gene. Histologic findings include epidermal atrophy with the presence of loose connective tissue replacing the dermis, diminished fragmented elastic tissue, and a lack of subcutaneous tissues and adnexal structures.\nDifferential diagnosis\nDifferential diagnosis may include membranous aplasia cutis congenita (see this term), but in FFDD4 cutaneous lesions are isolated and do not occur in combination with other extra-cutaneous manifestations.\nGenetic counseling\nAppropriate counseling should be provided for this autosomal recessive trait. The fact that not all the patients with FFDD4 had CYP26C1 mutations indicates the occurrence of genetic heterogeneity for this developmental disorder.\nManagement and treatment\nThere is limited experience with plastic surgery for the facial scar-like lesions\nPrognosis\nAffected individuals have normal life span.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Robert DESNICK  - Dr Beomhee LEE"}
{"Disease Name": "Focal facial dermal dysplasia", "Disease Definition": "Focal facial dermal dysplasias (FFDD) are rare ectodermal dysplasias, characterized by congenital bitemporal (resembling forceps marks) or preauricular scar-like lesions associated with additional facial and or systematic manifestations. 4 types of FFDD are described (FFDD I to IV; see these terms). FFDD types II and III present with a variable facial dysmorphism including distichiasis (upper lashes) or lacking eyelashes, and upward slanting and thinned lateral eyebrows with a flattened nasal bridge and full upper lip. FFDD types I and IV are infrequently associated with extra-cutaneous anomalies.", "ORPHA ID": 398166, "Summary": ""}
{"Disease Name": "Focal myositis", "Disease Definition": "A rare idiopathic inflammatory myopathy characterized by a localized swelling of skeletal muscle that is usually located in the lower extremities.", "ORPHA ID": 48918, "Summary": "Epidemiology\nFocal myositis prevalence is unknown. There have been approximately 200 cases described to date.\nClinical description\nThe disease can occur at any age. It presents as a mass (ranging in size from 1.0 to 20.0 cm) localized to a single skeletal muscle that may be painless or tender to the touch and that grows insidiously over several weeks to months. The mass is usually located in the lower extremities and the muscles most commonly affected include the adductor, vastus lateralis and gastrocnemius. It can rarely occur in muscles of the head and neck region. Additional rare systemic manifestations include fever, myalgia, generalized weakness and weight loss. It does not appear to invade the adjacent tendons, fascia or skin and usually regresses spontaneously with time. Recurrence is possible (seen in around 18% of cases) but uncommon. Rarely, classical inflammatory myopathies can present focally, thus mimicking focal myositis.\nEtiology\nThe etiology is unknown. Possible causes include trauma (20%), genetic factors (that remain unknown), viral infections and autoimmune disease. Some regard focal myositis as a localized form of polymyositis. Chronic nerve irritation caused by compression of a nerve is another suspected cause of muscle fiber hypertrophy that consequently leads to focal myositis.\nDiagnostic methods\nClinical and histological findings of an enlarged single muscle are indicative of focal myositis. Magnetic resonance imaging (MRI) is helpful to diagnose focal myositis as it reveals increased signal intensity and hypertrophy of the affected muscle. Electromyography shows spontaneous activity associated with a myopathic pattern. A minor elevation in the level of creatine kinase (CK) is sometimes seen.\nDifferential diagnosis\nClinically, focal myositis can be mistaken for many other conditions such as soft tissue sarcomas (rhabdomyosarcoma, liposarcoma, leiomyosarcoma), myositis ossificans progressiva, inflammatory myofibroblastic tumor, lymphoma, fibromatosis, rhabdomyoma, intramuscular lipoma, venous thrombosis and other conditions of inflammatory or vascular origin. Pathologically it can resemble an inflammatory myopathy and muscular dystrophy.\nManagement and treatment\nTreatment is often not necessary as most cases resolve spontaneously. Anti-inflammatory drugs (steroid or nonsteroidal) such as oral prednisolone can be given to minimize any pain and inflammation. In cases complicated by limited joint motion, physical and/or surgical therapy may be necessary.\nPrognosis\nPrognosis is very good as most cases of focal myositis resolve spontaneously.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Elisabeth RUSHING"}
{"Disease Name": "Focal palmoplantar and gingival keratoderma", "Disease Definition": "Focal palmoplantar and gingival keratoderma is a very rare form of focal palmoplantar keratoderma characterized by painful circumscribed hyperkeratotic lesions on weight-bearing areas of soles, moderate focal hyperkeratosis of palmar pressure-related areas and an asymptomatic leukokeratosis confined to labial- and lingual- attached gingiva. Additional occasional features may include hyperhidrosis, follicular keratosis and extended oral mucosa involvement.", "ORPHA ID": 2200, "Summary": ""}
{"Disease Name": "Focal palmoplantar keratoderma with joint keratoses", "Disease Definition": "A rare, genetic, isolated palmoplantar keratoderma characterized by focal hyperkeratotic lesions affecting the pressure- and mechanical trauma-bearing areas of the palms and soles, as well as hyperkeratotic plaques involving joints, including knees, elbows, ankles and dorsa of interphalangeal joints.", "ORPHA ID": 370002, "Summary": ""}
{"Disease Name": "Focal stiff limb syndrome", "Disease Definition": "A rare stiff person spectrum disorder characterized by painful episodic spasms (which are often precipitated by touch, pain, cold, movement, or negative emotions), increased stimulus sensitivity including hyperekplexia, as well as stiffness, in a lower or upper limb, typically with insidious onset and progression over months or years. The condition may eventually progress into classic stiff person syndrome. Fear of leaving the house and walking unaided is characteristic. Most patients have autoantibodies in serum and CSF, in particular anti-glutamic acid decarboxylase (GAD) antibodies. In rare cases, the syndrome is of paraneoplastic origin.", "ORPHA ID": 443804, "Summary": ""}
{"Disease Name": "Focal, segmental or multifocal dystonia", "Disease Definition": "A rare neurologic movement disorder characterized by sustained muscle contractions of a single body region, usually producing twisting and repetitive movements or abnormal postures or positions.", "ORPHA ID": 1866, "Summary": ""}
{"Disease Name": "Foix-Alajouanine syndrome", "Disease Definition": "Foix-Alajouanine syndrome, also called subacute ascending necrotising myelitis, results from chronic congestion of the extrinsic pial veins of the spinal cord and of the intrinsic subpial network. It is characterised by progressive ascending deficit over a period of several months or years.", "ORPHA ID": 79093, "Summary": "Epidemiology\nThe prevalence is unknown. The syndrome most commonly affects men over the age of 50.\nClinical description\nThe initial symptoms are variable and include dysesthesia of the inferior members (symmetrical in most cases) associated with progressive ascending motor deficit. The ascending paraplegia eventually leads to urinary incontinence. Unilateral or painful manifestations at presentation are rare but have been reported.\nEtiology\nThe causative lesion is a dural arteriovenous shunt of the medullary emissary vein. The arteriovenous shunt is acquired. It is fed by branches of the spinal meninges. The shunt is associated with reflux into the venous drainage of the cord, leading to congestion and chronic medullary ischemia.\nDiagnostic methods\nRadiological investigations and magnetic resonance imaging (MRI) of the spinal cord reveal dilated perimedullary veins associated with a hypersignal from the interior of the cord and, in chronic forms, variable degrees of spinal cord atrophy. Medullary angiography may be used to identify the arteriovenous shunt zone.\nManagement and treatment\nEndovascular treatment is possible in around two thirds of cases. In the remaining cases, surgical disconnection of the emissary vein from the shunt zone leads to resolution of the fistula. In 80% of cases, improvement is immediate and symptoms regress progressively in a manner that is chronologically inverse to that of their appearance. In more evolved cases, no improvement is obtained. In some rare forms, secondary thrombosis may occur, aggravating the preoperative clinical manifestations. Early diagnosis of the disease allows more effective treatment. The most severe forms are most often associated with delayed diagnosis.\n\n                            Last update: \n                            July 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Pierre LASJAUNIAS"}
{"Disease Name": "Foix-Chavany-Marie syndrome", "Disease Definition": "A rare cortico-subcortical suprabulbar or pseudobulbar palsy of the lower cranial nerves, characterized by severe dysarthria and dysphagia associated with bilateral central facio-pharyngo-glosso-masticatory paralysis, with prominent automatic-voluntary dissociation in which involuntary movements of the affected muscles are preserved.", "ORPHA ID": 2048, "Summary": "Epidemiology\nLess than 150 cases have been described in the literature so far.\nClinical description\nFoix-Chavany-Marie syndrome (FCMS) can occur at any age and patients present with acute-onset bilateral paresis of the facial, lingual, pharyngeal and masticatory muscles (innervated by the V, VII, IX, X and XII cranial nerves). However, the reflexive, emotional and automatic innervations of these muscles are preserved and smiling, crying or yawning under natural circumstances is possible. Facial appearance is atonic and the mouth is half open. Patients with FCMS have severe speech disturbances and most are mute. Chewing and swallowing are severely impaired. The oral stage of swallowing is severely disturbed in most patients, but the swallowing reflex can be adequate if the bolus is delivered into the pharynx. The tongue is almost immobile and does not show muscular atrophy and fibrillation. The jaw reflex is exaggerated (sometimes leading to trismus). In children, FCMS is usually associated with delayed psychomotor milestones and epilepsy.\nEtiology\nFCMS is caused by developmental or acquired bilateral lesions of the anterior opercula. In children, it presents congenitally (bilateral opercular polymicrogyria) or as an acquired disorder due to encephalitis, epilepsy and neurodegenerative disorders. The syndrome is generally sporadic but some familial cases have been described. In adults, FCMS is associated with vascular events (generally ischemic), infections of the central nervous system, neoplasms, trauma and epileptic disorders.\nDiagnostic methods\nDiagnosis is based on patient history, clinical examination and magnetic resonance imaging (showing bilateral opercular lesions).\nDifferential diagnosis\nDifferential diagnoses include syndromes that present with bulbar palsy (amyotrophic lateral sclerosis, myasthenia gravis and Brown-Vialetto-van Laere syndrome; see these terms). Clinical overlap of FCMS with congenital bilateral perisylvian polymicrogyria and Worster-Drought syndrome (see these terms) has been noted, suggesting a possible continuum of these conditions.\nManagement and treatment\nManagement depends on the degree of feeding difficulties and speech problems, and requires a multidisciplinary therapeutic approach. It aims at improving the patient's ability to return to oral feeding. Early percutaneous endoscopic gastrostomy and use of modified feeding techniques and postures may be of benefit.\nPrognosis\nThe disease may have a persistent or intermittent course. Reversible forms have also been described. The prognosis for life expectancy is usually good, but usually patients do not recover voluntary swallowing and speech ability.\n\n                            Last update: \n                            October 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Jaime CAMPOS-CASTELLÓ"}
{"Disease Name": "Folinic acid-responsive seizures", "Disease Definition": "Folinic acid-responsive seizures is a very rare neonatal epileptic encephalopathy disorder characterized clinically by myoclonic and clonic, or clonic seizures associated with apnea occurring several hours to 5 days after birth and responding to folinic acid.", "ORPHA ID": 79097, "Summary": ""}
{"Disease Name": "Follicular cholangitis and pancreatitis", "Disease Definition": "Follicular cholangitis and pancreatitis is a rare pancreatobiliary disease characterized by marked duct-centered lymphoid follicular inflammation that develops in both biliary and pancreatic ductal systems, mainly affecting the hilar bile ducts and the pancreatic head. Patients present with jaundice, abdominal pain, liver dysfunction, pruritus and/or weight loss. Histology shows lymphoplasmacytic infiltration with formation of numerous, large lymphpoid follicles around the affected bile and pancreatic ducts.", "ORPHA ID": 300552, "Summary": ""}
{"Disease Name": "Follicular dendritic cell sarcoma", "Disease Definition": "A rare dendritic cell neoplasm characterized by a proliferation of spindled to ovoid cells with morphological and immunophenotypic features of follicular dendritic cells. Conventional follicular dendritic cell sarcomas are negative for EBV. The tumor arises as a painless, slow-growing mass in lymph nodes (most often cervical), extranodal sites (such as tonsils, gastrointestinal tract, soft tissue, mediastinum, or lung, among others), or both. Paraneoplastic pemphigus may occur in rare cases. Predictive factors are tumor size, presence of coagulative necrosis, mitotic count, and presence of significant cytological atypia.", "ORPHA ID": 86902, "Summary": ""}
{"Disease Name": "Follicular lymphoma", "Disease Definition": "Follicular lymphoma is a form of non-Hodgkin lymphoma (see this term) characterized by a proliferation of B cells whose nodular structure of follicular architecture is preserved.", "ORPHA ID": 545, "Summary": "Epidemiology\nPrevalence of follicular lymphoma is estimated at about 1/3,000.\nClinical description\nThe median age at diagnosis is 60-65 years. The disease is extremely rare in children. Follicular lymphoma is located primarily in the lymph nodes, but can also involve the spleen, bone marrow, peripheral blood and Waldeyer's ring. The skin and central nervous system are affected in rare cases. Symptoms appear at an advanced stage of the disease and can include fever, night sweats and weight loss. At diagnosis, patients usually present with adenopathy and, in 50% of cases, splenomegaly.\nEtiology\nIn 85% of cases, follicular lymphomas are associated with a translocation t(14;18) (q32;q21), which activates the BCL2 gene encoding the BCL2 protein that is essential for some apoptosis processes.\nDiagnostic methods\nDiagnosis is based on histological analysis of the adenopathy, a complete blood count, measurement of lactate dehydrogenase (LDH) and biopsy analysis of a lymph node. Examination using imagery (particularly a chest radiograph) is required. The observation of the translocation t(14;18) by polymerase chain reaction (PCR), in addition to suggested histological results, confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include chronic lymphocytic B cell leukemia, diffuse large B cell lymphoma, mantle cell lymphoma and MALT lymphoma (see these terms).\nManagement and treatment\nIf the lymphoma is localized it should be treated by radiotherapy. In the case of advanced stage lymphoma, chemotherapy with immuno-chemotherapy should be offered (rituximab combined with CHOP). In cases of chemosensitive relapse, treatment can be intensified.\nPrognosis\nThe survival rate at five years is 80-90% and medial survival is approximately 10-12 years.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Vincent RIBRAG"}
{"Disease Name": "Folliculotropic mycosis fungoides", "Disease Definition": "A rare variant of mycosis fungoides (MF), a form of cutaneous T-cell lymphoma, characterized by the presence of folliculotropic infiltrates in patch-plaque lesions usually involving the head and neck area.", "ORPHA ID": 178512, "Summary": "Epidemiology\nThe annual incidence of MF and its variants is estimated at between 1/350,000 and 1/110,000, with folliculotropic MF accounting for about 5% of MF cases. Males are more frequently affected than females.\nClinical description\nFolliculotropic MF predominantly affects adults. Skin lesions usually consist of grouped follicular papules, plaques or tumors, preferentially located in the head and neck area. Infiltrated plaques under the eyebrows and alopecia are common. Pruritus is often severe. Most cases present with mucinous degeneration of the hair follicles: these cases are referred to as MF-associated follicular mucinosis. Secondary bacterial infections are frequent. Progression of the disease and involvement of the lymph nodes and/or internal organs may occur as in the classical variant of the disease (see this term).\nEtiology\nThe etiology remains unknown.\nDiagnostic methods\nThe diagnosis is based on clinical presentation and should be confirmed by a skin biopsy. Histological findings reveal variable infiltration of the follicular epithelium by small, medium-sized, or sometimes large hyperchromatic cells with cerebriform nuclei and sparing of the epidermis. Most cases show mucinous degeneration of the follicular epithelium. In most cases, immunohistology reveals a memory T-helper phenotype (CD3+, CD4+ and CD8-).\nDifferential diagnosis\nThe main differential diagnoses include inflammatory dermatoses with prominent involvement of the hair follicle, such as lichen planopilaris (see this term). The relationship between \"idiopathic\" follicular mucinosis and MF remains unclear.\nManagement and treatment\nManagement is symptomatic and includes the use of PUVA (photochemotherapy) combined with interferon alpha-2a and retinoids, total body electron beam irradiation, and local radiotherapy in cases of persistent tumors.\nPrognosis\nThe overall 5-year survival rate is 70-80%.\n\n                            Last update: \n                            June 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Lorenzo CERRONI"}
{"Disease Name": "Foodborne botulism", "Disease Definition": "Foodborne botulism is the most common form of botulism (see this term), a rare acquired neuromuscular junction disease with descending flaccid paralysis due to botulinum neurotoxins (BoNTs). It is caused by consumption of contaminated food containing BoNTs.", "ORPHA ID": 228371, "Summary": "Epidemiology\nPrevalence is unknown. The annual incidence in Europe is 1/900,000 to 1/500,000. To date, about 40,000 cases have been reported worldwide.\nClinical description\nOnset of symptoms occurs in adults generally within 12 to 36-48 hours (range: 6 hours-15 days) after ingestion of contaminated food. The disease is characterized by an acute or subacute afebrile symmetrical cranial nerve palsy, followed by symmetrical descending flaccid motor paralysis. Gastrointestinal symptoms of nausea, abdominal pain, vomiting and diarrhea may precede the neurological signs. In the severe forms, paralysis concerns the neck, shoulder, and proximal muscles, followed by involvement of the muscles of the upper distal extremities, the diaphragm and respiratory muscles, which may result in respiratory compromise or arrest. The sensory system and intellectual functions remain unaffected. The rapidity of onset and severity of the illness depend on the amount and type of BoNTs ingested.\nEtiology\nThe disease is caused by consumption of home-preserved foods (homemade or traditional canned-foods, ham, pork products, vegetables, etc.) contaminated by BoNT-producing Clostridia. Contamination results from the growth and toxin production in foods presenting an anaerobic medium, a pH of ≥4.5, low salt and sugar content, and stored at ≥ 3°C. Of the seven types of BoNTs (A-G), types A, B, E and, more rarely F, are associated with foodborne botulism. Microorganisms involved are Clostridium botulinum or, very rarely neurotoxigenic strains of C. butyricum and C. baratii. Ingested and absorbed BoNTs diffuse via the blood and lymphatic system to reach the neuromuscular junctions.\nDiagnostic methods\nDiagnosis is essentially clinical in the first stage, based on clinical suspicion together with a 2-5 day food history obtained from the patient. Ingestion of a suspected food, absence of fever, and possible gastrointestinal symptoms are considered typical of foodborne botulism. Confirmation is based on BoNT detection in serum, stools, vomit, gastric aspirate, and suspected food samples. The detection of BoNT-producing Clostridia in stool cultures of a patient presenting typical symptomatology is generally satisfactory for laboratory diagnosis.\nDifferential diagnosis\nDifferential diagnosis of foodborne botulism includes myasthenia gravis, Guillain-Barré and Miller-Fisher syndromes, Lambert-Eaton syndrome and, in addition, intestinal and wound botulism (see these terms).\nManagement and treatment\nAntitoxin therapy is effective when it is administrated at the onset of symptoms. The antitoxin therapy must be associated with supportive care in an intensive care unit (ICU). In Europe, the formulation currently available for adults is trivalent (anti A, B, E). A heptavalent (anti A to G) product is also available. In the USA, a bivalent (anti A, B) and a monovalent (anti E) antitoxin are available. Prevention is based on following good practice guidelines for the preparation and storage of foods with the aim of destroying spores, preventing spore germination and/or toxin production. Prompt notification to the public health authorities of suspected cases may prevent further consumption of a contaminated home-preserved or commercial food product.\nPrognosis\nFoodborne botulism carries an overall worldwide mortality rate of 5-10% (in the USA 3-5%). Prognosis varies according to the amount of ingested toxin and the rapidity of medical assistance. With early, appropriate treatment, the prognosis is generally good and no long-term complications are observed. Complications may occur during hospitalization, including nosocomial adverse events and respiratory failure.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Lucia FENICIA"}
{"Disease Name": "Formiminoglutamic aciduria", "Disease Definition": "A rare disorder of folate metabolism and transport characterized, biochemically, by elevated formiminoglutamate in urine and plasma due to glutamate formiminotransferase deficiency, associated with a highly variable clinical phenotype, ranging from developmental delay, intellectual disability and anemia to normal development without anemia. Increased hydantoin-5-propionic acid and/or folate in plasma may also be associated.", "ORPHA ID": 51208, "Summary": ""}
{"Disease Name": "Fountain syndrome", "Disease Definition": "Fountain syndrome is an extremely rare multi-systemic genetic disorder characterized by intellectual disability, deafness, skeletal abnormalities and coarse facial features.", "ORPHA ID": 3219, "Summary": "Epidemiology\nThe syndrome is exceedingly rare and has been reported in only a few patients to date. Male and female patients have been described.\nClinical description\nThe main clinical features of Fountain syndrome include moderate to severe intellectual deficit, congenital sensorineural hearing impairment, and broad, stubby hands and feet. A coarse face with full lips and cheeks is also found. These signs are reported to become more prominent with age. Additional reported signs are early-onset, generalized seizures, short stature, large head circumference, and remarkable behavior (friendly demeanor).\nEtiology\nThe etiology of Fountain syndrome has not been elucidated.\nGenetic counseling\nThe pattern of inheritance appears to be autosomal recessive.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Griet VAN BUGGENHOUT"}
{"Disease Name": "Fourth branchial cleft anomaly", "Disease Definition": "A rare otorhinolaryngeal malformation characterized by a soft, fluctuant mass, abscess or draining tract along the anterior border of the lower half of sternocleidomastoid muscle, occasionally leading to development of retropharyngeal absces, acute suppurative thyroiditis, stridor, respiratory distress, odynophagia, and dysphagia. Anomaly occurs as a tract from the piriform sinus to the thyroid gland. A fourth branchial cleft fistula passes deep to the superior laryngeal nerve but superficial to the recurrent laryngeal nerve, which is the main difference in comparison to the third branchial cleft fistula.", "ORPHA ID": 141037, "Summary": ""}
{"Disease Name": "Foveal hypoplasia-optic nerve decussation defect-anterior segment dysgenesis syndrome", "Disease Definition": "A rare, genetic, eye disease characterized by foveal hypoplasia, optic nerve misrouting with an increased number of axons decussating at the optic chiasm and innervating the contralateral cortex, and posterior embryotoxon or Axenfeld anomaly (indicating anterior segment dysgenesis), in the absence of albinism. Patients present congenital nystagmus, decreased visual acuity, refractive errors and, ocassionally, strabismus. Microphthalmia and retinochoroidal coloboma may also be associated.", "ORPHA ID": 397618, "Summary": ""}
{"Disease Name": "Foveal hypoplasia-presenile cataract syndrome", "Disease Definition": "A rare genetic ocular disease characterized by congenital nystagmus (horizontal, vertical and/or torsional), foveal hypoplasia, presenile cataracts (with typical onset in the second to third decade of life), and normal irides. Corneal pannus and/or optic nerve hypoplasia may also be present.", "ORPHA ID": 2253, "Summary": ""}
{"Disease Name": "Fowler urethral sphincter dysfunction syndrome", "Disease Definition": "A rare urogenital disease characterized by otherwise unexplained chronic urinary retention of more than 1 liter of sterile urine on catheterization, an asensitive bladder with loss of urge to void, and no help of straining. Poor tolerance of self-catheterization is typically reported. The condition occurs in women between menarche and menopause.", "ORPHA ID": 2795, "Summary": ""}
{"Disease Name": "Fowler vasculopathy", "Disease Definition": "A rare, genetic neurological disorder characterized by hydranencephaly, distinctive glomeruloid vasculopathy in the central nervous system and retina, polyhydramnios and fetal akinesia with arthrogryposis. The disorder is usually prenatally lethal. In rare reported cases that survived beyond infancy, severe intellectual and neurologic disability with seizures, microcephaly and absence of functional movements were reported.", "ORPHA ID": 221126, "Summary": ""}
{"Disease Name": "FOXG1 syndrome due to 14q12 microdeletion", "Disease Definition": "14q12 microdeletion syndrome is a recently described syndrome characterized by severe intellectual deficit, with a normal neonatal period, followed by a phase of regression at the age of 3-6 months.", "ORPHA ID": 261144, "Summary": "Epidemiology\nIt has been clinically and molecularly characterized in 3 patients so far.\nClinical description\nThe neurological picture evokes the congenital variant of atypical Rett syndrome (see this term). The phenotype includes other features: postnatal growth retardation and microcephaly, hypotonia, epilepsy, stereotypic movements and feeding problems. Dysmorphic features associate prominent metopic suture, bilateral epicanthic folds, bulbous nasal tip, tented upper lip, everted lower lip and large ears.\nEtiology\nThis syndrome is caused by an interstitial deletion encompassing 14q12. These de novo deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size and include FOXG1 as the gene responsible for the intellectual deficit and severe microcephaly.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "FOXG1 syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by early onset of microcephaly, severe global developmental delay and cognitive impairment, dyskinesia and hyperkinetic movements, visual impairment, autistic behavior, stereotypies, sleep disturbance, epilepsy, and cerebral malformations (such as corpus callosum hypogenesis, forebrain anomaly, and delayed myelination). Speech is minimal or absent, and ambulation is not attained. Patients with a larger 14q12 microdeletion show a more severe phenotype than those with intragenic alterations, with the addition of facial dysmorphism and agenesis of the corpus callosum.", "ORPHA ID": 561854, "Summary": ""}
{"Disease Name": "FOXP1 Syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder, with highly variable phenotype, typically characterized by mild to severe global development delay, severe speech and language impairment, mild to severe intellectual disability, dysphagia, hypotonia, relative to true macrocephaly, and behavioral problems that may include autistic features, hyperactivity, and mood lability. Facial gestalt typically features a broad, prominent forehead, hypertelorism, downslanting palpebral fissures, ptosis, a short bulbous nose with broad tip, thick vermilion border, wide, and open mouth with downturned corners. Brain, cardiac, urogenital and ocular malformations may be associated.", "ORPHA ID": 391372, "Summary": ""}
{"Disease Name": "Fragile X syndrome", "Disease Definition": "A rare genetic disease associated with mild to severe intellectual deficit that may be associated with behavioral disorders and characteristic physical features including a high forehead, prominent and large ears, hyperextensible finger joints, flat feet with pronation and, in adolescent and adult males, macroorchidism.", "ORPHA ID": 908, "Summary": "Epidemiology\nPrevalence is estimated at approximately 1/2400-1/6000 although the prevalence may vary, depending on where the screening is carried out in the world.\nClinical description\nFragile X syndrome (FXS) presents with a variable clinical phenotype. In males, the disease presents during childhood with delayed developmental milestones. Intellectual deficit can be of variable severity and may include problems with working and short-term memory, executive function, language, mathematics and visuospatial abilities. Behavioral anomalies can be mild (e.g. anxiety, mood instability) to severe (e.g. aggressive behavior, autism). Autistic-like behavior can include hand flapping, poor eye contact, hand biting, gaze avoidance, social phobia, social and communication deficits and tactile defensiveness. In females, intellectual and behavioral disorders are typically mild and usually consist of shyness, social anxiety, and mild learning problems with a normal IQ, although 25% of girls have an IQ less than 70. Attention deficit hyperactivity disorder (ADHD) is present in over 89% of males and 30% of females and behavioral disinhibition is very common. Recurrent otitis (60%) and seizures (16 to 20%) can also be observed.\nEtiology\nFXS is caused by the transcriptional silencing of the FMR1 gene (Xq27.3) due to the progressive expansion and subsequent methylation of (CGG)n trinuleotide repeats in the 5'-untranslated region of the gene. These full mutations originate from unstable alleles called premutations (55-200 CGG repeats). In some rare cases, FXS was shown to result from intragenic FMR1 point mutations or deletions. FMR1 codes for the FMRP, an RNA-binding protein that regulates protein synthesis and other signaling pathways in neuronal dendrites. FMR1 silencing is thought to reduce synaptic plasticity and modulation throughout the brain including the hippocampus.\nDiagnostic methods\nDiagnosis cannot be based on the clinical picture as physical features may be mild or absent and is therefore based on FMR1 DNA testing, that should be performed for all patients with an intellectual deficiency or autism.\nDifferential diagnosis\nThe differential diagnosis includes other X-linked intellectual deficiencies, Sotos syndrome, microdeletion syndromes (e.g. 22q11.2 deletion syndrome), fetal alcohol syndrome or idiopathic autism.\nAntenatal diagnosis\nPrenatal diagnosis is based on Southern blot hybridization and PCR on samples of chorionic villi or amniotic fluid.\nGenetic counseling\nFXS is an X-linked dominant disorder with reduced penetrance in females. Genetic counseling should be offered to families of an affected individual or carriers of the premutation.\nManagement and treatment\nManagement is symptom-based and requires a multidisciplinary approach. Speech, physical and sensory integration therapy as well as individualized educational plans and behavioral interventions may be combined with medication, such as stimulants for attention deficit-hyperactivity disorder; selective serotonin reuptake inhibitors (SSRIs) for anxiety, depression, obsessive-compulsive disorder; and atypical antipsychotic agents for self-injury and aggressive behaviors. New targeted treatments for FXS are being studied.\nPrognosis\nLife expectancy is assumed to be normal. The general outlook is variable and depends on the severity of the symptoms; independent living with limited support is possible although severely affected individuals will need more significant, life-long care due to intellectual disabilities and behavioral difficulties.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Randi HAGERMAN"}
{"Disease Name": "Fragile X-associated tremor/ataxia syndrome", "Disease Definition": "Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare neurodegenerative disorder characterized by adult-onset progressive intention tremor and gait ataxia.", "ORPHA ID": 93256, "Summary": "Epidemiology\nPrevalence and incidence are unknown. The disease primarily affects males and there is a lifetime cumulated risk for men in the general population of about 1/8,000.\nClinical description\nThe age of onset of tremor and/or ataxia in males is about 60 years. The clinical presentation is heterogeneous with variable dominant manifestations including: intention tremor, progressive cerebellar gait ataxia, frontal executive dysfunction, cognitive decline, peripheral neuropathy, and dysautonomia. Other signs include mild parkinsonism and psychiatric manifestations (depression, anxiety, agitation) with possible progression to dementia. Carrier females generally have less severe manifestations than males but also have an increased risk of primary ovarian insufficiency, chronic muscle pain, and hypothyroidism.\nEtiology\nFXTAS is caused by a CGG trinucleotide repeat expansion (55-200 repeats) in the permutation range of the FMR1 gene (Xq27.3). Approximately 1/260 females and 1/800 males in the general population are permutation carriers and penetrance is age dependent. The disease affects more than 33% of male and 10% of female carriers of the expansion. The severity of the clinical and neuropathological manifestations is correlated with the extent of the CGG expansion\nDiagnostic methods\nDiagnosis may be difficult because of the combination of signs that are common in elderly patients. Magnetic resonance imaging (MRI) shows global loss of brain volume, in particular cerebellar and cortical atrophy and hyperintensity white matter lesions around the periventricular area and in the middle cerebellar peduncles. Molecular genetic testing is needed to confirm diagnosis.\nDifferential diagnosis\nDifferential diagnoses include dementia, rare parkinsonian disorders and spinocerebellar ataxias (see these terms).\nAntenatal diagnosis\nAs this is an adult-onset disorder, no antenatal diagnosis is possible.\nGenetic counseling\nTransmission follows an X-linked dominant pattern with variable penetrance. Genetic counseling should be provided to patients and their families.\nManagement and treatment\nThere is no specific treatment for FXTAS that targets the underlying pathological mechanism. Symptomatic treatment for the psychiatric and neurological manifestations should therefore be provided, along with specific monitoring for progression and degeneration.\nPrognosis\nThe prognosis depends on the speed of progression of the disease, which is highly variable.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Ginevra ZANNI"}
{"Disease Name": "Frank-Ter Haar syndrome", "Disease Definition": "A rare primary bone dysplasia characterized by megalocornea, multiple skeletal anomalies, characteristic facial dysmorphism (wide fontanels, prominent forehead, hypertelorism, prominent eyes, full cheeks and micrognathia) and developmental delay.", "ORPHA ID": 137834, "Summary": ""}
{"Disease Name": "Fraser syndrome", "Disease Definition": "A rare congenital malformation mainly characterized by unilateral or bilateral cryptophthalmos, syndactyly and urogenital anomalies.", "ORPHA ID": 2052, "Summary": "Epidemiology\nThe estimated prevalence of Fraser syndrome (FS) in Europe is 1/500,000 births. The disorder affects both sexes equally.\nClinical description\nFS is usually characterized by eye (unilateral or bilateral cryptophthalmos, microphthalmos/anophthalmos), urinary tract (renal agenesis, bladder atresia/hypoplasia) and genital anomalies (ambiguous genitalia, cryptorchidism, underdevelopment of male genitalia). Cutaneous syndactyly occurs in both hands and feet. Patients may also present craniofacial (dysplastic ears, bifid nose, cleft lip/palate, microglossia), respiratory (laryngeal stenosis/hypoplasia), cardiac (atrial and ventricular septal defect), digestive tract (anal agenesis/imperforation, diaphragmatic hernia, large bowel obstruction) and skeletal anomalies (skull/spine malformations, clubfoot). In case of severe manifestations, the disease may be fatal for the fetus and the major causes of early death after birth include laryngeal and/or kidney anomalies.\nEtiology\nFS is a genetically heterogeneous disorder, caused by mutations in FRAS1 (4q21.21), FREM2 (13q13.3) and GRIP1 (12q14.3) genes, coding for extracellular matrix proteins essential for the adhesion between basement membrane of epidermis and connective tissues of dermic layer during embryological development. Mutations in these genes are suggested to be responsible for a failure in apoptosis.\nDiagnostic methods\nThe diagnosis of FS is based on clinical findings, imaging and genetic tests for causative mutations. Karyotype, and imaging of urogenital tract may be required in case of ambiguous genitalia. The diagnostic criteria for FS are divided into six major criteria (syndactyly, cryptophthalmos spectrum, urinary tract abnormalities, ambiguous genitalia, laryngeal and tracheal anomalies and a positive family history) and five minor criteria (anorectal defects, dysplastic ears, skull ossification defects, umbilical abnormalities, nasal anomalies). Diagnosis is confirmed in presence of either three major, or two major and two minor, or one major and three minor diagnostic criteria.\nDifferential diagnosis\nThe differential diagnoses include ablepharon-macrostomia, fronto-facio-nasal dysplasia, Fraser-like syndrome, Meckel syndrome, and syndromic microphthalmia caused by heterozygous mutations of SOX2 gene. Isolated cryptophthalmos, frontonasal dysplasia should also be considered.\nAntenatal diagnosis\nPre-implantation or prenatal genetic diagnosis is possible if pathogenic mutations responsible for the disease have been identified in the family. Polyhydramnios or oligohydramnios, cryptophthalmos, echogenic lungs, renal abnormalities or agenesis may be detected by antenatal ultrasound.\nGenetic counseling\nFS is an autosomal recessive disease. Genetic counseling should be proposed to at risk families (both parents are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThe treatment of FS is symptomatic and requires a multidisciplinary team (including surgeon, ear nose throat (ENT) specialist, nephrologist, ophthalmologist and other specialists). Emergency surgery is required in case of respiratory distress. Patients may also need corrective oculoplastic/corneal, ear, digital or genital surgery. In case of feeding difficulties, a nasogastric tube or gastrostomy may be used, along with physiotherapy to get rid of nasal and oral secretions. Symptomatic treatment of chronic kidney disease may be required. Other treatments may include visual/hearing aids, physiotherapy and psychomotor/occupational/speech therapy. Psychological support should be proposed to the patients and their family.\nPrognosis\nFS survival depends on the severity of associated anomalies, with laryngeal and/or kidney malformations as the major causes of fatality. The disease can be suspected during the prenatal period by ultrasound detection of related malformations; affected fetuses with severe anomalies are delivered stillborn (about 25%). Nevertheless, in less severe case anomalies, extended or normal life expectancy has been reported.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Maria Francesca BEDESCHI | ITHACA* - Dr A.M. [Albertien] VAN EERDE | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Frasier syndrome", "Disease Definition": "A rare genetic, syndromic glomerular disorder characterized by the association of progressive glomerular nephropathy and 46,XY complete gonadal dysgenesis with a high risk of developing gonadoblastoma.", "ORPHA ID": 347, "Summary": "Epidemiology\nTo date, less than 150 cases have been described.\nClinical description\nNephropathy is the hallmark of the disease. It develops during childhood presenting as persistent proteinuria and subsequently steroid-resistant nephrotic syndrome (SRNS) and progresses to end-stage renal disease (ESRD) in the second or third decade of life. On renal biopsy, focal segmental glomeruloscrelosis (FSGS) is the most common histopathological finding. Individuals have a 46, XY karyotype and present with female external genitalia, complete gonadal dysgenesis and have a higher risk of gonadoblastoma. These individuals are later evaluated for delayed puberty or primary amenorrhea. Since (modest) breast development occurs also without estrogen stimulus, failure to recognize a delayed puberty is not rare. In addition, the clinical picture may be confused by attributing pubertal delay to previous immunosuppressive therapy, renal insufficiency itself or renal transplantation. Complete gonadal dysgenesis results in infertility, female external genitalia and presence of Mullerian structures. Wilms tumor is not common in individuals with Frasier syndrome.\nEtiology\nFrasier syndrome has been associated to specific pathogenic variants affecting nucleotides 4-5 of the intron 9 (previously referred to as IVS9+4; IVS9+5) in the WT1 gene (11p13). WT1 encodes for a protein that serves as regulatory transcription factor important both for renal and gonadal development.\nDiagnostic methods\nThe diagnosis is suspected on childhood onset of progressive glomerulopathy with findings of FSGS on histological analysis. Phenotypic females with delayed puberty or primary amenorrhea, should be carefully evaluated for signs of nephropathy. When the clinical findings suggest the diagnosis of WT1 associated disorders, single gene testing of the hotspot 8-9 exons with adjacent introns can be performed. Karyotype testing is recommended for all individuals with WT1 intron 9 pathogenic variants.\nDifferential diagnosis\nThe main differential diagnosis is idiopathic steroid-resistant nephrotic syndrome, and other WT1 associated diseases including Denys-Drash syndrome, genetic steroid resistant nephrotic syndrome and disorders of testicular development.\nGenetic counseling\nMost affected individuals have a de novo pathogenic variant and hence negative family history; however, autosomal dominant inheritance has been reported. Where karyotyping is indicated, pre-testing genetic counselling on the possibility of detecting sex reversal should be offered.\nManagement and treatment\nManagement is multidisciplinary and should involve a nephrologist for management of chronic renal failure (initially with nephroprotective medical therapy and afterwards with renal replacement therapies or transplantation when ESRD occurs), an endocrinologists for treatment of associated disorder of testicular development, and oncologists and surgeons to evaluate the need for an early gonadectomy in order to prevent tumorigenesis. Preemptive bilateral gonadectomy at the time of renal transplant or placement of a peritoneal dialysis catheter might be an option.\nPrognosis\nThere is limited information on life expectancy. After kidney transplantation, nephrotic syndrome does not recur. 46,XY individuals with complete gonadal dysgenesis are infertile.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Beata LIPSKA-ZIETKIEWICZ | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "FRAXE intellectual disability", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by a variable clinical picture including developmental delay, mild to moderate intellectual disability, learning difficulties, communication deficits, and behavioral problems (such as aggression, attention deficit, hyperactivity, and autistic features). Personality disorder and psychotic behavior have also been reported.", "ORPHA ID": 100973, "Summary": ""}
{"Disease Name": "FRAXF syndrome", "Disease Definition": "FRAXF syndrome was originally identified in a family with developmental delay and an expanded CCG repeat at the folate-sensitive FRAXF fragile site. Since this initial description, FRAXF has been associated with a range of manifestations but no clear phenotype has been established.", "ORPHA ID": 100974, "Summary": "Epidemiology\nPrevalence is unknown.\nEtiology\nThe FRAXF fragile site is located at Xq28 within the 5'UTR of the TMEM185A gene.\n\n                            Last update: \n                            August 2008"}
{"Disease Name": "Free sialic acid storage disease", "Disease Definition": "A rare lysosomal storage disease characterized by a spectrum of clinical manifestations including neurological and developmental disorders with a severity ranging from the milder form, also called Salla disease (SD), to the most severe phenotype, also called infantile free sialic acid storage disease (ISSD).", "ORPHA ID": 834, "Summary": "Epidemiology\nThe worldwide prevalence is approximately 1/1,000,000. In the Salla region of Finland, where the carrier frequency of the p.Arg39Cys variant of SLC17A5 is 1/100, the prevalence is estimated to be around 1-9/1,000,000. There have been ~250 patients with bi-allelic mutations in SLC17A5 reported in the literature, reflective of the suspected underdiagnosis of free sialic acid storage disorder (FSASD).\nClinical description\nPatients with FSASD suffer from progressive neurologic deterioration with psychomotor delay and childhood onset of hypotonia, spasticity and ataxia. Other clinical signs include coarse facial features, organomegaly, bones anomalies, failure to thrive, short stature, neonatal ascites, microcephaly, seizures and cardiac anomalies. Patients with the intermediate form have earlier onset and more severe symptoms. Patients with the infantile form present with very severe symptoms and suffer from early death prenatally or in infancy.\nEtiology\nThe disease is caused by biallelic mutations to the SLC17A5 gene which encodes the sialin protein responsible for the efflux of free sialic acid from lysosomes and the transport of certain neurotransmitters into synaptic vesicles. Loss of function of this transporter causes the symptoms associated with FSASD. There have been approximatey 50 mutations reported to be linked to this disease to date.\nDiagnostic methods\nDiagnosis is established by measurement of free (unbound) sialic acid accumulation in fibroblast lysosomes, urine or cerebrospinal fluid, and confirmed by genetic testing confirming bi-allelic mutations in the SLC17A5 gene. Quantification of free sialic acid in fibroblasts lysosomes and cytoplasm provides discrimination between sialuria and FSASD. Predominant lysosomal sialic acid overload is suggestive of FSASD, whereas increased concentrations of this metabolite in the cytoplasm are suggestive of sialuria. Normal concentrations of sialic acid in the urine may correlate with milder forms of FSASD. FSASD patients often experience diagnostic delays due to the rarity of the disorder, non-specific clinical symptoms, and absence of routine urine sialic acid testing.\nDifferential diagnosis\nDifferential diagnosis includes sialuria (urinary and cellular free sialic acid elevation) and galactosialidosis (sialic acid bound to glycoproteins or glycolipids). FSASD is in the differential diagnosis for severe hypomyelinating leukodystrophies.\nAntenatal diagnosis\nAntenatal diagnosis is possible by measurement of free sialic acid concentration in chorionic villi or amniotic fluid cells and by genetic analysis of the SLC17A5 gene. Fetal ultrasound may reveal ascites, hydrops fetalis (NIHF), organomegaly, dysostosis, facial dysmorphia and in utero growth delay which can be indicative of lysosome overload.\nGenetic counseling\nTransmission of FSASD is autosomal recessive. Genetic counselling should be offered to at-risk couples (both individuals carry a mutation) informing them there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThere is no approved therapy for FSASD. Management is symptomatic and supportive and includes the provision of adequate nutrition, supplementation of calcium and vitamin D, the use of anticonvulsants (for seizures), physical therapy, speech therapy and adapted education.\nPrognosis\nLife expectancy fluctuates according to the severity of the disease, from 1 day for patients presenting symptoms before birth, to over 70 years for the least severe forms. Free sialic acid concentration correlates with the severity of the disease.\n\n                            Last update: \n                            October 2023\n\n\n                            - Expert reviewer(s): \n                            Dr David ADAMS  - Dr Marjan HUIZING  - Dr Melissa WASSERSTEIN"}
{"Disease Name": "Freeman-Sheldon syndrome", "Disease Definition": "A rare congenital, distal arthogryposis syndrome characterized by microstomia, whistling-face appearance, Chin with V- or H- shaped creased, and prominent nasolabial folds; most patients present club foot and congenital joint contractures of the hands and feet. It is the most severe form of distal arthrogryposis.", "ORPHA ID": 2053, "Summary": "Epidemiology\nApproximately 100 cases of Freeman-Sheldon syndrome (FSS) have been reported to date; no gender predominance is reported and the distribution is worldwide.\nClinical description\nFacial features include prominent forehead and eyebrow ridges, hypertelorism, epicanthus, telecanthus, down-slanting palpebral fissures, deep-set eyes, full cheeks, low-set ears, midface hypoplasia, a short nose and long philtrum, deep nasolabial folds, high-arched palate, and chin with a V- or H-shaped crease. The hallmark feature is small mouth with a whistling appearance. Dental crowding and difficulty in maintaining oral hygiene are reported, as well as hearing loss. Multiple contractures in the hands and feet are found at birth and are non-progressive; they cause camptodactyly, ulnar deviation of wrist and fingers, clubfoot, and overlapping fingers. Kyphoscoliosis is a frequent feature; congenital dislocation of the hip is rare. Ocular features include hypertelorism, strabismus, ptosis and blepharophimosis. Delayed growth is almost universal, but cognitive performances are generally normal. Infancy may be characterized by failure-to-thrive, due to microstomia, micrognathia and high palate. Other problems occurring with higher frequency in FSS are sleep apnea, dysglycemia, hyperhidrosis, diarrhea, constipation and gastro-esophageal reflux disease. An increased risk of adverse event during anesthesia is reported, mainly due to difficult intubation (because of orofacial contractures and structural anomalies, limited neck mobility, spinal deformities), difficult vascular access, and susceptibility to malignant hyperthermia.\nEtiology\nFSS is caused by homozygous mutations in MYH3, encoding for embryonic myosin heavy chain 3, a primary component of fetal myotubules; this protein has a central role during fetal muscular development, while postnatally it is progressively replaced by other isoforms. The switch in myosin expression pattern could explain why contractures are congenital and non-progressive. Mutations in NALCN have been identified in a few cases.\nDiagnostic methods\nDiagnosis is based on both physical findings and genetic testing on MYH3. Diagnostic criteria have been proposed and include two or more of the following signs: distal arthrogryposis, microstomia, whistling-face, nasolabial creases, and H-shaped chin dimple. In some cases of clinically diagnosed FSS, mutations in NALCN have been detected. Of note, at least 7% of clinical FSS cases are not explained by known pathological allelic variations.\nDifferential diagnosis\nDifferential diagnosis mainly includes other distal arthrogryposis such as digitotalar dymorphism (which lacks craniofacial features), Sheldon-Hall syndrome (clinically less severe), Gordon syndrome, trismus-pseudocamptodactyly syndrome, and autosomal dominant multiple pterygium syndrome. Schwartz-Jampel syndrome and CLIFAHDD (congenital contractures of the limbs and face, hypotonia, and developmental delay) are also to be considered.\nAntenatal diagnosis\nPre-conception and pre-natal tests are possible, when a relative carries a known pathogenic variant. Prenatal ultrasound can also be useful.\nGenetic counseling\nMost cases are sporadic (de novo) autosomal dominant mutations; an autosomal recessive inheritance pattern has also been described and seems to be associated with a more severe clinical presentation. Genetic counselling may be offered for patients who have a child with FSS.\nManagement and treatment\nNo specific pharmacological therapy is available. Patients should have craniofacial and orthopedic consultation as early in life as possible, in order to undertake proper operative measures (e.g. oral commissuroplasties, dental treatment, blepharoplasty, myringotomies). Operative correction of lower deformities often results in poor outcome. Bracing and physiotherapy (including the Ponseti method) are the cornerstones of non-operative therapy.\nPrognosis\nAspiration and respiratory complications may lead to early mortality. Surviving infants usually have normal life expectancy. Quality of life is generally impaired by the multiple malformations and functional repercussions.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Valeria CAPRA | ITHACA* - Dr Gianluca PICCOLO  - Dr Marcello SCALA \n\n\n                                * European Reference Network"}
{"Disease Name": "Fried syndrome", "Disease Definition": "Fried syndrome is a rare X-linked mental retardation (XLMR) syndrome characterized by psychomotor delay, intellectual deficit, hydrocephalus, and mild facial anomalies.", "ORPHA ID": 85335, "Summary": "Epidemiology\nPrevalence is unknown, but the syndrome was originally described in a large Scottish family.\nEtiology\nMutations in the AP1S2 gene (Xp22), coding for a subunit of the clathrin-associated adaptor protein complex involved in intracellular protein trafficking and synaptic vesicle recycling, have been identified in seven families.\nDiagnostic methods\nThe presence of basal ganglia calcifications, detectable by CT scan, and elevated CSF protein levels are characteristic features of Fried syndrome and should prompt genetic analysis when found in individuals with XLMR.\nManagement and treatment\nBeyond the management of hydrocephalus and follow-up of psychomotor development, no specific treatment is available.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Ginevra ZANNI"}
{"Disease Name": "Fried's tooth and nail syndrome", "Disease Definition": "A rare, ectodermal dysplasia syndrome characterized by hypodontia of primary or permanent dentition, and nail dysplasia manifesting as dystrophic fingernails and toenails, and thin, flat nail plates. Additional signs and symptoms may include sparse, slow-growing and fine scalp hair, thin scanty eyebrows, poor jaw development, everted lower lip, dry skin, and sweat gland involvement.", "ORPHA ID": 99672, "Summary": ""}
{"Disease Name": "Friedreich ataxia", "Disease Definition": "Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder classically characterized by progressive gait and limb ataxia, dysarthria, dysphagia, oculomotor dysfunction, loss of deep tendon reflexes, pyramidal tract signs, scoliosis, and in some, cardiomyopathy, diabetes mellitus, visual loss and defective hearing.", "ORPHA ID": 95, "Summary": "Epidemiology\nThe prevalence of FRDA in Caucasians is estimated at 1/20,000 to 1/50,000.\nClinical description\nThe classical presentation of FRDA begins in childhood or adolescence. General clumsiness and gait ataxia are usually the first signs to appear, often followed by pyramidal signs, upper-limb ataxia and dysarthria. Oculomotor manifestations present early and include fixation instability (square wave jerks) and nystagmus. Visual loss may occur later. Auditory neuropathy (8-39% of cases), leads to hearing difficulties. Intelligence seems unaffected. Areflexia and distal sensory loss is present in most cases. Dysphagia is mild at first but in advanced disease can lead to choking on foods and liquids. Scoliosis and foot deformities (pes cavus and talipesequinovarus) can be mild or debilitating. Spasticity, seen later in the disease course, can lead to discomfort, pain, positioning problems and contractures in some. Cardiac involvement (typically hypertrophic cardiomyopathy) usually develops later in the disease course, but may rarely precede neurological manifestations. Diabetes mellitus, seen in up to 30% of cases, often presents later. Bladder hyperactivity has been reported in some. The average time from symptom onset to wheelchair dependence is 15.5 years (range 3 to 44). Several atypical phenotypes have been described but overlap is significant.\nEtiology\nFRDA is caused by an unstable GAA expansion situated in intron 1 of the FXN gene (9q21.11) encoding frataxin. The function of this protein is currently unknown, but the most accepted theory is that it has a role in the biogenesis of iron-sulfur clusters. A deficiency in this protein leads to the progressive central and peripheral nervous system damage seen in FRDA. The length of the shorter allele is inversely correlated to both age of onset and time between onset and wheelchair confinement, and positively with the prevalence of cardiomyopathy.\nDiagnostic methods\nMotor nerve conduction studies reveal a velocity of greater than 40m/s with absent or reduced sensory nerve action potential. ECG reveals inferolateral or widespread T-wave inversion. MRI may show spinal and cerebellar atrophy. Molecular genetic testing identifies mutations in the FXN gene, confirming diagnosis.\nDifferential diagnosis\nDifferential diagnoses include Charcot-Marie-Tooth type 1 and 2, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia type 1 and 2 and other early-onset ataxias.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known mutation.\nGenetic counseling\nFRDA is inherited autosomal recessively. Genetic counseling is possible.\nManagement and treatment\nThere is no cure for FRDA and management is multidisciplinary. Physical therapy and the use of walking aids, prostheses and wheelchairs help maintain an active lifestyle. A speech therapist may be necessary. Stretching programs and the use of frame splints and pharmacologic agents (baclofen and botulinum toxin) help with spasticity. Treatment of cardiac disease includes anti-coagulants, anti-arrhythmic agents and pacemakers. Patients with diabetes mellitus usually require insulin. In later stages, a percutaneous endoscopic gastrostomy tube may be needed. Psychological counseling can be offered. Annual follow-up should include ECG, echocardiography and testing of blood glucose and glycated hemoglobin (HbA1c).\nPrognosis\nPrognosis has improved but quality of life is still significantly affected. Mean life expectancy is about 40 years, depending on age of onset and presence of diabetes and cardiomyopathy. Death is mainly due to heart disease (cardiac failure or arrhythmia) and bronchopneumonia.\n\n                            Last update: \n                            March 2014"}
{"Disease Name": "Frontal fibrosing alopecia", "Disease Definition": "Frontal fibrosing alopecia (FFA) is a rare variant of lichen planopilaris (see this term) characterized by symmetrical, progressive, band-like anterior hair loss of the scalp.", "ORPHA ID": 254492, "Summary": "Epidemiology\nPrevalence is unknown. It most commonly affects postmenopausal women, although it has also been reported in men and premenopausal women.\nClinical description\nProgressive recession of the frontal and temporal hairline is observed. Approximately half of all cases of FFA also have eyebrow loss; less often there is hair loss in other parts of the body. It is only very rarely associated with classic lichen planus lesions elsewhere. Histopathologically, perifollicular lymphocytic infiltrate and follicular hyperkeratosis are observed at the edge of the affected area, while the rest of the lesion appears pale with loss of the follicular ostia. It is histologically indistinguishable from other forms of lichen planopilaris.\nEtiology\nIt was suggested that the disease could have a hormonal origin, but to date the precise etiology remains unknown.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Stephanie ARNOLD  - Dr Susan COOPER"}
{"Disease Name": "Frontofacionasal dysplasia", "Disease Definition": "A rare genetic disease characterized by variable multiple congenital craniofacial anomalies, including brachycephaly, cranium bifidum occultum, hypertelorism, midface hypoplasia, nasal hypoplasia, or cleft lip/palate, among others, as well as abnormalities of the eyes and eyelids. Encephalocele and spina bifida have also been reported in association.", "ORPHA ID": 1791, "Summary": ""}
{"Disease Name": "Frontometaphyseal dysplasia", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by anomalous ossification and skeletal patterning of the axial and appendicular skeleton, facial dysmorphism and conductive and sensorineural hearing loss.", "ORPHA ID": 1826, "Summary": "Epidemiology\nTo date, over 100 cases have been described in the literature.\nClinical description\nFrontometaphyseal dysplasia (FMD) is a congenital disorder and the cardinal manifestations in males are skeletal dysplasia (skull base sclerosis; distal phalangeal hypoplasia; progressive contractures of the hand over the first two decades resulting in marked limitation of movement at the interphalangeal, metacarpophalangeal joints, wrists, elbows, knees, and ankles); mild but progressive scoliosis; limb bowing; campomelia), facial dysmorphism (supraorbital hyperostosis, downslanting palpebral fissures, ocular hypertelorism, broad nasal bridge and nasal tip, hypodontia, oligodontia and occasionally craniosynostosis) and conductive and sensorineural hearing loss. Extraskeletal manifestations include congenital heart malformation (interauricular communication, ventricular septal defect, congenital pulmonary valve stenosis, aortic dilatation), congenital subglottic stenosis, an asthenic build, and underdevelopment of the musculature, most notably around the shoulder girdle and in the intrinsic muscles of the hands (common). Males with FMD can present with ureteric and/or urethral obstruction most frequently at the vesicoureteric junction (leading to hydronephrosis). Intelligence is normal. Females are less severely affected and present the characteristic craniofacial features, scoliosis but absent or attenuated digital, cardiorespiratory, and urologic anomalies.\nEtiology\nThe exact pathogenesis of FMD is still unknown, however around half of cases of FMD are caused by gain of function mutations in the gene FLNA (Xq28) that encodes filamin A. There is evidence for a second autosomal locus for FMD that to date remains uncharacterized. FMD is allelic with 4 other skeletal dysplasias (otopalatodigital syndrome type 1 and 2 (OPD1 and OPD2, respectively), terminal osseous dysplasia - pigmentary defects (TOD) and Melnick-Needles syndrome (MNS)).\nGenetic counseling\nMany pedigrees are consistent with X-linked dominant inheritance. Male-to-male transmission has not been reported. The risk of transmitting the mutation in each pregnancy is 50%; males inheriting the mutation will be affected while females who inherit the mutation are less severely affected.\n\n                            Last update: \n                            May 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Stephen ROBERTSON"}
{"Disease Name": "Frontonasal arteriovenous malformation", "Disease Definition": "Frontonasal arteriovenous malformation is a rare vascular anomaly characterized by abnormal communication between arteries and veins, bypassing the capillary bed, located in the frontonasal area. It may present with intermittent nasal bleeding, blurred vision, pustule formation and/or disfigurement. Overlying skin may be of normal appearance or may manifest a red, pulsatile mass with local rise of temperature. Other features may include pain, ulceration, excessive growth and/or congestive heart failure.", "ORPHA ID": 141168, "Summary": ""}
{"Disease Name": "Frontonasal dysplasia-alopecia-genital anomalies syndrome", "Disease Definition": "A rare, genetic, frontonasal dysplasia characterized by coronal craniosynostosis, large skull defect with aplasia of ethmoid and nasal bones, hypertelorism, severely depressed nasal bridge and bifid nasal tip in association with total alopecia and hypogonadism. Intellectual disability is mild to moderate.", "ORPHA ID": 228390, "Summary": ""}
{"Disease Name": "Frontonasal dysplasia-bifid nose-upper limb anomalies syndrome", "Disease Definition": "A rare syndromic frontonasal dysplasia characterized by distinctive facial dysmorphic features including hypertelorism, almond-shaped palpebral fissures, nasal deformity with creased ridge, depressed or absent tip, and asymmetry and partial absence of nasal bones, and downturned corners of the mouth. Additional reported manifestations are limb anomalies (e. g. Poland anomaly, transverse limb agenesis, and anomalies of the hands and feet, such as camptodactyly, oligodactyly, clinodactyly, and syndactyly), frontonasal encephalocele, choanal atresia, congenital renal/cardiac malformations, and corpus callosum agenesis.", "ORPHA ID": 521308, "Summary": ""}
{"Disease Name": "Frontonasal dysplasia-severe microphthalmia-severe facial clefting syndrome", "Disease Definition": "Frontonasal dysplasia-severe microphthalmia-severe facial clefting syndrome is a rare, genetic, orofacial clefting malformation syndrome characterized by severe frontonasal dysplasia with complete cleft palate, facial cleft, extreme microphtalmia and hypertelorism, frequently associated with eyelid colobomata, sparse or absent eyelashes/eyebrows, wide nasal bridge with hypoplastic alae nasi, low-set, posteriorly rotated ears and caudal appendage in the sacral region.", "ORPHA ID": 306542, "Summary": ""}
{"Disease Name": "Frontonasal dysplasia", "Disease Definition": "A group of rare bone development disorders characterized by an array of abnormalities affecting the eyes, forehead, and nose, and linked to midfacial dysraphia. The clinical picture is highly variable, but the major findings include hypertelorism, a broad nasal root, a large and bifid nasal tip, and widow's peak. Occasionally, abnormalities can include accessory nasal tags, cleft lip, ocular abnormalities (coloboma, cataract, microphthalmia), conductive hearing loss, basal encephalocele and/or agenesis of the corpus callosum. Intellectual deficit is rare and more likely to occur in cases where hypertelorism is severe or where there is extra-cranial involvement.", "ORPHA ID": 250, "Summary": ""}
{"Disease Name": "Frontorhiny", "Disease Definition": "A rare frontonasal dysplasia characterized by hypertelorism, wide nasal bridge, broad columella, widened philtrum, widely separated narrow nares, poor development of nasal tip, midline notch of the upper alveolus, columella base swellings and a low hairline. Additional features reported in some include upper eyelid ptosis and midline dermoid cysts of craniofacial structures and philtral pits or rugose folding behind the ears.", "ORPHA ID": 391474, "Summary": ""}
{"Disease Name": "Frontotemporal dementia with motor neuron disease", "Disease Definition": "Frontotemporal dementia with motor neuron disease (FTD-MND) is a type of frontotemporal lobar degeneration characterized by the insidious onset (between the ages of 38-78 years) of dementia-associated psychiatric symptoms (e.g. personality changes, uninhibited behavior, irritability, aggressiveness), memory difficulties, global intellectual impairment, emotional disorders and transcortical motor aphasia that eventually leads to mutism, in addition to the manifestations of motor neuron disease such as neurogenic muscular wasting (similar to what is seen in amyotrophic lateral sclerosis; see this term). The disease is progressive, with death occurring 2-5 years after onset.", "ORPHA ID": 275872, "Summary": ""}
{"Disease Name": "Frontotemporal dementia", "Disease Definition": "Frontotemporal dementia (FTD) comprises a group of neurodegenerative disorders, characterized by progressive changes in behavior, executive dysfunction and language impairment, as a result of degeneration of the medial prefrontal and frontoinsular cortices. Four clinical subtypes have been identified: semantic dementia, progressive non-fluent aphasia, behavioral variant FTD and right temporal lobar atrophy (see these terms).", "ORPHA ID": 282, "Summary": ""}
{"Disease Name": "Fructose-1,6-bisphosphatase deficiency", "Disease Definition": "Fructose-1,6-biphosphatase (FBP) deficiency is a disorder of fructose metabolism (see this term) characterized by recurrent episodes of fasting hypoglycemia with lactic acidosis, that may be life-threatening in neonates and infants.", "ORPHA ID": 348, "Summary": "Epidemiology\nFBP deficiency birth prevalence has been estimated at 1/147,575 in Italy. This disorder has been reported in Japanese, Asian, European, North American, Arab and Moroccan patients.\nClinical description\nFBP deficiency may occur neonatally with hepatomegaly, but it usually presents in infants of 3-4 months of age or early childhood, with manifestations including fast-induced hypoglycemia and metabolic acidosis, episodes of tachypnea/apnea, hypoglycemia, ketosis and lactic acidosis. Episodes are often triggered by catabolic conditions such as prolonged fasting (more than 8 to 10 hours), fructose, sorbitol or glycerol ingestion, vomiting, diarrhea or febrile infectious diseases. Patients are asymptomatic between episodes.\nEtiology\nFBP deficiency is due to homozygous or compound heterozygous mutations in the FBP1(9q22) gene encoding fructose-1,6-bisphosphatase1, resulting in impaired gluconeogenesis. To date, 11deleterious mutations have been reported.\nDiagnostic methods\nFBP deficiency diagnosis is based on clinical presentation, along with glycemia and lactacidemia levels. Enzyme activity may be measured in leukocytes, and genetic testing of the FBP1 gene confirms diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes glycogen storage disease due to glucose-6-phosphatase deficiency (see this term).\nAntenatal diagnosis\nPrenatal diagnosis is feasible through molecular analysis of amniocytes or chorionic villous cells.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nFBP deficiency management aims at avoiding hypoglycemia and lactic acidosis through frequent feeding, enriched with glucose or maltodextrin, especially in illness associated with fever. Prevention and treatment of metabolic decompensation (with glucose orally or intravenously) is essential. Fasting periods longer than 8 hours should be avoided and infectious episodes should be carefully monitored. Fructose or sucrose should be avoided during acute episodes.\nPrognosis\nWith timely adapted management and proper treatment, FPB deficiency prognosis is excellent, even if this condition may be potentially fatal in the newborn period and early infancy.\n\n                            Last update: \n                            September 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe LABRUNE"}
{"Disease Name": "Fryns syndrome", "Disease Definition": "A rare multiple congenital anomaly syndrome characterized by congenital diaphragmatic hernia (CDH) and pulmonary hypoplasia, distal limb hypoplasia and facial anomalies in addition to variable expression of additional birth defects.", "ORPHA ID": 2059, "Summary": "Epidemiology\nThe birth prevalence of Fryns syndrome (FS) has been estimated at 1/14,000 births. FS has been estimated to be present in 4-10% of patients with CDH.\nClinical description\nPolyhydramnios is often noted during pregnancy and neonates present with a spectrum of anomalies at birth. The classical features of FS include CDH (unilateral in 75% of cases) together with the associated complications such as lung hypoplasia and left heart hypoplasia. Craniofacial anomalies include a 'coarse' facial appearance, widely spaced eyes, microphthalmia, low-set and anomalous ears, a wide and flat nasal bridge, thick nasal tip with anteverted nares, long philtrum, tented vermilion of the upper lip, wide mouth and small jaw. Distal limb hypoplasia is characteristic and includes short and broad hands, short digits and short terminal phalanges, small or absent nails, and clinodactyly. The thorax can be small with widely spaced nipples. Brain anomalies (ventricular dilation, hydrocephalus, Dandy-Walker malformation) and cardiac malformations (atrial and ventricular septal defects, aortic abnormalities) are reported frequently in affected individuals. Additional anomalies include orofacial clefting, malrotation of the gastrointestinal tract, anal atresia, omphalocele, uro-genital anomalies (renal cysts, ureteral dilation and cryptorchidism), talipes and broad clavicles. In those that survive the neonatal period, severe developmental delay and intellectual disability have been reported.\nEtiology\nThe etiology in many cases is not clear. Several recurrent chromosome aberrations, including microdeletions involving chromosome bands 15q26.2 and 8p23.1, have been reported in probands with clinical presentations similar to FS, but the causal genes in these intervals are yet to be identified. More recently, bi-alleic variants in PIGN have been associated with a FS phenotype. Variants in other genes involved in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway (PIGV and PIGA) have also been identified in several patients with a phenotype overlapping FS.\nDiagnostic methods\nDiagnosis is primarily based on clinical findings and six clinical criteria have been suggested, comprising CDH, pulmonary hypoplasia, characteristic facial anomalies, distal limb hypoplasia, at least one other characteristic additional anomaly and a family history consistent with autosomal recessive inheritance. FS is classically associated with a normal karyotype; thus array comparative genomic hybridization and copy number variation analysis can be useful in differentiating FS from other chromosomal conditions. Exome sequencing (particularly for PIGN variants or genes of the GPI-anchor biosynthesis pathway), skin biopsy and karyotyping can also be performed to rule out overlapping conditions.\nDifferential diagnosis\nDifferential diagnosis includes Donnai-Barrow syndrome, Matthew-Wood syndrome, Simpson-Golabi-Behmel syndrome, craniofrontonasal syndrome, Cornelia de Lange syndrome, tetrasomy 12p, distal monosomy 15q and other chromosome aberrations. Bi-allelic variants in PIGN can also cause multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1) that is not typically associated with CDH.\nAntenatal diagnosis\nCDH and the other anomalies associated with FS can be diagnosed by ultrasound scanning during a pregnancy.\nGenetic counseling\nClassically, FS has been inherited as an autosomal recessive (AR) condition. If no cytogenetic or molecular defect is identified, ultrasound scanning can be recommended in future pregnancies of at-risk couples.\nManagement and treatment\nManagement is multidisciplinary and may necessitate pediatric specialists in neurology, cardiology, gastroenterology, and nephrology as well as clinical geneticists, developmental pediatricians and regular follow-up in a specialized center. Supportive treatments are directed at the management of the CDH and include extra-corporeal membrane oxygenation (ECMO), nitric oxide and surfactant as therapies for persistent pulmonary hypertension. Other malformations are managed with standard treatment.\nPrognosis\nPrognosis depends on the severity of the anomalies present, although it is generally guarded with survival beyond the neonatal period being relatively rare. Patients without diaphragmatic defects have a better prognosis.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Anne SLAVOTINEK"}
{"Disease Name": "Fryns-Smeets-Thiry syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder characterized by severe psychomotor development delay (without development of primary motor abilities and speech) and severe intellectual disability, associated with marfanoid habitus, joint laxity, bilateral hip luxation, hypotonia, scoliosis, and characteristic facial dysmorphism (i.e. high nasal bridge, sharp nose, short philtrum, large mouth, full lips and maxillary hypoplasia). There have been no further description in the literature since 1994.", "ORPHA ID": 2058, "Summary": ""}
{"Disease Name": "FTH1-related iron overload", "Disease Definition": "A rare disorder of iron metabolism and transport characterized by elevated serum ferritin levels, increased serum iron, increased transferrin saturation, and heavy iron deposition in hepatocytes. Iron deposition has also been indicated in heart and bone marrow, while hematological examination of peripheral blood shows no abnormalities.", "ORPHA ID": 247790, "Summary": ""}
{"Disease Name": "Fuchs endothelial corneal dystrophy", "Disease Definition": "A disorder that is the most frequent form of posterior corneal dystrophy and is characterized by excrescences on a thickened Descemet membrane (corneal guttae), generalized corneal edema, with gradually decreased visual acuity.", "ORPHA ID": 98974, "Summary": "Epidemiology\nThe exact prevalence is not known but extreme geographical variability has been reported. FECD is the most prevalent corneal dystrophy in the USA but has been found to be uncommon in Saudi Arabia and in Singaporean Chinese, and very rare in Japan.\nClinical description\nThe condition is more common and more severe in women (sex ratio 3-4:1). Patients with FECD are initially asymptomatic. Clinical onset is generally in the 5th or 6th decade of life. Discomfort and painful episodes of recurrent corneal erosions occur, along with gradually developing opacification leading to hazy vision. Over time, discomfort may diminish but severe impairment of visual acuity, and even blindness in elderly patients, may be observed. The clinical course often spans 10 to 20 years. The condition is often associated with cataracts. Microbial keratitis and corneal neovascularization are extremely rare complications. Stromal edema produces a blue-gray haze anterior to Descemet membrane followed by eventual thickening of the entire corneal stroma and development of a ground-glass corneal appearance.\nEtiology\nThe etiology of FECD is unknown, but it seems to be a heterogenous complex inherited disorder caused by the interaction of genetic and environmental factors. Mutations in certain genes have been reported in some cases of FECD. Rare cases of early onset have been related to mutations in the COL8A2 gene (1p34.2-p32.3). Heterozygous mutation in the SLC4A11 gene (20p12) has been reported in some late-onset cases of FECD. Other cases have been mapped to chromosomes 13 (13pter-3q12.13) and 18 (18q21.2- q21.32)(TCF4) and to ZEB1 (10p11.22).\nGenetic counseling\nAlthough most patients with FECD lack a positive family history, blood relatives sometimes manifest corneal guttae. FECD may also affect siblings and two or more successive generations, apparently as an autosomal dominant disorder having incomplete penetrance, but a simple autosomal dominant pattern is unlikely.\nManagement and treatment\nMost patients with FECD ultimately require a penetrating keratoplasty or a procedure for repairing the posterior surface of the cornea, such as a deep lamellar endothelial keratoplasty (DLEK), Descemet stripping endothelial keratoplasty (DSEK), or Descemet stripping automated endothelial keratoplasty (DSAEK). Visual acuity is markedly improved after a penetrating keratoplasty, DSEK or DSAEK.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Fuchs heterochromic iridocyclitis", "Disease Definition": "Fuchs heterochromic iridocyclitis (FHI) is an ocular disease of unknown etiology occurring in a very small percentage (0.5-6.2%) of uvietis cases, characterized by diffuse iris heterochromia or atrophy, keratic precipitates in the absence of synechiae, and in some cases evolving to glaucoma and vitreous opacities.", "ORPHA ID": 263479, "Summary": ""}
{"Disease Name": "Fucosidosis", "Disease Definition": "A rare lysosomal storage disease characterized by widespread tissue buildup of glycolipids and oligosaccharides rich in fucose. Patients present with broad clinical characteristics such as intellectual disability, developmental delay associated with psychomotor regression and bone abnormalities, visceromegaly, hyperhidrosis, and dermatological abnormalities.", "ORPHA ID": 349, "Summary": "Epidemiology\nTo date, less than 200 cases have been reported in the literature. The estimated incidence is less than 1/200,000 births, but is higher in some regions of Southern Italy, Cuba, Tunisia, and some populations in the USA.\nClinical description\nThe disease manifests in a spectrum ranging from a rapidly progressing severe form which starts approximately at 6 months of age (type I) to a moderate form with slower evolution (type II). Clinical symptoms and signs primarily include neurological damage leading to intellectual deficiency, psychomotor regression, speech difficulties, posture and walking difficulties, seizures and spasticity. They are often accompanied by coarse facial features, small stature, and dermatological abnormalities such as angiokeratomas. Other symptoms include cardiomyopathy, hepatosplenomegaly, dysostosis multiplex, joint contractures, recurrent lung infections and eye problems.\nEtiology\nThe disease results from mutations in the FUCA1 gene (1p36-p34) which encodes the lysosomal α-L-fucosidase enzyme that catalyzes the hydrolysis of α-L-fucose residues in glycoproteins and oligosaccharides. Loss of function mutations in FUCA1 lead to a defect in synthesis or to the production of a non-functional enzyme and results in intralysosomal accumulation of fucosylated oligosaccharides and glycoproteins. To date, 60 pathogenic and likely pathogenic variants have been reported in the literature or genetic databases.\nDiagnostic methods\nDiagnosis is based primarily on clinical symptoms and signs as well as biochemical tests measuring fucosylated oligosaccharides and glycoprotein overload. An increase in fucosylated oligosaccharides in urine, accompanied by a reduction of α-L-fucosidase protein activity in the blood, is a strong indication of fucosidosis. The diagnosis may be further confirmed by genetic testing.\nDifferential diagnosis\nLysosomal storage diseases of the mucopolysaccharidosis type (MPS type 1 to 7), sphingolipidoses (Gaucher's and Fabry's disease), oligosaccharidoses (mannosidosis and Shindler's disease), and juvenile idiopathic arthritis all share some clinical features with fucosidosis. Careful clinical examination, biochemical analysis, and molecular genetic testing allow the exclusion of these diseases.\nAntenatal diagnosis\nAntenatal screening may be performed by amniocentesis or chorionic villus sampling for families with a pathogenic variant.\nGenetic counseling\nInheritance is autosomal recessive. Genetic counseling is recommended to at-risk couples to inform them that there is a 25% chance of having an affected child at each pregnancy.\nManagement and treatment\nEarly diagnosis with a multi-systemic supportive care approach, and a multidisciplinary follow-up, can improve the quality of life and the longevity of these patients. Treatment consists of symptom-specific supportive care, such as antibiotic therapy for chronic respiratory infections, and fluid replacement for hyperhidrosis. Hematopoietic stem cell transplantation from bone marrow performed before the onset of severe symptoms may be effective but long-term results have yet to be determined.\nPrognosis\nIn fucosidosis type I, severe neurologic deterioration happens rapidly and death from cachexia usually occurs between 5 and 10 years of age. In fucosidosis type II, neurological deterioration has a slower progression and most patients reach adulthood. There is no known correlation between location of the pathogenic variant in the FUCA1 gene and severity of clinical symptoms.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Elzbieta CIARA  - Pr Aleksandra JEZELA-STANEK  - Dr Karolina STEPIEN"}
{"Disease Name": "Fuhrmann syndrome", "Disease Definition": "Fuhrmann syndrome is mainly characterized by bowing of the femora, aplasia or hypoplasia of the fibulae and poly-, oligo-, and syndactyly.", "ORPHA ID": 2854, "Summary": "Epidemiology\nIt has been reported in 11 patients.\nClinical description\nMost of the patients also had a hypoplastic pelvis and hypoplasia of the fingers and fingernails. Some had congenital dislocation of the hip, absence or fusion of tarsal bones, absence of various metatarsals, and hypoplasia and aplasia of the toes. Autosomal recessive inheritance is presumed.\nEtiology\nThe syndrome is caused by a partial loss of WNT7A function (gene mapped to 3p25).\nDifferential diagnosis\nThe syndrome is allelic to Schinzel phocomelia (or Al-Awadi-Raas-Rothschild syndrome), which results from null mutations in the same gene.\n\n                            Last update: \n                            September 2006"}
{"Disease Name": "Fukutin-related limb-girdle muscular dystrophy R13", "Disease Definition": "A form of limb-girdle muscular dystrophy characterized by an infantile onset of hypotonia, axial and proximal lower limb weakness (with severe weakness noted after febrile illnesses), cardiomyopathy and normal or reduced intelligence. Hypertrophy of calves, thighs, and triceps have also been reported in some cases.", "ORPHA ID": 206554, "Summary": ""}
{"Disease Name": "Full NF2-related schwannomatosis", "Disease Definition": "Neurofibromatosis type 2 (NF2) is a tumor-prone disorder characterized by the development of multiple schwannomas and meningiomas.", "ORPHA ID": 637, "Summary": "Epidemiology\nPrevalence (initially estimated at 1: 200,000) is around 1 in 60,000.\nClinical description\nAffected individuals inevitably develop schwannomas, typically affecting both vestibular nerves and leading to hearing loss and deafness. The majority of patients present with hearing loss, which is usually unilateral at onset and may be accompanied or preceded by tinnitus. Vestibular schwannomas may also cause dizziness or imbalance as a first symptom. Nausea, vomiting or true vertigo are rare symptoms, except in late-stage disease. The other main tumors are schwannomas of the other cranial, spinal and peripheral nerves; meningiomas both intracranial (including optic nerve meningiomas) and intraspinal, and some low-grade central nervous system malignancies (ependymomas). Ophthalmic features are also prominent and include reduced visual acuity and cataract. About 70% of NF2 patients have skin tumors (intracutaneous plaque-like lesions or more deep-seated subcutaneous nodular tumors).\nEtiology\nNF2 is caused by mutations in the NF2 gene on chromosome 22. More than 50% of patients represent new mutations and as many as one-third are mosaic for the underlying disease-causing mutation. Although truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease, single and multiple exon deletions are common. A strategy for detection of the latter is vital for a sensitive analysis.\nDiagnostic methods\nDiagnosis is based on clinical and neuroimaging studies. Presymptomatic genetic testing is an integral part of the management of NF2 families.\nDifferential diagnosis\nThe main differential diagnosis of NF2 is schwannomatosis.\nAntenatal diagnosis\nPrenatal diagnosis and pre-implantation genetic diagnosis is possible.\nGenetic counseling\nNF2 is a dominantly inherited tumor predisposition syndrome.\nManagement and treatment\nNF2 represents a difficult management problem with most patients facing substantial morbidity and reducedlife expectancy. Surgery remains the focus of current management although watchful waiting with careful surveillance and occasionally radiation treatment have a role.\nPrognosis\nPrognosis is adversely affected by early age at onset, a higher number of meningiomas and having a truncating mutation.\n\n                            Last update: \n                            June 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Gareth EVANS  - Pr D GARETH"}
{"Disease Name": "Full schwannomatosis", "Disease Definition": "A rare form of neurofibromatosis characterized by the development of multiple schwannomas (nerve sheath tumors), without involvement of the vestibular nerves, and often associated with chronic pain. Dysesthesia and paresthesia may also be present. Common localizations include the spine, peripheral nerves, and the cranium.", "ORPHA ID": 93921, "Summary": ""}
{"Disease Name": "Fulminant viral hepatitis", "Disease Definition": "Fulminant viral hepatitis is a rapid and severe impairment of liver functions (acute liver failure) with hepatic encephalopathy developing less than 8 weeks after the onset of jaundice, secondary to viral hepatitis mainly due to HBV, but also to HAV.", "ORPHA ID": 35063, "Summary": ""}
{"Disease Name": "Fumaric aciduria", "Disease Definition": "Fumaric aciduria (FA), an autosomal recessive metabolic disorder, is most often characterized by early onset but non-specific clinical signs: hypotonia, severe psychomotor impairment, convulsions, respiratory distress, feeding difficulties and frequent cerebral malformations, along with a distinctive facies. Some patients present with only moderate intellectual impairment.", "ORPHA ID": 24, "Summary": "Epidemiology\nFA is very rare, fewer than 100 cases have been reported to date.\nClinical description\nNewborns are frequently microcephalic and may present with facial dysmorphisms. Severe encephalopathy manifests with poor feeding, failure to thrive, hypotonia, lethargy and epileptic seizures. In the most severe cases APGAR scores are low immediately following birth, and bradycardia and respiratory failure may follow. Most children do not achieve visual fixation and are unable to speak or walk. Less severely affected individuals survive beyond childhood, most nonetheless displaying moderate cognitive impairment. Some patients have been reported to present with only moderate cognitive deficits. An increased risk of certain tumors has also been reported, in particular familial leiomyomatosis (see this term).\nEtiology\nFA is caused by mutations in the FH gene (1q42.1) encoding fumarate hydratase, an enzyme that catalyzes the transformation of fumarate into malate in the Krebs cycle. Complete deletions of FH have been reported to be fatal, whereas more mildly affected individuals retain some residual enzymatic activity.\nDiagnostic methods\nChromatography of organic acids provides evidence of excreted fumaric acid, often associated with succinic acid and alphacetoglutaric acid. Hyperlactacidemia and moderate hyperammonemia are other common findings. Diagnosis can be confirmed by measuring fumarate hydratase activity in leukocytes or cultured fibroblasts. Brain MRI reveals a variety of anomalies including cerebral atrophy, enlarged ventricles and enlarged extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum and an abnormally small brain stem. Developmental malformations including bilateral polymicrogyria and absence of the corpus callosum may also be observed.\nDifferential diagnosis\nAn elevated level of fumaric acid in urine may be caused by metabolic stress; therefore testing for fumaric aciduria must be repeated after the patient has been stabilized. Differential diagnoses include polymicrogyria and Leigh syndrome (see these terms).\nAntenatal diagnosis\nPolyhydramnios, intrauterine growth delay and premature birth occur in over one third of cases. Fetal ultrasound reveals enlarged cerebral ventricles and other brain abnormalities.\nGenetic counseling\nFA is transmitted as an autosomal recessive trait.\nManagement and treatment\nOnly symptomatic treatment is available to FA patients. Gastrostomy may be necessary to facilitate feeding in newborns. Therapies to control seizures should not include a ketogenic diet, which is contraindicated for this family of enzymatic defects. Physical therapy to reduce scoliosis and improve mobility may be helpful in some cases. Special education and occupational therapy are required to attempt to improve motor skills and language development in less severely affected cases. For patients that survive long-term, regular tumor testing is required.\nPrognosis\nPrognosis is poor, except for those patients with only moderate cognitive impairment. Complete losses of enzymatic activity are fatal during childhood with severe psychomotor handicap: verbal communication and independent mobility remain limited. Some milder cases have been reported to survive longer, a diagnosis that is most likely underestimated.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Pascale DE LONLAY  - Dr Chris OTTOLENGHI"}
{"Disease Name": "Functioning gonadotropic adenoma", "Disease Definition": "Functioning gonadotropic adenoma is a very rare pituitary tumor, macroscopically characterized by a soft, well vascularized, variable sized adenoma, with occasional areas of hemorrage or necrosis, that secretes biologically active gonadotropins. In addition to common neurological signs due to mass effect (headache and/or visual field deterioration), additional clinical manifestations include menstrual irregularities (secondary amenorrhea, oligomenorhea or severe menorrhagia), galactorrhea, infertility or ovarian hyperstimulation syndrome (in premenopausal women), testicular enlargement and, occasionally, hypogonadism (in men) and isosexual precocious puberty (in children).", "ORPHA ID": 91348, "Summary": ""}
{"Disease Name": "Fundus albipunctatus", "Disease Definition": "Fundus albipunctatus is a rare, genetic retinal dystrophy disorder characterized by the presence of numerous small, round, yellowish-white retinal lesions that are distributed throughout the retina but spare the fovea. Patients present in childhood with non-progressive night blindness with prolonged cone and rod adaptation times. The macula may or may not be involved, which may result in a decrease of central visual acuity with age.", "ORPHA ID": 227796, "Summary": ""}
{"Disease Name": "Fundus pulverulentus", "Disease Definition": "Fundus pulverulentus is a rare form of patterned dystrophy of the retinal pigment epithelium characterized by a granular appearance in the macula, with coarse and punctiform mottling of the retinal pigment epithelium within the macular region. Association with choroidal neovascularization has been reported.", "ORPHA ID": 99004, "Summary": ""}
{"Disease Name": "Fungal keratitis", "Disease Definition": "A rare disorder of the anterior segment of the eye characterized by ocular infection by human-pathogenic fungi, most commonly Aspergillus, Candida, or Fusarium species, which gain access into the corneal stroma through a defect in the corneal epithelium. Risk factors include trauma, ocular surface disease, contact lenses, or immunocompromised state. Patients present with pain, foreign body sensation, redness, photophobia, tearing, secretion, or blurred vision. The condition may be complicated by corneal destruction and perforation, endophthalmitis, scleritis, and panophthalmitis.", "ORPHA ID": 519930, "Summary": ""}
{"Disease Name": "Fungal myositis", "Disease Definition": "A rare acquired skeletal muscle disease characterized by inflammation of a muscle due to infection with a fungus, usually occurring in an immunocompromised host. General symptoms are pain, tenderness, swelling, and/or weakness in the affected muscle. Most common causative agent are Candida species, with myositis developing in the setting of systemic candidiasis, typically as diffuse, multiple microabscesses. Other fungal pathogens potentially causing myositis are Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides species, or Aspergillus species, among others.", "ORPHA ID": 207000, "Summary": ""}
{"Disease Name": "Furuncular myiasis", "Disease Definition": "A parasitic disease characterized by infestation of the skin with larvae of a variety of fly species. Furuncular myiasis specifically involves flies whose eggs are able to breach healthy skin, which concerns three species: Cordylobia anthropophaga (also called the African tumbu fly or Cayor worm for the larvae) and Cordylobia rodhaini (the Lund's fly), and Dermatobia hominis (the human botfly).", "ORPHA ID": 591, "Summary": "Epidemiology\nThere is no solid data for the incidence of this tropical disease but the cases reported in Europe occur following visits to affected regions (Latin America, Sub-Saharan Africa) or in association with animal importation. The disease is probably underdiagnosed and its incidence underestimated.\nClinical description\nFuruncular myiasis only occur on healthy skin. The lesion looks like a bacterial furuncle. However, the head of the larva can be spotted through the central cavity. The patient often reports an intense pain and a feeling of creeping in his skin. The lesion occurs on uncovered areas (lower and upper limbs, head and neck mostly), usually during the rainy season. Infection becomes obvious within 10 to 15 days with the formation of a pseudo-furuncle or emergence of a maggot.\nEtiology\nFuruncular myiasis can be observed in most countries of Africa and South America, and is not uncommon among international travelers. In the case of Cordylobia anthropophaga and Cordylobia rodhaini, the females lay their eggs on damp fabric or on the ground. The larvae penetrate the skin following contact with the ground or with non-ironed contaminated fabric. Dermatobia hominis is found in Latin America. The egg is laid by the fly under the abdomen of a mosquito, through a phoresis process. The egg is then inoculated to a human during a mosquito bite. Poverty, lack of hygiene and proximity with animals are risk factors. Though primarily affecting low-resources populations in hot humid areas, the disease can also happen in wealthy individuals during outdoor activities in endemic countries.\nDiagnostic methods\nThe diagnosis relies on clinical examination. Ultrasound is rarely performed but can be useful in referral centers.\nDifferential diagnosis\nDifferential diagnosis includes furunculosis, abscess, insect bite, prurigo, cutaneous cyst and tungiasis.\nManagement and treatment\nThe treatment relies on manual extraction of the larva. It can be achieved by pressing around the lesions with two or four fingers. A punch biopsy can be used if the manual extraction is impossible. When available, intravenous ivermectin can be injected in the lesion cavity to kill the larva and make the extraction easier. Oral ivermectin is not useful. The larva should be extracted as a whole in order to leave no foreign body in the skin. Antibiotics should be used only in case of clinical secondary infection. Tetanus immunization status should be checked.\nPrognosis\nThe condition is not life-threatening and easily treated.\n\n                            Last update: \n                            June 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Romain BLAIZOT"}
{"Disease Name": "Fusariosis", "Disease Definition": "Fusariosis describes a superficial, locally invasive, disseminated infection with the pathogenic fungus species, Fusarium, often found in soil and water, which is mainly transmitted to humans through traumatic inoculation and that manifests with keratitis, onychomycosis and less frequently peritonitis and cellulitis. In the immunocompromised, disseminated fusariosis is more common and it manifests with refractory fever, skin lesions (ecthyma-like, target, and multiple subcutaneous nodules), severe myalgias and sino-pulmonary infections.", "ORPHA ID": 228119, "Summary": ""}
{"Disease Name": "Fused mandibular incisors", "Disease Definition": "Fused manidbular incisors is an extremely rare dental anomaly that is characterized by the union of two, normally separated, incisor tooth germs of the primary dentition. It is frequently associated with hypodontia (see this term) and an increased risk of pulp exposure.", "ORPHA ID": 2287, "Summary": ""}
{"Disease Name": "Gabriele-de Vries syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by variable developmental delay and intellectual disability, movement disorder or gait abnormalities, and dysmorphic craniofacial features (such as facial asymmetry, broad forehead, posteriorly rotated ears, thick lower lip, micrognathia, or cleft palate). A variety of congenital malformations have been reported in addition, including ocular, renal, cardiac, and joint anomalies, among others. Some patients show behavioral alterations (autism, hyperactivity, or anxiety).", "ORPHA ID": 506358, "Summary": ""}
{"Disease Name": "Gaisböck syndrome", "Disease Definition": "Gaisbock syndrome is characterised by secondary polycythemia.", "ORPHA ID": 90041, "Summary": "Epidemiology\nIt occurs mainly in male sedentary individuals, on a high-calorie diet. Prevalence is unknown.\nClinical description\nThe clinical picture includes mild obesity, hypertension and decrease in plasma volume with relative increase in hematocrit, blood viscosity, serum cholesterol, triglycerides and uric acid. The reduction in plasma volume seems related to the elevation of the diastolic blood pressure.\nPrognosis\nPrognosis is impaired by the development of cardiovascular complications.\n\n                            Last update: \n                            December 2007"}
{"Disease Name": "Galactokinase deficiency", "Disease Definition": "A rare mild form of galactosemia characterized by early onset of cataract and an absence of the usual signs of classic galactosemia, i.e. feeding difficulties, poor weight gain and growth, lethargy, and jaundice.", "ORPHA ID": 79237, "Summary": "Epidemiology\nPrevalence of this form of galactosemia is not known but is estimated to be less than 1/ 100,000.\nClinical description\nPatients with galactokinase deficiency generally have elevated plasma galactose and increased urinary excretion of galactitol. They develop cataracts during the first weeks or months of life as a result of accumulation of galactitol in the lens. Patients are otherwise healthy.\nEtiology\nGalactokinase deficiency is caused by mutations in the GALK1 gene (17q24) coding for the galactokinase enzyme.\nGenetic counseling\nThe disorder is inherited in an autosomal recessive manner.\nPrognosis\nDevelopment of cataracts appears to be fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Pr M.E. [Estela] RUBIO-GOZALBO"}
{"Disease Name": "Galactose epimerase deficiency", "Disease Definition": "A very rare, moderate to severe form of galactosemia characterized by moderate to severe signs of impaired galactose metabolism.", "ORPHA ID": 79238, "Summary": "Epidemiology\nOverall prevalence is not known but the disorder is thought to be very rare. Annual incidence is not known.\nClinical description\nThe disorder represents a continuum from peripheral to generalized states with corresponding disease severity. When ingesting breast milk or lactose-containing formula, patients may develop hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, splenomegaly, liver disorders, aminoaciduria, impaired growth, cataracts and cognitive deficiency. In severe cases, the disease can be life-threatening.\nEtiology\nGalactose epimerase deficiency is caused by mutations in the GALE gene (1p36) encoding the UDP-galactose 4-epimerase enzyme.\nGenetic counseling\nGalactose epimerase deficiency is inherited in an autosomal recessive manner.\nPrognosis\nOccurrence of these symptoms can be resolved or prevented by implementing a galactose-restricted diet.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Pr M.E. [Estela] RUBIO-GOZALBO"}
{"Disease Name": "Galactose mutarotase deficiency", "Disease Definition": "A rare disorder of galactose metabolism characterized by persistent congenital galactosemia due to deficiency of the enzyme galactose mutarotase. Patients may present bilateral cataract, while gastrointestinal symptoms or severe liver dysfunction are absent. The natural history of the disease is unknown. Severe complications, such as neurological symptoms, have not been reported under early treatment with a galactose-restricted diet.", "ORPHA ID": 570422, "Summary": ""}
{"Disease Name": "Galactosemia", "Disease Definition": "Galactosemia is a group of rare genetic metabolic disorders characterized by impaired galactose metabolism resulting in a range of variable manifestations encompassing a severe, life-threatening disease (classic galactosemia), a rare mild form (galactokinase deficiency) causing cataract, and a very rare form with variable severity (galactose epimerase deficiency) resembling classic galactosemia in the severe form (see these terms).", "ORPHA ID": 352, "Summary": "Epidemiology\nOverall prevalence is unknown. The annual incidence of classic galactosemia is estimated to be between 1/40,000 and 1/60,000 in Western countries. Incidence appears to be variable in other ethnic groups with a higher rate reported in the Irish Traveler population possibly due to consanguinity.\nClinical description\nInfants usually develop feeding difficulties, poor weight gain and growth, lethargy, and jaundice in the common severe form of the disorder, i.e. classic galactosemia. The rare, less severe clinical subtype of galactosemia (galactokinase deficiency) causes primarily cataracts while other signs of galactosemia are absent. The very rare subtype (galactose epimerase deficiency) has a variable clinical picture including the usual signs of galactosemia (hypotonia, poor feeding, vomiting, weight loss, jaundice) and complications such as impaired growth, cognitive deficit and cataracts.\nEtiology\nThe different galactosemia types are caused by mutations in the GALT, GALK1, and  GALE genes (9p13, 17q24, 1p36) coding for the three enzymes essential in galactose metabolism resulting in impairment of the Leloir galactose degradation metabolic pathway. All three diseases follow an autosomal recessive pattern of inheritance.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Pr M.E. [Estela] RUBIO-GOZALBO"}
{"Disease Name": "Galactosialidosis", "Disease Definition": "Galactosialidosis is a lysosomal storage disease characterized by coarse facial features, macular ''cherry red spot'', and dysostosis multiplex. Clinical presentation can be heterogenous ranging from a severe, early-onset, rapidly progressive infantile form to late onset, slowly progressive juvenile/adult form.", "ORPHA ID": 351, "Summary": ""}
{"Disease Name": "Gallbladder neuroendocrine tumor", "Disease Definition": "A rare, very aggressive neuroendocrine neoplasm characterized by the presence of nodular mass(es) arising from the neck, fundus or body of the gallbladder or by diffuse thickening of the gallbladder wall. Patients may be asymptomatic (diagnosed incidentally after surgical resection of the gallbladder) or may present epigastric pain, abdominal mass and/or non-specific symptoms, such as nausea, jaundice, flushing, cough, wheezing, ascites, and anepithymia. Paraneoplastic syndromes, such as Cushing syndrome, hypercalcemia, acanthosis nigricans, bullous pemphigoid, dermatomyositis and the Leser-Trélat sign, may be associated.", "ORPHA ID": 100086, "Summary": ""}
{"Disease Name": "Galloway-Mowat syndrome", "Disease Definition": "A rare, genetic multisystem disorder characterized by a neurodegenerative disorder associating global developmental delay, progressive microcephaly, and progressive cerebral and cerebellar atrophy with extrapyramidal involvement, progressive optic atrophy, and in many patients early-onset steroid-resistant nephrotic syndrome.", "ORPHA ID": 2065, "Summary": "Epidemiology\nMore than 100 cases have been reported to date. Males and females are equally affected.\nClinical description\nDisease onset is typically within the first few months of life, but may be detected in childhood with later onset nephrotic syndrome (NS). Clinical manifestations, primarily involving the kidney and central nervous system, are heterogeneous. Renal manifestations range from isolated proteinuria to full blown early-onset nephrotic syndrome (NS), which is multidrug resistant and rapidly progresses to end-stage kidney disease (ESKD). Neurodegenerative manifestations include progressive microcephaly of prenatal or postnatal onset, global development delay and often severe intellectual disability (most patients never reach independent ambulation and are not verbal) and, more variably, epilepsy, hypotonia, ataxia, spasticity and extrapyramidal dystonia. Structural brain abnormalities are variable and include neural migration defects (lissencephaly-pachygyria spectrum), cerebellar and cortical atrophy, ventricular dilation, encephalomalacia, porencephaly, leukomalacia, generalized hypomyelination, and/or thin corpus callosum. Dysmorphic features include short stature, facial dysmorphism (including a high, narrow forehead, hypertelorism, almond-shape eyes, large and low set ears, and micrognathia) and more variably arachnodactyly, camptodactyly and clasp thumb. Additional frequent features include hiatus hernia and ocular abnormalities (progressive optic atrophy, nystagmus and strabismus).\nEtiology\nGalloway-Mowat is a genetically heterogeneous condition with causative mutations in at least seven genes, four of which code subunits of Kinase, Endopeptidase and Other Proteins of small Size (KEOPS) complex. The most common form is associated with variations in OSGEP (14q11), are associated with early onset NS (median age 3 months). Whereas, mutations in WDR73 (15q25.2), encoding WD repeat-containing protein 73, or NUP107 (12q15), encoding Nuclear pore complex protein Nup107, are typically associated with a later onset NS.\nDiagnostic methods\nThe coexistence of albuminuria and CNS abnormalities, or of CNS anomalies and functional visual impairment in infants and children is suggestive of the diagnosis. Molecular analysis may confirm the diagnosis.\nDifferential diagnosis\nThe main differential diagnoses include Pierson syndrome, ARHGDIA mutations, coenzyme Q deficiency, other mitochondrial disorders, sialidosis and congenital disorders of glycosylation. In patients with no renal involvement at the time of assessment, differential diagnosis extend to syndromes with progressive microcephaly (including those of prenatal onset) and CNS malformations such as the complex cortical dysplasias with other brain malformations (which encompass among others several dominant syndromes causes by mutation in the tubulin genes).\nAntenatal diagnosis\nThe occurrence of microcephaly and intra-uterine growth retardation with oligohydramnios in late second trimester suggests the diagnosis and fetal MRI is recommended as further investigation. In cases with an identified causative mutation, prenatal diagnosis can be offered to the family.\nGenetic counseling\nThe pattern of inheritance is either X-linked (LAGE3) with a 50% risk of recurrence in male siblings of a carrier mother, or autosomal recessive with a 25% risk of recurrence in both male and female siblings.\nManagement and treatment\nThere is no specific treatment available. Epilepsy may be intractable. The nephrotic syndrome does not respond to either steroid or immunosuppressive therapy. Renal transplant may be considered for ESKD. Multidisciplinary approach is encouraged to offer a global symptomatic care.\nPrognosis\nThe prognosis is poor; children with early-onset NS typically die during the first year of life due to ESKD. Longer survival is reported for children with later onset NS.\n\n                            Last update: \n                            May 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Laurence HEIDET | ERKNet* - Pr Alain VERLOES | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Gamma-aminobutyric acid transaminase deficiency", "Disease Definition": "A rare disorder of gamma-aminobutyric acid (GABA) metabolism characterized by a severe neonatal-infantile epileptic encephalopathy (manifesting with symptoms such as seizures, hypotonia, hyperreflexia and developmental delay) and growth acceleration.", "ORPHA ID": 2066, "Summary": "Epidemiology\nFive patients from three affected families have been reported in the literature to date.\nClinical description\nOnset occurs in the neonatal/infantile period. Manifestations reported include hypotonia, impaired psychomotor development, hyperreflexia, lethargy, seizures, high-pitched cry, accelerated linear growth and developmental delay. The phenotype of GABA-T deficiency is more severe than what is seen in succinic semialdehyde dehydrogenase (SSADH) deficiency (see this term), although some patients have survived infancy but with severe neurodevelopmental impairment including myoclonic seizures and choreoathetosis.\nEtiology\nGABA-T deficiency is caused by a mutation in the ABAT gene (16p13.2) encoding mitochondrial 4-aminobutyrate aminotransferase (GABA-T). GABA-T is responsible for catalyzing the conversion of gamma-aminobutyrate to succinate semialdehyde in the GABA metabolic pathway. A mutation in this gene leads to an increased accumulation of GABA in central nervous tissue, leading to encephalopathy.\nGenetic counseling\nGABA-T deficiency is inherited in an autosomal recessive manner.\n\n                            Last update: \n                            February 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Mahsa PARVIZ  - Dr Phillip PEARL"}
{"Disease Name": "Gamma-glutamyl transpeptidase deficiency", "Disease Definition": "A disorder that is characterized by increased glutathione concentration in the plasma and urine.", "ORPHA ID": 33573, "Summary": "Epidemiology\nGamma-glutamyl transpeptidase deficiency has been detected in seven patients in five families worldwide.\nClinical description\nFive of the patients also had central nervous system involvement.\nEtiology\nGamma-glutamyl transpeptidase catalyses the first step in the degradation of glutathione. No mutations have been identified in patients with gamma-glutamyl transpeptidase deficiency.\nDiagnostic methods\nThe diagnosis is based on the finding of glutathionuria, elevated levels of glutathione in plasma and decreased activity of gamma-glutamyl transpeptidase in nucleated cells.\nGenetic counseling\nAs the disease is transmitted as an autosomal recessive trait, patients should be offered genetic counseling.\nManagement and treatment\nNo specific treatment has been proposed or tested.\nPrognosis\nThe prognosis of gamma-glutamyl transpeptidase deficiency is hard to predict as only seven patients have been described worldwide.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Agne LARSSON  - Dr Ellinor RISTOFF"}
{"Disease Name": "Gamma-heavy chain disease", "Disease Definition": "A type of HCD characterized by the production of incomplete monoclonal gamma-heavy chains without associated light chains. The clinical presentation most commonly resembles that of patients with systemic lymphoproliferative/autoimmune diseases.", "ORPHA ID": 100026, "Summary": "Epidemiology\nThe prevalence is unknown. There have only been about 120 cases reported in the worldwide literature but this condition is thought to be under-diagnosed.\nClinical description\nDisease onset usually occurs between the ages of 40 and 90 years but the disease has also been seen in younger persons. Disseminated lymphoproliferative disease with lymphadenopathy, splenomegaly and hepatomegaly is the most common feature of gamma-HCD. Localized lymphoproliferative disease may be extramedullary (commonly cutaneous involvement) or may be located exclusively in the bone marrow. In other patients the disease can present with no apparent proliferative lymphoplasmacytic disease but instead an underlying autoimmune disorder such as rheumatoid arthritis, autoimmune hemolytic anemia or thrombocytopenic purpura (see these terms).\nEtiology\nThe cause of gamma-HCD is unknown.\nDiagnostic methods\nThe diagnosis of gamma-HCD is based on identification of free gamma-chains without associated light chains by immunofixation of serum and a concentrated urine specimen by using specific antisera. Patients presenting with a lymphoplasma-cell proliferative disorder should be evaluated for gamma-HCD. Immunofixation of serum and urine should be performed on patients with atypical lymphoplasma-cell proliferative disorders.\nManagement and treatment\nBecause gamma-HCD is a heterogenous condition, the choice of therapy should rely on the underlying disorder. In an asymptomatic patient with minimal lymphoid proliferation no treatment is recommended. Any associated autoimmune disease should be managed with standard therapy without taking into account the existence of the abnormal monoclonal component. Melphalan and prednisone are used if proliferation is mainly plasmacytic. Chlorambucil, cyclophosphamide and vincristine may be beneficial if there is evidence of a progressive lymphoproliferative process. Radiation therapy and surgical removal of extramedullary plasmacytomas can be curative in some cases.\nPrognosis\nGamma-HCD has a highly variable clinical course and ranges from an asymptomatic, benign, or transient process to a rapidly progressive neoplasm leading to a very poor prognosis.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Robert KYLE  - Dr Dietlind WAHNER-ROEDLER"}
{"Disease Name": "Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5", "Disease Definition": "A subtype of autosomal recessive limb-girdle muscular dystrophy characterized by a childhood onset of progressive shoulder and pelvic girdle muscle weakness and atrophy frequently associated with calf hypertrophy, diaphragmatic weakness, and/or variable cardiac abnormalities. Mild to moderate elevated serum creatine kinase levels and positive Gowers sign are reported.", "ORPHA ID": 353, "Summary": ""}
{"Disease Name": "Gangliocytoma", "Disease Definition": "A rare, mixed neuronal-glial tumor characterized by slow growth and irregular arrangement of neoplastic ganglion cells (large, multipolar dysplastic neurons) within stroma composed of non-neoplastic glial elements. Most commonly it occurs in temporal lobe, but it can be located throughout central nervous system. Clinical manifestations vary depending on the location and include seizures, increased intracranial pressure, cerebellar signs and focal neurologic deficits. Memory disturbances, cranial nerve palsies and psychiatric symptoms have also been reported.", "ORPHA ID": 251937, "Summary": ""}
{"Disease Name": "Ganglioglioma", "Disease Definition": "Ganglioglioma is a rare, usually benign, well-circumscribed, often cystic, mixed neuronal-glial tumor (composed of both neoplastic glial and ganglionic elements) which is typically located in the temporal lobe and rarely invades the surrounding tissue. Patients usually present with seizures refractory to medical treatment. Association with neurofibromatosis type I and tuberous sclerosis has been reported.", "ORPHA ID": 251949, "Summary": ""}
{"Disease Name": "Ganglioneuroblastoma", "Disease Definition": "Ganglioneuroblastoma is a rare type of primitive neuroectodermal tumor (PNET; see this term), affecting almost exclusively infants and young children under the age of 10, usually occurring in the posterior mediastinum, adrenal medulla and extra-adrenal retroperitoneum (but sometimes in the neck and pelvis), with metastasis most often presenting in the bones, and characterized clinically by pain, stridor, shortness of breath, peripheral neurological signs, superior vena cava syndrome and congenital Horner syndrome (see this term), depending on the location of the tumor.", "ORPHA ID": 251877, "Summary": ""}
{"Disease Name": "Ganglioneuroma", "Disease Definition": "Ganglioneuroma is a rare tumor of neuroepithelial tissue, a benign and well-differentiated tumor of neural crest origin, arising from the sympathetic nervous system and composed of ganglion cells and stromal Schwann cells. It can arise anywhere from the base of the skull to the pelvis, with the most frequent locations being the adrenal glands, retroperitoneum, posterior mediastinum and the pelvis, or, in rare cases, the central nervous system, heart, bones, intestine or other sites. It may be asymptomatic or present with various symptoms due to mass effect. Association with neurofibromatosis type I, multiple endocrine neoplasia type 2B and Turner syndrome was reported.", "ORPHA ID": 251992, "Summary": ""}
{"Disease Name": "GAPO syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies syndrome characterized by growth retardation, alopecia, pseudoanodontia and ocular manifestations.", "ORPHA ID": 2067, "Summary": "Epidemiology\nApproximately 60 patients with GAPO syndrome have been reported in literature since the first description in 1947.\nClinical description\nPatients have a short stature, growth retardation and a typical facies with high and bossing forehead, hypertelorism, puffy eyelids, midfacial hypoplasia, depressed nasal bridge, anteverted wide nostrils, thick and everted lower lip, micrognathia, protruding, low-set and folded ears, and premature aging appearance mainly due to redundant hyperelastic skin with unusual wrinkles. Scalp hair may be primarily present but disappears after the first months of life resulting in complete or partial alopecia. Eyebrows and/or eyelashes are sparse or in some cases absent. Primary and permanent teeth are formed but fail to erupt. Ocular manifestations may include progressive optic atrophy, glaucoma, strabismus, photophobia, megalocornea, myelinated retinal nerve fiber layer, bilateral keratoconus, nystagmus and ptosis. Otorhinolaryngological features are choanal atresia, deafness and presence of flaccid and pulsatile masses with an audible murmur in the mastoid area associated with dilated and tortuous scalp veins. Patients have a mild intellectual deficit. Some patients have also been reported with umbilical hernia, hyperextensible joints, osseous anomalies (congenital dislocation of hips or delayed bone age) and cutaneous manifestations (hemangioma or depigmented areas). Other manifestations include intracranial hypertension in infancy, hypothyroidism, mitral valve dysfunction or cardiomyopathy, pulmonary diseases, headache, hepatomegaly, renal impairment and altered gonadal functions (irregular periods or amenorrhea, oligoasthenospermia). Cryptorchidism, ankyloglossia and hearing loss is also reported.\nEtiology\nHomozygous nonsense or splicing mutations in the ANTXR1 gene (2p13.3), encoding anthrax toxin receptor 1, also known as tumor endothelial marker 8 (TEM8) causes GAPO Syndrome.\nDiagnostic methods\nDiagnosis mostly relies on physical and ophtamologic examination. Additionally skin biopsy, cerebral angiography and magnetic resonance imaging contribute to more specific diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes cerebral alterations and cutaneous manifestations such as prominent cortical veins, occluded or absent left transverse sinus and left sigmoid sinus, agenesis of left jugular vein, prominent scalp veins, dermis anomalies including amorphous hyaline substance, and pyoderma vegetans.\nAntenatal diagnosis\nPrenatal diagnosis is not possible from fetal ultrasound (US). In utero growth retardation may be observed on US but is not specific.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of that the risk of having an affected child at each pregnancy is 25%.\nManagement and treatment\nThere is no curative treatment. Management mostly relies on ophthalmologic surveillance and symptomatic treatment of the multiple health problems.\nPrognosis\nGAPO patients are reported to have a reduced lifespan (until the fourth to sixth decade of life).\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Márcia Maria CASTANHOLE-NUNES  - Dr Ana Lívia GALBIATTI-DIAS  - Pr Eny Maria GOLONI-BERTOLLO  - Dr Érika Cristina PAVARINO"}
{"Disease Name": "Gardner syndrome", "Disease Definition": "Gardner syndrome is a severe form of familial adenomatous polyposis characterized by multiple adenomas in the colon and rectum associated with prominent extracolonic features including osteomas and multiple skin and soft tissue tumors.", "ORPHA ID": 79665, "Summary": ""}
{"Disease Name": "Gastric adenocarcinoma and proximal polyposis of the stomach", "Disease Definition": "Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare hereditary gastric cancer characterized by proximal gastric polyposis and increased risk of early-onset, intestinal-type adenocarcinoma of the gastric body, with no duodenal or colorectal polyposis.", "ORPHA ID": 314022, "Summary": ""}
{"Disease Name": "Gastric linitis plastica", "Disease Definition": "Gastric linitis plastica (gastric LP) is a malignant, diffuse, infiltrative gastric adenocarcinoma.", "ORPHA ID": 36273, "Summary": "Epidemiology\nGastric LP accounts for about 10% of all gastric cancers but the exact prevalence in the general population is unknown. Gastric LP predominantly affects individuals of Asian origin (Korean, Chinese, Taiwanese and Japanese populations) but it is becoming more frequent in Europe. Females are slightly more frequently affected than males.\nClinical description\nThe age of onset is lower than that of classical gastric carcinoma, with onset frequently before 40 years of age, sometimes in very young patients (20 to 25 years of age). Signs and symptoms are nonspecific: satiety, nausea and vomiting, epigastric pain, and weight loss. Patients may present progressive dysphagia. Gastric LP is characterized by malignant glandular proliferation of independent cells (signet-ring cells) in the fibrous stroma leading to thickening and rigidity of the gastric wall. The most common sites of gastric LP are the antral and pyloric regions. Unlike other stomach cancers, gastric LP frequently extends into the peritoneum and lymphatic system. Gastric LP may be primary or occur secondary to infiltrating lobular carcinoma of the breast.\nEtiology\nLP is generally a sporadic disease but familial cases have been described. Etiology is unknown. The PSCA gene, that appears to be involved in regulating gastric epithelial cell proliferation, may be a susceptibility gene for diffuse-type gastric cancers. Mutations in E-cadherin gene (CDH1, 16q22.1) were detected in several affected members from one family with gastric LP.\nDiagnostic methods\nDiagnosis is often problematic as the gastric mucosa is frequently spared from malignant invasion. It requires morphologic studies revealing an infiltrating stomach tumor, and is based on histopathologic findings including signet-ring cells and a fibrous stroma. Multiple endoscopic biopsies are needed. Endoscopic ultrasonography shows a thickening of the submucosal layer of the tumoral wall (up to 10 to 20 mm). CT scan and endoscopic ultrasound may be useful for the diagnosis and for evaluation of local extension.\nDifferential diagnosis\nThe differential diagnosis should include malignant diseases (adenocarcinoma and lymphoma) and some benign diseases with thickening of the gastric wall (Menetrier's disease, lymphoid hyperplasia and amyloidosis; see these terms).\nManagement and treatment\nTreatment options include surgical resection (mainly total gastrectomy) for localized disease. However, surgery with curative intent is possible in only 20% to 25% of cases due to the very high incidence of peritoneal and distant lymph node involvement. In these cases, chemotherapy provides the only alternative treatment but its efficacy is often limited in this form of cancer. The beneficial effects of adjuvant radiochemotherapy after complete excision of the primary tumour seem to be less pronounced for gastric LP than those observed for the classical form of gastric adenocarcinoma.\nPrognosis\nGastric LP has a very poor prognosis due to the frequent occurrence of peritoneal dissemination, lymphatic invasion and extension toward neighboring organs. The 5-year survival rate is around 10-20% in Japan and Europe.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Michel DUCREUX"}
{"Disease Name": "Gastrocutaneous syndrome", "Disease Definition": "A rare, syndromic, hyperpigmentation of the skin characterized by multiple lentigines and café-au-lait spots associated with hiatal hernia and peptic ulcer, hypertelorism and myopia. There have been no further descriptions in the literature since 1982.", "ORPHA ID": 2069, "Summary": ""}
{"Disease Name": "Gastrointestinal stromal tumor", "Disease Definition": "Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal (GI) tract, typically presenting in adults over the age of 40 (mean age 63), and only rarely in children, in various regions of the GI tract, most commonly the stomach or small intestine but also less commonly in the esophagus, appendix, rectum and colon. GISTs can be asymptomatic or present with various non-specific signs, depending on the location and size of tumor, such as loss of appetite, anemia, weight loss, fatigue, abdominal discomfort or fullness, nausea, vomiting, as well as an abdominal mass, blood in stool, and intestinal obstruction. GISTs can also be seen in familial syndromes such as Carney triad and neurofibromatosis type 1.", "ORPHA ID": 44890, "Summary": ""}
{"Disease Name": "Gastroschisis", "Disease Definition": "A rare abdominal wall malformation characterized by the bowel protruding from the fetal abdomen on the right lateral base of the umbilical cord, and without a covering sac.", "ORPHA ID": 2368, "Summary": "Epidemiology\nIn Europe, the average recorded prevalence of gastroschisis is 1/6,000 births with an increasing trend.\nClinical description\nThe disorder occurs around the tenth week of gestation, and results in bowel protruding, without a covering sac. If the defect is large enough, other viscera (stomach, bladder and gonads) might be exteriorized in some cases by the end of gestation. The liver always remains intra-abdominal. Intestinal damage, bowel atresia and even bowel perforation may occur as a result from the primary defect. When the hernia ring is tight or decreasing in size, necrosis or progressive ischemia of the protruding intestines may be observed, resulting in some cases with poorer prognosis. Intestinal lesions are linked to the quality of the mesenteric vascularization more than to the contact between intestinal loops and amniotic fluid. Other malformations are only exceptionally associated.\nEtiology\nGastroschisis is believed to be a defect of the umbilical cord and ring, but the exact etiology remains unknown. Maternal age ( less than 20 years old) and maternal exposure to cigarette smoke could be risk factors. Genetic mutations and maternal genitourinary tract infections have been associated with an increased risk, but the exact pathological mechanisms remain elusive. Few familial cases have been reported.\nDiagnostic methods\nDiagnosis is usually made before birth during prenatal ultrasound (US) in the first trimester, allowing the birth to be arranged in a specialized unit where surgery can be performed immediately and intensive neonatal support is available.\nDifferential diagnosis\nThe only differential diagnosis is omphalocele which is more frequent, occurs earlier in embryonic development, and is associated in half of the cases with other malformations.\nAntenatal diagnosis\nPrenatal diagnosis is nowadays made in the first trimester, and relies on the picture of intestinal loops floating freely outside the abdominal cavity, to the right of the cord. Fetal karyotype is not mandatory. Later in gestation, the US scan focuses on fetal growth, amniotic fluid amount, thickness and diameter of both intra and extra abdominal loops.\nManagement and treatment\nGastroschisis is a surgical emergency. Primary abdominal closure is not always possible and different techniques of delayed management may be resorted to. Neonatal nutritional support is paramount. Early delivery is often proposed when intestinal complication is suspected.\nPrognosis\nPrognosis is linked to the functional quality of the intestinal loops, but is excellent in more than 90% of cases.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Sylvie BEAUDOIN"}
{"Disease Name": "GATA2 deficiency spectrum", "Disease Definition": "A rare genetic primary immunodeficiency characterized by profound circulating monocytopenia, B- and NK-cell lymphopenia and severe dentritic cell decrease, which manifests clinically with disseminated mycobacterial and viral infections, as well as opportunistic fungal and parasitic infections and frequent pulmonary alveolar proteinosis. Predisposition to developping myeloid neoplasms is associated.", "ORPHA ID": 228423, "Summary": ""}
{"Disease Name": "Gaucher disease type 1", "Disease Definition": "Gaucher disease type 1 is the chronic non-neurological form of Gaucher disease (GD; see this term) characterized by organomegaly, bone involvement and cytopenia.", "ORPHA ID": 77259, "Summary": "Epidemiology\nIt represents around 90% of all cases of GD with an estimated prevalence of 1/100,000 in the general population.\nClinical description\nAlthough the disease can be diagnosed at any age, half of patients are under the age of 20 at diagnosis. The clinical presentation is heterogeneous with occasional asymptomatic forms. It is characterized by the association of frequent asthenia, growth retardation or delayed puberty, splenomegaly (90% of cases) that may be complicated by splenic infarctions (sometimes superinfected), hepatomegaly (80% of cases) and in rare cases can progress towards fibrosis followed by cirrhosis. Bone anomalies are present in 80% of cases. They manifest as deformations, osteopenia that sometimes causes pathological fractures or vertebral compression, bone infarctions or even aseptic osteonecrosis. Involvement of other organs (rarely symptomatic pulmonary, renal and cardiac involvement) is less common. Pancytopenia is frequent and is associated with various degrees of thrombocytopenia (sometimes severe), anemia and, less frequently, leukoneutropenia. Polyclonal hypergammaglobulinemia is often present and is sometimes complicated by monoclonal gammapathy.\nEtiology\nGD type 1 is a lysosomal storage disease caused by a mutation in the GBA gene (localized to 1q21) that codes for the lysosomal enzyme, glucocerebrosidase. The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramidase (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, of the spleen and the bone marrow (Gaucher cells).\nDiagnostic methods\nDiagnostic methods involve ultrasound and magnetic resonance imaging (MRI) for the initial evaluation and subsequent monitoring of hepatosplenomegaly, radiography and bone scintigraphy to detect bone lesions and complications, osteodensitometry for the evaluation of osteopenia of the lumbar spine and femoral neck, and cardiac ultrasound for the detection of pulmonary arterial hypertension. An increase in certain biological markers, that are important both for the initial diagnosis and monitoring with or without treatment, is also observed: chitotriosidase, angiotensin converting enzyme, ferritin and tartrate-resistant acid phosphatases. Diagnosis can be confirmed by demonstrating a deficit in the enzymatic activity of glucocerebrosidase. In rare cases, genotyping may be of prognostic value: a patient with a homozygous N370S mutation in the GBA gene will not develop neurological disease.\nDifferential diagnosis\nDifferential diagnoses include other lysosomal storage disorders. The presence of Gaucher-like cells can be found in certain hematologic diseases (lymphoma, Hodgkin's lymphoma and chronic lymphocytic leukemia; see these terms).\nGenetic counseling\nThe transmission is autosomal recessive\nManagement and treatment\nThe standard treatment for GD type 1 is enzyme substitution therapy, administered intravenously (e.g.: imiglucerase with European marketing authorization (MA) since 1997 and velaglucerase with a MA since 2010). Substrate reduction therapy (miglustat), administered orally, provides an alternative second-line treatment when enzyme substitution therapy is not suitable. Bisphophonates can also be proposed to prevent bone complications.\nPrognosis\nGD type 1 is not usually life-threatening. The functional prognosis, on the other hand, can be affected by sometimes serious bone complications.\n\n                            Last update: \n                            February 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN"}
{"Disease Name": "Gaucher disease type 2", "Disease Definition": "Gaucher disease type 2 is the acute neurological form of Gaucher disease (GD; see this term). It is characterized by early-onset and severe neurological involvement of the brainstem, associated with an organomegaly and generally leading to death before the age of 2.", "ORPHA ID": 77260, "Summary": "Epidemiology\nThe annual incidence of GD in the general population is around 1/60,000 and the prevalence is approximately 1/100,000. GD type 2 is very rare, with an incidence of approximately 5% of all GD patients and has a prevalence of virtually zero, taking into account its severity and early death.\nClinical description\nThe disease usually presents in infants aged 3 to 6 months with systemic manifestations of hepatosplenomegaly and an early onset and severe neurological syndrome. The first signs are oculomotor paralysis or bilateral fixed strabismus associated with bulbar signs, in particular severe swallowing difficulties, progressive spasticity and dystonic movements. Seizures occur later and manifest as myoclonic epilepsy that is refractory to treatment with antiepileptics.\nEtiology\nGD type 2 is a lysosomal storage disease caused by a mutation in the GBA gene (1q21) that codes for the lysosomal enzyme, glucocerebrosidase. The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramidase (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, of the spleen and the bone marrow (Gaucher cells).\nDiagnostic methods\nA definite diagnosis requires the demonstration of a deficit in the enzymatic activity of glucocerebrosidase.\nAntenatal diagnosis\nBiochemical prenatal diagnosis can be proposed to couples who have already had a child with GD type 2. It can be carried out by measuring the enzyme activity in chorionic villus samples at 10-12 weeks of pregnancy or in amniocytes in culture towards 16 weeks of pregnancy.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nThe treatment does not seem to have an effect on neurological manifestations and is therefore not indicated for patients with GD type 2.\nPrognosis\nPrognosis is poor with most patients dying before the age of 2.\n\n                            Last update: \n                            February 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN"}
{"Disease Name": "Gaucher disease type 3", "Disease Definition": "Gaucher disease type 3 is the subacute neurological form of Gaucher disease (GD; see this term) characterized by progressive encephalopathy and associated with the systemic manifestations (organomegaly, bone involvement, cytopenia) of GD type 1 (see this term).", "ORPHA ID": 77261, "Summary": "Epidemiology\nThe annual incidence of GD is about 1/60,000 and the prevalence is approximately 1/100,000. GD type 3 accounts for 5% of all patients with GD.\nClinical description\nThe clinical presentation is very heterogeneous. Neurological disease appears in childhood or adolescence, a much later onset than in GD type 2 (see this term). Encephalopathy can be the presenting sign of the disease or may occur later in the disease course. Some patients have moderate systemic involvement associated with ophthalmoplegia as the only neurological symptom. For the more severe forms, the neurological signs encountered are variable: supranuclear horizontal ophthalmoplegia, progressive myoclonic epilepsy, cerebellar ataxia, spasticity and dementia. GD type 3 is also associated with the clinical and biological signs of ''systemic'' disease, such as frequent asthenia, growth retardation or delayed puberty, splenomegaly and hepatomegaly. Bone anomalies may also be present and manifest as deformations, osteopenia, which sometimes leads to pathological fractures or vertebral compression, bone infarctions or even aseptic osteonecrosis. Involvement of other organs (rarely symptomatic pulmonary, renal and cardiac) is less common. Pancytopenia is frequent and involves varying degrees of thrombocytopenia (sometimes severe), anemia and, less frequently, leukoneutropenia. Polyclonal hypergammaglobulinemia is often present and is sometimes complicated by monoclonal gammapathy.\nEtiology\nGD type 3 is a lysosomal storage disease caused by a mutation in the GBA gene (1q21) that codes for the lysosomal enzyme, glucocerebrosidase. The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramidase (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, spleen and the bone marrow (Gaucher cells).\nDiagnostic methods\nDiagnostic methods involve ultrasound and magnetic resonance imaging (MRI) for initial evaluation and subsequent monitoring of hepatosplenomegaly, radiography and bone scintigraphy to detect bone lesions and complications, osteodensitometry for the evaluation of osteopenia of the lumbar spine and femoral neck, and cardiac ultrasound for the detection of pulmonary arterial hypertension. An increase in certain biological markers that are important both for the initial diagnosis and monitoring with or without treatment, is also observed: chitotriosidase, an angiotensin converting enzyme, ferritin and tartrate-resistant acid phosphatases. Diagnosis can be confirmed by demonstrating a deficit in the enzymatic activity of glucocerebrosidase in circulating leukocytes. In rare cases, genotyping may be of prognostic value: a patient with a homozygous L444P mutation in the GBA gene has a very high risk of developing neurological disease.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nThe treatment for patients with GD type 3 exhibiting clinically significant non neurological manifestations is enzyme substitution therapy (imiglucerase with marketing authorization (MA) since 1997). It appears to slow progression of the neurological symptoms and is effective against the systemic manifestations.\nPrognosis\nIn the absence of treatment, clinical progression leads to death within a few years.\n\n                            Last update: \n                            February 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN"}
{"Disease Name": "Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome", "Disease Definition": "Gaucher disease - ophthalmoplegia - cardiovascular calcification is a variant of Gaucher disease, also known as a Gaucher-like disease that is characterized by cardiac involvement.", "ORPHA ID": 2072, "Summary": "Epidemiology\nThis syndrome is rare with less than 30 cases reported in the literature.\nClinical description\nThe principle manifestation is progressive calcification of the aorta, and of the aortic and/or mitral valves. Other common features include mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia.\nEtiology\nThe disease is caused by homozygous D409H (1342G to C) mutations in the GBA gene (1q21) that encodes the lysosomal membrane-associated glycoprotein, glucosylceramidase. The enzyme deficiency resulting from the mutation leads to accumulation of glucosylceramide (GL1) and other glycolipids in the cells of the reticuloendothelial system.\nDiagnostic methods\nThe diagnosis can be made by measuring glucosylceramidaseactivity and is confirmed by identification of the D409H GBA gene mutation.\nAntenatal diagnosis\nPrenatal diagnosis is possible through detection of the glucosylceramidase deficiency in amniocytes or chorionic villus samples, or through screening for the GBA gene mutation in families in which the D409H allele has been identified in both parents or an affected brother or sister.\nGenetic counseling\nThe syndrome is transmitted in an autosomal recessive manner.\nManagement and treatment\nPatients with this syndrome require close monitoring by echocardiography as the cardiac complications require aortic and mitral valve replacement. Enzyme substitution therapy, involving regular intravenous infusions of the recombinant glucosylceramidase enzyme, imiglucerase, has been used successfully in the treatment of this disorder following surgery.\nPrognosis\nThe prognosis for patients depends on the outcome of the heart surgery.\n\n                            Last update: \n                            February 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN"}
{"Disease Name": "Gaucher disease", "Disease Definition": "Gaucher disease (GD) is a lysosomal storage disorder encompassing three main forms (types 1, 2 and 3), a fetal form and a variant with cardiac involvement (Gaucher disease - ophthalmoplegia - cardiovascular calcification or Gaucher-like disease).", "ORPHA ID": 355, "Summary": "Epidemiology\nThe prevalence is approximately 1/100,000. The annual incidence of GD in the general population is about 1/60,000, but it can reach up to 1/1,000 in Ashkenazi Jewish populations.\nClinical description\nThe clinical manifestations of this disease are highly variable. GD type 1 (90% of cases) is the chronic and non-neurological form associated with organomegaly (spleen, liver), bone anomalies (pain, osteonecrosis, pathological fractures) and cytopenia. Type 2, the acute neurological form, is characterized by early onset, rapidly progressing brainstem dysfunction, associated with organomegaly and leading to death before the age of 2. Type 3, the subacute neurological form, affects children or adolescents and is characterized by progressive encephalopathy (oculomotor apraxia, epilepsy and ataxia) with the systemic manifestations seen in type 1. The fetal form manifests with a decrease or absence of fetal movements or anasarca. Gaucher-like disease presents with progressive calcification of the aorta and the aortic and/ or mitral valves as its main feature.\nEtiology\nGD is due to mutations in the GBA gene (1q21) that codes for a lysosomal enzyme, glucocerebrosidase, or in very rare cases the PSAP gene that codes for its activator protein (saposin C). The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramide (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, the spleen and the bone marrow (Gaucher cells).\nDiagnostic methods\nFormal diagnosis of the disease is determined by the measurement of glucocerebrosidase levels in circulating leukocytes. Genotyping confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other lysosomal storage disorders. The presence of Gaucher-like cells can be found in certain hematologic diseases (lymphoma, Hodgkin's lymphoma and chronic lymphocytic leukemia; see these terms).\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nThere are two available treatments for GD type 1 and 3: enzyme substitution therapy (using imiglucerase or velaglucerase) and substrate reduction therapy (miglustat). These treatments are ineffective for GD type 2.\nPrognosis\nThe prognosis is good in GD type 1. In type 2, death usually occurs before the age of 2. Without specific treatment, GD type 3 progresses to death within a few years.\n\n                            Last update: \n                            February 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN"}
{"Disease Name": "GCGR-related hyperglucagonemia", "Disease Definition": "A rare tumor of pancreas caused by mutations in the GCGR gene characterized by pancreatic alpha cell hyperplasia, pancreatic neuroendocrine tumors and markedly increased serum glucagon levels in the absence of a glucagonoma syndrome. Clinical manifestations may include abdominal pain, pancreatitis, fatigue, diarrhea, and diabetes mellitus.", "ORPHA ID": 438274, "Summary": ""}
{"Disease Name": "Gelatinous drop-like corneal dystrophy", "Disease Definition": "Gelatinous drop-like corneal dystrophy (GDCD) is a form of superficial corneal dystrophy characterized by multiple prominent milky-white gelatinous nodules beneath the corneal epithelium, and marked visual impairment.", "ORPHA ID": 98957, "Summary": "Epidemiology\nWorldwide prevalence of this form of corneal dystrophy is not known. Cases have been reported in patients from India, Tunisia, Vietnam, Turkey, the USA and other countries, but most cases seem to be in Japan where prevalence is estimated to be 1/300,000.\nClinical description\nLesions generally develop in the first or second decade of life. The clinical features include severe photophobia, tearing, a corneal foreign body sensation and severe progressive loss of vision.\nEtiology\nGelatinous drop-like corneal dystrophy is mostly caused by mutations in the TACSTD2 gene (1p32) encoding tumor-associated calcium signal transducer 2. More than 20 mutations have been reported but some patients have been found not to have a mutation in this gene, which suggests genetic heterogeneity.\nDiagnostic methods\nFusiform deposits similar to those in lattice corneal dystrophy (LCD, see this term) in the deeper stroma may be found by light microscopy.\nGenetic counseling\nAn autosomal recessive pattern of inheritance has been reported.\nManagement and treatment\nAn unsatisfactory response has been observed to both lamellar keratoplasty (LKP) and penetrating keratoplasty (PK), as well as to a superficial keratectomy, since amyloid recurs in the graft within about 5 years.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Geleophysic dysplasia", "Disease Definition": "A rare skeletal dysplasia characterized by short stature, prominent abnormalities in hands and feet, and a characteristic facial appearance (described as \"happy'').", "ORPHA ID": 2623, "Summary": "Epidemiology\nFewer than 30 cases have been reported to date.\nClinical description\nThe characteristic facial appearance (''happy'' face) consists in a shortened nose, full cheeks, hypertelorism, long flat philtrum, and a thin upper lip. Additional clinical features include progressive cardiac valvular thickening often leading to an early death, contractions of the gastrocnemius muscle and Achilles tendon leading to tip toe walking, tracheal stenosis, bronchopulmonary insufficiency, and liver enlargement. Radiological manifestations include delayed bone age, cone-shaped epiphyses, shortened long tubular bones and ovoid vertebral bodies.\nEtiology\nMutations have been found in the ADAMTSL2 and FBN1 genes which appear to induce microfibrillar network disorganization and enhanced TGF-beta signaling. FBN1 encodes fibrillin-1 and ADAMTSL2 (Disintegrin And Metalloproteinase with Thrombospondin repeats- like 2) encodes a glycoprotein of unknown function.\nGenetic counseling\nTransmission is autosomal recessive in the cases with ADAMTSL2 gene mutations and autosomal dominant in the cases with FBN1 mutations.\n\n                            Last update: \n                            June 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Valérie CORMIER-DAIRE"}
{"Disease Name": "Gemignani syndrome", "Disease Definition": "Gemignani syndrome is a rare neurodegenerative disease characterized by slowly progressive ataxia, amyotrophy of the hands and distal arms, spastic paraplegia, progressive sensorineural hearing loss, hypogonadism and short stature. Additional features include generalized cerebellar atrophy and peripheral nervous system anomalies. Small cervical spinal cord, intellectual/language disability and localized vitiligo have also been reported. There have been no further descriptions in the literature since 1989.", "ORPHA ID": 2074, "Summary": ""}
{"Disease Name": "Generalized arterial calcification of infancy", "Disease Definition": "A rare genetic vascular disease characterized by early onset (between in utero to infancy) of extensive calcification and stenosis of the large and medium sized arteries. Presentation is typically with respiratory distress, congestive heart failure and systemic hypertension.", "ORPHA ID": 51608, "Summary": "Epidemiology\nApproximately 300 cases have been reported worldwide in the medical literature. The prevalence is unknown; however, based on carrier frequency of the recognized pathogenic variants, the frequency of 1/566,000 has been suggested.\nClinical description\nDisease onset is either early (in utero to within the first week of life) or late (median age three months). Early-onset disease presents variably with fetal distress, heart failure, polyhydramnios, hypertension, respiratory distress, hydrops fetalis, edema, visceral effusions, cyanosis, cardiomegaly, and ascites. Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension, and edema. Additional findings can include extravascular calcifications (particularly periarticular), typical skin and retinal manifestations of pseudoxanthoma elasticum, hearing loss, and development of rickets after infancy. Pathologically, the condition is characterized by deposition of calcium along the internal elastic membrane of arteries, accompanied by fibrous thickening of the intima, which causes luminal narrowing.\nEtiology\nCausal mutations have been identified in the genes ENPP1 (chromosome 6q23.2) and ABCC6 (chromosome 16p13.11) respectively encoding ectonucleotide pyrophosphatase/ phosphodiesterase 1 and multidrug resistance-associated protein 6, a transmembrane protein belonging to the family of ATP-binding cassette (ABC) transport proteins. Pathological variants lead to aberrant tissue mineralization, and the subsequent luminal narrowing invariably leads to coronary arterial occlusion and myocardial ischemia or stenoses of different arteries leading to end-organ damage. ENPP1 mutations also cause autosomal recessive hypophosphatemic rickets, which is associated with longer survival.\nDiagnostic methods\nDiagnosis of is made by the combination of clinical, imaging or histopathological findings, together with genetic results. The preferred imaging modality to assess calcifications extension is whole-body computed tomography combined with CT angiography.\nDifferential diagnosis\nDifferential diagnosis includes endocardial fibroelastosis, myocardititis, storage disorders, infarction, anomalous insertion of the coronary arteries, cardiac anomalies, metastatic calcification due to renal disease, hypervitaminosis D, infections, and non-immune fetal hydrops, Takayasu arteriitis.\nAntenatal diagnosis\nAntenatal diagnosis has been reported, with findings of arterial calcifications, hydrops, abnormal cardiac contractility, and hyperechoic kidneys. The diagnosis is essential for genetic counseling, and for screening of siblings at risk for developing the disease.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. The sibling-recurrence risk is 25%. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.\nManagement and treatment\nUse of bisphosphonates appears to significantly increase survival. Aspirin therapy is warranted in those with severe coronary stenosis who are at increased risk for coronary thrombosis. Anti-hypertensive therapy is warranted for hypertension. Treatment of hypophosphatemic rickets involves calcitriol and oral phosphate supplements. It seems prudent to avoid the use of warfarin if possible. Where endotracheal intubation is required, lateral cervical spine x-ray is recommended to evaluate for cervical spine fusion, and thereby avoid secondary complications.\nPrognosis\nPrognosis is poor; most infants die from myocardial infarction within the first year of life, with the greatest number of deaths occurring within the first six months. Nevertheless, long-term survival into the second and third decade has been reported.\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Yvonne NITSCHKE  - Pr Frank RUTSCH"}
{"Disease Name": "Generalized basaloid follicular hamartoma syndrome", "Disease Definition": "Generalized basaloid follicular hamartoma syndrome is a rare, genetic skin disease characterized by multiple milium-like, comedone-like lesions and skin-colored to hyperpigmented, 1 to 2 mm-sized papules, associated with hypotrichosis and palmar/plantar pits. Lesions are usually first noticed on cheeks or neck and gradually increase in size and number to involve the scalp, face, ears, shoulders, chest, axillas, and upper arms. In severe cases, lower back, lower arms, and back of the legs can be involved. Mild hypohidrosis has also been reported.", "ORPHA ID": 168632, "Summary": ""}
{"Disease Name": "Generalized epilepsy-paroxysmal dyskinesia syndrome", "Disease Definition": "Generalized epilepsy-paroxysmal dyskinesia syndrome is characterised by the association of paroxysmal dyskinesia and generalised epilepsy (usually absence or generalised tonic-clonic seizures) in the same individual or family. The prevalence is unknown. Analysis in one of the reported families led to the identification of a causative mutation in the KCNMA1 gene (chromosome 10q22), encoding the alpha subunit of the BK channel. Transmission is autosomal dominant.", "ORPHA ID": 79137, "Summary": ""}
{"Disease Name": "Generalized eruptive histiocytosis", "Disease Definition": "A rare non-Langerhans cell histiocytosis characterized by rapid onset of crops of asymptomatic small red to brown papules, typically distributed symmetrically over the face, trunk, and proximal extremities, occasionally with mucous membrane involvement. The lesions resolve spontaneously without scarring after a variable time span and do not recur in most cases. Histopathology reveals diffuse, uniform dermal infiltration with non-xanthomatous histiocytes staining positive for CD68 and Ki-M1p. Multinucleate giant cells may occasionally be found.", "ORPHA ID": 157991, "Summary": ""}
{"Disease Name": "Generalized eruptive keratoacanthoma", "Disease Definition": "Generalized eruptive keratoacanthoma (GEKA) is rare variant of keratoacanthoma (KA) that affects the skin and mucous membranes and which is characterized by a sudden generalized eruption of severely pruritic, hundreds to thousands of small follicular papules, often with a central keratotic plug.", "ORPHA ID": 411777, "Summary": ""}
{"Disease Name": "Generalized essential telangiectasia", "Disease Definition": "A rare skin disease characterized by widespread cutaneous telangiectases usually first appearing on the lower limbs and slowly progressing upwards to involve the trunk and arms. The lesions can be diffuse, localized, macular, plaque-like, discrete, or confluent. Recurrent bleeding from the skin and mucous membranes is not a common feature. Likewise, co-existing epidermal or dermal abnormalities, like atrophy, depigmentation, or purpura, are absent. The condition is non-hereditary, and to establish the diagnosis, other primary and secondary telangiectases must be excluded.", "ORPHA ID": 280774, "Summary": ""}
{"Disease Name": "Generalized glucocorticoid resistance syndrome", "Disease Definition": "A rare, adrenogenital syndrome characterized by generalized, partial tissue insensitivity to glucocorticoids leading to variable phenotype, including asymptomatic individuals with only biochemical alterations or patients with ambiguous genitalia at birth in females, hypertension, acne, hirsutism, precocious puberty, male-pattern hair loss, anxiety and depression in both sexes, menstrual irregularities in women, and oligospermia in men.", "ORPHA ID": 786, "Summary": ""}
{"Disease Name": "Generalized peeling skin syndrome", "Disease Definition": "A form of peeling skin syndrome characterized by a generalized distribution. It comprises two sub-types: the non-inflammatory (PSS type A) and the inflammatory (PSS type B) form. PSS type A is characterized by generalized white scaling with superficial non-inflammatory peeling of the skin, while PSS type B is characterized by superficial patchy peeling of the entire skin with underlying erythroderma, pruritus, and atopy.", "ORPHA ID": 263543, "Summary": ""}
{"Disease Name": "Generalized pseudohypoaldosteronism type 1", "Disease Definition": "A severe form of pseudohypoaldosteronism type 1 characterized by salt wasting in multiple organs including the kidney, colon, and sweat and salivary glands. Presentation is in the first few weeks of life with severe dehydration, vomiting and failure to thrive in association with hyponatremia, hyperkalemia and metabolic acidosis as well as elevated aldosterone and renin levels. No remission is reported and patients suffer from recurrent life-threatening episodes of salt loss.", "ORPHA ID": 171876, "Summary": ""}
{"Disease Name": "Generalized pustular psoriasis", "Disease Definition": "Generalized pustular psoriasis is a severe inflammatory skin disease that can be life-threatening and that is characterized by recurrent episodes of high fever, fatigue, episodic erythematous cutaneous eruptions with sterile cutaneous pustules formation on various parts of the body, and neutrophil leukocytosis.", "ORPHA ID": 247353, "Summary": ""}
{"Disease Name": "Genetic epilepsy with febrile seizure plus", "Disease Definition": "Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome in which family members display a seizure disorder from the GEFS+ spectrum which ranges from simple febrile seizures (FS) to the more severe phenotype of myoclonic-astatic epilepsy (MAE) or Dravet syndrome (DS) (see these terms).", "ORPHA ID": 36387, "Summary": "Epidemiology\nPrevalence is unknown but hundreds of cases have been described in the literature.\nClinical description\nPhenotypes in patients can be variable, ranging from simple FS to epileptic encephalopathies including MAE and DS. Disease onset is variable. FS plus (FS+) is the characteristic phenotype seen in most GEFS+ families, described as febrile seizures that persist beyond the age of 6 or that occur with other afebrile seizure types including generalized tonic-clonic seizures, myoclonic, or absence seizures that usually remit by late childhood or early adolescence. Occasional seizures in adulthood are possible. Partial seizure types can also be observed.\nEtiology\nMutations in SCN1A (2q24.3) (most commonly) and SCN1B (19q13.12) have been identified as causal in several families with GEFS+. These genes encode two subunits of the neuronal sodium channel. Other causal mutations include those in the gamma 2 subunit (GABRG2) gene (5q34). SCN2A (2q24.3), SCN9A (2q24), and GABRD (1p36.3) have been suggested as possible susceptibility genes for GEFS+.\nDiagnostic methods\nGEFS+ is diagnosed clinically through the seizure type of the patient and the family history. Molecular genetic testing can confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other genetic epilepsies such as benign familial infantile seizures (due to PRRT2 mutations) or encephalopathy due to GLUT1 deficiency (see these terms) or a sporadic epilepsy caused by injury or infections.\nAntenatal diagnosis\nGiven the broad phenotypic range of known GEFS+ mutations, prenatal diagnosis is usually not performed.\nGenetic counseling\nIn most large families, GEFS+ is inherited in an autosomal dominant manner, often with incomplete penetrance. In other families it follows complex inheritance where several genes or environmental factors are thought to be involved. Genetic counseling is possible in families with a known disease causing mutation. However, precise phenotypes cannot be predicted as wide phenotypic variability is seen within families.\nManagement and treatment\nAs most patients with GEFS+ have a mild phenotype, treatment may not be necessary. Seizure control with antiepileptic drugs is essential in patients with recurrent seizures. The drugs mainly used include valproic acid, benzodiazepines (i.e. clobazam), ethosuximide, levetiracetam and topiramate. Given the relatedness to DS, lamotrigine and phenytoin may not be considered. Temporal lobe surgery resulted in a positive outcome in two patients with GEFS+. Regular follow-up and neuropsychological evaluations are recommended along with electroencephalographic monitoring when a new seizure pattern is suspected. In patients with active epilepsy, activities where a seizure could lead to injury or death should be avoided.\nPrognosis\nThe overall prognosis depends on the exact phenotype within the GEFS+ spectrum. In patients with mild phenotypes (FS, FS+) seizures often remit by adolescence. Patients with more severe phenotypes may require life-long treatment and may have lasting neurocognitive sequelae.\n\n                            Last update: \n                            May 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Ingo HELBIG"}
{"Disease Name": "Genetic hyperferritinemia without iron overload", "Disease Definition": "Genetic hyperferritinemia without iron overload is a rare biological anomaly defined as high serum ferritin levels without elevations of transferrin saturation, tissue or serum iron and characterized by an apparently asymptomatic clinical phenotype.", "ORPHA ID": 254704, "Summary": ""}
{"Disease Name": "Genetic non-syndromic obesity", "Disease Definition": "A rare genetic disease characterized by early-onset severe obesity due to mutations in single genes acting on the development and function of the hypothalamus or the leptin-melanocortin pathway, leading to disruption of energy homeostasis and endocrine dysfunction. Patients present with a body mass index over three standard deviations above normal at less than five years of age, accompanied by a variety of signs and symptoms according to the mutated gene, including hyperphagia, insulin resistance, reduced basal metabolic rate, or hypogonadism, among others.", "ORPHA ID": 98267, "Summary": ""}
{"Disease Name": "Genetic recurrent myoglobinuria", "Disease Definition": "Genetic recurrent myoglobinuria is an inborn error of metabolism characterized by abnormal urinary excretion of myoglobin due to acute destruction of skeletal muscle fibers.", "ORPHA ID": 99845, "Summary": "Epidemiology\nThe exact prevalence remains unknown.\nClinical description\nIn the majority of cases, the disease manifests in childhood and is often triggered by exertion or infection (febrile illness). Hypertonia, muscle stiffness and muscle pain, impaired kidney function and elevated levels of serum creatine kinase are common clinical features.\nEtiology\nMutations in the mitochondrial DNA-encoded cytochrome C oxidase genes (MT-CO1 and MT-CO2) should be considered in patients with recurrent myoglobinuria. Recently, mutations in the LPIN1 gene (chromosome 2p21) have been reported to have a causative role in three patients with recurrent episodes of myoglobinuria, originating from consanguineous families.\nGenetic counseling\nThe disorder may occur sporadically, or be inherited in either a recessive or dominant manner.\n\n                            Last update: \n                            March 2010"}
{"Disease Name": "Genetic steroid-resistant nephrotic syndrome", "Disease Definition": "A rare, hereditary nephrotic syndrome characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia, with an absence of response to an initial trial of corticosteroids (i.e. steroid-resistant nephrotic syndrome; SRNS) and a generally complicated course.", "ORPHA ID": 656, "Summary": "Epidemiology\nThe annual incidence is 1/ 200,000- 500,000 children.\nClinical description\nDisease onset may occur anywhere between birth and adulthood but predominantly presents in younger populations. The nephrotic syndrome is defined by severe proteinuria (Urinary Protein/Creatinine ration > 200 mg/mmol) with low serum albumin (<30 g/l) and possible edema. Biopsy shows minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) or, more rarely, diffuse mesangial sclerosis (DMS), and podocyte foot process effacement by electron microscopy. It is multi-drug resistant and usually progresses to end-stage kidney failure; however, patients have a very low risk of recurrence after kidney transplantation.\nEtiology\nCausative pathogenic variants are identified in approximately 10-15% of young adults presenting with SRNS, 30% of children and at least 66% in congenital and infantile cases. Among these genes, NPHS1 (19q13.12) and NPHS2 (1q25.2) are by far the two main autosomal recessive genes implicated in SRNS while INF2 (14q32.33) and WT1 (11p13) are the leading cause of autosomal dominant SRNS. COQ8B (19q13.2) biallelic variants are commonly found in patients of Asian descent. So far, more than 60 single gene causes of SRNS have been reported, however most novel gene variants are rare and involve few families.\nDiagnostic methods\nComprehensive gene panels to include all currently known SRNS genes; alternatively cascade testing starting with screening for pathogenic variants in NPHS2 and WT1, the most commonly mutated genes in children, can be performed at the initial stage and if negative expanded to large next generation sequencing based test.\nDifferential diagnosis\nA number of hereditary renal disorders might present with persistent proteinuria, the hallmark of SRNS. These include defects in ciliary (eg. TTC21B) or tubular (eg. CLCN5, Dent disease) genes or atypical hemolytical syndrome (DGKE). There is also a number of syndromic (i.e. multiorgan) forms associated with defects in WT1, LMX1B, LAMB2, PAX2, etc.\nAntenatal diagnosis\nThe decision regarding preimplantation genetic diagnosis and prenatal genetic testing should be discussed with the family in light of the local financial, social, and legal settings.\nGenetic counseling\nRecurrence risk counseling should be provided in all cases. Family members who are candidates for living-related kidney donation have to undergo genetic testing as part of evaluation; only heterozygous carriers of a recessive SRNS genetic variant may be considered as a potential donor, while a family member having a variant associated with a dominant inheritance should be dissuaded from kidney donation.\nManagement and treatment\nInternational Pediatric Nephrology Association 2020 guidelines recommend discontinuing ineffective immunosuppressive therapies, and continuing non -immunosuppressive management, including RAASi and other supportive measures in patients with diagnosis of a hereditary nephrotic syndrome. There is high risk of progression to end-stage kidney disease; however, recurrence of the disease in the grafted kidney after transplantation is exceptional.\nPrognosis\nLife expectancy is not dramatically affected in SRNS patients, however individual outcome depends on prompt management and access to specific procedures, i.e. dialysis and kidney transplantation.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Olivia BOYER | ERKNet* - Pr Beata LIPSKA-ZIETKIEWICZ | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Genetic transient congenital hypothyroidism", "Disease Definition": "Genetic transient congenital hypothyroidism is a rare, thyroid disease characterized by a gene mutation induced, temporary deficiency of thyroid hormones at birth, which later reverts to normal with or without replacement therapy in the first few months or years of life.", "ORPHA ID": 226316, "Summary": ""}
{"Disease Name": "Genitopalatocardiac syndrome", "Disease Definition": "A rare, multiple congenital anomalies/dysmorphic syndrome characterized by male, 46,XY gonadal dysgenesis, cleft palate, micrognathia, conotruncal heart defects and unspecific skeletal, brain and kidney anomalies.", "ORPHA ID": 2075, "Summary": ""}
{"Disease Name": "Genitopatellar syndrome", "Disease Definition": "A rare congenital patellar anomaly syndrome characterized by patellar aplasia or hypoplasia associated with microcephaly, characteristic coarse facial features (microcephaly, bitemporal narrowing, large, broad nose with high nasal bridge, prominent cheeks and micro/retrognathia or prognathism), arthrogryposis of the hips and knees, urogenital abnormalities and intellectual deficiency.", "ORPHA ID": 85201, "Summary": ""}
{"Disease Name": "Genochondromatosis type 1", "Disease Definition": "A rare disorder characterized by chondromatosis, typically involving the clavicles, upper end of the humerus, and lower end of the femur. Lesions are bilateral and symmetrical. The clinical course is benign.", "ORPHA ID": 85197, "Summary": ""}
{"Disease Name": "Genochondromatosis type 2", "Disease Definition": "Genochondromatosis type 2 is a rare genetic bone development disorder characterized by normal clavicles and symmetrical, generalized metaphyseal enchondromas, particularly in the distal femur, proximal humerus, and bones of the wrists, hands, and feet. Lesions regress later in life with growth cartilage obliteration. Clinical examination is normal and the course of the disease is benign.", "ORPHA ID": 93398, "Summary": ""}
{"Disease Name": "German syndrome", "Disease Definition": "German syndrome is an autosomal recessive arthrogryposis syndrome, described in 5 cases. Three of the four known families with affected children were Ashkenazi Jews. German syndrome is characterized by arthrogryposis, hypotonia-hypokinesia sequence, and lymphedema. Patients present distinct craniofacial appearance (tall forehead and ''carp''-shaped mouth, cleft palate), contractures, severe hypotonia manifesting as motor delay, and swallowing difficulties. The disease has a severe morbidity and mortality rate and survivors present a small stature, hypotonia, frequent upper respiratory infections, and psychomotor delay. There have been no further descriptions in the literature since 1987.", "ORPHA ID": 2077, "Summary": ""}
{"Disease Name": "Germinoma of the central nervous system", "Disease Definition": "A rare primary germ cell tumor of central nervous system characterized by a space-occupying lesion usually arising in structures around the third ventricle, most commonly the region of the pineal gland and the suprasellar compartment. It is composed of uniform cells resembling primitive germ cells. Clinical manifestations depend on the tumor site and include hydrocephalus, visual disturbances, and endocrine abnormalities. Prognosis is favorable in pure germinomas due to high radiosensitivity.", "ORPHA ID": 91352, "Summary": ""}
{"Disease Name": "Geroderma osteodysplastica", "Disease Definition": "Geroderma osteodysplastica (GO) is characterized by lax and wrinkled skin (especially on the dorsum of the hands and feet and abdomen), progeroid features, hip dislocation, joint laxity, severe short stature/dwarfism, severe osteoporosis, vertebral abnormalities and spontaneous fractures, and developmental delay and mild intellectual deficit.", "ORPHA ID": 2078, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe severe osteoporosis and early spontaneous fractures, together with the absence of large, open fontanels are usually distinguishing features of GO.\nEtiology\nAlthough the etiology in some cases remains unknown, mutations in the GORAB gene (1q24.2) have been identified in some families. Mutations in the PYCR1 gene (17q25.3) have recently been identified in patients with the clinically overlapping phenotypes (wrinkly skin, osteopenia and progeroid features) of GO, autosomal recessive cutis laxa type 2 (ARCL2), wrinkly skin syndrome (WSS), and De Barsy syndrome (DBS; see these terms).\nGenetic counseling\nGO is transmitted in an autosomal recessive manner.\nManagement and treatment\nBisphosphonates can be successfully used in cases with severe osteopenia.\nPrognosis\nPatients with GO have a normal life expectancy and, in most cases, normal intelligence. There is a spontaneous improvement in the disease course. Bone fractures become less frequent with age.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS"}
{"Disease Name": "Gerstmann syndrome", "Disease Definition": "Gerstmann syndrome is a very rare neurological disorder characterized by the specific association of acalculia, finger agnosia, left-right disorientation, and agraphia, which is supposed to be secondary to a focal subcortical white matter damage in the parietal lobe.", "ORPHA ID": 221117, "Summary": ""}
{"Disease Name": "Gerstmann-Straussler-Scheinker syndrome", "Disease Definition": "A rare inherited human prion disease characterized by adult onset of slowly progressive cerebellar ataxia, with dementia developing relatively late in the disease course (classic ataxic phenotype). Patients may present with gait disturbances and frequent falls, dysarthria, dysphagia, nystagmus, dysmetry, and eventually pancerebellar syndrome, myoclonus, spasticity, severe dementia, and mutism. The disease is invariably fatal after five years on average. Neuropathological hallmark is the presence of numerous multicentric prion protein plaques in the cerebral and cerebellar cortex.", "ORPHA ID": 356, "Summary": ""}
{"Disease Name": "Gestational choriocarcinoma", "Disease Definition": "A form of gestational trophoblastic neoplasia characterized histologically by trophoblast proliferation, absence of chorionic villi (except in cases of intraplacental choriocarcinoma) and tissue necrosis with bleeding. The tumor occurs secondary to pregnancy (ectopic or normal), miscarriage, voluntary termination of pregnancy (VTP) or a hydatidiform mole. Indicative signs are persistent unexplained metrorrhagia or secondary increase, stagnation, or non-normalization at 6 months of total serum chorionic gonadotropin (hCG) levels after removal of a hydatidiform mole; persistent unexplained metrorrhagia following spontaneous abortion or VTP; occasionally unexplained metrorrhagia in the weeks or months following normal childbirth or an ectopic pregnancy. Occasionally, metastases (lung, liver, brain, kidneys, vagina) are indicative signs in women of childbearing age.", "ORPHA ID": 99926, "Summary": ""}
{"Disease Name": "Gestational trophoblastic neoplasm", "Disease Definition": "A rare, malignant group of gestational trophoblastic diseases always following pregnancy, most often molar pregnancy (hydatidiform mole). Four histological forms are described: invasive mole, gestational choriocarcinoma, placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT).", "ORPHA ID": 59305, "Summary": "Epidemiology\nGestational choriocarcinoma is the most frequent form of gestational trophoblastic neoplasia (GTN); whilst epidemiological data is limited, in the Netherland incidence is estimated at 1/33,000 deliveries and in the USA 1/41,000 pregnancies. This disease appears to be more frequent amongst the Asian population. The PSTT and ETT occur less frequently, with a reported incidence in the Netherlands of approximately 1/100,000 and 1/1,000,000, respectively.\nClinical description\nIndicative signs of GTN are an absence of normalization or a secondary elevation of total serum chorionic gonadotropin (hCG) levels after evacuation of a hydatidiform mole (more than 60% of cases), persistent unexplained metrorrhagia following spontaneous miscarriage or voluntary termination of pregnancy (about 30% of cases) and very occasionally, unexplained metrorrhagia in the weeks or months following normal childbirth or ectopic pregnancy (about 10% of cases). Exceptionally, metastasis may be a sign of the disease in women of childbearing age.\nEtiology\nThe etiology of GTN is not known. Identification of a GTN is based on a total serum hCG assay, which is recommended following hydatidiform moles in patients with metrorrhagia persisting for more than six weeks after pregnancy, and in any patient of childbearing age who has metastasis (lung, liver, brain, kidney, vagina) with no known primary tumor.\nDiagnostic methods\nDiagnosis of a post-molar GTN relies on one of the following four criteria: stable hCG levels (variation of less than 10%) with at least four weekly assays over a period of at least three weeks (days 1, 7, 14, 21), increase of at least 10% in hCG with at least three weekly assays over at least two weeks (days 1, 7, 14), persistence of detectable hCG values for more than six months following mole evacuation or based on histological diagnosis of a choriocarcinoma.\nDifferential diagnosis\nGTNs must not be confused with hydatidiform moles and, for choriocarcinomas, with non-gestational choriocarcinomas, which are most often ovarian.\nAntenatal diagnosis\nDiagnosis of hydatidiform mole is often by ultrasound and hCG concentration.\nGenetic counseling\nIn extremely rare cases, recurrent molar pregnancy with or without post-molar GTN can have a genetic cause (NLRP7 mutation) with an autosomal recessive pattern of inheritance (familial recurrent hydatidiform mole).\nManagement and treatment\nAs soon as the diagnosis is made, staging must be performed to identify frequent metastases. Staging involves pelvic ultrasound, pelvic and cerebral MRI, and abdominal/chest CT. A lung X-ray must be performed to calculate the FIGO 2000 score (International Federation of Obstetrics and Gynecology). This score makes it possible to distinguish between low-risk GTNs (score of 6 or lower) and high-risk GTNs (score of 7 or higher). Management should be multidisciplinary and must be discussed by a panel of physicians, preferably in a specialized center. Low-risk tumors are treated by systemic single-agent chemotherapy, e.g. methotrexate or dactinomycin. High-risk tumors are treated first line with systemic multi-agent chemotherapy. Hysterectomy can of course not be considered for first-line treatment in women who wish to become pregnant, unless there is no other option, but can be considered for older women or women who do not wish to bear children. Placental site trophoblastic tumors and epithelioid trophoblastic tumors are special cases: the FIGO score is not appropriate and total hysterectomy is the standard treatment as these tumors are usually chemo-resistant. For advanced stage disease, multi-agent chemotherapy is indicated. hCG levels should be surveyed during and following treatment.\nPrognosis\nThe overall recovery rate for low-risk GTN is around 99%. The prognosis is very closely related to the FIGO score and, in case of PSTT and ETT, FIGO stage.\n\n                            Last update: \n                            May 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Baljeet KAUR | EURACAN* - Dr Christianne LOK \n\n\n                                * European Reference Network"}
{"Disease Name": "Ghosal hematodiaphyseal dysplasia", "Disease Definition": "Ghosal hematodiaphyseal dysplasia syndrome (GHDD) is a rare disorder characterized by increased bone density (predominantly diaphyseal) and aregenerative corticosteroid-sensitive anemia.", "ORPHA ID": 1802, "Summary": "Epidemiology\nThe exact prevalence is unknown. GHDD has been reported in unrelated families of Indian and Middle East origin.\nEtiology\nGHDD is associated with mutations in the TBXAS1 gene (which encodes thromboxane synthase).\nGenetic counseling\nGHDD is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            March 2008"}
{"Disease Name": "Giant adenofibroma of the breast", "Disease Definition": "Giant adenofibroma of the breast is a rare, benign, fibroepithelial tumor which usually manifests as a unilateral, painless, firm, mobile, slow-growing mass in the breast that measures more than 5 cm. It can be associated with significant asymmetry and/or deformity of the breast and hormonal changes (e.g. puberty, pregnancy, oral contraceptives) can lead to its marked enlargement.", "ORPHA ID": 180267, "Summary": ""}
{"Disease Name": "Giant axonal neuropathy", "Disease Definition": "Giant axonal neuropathy (GAN) is a severe, slowly progressive neurodegenerative disorder characterized by progressive motor and sensory peripheral neuropathy, central nervous system involvement (including pyramidal and cerebellar signs), and characteristic kinky hair in most cases.", "ORPHA ID": 643, "Summary": "Epidemiology\nThe prevalence is unknown, but to date approximately 50 families have been reported. The frequency of this disease however, is likely to be underestimated, due to patients with incomplete phenotypes and high level of consanguinity among some populations. It occurs equally in both sexes.\nClinical description\nOnset of GAN ranges from early infancy to late childhood. Clinical hallmarks include progressive gait disturbance (frequent falls due to muscle weakness, sensory neuropathy and ataxia), everted feet, crouched gait, tightly curled hair, and early-onset central nervous system (CNS) involvement, including pyramidal and cerebellar signs that, when present together almost clinch the diagnosis. Patients usually present with intellectual disability, epilepsy, nystagmus and dysarthria that worsens in the second decade of life, and mortality typically occurs in the third decade. Other clinical signs include facial weakness, optic atrophy, ophthalmoplegia, skeletal deformations (e.g. foot deformities, scoliosis) and tremor. Clinically heterogeneous cases, with GAN presenting with a mild Charcot-Marie-Tooth (CMT)-like phenotype or manifesting with a later age of onset, absence of kinky hair, and slower progression, have recently been documented.\nEtiology\nGAN is associated with more than 50 different causative mutations in GAN gene (16q24.1), encoding the ubiquitously expressed cytoskeletal protein gigaxonin.\nDiagnostic methods\nDiagnosis is based on clinical findings and imaging. Cerebellum abnormalities, demyelination in white matter and glial proliferation in white and gray matter are shown by magnetic resonance imaging. Due to the presence of giant axons in other diseases, peripheral nerve biopsy is not sufficient to diagnose GAN. Genetic molecular testing or immunodetection of gigaxonin confirms diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes CMT-1F, -2E, -4A, -4B, -4C, -4D and -4E, the classic form of infantile neuroaxonal dystrophy, arylsulfatase A deficiency, spinal muscular atrophy, Friedreich ataxia, globoid cell leukodystrophy, n-hexane toxicity, and acrylamide toxicity.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease-causing mutation.\nGenetic counseling\nGAN is inherited as an autosomal recessive trait. Parents of an affected child are obligate heterozygotes and asymptomatic. Genetic counseling can inform parents that the risk of having an affected child is 25%. Carrier testing requires the GAN pathogenic variant to have been identified in an affected member of the family.\nManagement and treatment\nTreatment is symptomatic, focusing on stimulating intellectual and physical development, as well as communication skills, through physical, occupational and speech therapy, since the initiation of symptoms. Skeletal deformities and ophthalmoplegia may need surgery. Intrathecal administration of an AAV9-based gene therapy to restore GAN expression is currently being explored.\nPrognosis\nThe prognosis varies but is usually poor. Most patients become wheelchair-dependent in the second decade of life and eventually progress to a bedridden state in early adulthood. Secondary complications, such as respiratory failure, may occur. Life expectancy does not exceed the third decade. Lack of curly hair is correlated with milder disease and slower disease progression, which would suggest a less stark prognosis.\n\n                            Last update: \n                            August 2017\n\n\n                            - Expert reviewer(s): \n                            Dr Douglas SPROULE"}
{"Disease Name": "Giant cell arteritis", "Disease Definition": "A rare large vessel vasculitis (LVV) characterized by vasculitis predominantly involving the arteries originating from the aortic arch and the extracranial branches of the carotid arteries. Clinical manifestations are variable, the predominant cranial phenotype is characterized by headache, jaw claudication, scalp tenderness and visual symptoms and the predominant LVV type by constitutional symptoms, polymyalgia rheumatica and occasionally limb ischemia. Overlaps between these two phenotypes are common.", "ORPHA ID": 397, "Summary": "Epidemiology\nGiant cell arteritis (GCA) is the most common vasculitis in adulthood with an annual incidence of 1/5,000-1/17,000 adults over 50 years old. It is more frequent in populations of northern European background. GCA affects people of more than 50 years of age (median age at diagnosis between 70-75 years old) and occurs twice as frequently in women as in men.\nClinical description\nGCA often starts insidiously with constitutional symptoms (fever, weight loss, night sweats, malaise, asthenia), cranial manifestations (headache, jaw claudication, scalp tenderness, visual loss), and, in about 50% of patients, polymyalgia rheumatica. The temporal artery may be swollen and tender. Visual symptoms due to an ischemic optic neuropathy occur in up to 20-30% of patients, and can lead to irreversible blindness if not immediately treated with glucocorticoids. Thoracic aortitis with aneurysms occur in approximately 15% of patients. While aortic complications rarely affect patients at disease onset, they are often a late complication of GCA.\nEtiology\nThe etiology of giant cell arteritis is unknown. Studies have linked genetic factors, infectious agents and a prior history of cardiovascular disease to the development of giant cell arteritis.\nDiagnostic methods\nThe diagnosis of GCA is made in individuals over 50 years of age by a combination of characteristic symptoms as outlined above, increased acute phase reactants (erythrocyte sedimentation rate, C-reactive protein or both) and characteristic imaging findings (ultrasound, magnetic resonance imaging, computerized tomography or 18-fluorodeoxyglucose positron emission tomography) of temporal and/or other large arteries depicting inflammatory wall swelling. In case imaging is either not available or inconclusive, temporal artery biopsy is a valid alternative. In temporal artery biopsy, the most important (and mandatory) histological criterion for the diagnosis of GCA is a mononuclear cell infiltrate predominating at the media-intima junction or involving the entire vessel wall (panarteritis). Response to glucocorticoid treatment is neither sensitive nor specific enough to consider it as a diagnostic criterion.\nDifferential diagnosis\nIn elderly patients presenting with constitutional symptoms and elevated inflammatory markers, cancer and infection need to be ruled out. Symptoms of polymyalgia rheumatica can also point towards diagnoses of isolated polymyalgia rheumatica or rheumatoid arthritis. In some instances, biopsy-proven involvement of the temporal arteries can be seen in other systemic vasculitides, e.g. ANCA associated vasculitis or polyarteritis nodosa.\nManagement and treatment\nGlucocorticoids (initial dose 40-60mg/day) are highly effective in GCA but prolonged glucocorticoid therapy is often associated with substantial morbidity in the elderly population. Glucocorticoid pulse therapy (250-1000mg per day for 3 days) may be considered in case of acute visual loss or amaurosis fugax. Tocilizumab, or alternatively methotrexate should be considered in patients with refractory or relapsing GCA as well as in cases with the presence or an increased risk of glucocorticoid related adverse effects or complications. Concomitant prescription of antiplatelet or anticoagulant therapy is not indicated unless required to treat concomitant (e.g. cardiovascular) diseases. Regular monitoring for late vascular complications (e.g. aortic aneurysms) is needed.\nPrognosis\nThe disease is chronic and the clinical course is highly variable. Response to glucocorticoids is usually rapid and complete. However, at least 50% of patients experience subsequent disease flares. Visual loss is the most feared complication but can be prevented by rapid diagnosis and immediate treatment.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Christian DEJACO"}
{"Disease Name": "Giant cell tumor of bone", "Disease Definition": "A rare bone sarcoma characterized by a usually benign space-occupying lesion, which is nevertheless locally aggressive and massively damaging to surrounding bone tissue. The tumor is composed of giant multinucleated cells (osteoclast-like cells), mononuclear macrophages, and mononuclear stromal cells which secrete pro-myeloid and pro-osteoclastic factors. Metastasis and malignant transformation are rare, but the recurrence rate is high.", "ORPHA ID": 363976, "Summary": ""}
{"Disease Name": "Gingival fibromatosis-facial dysmorphism syndrome", "Disease Definition": "A very rare syndrome characterized by the association of gingival fibromatosis and craniofacial dysmorphism.", "ORPHA ID": 2025, "Summary": "Epidemiology\nIt has been described in two sibs.\nClinical description\nCraniofacial dysmorphism consists of relative macrocephaly, bushy eyebrows with synophris, hypertelorism, downslanting palpebral fissures, flattened nasal bridge and high arched palate. The patients have normal intellect.\nGenetic counseling\nThe condition seems to be hereditary, transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Gingival fibromatosis-hypertrichosis syndrome", "Disease Definition": "A rare autosomal dominant disorder characterized by a generalized enlargement of the gingiva occurring at birth or during childhood that is associated with generalized hypertrichosis developing at birth, during the first years of life, or at puberty and predominantly affecting the face, upper limbs, and midback.", "ORPHA ID": 2026, "Summary": ""}
{"Disease Name": "Gingival fibromatosis-progressive deafness syndrome", "Disease Definition": "A rare syndrome characterized by gingival fibromatosis associated with progressive sensorineural hearing loss. It has been described in two families (with at least 16 affected members spanning five generations in one of the families, and five affected members spanning three generations in the other family). It is transmitted as an autosomal dominant trait.", "ORPHA ID": 2027, "Summary": ""}
{"Disease Name": "Gitelman syndrome", "Disease Definition": "A rare syndrome characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion.", "ORPHA ID": 358, "Summary": "Epidemiology\nGitelman syndrome (GS) prevalence is estimated at 1 to 10 per 40,000 and potentially higher in Asia. GS is arguably the most frequent inherited tubulopathy.\nClinical description\nGS presents mainly in adolescents and adults but also encountered in children, as early as in the neonatal period. The diagnosis may be incidental, due to blood tests obtained for unrelated reasons. Clinical symptoms may include salt craving, thirst and nocturia, transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain. Paresthesias, especially in the face, may occur. Remarkably, some patients are completely asymptomatic. In adulthood, chondrocalcinosis may appear, which can be associated with inflammation over the affected joints. Blood pressure is typically lower than that in the general population, although reports of hypertension in adult patients exist. Sudden cardiac arrest has been described in case reports and long QT syndrome may be present. In general, growth is normal but can be delayed.\nEtiology\nGS is caused by biallelic inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive sodium-chloride cotransporter NCC expressed in the apical membrane of cells lining the distal convoluted tubule. At present, more than 350 different NCC mutations throughout the whole protein have been identified.\nDiagnostic methods\nDiagnosis is based on the clinical symptoms and biochemical abnormalities (chronic hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria) and can be confirmed by genetic testing.\nDifferential diagnosis\nBartter syndrome (especially type III, caused by mutation in CLCNKB) can be clinically indistinguishable from GS. Mutation in the HNF1B can mimic the electrolyte abnormalities (particularly hypomagnesemia) encountered in GS. Biochemical abnormalities are identical in EAST/SESAME syndrome, but the extra renal features allow it to be distinguished from GS. Chronic thiazide use can cause an acquired GS-like clinical picture.\nAntenatal diagnosis\nAntenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients.\nGenetic counseling\nGenetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThe management of GS should be individualized and at least annual follow-up in a nephrology clinic to monitor potential complications and evolution is advocated. It is recommended to encourage patients to follow their propensity for salt consumption. Lifelong supplementation of salt, potassium (KCl) or magnesium supplementation (magnesium-oxide and magnesium-sulfate) should be considered. Many symptoms are improved by supplementation, but there is no evidence correlating the severity of biochemical abnormalities with the severity of symptoms. Cardiac work-up should be offered to screen for risk factors for cardiac arrhythmias. All GS patients are encouraged to maintain a high sodium and high potassium diet.\nPrognosis\nTo date, there is no evidence that GS affects life expectancy.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Detlef BÖCKENHAUER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "GJC2-related late-onset primary lymphedema", "Disease Definition": "A rare genetic primary lymphedema characterized by lymphedema of all four limbs with age of onset ranging from birth to adulthood. Manifestations are of variable severity, and upper limb involvement may develop only later in the disease course. Recurrent episodes of cellulitis and skin infections are observed in severe cases. Varicose veins and venous incompetence have been reported in association.", "ORPHA ID": 568051, "Summary": ""}
{"Disease Name": "Glanzmann thrombasthenia", "Disease Definition": "Glanzmann thrombasthenia (GT) is a bleeding syndrome characterized by spontaneous mucocutaneous bleeding and an exaggerated response to trauma due to a constitutional thrombocytopenia.", "ORPHA ID": 849, "Summary": ""}
{"Disease Name": "Glassy cell carcinoma of the cervix uteri", "Disease Definition": "Glassy cell carcinoma of the cervix uteri is a rare cancer of the uterine cervix, composed of nests of large neoplastic cells with 'ground glass' cytoplasm, surrounded by a stroma with prominent eosinophilic infiltrates. It is a poorly differentiated, aggressive variant of adenosquamous carcinoma that usually affects young women and presents with dysfunctional vaginal bleeding and lower abdominal pain. Distant metastases to the lungs, liver spleen or bones are often present at the time of diagnosis. It is often associated with high-risk HPV-infection (types 18, 16 and 32).", "ORPHA ID": 213833, "Summary": ""}
{"Disease Name": "Glaucoma secondary to spherophakia/ectopia lentis and megalocornea", "Disease Definition": "Glaucoma secondary to spherophakia/ectopia lentis and megalocornea is a rare, genetic, non-syndromic developmental defect of the eye disorder characterized by congenital megalocornea associated with spherophakia and/or ectopia lentis leading to pupillary block and secondary glaucoma. Additional features may include flat irides, iridodonesis, axial myopia, very deep anterior chambers, miotic, oval pupils without well-defined borders, ocular pain and irritability manifesting as conjunctival injection, corneal edema and central scarring, as well as a high arched palate.", "ORPHA ID": 238763, "Summary": ""}
{"Disease Name": "Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome", "Disease Definition": "A rare genetic, syndromic eye disorder characterized by progressive joint stiffness, glaucoma, short stature and lens dislocation. This syndrome shows similarities to Moore-Federman syndrome.", "ORPHA ID": 2084, "Summary": ""}
{"Disease Name": "Glaucoma-sleep apnea syndrome", "Disease Definition": "Glaucoma-sleep apnea syndrome is characterized by sleep apnoea associated with glaucoma. It has been described in five members of a family (the mother and four of her children).", "ORPHA ID": 2085, "Summary": ""}
{"Disease Name": "Glioblastoma", "Disease Definition": "Glioblastomas are malignant astrocytic tumors (grade IV according to the WHO classification).", "ORPHA ID": 360, "Summary": "Epidemiology\nGlioblastomas represent the most frequent brain tumors in adults, with an annual incidence of around 1/33,330. Prevalence is estimated at 1/100,000.\nClinical description\nThey may occur at any age, but 70% of cases are seen in patients between 45 and 70 years of age. The tumors are usually located in the brain hemispheres, but can be found anywhere in the central nervous system. The disease often progresses rapidly (over 2 to 3 months), except when the glioblastoma develops within a pre-existing low grade astrocytoma (secondary glioblastoma). Neurological signs are nonspecific as they result from intracranial hypertension and include headaches and vomiting, often associated with behavioral changes or focal neurological deficits. Histological variants (gliosarcoma and giant cell glioblastoma) have been described for which the treatment protocols and prognosis are similar to those of glioblastoma.\nEtiology\nThe cause of the disease is unknown, except when it occurs after therapeutic irradiation of the brain for another disease. The genetic abnormalities detected (amplification of the EGFR gene (7p12), mutations in the TP53 gene (17p13.1), loss of chromosome 10) vary depending on the nature of the tumor: primary glioblastoma (de novo) or a secondary glioblastoma (developing from a benign astrocytic tumor).\nDiagnostic methods\nRadiologic studies, computerized tomography (CT) and magnetic resonance imaging (MRI) demonstrate characteristic features such as an infiltrating tumor associated with heterogeneous contrast enhancement and areas of necrosis.\nDifferential diagnosis\nThe differential diagnosis should include infectious and parasitic diseases with central nervous system involvement. Familial forms of glioblastoma are very rare but the tumor may occur as part of a syndrome such as Turcot syndrome, neurofibromatosis type 1 or Li-Fraumeni syndrome (see these terms).\nManagement and treatment\nThe first-line treatment is usually surgery, either to confirm the diagnosis with a biopsy or to remove as much of the tumor as possible. Complete resection is rarely feasible, since tumor cells usually infiltrate the surrounding brain. Treatment is then completed with radiotherapy targeted at the tumor bed, combined with chemotherapy (nitrosoureas and temozolomide). In terms of survival, the benefits from adjuvant treatments after surgery are significant, although they remain modest. In case of relapse, second-line chemotherapy or reoperation may be performed. Due to the relative rarity of this tumor, management of glioblastoma patients should be carried out by multidisciplinary teams with expertise in neuro-oncology within prospective studies aiming to improve patient survival and quality of life.\nPrognosis\nPrognosis is poor, especially in the absence of gross total resection, in older patients and in case of severe neurological deficits.\n\n                            Last update: \n                            November 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Jacques GRILL"}
{"Disease Name": "Glioependymal/ependymal cyst", "Disease Definition": "Glioependymal/ependymal cyst is a rare central nervous system malformation defined as a subarachnoid, supratentorial, interventricular or intraspinal, sometimes intracerebral or intramedullar cyst with an internal ependymal lining, possibly surrounded by glial tissue. It may be an incidental finding or may present at different ages with clinical features depending on its size and location. It may distort adjacent brain structures and cause macrocephaly, ventriculomegaly, hydrocephalus, focal neurological signs and other signs and symptoms. In some cases, it is associated with other cerebral malformations (e.g. corpus callosum agenesis, polymicrogyria, heterotopias).", "ORPHA ID": 269197, "Summary": ""}
{"Disease Name": "Gliomatosis cerebri", "Disease Definition": "A rare glial tumor characterized by extensive infiltration of the brain, often extending to infratentorial structures and even the spinal cord. The tumor corresponds to WHO grade III and is composed of elongated glial cells typically resembling astrocytes. Cases in which the predominant cell type is oligodendroglial have also been described. Some tumors develop a circumscribed neoplastic mass in addition to the diffuse lesion, usually showing features of high-grade glioma. Clinical symptoms include dementia, headache, seizures, signs of increased intracranial pressure, and a variety of neurological deficits. Prognosis is generally poor.", "ORPHA ID": 251582, "Summary": ""}
{"Disease Name": "Global developmental delay-alopecia-macrocephaly-facial dysmorphism-structural brain anomalies syndrome", "Disease Definition": "A rare disorder of ornithine metabolism characterized by global developmental delay, alopecia, macrocephaly, and dysmorphic facial features (including high and broad forehead, hypertelorism, ptosis, blepharophimosis, downslanting palpebral fissures, deep-set eyes, large ears, and retrognathia or high arched palate). Additional reported manifestations are sensorineural hearing loss, spasticity, hypotonia, hypoplastic nails, cryptorchidism, and clinodactyly, among others. Brain imaging may show white matter abnormalities, periventricular cysts, enlarged lateral ventricles, or prominent perivascular spaces.", "ORPHA ID": 544488, "Summary": ""}
{"Disease Name": "Global developmental delay-lung cysts-overgrowth-Wilms tumor syndrome", "Disease Definition": "Global developmental delay-lung cysts-overgrowth-Wilms tumor syndrome is a rare, genetic, overgrowth syndrome characterized by global developmental delay, macrosomia with subsequent somatic overgrowth, bilateral cystic lung lesions, congenital nephromegaly and bilateral Wilms tumor. Craniofacial dysmorphism includes macrocephaly, frontal bossing, large anterior fontanelle, mild hypertelorism, ear pit, flat nasal bridge, anteverted nares and mild micrognathia. Additional features may include brain and skeletal anomalies, enlarged protuberant abdomen, fat pads on dorsum of feet and toes, and rugated soles with skin folds, as well as umbilical/inguinal hernia and autistic behavior.", "ORPHA ID": 404476, "Summary": ""}
{"Disease Name": "Global developmental delay-neuro-ophthalmological abnormalities-seizures-intellectual disability syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by infantile to childhood onset of global developmental delay, hypotonia, seizures, growth delay, and intellectual disability. Additional variable features include strabismus, cortical visual impairment, nystagmus, movement disorder (such as dystonia, ataxia, or chorea), or mild dysmorphic features, among others.", "ORPHA ID": 488613, "Summary": ""}
{"Disease Name": "Global developmental delay-osteopenia-ectodermal defect syndrome", "Disease Definition": "A rare genetic disease characterized by global developmental delay with language and cognition deficiencies, behavioral problems, osteopenia, joint laxity, skin defects consisting of hyperkeratosis and sweat gland and melanocyte abnormalities with hypopigmented areas, and abnormal hair structure. Mild facial dysmorphism (prominent forehead, thick eyebrows, epicanthal folds, broad nasal bridge, long philtrum, and micrognathia), abnormalities of the teeth, and skeletal and cardiac anomalies have also been described.", "ORPHA ID": 73223, "Summary": ""}
{"Disease Name": "Global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome", "Disease Definition": "Global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome is a rare, genetic, neurological disorder characterized by mild to severe developmental delay and speech impairment, truncal hypotonia, abnormalities of vision (including cortical visual impairment and abnormal visual-evoked potentials), progressive brain atrophy mainly affecting the cerebellum, and shortened or atrophic corpus callosum. Other clinical findings may include increased muscle tone in the extremities, dystonic posturing, hyporeflexia, scoliosis, postnatal microcephaly and variable facial dysmorphism (e.g. deep-set eyes, gingival hyperplasia, short philtrum and retrognathia).", "ORPHA ID": 480898, "Summary": ""}
{"Disease Name": "Glomus tumor", "Disease Definition": "A rare soft tissue tumor characterized by a nodular lesion composed of cells closely resembling the modified smooth muscle cells of the normal glomus body. The tumors most often arise in the skin or soft tissues of the distal extremities, in particular the subungual region, but have been reported in almost any location. They occur as typical glomus tumors, glomangiomatosis (multiple nodules of solid glomus tumor investing the vascular walls), symplastic (showing striking nuclear atypia without mitotic activity or necrosis) or malignant glomus tumors, and glomus tumors of uncertain malignant potential.", "ORPHA ID": 391651, "Summary": ""}
{"Disease Name": "Glomuvenous malformation", "Disease Definition": "A rare vascular anomaly or angioma characterized by the presence of small, multifocal bluish-purple venous lesions mainly involving the skin.", "ORPHA ID": 83454, "Summary": "Epidemiology\nGlomuvenous malformations (GVMs) prevalence is unknown; over 200 families or cases have been reported in the literature. It is estimated that GVMs account for 70-80% of inherited venous-type malformations ; the rest being cutaneomucosal venous malformations (VMCMs).\nClinical description\nGVMs may be present at birth, and slowly expand during childhood. New small lesions appear with time. They are usually hyperkeratotic, raised and nodular with a cobblestone surface. Color varies from pink to purplish-dark blue. However, in some cases (especially in newborns) the lesions may be flat and purple in color; this plaque-like GVM usually darkens with time. GVMs are often painful on palpation and cannot be completely emptied by compression. They are usually multifocal and are located mainly on the extremities, involving the skin and subcutis. They are rarely encountered in mucosae and intestinal hemorrhage is not a feature of this condition. There is significant clinical variation with respect to the size, location and number of lesions, even between affected individuals from the same family. For example, plaque-like GVM-lesions on the thorax can be associated with pleural effusions. Patients with GVMs have normal mental and physical development.\nEtiology\nGVMs are caused by mutations in the gene encoding glomulin (GLMN; 1p22.1). Inheritance pattern is autosomal dominant. The inherited mutations cause loss-of-function of glomulin. The lesions develop in areas where a double-hit mutation has occurred, indicating that GVM lesions are due to complete localized loss of glomulin. The most frequent somatic second hit is an acquired uniparental isodisomy, which leads to loss of the normal copy, and duplication of the mutated copy in cells within the lesion.\nDiagnostic methods\nDiagnosis of GVM is based on clinical evaluation of the cutaneous lesions. Confirmation can be obtained via a blood sample for molecular genetic testing. Doppler ultrasound examination and MRI can be used to confirm the venous component and the common superficial extent of the lesions. Histologically, GVMs are characterized by the presence of abnormal mural cells called \"glomus cells'' which help differentiate from common venous malformations and VMCM.\nDifferential diagnosis\nThe differential diagnosis should include mucocutaneous venous malformations (VMCMs, which are also commonly seen on mucosal membranes, are lighter purple in color than GMVs, and are compressible and generally not painful on palpation, and caused by inherited TIE2/TEK mutations) and Blue rubber bleb nevus syndrome (characterized by the association of cutaneous and mucosal venous-like lesions with gastrointestinal lesions, and caused by somatic TIE2/TEK mutations).\nAntenatal diagnosis\nPrenatal diagnosis is feasible for affected families in which the disease-causing mutation has been identified, but is not widely available.\nGenetic counseling\nGVMs are inherited in an autosomal dominant manner. Genetic counseling should be provided for affected families, informing patients of a 50% risk of inheriting the disease-causing mutation and of the variability in clinical expression.\nManagement and treatment\nThe most effective treatment is plastic and reconstructive surgery, used depending on the size and location of the lesions. Laser can be effective, especially for small flat lesions as well as plaque-like lesions. Sclerotherapy may be indicated in some cases: the sclerosing agent such as foam aethoxysclerol is associated with less skin necrosis than ethanol (96%). Another sclerosing agent is ethanol (96%) in the form of a gel for injection, which obtained EU orphan drug designation in April 2005 for the treatment of congenital venous malformations.\nPrognosis\nThe prognosis for patients is good, malignant transformation has not been reported and the life expectancy for patients is not reduced.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence BOON  - Pr Miikka VIKKULA"}
{"Disease Name": "Glossopalatine ankylosis", "Disease Definition": "A rare oromandibular-limb hypogenesis syndrome (OLHS) characterised by the presence of an intraoral band of variable thickness attaching the tongue to the hard palate or maxillary alveolar ridge. It may be associated with other abnormalities such as cleft palate (in which case the tongue may be attached to the nasal septum), mandibular hypoplasia, upper-lip hypoplasia, hypodontia and variable limb anomalies (e.g. oligodactyly, syndactyly and polydactyly).", "ORPHA ID": 141163, "Summary": ""}
{"Disease Name": "Glossopharyngeal neuralgia", "Disease Definition": "A rare cranial neuralgia characterized by paroxysmal, usually unilateral stabbing pain within the sensory distributions of the auricular and pharyngeal branches of the glossopharyngeal and sometimes the vagus nerve (i. e. the posterior part of the tongue, the tonsillar fossa, oropharynx, larynx, angle of the mandible, and/or ear). The attacks last seconds to minutes with intervals between the paroxysms ranging from a few minutes to a few hours, and appear in clusters lasting weeks to months, again with irregular intervals in between. Pain attacks are usually triggered by a specific stimulus but may also occur spontaneously. The condition can sometimes be associated with bradycardia, syncope, seizures, and even asystole, and is then termed vagoglossopharyngeal neuralgia.", "ORPHA ID": 221098, "Summary": ""}
{"Disease Name": "Glucagonoma", "Disease Definition": "Glucagonoma is a rare, functioning type of pancreatic neuroendocrine tumor (PNET; see this term) that hypersecretes glucagon, leading to a syndrome comprised of necrolytic migratory erythema, diabetes mellitus, anemia, weight loss, mucosal abnormalities, thromboembolism, gastrointestinal and neuropsychiatric symptoms.", "ORPHA ID": 97280, "Summary": "Epidemiology\nThe estimated incidence in the general population is 1/20, 000,000.\nClinical description\nGlucagonoma usually presents in the fifth decade of life with the initial symptom often being necrolytic migratory erythema. This skin condition is characterized by a red, blistering and migratory rash, associated with an intense pruritus and that is mainly localized to the lower extremities and the groin. Diabetes is present in most cases and requires insulin therapy. Weight loss, anemia, mucosal abnormalities (glossitis, cheilitis, stomatitis), gastrointestinal disturbances, thromboembolism and neuropsychiatric symptoms (depression) are other frequent manifestations. Most glucagonomas have already metastasized by the time that they are diagnosed, mainly to the liver. In some cases glucagonoma may be associated with multiple endocrine neoplasia type 1 (MEN1; see this term). Glucogonoma can be non-functioning in rare cases.\nEtiology\nThe etiology is unknown. These tumors of 2-25 cm mainly occur in the tail of the pancreas. They synthesize and secrete glucagon, which is responsible for balancing the effects of insulin, and is therefore essential in regulating blood sugar levels.\nDiagnostic methods\nDiagnosis is based on clinical findings and endocrine tests. Serum glucagon levels are markedly elevated (>500 pg/mL) and levels of more than 1000 pg/mL are considered diagnostic if the patient also displays features of glucagonoma syndrome. Other hormones such as insulin, somatostatin and vasoactive intestinal peptide may also be elevated. Levels of blood chromogranin A are increased. Localization of tumors is possible by computed tomography (CT) scan, octreotide scan, magnetic resonance imaging (MRI) and/or endoscopic ultrasound.\nDifferential diagnosis\nDifferential diagnoses include familial hyperglucagonemia, autoimmune and hereditary chronic pancreatitis, Mahvash disease, acrodermatitis enteropathica (see these terms) and cirrhosis.\nManagement and treatment\nSomatostatin analogues (octreotide or lanreotide) are usually effective in leading to a remission of rash in most patients as well as improving the symptoms of weight loss, abdominal pain and diarrhea. Glycemia is managed by insulin injections or anti-diabetic drugs. Parenteral nutrition (with essential fatty acids, amino acids, vitamins and minerals) may also be necessary. Surgical resection is the only curative option in localized cases. Surgical debulking followed by chemotherapy may be an option in extensive tumors. Resection of the lymph nodes, spleen and parts of the liver containing metastasized glocagonoma may also be necessary. As thromboembolic complications can occur, blood thinners (antiplatelets and anticoagulants) may be recommended.\nPrognosis\nThe prognosis of glucagonoma is usually poor as most have metastasized by the time that they are discovered. Those associated with MEN1 usually have a fairer prognosis as they are diagnosed sooner.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Run YU"}
{"Disease Name": "Glucose-galactose malabsorption", "Disease Definition": "A rare, potentially lethal, autosomal recessive metabolic disease characterized by impaired glucose-galactose absorption resulting in severe watery diarrhea and dehydration with onset in the neonatal period.", "ORPHA ID": 35710, "Summary": "Epidemiology\nGlucose-galactose malabsorption (GGM) is a rare disease, with fewer than 1,000 cases reported worldwide, which is most frequently reported in populations with a high incidence of consanguinity. The frequency of the Northern-Sweden founder mutation, Q457R, is 45-fold higher than other mutations linked to the disease in the general European population.\nClinical description\nThis disease usually presents within the first week of life with severe life-threatening diarrhea, metabolic acidosis, and hyperosmolar dehydration.\nEtiology\nGGM is due to mutations in the gene coding for the intestinal brush border sodium-glucose cotransporter protein SGLT1 (SLC5A1), disrupting the absorption of glucose and galactose from lactose in breast milk. As this disease is mainly reported in populations with high incidence of consanguinity, many mutations causing the disease are homozygous missense, nonsense, frame-shift, or splice-site mutations. In non-consanguineous probands, heterozygous mutations are inherited from each parent. Mutations producing premature stop codons result in non-functional truncated proteins, while missense mutations generally result in proteins that do not reach the brush border membrane. It should be cautioned that not all identified missense mutations produce inactive transporters. In the oldest known GGM pedigree -dating back to the 17th century in Northern Sweden- a homozygous missense mutation identified in 14 patients results in a non-functional protein in the brush border membrane.\nDiagnostic methods\nIf the child is in hospital, i) a duodenal biopsy is frequently taken to ensure normal histology, and ii) an oral glucose tolerance test or a hydrogen breath test is conducted to evaluate glucose absorption. However, the most straightforward test in the hospital or at home is to eliminate lactose, glucose, and galactose from the feeds by withholding breast milk and feeding with a sugar-free formula. The diarrhea will cease but return immediately on refeeding breast milk or formula with glucose, but not with fructose. Sanger and next-generation sequencing methods are readily available. Molecular testing is not required if the intestinal biopsy is normal, and the child's diarrheal symptoms resolve on a glucose/galactose restricted-diet.\nDifferential diagnosis\nThe differential diagnosis GGM includes other forms of nutrient-specific congenital diarrhea such as congenital lactase deficiency and congenital sucrase-isomaltase deficiency.\nAntenatal diagnosis\nAntenatal diagnosis is possible when molecular testing has previously identified the mutation causing glucose malabsorption.\nGenetic counseling\nAs GGM is an autosomal recessive disorder, the parents of children with GGM should be advised that additional children have a 25% chance of inheriting the disease. Carriers of GGM mutations have an extremely low chance of parenting children with the disease, as the frequency of mutation in the general population is less than 1 in 15,000. The only exception is where carriers are restricted by geography or culture to communities where GGM is prevalent, and in these cases, prospective partners ought to be screened for mutations.\nManagement and treatment\nThe symptoms of GGM are resolved on a diet free of glucose, galactose, and lactose, and several infant formulas are available for young children in Europe and North America. As children enter late infancy, it becomes more challenging to maintain a carbohydrate-free diet and parents are encouraged to consult a well-qualified-dietician or parent-support group.\nPrognosis\nAfter dealing with the challenges of dietary carbohydrates (lactose, sucrose, glucose, galactose) restriction to control diarrhea and dehydration in newborns and young children, the prognosis is excellent for adults who lead a normal healthy life.\n\n                            Last update: \n                            November 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Martin MARTIN  - Pr Ernest WRIGHT"}
{"Disease Name": "Glutamate-cysteine ligase deficiency", "Disease Definition": "A disorder that is principally characterized by hemolytic anemia, (usually rather mild), however, the presence of neurological symptoms has also been reported.", "ORPHA ID": 33574, "Summary": "Epidemiology\nGamma-glutamylcysteine synthetase deficiency has been detected in nine patients from seven families worldwide.\nEtiology\nGamma-glutamylcysteine synthetase catalyses the first and rate-limiting step in the synthesis of glutathione. Its deficiency results in low cellular levels of glutathione and gamma-glutamylcysteine. Four different mutations in the heavy subunit have been identified in four families affected by gamma-glutamylcysteine synthetase deficiency.\nDiagnostic methods\nThe diagnosis consists of the following stages: clinical findings, the finding of low cellular levels of glutathione, low activity of gamma-glutamylcysteine synthetase, and mutation analysis of the gamma-glutamylcysteine synthetase genes.\nDifferential diagnosis\nThe differential diagnosis should include glutathione synthetase deficiency (see this term), which is also associated with low levels of glutathione.\nAntenatal diagnosis\nAntenatal diagnosis could be performed by measurement of gamma-glutamylcysteine synthetase activity or mutational analysis (if the mutation in the family is known) of chorionic villi samples or cultured amniocytes.\nGenetic counseling\nAs transmission is autosomal recessive, families should be referred for genetic counselling.\nManagement and treatment\nPatients with gamma-glutamylcysteine synthetase deficiency should avoid drugs known to precipitate hemolytic crises in patients with glucose-6-phosphate dehydrogenase deficiency, e.g. phenobarbital, acetylsalicylic acid and sulfonamides. It is possible that patients would benefit from treatment with anti-oxidants but no studies have been made.\nPrognosis\nThe prognosis is difficult to predict, as only nine patients are known worldwide.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Agne LARSSON  - Dr Ellinor RISTOFF"}
{"Disease Name": "Glutaric acidemia type 3", "Disease Definition": "A rare inborn error of metabolism characterized by abnormally high urinary excretion of glutaric acid due to peroxisomal glutaryl-CoA oxidase deficiency. There is no association with a specific clinical phenotype.", "ORPHA ID": 35706, "Summary": ""}
{"Disease Name": "Glutaryl-CoA dehydrogenase deficiency", "Disease Definition": "Glutaryl-CoA dehydrogenase (GCDH) deficiency (GDD) is an autosomal recessive neurometabolic disorder clinically characterized by encephalopathic crises resulting in striatal injury and a severe dystonic dyskinetic movement disorder.", "ORPHA ID": 25, "Summary": "Epidemiology\nWorldwide prevalence is estimated at 1 in 100,000 births. GDD is more prevalent in the old order Amish community, Canadian Oji-Cree natives, Irish travelers and Lumbee Native Americans.\nClinical description\nNeonates are mainly asymptomatic, although 75 % present with macrocephaly and possibly show hypotonia and irritability. If undiagnosed, the initial acute encephalopathic crisis occurs between 3-36 months, typically precipitated by an intercurrent febrile illness, vaccination or a surgical intervention, and characterized by hypotonia, loss of motor skills and convulsions resulting in bilateral striatal injury with severe secondary dystonia and occasionally subdural and retinal hemorrhage. GDD can exceptionally present with hypoglycemia or acidosis. With age (>6 years) and with appropriate treatment, the risk of encephalopathic crises subsides. In some patients, hypotonia and dystonia develop gradually with no encephalopathic crisis, which is known as late-onset or insidious-onset GDD.\nEtiology\nGDD is caused by mutations in the GCDH gene, located to 19p13.2, and involved in L-lysine, L-hydroxylysine and L-tryptophane catabolic pathways. Over 200 GCDH mutations have been reported. GDD has a distinctive pathological appearance due to the accumulation of glutaric acid (GA), 3-hydroxyglutaric (3-OH-GA) and glutaconic acids and glutarylcarnitine in body fluids.\nDiagnostic methods\nPresymptomatic detection can be offered through routine newborn screening programs implemented in some countries. If not available, diagnosis should be suspected on the basis of clinical findings and can be supported by neuroradiological findings including widely open opercula and basal ganglia injury. Diagnosis is confirmed by genetic analysis or by measuring elevated levels of GA, 3-OH-GA, glutaconic acid and glutarylcarnitine by quantitative urinary organic acid analysis, gas chromatography-mass spectrometry and/or tandem mass spectrometry (acylcarnitines).\nDifferential diagnosis\nGDD is often misdiagnosed. Differential diagnosis includes encephalitis, Reye's syndrome, familial infantile bilateral striatal necrosis, familial megalencephaly, postencephalitic Parkinsonism (see these terms), dystonic cerebral palsy, battered child syndrome with chronic subdural effusions, sudden infant death syndrome and vaccine induced brain-injury.\nAntenatal diagnosis\nPrenatal testing can be performed by genetic and GCDH enzyme analysis of chorionic villi sample or through measuring GA levels in amniotic fluid in at-risk families. Genetic testing is necessary to confirm antenatal diagnosis.\nGenetic counseling\nGenetic counseling is recommended and should be offered to affected families together with genetic testing, as inheritance is autosomal recessive.\nManagement and treatment\nDaily management comprises a low lysine diet, carnitine supplementation in association with prompt emergency treatment during intercurrent illness. During acute episodes, management includes, most importantly, increasing energy supply (20-100 % above RDI); omission of natural protein for 24-48 hours followed by a gradual reintroduction; L-carnitine supplementation doubling and close monitoring of glucose, electrolyte and fluid balance, as well as urea and liver status by an informed skilled interdisciplinary team. Adherence to emergency treatment recommendations is imperative in preventing neuronal damage and subsequent secondary dystonia.\nPrognosis\nPrognosis depends on a timely diagnosis and consequential management and treatment. GDD is now regarded as a treatable neurometabolic disorder.\n\n                            Last update: \n                            April 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Georg HOFFMANN"}
{"Disease Name": "Glutathione synthetase deficiency", "Disease Definition": "A rare disorder characterised by hemolytic anemia, associated with metabolic acidosis and 5-oxoprolinuria in moderate forms, and with progressive neurological symptoms and recurrent bacterial infections in the most severe forms.", "ORPHA ID": 32, "Summary": "Epidemiology\nThis disease has been detected in at least 70 patients in more than 50 families worldwide.\nEtiology\nSeveral mutations have been identified in the gene encoding glutathione synthetase, localized to chromosome 20q11.2. Glutathione synthetase catalyses the last step in the synthesis of glutathione and a deficiency results in low levels of glutathione. Acidosis is due to reduced feedback inhibition of gamma-glutamyl cysteine synthetase in the gamma-glutamyl cycle, which ultimately leads to overproduction and accumulation of 5-oxoproline.\nDiagnostic methods\nThe diagnosis usually involves the following: clinical findings, the finding of 5-oxoprolinuria, low levels of glutathione, low activity of glutathione synthetase, and mutation analysis of the glutathione synthetase gene.\nDifferential diagnosis\nOther causes of 5-oxoprolinuria include 5-oxoprolinase deficiency (see this term), diet (certain infant formulas and tomato juice), severe burns, Stevens-Johnson syndrome (see this term), inborn errors of metabolism not involving the gamma-glutamyl cycle, e.g. X-linked ornithine trancarbamylase deficiency, urea cycle defects, tyrosinemia, as well as homocystinuria (see these terms), drug metabolism (paracetamol, vigabatrin, flucloxacillin, netimicin), prematurity, malnutrition, pregnancy and nephropatic cystinosis.\nAntenatal diagnosis\nAntenatal diagnosis is possible.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nManagement includes correction of the acidosis, supplementation with antioxidants and avoidance of drugs known to precipitate hemolytic crises in patients with glucose-6-phosphate dehydrogenase deficiency, e.g. phenobarbital, acetylsalicylic acid and sulfonamides.\nPrognosis\nA long-term follow up study of 28 patients with glutathione synthetase deficiency has showed that the factors most predictive of survival and long-term outcome are early diagnosis, correction of acidosis and early supplementation with vitamin C and vitamin E.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Agne LARSSON  - Dr Ellinor RISTOFF"}
{"Disease Name": "Glycerol kinase deficiency, adult form", "Disease Definition": "A rare form of glycerol kinase deficiency (GKD) characterized by pseudohypertriglyceridemia in otherwise healthy adults and diagnosed fortuitously.", "ORPHA ID": 284414, "Summary": ""}
{"Disease Name": "Glycerol kinase deficiency, juvenile form", "Disease Definition": "Juvenile glycerol kinase deficiency (GKD) is an uncommon form of GKD (see this term) characterized by Reye-like clinical manifestations including episodic vomiting, acidemia, and disorders of consciousness.", "ORPHA ID": 284411, "Summary": ""}
{"Disease Name": "Glycine encephalopathy", "Disease Definition": "Glycine encephalopathy (GE) is an inborn error of glycine metabolism characterized by accumulation of glycine in body fluids and tissues, including the brain, resulting in neurometabolic symptoms of variable severity.", "ORPHA ID": 407, "Summary": "Epidemiology\nIn Finland, an incidence at birth of 1/55,000 is reported and in British Columbia, Canada, 1/63,000, with a calculated carrier rate of 1/125.\nClinical description\nThree forms of GE have been recognized based on the age of onset: neonatal, infantile and atypical glycine encephalopathy (see these terms). Most patients have the life-threatening neonatal form and present mild to severe disease manifestations starting within a few days of birth including lethargy or even coma, hypotonia, hiccups, myoclonic jerks, and breathing/swallowing disorders, with subsequent intellectual deficit, spasticity and intractable seizures. A smaller proportion of patients show developmental delay and generally mild seizures in the infantile period, while others do not develop symptoms until late infancy or adulthood. Although patients usually have either a mild or severe course, there is a continuous clinical spectrum. Some patients develop choreic movements. Atypical glycine encephalopathy indicates hyperglycinemic patients whose clinical presentations are different from those of neonatal or infantile form, for example, transient or late-onset hyperglycinemia and patients with spastic paraparesis.\nEtiology\nMutations in two genes are known to cause glycine encephalopathy: GLDC (9p22) and AMT (3p21.2-p21.1). These genes encode the P-protein and T-protein components of the enzymatic glycine cleavage system (GCS), respectively. Although GCSH is another GCS gene, no mutations have been identified in neonatal or infantile forms. Deficient GCS activity results in defective glycine metabolism and accumulation of the amino acid in body tissues. In some patients with deficient GCS enzyme activity no mutation could be identified by exon sequencing analysis of any GCS gene. The vast majority of patients have no detectable enzyme activity. Etiology of atypical forms remains largely unknown.\nDiagnostic methods\nGE should be suspected in cases of elevated glycine levels in blood and cerebrospinal fluid (CSF). Increased CSF-to-plasma glycine ratios also suggest the diagnosis. Measurement of GCS activity of biopsied liver sample or by 13C-glycine breath test and genetic testing may confirm diagnosis. Brain MRI may reveal hypogenesis of corpus callosum, abnormal gyrus, and hypogenesis of cerebellum in the neonatal form. Suppression burst and hypsarrhythmia are common in EEG. Subsequently, delayed myelination and atrophy may be observed.\nDifferential diagnosis\nDifferential diagnosis includes organic acidemias that may present hyperglycinemia such as D-glyceric acidemia, propionic acidemia, methylmalonic acidemia, isovaleric acidemia, and ketoacidosis due to beta-ketothiolase deficiency (see these terms). Conditions characterized by neonatal seizures should also be considered. Valproate treatment may cause hyperglycinemia.\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies can be performed either by molecular genetic testing of the causative genes or by GCS enzyme analysis of chorionic villi sample.\nGenetic counseling\nGlycine encephalopathy is inherited in an autosomal recessive manner.\nManagement and treatment\nThe following tests should be used to guide treatment: brain MRI, EEG, and developmental and neurological assessment. There are only supportive and symptomatic measures for GE including antiepileptics for seizure control, placement of a gastrostomy tube for swallowing disorders, and treatment for gastroesophageal reflux. Sodium benzoate is used to reduce plasma glycine levels. NMDA receptor antagonists may ameliorate neurological symptoms although it remains to be established whether they improve long term outcome.\nPrognosis\nPrognosis depends on disease severity. Most patients with neonatal or infantile forms have a severe outcome. In the neonatal form, early death sometimes occurs due to apnea. Prognosis in atypical cases is variable.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                             Shigeo KURE"}
{"Disease Name": "Glycogen storage disease due to acid maltase deficiency, infantile onset", "Disease Definition": "Glycogen storage disease due to acid maltase deficiency, infantile onset is the most severe form of glycogen storage disease due to acid maltase deficiency, characterized by cardiomegaly with respiratory distress, muscle weakness and feeding difficulties. It is often fatal.", "ORPHA ID": 308552, "Summary": ""}
{"Disease Name": "Glycogen storage disease due to acid maltase deficiency, late-onset", "Disease Definition": "A rare form of glycogen storage disease due to acid maltase deficiency characterized by excessive accumulation of glycogen in lysosomes most notably in skeletal muscle, leading to slowly progressive muscle weakness with walking disability and reduced respiratory function. The late-onset form includes all cases in which hypertrophic cardiomyopathy did not manifest or was not diagnosed at or under the age of 1 year, as well as all cases with symptom onset above the age of 1 year.", "ORPHA ID": 420429, "Summary": ""}
{"Disease Name": "Glycogen storage disease due to acid maltase deficiency", "Disease Definition": "A rare lysosomal storage disease characterized by lysosomal accumulation of glycogen particularly in skeletal, cardiac, and respiratory muscles, as well as the liver and nervous system, due to acid maltase deficiency. The clinical spectrum comprises infantile-onset disease with severe hypertrophic cardiomyopathy, generalized muscle weakness, poor feeding and failure to thrive, and respiratory insufficiency, and late-onset disease manifesting before or after twelve months of age without cardiomyopathy, with proximal muscle weakness and respiratory insufficiency.", "ORPHA ID": 365, "Summary": ""}
{"Disease Name": "Glycogen storage disease due to aldolase A deficiency", "Disease Definition": "Glycogen storage disease due to aldolase A deficiency is an extremely rare glycogen storage disease (see this term) characterized by hemolytic anemia with or without myopathy or intellectual deficit. Myopathy can be severe enough to result in fatal rhabdomyolysis in some patients. A family with episodic rhabdomyolysis (triggered by fever) without hemolytic anemia has recently been reported.", "ORPHA ID": 57, "Summary": ""}
{"Disease Name": "Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia", "Disease Definition": "Glycogenosis due to glucose-6-phosphatase deficiency (G6P) type a, or glycogen storage disease (GSD) type 1a, is a type of glycogenosis due to G6P deficiency (see this term).", "ORPHA ID": 79258, "Summary": "Epidemiology\nPrevalence is unknown. Annual incidence at birth of glycogenosis due to G6P deficiency is around 1/100,000. Type a is the more frequent type, affecting about 80% of patients.\nClinical description\nThe disease may manifest at birth by enlarged liver or, more commonly, between the ages of three to four months by symptoms of fast-induced hypoglycemia (tremors, seizures, cyanosis, and apnea). Patients present disturbed glucose homeostasis usually characterized by poor tolerance to fasting, significant hepatomegaly (sometimes eight to ten cm below the right costal margin), growth retardation (short stature and delayed puberty), generally improved by an appropriate diet, osteopenia and, in some cases, osteoporosis, round doll-like facial appearance with full cheeks, mild hypotonia, nephromegaly, and platelet dysfunction that may lead to frequent epistaxis. Diarrhea may be encountered. Late complications are hepatic (adenomas with rare but possible transformation into hepatocellular carcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal failure), but also include anemia, sometimes severe, and a risk of hypoglycemic brain damage. Pulmonary hypertension has been reported in few cases.\nEtiology\nThe disease is due to a dysfunction in the G6P system, a key step in glycemia regulation. Type a is due to mutations in the G6PC gene (17q21), which cause a deficit of the catalytic subunit G6P-alpha expressed in the liver, kidney and intestine. Many mutations have been identified, illustrating the allelic heterogeneity of the condition.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nManagement is similar in both types of glycogenosis due to G6P deficiency (see this term).\n\n                            Last update: \n                            November 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe LABRUNE"}
{"Disease Name": "Glycogen storage disease due to glucose-6-phosphatase deficiency type Ib", "Disease Definition": "Glycogenosis due to glucose-6-phosphatase deficiency (G6P) type b, or glycogen storage disease (GSD) type 1b, is a type of glycogenosis due to G6P deficiency (see this term).", "ORPHA ID": 79259, "Summary": "Epidemiology\nPrevalence is unknown. Annual incidence at birth of glycogenosis due to G6P deficiency is around 1/100,000. Type b is the less frequent type, affecting about 20% of patients.\nClinical description\nClinical presentation is similar to that of glycogenosis due to G6P deficiency type a (see this term). In addition, in type b, neutropenia, and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphthous gingivostomatitis, and inflammatory bowel disease.\nEtiology\nThe disease is due to a dysfunction in the G6P system, a key step in glycemia regulation. Type b is due to mutations in the SLC37A4 gene (11q23), which cause a deficit of the ubiquitously expressed G6P transporter, or G6P translocase (G6PT). Many mutations have been identified, illustrating the allelic heterogeneity of the condition.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nManagement is similar in both types of glycogenosis due to G6P deficiency (see this term). However, in type b, periodic antibiotic therapy may be needed, and, under careful monitoring, granulocyte colony-stimulating factor (G-CSF or GCSF) enables correction of neutropenia with reduction of infections and inflammatory bowel disease.\n\n                            Last update: \n                            November 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe LABRUNE"}
{"Disease Name": "Glycogen storage disease due to glucose-6-phosphatase deficiency", "Disease Definition": "A rare inherited metabolic disease (comprising two major subtypes: type Ia and Ib) characterized by poor tolerance to fasting, growth delay and hepatomegaly resulting from accumulation of glycogen and fat in the liver.", "ORPHA ID": 364, "Summary": "Epidemiology\nPrevalence is unknown. Annual incidence at birth is around 1/100,000. Type Ia affects 80% of patients, and type Ib 20%.\nClinical description\nThe disease may manifest at birth by hepatomegaly or, more commonly, between the ages of three to four months by symptoms of fast-induced hypoglycemia. Patients have enlarged liver, growth delay, osteopenia, sometimes osteoporosis, full-cheeked round face, nephromegaly and frequent epistaxis due to platelet dysfunction. In addition, in type b, infections and inflammatory bowel disease are due to neutropenia and neutrophil dysfunction. Late complications are hepatic (hepatocellular adenomas and more rarely hepatocellular carcinoma) and renal (proteinuria and sometimes renal insufficiency).\nEtiology\nThe disease is due to a dysfunction in the G6P system, a key step in glycemia regulation. Mutations in the G6PC gene (17q21) cause a deficit of the catalytic subunit G6P-alpha restricted to expression in the liver, kidney and intestine (type a), and mutations in the SLC37A4 gene (11q23) cause a deficit of the ubiquitously expressed G6P transporter (G6PT) or G6P translocase (type b).\nDiagnostic methods\nDiagnosis is based on clinical presentation, and glycemia and lactacidemia levels, after a meal (hyperglycemia and hypolactacidemia), and after three to four hours fasting (hypoglycemia and hyperlactacidemia). Uric acid, triglycerides, and cholesterol serum levels are increased. There is no glycemic response to glucagon. Molecular genetic testing enables confirmation of diagnosis. Liver biopsy to measure G6P activity is no longer performed.\nDifferential diagnosis\nDifferential diagnoses include the other glycogenoses, in particular glycogen storage disease due to glycogen debranching enzyme deficiency (GDE deficiency) or GSD type III but in this case, glycemia and lactacidemia are high after a meal and low in a fasting period. Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but easily ruled out through clinical and ultrasound data.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube or a gastrostomy (only in type Ia patients), and later oral addition of uncooked starch), acidosis (restricted fructose and galactose intake, oral supplementation in bicarbonate), hypertriglyceridemia (diet, cholestyramine, statines), hyperuricemia (allopurinol) and hepatic complications. Renal protection using converting enzyme inhibitors must be started should microalbuminuria be detected. Liver transplantation, performed on the basis of poor metabolic control or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type b. Kidney transplantation can be performed in case of severe renal failure. Combined liver-kidney grafts have been performed in a few cases.\nPrognosis\nWith adapted management, prognosis is better: patients have almost normal life span.\n\n                            Last update: \n                            October 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe LABRUNE | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Glycogen storage disease due to glycogen branching enzyme deficiency", "Disease Definition": "Glycogen branching enzyme (GBE) deficiency (Andersen's disease or amylopectinosis), or glycogen storage disease type 4 (GSD4), is a rare and severe form of glycogen storage disease which accounts for approximately 3% of all the glycogen storage diseases (see these terms).", "ORPHA ID": 367, "Summary": "Clinical description\nClinical presentation is extremely heterogeneous and involves the liver or the neuromuscular system. In the classical form, children are normal at birth, but develop hepatomegaly, hypotonia, and developmental delay during their first months. The disease then rapidly progresses to cirrhosis with portal hypertension and ascites, ultimately causing death in early childhood. A non-progressing hepatic form has been reported in a few cases. In the neuromuscular presentation, the age of onset ranges from fetal to adult age. The most severe form starts before birth with decrease or absence of fetal movements, arthrogryposis, hypoplastic lungs, and perinatal death. Patients with congenital forms have severe hypotonia, cardiomyopathy, depressed respiration and neuronal involvement. Milder forms have been reported with later-onset, marked by muscular weakness or cardiomyopathy and heart failure. Neurological adult forms with central and peripheral nervous system dysfunction have also been described, such as Adult Polyglucosan Body Disease (APBD; see this term), which is characterized by widespread upper and lower motor neuron lesions.\nEtiology\nThe disease is caused by mutations in the GBE1 gene (3p12) encoding GBE. GBE deficiency results in storage of abnormal glycogen that resembles an amylopectin-like structure (polyglucosan).\nDiagnostic methods\nThe diagnosis is based on biochemical findings from a liver biopsy, revealing an abnormal glycogen content, and on the evidence of enzymatic deficiency in the liver, muscle, erythrocytes, or fibroblasts, and in the trophoblast or cultured amniotic cells.\nDifferential diagnosis\nDifferential diagnoses include galactosemia, hydrops fetalis, and tyrosinemia (see these terms).APBD can also present with or without GBE deficiency indicating that different biochemical defects could result in an identical phenotype.\nAntenatal diagnosis\nPrenatal diagnosis is possible by enzyme assay and/or DNA analysis.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nThere is no specific treatment. A liver transplant can be proposed in severe forms without associated heart disease.\nPrognosis\nPrognosis is unfavorable for patients with perinatal onset and classic forms who do not undergo liver transplantation. Long-term prognosis for others depends on the extent, severity, and progression of the condition.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART"}
{"Disease Name": "Glycogen storage disease due to glycogen debranching enzyme deficiency", "Disease Definition": "Glycogen debranching enzyme (GDE) deficiency, or glycogen storage disease type 3 (GSD 3), is a form of glycogen storage disease characterized by severe muscle weakness and hepatopathy.", "ORPHA ID": 366, "Summary": "Epidemiology\nEstimated prevalence is approximately 1/100,000 births (it may be higher among North Africans).\nClinical description\nGSD 3 commonly occurs in early childhood. Children present with hepatomegaly, growth retardation and occasional seizures related to hypoglycemia. Hepatomegaly may disappear with adulthood. Muscle weakness is slowly progressive. Other frequently associated signs include muscular hypotonia and hypertrophic cardiomyopathy. Symptoms often improve at puberty, except in the few cases where cirrhosis or myopathy appears. Biological findings include hypoglycemia without acidosis, hypertriglyceridemia, and hypertransaminasemia during childhood.\nEtiology\nThe disease is caused by mutations in the AGL gene (1p21), leading to a deficiency in the GDE that works with the glycogen phosphorylase to catabolize glycogen. The deficiency may occur in the liver and muscle (GSD 3a) or only in the liver (GSD 3b).\nDiagnostic methods\nThe diagnosis is based on the evidence of enzymatic deficiency in fresh leukocytes, fibroblasts, or on a liver or a muscle biopsy. Unlike GSD type 1 (see this term), there is a response to glucagon after meals.\nDifferential diagnosis\nDifferential diagnoses include the other forms of glycogen storage diseases (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible by enzyme assay and/or DNA analysis.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment is based on a specific diet, with enteral nasogastric drip feeding at night in case of hypoglycemia, frequent meals, and uncooked starch supplements. For patients with myopathy, a high protein diet is also recommended.\nPrognosis\nRarely, patients may develop complications such as hepatic failure or hepatocellular carcinoma.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART"}
{"Disease Name": "Glycogen storage disease due to hepatic glycogen synthase deficiency", "Disease Definition": "A genetically inherited anomaly of glycogen metabolism and a form of glycogen storage disease (GSD) characterized by fasting hypoglycemia. This is not a glycogenosis, strictly speaking, as the enzyme deficiency decreases glycogen reserves.", "ORPHA ID": 2089, "Summary": "Epidemiology\nIt is an extremely rare disease; about 20 cases have been reported in the literature so far.\nClinical description\nIt commonly appears in infancy or in early childhood. Patients present with morning fatigue and fasting hypoglycemia (without hepatomegaly) associated with hyperketonemia but without hyperalaninemia or hyperlactacidemia. After meals, major hyperglycemia associated with lactate and alanine increase and hyperlipidemia is observed.\nEtiology\nGlycogen synthetase deficiency is caused by mutations in the GYS2 gene (12p12.2).\nDiagnostic methods\nBiological results after glucose loading test strongly suggest the diagnosis, but formal diagnosis requires a liver biopsy showing a slightly decreased glycogen concentration and evidence of the enzyme deficiency (it is not expressed in muscles, erythrocytes, leukocytes, or fibroblasts). Molecular analysis revealing a mutation in the GYS2 gene confirms the diagnosis. Mutation analysis is an alternative to liver biopsy.\nDifferential diagnosis\nDifferential diagnoses include fructose intolerance, GSD type 1 (see these terms), and hypoglycemia.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nThe condition is treated with a specific diet that includes frequent meals with high protein intake during the day and addition of uncooked starch in the evening.\nPrognosis\nPrognosis is favorable when the disease is correctly managed.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART"}
{"Disease Name": "Glycogen storage disease due to lactate dehydrogenase deficiency", "Disease Definition": "A rare genetic glycogen storage disease characterized by either lactate dehydrogenase (LDH) M- or H-subunit deficiency. Main features of LDH M-subunit deficiency are exertional fatigue and muscle pain potentially accompanied by myoglobinuria. Some patients may develop pustular psoriasis-like skin lesions. Complications of pregnancy, such as frequent abdominal pains and increased uterine tone with a risk of dystocia have also been described. LDH H-subunit deficiency manifests with low serum LDH activity of unclear clinical relevance.", "ORPHA ID": 2364, "Summary": ""}
{"Disease Name": "Glycogen storage disease due to lactate dehydrogenase M-subunit deficiency", "Disease Definition": "A rare glycogen storage disease characterized by easy fatigue, exertional myalgia, painful muscle stiffness, and cramps, with or without myoglobinuria. Pustular psoriasis-like eruptions with antecedent annular scaly plaques may be observed in some patients. In affected women, pregnancy may be complicated by abdominal pain and dystocia.", "ORPHA ID": 284426, "Summary": ""}
{"Disease Name": "Glycogen storage disease due to liver and muscle phosphorylase kinase deficiency", "Disease Definition": "A benign inborn error of glycogen metabolism. It is the mildest form of GSD due to PhK deficiency.", "ORPHA ID": 79240, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe disease manifests in childhood. Patients have marked hepatomegaly and mild muscular hypotonia. Hypoglycemia may occur only after prolonged fasting. These symptoms improve with age and adults are generally asymptomatic.\nEtiology\nPhosphorylase kinase (PhK) is an enzyme which plays a key role in the regulation of glycogenolysis as it is required for glycogen phosphorylase activation. It consists of four copies of each four subunits (alpha, beta, gamma and calmoduline) encoded by different genes on different chromosomes and differentially expressed in various tissues. GSD due to liver and muscle PhK deficiency is due to mutations in the PHKB gene (16q12-q13) which encodes the beta subunit.\nDiagnostic methods\nBiochemical diagnosis can be made by measuring phosphorylase kinase activity in blood cells or in a liver or muscle biopsy. Serum transaminase levels may also be elevated. Genetic testing is useful to confirm or establish the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other glycogen storage diseases such as GSD due to liver phosphorylase deficiency (GSD type VI), GSD due to glycogen debranching enzyme deficiency (GSD type III), and GSD due to glucose-6-phosphatase (GSD type I) (see these terms).\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nMost patients do not require any specific treatment; a few patients may need to use cornstarch snacks.\nPrognosis\nPrognosis is good.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART  - Pr Philippe LABRUNE"}
{"Disease Name": "Glycogen storage disease due to liver glycogen phosphorylase deficiency", "Disease Definition": "Liver phosphorylase deficiency, or glycogen storage disease type 6b (Hers' disease, GSD 6b) is a benign and rare form of glycogen storage disease.", "ORPHA ID": 369, "Summary": "Clinical description\nThe disease usually occurs in childhood and is characterized by hepatomegaly and growth delay. Hypoglycemic episodes are mild or absent, and hypertransaminasemia and hyperlipidemia are moderate and unconstant. Hepatomegaly usually improves with age and disappears entirely at puberty.\nEtiology\nTransmission is autosomal recessive and mutations in the PYGL gene (14q21-q22) have been identified in patients.\nDiagnostic methods\nDiagnosis is based on biochemical findings revealing excess glycogen and partial deficiency of total and active phosphorylase in liver biopsy.\nManagement and treatment\nA diet with high carbohydrate intake and regular meals prevents hypoglycemia in children, but most patients require no specific treatment.\nPrognosis\nPrognosis is usually good.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART"}
{"Disease Name": "Glycogen storage disease due to liver phosphorylase kinase deficiency", "Disease Definition": "Glycogen storage disease (GSD) due to liver phosphorylase kinase (PhK) deficiency is a benign inborn error of glycogen metabolism characterized by hepatomegaly, growth retardation, and mild delay in motor development during childhood.", "ORPHA ID": 264580, "Summary": "Epidemiology\nIt is the most common presentation of glycogen storage disease due to PhK deficiency (see this term) with an incidence estimated at less than 1/100,000 births.\nClinical description\nPatients usually present in early childhood with hepatomegaly, growth retardation, and mild delay in motor development. Fast-induced hypoglycemia and hyperlipidemia are variable and, if present, are generally mild. Adults are generally asymptomatic. Full-cheeked round face and osteopenia have been reported on exceptional occasions in cases with an X-linked inheritance. An increased risk of cirrhosis due to liver fibrosis is observed in cases with autosomal recessive inheritance.\nEtiology\nPhosphorylase kinase (PhK) is an enzyme which plays a key role in the regulation of glycogenolysis as it is required for glycogen phosphorylase activation. It consists of four copies of each four subunits (alpha, beta, gamma and calmodulin) encoded by different genes on different chromosomes and differentially expressed in various tissues. The most frequent type of GSD due to liver PhK deficiency is the X-linked recessive (XLG) type that is due to mutations in the PHKA2 gene (Xp22.2-p22.1) encoding the liver isoform of the alpha-subunit. When the enzymatic deficiency is found both in erythrocytes and liver cells, the disorder is classified as XLG1, whereas when the deficiency can only be demonstrated in liver cells, it is classified as XLG2, although studies have shown that, in both cases, mutations occur within the same subunit. The autosomal recessive type is due to mutations in the PHKG2 gene (16p12.1-p11.2) encoding the liver isoform of the gamma-subunit. PhK deficiency due to all these mutations leads to glycogen accumulation in the liver.\nDiagnostic methods\nBiochemical diagnosis is made by measuring phosphorylase kinase activity in blood cells or in a liver biopsy. Some patients may have normal activity in red blood cells (XLG2 variant). Serum transaminase levels may be elevated. Genetic testing is useful to confirm or establish the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other glycogen storage diseases such as GSD due to liver phosphorylase deficiency (GSD type VI), GSD due to glycogen debranching enzyme deficiency (GSD type III), and GSD due to glucose-6-phosphatase deficiency (GSD type I) (see these terms).\nManagement and treatment\nMost patients require no specific treatment. Hypoglycemia can be controlled by adequate dietary treatment (frequent meals rich in carbohydrates, and supplements of uncooked starch).\nPrognosis\nThe clinical course is benign with patients reaching their full height and weight during adulthood. Life expectancy is normal.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART  - Pr Philippe LABRUNE"}
{"Disease Name": "Glycogen storage disease due to muscle and heart glycogen synthase deficiency", "Disease Definition": "Glycogen storage disease due to muscle and heart glycogen synthase deficiency is characterised by muscle and heart glycogen deficiency. It has been described in three siblings (two brothers and their younger sister). The older brother died at 10.5 years of age as a result of sudden cardiac arrest and the younger brother presented with hypertrophic cardiomyopathy, abnormal heart rate and blood pressure during exercise, and muscle fatigability. The sister showed no symptoms but a lack of glycogen was identified through muscle biopsy. The syndrome is caused by homozygous missense mutations in the gene encoding muscle glycogen synthase.", "ORPHA ID": 137625, "Summary": ""}
{"Disease Name": "Glycogen storage disease due to muscle beta-enolase deficiency", "Disease Definition": "A rare glycolysis disorder characterized clinically by exercise intolerance and myalgia due to severe enolase deficiency in muscle.", "ORPHA ID": 99849, "Summary": ""}
{"Disease Name": "Glycogen storage disease due to muscle glycogen phosphorylase deficiency", "Disease Definition": "Myophosphorylase deficiency (McArdle's disease), or glycogen storage disease type 5 (GSD5) , is a severe form of glycogen storage disease characterized by exercise intolerance.", "ORPHA ID": 368, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nOnset occurs in childhood. Patients present with a syndrome of muscular exercise intolerance with myalgia, cramps, fatigue, and muscle weakness. Massive elevation of creatine-kinase and rhabdomyolysis with myoglobinuria (dark urine) after exercise is noted in around 50% of patients, potentially leading to acute kidney failure. A 'second wind' phenomenon with relief of myalgia and fatigue after a few minutes of rest is observed in many patients. The clinical presentation is usually very classical, but some patients may have very moderate forms. In a few cases, onset very early in life with hypotonia, generalized muscle weakness and progressive respiratory failure has been described.\nEtiology\nThe condition is caused by mutations in the PYGM gene (11q13), leading to muscle phosphorylase deficiency. Mutation p.R50X may account for 40% to 50% of the alleles in Caucasian populations.\nDiagnostic methods\nThe diagnosis is based on biological findings revealing a lack of lactate elevation in blood during ischemic forearm test, excess glycogen, and deficient phosphorylase activity in the muscle biopsy.\nDifferential diagnosis\nThe differential diagnosis should include GSD type 7 (see this term).\nGenetic counseling\nThe condition is autosomal recessive.\nManagement and treatment\nTreatment is based on controlled physical training in order to develop mitochondrial oxidation capacities in muscles, and programmed glucose intake according to exercising periods. Diets with high protein intake have yielded variable results.\nPrognosis\nPrognosis is favorable when severe rhabdomyolysis is avoided. However, myoglobinuria may lead to potentially life-threatening renal failure.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART"}
{"Disease Name": "Glycogen storage disease due to muscle phosphofructokinase deficiency", "Disease Definition": "Muscle phosphofructokinase (PFK) deficiency (Tarui's disease), or glycogen storage disease type 7 (GSD7), is a rare form of glycogen storage disease characterized by exertional fatigue and muscular exercise intolerance. It occurs in childhood.", "ORPHA ID": 371, "Summary": "Epidemiology\nAbout 100 cases have been reported worldwide.\nClinical description\nClinical signs are muscular exercise intolerance (more severe than in type 5; see this term). Compensated hemolysis (increased bilirubin and reticulocytes) and hyperuricemia are associated. A rapidly fatal infant form has also been observed in 6 families.\nEtiology\nThe condition is caused by mutations in the PFKM gene (12q13) encoding the muscular isoenzyme of PFK, a key enzyme in the regulation of anaerobic glycolysis which has 3 isoenzymes (for the muscle, liver, and platelets).\nDiagnostic methods\nThe diagnosis is based on biological findings, revealing increased amounts of abnormal glycogen and enzyme deficiency (1 to 33% residual activity) in a muscle biopsy, whereas activity in erythrocytes is over 50%.\nDifferential diagnosis\nDifferential diagnoses include the other forms of glycogen storage disease (see these terms).\nGenetic counseling\nThe condition is autosomal recessive, although a few cases with pseudodominance or symptomatic heterozygous individuals have been found.\nManagement and treatment\nThe only treatment is to avoid intensive exercise. It should be noted that carbohydrates induce lower muscular performance (due to the decreased amounts of free fatty acids and ketone bodies).\nPrognosis\nMyoglobinuria may lead to renal failure.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART"}
{"Disease Name": "Glycogen storage disease due to muscle phosphorylase kinase deficiency", "Disease Definition": "Glycogen storage disease due to muscle phosphorylase kinase (PhK) deficiency is a benign inborn error of glycogen metabolism characterized by exercise intolerance.", "ORPHA ID": 715, "Summary": "Epidemiology\nThe disease is very rare with less than 30 patients reported in the literature.\nClinical description\nThe disease starts generally in adolescence or adulthood. Patients may present with exercise intolerance with myalgia, cramps, fatigue, and sometimes myoglobinuria. In some cases, patients may present with progressive muscle weakness. Symptoms are usually mild, and myopathy may be asymptomatic. A neonatal form with generalized muscular hypotonia and respiratory insufficiency has also been described.\nEtiology\nPhosphorylase kinase (PhK) is an enzyme which plays a key role in the regulation of glycogenolysis as it is required for glycogen phosphorylase activation. It consists of four copies of each four subunits (alpha, beta, gamma and calmoduline) encoded by different genes on different chromosomes and differentially expressed in various tissues. Muscle-specific isoforms of the alpha and gamma subunits are encoded by the PHKA1 gene and the PHKG1 gene respectively, but until now mutations have been only identified in the PHKA1 gene and the transmission is X-linked.\nDiagnostic methods\nBiochemical diagnosis of the muscle form can be made by measuring phosphorylase kinase activity in a muscle biopsy. Genetic testing is useful to confirm or establish the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include GSD due to myophosphorylase deficiency (GSD type V), and other GSDs affecting the muscle (GSD types XI, XII, XIII and XIV) (see these terms).\nManagement and treatment\nMost patients do not require any specific treatment.\nPrognosis\nPrognosis is generally good.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART  - Pr Philippe LABRUNE  - Pr Pascal LAFORET"}
{"Disease Name": "Glycogen storage disease due to phosphoglycerate kinase 1 deficiency", "Disease Definition": "A rare inborn errors of metabolism characterized by variable combinations of non-spherocytic hemolytic anemia, myopathy, and various central nervous system abnormalities.", "ORPHA ID": 713, "Summary": "Epidemiology\nPhosphoglycerate kinase (PGK) deficiency prevalence is unknown but about 30 unrelated affected families have been reported so far.\nClinical description\nThe majority of patients present with chronic hemolytic anemia, which may be severe in some cases. Myopathy is a common finding and is characterized by exercise-intolerance, muscle weakness, cramping, myalgia and episodes of myoglobinuria. Rhabdomyolysis has also been reported in a few patients. Intellectual deficit is frequent, and other central nervous system manifestations may be also present including hemiplegic migraines, epilepsy, ataxia and tremor. Only a few patients show all three cardinal features of the disorder (hemolytic anemia, central nervous system abnormalities and myopathy), and several cases of PGK deficiency with myopathy in the absence of hemolytic anemia have been reported. Only one asymptomatic patient has been described with mild PGK deficiency.\nEtiology\nPGK deficiency is caused by mutations in the PGK1 gene (Xq13.3) and around 20 different disease-causing variants have been identified so far in affected families. PGK is a key enzyme in the glycolytic pathway catalyzing the conversion of 1,3-bisphosphoglycerate into 3-phosphoglycerate and generating ATP. PGK is a ubiquitous enzyme expressed in all tissues except the testes.\nDiagnostic methods\nDiagnosis is made on the basis of the clinical picture, together with biochemical studies revealing low erythrocyte and muscle PGK enzyme activity (below 23% and 25% of normal respectively), and identification of PGK1 gene mutations by molecular analysis.\nDifferential diagnosis\nThe differential diagnosis should include other causes of hereditary non-spherocytic hemolytic anemia.\nAntenatal diagnosis\nMolecular prenatal diagnosis is feasible for families of an index case.\nGenetic counseling\nPGK deficiency is inherited as an X-linked trait and most of the reported patients were hemizygous males. However, heterozygous females may have a variable degree of hemolytic anemia. All women born to affected men will be carriers (mild manifesting or not) with no male to male transmission. Female carriers have a 50 % risk of an affected male or female carrier with each pregnancy.\nManagement and treatment\nIn patients with severe chronic anemia, regular blood transfusions are required. Splenectomy has been shown to be beneficial in some cases.\nPrognosis\nThe prognosis is variable, depending on the severity of the anemia and on the presence of the other manifestations.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Mark TARNOPOLSKY"}
{"Disease Name": "Glycogen storage disease due to phosphoglycerate mutase deficiency", "Disease Definition": "A rare glycogen storage disease characterized by susceptibility to rhabdomyolysis complicated by episodes of exercise-induced muscle pain, cramping, and myoglobinuria. Tubular aggregates may be present on muscle biopsy.", "ORPHA ID": 97234, "Summary": "Epidemiology\nThe prevalence of this disease is still unknown. Fewer than 50 cases were reported worldwide. About half of the identified cases are related to the p.W78X variant (most common in patients with African American ancestry) with the remaining cases coming from other ethnic groups in the United States, Europe, and the Middle East.\nClinical description\nGlycogen storage disease due to phosphoglycerate mutase deficiency (also known as GSD type X) is characterized by exercise intolerance leading to rhabdomyolysis which manifests through muscle cramps and pain accompanied by acute renal symptoms such as myoglobinuria. In the majority of cases, intense physical exercise is accompanied by abnormal elevation of creatine kinase, which persists between exertional episodes. Some patients present with glycogen accumulation and tubular aggregates within the skeletal muscle cells on muscle biopsy. Due to low specificity of the symptoms, many patients remain undiagnosed.\nEtiology\nThe disease is caused by homozygous or compound heterozygous variants of the PGAM2 gene which encodes the muscle isoenzyme of phosphoglycerate mutase (PGAM2), a terminal glycolysis enzyme. PGAM2 reversibly catalyzes the conversion reaction of 3-phosphoglycerate (3-PGA) to 2-phosphoglycerate (2-PGA), which is then further metabolized to produce pyruvate. During exercise, insufficient residual PGAM2 activity results in the inability to catabolize enough glucose to meet the increased energy needs of the muscle cells. This leads to a decrease in intracellular ATP levels and an increase in intracellular calcium levels which cause the breakdown of skeletal muscle (rhabdomyolysis), resulting in symptoms of muscle soreness, cramping, and dark urine.\nDiagnostic methods\nA patient presenting with exercise intolerance with episodes of rhabdomyolysis characterized by abnormal creatine kinase levels persisting after exercise, abnormally elevated aspartate aminotransferase and alanine aminotransferase levels (which are secondarily elevated in the setting of hyperCKemia), and detection of myoglobinuria, should raise suspicion of a metabolic myopathy. Forearm ischemic exercise test (FIET) will produce an abnormally low increase of lactate concentration. Skeletal muscle biopsy reveals tubular aggregates and may show glycogen accumulation. To establish the final diagnosis, the most reliable method is sequencing of PGAM2 for biallelic pathogenic or likely pathogenic variants.\nDifferential diagnosis\nThe differential diagnosis is based on a clinical picture of myalgia and includes beta-oxidation defects, mitochondrial diseases, and other glycogen storage diseases (GSD), particularly GSD type V and GSD type VII which share features of sensitivity to rhabdomyolysis with GSD type X, as well as a lesser increase in lactate production compared to the norm following exercise. Tubular aggregates visible on muscle biopsy are specific to GSD type X.\nGenetic counseling\nThe transmission is autosomal recessive. Genetic counseling can be offered to at-risk couples to inform them of the 25% risk of transmission to offsprings.\nManagement and treatment\nThe management of the disease is adapted to the patient's symptoms. Patients should be informed that strenuous exercises can trigger episodes of rhabdomyolysis and myoglobinuria. Limitation of simple carbohydrates in the diet is of theoretical benefit; dietary therapy has not been systemically studied in GSD type X. Regular, low-intensity exercise under optimal hydration conditions may reduce the intensity of muscle symptoms. To date, there is no treatment that replaces or restores PGAM2 activity.\nPrognosis\nGSD type X is not thought to impact the longevity of affected individuals. It is important to recognize and treat episodes of rhabdomyolysis promptly should they occur, as rhabdomyolysis can lead to significant morbidity and mortality, including multiorgan failure, if left untreated.\n\n                            Last update: \n                            September 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Benjamin COCANOUGHER  - Dr Priya KISHNANI  - Dr Rebecca KOCH"}
{"Disease Name": "Glycogen storage disease due to phosphorylase kinase deficiency", "Disease Definition": "Glycogen storage disease (GSD) due to phosphorylase kinase deficiency is a group of inborn errors of glycogen metabolism that is clinically and genetically heterogeneous. This group comprises GSD due to liver phosphorylase kinase (PhK) deficiency, GSD due to muscle PhK deficiency and GSD due to liver and muscle PhK deficiency (see these terms).", "ORPHA ID": 370, "Summary": "Epidemiology\nThe prevalence at birth is estimated at around 1/100,000.\nClinical description\nGSD due to liver PhK deficiency is the most common sub-type and presents in early childhood with hepatomegaly, growth retardation, and mild delay in motor development. During adulthood, symptoms usually disappear. Patients with GSD due to liver and muscle PhK deficiency may have marked hepatomegaly and mild muscular hypotonia in childhood. GSD due to muscle PhK deficiency presents in adolescence or adulthood with exercise intolerance, myalgia, and sometimes myoglobinuria but symptoms are generally mild.\nEtiology\nPhosphorylase kinase (PhK) is an enzyme which plays a key role in the regulation of glycogenolysis as it is required for glycogen phosphorylase activation. It consists of four copies of each four subunits (alpha, beta, gamma and calmoduline) encoded by different genes on different chromosomes and differentially expressed in various tissues. GSD due to liver PhK deficiency is due to mutations in the PHKA2 or PHKG2 genes encoding the liver isoforms of the alpha and gamma subunits of PhK. Transmission is X-linked and autosomal recessive, respectively. GSD due to liver and muscle PhK deficiency is transmitted in an autosomal recessive manner and is due to mutations in the PHKB gene which encodes the beta subunit of PhK. The muscle-specific isoforms of the alpha and gamma subunits of PhK are encoded by the PHKA1 and PHKG1 genes respectively, but until now mutations have only been found in the PHKA1 gene in patients with GSD due to muscle PhK deficiency. Transmission is X-linked.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART  - Pr Philippe LABRUNE  - Pr Pascal LAFORET"}
{"Disease Name": "Glycogen storage disease with severe cardiomyopathy due to glycogenin deficiency", "Disease Definition": "A rare autosomal recessive glycogen storage disease characterized by severe cardiomyopathy and cardiac dilatation potentially progressing to heart failure requiring transplantation. Cardiomyocytes show large inclusions of storage material consistent with polyglucosan. Clinical evidence of skeletal muscle involvement is usually absent.", "ORPHA ID": 263297, "Summary": ""}
{"Disease Name": "GM1 gangliosidosis type 1", "Disease Definition": "GM1 gangliosidosis type 1 is the severe infantile form of GM1 gangliosidosis (see this term) with variable neurological and systemic manifestations.", "ORPHA ID": 79255, "Summary": "Epidemiology\nType 1 is the most frequent form of GM1 gangliosidosis but the exact prevalence is not known. About 200 cases have been reported to date. Overall prevalence at birth of GM1 gangliosidosis is estimated to be approximately 1:100,000 to 200,000 live births.\nClinical description\nThe onset of this disorder may be in utero (non immune hydrops fetalis) or by the age of six months. Clinical signs are variable and include arrest/regression of neurological development, hypotonia, visceromegaly, macular cherry-red spots, dysostosis and coarse facial features. Cardiomyopathy may occur.\nEtiology\nGM1 gangliosidosis is caused by mutations in the GLB1 gene (3p22.3) coding for beta-galactosidase.\nDiagnostic methods\nDiagnosis is based on clinical signs although classic signs are not always present at diagnosis. Biochemical and/or molecular genetic tests confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes mucopolysaccharidoses, sphingolipidoses and oligosaccharidoses (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis can be performed by analysis of beta-galactosidase activity and/or by GLB1 molecular analysis in either chorionic villus (CV) cells or amniotic fluid cells if mutations are found in an index case.\nGenetic counseling\nGM1 gangliosidosis is an autosomal recessive disease. Genetic counseling should be provided to affected families.\nManagement and treatment\nTreatment for patients with GM1 gangliosidosis is symptomatic and supportive.\nPrognosis\nPrognosis is very poor with life-expectancy rarely exceeding 2 years. Causes of death include pneumonia due to recurrent aspiration and cardiopulmonary failure.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Anna CACIOTTI  - Dr Maria Alice DONATI  - Dr Amelia MORRONE"}
{"Disease Name": "GM1 gangliosidosis type 2", "Disease Definition": "GM1 gangliosidosis type 2 is a clinically variable, infancy or childhood-onset form of GM1 gangliosidosis (see this term) characterized by normal early development and psychomotor regression between seven months and three years of age.", "ORPHA ID": 79256, "Summary": "Epidemiology\nType 2 is a less frequent form of GM1 gangliosidosis compared to infantile type 1 disease but the exact prevalence, although unknown, is likely to be underestimated. Fewer than 50 cases have been reported to date. Overall prevalence at birth of GM1 gangliosidosis is estimated to be approximately 1:100,000 to 200,000 live births.\nClinical description\nPatients with the childhood form of this disorder develop signs and symptoms of intermediate severity including locomotor disturbances, strabismus, muscle weakness, seizures, lethargy and lung infections. Compared to type 1, visceromegaly and skeletal anomalies are milder or may be absent. Macular cherry-red spots are infrequent. The course of the disorder is characterized by slower progression. Facial coarsening develops over time.\nEtiology\nGM1 gangliosidosis is caused by mutations in the GLB1 gene (3p22.3) coding for beta-galactosidase.\nDiagnostic methods\nDiagnosis is suggested by clinical signs, such as psychomotor regression and facial coarsening. Biochemical and/or genetic tests confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes mucopolysaccharidoses, sphingolipidoses and oligosaccharidoses (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis can be performed by analysis of beta-galactosidase activity and/or by GLB1 molecular analysis in either chorionic villus (CV) cells or amniotic fluid cells if mutations are identified in an index case.\nGenetic counseling\nGM1 gangliosidosis is an autosomal recessive disease. Genetic counseling should be provided to affected families.\nManagement and treatment\nTreatment for patients with GM1 gangliosidosis is symptomatic and supportive.\nPrognosis\nPrognosis is poor with survival into mid-childhood or early adulthood.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Anna CACIOTTI  - Dr Maria Alice DONATI  - Dr Amelia MORRONE"}
{"Disease Name": "GM1 gangliosidosis type 3", "Disease Definition": "GM1 gangliosidosis type 3 is a mild, chronic, adult form of GM1 gangliosidosis (see this term) characterized by onset generally during childhood or adolescence and by cerebellar dysfunction.", "ORPHA ID": 79257, "Summary": "Epidemiology\nType 3 is a less frequent form of GM1 gangliosidosis compared to infantile type 1 disease but the exact prevalence, although unknown, is likely to be underestimated. About 70 cases have been reported to date. Overall prevalence at birth of GM1 gangliosidosis is estimated to be approximately 1:100,000 to 200,000 live births. Most reported cases are in patients of Japanese origin.\nClinical description\nMarked variability of clinical signs and age of onset has been reported. Patients generally show slowly progressive dementia, dysarthria, dystonia, short stature, mild vertebral anomalies and ataxia. Eye movements are normal.\nEtiology\nGM1 gangliosidosis is caused by mutations in the GLB1gene (3p22.3) coding for beta-galactosidase.\nDiagnostic methods\nDiagnosis is clinically suggested by dystonia and slurred speech, usually detected at school age. Biochemical and/or molecular genetic tests confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes mucopolysaccharidoses, sphingolipidoses and oligosaccharidoses (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis can be performed by analysis of beta-galactosidase activity and/or by GLB1 molecular analysis in either chorionic villus (CV) cells or amniotic fluid cells if mutations are identified in an index case.\nGenetic counseling\nGM1 gangliosidosis is an autosomal recessive disease. Genetic counseling should be provided to affected families.\nManagement and treatment\nTreatment for patients with GM1 gangliosidosis is symptomatic and supportive.\nPrognosis\nPrognosis is variable.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Anna CACIOTTI  - Dr Maria Alice DONATI  - Dr Amelia MORRONE"}
{"Disease Name": "GM1 gangliosidosis", "Disease Definition": "GM1 gangliosidosis is a rare lysosomal storage disorder characterized biochemically by deficient beta-galactosidase activity and clinically by a wide range of variable neurovisceral, ophthalmological and dysmorphic features.", "ORPHA ID": 354, "Summary": "Epidemiology\nThe disorder is panethnic but worldwide prevalence is not known. Prevalence at birth is estimated to be approximately 1:100,000 to 200,000 live births. High prevalence has been found in Malta and Brazil, and in the Cypriot and Roma populations.\nClinical description\nThere are three types of GM1 gangliosidosis based on the age of onset: a severe rapidly progressive infantile form with onset before six months of age (type 1 GM1 gangliosidosis), a late infantile or juvenile form with onset between seven months and 3 years of age with delayed motor and cognitive development (type 2 GM1 gangliosidosis), and an adult, chronic form with late onset between 3 and 30 years of age (type 3 GM1 gangliosidosis) characterized primarily by generalized dystonia (see these terms). Disease severity appears to be related to the level of beta-galactosidase activity.\nEtiology\nThe disorder is caused by mutations in the GLB1gene (3p22.3) coding for beta-galactosidase. To date, more than 165 mutations have been identified. Deficient enzyme activity leads to toxic accumulation of gangliosides in body tissues, and particularly in the central nervous system (CNS).\nDiagnostic methods\nDiagnosis may be difficult due to the wide clinical spectrum of the disease. Clinical suspicion is based on signs of storage such as facial coarsening, hypertrophic gums, cherry-red macula, visceromegaly, dysostosis and psychomotor delay. Peripheral blood smear (testing vacuolated lymphocytes) and urine oligosaccharides are good orientation tests. Gaucher-like foam cells have been reported on bone marrow examination. Diagnosis is confirmed by biochemical assay of beta-galactosidase activity and/or by molecular genetic testing. A secondary combined defect of both GLB1 and neuraminidase (NEU1) (causing galactosialidosis; see this term) has to be excluded.\nDifferential diagnosis\nDifferential diagnosis includes mucopolysaccharidoses, sphingolipidoses and oligosaccharidoses (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis can be performed by analysis of beta-galactosidase activity and/or by GLB1 molecular analysis in either chorionic villus (CV) cells or amniotic fluid cells, if mutations are identified in an index case.\nGenetic counseling\nGM1 gangliosidosis is an autosomal recessive disease. Genetic counseling should be provided to affected families.\nManagement and treatment\nTreatment for patients with GM1 gangliosidosis is symptomatic and supportive. Substrate reduction therapy is a potential approach for clinical trials in late-onset forms.\nPrognosis\nPrognosis depends on the type of GM1 gangliosidosis and is extremely poor in the severe infantile form and variable in the chronic adult form of the disease.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Anna CACIOTTI  - Dr Maria Alice DONATI  - Dr Amelia MORRONE"}
{"Disease Name": "GM2 gangliosidosis, AB variant", "Disease Definition": "GM2 gangliosidosis, AB variant is an extremely rare, severe genetic disorder characterized by progressive neurological decline due to ganglioside activator deficiency.", "ORPHA ID": 309246, "Summary": ""}
{"Disease Name": "GM3 synthase deficiency", "Disease Definition": "GM3 synthase deficiency is a rare congenital disorder of glycosylation due to impaired synthesis of complex ganglioside species initially characterized by irritability, poor feeding, failure to thrive and early-onset refractory epilepsy, followed by postnatal growth impairment, severe developmental delay or developmental regression, profound intellectual disability, deafness and abnormalities of skin pigmentation (mostly freckle-like hyperpigmented and depigmented macules). Visual impairment due to cortical atrophy (visible on magnetic resonance imaging), choreoathetosis and hypotonic tetraparesis usually appear gradually. Dysmorphic facial features may be associated.", "ORPHA ID": 370933, "Summary": ""}
{"Disease Name": "GMPPB-related limb-girdle muscular dystrophy R19", "Disease Definition": "A form of limb-girdle muscular dystrophy, that can present from birth to early childhood, characterized by hypotonia, microcephaly, mild proximal muscle weakness (leading to delayed walking and difficulty climbing stairs), mild intellectual disability and epilepsy. Additional manifestations reported in some patients include cataracts, nystagmus, cardiomyopathy, and respiratory insufficiency.", "ORPHA ID": 363623, "Summary": ""}
{"Disease Name": "GMS syndrome", "Disease Definition": "GMS syndrome describes an extremely rare syndrome involving goniodysgenesis, intellectual disability and short stature in addition to microcephaly, short nose, small hands and ears, and that has been seen in one family to date. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 2090, "Summary": ""}
{"Disease Name": "GNAO1-related developmental delay-seizures-movement disorder spectrum", "Disease Definition": "A rare genetic neurological disorder characterized by a phenotypic spectrum of mild to severe developmental delay and hypotonia, variably associated with intellectual disability, early-onset seizures, and movement disorders, such as dystonia, ataxia, chorea, and dyskinesia. Brain imaging may show delayed myelination, thin corpus callosum, or cerebral atrophy.", "ORPHA ID": 592564, "Summary": ""}
{"Disease Name": "Gnathodiaphyseal dysplasia", "Disease Definition": "Gnathodiaphyseal dysplasia (GDD) is a bone dysplasia characterized by bone fragility, frequent bone fractures at a young age, cemento-osseous lesions of the jaw bones, bowing of tubular bones (tibia and fibula) and diaphyseal sclerosis of long bones associated with generalized osteopenia. GD follows an autosomal dominant mode of transmission.", "ORPHA ID": 53697, "Summary": ""}
{"Disease Name": "GNB5-related intellectual disability-cardiac arrhythmia syndrome", "Disease Definition": "A rare genetic disease characterized by intellectual disability, developmental delay, language deficits, and cardiac arrhythmia (most commonly sick sinus syndrome). Additional reported features include epilepsy, hypotonia, retinal abnormalities, nystagmus, attention deficit hyperactivity disorder, autism, and gastroesophageal reflux. The severity of the phenotype is highly variable.", "ORPHA ID": 542306, "Summary": ""}
{"Disease Name": "GNE myopathy", "Disease Definition": "GNE myopathy is a rare autosomal recessive distal myopathy characterized by early adult-onset, slowly to moderately progressive distal muscle weakness that preferentially affects the tibialis anterior muscle and that usually spares the quadriceps femoris. Muscle biopsy reveals presence of rimmed vacuoles.", "ORPHA ID": 602, "Summary": "Epidemiology\nWorldwide prevalence is estimated at 1/1,000,000, however it is more frequent in populations of Persian Jewish and Japanese ethnicity.\nClinical description\nThe disease usually starts during the third decade of life (but the onset may range from the early teens to the 5th decade). Typically, distal weakness in the legs with foot drop is the first sign, followed by (usually) slow progression to the proximal muscles (thigh) and the upper limbs (hand muscles). Shoulder girdle muscles are subsequently involved, with relative sparing of the triceps. Neck flexor muscles are also commonly affected. A unique clinical pattern of this myopathy is sparing of quadriceps in spite of major involvement of other thigh muscles. Unusual patterns of onset in proximal lower limb musculature and even in the upper limbs have been observed. Ocular, pharyngeal, and cardiac muscles are usually spared. Respiratory muscles are generally not affected until the very late stages in wheelchair-bound patients. Occasionally, affected individuals may present facial weakness.\nEtiology\nGNE myopathy is caused by biallelic mutations in the GNE gene (9p13.3) which encodes a bi-functional enzyme involved in the sialic acid biosynthetic pathway. Mutations in this gene result in a 30-60% decrease in enzyme activity leading to a decreased sialylation of glycoproteins and glycolipids. Hyposialylation appears to be involved in disease pathogenesis, but the process by which a defect in GNE leads to muscle disease is still elusive. With increasing number of patients, genotype-phenotype correlations are currently emerging.\nDiagnostic methods\nDiagnosis is suspected in individuals with early-onset foot drop, negative dominant family history, sustained quadriceps sparing despite marked weakness of all other thigh muscles, modest elevation of serum creatine kinase (2-5x), muscle biopsy showing fiber size variation (with atrophy) and presence of rimmed vacuoles and congophilic protein aggregates. MRI reveals a characteristic pattern of muscle involvement with (from the early stages of the disease) severe fatty-fibrous replacement of the biceps femoris short head muscles, accompanied by less severe involvement of the gluteus minimus, tibialis anterior, extensor hallucis and digitorum longus, soleus and gastrocnemius medialis muscles. Genetic screening revealing pathogenic variants in GNE confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other adult-onset distal myopathies with rimmed vacuolar pathology (i.e. distal myopathy, Welander type; tibial muscular dystrophy; adult-onset distal myopathy due to VCP mutation; and vocal cord and pharyngeal distal myopathy), myofibrillar myopathies, and Laing early-onset distal myopathy.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\nManagement and treatment\nIn the absence of a proven effective therapy, management remains mainly supportive. Metabolic supplementation with sialic acid or a precursor of sialic acid, as well as gene therapy, are under investigation.\nPrognosis\nMost patients become wheelchair-bound after 15-20 years of disease onset. About 5% of patients have atypical early involvement of the quadriceps muscle resulting in earlier non-ambulation.\n\n                            Last update: \n                            September 2018\n\n\n                            - Expert reviewer(s): \n                            Dr Johanna PALMIO  - Pr Bjarne UDD"}
{"Disease Name": "Goblet cell carcinoma", "Disease Definition": "Goblet cell carcinoma (GCC) is an aggressive type of endocrine tumor of the appendix (see this term) presenting equally in males and females in the fifth decade of life and manifesting with a palpable mass and abdominal pain or acute appendicitis. Metastasis to the ovaries, peritoneum or right colon has usually already occurred in half of patients at the time of diagnosis.", "ORPHA ID": 329984, "Summary": ""}
{"Disease Name": "Goldberg-Shprintzen megacolon syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by Hirschsprung disease, facial dysmorphism (sloping forehead, high arched eyebrows, long eyelashes, telecanthus/hypertelorism, ptosis, prominent ears, thick earlobes, prominent nasal bridge, thick philtrum, everted lower lip vermillion and pointed chin), global developmental delay, intellectual disability and variable cerebral abnormalities (focal or generalized polymicrogyria, or hypoplastic corpus callosum).", "ORPHA ID": 66629, "Summary": "Epidemiology\nWorldwide prevalence is less than 1/1,000,000; to date 24 cases have been described in the scientific and medical literature.\nClinical description\nDisease onset is typically in the neonatal period with microcephaly and Hirschsprung disease. The clinical spectrum of Hirschsprung disease is broad, ranging from chronic constipation to life-threatening intestinal obstruction in neonates. Facial dysmorphism is present at birth but becomes more evident later on. Additional dysmorphic features may include maxillary hypoplasia, hypodontia, high arched palate, short neck, small hands, brachydactyly, fifth finger clinodactyly, fetal finger pads and flatfoot. Hypotonia, severe global developmental delay (with greatest impairment in expressive language skills) and moderate to severe intellectual disability are constant features. Cerebral magnetic resonance imaging reveals abnormalities in half of patients and may include polymicrogyria, corpus callosum hypoplasia, or subarachnoid space enlargement. Other highly variable features include ocular abnormalities (e.g. hyperopia, bilateral megalocornea), congenital heart defects (such as ventricular septal defects, aortic valve incompetence), urogenital abnormalities (incl. cryptorchidism, vesicoureteral reflux, multicystic renal dysplasia), skeletal involvement (e.g. short stature, scoliosis, femoral neck anteversion), and recurrent respiratory infections.\nEtiology\nDisease is caused by bi-allelic mutations in KIF1BP (10q21.3-q22.1), encoding kinesin family member 1 binding protein. KIF1BP loss of function disrupts cytoskeletal homeostasis.\nDiagnostic methods\nDiagnosis is based on clinical presentation of the typical features and should be confirmed with genetic testing. Hirschsprung disease is confirmed by rectal biopsy with histological findings of aganglionosis of the submucosal plexus.\nDifferential diagnosis\nMain differential diagnoses include Mowat-Wilson (MWS) and Baraitser-Winter syndromes. Different facial characteristics (thick, horizontal eyebrows and uplifted earlobes with a central depression), presence of seizures and hypospadias, and absence of polymicrogyria and oligodontia distinguish MWS. Key overlapping features with Baraitser-Winter syndrome include intellectual disability, microcephaly, congenital ptosis, high-arched eyebrows, ocular coloboma and short stature; however, Hirschsprung disease, congenital heart defects, and urogenital malformations have not been reported in this syndrome.\nAntenatal diagnosis\nGenetic prenatal diagnosis is possible if bi-allelic mutations have previously been identified in the family. In absence of a familial case, diagnostic antenatal ultrasound is challenging. Antenatal detection of brain developmental anomalies, microcephaly, growth retardation and/or hyperechogenic gut are suspicious for the disease but must be confirmed by genetic testing.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. For parents of an affected child the sibling-recurrence risk is 25%.\nManagement and treatment\nMultidisciplinary medical care and preventive actions, such as treatment of cardiac, ocular, urogenital and skeletal issues and Hirschsprung disease, are required. Developmental assessments are needed to tailor medical care to individual needs and to increase the individual's quality of life.\nPrognosis\nLittle information is available about the long-term outlook for individuals with Goldberg-Shprintzen megacolon syndrome. Quality of life and life expectancy depend on the presence and severity of birth defects.\n\n                            Last update: \n                            March 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Irina GIURGEA"}
{"Disease Name": "Goldmann-Favre syndrome", "Disease Definition": "Goldmann-Favre syndrome (GFS) is a vitreoretinal dystrophy characterized by early onset of night blindness, reduced bilateral visual acuity, and typical fundus findings (progressive pigmentary degenerative changes, macular edema, retinoschisis).", "ORPHA ID": 53540, "Summary": "Epidemiology\nLess than 20 cases have been reported so far, some of them born to consanguineous families. Both sexes seem equally affected.\nClinical description\nThe onset is usually in childhood. GFS manifests with progressive loss of visual acuity and night blindness. Peripheral vision can be decreased. Cataract is a frequent complication. Optic atrophy has been occasionally reported. The vitreous changes are degenerative and may include microfibrillar strands, liquefaction and posterior vitreous detachment. The fundus features include annular pigmentary changes (clumped pigment deposits), central or peripheral retinoschisis, cystoid macular edema. The GFS features are usually bilateral and symmetrical. The electroretinogram (ERG) is abnormal: both rod and cone ERGs are markedly diminished and may be non-detectable. Patients may have an increased sensitivity to blue light due to increased S-cone sensitivity.\nEtiology\nMutations in the NR2E3 gene (formerly called PNR) have been identified in some patients with GFS. NR2E3 (15q23) encodes a retinal nuclear receptor that is involved in the differentiation of photoreceptors. GFS, some forms of autosomal recessive and dominant retinitis pigmentosa and enhanced S-cone syndrome (ESCS) are caused by mutations in the NR2E3 gene.\nDiagnostic methods\nDiagnosis is based on clinical findings, ocular investigations including fundus autofluorescence, optical coherence tomography, electroretinogram and mutations in NR2E3.\nDifferential diagnosis\nGFS should be distinguished from X-linked retinoschisis, retinitis pigmentosa and autosomal dominant hyaloideoretinal degeneration (Wagner disease) (see these terms).\nGenetic counseling\nGFS is inherited as an autosomal recessive trait.\nPrognosis\nGFS has a progressive course. In most cases, visual loss occurs in the first two decades of life. Some improvement of visual acuity has been reported after treatments with cyclosporin A and bromocriptine.\n\n                            Last update: \n                            July 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Christian HAMEL"}
{"Disease Name": "Gollop-Wolfgang complex", "Disease Definition": "A rare congenital limb malformation characterized by bifid femur, absent or hypoplastic tibia and ulna with limb shortening, oligodactyly, and ectrodactyly.", "ORPHA ID": 1986, "Summary": "Epidemiology\nApproximately 200 cases have been reported worldwide.\nClinical description\nThe malformation presents with congenital aplasia/hypoplasia of the tibia, bifurcation of the distal femur, more commonly unilateral, accompanied by pre-axial oligodactyly or monodactyly of the feet. There is oligodactyly and ectrodactyly, often associated with an abnormality of the ulna. The pattern is frequently asymmetric. Occasionally other abnormalities can be present, namely congenital heart defects, cleft lip and palate and tracheo-oesophageal fistula.\nEtiology\nThe etiology remains unknown. In two Japanese patients, a duplication and a triplication of a 210 Kb chromosomal segment in 17p13.3, including BHLHA9, has been detected, and considered a susceptibility factor for the limb malformation.\nDiagnostic methods\nDiagnosis is based on clinical and radiological findings.\nDifferential diagnosis\nDifferential diagnoses includes hypoplastic tibiae-postaxial-polydactyly syndrome and split hand foot malformation syndromes.\nAntenatal diagnosis\nPrenatal diagnosis can be performed by ultrasound scans in the second trimester of pregnancy.\nGenetic counseling\nWhilst the pattern of inheritance is currently unknown, autosomal dominant and autosomal recessive inheritance models have been suggested.\nManagement and treatment\nPatients should be offered orthopedic and reconstructive surgery (involving prosthetics) and regular monitoring.\nPrognosis\nLife expectancy is not reduced but, in the absence of treatment, the functional prognosis is poor.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Francesca FORZANO"}
{"Disease Name": "Gonadoblastoma", "Disease Definition": "Gonadoblastoma is a rare benign neoplasm of mixed sex cord and germ cells, arising mostly in the dysgenic gonads of young women with a chromosome Y anomaly, presenting with abdominal enlargement, variable feminization or virilization or, in some cases, being asymptomatic. It is often associated with dysgerminoma.", "ORPHA ID": 206484, "Summary": ""}
{"Disease Name": "Gonococcal conjunctivitis", "Disease Definition": "A rare disorder of the anterior segment of the eye caused by Neisseria gonorrhoeae, characterized by a severe mucopurulent conjunctivitis associated with lid edema, often also with localized lymphadenopathy. It may be complicated by uveitis or keratitis which can eventually lead to corneal perforation. The disease most often occurs in teenagers and young adults with a male predominance, while infections are much less common in newborns, where they are typically bilateral.", "ORPHA ID": 1482, "Summary": ""}
{"Disease Name": "Good syndrome", "Disease Definition": "Good syndrome, also known as thymoma-immunodeficiency, is a very rare acquired immunodeficiency syndrome characterized by the association of thymoma and combined B-cell and T-cell immunodeficiency of adult onset with increased susceptibility to infections.", "ORPHA ID": 169105, "Summary": ""}
{"Disease Name": "Gordon syndrome", "Disease Definition": "Gordon syndrome, also known as distal arthrogryposis type 3, is an extremely rare multiple congenital malformation syndrome characterized by congenital contractures of hand and feet with variable degrees of severity of camptodactyly, clubfoot and, less frequently, cleft palate. Intelligence is normal but in some cases, additional abnormalities, such as short stature, kyphoscoliosis, ptosis, micrognathia, and cryptorchidism may also be present. Gordon syndrome, Marden-Walker syndrome and arthrogryposis with oculomotor limitation and electroretinal anomalies clinically and genetically overlap, and could represent variable expressions of the same condition.", "ORPHA ID": 376, "Summary": ""}
{"Disease Name": "Gorham-Stout disease", "Disease Definition": "Gorham-Stout disease (GSD) is a rare disease of massive osteolysis associated with proliferation and dilation of lymphatic vessels. GSD may affect any bone in the body and can be monostotic or polyostotic. Symptoms at presentation are dependent upon the location(s) of the disease; the most common symptom is localized pain. The disease may be discovered after a pathological fracture.", "ORPHA ID": 73, "Summary": "Epidemiology\nTo date around 300 cases have been reported in the literature. GSD does not display a clear race, sex predilection (1.6:1; male: female ratio) or geographic distribution.\nClinical description\nGSD can present at any age, but is commonly diagnosed in children and young adults (average 13 years). GSD may affect any bone in the body but most commonly affects the ribs, followed by the cranium, clavicle and cervical spine. Additional affected areas include maxillofacial bones (mostly the mandible), sternum, humerus, hand, femur, and foot. GSD can be monostotic or polyostotic and symptoms vary according to the body sites affected. The most common symptom is localized pain. Swelling, weakness and functional impairment of affected limbs are also noticed. In the dentoalveolar region, mobile teeth, malocclusion, mandibular deviation and bony deformity may be observed. Patients with thoracic involvement may present respiratory distress (caused by chylothorax). Severe neurological defects and paralysis, secondary to vertebral involvement, are also observed. Patients with cervical spine or base of skull disease can develop cerebrospinal fluid leak. GSD may be discovered after a bone fracture (spontaneous or following minor trauma).\nEtiology\nEtiology of GSD is still elusive. The pathological process is the benign vascular proliferation of endothelial channels adjacent to or within bone, leading to extreme thinning of bony trabecula, osteoclast-mediated resorption, and replacement of bone with fibrous tissue. Tissue samples test positive for lymphatic endothelial cell markers, suggesting that GSD is a disease involving disordered lymphangiogenesis.\nDiagnostic methods\nDiagnosis relies on radiographic findings revealing progressive osteolysis and cortical destruction. Magnetic resonance imaging shows complete resorption of bone and replacement with infiltrative soft tissue that is of low signal intensity on T1-weighted imaging and high signal intensity on T2, with intense enhancement on contrast imaging. Immunohistochemical markers of lymphatic endothelial cells (LYVE-1, podoplanin/D2-40) reveal presence of lymphatic vessels in medullary and cortical regions of bones, and in affected soft tissues. Rib lesions should not be biopsied, as this procedure may elicit a refractory chylous effusion.\nDifferential diagnosis\nDifferential diagnosis includes generalized lymphatic anomaly (the major distinguishing characteristic is the progressive osteolysis seen in GSD), acroosteolysis dominant type, multicentric carpo-tarsal osteolysis with or without nephropathy, autosomal recessive carpotarsal osteolysis, hereditary sensory and autonomic neuropathy type 2, Farber lipogranulomatosis, Torg-Winchester syndrome, and idiopathic phalangeal acro-osteolysis (see these terms). Other causes of osteolysis such as infection, cancer (primary or metastatic), inflammatory or endocrine disorders should also be considered.\nGenetic counseling\nGSD occurs sporadically.\nManagement and treatment\nTreatment of GSD includes drugs (bisphosphonates and/or interferon alpha 2b, sirolimus is also being studied) to stabilize progressive disease, and supportive procedures that may reduce or halt chylothorax (pleurectomy, pleurodesis, thoracentesis, and thoracic duct embolization or ligation), or may stabilize affected regions of the skeleton. Radiotherapy may be used in combination with these therapies, but is generally reserved for refractory or rapidly progressive disease.\nPrognosis\nPrognosis depends on the extent and location of affected areas. Mild disease may remain stable for many years, while severe cases involving the craniofacial and/or thoracic areas may be fatal. Pulmonary involvement may herald a worsened prognosis.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Gulraiz CHAUDRY  - Dr Cameron TRENOR"}
{"Disease Name": "Gorlin syndrome", "Disease Definition": "A rare hereditary disorder due to autosomal dominant transmission with hamartosis characterized by multiple early-onset basal cell carcinoma (BCC), multiple jaw keratocysts and skeletal abnormalities.", "ORPHA ID": 377, "Summary": "Epidemiology\nThe prevalence of Gorlin syndrome (GS) is estimated to be 1/31,000-1/164,000 in Europe. Birth prevalence in the UK is reported to be 1/19,000. Males and females are equally affected.\nClinical description\nGS is characterized by the early onset of mandibular odontogenic keratocysts (2nd decade of life) and/or multiple BCCs (most commonly seen on the face, back and chest - 3rd decade of life). Approximately 60% of individuals have a recognizable appearance with macrocephaly, frontal bossing, coarse facial features, and facial milia. Ectopic calcification, particularly in the falx, is present in more than 90% of affected individuals by age 20 years. Palmar or plantar pits (asymmetrical, 2-3 mm in diameter, 1-3 mm in depth and developing in the 2nd decade) and skeletal anomalies (fusion of vertebrae, wedge-shaped vertebrae, bifid or fused ribs, hemivertebra, kyphoscoliosis, pectus deformity, sprengel deformity, syndactyly, polydactylia) are also reported. Additional features include facial dysmorphism (cleft lip/palate, macrocephaly), eye anomalies (cataract, coloboma, microphthalmos) and lymphomesenteric cysts. A predisposition to malignant or benign tumors such as medulloblastoma, meningioma, papillary fibroelastoma of the heart, ovarian fibroma (commonly bilateral and calcified), fibrosarcoma, nephroblastoma is observed.\nEtiology\nGS is caused by loss of functions due to mutations in the tumor suppressor gene PTCH1 (9q22.1-q31), which encodes the receptor of the sonic hedgehog ligand. Environmental exposure and other modifier genes (SUFU; PTCH2) may contribute to the variable expressivity observed in the clinical presentation. Mutations in PTCH1 also account for the majority of features in monosomy 9q22.3.\nDiagnostic methods\nDiagnosis is based upon presence of two major criteria and one minor criterion or one major and three minor criteria. Physical examination, radiography, ophthalmologic evaluation, dentist or orthodontist examination, skin examination, ultrasound test and echocardiography are essential to identify the criteria leading the diagnosis. Identification of a heterozygous germline PTCH1 or SUFU pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.\nDifferential diagnosis\nDifferential diagnosis includes: Sotos syndrome, Brooke-Spiegler syndrome, Bazex syndrome, Rombo syndrome, Muir-Torre syndrome, Beckwith-Wiedemann syndrome, isolated hydrocephaly or megalencephaly, an autosomal dominant or X-linked syndrome of hypotrichosis.\nAntenatal diagnosis\nAntenatal diagnosis is possible with ultrasound scans and DNA analysis extracted from fetal cells after amniocentesis or chronic villus sampling. Preimplantation genetic diagnosis may be proposed to families in which the pathogenic variant has been identified.\nGenetic counseling\nTransmission is autosomal dominant, with high penetrance and variable expressivity. Genetic counselling, including testing family members to distinguish familial mutations from de novo pathogenic variants, and assessment of genetic cancer risk should be offered. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.\nManagement and treatment\nThe treatment of choice for multiple BCC consists of a combined approach including surgery supplemented by cryotherapy, laser, photodynamic therapy or topical treatments. Use of oral retinoids is also suggested. Oral vismodegib may reduce development of BCC but adverse events are common. Sonic hedgehog inhibitors may be particularly helpful with lesions around the eyes. Radiation therapy must be avoided as it can cause invasion of BCC years later. Photodynamic therapy is particularly suitable for thin lesions of <2 mm on ultrasound. Surgical treatment using Mohs' microsurgery appears particularly effective. Jaw keratocysts are often recurrent and demand repeated surgical excisions. Ovarian fibroma is usually managed with conservative surgery to preserve normal ovarian tissue.\nPrognosis\nLife expectancy in GS is not affected. Early diagnosis is important due to susceptibility to multiple neoplasms in early age. Ovarian tumors are usually benign with risk of recurrence. In young patients, mandibular odontogenic keratocysts can cause displacement of developing teeth and may be associated with unerupted teeth and cause root resorption.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Lorenzo LO MUZIO"}
{"Disease Name": "Gorlin-Chaudhry-Moss syndrome", "Disease Definition": "Gorlin-Chaudhry-Moss (GCM) syndrome is a multiple congenital anomaly syndrome characterized by craniofacial dysostosis, facial dysmorphism, conductive hearing loss, generalized hypertrichosis, and extremity, ocular and dental anomalies.", "ORPHA ID": 2095, "Summary": "Epidemiology\nTo date, 7 cases of GCM have been described in the world literature and all patients are female with no known parental consanguinity.\nClinical description\nGCM is a congenital disorder in which patients present with a stocky body build, normal intelligence, coronal craniosynostosis, facial dysmorphism (brachy/turricephaly, low anterior and posterior hairline, coarse hair, synophrys, depressed supraorbital ridges, short and downslanted or upslanted palpebral fissures, ectropion of lower eyelid, underdeveloped ala nasi, prominent columella, midface hypoplasia, and underdeveloped small ears with increased posterior angulation), conductive hearing loss, ocular (coloboma of the eyelid (see this term), hyperopia, microphthalmia) and oro-dental (microdontia, irregularly shaped widely spaced teeth, oligodontia (see this term), narrow, and high arched narrow palate with medial cleft) anomalies and generalized hypertrichosis. Anomalies of the extremities (hypoplastic distal phalanges, small/aplastic nails, cutaneous syndactyly, absent flexion crease of the thumbs, single transverse palmar creases), umbilical hernia, and hypoplasia of labia majora are also observed. Other additional features that may be observed include congenital laryngomalacia and heart disease (patent arterial duct) (see these terms). Progeroid syndrome, Petty type and Saethre-Chotzen syndrome (see these terms) have overlapping features with GCM syndrome and should be considered in the differential diagnosis.\nEtiology\nThe etiology is still unknown and, to date, no causative gene has been implicated in the physiopathology of GCM.\nGenetic counseling\nGCM is considered to be inherited in an autosomal recessive manner. However, the lack of consanguinity combined with the fact that all affected patients are female could suggest a de novo X-linked dominant disorder with male lethality.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Rasim ROSTI"}
{"Disease Name": "GRACILE syndrome", "Disease Definition": "An inherited lethal mitochondrial disorder characterized by fetal growth restriction (GR), aminoaciduria (A), cholestasis (C), iron overload (I), lactacidosis (L), and early death (E).", "ORPHA ID": 53693, "Summary": "Epidemiology\nThe typical GRACILE syndrome is prevalent in Finland, where it has an incidence of about 1/50,000 births. It has also rarely been found in Sweden and the U.K.\nClinical description\nFetal growth restriction appears early during the pregnancy without signs of chronic hypoxia. Because of small fetal size, the pregnancies are usually interrupted a few weeks before the estimated due date (median 38 gestational weeks). The newborn infant is small for gestational age (birth weight approximately 1,700 g) and develops fulminant lactic acidosis (median pH 7.02, lactate 12.8 mmol/l) during the first day of life. In metabolic screening, marked aminoaciduria is found due to renal proximal tubulopathy of Fanconi type. Iron overload is illustrated by increased plasma ferritin and decreased transferrin concentrations and accumulation of iron in the liver. Further signs of hepatopathy are cholestasis with steatosis, fibrosis and cirrhosis. No dysmorphic features are noted. No distinct cerebral abnormalities have so far been found, however in some infants, EEG has been abnormal, maybe as a result of severe metabolic acidosis. The hearing response assessed with BAEP has been abnormal.\nEtiology\nGRACILE syndrome is caused by a mutation in BCS1L, located on chromosome 2q35, encoding a protein essential in the assembly of complex III in the mitochondrial respiratory chain. In Finnish patients, the disease is caused by one homozygous mutation (c.232A>G) leading to an amino acid change (Serine on position 78 to Glycine) in the BCS1L protein. Several recently discovered mutations in the gene can cause variable phenotypes ranging from neonatal GRACILE-like hepatopathy and tubulopathy to those presenting during infancy or childhood with encephalopathy and psychiatric disorders.\nDiagnostic methods\nGRACILE syndrome is suspected if an infant is severely small for gestational age, develops hypoglycemia and lactic acidosis, has tubulopathy and increased ferritin levels and shows signs of liver dysfunction. Iron overload is illustrated by increased plasma ferritin and decreased transferrin concentrations and accumulation of iron in the liver. In patients of Finnish descent, the diagnosis is confirmed by assessing the single-nucleotide polymorphism (accredited method in HUS-LAB, Helsinki). In other patients, the entire BCS1L gene should be sequenced. Respirometry should be performed in a mitochondrial laboratory.\nDifferential diagnosis\nOther mitochondrial hepatopathies such as Pearson syndrome should be excluded. Disorders of mitochondrial fatty acid oxidation and Krebs cycle disorders may also mimic GRACILE syndrome.\nAntenatal diagnosis\nIn families with a previous case of GRACILE syndrome or renal tubulopathy, encephalopathy, liver failure, the causative BCS1L mutation can be investigated antenatally.\nGenetic counseling\nGRACILE syndrome is inherited autosomal recessively so genetic counseling should be offered to affected families. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for the disease and treatments are purely symptomatic. Infants require intensive care, including alkali therapy and supplementation of urinary losses. Lactic acidosis responds only slightly to treatment.\nPrognosis\nThe prognosis is life threatening with half of infants decease during the first days of life and the other half not living past 4 months of age, mainly because of energy depletion.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Vineta FELLMAN"}
{"Disease Name": "Graft versus host disease", "Disease Definition": "A rare disease that occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues. Activated donor T cells damage host epithelial cells after an inflammatory cascade that begins with the preparative regimen.", "ORPHA ID": 39812, "Summary": "Epidemiology\nAbout 35%-50% of hematopoietic stem cell transplant (HSCT) recipients will develop acute Graft versus host disease (GVHD). Given the number of transplants performed, it is estimated that about 5500 patients/year will develop acute GVHD.\nClinical description\nThree organs are involved: the skin (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea). Either one or more of these organs may be affected.\nEtiology\nThe exact risk is dependent on the stem cell source, age of the patient, conditioning, and GVHD prophylaxis used.\nDiagnostic methods\nGVHD is a clinical diagnosis that may be supported with appropriate biopsies. The reason to pursue a tissue biopsy is to help differentiate from other diagnoses which may mimic GVHD, such as a viral infection (hepatitis, colitis) or drug reaction (causing skin rash). Acute GVHD is staged and graded (grade 0-IV) by the number and extent of organ involvement.\nManagement and treatment\nGenerally the patient is treated by optimizing immunosuppression and adding methylprednisolone to the treatment regimen. About 50% of patients will have a solid response to methylprednisolone. If patients progress after 3 days or show no improvement after 7 days, they should receive a salvage (second-line) immunosuppressive therapy for which there is currently no standard-of-care. Well-organized clinical trials are imperative for better defining second-line therapies for this disease. Additional management issues are attention to wound infections in skin GVHD and fluid/nutrition management in gastrointestinal GVHD.\nPrognosis\nAbout 50% of patients with acute GVHD will eventually have manifestations of chronic GVHD. Patients with grade III/IV acute GVHD tend to have a poor outcome.\n\n                            Last update: \n                            September 2007\n\n\n                            - Expert reviewer(s): \n                            Dr David JACOBSOHN  - Dr Georgia VOGELSANG"}
{"Disease Name": "Graham Little-Piccardi-Lassueur syndrome", "Disease Definition": "A variant of lichen planopilaris characterized by the clinical triad of progressive cicatricial (scarring) alopecia of the scalp, follicular keratotic papules on glabrous skin, and variable alopecia of the axillae and groin.", "ORPHA ID": 505, "Summary": "Epidemiology\nIt is a very rare disease but the exact prevalence is not known. It mainly affects women during adulthood (30-60 years of age).\nClinical description\nScarring alopecia presents as small confluent patches that are atrophic and cicatricial in the center but erythematous and squamous around the edges. Follicular keratosis presents as pruritic, red-brown, follicular spiny papules on the trunk and extremities. Generally, the three clinical features appear simultaneously but in some cases, scalp alopecia precedes the follicular keratosis.\nEtiology\nEtiology is unknown.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Stephanie ARNOLD  - Dr Susan COOPER"}
{"Disease Name": "Grange syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by early onset of hypertension and multifocal stenotic lesions of various arteries (including cerebral, renal, abdominal, and coronary). Variable additional features include learning difficulties, mild facial dysmorphism, anomalies of the fingers and toes, bone fragility, and congenital heart defects.", "ORPHA ID": 79094, "Summary": ""}
{"Disease Name": "Grant syndrome", "Disease Definition": "Grant syndrome is a rare osteogenesis imperfecta-like disorder, described in two patients to date, characterized clinically by persistent wormian bones, blue sclera, mandibular hypoplasia, shallow glenoid fossa, and campomelia. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 2097, "Summary": ""}
{"Disease Name": "Granular corneal dystrophy type I", "Disease Definition": "Type I granular corneal dystrophy (GCDI) is a rare form of stromal corneal dystrophy (see this term) characterized by multiple small deposits in the superficial central corneal stroma, and progressive visual impairment, which may sometimes be severe.", "ORPHA ID": 98962, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is not known. GCDI appears to be more prevalent in Europe than in other regions.\nClinical description\nLesions appear within the first decade of life and may be evident by 3 years of age. Early symptoms include glare and photophobia that usually start before the end of the first decade of life. Visual acuity decreases as opacification progresses with age. Recurrent erosions are seen frequently. Homozygotes have more severe manifestations.\nEtiology\nGCDI is caused by a p. Arg555Trp mutation in the multifunctional TGFBI gene (5q31).\nDiagnostic methods\nLesions resemble white, discrete, irregularly-shaped, sharply-demarcated spots in the stroma.\nDifferential diagnosis\nThe appearance of the granular deposits in GCDI differs from those in GCDII and unlike GCDII, amyloid deposits do not occur. The features of GCD may be very similar to the corneal features of monoclonal gammopathies (see these terms).\nGenetic counseling\nBoth forms of GCD usually follow an autosomal dominant pattern of inheritance, but sporadic de novo mutations have been reported.\nManagement and treatment\nWhen indicated, a penetrating keratoplasty is the ideal form of therapy.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Granular corneal dystrophy type II", "Disease Definition": "Type II granular corneal dystrophy (GCDII) is a rare form of stromal corneal dystrophy (see this term) characterized by irregular-shaped well-demarcated granular deposits in the superficial central corneal stroma, and progressive visual impairment.", "ORPHA ID": 98963, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is not known. GCDII appears to be more prevalent in Japan, Korea and the USA.\nClinical description\nLesions appear within the first decade of life and may be evident by 3 years of age. Onset is generally earlier in homozygous patients. Pain may accompany mild corneal erosions. Visual acuity usually remains good until late in the course of the condition. The course is slowly progressive but homozygotes may demonstrate more rapid progression.\nEtiology\nGCDII is caused by a p. Arg124His mutation in the TGFBI gene (5q31).\nDiagnostic methods\nOpacities are initially small superficial whitish dots. Subsequently, ring or stellate-shaped stromal opacities develop. Final-stage opacities are more superficial and translucent, and may coalesce in the anterior stroma.\nDifferential diagnosis\nDeposits are less numerous than in type I granular corneal dystrophy, and are sometimes lattice-like linear deposits and may superficially resemble lattice corneal dystrophy (see these terms). The features of GCD may be very similar to the corneal features of monoclonal gammopathies (see these terms).\nGenetic counseling\nBoth forms of GCD usually follow an autosomal dominant pattern of inheritance, but sporadic de novo mutations have been reported.\nManagement and treatment\nA penetrating keratoplasty is usually indicated, but superficial stromal opacities can sometimes be ablated without the removal of the entire cornea.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Granulomatosis with polyangiitis", "Disease Definition": "A rare anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis characterized by necrotizing inflammation of small and medium vessels (capillaries, venules and arterioles), resulting in tissue ischemia.", "ORPHA ID": 900, "Summary": "Epidemiology\nThe prevalence is estimated between 1/6,400 - 42,000 worldwide with annual incidence between 1/84,000-475,000. There is geographic and/or ethnic variation, with a higher incidence in colder regions and among Caucasians. Childhood-onset disease is characterized by female predominance, and adult-onset by a slight male predominance.\nClinical description\nThe average age of onset is 45 years but the disease may manifest at any age including childhood. The disease may present with various organ manifestations. Ear, nose and throat symptoms are present in 50-95% (persistent nasal obstruction, destructive sinusitis, crusting and/or hemorrhagic rhinitis, nasal septum deformity, saddle nose deformity, and otitis media), bronchopulmonary symptoms in 60-80% (nodules, alveolar hemorrage, bronchial and/or subglottic stenosis), and renal disease (typically extra-capillary necrotizing glomerulonephritis) in 60-80% of affected individuals. General signs (fever, arthralgia, myalgia, weight loss) are common. Skin lesions (purpura and cutaneous nodules) are observed in 10-50%, peripheral neuropathy (multineuritis) in 25%, central nervous system manifestations (headaches, sensorimotor deficit, hemiplegia and epilepsy) in 10%, and ocular anomalies (scleritis and orbital tumors) in 7-8% of patients.\nEtiology\nThe pathogenesis of GPA is still under study. Genetic susceptibility factors, environmental agents, infectious episodes and anomalies in innate and adaptive immunity seem to play a role in the development of all ANCA-associated vasculitides. Genetic variants appear to correlate with antineutrophil cytoplasmic antibody (ANCA) antigen specificity rather than with clinical phenotype. Thus, cytoplasmic-ANCAs directed to proteinase 3 (PR3-ANCA), found in 60-80% of GPA cases, are associated with genetic variants in HLA-DP1A and HLA-DP1B (6p21.32) which encode a class II major histocompatibility complex, SERPINA1 (14q32.13) encoding alpha-1 antitrypsin, and PRTN3 (19p13.3) encoding the autoantigen proteinase 3.\nDiagnostic methods\nDiagnosis relies on clinical findings, imaging studies and biochemical testing, and detection of ANCAs in the serum, principally PR3-ANCAs. Histological analysis of biopsy specimens from affected organs confirms the diagnosis, showing necrotizing vasculitis and granulomatous inflammation.\nDifferential diagnosis\nDifferential diagnoses include other ANCA-associated vasculitides such as microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis.\nManagement and treatment\nInduction therapy comprises steroid pulses combined with either intravenous Rituximab or Cyclophosphamide. Disease remission is achieved in more than 80% of patients with these protocols. In cases of lacking or insufficient response, plasma exchange can be considered. Azathioprine and Methotrexate are efficacious agents for maintenance immunosuppression whereas Mycophenolate-Mofetil is less effective. Leflunomide is an alternative option for individuals intolerant to Azathioprine or Methotrexate. Anti-TNF antibodies (e.g. Infliximab and Adalimumab) have shown promising results in clinical trials as steroid-sparing agents.\nPrognosis\nWhile remission is achieved with treatment in 70-100% of cases, the disease relapses in more than 80% of patients within 10 years. Significant morbidity may emerge both from the disease and its treatment. Ten-year patient survival is around 75%.\n\n                            Last update: \n                            January 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Laura CESCA  - Pr Franz SCHAEFER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Granulomatous mastitis", "Disease Definition": "A rare gynecologic or obstetric disease characterized by a painful, palpable breast mass with relative sparing of the subareolar regions, often associated with inflammation of the overlying skin and accompanied by axillary lymphadenopathy. It usually occurs in young parous women with a history of breast-feeding. The diagnosis of idiopathic granulomatous mastitis requires that other granulomatous lesions in the breast be excluded.", "ORPHA ID": 64722, "Summary": ""}
{"Disease Name": "Granulomatous slack skin", "Disease Definition": "Granulomatous slack skin (GSS) is a variant of mycosis fungoides (MF; see this term), a form of cutaneous T-cell lymphoma, and is characterized by the presence of circumscribed areas of pendulous lax skin.", "ORPHA ID": 33111, "Summary": "Epidemiology\nLess than 50 cases have been reported in the literature so far. GSS predominantly affects males (sex ratio: 2.9:1).\nClinical description\nOnset usually occurs in adulthood. The disease is characterized by the slow development of large areas of pendulous, lax skin in the major skin folds (axillae and groins). Although GSS is considered as a variant of MF, an association with Hodgkin lymphoma was observed in approximately one-third of the reported patients.\nEtiology\nThe etiology is unknown. A chromosomal translocation, t(3;9)(q12;p24), was found in one case.\nDiagnostic methods\nThe diagnosis is based on typical clinical findings and on histologic features revealing a dermal infiltrate of T-cells (with a CD3+, CD4+ and CD8- phenotype) with granulomatous features and the presence of multinucleated giant cells. Molecular analyses reveal a monoclonal rearrangement of the T-cell receptor genes.\nDifferential diagnosis\nAcquired cutis laxa (see this term) can be differentiated from granulomatous slack skin by histological examination.\nManagement and treatment\nNo reliable treatment exists. Surgical excision of the pendulous skin folds is usually performed, but is only palliative and recurrence is the rule. Radiotherapy has been used in some patients. A variety of other therapies (mostly treatments for MF) have been tested in anecdotal cases with variable success.\nPrognosis\nMost patients have an indolent clinical course.\n\n                            Last update: \n                            June 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Lorenzo CERRONI"}
{"Disease Name": "Gray platelet syndrome", "Disease Definition": "Gray platelet syndrome (GPS) is a rare inherited bleeding disorder characterized by macrothrombocytopenia, myelofibrosis, splenomegaly and typical gray appearance of platelets on Wright stained peripheral blood smear.", "ORPHA ID": 721, "Summary": "Epidemiology\nExact prevalence of the disorder is not known. About 60 cases from various populations around the world have been described in the literature to date. It affects males and females equally.\nClinical description\nOnset of clinical symptoms is generally in the neonatal period or in early childhood while age of diagnosis is variable. Presenting features include low platelet counts, easy bruising (petechiae), prolonged bleeding and epistaxis. Patients often have myelofibrosis and splenomegaly. Bleeding tendency is usually mild to moderate in GPS patients with mild thrombocytopenia. However, thrombocytopenia and myelofibrosis in GPS are progressive in nature; GPS may result in fatal hemorrhage especially in adulthood when platelet counts are further decreased. Female patients may develop menorrhagia.\nEtiology\nGPS is caused by mutations in the NBEAL2 gene. Absence or marked reduction of alpha-granules in platelets underlie the disorder. Alpha-granules are the most abundant vesicles in platelets and store proteins that promote platelet adhesiveness and wound healing when secreted during platelet activation.\nDiagnostic methods\nDiagnosis is based on clinical findings and requires demonstration of absence or marked reduction of alpha-granules by electron microscopy (EM). Absence of alpha-granules is an isolated finding in GPS; dense bodies and other platelet organelles and polymorphonuclear leukocytes are normal on EM. Peripheral smears show typical large, pale gray platelets. Most patients also have high serum vitamin B12 levels. Bone marrow sampling is not required for diagnosis of GPS, but might be needed to evaluate myelofibrosis occurring in GPS and to exclude other disorders.\nDifferential diagnosis\nDifferential diagnosis includes other platelet disorders such as macrothrombocytopenias (Bernard-Soulier syndrome, MYH9-related thrombocytopenia, macrothrombocytopenia with mitral valve insufficiency, Mediterranean macrothrombocytopenia), idiopathic thrombocytopenic purpura (ITP) (see these terms), as well as other disorders with hypogranular or gray platelets such as myelodysplastic syndrome (MDS, see this term), myocardial infarction, other causes of hypersplenism, and congenital conditions such as alpha-delta granule deficiency, white platelet syndrome and Quebec platelet disorder (see these terms). Electron microscopy of platelets differentiates GPS from the autosomal dominant variant and from the X-linked variant described as X-linked thrombocytopenia with thalassemia, caused by mutations in GATA1 gene (see this term). These variants display abnormalities not limited to alpha-granules.\nAntenatal diagnosis\nPrenatal diagnosis is possible if the NBEAL2 mutation has been identified in the family.\nGenetic counseling\nGPS is inherited in an autosomal recessive manner (autosomal dominant inheritance has been reported in only 1 family). Siblings of an affected patient are at 25 % risk for GPS, while the risk for offspring of a GPS patient is not significantly higher than for the general population.\nManagement and treatment\nThere is no specific treatment but management involves anticipating and preventing risks of bleeding (e.g. possible platelet transfusions before surgery). Treatment may include administration of desmopressin. Splenectomy should be considered to increase the platelet counts in patients whose platelet counts decrease to approximately 30,000/microliter.\nPrognosis\nPrognosis is generally good early in life when thrombocytopenia is mild. GPS patients with platelet counts less than 30,000/microliter are at risk for life-threatening bleeding.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr William GAHL  - Dr Meral GUNAY-AYGUN"}
{"Disease Name": "Grayson-Wilbrandt corneal dystrophy", "Disease Definition": "Grayson-Wilbrandt corneal dystrophy (GWCD) is an extremely rare form of corneal dystrophy characterized by variable patterns of opacification in the Bowman layer of the cornea which extend anteriorly into the epithelium with decreased to normal visual acuity.", "ORPHA ID": 293375, "Summary": "Epidemiology\nPrevalence of this form is unknown and the existence of GWCD as a distinct entity is questionable. Only one incompletely studied family has been reported.\nClinical description\nOnset is in the first to second decade of life. Patients develop painful erosions that are less severe than those in Reis-Bücklers corneal dystrophy and Thiel-Behnke corneal dystrophy (see these terms). Visual acuity is normal or sometimes slightly decreased. The condition has a progressive course.\nEtiology\nThe etiology is unknown but is thought to be genetic.\nDiagnostic methods\nOn slit-lamp examination, Bowman layer demonstrates variable patterns of opacification from diffuse mottling to diffuse gray-white opacities, which extend anteriorly into the epithelium. The cornea between the deposits is clear.\nGenetic counseling\nAn autosomal dominant pattern of inheritance has been reported.\nManagement and treatment\nA superficial keratectomy or penetrating keratoplasty can improve vision.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Greenberg dysplasia", "Disease Definition": "Greenberg dysplasia is a very rare lethal skeletal dysplasia characterized by fetal hydrops, short limbs and abnormal chondro-osseous calcification. The disease is characterized by early in utero lethality and affected fetuses are considered as nonviable.", "ORPHA ID": 1426, "Summary": "Epidemiology\nLess than ten cases have been published so far.\nClinical description\nThe main features include fetal hydrops, severe short-limbed dwarfism and a marked disorganization of chondro-osseous calcification. Unusual facial features, cystic hygroma, incomplete lung lobation, pulmonary hypoplasia, extramedullary hematopoiesis, intestinal malrotation and polydactyly may occur.\nEtiology\nThe causative gene has been recently identified as that encoding the lamin B receptor (LBR gene), a member of the sterol reductase family. Mutations in LBR have also been reported to cause Pelger-Huët anomaly (PHA), but in this case transmission occurs in an autosomal dominant manner. PHA is characterized by hypolobulated granulocyte nuclei and abnormal chromatin structure in granulocytes. It has been suggested that homozygous LBR mutations result in distinct mild (PHA homozygosity) or severe (Greenberg skeletal dysplasia) phenotypes based on allelic heterogeneity.\nDiagnostic methods\nRadiologic abnormalities include a distinctive 'moth-eaten'' appearance of the long bones, marked platyspondyly with multiple abnormal ossification centers, ectopic ossification of the ribs, sternum, pelvis and epiphysis, and deficient ossification of the skull. Histological characterization shows marked disorganization of the cartilaginous architecture, with absence of cartilage column formation, nodular calcifications in cartilage and islands of cartilage surrounded by bone. Greenberg dysplasia has been shown to be associated with an abnormality of cholesterol biosynthesis.\nDifferential diagnosis\nGreenberg dysplasia should be considered in differential diagnosis of cases with severe fetal hydrops (see this term) and phokomelia on antenatal sonography.\nAntenatal diagnosis\nPrenatal ultrasound diagnosis at 20 weeks of gestation will usually reveal the polyhydramnios, hydrops fetalis, severely short limbs, and cystic hygroma. Sterol profile analysis may be a useful diagnostic tool and can be used for prenatal diagnosis, as can molecular analysis if the mutation in the family is known.\nGenetic counseling\nIt is inherited as an autosomal recessive trait.\n\n                            Last update: \n                            November 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM"}
{"Disease Name": "Greig cephalopolysyndactyly syndrome", "Disease Definition": "A rare developmental defect during embryogenesis with digit duplication, polydactyly, syndactyly, and/or hyperphalangy characterized by multiple congenital anomaly syndrome.", "ORPHA ID": 380, "Summary": "Epidemiology\nThe precise estimates of birth prevalence are difficult to determine, as ascertainment is erratic (estimated range 1-9/1,000,000).\nClinical description\nThe primary findings include widely spaced eyes, macrocephaly with frontal bossing, and pre- or post-axial polydactyly and cutaneous syndactyly. The polydactyly is most commonly preaxial in the feet and postaxial in the hands, with variable cutaneous syndactyly, but the limb findings vary significantly. Other low frequency findings include central nervous system (CNS) anomalies, hernias, and cognitive impairment.\nEtiology\nGCPS is caused by loss of function on chromosome 7p14.1 in the transcription factor gene GLI3.\nDiagnostic methods\nClinical diagnosis is challenging because the findings of GCPS are relatively non-specific, and no specific and sensitive clinical criteria have been delineated. A presumptive diagnosis of GCPS can be made if the patient has the classic triad of preaxial polydactyly with cutaneous syndactyly of at least one limb, hypertelorism, and macrocephaly. Individuals with a phenotype consistent with GCPS (but which may not manifest all three attributes listed above) and a GLI3 pathogenic variant may be diagnosed definitively with GCPS. In addition, individuals with a GCPS-consistent phenotype who are related to a definitively diagnosed family member in a pattern consistent with autosomal dominant inheritance may also be diagnosed definitively.\nDifferential diagnosis\nDifferential diagnoses include preaxial polydactyly type 4, the GCPS contiguous gene syndrome, acrocallosal syndrome, Gorlin syndrome, Carpenter syndrome, and Teebi syndrome. The disorder is allelic to Pallister-Hall syndrome and one form of the acrocallosal syndrome.\nAntenatal diagnosis\nAntenatal molecular diagnosis is technically feasible.\nGenetic counseling\nThe disorder is inherited in an autosomal dominant manner. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the pathogenic variant to offspring.\nManagement and treatment\nTreatment of the disorder is symptomatic, with plastic or orthopedic surgery indicated for significant limb malformations.\nPrognosis\nThe prognosis for is generally excellent. There may be a slight increase in the incidence of developmental delay or cognitive impairment. Patients with large deletions that include GLI3 may have a poorer prognosis.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Leslie BIESECKER"}
{"Disease Name": "GRFoma", "Disease Definition": "GRFoma is a type of pancreatic endocrine tumor (see this term) that hypersecretes growth hormone-releasing factor (GRF or GHRH) and that clinically resembles a pituitary adenoma (see this term) as patients present with acromegaly. In addition to the pancreas, this tumor can also occur in the lungs or small intestine, are usually large > 6cm and approximately 1/3 have metastasized at the time of diagnosis. It often co-occurs with Zollinger-Ellison syndrome or multiple endocrine neoplasia type 1 (MEN 1; see these terms).", "ORPHA ID": 97261, "Summary": ""}
{"Disease Name": "GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder", "Disease Definition": "A rare genetic syndromic intellectual disability characterized by infantile or childhood onset of mild to profound developmental delay and intellectual disability in all affected individuals, as well as variable occurrence of epilepsy, autism spectrum disorder / behavioral issues, microcephaly, muscle tone abnormalities such as hypotonia and spasticity, dystonic, dyskinetic, or choreiform movement disorder, and cortical visual impairment. Brain MRI may reveal abnormal cortical development, hypoplastic corpus callosum, enlarged/dysplastic basal ganglia, and hippocampal dysplasia.", "ORPHA ID": 589547, "Summary": ""}
{"Disease Name": "Griscelli syndrome type 2", "Disease Definition": "A rare subtype of Griscelli syndrome characterized by pigmentary dilution in skin and hair with irregular clumps of pigment in hair shafts resulting in silvery hair, in association with increased susceptibility to recurrent infections and immunological abnormalities, in particular impairment of T-cell and natural killer cytotoxic activity eventually leading to hemophagocytic lymphohistiocytosis. Patients may present neurological manifestations related to infiltration of the central nervous system in the context of the hemophagocytic syndrome. The disease is mostly fatal in the first decade of life.", "ORPHA ID": 79477, "Summary": ""}
{"Disease Name": "Griscelli syndrome", "Disease Definition": "Griscelli syndrome (GS) is a rare cutaneous disease characterized by a silvery-gray sheen of the hair and hypopigmentation of the skin, which can be associated to primary neurological impairment (type 1), immunologic impairment (type 2) or be isolated (type 3).", "ORPHA ID": 381, "Summary": "Epidemiology\nTo date, approximately 150 cases have been reported, predominantly in Turkish and Mediterranean populations. GS type 2 appears to be the most common of the three known types, while GS type 3 is the least common.\nClinical description\nGS occurs in infancy to childhood. In addition to the silvery-gray sheen of the hair and the light-colored skin, GS type 1 patients present with delayed motor development, intellectual disability and hypotonia. GS type 2 patients have the same hypopigmentation features but in association with immune pathology. Patients exhibit a lymphocyte cytotoxic defect resulting in an uncontrolled T-lymphocyte and macrophage-activation syndrome, also known as hemophagocytic syndrome (HLH), in which activated T cells and macrophages infiltrate the lymph nodes and other organs (including the brain), producing hemophagocytosis. Patients with GS type 2 can present neurological symptoms due to brain infiltration by the activated hematopoietic cells. In GS type 3 patients, hypopigmentation of the skin and hair is the only feature.\nEtiology\nGS type 1 is caused by a mutation in the myosin Va (MYO5A) gene located on chromosome 15q21 and likely corresponds to Elejalde disease. GS type 2 is caused by mutations in the RAB27A encoding gene. Myosin-5a and RAB27A genes have been localized to the same chromosomal 15q21 region and encode for proteins which are key effectors of intracellular vesicular transport. Myosin Va regulates organelle transport in both melanocytes and neuronal cells, whereas RAB27A, regulates exocytic pathways, especially the cytotoxic granule exocytosis. The cytotoxic defect caused by RAB27A mutations is responsible for the hemophagocytic syndrome observed. GS type 3 is due to mutations in the MLPH gene, a gene encoding melanophilin, which forms a protein complex with Rab 27a and myosin Va, and participates in melanosome transport in melanocytes.\nDiagnostic methods\nThe diagnosis of the three types of GS can be established by the clinical signs and light microscopic examination, evidencing large clumps of pigment in hair shafts and the accumulation of mature melanosomes in melanocytes. A decrease in T and NK lymphocyte degranulation and cytotoxicity characterize GS type 2. No immunological or cytotoxic defects have been observed in GS type 1 or 3. Thus, based on the patient's clinical and biological features, sequencing of the corresponding causative gene allows confirmation of the type of GS.\nDifferential diagnosis\nGS can be distinguished from Chediak-Higashi syndrome by the lack of giant granules in granulocytes of GS patients. The differential diagnosis of GS type 1 also includes Elejalde disease.\nAntenatal diagnosis\nAntenatal diagnosis of GS type 1 and 2 can be performed through chorionic villus sampling by the sequencing of the MYO5A or RAB27A gene, respectively.\nGenetic counseling\nGS is an autosomal recessive disorder and genetic counseling informing affected couples of a 25% risk of having an affected child is possible.\nManagement and treatment\nTreatment for GS type 1 is only symptomatic. In GS type 2, the hemophagocytic syndrome is often fatal and the only cure is hematopoietic stem cell transplantation (HSCT). Currently there is no specific management for GS type 3.\nPrognosis\nIf not treated by HSCT, the prognosis for long-term survival in GS type 2 is relatively poor, with many patients not surviving the first decade. The prognosis of GS type 1 is good. GS type 3 should be better considered as a pigmentation phenotype rather than a pathology with a prognosis similar to the control population.\n\n                            Last update: \n                            November 2018\n\n\n                            - Expert reviewer(s): \n                            Dr Geneviève DE SAINT-BASILE - CHAZELAS"}
{"Disease Name": "Growing teratoma syndrome", "Disease Definition": "A rare neoplastic disorder characterized by benign metastatic masses increasing in size and number after chemotherapy for non-seminomatous germ cell tumors of testis or ovary. It may present at any time after chemotherapy, with a median occurrence within 24 months after treatment completion. Per definition, the resected specimen exclusively contains mature teratoma components, and serum tumor markers have normalized. The retroperitoneum is the most common site, although almost any other localization has been reported. Increased tumor size may cause mechanical compression of vital organs, with renal dysfunction, bowel ischemia, and biliary obstruction as major complications.", "ORPHA ID": 314613, "Summary": ""}
{"Disease Name": "Growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome", "Disease Definition": "A rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by intrauterine growth retardation, microcephaly, hypotonia, vision impairment, speech and language delay and lactic acidosis with reduced respiratory chain activity (typically complex I). Additonal features may include macrocytic anemia, tremor, muscular atrophy, dysmetria and mild intellectual disability.", "ORPHA ID": 391348, "Summary": ""}
{"Disease Name": "Growth delay due to insulin-like growth factor I resistance", "Disease Definition": "Growth delay due to IGF-I resistance is characterised by variable intrauterine and postnatal growth retardation and elevated serum IGF-I levels. Addition features include variable degrees of intellectual deficit, microcephaly and dysmorphism (broad nasal bridge and tip, smooth philtrum, thin upper and everted lower lips, short fingers, clinodactyly, wide-set nipples and pectus excavatum).", "ORPHA ID": 73273, "Summary": "Epidemiology\nPrevalence is unknown.\nEtiology\nIGF-I resistance may be caused by a variety of genetic defects: ring chromosome 15, distal heterozygous 15q deletions encompassing the IGF1R gene (15q26.3), or IGF1R gene mutations. Intellectual deficit is pronounced in patients with ring chromosome 15 but varies depending on the size of the deletion and on the functions of other deleted genes in patients with 15q deletions. Partial IGF-I insensitivity due to IGF1R haploinsufficiency has been reported in one patient with a small deletion encompassing one allele of the IGF1R gene and was characterised by small size for gestational age, persistent growth failure that improved considerably with GH therapy, and the absence of intellectual deficit. IGF1R mutations have been described in six patients so far and were associated with variable growth delay and degrees of intellectual deficit.\nDiagnostic methods\nDiagnosis relies on karyotyping for detection of ring chromosome 15, detection of small deletions encompassing IGF1R and detection of IGF1R mutations by sequence variation screening methods or by direct sequencing of the 21 IGF1R exons and their intron-exon junctions.\nDifferential diagnosis\nThe differential diagnosis should include bio-inactive IGF-I resulting in IGF-I deficiency (see this term). Measurement of IGF-I levels can be used for diagnosis but circulating levels of IGF-I may vary over time for the same patient and may not be elevated in case of poor nutritional status.\nAntenatal diagnosis\nPrenatal diagnosis has not been reported and is complicated by the variable expressivity (even within the same family) of some of the reported mutations, especially in terms of their impact on intellectual development.\nGenetic counseling\nIn all but one of these patients, the mutations were heterozygous and transmitted as an autosomal dominant trait. Affected families should be offered genetic counselling and informed of a 50% risk of recurrence for dominant inheritance and of a 25% risk of recurrence for recessive transmission.\nManagement and treatment\nManagement involves nutritional and developmental support. Although deafness has not yet been reported in patients with IGF-I resistance, it is present in some patients with IGF-I deficiency (caused by mutations in the gene encoding the IGF1R ligand, IGFI). As a result, screening for deafness should be proposed for all patients with IGF-I resistance. Some patients with IGF-I resistance show increased growth velocity with recombinant GH therapy while others show no response.\nPrognosis\nPrognosis varies depending on the underlying molecular anomaly.\n\n                            Last update: \n                            May 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Yves LE BOUC  - Pr Irène NETCHINE"}
{"Disease Name": "Growth delay due to insulin-like growth factor type 1 deficiency", "Disease Definition": "Growth delay due to insulin-like growth factor I deficiency is characterised by the association of intrauterine and postnatal growth retardation with sensorineural deafness and intellectual deficit.", "ORPHA ID": 73272, "Summary": "Epidemiology\nThe syndrome is extremely rare and only four cases have been reported in the literature so far.\nClinical description\nAddition clinical features include microcephaly, adiposity, and insulin resistance. Partial gonadal dysfunction and osteoporosis may also be present. A case of partial IGF-I deficiency has also been described and was associated with pre- and postnatal growth retardation and microcephaly but the developmental delay was mild and hearing tests were normal.\nEtiology\nIGF-I deficiency is caused by homozygous mutations in the insulin-like growth factor 1 gene (IGFI; 12q22-q24.1). IGF-I is essential for foetal and postnatal growth, brain development and metabolism.\nDiagnostic methods\nDiagnosis relies on direct sequencing of the five IGF1 exons and of the intron-exon junctions. Measurement of IGF-I levels can be used for diagnosis but the circulating levels of IGF-I vary between patients (ranging from undetectable, low to very high) depending on the molecular defect present and on the immunoassay used.\nDifferential diagnosis\nThe differential diagnosis should include growth hormone deficiency and growth hormone resistance (caused by GH receptor or STAT5b anomalies), growth delay due to insulin-like growth factor I resistance and primary acid-labile subunit (ALS) deficiency syndrome (see these terms), as well as secondary IGF-I deficiency due to nutritional problems.\nAntenatal diagnosis\nPrenatal diagnosis is feasible for families with an identified IGF1 mutation proven to be responsible for the disease phenotype of intrauterine and postnatal growth delay associated with intellectual deficit.\nGenetic counseling\nIGF-I deficiency is transmitted as an autosomal recessive trait. Affected families should be offered genetic counselling and informed of a 25% risk of recurrence.\nManagement and treatment\nManagement involves nutritional and developmental support, together with screening for deafness. Growth velocity in patients with partial IGF-I deficiency can be increased by recombinant growth hormone (GH) therapy. Recombinant IGF-I therapy can be used in patients with complete IGF-I deficiency or those showing an insufficient response to recombinant GH treatment.\n\n                            Last update: \n                            April 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Yves LE BOUC  - Pr Irène NETCHINE"}
{"Disease Name": "Growth delay-hydrocephaly-lung hypoplasia syndrome", "Disease Definition": "Growth delay - hydrocephaly - lung hypoplasia, also named Game-Friedman-Paradice syndrome, is a rare developmental disorder described in 4 sibs so far and characterized by delayed fetal growth, hydrocephaly with patent aqueduct of Sylvius, underdeveloped lungs and various other anomalies such as small jaw, intestinal malrotation, omphalocele, shortness of lower limbs, bowed tibias and foot deformities.", "ORPHA ID": 3035, "Summary": ""}
{"Disease Name": "Growth delay-intellectual disability-hepatopathy syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disease characterized by severe intrauterine and post-natal growth delay, moderate to severe intellectual disability, and neonatal-onset hepatopathy with fibrosis, steatosis, and/or cholestasis, occasionally leading to liver failure. Additional variable manifestations include muscular hypotonia, zinc deficiency, recurrent infections, diabetes mellitus, joint contractures, skin and joint laxity, hypervitaminosis D, and sensorineural hearing loss.", "ORPHA ID": 541423, "Summary": ""}
{"Disease Name": "Growth hormone insensitivity syndrome", "Disease Definition": "Growth hormone insensitivity syndrome (GHIS) is a group of diseases characterized by marked short stature associated with normal or elevated growth hormone (GH) concentrations, which fail to respond to exogenous GH administration. GHIS comprises growth delay due to IGF-1 deficiency, growth delay due to IGF-1 resistance, Laron syndrome, short stature due to STAT5b deficiency and primary acid-labile subunit (ALS) deficiency (see these terms).", "ORPHA ID": 181393, "Summary": "Epidemiology\nA few cases of IGF-1 deficiency, IGF-1 resistance, STAT5B and ALS deficiencies, and more than 250 cases of Laron syndrome have been reported in the literature so far. Males and females are equally affected.\nClinical description\nIntrauterine growth and birth size are usually subnormal. Postnatal growth is slowed. Facial dysmorphism is common and includes microcephaly, thin upper and everted lower lips and small chin. Disproportional growth, delayed motor development and delayed puberty have been described in some cases and relative obesity may occur in young adults. Intellectual development varies from normal intelligence to intellectual deficiency. Despite sharing short stature and the classical biochemical features of GH insensitivity, affected individuals present heterogeneous clinical features depending on the genetic condition. Immune deficiency has been described in some cases of STAT5b deficiency. Hearing loss has been described in some cases of IGF-1 deficiency.\nEtiology\nGHIS is due to mutations in the growth hormone receptor (GHR) gene (Laron syndrome) or to post receptor defects due to mutations in the IGF-1 (IGF-1 deficiency and IGF-1 resistance), IGFALS (short stature due to primary ALS deficiency) or STAT5B genes (STAT5b deficiency). Transmission is autosomal recessive.\nDiagnostic methods\nThe diagnosis is based on clinical and biological findings. Hormonal tests reveal normal or high serum concentrations of GH. IGF-1 and growth hormone binding protein (GHBP) levels depend on the disease-causing mutations. IGF-1 levels are low in cases ofGHR defects, STAT5b, IGF-1 and ALS deficiencies, and high in cases of IGF-1 resistance. GHBP levels are low in cases of mutations in the extracellular domain of GHR and normal in cases of mutations in the intracellular domain of GHR or post receptor defects. IGF-BP 3 levels are low in cases of GHR, STAT5b, and ALS deficiencies, normal in cases of IGF-1 deficiency. ALS levels are low in cases of ALS deficiencies. Genetic tests should be performed to make a precise etiological diagnosis.\nDifferential diagnosis\nThe differential diagnosis should include secondary IGF-1 deficiency due to nutritional problems or chronic pediatric diseases.\nGenetic counseling\nGenetic counseling should be proposed to parents of an affected individual before any further pregnancy, informing them of the risks and the available diagnostic methods.\nManagement and treatment\nManagement aims at improving growth and, except for IGF-1 resistance, includes treatment with daily subcutaneous injections of mecasermin, a recombinant human IGF-1, and diet with adequate caloric intake. In August 2005, mecasermin was granted EC orphan drug designation. Growth hormone treatment may partially improve growth in cases of IGF-1 resistance. There is no treatment that cures or prevents the disease.\nPrognosis\nWith age, osteoporosis can become apparent. Patients may develop obesity, hypercholesterolemia, insulin resistance, glucose intolerance and even type II diabetes.\n\n                            Last update: \n                            November 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Juliane LEGER"}
{"Disease Name": "Growth retardation-mild developmental delay-chronic hepatitis syndrome", "Disease Definition": "Growth retardation-mild developmental delay-chronic hepatitis syndrome is a rare, genetic, parenchymatous liver disease characterized by pre- and postnatal growth retardation, mild global developmental delay, chronic hepatitis with hepatosplenomegaly, Hashimoto thyroiditis, thrombocytopenia, anemia, and B-precursor acute lymphoblastic leukemia.", "ORPHA ID": 391366, "Summary": ""}
{"Disease Name": "Grubben-de Cock-Borghgraef syndrome", "Disease Definition": "Grubben-de Cock-Borghgraef syndrome is a rare intellectual disability syndrome characterized by pre- and postnatal growth deficiency, generalized muscular hypotonia, developmental delay (particularly of speech and language), hypotrophy of distal extremities, small and puffy hands and feet, eczematous skin and dental anomalies (i.e. small, widely-spaced teeth). Partial agenesis of the corpus callosum and a selective immunoglobulin IgG2 subclass deficiency have also been reported in some patients.", "ORPHA ID": 2101, "Summary": ""}
{"Disease Name": "GTP cyclohydrolase I deficiency", "Disease Definition": "GTP-cyclohydrolase I deficiency, an autosomal recessive genetic disorder, is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. Not only does tetrahydrobiopterin deficiency cause hyperphenylalaninemia, it is also responsible for defective neurotransmission of monoamines because of malfunctioning tyrosine and tryptophan hydroxylases, both tetrahydrobiopterin-dependent hydroxylases.", "ORPHA ID": 2102, "Summary": "Clinical description\nWhen left untreated, the deficiency causes neurological signs at age 4 or 5 months, although clinical signs are often obvious from birth. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing.\nDiagnostic methods\nGTP-cyclohydrolase I deficiency should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when hyperphenylalaninemia is moderate. The most effective way to diagnose the disorder is to measure pteridine levels in urine and to confirm the result by measuring neurotransmitters (5-hydroxyindolacetic acid, homovanillic acid) in cerebrospinal fluid and with an oral tetrahydrobiopterin-loading test (20 mg/kg).\nManagement and treatment\nThe treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of tetrahydrobiopterin) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophane).\n\n                            Last update: \n                            February 2005\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Louis DHONDT"}
{"Disease Name": "Guanidinoacetate methyltransferase deficiency", "Disease Definition": "Guanidinoacetate methyltransferase (GAMT) deficiency is a creatine deficiency syndrome characterized by global developmental delay/intellectual disability (DD/ID), prominent speech delay, autistic/hyperactive behavioral disorders, seizures, and various types of pyramidal and/or extra-pyramidal manifestations.", "ORPHA ID": 382, "Summary": "Epidemiology\nLess than 100 patients are known worldwide.\nClinical description\nOnset of manifestations of GAMT deficiency occurs between 3 months and 3 years of age. Affected individuals have mild to severe intellectual disability with a distinctive deficit in expressive language, regardless of the degree of the intellectual deficit. Seizures, of different types, are observed in most individuals and are often intractable. Behavioral disorders such as hyperactivity and autistic features are also frequent. Patients may also have movement disorders which mainly affect the extra-pyramidal system and manifest as chorea, athetosis and ataxia.\nEtiology\nGAMT deficiency is due to mutations in the GAMT gene (19p13.3). Different mutations (missense, nonsense, splice site, insertions, deletions) have been identified, located on various exons of the GAMT gene. The most frequently identified mutation, c.327G>A (p.K109K, splice site exon 2), is present in at least one allele in over 50% of families. c.59G>C is most frequently encountered in Portuguese patients. To date no genotype phenotype correlation has been established.\nDiagnostic methods\nThe diagnosis is clinically suspected in children with DD/ID, speech/language delay, autistic behavior and seizures. Diagnosis is based on the presence of high levels of guanidinoacetate (GAA) in the urine/blood and low levels of creatine in the brain. Diagnosis is confirmed by genetic testing for mutations in the GAMT gene. In case of unknown significance of a gene variant, measurement of GAMT enzyme catalytic activity helps to confirm a functional deficiency. Methods for newborn screening have been established and pilot projects are currently being conducted in various newborn screening programs.\nDifferential diagnosis\nThe differential diagnosis in children with a cerebral creatine deficiency includes L-Arginine:glycine amidinotransferase (AGAT) deficiency and X-linked creatine transporter deficiency. In the case of a partial cerebral creatine deficiency, argininosuccinic aciduria, citrullinemia type I, and gyrate atrophy of the choroid and retina (see these terms) should be considered.\nAntenatal diagnosis\nPreimplantation or prenatal genetic diagnosis is possible for at risk couples.\nGenetic counseling\nTransmission is autosomal recessive. In case of family history, genetic testing for the family of the proband and genetic counseling with regards to family planning is recommended.\nManagement and treatment\nTreatment consists of oral high dose creatine monohydrate, in combination with ornithine supplementation (100-800mg/kg/day given in 3-6 doses daily) and/or dietary restriction of arginine (15-25mg/kg/day). Management of GAMT deficiency involves regular measurement of plasma guanidinoacetate and ornithine levels. Treatment improves seizures and behavioral and movement disorders, but it cannot reverse intellectual disability and developmental delay incurred before diagnosis. Early detection is essential in avoiding irreversible brain damage.\nPrognosis\nGAMT deficiency is a treatable disease and is not life threatening, however life expectancy is limited, particularly in those who have multiple disabilities and severe seizures.\n\n                            Last update: \n                            December 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Sylvia STOCKLER"}
{"Disease Name": "Guillain-Barré syndrome", "Disease Definition": "A clinically heterogeneous spectrum of rare post-infectious neuropathies that usually occur in otherwise healthy patients and encompasses acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN), Miller-Fisher syndrome (MFS) and some other regional variants.", "ORPHA ID": 2103, "Summary": "Epidemiology\nThe overall annual incidence of GBS varies between 1/91,000 and 1/55,000. In Europe and North America, AIDP is the most frequent form of GBS (accounting for around 90% of cases) and thus the term GBS in general is synonymous with AIDP in Western countries. The axonal forms account for only 3-5% of cases in Western countries but are much more frequent (30%-50% of GBS cases) in Asia and Latin America.\nEtiology\nIn the majority of cases, an infectious disease precedes the onset of limb weakness with Campylobacter jejuni infection being the most frequently identified initiating event. GBS has also been reported to occur after vaccination or following a surgical intervention.\nManagement and treatment\nTreatment consists of rapid administration of intravenous immunoglobulin (IVIg) or plasma exchange (PE). Physiotherapy and rehabilitation are also important.\nPrognosis\nThe prognosis is variable depending on the form of GBS and ranges from patients with complete recovery, to those who are unable to walk 6 months after disease onset, and to patients in whom the disease has a fatal outcome.\n\n                            Last update: \n                            December 2009\n\n\n                            - Expert reviewer(s): \n                            Pr P.A. [Pieter] VAN DOORN"}
{"Disease Name": "Guttmacher syndrome", "Disease Definition": "Guttmacher syndrome is an extremely rare syndrome characterized by hypoplastic thumbs and halluces, 5th finger clinobrachydactyly, postaxial polydactyly of the hands, short or uniphalangeal 2nd toes with absent nails and hypospadias.", "ORPHA ID": 2957, "Summary": "Epidemiology\nIt has been described in a father and his son and daughter.\nClinical description\nThe affected patients have normal mental development. Except for postaxial polydactyly of the hands and uniphalangeal 2nd toes with absent nails, features are in common with hand-foot-genital syndrome (HFGS, see this term) caused by mutations in the HOXA13 gene.\nEtiology\nIn all three affected individuals with Guttmacher syndrome, two different sequence alterations were identified in HOXA13 gene: a de novo missense mutation and a deletion in the promoter region of the gene, inherited from an unaffected parent, which may contribute to the phenotype in the affected individuals.\nGenetic counseling\nThe condition is inherited in an autosomal dominant manner.\n\n                            Last update: \n                            January 2011"}
{"Disease Name": "Gyrate atrophy of choroid and retina", "Disease Definition": "Gyrate atrophy of the choroid and retina (GACR) is a very rare, inherited retinal dystrophy, characterized by progressive chorioretinal atrophy, myopia and early cataract.", "ORPHA ID": 414, "Summary": "Epidemiology\nPrevalence has been estimated to be 1/50,000 in Finland. More than 200 biochemically-confirmed cases have been reported in the international literature. Cases have also been reported from Canada, Germany, Italy, Israel, Japan, the Netherlands and the USA.\nClinical description\nAge at diagnosis is highly variable (1 month - 44 years). High phenotypic variability is noted among patients even within the same family, as well variable disease progression. The first complaints of the patients are night blindness (nyctalopia) and constriction of the visual field caused by multiple round areas of chorioretinal atrophy in the periphery. Over the years, the atrophic areas increase, coalesce and spread towards the macula leading to central visual loss in the 4th to 7th decade of life. Other ocular manifestations include myopia with marked astigmatism, early posterior subcapsular cataract, and cystoid macular edema.\nEtiology\nGACR is caused by homozygous or compound heterozygous mutations in the ornithine aminotransferase OAT gene (10q26) which codes for the ornithine-degrading, pyridoxal phosphate-dependent enzyme ornithine aminotransferase. More than 60 OAT mutations have been identified to date. Deficient OAT enzyme activity results in hyperornithinemia. The exact mechanism leading to chorioretinal atrophy is still unknown.\nDiagnostic methods\nDiagnosis is based on ophthalmological examination showing the typical sharply demarcated round patches of chorioretinal atrophy located circumferentially in the periphery, and the other clinical manifestations such as myopia and early cataract. Cystoid macular edema can be detected with optical coherence tomography. Fundus autofluorescence is absent in the atrophic areas. The full-field electroretinogram shows severely reduced or undetectable amplitudes even at an early stage of the disease. Serum, urine, and spinal fluid ornithine levels are 10 to 20 times higher than those in healthy subjects. The diagnosis can be confirmed by molecular genetic testing of the OAT gene.\nDifferential diagnosis\nCareful fundoscopy, fundus autofluorescence images and pointed family history help to delimit autosomal recessive GACR from X-chromosomal choroideremia. At the slightest suspicion of GACR, serum ornithine levels should be measured to detect hyperornithinemia.\nGenetic counseling\nGACR follows an autosomal recessive pattern of inheritance. Genetic counseling should be provided to affected families.\nManagement and treatment\nPatients with GACR should be referred to a diet expert, because several studies report that an arginine-restricted diet (precursor of ornithine) or a low-protein diet may reduce the ornithine serum level and may slow the progression of chorioretinal atrophy and visual loss. Pyridoxine (vitamin B6) supplementation may also be given but most patients appear to be non-responsive. Cataract surgery may be required. In late stages with visual loss, magnifying visual devices should be provided.\nPrognosis\nThe ocular prognosis is poor because constriction of the visual field and visual loss are progressive and can cause blindness. Early diagnosis and successful diet treatment are important prognostic factors.\n\n                            Last update: \n                            May 2015"}
{"Disease Name": "Gómez-López-Hernández syndrome", "Disease Definition": "A rare neurocutaneous syndrome characterized by the association of cerebellum (rhombencephalosynapsis), cranial nerves (trigeminal anesthesia), and scalp (alopecia) abnormalities. Other features observed in patients were craniosynostosis, midfacial hypoplasia, bilateral corneal opacities, low-set ears, short stature, moderate intellectual impairment and ataxia. Hyperactivity, depression, self-injurious behaviour and bipolar disorder have also been reported.", "ORPHA ID": 1532, "Summary": ""}
{"Disease Name": "H syndrome", "Disease Definition": "A rare cutaneous disease and a systemic inherited histiocytosis mainly characterized by hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and occasionally, hyperglycemia/diabetes mellitus. Due to overlapping clinical features, it is now considered to include pigmented hypertrichosis with insulin dependent diabetes mellitus syndrome (PHID), Faisalabad histiocytosis (FHC) and familial sinus histiocytosis with massive lymphadenopathy (FSHML). Some cases of dysosteosclerosis may also represent the syndrome.", "ORPHA ID": 168569, "Summary": "Epidemiology\nTo date, around 130 patients have been described in the world literature.\nClinical description\nH syndrome becomes clinically apparent mostly during childhood, but cases during infancy and late-onset cases have been reported too. Cutaneous features are the most prevalent. Hyperpigmentation, associated with induration and hypertrichosis, usually appears initially on the medial thighs and shins, but may be more extensive. Sensorineural hearing loss is the second most common manifestation. Additional features include heart anomalies, hepatosplenomegaly, lymphadenopathy, insulin dependent diabetes mellitus, hypogonadism (short stature, gynecomastia, delayed puberty, primary amenorrhea), angiopathy (varicosities, dilated lateral scleral vessels, and facial telangiectasias) and genital masses. Exophthalmos (with normal thyroid function), malabsorption (due to pancreatic exocrine insufficiency), renal anomalies, flexion contractions of interphalangeal joints and hallux valgus (with fixed flexion contractures of the toe), and lytic bone lesions as well as osteosclerosis are also seen. Early-onset recurrent febrile episodes, lateral tibial torsion, and hypertriglyceridemia may be observed. Various hematological abnormalities have been described, including microcytic anemia, myelofibrosis and pure red cell aplasia.\nEtiology\nH syndrome is caused by mutations in SLC29A3 (10q22.2) (encoding a nucleoside transporter, hENT3), which result in defective nucleoside transport functions of hENT3. This leads to histiocytic infiltration of numerous organs. There are no clear genotype-phenotype correlations for SLC29A3 mutations. Four allelic disorders have been described: PHID, FHC, FSHML and dysosteosclerosis. However, since H syndrome encompasses the clinical features of the first three allelic disorders, and all share identical mutations in SLC29A3, these disorders are now considered as the same entity.\nDiagnostic methods\nDiagnosis is suspected by the pathognomonic cutaneous features. If these are lacking, the constellation of additional findings such as hearing loss, fixed flexion contractures of fingers and toes, short stature and hepatosplenomegaly should raise suspicion for H syndrome. Laboratory tests show extremely elevated erythrocyte sedimentation rate, mild microcytic anemia, and elevated liver enzymes. Hypogonadism (hyper- or hypogonadotropic) and azoospremia may be observed. Histopathological examination of involved skin shows a characteristic dermal and subcutaneous interstitial mononuclear infiltrate, composed mainly of small to medium-sized CD68+S100+CD1a- histiocytes (occasionally with emperipolesis) and fibrosis. Diagnosis is confirmed by genetic screening of SLC29A3.\nDifferential diagnosis\nDifferential diagnosis includes Torg-Winchester syndrome, hemochromatosis, POEMS syndrome and Rosaï-Dorfman disease.\nAntenatal diagnosis\nPrenatal molecular diagnosis is feasible by DNA testing in chorionic villi or amniotic cells.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling should be offered to at-risk couples, informing them of the 25% risk to transmit the causal mutation to their offspring. The clinical picture is highly variable, even within affected families.\nManagement and treatment\nManagement is mainly supportive. Oral steroids may temporarily improve cutaneous changes in some patients, but are inappropriate for long term use due to side effects. Tocilizumab has been found to be effective in a number of patients. Early screening for sensorineural hearing loss and diabetes mellitus should be performed.\nPrognosis\nThe disease usually runs a variable but progressive course, and early-death has been described.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Abraham ZLOTOGORSKI"}
{"Disease Name": "Haddad syndrome", "Disease Definition": "Haddad syndrome is a rare congenital disorder in which congenital central hypoventilation syndrome (CCHS), or Ondine syndrome, occurs concurrently with Hirschsprung disease (see these terms).", "ORPHA ID": 99803, "Summary": "Epidemiology\nBirth incidence of Ondine syndrome is 1 in 200,000 live-births and Hirschsprung disease occurs concurrently in 16% of cases.\nClinical description\nIntestinal aganglionosis is more extensive, and the gender ratio is 1:1, unlike in classical Hirschsprung disease.\nEtiology\nMutations in the PHOX2B gene are found in a significant number of patients with Haddad syndrome.\n\n                            Last update: \n                            November 2010"}
{"Disease Name": "Hailey-Hailey disease", "Disease Definition": "A rare, genetic, chronic epidermal disorder characterized by diffuse bilateral (or, rarely, localized segmental) erythematous plaques with blistering, erosions, maceration, and frequent secondary infection involving the flexural areas.", "ORPHA ID": 2841, "Summary": "Epidemiology\nThe prevalence of familial benign chronic pemphigus (FBCP) is unknown, but no significant difference in sex or ethnic frequency has been noted.\nClinical description\nSkin lesions starting as flaccid vesicles on erythematous to normal skin, appear during adolescence or more commonly between the age of 20 and 40 years. Large, macerated, exudative plaques of superficial erosions with crusting are usually seen at the time of diagnosis. Further progression to large, vegetative, malodorous plaques with painful fissures can occur. Involvement sites consist of areas of friction and intertriginous regions (including the neck, axillae, groin, perineum, and the submammary area), affected in a symmetric fashion. Additional feature, observed in approximately 70% of patients, is the presence of longitudal white bands in the fingernails. Segmental forms of the disease present as unilateral, linear, patchy or otherwise confined involvement, often in relation to the Blashko lines. FBPC has a chronic course of repeated remissions and relapses. Triggering or exacerbating factors include sweating, friction, ultraviolet radiation, and secondary infections. Postinflammatory hyperpigmentation is a common sequela.\nEtiology\nFBCP is caused by heterozygous, loss-of-function mutations in the ATP2C1 gene (3q22.1) which encodes the calcium(Ca2+)-transporting ATPase type 2C member 1 protein, an adenosine triphosphate (ATP)-powered, magnesium-dependent Ca2+ pump involved in Ca2+ sequestering inside the Golgi apparatus. The exact mechanism is unknown, but mutations in ATP2C1 result in altered cellular connections within desmosomes and adherens junctions of the epidermis, secondary to high cytosolic Ca2+ levels.\nDiagnostic methods\nHistopathological analysis of the lesions shows a widespread and often incomplete acantholysis in the suprabasal layer, which produces a characteristic \"dilapidated brick wall\" appearance. Direct immunofluorescence staining is negative. Family history and molecular analysis of the ATP2C1 can contribute to confirming the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes intertrigo, candidiasis, inverse psoriasis, lichen simplex chronicus, other subtypes of pemphigus (such as pemphigus vegetans), tinea corporis, and Darier disease.\nAntenatal diagnosis\nPrenatal testing is possible when the pathogenetic variant has been identified in the family, but is a subject of ethical consideration.\nGenetic counseling\nFBCP is inherited in an autosomal dominant manner with full penetrance and variable expressivity. About one third of cases occur de novo. Somatic mutations underlie segmental forms of the disease. Genetic counseling can inform the affected individuals of the 50% risk of disease occurrence in their children.\nManagement and treatment\nThere is no specific therapy, but drying the affected areas and avoiding friction is essential as well as employing measures to prevent bacterial, fungal and viral infections. Topical medical treatment (including antimicrobials, corticosteroids, calcineurin inhibitors and botulinum toxin injections) may alleviate milder symptoms. There is no strong evidence to support the use of systemic therapies although doxycycline and low-dose naltrexone may provide some benefit. For those with refractory disease, more aggressive treatment with laser ablation, dermabrasion and/or surgery may be considered.\nPrognosis\nThe quality of life in patients with FBCP is significantly impaired, but they have a normal life expectancy, and the intensity of the disease usually diminishes with age.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Sung Kyung CHO  - Dr Victoria WERTH"}
{"Disease Name": "Haim-Munk syndrome", "Disease Definition": "Haim-Munk syndrome (HMS) is characterized by palmoplantar hyperkeratosis, severe early-onset periodontitis, onychogryposis, pes planus, arachnodactyly and acroosteolysis.", "ORPHA ID": 2342, "Summary": "Epidemiology\nHMS is rare with less than 100 cases reported in the literature so far. The majority of reported cases are descendants of a few consanguineous families from a religious isolate in Cochin, India. One unrelated Brazilian patient has also been reported.\nClinical description\nHMS presents with severe and extensive skin manifestations. In addition to the marked palmoplantar keratosis, patients have scaly erythematous and circumscribed patches on the elbows, knees, forearms, shins and dorsum of the hands. Severe, early-onset progressive periodontitis that affects both the deciduous and permanent dentitions and presents with gingival inflammation and alveolar bone destruction is a hallmark of the disease. Onychogryposis, arachnodactyly, acroosteolysis and pes planus are additional features that help to distinguish HMS from other forms of palmoplantar hyperkeratosis. A peculiar deformity of the fingers (tapered, pointed phalangeal ends and a claw-like volar curve) is typical. Destructive arthritis of the wrist and shoulder joints has been reported in isolated cases. Patients with HMS have increased susceptibility to infections.\nEtiology\nHMS is caused by germline mutations in the lysosomal protease cathepsin C (CTSC) gene mapped to chromosome 11q14.1-q14.3. Mutations in the same gene cause the clinically related disorders Papillon-Lefèvre syndrome (PLS) and prepubertal periodontitis (see these terms).\nDiagnostic methods\nDiagnosis is clinical but can be confirmed by detection of the disease-causing mutation.\nDifferential diagnosis\nDifferential diagnosis includes the allelic disorder PLS and disorders with palmoplantar hyperkeratosis and prepubertal periodontitis.\nGenetic counseling\nHMS is transmitted as an autosomal recessive trait.\nManagement and treatment\nManagement of the skin manifestations requires topical emollients, keratolytics (including salicylic acid and urea) and oral retinoids (acitretin, etretinate, and isotretinoin). Periodontitis in HMC is usually unresponsive to traditional periodontal therapies. Patients may benefit from extraction of the primary teeth combined with oral antibiotics and professional tooth cleaning. Synovectomy has been shown to alleviate the inflammation associated with destructive arthritis but may lead to loss in the range of the joint motion.\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN"}
{"Disease Name": "Hairy cell leukemia variant", "Disease Definition": "A rare, malignant splenic B-cell lymphoma/leukemia characterized by circulating abnormal lymphocytes with intermediate morphology between prolymphocytes and hairy cells with positive expression of CD11c and negative expression of CD25, CD123 and the BRAFV600E mutation. Manifestations include splenomegaly, elevated white blood cell (WBC) count, hyper-cellular bone marrow and anemia/thrombocytopenia, but no monocytopenia.", "ORPHA ID": 300878, "Summary": "Epidemiology\nHairy cell leukemia variant (HCL-V) constitutes about 10% to 20% of patients with hairy cell leukemia (HCL) and 0.4% of all lymphoid malignancies. There is a slight male predominance (male/female: 1.6).\nClinical description\nHCL-V onset is in adulthood, most frequently in the elderly population (median age: 71 years). Initial manifestations are typically of abdominal discomfort or distension, usually related to splenomegaly, hepatomegaly and manifestations derived from cytopenias such as anemia, bleeding and/or infections. HCL-V is more aggressive and resistant to therapy than classical HCL (HCL-C). A disease closely resembling HCL-V has been described in Japan and has been called the HCL Japanese variant (HCL-Jv).\nEtiology\nThe etiology is unknown but there is no evidence of an association between exposure to carcinogens, radiation or viral infections. P53 dysfunction, due to either monosomy, monoallelic deletion or a TP53 mutation (17p13.1), has been reported in many patients (estimate 30% of patients) as well as mutations in the gene  MAP2K1 (15q22.31) (estimate 50%). The VH gene family, IGHV4-34, appears to be over-expressed, but is also found in other B-cell malignancies. HCL-V is not considered to be biologically related to HCL-C, and HCL-V patients are negative for the BRAF-V600E mutation.\nDiagnostic methods\nDiagnosis is suspected on physical examination, bone marrow biopsy, and abdominal computed tomography (CT) scan, as well as laboratory tests which show raised white blood cell count (>10×109/l). HCL-V cells do not demonstrate reactivity to annexin A1 and are either weakly positive or negative for tartrate-resistant acid phosphatase (TRAP). HCL-V cells are negative for BRAFV600E mutation. The diagnosis of HCL-V is confirmed by flow cytometry immunophenotyping (positive for CD11C, and negative for CD123 and CD25 with variable expression of CD103, CD19, CD20, and CD22).\nDifferential diagnosis\nDifferential diagnosis includes splenic marginal zone lymphoma, splenic diffuse red pulp lymphoma (SRPL), HCL-C, mantle-cell lymphoma, and B-cell prolymphocytic leukemia (B-PLL).\nManagement and treatment\nAsymptomatic patients with moderate splenomegaly and no cytopenias may be managed with close monitoring. Therapy is indicated for symptomatic disease (progressive splenomegaly and/or elevated lymphocyte counts with cytopenias). There are no formal guidelines for management and treatment, and information on the efficacy of the various agents is derived from the results on small series of patients or single case reports with limited follow-up. Splenectomy has been utilized in some patients resulting in improvement in anemia and thrombocytopenia; however, the response eventually results in progressive disease. A combination of purine analog (cladribine) and a monoclonal anti-CD20 antibody has resulted in complete remission in patients treated (although follow-up is limited). Immunotherapy alone may be considered and include rituximab (successful treatment in several case reports), and anti-CD22 recombinant immunotoxins (response observed in a limited number of patients but relapse reported). Treatment with interferon alpha and purine analogs alone is unsatisfactory and fails to achieve a durable, high complete remission rate.\nPrognosis\nHCL-V is an aggressive disorder with a chronic clinical course. The reported survival at five years is approximately 60%; however, complete remission has been reported, in particular with combined purine analog and rituximab treatment or immunotherapy alone. In general, significant anemia, older age, and mutations in TP53 are associated with a worse prognosis.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Michael GREVER"}
{"Disease Name": "Hajdu-Cheney syndrome", "Disease Definition": "A rare autosomal dominant skeletal disorder, characterized by progressive bone resorption in the distal phalanges (acro-osteolysis), progressive osteoporosis, distinct craniofacial changes, dental anomalies, and occasional association with renal abnormalities.", "ORPHA ID": 955, "Summary": "Epidemiology\nLess than 100 cases are confirmed to date.\nClinical description\nWhilst affected individuals may appear normal at birth and during infancy, minor facial abnormalities, such as a small mandible, may come to clinical attention in half of affected infants. With age, affected children develop facial dysmorphism (dolicho-bathrocephaly, coarse hair, synophrys, hypertelorism, downslanting palpebral fissures, low set ears, midface flattening, long philtrum, and micrognathia). The fontanels are delayed in closure. Short stature manifests in early childhood and is progressive, presumably due to vertebral compression. Acroosteolysis becomes manifest between preschool age and mid-childhood and clinically presents as short finger tips and nails with pseudoclubbing. Osteoporosis is evident even in childhood, but is conspicuously progressive in late adolescent to adulthood, leading to biconcave codfish vertebrae and kyphoscoliosis. Bone weakness at the craniovertebral junction causes platybasia and basilar invagination, resulting in syringomyelia, hydrocephalus and neurologic deficits. Dental anomalies include severe crowding, periodontitis, and premature loss of teeth. Some patients are at potential risk of renal failure due to multiple renal cysts. Serpentine fibula-polycystic kidney syndrome (SFPKS) is the most severe manifestation of Hajdu-Cheney syndrome, which manifests with bent (serpentine) fibulae and radii as well as congenital renal cysts.\nEtiology\nThe disorder is caused by heterozygous pathogenic variants in the NOTCH2 gene mapped on 1p12 and encoding the neurogenic locus notch homolog protein 2 (Notch2). All known disease-causing variants are located in exon 34, and cause abnormally increased Notch2 signaling (gain-of-function). Of note, pathogenic variants in NOTCH2 also cause a different malformation syndrome, Alagille syndrome type 2.\nDiagnostic methods\nThe diagnosis is made on clinical and radiological grounds, and is confirmed by molecular detection of pathogenic variants in the NOTCH2 gene.\nDifferential diagnosis\nThe facial abnormalities are commonly misdiagnosed with Noonan syndrome in infancy and early childhood. The differential diagnosis includes genetic syndromes with pediatric acroosteolysis, such as pyknodysostosis, mandibuloacral dysplasia, as well as congenital insensitivity to pain.\nAntenatal diagnosis\nPrenatal diagnosis is theoretically possible in affected families in which the causal NOTCH2 variant has been previously identified. The fetal manifestation of SFPKS can be detected on prenatal ultrasonography.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. The offspring of an affected individual is at a 50% risk of having the pathogenic variant in NOTCH2. However, most cases are sporadic in occurrence.\nManagement and treatment\nOnly symptomatic treatment is available for the specific symptoms. Bisphosphonate therapy is beneficial for osteoporosis, though it is not helpful for acroosteolysis. Individuals with renal failure require the standard medical intervention. Regular dental examinations are important.\nPrognosis\nThe life expectancy of patients is not severely impaired. Osteoporosis and associated fractures cause significant morbidity. Basilar invagination occasionally leads to syringomyelia and seldom hydrocephalus. Dental management is important for the quality of life.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Soren FAERGEMAN | ITHACA* - Dr Pernille GREGERSEN | ITHACA* - Dr Gen NISHIMURA \n\n\n                                * European Reference Network"}
{"Disease Name": "Hall-Riggs syndrome", "Disease Definition": "Hall-Riggs syndrome is a very rare syndrome consisting of microcephaly with facial dysmorphism, spondylometaepiphyseal dysplasia and severe intellectual deficit.", "ORPHA ID": 2107, "Summary": "Epidemiology\nEight cases have been reported in the literature in two unrelated families.\nClinical description\nDysmorphic features include hypertelorism, depressed nasal bridge, large nose with a large nasal tip, anteverted nostrils and wide mouth with thick lips. Affected patients do not achieve language ability.\nGenetic counseling\nThe condition is probably hereditary, and transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            January 2010"}
{"Disease Name": "Hallermann-Streiff syndrome", "Disease Definition": "Hallermann-Streiff syndrome is a rare genetic syndrome characterized mainly by head and facial abnormalities such as bird-like facies (with beak-shaped nose and retrognathia), hypoplastic mandible, brachycephaly with frontal bossing, dental abnormalities (e.g. absence of teeth, natal teeth, supernumerary teeth, severe agenesis of permanent teeth, enamel hypoplasia) hypotrichosis, various ophthalmic disorders (e.g. congenital cataracts, bilateral microphthalmia, ptosis, nystagmus) and atrophy of skin (especially around the center of face and nose) as well as telangiectasia and proportionate short stature. Intellectual disability is reported in some cases.", "ORPHA ID": 2108, "Summary": ""}
{"Disease Name": "Hallermann-Streiff-like syndrome", "Disease Definition": "A rare genetic bone development disorder characterized by multiple congenital fractures, slender ribs and long bones, deficient ossification of the skull, and dysmorphic facial features reminiscent of Hallermann-Streiff syndrome (such as high forehead and triangular face with small jaw, deep-set eyes, beaked, narrow nose, downturned mouth, and posteriorly angulated ears). Bilateral microphthalmia, cataracts, and pulmonary hypoplasia have also been reported. The disease is fatal in the neonatal period. There have been no further descriptions in the literature since 1995.", "ORPHA ID": 2109, "Summary": ""}
{"Disease Name": "Hallux varus-preaxial polysyndactyly syndrome", "Disease Definition": "Hallux varus-preaxial polysyndactyly syndrome is a rare, genetic, congenital limb malformation disorder characterized by bilateral medial displacement of the hallux and preaxial polysyndactyly of the first toes. Radiographs show broad, shortened, misshapen first metatarsals and may associate incomplete or complete duplication of proximal phalanges and duplication or triplication of distal phalanges. There have been no further descriptions in the literature since 1980.", "ORPHA ID": 2110, "Summary": ""}
{"Disease Name": "Hamel cerebro-palato-cardiac syndrome", "Disease Definition": "An X-linked intellectual disability syndrome (XLMR) characterized by intellectual deficiency, microcephaly and short stature. It belongs to the group of disorders collectively referred to as Renpenning syndrome.", "ORPHA ID": 93946, "Summary": "Epidemiology\nThe prevalence is unknown. It has been reported in a family with 2 brothers and their 2 maternal uncles who presented with severe intellectual deficiency.\nClinical description\nMarked facial characteristics (abnormal ears, bulbous nose, broad nasal bridge, malar hypoplasia, small mouth, and micrognathia), cleft or highly arched palate, and atrial septal defects were observed. Three out of four patients died in infancy or early childhood. Hamel cerebro-palato-cardiac syndrome represents the more severe phenotypic variant.\nEtiology\nThe syndrome is caused by mutations in the PQBP1 gene. Expansions or reductions in the DR/ER repeat in the polar-amino-acid-rich domain (PRD) are responsible for a truncated protein that is thought to disrupt polyglutamine binding.\nGenetic counseling\nHamel cerebro-palato-cardiac syndrome follows an X-linked recessive pattern of inheritance. Genetic testing is possible to identify carrier females and to inform them of the risk of passing on the gene to their offspring.\n\n                            Last update: \n                            June 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Vincent DES PORTES"}
{"Disease Name": "HANAC syndrome", "Disease Definition": "A rare multisystemic disease characterized by small-vessel brain disease, cerebral aneurysm, and extracerebral findings involving the kidney, muscle, and small vessels of the eye.", "ORPHA ID": 73229, "Summary": "Epidemiology\nThe prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date.\nClinical description\nTypical clinical manifestations of HANAC syndrome are the presence of bilateral retinal arteriolar tortuosity (systematically observed), small-vessel brain disease (including porencephaly, leukoencephalopathy, dilated perivascular spaces, lacunar infarcts, and microbleeds, with variable clinical expression), single or multiple intracranial aneurysms (mainly located on the carotid siphon), bilateral cortical and medullary renal cysts, muscle cramps, hematuria, and persistent elevation of serum creatine kinase (CK) concentration. Other eye defects (non-syndromic autosomal dominant congenital cataract, eye anterior segment anomaly of Axenfeld-Rieger type) and glomerular filtration rate decrease have also been reported. More occasional clinical signs include Raynaud phenomenon and supraventricular arrhythmia.\nEtiology\nThe causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in embryogenesis and cell migration/differentiation. To date, six pathogenic variants have been identified; all localized in exons 24 and 25 within the CB3 [IV] domain of COL4A1. They affect glycine residues localized in a 30-amino acid region of the protein.\nDiagnostic methods\nThe diagnosis is based on the characteristic clinical findings. Testing to establish the diagnosis includes fundoscopic examination (retinal arterial tortuosity), renal ultrasound examination (cysts), and brain MRI (white matter lesion, chronic hemorrhagic foci, cerebral arterial aneurysm). Diagnosis is established in an individual with suggestive features of HANAC and the identification of a heterozygous pathogenic variant in COL4A1 by molecular genetic testing.\nDifferential diagnosis\nThe differential diagnosis includes anophthalmia/microphthalmia (A/M), autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), brain small-vessel with hemorrhage, cerebral autosomal dominant/recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL/CARASIL), COL4A2-related porencephaly and intracerebral hemorrhages, and porencephaly type I.\nAntenatal diagnosis\nPrenatal diagnosis is possible for pregnancies at increased risk for a COL4A1-related disorder if the COL4A1 pathogenic variant has been identified in an affected family member.\nGenetic counseling\nThe pattern of inheritance of HANAC syndrome is autosomal dominant. Genetic counseling can inform parents that the risk of transmitting the mutation responsible for the disease to their children is 50%. The proportion of HANAC syndrome cases caused by a de novo pathogenic variant has been estimated to be at least 27%.\nManagement and treatment\nThere is no effective treatment to date for individuals with COL4A1-related disorders. Possible symptomatic therapies include supportive care (based on individual needs, e.g. cataract surgery for severe lens opacities), treatment of hypertension to reduce risk of stroke and avoiding (unless if absolutely necessary) anticoagulant and platelet anti-aggregant use.\nPrognosis\nVery rarely, end stage renal disease or hemorrhagic stroke may occur.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Laura CESCA  - Pr Emmanuelle PLAISIER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hand-foot-genital syndrome", "Disease Definition": "Hand-foot-genital syndrome (HFGS) is a very rare multiple congenital abnormality syndrome characterized by distal limb malformations and urogenital defects.", "ORPHA ID": 2438, "Summary": ""}
{"Disease Name": "Hantavirus pulmonary syndrome", "Disease Definition": "A rare viral hemorrhagic fever characterized by virus-induced microvascular leakage rapidly leading to a severe illness with diffuse pulmonary edema and respiratory failure. These symptoms set in after a short first disease stage with fever, myalgia, and headache, followed by severe gastrointestinal symptoms such as abdominal pain, vomiting, and diarrhea. The high lethality of the disease is due to the possible development of hypotension and cardiogenic shock.", "ORPHA ID": 319247, "Summary": ""}
{"Disease Name": "Hao-Fountain syndrome due to 16p13.2 microdeletion", "Disease Definition": "A partial deletion of the short arm of chromosome 16 characterized by developmental delay, intellectual disability, speech delay, autism spectrum disorder, epilepsy, hypogonadism, and hypotonia. The behavioral profile includes impulsivity, compulsivity, stubbornness, manipulative behaviors, temper tantrums, and aggressive behaviors.", "ORPHA ID": 500055, "Summary": ""}
{"Disease Name": "Hardikar syndrome", "Disease Definition": "A rare multiple congenital malformation syndrome, characterized by an association of cleft lip and palate, patchy pigmentary retinopathy (cat's paw), obstructive liver disease (cholestasis, portal hypertension etc.) and obstructive renal disease (ectopic ureteric insertion, obstruction, vesicouretral reflux and hydronephrosis). Gastrointestinal tract involvement (malrotation, gastresophageal reflux etc.) and cardiac involvement (coarctation of aorta, pulmonary artery stenosis, etc.) have also been reported. An overlap with Kabuki syndrome is debated.", "ORPHA ID": 1415, "Summary": ""}
{"Disease Name": "Harlequin ichthyosis", "Disease Definition": "A rare autosomal recessive congenital ichthyosis characterized at birth by the presence of large, thick, plate-like shell over the whole body associated with severe ectropion, eclabium, and flattened ears, that later develops into a severe scaling erythroderma. Harlequin ichthyosis is the most severe disorder of this group.", "ORPHA ID": 457, "Summary": "Epidemiology\nThe incidence is estimated to be less than 1/300,000 births.\nClinical description\nAffected infants born encased in a collodion membrane (taut, shiny, translucent membrane appearing as an extra skin layer) with armorlike white-grayish scales, distributed throughout the body, and divided into irregular and quadrangular plates by deep fissures, with severe restriction of movements. Facial features are distorted due to extreme ectropion, conjunctival edema, eclabium and broadened nose. Infants also present with contractures, synechiae of auricles and/or toes with a possible risk of autoamputation. The risk of death is high during the neonatal period, babies being susceptible to severe temperature dysregulation, feeding difficulties, infections and respiratory problems. When they survive, the collodion membrane sheds after a few weeks and transforms into severe erythroderma with severe scaling and persistent ectropion. Other clinical features are often associated such as palmoplantar keratoderma, failure to thrive, short stature, malformed ears and digits, nail deformities and alopecia.\nEtiology\nHI is due to recessive mutations in the ABCA12 gene encoding the ATP-binding cassette (ABC) transporter, involved in lipid transport from lamellar granules to the apical surface of granular layer keratinocytes. Homozygous mutations in this gene cause protein function loss and affect important nucleotide-binding fold domains and transmembrane domains resulting in impaired lipid barrier function.\nDiagnostic methods\nDiagnosis is based on clinical examination. Biopsy is not useful but reveals massive compact orthohyperkeratosis. Skin ultrastructure shows vesicular lamellar bodies ghosts and a paucity of secreted lamellar granules in the stratum corneum. Molecular analysis reveals homozygous ABCA12 mutations.\nDifferential diagnosis\nHI may be confused with less severe forms of ichthyosis. Later in life, the differential diagnosis includes other disorders from the autosomal recessive congenital ichthyosis (ARCI) group, restrictive dermopathy, infantile systemic hyalinosis, and Neu-Laxova syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is mandatory and consists in DNA analysis of amniocentesis and chorion villus sampling materials, rather than fetal skin biopsies. Ultrasonography shows diffuse scaling, digital contractures, flattened rudimentary external ear, nasal hypoplasia, everted eyelids, typical fish mouth, open fetal mouth, and macroglossia.\nGenetic counseling\nThe disease is transmitted as an autosomal recessive trait. Genetic counseling should be offered to the affected families informing them of the 25% risk of recurrence in each pregnancy.\nManagement and treatment\nIn the neonatal period, management requires a multidisciplinary approach (dermatologists, neonatologists, ophthalmologists, surgeons, dieticians, and psychologists for family support). Gastrostomy may be necessary. Emollients and oral retinoids (1-2mg/kg/day) are recommended. It is important to keep invasive procedures to a minimum in order to avoid skin infections. Management of survivors is similar for all severe ARCIs and includes the use of emollients, keratolytics, and retinoids.\nPrognosis\nHI is associated with substantial (50%) morbidity and mortality soon after birth and throughout childhood due to sepsis and/or respiratory failure (75% of cases). Survivors can have a normal life expectancy but may develop severe skin disease with eye complications related to persistent ectropion, delayed developmental and motor milestones, and social difficulties. Current medical treatments achieved a significant improvement in quality and expectancy of life, however the severity of the disease might still affect life duration. The prognosis of the disease with actual treatments is still under evaluation.\n\n                            Last update: \n                            December 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Michela BRENA | ERN-Skin* - Dr Sophie GUEZ | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Harlequin syndrome", "Disease Definition": "Harlequin syndrome (HSD) is an autonomic disorder occurring at any age and characterized by unilateral flushing and sweating, involving the face and sometimes arm and chest, in condition of thermal, exercise or emotional stress without sympathetic ocular manifestations. However, tonic pupils, parasympathetic oculomotor lesion and pre- or postganglionic sudomotor sympathetic deficit can rarely occur.", "ORPHA ID": 199282, "Summary": ""}
{"Disease Name": "Harrod syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by the association of intellectual deficit, facial dysmorphism (a highly arched palate, pointed chin, and small mouth, hypotelorism, a long nose and large protruding ears), arachnodactyly, hypogenitalism (undescended testes and hypospadias) and failure to thrive.", "ORPHA ID": 2115, "Summary": ""}
{"Disease Name": "Hartnup disease", "Disease Definition": "A rare metabolic disorder belonging to the neutral aminoacidurias, mainly characterized by skin photosensitivity, ocular and neuropsychiatric features, due to abnormal renal and gastrointestinal transport of neutral amino acids (tryptophan, alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tyrosine and valine).", "ORPHA ID": 2116, "Summary": "Epidemiology\nThe estimated prevalence is approximately 1 in 30,000.\nClinical description\nMost subjects who fulfil the biochemical diagnostic criteria (mostly detected by newborn screening programs) remain asymptomatic. In the few symptomatic subjects, clinical symptoms usually appear in childhood (3-9 years of age), but sometimes manifest as early as 10 days after birth, or as late as early adulthood. Symptomatic subjects usually present with skin photosensitivity (pellagra-like skin eruption), neurological symptoms (intermittent cerebellar ataxia, spasticity, delayed motor development, trembling, headaches, and hypotonia), and psychiatric symptoms (anxiety, emotional instability, delusions, and hallucinations). Ocular manifestations may occur (double vision, nystagmus, photophobia, and strabismus). Intellectual deficit and short stature have been described in a few patients. Exacerbations are seen most frequently in the spring or early summer after sunlight exposure. Symptoms may also be triggered by fever, drugs, and emotional or physical stress. They progress over several days and last for 1-4 weeks before spontaneous remission occurs.\nEtiology\nHartnup disease is caused by mutations in SLC6A19 gene (5p15.33), encoding the sodium-dependent and chloride-independent neutral amino acid transporter B(0)AT1, expressed predominately in proximal renal tubules and intestinal epithelium.\nDiagnostic methods\nNeutral hyperaminoaciduria (determined by urine chromatography) is the diagnostic hallmark. Diagnostic confirmation relies upon the mutation analysis of the SLCA19 gene (broad allelic heterogeneity).\nDifferential diagnosis\nPellagra is the main differential diagnosis. Blue diaper syndrome, ataxia-telangiectasia, hydroa vacciniforme, pityriasis alba, and xeroderma pigmentosum should be excluded.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nSymptomatic subjects benefit from a high-protein diet, sunlight protection, and avoidance of photosensitizing drugs. Treatment includes nicotinamide supplements (40 to 200 mg per day). Some patients may respond to a tryptophan-rich diet. Patients with severe central nervous system involvement require neurologic and psychiatric treatment.\nPrognosis\nThe presentation of the disorder is commonly benign. Hartnup disease probably does not adversely affect pregnancy and would be harmless to the fetus.\n\n                            Last update: \n                            July 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Udo WENDEL"}
{"Disease Name": "Hartsfield syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies syndrome characterized by variable expression of the holoprosencephaly (HPE) spectrum in association with ectrodactyly, cleft lip/palate and/or other ectodermal anomalies. Developmental delay of variable severity and endocrine abnormalities are often associated.", "ORPHA ID": 2117, "Summary": "Epidemiology\nApproximately 35 patients have been described in the literature to date.\nClinical description\nPresentation is heterogeneous; cerebral malformations may present as lobar, semi-lobar and alobar HPE, or milder midline anomalies, such as arhinencephaly, or corpus callosum agenesis. Microcephaly, hypotelorism or hypertelorism, and malformed ears may be observed. Ectrodactyly affects hands and/or feet with variable severity and may involve one to four limbs. Over half of reported individuals have cleft lip and/or palate, which may be uni- or bilateral. Midline brain malformation involving the hypothalamo-pituitary axis may lead a range of endocrine disorders including growth hormone deficiency and subsequent short stature, central diabetes insipidus with a risk of hypernatremic dehydratation, hypogonadotropic hypogonadism, cryptorchidism, micropenis or hypospadias, as well as temperature dysregulation and erratic sleep patterns. Developmental delay is often observed and intellectual disability ranges from mild to severe. In severe cases, individuals are nonverbal, spastic and non-ambulatory. The severity of the neurological impairment in part correlates to the severity of the brain malformation. Seizures are possible. There has been anecdotal reports of skull defects, vertebral anomalies, radial aplasia, eye anomalies, and cardiac malformation.\nEtiology\nHartsfield syndrome is most often caused by the presence of heterozygous pathogenic variants in the FGFR1 gene (8p11.23), although bi-allelic pathogenic variants have been described in a minority of patients.\nDiagnostic methods\nConfirmation of clinical diagnosis is based on FGFR1 sequencing by targeted sanger sequencing, or via NGS (next generation sequencing) multigene panel including FGFR1.\nDifferential diagnosis\nThe association of HPE and ectrodactyly is quite unique to Hartsfield syndrome. Phenotypic overlap can be observed in Kallman syndrome, isolated congenital hypogonadotropic hypogonadism, EEC (ectrodactyly ectodermal dysplasia and cleft lip/palate syndrome), HPE, and septo-optic dysplasia spectrum.\nAntenatal diagnosis\nFor parents of an index individual, prenatal diagnosis in subsequent pregnancies should be discussed. Diagnosis involves genetic testing for FGFR1 in the presence of the ultrasound findings of HPE and/or ectrodactyly.\nGenetic counseling\nDepending on the variants identified, transmission of Hartsfield syndrome can follow an autosomal dominant or recessive mode of inheritance. In most cases, heterozygous FGFR1 variants occur de novo. Several occurrences of parental germline mosaicisms, with recurrences in the sibship, have been reported. Although not known, the recurrence risk in siblings is thus much higher than the usual theoretical 1% estimated risk in the presence of an apparent de novo variant. Recurrence risk is 25% in each pregnancy if bi-allelic variants are identified in the index sib.\nManagement and treatment\nManagement and treatment are based on the phenotype. Severity of the HPE must be evaluated by neuroimaging. Spasticity and the possibility of seizures must be assessed. Antiepileptic drugs, physical and occupational therapy may be needed. Nutritional and feeding status should be evaluated. Surgery may be required to treat cleft lip/palate and ectrodactyly. The possibility of endocrine deficiency must be evaluated (growth hormone deficiency, hypogonadotropic hypogonadism, and central diabetes insipidus). Central diabetes insipidus may require treatment with desmopressin.\nPrognosis\nPrognosis depends on the severity of the phenotype.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Catheline VILAIN | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hawkinsinuria", "Disease Definition": "A rare inborn error of tyrosine metabolism characterized by failure to thrive, persistent metabolic acidosis, fine and sparse hair, and excretion of the unusual cyclic amino acid metabolite, hawkinsin ((2-l-cystein-S-yl, 4-dihydroxycyclohex-5-en-1-yl)acetic acid), in the urine.", "ORPHA ID": 2118, "Summary": ""}
{"Disease Name": "Hb Bart's hydrops fetalis", "Disease Definition": "A severe form of alpha-thalassemia that is mostly lethal, and associated with severe long-term outcome and lifelong transfusions in survivors. It is characterized by fetal onset of generalized edema, pleural and pericardial effusions, and severe hypochromic anemia.", "ORPHA ID": 163596, "Summary": "Epidemiology\nThe disease occurs predominantly in Southeast Asia. Prevalence at birth in this region is estimated to be between 1/200-2,000. Exact prevalence in other regions is not known.\nClinical description\nAffected fetuses suffer from severe anemia in utero, causing severe tissue hypoxia, heart failure and a range of developmental abnormalities associated with hydrops fetalis (marked hepatosplenomegaly, urogenital and limb abnormalities). In survivors, the neonatal period is often stormy, and growth retardation and neurodevelopmental delay are the major adverse long-term outcomes. Maternal complications during pregnancy include preeclampsia, polyhydramnios or oligohydramnios, antepartum hemorrhage, and premature delivery. Although intrauterine transfusions and perinatal intensive care have resulted in increasing fetal survival to the perinatal period. Early therapeutic termination of at-risk pregnancies is usually recommended due to the severity of the syndrome and the risk of potentially serious maternal complications during pregnancy.\nEtiology\nBart's hydrops fetalis is caused by deletion or inactivation of all four alpha-globin alleles leading to a severe deficiency in alpha-globin chains of Hb, and to the production of gamma-4 tetramers (Hb Bart's) during fetal life, and beta-4 tetramers (HbH) postnatally. Hb Bart's and HbH have increased oxygen affinity resulting in ineffective tissue oxygen delivery. The disease is mostly the result of combined, biallelic deletions in the HBA1 and HBA2 genes (16p13.3).\nDiagnostic methods\nThe disease can be diagnosed on ultrasound as early as 10 weeks gestation, from ultrasonographic findings of hydrops fetalis followed by fetal DNA analysis and cord blood Hb electrophoresis revealing Hb Bart's.\nDifferential diagnosis\nThe main differential diagnosis is hydrops fetalis without alpha-thalassemia, which is a common non-specific sign of numerous fetal or maternal disorders.\nAntenatal diagnosis\nPrenatal genetic diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nDeath usually occurs in utero or shortly after birth, but fetuses can survive following intrauterine transfusions, and perinatal intensive care. Early intrauterine intervention leads to prolonged gestation, improved Apgar scores, and shortened neonatal mechanical ventilation, but with no clear additional benefits to long-term growth and neurodevelopment. After birth, patients require lifelong and intensive transfusion regimen, targeted at reducing HbH levels, and increasing functional HbA. Treatment is controversial since most treated infants surviving the immediate postnatal period subsequently show abnormal development. These patients may be considered for hematopoietic stem cell transplantation.\nPrognosis\nMost surviving infants experience a complicated perinatal course and a high prevalence of congenital urogenital and limb defects.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Corinne PONDARRE"}
{"Disease Name": "Hearing loss-familial salivary gland insensitivity to aldosterone syndrome", "Disease Definition": "Hearing loss-familial salivary gland insensitivity to aldosterone syndrome is characterised by bilateral moderate-to-severe sensorineural hearing loss and salivary gland insensitivity to aldosterone resulting in hyponatremia. It has been described in two brothers. Transmission appeared to be autosomal recessive.", "ORPHA ID": 3225, "Summary": ""}
{"Disease Name": "Heart defect-tongue hamartoma-polysyndactyly syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies syndrome characterized by congenital heart defects (e.g. coarctation of the aorta with or without atrioventricular canal and subaortic stenosis), associated with tongue hamartomas, postaxial hand polydactyly and toe syndactyly.", "ORPHA ID": 1338, "Summary": ""}
{"Disease Name": "Heart defects-limb shortening syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by skeletal dysplasia (including coronal clefting of the vertebral bodies and short limbs and variable congenital heart malformations, such as atrial and ventricular septal defects, right ventricular hypoplasia, and valve defects). There have been no further descriptions in the literature since 1990.", "ORPHA ID": 1354, "Summary": ""}
{"Disease Name": "Heart-hand syndrome type 2", "Disease Definition": "Heart-hand syndrome type 2 is an extremely rare heart-hand syndrome (see this term) described in two families to date, that is characterized by upper limb malformations (brachytelephalangy type D, hypoplastic deltoids, mild shortening of the fourth and fifth metacarpals in some individuals, skeletal anomalies in the humerus, radius, ulnae, and thenar bones) and cardiac arrhythmias (junctional rhythms and atrial fibrillation).", "ORPHA ID": 1350, "Summary": ""}
{"Disease Name": "Heart-hand syndrome type 3", "Disease Definition": "Heart-hand syndrome type 3 is a very rare heart-hand syndrome (see this term), described in three members of a Spanish family to date, which is characterized by a cardiac conduction defect (sick sinus, bundle-branch block) and brachydactyly, resembling brachydactyly type C of the hands (see this term), affecting principally the middle phalanges in conjunction with an extra ossicle on the proximal phalanx of both index fingers. Feet abnormalities are more subtle.", "ORPHA ID": 1342, "Summary": ""}
{"Disease Name": "Heart-hand syndrome, Slovenian type", "Disease Definition": "A rare autosomal dominant form of heart-hand syndrome that is characterized by adult onset, progressive cardiac conduction disease, tachyarrhythmias that can lead to sudden death, dilated cardiomyopathy and brachydactyly, with the hands less severely affected than the feet. Muscle weakness and/or myopathic electromyographic findings have been observed in some cases.", "ORPHA ID": 168796, "Summary": ""}
{"Disease Name": "Heart-hand syndrome", "Disease Definition": "Heart-hand syndrome refers to a group of congenital disorders characterized by malformations of the upper limbs and heart. To date, heart-hand syndrome comprises the following rare syndromes; Holt-Oram syndrome; heart-hand syndrome type 2; heart-hand syndrome type 3; heart hand syndrome, Slovenian type, brachydactyly-long thumb; and patent ductus arteriosus-bicuspid aortic valve - hand anomalies (see these terms).", "ORPHA ID": 228184, "Summary": ""}
{"Disease Name": "Heavy chain deposition disease", "Disease Definition": "A rare non-amyloid monoclonal immunoglobulin deposition disease characterized by production of monoclonal immunoglobulins with truncated heavy chains and no detectable light chains, which are deposited in tissues and cause organ dysfunction, but do not form amyloid beta-pleated sheets or contain an amyloid P component. The condition frequently occurs in association with multiple myeloma. Patients most commonly present with renal involvement (manifesting as hypertension, progressive renal dysfunction, anemia, and nephrotic syndrome with microhematuria), but other organs (such as the liver or skin) may also be affected. Production of IgG1 or IgG3 isotypes results in hypercomplementemia.", "ORPHA ID": 93556, "Summary": ""}
{"Disease Name": "Heavy chain disease", "Disease Definition": "Heavy-chain diseases (HCDs) are rare monoclonal lymphoplasma-cell proliferative disorders involving B cells and are characterized by the synthesis of truncated heavy chains without associated light chains.", "ORPHA ID": 86864, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nHCDs have been described for the three main immunoglobulin classes: alpha-HCD (see this term) is the most common and has the most uniform presentation whereas gamma- and mu-HCDs (see these terms) have variable clinical presentations and histopathologic features. HCDs can be thought of as variant types of non-Hodgkin lymphoma (NHL; see this term), with alpha-HCD presenting as an extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue, gamma-HCD as lymphoplasmacytoid NHL, and mu-HCD as small lymphocytic NHL or chronic lymphocytic leukemia (CLL; see this term).\nDiagnostic methods\nDiagnosis of these conditions requires documentation of a deleted immunoglobulin heavy chain without a bound light chain in the serum or urine.\nPrognosis\nPrognosis is variable, and no standardized effective treatment programs are available except for alpha-HCD, which in its early stage may respond to antibiotics.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Robert KYLE  - Dr Dietlind WAHNER-ROEDLER"}
{"Disease Name": "HEC syndrome", "Disease Definition": "A rare syndromic cardiac disease characterized by communicating hydrocephalus, endocardial fibroelastosis, and congenital cataracts. A history of upper respiratory infection in the mother during the first trimester of pregnancy and polyhydramnios in the third trimester has been associated. No evience of toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis, and galactosemia is reported. There have been no further descriptions in the literature since 1995.", "ORPHA ID": 2119, "Summary": ""}
{"Disease Name": "Heiner syndrome", "Disease Definition": "Heiner syndrome, also called cow's milk hypersensitivity, is a food induced pulmonary hypersensiting syndrome that affects primarily infants and that is characterized by pulmonary hemosiderosis (see this term), digestive bleeding, anemia and poor growing, improving with elimination of cow's milk from the diet.", "ORPHA ID": 99932, "Summary": ""}
{"Disease Name": "Helicoid peripapillary chorioretinal degeneration", "Disease Definition": "Helicoid peripapillary chorioretinal degeneration is a rare autosomal dominantly inherited chorioretinal degeneration disease, presenting at birth or infancy, characterized by progressive bilateral retinal and choroidal atrophy, appearing as lesions on the optic nerve and peripheral ocular fundus and leading to central vision loss. Congenital anterior polar cataracts are sometimes associated with this disease.", "ORPHA ID": 86813, "Summary": ""}
{"Disease Name": "HELLP syndrome", "Disease Definition": "A rare hemorrhagic disorder due to an acquired platelet anomaly characterized by hemolysis, elevated liver enzymes and thrombocytopenia that affects pregnant or post-partum women, and is frequently associated with severe preeclampsia. Symptoms are variable, typically including right upper quadrant or epigastric abdominal pain, nausea, vomiting, excessive weight gain, generalized edema, hypertension, general malaise, right shoulder pain, backache, and/or headache. Hepatic hemorrhage and rupture, renal failure, and pulmonary edema can result in maternal and/or fetal death.", "ORPHA ID": 244242, "Summary": ""}
{"Disease Name": "Hemangioblastoma", "Disease Definition": "Hemangioblastoma is a rare, benign, highly vascularized tumor of the central nervous system, most often located in the cerebellum or spinal cord, presenting in adulthood and manifesting with dizziness, nausea, malaise, headache, bladder or bowel dysfunction, numbness, weakness and pain in the upper or lower extremities, and often associated with von Hippel-Lindau disease (VHL; see this term). Exceptional cases of hemangioblastoma arising outside of the central nervous system have been reported.", "ORPHA ID": 252054, "Summary": ""}
{"Disease Name": "Heme oxygenase-1 deficiency", "Disease Definition": "A rare inborn error of metabolism characterized by congenital asplenia and childhood or adolescent onset of generalized inflammation, persistent intravascular hemolysis and anemia, severe endothelial injury with abnormal coagulation, bleeding diathesis, and nephropathy. Additional reported manifestations include growth retardation, mild facial dysmorphism, and hepatomegaly.", "ORPHA ID": 562509, "Summary": ""}
{"Disease Name": "Hemicrania continua", "Disease Definition": "A rare trigeminal autonomic cephalalgia characterized by indomethacin-sensitive, persistent, strictly unilateral headache lasting for more than three months, associated with ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, eyelid edema, and/or restlessness or agitation, and not better accounted for by another type of headache. Migrainous symptoms such as photophobia are often observed. The headache may be continuous (unremitting subtype) or interrupted by remission periods of more than 24 hours (remitting subtype).", "ORPHA ID": 443070, "Summary": ""}
{"Disease Name": "Hemidystonia-hemiatrophy syndrome", "Disease Definition": "Hemidystonia-hemiatrophy (HD-HA) is a rare dystonia, usually caused by a static cerebral injury occurring at birth or during infancy, that is characterized by a combination of hemidystonia (HD), involving one half of the body, and hemiatrophy (HA) on the same side as the HD.", "ORPHA ID": 306741, "Summary": "Epidemiology\nThe prevalence is unknown but between 30 to 100 cases of HD-HA have been described to date.\nClinical description\nThe mean age of HD onset is 14.9 years (range 1-46 years). HD (sustained and repetitive muscle contractions resulting in abnormal movements or posture involving a single side of the body) is preceded in 90 % of cases by hemiparesis with a marked improvement before the onset of HD. Pyramidal syndrome and seizures may also be observed. In HD-HA, dystonia is associated with ipsilateral somatic atrophy.\nEtiology\nCommon causes of HD-HA are childbirth or perinatal complications, delayed sequelae of stroke or head trauma. The causative injury generally occurs at birth or during early infancy.\nDiagnostic methods\nDiagnosis of HD-HA is clinical, based on a careful anamnesis of the patient's birth and early childhood period and physical examinations, as well as brain imaging. Cerebral hemiatrophy, nonspecific diffuse atrophy, lesions involving the basal ganglia and thinning of the periventricular white matter with ipsilateral ventricular dilatation may be observed with magnetic resonance imaging (MRI). Brain imaging is characterized by lesions involving the basal ganglia or by cerebral hemiatrophy contralateral to the HD. Cerebral HA can lead to ipsilateral skull thickening and hyperpneumatization of paranasal sinuses, resulting in Dyke-Davidoff syndrome.\nDifferential diagnosis\nHD-HA syndrome should be differentiated from other causes of primary dystonia or dystonia secondary to inherited disorders or neurodegenerative diseases.\nManagement and treatment\nHD responds poorly to medical therapy and drugs such as anticholinergics, baclofen, benzodiazepines, and levodopa, in monotherapy or in combination, result in a modest or transient response. Botulinum toxin injections may be useful for HD if a relevant focal target can be identified. Deep brain stimulation mainly targeting the globus pallidus is not a routine treatment of HD-HA syndrome, but may be discussed in the most severe cases on an individual basis.\nPrognosis\nThe younger the age of the offending cerebral insult, the longer is the delay in the onset of dystonia. The symptoms of delayed HD usually diminish and attain a plateau a few years after initial presentation; while HA of the affected body part usually remains stationary as the patient approaches the second decade of life.\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                            Dr David GRABLI"}
{"Disease Name": "Hemifacial hyperplasia", "Disease Definition": "Hemifacial hyperplasia is a rare morphological anomaly of the maxillofacial region characterized by unilateral overgrowth of all facial structures (bone, soft tissues, teeth), called true hemifacial hypertrophy, or overgrowth of one or more but not all facial structures, called partial hemifacial hypertrophy. It may be isolated or related to some syndromes (e.g. Beckwith-Wiedemann, Proteus, Klippel-Trenaunay-Weber, McCune-Albright syndrome, Neurofibromatosis type 1). It may be associated with airway obstruction, sensorineural hearing loss or swallowing difficulties.", "ORPHA ID": 141145, "Summary": ""}
{"Disease Name": "Hemifacial myohyperplasia", "Disease Definition": "Hemifacial myohyperplasia is a rare developmental defect during embryogenesis characterized by unilateral hyperplasia of the facial musculature with no evidence of hyperplasia of bone or other organ systems. It clinically present with dimpling of the skin, ptosis, enophthalmos, narrow palpebral fissure, auricular displacement, smaller nasal vestibule, and nasal and chin deviation on the affected side. Facial paresis of the affected side and mild ipsilateral hypoplasia of the facial skeleton might be present.", "ORPHA ID": 141148, "Summary": ""}
{"Disease Name": "Hemifacial spasm", "Disease Definition": "A rare primary myoclonus characterized by progressive, involuntary, irregular, clonic or tonic contractions of the muscles innervated by the facial nerve (cranial nerve VII). The symptoms are typically strictly unilateral, mostly persist during sleep, and often occur in the region of the orbicularis oculi muscle first and gradually spread to other parts of the affected half of the face as the disease progresses. Both familial and acquired forms are reported.", "ORPHA ID": 221083, "Summary": ""}
{"Disease Name": "Hemihyperplasia-multiple lipomatosis syndrome", "Disease Definition": "Hemihyperplasia-multiple lipomatosis syndrome is a rare, genetic overgrowth syndrome characterized by non- progressive, asymmetrical, moderate hemihyperplasia (frequently affecting the limbs) associated with slow growing, painless, multiple, recurrent, subcutaneous lipomatous masses distributed throughout entire body (in particular back, torso, extremities, fingers, axillae). Superficial vascular malformations may also be associated. Increased risk of intra-abdominal embryonal malignancies may be associated.", "ORPHA ID": 276280, "Summary": ""}
{"Disease Name": "Hemimegalencephaly", "Disease Definition": "Hemimegalencephaly is a rare cerebral malformation characterized by overgrowth of all or part of a cerebral hemisphere, often with ipsilateral severe cortical dysplasia or dysgenesis, white matter hypertrophy and dilated lateral ventricle, presenting in early infancy with progressive hemiparesis, severe psychomotor retardation and intractable seizures. Hemimegalencephaly may be an isolated finding or associated with other syndromes such as angioosteohypertrophic syndrome, epidermal nevus syndrome and Ito hypomelanosis (see these terms). Management includes seizure control by antiepileptic medications and early hemispherectomy.", "ORPHA ID": 99802, "Summary": ""}
{"Disease Name": "Hemiparkinsonism-hemiatrophy syndrome", "Disease Definition": "Hemiparkinsonism-hemiatrophy syndrome is a rare parkinsonian disorder characterized by unilateral body atrophy and slowly progressive, ipsilateral, hemiparkinsonian signs (bradykinesia, rigidity, and tremor). Patients typically present with unilateral, action-induced dystonia, in upper or lower limbs, that progresses and becomes bilateral or with tremor which occurs predominantly at rest and progresses to hemiparkinsonism. Scoliosis, scapular winging, raised shoulders, brisk reflexes and extensor plantar responses are frequently associated.", "ORPHA ID": 306669, "Summary": ""}
{"Disease Name": "Hemoglobin C disease", "Disease Definition": "Hemoglobin C disease (HbC) is a hemoglobinopathy characterized by production of abnormal variant hemoglobin known as hemoglobin C, with no or mild clinical manifestations (hemolytic anemia).", "ORPHA ID": 2132, "Summary": ""}
{"Disease Name": "Hemoglobin C-beta-thalassemia syndrome", "Disease Definition": "Hemoglobin C - beta-thalassemia (HbC - BT) is a form of beta-thalassemia (see this term) resulting in moderate hemolytic anemia.", "ORPHA ID": 231242, "Summary": "Epidemiology\nPrevalence of this form is not known but it is predominant in African populations.\nClinical description\nPatients are usually asymptomatic and diagnosed during routine tests. When present, clinical manifestations are moderate anemia and splenomegaly. Blood transfusions are rarely needed.\nEtiology\nHbC - BT patients are compound heterozygotes for hemoglobin C and beta-thalassemia.\nDiagnostic methods\nHematological findings always reveal microcytosis and hypochromia. Blood smear shows distinctive HbC crystals with straight parallel edges, target cells, and irregularly contracted cells with features of thalassemia such as microcytosis.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA"}
{"Disease Name": "Hemoglobin D disease", "Disease Definition": "Hemoglobin D disease(HbD) is a hemoglobinopathy characterized by production of abnormal variant hemoglobin known as hemoglobin D, with no or mild clinical manifestations (splenomegaly, very mild anemia).", "ORPHA ID": 90039, "Summary": ""}
{"Disease Name": "Hemoglobin E disease", "Disease Definition": "Hemoglobin E disease (HbE) is a hemoglobinopathy characterized by production of abnormal variant hemoglobin known as hemoglobin E, with a generally benign, asymptomatic presentation.", "ORPHA ID": 2133, "Summary": ""}
{"Disease Name": "Hemoglobin E-beta-thalassemia syndrome", "Disease Definition": "Hemoglobin E - beta-thalassemia (HbE - BT) is a form of beta-thalassemia (see this term) that results in a mild to severe clinical presentation ranging from a condition indistinguishable from beta-thalassemia major to a mild form of beta-thalassemia intermedia (see these terms).", "ORPHA ID": 231249, "Summary": "Epidemiology\nPrevalence of this form is not known but HbE - beta-thalassemia is predominant in Southeast Asia.\nClinical description\nMild HbE - BT (about 15% of cases) is characterized by normal Hb levels (9-12 g/dl) and patients usually do not develop clinically significant symptoms. No treatment is required. Moderately severe forms (most cases) are characterized by decreased Hb levels (6-8 g/dl) and the clinical manifestations are similar to those of beta-thalassemia intermedia. Transfusions are not required unless infections precipitate further anemia. Iron overload may occur. Severe forms are characterized by very low Hb levels (4-5 g/dl) and patients present with manifestations similar to beta-thalassemia major and are treated as thalassemia major patients.\nGenetic counseling\nHbE - BT patients are compound heterozygotes for hemoglobin E and beta-thalassemia.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA"}
{"Disease Name": "Hemoglobin H disease", "Disease Definition": "An intermediate form of alpha-thalassemia characterized by increased hemolysis and mild to severe anemia with marked microcytosis and hypochromia. Hemoglobin H disease (HbH) disease belongs to the group of nontransfusion-dependent thalassemia.", "ORPHA ID": 93616, "Summary": "Epidemiology\nHbH disease predominates in people of Southeast Asian, Middle Eastern and Mediterranean descent. Exact prevalence is not known but birth prevalence from newborn screening programs in the USA is estimated at 1/14,000, with individuals of south eastern ethnicity most affected.\nClinical description\nClinical features are highly variable and generally develop in the first years of life. Initial signs may be noticed only during routine hematologic analyses. Patients have variable microcytic hypochromic hemolytic anemia, requiring no or occasional blood transfusions during infectious episodes, exposure to oxidizing agents or pregnancy. Splenomegaly is frequently found. Non-deletional forms of alpha-thalassemia typically have more severe anemia, splenomegaly, hepatomegaly, cholelithiasis, growth retardation, decreased bone density; and have earlier and more frequent transfusion requirements. Skeletal changes mainly affecting the face can rarely occur in non-deletional forms. Iron overload develops secondary to increased intestinal iron absorption even in the absence of transfusion.\nEtiology\nHbH disease is usually caused by inactivation of three alpha-globin alleles leading to underproduction of alpha-globin chains of Hb, with the formation of beta-4 tetramers (HbH). HbH tetramers have a high affinity for oxygen, and are highly unstable, precipitating as toxic Heinz bodies which predominate in mature red blood cells, leading to premature hemolysis rather than ineffective erythropoiesis. It is increased under oxidative stress, which explains the hyperhemolysis associated with infection or ingestion of oxidant drugs. The disease is typically caused by compound heterozygous or homozygous variants in either of the alpha globulin genes (HBA1 and HBA2; 16p13.3), accompanied by a heterozygous mutation in the other gene. In some cases, the disease is due to homozygous variants in HBA2. The severity of the disease is related to its molecular basis: patients with non-deletional types of HbH disease, such as Constant Spring mutation, are more severely affected than those with the common deletional types.\nDiagnostic methods\nHbH disease should be considered in infants or children with mild-to-moderate microcytic hypochromic hemolytic anemia and hepatosplenomegaly. Heinz bodies can be detected on blood smears after cresyl blue staining. Hb biochemical analysis reveals the presence of HbH (5-30%). Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes other hemolytic anemias and alpha-thalassemia X-linked intellectual deficit (ATRX).\nAntenatal diagnosis\nPrenatal diagnosis is possible when a severe form of HbH disease has previously been identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling depends on the genotype of the parents; where the couple has already an affected offspring, the risk of having an affected offspring in subsequent pregnancies is 25%.\nManagement and treatment\nIn the more common milder form, patients may require occasional blood transfusion therapy. In more severe cases, regular transfusions are needed. Splenectomy should be performed only in the presence of manifest hypersplenism, because it is associated with increased thromboembolic and infectious complications. Iron overload should be monitored from adolescence by liver magnetic resonance imaging . Iron chelation is indicated in all patients with hemosiderosis. Management also requires ongoing monitoring of growth, bone health, spleen size, and fatigue level. Supplementation with folic acid is recommended.\nPrognosis\nOverall survival is variable but usually good. Many patients survive into adulthood but some have a more complicated course.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Corinne PONDARRE"}
{"Disease Name": "Hemoglobin Lepore-beta-thalassemia syndrome", "Disease Definition": "A rare beta-thalassemia associated with another hemoglobin anomaly characterized by the presence of the hemoglobin Lepore variant in association with beta-thalassemia. Clinical presentation is highly variable, depending on the type of beta-thalassemia, and ranges from severe hypochromic microcytic anemia and complete transfusion dependency to moderate, compensated anemia without a need for regular blood transfusions.", "ORPHA ID": 330032, "Summary": ""}
{"Disease Name": "Hemoglobin M disease", "Disease Definition": "A rare hemoglobinopathy characterized by the presence of hemoglobin variants with structural abnormalities in the globin portion of the molecule which lead to auto-oxidation of heme iron, resulting in methemoglobinemia. Patients present with cyanosis for which no treatment is necessary. Mode of inheritance is autosomal dominant.", "ORPHA ID": 330041, "Summary": ""}
{"Disease Name": "Hemoglobinopathy Toms River", "Disease Definition": "Hemoglobinopathy Toms River is a rare, genetic hemoglobinopathy disorder, due to a defect in the gamma subunit of the fetal hemoglobin, characterized by neonatal cyanosis, low hemoglobin oxygen saturation levels without arterial hypoxemia, moderate anemia and reticulocytosis, not associated with heart or lung disease. Symptoms progressively subside within the first months of life.", "ORPHA ID": 280615, "Summary": ""}
{"Disease Name": "Hemolytic anemia due to adenylate kinase deficiency", "Disease Definition": "Hemolytic anemia due to adenylate kinase deficiency is a rare hemolytic anemia due to an erythrocyte nucleotide metabolism disorder characterized by moderate to severe chronic nonspherocytic hemolytic anemia that may require regular blood transfusions and/or splenectomy and may be associated with psychomotor impairment.", "ORPHA ID": 86817, "Summary": ""}
{"Disease Name": "Hemolytic anemia due to erythrocyte adenosine deaminase overproduction", "Disease Definition": "Hemolytic anemia due to erythrocyte adenosine deaminase overproduction is a rare, genetic, hematologic disease characterized by mild, chronic hemolytic anemia (due to highly elevated adenosine deaminase activity in red blood cells resulting in their premature destruction), elevated reticulocyte count, splenomegaly and mild hyperbilirubinemia. Other cells and tissues are not affected.", "ORPHA ID": 99138, "Summary": ""}
{"Disease Name": "Hemolytic anemia due to glucophosphate isomerase deficiency", "Disease Definition": "A rare hemolytic anemia due to a defect of the glycolytic enzyme glucose 6-phosphate isomerase (GPI) characterized by chronic nonspherocytic hemolytic anemia and, rarely, neurological impairment.", "ORPHA ID": 712, "Summary": "Epidemiology\nPrevalence is unknown. Around 100 cases have been described in the literature so far. GPI deficiency is the second most frequent glycolytic erythroenzymopathy after pyruvate kinase deficiency. Both sexes are equally affected.\nClinical description\nGPI deficiency is characterized by splenomegaly and chronic hemolytic anemia of variable degree, from mild to severe, with episodes of crises triggered by viral or bacterial infections. In rare cases, additional manifestations have been observed, including a variable degree of intellectual deficit, hypotonia, muscle weakness, ataxia and dysarthria. In very rare cases, severe GPI deficiency may be associated with hydrops fetalis and neonatal death.\nEtiology\nGPI deficiency is caused by homozygous or compound heterozygous mutations in the GPI gene (19q13.1). More than 50 different GPI molecular variants have been identified in affected individuals. GPI is a ubiquitous enzyme that catalyses the conversion glucose-6-phosphate into fructose-6-phosphate, the second step in the glycolytic pathway.\nDiagnostic methods\nDiagnosis is based on the demonstration of a reduced erythrocytic GPI activity and the identification of one homozygote, or two compound heterozygote pathogenic variants in the GPI gene.\nDifferential diagnosis\nThe differential diagnosis should include other causes of chronic hereditary hemolytic anemia.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTransfusion support may be required for patients with severe anemia. Splenectomy doesn't cure anemia but reduce the transfusion need, and may increase hemoglobin levels. Indication to splenectomy is based on the severity of clinical presentation.\nPrognosis\nThe prognosis is variable depending on the severity of the anemia and on the presence of neurological manifestations.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Paola BIANCHI | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hemolytic anemia due to glutathione reductase deficiency", "Disease Definition": "Haemolytic anaemia due to glutathione reductase (GSR) deficiency is characterised by nearly complete absence of GSR activity in erythrocytes.", "ORPHA ID": 90030, "Summary": "Epidemiology\nIt has been described in three children (one male and two females) born to consanguineous parents.\nClinical description\nBoth parents had intermediate levels of GSR activity. One child presented with favism and two with cataracts.\nDifferential diagnosis\nThis disease should be distinguished from glutathione reductase deficiency secondary to dietary riboflavin deficiency and from the acute pharmacologic phenocopy induced by carmustine (BCNU).\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nGSR activity is not restored by riboflavin in vivo or by FAD in vitro.\n\n                            Last update: \n                            December 2007"}
{"Disease Name": "Hemolytic anemia due to pyrimidine 5' nucleotidase deficiency", "Disease Definition": "Hemolytic anemia due to pyrimidine 5' nucleotidase deficiency is a rare, hereditary, hemolytic anemia due to an erythrocyte nucleotide metabolism disorder characterized by mild to moderate hemolytic anemia associated with basophilic stippling and the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. Patients present with variable features of jaundice, splenomegaly, hepatomegaly, gallstones, and sometimes require transfusions. Rare cases of mild development delay and learning difficulties are reported.", "ORPHA ID": 35120, "Summary": ""}
{"Disease Name": "Hemolytic anemia due to red cell pyruvate kinase deficiency", "Disease Definition": "A rare, genetic metabolic disorder due to pyruvate kinase deficiency characterized by a variable degree of chronic nonspherocytic hemolytic anemia resulting in a variable clinical manifestations ranging from fatal anemia at birth to a to a fully compensated hemolysis without apparent anemia.", "ORPHA ID": 766, "Summary": "Epidemiology\nPyruvate kinase (PK) deficiency is the most frequent cause of congenital nonspherocytic hemolytic anemia with a prevalence estimated at 1/20,000 in the general white population.\nClinical description\nClinically, PK-deficient patients suffer from a highly variable degree of chronic hemolysis, ranging from severe neonatal jaundice and fatal anemia at birth, severe transfusion-dependent chronic hemolysis, moderate hemolysis with exacerbation during infection, to a fully compensated hemolysis without apparent anemia. Symptoms are usually present at birth but, due to the variable severity, may not be recognized or acknowledged until later. Chronic icterus, gallstones, iron overload and splenomegaly are common findings.\nEtiology\nErythrocyte PK deficiency is caused by mutations in the PKLR gene (1q22). To date, more than 290 mutations in PKLR have been reported. PK is a key regulatory enzyme of glycolysis and two major metabolic abnormalities result from PK deficiency: ATP depletion and increased 2,3-diphosphoglycerate (2,3-DPG) content. The precise mechanisms that cause extravascular hemolysis are as yet unknown, but an important feature involves the selective sequestration of PK-deficient young red blood cells, in particular reticulocytes, by the spleen. The increased 2,3-DPG levels ameliorate the anemia by lowering the oxygen-affinity of hemoglobin.\nDiagnostic methods\nDiagnosis may be considered on the basis of the clinical features and laboratory findings: a variable degree of anemia, reticulocytosis, increased non-conjugated bilirubin, and decreased levels of haptoglobin. Red blood cell morphology is essentially normal. PK deficiency is diagnosed by measuring PK enzymatic activity. Importantly, due to the fact that the enzymatic activity is red cell age-dependent, a deficiency of PK may be masked by reticulocytosis. Simultaneous measurement of another red cell age-specific enzyme, e.g. hexokinase, may therefore be helpful. Confirmation of the diagnosis requires genetic testing.\nDifferential diagnosis\nSecondary PK deficiency has also been reported, occurring in the context of hematological diseases (acute/chronic leukemia, myelodysplastic syndromes and sideroblastic anemia). In case of persistent normocytic hemolytic anemia in which hemoglobin abnormalities and antiglobulin reactions have been excluded, spherocytes are absent, and osmotic fragility is normal, the diagnosis of hereditary nonspherocytic hemolytic anemia should be considered.\nGenetic counseling\nErythrocyte PK deficiency is an autosomal recessive disease and genetic counseling should be offered to affected families. Where both parents are unaffected carriers, there is a 25% risk of disease transmission to offspring.\nManagement and treatment\nThe mainstay of treatment is blood transfusion and, in severe cases, splenectomy. The latter should be based on the patient's ability to tolerate the anemia. As a result of splenectomy, transfusion needs are reduced in many patients. Splenectomy is often accompanied by a considerable increase in reticulocyte counts. Bone marrow transplantation can cure PK deficiency but is rarely performed. Small molecule activator therapy is currently in clinical trials.\nPrognosis\nPrognosis is variable depending on the severity of the anemia, but as in other chronic hemolytic disorders, gallstones and iron overload may develop, requiring appropriate treatment.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr R. [Richard] VAN WIJK"}
{"Disease Name": "Hemolytic disease of the newborn with Kell alloimmunization", "Disease Definition": "A rare hematologic disease characterized by the transfer of maternal alloantibodies against red blood cell antigens of the Kell family to a fetus positive for this antigen across the placental barrier, causing suppression of erythropoiesis with reticulocytopenia and anemia, as well as alloimmune hemolysis. Severe anemia may lead to hydrops fetalis. Significant hyperbilirubinemia is rare in this condition.", "ORPHA ID": 275944, "Summary": ""}
{"Disease Name": "Hemolytic uremic syndrome with DGKE deficiency", "Disease Definition": "A rare genetic hemolytic uremic syndrome (HUS) characterized by infantile onset of relapsing episodes of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The episodes are often preceded by viral infections. Affected individuals typically present persistent hypertension, hematuria, and proteinuria (sometimes in the nephrotic range) and develop chronic kidney disease with age.", "ORPHA ID": 357008, "Summary": ""}
{"Disease Name": "Hemophagocytic syndrome", "Disease Definition": "Hemophagocytic syndrome (HPS) is a rare immune disease (see this term) and a potentially life-threatening disorder characterized by cytokine storm and overwhelming inflammation causing fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis in bone marrow, liver, spleen or lymph nodes. It can be either primary due to a genetic defect (primary hemophagocytic lymphohistiocytosis ; see this term), or secondary to malignancies, to infections, most commonly with viruses such as Epstein-Barr virus or cytomegalovirus, human immunodeficiency virus, or to autoimmune disorders such as systemic lupus erythematosus or adult-onset Still disease (secondary hemophagocytic lymphohistiocytosis) (see these termes).", "ORPHA ID": 158032, "Summary": ""}
{"Disease Name": "Hemophilia A", "Disease Definition": "A rare genetic hematological disorder characterized by spontaneous or prolonged hemorrhages due to factor VIII deficiency.", "ORPHA ID": 98878, "Summary": "Epidemiology\nHemophilia A is the most common form of hemophilia. Prevalence is estimated at around 1 in 6,000 males. It primarily affects males, but females may also be symptomatic with a generally milder clinical picture.\nClinical description\nIn general, onset of bleeding anomalies occurs when affected infants start to learn to walk. However, newborns with hemophilia are at risk of intra- or extracranial hemorrhage and other bleeding complications. The severity of clinical manifestations depends on the extent of factor VIII deficiency in both males and females. If the biological activity of factor VIII is below 1 IU/dL, hemophilia is severe and manifests as frequent spontaneous hemorrhages and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction (severe hemophilia A). If the biological activity of factor VIII is between 1 and 5 IU/dL, hemophilia is moderately severe with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage is rare (moderately severe hemophilia A). If the biological activity of factor VIII is between 5 and 40 IU/dL, hemophilia is mild with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage does not occur (mild hemophilia A). Patients may also be labeled as having mild hemophilia A if they have a FVIII >40 IU/dL and a DNA change in the F8 gene and one of the following: (i) a family member with the same DNA change and FVIII of <40 IU/dL, and the DNA change is found in <1% of the population; and (ii) the international databases list the DNA change as being associated with hemophilia A and <40 IU/dL FVIII. Bleeding most often occurs in joints (hemarthroses) and muscles (hematomas), but any site may be involved following trauma or injury. Spontaneous hematuria is a frequent and highly characteristic sign of the disorder.\nEtiology\nHemophilia A is caused by mutations in the F8 gene (Xq28) encoding coagulation factor VIII.\nDiagnostic methods\nDiagnosis is suspected based on prolonged coagulation times (activated partial thromboplastin time, aPTT) and can be confirmed by measuring factor VIII activity and antigen levels.\nDifferential diagnosis\nDifferential diagnosis includes von Willebrand disease (VWD), including type 2N VWD and other coagulation anomalies leading to prolonged coagulation times, in particular combined factor V and factor VIII deficiency.\nAntenatal diagnosis\nPrenatal diagnosis on chorionic villi or amniocytes is rapid and informative when the familial, causative mutation is known. Knowing the familial mutation status in the fetus allows for preparation of delivery and early newborn medical management.\nGenetic counseling\nInheritance is X-linked recessive and genetic counseling is recommended for affected families. For a female carrier, there is a 50% risk that male offspring will be affected and a 50% risk that each female offspring will be carriers. Overall, there is a 25% risk for each pregnancy that the baby will be a male offspring with hemophilia and a 25% risk that the baby will be a heterozygous female offspring.\nManagement and treatment\nManagement is provided by multidisciplinary comprehensive hemophilia care centers. Replacement therapy consisting of administration of the missing factor VIII is the most straight forward treatment approach, using plasma-derived or recombinant factor VIII concentrates. Treatment may be administered after a hemorrhage or prophylactically, to prevent bleeding. The most frequent complication is the production of inhibitory antibodies against the administered coagulation factor. Recently, bioengineered prolonged half-life factor VIII products and non-factor therapeutics such as emicizumab (a bispecific antibody that mimics the function of factor VIIIa) were approved. Emicizumab is approved for bleeding prophylaxis in hemophilia A with and without inhibitors. Other non-factor therapies and gene therapy are under development. Surgical interventions, most notably orthopedic surgery, may be carried out but should be conducted in specialized centers.\nPrognosis\nLeft untreated, the disease course is severe in severe hemophilia A. Insufficient or incorrect treatment of recurrent hemarthroses and hematomas leads to physical impairment with severe disability associated with stiffness, joint deformation and physical disability. However, current treatment approaches (early prophylaxis) prevent these complications and prognosis is favorable. Hemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death.\n\n                            Last update: \n                            March 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Yesim DARGAUD | EuroBloodNet* - Dr Anne LIENHART | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hemophilia B", "Disease Definition": "A rare hematological disorder characterized by spontaneous or prolonged hemorrhages due to factor IX deficiency.", "ORPHA ID": 98879, "Summary": "Epidemiology\nPrevalence is estimated at around 1 in 30,000 males. Hemophilia primarily affects males, but a symptomatic form of hemophilia B in female carriers has also been described with a generally milder clinical picture.\nClinical description\nIn general, onset of the bleeding anomalies occurs when affected infants start to learn to walk. However, newborns with hemophilia are at risk of intra- or extracranial hemorrhage and other bleeding complications. The severity of the clinical manifestations depends on the extent of the factor IX deficiency, both in males and in females. If the biological activity of factor IX is below 1 IU/dL, hemophilia is severe and manifests as frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction (severe hemophilia B). If the biological activity of factor IX is between 1 and 5 IU/dL, hemophilia is moderately severe with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage is rare (moderately severe hemophilia B). If the biological activity of factor IX is between 5 and 40 IU/dL, hemophilia is mild with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage does not occur (mild hemophilia B). Bleeding most often occurs in joints (hemarthroses) and muscles (hematomas), but any site may be involved following trauma or injury. Spontaneous hematuria is a frequent and highly characteristic sign of the disorder.\nEtiology\nHemophilia B is caused by mutations in the F9 gene (Xq27) encoding coagulation factor IX.\nDiagnostic methods\nDiagnosis is suspected on the basis of coagulation tests revealing prolonged blood coagulation times (activated partial thromboplastin time - aPTT) and can be confirmed by specific measurements of factor IX activity and antigen levels.\nDifferential diagnosis\nThe differential diagnosis should include hemophilia A, von Willebrand disease, and other coagulation anomalies leading to prolonged blood coagulation times.\nAntenatal diagnosis\nPrenatal diagnosis performed on chorionic villi or amniocytes is rapid and informative when the familial, causative F9 mutation is known. Knowing the familial F9 mutation status in the fetus allows for preparation of delivery and early newborn medical management.\nGenetic counseling\nInheritance is X-linked recessive and genetic counseling is recommended for affected families. For a female carrier, there is a 50% risk that male offspring will be affected and a 50% risk that each female offspring will be carriers. Female carriers may express mild to moderate symptoms. Overall, there is a 25% risk for each pregnancy that the baby will be a male offspring with hemophilia and a 25% risk that the baby will be a heterozygous female offspring.\nManagement and treatment\nTreatment is provided by multidisciplinary comprehensive hemophilia care centers. Replacement therapy consisting of administration of the missing factor IX (plasma-derived or recombinant factor IX concentrates) is the usual treatment approach. Recently, bioengineered prolonged half-life factor IX products were approved for the treatment of hemophilia B and significantly improve the quality of life of patients. Treatment may be administered after a hemorrhage (treatment on demand) or to prevent bleeding (prophylactic treatment). The most serious complications are production of inhibitory antibodies against the administered coagulation factor and anaphylactic shock in response to factor IX therapy. Surgical interventions, most notably orthopedic surgery, may be carried out but should be conducted in specialized centers.\nPrognosis\nLeft untreated, the disease course is severe and in, severe hemophilia B, is generally fatal. Insufficient or incorrect treatment of recurrent hemarthroses and hematomas leads to physical impairment with severe disability associated with stiffness, joint deformation and physical disability. However, current treatment approaches (early prophylaxis) prevent these complications and the prognosis is favorable. Hemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death in patients with hemophilia.\n\n                            Last update: \n                            March 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Yesim DARGAUD | EuroBloodNet* - Dr Anne LIENHART | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hemophilia", "Disease Definition": "A rare hematological disorder characterized by spontaneous hemorrhage or prolonged bleeding due to factor VIII or IX deficiency.", "ORPHA ID": 448, "Summary": "Epidemiology\nPrevalence in the general population is estimated at 1/12,000. Prevalence at birth is estimated at 1/5,000 in males.\nClinical description\nHemophilia primarily affects males, but female carriers of disease-causing mutations may also manifest generally milder forms of the disease. In general, onset of bleeding anomalies occurs when affected infants start to learn to walk. However, newborns with hemophilia are at risk of intra- or extracranial hemorrhage and other bleeding complications. The severity of clinical manifestations depends on the extent of the coagulation factor deficiency. If the biological activity of the coagulation factor is below 1 IU/dL, hemophilia is severe and manifests as frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction (severe hemophilia A and B). If the biological activity of the coagulation factor is between 1 and 5 IU/dL, hemophilia is moderately severe with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage is rare (moderately severe hemophilia A and B). If the biological activity of the coagulation factor is between 5 and 40 IU/dL, hemophilia is mild with abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction but spontaneous hemorrhage does not occur (mild hemophilia A and B). In patients with severe hemophilia, bleeding most often occurs in joints (hemarthroses) and muscles (hematomas), but any site may be involved following trauma or injury. Spontaneous hematuria is a frequent and highly characteristic sign of the disorder.\nEtiology\nThe disorder is caused by mutations in the F8 gene (Xq28) encoding coagulation factor VIII, or in the F9 gene (Xq27) encoding coagulation factor IX, which are implicated in hemophilia types A and B, respectively.\nDiagnostic methods\nDiagnosis is made on the basis of coagulation tests revealing prolonged coagulation times (activated partial thromboplastin time, aPTT). Type and severity of hemophilia are determined through specific measurements of factor VIII and IX activity and antigen levels.\nDifferential diagnosis\nDifferential diagnosis includes von Willebrand disease, combined factor VIII and factor V deficiency and other coagulation anomalies leading to prolonged coagulation times.\nAntenatal diagnosis\nPrenatal diagnosis performed on chorionic villi or amniocytes is rapid and informative when the familial, causative mutation is known. Knowing the familial mutation status in the fetus allows for preparation of delivery and early newborn medical management.\nGenetic counseling\nInheritance is X-linked recessive and genetic counseling is recommended for affected families. For female carriers, there is a 50% risk that male offspring will be affected and a 50% risk that female offspring will be carriers. Overall, there is a 25% risk for each pregnancy that the baby will be a male offspring with hemophilia and a 25% risk that the baby will be a heterozygous female offspring.\nManagement and treatment\nManagement is provided by multidisciplinary comprehensive hemophilia care centers. Replacement therapy consisting of administration of the missing factor VIII (hemophilia A) or factor IX (hemophilia B) is the most straightforward treatment approach. Plasma-derived and recombinant factor VIII and factor IX concentrates are available. Non-factor therapies also exist for hemophilia A and new therapeutical approaches including gene therapy are under development. Treatment may be administered after a hemorrhage or prophylactically, to prevent bleeding. The most frequent complication is the production of inhibitory antibodies against the administered coagulation factor. Surgical interventions, most notably orthopedic surgery, may be carried out but should be conducted in specialized centers.\nPrognosis\nLeft untreated, the disease course is severe and, in severe hemophilia, is generally fatal. Insufficient or incorrect treatment of recurrent hemarthroses and hematomas leads to physical impairment with severe disability associated with stiffness, joint deformation and physical disability. However, current treatment approaches (early prophylaxis) prevent these complications and the prognosis is favorable. Hemorrhage, HIV and HCV infections, and hepatic disease are the leading causes of death.\n\n                            Last update: \n                            March 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Yesim DARGAUD | EuroBloodNet* - Dr Anne LIENHART | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation", "Disease Definition": "A rare, genetic, constitutional coagulation factor defect disorder characterized by a bleeding tendancy of variable severity due to methionine 358 to arginine replacement (Pittsburgh mutation) in the alpha-1-antitrypsin protein. Patients present with spontaneous hematomas, hematomas following minor trauma or surgery and, in female patients, ovarian hematomas after ovulation.", "ORPHA ID": 178396, "Summary": ""}
{"Disease Name": "Hemorrhagic fever-renal syndrome", "Disease Definition": "A rare rodent-borne, potentially severe, hemorrhagic disease caused by Old World Hantaviruses characterized by high fever, malaise, headache, myalgia, arthralgia, backache, abdominal pain, oliguria/renal failure and systemic hemorrhagic manifestations.", "ORPHA ID": 340, "Summary": ""}
{"Disease Name": "Hendra virus infection", "Disease Definition": "Hendra virus infection is a rare viral infection disorder caused by the Hendra virus characterized by onset of flu-like symptoms (fever, myalgia, headaches, lethargy) approximately one week after having been in close contact with bodily fluids of infected horses. Neurological manifestations (e.g. vertigo, confusion, ataxia) and progressive respiratory failure, leading to death, have also been reported.", "ORPHA ID": 324632, "Summary": ""}
{"Disease Name": "Hennekam syndrome", "Disease Definition": "A rare syndromic lymphedema characterized by the association of primary lymphedema, intestinal lymphangiectasia, intellectual deficit and unusual facial characteristics.", "ORPHA ID": 2136, "Summary": "Epidemiology\nThe exact prevalence is unknown but around 100 cases have been reported in the literature. The entity occurs in all ethnic groups.\nClinical description\nThe lymphedema has invariably been present at birth, and is mainly present in the lower limbs and genitalia, although it can also be present elsewhere, including ascites. Lymphangiectasia is common in the intestines but can also be present in lungs, pericardium, thyroid and kidneys. The degree of intellectual deficit is highly variable, even within a single family. Facial characteristics are a flat face, a broad and depressed nasal bridge, hypertelorism, epicanthi, a small mouth, and low-set ears with a narrow meatus. Other features include mild growth retardation, delayed puberty, tooth anomalies, gingival hypertrophy, seizures, and blood vessel anomalies.\nEtiology\nThe syndrome can be caused by bi-allelic variants in CCBE1 (18q21.32), FAT4 (4q28.1) or ADAMTS3 (4q13.3).\nDiagnostic methods\nThe diagnosis is based on the clinical phenotype. Intestinal lymphangiectasia may be suspected because of hypogammaglobulinemia, hypoalbuminemia, and lymphopenia, but a definitive diagnosis can only be made by biopsies (often several are needed). Molecular studies may confirm the clinical diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes other entities associated with congenital lymphedema such as Noonan syndrome, Milroy syndrome and cholestasis-lymphedema syndrome, and Van Maldergem syndrome.\nAntenatal diagnosis\nPrenatal genetic testing is possible in families with known mutations.\nGenetic counseling\nThe syndrome is transmitted as an autosomal recessive trait and genetic counseling is recommended.\nManagement and treatment\nThere is no curative therapy, only supportive management including decongestive therapy for edema control, typically needing lymphologists. Rarely surgery is performed. Medium-chain triglyceride-rich diet is usually helpful because of the intestinal lymphangiectasias but recurrent albumin infusions are not uncommon. Vitamin and electrolyte supplements should be considered. Pulmonary lymphangiectasia may need temporary artificial ventilation (positive end-expiratory pressure). Penicillin prophylaxis may be needed to prevent erysipelas.\nPrognosis\nThe signs and symptoms vary widely among affected individuals and even those within the same family. The course of the lymphedema may vary considerably within a person, for instance by hormonal influences, but often for unknown reasons. Life expectancy depends on the severity of manifestations, and may lead to early death.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hennekam-Beemer syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by cutaneous mastocytosis, microcephaly, microtia and/or hearing loss, hypotonia and skeletal anomalies (e.g. clinodactyly, camptodactyly, scoliosis). Additional common features are short stature, intellectual disability and difficulties. Facial dysmorphism may include upslanted palpebral fissures, highly arched palate and micrognathia. Rarely, seizures and asymmetrically small feet have been reported.", "ORPHA ID": 2135, "Summary": ""}
{"Disease Name": "Heparin-induced thrombocytopenia", "Disease Definition": "A rare drug-induced, immune-mediated prothrombotic disorder associated with thrombocytopenia and venous and/or arterial thrombosis.", "ORPHA ID": 3325, "Summary": "Epidemiology\nApproximately 1% of patients exposed to unfractionated heparin for at least 5 days develop heparin-induced thrombocytopenia (HIT), and approximately 30-50% of them will have thrombosis. HIT is less frequent (incidence approximately 0.1%) in patients treated with low-molecular weight heparins.\nClinical description\nHIT may develop at any age (>3 months) but pediatric cases are rare. Moderate thrombocytopenia begins typically 5- 10 days after heparin administration. If the patient had already been exposed to heparin within the last 100 days, rapid-onset is possible, with the platelet count drop occurring within minutes or hours after heparin administration. Delayed-onset HIT is also possible with thrombocytopenia beginning after heparin has already been discontinued. Thrombocytopenia is usually asymptomatic; bleeding is rare. HIT is associated with a high risk of thrombotic complications (e.g. pulmonary embolism, myocardial infarction, stroke), with a predilection for arterial thrombosis involving limb arteries and deep vein thrombosis. Additional microvascular thrombosis can lead to venous limb gangrene/amputation. Other complications include skin necrosis at heparin injection sites and anaphylactoid reactions (e.g. fever, hypotension, chest pain, dyspnea, cardiorespiratory arrest) that could be secondary to post-intravenous heparin bolus.\nEtiology\nHIT results from a humoral immune reaction directed against a complex involving endogenous platelet factor 4 (PF4) and exogenous heparin. Rarely, auto-antibodies recognize PF4 alone. PF4/heparin/IgG immune complexes activate circulating platelets via low affinity immunoglobulin gamma Fc region receptor II-a, leading to consumptive thrombocytopenia and hypercoagulability. The source of heparin (bovine > porcine), its formulation (unfractionated >low molecular weight > fondaparinux), the dose (prophylactic > therapeutic > heparin flushes), route of administration (subcutaneous > intravenous) and duration of administration (over 4 days > 4 days or less) are determining factors.\nDiagnostic methods\nDiagnosis of HIT is suspected from the clinical picture based on the ''4 T's'' (Thrombocytopenia, Timing, Thrombosis, no oTher cause of platelet fall) or the HIT Expert Probability (HEP) scoring system. It is supported by detection of anti-PF4/heparin antibodies, most often by ELISA (although 50% of ELISA-positive patients do not have HIT), and confirmed by detection of pathologic platelet-activating antibodies with functional assays such as serotonin-release assay or heparin-induced platelet activation test.\nDifferential diagnosis\nDifferential diagnosis includes nonimmune heparin-associated thrombocytopenia (due to the direct interaction of heparin with circulating platelets, occurring during the first days of heparin administration), as well as postoperative hemodilution, sepsis, non-HIT drug-induced thrombocytopenia, vaccine-induced immune thrombotic thrombocytopenia, disseminated intravascular coagulation, and multiorgan system failure.\nManagement and treatment\nFor certain patient populations receiving heparin, a regular monitoring of platelet counts is recommended. In case of strongly-suspected or confirmed HIT, treatment consists of stopping heparin and initiating alternative anticoagulant treatment, either with non-heparin anti-factor Xa therapies (danaparoid, fondaparinux, rivaroxaban), or with direct thrombin inhibitors (e.g., argatroban, bivalirudin). Warfarin is contraindicated during the acute thrombocytopenic phase as it can cause microvascular thrombosis, with potential for ischemic limb necrosis (venous limb gangrene syndrome). Thrombocytopenia generally resolves to greater than 150 x 109/L at a median of 4 days, although 1 week to 1 month can be required in some cases.\nPrognosis\nThe prognosis for platelet count recovery is excellent; however, long-term post-thrombotic sequelae (e.g. limb amputation in 5-10% of HIT patients, disabling stroke, bilateral adrenal hemorrhagic necrosis with adrenal failure) can occur. HIT-related mortality (e.g. fatal pulmonary embolism) is observed in 5-10% of cases.\n\n                            Last update: \n                            October 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Yves GRUEL"}
{"Disease Name": "Hepatic cystic hamartoma", "Disease Definition": "Hepatic cystic hamartoma, also named Mesenchyma hamartoma of liver, is a rare benign liver tumor of childhood, usually before the age of 2, of mesenchymal origin and variable clinical presentation (abdominal dissension, abdominal mass, pain, vomiting and signs of inferior vena cava compression).", "ORPHA ID": 386, "Summary": ""}
{"Disease Name": "Hepatic fibrosis-renal cysts-intellectual disability syndrome", "Disease Definition": "Hepatic fibrosis-renal cysts-intellectual disability syndrome is a rare, syndromic intellectual disability characterized by early developmental delay with failure to thrive, intellectual disability, congenital hepatic fibrosis, renal cystic dysplasia, and dysmorphic facial features (bilateral ptosis, anteverted nostrils, high arched palate, and micrognathia). Variable additional features have been reported, including cerebellar anomalies, postaxial polydactyly, syndactyly, genital anomalies, tachypnea. There have been no further descriptions in the literature since 1987.", "ORPHA ID": 2031, "Summary": ""}
{"Disease Name": "Hepatic veno-occlusive disease-immunodeficiency syndrome", "Disease Definition": "A rare syndrome with combined immunodeficiency characterized by the association of severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, absent tissue plasma cells and hepatic veno-occlusive disease.", "ORPHA ID": 79124, "Summary": ""}
{"Disease Name": "Hepatic veno-occlusive disease", "Disease Definition": "A rare vascular liver disease characterized by toxic injury to the hepatic sinusoidal capillaries that leads to obstruction of the small hepatic veins and sinusoids. Clinical manifestations include painful hepatomegaly, jaundice, and fluid retention that manifests by weight gain, edemas, and ascites.", "ORPHA ID": 890, "Summary": "Epidemiology\nPrevalence is difficult to estimate as the frequency varies according to the underlying cause. The incidence due to pyrrolizidine alkaloid plant exposure is unknown, although in Ethiopia it has been estimated at 29.6/mill/year. In addition, epidemics may occur due to harvest contamination with these plants. Hepatic veno-occlusive disease (HVOD) develops in between 0. 3- 2.3% of patients who receive liver transplant; in up to 15% of those treated with gemtuzumab ozogamicin (GO); and in 2-15% of those who receive hematopoietic stem cell transplantation (HSCT), rising to 40% in patients with a history of GO treatment.\nClinical description\nIt affects children and adults. The clinical picture is characterized by painful hepatomegaly, jaundice, and fluid retention that manifests by weight gain, edemas, and ascites. Hepatic insufficiency manifesting as jaundice, and hepatic encephalopathy may occur. Functional renal insufficiency is common. In severe cases, multiple organ failure or severe bacterial infections may occur. In developed countries, the disease is mainly associated with the conditioning regimen for HSCT, with currently less than 10% of transplant patients (depending on the conditioning regimen protocol used) developing HVOD. HVOD may also occur after chemotherapy or radiation therapy.\nEtiology\nHepatic sinusoidal endothelial cell lesions appear to be the primary cause of the disease, leading to non-thrombotic occlusion of hepatic veins with concentric subendothelial thickening associated with edema and eventually fibrosis.\nDiagnostic methods\nDiagnosis is based on recognition of the clinical manifestations (hepatomegaly, jaundice, and weight gain) and their association with a potential cause of HVOD (HSCT or chemotherapy, exposure to pyrrolizidine alkaloids), together with exclusion of other causes of liver disease. Liver biopsy is often indicated, and recent data support its indication. Imaging studies, particularly hepatic Doppler-ultrasonography, may help to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other causes of acute or chronic liver disease, and, in the case of HSCT, graft-versus-host disease and severe infections.\nManagement and treatment\nNo specific treatment is available. Defibrotide is recommended for severe sinusoidal obstruction syndrome, mainly on the basis of limited studies (historic comparisons) and because side effects are uncommon. Management is with supportive care (nutritional support, intensive care unit if needed for respiratory or renal support), renal function monitoring, and avoidance of other liver drug toxicity. Preventive treatment with ursodeoxycholic acid is indicated from beginning of conditioning to 90 days post-transplantation. In case of HSCT, the risk of disease is managed prophylactically by the characterization of risk factors prior to transplantation. Liver transplantation should be discussed in patients with excellent hematologic prognosis.\nPrognosis\nSeverity and course of the disease varies between patients. In severe cases, the prognosis is poor with a high mortality rate (up to 90%) due to multiple organ failure.\n\n                            Last update: \n                            December 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Aurélie PLESSIER | RARE-LIVER*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hepatitis B reinfection following liver transplantation", "Disease Definition": "A rare hepatic disease characterized by graft infection with the hepatitis B virus (HBV) after liver transplantation, due to persistence and reactivation of HBV in extrahepatic sites (also despite previous clearance of the HBs antigen from serum, as shown by laboratory examination), followed by re-invasion of the graft. It may develop between two weeks and several years post transplantation. Clinico-pathological features are variable and range from mild self-limited hepatitis, chronic active hepatitis, and fulminant hepatitis, to fibrosing cholestatic hepatitis. The condition is associated with significantly reduced graft survival rates and overall patient survival.", "ORPHA ID": 90073, "Summary": ""}
{"Disease Name": "Hepatitis delta", "Disease Definition": "Hepatitis delta is a rare hepatic disease characterized by variable degrees of acute hepatitis resulting from infection with the hepatitis delta virus. Occasionally it may present a benign course, but most frequently it manifests with severe liver disease that may include fulminant liver failure, hepatic decompensation and rapid progression to cirrhosis. All patients present concomitant hepatitis B virus infection and an increased risk of developing hepatocellular carcinoma has been reported.", "ORPHA ID": 402823, "Summary": ""}
{"Disease Name": "Hepatoblastoma", "Disease Definition": "A malignant hepatic tumor, typically affecting the pediatric population, arising mostly in an otherwise healthy liver. The most common signs are abdominal distension and abdominal mass. Sometimes patients present with anorexia, weight loss, fatigue. Most HBLs are sporadic, but some cases are associated with genetic factors, especially overgrowth syndromes, such as Beckwith-Wiedemann syndrome (BWS) or hemihypertrophy, and familial adenomatous polyposis (FAP).", "ORPHA ID": 449, "Summary": "Epidemiology\nHepatoblastoma (HB) accounts for about 0,5-2% of all pediatric tumors and for 2/3 of primary hepatic tumors in children. Its incidence is estimated to be 1/1,000,000 in Europe and 1-1,5/1,000,000 in USA. A slight male predilection (1.5:1 to 2:1) has been observed. The incidence of HBL in children has been increasing by about 5% annually.\nClinical description\nThe age of disease onset lies in infancy or early childhood (median age of occurrence is 18 months and 90% of HBs present before 5 years). The most common signs are: (1) abdominal distension and abdominal mass, (2) anorexia, weight loss, fatigue, (3) abdominal pain, nausea and vomiting, (4) jaundice is less frequently observed, (5) anemia and thrombocytosis detected by laboratory tests. Rare cases present with precocious puberty/virilization due to beta-human chorionic gonadotropin (hCG) secretion by the tumor. FAP and BWS are associated with an increased risk of HB. Trisomy 13 and 18, Goldenhar syndrome, Noonan syndrome, Fragile X syndrome, Sotos syndrome, Prader-Willi syndrome, Prune belly syndrome, Aicardi syndrome and neurofibromatosis type 1 may also predispose to HB. Genetic syndromes are associated with 20% of HB cases. High-risk patients are those with distant metastases, very low initial alpha-fetoprotein (AFP) level (under 100 ng/ml), older age (over 8 years), tumor rupture at diagnosis and/or tumor involvement of all 4 hepatic sections.\nEtiology\nThe etiology of HB is still unknown. However, it is hypothesized to derive from primary hepatoblasts, and likely from less differentiated hepatic stem cells or human fetal liver multi-potent progenitor cells (hFLMPCs). Mutations of the genes APC (5q21-q22), AXIN1 (16p13.3) and AXIN2 (17q24.1), that prevent degradation of beta-catenin, have been found in syndromic forms of HB but have rarely been described in sporadic HB. However, a high rate of oncogenic mutations of the beta-catenin gene (CTNNB1; 3p21) (60%-70%) has been reported in HB and it is thought to be associated with constitutive activation of the Wnt/beta-catenin signaling pathway. Overall, Wnt pathway abnormalities account for up to 90% of genetic defects in hepatoblastoma tumor.\nDifferential diagnosis\nDifferential diagnosis includes: (1) hemangioma and infantile hemangioendothelioma (IHE), (2) hepatic mesenchymal hamartoma, (3) focal nodular hyperplasia (FNH), (4) pediatric hepatocellular carcinoma (HCC), (5) undifferentiated embryonal sarcoma of the liver (UESL), (6) embryonal rhabdomyosarcoma (eRMS), (7) rhabdoid tumor of the liver, (8) hepatic adenoma.\nManagement and treatment\nA diagnostic tumor biopsy should be mandatory for all patients with primary liver tumor. HB is definitely a surgical tumor. Surgery remains the cornerstone of management and complete resection is crucial for cure. In most cases complete resection of the tumor can be achieved with a partial hepatectomy (hemihepatectomy). The PRETEXT (PRETreatment EXtent of Disease) system (based on liver anatomy and imaging) is used for assessment of chemotherapy response and planning the extent of liver resection. Resection at diagnosis is currently recommended for very low risk tumors (PRETEXT I/II, M-, surgically resectable at diagnosis (VPEFR-), and additionally in PRETEXT II: age under 8 years, AFP over100 ng/ml) and only when a segmentectomy or hemihepatectomy with at least 1 cm margin on middle hepatic vein and/or bifurcation of portal vein is possible. For unresectable tumors, preoperative chemotherapy (mostly systemic or, in highly selected cases, transcatheter arterial chemoembolization [TACE], sometimes combined with systemic chemotherapy) is used. Total hepatectomy with liver transplantation is a treatment option for HB in conditions where the tumors remain unresectable after chemotherapy or for multifocal HB invading all 4 sections of the liver. 10-20% of all HB cases require liver transplantation. In most cases postoperative chemotherapy is used routinely.\nPrognosis\nCurrent prognosis for patients with resectable tumors and no high risk features is fairly favorable (90%), whereas the outcome for those with metastases is around 50-70%, while the prognosis of patients with non-resectable or recurrent disease is relatively poor (around 20-30%). Relapse in HB occurs in less than 12% of the children who have achieved complete remission.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Piotr CZAUDERNA  - Dr Maciej MURAWSKI"}
{"Disease Name": "Hepatocellular adenoma", "Disease Definition": "Hepatocellular adenoma (HA) is a rare benign tumor of the liver.", "ORPHA ID": 54272, "Summary": "Epidemiology\nAnnual incidence is estimated at one case per million.\nClinical description\nMean age at diagnosis is 34 years (ranging from 15 to 64 years). HA rarely occurs in children. Most patients with HA are asymptomatic and lesions are found incidentally during laparotomy or radiologic studies performed for other reasons. Pain or discomfort in the right upper quadrant or epigastric region is common, but not always related to the adenoma. HA may be revealed by spontaneous rupture or hemorrhage (leading to acute abdominal pain and possibly progressing to hemorrhagic shock, hypotension and even death). These complications are estimated to occur in 30% of patients with an adenoma over 5 cm in diameter. HA patients have normal liver function and no elevation of serum tumor markers. Serum aminotransferases and gamma-glutamyl transpeptidase may be mildly elevated. HA is typically solitary, although multiple lesions have been reported under the denomination `hepatocellular adenomatosis'. Size varies from about 1 cm (the detection limit for usual imaging methods) to over 20 cm. There appears to be a zero risk of complications for patients with a HA below 5 cm in diameter. In rare cases, and more frequently in males, the largest tumors may harbor malignant features. Histologically, adenoma cells are larger than normal hepatocytes but do not show cytonuclear atypia. Few or no portal tracts, central veins or bile ducts are present but there are isolated arteries. Kupffer cells are less numerous or absent.\nEtiology\nIn most cases, adenomas develop for unclear reasons in an otherwise healthy liver. Some predisposing conditions have been identified: prolonged oral contraceptive use, glycogenosis type III and IV, congenital portocaval shunt and, in males, use of anabolic steroids. Molecular analysis has disclosed specific mutations in adenomatous cells, each associated with specific histological features: HNF1 mutations are associated with fatty hepatocytes, and mutations in beta-catenin are associated with dysplasia and malignant transformation. An additional type of hepatic adenoma has recently been characterized as telangiectatic adenoma. This type of adenoma features sinusoidal dilatation and inflammatory infiltrates.\nDiagnostic methods\nDiagnosis is made by a characteristic pattern of enhancement after injection of intravascular contrast medium, using contrast enhanced ultrasound, multiphasic computed tomography, or gadolinium-enhanced MRI. Biopsy and/or resection may be necessary to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes some forms of angiomas, focal nodular hyperplasia, hepatocellular carcinoma (see these terms), and certain types of liver metastases.\nManagement and treatment\nOral contraceptives are contraindicated and should be stopped. Surgical resection is advocated in most patients with a HA greater than 5 cm in diameter. When diagnosis is certain, and the tumor is less than 5 cm in diameter and asymptomatic, it can be left in place but surveillance is required.\nPrognosis\nMalignant transformation is rare and the long-term prognosis is good.\n\n                            Last update: \n                            April 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Dominique VALLA"}
{"Disease Name": "Hepatocellular carcinoma", "Disease Definition": "Hepatocellular carcinoma is a primary hepatic cancer derived from well-differentiated hepatocytes. It is more frequent in adults than in childhood. Symptoms are hepatic mass, abdominal pain and, in advanced stages, jaundice, cachexia and liver failure.", "ORPHA ID": 88673, "Summary": ""}
{"Disease Name": "Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1", "Disease Definition": "A rare, inherited mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by intrauterine growth retardation, metabolic decompensation with recurrent vomiting, persistent severe lactic acidosis, encephalopathy, seizures, failure to thrive, severe global developmental delay, poor eye contact, severe muscular hypotonia or axial hypotonia with limb hypertonia, hepatomegaly and/or liver dysfunction and/or liver failure, leading to fatal outcome in severe cases. Neuroimaging abnormalities may include corpus callosum thinning, leukodystrophy, delayed myelination and basal ganglia involvement.", "ORPHA ID": 137681, "Summary": ""}
{"Disease Name": "Hepatoerythropoietic porphyria", "Disease Definition": "A rare form of hepatic porphyria characterized by bullous photodermatosis.", "ORPHA ID": 95159, "Summary": "Epidemiology\nFewer than a hundred cases of hepato-erythropoietic porphyria (HEP) have been described worldwide.\nClinical description\nThe disease begins in childhood. The main clinical signs include skin fragility, and sometimes erosive or even mutilating bullous skin lesions on sun-exposed surfaces (hands, face). Anemia and splenomegaly may be present. At bone level, delayed metacarpophalangeal growth is usually present. Hepatoerythropoietic porphyria corresponds to homozygous or heterozygous compound cases of porphyria cutanea tarda.\nEtiology\nThe disease is due to a deficiency of uroporphyrinogen decarboxylase (UROD; the fifth enzyme in the heme biosynthesis pathway) resulting from a mutation in the UROD gene (NM_000374.5), which leads to an accumulation of porphyrins mostly in the liver. At least 30 different mutations have been described in the UROD gene, including one predominant substitution: G281D.\nDiagnostic methods\nDiagnosis is based on evidence of porphyrin accumulation in urine and stool with a characteristic chromatographic profile, and very high porphyrin concentrations in plasma and erythrocytes. The presence of a major (< 10%) UROD deficiency in red blood cells confirms the diagnosis. Skin biopsy is not very informative and is not recommended.\nDifferential diagnosis\nGünther's disease is the main differential diagnosis.\nAntenatal diagnosis\nAntenatal diagnosis is theoretically possible, but is not proposed.\nGenetic counseling\nTransmission pattern is autosomal recessive. Genetic counseling should be offered to affected families to identify individuals likely to develop or transmit the disease. Genetic counselling should be offered to at-risk couples (both individuals are carriers of a heterozygous pathogenic variant) informing them that there is a 25 % risk of having an affected child at each pregnancy.\nManagement and treatment\nCare and support mainly involves protecting the skin against light, and blood transfusions in case of anemia. Treatment with hydroxyurea and splenectomy are rarely necessary. Chloroquine and phlebotomy are of limited effectiveness in the treatment of hepato-erythropoietic porphyria.\nPrognosis\nThe long-term prognosis is good.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Neila TALBI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hepatoportal sclerosis", "Disease Definition": "A form of portosinusoidal vascular disease characterized histologically by varying degrees of phlebosclerosis, primarily involving the small and medium branches of the portal vein with heterogeneous distribution, in the absence of cirrhosis.", "ORPHA ID": 64743, "Summary": ""}
{"Disease Name": "Hepatosplenic T-cell lymphoma", "Disease Definition": "A rare T-cell non-Hodgkin lymphoma characterized by a proliferation of cytotoxic T-cells, usually gamma delta T-cells, with involvement of the liver and spleen, but without involvement of lymph nodes. The bone marrow is consistently affected. Patients typically present during adolescence or young adulthood with hepatosplenomegaly, pancytopenia, and systemic symptoms. Peripheral blood involvement may develop later in the disease course. There is a clear male preponderance. The disease often occurs in the context of long-term immunosuppression. The course is aggressive with poor therapy response.", "ORPHA ID": 86882, "Summary": ""}
{"Disease Name": "Hereditary acrokeratotic poikiloderma", "Disease Definition": "A rare hereditary poikiloderma characterized by infantile onset of vesicopustule formation on hands and feet and widespread eczematoid dermatitis (both spontaneously resolving during childhood), as well as gradually developing diffuse poikiloderma with striate and reticulate atrophy (excluding the face, scalp, and ears), and development of keratotic papules on hands, feet, elbows, and knees, beginning in early childhood. There have been no further descriptions in the literature since 1981.", "ORPHA ID": 2907, "Summary": ""}
{"Disease Name": "Hereditary amyloidosis with primary renal involvement", "Disease Definition": "A group of rare renal diseases, characterized by amyloid fibril deposition of apolipoprotein A-I or A-II (AApoAI or AApoAII amyloidosis), lysozyme (ALys amyloidosis) or fibrinogen A-alpha chain (AFib amyloidosis) in one or several organs. Renal involvement leading to chronic renal disease and renal failure is a common sign. Additional manifestations depend on the organ involved and the type of amyloid fibrils deposited.", "ORPHA ID": 85450, "Summary": ""}
{"Disease Name": "Hereditary angioedema type 1", "Disease Definition": "A form of hereditary angioedema characterized by acute edema in subcutaneous tissues, viscera and/or the upper airway.", "ORPHA ID": 100050, "Summary": "Epidemiology\nPrevalence is unknown but HAE type 1 is the most common form of HAE accounting for 85% of the cases and is seen equally in males and females.\nClinical description\nLike HAE 2 and 3 (see these terms), it occurs generally in childhood with symptoms becoming more severe in adolescence. Precipitating factors of HAE 1 thought to trigger attacks include: trauma, anxiety, puberty, infection, alcohol consumption, exercise and stress.\nEtiology\nIt is caused by a missence mutation in the SERPING1 gene encoding the C1 inhibitor (C1-INH). These mutations cause C1-INH levels to decrease leading to an increase in bradykinin formation.\nManagement and treatment\nTreatment usually consists of intravenous C1 inhibitor concentrate or subcutaneous administration of the orphan drug icatibant (bradykinin receptor antagonist). Prophylaxis with danazol is often given before surgical procedures.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence BOUILLET"}
{"Disease Name": "Hereditary angioedema type 2", "Disease Definition": "Hereditary angioedema type 2 (HAE 2) is a form of hereditary angioedema (see this term) characterized by acute edema in subcutaneous tissues, viscera and/or the upper airway.", "ORPHA ID": 100051, "Summary": "Epidemiology\nPrevalence is unknown. HAE 2 is the less common form of HAE, accounting for 15% of HAE cases and is seen equally in men and women.\nClinical description\nLike HAE 1 and 3 (see these terms) it occurs generally in childhood with symptoms becoming more severe in adolescence. Precipitating factors of HAE 2 thought to trigger attacks include: trauma, anxiety, puberty, infection, alcohol consumption, exercise and stress.\nEtiology\nIt is caused by deletions, frameshift or splice mutations in the SERPING1 gene encoding the C1 inhibitor (C1-INH). These mutations cause a decrease in C1-INH activity (while C1 inhibitor serum levels remain normal) leading to an increase in bradykinin formation.\nManagement and treatment\nTreatment usually consists of intravenous C1 inhibitor concentrate or subcutaneous administration of the orphan drug icatibant (bradykinin receptor antagonist). Prophylaxis with danazol is often given before surgical procedures.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence BOUILLET"}
{"Disease Name": "Hereditary angioedema with C1Inh deficiency", "Disease Definition": "A rare hereditary angioedema characterized by potentially life-threatening episodes of subcutaneous and/or submucosal edema without urticaria, associated with C1 esterase inhibitor (C1-INH) deficiency. Hereditary angioedema (HAE) type 1 is caused by quantitative, HAE type 2 by qualitative defects of C1-INH. The two subtypes are clinically indistinguishable. Patients may present at any age (but most commonly in childhood) with recurrent attacks of nonpitting edema of the skin, severe abdominal symptoms such as pain and swelling, and/or respiratory distress due to upper respiratory airways involvement. Genital, bladder, muscle, or joint swelling may occur in some cases.", "ORPHA ID": 528623, "Summary": ""}
{"Disease Name": "Hereditary angioedema with normal C1Inh", "Disease Definition": "A rare hereditary angioedema characterized by potentially life-threatening episodes of subcutaneous and/or submucosal edema without urticaria and with normal levels and function of C1 esterase inhibitor. Patients present with prolonged attacks which last for approximately two to five days and may include nonpitting edema of the skin, severe abdominal symptoms such as pain and swelling, and/or respiratory distress due to upper respiratory airways involvement. Affected locations and frequency of attacks differ slightly between subtypes. Estrogen-containing oral contraceptives and pregnancy are precipitating factors, especially in patients with a factor XII mutation.", "ORPHA ID": 528647, "Summary": ""}
{"Disease Name": "Hereditary angioedema", "Disease Definition": "Hereditary angioedema (HAE) is a genetic disease characterized by the occurrence of transitory and recurrent subcutaneous and/or submucosal edemas resulting in swelling and/or abdominal pain.", "ORPHA ID": 91378, "Summary": "Epidemiology\nPrevalence has been estimated at 1/100,000.\nClinical description\nOnset may occur at any age but is most common during childhood or adolescence. Patients present with white, circumscribed nonpruritic edemas that remain for a period of 48 to 72 hours and recur with variable frequency. Edemas may involve the digestive tract resulting in a clinical picture similar to that seen in intestinal occlusion syndrome, sometimes associated with ascites and hypovolemic shock. Laryngeal edema can be life-threatening with a risk of death of 25% in the absence of appropriate treatment. Dental procedures are a triggering factor for laryngeal edema. Edemas of the face are a risk factor for laryngeal involvement.\nEtiology\nThree types of HAE have been described. HAE types 1 and 2 are caused by anomalies in the SERPING1 gene (11q12-q13-1) encoding the C1 inhibitor (C1-INH): type 1 is caused by deletion or by expression of a truncated transcript leading to a quantitative defect in C1-INH; type 2 is caused by point mutations leading to a qualitative defect in C1-INH. Transmission is autosomal dominant and most cases involve heterozygotes. The edemas are triggered by increased permeability of the blood vessels in response to elevated levels of bradykinin as a result of the C1-INH deficiency. HAE type 3 predominantly involves females, with the use of estrogen-containing oral contraceptives and pregnancy being precipitating factors. HAE type 3 is not caused by C1-INH deficiency but is associated with an increase in kininogenase activity leading to elevated levels of bradykinin. Some cases are associated with coagulation factor 12 (Hageman factor; F12; 5q33-qter) gain-of-function mutations but other genetic anomalies remain to be identified.\nDiagnostic methods\nDiagnosis of HAE types 1 and 2 relies on measurement of C4 concentrations and on quantitative and functional analysis of C1-INH. Diagnosis of HAE type 3 revolves around recognition of the clinical picture; C4 and C1-INH levels are normal. Analysis for mutations in the F12 gene may be proposed but are present in only 15% of patients.\nDifferential diagnosis\nThe differential diagnosis should include acquired angioedema (see this term), intestinal occlusion syndrome and histamine-induced angioedema (of allergenic or nonallergenic origin) generally associated with urticaria. Screening of family members, including asymptomatic individuals, is recommended.\nManagement and treatment\nCorticosteroid treatments are not effective. In Europe, acute attacks should be treated with subcutaneous icatibant (a bradykinin receptor antagonist) or intravenous administration of C1-INH concentrate. Prophylactic treatment with tranexamic acid or danazol may be proposed for patients with frequent episodes.\nPrognosis\nThe vital prognosis is good for patients who have been diagnosed and have access to the proper treatment in case of an ear-nose-throat (ENT) edema. Significant morbidity may be associated with digestive involvement resulting in pain and patients becoming bedridden for at least three days following an episode.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence BOUILLET"}
{"Disease Name": "Hereditary arginine vasopressin deficiency", "Disease Definition": "Hereditary central diabetes insipidus is a rare genetic subtype of central diabetes insipidus (CDI, see this term) characterized by polyuria and polydipsia due to a deficiency in vasopressin (AVP) synthesis.", "ORPHA ID": 30925, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nSymptoms usually develop between 1 and 6 years of age but onset in the neonatal period or in elderly patients has been described. They include polyuria, polydipsia and nocturia (often manifesting as enuresis in children). Additional symptoms seen in children can include: lethargy, irritability, growth retardation, weight loss, fever, vomiting or diarrhea. In the autosomal recessive form, symptoms are secondary to reduced biological activity of mutant AVP; heterozygous carriers have subclinical manifestations or are asymptomatic.\nEtiology\nThe origin of the disease is genetic and is usually due to a mutation in the AVP gene located on chromosome 20p13 that encodes a precursor protein consisting of arginine vasopressin and two associated proteins, neurophysin 2 and copeptin. All except a few cases show an autosomal dominant pattern of inheritance. Rarely, an autosomal recessive or X-linked pattern of inheritance is reported.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Stefano GHIRARDELLO"}
{"Disease Name": "Hereditary arterial and articular multiple calcification syndrome", "Disease Definition": "Hereditary arterial and articular multiple calcification syndrome is a very rare genetic vascular disease of autosomal recessive inheritance, described in less than 20 patients to date, characterized by adult-onset (as early as the second decade of life) isolated calcification of the arteries of the lower extremities (including the iliac, femoral, and tibial arteries) as well as the capsule joints of the fingers, wrists, ankles and feet, and that usually manifests with mild paresthesias of the lower extremities, intense joint pain and swelling, and early onset arthritis of affected joints.", "ORPHA ID": 289601, "Summary": ""}
{"Disease Name": "Hereditary ATTR amyloidosis", "Disease Definition": "A rare genetic systemic disease characterized by adult onset, progressive sensorimotor and autonomic neuropathy and infiltrative cardiomyopathy. Neurological involvement usually starts with sensory loss in the extremities and progresses with motor neuropathy. Cardiomyopathy presents with rhythm abnormalities and heart failure. The disease also frequently manifests with a range of additional clinical signs and symptoms due to associated ocular, renal, central nervous system and gastrointestinal involvement.", "ORPHA ID": 271861, "Summary": "Epidemiology\nHereditary ATTR amyloidosis (hATTR) is estimated to affect >10,000 individuals globally.\nClinical description\nDisease onset typically occurs in adult life, with age and presenting symptoms largely depending on genotype. Initial signs usually include pain, temperature sensation loss, numbness or tingling in lower limbs extremities. Motor neuropathy progressively ensues causing walking instability, inability to walk unassisted and ultimately need for a wheelchair. Autonomic symptoms, including bowel abnormalities, early satiety, orthostatic hypotension and erectile dysfunction may appear in the initial stages of the disease, particularly in patients with an early onset phenotype. Heart involvement, with signs of infiltrative cardiomyopathy leading to heart failure, develops in the majority of patients. Most patients are therefore classified as mixed phenotype (both neurological and cardiac). With respect to drug prescription, impairment due to polyneuropathy is scored with the familial amyloidotic polyneuropathy (FAP) staging system which has three stages : stage 1 is defined by unassisted walking; stage 2 is defined by need for assisted walking and stage 3 is defined by wheelchair-bound or bedridden patient.\nEtiology\nOver 140 mutations in the TTR gene are presently associated with hATTR. Mutations cause TTR tetramer instability, proteolytic remodeling and dissociation into monomers, leading to misfolding, aggregation and deposition as amyloid in tissues and organs.\nDiagnostic methods\nGenetic testing revealing a heterozygous pathogenic TTR and tissue biopsy (preferably non-invasive like minor labial salivary gland, subcutaneous fat tissue or rectal mucosa) are required for a complete diagnosis. Green birefringence on polarized light microscopy after Congo red staining reveal amyloid deposits. In the absence of a serum and/or urinary monoclonal gammopathy, bone tracer scintigraphy with a Perugini score ≥2 represents indirect evidence of TTR amyloid deposition. Amyloid deposits must be typed by immunohistochemistry or mass spectrometry for definite diagnosis when a patient also presents with a serum and/or urinary monoclonal gammopathy.\nDifferential diagnosis\nThe differential diagnosis includes diabetic neuropathy, chronic inflammatory demyelinating polyneuropathy, and AL, AGel and AApoAI amyloidosis. Increased left ventricular wall thickness should be differentiated from hypertensive heart disease, concentric hypertrophy from aortic stenosis, hypertrophic cardiomyopathy or other infiltrative cardiomyopathies, such as Fabry disease.\nAntenatal diagnosis\nPrenatal and preimplantation diagnosis is possible when the pathogenic variant has previously been identified in a family member. However for TTR variants associated with a late-onset phenotype antenatal diagnosis is very rarely requested, particularly in light of emerging disease-modifying therapies.\nGenetic counseling\nhATTR is dominantly transmitted. Genetic counseling is highly recommended to at-risk patients' relatives, informing them there is a 50% risk of inheritance in siblings and offspring. Pre-symptomatic testing is increasingly offered in hATTR due to emerging disease-modifying therapies.\nManagement and treatment\nThere are two different classes of disease-modifying therapies for hereditary transthyretin amyloidosis: TTR stabilizers and gene-silencing agents. Tafamidis is the first-in-class transthyretin stabilizer that prevents misfolding and aggregation by stabilizing the native protein structure. It is approved for hATTR with FAP stage 1 polyneuropathy at the dose of 20 mg/daily and for hATTR with cardiomyopathy at the dose of 61 mg/daily. Gene-silencing agents approved by EMA for hATTR with polyneuropathy (FAP stages 1 and 2) include RNAi agents patisiran and vutrisiran and the antisense oligonucleotide (ASO) inotersen.\nPrognosis\nPrognosis depends on disease stage at treatment start. Advanced heart involvement is associated with worse prognosis.\n\n                            Last update: \n                            May 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Laura OBICI | RITA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hereditary benign intraepithelial dyskeratosis", "Disease Definition": "A rare, genetic, superficial corneal dystrophy disease characterized by white, elevated, epithelial plaques located on the bulbar conjunctiva (sometimes with encroachment of the cornea) and oral mucosa (in any part of the oral cavity), associated with dilated, hyperemic, conjunctival blood vessels, observed mainly in Haliwa-Saponi Native American descendents. Patients may be asymptomatic or present with ocular itching, superficial corneal scarring, excessive lacrimation, photophobia and visual loss due to corneal opacity. Histologically, both ocular and oral lesions display acanthosis with hyperkeratosis and prominent dyskeratosis.", "ORPHA ID": 352657, "Summary": ""}
{"Disease Name": "Hereditary breast and/or ovarian cancer syndrome", "Disease Definition": "A genetic condition characterized by hereditary susceptibility to breast and/or ovarian cancer. It can be defined using family history criteria, or through identification of germline pathogenic variants (GPVs) in clinically validated HBOC genes. However, the genetic basis of about half of clinical HBOC is currently unknown or unexplained by single-gene variants, and approximately half of individuals who harbour PVs in HBOC genes do not have a suggestive family history.", "ORPHA ID": 145, "Summary": "Epidemiology\nThe prevalence of any germline HBOC-related pathogenic variant has been estimated to be about 1:70 women in the general population.\nClinical description\nHBOC is not associated with specific phenotypic features. Individuals with breast cancer may have any histological subtypes, the most common being ductal adenocarcinoma. Early-onset of cancer, bilateral breast cancer, familial occurrence of cancer over several generations, male breast cancer, multiple tumors in a same individual, multifocality and triple negative cancer are features suggestive of hereditary HBOC.\nEtiology\nGenes associated with HBOC are classified as 1) high-risk genes, increasing breast and/or tubo-ovarian cancer risk by at least fourfold, and 2) moderate-risk genes, increasing risk by two- to fourfold. However, there is considerable overlap between these two groups. Autosomal dominant alterations in BRCA1 and BRCA2 are likely to account for most HBOC cases. Other genes linked to hereditary breast or ovarian cancer are PALB2, ATM, CHEK2, BARD1 (only breast), RAD51C, RAD51D (breast and ovary) and BRIP1 (only ovary). TP53, PTEN, CDH1, and STK11 are linked to increased breast cancer susceptibility and also to other specific syndromes. Disease severity and age at onset may show variability within and between families harboring the same pathogenic variant, suggesting the involvement of other genetic as well as non-genetic factors. These PVs may also increase susceptibility to other cancer types such as prostate cancer and pancreatic cancer.\nDiagnostic methods\nDiagnosis is based on suggestive clinical features associated with significant family history. Individuals should be offered genetic testing with multigene panels of clinically validated HBOC genes. Analysis of single nucleotide variants and large rearrangements are needed for comprehensive genetic testing. If a pathogenic variant is identified through tumor testing, germline testing can be considered to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes familial breast cancer not associated with known genetic susceptibility.\nAntenatal diagnosis\nOnce the PV in HBOC-related genes has been identified in the family, prenatal and preimplantation genetic testing for known highly penetrant high cancer risk PV are possible.\nGenetic counseling\nHBOC-related genes are inherited in an autosomal dominant manner. The vast majority of probands inherited it from a parent, with very few being de novo. Offsprings of affected individuals have a 50% chance of inheriting the PV, but the penetrance of the disease is currently unknown. Molecular genetic testing should be offered to both parents and their at-risk relatives who should be counseled regarding their cancer risk, the risk of transmission, and recommendations for cancer screening and prophylactic surgery. Counseling should also mention possible rare autosomal recessive conditions, such as Fanconi anemia, when biallelic PVs in some genes are inherited (i.e. BRCA2, BRCA1, PALB2) and if the partner's family history is also suggestive of HBOC. Testing of asymptomatic individuals < 18 years of age is not recommended and should be deferred until they reach adulthood and can make independent decisions.\nManagement and treatment\nThe management strategies in healthy carriers include yearly surveillance and surgical risk-reduction options. For patients with a BRCA1/2-associated cancer, there are personalized approaches based on DNA-damaging agents or targeted therapies such as poly-ADP-ribose polymerase (PARP) inhibitors. Secondary preventive measures might be considered, such as contralateral risk reducing mastectomy or prophylactic bilateral salpingoophorectomy.\nPrognosis\nBreast and/or ovarian cancers in carriers of a BRCA1 or BRCA2 pathogenic variant may have increased chemosensitivity which might be linked to a slight survival advantage in the first few years after diagnosis compared to other patients.\n\n                            Last update: \n                            June 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Judith BALMAÑA | ERN GENTURIS* - Dr Maria HAANPÄÄ | ERN GENTURIS* -  Tamara HUSSONG MILAGRE | ERN GENTURIS* - Dr Arvids IRMEJS | ERN GENTURIS* - Dr Mateja KRAJC | ERN GENTURIS* - Pr Svetlana Bajalica LAGERCRANTZ | ERN GENTURIS* - Dr Salvatore TESTA | ERN GENTURIS* - Pr Marc TISCHKOWITZ | ERN GENTURIS*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hereditary breast cancer", "Disease Definition": "A rare genetic, malignant breast tumor characterized by early onset breast cancer in association with a germline mutation. Tumors arising in carriers of BRCA1 and BRCA2 mutations differ morphologically and genetically from each other, as well as from sporadic breast cancers. Most BRCA1-associated tumors are invasive ductal adenocarcinomas of no special type, typically of higher grade than sporadic tumors, and more often negative for hormone receptors. In addition, more cases with features of typical or atypical medullary carcinoma are seen in these patients. Likewise, BRCA2-associated tumors tend to be of higher grade than sporadic ones, although their phenotype is similar. They show a low frequency of HER-2 expression.", "ORPHA ID": 227535, "Summary": ""}
{"Disease Name": "Hereditary bullous dystrophy, macular type", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by intellectual deficit, microcephaly, short stature, and ectodermal anomalies (including alopecia, spontaneous formation of bullae without evident trauma, hyper- or hypopigmented maculae, acrocyanosis, and dystrophic nails) in male patients. Additional reported features are short, tapering fingers, ocular anomalies (such as corneal opacities and cataract), and hypogenitalism. There have been no further descriptions in the literature since 1995.", "ORPHA ID": 1867, "Summary": ""}
{"Disease Name": "Hereditary butyrylcholinesterase deficiency", "Disease Definition": "Butyrylcholinesterase (BChE) deficiency is a metabolic disorder characterised by prolonged apnoea after the use of certain anaesthetic drugs, including the muscle relaxants succinylcholine or mivacurium and other ester local anaesthetics. The duration of the prolonged apnoea varies significantly depending on the extent of the enzyme deficiency.", "ORPHA ID": 132, "Summary": "Epidemiology\nThe prevalence of BChE deficiency is highest in the Caucasian population with between 3.4 and 4% of the population displaying a partial enzyme deficiency leading to slightly prolonged apnoea (between 5 minutes and 1 hour) and 1 in 2500 individuals showing a prolongation of more than 1 hour. Individuals with undetectable levels of BChE activity display a severe prolongation lasting more than 8 hours. The prevalence of this severe form is estimated at 1 in 100 000 individuals.\nEtiology\nBChE deficiency is a multifactorial disorder. It is caused by mutations in the BChE gene. The BChE gene is located at the E1 locus on chromosome 3 (3q26.1-q26.2) and multiple atypical variants have been identified. However, BChE deficiency and sensitivity to anaesthetic drugs may also occur during pregnancy, in neonates or in association with other pathologies (chronic infections, malnutrition, liver disease, certain cancers etc.).\nDiagnostic methods\nDiagnosis can be made by analysis of enzyme activity in plasma samples, combined with dibucaine and fluoride inhibition tests. DNA analysis, although not carried out routinely, can be used to identify heterozygous carriers of atypical alleles.\nGenetic counseling\nThe hereditary condition is transmitted as an autosomal recessive trait.\nManagement and treatment\nAffected individuals are asymptomatic unless exposed to neuromuscular blocking agents, however, prolonged respiratory paralysis following anaesthesia makes mechanical ventilation essential until the excess aesthetic agent is metabolised permitting normal neuromuscular function.\n\n                            Last update: \n                            October 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Pascale DE LONLAY"}
{"Disease Name": "Hereditary chronic pancreatitis", "Disease Definition": "A rare gastroenterologic disease characterized by recurrent acute pancreatitis and/or chronic pancreatitis in at least 2 first-degree relatives, or 3 or more second-degree relatives in 2 or more generations, for which no predisposing factors are identified. This rare inherited form of pancreatitis leads to irreversible damage to both exocrine and endocrine components of the pancreas.", "ORPHA ID": 676, "Summary": "Epidemiology\nThe estimated prevalence of hereditary chronic pancreatitis (HCP) is approximately 1/300,000 people in Europe (1/800,000 in Germany, approximately 1/333,000 in France and approximately 1/175,000 in Denmark).\nClinical description\nOnset of HCP is typically early in life, during childhood and adolescence. The clinical presentation is highly variable and includes chronic or intermittent mild to severe abdominal pain associated with exocrine pancreatic insufficiency, leading to maldigestion and/or pancreatic endocrine insufficiency (glucose intolerance progressing to diabetes mellitus type 3c) in some cases. The disease is slowly progressive. The risk of developing pancreatic carcinoma after the age of 50 is elevated in patients with HCP. However, the exact risk increase is difficult to assess.\nEtiology\nMutations in the PRSS1 (7q34) gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin and thus probably cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2; 7q34), the serine protease inhibitor, Kazal type 1 (SPINK1; 5q32) and the cystic fibrosis transmembrane conductance regulator (CFTR; 7q31.2) have been found to be associated with chronic pancreatitis (idiopathic and hereditary). Recently, mutations in carboxypeptidase A1 (CPA1; 7q32.2), carboxylesterlipase (CEL; 9q34.13) and pancreatic lipase (PNLIP; 10q25.3) have been found to be associated with HCP and idiopathic chronic pancreatitis with early onset.\nDiagnostic methods\nDiagnosis of HCP is based on clinical features along with family history of chronic pancreatitis, absence of precipitating factors and a negative workup for known causes of chronic pancreatitis. Imaging (abdominal ultrasound, endoscopic ultrasound, exceptionally with endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP) reveals morphological changes like pancreatic calcifications, pancreatic duct changes, pseudocysts, bile duct and duodenal obstruction. The diagnosis might be substantiated by variants in the genes mentioned above.\nDifferential diagnosis\nDifferential diagnoses include other forms of chronic pancreatitis mainly alcoholic chronic pancreatitis, idiopathic chronic pancreatitis, autoimmune pancreatitis.\nAntenatal diagnosis\nAntenatal diagnosis is not encouraged.\nGenetic counseling\nGenetic testing should only be performed in carefully selected patients by direct DNA sequencing. Mutation in the PRSS1 gene is transmitted in an autosomal dominant manner with incomplete penetrance.\nManagement and treatment\nMainstays of medical management involve pain control, nutritional support, treatment for diabetes mellitus, and pancreatic enzyme supplementation for exocrine insufficiency. Surgery may be indicated for the management of acute and chronic complications of HCP and includes debridement, drainage, decompression and only very rarely pancreatectomy. Additional risk factors for chronic pancreatitis (smoking, alcohol) should be avoided.\nPrognosis\nThe prognosis of patients with HCP is unpredictable with an increased risk of development of pancreatic carcinoma.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Jonas ROSENDAHL"}
{"Disease Name": "Hereditary clear cell renal cell carcinoma", "Disease Definition": "Hereditary clear cell renal cell carcinoma (ccRCC) is a hereditary renal cancer syndrome defined as development of ccRCC in two or more family members without evidence of constitutional chromosome 3 translocation, von Hippel-Lindau disease or other tumor predisposing syndromes associated with ccRCC, such as tuberous sclerosis or Birt-Hogg-Dubbé syndrome.", "ORPHA ID": 422526, "Summary": ""}
{"Disease Name": "Hereditary combined deficiency of vitamin K-dependent clotting factors", "Disease Definition": "Combined vitamin K-dependent clotting factors deficiency (VKCFD) is a congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX and X, as well as natural anticoagulants protein C, protein S and protein Z.", "ORPHA ID": 98434, "Summary": "Epidemiology\nPrevalence is unknown but less than 30 affected families have been reported in the literature so far.\nClinical description\nThe spectrum of bleeding symptoms ranges from mild to severe with onset in the neonatal period in severe cases. The bleeding symptoms are often life-threatening, occur both spontaneously and in a surgical setting and usually involve the skin and mucosae. A range of nonhemostatic symptoms are often present, including developmental and skeletal anomalies (stippling of the long bones, shortness of the distal phalanges of the fingers, osteoporosis) and pseudoxanthoma elasticum-like syndrome (see this term).\nEtiology\nVKCFD is an autosomal recessive disorder caused by mutations in the genes encoding either gamma-glutamyl carboxylase (GGCX; 2p12) or the vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1; 16p11.2). These two proteins are necessary for gamma-carboxylation, a postsynthetic modification that allows coagulation proteins to display their proper function. The developmental and skeletal anomalies seen in VKCFD are the result of defective gamma-carboxylation of a number of nonhemostatic proteins.\nDiagnostic methods\nDiagnosis of VKCFD should only be considered after exclusion of acquired forms of the disease, associated with intestinal malabsorption of vitamin K in patients with inflammatory bowel diseases or celiac disease (see these terms), liver cirrhosis or accidental ingestion of warfarins and superwarfarins. After exclusion of other causes, diagnosis of VKCFD is suspected in the context of an excessive bleeding pattern compared to the extent of the decrease in individual clotting factors, and is confirmed by molecular analysis.\nDifferential diagnosis\nOther congenital clotting defects such as isolated factor II, VII, IX (hemophilia B) and X deficiencies, combined factor VII and X deficiency (see these terms) and acquired bleeding anomalies due to the presence of autoantibodies (acquired hemophilia [see this term] and factor VII deficiency due to the presence of autoantibodies against factor VII) must also be considered as differential diagnoses.\nAntenatal diagnosis\nPrenatal genetic testing is not generally recommended.\nGenetic counseling\nGenetic counseling may be offered to affected families.\nManagement and treatment\nAdministration of vitamin K during the third trimester of pregnancy may be useful in women suspected of carrying a child with VKCFD. Vitamin K administration (oral or intravenously) is the mainstay of therapy in symptomatic VKCFD. Plasma supplementation and prothrombin complex concentrates are needed during surgery or severe bleeding episodes. In addition, combination therapy with both recombinant activated FVII (eptacog alfa) and vitamin K supplementation may constitute an alternative treatment option for surgical procedures and severe manifestations.\nPrognosis\nThe overall prognosis is good and, with the availability of several effective therapeutic options, VKCFD has only a small impact on the quality of life of affected patients.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Mario LAPECORELLA  - Dr G MARIANI  - Dr Mariasanta NAPOLITANO"}
{"Disease Name": "Hereditary continuous muscle fiber activity", "Disease Definition": "Hereditary continuous muscle fiber activity is a rare, non-dystrophic myopathy characterized by generalized myokymia and increased muscle tone associated with delayed motor milestones, leg stiffness, spastic gait, hyperreflexia and Babinski sign. Symptoms may be worsened by febrile illness or anesthesia.", "ORPHA ID": 972, "Summary": ""}
{"Disease Name": "Hereditary coproporphyria", "Disease Definition": "A rare acute hepatic porphyria characterized by neurovisceral attacks and, more rarely, skin lesions.", "ORPHA ID": 79273, "Summary": "Epidemiology\nPrevalence in Europe is estimated at about 1/1,000,000.\nClinical description\nThe disease manifests after puberty, predominantly affecting women. Patients suffer neurovisceral episodes that can persist for several weeks, manifesting severe abdominal pain (85-95% of cases), neurological disorders, and psychological disturbances. Abdominal pain is very often associated with low back pain irradiating to the legs, and with nausea, vomiting and constipation. Several psychological disturbances can be observed: irritability, emotional sensitivity, depressive disorder, anxiety and, more rarely, auditory or visual hallucinations, disorientation, and mental confusion. Neurological manifestations can affect both the central and peripheral nervous systems (myalgia, paresis, ascending flaccid paralysis of the limbs or convulsions), and can lead to severe complications such as motor paralysis. Tachycardia and hyponatremia are common during these episodes. In the rare case of cardiac arrhythmia or respiratory paralysis, it can be fatal. Such episodes are most commonly triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, a low-calorie diet, stress), and/or endogenous factors (hormonal, linked to menstrual cycle). In 30% of cases, patients develop skin lesions as a result of photosensitivity. Lesions predominantly appear on sun-exposed areas (hands, face) and come with more or less painful bullae, usually leaving hyperpigmented scars.\nEtiology\nThe disease is caused by a deficiency in coproporphyrinogen oxidase (CPOX, the sixth enzyme in the heme biosynthesis pathway) which leads to an accumulation of porphyrins and their precursors (delta aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver. The enzyme deficiency is due to mutations of the CPOX gene (NM_000088; 3q12) coding for CPOX.\nDiagnostic methods\nReddish or brown coloration of urine following exposure to warm light is suggestive of the disease. Diagnosis is based on significantly elevated concentrations of PBG (pathognomonic of acute porphyria attack) and ALA in urine, and defective CPOX enzyme activity in circulating lymphocytes. Identification of a causal mutation of the CPOX gene confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include acute intermittent porphyria, porphyria cutanea tarda and, above all, variegate porphyria.\nAntenatal diagnosis\nAntenatal diagnosis is possible if a pathogenic variant has been identified in the family. It is offered to families at risk of homozygous form.\nGenetic counseling\nGenetic counseling is recommended to patients and families to identify individuals at risk of developing or transmitting the disease. Transmission is autosomal dominant. Affected individuals have a 50% risk of transmitting the disease on to their offspring.\nManagement and treatment\nAcute episodes must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Management includes elimination of one or more triggers, relief of pain (opioids), vomiting, and anxiety, and prevention of acute attacks (avoidance of triggers, particularly drugs).\nPrognosis\nWith early diagnosis and management, acute episodes are rarely severe. In hereditary coproporphyria, acute episodes are less frequent compared to acute intermittent porphryia, and the disease is rarely progressive if the triggering factors are eliminated.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Neila TALBI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hereditary cryohydrocytosis with normal stomatin", "Disease Definition": "Hereditary cryohydrocytosis with normal stomatin is a rare, hereditary, hemolytic anemia due to a red cell membrane anomaly characterized by fatigue, mild anemia and pseudohyperkalemia due to a potassium leak from the red blood cells. A hallmark of this condition is that red blood cells lyse on storage at 4 degrees centigrade.", "ORPHA ID": 398088, "Summary": ""}
{"Disease Name": "Hereditary cryohydrocytosis with reduced stomatin", "Disease Definition": "A rare hemolytic anemia characterized by combination of neurologic features, such as psychomotor delay, seizures, variable movement disorders, and hemolytic anemia with stomatocytosis, resulting in cation-leaky erythrocytes, pseudohyperkalemia, hemolytic crises and hepatosplenomegaly. Cataracts are also a presenting feature.", "ORPHA ID": 168577, "Summary": ""}
{"Disease Name": "Hereditary dentin defect", "Disease Definition": "The hereditary dentin disorders, dentinogenesis imperfecta (DGI) and dentin dysplasia (DD), comprise a group of conditions characterized by abnormal dentin structure affecting either the primary or both the primary and secondary dentitions.", "ORPHA ID": 167759, "Summary": "Epidemiology\nDGI is reported to have an incidence of 1 in 6,000 to 1 in 8,000 births, whereas that of DD type 1 is 1 in 100,000.\nClinical description\nClinically, the teeth are discolored and show structural defects such as bulbous crowns and small pulp chambers on radiographs. The underlying defect of mineralization often results in shearing of the overlying enamel leaving exposed weakened dentin which is prone to wear. Currently, three subtypes of DGI and two subtypes of DD are recognized but this categorization may change when further causative mutations are identified.\nEtiology\nDGI type 1 is inherited with osteogenesis imperfecta and recent genetic studies have shown that mutations in the genes encoding collagen type 1, COL1A1 and COL1A2, underlie this condition. All other forms of DGI and DD, except DD type 1, appear to result from mutations in the gene encoding dentine sialophosphoprotein (DSPP).\nDiagnostic methods\nDiagnosis is based on family history, pedigree construction and detailed clinical examination, but genetic diagnosis may become useful in the future once a sufficient number of disease-causing mutations have been identified.\nDifferential diagnosis\nDifferential diagnoses include hypocalcified forms of amelogenesis imperfecta, congenital erythropoietic porphyria, conditions leading to early tooth loss (Kostmann syndrome, cyclic neutropenia, Chediak-Higashi syndrome, histiocytosis X and Papillon-Lefevre syndrome), permanent teeth discoloration due to tetracyclines, and Vitamin D-dependent and vitamin D-resistant rickets (see these terms).\nGenetic counseling\nBoth DGI and DD are transmitted as autosomal dominant conditions.\nManagement and treatment\nTreatment involves removal of sources of infection or pain, improvement of aesthetics and protection of the posterior teeth from wear. Beginning in infancy, treatment usually continues into adulthood with a number of options including the use of crowns, over-dentures and dental implants depending on the age of the patient and the condition of the dentition.\nPrognosis\nWhere diagnosis occurs early in life and treatment follows the outlined recommendations, good esthetics and function can be obtained.\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martin BARRON  - Pr Mike DIXON  - Dr Iain MACKIE  - Dr Sinead MCDONNELL"}
{"Disease Name": "Hereditary diffuse gastric cancer", "Disease Definition": "Hereditary diffuse gastric cancer is a rare epithelial tumor of the stomach, characterized by the development of diffuse (signet ring cell) gastric cancer at a young age, associated with germline heterozygous mutations of CDH1, MAP3K6 and CTNNA1 genes. In early stages it presents with non-specific and vague symptoms, in advanced stages it may cause nausea and vomiting, dysphagia, loss of appetite, abdominal mass or weight loss. Women have an increased risk of lobular breast cancer as well.", "ORPHA ID": 26106, "Summary": ""}
{"Disease Name": "Hereditary elliptocytosis", "Disease Definition": "Hereditary elliptocytosis (HE) is a rare clinically and genetically heterogeneous disorder of the red cell membrane characterized by manifestations ranging from mild to severe transfusion-dependent hemolytic anemia but with the majority of patients being asymptomatic.", "ORPHA ID": 288, "Summary": "Epidemiology\nHE is ubiquitously distributed with an estimated prevalence of 1/1,000-1/4,000 but may be underestimated due to asymptomatic patients. The prevalence may reach up to 1/50 in malaria endemic areas like West and Central Africa. Less than 10% of HE patients manifest with the severe variant of hereditary pyropoikilocytosis (HPP).\nClinical description\nHE can present at any age and the clinical picture is heterogeneous. Most have common HE, which is mainly asymptomatic or which can present with mild hemolytic anemia as well as jaundice, splenomegaly and gallstones. Hydrops fetalis (see this term) may be seen in rare cases. A neonatal poikilocytic HE variant may be severe during the first year of life but afterwards (from 4 months-2 years) hemolysis declines and the phenotype becomes that of common HE. Transient poikilocytosis may also occur during infections or pregnancy, leading to hemolytic anemia in previously asymptomatic patients. The HPP variant is characterized by severe, transfusion-dependent hemolytic anemia with onset in infancy and that can also manifest with neonatal jaundice. Complications that can occur due to severe anemia include growth retardation, frontal bossing, marked splenomegaly and early gallbladder disease. Aplastic crisis, brought on by a Parvovirus B19 infection, may occur in some cases.\nEtiology\nHE is caused by abnormalities of proteins involved in the red cell membrane horizontal skeletal network including the spectrin dimer-dimer interaction or the spectrin-actin-protein 4.1 junctional complex. The genes involved in HE are: alpha-spectrin erythrocytic 1 (SPTA1) located to 1q21, beta-spectrin erythrocytic (SPTB) located to 14q24.1-q24.2, erythrocyte membrane protein band 4.1 (EPB41) located to 1p33-p32 or glycophorin C (Gerbich blood group) (GYPC) located to 2q14-q21. Heterozygous mutations usually result in common HE. Patients with HPP are either compound heterozygotes or homozygotes for a missense mutation of alpha/beta spectrin. HPP is also due to the presence of one alpha-spectrin mutation in trans to a low-expression alpha-spectrin allele (alpha-LELY).\nDiagnostic methods\nThe laboratory hallmark of HE is the presence of elliptocytes (sometimes also ovalocytes, spherocytes, stomatocytes and fragmented cells) on peripheral blood smears. Osmotic fragility is not informative in common HE, but is usually increased in HPP. SDS-PAGE analysis of red cell membrane proteins may reveal quantitative/qualitative abnormalities of cytoskeletal proteins. The mean corpuscular volume in HPP is of 50-60 fL and marked poikilocytosis and red cell fragmentation is present. Genetic mutation analysis can identify causal mutations, confirming diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other acquired causes of elliptocytic or fragmented red cells (i.e. iron, vitamin B12 and folate deficiency, and microangiopathic hemolytic anemia), congenital dyserythropoietic anemia and alpha and beta thalassemia (see these terms).\nAntenatal diagnosis\nSince HE is very rarely life threatening, antenatal diagnosis is not necessary, except for HPP cases, where screening for low expression polymorphism (i.e. alpha- LELY) is also needed.\nGenetic counseling\nAll HE variants, apart from HPP (inherited autosomal recessively), follow an autosomal dominant pattern of inheritance and genetic counseling is possible.\nManagement and treatment\nIn most cases treatment is not necessary. In the most severe variants, folic acid, red cell transfusion and splenectomy (after the age of 5) may be required. Patients should be monitored during events known to precipitate hemolysis.\nPrognosis\nIn the majority of cases HE is not life threatening and has no effect on life expectancy.\n\n                            Last update: \n                            April 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Alberto ZANELLA"}
{"Disease Name": "Hereditary episodic ataxia", "Disease Definition": "Hereditary episodic ataxia (EA) represents a group of neurological disorders characterized by recurrent episodes of ataxia and vertigo which may be progressive. Weakness, dystonia and ataxia are sometimes present in the interictal period. Seven types of EA have been described to date (EA type 1 to EA type 7, see these terms), but most of the reported cases belong to EA1 and EA2.", "ORPHA ID": 211062, "Summary": ""}
{"Disease Name": "Hereditary fibrosing poikiloderma-tendon contractures-myopathy-pulmonary fibrosis syndrome", "Disease Definition": "Hereditary fibrosing poikiloderma-tendon contractures-myopathy-pulmonary fibrosis syndrome is a rare, genetic, hereditary poikiloderma syndrome characterized by early-onset poikiloderma (mainly on the face), hypotrichosis, hypohidrosis, muscle and tendon contractures with varus foot deformity, progressive proximal and distal muscle weakness in all extremities, and progressive pulmonary fibrosis. Mild lymphedema of the extremities, growth retardation, liver impairment, exocrine pancreatic insufficiency and hematologic abnormalities are additional variable features.", "ORPHA ID": 221043, "Summary": ""}
{"Disease Name": "Hereditary folate malabsorption", "Disease Definition": "Hereditary folate malabsorption (HFM) is an inherited disorder of folate transport characterized by a systemic and central nervous system (CNS) folate deficiency manifesting as megaloblastic anemia, failure to thrive, diarrhea and/or oral mucositis, immunologic dysfunction and neurological disorders.", "ORPHA ID": 90045, "Summary": "Epidemiology\nThe prevalence is unknown. Approximately 30 cases have been reported to date.\nClinical description\nDisease onset usually occurs a few months after birth. Manifestations include failure to thrive, diarrhea and/or mouth ulcers, various neurological manifestations (motor impairment, seizures, developmental delay, cognitive and behavioral disorders), megaloblastic anemia and hypoimmunoglobulinemia. Megaloblastic anemia is the primary manifestation of HFM and can be very severe if untreated. Hypoimmunoglobulinemia results in unusual infections with Pneumocystis jiroveccii, C. difficile and cytomegalovirus (CMV) which can be recurrent and life-threatening in undiagnosed infants. Neurological manifestations may be the presenting symptoms in some but are absent in others. Seizures, if present, begin in infancy or later in childhood. Intracranial calcifications have been observed in some.\nEtiology\nHFM is caused by mutations in the SLC46A1 gene found on chromosome 17q11.2 which encodes the proton-coupled folate transporter (PCFT). PCFT is essential for intestinal folate absorption and transport of folates across the blood-cerebrospinal fluid (CSF) barrier. A defect in this protein leads to a systemic folate and CNS folate deficiency. Infants cannot absorb adequate folate from breast milk/formula and become deficient once their stores accumulated during gestation are exhausted.\nDiagnostic methods\nDiagnosis is based on clinical and laboratory findings. It is confirmed by findings of an impaired absorption of an oral folate load (even after correction of serum folate concentration) and a low CSF folate concentration (0-1.5nM). Bone marrow biopsy confirms the presence of megaloblastic anemia. Sequence analysis of the SLC46A1 coding region can identify any mutations present in the gene, also confirming diagnosis of HFM.\nDifferential diagnosis\nThe immunodeficiency seen in HFM may resemble severe combined immune deficiency (SCID; see this term). Other differential diagnoses include methionine synthase deficiency with megaloblastic anemia and developmental delay, formiminoglutamic aciduria, tyrosinemia type 1, methylenetetrahydrofolate reductase deficiency and erythroleukemia (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible via prenatal testing. Screening of newborns with a family history of HFM allows for early diagnosis and treatment with folate immediately after birth, before symptoms occur.\nGenetic counseling\nHFM is inherited autosomal recessively. Genetic counseling is possible.\nManagement and treatment\nHigh dose oral or parenteral 5-formyltetrahydrofolate (5-formylTHF) and oral L-5-methyltetrahydrofolate (L-5-methylTHF) are the two types of reduced folates used to treat HFM. Dosage is monitored and adjusted (individualized for each patient) so that the CSF folate levels remain within the normal range (around 100nM in infants-2 year olds). Folic acid should not be used as it binds to folate receptors and blocks folate transport. If anemia is severe, a transfusion may be necessary. Early treatment with reduced folates before the appearance of symptoms can prevent the metabolic consequences of HFM. Patients should have regular blood tests to monitor complete blood count, serum and CSF folate and homocysteine concentrations and serum immunoglobulin concentrations.\nPrognosis\nWith proper treatment the prognosis is good and reversal of most of the systemic consequences of the disease is usually achieved. Only when untreated is the prognosis poor.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Hereditary fructose intolerance", "Disease Definition": "Hereditary fructose intolerance (HFI) is an autosomal recessive disorder of fructose metabolism (see this term), resulting from a deficiency of hepatic fructose-1-phosphate aldolase activity and leading to gastrointestinal disorders and postprandial hypoglycemia following fructose ingestion. HFI is a benign condition when treated, but it is life-threatening and potentially fatal if left untreated.", "ORPHA ID": 469, "Summary": "Epidemiology\nThe estimated prevalence is 1 in 20,000 in Europe and the carrier frequency is about 1 in 70. The prevalence of HFI in adult population is not known.\nClinical description\nHFI usually presents in infancy at the time of weaning (when fructose is added to the diet), manifesting with hypoglycemia, lactic acidosis, ketosis with recurrent vomiting, abdominal pain and systemic manifestations following consumption of fructose-containing foods. Persistent ingestion of fructose and related sugars (such as sucrose and sorbitol) may lead to growth retardation, hepatomegaly, proximal tubular dysfunction, liver and renal failure, seizures, coma and risk of death. All patients achieve adulthood, develop a natural aversion to fruit/sweets and report a life long history of vomiting and hypoglycemia following fructose ingestion. Dental caries are absent in a significant proportion of adult population with HFI (which may give a clue to the diagnosis). Sometimes, the diagnosis may be made in an adult who has, owing to his aversion to fructose, excluded all fructose-containing food since childhood.\nEtiology\nHFI is caused by mutations in the ALDOB (9q22.3) gene, encoding the enzyme aldolase B. Affected individuals fail to metabolize fructose completely in the liver, intestine and kidneys because of fructose-1-phosphate aldolase B deficiency, leading to accumulation of the substrate fructose-1-phosphate and subsequent depletion of adenosine triphosphate.\nDiagnostic methods\nEarly diagnosis is essential, as patients can live a symptom-free life by eliminating fructose from their diet. When clinical features, nutritional and family history are suggestive, HFI is confirmed by molecular diagnosis on DNA from peripheral leucocytes. Very rarely, when no mutation can be found, liver biopsy may be performed to assess aldolase B activity.Early diagnosis is essential, as patients can live a symptom-free life by eliminating fructose from their diet. When clinical features, nutritional and family history are suggestive, HFI is confirmed by molecular diagnosis on DNA from peripheral leucocytes. Very rarely, when no mutation can be found, liver biopsy may be performed to assess aldolase B activity.\nDifferential diagnosis\nDifferential diagnoses include pyloric stenosis, gastro-esophageal reflux,galactosemia, tyrosinemia, glycogen storage disease, ornithine transcarbamoylase deficiency, Wilson disease, tumor of hematopoietic and lymphoid tissue (see these terms) and fructose malabsorption.\nAntenatal diagnosis\nPrenatal diagnosis is technically possible in families with known mutations, but it is not indicated due to the benign nature of this condition.\nGenetic counseling\nHFI is an autosomal recessive condition.\nManagement and treatment\nWhenever HFI is suspected, fructose should be eliminated from diet. This involves avoiding all types of food in which fructose, sucrose and/or sorbitol is found, either naturally or added during processing, including certain pharmacological preparations and infant formulae. The beneficial clinical and chemical effects of withdrawal are usually seen within a few days. Multivitamin preparation may be prescribed to substitute vitamins, especially vitamin C and folates. Intensive care and supportive measures may be required in case of acute intoxication\nPrognosis\nHFI prognosis is favorable with normal growth, intelligence and lifespan.\n\n                            Last update: \n                            September 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe LABRUNE"}
{"Disease Name": "Hereditary gastric cancer", "Disease Definition": "Hereditary gastric cancer refers to the occurrence of gastric cancer in a familial context and is described as two or more cases of gastric cancer in first or second degree relatives with at least one case diagnosed before the age of 50. Familial clustering is observed in 10% of all cases of gastric cancer, and includes hereditary diffuse gastric cancer (early onset diffuse-type gastric cancer), gastric adenocarcinoma and proximal polyposis of the stomach (see these terms) and familial intestinal gastric cancer (familial clustering of intestinal type gastric adenocarcinoma). Hereditary gastric cancer can also occur in other hereditary cancer syndromes such as Lynch syndrome, Li-Fraumeni syndrome, familial adenomatous polyposis and juvenile polyposis syndrome (see these terms).", "ORPHA ID": 423776, "Summary": ""}
{"Disease Name": "Hereditary geniospasm", "Disease Definition": "A rare genetic tremor disorder characterized by recurrent episodes of involuntary tremor of the chin and lower lip due to isolated myoclonus of the mentalis muscle. Patients may present more severe symptoms such as tongue biting and psychological distress. Even though neurological abnormalities are not associated, occasional involvement of sleep disorders and other facial muscles have been described. Sporadic cases were also reported.", "ORPHA ID": 53372, "Summary": ""}
{"Disease Name": "Hereditary gingival fibromatosis", "Disease Definition": "Hereditary gingival fibromatosis (HGF) is a rare benign, slowly progressive, non-inflammatory fibrous hyperplasia of the maxillary and mandibular gingivae that generally occurs with the eruption of the permanent (or more rarely the primary) dentition or even at birth. It presents as a localized or generalized, smooth or nodular overgrowth of the gingival tissues of varying severity. It can be isolated, with autosomal dominant inheritance, or as part of a syndrome.", "ORPHA ID": 2024, "Summary": ""}
{"Disease Name": "Hereditary hemorrhagic telangiectasia", "Disease Definition": "An inherited disorder of angiogenesis characterized by mucocutaneous telangiectases and visceral arteriovenous malformations.", "ORPHA ID": 774, "Summary": "Epidemiology\nThe prevalence is approximately 1/6,000\nClinical description\nThe most common clinical signs of hereditary hemorrhagic telangiectasia (HHT) include recurrent epistaxis (nosebleeds), frequently from childhood, and cutaneous or mucosal telangiectases generally presenting later, and increasing with age, where anemia may become an important part of the disease. Visceral arteriovenous malformations (AVMs) are usually asymptomatic but can lead to complications that produce highly variable manifestations. The age of onset of AVM-related complications is variable, ranging from childhood to geriatric age, with a few cases reported during the neonatal period. Pulmonary AVMs may manifest with brain abscesses, strokes, transient ischemic attacks, signs of chronic hypoxaemia or, rarely, haemorrhagic rupture. AVMs of the central nervous system can be haemorrhagic or, rarely, produce signs of slow compression. Hepatic AVMs, which can remain latent for a long time, in a limited proportion of patients become severe leading to high-output cardiac failure, portal hypertension, pulmonary hypertension or ischemic cholangitis. Hemorrhagic digestive telangiectases increase with age and can worsen chronic anemia.\nEtiology\nThis genetic disorder is due to pathogenic variants primarily in ENG (9q34.11) or ACVRL1 (12q13.13), encoding proteins involved in vascular development and angiogenic homeostasis of capillaries. Mutations in SMAD4 (18q21.2) occur in rare cases (1-3%) and result in HHT associated with juvenile polyposis. In a small proportion of HHT families, the pathogenic gene variant has not yet been identified.\nDiagnostic methods\nThe diagnosis is clinical and/or molecular. The clinical diagnosis is based on having at least three of the four Curaçao criteria: recurrent epistaxis, cutaneous/mucosal telangiectases, visceral involvement, and a first line family member with HHT. Genetic testing can be used to screen, to confirm a diagnosis, or to rule out the diagnosis if the pathogenic variant is known in the family.\nDifferential diagnosis\nThe differential diagnosis includes limited cutaneous systemic sclerosis, digestive angiodysplasias, isolated sporadic AVMs in the lungs, liver and brain, other vascular anomaly syndromes that cause AVMs; benign hereditary telangiectasia; and other causes of recurrent epistaxis (coagulation disorders or other local nasal factors).\nAntenatal diagnosis\nPrenatal genetic testing is possible in families where the pathogenic variant has been identified in the family, but is not necessary for proper pregnancy and delivery management. Decisions about prenatal genetic testing are the choice of the parents, but discussion of all related issues is appropriate. The usual antenatal scans will be offered, and sonographers aware of the presence of HHT in the family will detect most major AVMs.\nGenetic counseling\nTransmission is autosomal dominant. Penetrance is age dependent, the majority having symptoms before 50 years of age. The phenotype is highly variable, even between members of the same family.\nManagement and treatment\nDisease management includes prevention and treatment of epistaxis and anaemia, screening for AVMs, and guidance regarding pregnancy-related issues. The management of pulmonary AVM(s) relies on early detection, occlusion where feasible, and ongoing care in cases of persistent pulmonary AVMs. For severe liver involvement, multidisciplinary patient assessment in a center with expertise in HHT is recommended. Usually, cerebral AVMs that have not bled are not treated, whereas cerebral AVMs that have already bled or have become symptomatic usually require treatment. Gastrointestinal telangiectases may sometimes be the cause of significant anemia, especially in older patients, and need specific management. Awareness of the possibility of AVMs/HHT is important for optimal management of diverse medical states. HHT due to a SMAD4 pathogenic variant requires polyposis screening and aortic follow up.\nPrognosis\nLife expectancy is reduced in unscreened patients. In patients assessed and treated for pulmonary AVMs in an HHT Center, life expectancy is comparable to the general population. Pregnancy-related death has been reported, and is a particular risk for women with pulmonary arteriovenous malformations.\n\n                            Last update: \n                            January 2019\n\n\n                            - Expert reviewer(s): \n                             HHT WORKING GROUP | VASCERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hereditary hypercarotenemia and vitamin A deficiency", "Disease Definition": "Hereditary hypercarotenemia and vitamin A deficiency is an extremely rare metabolic disorder characterized clinically by skin discoloration, elevated levels of carotene and low levels of vitamin A described in fewer than 5 patients to date.", "ORPHA ID": 199285, "Summary": ""}
{"Disease Name": "Hereditary hyperekplexia", "Disease Definition": "Hereditary hyperekplexia is a hereditary neurological disorder characterized by excessive startle responses.", "ORPHA ID": 3197, "Summary": "Epidemiology\nTo date about 150 cases have been reported in the literature.\nClinical description\nHereditary hyperekplexia manifests shortly after birth with violent jerking to noise and touch, and massive and sustained stiffening of the trunk and limbs, clenching fists, and attacks of a high-frequency trembling. Newborns are at risk for sudden infant death due to laryngospasm and cardiorespiratory failure. Stiffness attacks may resemble epileptic seizures, although sleep can reduce or even abolish stiffness and jerking and EEG is normal. In the months after birth, muscle stiffness subsides, but excessive jerking to external stimulation or excitement persists. Motor milestones are often mildly delayed, but intellectual development is usually normal. Affected children walk toddling, and often seek assistance or a hold. Gait disturbance increases when in a hurry, amongst a crowd, or if forced. Stumbling or an unexpected jolt may induce uncontrolled falls (''like a log'') with the risk of serious injuries.\nEtiology\nMutations in the GLRA1 gene (5q32) are found in about 30% of patients with hereditary hyperekplexia (and a considerable number of patients without an obviously affected parent). These mutations are transmitted as an autosomal dominant or recessive trait. The GLRA1 gene encodes the alpha1 subunit of the juvenile neuronal receptor for the inhibitory neurotransmitter, glycine. Mutations of this subunit cause a variety of dysfunctions of the neuronal chloride (Cl-) channel, and therefore hereditary hyperekplexia is regarded as a channelopathy. Mutations in the GLRB, GPHN and SLC6A5 genes (4q31.3, 14q24 and 11p15.2-p15.1) have also been observed.\nDiagnostic methods\nDiagnosis is based on the clinical signs, molecular genetic testing and electrophysiology.\nDifferential diagnosis\nDifferential diagnoses include symptomatic hyperekplexia and spasticity, and epilepsy in perinatal brain damage and metabolic brain diseases, which can be excluded by normal EEG and reduction or abolition of stiffness and jerking with sleep.\nManagement and treatment\nSymptomatic treatment in adults involves clonazepam (1mg per day). In children lower doses are required. Vigabatrin is ineffective. Children gain benefit from repeated trials of physical exercise rather than from established physiotherapies or from resolute or demanding training. Extensive activities on soft or sandy ground are particularly effective. Intervention against incomprehension, mockery or pressure from uninformed teachers, relatives and friends may be required.\nPrognosis\nIn most patients, fear of falling and the toddling gait normalizes in adolescence. However, brisk startle and jerkiness to unexpected stimulation persist lifelong, and a minority of patients suffer phobic anxiety of crossing open spaces and an insecure and hesitating gait disorder.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Hans-Michael MEINCK"}
{"Disease Name": "Hereditary hyperferritinemia-cataract syndrome", "Disease Definition": "A rare genetic disease characterized by the association of early onset cataract with persistently raised plasma ferritin concentrations in the absence of iron overload.", "ORPHA ID": 163, "Summary": "Epidemiology\nThe exact worldwide prevalence of hereditary hyperferritinemia-cataract syndrome (HHCS) remains unknown. It is estimated to be at least 1/200,000 in Australia.\nClinical description\nThe single clinical presentation of the disease is bilateral cataract that usually manifests after birth, as early as infancy, but also in adolescence or in early adulthood. Age of diagnosis ranges from 6 to 40 years old. Cataracts are described as numerous, pulverulent (dust-like) opacities of the lens causing glare and decreasing visual acuity. HHCS is characterized by variable severity of ocular involvement, and variable serum ferritin levels without iron overload. Ophthalmologic follow-up studies indicate an age-related evolution of lens opacities that might be related to the progressive accumulation of insoluble L-ferritin aggregates. The recognition of HHCS as a distinct disease is important for two main reasons: 1) to enable early detection of cataract even in asymptomatic patients, allowing adequate follow-up and scheduled surgical removal; 2) to avoid misdiagnosis that can lead to useless diagnostic procedures and inadequate treatment.\nEtiology\nThe disease is caused by a mutation in a translational regulatory element, a stem-loop structure called iron responsive element (IRE), in the 5' non-coding region of the light ferritin (FTL) gene located on 19q13.4-qter. In the absence of iron, the iron regulatory protein (IRP) binds to IRE and represses ferritin synthesis. Mutations affecting the IRE loop, bulge, and two partial deletions affecting either part of the IRE, have been reported. The most widely accepted pathophysiological mechanism is accumulation of insoluble crystalline aggregates of iron-poor L-ferritin protein causing cataract formation, which was demonstrated by immunohistochemical analysis and transmission electron microscopy of HHCS patients' lens aspirate. Age of onset and severity of lens damage vary in patients with the same mutations, even within one family, which suggests that other factors, acquired or genetic, may modulate clinical presentation.\nDiagnostic methods\nDiagnosis is suspected in patients presenting with isolated hyperferritinemia in the absence of other evident cause of hyperferritinemia and iron overload. A personal or family history of early onset cataract should be investigated. Given that the cataract may not immediately be symptomatic, and that cases of de novo mutations have been reported, a comprehensive eye exam including a visual acuity test and a slit lamp examination may be recommended.\nDifferential diagnosis\nAcquired causes of isolated hyperferritinemia should be evaluated and excluded. They include infections and inflammatory diseases, acute and chronic liver diseases, high alcohol intake, metabolic disorders, fatty liver disease, and hypothyroidism. Other inherited diseases may be considered such as genetic hyperferritinemia without iron overload, ferroportin disease, aceruloplasminemia, and Gaucher disease.\nGenetic counseling\nThe disorder is autosomal dominant, with only few reports of spontaneous cases. Genetic counselling should be offered to affected individuals informing them that one of the parents is likely affected and there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nPatients are treated by cataract surgery when they suffer visual impairment due to cataracts formation. Hyperferritinemia is not associated with iron overload and doesn't require treatment. Thus, venesections should be avoided as they could induce iron deficiency and iron deficient anemia without significant change of ferritin level.\nPrognosis\nBesides cataracts, there is no other clinical manifestation associated with this disease and the prognosis is good.\n\n                            Last update: \n                            April 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Alberto PIPERNO | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hereditary hypophosphatemic rickets with hypercalciuria", "Disease Definition": "A rare hereditary disorder of renal phosphate wasting characterized by hypophosphatemia and hypercalciuria associated with rickets and/or osteomalacia. Other features include slow growth, short stature, skeletal deformities, muscle weakness and bone pain that are associated with normal or elevated plasma levels of calcitriol and hyperphosphaturia.", "ORPHA ID": 157215, "Summary": ""}
{"Disease Name": "Hereditary hypotrichosis with recurrent skin vesicles", "Disease Definition": "Hereditary hypotrichosis with recurrent skin vesicles is a very rare inherited hair loss disorder described in a family and characterized by sparse, fragile or absent hair on the scalp, eyebrows, eyelashes, axillae and rest of the body, associated with vesicle formation on various parts of the scalp and body which regularly burst and release watery fluid.", "ORPHA ID": 217407, "Summary": ""}
{"Disease Name": "Hereditary inclusion body myopathy type 4", "Disease Definition": "Hereditary inclusion body myopathy type 4 is a rare non-dystrophic myopathy characterized by slowly progressive muscular weakness and atrophy initially involving proximal lower limbs and hip girdle and later on shoulder girdle, proximal upper limbs and axial muscles. Ambulation is usually preserved. Congophilic inclusions with cytoplasmic inclusions of 15-21 nm filaments on electron microscopy are revealed in muscle biopsy.", "ORPHA ID": 324381, "Summary": ""}
{"Disease Name": "Hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome", "Disease Definition": "A rare genetic neuromuscular disease characterized by early onset of proximal or generalized muscle weakness, external ophthalmoplegia with or without ptosis, and joint contractures. Hypotonia, neonatal respiratory distress necessitating ventilation, and severe dysphagia have also been reported. The disease is of variable severity and non- or slowly progressive. Patients typically remain ambulatory. Muscle biopsy may show predominance of type 1 fibers, marked variability in fiber size, increased internal nuclei, and proliferation of perimysial and endomysial connective tissue.", "ORPHA ID": 79091, "Summary": ""}
{"Disease Name": "Hereditary isolated aplastic anemia", "Disease Definition": "Hereditary isolated aplastic anemia is a rare, genetic, constitutional aplastic anemia disorder characterized by severe peripheral blood pancytopenia and bone marrow hypoplasia in multiple individuals of a family, in the absence of any somatic symptoms. Abnormal bleeding, as well as erythrocyte macrocytosis, is reported and patients usually become transfusion-dependent.", "ORPHA ID": 397692, "Summary": ""}
{"Disease Name": "Hereditary late-onset Parkinson disease", "Disease Definition": "Hereditary late-onset Parkinson disease (LOPD) is a form of Parkinson disease (PD), characterized by an age of onset of more than 50 years, tremor at rest, gait complaints and falls, bradykinesia, rigidity and painful cramps. Patients usually present a low risk of developing non motor symptoms, dystonia, dyskinesia and levodopa-induced dyskinesia (LID).", "ORPHA ID": 411602, "Summary": "Epidemiology\nPrevalence of LOPD is unknown. The prevalence of PD is estimated at about 1% in people over 60 years of age in the general population in Europe and only 10% of the reported PD has shown to be hereditary.\nClinical description\nOnset of LOPD is > 50 years with predominant symptoms including tremor at rest (70% of cases), gait complaints and falls (20%), bradykinesia (20%), rigidity and painful cramps (8%). Compared to young onset PD (YOPD; see this term), a higher risk of developing gait freezing and falls but a lower risk of developing dystonia, dyskinesia and LID have been reported. Patients with hereditary LOPD are also more affected by severe diplopia, cognitive impairment, and gastrointestinal and urinary disorders. LOPD patients report a lower prevalence of non-motor symptoms such as depression, hallucinations, behavioral disturbances (i.e. agitation or impulse control disorder), dementia and apathy.\nEtiology\nThe exact etiology of hereditary LOPD is still unknown but mutations in the genes SNCA (4q21.3-q22), LRRK2 (12q12), and VPS35 (16q12) have been implicated in its pathogenesis. Heterozygous mutations in GBA (1p22; glucocerebrosidase) are the most common risk factor for PD.\nGenetic counseling\nTransmission is autosomal dominant. Genetic counseling should be offered to the affected families informing them of the 50% risk the offspring has of inheriting the disease-causing mutation and therefore being affected with the disorder.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Coro PAISAN-RUIZ"}
{"Disease Name": "Hereditary leiomyomatosis and renal cell cancer", "Disease Definition": "Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome characterized by a predisposition to cutaneous and uterine leiomyomas and, in some families, to renal cell cancer.", "ORPHA ID": 523, "Summary": "Epidemiology\nThe prevalence is unknown. Over 200 families with HLRCC have been reported.\nClinical description\nDisease onset can occur at any age, but is more common in young adults and elderly patients. Multiple or single benign cutaneous leiomyomas are common and usually present at around the age of 25 (range from 10-47 years) as firm papules or nodules that are skin colored to light brown. They are usually localized to the trunk and extremities but sometimes on the face. They tend to increase in size and number with age and are usually sensitive to touch and/or cold temperature and, in some, are painful. Uterine leiomyomas (present in 77% of women with HLRCC), also known as fibroids, usually appear around the age of 30 but age at diagnosis can range from 18-52 years. Symptoms of pelvic pain and irregular or heavy menstrual bleeding often occur before they are discovered. Renal tumors (mean age of presentation: 44) are less commonly seen in this syndrome (10-16% of cases) and may present with back pain, although some may be asymptomatic. They are mainly papillary type II renal cell carcinoma and are usually aggressive, often rapidly progressing to metastatic disease and death.\nEtiology\nHLRCC is caused by a mutation in the FH gene (1q42.1),which is thought to act as a tumor suppressor gene, encoding the enzyme fumarate hydratase (FH) that metabolizes the fumarate produced during the purine nucleotide cycle and arginine synthesis in the cytoplasm. It is still unclear how a deficiency in FH is involved in oncogenesis.\nDiagnostic methods\nDiagnosis of HLRCC is based on either the presence of multiple cutaneous leiomyomas with at least 1 histologically confirmed leiomyoma (interlacing bundles of smooth muscle fibers with centrally located long blunt-edged nuclei, occasional multinucleated cells, and no mitotic figures) or the presence of a single leiomyoma with a positive family history of the disease. Reduced enzymatic activity of FH is found in all patients and can be measured in cultured skin fibroblasts or lymphoblastic cells. MRI is the most accurate imaging technique for visualizing uterine leiomyomas. Molecular genetic testing can identify mutations in the FH gene, confirming diagnosis.\nDifferential diagnosis\nDifferential diagnoses include familial renal cancer syndromes such as Von Hippel-Lindau syndrome, Birt-Hogg-Dubé syndrome and hereditary papillary renal cancer (see these terms), as well as uterine fibroids and cutaneous lesions.\nAntenatal diagnosis\nPrenatal testing is possible in families with a known disease causing mutation.\nGenetic counseling\nHLRCC is inherited autosomal dominantly and genetic counseling is recommended.\nManagement and treatment\nManagement and treatment are multidisciplinary. Cutaneous leiomyomas can be treated by botulinum toxin type A injections, cryoablation and lasers. Solitary painful lesions can be surgically removed. Medications given to reduce pain include alpha blockers, calcium channel blockers (ex. nifedepine), antiepileptic drugs, nitroglycerine and antidepressants. Uterine fibroids can be treated with gonadotropin-releasing hormone agonists, pain relievers and antihormonal medications or surgically with a myomectomy. In some severe cases a hysterectomy may be necessary. As renal tumors associated with HLRCC are highly aggressive, a total nephrectomy is recommended for those with a renal mass. Adjuvant therapy (i.e. VEGF inhibitors) may be necessary in advanced cases. Annual clinical examinations and imaging assessments are recommended to monitor any changes. Family members of patients with HLRCC should equally be screened for the presence of lesions.\nPrognosis\nThe prognosis of HLRCC is poor but treatments with new molecular targets may improve survival in the future.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Maria MERINO"}
{"Disease Name": "Hereditary methemoglobinemia", "Disease Definition": "A rare red cell disorder classified principally into two clinical phenotypes: autosomal recessive congenital (or hereditary) methemoglobinemia types I and II (RCM/RHM type 1; RCM/RHM type 2).", "ORPHA ID": 621, "Summary": "Clinical description\nIn RCM type 1, cyanosis from birth is the only symptom. It is well-tolerated and is associated with mild complaints of headaches, fatigue and shortness of breath upon exertion. RCM type 2 is much more severe; the cyanosis is accompanied by neurological dysfunction (with intellectual deficit, microcephaly, growth retardation, opisthotonus, strabismus and hypertonia), which usually becomes evident during the first four months of life. Two additional forms of RCM have also been reported. RCM type 3 was the term used to define a phenotype with cyanosis but without neurological abnormalities in which Cb5R deficiency was identified in leucocytes and platelets as well as erythrocytes. This distinction has been largely ignored in subsequent reports of other CYB5R3 variants, so the term RCM type 3 is rarely used. RCM type 4 is a very rare disease associated with chronic cyanosis caused by mutations in the CYB5A gene (18q23) encoding cytochrome b5. In addition, there have been two reports of NADPH reductase deficiency, but in one case (identified though an inability to metabolize methylene blue) methemoglobinemia was not present suggesting that this pathway has limited physiological importance. It is also possible that mutations of the substrate of NADPH reductase, which remains to be identified, could have a minor effect on the reduction of methemoglobin.\nEtiology\nRCM type 1 is caused by mutations of the CYB5R3 gene (22q13.31-qter) encoding the NADH-cytochrome b5 reductase (Cb5R) and Cb5R deficiency is limited to the erythrocytes. RCM type 2 is caused by global loss of Cb5R function. Over 40 different CYB5R3 mutations have been identified so far, some of which have been identified in both types. RCM type 1 is generally associated with missense mutations, whereas RCM type 2 is more commonly associated with truncating mutations, splicing errors or mutations that lead to disruption of the active site.\nManagement and treatment\nTreatment of methemoglobinemia revolves around administration of methylene blue and/or ascorbic acid. Although ascorbic acid alone is sufficient to alleviate the cyanosis in milder cases, the reaction rate is slower than that of the combined treatment. However, these treatments have no effect on the neurological dysfunction in RCM type 2.\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Terry LAPPIN  - Dr Melanie PERCY"}
{"Disease Name": "Hereditary mixed polyposis syndrome", "Disease Definition": "Hereditary mixed polyposis syndrome (HMPS) describes an autosomal dominantly inherited large-bowel disease characterized by the presence of a mixture of hyperplastic, atypical juvenile and adenomatous polyps that are associated with an increased risk of developing colorectal cancer if left untreated.", "ORPHA ID": 157794, "Summary": ""}
{"Disease Name": "Hereditary motor and sensory neuropathy type 5", "Disease Definition": "Hereditary motor and sensory neuropathy type 5 is a rare axonal hereditary motor and sensory neuropathy characterized by slowly progressive distal muscle weakness and atrophy with or without sensory loss resulting in difficulty in walking, foot drop and pes cavus, that may be associated with pyramidal signs (extensor plantar responses, mild increase in tone, brisk tendon reflexes), muscle cramps, pain and spasticity.", "ORPHA ID": 64751, "Summary": ""}
{"Disease Name": "Hereditary motor and sensory neuropathy type 6", "Disease Definition": "A rare axonal hereditary motor and sensory neuropathy disease characterized by progressive, peripheral, axonal sensorimotor neuropathy (of variable severity), affecting predominantly the distal lower limbs, associated with progressive, variably severe, optic atrophy, which frequently leads to visual loss. Patients typically present distal limb muscle weakness and atrophy, hypo/areflexia, foot deformities, poor visual acuity (often with a central scotoma), nystagmus, and reduced peripheral and nocturnal vision. Additional reported manifestations include sensorineural hearing loss, major joint contractures, anosmia, scoliosis/lumbar hyperlordosis, cognitive impairment and vocal cord paresis.", "ORPHA ID": 90120, "Summary": ""}
{"Disease Name": "Hereditary motor and sensory neuropathy with acrodystrophy", "Disease Definition": "Hereditary motor and sensory neuropathy with acrodystrophy is a rare axonal hereditary motor and sensory neuropathy characterized by progressive axonal neuropathy with limb weakness and severe distal sensory loss in all limbs and acrodystrophic changes leading to painless non-healing ulcers, osteomyelitis, contractures and mutilating lesions with loss of terminal phalanges. One family with three affected siblings is described and there have been no further descriptions in the literature since 1999.", "ORPHA ID": 90119, "Summary": ""}
{"Disease Name": "Hereditary motor and sensory neuropathy, Okinawa type", "Disease Definition": "Hereditary motor and sensory neuropathy, Okinawa type is a rare, genetic, axonal hereditary motor and sensory neuropathy characterized by the adult-onset of slowly progressive, symmetric, proximal dominant muscle weakness and atrophy, painful muscle cramps, fasciculations and distal sensory impairment, mostly (but not exclusively) in individuals (and their descendents) from the Okinawa region in Japan. Absent deep tendon reflexes, elevated creatine kinase levels and autosomal dominant inheritance are also characteristic.", "ORPHA ID": 90117, "Summary": ""}
{"Disease Name": "Hereditary mucoepithelial dysplasia", "Disease Definition": "A rare, genetic, immune deficiency with skin involvement characterized by clinical triad of non-scarring alopecia affecting mainly the scalp, well-demarcated mucosal erythema and psoriasiform erythematous intertriginous plaques. Follicular keratosis, keratoconjuctivitis, cataracts, angular cheilitis, fissured tongue, and recurrent infections are additional clinical features. Histopathology of mucosal lesions show characteristic findings of dyskeratotic keratinocytes, vacuolated basal cells, lack of epithelial maturation and decreased number of desmosomes.", "ORPHA ID": 1839, "Summary": ""}
{"Disease Name": "Hereditary myopathy with early respiratory failure", "Disease Definition": "A rare genetic neuromuscular disease characterized by adult onset of slowly progressive distal and/or proximal muscle weakness in the upper and lower extremities, and early involvement of respiratory muscles leading to respiratory failure. Additional features are neck flexor weakness, foot extensor weakness, and, in rare cases, mildly impaired cardiac function. Muscle biopsy shows eosinophilic myofibrillar inclusions referred to as cytoplasmic bodies, as well as fiber size variation, increased internal nuclei and connective tissue, fiber splitting, and rimmed vacuoles.", "ORPHA ID": 178464, "Summary": ""}
{"Disease Name": "Hereditary myopathy with lactic acidosis due to ISCU deficiency", "Disease Definition": "A rare disorder of energy metabolism characterized clinically by myopathy with severe exercise intolerance, and biochemically by deficiencies of skeletal muscle mitochondrial respiratory chain enzymes, succinate dehydrogenase and aconitase.", "ORPHA ID": 43115, "Summary": "Epidemiology\nISCU myopathy is an ultra-rare disease reported in approximately 20 individuals in the world. Most patients are of Swedish heritage, though patients from other ethnic backgrounds have also been identified.\nClinical description\nThe cardinal feature of this condition is childhood-onset exercise intolerance, with muscle fatigue, pain, tachycardia and dyspnea occurring within a few minutes of mild physical activity. More prolonged or substantial exertion can result in an episode of profound muscle weakness associated with lactic acidosis and severe rhabdomyolysis. Cardiomyopathy has also been reported in patients of non-Swedish ancestry.\nEtiology\nThis genetic condition occurs due to bi-allelic variants in the gene ISCU (autosomal recessive inheritance). There is one report of a patient with a de novo heterozygous variant in ISCU, but thus far no other cases support an autosomal dominant inheritance pattern. The ISCU protein acts as a scaffold for iron-sulfur cluster assembly. Iron-sulfur clusters are essential components of various proteins, including some involved in mitochondrial function. Dysfunction of ISCU prevents mitochondria (particularly in muscle) from generating energy efficiently, resulting in exercise intolerance. All Swedish patients described to date are homozygous for the same genetic change in ISCU (c.418+382G>C).\nDiagnostic methods\nISCU myopathy should be considered in patients with the above clinical features. High blood lactate levels are usually present at baseline: with exercise physiology testing, further elevations in lactate and pyruvate occur, significantly limiting VO2 max. Confirmation of the diagnosis is now primarily via molecular (genetic) testing: possibilities include targeted sequencing for the Swedish variant, a gene panel for myopathy, or a broader test such as whole exome sequencing. Specialized biochemical testing can add confidence to the diagnosis, especially if the molecular testing identifies variants of uncertain significance. Most patients have high plasma fibroblast growth factor 21 levels. Analysis of muscle biopsy specimens can identify deficiency of mitochondrial aconitase, succinate dehydrogenase and specific respiratory chain complexes (I, II and III), as well as histochemical evidence of mitochondrial iron accumulation.\nDifferential diagnosis\nThe differential diagnosis includes other mitochondrial disorders, muscle-specific glycogen storage diseases, fatty acid oxidation disorders, glycolytic pathway defects (eg. phosphoglycerate kinase deficiency), TANGO2 deficiency and other genetic myopathies.\nAntenatal diagnosis\nAntenatal diagnosis is possible if the disease-causing variants have been previously identified in an affected family member. The decision to undertake testing should be discussed with the couple with input from genetic counseling and obstetric teams.\nGenetic counseling\nBecause this is a recessive condition, couples where each partner carries a pathogenic variant in ISCU have a 25% chance of having an affected child with each pregnancy. Specialized genetic counseling can help such couples contextualize this risk and understand their reproductive options.\nManagement and treatment\nCurrently, the focus of treatment for this condition is supportive management during episodes of rhabdomyolysis and a specialized exercise program to maintain muscle function without precipitating symptoms. Antisense oligonucleotide therapy has been trialled in vitro on patient myotubular cell lines. It appeared to correct the c.418+382G>C splicing abnormality, leading to improvements in biochemical abnormalities. However, there have been no subsequent clinical trials or other studies of such a treatment in humans.\nPrognosis\nMost patients live well into adulthood, with preserved quality of life despite their limited exercise tolerance. Acute decompensations with rhabdomyolysis and lactic acidosis can be fatal in rare instances, especially if supportive management is not initiated in these situations.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Parayil Sankaran BINDU  - Dr Arthavan SELVANATHAN"}
{"Disease Name": "Hereditary neurocutaneous malformation", "Disease Definition": "A rare genetic vascular anomaly characterized by the presence of angiomatous lesions affecting the skin, brain, and spinal cord. Lesions of the central nervous system have a marked tendency to bleed. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 1062, "Summary": ""}
{"Disease Name": "Hereditary neuroendocrine tumor of small intestine", "Disease Definition": "A rare inherited cancer-predisposing syndrome characterized by occurrence of multiple synchronous primary carcinoids of the small intestine. Clinical presentation is otherwise indistinguishable from sporadic carcinoids and includes abdominal pain, flushing, and diarrhea, often becoming manifest only after a long asymptomatic period. Most patients present with low grade tumors. Occurrence of pulmonary carcinoids has also been reported.", "ORPHA ID": 456333, "Summary": ""}
{"Disease Name": "Hereditary neuropathy with liability to pressure palsies", "Disease Definition": "A rare neurologic disease characterized by recurrent mononeuropathies usually triggered by minor physical activities innocuous to healthy people.", "ORPHA ID": 640, "Summary": "Epidemiology\nHereditary neuropathy with liability to pressure palsies (HNPP) actual prevalence is unknown due to under-diagnosis but estimates range between 1/50,000 -1/20,000 worldwide. In Finland, the prevalence is reported to be 1/6250.\nClinical description\nDisease onset usually occurs in the 2nd to 3rd decade of life, but may present in childhood. Some patients are asymptomatic and never diagnosed. The most common presenting symptom is the sudden onset of focal sensory loss and muscle weakness in the distribution of a single nerve. In many cases, these acute focal symptoms are triggered by mechanical stresses to the nerve, such as compression, repetitive movement or stretching of the affected limbs. Commonly affected nerves include the peroneal nerve at the fibular head, ulnar nerve at the elbow, median nerve at the wrist, brachial plexus and radial nerve. Clinical manifestations caused by these mononeuropathies include foot drop, hand numbness and weakness, arm weakness, and sensory loss over the index finger and thumb or lateral aspect of the hand. In 50% of cases, patients recover from these episodes within a few days to months but others have incomplete recovery and suffer from recurrent focal sensory and motor deficits. In rare cases, brachial plexopathy with unilateral painless arm paralysis and sensory loss may be a presenting symptom. Occasionally, mild impairments of cranial nerve functions may be seen. Absent deep tendon reflexes and pes cavus foot deformity are seen in some patients but not in others. The phenotype of HNPP often evolves into a symmetric sensory motor polyneuropathy in aged patients. Many patients with HNPP complain of diffuse pain and severe fatigue. HNPP may cause severe limb paralysis when asymptomatic patients with unknown diagnosis of HNPP are challenged by strenuous physical activities. This imposes a catastrophic risk in a fraction of patients with HNPP.\nEtiology\nHNPP is due to a mutation in the chromosome 17p12 containing PMP22 and other genes. PMP22 encodes the peripheral myelin protein-22 (PMP22) that is predominantly expressed in the compact myelin of the peripheral nervous system. In 80% of cases, a 1.4Mb deletion at 17p11.2 that includes the PMP22 gene is found, and in the remaining 20%, patients may carry a point mutation or small deletion in PMP22 or mutations in as yet unidentified genes.\nDiagnostic methods\nDiagnosis of HNPP is typically suggested by the presence of recurrent focal mononeuropathies and the evidence of a family history. Electrophysiologic testing shows prolonged distal latency at the sites susceptible to mechanical stress. Conduction velocities out of these sites are often either normal or only mildly slowed. Tomacula (focal thickening of the myelin sheath) is the characteristic histological finding in sural nerve biopsies. It may however be seen in other types of neuropathies. A DNA test showing the PMP22 heterozygous deletion confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes both compression induced mononeuropathies and generalized polyneuropathies. HNPP can sometimes be mistaken for neuralgic amyotrophy, stroke or multiple sclerosis.\nAntenatal diagnosis\nPrenatal testing is theoretically possible in families where the disease causing gene has been identified.\nGenetic counseling\nThe disorder is inherited autosomal dominantly. Genetic counseling should be done for individuals having the disease and informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nConsultation should be provided to the patient about physical activities that may trigger the sensory/motor deficits. Those with foot drop or wrist drop may benefit from an ankle-foot orthosis or a wrist splint. Protective pads for the elbows and knees can alleviate nerves from mechanical stresses. Activities that involve prolonged sitting with crossed legs, leaning on elbows and repetitive movements of the wrists, as well as rapid weight loss should be avoided. Vincristine should equally be avoided. Cautions should be taken when new medications are prescribed with potential side-effect to the peripheral nerves.\nPrognosis\nHNPP is not life threatening and does not appear to affect longevity. However, many patients may have incomplete recovery in their sensory moto deficits. In some cases, severe and prolonged limb paralysis can occur, particularly after strenuous physical activities. Many patients with HNPP suffer from pain and fatigue. Unfortunately, these issues have not been well studied and should be addressed in future investigations.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jun LI"}
{"Disease Name": "Hereditary neutrophilia", "Disease Definition": "A rare, genetic, immune disease characterized by chronic neutrophilia, increase in the percentage of circulating CD34+ cells in peripheral blood, increase in granulocyte precursors in bone marrow and splenomegaly. Patients are predominantly asymptomatic, but may present with systemic inflammatory response syndrome with fever, dyspnea, tachycardia, pleural and pericardial effusion, or myelodysplastic syndrome.", "ORPHA ID": 279943, "Summary": ""}
{"Disease Name": "Hereditary nonpolyposis colon cancer", "Disease Definition": "A cancer-predisposing condition characterized by the development of colorectal cancer not associated with colorectal polyposis, endometrial cancer, and various other cancers (such as malignant epithelial tumor of ovary, gastric, biliary tract, small bowel, and urinary tract cancer) that are frequently diagnosed at an early age.", "ORPHA ID": 443909, "Summary": ""}
{"Disease Name": "Hereditary North American Indian childhood cirrhosis", "Disease Definition": "Hereditary North American Indian childhood cirrhosis is a severe autosomal recessive intrahepatic cholestasis that has only been described in aboriginal children from northwestern Quebec. Manifesting first as transient neonatal jaundice, the disease evolves into periportal fibrosis and cirrhosis during a period ranging from childhood to adolescence.", "ORPHA ID": 168583, "Summary": ""}
{"Disease Name": "Hereditary orotic aciduria", "Disease Definition": "A rare genetic disorder of pyrimidine metabolism characterized by early onset of megaloblastic anemia, global developmental delay, and failure to thrive, associated with massive urinary overexcretion of orotic acid (sometimes with orotic acid crystalluria). Patients without megaloblastic anemia, but with additional manifestations such as epilepsy, have also been reported.", "ORPHA ID": 30, "Summary": ""}
{"Disease Name": "Hereditary painful callosities", "Disease Definition": "A rare focal palmoplantar keratoderma disorder characterized by the development of thick, painful, non-erythematous, nummular keratotic lesions over pressure points of feet and possibly hands. Occasionally, knee and shin involvement, periungual/subungual hyperkeratoses, and blistering at the edge of the calluses, may be observed.", "ORPHA ID": 79141, "Summary": ""}
{"Disease Name": "Hereditary palmoplantar keratoderma, Gamborg-Nielsen type", "Disease Definition": "Hereditary palmoplantar keratoderma, Gamborg-Nielsen type is characterised by the presence of diffuse palmoplantar keratoderma without associated symptoms. The syndrome has been described in multiple families from the northernmost county of Sweden (Norrbotten). The palmoplantar keratoderma found in the Gamborg-Nielsen type disease is milder than that found in Mal de Meleda but more severe than that found in Thost-Unna palmoplantar keratoderma (see these terms). Transmission is autosomal recessive.", "ORPHA ID": 86923, "Summary": ""}
{"Disease Name": "Hereditary papillary renal cell carcinoma", "Disease Definition": "A rare familial renal cancer syndrome characterized by a predisposition for developing bilateral and multifocal classic type papillary renal cell carcinomas (formerly known as type 1 papillary renal cell carcinoma until the 2022 WHO classification of renal tumors).", "ORPHA ID": 47044, "Summary": "Epidemiology\nRenal cell carcinoma (RCC) accounts for approximately 2% of all malignancies with about 400,000 new cases diagnosed annually worldwide. Papillary RCC, accounting for 15% of cases, is the second most common form of RCC after clear cell RCC (75%). Hereditary cases account for about 5% of all RCC and include a dozen of syndromes with four major conditions: von Hippel-Lindau (VHL), Birt-Hogg-Dubé (BHD), hereditary leiomyomatosis and renal cell cancer (HLRC) and hereditary papillary renal cell carcinoma (HPRC). Less than 60 kindreds with HPRC have been reported to date in the literature and the prevalence is unknown (estimated at 1/500,000).\nClinical description\nHPRC is a highly penetrant autosomal dominant disease predisposing to the occurrence of bilateral and multifocal classic papillary RCC. Recently biphasic squamoid alveolar papillary RCC (an emerging variant of papillary RCC) have also been described in association with the disease. Most of the tumors are low-grade, but a small subset of tumors may be high-grade and metastasize. In addition, numerous microscopic papillary adenomas are commonly seen in the background renal parenchyma. In HPRC, renal tumors occur over a wide age range from 19 to 66 years but typically occur later than other forms of hereditary RCC (median age of 41 years). Unlike other major hereditary renal cancer syndromes, there are no extrarenal manifestations in HPRC.\nEtiology\nHPRC is associated with activating germline mutations in the MET proto-oncogene (7q31) encoding the hepatocyte growth factor-responsive tyrosine kinase receptor. The activation subsequently triggers downstream signaling pathways that promote cell survival, proliferation and inhibition of apoptosis. Tumorigenesis in HPRC patients is most frequently associated with duplication of the chromosome 7 carrying the mutated MET allele (trisomy 7).\nDiagnostic methods\nDiagnosis is suspected in patients with bilateral or multifocal classic type papillary RCC even in absence of familial history and can be confirmed by detection of a germline mutation in the MET gene. Papillary RCC are classically poorly enhancing on computed tomography (CT) scan and magnetic resonance imaging (MRI) is more performant for their diagnosis.\nDifferential diagnosis\nNo other known syndrome predisposes to occurrence of classic type papillary renal cell carcinomas without extrarenal manifestations. In Birt-Hogg Dubé syndrome, such renal tumors can sometimes occur but are associated with other characteristic histologic types (hybrid chromophobe-oncocytomas RCC and chromophobe RCC) as well typical cutaneous and pulmonary lesions. With the advent of multi-gene renal cancer panel tests, the distinction is easily made in case of atypical presentation.\nAntenatal diagnosis\nThere is no indication to prenatal diagnostic testing or preimplantation genetic testing.\nGenetic counseling\nThe transmission is autosomal dominant. At-risk individuals have a 50% chance of transmitting the pathogenic variant to their offspring. Genetic testing is recommended for relatives from the age of 18 years.\nManagement and treatment\nClinical management should include regular surveillance, preferably by contrast-enhanced MRI, to allow early detection of renal carcinomas. The surveillance should be offered to patients and at-risk relatives, every 1-2 years starting at age 30, until the largest tumor reaches 3 cm, at which time nephron-sparing surgery (tumor excision or partial nephrectomy) is recommended. Percutaneous thermal ablation may provide a safe and alternative treatment to surgery for small tumors.\nPrognosis\nCompared to other hereditary renal cell carcinomas, HPRC tend to be of indolent nature but patients have a risk of recurrent tumors throughout life with need of often repeated surgeries. In some cases, multiplicity of tumors may ultimately lead to binephrectomy and dialysis. In case of metastatic disease, MET pathway inhibitors have shown promising results.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Stéphane RICHARD"}
{"Disease Name": "Hereditary persistence of alpha-fetoprotein", "Disease Definition": "Hereditary persistence of alpha-fetoprotein is a benign genetic condition characterized by persistence of high alpha-fetoprotein (AFP) levels throughout life, with no associated clinical disability and thus no need for specific therapy", "ORPHA ID": 168615, "Summary": ""}
{"Disease Name": "Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome", "Disease Definition": "Hereditary persistence of fetal hemoglobin (HPFH) associated with beta-thalassemia (see this term) is characterized by high hemoglobin (Hb) F levels and an increased number of fetal-Hb-containing-cells.", "ORPHA ID": 46532, "Summary": "Epidemiology\nPrevalence of this form is not known.\nClinical description\nThe association of HPFH with beta-thalassemia mitigates the clinical manifestations which vary from a normal state to beta-thalassemia intermedia (see this term).\nEtiology\nHPFH is due to deletions in the beta-globin gene cluster or point mutations in the HBG1 and HBG2 genes (11p15.5).\nDiagnostic methods\nDiagnosis is based on the presence of a significant elevation in HbF ranging from 10-40% in heterozygotes with normal or near normal red blood cell indices. HbF is homogeneously distributed among the erythrocytes and HbA2 is normal or reduced.\nDifferential diagnosis\nThe distinction between HPFH and delta-beta-thalassemia (see this term) is subtle and should be confirmed by alpha-beta-globin chain synthesis ratio and DNA analysis since the distinction between these two conditions is not always possible from routine hematologic analyses.\nGenetic counseling\nHPFH transmission is co-dominant. Homozygosis for the non-deletional form has to date been reported in rare cases.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA"}
{"Disease Name": "Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome", "Disease Definition": "A rare, genetic, hemoglobinopathy characterized by generally mild clinical phenotype, high fetal hemoglobin levels and mild microcytosis and hypochromia. In some cases, acute sickle cell disease manifestations were reported, namely acute chest syndrome and acute pain crisis. The genotype is characterized by the combination of an HbS and HbF allele; symptoms depend on the degree of HbF:HbS expressivity with patients with more than 35% pancellular HbF expression being asymptomatic. Symptomatic patients have heterocellular expression of HbF.", "ORPHA ID": 251380, "Summary": ""}
{"Disease Name": "Hereditary pheochromocytoma-paraganglioma", "Disease Definition": "A rare, hereditary, pheochromocytoma/paraganglioma tumor arising from neuroendocrine chromaffin cells of the adrenal medulla (pheochromocytoma) or from any paraganglia from the skull base to the pelvic floor (paraganglioma). Clinical manifestations are often linked to excess catecholamines production causing sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, palpitations, pallor and apprehension or anxiety. Hereditary pheochromocytoma/paraganglioma tumors tend to present at younger ages, to be multi-focal, bilateral, and recurrent, or to have multiple synchronous neoplasms.", "ORPHA ID": 29072, "Summary": ""}
{"Disease Name": "Hereditary progressive mucinous histiocytosis", "Disease Definition": "Hereditary progressive mucinous histiocytosis is a rare, benign, non-Langerhans cell histiocytosis characterized by childhood or adolescence onset of multiple, small, asymptomatic, slowly progressing, skin-colored to red-brown papules with predilection for the face, dorsal hands, forearms and legs, without associated mucosal or visceral involvement. Histologically, papules are well-circumscribed, unencapsulated, nodular aggregates of histiocytes with abundant mucin in the upper and middermis.", "ORPHA ID": 158025, "Summary": ""}
{"Disease Name": "Hereditary pulmonary alveolar proteinosis", "Disease Definition": "A rare, genetic, interstitial lung disease due to mutations in the CSF2R (colony-stimulating factor 2 receptor) alpha or beta subunits and characterized by alveolar accumulation of pulmonary surfactant, presenting a highly variable clinical presentation, ranging from asymptomatic to severe respiratory failure. Characteristic lung biopsy findings include periodic acid-Schiff-positive, granular eosinophilic material, enlarged foamy alveolar macrophages, and well-preserved alveolar walls. The Granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function is impaired but GM-CSF receptor autoantibodies are absent.", "ORPHA ID": 264675, "Summary": "Epidemiology\nThe disease is very rare; it has been suggested to represent between less than 1-6% of the total cases of pulmonary alveolar proteinosis. Most reported cases have mutations due to CSF2RA  mutations rather than CSF2RB mutations. Females are predominantly affected.\nClinical description\nThe onset of clinical disease is typically insidious, with a subacute, symptom-free period ranging from months to several years. Age of onset is typically in infancy or childhood but may also occur in adulthood, particularly in patients with CSF2RB  mutations. Presenting symptoms include dyspnea (70%), hypoxemia (55%), and cough (56%) and more variably tachypnea (15%) and global respiratory failure (one third). In children and young adults, comorbidities may include failure to thrive, clubbing, pectus excavatum and hepatomegaly. The clinical course may be complicated by respiratory tract infections. Laboratory findings may include elevated serum GM-CSF level (specificity not known) and absence of GM-CSF autoantibodies.\nEtiology\nDisease is due to disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which is crucial for clearing of pulmonary surfactant by alveolar macrophages. Causal mutations have been identified in CSF2RA (Xp22.32) and CSF2RB (22q12.2-q13.1), genes encoding for the GM-CSF receptor.\nDiagnostic methods\nDisease is suspected based on clinical presentation and chest computed tomography findings of diffuse bilateral ground-glass opacifications and a superimposed reticular pattern (crazy paving pattern). Characteristic bronchoalvelolar lavage (BAL) findings indicative of hereditary PAP include a milky fluid with substantial amount of sediment and alveoli filled with numerous foamy, lipid- or surfactant-laden macrophages and secreted functional surfactant debris (staining with periodic acid Schiff). Genetic testing is necessary to establish this diagnosis. Testing of asymptomatic siblings requires genetic counseling.\nDifferential diagnosis\nDifferential diagnosis includes Autoimmune PAP, PAP related to the production of surfactant (e.g. due to mutations in SP-B or SP-C,  ABCA3, and NKX2-1), PAP secondary to hematologic disorders and malignancies, toxic dust inhalations, and immune deficiency syndromes, rare infections, mutations affecting functions or numbers of mononuclear phagocytes, and mutations affecting lung development.\nGenetic counseling\nAutosomal recessive inheritance has been reported for GM-CSF receptor mutations and genetic counseling is recommended for affected families. The disease can also occur from deletion of the GM-CSFR gene in the X chromosome pseudoautosomal region 1. Incomplete penetrance is observed. Due to the insidious nature of hereditary PAP, some vigilance for asymptomatic first-degree relatives for disease is advised.\nManagement and treatment\nWhole lung lavage (WLL) is the only effective therapy, and is indicated when respiratory symptoms impair the quality of life, failure to thrive is observed, or lung function deviates from normal. In cases of severe hypoxemia, patients might be need to be supported by extracorporeal membrane oxygenation, allowing for recovery prior to WLL.\nPrognosis\nThe overall prognosis for hereditary PAP treated by WLL is fair. Sometimes intense WLL treatments are necessary, which may significantly impair quality of life. Patients may be susceptible to opportunistic infections, as GM-CSF receptor has been associated with immune deficiency. Immunosuppressive therapy should be avoided, as it increases the risk of infections. The overall outcome reported so far is favorable, although a significant number will continue to have respiratory symptoms.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Matthias GRIESE"}
{"Disease Name": "Hereditary renal hypouricemia", "Disease Definition": "A genetic renal tubular disorder characterized by urinary urate wasting that typically leads to asymptomatic hypouricemia and predisposes to urolithiasis and exercise-induced acute renal failure (EIARF).", "ORPHA ID": 94088, "Summary": "Epidemiology\nWhilst the prevalence is not known in Europe, hereditary renal hypouricemia (RHUC) is reported as common in Japan and South Korea. RHUC is likely underdiagnosed as patients are typically asymptomatic; however, there are increasing reports for European countries and North America.\nClinical description\nRHUC may be silent and sometimes the diagnosis is incidental; thus, clinical presentation may be at any age. However, chronic urinary urate wasting predisposes to several complications, such as nephrolithiasis, hematuria, pyelonephrithisis and nephrocalcinosis. In additions, several reports indicate that this disorder increases the risk of EIARF.\nEtiology\nThe disorder is the result of impaired urate reabsorption along the proximal tubule, leading to increased urinary urate excretion and secondary hypouricemia. Two genetic loci have been associates with the disorder: SLC22A12 (11q13.1), encoding the urate transporter 1 (URAT1), and SLC2A9 (4p16.1), encoding for the urate transporter called glucose transporter 9 (GLUT9).\nDiagnostic methods\nDiagnosis is typically suspected on the incidental finding of low serum uric acid levels (SUA). According to the current clinical practice guideline, diagnosis is confirmed by the presence of the following findings : (1) SUA lower than 2 mg/dl in two consecutive blood examinations, (2) high urinary fractional excretion of urate (greater than 10%) and/or uric acid clearance, (3) in the absence of other causes of hypo-uricemia. Identification of the causative genes, a history of excercise-induced acute kidney injury (EIAKI) or a family history of RHUC is supportive of diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes several conditions resulting in (1) increased excretion and (2) reduced uric acid production. The first group of disorders includes Fanconi syndrome, Wilson's disease, syndrome of inappropriate secretion of vasopressin (SIADH), neoplasia, some drugs (as probenecid), diabetes mellitus. The second one includes some rare inherited disorders affecting purine metabolism, as xanthinuria types 1 and 2 and purine nucleoside phosphorylase deficiency (PNP deficiency). In addition, severe liver diseases, malnutrition, some medications (allopurinol) and molybdenum cofactor deficiency may cause urate underproduction.\nGenetic counseling\nThe disorder has both an autosomal recessive and autosomal dominant pattern of inheritance. Biallelic loss-of-function mutations of SLC22A12 and either homozygote and heterozygote SLC2A9 mutations have been described in RHUC patients.\nManagement and treatment\nComplications of RHUC, such as nephrolithiasis and EIAKI, should be treated as in the general population. Asymptomatic patients should be considered at high risk to develop these complications, thus prophylactic measures, such as increased fluid intake and urine alkalization, should be undertaken. There is little consensus on the use of xanthine oxidoreductase inhibitors (XOR) to protect from EIAKI. The rationale to use this medication is to counteract the increased uric acid (UA) production during exercise, reducing the filtered load and lowering the risk of UA precipitation in the tubules. Some reports suggest that XOR might protect from EIAKI onset and/or recurrence, but further studies are required.\nPrognosis\nRHUC is not lethal and may be asymptomatic. Affected individuals have a higher risk to develop renal complications (renal stones, EIAKI) compared with the general population.\n\n                            Last update: \n                            May 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Miriam ZACCHIA | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hereditary sclerosing poikiloderma, Weary type", "Disease Definition": "A rare genetic skin disease characterized by generalized poikiloderma with marked accentuation in flexural regions and on extensor surfaces, sclerosis of palms and soles, and linear and reticulated hyperkeratotic and sclerotic bands in the axilla and the antecubital and popliteal fossae. Subcutaneous calcification, finger clubbing, Raynaud phenomenon, and cardiac abnormalities (such as severe aortic stenosis) have also been reported.", "ORPHA ID": 221039, "Summary": ""}
{"Disease Name": "Hereditary sensorimotor neuropathy with hyperelastic skin", "Disease Definition": "A rare, genetic, demyelinating hereditary motor and sensory neuropathy disorder characterized by slowly progressive, mild to moderate, distal muscle weakness and atrophy of the upper and lower limbs and variable distal sensory impairment, associated with variable hyperextensible skin and age-related macular degeneration. Hypermobility of distal joints, high palate, and minor skeletal abnormalities (e.g. pectus excavatum, dolichocephaly) may also be associated.", "ORPHA ID": 280598, "Summary": ""}
{"Disease Name": "Hereditary sensory and autonomic neuropathy due to TECPR2 mutation", "Disease Definition": "A rare genetic peripheral neuropathy characterized by early hypotonia evolving to spastic paraparesis, areflexia, decreased pain and temperature sensitivity, autonomic neuropathy, gastroesophageal reflux disease, recurrent pneumonia and respiratory problems. Patients also have intellectual disability and dysmorphic features, including mild brachycephalic microcephaly, short broad neck, low anterior hairline and coarse face.", "ORPHA ID": 320385, "Summary": ""}
{"Disease Name": "Hereditary sensory and autonomic neuropathy type 1", "Disease Definition": "A rare slowly progressive neurological disorder characterized by prominent predominantly distal sensory loss, autonomic disturbances in some patients, autosomal dominant inheritance, and juvenile or adulthood disease onset.", "ORPHA ID": 36386, "Summary": "Epidemiology\nThe exact prevalence is unknown, but is estimated as very low.\nClinical description\nDisease onset varies between the 2nd and 5th decade of life. Early onset is occasionally reported. The main clinical feature of hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a reduction of sensation sense, mainly distributed around the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Spastic paraparesis, or cough and gastroesophageal reflux have been observed in rare cases.\nEtiology\nHSAN1 is a genetically heterogenous condition with several loci and mutations in four genes (SPTLC1, SPTLC2, ATL1, ATL3) identified so far. DNMT1 gene variants also lead to a specific form of the disease, HSAN1E, clinically distinct due to the presentation of dementia and hearing loss.\nDiagnostic methods\nDiagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when complications such as bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the above mentioned genes. DNMT1-associated disease is clinically distinct from the other HSAN1 subtypes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counseling and prognosis.\nDifferential diagnosis\nDifferential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin tumors like amelanotic melanoma.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. However, availability depends on country-specific regulations.\nGenetic counseling\nTransmission is autosomal dominant; whilst several cases occur sporadically, genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement of HSAN1 largely follows the guidelines given for diabetic foot care (removal of pressure to the ulcer and eradication of infection, followed by the use of specific protective footwear) and starts with early and accurate counselling of patients about risk factors for developing foot ulcerations. Preclinical and clinical trials are ongoing for SPTLC-associated disorders (L-Serine therapy).\nPrognosis\nThe disorder is slowly progressive and may not influence life expectancy in many cases but is often severely disabling after a long duration of the disease. Early-onset severe cases are reported.\n\n                            Last update: \n                            April 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Ingo KURTH"}
{"Disease Name": "Hereditary sensory and autonomic neuropathy type 1B", "Disease Definition": "Hereditary sensory and autonomic neuropathy, type 1B (HSAN1B) is characterized by the association of type 1 HSAN with paroxysmal cough and gastroesophageal reflux (GOR).", "ORPHA ID": 139564, "Summary": "Epidemiology\nSo far, it has been described in two families.\nClinical description\nOnset occurs in adulthood with distal sensory loss due to an axonal neuropathy, GOR, and cough triggered by noxious odors or by pressure in the external auditory canal. The cough may be severe leading to syncope and retinal detachment. Additional features include throat clearing, a hoarse voice, and sensorineural hearing loss.\nEtiology\nLinkage to chromosome 3p22-p24 was found in both reported families.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            January 2009"}
{"Disease Name": "Hereditary sensory and autonomic neuropathy type 2", "Disease Definition": "A rare hereditary sensory and autonomic neuropathy characterized by profound and universal sensory loss involving large and small fiber nerves.", "ORPHA ID": 970, "Summary": "Epidemiology\nTo date, less than 100 cases have been reported. There is no sex preference or particular ethnic preponderance.\nClinical description\nDisease onset is typically in infancy and is non-progressive. Initial symptoms (from birth to 3 years) include lack of crying with trauma, self-mutilation (tongue, lips), swallowing and feeding problems. Gastroesophageal reflux is common. Sensory dysfunction is manifested by reduced or absent pain and temperature perception, and depressed or absent deep tendon reflexes. Corneal reflexes are reduced or absent. Muscle strength is preserved and there is no atrophy. Sensation to fine touch, position, vibration, taste, and gag reflexes may be diminished. Unrecognized injuries (e.g., burns, skin and corneal ulcers) and fractures of hands, feet, and limbs, sometimes resulting in osteomyelitis, as well as Charcot joints are frequent. Some patients have hearing loss. Autonomic involvement is limited to reduced lacrimation. Patients do not typically have orthostatic hypotension or sweating abnormalities.\nEtiology\nCausal mutations in several genes have been identified and include SCN9A (2q24.3), WNK1 (12p13.33), RETREG1  (5p15.1), and KIF1A  (2q37.3), all of which appear to be involved in the development of sensory nerves.\nDiagnostic methods\nDiagnosis is based upon clinical features (congenital onset of severe reduction in sensory modalities and deep tendon reflexes resulting in injuries and self-mutilation). Neurophysiological evaluation (showing slow sensory conduction velocities and amplitudes), electromyogram and electroencephalographic studies support the diagnosis. Targeted genetic testing identifying described mutations in causatives genes is confirmatory. For cases in which no genetic mutation can be identified with targeted genetic testing, whole exome sequencing may identify novel variants/genes.\nDifferential diagnosis\nDifferential diagnosis includes the other hereditary sensory and autonomic neuropathies, the most similar of which include hereditary sensory and autonomic neuropathy type 4 (characterized by complete lack of pain and complete lack of sweating), familial dysautonomia (accompanied by baroreflex abnormalities with paroxysmal episodes of nausea, retching, vomiting and hypertension) and hereditary sensory and autonomic neuropathy type 1 (typically adult-onset).\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of affected individuals are obligate carriers. Penetrance is always complete, but the severity of the disease is variable.\nManagement and treatment\nManagement is symptomatic and preventative. If feeding problems compromise nutrition and if gastroesophageal reflux is also present, fundoplication with gastrostomy might be considered. Parents' and patients' education is required to learn how to avoid injury and be alert for signs of unrecognized trauma. Reduced lacrimation requires artificial tears and corneal protective lenses to prevent corneal ulcers.\nPrognosis\nNo natural history studies have been performed. Most patients reach adulthood.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Horacio KAUFMANN  - Pr Jose-Alberto PALMA"}
{"Disease Name": "Hereditary sensory and autonomic neuropathy type 4", "Disease Definition": "A rare hereditary sensory and autonomic neuropathy characterized by anhidrosis, insensitivity to pain, self-mutilating behavior and episodes of fever.", "ORPHA ID": 642, "Summary": "Epidemiology\nWhilst several hundred cases have been reported worldwide, the exact prevalence is unknown. Most of the cases described were from the Israeli Bedouin population and Japan where the prevalence is estimated at 1/600,000-950,000.\nClinical description\nThe disease typically presents in early infancy, but may occasionally present during the neonatal period. Consanguinity has been reported in 50% of patients. Episodic fevers without obvious infections, extreme hyperpyrexia and febrile convulsions due to inability to dissipate heat as a result of anhidrosis as well as self-mutilation are usually the earliest signs of the disease. The cardinal feature is absence of sweating on the trunk and extremities, with occasional patients producing some moisture on the forehead, tip of the nose and gluteal sulcus. The skin becomes thick and callused with lichenification of palms, areas of hypotrichosis on the scalp and dystrophic nails. Deep tendon reflexes are usually present. Pain insensitivity is profound resulting in self-mutilation, auto-amputation, and corneal scarring but some patients retain temperature perception. Vibration sense and proprioception are normal or moderately decreased Bone fractures are slow to heal and large weight bearing joints are particularly susceptible to repeated trauma and frequently go on to the development of Charcot joints and osteomyelitis. Hypotonia and delayed developmental milestones are frequent in the early years, but sometimes normalize with age. Speech is usually clear, but patients have severe learning difficulties, irritability, hyperactivity, and cognitive impairment. Normal intelligence, however, has been reported in a few patients. Mild postural hypotension with compensatory tachycardia may be present, but not episodic hypertension. Around 20% of patients have scoliosis.\nEtiology\nThe disease is due to mutations in the gene NTRK1 (1q21-22).\nDiagnostic methods\nDiagnosis requires two clinical criteria: anhidrosis and decreased pain perception, and is confirmed by genetic testing identifying variants in NTRK1. Skin biopsy reveals deficient C and A-delta fibers in the epidermis and hypoplastic dermal sweat glands without innervation. Plasma concentration of norepinephrine is extremely low or undetectable but epinephrine, vasopressin and plasma renin activity are normal.\nDifferential diagnosis\nDifferential diagnosis includes other hereditary sensory and autonomic neuropathies from which it is distinguished by absent or markedly decreased sweating.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of affected individuals are obligate carriers.\nManagement and treatment\nManagement is supportive and oriented to control hyperthermia, prevention of self-mutilation and treatment of orthopedic problems that potentially can cause severe and invalidating deformities. It is necessary to help families cope with behavioral and educational issues.\nPrognosis\nThe prognosis for independent functions depends on the degree of disease expression and the ability to control the secondary clinical problems.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Horacio KAUFMANN  - Pr Jose-Alberto PALMA"}
{"Disease Name": "Hereditary sensory and autonomic neuropathy type 5", "Disease Definition": "A disorder that is characterized by loss of pain perception and impaired temperature sensitivity, in the absence of any other major neurological anomalies.", "ORPHA ID": 64752, "Summary": "Epidemiology\nPrevalence is unknown. Only a small number of cases have been described in the literature, although one large multigenerational consanguineous family from northern Sweden has been reported.\nClinical description\nOther findings include ulcers, self-mutilation and damaged joints. Intelligence is normal.\nEtiology\nMutations in the NGF gene (1p13.1) were detected in affected members of the large Swedish family. However, mutations in the NTRK1 gene (1q21-q22) have been identified in one patient diagnosed with HSAN5 with the additional finding of mild anhidrosis. Mutations in the NTRK1 gene have also been implicated in the more severe HSAN subform, HSAN4 (congenital insensitivity to pain with anhidrosis; see this term).\nGenetic counseling\nThe syndrome is transmitted in an autosomal recessive manner\n\n                            Last update: \n                            January 2009"}
{"Disease Name": "Hereditary sensory and autonomic neuropathy type 6", "Disease Definition": "A rare hereditary sensory and autonomic neuropathy characterized by hypotonia in infancy, variable psychomotor retardation, markedly impaired pain sensitivity with poorly healing distal ulcerations and painless fractures leading to joint deformities and amputation of fingers and toes, altered deep tendon reflexes, and dysautonomic symptoms including hypohidrosis and heat intolerance, chronic diarrhea, pupillary abnormalities, or urinary incontinence. Sensorineural hearing loss has also been reported. The severity of the disease is highly variable, with severe cases being potentially lethal in infancy.", "ORPHA ID": 314381, "Summary": ""}
{"Disease Name": "Hereditary sensory and autonomic neuropathy type 7", "Disease Definition": "A rare, genetic, periphery neuropathy characterized by a congenital insensitivity to pain, muscular hypotonia and gastrointestinal disturbances. Patients present with delayed motor milestones achievement, self-mutilations, skin ulcers, poor wound healing, painless fractures, hyperhidrosis, abdominal discomfort, diarrhea and/or constipation. Cognitive development is normal.", "ORPHA ID": 391397, "Summary": ""}
{"Disease Name": "Hereditary sensory and autonomic neuropathy type 8", "Disease Definition": "A rare autosomal recessive hereditary sensory and autonomic neuropathy characterized by congenital impaired sensation of acute or inflammatory pain in combination with an inability to identify noxious heat or cold, leading to numerous painless mutilating lesions and injuries. Further manifestations are absence of corneal reflexes resulting in corneal scarring, reduced sweating and tearing, and recurrent skin infections. Large-fiber sensory modalities such as light touch, vibration, and proprioception are normal.", "ORPHA ID": 478664, "Summary": ""}
{"Disease Name": "Hereditary sensory and autonomic neuropathy with deafness and global delay", "Disease Definition": "This syndrome is characterized by a sensory and autonomic axonal neuropathy, sensorineural hearing loss and persistent global developmental delay.", "ORPHA ID": 139573, "Summary": "Epidemiology\nIt has been described in four individuals from a consanguineous Lebanese family.\nClinical description\nOnset occurred in infancy with moderate developmental delay, hypotonia and areflexia. Other less constant findings included weakness, variable dysmorphic features, unsteadiness, and optic atrophy.\nGenetic counseling\nTransmission appears to be autosomal recessive.\n\n                            Last update: \n                            January 2009"}
{"Disease Name": "Hereditary sensory neuropathy-deafness-dementia syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by sensorineural hearing loss, sensory neuropathy, behavioral abnormalities, and dementia. Occurrence of seizures has also been reported. Age of onset is between adolescence and adulthood. The disease is progressive, with fatal outcome typically in the fifth to sixth decade.", "ORPHA ID": 456318, "Summary": ""}
{"Disease Name": "Hereditary sodium channelopathy-related small fibers neuropathy", "Disease Definition": "A rare, genetic, peripheral neuropathy disorder due to gain-of-function mutations in voltage-gated sodium channels present in the small peripheral nerve fibers characterized by neuropathic pain of varying intensity (often beginning in the distal extermities and with a burning quality) associated with autonomic dysfunction (e.g. orthostatic dizziness, palpitations, dry eyes and mouth), abnormal quantitative sensory testing, and reduction in intraepidermal nerve fiber density. Large fiber functions (i.e. normal strength, tendon reflexes, and vibration sense) and nerve conduction studies are typically normal.", "ORPHA ID": 306577, "Summary": ""}
{"Disease Name": "Hereditary spastic paraplegia", "Disease Definition": "A genetically and clinically heterogeneous group of slowly progressive neurological disorders which in the pure form is characterized by pyramidal signs (weakness, spasticity, brisk tendon reflexes, and extensor plantar responses) predominantly affecting the lower limbs and with possible association of sphincter disturbances and deep sensory loss; and in the complex form by the addition of variable neurological or non-neurological features.", "ORPHA ID": 685, "Summary": "Epidemiology\nThe prevalence of hereditary spastic paraplegia (HSP) is highly variable, ranging from 1/11,000-77,000 in Europe.\nClinical description\nClinically, HSPs can be divided into the pure and complex form. Pure HSPs are characterized by slowly progressive lower extremity spasticity and weakness, often associated with urinary disturbances, and deep sensory abnormalities (reduction of lower extremity vibration sense). Complex forms of HSP forms are characterized by the presence of additional neurological or non-neurological features. Neurological features may include cerebellar dysfunction (ataxia, nystagmus, tremor), axonal or demyelinating peripheral neuropathy (sensory and/or motor disturbances), cognitive impairment (dysexecutive syndrome, dementia), sensory impairment (optic, auditive neuropathy), epilepsy, myopathic features (ptosis, opthalmoparesis), extrapyramidal features (Parkinsonism, chorea, dystonia), psychiatric disturbances, and brain and spine imaging abnormalities (brain white matter alterations, thin corpus callosum, brain iron accumulation, cerebellar atrophy) which may be suggestive of a genetic subtype. Non-neurological manifestations may include ophthalmological abnormalities (cataracts, retinitis pigmentosa, macular degeneration), and orthopedic abnormalities (scoliosis, joint dislocation, and different foot deformities).\nEtiology\nThe disease is due to the dysfunction of the upper motor neurons of the corticospinal tract. To date, more than 80 genes have been linked. The encoded proteins are involved in many processes, including axonal transport, myelination, endo-membrane trafficking, mitochondria functions, complex lipid and nucleotide metabolism. The most common causative genes include SPAST (2p22.3), ATL1 (14q22.1), REEP1 (2p11.2) and KIF5A (12q.13.3) for autosomal dominant HSPs, and SPG7 (16q24.3), SPG11  (15q21.1), and CYP7B1 (8q12.3) for autosomal recessive HSP. However, a significant number of patients are without a genetic diagnosis after systematic testing.\nDiagnostic methods\nDiagnosis is based on the clinical symptoms, neurological examination, progressive course of the disease, biomarker dosages, brain and spine MRI, family history, molecular genetic testing, and exclusion of the differential diagnoses.\nDifferential diagnosis\nDifferential diagnosis includes multiple sclerosis, spinal vascular abnormality, vitamin B12 deficiency, HTLVI infection, primary lateral sclerosis, diplegic cerebral palsy, metabolic genetic diseases (dopa-responsive dystonia, leukodystrophies, brain metal accumulation disorders).\nAntenatal diagnosis\nGenetic testing is possible where a mutation has previously been identified in a family.\nGenetic counseling\nPatterns of inheritance include mostly autosomal dominant and autosomal recessive, and rarely X-linked and mitochondrial. In addition, multiple recessive and dominant forms exist for the genes KIF1C (17p13.2), REEP2  (5q31.2), ALDH18A1  (10q24.1), ERLIN2 (8p11.23). SPAST (2p22.3), ATL1 (14q22.1), REEP1 (2p11.2) are usually associated with the pure form, autosomal recessive forms often lead to more complicated phenotypes, while some genes are associated with both phenotypes. High intrafamilial variability and incomplete penetrance are frequent.\nManagement and treatment\nManagement is symptomatic with physiotherapy, anti-spasticity drugs (baclofen, tizanidine, diazepam, botulinum toxin), and orthoses.\nPrognosis\nPrognosis depends on the phenotype (pure/complex form), genotype, and is highly variable due to incomplete penetrance and variable gene expression.\n\n                            Last update: \n                            March 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Guillaume BANNEAU  - Dr Claire EWENCZYK  - Pr Cyril GOIZET"}
{"Disease Name": "Hereditary spherocytosis", "Disease Definition": "Hereditary spherocytosis is a congenital hemolytic anemia with a wide clinical spectrum (from symptom-free carriers to severe hemolysis) characterized by anemia, variable jaundice, splenomegaly and cholelithiasis.", "ORPHA ID": 822, "Summary": "Epidemiology\nHS is the most common cause of inherited chronic hemolysis in North America with a prevalence of 1/5,000 births. However, osmotic fragility studies suggest the existence of extremely mild or subclinical forms, raising the prevalence to 1/2,000 in Northern Europe.\nClinical description\nJaundice is usually the first clinical manifestation in newborns (50% of cases) with anemia developing a few days after birth and requiring exchange transfusion (~10%) and transfusion support (~35%). Splenomegaly is frequently observed. Age of onset and severity vary considerably depending on the degree of anemia and hemolysis. Four HS categories have been identified: trait (normal hemoglobin (Hb), reticulocytes < 3%, bilirubin < 17micromoles/L), mild (Hb 11-15 g/dL, reticulocytes 3-6%, bilirubin 17-34 micromoles/L), moderate (Hb 8-12 g/dL, reticulocytes > 6%, bilirubin > 34 micromoles/L), and severe (Hb < 8 g/dL, reticulocytes > 10%, bilirubin > 51 micromoles/L). Aplastic crisis, often associated with viral infections, is observed in 10-15% of cases, particularly pediatric. Rare complications include poor growth, skin ulceration, chronic dermatitis, high output heart failure, and secondary iron overload.\nEtiology\nHS is caused by mutations in one of the following genes: SPTA1 (1q21), SPTB (14q23.3), ANK1 (8p11.21), SLC4A1 ( 17q21.31) and EPB42 (15q15-q21), that encode the red blood cell (RBC) membrane proteins erythrocytic 1 spectrin alpha chain, erythrocytic 1 spectrin beta chain, ankyrin-1, band 3 anion transport protein, and erythrocyte membrane protein band 4.2, respectively. Defects in these proteins lead to a loss in RBC membrane cohesion and membrane surface area, resulting in erythrocyte sphering, decreased deformability and premature destruction in the spleen.\nDiagnostic methods\nDiagnosis is based on clinical and family history, physical examination and laboratory test results. Red cell morphology, osmotic resistance, hypertonic cryohemolysis test, eosin-5-maleimide binding in flow cytometry, sodium dodecyl sulfate-poly acrylamide gel electrophoresis and ektacytometry are all used to diagnose HS. Mean cellular Hb concentration is usually above normal range (~35 g/dl), reticulocyte count normal or increased, and indirect bilirubin moderately increased. Molecular genetic testing is not routinely used to confirm diagnosis.\nDifferential diagnosis\nDifferential diagnoses include hereditary elliptocytosis, hereditary stomatocytosis, Southeast Asian ovalocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, autoimmune hemolytic anemia, and alpha-thalassemia (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies is possible if disease-causing mutations have been identified in a family, but it is not routinely performed due to the usually mild disease course.\nGenetic counseling\nHS is inherited autosomal dominantly in 75% of cases. Autosomal recessive inheritance and de novo mutations have also been reported, but are less common. Genetic counseling is recommended in families with a history of HS.\nManagement and treatment\nTreatment involves management of jaundice (phototherapy and even exchange blood transfusion to prevent hyperbilirubinemic encephalopathy) and RBC transfusions in case of severe, symptomatic anemia. Splenectomy usually results in disappearance of anemia and clear amelioration of hemolytic markers. It is not indicated in patients with HS trait, whereas it is usually necessary in severe cases, albeit delayed if possible until the age of 6 years. For intermediate categories the indication is less clear, being useful in moderate cases before puberty. Laparoscopic splenectomy is preferred if performed by experienced surgeons. A combined splenectomy and cholecystectomy may be beneficial in patients with gallstones. Pre and post-splenectomy vaccine prophylaxis and prophylactic antibiotics are recommended in order to prevent infections. Folate supplement is recommended particularly after infectious events. Serum ferritin levels should be checked annually.\nPrognosis\nThe prognosis is variable and depends on the severity of the disease and any associated complications.\n\n                            Last update: \n                            October 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Wilma BARCELLINI"}
{"Disease Name": "Hereditary thermosensitive neuropathy", "Disease Definition": "Hereditary thermosensitive neuropathy is a rare, demyelinating, hereditary motor and sensory neuropathy characterized by reversible episodes of ascending muscle weakness, paresthesias and areflexia triggered by a febrile episode, with or without pressure palsy.", "ORPHA ID": 84093, "Summary": ""}
{"Disease Name": "Hereditary thrombocytopenia with early-onset myelofibrosis", "Disease Definition": "A rare syndromic constitutional thrombocytopenia characterized by thrombocytopenia with increased bleeding tendency (leading to epistaxis, menorrhagia, and petechiae), in combination with myelofibrosis and splenomegaly. Platelets may be abnormally large or small and partly hypo- or agranular, plasma thrombopoietin is elevated, and the number of megakaryocytes in the bone marrow increased. Additional non-hematologic manifestations have been described in some patients, including mild bone abnormalities and facial dysmorphism with large forehead, hypertelorism, deep-set eyes, and wide nostrils.", "ORPHA ID": 480851, "Summary": ""}
{"Disease Name": "Hereditary thrombocytopenia with normal platelets", "Disease Definition": "A rare, genetic, isolated constitutional thrombocytopenia disease characterized by decreased platelet counts, not associated with platelet morphology or function impairment, in multiple members of a family. Manifestations are variable, typically ranging from asymptomatic to mild bleeding diathesis (e.g. easy bruising, epistaxis, petechiae). Occasionally, a more severe bleeding tendency has been associated and a mild predisposition to infection and eczema has been reported.", "ORPHA ID": 268322, "Summary": ""}
{"Disease Name": "Hereditary thrombophilia due to congenital antithrombin deficiency", "Disease Definition": "Hereditary thrombophilia due to congenital antithrombin deficiency is a rare, genetic, hematological disease characterized by decreased levels of antithrombin activity in plasma resulting in impaired inactivation of thrombin and factor Xa. Patients have an increased risk for venous thromboembolism, usually in the deep veins of the arms, legs and pulmonary system and, on occasion, in other venous territories (e.g. cerebral veins or sinus, mesenteric, portal, hepatic, renal and/or retinal veins).", "ORPHA ID": 82, "Summary": ""}
{"Disease Name": "Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency", "Disease Definition": "A rare, genetic, coagulation disorder characterized by a tendency to develop thrombosis, resulting from decreased histidine-rich glycoprotein (HRG) plasma levels. Manifestations are variable depending on location of thrombosis, but may include headaches, diplopia, progressive pain, limb swelling, itching or ulceration, and brownish skin discoloration, among others.", "ORPHA ID": 217467, "Summary": ""}
{"Disease Name": "Hereditary xanthinuria", "Disease Definition": "A rare purine metabolism disorder due to inherited deficiency of the xanthine dehydrogenase/oxidase enzyme and is characterized by very low (or undetectable) concentrations of uric acid in blood and urine and very high concentration of xanthine in urine, leading to urolithiasis.", "ORPHA ID": 3467, "Summary": "Epidemiology\nPrevalence of hereditary xanthinuria is not known, but about 150 patients have been described so far. Annual incidence has been estimated to be between 1:6,000 and 1:69,000. These rough estimates are due to the high rate of asymptomatic cases leading to underdiagnosis and the lack of newborn screening.\nClinical description\nSymptom onset may be at any age. Approximately 50 % of the patients with classical hereditary xanthinuria present with symptoms of urinary tract infection, hematuria, renal colic, acute renal failure, crystalluria or urolithiasis. In some rare patients, renal disease may evolve to renal failure, or may even induce arthropathy, myopathy or duodenal ulcer.\nEtiology\nHereditary xanthinuria is due to mutations in the xanthine dehydrogenase (XDH, 2p23.1) or molybdenum cofactor sulfurase (MOCOS, 18q12.2) genes, resulting in failure to degrade hypoxanthine and xanthine to uric acid and leading to the accumulation of xanthine and, to a lesser extent, of hypoxanthine. Classical hereditary xanthinuria encompasses xanthinuria type I and II: type I is a simple xanthine dehydrogenase/oxidase deficiency, due to mutations in XDH, whereas type II results from a combined deficiency of xanthine dehydrogenase and aldehyde oxidase, due to mutations in MOCOS. Both enzymatic deficiencies lead to an identical clinical phenotype.\nDiagnostic methods\nDiagnosis is based on estimation of uric acid in blood and urine. If hypouricemia is confirmed, detailed purine metabolic investigation follows, and includes measurement of xanthine and hypoxanthine in urine and plasma. High urinary levels of xanthine are then typical for classical hereditary xanthinuria. In about half of patients, ultrasonography reveals the presence of xanthine urolithiasis. Additional methods for diagnostic confirmation and/or identification of the type of xanthinuria include allopurinol loading test, xanthine oxidase assay and molecular analysis.\nDifferential diagnosis\nHereditary xanthinuria is a clinical feature of molybdenum cofactor deficiency (see this term). The clinical picture of this disease is however much more severe, given the associated neurological damage and frequent infant death. Hypouricemia is also a biochemical marker for primary hereditary renal hypouricemia (see this term). Unlike hereditary xanthinuria, the excretion fraction of uric acid is elevated in renal hypouricemia.\nGenetic counseling\nHereditary xanthinuria is an autosomal recessive disease, with a subsequent 25% recurrence risk.\nManagement and treatment\nThere is no curative treatment. Low purine diet and high fluid intake is recommended. Since the solubility of xanthine is not affected by urinary pH, alkalization is of no value. When calculi are present, a pyelolithotomy might be necessary.\nPrognosis\nThe overall prognosis is favorable, even though, in some cases, the disease progresses to end-stage renal insufficiency.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Ivan SEBESTA  - Dr Blanka STIBURKOVA"}
{"Disease Name": "Heritable pulmonary arterial hypertension", "Disease Definition": "Heritable pulmonary arterial hypertension (HPAH) is a form of pulmonary arterial hypertension (PAH, see this term), occurring due to mutations in PAH predisposing genes or in a familial context. HPAH is characterized by elevated pulmonary arterial resistance leading to right heart failure. HPAH is progressive and potentially fatal.", "ORPHA ID": 275777, "Summary": "Epidemiology\nHPAH represent less than 4% of PAH. Prevalence is estimated at < 1/million people.\nClinical description\nHPAH develop usually in adults, and rarely in children; women are twice as likely as men to be affected. Usual age at diagnosis is mid thirties. Initial symptoms include dyspnea, fatigue, syncope, chest pain, palpitations and pedal edema. Precordial signs include loud and palpable second heart sound, right ventricular heave, pulmonary ejection click and murmurs of pulmonary and tricuspid regurgitation.70% of patients present heart failure (classed as New York heart association functional classification (NYHA FC) III or IV).Rarely, clubbing and Raynaud phenomenon (mostly in females) have been observed. Hemoptysis has also been reported. HPAH patients have a severe clinical with less response to acute vasodilator challenge, lower cardiac index, and higher pulmonary vascular resistance. HPAH due to ACVRL1or TBX4gene mutations occurs more commonly in children with rapid progression and poor prognosis.\nEtiology\nHPAH has been linked to mutations in BMPR2 ((2q33) in majority of cases. However, other genes implicated in HPAH have been described in few cases, and include ACVRL1 ((12q13)), KCNK3 (2p23),CAV1(7q31), TBX4 (17q21) and SMAD9(13q12) .\nGenetic counseling\nPatients displaying a sporadic PAH or a PAH occurring in a familial context, should be tested in priority for mutations in BMPR2 gene. If no mutations in BMPR2gene were identified in a patient displaying a familial form of PAH, mutations in all other PAH predisposing genes have to searched successively. All PAH predisposing genes are transmitted in an autosomal dominant manner with an incomplete penetrance. In the cases ofBMPR2 mutations the penetrance is estimated to be 42% in female mutation carriers and 14% in male mutation carriers. Prenatal genetic testing and preimplantation diagnosis are considered in patients and asymptomatic relatives carriers of a mutation in PAH predisposing genes.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Barbara GIRERD  - Pr David MONTANI"}
{"Disease Name": "Hermansky-Pudlak syndrome due to BLOC-2 deficiency", "Disease Definition": "Hermansky-Pudlak syndrome without pulmonary fibrosis as a complication includes three relatively mild types (HPS-3, HPS-5 and HPS-6) of Hermansky-Pudlak syndrome (HPS; see this term), a multi-system disorder characterized by ocular or oculocutaneous albinism, bleeding diathesis and, in some cases, granulomatous colitis.", "ORPHA ID": 231512, "Summary": "Epidemiology\nHPS-3 occurs as a genetic isolate in central Puerto Rico with a prevalence of 1/4000; additionally, around 15 non-Puerto-Rican cases of HPS-3 have been reported. Ten cases of HPS-5 have been reported and 25 cases of HPS-6, from which 20 come from an Israeli-Bedouin tribe.\nClinical description\nThese three types present with features of HPS including ocular or oculocutaneous albinisim, reduced visual acuity, horizontal nystagmus, easy bruising of soft tissues, epistaxis, and prolonged bleeding after dental extraction, surgery or childbirth. Women may present with medically significant menstrual bleeding. Complications of HPS may include reduced renal function and granulomatous colitis. Pulmonary fibrosis has not been found to develop in HPS-3, HPS-5 or HPS-6. The course of HPS with no pulmonary involvement is mild.\nEtiology\nHPS-3 is caused by mutations in the HPS3 gene (3q24), HPS-5 is caused by mutations in the HPS5 gene (11p15-p13) and HPS-6 is caused by mutations in the HPS6 gene (10q24.32). The gene products, HPS3, HPS5 and HPS6, are part of the multi-subunit complex BLOC-2 (biogenesis of lysosome-related organelles complex 2).\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr William GAHL  - Dr Marjan HUIZING"}
{"Disease Name": "Hermansky-Pudlak syndrome due to BLOC-3 deficiency", "Disease Definition": "Hermansky-Pudlak syndrome with pulmonary fibrosis as a complication includes two types (HPS-1 and HPS-4) of Hermansky-Pudlak syndrome (HPS; see this term), a multi-system disorder characterized by oculocutaneous albinism, bleeding diathesis and, in some cases, pulmonary fibrosis or granulomatous colitis.", "ORPHA ID": 231500, "Summary": "Epidemiology\nPrevalence of all types of HPS is estimated at between 1/500,000 and 1/1,000,000 in non-Puerto Rican populations. In northwestern Puerto Rico the prevalence of HSP-1 is 1/1,800 due to a founder effect. HSP-1 is reported in sporadic patients worldwide; founder effects have (apart from Puerto Rico) also been reported in a small isolate in a Swiss village and in Japan. Prevalence of HSP-4 is unknown, but to date around 20 patients have been described worldwide.\nClinical description\nHPS-1 and HPS-4 present with features of HPS including oculocutaneous albinisim, reduced visual acuity, horizontal nystagmus, easy bruising of soft tissues, epistaxis, and prolonged bleeding after dental extraction, surgery or childbirth. Women may present with medically significant menstrual bleeding. Complications of HPS may include granulomatous colitis and pulmonary fibrosis. Pulmonary fibrosis is the most serious complication of HPS-1 and HPS-4 and usually presents in the fourth or fifth decade.\nEtiology\nHPS-1 is caused by mutations in the HPS1 gene (10q23.1) and HPS-4 is caused by mutations in the HPS4 gene (22q11.2-q12.2). The gene products, HPS1 and HPS4, are part of the multi-subunit complex BLOC-3 (biogenesis of lysosome-related organelles complex 3).\nGenetic counseling\nHPS1 and HPS4 are both transmitted in an autosomal recessive manner.\nManagement and treatment\nLung transplant is the only known treatment for pulmonary fibrosis in HPS-1 and HPS-4. Pirfenidone may slow progression but only in patients who have significant residual lung function. Steroid therapy is not effective.\nPrognosis\nPrognosis is poor as the pulmonary fibrosis is fatal.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr William GAHL  - Dr Marjan HUIZING"}
{"Disease Name": "Hermansky-Pudlak syndrome", "Disease Definition": "Hermansky-Pudlak syndrome (HSP) is a multi-system disorder characterized by oculocutaneous albinism, bleeding diathesis and, in some cases, neutropenia, pulmonary fibrosis, or granulomatous colitis. HPS comprises eight known disorders (HPS-1 to HPS-8), the majority of which present with the same clinical phenotype to varying degrees of severity.", "ORPHA ID": 79430, "Summary": "Epidemiology\nPrevalence is estimated at 1/500,000 - 1/1,000,000 in non-Puerto Rican populations. In northwestern Puerto Rico the prevalence of HPS-1 is 1/1,800.\nClinical description\nHPS usually presents in early childhood, but may present at older ages, with oculocutaneous albinism (varying degrees of hypopigmentation), reduced visual acuity (often at/below the level of legal blindness), horizontal nystagmus, easy bruising of soft tissues, epistaxis, prolonged bleeding after dental extraction, surgery or childbirth and, in HPS-2 (see this term), neutropenia and recurrent infections. Women may present with medically significant menstrual bleeding. Complications may include granulomatous colitis and, in HPS-1 or HPS-4, pulmonary fibrosis (PF) (HPS with PF as a complication; see this term). PF is the most serious complication and usually presents in the fourth or fifth decade.\nEtiology\nHPS is characterized by a storage pool deficiency of platelets and can be caused by mutations in one of several genes: HPS1 (10q23.1), AP3B1 (5q14.1; causing HPS-2), HPS3 (3q24), HPS4 (22q11.2-q12.2), HPS5 (11p15-p13), HPS6 (10q24.32), DTNBP1 (6p22.3; HPS-7), and BLOC1S3 (19q13; HPS-8). The product of AP3B1 codes for the beta 3A subunit of adaptor complex-3 (AP-3), involved in vesicle formation and protein sorting. The function of the other HPS gene products is unknown, but they interact with each other in biogenesis of lysosome related organelle complexes (BLOCs); BLOC-3: HPS1 and HPS4; BLOC-2: HPS3, HPS5 and HPS6; BLOC-1: HPS7 and HPS8. Affected lysosome-related organelles include melanosomes in melanocytes, delta granules in platelets, lamellar bodies in pulmonary type II cells, and secretory granules in T cells.\nDiagnostic methods\nDiagnosis is based on clinical findings of oculocutaneous albinism in combination with a bleeding diathesis, confirmed by an absence of platelet dense bodies and genetic testing. Accurate diagnosis of the HPS subtype has important prognostic and treatment implications.\nDifferential diagnosis\nDifferential diagnoses include other forms/causes of oculocutaneous albinism, i.e., X-linked ocular albinism, Chediak-Higashi syndrome, Griscelli syndrome, Cross syndrome, pulmonary fibrosis and hemophagocytic lymphohistiocytosis.\nAntenatal diagnosis\nAntenatal testing may be available for families in which disease-causing mutations have been identified.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nThere is no known cure. The bleeding diathesis is a major concern during surgery, dental extraction or childbirth and may be treated with transfusion of platelets or whole blood. Desmopressin may be used prophylactically. Recombinant activated factor VII (VIIa) may also be used. Avoidance of aspirin products is essential. Sunscreen and avoidance of sunlight are important to reduce the risk of solar damage and skin malignancies. Lung transplant is the only known treatment for PF (in HPS-1, HPS-2, and HPS-4). Pirfenidone may slow the progression of PF but only in patients who have significant residual lung function. Steroid therapy is not effective. Neutropenia in HPS-2 can be treated with granulocyte-cell stimulating factor (G-CSF).\nPrognosis\nThe course of HPS-3, HPS-5 and HPS-6 (or HPS without PF as a complication; see this term) is mild with no pulmonary involvement. Prognosis of HPS-1 and HPS-4 is poor as PF is fatal. Prognosis for HPS-7 and HPS-8 (only one case of each reported) has not been well characterized.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr William GAHL  - Dr Marjan HUIZING"}
{"Disease Name": "Hernández-Aguirre Negrete syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, mild intellectual disability, seizures, obesity, and dysmorphic facial features (including large, bulbous nose, prominent philtrum, wide mouth). Additional reported features are bilateral pes planus, scoliosis, and spina bifida occulta. Brain MRI may show mild ventricular dilatation.", "ORPHA ID": 2139, "Summary": ""}
{"Disease Name": "Herpes simplex virus encephalitis", "Disease Definition": "A rare disorder caused by infection of the central nervous system by Herpes simplex virus (HSV) that could have a devastating clinical course and a potentially fatal outcome particularly with delay or lack of treatment. This disorder often involves the frontal and temporal lobes, usually asymmetrically, resulting in personality changes, cognitive impairment, aphasia, seizures, and focal weakness.", "ORPHA ID": 1930, "Summary": "Epidemiology\nHSVE accounts for 20 % of encephalitis cases and its annual incidence is 1/250,000-1/500,000 in industrialized nations and is presumed to be the same across the globe.\nClinical description\nHSVE usually peaks in childhood (between 3 months and 6 years during primary infection with HSV-1) and in older people (bimodal distribution). The manifestations of HSVE include low-grade pyrexia accompanied by severe headache, nausea, vomiting, and lethargy, followed by neurological features, which may include cognitive dysfunction (confusion, acute memory disturbances and disorientation), behavioral changes (irritability, hallucinations, psychosis, personality changes, agitation), focal neurological abnormalities (such as focal weakness, anomia, aphasia, dysphasia,), hemiparesis and seizures. There may be marked temporal lobe edema and occasionally brainstem herniation. 20 % of HSVE cases may present a relatively mild or atypical disease.\nEtiology\nHSV-1 causes 90 % of cases of HSVE with 10 % of cases caused by HSV-2; the latter is a common cause in neonates (during vaginal delivery) and the immunosuppressed. HSVE results from primary infection in 1/3 of cases and reactivation in 2/3. Mutations in genes such as TLR3 (4q35) and TRAF3 (14q32.32) have been observed suggesting an influence of genetic factors, presumably by an impaired type I and type III IFN production in response to HSV-1. In 7 % of patients with HSVE, antibodies against NMDAR (N-methyl-D-aspartate receptor), may be detected. Post-HSVE, abnormal movements or relapse of symptoms may be related to these antibodies.\nDiagnostic methods\nThe mainstay of diagnosis is detection of HSV in cerebrospinal fluid (CSF) by Polymerase Chain Reaction (PCR), although it may be negative for HSV-1 during the first 3 days of illness or after 10-14 days. CSF examination shows lymphocytosis (≥10-200/mm3) and raised protein (> or equal to 0.5-1.0 g/l). Magnetic resonance imaging findings show the characteristic abnormalities of edema and/or abnormal enhancement in one or both temporal and frontal lobes, the insular cortex, and the angular gyrus.\nDifferential diagnosis\nDifferential diagnosis includes: other viral causes of encephalitis, (varicella zoster virus, enteroviruses etc); bacterial infections, including ricketsial disease, mycoplasma pneumonia, chlamydophila infections; autoimmune diseases, such as paraneoplastic limbic encephalitis, acute disseminated encephalomyelitis, Rasmussen subacute encephalitis; and other causes including space occupying lesion and non-infectious encephalopathy.\nGenetic counseling\nHSVE occurs sporadically.\nManagement and treatment\nThe mainstay of treatment is intravenous injection (IV) of acyclovir (10mg/kg) 3 times daily for 14 days-21 days. CSF examination could be repeated at the end of that period to check if the virus has been cleared. Dosage should be adjusted in cases of renal malfunction. In immunocompromised patients, acyclovir should be continued for at least 21 days. Corticosteroids such as dexamethasone have been used in patients with HSVE, but the benefits are uncertain. The beneficial effects of methylprednisolone in children with antibodies against the NMDAR have yet to be established, as well as the possible benefits of steroid therapy or oral valacyclovir following IV acyclovir.\nPrognosis\nIf untreated, mortality rates are 70 % that can be reduced to 28% following treatment. However morbidity remains high and survivors often have residual deficit such as chorea or epilepsy. A delay of 48 hours or more in starting acyclovir is associated with poor outcome.\n\n                            Last update: \n                            June 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Jeoffrey SEGURA  - Pr Tom SOLOMON"}
{"Disease Name": "Herpes simplex virus stromal keratitis", "Disease Definition": "Herpes simplex (HSV) stromal keratitis is an infectious ocular disease of either necrotizing or non-necrotizing form, due to an HSV infection, and characterized by corneal stromal necrosis, inflammation, ulceration and infiltration by leukocytes. Corneal perforation and blindness can also occur in severe cases.", "ORPHA ID": 137599, "Summary": ""}
{"Disease Name": "Herpetiform pemphigus", "Disease Definition": "A rare superficial pemphigus disease characterized by severe intractable pruritus with erythematous or urticarial plaques and sometimes vesicles organized in a herpetiform pattern. Mucosae are generally spared. Eosinophilia in peripheral blood and low titers of circulating autoantibodies are observed in many cases. Histology can show an aspect of either pemphigus (superficial or deep), or an intraepidermal infiltrate rich in eosinophils (eosinophilic spongiosis).", "ORPHA ID": 208524, "Summary": ""}
{"Disease Name": "HIDEA syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by profound intellectual disability, hypotonia, coarse facial features, strabismus and impaired visual fixation, hypermobility of interphalangeal joints, contractures in the elbow joints, and pes planovalgus. Seizures and episodes of aggressive behavior during sleep have also been reported.", "ORPHA ID": 436141, "Summary": ""}
{"Disease Name": "Hidrotic ectodermal dysplasia, Christianson-Fourie type", "Disease Definition": "Hidrotic ectodermal dysplasia, Christianson-Fourie type is a rare ectodermal dysplasia syndrome characterized by tricho- and onychodysplasia in association with cardiac rhythm abnormalities. Patients present with sparse scalp hair and eyelashes, absent or sparse eyebrows, dystrophic thickened nails (on fingers distal end may be lifted from the nail bed) and supraventricular tachicardia or sinus bradicardia.", "ORPHA ID": 1808, "Summary": ""}
{"Disease Name": "Hidrotic ectodermal dysplasia, Halal type", "Disease Definition": "Hidrotic ectodermal dysplasia, Halal type is a form of ectodermal dysplasia syndrome (see this term) characterized by trichodysplasia, with absent eyebrows and eyelashes, onychodysplasia, mild retrognathia, abnormal dermatoglyphics (excess of whorls on fingertips, radial loop on finger, hypothenar pattern), intellectual disability and normal teeth and sweating. Additional variable manifestations include high implanted or prominent ears, mild hearing loss, supernumerary nipple, café-au-lait spots, keratosis pilaris, and irregular menses. To date, four individuals from 2 generations of a consanguineous family of Portuguese descent have been described in the literature. Males and females were equally affected. Hidrotic ectodermal dysplasia, Halal type is inherited in an autosomal recessive manner.", "ORPHA ID": 1809, "Summary": ""}
{"Disease Name": "Hidrotic ectodermal dysplasia", "Disease Definition": "Clouston syndrome (or hidrotic ectodermal dysplasia) is characterised by the clinical triad of nail dystrophy, alopecia, and palmoplantar hyperkeratosis.", "ORPHA ID": 189, "Summary": "Epidemiology\nThe disease was first described in the French-Canadian population (in which it is associated with a founder effect), but has since been identified in several other ethnic groups. The exact prevalence is unknown and the syndrome is likely to be underdiagnosed.\nClinical description\nNail abnormalities are the most consistent feature and frequently manifest at birth or in early infancy. The nails are thickened, slow growing, brittle, often hyperconvex and discoloured with striation. Additional reported features include micronychia, onycholysis and recurrent paronychial infections leading to nail loss. Hair involvement manifests at birth or later during infancy or childhood, and ranges from total to partial, often progressive, alopecia. Residual scalp hair is slow growing, sparse, fine and brittle. Eyebrows and eyelashes are also frequently sparse and axillary, pubic and body hair can be affected. Palmoplantar hyperkeratosis is not a constant finding. When present, it usually begins in childhood and tends to worsen with age; some patients also develop hyperkeratosis and hyperpigmentation over the joints and bony prominences. The teeth are usually unaffected and sweating is normal.\nEtiology\nClouston syndrome is caused by mutations in the GJB6 gene (13q12), encoding the gap junction protein connexin 30 (Cx30).\nDiagnostic methods\nDiagnosis may be suspected on the basis of the clinical triad of nail dystrophy, hypotrichosis and hyperkeratosis of the palms and soles. The diagnosis can be confirmed by molecular analysis of the GJB6 gene.\nDifferential diagnosis\nThe differential diagnosis should include pachyonychia congenita and other forms of ectodermal dysplasia (see these terms).\nAntenatal diagnosis\nPrenatal testing is possible in families where the disease-causing mutation has been identified.\nGenetic counseling\nClouston syndrome is transmitted as an autosomal dominant trait. Disease penetrance is complete, but expression is quite variable even between affected individuals from the same family.\nManagement and treatment\nAt present there is no treatment for the disease and management is purely supportive.\nPrognosis\nThe life-span for patients is normal.\n\n                            Last update: \n                            April 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "High altitude pulmonary edema", "Disease Definition": "A rare pulmonary condition characterized by non-cardiogenic pulmonary edema occurring in otherwise healthy individuals within days of an ascent above 2500-3000 m. Early symptoms include exertional dyspnea, non-productive cough, chest tightness, and reduced exercise performance, followed by dyspnea at rest and possibly orthopnea, as well as gurgling in the chest and pink frothy sputum in advanced cases. Clinical signs are cyanosis, tachypnea, tachycardia, crackles or wheezing, and elevated body temperature (generally not exceeding 38.5°C). Signs of concomitant high-altitude cerebral edema may also be observed. Chest x-rays typically show patchy opacities predominantly in the right middle lobe.", "ORPHA ID": 330012, "Summary": ""}
{"Disease Name": "High bone mass osteogenesis imperfecta", "Disease Definition": "High bone mass osteogenesis imperfecta is a rare, genetic, primary bone dysplasia disorder characterized by increased bone fragility, manifesting with multiple, childhood-onset, vertebral and peripheral fractures, associated with increased bone mass density on radiometric examination. Patients typically present normal or mild short stature and dentinogenesis, hearing, and sclerae are commonly normal.", "ORPHA ID": 314029, "Summary": ""}
{"Disease Name": "High grade B-cell lymphoma with MYC and/ or BCL2 and/or BCL6 rearrangement", "Disease Definition": "A rare aggressive B-cell non-Hodgkin lymphoma characterized by a rearrangement in MYC and BCL2 and/or BCL6 (so-called double-hit or triple-hit lymphoma). The category includes double-hit cases with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, blastoid cases with a double-hit, and cases with a DLBCL, not otherwise specified, morphology with a double-hit. It refers only to de novo cases, not to lymphomas with a history of pre-existing or coexistent indolent lymphoma. Patients typically present with widespread disease, including involvement of lymph nodes, bone marrow, and central nervous system.", "ORPHA ID": 480541, "Summary": ""}
{"Disease Name": "High myopia-sensorineural deafness syndrome", "Disease Definition": "High myopia-sensorineural deafness syndrome is a rare genetic disease characterized by high myopia, typically ranging from -6.0 to -11.0 diopters, and moderate to profound, bilateral, progressive sensorineural hearing loss with prelingual-onset. Affected individuals do not present other systemic, ocular or connective tissue manifestations.", "ORPHA ID": 363396, "Summary": ""}
{"Disease Name": "High-grade neuroendocrine carcinoma of the cervix uteri", "Disease Definition": "High-grade neuroendocrine carcinoma of the cervix uteri is a rare, aggressive, primary cervical neoplasm, originating from neuroendocrine cells present in the lining epithelium of the cervix, characterized, macroscopically, by usually large lesions, sometimes with a barrel-shaped appearance. Patients often present with abnormal vaginal bleeding or discharge, pelvic/abdominal pain, post-coital spotting and/or dysuria, while symptoms related to carcinoid syndrome are not frequent.", "ORPHA ID": 213777, "Summary": ""}
{"Disease Name": "High-grade neuroendocrine carcinoma of the corpus uteri", "Disease Definition": "High-grade neuroendocrine carcinoma of the corpus uteri is an extremely rare, aggressive, primary uterine neoplasm, originating from neuroendocrine cells scattered within the endometrium, characterized, macroscopically, by a bulky, frequently polypoid, mass with abundant necrosis located in the uterus and, histologically, by rosette-like and cord-like structures consisting of small, rounded cells with oval nuclei and scarce cytoplasm. Patients often present with dysfunctional uterine bleeding, pelvic or abdominal mass and, especially in later stages of the disease, abdominal pain. Symptomatic metastatic spread or symptoms related to a paraneoplastic syndrome, such as retinopathy, or Cushing syndrome due to ectopic ACTH production, may be associated.", "ORPHA ID": 213731, "Summary": ""}
{"Disease Name": "Hinman syndrome", "Disease Definition": "Hinman syndrome (HS) or non-neurogenic neurogenic bladder is a voiding dysfunction of the bladder of neuropsychological origin that is characterized by functional bladder outlet obstruction in the absence of neurologic deficits.", "ORPHA ID": 84085, "Summary": "Epidemiology\nPrevalence is not known.\nClinical description\nThe syndrome typically occurs in early to late childhood but some adult cases have been observed. It typically manifests at some point after toilet training in early to late childhood. Patients present with enuresis, urgent voiding with incontinence, infrequent voiding, intermittency, straining, urinary tract infections and diffuse abdominal pain.\nEtiology\nThe syndrome is probably caused by acquired behavioral and psychological disorders manifested by bladder dysfunction mimicking neurologic disease. The dysfunction is associated with abnormal family dynamics in 50% of cases. Individuals under psychosocial pressure try to inhibit enuresis by voluntarily contracting the external sphincter. These voluntary contractions lead to an obstruction of the urinary tract, characterized by an intermittent stream, increased residual urine and increased intravesicular pressure. The resultant destruction of the urinary tract simulates true neurogenic bladder.\nDiagnostic methods\nDiagnosis is based on the presence of the clinical and radiographic manifestations of neurogenic bladder in the absence of an underlying neurogenic abnormality. The diagnosis of HS should be considered at uroradiography in any child with unexplained bladder trabeculations, residual urine, incontinence or posterior urethral distention. The observation of posterior urethral distention following voluntary contraction of the external sphincter using a voiding cystourethrogram is suggestive of the condition.\nDifferential diagnosis\nDifferential diagnoses include neurogenic bladder, enuresis and urinary tract infection. HS can be differentiated from neurogenic bladder by five criteria: a) intact perineal sensation and anal tone, b) normal anatomy and function of the lower extremities, c) absence of skin lesions overlying the sacrum, d) normal lumbosacral spine at plain radiography, and e) normal spinal cord and magnetic resonance imaging (MRI). It is important to distinguish between true neurogenic bladder and HS because true neurogenic bladder requires surgery.\nManagement and treatment\nTreatment for HS focuses on helping the child void normally through alleviating psychosocial pressures which are likely to be causing the problem with voiding through suggestion therapy including hypnosis, bladder retraining and timed voiding. Catheterization may be used if the bladder does not empty completely and if the bladder has uninhibited contractions. Antispasmodic drugs may be of benefit. Occasionally external sphincterotomy is required.\nPrognosis\nHS can result in trabeculated bladder, ureterovesical obstruction, dilation of the upper tracts and renal damage and is often associated with urinary tract infections. However, improvements in patients with HS have been seen with bladder retraining and suggestion therapy.\n\n                            Last update: \n                            February 2012\n\n\n                            - Expert reviewer(s): \n                             Pierre CLAUDON"}
{"Disease Name": "Hip dysplasia, Beukes type", "Disease Definition": "A primary bone dysplasia, characterized by premature degenerative arthropathy of the hip. The disease presents with hip joint discomfort/pain and gait disturbances that usually develop in childhood and that progress to severe functional disability and limited mobility by early adulthood. Involvement of the vertebral bodies and other joints is minimal, height is not significantly reduced, and general health is unimpaired. Radiographically, the femoral heads are flattened and irregular and degenerative osteoarthritis develops in the hip joints, as evidenced by the presence of periarticular cysts, sclerosis, and joint space narrowing.", "ORPHA ID": 2114, "Summary": ""}
{"Disease Name": "Hirschsprung disease-deafness-polydactyly syndrome", "Disease Definition": "Hirschsprung disease-deafness-polydactyly syndrome is an extremely rare malformative association, described in only two siblings to date, characterized by Hirschsprung disease (defined by the presence of an aganglionic segment of variable extent in the terminal part of the colon that leads to symptoms of intestinal obstruction, including constipation and abdominal distension), polydactyly of hands and/or feet, unilateral renal agenesis, hypertelorism and congenital deafness. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 2155, "Summary": ""}
{"Disease Name": "Hirschsprung disease-ganglioneuroblastoma syndrome", "Disease Definition": "A rare, genetic, developmental defect during embryogenesis syndrome characterized by total or partial colonic aganglionosis associated with peripheral, usually multifocal, neuroblastic tumors (ganglioneuroblastoma, neuroblastoma, ganglioneuroma). Congenital central hypoventilation syndrome, with variable severity of respiratory compromise, cardiovascular and ophthalmologic symptoms, consistent with autonomic nervous system dysfunction, is occasionally associated.", "ORPHA ID": 2151, "Summary": ""}
{"Disease Name": "Hirschsprung disease-nail hypoplasia-dysmorphism syndrome", "Disease Definition": "Hirschsprung disease-nail hypoplasia-dysmorphism syndrome is a fatal malformative disorder that is characterized by Hirschsprung disease, hypoplastic nails, distal limb hypoplasia and minor craniofacial dysmorphic features (flat facies, upward slanting palpebral fissures, narrow philtrum, narrow, high arched palate, micrognathia, low set ears with abnormal helices). Hydronephrosis has also been reported. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 2153, "Summary": ""}
{"Disease Name": "Hirschsprung disease-type D brachydactyly syndrome", "Disease Definition": "Hirschsprung disease-type D brachydactyly syndrome is characterized by Hirschsprung disease and absence or hypoplasia of the nails and distal phalanges of the thumbs and great toes (type D brachydactyly). It has been described in four males from one family (two brothers and two maternal uncles). Transmission appears to be X-linked recessive but autosomal dominant inheritance with incomplete penetrance in females can not be ruled out.", "ORPHA ID": 2150, "Summary": ""}
{"Disease Name": "Hirschsprung disease", "Disease Definition": "A rare congenital intestinal motility disorder that is characterized by signs of intestinal obstruction due to the presence of an aganglionic segment of variable extent in the terminal part of the colon.", "ORPHA ID": 388, "Summary": "Epidemiology\nHirschsprung disease (HSCR) has an estimated prevalence at birth of 1/5,000-10,000 worldwide. In rectosigmoid HSCR, there is a male predominance of 4:1.\nClinical description\nHSCR generally manifests shortly after birth with symptoms of lower intestinal obstruction such as failure to pass meconium within the first 48 hours of life, abdominal pain, constipation, progressive abdominal distention, vomiting, and occasionally diarrhea. Rarely, it presents later in childhood with symptoms of severe constipation and failure to thrive. Four forms of the disease are recognized on the basis of the extent of aganglionosis: in the classic form (HSCR; 80% of cases), aganglionosis is restricted to the rectosigmoid. In long-segment HSCR (15%), aganglionosis extends above the sigmoid colon, while in total colonic aganglionosis (5%), aganglionosis involves the entire large intestine. Total intestinal aganglionosis is the most severe form and is extremely rare.\nEtiology\nHSCR is a neurocristopathy and is due to a defect in the development of the enteric nervous system. It is characterized by the absence of neuronal ganglion cells (aganglionosis) in the terminal part of the intestine. The affected bowel segment maintains a state of tonic contraction, resulting in a functional bowel obstruction. Genetic and environmental factors play a role in its pathogenesis. Several genes are associated with HSCR, particularly: the RET proto-oncogene (RET; 10q11.21), the glial cell derived neurotrophic factor gene (GDNF), the neurturin gene (NRTN), the endothelin B receptor gene (EDNRB), the endothelin-3 gene (EDN3), the endothelin-converting enzyme 1 gene ECE1, and the L1 cell adhesion molecule gene L1CAM.\nDiagnostic methods\nDiagnosis is based on suction rectal biopsy of rectal mucosa and submucosa that shows aganglionosis, thickened extrinsic nerve fibers and overexpression of acetylcholinesterase. Recently, it has been shown that calretinin immunohistochemistry is useful. Assessment for associated anomalies allows the detection of syndromic HSCR. Plain abdominal radiography, lower gastrointestinal contrast studies, and ultrasound are useful in excluding alternative diagnoses.\nDifferential diagnosis\nDifferential diagnosis includes gastrointestinal malformations such as anorectal malformation, chronic intestinal pseudo-obstruction, meconium ileus, anorectal stenosis and pelvic tumors. HSCR can also be associated with syndromes such neurologic Waardenburg-Shah syndrome, Bardet-Biedl syndrome, Mowat-Wilson syndrome, Haddad syndrome, or multiple endocrine neoplasia syndrome type 2A, Goldberg Shprintzen syndrome, Smith-Lemli-Opitz syndrome, Kaufman-McKusick syndrome, orofaciodigital syndrome type 5, PCWH syndrome, cartilage-hair-hypoplasia, and Down syndrome.\nAntenatal diagnosis\nThere are currently no practical capabilities for the prenatal diagnosis of HSCR, as abnormal sonographic findings are absent in the majority of fetuses with HSCR.\nGenetic counseling\nMost cases of non-syndromic HSCR are sporadic although familial cases are possible and thus genetic testing of both parents and the index patient may give a more accurate estimation of the risk of recurrence in future pregnancies. Genetic testing of RET to exclude the rare possibility of a MEN 2A associated RET mutation should be considered.\nManagement and treatment\nTreatment is surgical. It consists in resection of the aganglionic segment together with the transition zone followed by anastomosis of the proximal bowel to the anal margin. Different techniques including minimal invasive surgery as well as transanal surgery are applied. Type of surgery is dependent on the patient, length of aganglionosis and preference of the surgeon. Small bowel aganglionosis can lead to intestinal failure. In case of total intestinal aganglionosis, intestinal transplantation may be required.\nPrognosis\nOverall survival and functional prognosis are good in rectosigmoid or long-segment Hirschsprung, despite issues with constipation and continence even following surgical correction. Functional prognosis of total colonic Hirschsprung's is acceptable. The prognosis for children with small bowel or total intestinal aganglionosis leading to intestinal failure can be poor although intestinal transplantation is attempted to offer long term survival in complicated cases. Hirschsprung enterocolitis occurs in 30-50% of the cases but reacts well to treatment in most cases.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Dr A.S. [Alice] BROOKS | ERNICA* - Pr Mikko PAKARINEN | ERNICA* - Dr Pim SLOOTS | ERNICA* - Pr Tomas WESTER | ERNICA*\n\n\n                                * European Reference Network"}
{"Disease Name": "His bundle tachycardia", "Disease Definition": "His bundle tachycardia is a very rare congenital genetic tachyarrhythmia characterized by incessant tachycardia and high morbidity and mortality.", "ORPHA ID": 3283, "Summary": ""}
{"Disease Name": "Histidinemia", "Disease Definition": "Histidinemia is a rare metabolic disorder characterized by elevated histidine levels in blood, urine, and cerebrospinal fluid, generally with no clinical repercussions.", "ORPHA ID": 2157, "Summary": "Epidemiology\nReported prevalence varies widely from 1/8,600 to 1/180,000, probably as a result of differing screening programs.\nClinical description\nHistidinemia is defined biochemically as elevated histidine in blood, urine and cerebrospinal fluid, and decreased levels of the metabolite urocanic acid in blood, urine, and the skin. In most individuals with histidinemia, the condition is clinically silent and considered benign, with no need for treatment or a specific diet. In a small subset of patients with specific events in the neonatal period, such as low oxygen, it has been suggested that histidinemia may contribute to development of intellectual disability, behavioral or learning disorders. Growth is normal in patients with the disorder. Histidinemia is important because in the 1960s and 1970s the condition was unnecessarily added to universal newborn screening before the natural history was fully understood.\nEtiology\nHistidinemia is caused by impaired conversion of histidine to urocanic acid via the histidase enzyme. Deficiency in this enzyme is related to mutations in the histidine ammonia-lyase HAL gene (12q22-q24.1).\nDiagnostic methods\nThe disease can be diagnosed with blood and urine tests. Nano optical probe samarium tetracycline can be used. The diagnosis can be confirmed by demonstrating the absence or marked reduction of histidase activity in skin or the absence of urocanic acid in skin.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nRestricting dietary histidine brings the blood histidine level back to normal and eliminates the urinary imidazole metabolites in patients with histidinemia and urocanase deficiency. However, no urgent treatment is required because of the benign nature of this condition.\nPrognosis\nThe life expectancy is not affected. Patients with histidinemia show good prognosis.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Jeffrey BROSCO"}
{"Disease Name": "Histidinuria-renal tubular defect syndrome", "Disease Definition": "A rare disorder of histidine metabolism characterized by histidinuria without histidinemia due to impaired intestinal and renal tubular absorption of histidine. Developmental delay, intellectual disability, seizures, and mild dysmorphic features have been reported in association. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 2158, "Summary": ""}
{"Disease Name": "Histiocytic sarcoma", "Disease Definition": "A rare histiocytic tumor characterized by a malignant proliferation of cells showing morphological and immunophenotypic features of mature tissue histiocytes. Most cases occur in extranodal sites, most commonly the intestinal tract, skin, and soft tissue. Patients may present with a solitary mass, lymphadenopathy, a skin rash or numerous tumors on the trunk and extremities, lytic bone lesions, hepatosplenomegaly with pancytopenia, intestinal obstruction, and/or systemic symptoms. The neoplasm is aggressive with typically poor therapy response.", "ORPHA ID": 86896, "Summary": ""}
{"Disease Name": "Histiocytoid cardiomyopathy", "Disease Definition": "A rare arrhythmogenic disorder characterized by cardiomegaly, severe cardiac arrhythmias or sudden death, and the presence of histiocyte-like cells within the myocardium.", "ORPHA ID": 137675, "Summary": "Epidemiology\nApproximately 100 patients have been described in the literature to date. There is a female predominance with a female:male ratio between 3:1 to 4:1.\nClinical description\nThe majority of reported cases involve children under 2 years of age, indeed histiocytoid cardiomyopathy is a disease of infancy and early childhood. Clinically, the disease may manifest as various types of incessant arrhythmia (including atrial and ventricular fibrillation, supraventricular and ventricular tachycardia and Wolff-Parkinson-White syndrome) but sudden death due to cardiac arrest is a common presentation (20%). Lethal arrhythmias might be triggered by fever. Association with other cardiac defects (ventricular and atrial septal defects, hypoplastic left heart syndrome, endocardial fibroelastosis and left ventricle noncompaction) and with extracardiac anomalies (hypotonia, MIDAS syndrome, Peters anomaly, and congenital glaucoma) has also been reported in 16 and 17% of cases respectively.\nEtiology\nEtiology of histiocytic cardiomyopathy remains unknown. It was largely suspected to be caused by a developmental anomaly of the conduction system; however, genetic testing support various molecular basis. Mutation in cytochrome b, as well as A8344G mitochondrial DNA mutation have been described but seem to be sporadic variants. Whole Genome Expression Analysis support cluster of candidate gene at 1q21.3c, 2q12.1a and a decrease in copy number of the genes encoding S100A calcium binding protein, along with a strong decrease in interleukin 33 expression.\nDiagnostic methods\nHistiocytoid cardiomyopathy is suspected on the basis of clinical presentation, electrocardiogram, echocardiography, cardiac magnetic resonance imaging, myocardial biopsy or at autopsy. Unfortunately diagnosis is, typically post-mortem by histological evaluation, findings are pathognomonic for the disease and include yellow-tan nodules in the myocardium and, in some cases, in the subendocardial and subepicardial areas. The nodules are composed of nests of foamy histiocyte-like cells with a granular cytoplasm containing lipid droplets and abundant atypical mitochondria. These abnormal myocytes are found mainly in the ventricles but involvement of the valves has also been reported.\nDifferential diagnosis\nAs sudden infant death is frequently the presenting manifestation, sudden infant death syndrome (SIDS) is often the initial diagnosis in these cases but can be ruled out by histological evaluation of the myocardial tissue.\nGenetic counseling\nThere is a familial tendency of 5%; however, mode of inheritance (X-linked dominant inheritance and autosomal recessive) is still debated. Female predominance is not understood.\nManagement and treatment\nManagement options for patients presenting with arrhythmias include surgical removal of the nodular lesions, electrophysiological mapping and radiofrequency ablation of the arrhythmias. Heart transplantation have been proposed for few patients. Antiarrhythmics are generally ineffective but one patient showed a good response to treatment with amiodarone.\nPrognosis\nThe prognosis in general is poor and the disease is usually fatal.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Alice MALTRET"}
{"Disease Name": "Histoplasmosis", "Disease Definition": "A rare mycosis characterized by granulomatous inflammation primarily of the lung after inhalation of spores of Histoplasma capsulatum. The severity of clinical disease depends on the immune status of the individual and the size of the inoculum. In immunocompetent persons, the infection usually takes a self-limiting and asymptomatic or relatively mild, flu-like course. In immunocompromised patients, it can become progressive and disseminated, involving multiple organs and presenting with fever, pneumonia, hepatosplenomegaly, skin infiltrates, and endocarditis, among others.", "ORPHA ID": 390, "Summary": ""}
{"Disease Name": "HIV-associated cancer", "Disease Definition": "A rare neoplastic disease characterized by occurrence in association with human immunodeficiency virus (HIV) infection. Kaposi sarcoma, aggressive B-cell lymphomas, and invasive cervical cancer are considered AIDS-defining cancers, while a variety of other cancers are known to be related to HIV, including Hodgkin lymphoma, hepatocellular carcinoma, and lung, anal, oral cavity and oropharyngeal, vulvar, and penile cancer. The majority of cancers in AIDS patients are associated with co-infection with oncogenic viruses, such as Epstein-Barr virus, human herpesvirus 8, and human papillomavirus.", "ORPHA ID": 443291, "Summary": ""}
{"Disease Name": "HJV or HAMP-related hemochromatosis", "Disease Definition": "An early-onset and most severe form of rare hemochromatosis characterized by the usual features of hemochromatosis accompanied by cardiomyopathy and hypogonadism.", "ORPHA ID": 79230, "Summary": "Epidemiology\nLess than 100 reported cases were reported with a broad geographical distribution. Both sexes are equally affected.\nClinical description\nAge of onset is usually less than 30 years. This juvenile form of hemochromatosis has the classical features of symptomatic HC but is also characterized by severe cardiomyopathy and hypogonadism. Arthropathy, hepatic fibrosis, glucose intolerance, and increased skin pigmentation are frequent. Biochemical abnormalities include elevated serum iron, transferrin saturation and ferritin.\nEtiology\nTwo types of the disease have been described, both being transmitted in an autosomal recessive way. The most frequent form is caused by mutations in the hemojuvelin (HJV) gene on chromosome 1 and the second form is caused by mutations in the hepcidin (HAMP) gene on chromosome 19. These mutations result in complete or major hepcidin deficiency, thus increasing drastically duodenal iron absorption and iron release from the spleen.\nDiagnostic methods\nDiagnosis is based on biochemical testing for serum transferrin saturation (>90%), serum ferritin concentration (often >2000 microg/L), and on magnetic resonance imaging (MRI) for quantifying visceral (especially hepatic and cardiac) iron overload. Molecular genetic blood testing allows, in most cases, to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes TFR2-related hemochromatosis and post-transfusional iron overload in the case of hematological diseases such as thalassemia major, sickle cell disease, and other rare anemias.\nGenetic counseling\nGenetic counseling should be offered to first-degree relatives of patients with genetically confirmed HJV or HAMP-related hemochromatosis. Particular focus should be given to siblings as they are at the highest risk (25%).\nManagement and treatment\nIntensive phlebotomies, sometimes combined with iron chelation therapy, form the basis of treatment.\nPrognosis\nComplications like heart failure are often fatal. Early and intensive iron depletive therapy can significantly improve an otherwise devastating prognosis.\n\n                            Last update: \n                            August 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Graça PORTO | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "HNF1B-related autosomal dominant tubulointerstitial kidney disease", "Disease Definition": "A form of autosomal dominant tubulointerstitial kidney disease (ADTKD) due to variants in or whole gene deletions of HNF1B, which is characterized by chronic tubulo-interstitial nephritis, that manifests with nonsignificant urinalysis and slowly progressive renal failure. It can be associated with cystic kidney dysplasia, early onset diabetes and extrarenal manifestations.", "ORPHA ID": 93111, "Summary": "Epidemiology\nADTKD is estimated to account for approximately 2-5% of monogenic causes of chronic kidney disease. The prevalence of HNF1B-related ADTKD is unknown.\nClinical description\nHNF1B-related ADTKD is a congenital disorder of kidney development and can manifest as early as in the prenatal period with large and hyperechogenic kidneys. Postnatally, tubulointerstitial kidney disease with or without bilateral cystic kidney dysplasia can be apparent. Chronic renal insufficiency generally has a slow-progressive course; however, some infants present with early manifestation of end-stage kidney disease (ESKD). Additional malformations of the genitourinary tract are diagnosed in the antenatal or immediate postnatal period. In most patients, hypomagnesemia, hyperuricemia, elevated liver enzymes and maturity onset diabetes of the young manifest later during the clinical course (e.g. in school-aged children, adolescents or young adults). Due to the phenotypic overlap with 17.2q microdeletion syndrome, it is currently unclear if HNF1B-related ADTKD is also associated with neuropsychiatric symptoms.\nEtiology\nHNF1B-related ADTKD is caused by heterozygous variants in the human transcription factor 2 gene (HNF1B; 17q12) or large heterozygous deletions of 17q12 including HNF1B and a large number of additional genes. HNF1B encodes for hepatocyte nuclear factor-1 beta (HNF-1 beta), a transcription factor that is expressed early in embryonic development. HNF-1 beta acts as a homo- or heterodimer with HNF-1 alpha and plays a key role for tissue-specific regulations of gene expression in various organs such as kidneys, liver, biliary ducts, pancreas and the urogenital tract. However, it must be noted that HNF1B variants are associated with a spectrum of clinical phenotypes ranging from renal dysplasia, multicystic dysplastic kidney and other congenital anomalies of kidneys and urinary tract (CAKUT).\nDiagnostic methods\nDiagnosis may be difficult due to the heterogenous picture associated with HNF1B variants or gene deletions. Renal biopsy confirms a picture of interstitial fibrosis and tubular atrophy; however, renal ultrasound followed by genetic gene panel testing is the gold standard of diagnostic procedures.\nDifferential diagnosis\nDifferential diagnosis is complex, as the disease may mimic a variety of renal disorders. The clinical picture is shared with other forms ADTKD (UMOD-, MUC1-, REN-related). Other cystic kidney diseases (e.g. ARPKD, ADPKD, and other ciliopathies) may also present with renal ultrasound images similar to ADTKD-HNF1B. In 17.2q microdeletion syndrome, neurological involvement is possible in patients initially presenting with the kidney phenotype.\nAntenatal diagnosis\nPrenatal diagnosis is possible by fetal ultrasound or where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant with de novo variants or gene deletions in about 50% of cases. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. However, there is variable intrafamilial expression and it should be noted that HNF1B is associated with a variable degree of renal insufficiency.\nManagement and treatment\nTreatment is symptomatic and interdisciplinary, requiring pediatric nephrologists and diabetologists. Chronic renal disease and diabetes are treated according to international standards. Hypomagnesemia can be managed with magnesium supplementation; hyperuricemia with allopurinol in severe cases. Gene therapy is currently not available.\nPrognosis\nThe prognosis is largely dependent on renal function and sufficient treatment of diabetes at later ages. When kidney transplantation is required, there is no risk of recurrence after transplantation. However, when using steroids and calcineurin inhibitors, especially tacrolimus, there is an enhanced risk of post-transplant diabetes.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Stefanie WEBER"}
{"Disease Name": "HNRNPDL-related limb-girdle muscular dystrophy D3", "Disease Definition": "A rare, mild subtype of autosomal dominant limb-girdle muscular dystrophy characterized by a typically adult onset of mild, progressive, proximal weakness of pelvic and shoulder girdle muscles and progressive, permanent finger and toes flexion limitation without flexion contractures. Normal to highly elevated creatine kinase serum levels are observed.", "ORPHA ID": 55596, "Summary": ""}
{"Disease Name": "Hodgkin lymphoma", "Disease Definition": "Hodgkin lymphoma (HL) is a heterogeneous group of malignant lymphoid neoplasms of B-cell origin characterized histologically by the presence of Hodgkin and Reed-Sternberg (HRS) cells in the vast majority of cases.", "ORPHA ID": 98293, "Summary": "Epidemiology\nHL is an uncommon cancer with an incidence of about 1/40,000 in North America and Europe. There are about 8500 new cases reported in the U.S. each year.\nClinical description\nHL is comprised of 2 major forms: classical Hodgkin lymphoma (CHL; see this term), seen in 95% of all HL cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL; see this term), seen in only 5% of all HL cases. Disease onset occurs most frequently in young adults (age 15-35) followed by older adults (over the age of 55) and usually begins with the painless swelling of a lymph node in the upper body. Disease can spread to multiple lymph node regions or lymphoid structures and associated systemic symptoms (weight loss > 10% of baseline, fevers, night sweats) are observed in about 20% of patients.\nEtiology\nThe exact cause is unknown but immunological, genetic and environmental factors are thought to be involved.\nManagement and treatment\nTreatment with radiotherapy and systemic chemotherapy leads to a very good prognosis. Follow-up physical exams, blood tests and x-rays are needed to check for recurrence and check for any long-term side effects of the toxic treatments. Possible long-term side effects include secondary cancers, infertility, reduced immunity, thyroid problems, heart disease and stroke.\nPrognosis\nThe international prognostic score (IPS) is a score given based on the presence of 7 risk factors (male sex, >45 years of age, stage 4 disease, serum albumin <4g/dl, hemoglobin <10.5 g/l, lymphocytopenia and WBC count >15,000/mm3) at the time of diagnosis. The more factors present, the less favorable the prognosis. The cure rates are 90% for early-stage HL and 70% for advance stage HL.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Joseph CONNORS"}
{"Disease Name": "Holmes-Adie syndrome", "Disease Definition": "A rare ophthalmic disorder characterized by the unilateral or bilateral occurrence of a tonic pupil (showing sectorial denervation of the sphincter pupillae, so that the pupil constricts poorly to light, while the response to near is present but abnormally prolonged), in association with the absence of deep tendon reflexes. In some patients, patchy hypo- or anhidrosis may also be present (a variant known as Ross syndrome). The condition typically occurs in young adults, with a female preponderance.", "ORPHA ID": 454718, "Summary": ""}
{"Disease Name": "Holocarboxylase synthetase deficiency", "Disease Definition": "A rare, early-onset and life-threatening, multiple carboxylase deficiency that when left untreated, is characterized by vomiting, tachypnea, irritability, lethargy, exfoliative dermatitis, and seizures that can worsen to coma and death.", "ORPHA ID": 79242, "Summary": "Epidemiology\nThe exact prevalence of holocarboxylase synthertase deficiency (HCSD) is unknown, but the condition is one of the rarest inborn errors of metabolism. Prevalence at birth is estimated to be less than 1/200,000.\nClinical description\nClinical onset is usually within hours, days or weeks of birth, although it may occur during infancy or early childhood. Individuals with the disorder usually exhibit poor appetite, vomiting, lethargy, irritability, hypotonia and exfoliative dermatitis. Metabolically, they have ketolactic acidosis, organic acidemia (-uria) and hyperammonemia. Without treatment, affected infants may progress to intractable seizures, cerebral edema and coma. These children often develop growth and developmental delays.\nEtiology\nHCSD is caused by mutations in the HLCS gene (21q22.1) resulting in reduced holocarboxylase synthetase (HCS) activity. This enzyme is important in covalent binding of biotin to the various biotin-dependent carboxylases that require the vitamin for activity. Failure to attach the biotin results in multiple carboxylase deficiency and accumulation of various, specific abnormal organic acids.\nDiagnostic methods\nSome affected individuals are identified through newborn screening by demonstration of abnormal organic acids, consistent with multiple carboxyalse deficiency. Diagnosis is based on clinical signs and typical organic acid abnormalities. Diagnosis can be confirmed by enzyme activity assays in leukocytes or fibroblast extracts, or by mutation analysis.\nDifferential diagnosis\nBased on organic acids, conditions to be considered in the differential diagnosis include biotinidase deficiency and isolated carboxylase deficiencies. Other conditions to be consider include urea cycle defects (based on presence of hyperammonemia) and sepsis and other inborn errors of metabolism (based on neurological compromise and seizures in the neonatal period).\nAntenatal diagnosis\nPrenatal diagnosis can be performed by organic acid analysis by stable isotope dilution techniques in amniotic fluid, enzymatic determination of HCS activity in amniocytes, or mutation analysis on DNA from chorionic villus biopsy or amniocentesis.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child for each pregnancy.\nManagement and treatment\nThe primary treatment for HCSD is free biotin supplementation which can improve the clinical status of symptomatic individuals with the enzyme deficiency and prevent some or all symptoms from developing in asymptomatic individuals with the disorder. Treatment should be started as soon as possible after diagnosis and must be continued lifelong. Affected individuals should be monitored for later-onset complications and for compliance with therapy. Timely and ongoing treatment makes it possible to reduce symptoms considerably, although some patients develop complications despite appropriate treatment often requiring higher doses of biotin.\nPrognosis\nIn the absence of early diagnosis and treatment, mortality is high. Morbidity in surviving affected individuals depends on the time of diagnosis and on the degree of damage related to metabolic crises.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Barry WOLF"}
{"Disease Name": "Holoprosencephaly-caudal dysgenesis syndrome", "Disease Definition": "Holoprosencephaly-caudal dysgenesis syndrome is a central nervous system malformation syndrome characterized by holoprosencephaly with microcephaly, abnormal eye morphology (hypotelorism, cyclopia, exophthalmos), nasal anomalies (single nostril or absent nose), and cleft lip/palate, combined with signs of caudal regression (sacral agenesis, sirenomelia with absent external genitalia).", "ORPHA ID": 2165, "Summary": ""}
{"Disease Name": "Holoprosencephaly-craniosynostosis syndrome", "Disease Definition": "Holoprosencephaly-craniosynostosis syndrome is a rare developmental defect during embryogenesis syndrome characterized by the association of primary craniosynostosis (usually involving the coronal and metopic sutures) with holoprosencephaly (ranging from alobar to, most commonly, semilobar) and various skeletal anomalies (typically, hand and feet anomalies including fifth digit clinodactyly, hypoplastic phalanges and cone-shaped epiphyses, small vertebral bodies, scoliosis, coxa valga and/or flexion deformities of hips). Craniofacial asymmetry, microcephaly, brachy/plagiocephaly, short stature and psychomotor delay are additional common features.", "ORPHA ID": 2163, "Summary": ""}
{"Disease Name": "Holoprosencephaly-postaxial polydactyly syndrome", "Disease Definition": "Holoprosencephaly-postaxial polydactyly syndrome associates, in chromosomally normal neonates, holoprosencephaly, severe facial dysmorphism, postaxial polydactyly and other congenital abnormalities, suggestive of trisomy 13 (see this term).", "ORPHA ID": 2166, "Summary": "Epidemiology\nIncidence is unknown.\nClinical description\nDysmorphic features include hypotelorism, severe eye anomalies such as microphtalmia or anophtalmia, premaxillary region aplasia and cleft lip and palate. Congenital cardiac anomalies are common.\nAntenatal diagnosis\nAntenatal diagnosis is possible by ultrasonographic monitoring.\nGenetic counseling\nThe condition seems to be inherited as an autosomal recessive trait.\nPrognosis\nPrognosis is poor.\n\n                            Last update: \n                            January 2010"}
{"Disease Name": "Holoprosencephaly-radial heart renal anomalies syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterised by holoprosencephaly, predominantly radial limb deficiency (absent thumbs, phocomelia), heart defects, kidney malformations and absence of gallbladder. Variable manifestations include vertebral anomalies, cleft lip/palate, microphthalmia, absent nose, dysplastic ears, hearing loss, colobomas of the iris and retina and/or bifid uvula.", "ORPHA ID": 3186, "Summary": ""}
{"Disease Name": "Holoprosencephaly", "Disease Definition": "A rare complex brain malformation characterized by incomplete cleavage of the prosencephalon, and affecting both the forebrain and face and resulting in neurological manifestations and facial anomalies of variable severity.", "ORPHA ID": 2162, "Summary": "Epidemiology\nPrevalence is estimated to be 1/10,000 live and still births and 1/250 conceptuses, with worldwide distribution.\nClinical description\nThree classical forms of holoprosencephaly (HPE) of increasing severity are described based on the degree of anatomical separation: lobar, semi-lobar and alobar HPE. Milder subtypes include midline interhemispheric variant and septopreoptic HPE. There is, however, a continuous spectrum of abnormal separation of the hemispheres that extends from aprosencephaly/atelencephaly, the most severe end of the spectrum, to microform HPE, a less severe midline defect without the typical HPE brain characteristics. There is significant inter- and intrafamilial clinical variability across this spectrum. In most cases, there is a correlation between the severity of the facial anomalies and the brain defect (except in cases of mutation in the ZIC2 gene). In decreasing severity, the main craniofacial features are cyclopia, proboscis, premaxillary agenesis, median or bilateral cleft lip/palate, coloboma, retinal dysplasia, choanal stenosis, pyriform sinus stenosis, hypotelorism, solitary maxillary median incisor (SMMI) or even normal face. Severe forms are often fatal and mortality is correlated with the severity of brain malformation and associated defects. In surviving children, a wide range of associated manifestations are reported: developmental delay, hydrocephalus, motor impairment, spasticity, feeding difficulties and oromotor dysfunction, epilepsy, hypothalamic dysfunction. Endocrine disorders due to pituitary defects such as central diabetes insipidus are frequent.\nEtiology\nHPE is due to incomplete cleavage of the prosencephalon between the 18th and 28th day of gestation. The etiology is typically genetic and often oligogenic; however, environmental factors during this period (maternal diabetes or hypocholesterolemia during gestation) may contribute. HPE may also be associated with certain syndromes or chromosomal abnormalities (such as Smith-Lemli-Opitz syndrome, Hartsfield Syndrome and trisomy 13). In isolated HPE, at least 20 genes have been implicated: major genes include SHH (7q36), ZIC2  (13q32), SIX3 (2p21), GLI2 (2q14), FGF8 (10q24) and FGFR1 (8p11) in addition to more than 15 minor genes. The major common effect of the identified pathogenic mutations is the impairment of SHH activity leading to disruption of the ventral midline of the brain, and interference with the early stages of forebrain and eye development. SHH-dosage is crucial in the disease mechanism and might determine disease severity.\nDiagnostic methods\nMost severe cases are detected by systematic ultrasound scan and magnetic resonance imaging (MRI) during pregnancy or after birth. At the other end of the spectrum, diagnosis is based on clinical features.\nDifferential diagnosis\nDifferential diagnosis includes anencephaly, severe congenital hydrocephalus, Walker-Warburg syndrome, large interhemispheric cyst, otocephaly and other midline defects, as well as syndromic and chromosomal-related forms.\nAntenatal diagnosis\nDue to the high clinical and genetic variability, prenatal diagnosis is based on ultrasound scans and MRI rather than on molecular diagnosis, and may be useful in mothers with diabetes and those with a family history of HPE. Some parents of a child with a structural unbalanced chromosome rearrangement (e.g., deletion, duplication) have a balanced chromosome rearrangement and should be offered chromosome analysis by chorionic villus biopsy or amniocentesis.\nGenetic counseling\nGenetic counseling (GC) is strongly recommended for affected families; it is particularly complex and requires thorough clinical evaluation and family history, with close attention to possible risk factors (especially maternal diabetes), microform findings in relatives, and associated signs. If a genetic etiology is established in a proband, specific counseling for recurrence risk is indicated. In non-syndromic HPE, all modes of inheritance have been described; however, most cases are complex with digenic or oligogenic inheritance.\nManagement and treatment\nTreatment is symptomatic and supportive, and requires a multidisciplinary approach.\nPrognosis\nPrognosis depends on severity and the associated complications.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Christèle DUBOURG  - Dr Alinoë LAVILLAUREIX  - Pr Sylvie ODENT | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Holt-Oram syndrome", "Disease Definition": "A genetic syndrome with limb reduction defects characterized by skeletal abnormalities of the upper limbs and mild-to-severe congenital cardiac defects.", "ORPHA ID": 392, "Summary": "Epidemiology\nHolt-Oram syndrome (HOS) prevalence is estimated at 1/ 100,000 live births (in Hungary), but various cases have been published worldwide.\nClinical description\nThe clinical picture of HOS covers a wide spectrum of upper extremity defects, always including the radial ray, and cardiac defects. Radial ray upper limb anomalies include carpal bone malformation(s) as well as triphalangeal or absent thumb(s), phocomelia, hypoplasia or aplasia involving the radius often resulting in unequal arm lengths, transverse upper limb defects including abnormal forearm pronation and supination. Patients may have more severe left than right upper-limb abnormalities. Most frequent congenital cardiac malformations observed are atrial septal defect, ostium secundum type (ASD) and ventricular septal defect (VSD). Conduction abnormalities like paroxysmal atrial fibrillation, sometimes associated with various degrees of atrioventricular block, have been reported. Other variable anomalies reported include craniofacial, axillary, tracheal, vertebral and lower-limb anomalies, as well as deafness, abdominal situs inversus and renal abnormalities, but in many cases these findings reflect phenocopy syndromes rather than HOS itself.\nEtiology\nHOS is caused by a mutation in the TBX5 gene located on the long arm of chromosome 12 (12q24.1). The TBX5 gene encodes T-box5, a transcription factor regulating the expression of other genes in developing heart and limbs. More than 85% of the clinically diagnosed HOS individuals carry a TBX5 mutation.\nDiagnostic methods\nDiagnosis of HOS is based on clinical findings and family history. It can be confirmed by molecular genetic analyses.\nDifferential diagnosis\nDifferential diagnosis includes heart-hand syndrome type 2, heart-hand syndrome type 3, brachydactyly-long thumb, SAL4-related disorders (Okihiro and acro-renal-ocular syndrome), ulnar-mammary syndrome, Slovenian type heart-hand syndrome, Fanconi anemia, distal 22q11.2 microdeletion syndrome, VACTERL association, thalidomide embryopathy, fetal valproate syndrome.\nAntenatal diagnosis\nPrenatal testing is based on DNA analysis of amniocentesis and chorionic villus sampling and may be useful to confirm ultrasound and echocardiography findings in families with a known HOS mutation. In women with HOS, cardiac defects should be evaluated by a cardiologist to determine what monitoring and care may be needed during pregnancy.\nGenetic counseling\nThe majority of the HOS mutations occur de novo. HOS is inherited in an autosomal dominant manner with complete penetrance for upper-limb malformations, and 75% penetrance for congenital heart malformations and with variable expressivity leading to a wide spectrum of phenotypes. Genetic counseling should be offered to parents with a TBX5 mutation informing them of their 50% risk of transmitting it on to their children. Molecular genetic testing is not sufficient to precisely predict the severity of upper-limb and congenital heart anomalies.\nManagement and treatment\nManagement is multidisciplinary and includes geneticists, cardiologists, orthopedic surgeons and pediatric orthopedics as well as social support networks. Patients with advanced heart block may require a permanent pacemaker. An echocardiogram is recommended every one to five years if cardiac defects are present. Electrocardiograms (EKGs) are recommended annually for adults.\nPrognosis\nPrognosis is variable. Functional impact in everyday life is based on the type and severity of upper-limb anomalies. Life expectancy depends on the severity of cardiac anomalies.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Craig BASSON"}
{"Disease Name": "Holzgreve syndrome", "Disease Definition": "Holzgreve syndrome is an extremely rare, lethal, multiple congenital anomalies/dysmorphic syndrome characterized by renal agenesis with Potter sequence, cleft lip/palate, oral synechiae, cardiac defects, and skeletal abnormalities including postaxial polydactyly. Intestinal nonfixation and intrauterine growth restriction are also associated. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 2167, "Summary": ""}
{"Disease Name": "Homocystinuria due to cystathionine beta-synthase deficiency", "Disease Definition": "A rare metabolic disease of methionine catabolism characterized by accumulation of methionine and homocysteine with clinical involvement of the eye, skeletal system, vascular system and central nervous system (CNS).", "ORPHA ID": 394, "Summary": "Epidemiology\nThe prevalence of the disease varies widely depending on ethnicity and the method of ascertainment, from 1/300,000 in historical clinical descriptions, to 1/1800 in Qatar (highest prevalence in the world), and an estimated 1/17,800 in Germany by molecular genetic screening of a normal population.\nClinical description\nPatients exhibit a spectrum of progressively appearing clinical manifestations, ranging from asymptomatic to severe, with one or multiple organ systems involved. Symptoms essentially affect four types of organ: eyes (ectopia lentis), skeletal system (high stature, marfanoid morphotype, skeletal deformations, osteoporosis), vascular system (arterial or veinous thromboembolism), and CNS (developmental delay, autism spectrum disorders, psychiatric disorders). The phenotype and severity of the disease are essentially defined by the degree of response to vitamin B6, the cofactor of the cystathionine beta-synthase (CBS) enzyme.\nEtiology\nThe disease is caused by mutations in the CBS gene (21q22.3) leading to the accumulation of homocysteine and methionine, which are toxic for the endothelium, and causes neurocognitive impairment. Cysteine deficiency probably plays a role in connective tissue abnormalities, including lens dislocation.\nDiagnostic methods\nThe diagnosis is suspected in patients with increased plasma concentrations of total homocysteine (Hcyt) and methionine (Met), and confirmed by the identification of biallelic pathogenic variants in the CBS gene.\nDifferential diagnosis\nThe spectrum of differential diagnosis is broad. Clinically, severe forms of CBS deficiency share certain clinical features with Marfan syndrome (FBN1 gene), and lens dislocations are associated with a number of malformative syndromes. The differential diagnoses of hyperhomocysteinemia include some acquired pathologies such as severe chronic renal failure, vitamin B12 or folate deficiency (which can be caused by certain treatments such as methotrexate, metformin, nitrous oxide) and inborn errors of vitamin B12 or folate metabolism.\nAntenatal diagnosis\nPrenatal testing is possible if mutations have been identified in the index case.\nGenetic counseling\nThe disease is autosomal recessive. At conception, each sib of heterozygous parents has a 25% risk of being affected.\nManagement and treatment\nThere are currently three recognized modalities of treatment. For patients who are pyridoxine responsive, treatment includes pyridoxine only in pharmacological doses (maximum 500 mg/day) in combination with folic acid and vitamin B12 supplements if necessary. In pyridoxine nonresponsive individuals, the recommended treatment is a strict methionine-restricted diet in combination with pyridoxine in partial responders. Betaine anhydrous is a methyl donor that can be used as an adjunct to the diet.\nPrognosis\nThe consequences of untreated, or partially treated, CBS deficiency include thromboembolic events, intellectual disability, ocular and skeletal manifestations. Untreated CBS patients showed that the risk of complications increases with age. The prognosis of patients treated from the neonatal period is good, with virtually complete prevention of all abnormalities. In late-treated patients, therapy aims at preventing thromboembolic events and further escalation of the complications.\n\n                            Last update: \n                            September 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Juliette BOUCHEREAU | MetabERN* - Pr Manuel SCHIFF | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Homocystinuria due to methylene tetrahydrofolate reductase deficiency", "Disease Definition": "Homocystinuria due to methylene tetrahydrofolate reductase (MTHFR) deficiency is a metabolic disorder characterised by neurological manifestations.", "ORPHA ID": 395, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nOnset usually occurs during the first year of life with severe neurological signs, recurrent apnoea, microcephaly and convulsions. There is no megaloblastic anaemia. There are some forms with onset during childhood, adolescence, or adulthood beginning with mental regression, ataxia, and, most often, common psychiatric disorders of the schizophrenic type that may be linked to cerebrovascular accidents. Other symptoms such as subacute degeneration of the spinal chord have been reported.\nEtiology\nIt is caused by mutations in the MTHFR gene (1p36.3). MTHFR deficiency results in abnormal intracellular folic acid metabolism and prevents reduction of 5-10 methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor for the remethylation of homocysteine into methionine. As a result, the disorder leads to methyltetrahydrofolate deficiency and consequently to homocystinuria and hypomethioninemia.\nDiagnostic methods\nDiagnosis may be suspected after analysis of amino acids by chromatography and measurements of total plasma homocysteine levels revealing highly elevated values of >100 micromol/L. Other biological findings include low levels of methyltetrahydrofolate in both the plasma and cerebrospinal fluid. Diagnosis is confirmed by measuring enzyme activity in lymphocytes or fibroblasts.\nDifferential diagnosis\nThe differential diagnosis should include other homocysteine remethylation disorders.\nAntenatal diagnosis\nPrenatal diagnosis is feasible through molecular or enzymatic analysis.\nGenetic counseling\nThe disorder is transmitted as an autosomal recessive trait.\nManagement and treatment\nTreatment of severe deficiency revolves around the administration of high-dose betaine, in combination with methionine, pyridoxine, vitamin B12 and folic or folinic acid supplements.\nPrognosis\nThe prognosis is variable.\n\n                            Last update: \n                            January 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Pascale DE LONLAY"}
{"Disease Name": "Homocystinuria without methylmalonic aciduria", "Disease Definition": "Homocystinuria without methylmalonic aciduria is an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, encephalopathy and, sometimes, developmental delay, and associated with homocystinuria and hyperhomocysteinemia. There are three types of homocystinuria without methylmalonic aciduria; cblE, cblG and cblD-variant 1 (cblDv1).", "ORPHA ID": 622, "Summary": "Epidemiology\nPrevalence is unknown. To date, about 30 cases of cblE, about 38 cases of cblG, and 5 cases of cblDv1 have been reported.\nClinical description\nHomocystinuria without methylmalonic aciduria manifests mainly in early childhood with failure to thrive, megaloblastic anemia, developmental delay, hypotonia, seizures and cerebral atrophy with white matter abnormalities. Some patients may have an acute expression in the first few months of life, with vomiting, poor feeding and lethargy. Patients develop homocystinuria, hyperhomocysteinemia and, sometimes, hypomethioninemia. A mild clinical phenotype and late-onset disease in the absence of neurological involvement have also been described for the cblE disorder. Presentation in adulthood with ataxia, dementia or psychosis has been observed in cblG.\nEtiology\nThese disorders are caused by a functional deficiency of the cytoplasmic enzyme methionine synthase (MS), which catalyzes remethylation of homocysteine to form methionine. cblG is caused by mutations of the MTR gene (1q43), which encodes MS, while cblE is caused by mutations of the MTRR gene (5p15.3-15.2), which encodes methionine synthase reductase, an accessory protein required to maintain MS-bound cobalamin in its active form. The cblDv1 disorder results in decreased provision of the cobalamin coenzyme required for MS activity.\nDiagnostic methods\nDiagnosis is based on evidence of increased levels of homocystine in urine, and homocysteine or homocystine in plasma, and presence of megaloblastic anemia. Plasma methionine is frequently low. Genetic complementation analysis or identification of mutations in the MTR, MTRR or MMADHC genes can confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes multiple sclerosis, particularly for cblG. The forms of homocystinuria without methylmalonic aciduria can be distinguished on the basis of complementation analysis in cultured cells. In contrast to patients with classical homocystinuria due to cystathionine synthase deficiency, methionine is not elevated.\nAntenatal diagnosis\nPrenatal diagnosis is possible by identification of elevated homocysteine in amniotic fluid or by biochemical studies of cultured amniocytes. Mutation analysis is possible when the disease causing mutations have been identified in the index case. Treatment of the mother of an affected fetus with cobalamin during pregnancy has been carried out, and appears to have been successful in preventing development of disease.\nGenetic counseling\nAll three types of methylcobalamin deficiency are inherited in an autosomal recessive manner.\nManagement and treatment\nTreatment is based on daily intramuscular injections of 1 mg hydroxycobalamin (OHCbl), tapering the frequency of injections over time to one dose, one to three times a week. A few patients with cblG have required additional treatment with folates and betaine.\nPrognosis\nWith treatment, biochemical parameters rapidly normalize and clinical symptoms of hypotonia, lethargy and impaired responsiveness improve within 24-48 hours. Hematologic parameters also improve. The improvement in psychomotor status is slow and often incomplete.\n\n                            Last update: \n                            March 2012\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Homozygous familial hypercholesterolemia", "Disease Definition": "A rare disorder of lipid metabolism characterized by severely elevated plasma total cholesterol, low-density lipoprotein (LDL) cholesterol levels, and subsequent premature formation of atherosclerotic plaques in the coronary arteries, proximal aorta, and other arteries, significantly increasing the risk of premature cardiovascular disease and death. Xanthomas of the skin and in tendons are also a hallmark of the disease. Lethality is high due to early complications, in particular myocardial infarction and aortic valvular disease.", "ORPHA ID": 391665, "Summary": "Epidemiology\nThe current prevalence estimate of homozygous familial hypercholesterolemia (FH) is approximately 1/315,000 (range 1/100,000-1,000,000) individuals, with a higher prevalence in founder populations (e.g. in the Middle East, Quebec and South Africa).\nClinical description\nClassical clinical presentation is in childhood when xanthomas are first noted on extremities, trunk and in extensor tendons. Patients may also have corneal arcus, xanthelasmas, arterial bruits, cardiac ejection murmurs and diminished peripheral arterial pulses. A lipid profile demonstrates profoundly elevated levels of total and LDL cholesterol.\nEtiology\nThe core molecular defect involves loss of function of the LDL receptor on hepatocytes due to bi-allelic pathogenic variants in the LDLR gene in 80-90% of cases. There are >3000 reported pathogenic variants in LDLR. Clinical severity varies in relation to the extent of functional impairment imparted by the particular variant. A similar phenotype can result from bi-allelic binding-defective variants in APOB which encodes apolipoprotein B, the ligand for the LDL receptor. About 1-2% of cases result from bi-allelic gain-of-function variants in PCSK9 which encodes proprotein convertase subtilisin kexin type 9. A true recessive phenotype results from bi-allelic loss-of-function variants in LDLRAP1 encoding the LDL receptor adaptor protein. Even rarer variants in other genes can sometimes produce a phenotype that resembles homozygous HF.\nDiagnostic methods\nDiagnosis is made based on clinical features, the degree of LDL cholesterol elevation, family history, plus DNA sequencing for a definitive diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes severe heterozygous FH, sitosterolemia, lysosomal acid lipase deficiency.\nAntenatal diagnosis\nPrenatal diagnosis of homozygous FH is possible.\nGenetic counseling\nTransmission is semi-dominant when the causal gene is LDLR, APOB or PCSK9, meaning that heterozygous parents express an abnormal clinical and biochemical phenotype that is intermediate between a normal individual and a patient with homozygous FH. Parents either already know their own heterozygous status in advance, or sometimes are diagnosed retrospectively when a child is born with homozygous FH. Genetic counseling should be offered to at-risk couples: 25% of their children will have a normal lipid profile, 50% will have heterozygous FH which will require monitoring and sometimes pharmacotherapy starting at ages 8-10 years, and 25% will have homozygous FH requiring immediate attention. In true autosomal recessive FH due to bi-allelic loss-of-function variants in LDLRAP1, both parents are asymptomatic carriers of a disease-causing mutation with a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThe mainstay of treatment is serial (i.e. weekly or bi-weekly) lipoprotein apheresis, since statins and other commonly used lipid-lowering medications are minimally effective. Inhibitors of proprotein convertase subtilisin kexin type 9 have a variable but typically modest effect on LDL cholesterol. A new biologic medication - evinacumab, which is an intravenously administered monoclonal antibody against angiopoietin like protein 3 - is an extremely effective treatment recently made available in many jurisdictions.\nPrognosis\nLife expectancy without treatment is reduced by three to five decades. With apheresis, patients now survive into their fifth and sixth decades of life, but still can develop clinical end points of severe premature atherosclerotic cardiovascular disease and aortic disease.\n\n                            Last update: \n                            March 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Robert HEGELE"}
{"Disease Name": "Horizontal gaze palsy with progressive scoliosis", "Disease Definition": "Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare congenital autosomal recessive disease, presenting in children and adolescents, and characterized by progressive scoliosis along with the absence of conjugate horizontal eye movements and associated with failure of the somatosensory and corticospinal neuronal tracts to decussate in the medulla.", "ORPHA ID": 2744, "Summary": ""}
{"Disease Name": "Hot water reflex epilepsy", "Disease Definition": "Hot water reflex epilepsy is a rare neurologic disease characterized by the onset of generalized or focal seizures following immersion of the head in hot water, or with hot water being poured over the head. Primary generalized tonic-clonic seizures have been reported in rare cases.", "ORPHA ID": 166412, "Summary": ""}
{"Disease Name": "House allergic alveolitis", "Disease Definition": "House allergic alveolitis is a hypersensitivity pneumonitis (see this term) resulting from the inhalation of an antigen to which an individual has been previously sensitized in his/her domestic environment. House allergic alveolitis encompasses summer hypersensitivity pneumonitis, humidifier-induced lung diseases, hot tub lung and legionellosis (see this term).", "ORPHA ID": 99907, "Summary": ""}
{"Disease Name": "Hoyeraal-Hreidarsson syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability considered to be a severe variant of dyskeratosis congenita characterized by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, progressive combined immune deficiency and aplastic anemia.", "ORPHA ID": 3322, "Summary": "Epidemiology\nHoyeraal-Hreidarsson syndrome (HHS) prevalence is unknown. The syndrome may be underdiagnosed due to high mortality rates.\nClinical description\nThe disease generally presents in early childhood and primarily affects males. Growth retardation is usually of prenatal onset. Other clinical manifestations include microcephaly, mucocutaneous lesions (hyperpigmentation, nail dystrophy, premalignant leukoplakia affecting oral and gastrointestinal mucosa), early onset bone marrow failure, immunodeficiency and pancytopenia. Cancer predisposition is also reported.\nEtiology\nHSS is caused by mutations in the DKC1 gene (Xq28), encoding the nucleolar protein dyskerin which interacts with the human telomerase RNA complex. Mutations in other genes (TERT, RTEL1 or TINF2, ACD, PARN) involved in telomere maintenance may be associated with this disorder.\nDiagnostic methods\nThe disorder diagnosis is based on neuroimaging. Molecular genetic testing is needed to confirm diagnosis.\nDifferential diagnosis\nDifferential diagnoses include dyskeratosis congenita, Revesz-Debuse syndrome, Pseudo-TORCH syndrome, Fanconi anemia and Nijmegen breakage syndrome.\nAntenatal diagnosis\nIntrauterine growth failure and cerebellar hypoplasia can be detected by prenatal imaging (ultrasounds, MRI). If the familial mutation is known, prenatal genetic testing can be proposed.\nGenetic counseling\nHHS follows an X-linked recessive pattern of inheritance. The disorder is very rarely inherited as an autosomal recessive form.\nManagement and treatment\nThe aplastic anemia and immunodeficiency can be treated by bone marrow transplantation. Supportive treatment for gastrointestinal complications and infections is required.\nPrognosis\nThe prognosis is poor as the disease follows a very severe course and premature death in childhood can occur due to bone marrow failure, but survival into adulthood is possible.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Eugen BOLTSHAUSER"}
{"Disease Name": "HSD10 disease, infantile type", "Disease Definition": "A clinical subtype of HSD10 disease, a rare neurometabolic disorder. Affected boys may show lethargy, poor feeding and evidence of mitochondrial dysfunction in the newborn period, with subsequent mild developmental delay and abnormal muscle tone. Hallmark of the disease is progressive neurodegeneration and cardiomyopathy, which usually manifests between ages 6 months and 2 years with developmental regression, progressive visual and hearing loss, epilepsy and other neurological symptoms, and severe cardiomyopathy. Laboratory investigations show signs of mitochondrial dysfunction, and increased urinary excretion of specific isoleucine metabolites. The disease is often fatal around 2-4 years of age.", "ORPHA ID": 391428, "Summary": ""}
{"Disease Name": "HSD10 disease, neonatal type", "Disease Definition": "HSD10 disease, neonatal type is the most severe form of HSD10 disease, a rare neurometabolic disorder. It is characterized by severe metabolic/lactic acidosis in the neonatal period, little psychomotor development, seizures and severe progressive hypertrophic cardiomyopathy. Hepatic involvement and coagulopathy are rare. The disease is fatal within the first months of life.", "ORPHA ID": 391457, "Summary": ""}
{"Disease Name": "HSD10 disease", "Disease Definition": "HSD10 disease is a rare, life-threatening neurometabolic disease characterized by a progressive neurodegenerative course, epilepsy, retinopathy and progressive cardiomyopathy.", "ORPHA ID": 391417, "Summary": "Epidemiology\nPrevalence is unknown. So far, fewer than 40 cases have been reported worldwide.\nClinical description\nHSD10 disease is heterogeneous, including several clinical subtypes, and manifests by severe manifestations in males only; females are either asymptomatic or show non-progressive cognitive impairment ranging from learning difficulties to intellectual disability, as well as variable neurological abnormalities. HSD10 disease, infantile form is the classical presentation. Affected boys may show lethargy, poor feeding and evidence of mitochondrial dysfunction in the newborn period, with subsequent mild developmental delay and abnormal muscle tone. Hallmark of the disease is progressive neurodegeneration and cardiomyopathy, which usually manifests between ages 6 months and 2 years with loss of cognitive and motor skills, epilepsy, progressive visual impairment leading to blindness, and/or hearing loss. As neurodegeneration advances, patients develop progressive ataxia, choreoathetosis, and restlessness. The disease is generally fatal with death usually occurring between 2-4 years of age. Laboratory findings include lactic acidosis, hypoglycemia, hyperammonemia, and increased urinary excretion of specific organic acids. HSD10 disease, neonatal form is the most severe subtype. It is characterized by severe metabolic/lactic acidosis in the neonatal period, scarce neurological development, severe progressive cardiomyopathy and death within the first months of life. Other variants of HSD10 disease are less well defined and usually reflect attenuated forms. Affected individuals may have variable neurological and behavioral symptoms, intellectual disability which may be non-progressive, variable metabolic/non-neurological manifestations, or may be asymptomatic.\nEtiology\nHSD10 disease is mostly due to missense mutations in the HSD17B10 gene (Xp11.22), coding for 3-hydroxyacyl-CoA dehydrogenase type 2. This mitochondrial protein has at least dual function: (a) it is one of three proteins that constitute mitochondrial ribonuclease (RNase) P which is responsible for the cleavage of the mtDNA polycistronic transcript between mRNA and tRNA sequences; (b) the enzyme's dehydrogenase function is required for the breakdown of 2-methyl-3-hydroxybutyrate in isoleucine metabolism (MHBD) and may be active on other metabolites such as neuroactive steroids. Null mutations in the HSD17B10 gene are incompatible with life. The clinical manifestations of HSD10 disease are thought to be due to defective RNase P leading to mitochondrial dysfunction, whereas some metabolic abnormalities including the typical urinary organic acids findings are caused by impaired dehydrogenase function.\nDiagnostic methods\nDiagnosis is based on urinary organic acid analysis, as well as molecular studies. Elevated levels of isoleucine metabolites (in particular 3-hydroxy-2-methylbutyrate and tiglylglycine in conjunction with normal methylacetoacetate) are hallmark findings of the disease, although they reflect dehydrogenase and not RNase P dysfunction. Some individuals with HSD10 disease may show no biochemical abnormalities, whereas others with isolated dehydrogenase dysfunction may have little or no symptoms. Frequently there is biochemical or histological evidence of mitochondrial dysfunction such as rounded mitochondria with depleted cristae observed by microscopy. Diagnosis is confirmed by genetic analysis identifying a hypomorphic disease-causing mutation.\nDifferential diagnosis\nBiochemical abnormalities may resemble beta-ketothiolase deficiency. Clinical abnormalities are similar in other disorders affecting mtDNA transcript processing, in particular ELAC2-associated disease (combined oxidative phosphorylation defect type 17).\nAntenatal diagnosis\nPrenatal diagnosis is possible by molecular analysis.\nGenetic counseling\nHSD10 disease follows an X-linked inheritance with variable manifestation in females. Genetic counseling should be proposed to at-risk families.\nManagement and treatment\nAt present, there is no effective treatment for the disease. A low-protein, high-energy dietary regimen with carnitine supplementation reduces the accumulation of isoleucine metabolites in blood and urine, but does not improve psychomotor deterioration. Due to its ability to interfere with mitochondrial energy metabolism, valproic acid should be avoided.\nPrognosis\nThe prognosis is poor, especially for the neonatal and infantile forms of the disease. The prognosis for the attenuated or asymptomatic variants of the disease is currently unknown.\n\n                            Last update: \n                            October 2018\n\n\n                            - Expert reviewer(s): \n                            Pr Johannes ZSCHOCKE"}
{"Disease Name": "HTRA1-related autosomal dominant cerebral small vessel disease", "Disease Definition": "A rare genetic cerebral small vessel disease characterized by subcortical ischemic events associated with cognitive decline and gait disturbance with an age of onset typically in the sixth or seventh decade of life. Imaging reveals white matter hyperintensities, status cribrosus, lacunar infarcts, and sometimes microbleeds. Extra-neurological manifestations are absent.", "ORPHA ID": 482077, "Summary": ""}
{"Disease Name": "Hughes-Stovin syndrome", "Disease Definition": "Hughes-Stovin syndrome (HSS) is a life-threatening disorder, believed to be a cardiovascular clinical variant manifestation of Behçet's disease (BD; see this term). It is characterized by the association of multiple pulmonary artery aneurysms (PAAs) and peripheral venous thrombosis.", "ORPHA ID": 228116, "Summary": "Epidemiology\nPrevalence is unknown but fewer than 30 cases have been reported in the literature since its first description in 1959 by Hughes and Stovin.\nClinical description\nPatients (mostly men aged 12-40 years) generally present with the nonspecific signs of PAA (hemoptysis, cough, dyspnea, chest pain, and signs of pulmonary hypertension), following a history of peripheral venous thrombosis. Other associated signs may include fever and intracranial hypertension. Aneurysms usually involve the pulmonary arteries and the bronchial arteries resulting in subsequent hemoptysis. However, they can occur anywhere in systemic circulation. Recurrent phlebitis also commonly involves the large vessels, resulting in thrombus formation. In general, there is a predisposition for thrombus formation affecting the peripheral veins. Thrombosis of the vena cava and of the right atrium has also been described.\nEtiology\nThe etiology of HSS is unknown; however, it is assumed that HSS is a form of vasculitis following a similar mechanism of pathogenesis to that thought to be involved in BD.\nDiagnostic methods\nDiagnosis of HSS is made on the basis of the clinical picture (association of venous thrombosis and PAAs in a young patient), patient history and imaging studies (chest radiographs, conventional angiography or helical computed tomography) for detection and evaluation of the PAAs. Histologic studies show destruction of the arterial wall and perivascular lymphomonocytic infiltration of capillaries and venules.\nDifferential diagnosis\nThe pulmonary manifestations of HSS and BD have been reported to be identical, but the two syndromes can be distinguished on the basis of the absence of mucocutaneous findings in HSS.\nManagement and treatment\nInitial management of HSS often involves administration of corticosteroids, usually in combination with cytotoxic agents (intravenous cyclophosphamide followed by oral azathioprine) to stabilize the PAAs. Despite the presence of thrombosis, anticoagulants are contraindicated due to the risk of life-threatening PAA rupture. Surgical resection provides an effective treatment option for patients with unilateral or localized PAAs and less invasive approaches such as transcatheter embolization may be feasible in some cases.\nPrognosis\nAs most patients with HSS are diagnosed late in the disease course, the syndrome is associated with significant mortality due to massive hemoptysis resulting from PAA rupture or systemic bronchial artery hypertrophy secondary to ischemia related to the pulmonary artery occlusion.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Pr David SAADOUN  - Pr Bertrand WECHSLER"}
{"Disease Name": "Human infection by orthopoxvirus", "Disease Definition": "A rare viral disease characterized by fever, malaise, lymphadenopathy, and a maculopapular exanthema spreading from the site of infection to other regions of the body. The skin lesions eventually dry out and may leave behind scars. The most relevant orthopox species for human disease after the eradication of the variola virus, which was responsible for smallpox, are the monkeypox virus and the cowpox virus. Infections with these viruses typically take a benign course.", "ORPHA ID": 438279, "Summary": ""}
{"Disease Name": "Human prion disease", "Disease Definition": "A group of rare neurodegenerative diseases characterized by the accumulation of prions, abnormal variants of the cellular prion protein, primarily in brain tissue of affected individuals, as well as massive, rapid neuronal death, and an invariably fatal course. Human prion diseases most often occur sporadically but may also be of genetic origin or infectiously acquired. Irrespective of etiology, they are transmissible to other individuals.", "ORPHA ID": 56970, "Summary": ""}
{"Disease Name": "Humerus trochlea aplasia", "Disease Definition": "An extremely rare familial bone deformity described only in Japanese patients to date. The deformity is bilateral in nearly half of patients (with bilateral involvement, the condition is symmetrical) and sometimes causes ulnar nerve palsy or cubitus varus.", "ORPHA ID": 3383, "Summary": ""}
{"Disease Name": "Hunter-McAlpine syndrome", "Disease Definition": "Hunter-McAlpine craniosynostosis is characterised by craniosynostosis, intellectual deficit, short stature, facial dysmorphism (oval face with almond-shaped palpebral fissures, droopy eyelids and a small nose) and minor distal anomalies. It has been described in 10 patients. Transmission is autosomal dominant and the syndrome is associated with partial duplication of the long arm of chromosome 5 (5q35-5qter).", "ORPHA ID": 97340, "Summary": ""}
{"Disease Name": "Huntington disease-like 1", "Disease Definition": "A rare, genetic, human prion disease characterized by adult-onset neurodegenerative manifestations associated with a movement disorder and psychiatric/behavioral disturbances. Patients typically present personality changes, aggressiveness, manias, anxiety and/or depression in conjunction with rapidly progressive cognitive decline (presenting with dysarthria, apraxia, aphasia, and eventually leading to dementia) as well as ataxia (manifesting with gait disturbances, unsteadiness, coordination problems), Parkinsonism, myoclonus, and/or chorea. Additional features may include generalized spasticity, seizures, urine incontinence and pyramidal abnormalities.", "ORPHA ID": 157941, "Summary": ""}
{"Disease Name": "Huntington disease-like 2", "Disease Definition": "A rare severe neurodegenerative disorder that is considered one of the phenocopies of Huntington Disease (HD) affecting patients of African descent and characterized by a triad of movement (chorea, oculomotor, parkinsonism), psychiatric (prominently sadness, irritability and anxiety), and cognitive abnormalities (early cognitive decline and subcortical-like dementia).", "ORPHA ID": 98934, "Summary": "Epidemiology\nHuntington disease-like 2 (HDL2) has been exclusively reported in patients of African descent. Although the prevalence and incidence are unknown it is the most common HD phenocopy in African populations with the highest frequency of HDL2 reported in Johannesburg, South Africa.\nClinical description\nHDL2 usually presents in adulthood, but, as in Huntington disease (HD), the age of onset is inversely related to the size of the trinucleotide repeat expansion underlying the disorder. HDL2 manifests with chorea, and oculomotor abnormalities. This then progresses to parkinsonism with rigidity, bradykinesia and dystonia with dysphagia and weight loss finally dominating the clinical features. HDL2 has a heterogeneous neuropsychological profile characterized by early cognitive decline that progresses to a subcortical-like dementia in a heterogeneous fashion. The neuropsychiatric presentation is also variable but the most prominent symptoms include sadness, irritability and anxiety. Over the duration of the disease, the HDL2 and HD phenotypes are indistinguishable when comparing the cognitive, psychiatric and motor features. This makes HDL2 the disease which most closely resembles the HD phenotype.\nEtiology\nHDL2 is caused by expanded trinucleotide repeats of the JPH3 junctophilin 3 gene (16q24.3). Affected individuals have CTG/CAG repeat expansions of 41-60 triplets (normal range of repeats: 6-27).\nDiagnostic methods\nDiagnosis is based on analysis of the JPH3 gene in the presence of a clinical syndrome consistent with HDL2. Acanthocytosis was found in three cases but subsequently, this has not been found in other patients. Neuroimaging reveals bilateral striatal atrophy, in particular of the caudate nucleus. Generalized cortical atrophy may develop during the disease course. Neuropathologically, ubiquitin-immunoreactive intracellular neuronal inclusions are found in both HD and HDL2, however these only extend and become intranuclear inclusions in HD.\nDifferential diagnosis\nDifferential diagnoses include Huntington disease, Huntington-like disorders, McLeod neuroacanthocytosis syndrome, Parkinson disease, neuroferritinopathy, dentarubralpallidoluysian atrophy, chorea-acanthocytosis, benign hereditary chorea, spinocerebellar ataxia types 2,3,17, familial Creutzfeldt-Jakob disease, Wilson disease, aceruloplasminemia, pantothenate kinase-associated neurodegeneration, mitochondrial disorders, polycythemia rubra vera, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, familial Alzheimer, and Tourette syndrome.\nAntenatal diagnosis\nRoutine methods for prenatal genetic testing can be applied.\nGenetic counseling\nHDL2 follows an autosomal dominant pattern of inheritance and genetic counseling is recommended. Anticipation has not been established yet in HDL2. Concerning pre-symptomatic testing, the same considerations as in Huntington disease should be followed: testing is usually requested or proposed when an individual has a parent who is known to have or is suspected of having a Huntington-like disease.\nManagement and treatment\nNo curative or disease-modifying treatments are currently available and management is symptomatic and is similar to that of HD.\nPrognosis\nHDL2 is a relentlessly progressive disorder with a poor prognosis.\n\n                            Last update: \n                            April 2022\n\n\n                            - Expert reviewer(s): \n                            Dr David ANDERSON  -  Aline FERREIRA-CORREIA"}
{"Disease Name": "Huntington disease-like 3", "Disease Definition": "Huntington disease-like 3 is a rare Huntington disease-like syndrome characterized by childhood-onset progressive neurologic deterioration with pyramidal and extrapyramidal abnormalities, chorea, dystonia, ataxia, gait instability, spasticity, seizures, mutism, and (on brain MRI) progressive frontal cortical atrophy and bilateral caudate atrophy.", "ORPHA ID": 157946, "Summary": ""}
{"Disease Name": "Huntington disease-like syndrome due to C9ORF72 expansions", "Disease Definition": "A rare, genetic neurodegenerative disease characterized by movement disorders, including dystonia, chorea, myoclonus, tremor and rigidity. Associated features are also cognitive and memory impairment, early psychiatric disturbances and behavioral problems.", "ORPHA ID": 401901, "Summary": ""}
{"Disease Name": "Huntington disease", "Disease Definition": "Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia.", "ORPHA ID": 399, "Summary": "Epidemiology\nPrevalence in the Caucasian population is estimated at 1/20, 000-1/10,000.\nClinical description\nMean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington disease, JHD; see this term). The classic sign is chorea that gradually spreads to all muscles. Other unwanted movements include tics, comparable to those seen in Tourette syndrome (see this term), but these are fairly rare. Cerebellar signs can appear sporadically, similar to the presence of hypo- and hypermetria. Dystonia (e.g. torticollis) can be the first motor sign in Huntington disease. Other less well-known, but prevalent and often debilitating features of HD include unintended weight loss, sleep- and circadian rhythm disturbances and autonomic nervous system dysfunction. Dysarthria and dysphagia become very prominent during the course of the disease. Talking and swallowing gradually become more problematic leading to choking at any time in some patients. All patients develop hypokinesia and rigidity leading to bradykinesia and severe akinesia. All psychomotor processes become severely impaired. Patients also experience cognitive decline. Psychiatric symptoms are very common in the early stage of the disease, often prior to onset of motor symptoms. The percentage of patients with psychiatric signs, such as low self-esteem, feelings of guilt, anxiety and apathy, varies between 33% and 76%. Suicide occurs more frequently in early symptomatic patients and also in premanifest gene carriers. The most risky periods for suicide are around the time of the gene test and when independence starts to diminish.\nEtiology\nHD is caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4 (4p16.3) in the huntingtin gene, HTT. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD, the repeat often exceeds 55.\nDiagnostic methods\nDiagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD and is confirmed by DNA determination Premanifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not.\nDifferential diagnosis\nDifferential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed.\nAntenatal diagnosis\nPrenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Pre-implantation diagnosis with in vitro fertilization is offered in several countries.\nGenetic counseling\nHD is transmitted in an autosomal dominant manner.\nManagement and treatment\nTo date, no cure is available. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required.\nPrognosis\nThe progression of the disease leads to complete dependency in daily life, which results in patients requiring full-time care, and finally death. The most common cause of death is pneumonia, followed by suicide.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr R.A.C. [Raymund] ROOS"}
{"Disease Name": "Huriez syndrome", "Disease Definition": "A rare genetic skin disease characterized by the triad of congenital scleroatrophy predominantly of the hands with sclerodactyly, palmoplantar keratoderma, and nail changes (consisting of hypoplasia, ridging, clubbing, and white discoloration). Additional features include palmar hypohidrosis and a high susceptibility to early-onset squamous cell carcinoma of affected skin areas.", "ORPHA ID": 384, "Summary": ""}
{"Disease Name": "Hurler syndrome", "Disease Definition": "Hurler syndrome is the most severe form of mucopolysaccharidosis type 1 (MPS1; see this term), a rare lysosomal storage disease, characterized by skeletal abnormalities, cognitive impairment, heart disease, respiratory problems, enlarged liver and spleen, characteristic facies and reduced life expectancy.", "ORPHA ID": 93473, "Summary": "Epidemiology\nThe prevalence of the Hurler subtype of MPS1 is estimated at 1/200,000 in Europe.\nClinical description\nPatients present within the first year of life with musculoskeletal alterations including short stature, dysostosis multiplex, thoracic-lumbar kyphosis, progressive coarsening of the facial features (including large head with bulging frontal bones, depressed nasal bridge with broad nasal tip and anteverted nostrils, full cheeks and enlarged lips), cardiomyopathy and valvular abnormalities, neurosensorial hearing loss, enlarged tonsils and adenoids, and nasal secretion. Developmental delay is usually observed between 12 and 24 months of life and is primarily in the realm of speech with progressive cognitive and sensorial deterioration. Hydrocephaly can occur after the age of two. Diffuse corneal compromise leading to corneal opacity becomes detectable from three years of age onwards. Other manifestations include organomegaly, hernias and hirsutism.\nEtiology\nHurler syndrome is caused by mutations in the IDUAgene (4p16.3) leading to a complete deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate.\nDiagnostic methods\nEarly diagnosis is difficult as the first clinical manifestations are not specific. Diagnosis is based on detection of increased urinary excretion of heparan and dermatan sulfate and confirmed by demonstration of enzymatic deficiency in leukocytes or fibroblasts. Genetic testing is available.\nDifferential diagnosis\nDifferential diagnoses include the milder form of mucopolysaccharidosis type 1, the Hurler-Scheie syndrome (see this term), although this form is associated with only slight cognitive impairment. Differential diagnoses also include mucopolysaccharidosis type 6 and type 2 and mucolipidosis type 2 (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible by measurement of enzymatic activity in cultivated chorionic villus or amniocytes and by genetic testing if the disease-causing mutation is known.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling and testing should be offered to couples with a positive family history.\nManagement and treatment\nManagement is multidisciplinary. Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for patients with Hurler syndrome under 2.5 years of age (and in selected patients over this age limit) as it can prolong survival, preserve neurocognition, and ameliorate some somatic features. HSCT should be performed early in the disease course, before developmental deterioration begins. Enzyme replacement therapy (ERT) with laronidase is recommended for all Hurler patients and is a lifelong therapy which alleviates non neurological symptoms. The early use of ERT has been shown to delay or even prevent the development of some of the clinical features of this condition. Additional management of Hurler syndrome is largely supportive, and includes surgical interventions (e.g. adenotonsillectomy, hernia repair, ventriculoperitoneal shunt, cardiac valve replacement, carpal tunnel release, spinal decompression); physical, occupational, and speech therapies; respiratory support (e.g., continuous positive pressure ventilation with oxygen supplementation); hearing aids; and medications for pain and gastrointestinal disturbances.\nPrognosis\nPatients often succumb to the condition in the first decade from respiratory and cardiac complications but ERT and HSCT can improve life expectancy. The timing of diagnosis, and therefore of treatment initiation, is an important factor for the success of both HSCT and laronidase.\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Michael BECK"}
{"Disease Name": "Hurler-Scheie syndrome", "Disease Definition": "Hurler-Scheie syndrome is the intermediate form of mucopolysaccharidosis type 1 (MPS1; see this term) between the two extremes Hurler syndrome and Scheie syndrome (see these terms); it is a rare lysosomal storage disease, characterized by skeletal deformities and a delay in motor development.", "ORPHA ID": 93476, "Summary": "Epidemiology\nThe prevalence of MPS I has been estimated at 1/100,000, with Hurler-Scheie syndrome accounting for 23% of cases or a prevalence of approximately 1/435,000.\nClinical description\nPatients with Hurler-Scheie syndrome have normal or almost normal intelligence but exhibit various degrees of physical impairment. Patients present in the first years of life with musculoskeletal alterations to different degrees including short stature, multiple dysostosis, thoracic-lumbar kyphosis, progressive coarsening of the facial features to different degrees, cardiomyopathy and valvular abnormalities, neurosensorial hearing loss, enlarged tonsils and adenoids, and nasal secretion. Hydrocephaly can occur after the age of two. Corneal opacity is seen between two and four years of age and requires keratoplasty to restore sight. Other manifestations may include organomegaly, hernias and hirsutism.\nEtiology\nHurler-Scheie syndrome is caused by mutations in the IDUA gene (4p16.3) leading to partial deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate.\nDiagnostic methods\nEarly diagnosis is difficult because the first clinical signs are not specific, but is very important to allow early treatment. Diagnosis is based on detection of increased urinary secretion of heparan and dermatan sulfate through 1,9-dimethylmethylene blue (DMB) test and glycosaminoglycan (GAG) electrophoresis, and demonstration of enzymatic deficiency in leukocytes or fibroblasts. Genetic testing is available.\nDifferential diagnosis\nDifferential diagnoses include the milder and more severe forms of mucopolysaccharidosis type 1 (Scheie syndrome and Hurler syndrome respectively), mucopolysaccharidosis typeVI and mucopolysaccharidosis type II (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible by measurement of enzymatic activity in cultivated chorionic villus or amniocytes and by genetic testing if the disease-causing mutation is known.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling is recommended.\nManagement and treatment\nManagement should be carried out by a multidisciplinary team and should include physiotherapy to maintain range of movement. Bone marrow or umbilical cord blood transplant has been successful and can preserve neurocognition, improve some aspects of the somatic disease and increase survival. However it is associated with many risks and most of the positive effects occur only if the procedure is performed in the first two years of life. The enzyme substitute (laronidase) obtained EU marketing authorization as an orphan drug in 2003. Given through weekly infusions it leads to improvement of lung function and joint mobility. Enzyme replacement therapy (ERT) should be started at diagnosis and may be beneficial in patients awaiting hematopoietic stem cell transplantation (HSCT). Early treatment slows the progression of the disease. In individual patients with MPS1 of intermediate severity, HSCT may be considered if there is a suitable donor. There are however no data on the efficacy of HSCT in patients with this form of the disease.\nPrognosis\nLife expectancy for Hurler-Scheie syndrome may be reduced, with death occurring before adolescence due to serious cardiovascular and respiratory complications.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Michael BECK"}
{"Disease Name": "Hutchinson-Gilford progeria syndrome", "Disease Definition": "Hutchinson-Gilford progeria syndrome is a rare, fatal, autosomal dominant and premature aging disease, beginning in childhood and characterized by growth reduction, failure to thrive, a typical facial appearance (prominent forehead, protuberant eyes, thin nose with a beaked tip, thin lips, micrognathia and protruding ears) and distinct dermatologic features (generalized alopecia, aged-looking skin, sclerotic and dimpled skin over the abdomen and extremities, prominent cutaneous vasculature, dyspigmentation, nail hypoplasia and loss of subcutaneous fat).", "ORPHA ID": 740, "Summary": ""}
{"Disease Name": "Hyaline fibromatosis syndrome", "Disease Definition": "A rare genetic disease characterized by infantile or childhood onset of abnormal growth of hyalinized fibrous tissue, giving rise to multiple cutaneous nodules and/or pearly papules predominantly affecting the scalp, ears, neck, face, hands, and feet. Involvement of other organs results in gingival hyperplasia, osteolytic bone lesions, and joint contractures. Some patients exhibit visceral involvement with intractable diarrhea, increased susceptibility to infections, and severe failure to thrive.", "ORPHA ID": 498474, "Summary": ""}
{"Disease Name": "Hyaluronidase deficiency", "Disease Definition": "A rare form of mucopolysaccharidosis characterized by abnormal storage of hyaluronan in lysosomes due to deficiency of hyaluronidase 1. Clinical manifestations include knee and/or hip pain associated with swelling, diffuse joint involvement with proliferative synovitis and occurrence of multiple periarticular soft-tissue masses, short stature, and dysmorphic craniofacial features (such as flattened nasal bridge, bifid uvula, and cleft palate).", "ORPHA ID": 67041, "Summary": ""}
{"Disease Name": "Hydatidiform mole", "Disease Definition": "A rare, benign gestational trophoblastic disease that develops during pregnancy and is characterized by the abnormal fertilization, trophoblastic proliferation, and abnormal or absent embryo development. Hydatidiform moles can be either complete or partial.", "ORPHA ID": 99927, "Summary": "Epidemiology\nIn Europe, the condition occurs in approximately 1/1,000 pregnancies.\nClinical description\nComplete moles are asymptomatic in 40% of cases. Most often, a mole is detected upon suspicion of miscarriage in the first trimester, with bleeding and pelvic pain. The clinical signs in the second trimester (vomiting, metrorrhagia, abnormal increase in the size of the uterus, and more rarely anemia or preeclampsia) are observed less often, due to early detection by ultrasound examination. Hyperthyroidism is exceptional. The clinical signs of a partial mole (metrorrhagia, vomiting, etc.) are rare. A mole is usually detected histologically on analysis of aspiration samples from a suspected miscarriage.\nEtiology\nThe moles are caused by abnormal fertilization with an excess of paternal chromosome material. Complete moles result from fertilization of an enucleated ovocyte by one or two haploid spermatozoa. The karyotype is 46,XX (75% of cases) or 46,XY (25%). The mole is characterized by trophoblastic hyperplasia associated with generalized degeneration of chorionic villi and absence of an amniotic cavity and embryonal tissue. Partial moles result from fertilization of a normal ovocyte by two spermatozoa or one abnormal spermatozoon. This type of mole is characterized by focal trophoblastic hyperplasia, localized degeneration of chorionic villi and identifiable embryonal tissue. The karyotype is triploid in 99% of cases.\nDiagnostic methods\nUltrasound of a complete mole may show a classic ''snow storm'' appearance (solid, hyperechoic areas of varying forms interspersed with liquid areas of various sizes) occupying the entire uterine cavity. Earlier ultrasound before 9-10 weeks of pregnancy can show a limited vesicular appearance of the placenta. Ultrasound of a partial mole may sometimes show focal vesicular change. Embryonic structures without an increase in uterine size are commonly found. Diagnosis is based on histological examination of the product of fertilization. Expert pathology review is often useful. When hydatidiform mole is suspected, determination of total chorionic gonadotropin (hCG) must be performed.\nDifferential diagnosis\nMoles may be, but should not be, confused with gestational trophoblastic neoplasms or with prolonged retention of a ''classic'' spontaneous miscarriage.\nGenetic counseling\nAside from very rare cases of recurrent moles in the same patient or in the same family (1% of cases, in which a mutation in the NLRP7, KHDC3L, MEI1 or C11orf80 genes have sometimes been found), genetic counseling is not required.\nManagement and treatment\nTreatment of moles consists of suction evacuation of the uterine contents. Ultrasound guidance may be useful. Evacuation must be scheduled rapidly due to the risk of complications which increases with gestational age. Due to possible progression to gestational trophoblastic neoplasia (GTN), plasma hCG should be monitored until the levels normalize. Diagnosis of GTN warrants disease staging and appropriate chemotherapy.\nPrognosis\nAfter removal, the prognosis is excellent. The main risk is retention by incomplete aspiration (up 25% of cases) which may justify ultrasound follow-up in the weeks following aspiration. Retention (ultrasound image of more than 17 mm in anteroposterior diameter) may require a repeated aspiration in certain clinical circumstances. In about 15 % of cases of complete moles and in 0.5 to 5% of partial moles, the condition leads to gestational trophoblastic neoplasia in the weeks and months following mole evacuation.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Dr John COULTER"}
{"Disease Name": "Hydranencephaly", "Disease Definition": "A rare cerebral malformation characterized by an almost or complete lack of cortex, specifically the cerebral hemispheres, with the cranium and meninges completely intact. In most cases, death occurs in utero or in the first weeks of life. Developmental delay, drug-resistant seizures, spastic diplegia, severe growth failure, deafness and blindness are typical.", "ORPHA ID": 2177, "Summary": ""}
{"Disease Name": "Hydroa vacciniforme-like lymphoma", "Disease Definition": "A very rare Epstein-Barr virus-associated lymphoproliferative disorder characterized by a chronic, recurrent, vesiculopapular rash, which subsequently ulcerates and scars, located mainly on sun-exposed areas and which is associated with systemic manifestations, such as fever, weight loss, asthenia, facial edema, arthralgia, lymphadenopathy, hepatosplenomegaly and/or increased liver enzymes. Hypersensitivity to mosquito bites has been associated and an increased risk of developing systemic lymphoma has been reported.", "ORPHA ID": 364039, "Summary": ""}
{"Disease Name": "Hydroa vacciniforme", "Disease Definition": "A rare photodermatosis characterized by the development of pruritic or painful vesicles in a photodistributed pattern in response to sunlight exposure. The lesions heal with permanent varioliform scarring. Ocular involvement, deformities of ears and nose, or contractures of the fingers may occasionally be observed. Systemic signs and symptoms are absent. The condition typically occurs in childhood and regresses spontaneously in adolescence or young adulthood.", "ORPHA ID": 330058, "Summary": ""}
{"Disease Name": "Hydrocephalus with stenosis of the aqueduct of Sylvius", "Disease Definition": "A congenital, X-linked, clinical subtype of L1 syndrome characterized by severe hydrocephalus often of prenatal onset, adducted thumbs, spasticity (mostly evidenced by brisk tendon reflexes and extensor plantar responses) and moderate to severe intellectual disability. This subtype represents the severe end of the L1 syndrome spectrum and is associated with poor prognosis.", "ORPHA ID": 2182, "Summary": ""}
{"Disease Name": "Hydrocephalus-blue sclerae-nephropathy syndrome", "Disease Definition": "A rare, genetic, renal malformation syndrome characterized by nephrotic syndrome with focal segmental sclerosis associated with hydrocephalus, thin skin and blue sclerae. There have been no further descriptions in the literature since 1978.", "ORPHA ID": 2186, "Summary": ""}
{"Disease Name": "Hydrocephalus-costovertebral dysplasia-Sprengel anomaly syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized principally by Sprengel anomaly (upward displacement of the scapula) and hydrocephaly. Other anomalies such as global developmental delay, psychosis, brachydactyly, and costovertebral dysplasia may also be present.", "ORPHA ID": 2180, "Summary": ""}
{"Disease Name": "Hydrocephalus-obesity-hypogonadism syndrome", "Disease Definition": "A rare form of syndromic obesity characterized by the association of congenital hydrocephalus, centripetal obesity, hypogonadism, intellectual deficit and short stature.", "ORPHA ID": 2183, "Summary": "Epidemiology\nIt has been described in two males from one family.\nGenetic counseling\nAn X-linked recessive mode of inheritance was suggested.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "Hydrocephaly-cerebellar agenesis syndrome", "Disease Definition": "A rare developmental defect during embryogenesis malformation syndrome characterized by congenital, non-communicating hydrocephalus, cerebellar agenesis and absence of the Luschka and Magendie foramina. Patients present with hypotonia, areflexia or hyporeflexia, seizures and/or cyanosis shortly after birth. The condition is fatal in the neonatal period. There have been no further descriptions in the literature since 1978.", "ORPHA ID": 1397, "Summary": ""}
{"Disease Name": "Hydrocephaly-low insertion umbilicus syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by congenital hydrocephalus involving the lateral ventricles, low-set umbilicus, bilateral inguinal hernia, and mild facial dysmorphism (such as epicanthal folds, broad, flat nasal bridge, and small, bulbous nose). Additional reported manifestations include unilateral cryptorchidism, vesicoureteral reflux, and tetralogy of Fallot. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 2184, "Summary": ""}
{"Disease Name": "Hydrocephaly-tall stature-joint laxity syndrome", "Disease Definition": "Hydrocephaly-tall stature-joint laxity syndrome is a multiple congenital anomalies syndrome described in two sisters and characterized by the presence of hydrocephalus (onset in infancy), tall stature, joint laxity, and thoracolumbar kyphosis. There have been no further descriptions in the literature since 1989.", "ORPHA ID": 2181, "Summary": ""}
{"Disease Name": "Hydrolethalus", "Disease Definition": "Hydrolethalus (HLS) is a severe fetal malformation syndrome characterized by craniofacial dysmorphic features, central nervous system, cardiac, respiratory tract and limb abnormalities.", "ORPHA ID": 2189, "Summary": "Epidemiology\nHLS is mostly present in families of Finnish descent, and annual incidence has been estimated at 1/20,000 in Finland. The mutation carrier frequency in the Western parts of Finland is 1.1% and 2.5% in Central and Eastern parts. The disease is much rarer in other geographical areas. The prevalence is not known.\nClinical description\nMicrognathia and retrognathia, cleft lip/palate, a poorly formed nose, posteriorly rotated ears and deep-set eyes are the main craniofacial dysmorphic features observed in HLS. A midline defect in the occipital bone dorsal to the foramen magnum is present, resulting in a keyhole-shaped defect. Brain abnormalities include hydrocephaly and agenesis of midline structures such as corpus callosum, cerebellar vermis and septum pellucidum, leading to a wide opened fluid-filled space between lateral ventricles. HLS is also characterized by postaxial and preaxial polydactyly, respectively in the hands and feet, the latter being clubbed. About half of the patients have large septal cardiac defect. Abnormal lobulation of the lungs, stenosis of the airways (larynx, trachea or bronchus), and abnormal genitalia (including uterus duplex in females and ectopic testis in males) are also found.\nEtiology\nHLS is caused by mutations in HYLS1 (11q24.2) and KIF7 (15q26.1). All Finnish cases are homozygous for an A to G mutation in exon 6 of i>HYLS1 resulting in D211G substitution. The KIF7 mutation has been characterized in only one HLS family to date. Both genes code for ciliary or centriolar proteins that seem to be involved in early embryonic development of the midline.\nDiagnostic methods\nUltrasound scan during pregnancy often reveals hydrocephaly and an abnormal structure of the brain. Cleft lip/palate, polydactyly, especially double big-toe with club-feet, and the heart defect may also be visible. Diagnosis of a newborn is based on physical examination, brain imaging autopsy, and/or genetic tests. Genetic testing of the affected child to verify the mutation helps prenatal diagnosis in future pregnancies.\nDifferential diagnosis\nDifferential diagnosis of HLS includes, in the absence of an index case, other midline multiple malformation syndromes like Pallister-Hall, pseudo-trisomy 13, oro-facio-digital type IV or VI, Joubert syndromes, as well as the severe form of Smith-Lemli-Opitz syndrome (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis by ultrasonography and/or genetic testing is feasible at the end of the first trimester when a previous pregnancy was affected. HLS is associated with hydramnios (often severe) and preterm delivery when pregnancy evolves spontaneously.\nGenetic counseling\nAs an autosomal recessive syndrome, HLS has a 25% recurrence risk after an affected pregnancy. Genetic counseling should be offered to affected families.\nManagement and treatment\nThere is no treatment for HLS.\nPrognosis\nStillbirth or neonatal death is the rule, although rare cases with several months survival have been reported.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Riitta SALONEN-KAJANDER"}
{"Disease Name": "Hydrops fetalis", "Disease Definition": "Hydrops fetalis is a severe and challenging fetal condition usually defined as the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities that manifests as edema, pleural and pericardial effusion and ascites. It is the end-stage of a wide variety of disorders. The cause may be immunologic (immune hydrops fetalis, IHF) or non immunologic (non-immune hydrops fetalis, NIHF), depending on the presence or absence of maternal antibodies against fetal red cell antigens (ABO incompatibility or rhesus (Rh) incompatibility).", "ORPHA ID": 1041, "Summary": ""}
{"Disease Name": "Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome", "Disease Definition": "A rare mitochondrial disease characterized by prenatal complications including oligohydramnios, fetal growth restriction, hydrops, and anemia, followed by severe lactic acidosis, hyaline membrane disease, pulmonary hypertension, cardiac anomalies, liver dysfunction, urogenital abnormalities and progressive renal disease, seizures, thrombocytopenia, and sideroblastic anemia resulting in multisystem organ failure and death shortly after birth. Less severely affected patients surviving the neonatal period and showing sensorineural hearing loss and developmental delay have been reported.", "ORPHA ID": 528091, "Summary": ""}
{"Disease Name": "Hydroxykynureninuria", "Disease Definition": "A rare, genetic disorder of tryptophan metabolism characterized by massive urinary excretion of xanthurenic acid (XA), 3-hydroxykynurenine and kynurenine and increased XA concentration in plasma. The clinical phenotype is highly variable, ranging from asymptomatic or mild cases presentating with jaundice and vomiting, with subsequent normal development and growth, to more severe cases with manifestions which include intellectual disability, cerebellar ataxia, pellagra, progressive encephalopathy with muscular hypotonia, global developmental delay, stereotyped gestures and/or congenital deafness.", "ORPHA ID": 79155, "Summary": ""}
{"Disease Name": "Hymenolepiasis", "Disease Definition": "Hymenolepiasis is a cosmopolitan parasitosis caused by a hymenolepidid tapeworm infection, most commonly Hymenolepis nana, that is reported worldwide but particularly in tropical and subtropical countries and which is usually asymptomatic but in severe cases can also manifest with nausea, abdominal pain, anorexia, diarrhea and overall weakness.", "ORPHA ID": 401, "Summary": ""}
{"Disease Name": "Hyper-beta-alaninemia", "Disease Definition": "A rare, genetic disorder of pyrimidine metabolism characterized by increased serum beta-alanine levels and severe phenotype including hypotonia, malaise, seizures, respiratory distress, lethargy and encephalopathy. Urinary excretion of beta-alanine, beta-amino-isobutyric acid, taurine, and gamma-amino-butyric acid is also elevated. There have been no further descriptions in the literature since 1994.", "ORPHA ID": 309147, "Summary": ""}
{"Disease Name": "Hyper-IgM syndrome with susceptibility to opportunistic infections", "Disease Definition": "Hyper-IgM syndrome with susceptibility to opportunistic infections is a rare, genetic, non-severe combined immunodeficiency disorder characterized by normal or elevated IgM serum levels with low or absent IgG, IgA and IgE serum concentrations, which manifests with recurrent or severe bacterial infections and increased susceptibility to opportunistic infections (in particular, pneumonia due to P. jiroveci, but also chronic cryptosporidial, cryptococcal, cytomegalovirus and toxoplasma infections). Hematologic disorders (neutropenia, anemia, thrombocytopenia) are frequently associated. Immunologic findings reveal decreased numbers of CD27+ memory B cells and lack of germinal center formation.", "ORPHA ID": 183663, "Summary": ""}
{"Disease Name": "Hyper-IgM syndrome without susceptibility to opportunistic infections", "Disease Definition": "Hyper-IgM syndrome without susceptibility to opportunistic infections is a rare, genetic, primary immunodeficiency due to a defect in adaptive immunity disorder characterized by normal or elevated IgM serum levels with low or absent IgG, IgA and IgE serum concentrations, which manifests with recurrent bacterial sinopulmonary and gastrointestinal infections, with frequent lymphoid hyperplasia (peripheral lymphadenopathy, tonsillar hypertrophy), with no increased susceptibility to opportunistic infections. Autoimmune manifestations (including immune cytopenias, arthritis and hepatitis) are occasionally associated. Immunologic findings reveal absent immunoglobulin class switch recombination and lack of defect of immunoglobulin somatic hypermutations in the presence of normal numbers of CD27+ memory B cells.", "ORPHA ID": 183666, "Summary": ""}
{"Disease Name": "Hyperammonemia due to N-acetylglutamate synthase deficiency", "Disease Definition": "A rare disorder of urea cycle metabolism causing a deficit of ammonia detoxification and arginine synthesis, and characterized by hyperammonemia of variable severity. Manifestations range from neonatal presentation of poor feeding, vomiting, lethargy, tachypnea, convulsions and coma to adult-onset headaches, hazy gastrointestinal symptoms, seizures, behavioral/psychiatric problems, confusion and lethargy.", "ORPHA ID": 927, "Summary": "Epidemiology\nTo date, approximately 100 cases have been reported worldwide.\nClinical description\nOnset occurs at any age... The clinical manifestations are variable but common features include vomiting, hyperactivity or lethargy, diarrhea, poor feeding, seizures, hypotonia, global development delay, psychiatric symptoms and respiratory distress. The hyperammonemia might be severe and may lead to hyperammonemic coma.\nEtiology\nThe primary disorder is caused by mutations in the NAGS gene (17q21.31), leading to a total or partial lack of activity in the encoded protein, N-acetylglutamate synthase (NAGS). NAGS is an allosteric activator of carbamylphosphate synthetase I (CPSI), the enzyme catalyzing the first step in ureagenesis. NAGS deficiency may also be secondary to certain organic acid disorders, defects in fatty acid metabolism or valproic acid treatment.\nDiagnostic methods\nBesides the hyperammonemia, diagnosis is evoked by a rise in glutamine coupled with decrease of citrulline/arginine and absence of urinary orotic acid. Confirmation by DNA analysis is mandatory. If the latter is not conclusive, enzymatic NAGS activity upon liver biopsy can help in the definite diagnosis.\nDifferential diagnosis\nThe principle differential diagnosis is carbamoyl phosphate synthetase 1 deficiency.\nGenetic counseling\nThe primary disorder is transmitted as an autosomal recessive trait. The risk to siblings of inheriting the disease is 25%. Offspring of affected individuals are obligate carriers.\nManagement and treatment\nAcute treatment of hyperammonemia of unknown etiology consists in high glucose perfusion (with withdrawal of proteins and lipids) and administration of ammonia scavengers (sodium benzoate and/or sodium phenylbutyrate), L-Arginine and N-carbamylglutamate. Once definite diagnosis of NAGS deficiency is established, daily administration of N-carbamylglutamate, a structural analogue of NAGS that activates CPSI, might be sufficient as a unique treatment without protein restriction.\nPrognosis\nIn most cases, early treatment with N-carbamylglutamate (i.e. before the onset of permanent neurological sequelae) allows normal global development and an excellent quality of life without diet. Although the severity of the disorder is variable, the prognosis without treatment may be poor with neurological deficit and a potentially fatal outcome.\n\n                            Last update: \n                            May 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Dries DOBBELAERE"}
{"Disease Name": "Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency", "Disease Definition": "A rare, hereditary inborn error of metabolism characterized by an acute onset of encephalopathy in infancy or early childhood. Apart from these episodic acute events, the disorder shows a relatively benign course. Multiple metabolic abnormalities are present, including metabolic acidosis, respiratory alkalosis, hypoglycemia, increased serum lactate and alanine.", "ORPHA ID": 401948, "Summary": ""}
{"Disease Name": "Hyperandrogenism due to cortisone reductase deficiency", "Disease Definition": "A rare, genetic, endocrine disease characterized by defect in conversion of cortisone to active cortisol, resulting in ACTH-mediated excessive androgen release from adrenal glands. Premature adrenarche is typical with precocious pseudopuberty, proportionate tall stature and accelerated bone maturation in males, and hirsutism, oligoamenorrhea, central obesity and infertility in females. Imaging studies may indicate adrenal hyperplasia.", "ORPHA ID": 168588, "Summary": ""}
{"Disease Name": "Hyperbiliverdinemia", "Disease Definition": "Hyperbiliverdinemia is a rare, genetic hepatic disease characterized by the presence of green coloration of the skin, urine, plasma and other body fluids (ascites, breastmilk) or parts (sclerae) due to increased serum levels of biliverdin in association with biliary obstruction and/or liver failure. Association with malnutrition, medication, and congenital biliary atresia has also been reported.", "ORPHA ID": 276405, "Summary": ""}
{"Disease Name": "Hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency", "Disease Definition": "A rare sterol metabolism disorder characterized by increased LDL cholesterol serum levels (which are resistant to treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors), hypertriglyceridemia, and decreased rate of bile acid excretion, resulting from cholesterol 7alpha-hydroxylase deficiency. Premature gallstone disease and/or premature coronary and peripheral vascular disease are frequently associated.", "ORPHA ID": 209902, "Summary": ""}
{"Disease Name": "Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency", "Disease Definition": "A rare congenital disorder of glycosylation characterized by cerebral and portal vein thrombosis, portal hypertension, macrocephaly, and persistent absence seizures. Additional reported features include mild to moderate global developmental delay and intellectual disability, as well as thrombocytopenia. Brain imaging may show variable stages of infarction and cerebral and cerebellar atrophy.", "ORPHA ID": 83639, "Summary": ""}
{"Disease Name": "Hyperekplexia-epilepsy syndrome", "Disease Definition": "A rare, X-linked, syndromic intellectual disability disease characterized by neonatal hypertonia which evolves to hypotonia and an exaggerated startle response (to sudden visual, auditory or tactile stimuli), followed by the development of early-onset, frequently refractory, tonic or myoclonic seizures. Progressive epileptic encephalopathy, intellectual disability, and psychomotor development arrest, with subsequent decline, may be additionally associated.", "ORPHA ID": 163985, "Summary": ""}
{"Disease Name": "Hypereosinophilic syndrome", "Disease Definition": "Hypereosinophilic syndrome (HES) constitutes a rare and heterogeneous group of disorders, defined as persistent and marked blood eosinophilia and/or tissue eosinophilia associated with a wide range of clinical manifestations reflecting eosinophil-induced tissue/organ damage.", "ORPHA ID": 168956, "Summary": "Epidemiology\nPrevalence is unknown. It frequently occurs in middle-aged patients, but may concern any age group.\nClinical description\nTarget-organ damage mediated by eosinophils is highly variable among patients, and consists of dermatological involvement (urticaria, eczema, angioedema, pruriginous papules, nodules, erythroderma) in more than 50% of cases, followed by involvement of lungs (cough, breathlessness and wheezing) and digestive tract (nausea, vomiting, abdominal pain, diarrhea, ascites) in roughly 40%. Cardiac involvement is less frequent, but must be recognized early due to irreversible and life-threatening complications such as acute myocarditis, intraventricular thrombus, endomyocardial fibrosis and valve thickening and/or destruction. Constitutional symptoms of fever, myalgia and fatigue may occur. Other common complications include central or peripheral nervous system involvement, hepato- and/or splenomegaly, and coagulation disorders. Skin involvement is more frequently seen in lymphocytic HES and cardiac damage in FIP1L1-PDGFRA (F/P) fusion gene positive (+) chronic eosinophilic leukemia (CEL; see this term).\nEtiology\nRecent advances in underlying pathogenesis have established that what was once thought to be ''idiopathic'' HES may in some cases be due to either primitive involvement of myeloid cells (primary HES), essentially due to occurrence of an interstitial chromosomal deletion on 4q12 leading to creation of the F/P fusion gene (CEL), or to increased interleukin (IL)-5 production by a clonally expanded T cell population (lymphocytic variant HES), most frequently characterized by a CD3-CD4+ phenotype, or due to other reactive causes (secondary HES) such as helminthic infection. However, in roughly 3/4 of cases, pathogenesis remains unknown, now defining idiopathic HES. In those with unexplained persistent asymptomatic hypereosinophilia (HE), the provisional term HE of undetermined significance is given. A small subgroup of patients have HES that shows familial clustering (familial HES), presumably due to an as of yet unknown inherited gene.\nDiagnostic methods\nDiagnosis of HES relies on the observation of persistent and marked HE (> 1.5 × 109/L) and /or eosinophilic infiltration of tissue(s) responsible for target-organ damage. Once these criteria are fulfilled, further testing for eventual pathogenic classification is warranted using appropriate cytogenetic, phenotypic, and functional approaches. If underlying causes of HE have been excluded, the term idiopathic HES is appropriate.\nDifferential diagnosis\nDifferential diagnoses include drug allergies and parasitic infections, solid and hematological malignancies (i.e. chronic myeloid leukemia), eosinophilic granulomatosis with polyangiitis and human T cell lymphotropic virus infection (see these terms).\nManagement and treatment\nTherapeutic management should be adjusted to disease severity and eventual detection of pathogenic variants. For F/P+ patients, imatinib has undisputedly become first line therapy. For others, corticosteroids are generally administered initially, followed by agents such as hydroxycarbamide, interferon-alpha, and imatinib, for corticosteroid-resistant cases, as well as for corticosteroid-sparing purposes. Recent data suggest that mepolizumab, an anti-IL-5 antibody that is currently available only in the setting of clinical trials or on a compassionate use basis for severe treatment-refractory disease, is an effective corticosteroid-sparing agent for F/P-negative patients.\nPrognosis\nPrognosis has improved significantly since defining HES, and currently depends on the development of irreversible endomyocardial fibrosis, as well as eventual malignant transformation of myeloid or lymphoid cells.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Florence ROUFOSSE"}
{"Disease Name": "Hypergonadotropic hypogonadism-cataract syndrome", "Disease Definition": "A rare syndromic endocrine disease characterized by the association of hypergonadotropic hypogonadism and cataracts with onset during adolescence.", "ORPHA ID": 2410, "Summary": ""}
{"Disease Name": "Hyperimmunoglobulinemia D with periodic fever", "Disease Definition": "A rare autoinflammatory disease, and form of mevalonate kinase deficiency (MKD), characterized by periodic attacks of fever and a systemic inflammatory reaction (cervical lymphadenopathy, abdominal pain, vomiting, diarrhea, arthralgia and skin manifestations.", "ORPHA ID": 343, "Summary": "Epidemiology\nThe prevalence is unknown but several hundred patients have been reported worldwide. This is unquestionably an under-representation as many patients remain undiagnosed. A founder mutation (p.V377I) may account for the large number of cases reported from the Netherlands.\nClinical description\nThe disease usually begins in the first year of life and rarely after 5 years of age, and involves recurrent attacks of fever with abdominal pain, vomiting and diarrhea. Joint involvement (arthralgia/arthritis), swollen lymph nodes, skin lesions (maculopapular rash, vasculitis with purpura or erythema nodosum), early-onset colitis, and headaches may also be observed. Aphthous ulcers may be found and affect the oral mucosa or more rarely the genital and rectal mucosa. Attacks usually last 3 to 7 days and recur every 2 to 8 weeks, but can vary between patients. Frequency of attacks is highest during childhood and usually decreases with age. Severity of attacks also appears to decrease with age. These attacks can occur spontaneously or can be triggered by vaccination, infection and emotional or physical stress. Growth and development is usually not affected, unlike in patients with more severe disease (mevalonic aciduria; MVA). Disease complications are rarely seen in hyperimmunoglobulinemia D with periodic fever (HIDS) patients, but can include AA-amyloidosis, hemophagocytosis, glomerulonephritis, abdominal adhesions, and very rarely joint contractures.\nEtiology\nHIDS is an inherited syndrome caused by mutations in the mevalonate kinase (MVK) gene (12q24). These MVK mutations lead to reduced, but not abolished enzyme activity. This in turn leads to impaired control of the production of inflammatory mediators, which in turn cause inflammatory (fever) attacks.\nDiagnostic methods\nDiagnosis is based on clinical manifestations of the disease along with genetic or biochemical evidence of MVK deficiency. Immunoglobulin A (IgA) and IgD levels may be elevated. However, measurement of IgD cannot confirm nor rule out the diagnosis of HIDS. During an attack, erythrocyte sedimentation rate (ESR) is increased, as well as serum C-reactive protein (CRP), IL-1, IL-6 and TNF-alpha levels. The diagnosis can be made when genetic testing reveals two pathogenic MVK mutations or when a decreased mevalonate kinase activity is found in leukocytes or fibroblasts. Measurement of urinary mevalonic acid might be useful to select patients for MVK gene-analysis or enzyme assay.\nDifferential diagnosis\nUnlike HIDS, the severe form of MKD, MVA, results in nearly complete MVK deficiency. Other autoinflammatory disorders like familial Mediterranean fever (FMF), Tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS) and Muckle-Wells syndrome should be considered. In children, the clinical picture of HIDS can be indistinguishable from PFAPA syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is theoretically possible, but is not usually done.\nGenetic counseling\nHIDS follows an autosomal recessive pattern of inheritance. When a couple has an affected child, there is a 25% recurrence risk in a next child. Genetic counselling is therefore recommended.\nManagement and treatment\nThere is no curative treatment for HIDS and currently no established standard therapy. Treatment with NSAIDs might relieve symptoms during attacks. Some patients have responded to high-dose prednisone, especially when given at the beginning of an attack. Interleukin-1 blockade with canakinumab or anakinra (IL-1 receptor antagonist) has also been successful in many cases. Etanercept has also been effective in some patients. Patients should be monitored closely for complications.\nPrognosis\nThe prognosis in HIDS is good. Life expectancy is not shortened except in rare cases where severe infections or renal amyloidosis occur. Spontaneous complete disease remission is possible.\n\n                            Last update: \n                            February 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Joost FRENKEL  - Dr Jerold JEYARATNAM"}
{"Disease Name": "Hyperinsulinism due to HNF1A deficiency", "Disease Definition": "Hyperinsulinism due to HNF1A deficiency is a form of diazoxide-sensitive diffuse hyperinsulinism (DHI), characterized by transient or persistent hyperinsulinemic hypoglycemia (HH) in infancy that is responsive to diazoxide, evolving in to maturity-onset diabetes of the young subtype 1 (MODY-1; see this term) later in life.", "ORPHA ID": 324575, "Summary": ""}
{"Disease Name": "Hyperinsulinism due to INSR deficiency", "Disease Definition": "A rare autosomal dominant form of familial hyperinsulinism characterized clinically by postprandial hypoglycemia, fasting hyperinsulinemia, and an elevated serum insulin-to-C peptide ratio, and a variable age of onset.", "ORPHA ID": 263458, "Summary": ""}
{"Disease Name": "Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency", "Disease Definition": "A rare form of congenital diazoxide-sensitive diffuse hyperinsulinism due to short chain 3 hydroxylacyl-CoA dehydrogenase (SCHAD; HADH gene) deficiency and characterized by hyperinsulinemic hypoglycemia with seizures and reported to respond well to diazoxide. It presents with the classical manifestations of hyperinsulinemic hypoglycemia. Exceptional complications include sudden death, and in one case fulminant hepatic failure.", "ORPHA ID": 71212, "Summary": ""}
{"Disease Name": "Hyperinsulinism due to UCP2 deficiency", "Disease Definition": "A rare form of congenital diazoxide-sensitive diffuse hyperinsulinism due to UCP2 deficiency and characterized by hypoglycemic episodes from the neonatal period, a good clinical response to diazoxide and a probable transient nature of the disease with spontaneous resolution.", "ORPHA ID": 276556, "Summary": ""}
{"Disease Name": "Hyperinsulinism-hyperammonemia syndrome", "Disease Definition": "A rare diffuse form of congenital hyperinsulinism characterized by an excessive/ uncontrolled insulin secretion (inappropriate for the level of glycemia), chronic hyperammonemia and recurrent episodes of hypoglycemia induced by fasting and protein rich meals. Epilepsy and cognitive deficit, which are unrelated to hypoglycemia but possibly related to the chronic hyperammonemia, may also occur. This disorder is usually responsive to diazoxide treatment.", "ORPHA ID": 35878, "Summary": ""}
{"Disease Name": "Hyperkalemic periodic paralysis", "Disease Definition": "A rare muscle disorder characterized by episodic attacks of muscle weakness associated with an increase in serum potassium concentration.", "ORPHA ID": 682, "Summary": "Epidemiology\nThe prevalence is estimated at around 1/200,000.\nClinical description\nAttacks of muscle weakness generally begin during childhood (first decade). They vary in frequency, duration (a few minutes to hours) and severity (focal paresis to total paralysis). They generally involve the limb muscles and spare the facial and respiratory musculature. Episodes are triggered by rest after exercise, fasting and cold exposure. Other factors may include ingestion of potassium-rich food, stress, infection, glucocorticoids, anesthesia and pregnancy. Maintaining exercise alleviates symptoms. 12.5% of patients present with clinical moderate and permanent myotonia that frequently involves facial muscles (lid-lag sign, eye closure myotonia) while electrical myotonia can be demonstrated in at least 50% of patients on electromyography (EMG). When clinical and electrical myotonia are a feature of the disease, the condition is called hyperkalemic periodic paralysis with myotonia (see this term). Another particular form of the disease, periodica paramyotonia, shares features with paramyotonia congenita (see this term) i.e. weakness is preceded by muscle stiffness provoked by cold and exercise.\nEtiology\nHyperPP is a sodium muscle channelopathy due to point mutations (Thr704Met and Met1592Val mutations in 80% of cases) in the SCN4A gene encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4. These mutations lead to defective inactivation of the channel.\nDiagnostic methods\nDiagnosis is based on clinical history, EMG and genetic tests. Hyperkalemia during attacks can be very mild and fugitive. Serum creatinine kinase (CK) levels can be slightly elevated. Classical EMG may record myotonic discharges and/or myopathic features. The prolonged exercise test is positive in 80% of cases (decrease of over 30% of the compound muscle actionpotential after exercise). Muscle biopsy may show non-specific results (muscle fibers atrophy with vacuoles).\nDifferential diagnosis\nDifferential diagnoses include secondary hyperPP caused by renal or endocrine diseases, other familial periodic paralyses such as hypokalemic or normokalemic PP (see these terms) and non dystrophic myotonias such as paramyotonia congenita (see this term).\nAntenatal diagnosis\nPrenatal diagnosis is theoretically possible if the disease-causing mutation in the family has been identified but is rarely performed because of the non life-threatening prognosis.\nGenetic counseling\nTransmission is autosomal dominant with almost complete penetrance but variable expression in severity within and between families. Genetic counseling should be offered to affected families informing them of the 50% risk the child of an affected parent has of inheriting the disease-causing mutation.\nManagement and treatment\nManagement of patients consists in medical therapy and avoidance of triggering factors. Gentle physical activity, ingestion of carbohydrate-rich drinks/snacks or inhaled salbutamol at the onset of attacks may abort them. Daily use of carbonic anhydrase inhibitors or thiazide diuretics helps in preventing attacks. Dietary advice includes regular meals (to prevent fasting) and avoidance of potassium-rich foods.\nPrognosis\nWith age (generally after 40 years of age), the frequency of the episodes declines but some patients may develop chronic myopathy of variable severity that may cause permanent muscle weakness.\n\n                            Last update: \n                            October 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Savine VICART"}
{"Disease Name": "Hyperkeratosis lenticularis perstans", "Disease Definition": "A rare skin disease characterized by usually asymptomatic, hyperkeratotic, reddish-brown papules primarily located on the lower extremities. Histological examination shows lamellar hyperkeratosis with abrupt peripheral basket-weave orthokeratosis, irregular acanthosis, and underlying lichenoid lymphocytic infiltrate. The condition may be sporadic or familial.", "ORPHA ID": 409, "Summary": ""}
{"Disease Name": "Hyperkeratosis-hyperpigmentation syndrome", "Disease Definition": "Hyperkeratosis-hyperpigmentation syndrome describes a very rare hyperpigmentation of the skin characterized by tiny hyperpigmented spots mainly on skin exposed to sunlight, together with mild punctate palmoplantar papular hyperkeratosis as a major feature. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 1336, "Summary": ""}
{"Disease Name": "Hyperlipidemia due to hepatic triacylglycerol lipase deficiency", "Disease Definition": "A rare hyperalphalipoproteinemia characterized by elevated plasma cholesterol and triglyceride (TG) levels with a marked TG enrichment of low- and high-density lipoproteins (HDL), presence of circulating beta-very low density lipoproteins and elevated HDL cholesterol levels, in the presence of a very low, or undetectable, postheparin plasma hepatic lipase activity. Premature atherosclerosis and/or coronary heart disease may be associated.", "ORPHA ID": 140905, "Summary": ""}
{"Disease Name": "Hyperlysinemia", "Disease Definition": "A rare autosomal recessive disorder of lysine metabolism characterized by elevated levels of lysine in the cerebrospinal fluid and blood. Hyperlysinemia type I has been associated with a highly variable phenotype including seizures, hypotonia, and mild psychomotor delay, although isolated hyperlysinemia is probably a benign condition.", "ORPHA ID": 2203, "Summary": ""}
{"Disease Name": "Hypermethioninemia due to glycine N-methyltransferase deficiency", "Disease Definition": "Hypermethioninemia due to glycine N-methyltransferase deficiency is a rare, genetic inborn error of metabolism characterized by a relatively benign clinical phenotype, with only mild to moderate hepatomegaly reported, in addition to laboratory studies revealing permanent, greatly increased hypermethioninemia, mild to moderate elevation of aminotransferases and highly elevated plasma S-adenosyl-methionine with normal S-adenosylhomocysteine and total homocysteine.", "ORPHA ID": 289891, "Summary": ""}
{"Disease Name": "Hypermethioninemia encephalopathy due to adenosine kinase deficiency", "Disease Definition": "Hypermethioninemia encephalopathy due to adenosine kinase deficiency is a rare inborn error of metabolism disorder characterized by persistent hypermethioninemia with increased levels of S-adenosylmethionine and S-adenosylhomocysteine which manifests with encephalopathy, severe global developmental delay, mild to severe liver dysfunction, hypotonia and facial dysmorphism (most significant is frontal bossing, macrocephaly, hypertelorism and depressed nasal bridge). Epileptic seizures, hypoglycemia and/or cardiac defects (pulmonary stenosis, atrial and/or ventricular septal defect, coarctation of the aorta) may be associated. Clinical picture may range from neurological symptoms only to multi-organ involvement.", "ORPHA ID": 289290, "Summary": ""}
{"Disease Name": "Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome", "Disease Definition": "A rare, genetic disorder of urea cycle metabolism characterized by either a neonatal-onset with manifestations of lethargy, poor feeding, vomiting and tachypnea or, more commonly, presentations in infancy, childhood or adulthood with chronic neurocognitive deficits, acute encephalopathy and/or coagulation defects or other chronic liver dysfunction.", "ORPHA ID": 415, "Summary": "Epidemiology\nMore than 100 cases have been reported in the literature to date. The prevalence in Northern Saskatchewan, Canada is especially high due to a founder effect and is estimated in this population at 1/1550 live births.\nClinical description\nAge of onset can range from the neonatal period to adulthood and a wide phenotypic spectrum is noted. The neonatal presentation usually begins a few days after birth with lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures. Onset of symptoms (ranging from mild to severe) in the majority of patients occurs in infancy, childhood and adulthood with episodes of confusion, forgetfulness, hyperammonemic coma, intellectual disability, developmental delay, spastic paraplegia, cerebellar ataxia, learning difficulties, unexplained seizures, liver dysfunction (rarely failure) and coagulopathy with factor VII-, IX- and X-deficiencies. An aversion to protein-rich foods before diagnosis is often reported.\nEtiology\nThe syndrome is due to mutations in the SLC25A15 gene (13q14) encoding the mitochondrial ornithine transporter 1 (ORNT1) which plays a role in ornithine transport across the mitochondrial membrane and consecutively in mitochondrial protein synthesis, metabolism of arginine and lysine, and synthesis of polyamines. Mutations in this protein disrupt the urea cycle, resulting in hyperornithinemia, hyperammonemia and homocitrullinuria. Patients with a complete ORNT1 deficiency present in the neonatal period with severe hyperammonemia whereas those with a partial deficiency present later, between infancy to adulthood.\nDiagnostic methods\nDiagnosis is based on clinical findings and specific metabolic abnormalities. Laboratory tests usually reveal increased urinary excretion of orotic acid, homocitrulline and uracil, and a rise in the levels of plasma polyamines, ornithine, glutamine, alanine, and liver transaminases. Plasma ammonia levels are elevated episodically or postprandially and plasma ornithine is chronically elevated and is a hallmark of the disease as is the presence of homocitrulline in urine. Molecular genetic testing confirms diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other urea cycle disorders as well as lysinuric protein intolerance. Hyperinsulinism-hyperammonemia syndrome, pyruvate carboxylase deficiency and secondary causes of hyperammonemia should also be considered.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease causing mutation on both alleles.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive; where both parents are unaffected carriers, there is a 25% risk of inheriting the disease.\nManagement and treatment\nTreatment involves the adherence to a low protein diet along with citrulline or arginine supplementation. In resistant cases, sodium benzoate and/or sodium or glycerol phenylbutyrate may be necessary for control of plasma ammonia levels. Patients should be monitored during times of stress (e.g. pregnancy, surgery, intercurrent infections) and when taking certain medications (i.e. corticosteroids) as they can trigger an episode of hyperammonemia. Hyperammonemic coma is treated in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration), ammonia scavenger therapy implemented, catabolism reversed (with glucose and lipid infusions) and special care taken to reduce the risk of neurological damage.\nPrognosis\nWith early diagnosis and proper adherence to treatment protocol the prognosis is better than for most other urea cycle defects. However, patients remain at risk for metabolic decompensation throughout life and irreversible neurological complications can occur if treatment is delayed.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Johannes HÄBERLE"}
{"Disease Name": "Hyperostosis corticalis generalisata", "Disease Definition": "Hyperostosis corticalis generalisata, also known as van Buchem disease, is a rare craniotubular hyperostosis characterized by hyperostosis of the skull, mandible, clavicles, ribs and diaphyses of the long bones, as well as the tubular bones of the hands and feet. Clinical manifestations include increased skull thickness with cranial nerve entrapment causing inconsistent cranial nerve palsies.", "ORPHA ID": 3416, "Summary": ""}
{"Disease Name": "Hyperostosis cranialis interna", "Disease Definition": "A rare primary bone dysplasia with increased bone density characterized by slowly progressive endosteal hyperostosis and osteosclerosis exclusively of the skull base and the calvaria, resulting in entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII. First symptoms often appear during the second decade of life and include disturbances in smell, vision, facial sensation and expression, hearing, and balance, as well as headaches due to increased ocular and intracranial pressure. After the fourth decade, radiological progression is minimal, although decreased intracranial volume can lead to death in severe cases.", "ORPHA ID": 443098, "Summary": ""}
{"Disease Name": "Hyperparathyroidism-jaw tumor syndrome", "Disease Definition": "A rare genetic disease characterized by synchronous or metachronous occurrence of primary hyperparathyroidism and ossifying fibroma of the maxilla and/or mandible, associated with an increased risk of parathyroid carcinoma. Occurrence of renal cysts or tumors, multiple uterine polyps, and thyroid tumors has also been reported.", "ORPHA ID": 99880, "Summary": ""}
{"Disease Name": "Hyperphenylalaninemia due to DNAJC12 deficiency", "Disease Definition": "A rare inborn error of metabolism characterized by increased serum phenylalanine, associated with variable neurological symptoms ranging from mild autistic features or hyperactivity to severe intellectual disability, dystonia, and parkinsonism. Laboratory analyses show normal tetrahydrobiopterin (BH4) metabolism and low levels of the CSF monoamine neurotransmitter metabolites homovanillic acid and 5-hydroxyindoleacetic acid.", "ORPHA ID": 508523, "Summary": ""}
{"Disease Name": "Hyperphenylalaninemia due to tetrahydrobiopterin deficiency", "Disease Definition": "A disorder of pterin metabolism characterized by tetrahydropterin (BH4) biosynthesis or recycling deficiencies, leading to central dopamine and serotonin deficiency, characterized by infantile-onset neurological disease of variable severity ranging from mild forms with minor neurological development to severe forms with hypotonia, developmental delay, complex movement disorder dominated by dystonia or dystonia parkinsonism.", "ORPHA ID": 238583, "Summary": "Epidemiology\nThe global prevalence of BH4 deficiencies remains unknown and great variance can be found among different countries. European newborn screening programs (NBS) reveal that the mean incidence of all hyperphenylalaninemias (HPA) is approximately 1/10,000, with BH4 deficiencies representing 1-2% of cases.\nClinical description\nWhen left untreated, the deficiency leads to neurological symptoms starting shortly after birth. While the overall clinical phenotype of BH4Ds may overlap with numerous other disorders (e.g. cerebral palsy) certain clinical features may raise the clinical suspicion for a disorder of impaired neurotransmission (e.g. early onset parkinsonism, oculogyric crises, diurnal fluctuation of symptoms, or an unexplained cerebral palsy-like picture). It is important to note that patients may show a wide spectrum of clinical severity, ranging from asymptomatic individuals requiring no treatment to very severe disease courses.\nEtiology\nBH4Ds are caused by variants in the GCH1, PTS, SPR, QDPR and PCBD1 genes, which encode enzymes required for the BH4 biosynthesis or recycling. BH4 is an essential cofactor for phenylalanine hydroxylase (PAH), tyrosine (TH) and tryptophan hydroxylase (TPH). While variants in PTS, QDRP and PCBD1 cause a central dopamine and serotonin deficiency and HPA, patients with variants in GCH1 and SPR mostly have normal phenylalanine concentrations.\nDiagnostic methods\nBH4D should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when HPA is moderate. Since phe levels can be normal in GTP cyclohydrolase I and sepiapterin reductase deficiency, the occurrence of certain clinical features should raise the clinical suspicion for a disorder of impaired neurotransmission. The analysis of pterins in urine or dried blood spot (DBS) in patients and the analysis of dihydropteridine reductase (DHPR) enzyme activity in DBS has to follow in all patients with HPA on NBS. With suspicion clinical picture and missing HPA or the confirm the biochemical diagnosis by genetic evaluation of the respective gene is recommended. Depending on availability the measuring of the neurotransmitters 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and pterins in cerebrospinal fluid can be helpful for the diagnosis or during follow-up of BH4Ds.\nDifferential diagnosis\nBH4Ds should be differentiated from each other, namely hyperphenylalaninemia due to autosomal recessive GTP cyclohydrolase I deficiency, pterin-4-alpha-carbinolamine dehydratase deficiency (PCDD) and 6-pyruvoyl-tetrahydropterin synthase deficiency. The differential diagnosis of BH4 deficiencies also includes classic phenylketonuria and hyperphenylalaninemia due to DNAJC12 deficiency.\nAntenatal diagnosis\nPrenatal diagnosis is possible by molecular analysis where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nAll BH4 deficiencies are autosomal recessive genetic disorders. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of sapropterin hydrochlorid) in disorders with HPA. In all disoders apart from PCDD, restoration of normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophan) should be achieved. In case of insufficient clinical response or L-dopa-induced hyperkinesia long-acting dopamine agonists (e.g. pramipexole) can be used to stabilize the clinical and biochemical picture. Monoamino oxidase inhibitors (selegiline) are also useful to prolong the action of neurotransmitter precursors. PCDD patients receive sapropterin hydrdochlorid to control Phe levels.\nPrognosis\nEarly treatment drastically improves, often even reconstitutes motor function. However, long-term prognosis correlates with early diagnosis and treatment initiation.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Oya KUSEYRI HÜBSCHMANN | MetabERN* - Pr Thomas OPLADEN | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hyperphosphatasia-intellectual disability syndrome", "Disease Definition": "A rare, congenital disorder of glycosylation-related bone disorder characterized by hypotonia, severe developmental delay, intellectual disability, seizures, increased serum alkaline phosphatase, short distal phalanges with hypoplastic nails, and dysmorphic facial features. In some cases, cleft palate, megacolon, anorectal malformations, and congenital heart defects have been reported.", "ORPHA ID": 247262, "Summary": ""}
{"Disease Name": "Hyperprolinemia type 1", "Disease Definition": "A rare disorder of proline metabolism characterized biochemically by markedly elevated levels of proline in plasma and urine due to deficiency of proline oxidase. The reported clinical phenotype ranges from asymptomatic to variable neurologic and psychiatric manifestations (including global developmental delay, seizures, autistic features, and hyperactivity).", "ORPHA ID": 419, "Summary": ""}
{"Disease Name": "Hyperprolinemia type 2", "Disease Definition": "Hyperprolinemia type 2 is an autosomal recessive proline metabolism disorder due to pyroline-5-carboxylate dehydrogenase deficiency. The condition is often benign but clinical signs may include seizures, intellectual deficit and mild developmental delay.", "ORPHA ID": 79101, "Summary": ""}
{"Disease Name": "Hypersensitivity pneumonitis", "Disease Definition": "A rare, immunologically mediated, interstitial lung disease characterized by respiratory symptoms (cough, dyspnea) due to sensitization and subsequent hypersensitivity to environmental antigens. The disorder may be accompanied by systemic manifestations (weight loss, fatigue).", "ORPHA ID": 31740, "Summary": "Epidemiology\nThe estimated worldwide incidence of hypersensitivity pneumonitis (HP) is in the 1/125,000-143,000 range and is highly dependent on climatic, geographical, occupational and industrial factors. It has a higher incidence rate among pigeon breeders and farmers. The prevalence is 1/33,000-100,000 in the general population. A large number of acute cases and chronic cases related to mold probably go undiagnosed.\nClinical description\nHP covers a very wide spectrum of clinical presentations with acute, subacute, and chronic forms. The disease can develop in any age group and the main clinical signs in all forms are cough, dyspnea, and fatigue. The manifestations overlap with a large number of other pulmonary disorders. HP is distinguished between fibrotic (always chronic) and non-fibrotic forms (mostly with acute or subacute manifestations). Acute manifestations, occurring a few hours after intense exposure (4-16 hours), may involve fever, headache, cough, dyspnea and myalgia. Chronic disease develops due to low level continual exposure over months to years manifesting with severe dyspnea, cough, clubbing, weight loss and hypoxemia, which may worsen gradually in patients with progressive pulmonary fibrosis. Acute and subacute disease can progress to a chronic presentation in the absence of appropriate treatment. The most common long-term complication in chronic disease is pulmonary fibrosis that may be accompanied by emphysema, which may lead to respiratory failure or cor pulmonale.\nEtiology\nAn extremely broad range of antigens, generally smaller than 5 µ in size, may trigger HP. The most common sources of these antigens (thermophilic actinomycetes) include farming activities (moldy hay), feces/urine of wild and domestic birds and animals (e.g pigeons and most birds), sources of humidity and exposure to mold, air conditioners, and a long list of rare (often occupational) causes. The disease is caused by a type III or IV hypersensitivity reaction following repeated exposure, possibly in genetically susceptible individuals. This causes diffuse inflammation of the lung parenchyma and airways. Mutations in telomerase-related genes, and polymorphism of the MUC5B gene, have been linked with increased risk of fibrotic HP.\nDiagnostic methods\nThe diagnosis is based on the combination of features, including clinical manifestations, which are determined by performing a physical examination, imaging (HRCT showing diffuse nodules or ground glass opacities in non-fibrotic HP; mosaicism and air trapping in addition to fibrotic features in fibrotic HP), bronchoalveolar lavage (showing an increased level of lymphocytes), positive serology testing (IgG: precipitins), and rarely, lung biopsy. HP may be difficult to diagnose due to non-specific clinical signs. It may be suspected in individuals with manifestations suggestive of HP who have occupational, recreational, or domestic exposure to specific antigens.\nDifferential diagnosis\nNon-fibrotic HP may be confused with allergic asthma, chronic obstructive pulmonary disease, bacterial pneumonia, and recurrent infections. Fibrotic HP may be confused with : idiopathic pulmonary fibrosis, sarcoidosis, and other forms of pulmonary fibrosis.\nManagement and treatment\nAcute forms generally resolve spontaneously on removal of the causative antigen. Short-term treatment of non-fibrotic cases is based on oral corticosteroids. The recommended treatment is prednisone, which may be initiated at 0.5 mg/kg/day and tapered over 2 to 8 weeks. Inhaled corticosteroids and bronchodilators, may also be beneficial. Fibrotic HP may be treated with low-dose prednisone, immunosuppressive therapy especially mycophenolate, and in case of progressive pulmonary fibrosis, antifibrotics. Longer term treatment relies on avoidance of the offending allergen. In occupational settings, risk avoidance may be difficult but can include preventive measures and personal protection equipment.\nPrognosis\nIf the offending antigen is removed, the prognosis of non-fibrotic HP is very good. When detected and treated early, the disease is self-limiting with antigen avoidance. Fibrotic HP is more complicated possibly leading to permanent damage and disability.\n\n                            Last update: \n                            January 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Vincent COTTIN"}
{"Disease Name": "Hypertelorism-hypospadias-polysyndactyly syndrome", "Disease Definition": "Hypertelorism-hypospadias-polysyndactyly syndrome is a very rare syndrome associating an acro-fronto-facio-nasal dysostosis with genitourinary anomalies.", "ORPHA ID": 2211, "Summary": "Epidemiology\nIt has been described in three families.\nClinical description\nCraniofacial manifestations include wide anterior fontanel, flat occiput, hypertelorism, ptosis, proptosis, broad nasal bridge and nasal tip, long philtrum and posteriorly rotated or low set ears. Hypospadias and shawl scrotum are present in all males. Acral manifestations include syndactyly of fingers, broad thumbs or halluces or preaxial polydactyly. The affected patients have no intellectual deficit.\nGenetic counseling\nThe condition seems to be hereditary, and transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Hypertelorism-microtia-facial clefting syndrome", "Disease Definition": "Hypertelorism-microtia-facial clefting syndrome, or HMC syndrome, is a very rare syndrome characterized by the combination of hypertelorism, cleft lip and palate and microtia.", "ORPHA ID": 2213, "Summary": "Epidemiology\nNine cases have been reported in the literature in seven families.\nClinical description\nSome patients have associated cardiac or renal congenital malformations. Short stature and intellectual deficiency are common.\nAntenatal diagnosis\nAntenatal diagnosis is possible by ultrasonographic monitoring.\nGenetic counseling\nThe reported cases support autosomal recessive inheritance.\n\n                            Last update: \n                            March 2010"}
{"Disease Name": "Hypertelorism-preauricular sinus-punctual pits-deafness syndrome", "Disease Definition": "A rare developmental defect during embryogenesis syndrome characterized by hypertelorism, bilateral preauricular sinus, bilateral punctal pits, lacrimal duct obstruction, hearing loss, abnormal palmar flexion creases and bilateral distal axial triradii. Shawl scrotum has also been reported.", "ORPHA ID": 293958, "Summary": ""}
{"Disease Name": "Hypertension due to gain-of-function mutations in the mineralocorticoid receptor", "Disease Definition": "A rare genetic cause of hypertension characterized by severe early-onset therapy-resistant hypertension due to a gain-of-function mutation in the mineralocorticoid receptor. The condition is associated with suppressed plasma renin activity and low serum aldosterone levels and is markedly exacerbated during pregnancy.", "ORPHA ID": 88660, "Summary": ""}
{"Disease Name": "Hypertrichosis cubiti", "Disease Definition": "Hypertrichosis cubiti is a rare hair anomaly characterized by symmetrical, congenital or early-onset, bilateral hypertrychosis localized on the externsor surfaces of the upper extremities (especially the elbows). Short stature, or other abnormalities, such as developmental delay, facial anomalies and intellectual disability, may or may not be associated.", "ORPHA ID": 2220, "Summary": ""}
{"Disease Name": "Hypertrichosis lanuginosa congenita", "Disease Definition": "Hypertrichosis lanuginosa congenita is a rare congenital skin disease characterized by the presence of 3 to 5cm long lanugo-type hair on the entire body, with the exception of palms, soles, and mucous membranes.", "ORPHA ID": 2222, "Summary": ""}
{"Disease Name": "Hypertrophic cardiomyopathy with kidney anomalies due to mitochondrial DNA mutation", "Disease Definition": "A mitochondrial oxidative phosphorylation disorder characterized by hypertrophic and dilated cardiomyopathy, failure to thrive, myopathy with generalized hypotonia and increased creatine kinase, developmental delay and/or regression with cerebral atrophy on brain MRI, renal manifestations including chronic renal failure, renal tubular acidosis and lactic acidosis. Additional clinical features include seizures and respiratory failure.", "ORPHA ID": 324525, "Summary": ""}
{"Disease Name": "Hypertrophic or verrucous lupus erythematosus", "Disease Definition": "Hypertrophic or verrucous lupus erythematosus is a rare type of chronic cutaneous lupus erythematosus characterized by the appearance of lesions on sun-exposed areas (frequently the extensor surfaces of forearms, face, upper trunk) which vary from squamous violet, painful papules and blackish hyperkeratotic ulcers to depigmented atrophic plaques on the back, hyperkeratotic papules on upper extremities, and disseminated keratoacanthoma-like papulonodular verrucous lesions. Classic discoid lesions and squamous cell carcinoma may be associated. Histopathology reveals follicular plugging, liquefactive basal layer degeneration and a perivascular lymphocytic infiltrate.", "ORPHA ID": 90282, "Summary": ""}
{"Disease Name": "Hypertryptophanemia", "Disease Definition": "A rare inborn error of metabolism characterized by congenital hypertryptophanemia and hyperserotonemia. Patients are typically asymptomatic, although developmental delay, intellectual disability, and behavioral abnormalities, among others, have been reported in association.", "ORPHA ID": 2224, "Summary": ""}
{"Disease Name": "Hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome", "Disease Definition": "A rare, genetic, mitochondrial disease characterized by early-onset progressive renal failure, manifesting with hyperuricemia, hyponatremia, hypomagnesemia, hypochloremic metabolic alkalosis, elevated BUN and polyuria, associated with systemic manifestations which include pulmonary hypertension, failure to thrive, global developmental delay, hypotonia and ventricular hypertrophy. Additional features include prematurity, elevated serum lactate, diabetes mellitus and, in some, pancytopenia.", "ORPHA ID": 363694, "Summary": ""}
{"Disease Name": "Hyperzincemia and hypercalprotectinemia", "Disease Definition": "A rare inborn error of zinc metabolism characterized by recurrent infections, hepatosplenomegaly, anemia (unresponsive to iron supplementation) and chronic systemic inflammation in the presence of high plasma concentrations of zinc and calprotectin. Patients typically present dermal ulcers or other cutaneous manifestations (e.g. inflammation) and arthralgia. Severe epistaxis and spontaneous hematomas have also been reported.", "ORPHA ID": 251523, "Summary": ""}
{"Disease Name": "Hypnic headache", "Disease Definition": "A rare headache characterized by recurrent brief, intense headache attacks occurring exclusively during sleep, typically at the same time of the night, causing the patient to wake up. The pain usually lasts more than 15 minutes after waking. It is mostly bilateral and may be associated with nausea, photophobia, or phonophobia, while characteristically no autonomic symptoms are present.", "ORPHA ID": 276429, "Summary": ""}
{"Disease Name": "Hypo- and hypermelanotic cutaneous macules-retarded growth-intellectual disability syndrome", "Disease Definition": "Hypo- and hypermelanotic cutaneous macules-retarded growth-intellectual disability syndrome is a rare, genetic pigmentation anomaly of the skin disorder characterized by congenital hypomelanotic and hypermelanotic cutaneous macules associated with, in some patients, retarded growth and intellectual disability. There have been no further descriptions in the literature since 1978.", "ORPHA ID": 2435, "Summary": ""}
{"Disease Name": "Hypobetalipoproteinemia", "Disease Definition": "Hypobetalipoproteinemia (HBL) constitutes a group of lipoprotein metabolism disorders that are characterized by permanently low levels (below the 5th percentile) of apolipoprotein B and LDL cholesterol.", "ORPHA ID": 31154, "Summary": "Epidemiology\nHBL affects around 1/1,000 individuals.\nClinical description\nThere are two types of HBL: familial hypobetalipoproteinemia and chylomicron retention disease (CMRD; see these terms). The familial form can be severe with early onset (abetalipoproteinemia/homozygous familial hypobetalipoproteinemia; see this term) or benign (benign familial hypobetalipoproteinemia; see this term). Severe familial HBL and CMRD appear in infancy or childhood. As a result they are often associated with growth delay, diarrhea with steatorrhea, and fat malabsorption. Infants with severe familial hypobetalipoproteinemia have hepatomegaly with steatosis, spastic ataxia, atypical retinitis pigmentosa, acanthocytosis, low levels of liposoluble vitamins (A, E and K), and major cytolysis and even cirrhosis. Benign familial hypobetalipoproteinemia is generally asymptomatic, but in adults is occasionally associated with dietary intolerance to fat, steatorrhea after oral intake of lipids, moderate cytolysis, cholelithiasis, moderately low levels of liposoluble vitamins and acanthocytosis. Moderate hepatic steatosis and paresthesia of the extremities are sometimes observed.\nEtiology\nHBL disorders are caused by mutations in proteins involved in the synthesis, secretion and catabolism of lipoproteins containing apolipoprotein B (LDL, VLDL and chylomicrons). Abetalipoproteinemia is inherited in a recessive manner and is a result of mutations of two alleles of the MTTP gene (MTP; 4q24). Other severe early familial hypobetalipoproteinemias are inherited in a codominant manner and are a result of mutations of two alleles of the APOB gene (2p24-p23). Benign familial hypobetalipoproteinemia, which is also inherited in a codominant manner, can be caused by heterozygous mutations of the APOB gene or the PCSK9 gene (1p34.1-p32). CMRD, which is inherited in an autosomal recessive manner, is caused by mutations of two alleles of the SAR1B gene (SARA2; 5q31.1).\nDiagnostic methods\nDiagnosis of familial hypobetalipoproteinemia is based on lipid analysis, after 12 hours of fasting, carried out on the patient and their parents to measure serum levels of LDL (<0.10g/L for the severe form; <0.80g/L for the moderate form), triglycerides (<0.20 g/L for the severe form; <0.50g/L for the moderate form), and apolipoprotein B (<0.10g/L for the severe form; <0.50g/L for the moderate form). Evaluation of steatorrhea and truncated apolipoprotein B after oral lipid intake, measurement of liposoluble vitamins (A, E, K), testing for acanthocytosis (on blood smears), complete neurological examination, hepatic ultrasound and eye examination can also be carried out. Diagnosis of CMRD is based on the absence in serum, after oral lipid intake, of intestinal apolipoprotein B (ApoB-48) and the appearance of `white intestine' seen endoscopically.\nDifferential diagnosis\nDifferential diagnoses of HBL include metabolic diseases with hepatic overload, with steatosis and/or hepatomegaly, atypical diseases of the central and peripheral nervous system, and secondary causes of hypocholesterolemia (iatrogenic or systemic).\nAntenatal diagnosis\nPrenatal diagnosis is feasible when the causal mutations in both parents are known.\nManagement and treatment\nManagement of the moderate forms of HBL includes reduction of the proportion of fat in the patient's diet and vitamin E supplementation. Management of the severe forms of HBL and CMRD should take place in specialized centers.\nPrognosis\nThe prognosis of HBL is severe when the disease manifests in early childhood, and is excellent for the moderate form without cytolysis and steatosis. A familial syndrome of longevity has been observed in the benign forms of HBL (many patients live over the age of 85).\n\n                            Last update: \n                            May 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Pascale BENLIAN"}
{"Disease Name": "Hypocalcemic rickets", "Disease Definition": "A group of rare genetic, vitamin D metabolism disorders characterized by hypocalcemia and rickets, and comprising of hypocalcemic vitamin D dependent rickets (VDDR-I) and hypocalcemic vitamin D resistant rickets (HVDRR). Characteristic clinical features include slow growth, bone pain and bone deformities. HVDRR is associated with resistance to vitamin D treatment.", "ORPHA ID": 289103, "Summary": ""}
{"Disease Name": "Hypocalcemic vitamin D-dependent rickets", "Disease Definition": "A rare, genetic disorder of vitamin D metabolism characterized by severe hypocalcemia leading to osteomalacia and rachitic bone deformations, and moderate hypophosphatemia.", "ORPHA ID": 289157, "Summary": "Epidemiology\nThe worldwide prevalence in the general population of hypocalcemic vitamin D-dependent rickets (VDDR) is unknown. In Denmark the prevalence among children under 15 years of age is estimated at 1/250,000.\nClinical description\nThe signs and symptoms vary depending on the severity of the disease. Symptoms can appear within the first year of life with manifestations of chronic hypocalcemia: hypotonia, tetany, seizures, muscle weakness, and poor growth. Progressively, patients present with signs and symptoms of rickets (bowed legs, rachitic rosary...).\nEtiology\nThe disorder is commonly due to inactivating mutations in the CYP27B1 gene (12q14; disorder referred to as VDDR1A) which codes for the enzyme which converts the vitamin D precursor calcidiol to calcitriol. Less commonly, the disorder is due to variants in CYP2R1 (11p15.2; VDDR1B) resulting in decreased expression of vitamin D 25-hydroxylase enzyme which converts calciferol to calcidiol. These defects in the biosynthesis of active vitamin D leads to an impaired intestinal absorption of calcium and phosphate, consequently leading to hypocalcemia and abnormal bone mineralization.\nDiagnostic methods\nDiagnosis is based on biochemical and radiological findings. Classical radiological signs include rickets and/or osteomalacia and decreased bone mineralization. Biochemical findings include severe hypocalcemia, moderate hypophosphatemia and increase parathyroid hormone and alkaline phosphatase levels. In VDDR1A, additional biochemical anomalies include normal serum levels of calcidiol (25-hydroxyvitamin D) associated with low serum levels of calcitriol (1,25-dihydroxyvitamin D3). In VDDR1B, serum levels of calcidiol (25-hydroxyvitamin D) are undetectable and are associated with normal to high serum levels of calcitriol (1,25-dihydroxyvitamin D3). Diagnosis is confirmed by DNA analysis.\nDifferential diagnosis\nDifferential diagnosis includes nutritional vitamin D deficiency, vitamin D resistant rickets and bone dysplasia.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment aims at improving growth and restoring normal serum levels of calcium, phosphorus, alkaline phosphatase, and parathyroid hormone and at healing/preventing skeletal deformities. It consists of daily administration of calcitriol (VDDR1A and VDDR1B). Patients with VDDR1B are also responsive to calcidiol. Nephrocalcinosis, hypercalciuria, and hypercalcemia can be observed as complications of the therapy. Regular monitoring (physical and biochemical examination, hand radiographs, renal ultrasound) is thus required.\nPrognosis\nWith treatment, prognosis is good.\n\n                            Last update: \n                            August 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès LINGLART | Endo-ERN* - Dr Anya ROTHENBUHLER | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hypocalcemic vitamin D-resistant rickets", "Disease Definition": "A rare genetic, disorder of vitamin D metabolism characterized by hypocalcemia, severe rickets and in many cases alopecia.", "ORPHA ID": 93160, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nProgressive rickets manifest during the first years of life with poor growth and skeletal deformities. Total body alopecia is present in severe forms of the disease (2/3 of cases). In some cases, skin lesions or epidermal cysts can be observed along with alopecia. The disease presents a broad clinical picture that largely depends on the genotype.\nEtiology\nThe disease is due to mutations in the vitamin D receptor gene (VDR; 12q13-14) that decrease the receptor's action thereby preventing calcitriol's action. This leads to an impaired intestinal absorption of calcium and phosphate.\nDiagnostic methods\nDiagnosis is based on clinical, biochemical and radiological findings. Biochemical features are severe hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, normal serum levels of calcidiol (25-hydroxyvitamin D), elevated serum levels of calcitriol (1,25-dihydroxyvitamin D3, the active form of vitamin D), and high serum levels of alkaline phosphatase. Radiological findings include typical rickets and/or osteomalacia and decreased bone mineralization. Osteitis fibrosa cystica due to secondary hyperparathyroidism is commonly observed.\nDifferential diagnosis\nDifferential diagnosis includes other forms of rickets (hereditary and nutritional) and atrichia with papular lesions (APL) and hypocalcemic vitamin D-dependent rickets.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment aims at improving growth, correcting hypocalcemia and hyperparathyroidism, and at enhancing mineralization of bones. In patients with mild forms it consists of daily administration of high doses of calcitriol and calcium; intravenous administration may be needed in severe phenotypes. Response to treatment largely depends on the severity of the disease. Patients with alopecia generally do not respond to oral treatment and need intravenous calcium infusions. Regular monitoring of biochemical parameters is required.\nPrognosis\nCorrection of rachitic deformities depends on the severity of the disease.\n\n                            Last update: \n                            August 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès LINGLART | Endo-ERN* - Dr Anya ROTHENBUHLER | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Hypochondroplasia", "Disease Definition": "A primary bone dysplasia with micromelia characterized by disproportionate short stature, mild lumbar lordosis and limited extension of the elbow joints.", "ORPHA ID": 429, "Summary": "Epidemiology\nHypochondroplasia estimated incidence is 1/50,000. The exact prevalence is unknown.\nClinical description\nHypochondroplasia is a skeletal dysplasia characterized by short stature; stocky build; disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly. Radiologic features include shortening of long bones with mild metaphyseal flare; narrowing of the inferior lumbar interpedicular distances; short, broad femoral neck; and squared, shortened ilia. The skeletal features are very similar to those seen in achondroplasia but tend to be milder. Medical complications common to achondroplasia (e.g., spinal stenosis, tibial bowing, obstructive apnea) occur less frequently in hypochondroplasia. Children usually present as toddlers or school-age children with decreased growth velocity leading to short stature and limb disproportion. However, some more severe cases are detected prenatally, at birth or in early infancy. Other features also become more prominent over time.\nEtiology\nThe disorder is caused by mutations in the fibroblast growth factor receptor-3 gene (FGFR3; 4p16.3).\nDiagnostic methods\nHypochondroplasia is diagnosed by the recognition of characteristic clinical and radiologic findings that remain controversial. DNA-based testing is possible and about 70% of affected individuals are heterozygous for a pathogenic variant in FGFR3. The most frequent variant is NM_000142.4:c.1620C>A; p.Asn540Lys (p.N540K), which accounts for approximately 60% of affected individuals.\nDifferential diagnosis\nHypochondroplasia closely resembles achondroplasia (also caused by variants in the FGFR3 gene). Differential diagnosis also includes mild forms of mesomelic dwarfism, mild forms of spondyloepiphyseal-metaphyseal dysplasias, Leri-Weill dyschondrosteosis, Pseudohypoparathyroidism and pseudopseudohypoparathyroidism.\nGenetic counseling\nThe disorder is transmitted in an autosomal dominant manner. Genetic counseling should be proposed to individuals having the disease-causing variant informing them that there is 50% risk of passing the variant to offspring.\nManagement and treatment\nManagement of short stature in hypochondroplasia is influenced by parental expectations and concerns; one approach is to address these concerns rather than trying to treat the child. Laminectomy relieves symptoms of spinal stenosis; about 70% of individuals experience relief of symptoms following decompression without laminectomy. Developmental milestones are followed closely during early childhood so that cognitive impairments are addressed with special educational programs. Epilepsy is treated in the standard fashion.\nPrognosis\nFinal adult height varies between 132 and 147 cm and life expectancy is normal.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Karen HEATH"}
{"Disease Name": "Hypocomplementemic urticarial vasculitis", "Disease Definition": "A rare immune complex-mediated small vessel vasculitis characterized by urticaria and hypocomplementemia (low C3, C4 and/or C1q), and usually associated with circulating anti-C1q autoantibodies. Arthritis, pulmonary disease, ocular inflammation are common systemic manifestations.", "ORPHA ID": 36412, "Summary": "Epidemiology\nPrevalence is unknown but less than 500 cases have been reported in the literature. Women are more frequently affected than men (female to male ratio of 8:1).\nClinical description\nPatients most commonly present during the fifth decade of life but onset during childhood has been rarely described. Patients present with generalized urticarial eruptions located on the trunk, proximal extremities and face that are often associated with itching or pain and persist for more than 24 hours, with hyperpigmentation after resolution. Angioedema is common and may also be a presenting feature. Cardiorespiratory manifestations include cough, dyspnea, pleural and pericardial effusions, and emphysema, with chronic obstructive pulmonary disease reported in less than 20% of patients. Renal disease is present in 20 to 30% of patients and is generally mild with proteinuria and hematuria caused by glomerulonephritis. However, renal insufficiency and end-stage renal failure have been reported and renal involvement tends to be more severe in patients with childhood onset. Other systemic findings include gastrointestinal symptoms (abdominal pain, nausea, diarrhea, vomiting), musculoskeletal manifestations (arthritis and transient arthralgia affecting the hands, elbows, knees, ankles, and feet), and ocular inflammation (episcleritis, uveitis and conjunctivitis).\nEtiology\nHypocomplementemic urticarial vasculitis (HUV) generally occurs sporadically; however, a few familial cases associated with mutations in DNASE1L3 (3p14.3) have been reported. For the majority of cases the etiology is unknown but anti-C1q autoantibodies are believed to be involved in the pathogenesis of the disorder.\nDiagnostic methods\nDiagnosis requires the presence of two major criteria (recurrent urticaria for > 3 months and hypocomplementemia) and at least two minor criteria (leukocytoclastic vasculitis on biopsy, arthralgia and arthritis, ocular inflammation, abdominal pain, glomerulonephritis and positive anti-C1q autoantibodies).\nDifferential diagnosis\nThe relationship of HUV to systemic lupus erythematosus (SLE) is complex with many overlapping features (manifestations of HUV are present in 10% of SLE patients and 50% of patients with HUV will later be diagnosed as having SLE). Other syndromes such as mixed cryoglobulinemia and Schnitzler syndrome should be excluded.\nGenetic counseling\nThe pattern of inheritance for the familial cases associated to DNASE1L3 is autosomal recessive. Genetic counseling is recommended for at risk families.\nManagement and treatment\nTreatment requires tailored therapy with drugs ranging from colchicine, disulone or hydroxychloroquine to more aggressive therapy, such as steroids and immunosuppressives. For example, patients with cutaneous disease and arthralgias but no major organ involvement may be managed with colchicine, hydroxychloroquine, or dapsone; whereas patients with major organ involvement, such as glomerulonephritis, may require high doses of corticosteroids and cytotoxic agents similar to the treatment for active SLE. Response to treatment is usually accompanied by a decrease in circulating anti-C1q titer and normalization of C3 and C4 levels.\nPrognosis\nThe prognosis for HUV patients is variable and influenced primarily by the severity of the rare pulmonary, cardiac and renal disease. When present, pulmonary disease is the major cause of death. Acute laryngeal edema can be life-threatening.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Xavier PUECHAL  - Pr Benjamin TERRIER"}
{"Disease Name": "Hypodontia-dysplasia of nails syndrome", "Disease Definition": "Hypodontia-nail dysplasia syndrome is a form of ectodermal dysplasia.", "ORPHA ID": 2228, "Summary": "Epidemiology\nIts incidence has been estimated at around 1-2 in 10,000.\nClinical description\nThe primary teeth are usually normal but the permanent teeth often fail to erupt. The mandibular incisors, second molars, and maxillary canines are frequently absent and the crowns may be small and conical. Lip eversion may be present. Nails are usually small, thin and brittle with longitudinal ridges, pitting and koilonychias. Congenital absence of the nail plate has also been reported. Toenails are usually more severely affected than fingernails. Sweat glands, heat tolerance and hair are normal, although fine hair has been described in some cases.\nEtiology\nThe syndrome is caused by a mutation in the MSX1 gene (4p16.1).\nDiagnostic methods\nDiagnosis is usually made during mid-childhood when persistence of the primary dentition becomes apparent, but the syndrome may be difficult to diagnose as the nail defects may be mild.\nDifferential diagnosis\nThe differential diagnosis should include other forms of ectodermal dysplasia, in particular hypohidrotic ectodermal dysplasia (see these terms).\nGenetic counseling\nTransmission is autosomal dominant.\nManagement and treatment\nThere is no specific treatment but oral health care and dental management are recommended.\nPrognosis\nThe prognosis is good. The nail defects usually become less apparent with age and the nails often appear normal by adulthood.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES"}
{"Disease Name": "Hypoglossia-hypodactyly syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by hypoglossia, micrognathia and variable limb abnormalities. Limb defects can involve any limb (usually all four) and the severity may vary from the absence of distal phalanges to total absence of digits or limbs. Synbrachydactyly may also be present. Patients have problems with speech, swallowing and mastication, and they have additional craniofacial anomalies (including telecanthus, lower eyelid defects, broad nose, microstomia, variable clefting or aberrant attachments of tongue, mandibular hypodontia, cleft palate, cranial nerve palsies, and facial asymmetry). Gingival abnormalities are frequently observed. Intelligence and stature are generally normal.", "ORPHA ID": 989, "Summary": ""}
{"Disease Name": "Hypogonadism-mitral valve prolapse-intellectual disability syndrome", "Disease Definition": "This syndrome is characterized by the association of hypogonadism due to primary gonadal failure, mitral valve prolapse, mild intellectual deficit and short stature.", "ORPHA ID": 2233, "Summary": "Epidemiology\nIt has been described in two brothers.\nClinical description\nGrowth hormone (GH) levels and the response to gonadotropin stimulation tests were also abnormal.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "Hypogonadotropic hypogonadism-frontoparietal alopecia syndrome", "Disease Definition": "This syndrome is characterized by the association of hypogonadotropic hypogonadism and frontoparietal alopecia.", "ORPHA ID": 2230, "Summary": "Epidemiology\nIt has been described in six members (four males and two females) of a consanguineous Lebanese family.\nClinical description\nIn addition to frontoparietal alopecia, the remaining scalp hair was also sparse, and axillary and pubic hair was absent.\nEtiology\nIn contrast to the syndrome of primary hypergonadotropic hypogonadism and partial alopecia (see this term), streak or absent ovaries, hypoplastic uterus, and microcephaly were not reported in the affected female members of this Lebanese family.\nGenetic counseling\nDespite the family history of consanguinity, autosomal dominant inheritance with reduced penetrance was considered as the most likely mode of transmission.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "Hypogonadotropic hypogonadism-retinitis pigmentosa syndrome", "Disease Definition": "A rare endocrine syndrome characterized by the association of hypogonadotropic hypogonadism (with primary amenorrhea and lack of secondary sexual development) and retinitis pigmentosa.", "ORPHA ID": 2235, "Summary": ""}
{"Disease Name": "Hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome", "Disease Definition": "Hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome is a rare, non-acquired pituitary hormone deficiency syndrome characterized by severe, congenital microcephaly, facial dysmorphism (highly arched eyebrows, hypertelorism, convex nasal ridge, protruding ears with underdeveloped superior antihelix crus, micrognathia), bilateral sensorineural deafness and hypogonadotropic hypogonadism, in association with early feeding problems, myopia, moderate intellectual disability and moderate short stature.", "ORPHA ID": 293967, "Summary": ""}
{"Disease Name": "Hypohidrosis-electrolyte imbalance-lacrimal gland dysfunction-ichthyosis-xerostomia syndrome", "Disease Definition": "A rare genetic disease characterized by abnormalities in renal ion transport, ectodermal gland homeostasis, and epidermal integrity, resulting in generalized hypohidrosis, heat intolerance, salt-losing nephropathy, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia. Development of nephrolithiasis and severe enamel wear have also been described. Laboratory findings include hypermagnesemia, hypokalemia, hypercalcemia, and hypocalciuria.", "ORPHA ID": 528105, "Summary": ""}
{"Disease Name": "Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome", "Disease Definition": "Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome is a rare, genetic, syndromic intellectual disability disorder characterized by severe intellectual disability with significant speech and language impairment, hypohydrosis (often resulting in hyperthermia) with normal sweat gland appearance, tooth enamel hypoplasia, palmoplantar hyperkeratosis and a high frequency of acquired microcephaly. Mild facial dysmorphism, including lateral flaring of the eyebrows, broad nasal tip, and thick vermilion border, may also be observed.", "ORPHA ID": 363523, "Summary": ""}
{"Disease Name": "Hypohidrotic ectodermal dysplasia with immunodeficiency", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by signs of ectodermal dysplasia (sparse hair, abnormal or missing teeth, decrease or absent sudation), typical facial features (protruding forehead, wrinkles under the eyes, characteristic periorbital hyperpigmentation), and immunodeficiency.", "ORPHA ID": 98813, "Summary": "Epidemiology\nPrevalence is not known. The incidence is approximately 1/250,000 live male births for the X-linked form. Fewer than 10 patients with the autosomal-dominant form have been reported.\nClinical description\nThe clinical picture is variable. Typical signs of HED may be observed, such as sparse hair (atrichosis/ hypotrichosis), abnormal (e.g. conical) or missing teeth (anodontia/ hypodontia), decreased or absent sudation due to a lack of sweat glands (anhidrosis/ hypohidrosis), and typical facial features (protruding forehead, wrinkles under the eyes, characteristic periorbital hyperpigmentation) which are associated with immunologic defects such as susceptibility to opportunistic infections, hypogammaglobulinemia, impaired antibody response to polysaccharides or impaired NK-cell activity. Many patients fail to thrive. Ectodermal dysplasia-related symptoms of HED-ID, however, tend to be milder than in patients with other forms of HED. The disease can also be associated with osteopetrosis and lymphedema (hypohidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, lymphedema; see this term).\nEtiology\nHED-ID is caused by hypomorphic mutations in the coding region of the IKBKG (or NEMO) gene (Xq28) or, less often, mutations in the NFKBIA gene (14q13), both involved in NF-κB activation.\nGenetic counseling\nTransmission is X-linked recessive in case of IKBKG mutations and autosomal-dominant in case of NFKBIA mutations. Somatic mosaicism seems to occur frequently in HED-ID patients.\n\n                            Last update: \n                            April 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Holm SCHNEIDER"}
{"Disease Name": "Hypohidrotic ectodermal dysplasia-hypothyroidism-ciliary dyskinesia syndrome", "Disease Definition": "A rare, genetic, ectodermal dysplasia syndrome characterized by the association of hypohidrotic ectodermal dysplasia (manifesting with the triad of hypohidrosis, anodontia/hypodontia and hypotrichosis) with primary hypothyroidism and respiratory tract ciliary dyskinesia. Patients frequently present urticaria pigmentosa-like skin pigmentation, increased mast cells and melanin depositions in the dermis and severe, recurrent chest infections. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 1882, "Summary": ""}
{"Disease Name": "Hypohidrotic ectodermal dysplasia", "Disease Definition": "A rare genetic ectodermal dysplasia syndrome characterized by sparse hair, abnormal or missing teeth, decrease or absent sudation and typical facial features.", "ORPHA ID": 238468, "Summary": "Epidemiology\nHED has a prevalence of approximately 1/15,000. CST syndrome is the most frequent sub-type (80% of cases) with an incidence in males of 1/50,000 to 1/100,000 births.\nClinical description\nHED is characterized by a triad of signs comprising sparse hair (atrichosis/hypotrichosis), abnormal (e.g. conical) or missing teeth (anodontia/hypodontia), and decreased or absent sudation due to a lack of sweat glands (anhidrosis/hypohidrosis) which leads to heat intolerance and may cause recurrent, potentially life-threatening hyperthermic episodes. The skin is thin, dry and eczematous with regional hyperkeratosis. Most of the patients suffer from ''dry eye'' problems (e.g. chronic conjunctivitis, blepharitis), nasopharyngeal dryness and asthma-like symptoms. HED is associated with typical facial features such as a protruding forehead, sparse and fine eyebrows and eyelashes, wrinkles under the eyes, characteristic periorbital hyperpigmentation, a saddle-bridged nose, and hypoplasia of the mandible. Hair pigmentation is often absent or light. Failure to thrive may be observed. The AD and AR forms affect both sexes equally. In the X-linked form, female carriers can be asymptomatic or have a milder phenotype that may include oligodontia, conical incisors, hypotrichosis and moderate hypohidrosis.\nEtiology\nHED is due to mutations in genes of the ectodysplasin/NF-κB pathway, necessary for the correct development of several ectodermal structures. Mutations in EDA (Xq12-q13.1), encoding the epithelial morphogen ectodysplasin-A of the tumor necrosis factor family, cause the CST syndrome. Mutations in EDAR (2q13), encoding the Ectodysplasin-A receptor, or EDARADD(1q42.3), encoding the EDAR-associated death domain (EDARADD) protein, cause both AR and AD HED.  IKBKG (Xq28) mutations cause HED with immunodeficiency. WNT10A, TRAF6, NFKBIA or EDA2R mutations may be responsible for some HED cases.\nDiagnostic methods\nThe diagnosis is often established after hyperthermic episodes or with delayed teeth eruption. Lack of sweat glands can be evidenced by a skin biopsy or non-invasively by confocal microscopy or graphite prints of feet/hands. Sweat gland function can be assessed by quantifying pilocarpine-induced sweat production. Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnoses include other types of ED like odonto-onycho-dermal dysplasia and certain forms of ichthyosis.\nManagement and treatment\nUncontrolled exposure to heat must be avoided. Continuous monitoring of body temperature is required for babies placed in an incubator. Older children should adopt physical cooling measures, e.g. frequent consumption of cool liquids, wetting the clothes or wearing special cooling vests/caps. Early dental treatment aims at restoring function and improving the appearance of the teeth. Orthodontic treatment often comprises bone grafting or sinus-lift procedures followed by placement of dental implants supporting dental prostheses. HED with immunodeficiency requires immune-based therapies plus aggressive management of infections or hematopoietic stem cell transplantation.\nPrognosis\nIf the disease is not diagnosed early enough in infancy, hyperthermia may lead to brain damage and eventually death. With early diagnosis and adequate management, most patients have a normal life expectancy.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Holm SCHNEIDER"}
{"Disease Name": "Hypoinsulinemic hypoglycemia and body hemihypertrophy", "Disease Definition": "Hypoinsulinemic hypoglycemia and body hemihypertrophy is a rare, genetic, endocrine disease characterized by neonatal macrosomia, asymmetrical overgrowth (typically manifesting as left-sided hemihypertrophy) and recurrent, severe hypoinsulinemic (or hypoketotic hypo-fatty-acidemic) hypoglycemia in infancy, which results in episodes of reduced consciousness and seizures.", "ORPHA ID": 293964, "Summary": ""}
{"Disease Name": "Hypokalemic periodic paralysis", "Disease Definition": "A rare genetic, muscle channelopathy characterized by recurrent episodic attacks of generalized muscle weakness associated with a decrease in blood potassium levels.", "ORPHA ID": 681, "Summary": "Epidemiology\nPrevalence is estimated at around 1/100,000 in Europe.\nClinical description\nAttacks of muscle weakness generally begin during childhood/adolescence (second decade). They vary in frequency, duration (hours to days) and severity (focal paresis to total paralysis). They generally involve the limbs muscles and spare the facial and respiratory musculature. Episodes are triggered by rest after strenuous exercise, meals rich in carbohydrates and prolonged immobility. Other factors may include stress, infection, glucocorticoids, anesthesia and pregnancy. In an undefined number of cases, hypokalemic periodic paralysis (hypoPP) may be associated with a vacuolar myopathy resulting in a permanent and progressive muscle weakness predominantly in proximal lower limb muscles. The myopathy may occur independent of paralytic symptoms.\nEtiology\nAround 70% of cases are associated with mutations in the muscle calcium channel gene CACNA1S (1q32.1) and 10% of cases are linked to mutations in the muscle sodium channel gene SCN4A (17q23.3).\nDiagnostic methods\nDiagnosis is based on clinical history, electromyographic and genetic tests. Hypokalemia during attacks can be very low. Serum creatinine kinase (CK) levels can be softly elevated. EMG reveals muscle excitability anomalies after a prolonged exercise test (decrement > 30% of the compound muscle action potential). Muscle biopsy may show non-specific results (muscle fibers atrophy with vacuoles). Molecular diagnosis is feasible through analysis of the causative genes identified so far.\nDifferential diagnosis\nDifferential diagnoses should include hyper/normokalemic periodic paralysis, Andersen-Tawil syndrome and secondary hypoPP caused by renal or endocrine diseases such as thyrotoxicosis (thyrotoxic periodic paralysis).\nAntenatal diagnosis\nOnce the pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible but rarely performed because of the non life-threatening prognosis.\nGenetic counseling\nHypoPP is transmitted as an autosomal dominant disease with a possible incomplete penetrance, especially in females. Genetic counseling should be offered to affected families. Sporadic cases and de novo mutations have been reported. Offspring of a proband are at a 50% risk of inheriting the pathogenic variant.\nManagement and treatment\nManagement of patients consists in medical therapy and avoidance of triggering factors. Gentle physical activity, and ingestion of oral potassium salts at the onset of attacks may abort them. Severe attacks require more intensive medical management with intravenous potassium infusion. Daily potassium supplementation or intake of carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide) or potassium-sparing diuretics help in preventing attacks. Dietary advice includes a diet low in carbohydrates and rich in potassium. There is no known curative treatment for hypoPP-related myopathy; physiotherapy may help to maintain strength and motor skills.\nPrognosis\nWith age, the frequency of the episodes decline but some patients may develop a chronic myopathy of variable severity that may cause a permanent muscle weakness.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Savine VICART"}
{"Disease Name": "Hypomandibular faciocranial dysostosis", "Disease Definition": "Hypomandibular faciocranial dysostosis is a cranial malformation characterized by facial dysmorphism (proptosis, frontal bossing, midface and zygomatic arches hypoplasia, short nose with anteverted nostrils, microstomia with persistent buccopharyngeal membrane, severe hypoglossia with glossoptosis, severe mandibular hypoplasia, and low set ears) associated with laryngeal hypoplasia and craniosynostosis. Other variable features include cleft palate, optic nerve coloboma and choanal stenosis.", "ORPHA ID": 1790, "Summary": ""}
{"Disease Name": "Hypomyelination neuropathy-arthrogryposis syndrome", "Disease Definition": "Hypomyelination neuropathy-arthrogryposis syndrome is a rare, genetic, limb malformation syndrome characterized by multiple congenital distal joint contractures (incl. talipes equinovarus and both proximal and distal interphalangeal joint contractures of the hands) and very severe motor paralysis at birth (i.e. lack of swallowing, autonomous respiratory function and deep tendon reflexes), leading to death within first 3 months of life. Fetal hypo- or akinesia, late-onset polyhydramnios and dramatically reduced, or absent, motor nerve conduction velocities (<10 m/s) are frequently associated. Nerve ultrastructural morphology shows severe abnormalities of the nodes of Ranvier and myelinated axons.", "ORPHA ID": 2680, "Summary": ""}
{"Disease Name": "Hypomyelination of early myelinating structures", "Disease Definition": "A rare genetic neurological disorder characterized by hypomyelination of early myelinating structures such as the brainstem, cerebellar white matter, optic radiation, and periventricular white matter, while structures acquiring myelin later are better myelinated. Patients present in infancy with nystagmus, developmental delay, and progressive ataxic-spastic or ataxic syndrome. Cognitive functions are normal or only mildly impaired.", "ORPHA ID": 599376, "Summary": ""}
{"Disease Name": "Hypomyelination with atrophy of basal ganglia and cerebellum", "Disease Definition": "A rare disorder characterized by slowly progressive spasticity, extrapyramidal movement disorders (dystonia, choreoathetosis and rigidity), cerebellar ataxia, moderate to severe cognitive deficit, and anarthria/dysarthria.", "ORPHA ID": 139441, "Summary": "Epidemiology\nSo far, around 20 cases have been reported in the literature. The syndrome affects both males and females and onset occurs in infancy or early childhood.\nEtiology\nThe etiology is unknown.\nDiagnostic methods\nH-ABC is diagnosed on the basis of the distinctive MRI findings of diffuse but partial hypomyelination of the cerebral hemispheres, mild to severe cerebellar atrophy and atrophy of the basal ganglia.\nGenetic counseling\nAll of the reported cases were sporadic and the mode of inheritance remains unclear.\n\n                            Last update: \n                            September 2008"}
{"Disease Name": "Hypomyelination with brain stem and spinal cord involvement and leg spasticity", "Disease Definition": "A rare genetic leukodystrophy characterized by diffuse hypomyelination in the supratentorial brain white matter, brain stem and spinal cord. Patients usually present nystagmus, lower limb spasticity, hypotonia, and motor developmental delay, as well as MRI signal abnormalities involving the corpus callosum, anterior brainstem, pyramidal tracts, superior and inferior cerebellar peduncles, dorsal columns and/or lateral corticospinal tracts.", "ORPHA ID": 363412, "Summary": ""}
{"Disease Name": "Hypomyelination-congenital cataract syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by congenital or early onset cataracts (usually bilateral), developmental delay, progressive neurologic symptoms (including ataxia, spasticity and sometimes seizures) and mild-to-moderate cognitive impairment. Other major clinical features include truncal hypotonia, dysarthia, cerebellar signs (e.g: truncal titubation and intention tremor) and peripheral neuropathy (e.g: progressive weakness of the muscles in the lower limbs). Hypomyelination associated with periventricular white matter abnormalities is observed. Some patients may have mild lens opacity and cataracts could be absent.", "ORPHA ID": 85163, "Summary": ""}
{"Disease Name": "Hypoparathyroidism-sensorineural deafness-renal disease syndrome", "Disease Definition": "Hypoparathyroidism-sensorineural deafness-renal disease syndrome is a rare, clinically heterogeneous genetic disorder characterized by the triad of hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R).", "ORPHA ID": 2237, "Summary": "Epidemiology\nThe exact prevalence is unknown, but the syndrome is considered to be very rare. So far, about 180 individuals from different racial and ethnic groups have been reported in the worldwide medical literature. Patients of both sexes have been described.\nClinical description\nHDR syndrome may present at any age with deafness, hypocalcemia, tetany and afebrile convulsions. Since prenatal ultrasonography is now a routine, congenital kidney and urinary tract anomalies could be the first presenting finding. ''H'' occurs in 93% of patients. ''D'' occurs in 96% of patients and is usually bilateral, ranging from moderate to profound impairment. ''R'' occurs in 72% of patients and includes congenital anomalies of the kidney and urinary tract (cystic, dysplastic, hypoplastic or aplastic kidneys, pelvicalyceal deformity, vesicoureteral reflux), chronic kidney disease, nephrotic syndrome, hematuria, proteinuria and others. Several additional features, such as congenital heart disease, facial and ocular abnormalities (retinitis pigmentosa, nystagmus, pseudopapilledema), basal ganglia calcifications, psoriasis, growth failure, and cognitive disability, among others, have also been described.\nEtiology\nHDR syndrome is primarily caused by mutations in GATA3, located on chromosome 10p (10p14). However, since GATA3 defects have not been detected in all reported patients, the presence of other gene defects being associated is possible. GATA3 belongs to a family of dual zinc-finger transcription factors involved in vertebrate embryonic development of the parathyroid glands, auditory system, and kidneys, as well as the thymus and central nervous system. Variability of expression and incomplete penetrance of GATA3 mutations results in the phenotypic heterogeneity observed.\nDiagnostic methods\nDiagnosis is based on the clinical findings and may be assisted by measurement of parathormone levels, an audiogram or auditory brain stem response study, renal imaging studies, and, if indicated, a renal biopsy. Although the syndrome is phenotypically defined by the ''HDR'' triad, only 65% of reported patients present it, while the others have various combinations of ''H'', ''D'', and ''R''. Diagnosis is confirmed in patients who have the ''HDR'' triad or, alternatively, have two out of three features plus a positive family history. Patients with isolated deafness or renal disease and those who do not fit the above criteria need positive GATA3 testing to confirm the diagnosis. GATA3 mutations have not been associated with isolated hypoparathyroidism.\nDifferential diagnosis\nDifferential diagnoses include familial idiopathic hypoparathyroidism, progressive sensorineural deafness without renal disease, autosomal recessive hypoparathyroidism with renal insufficiency and developmental delay, and deletion 22q11 syndrome. HDR syndrome should be considered in infants prenatally diagnosed with chromosome 10p defect or congenital anomalies of the kidney and urinary tract.\nGenetic counseling\nInheritance is autosomal dominant. Family members of affected patients should be studied, investigating for ''H'', ''D'', and ''R''. GATA3 testing should be considered.\nManagement and treatment\nTreatment of patients with HDR syndrome should be comprehensive and should include genetic counseling. Management is essentially symptomatic and depends on the specific clinical findings and severity of the disease. Hypocalcemia is usually the most common problem requiring treatment. Deafness should be treated early with hearing amplification, and, if needed, cochlear implantation. Treatment of kidney disease depends on the particular abnormality and ranges from close observation, such as for cysts, to medical or surgical treatment, including renal transplantation. Chronic kidney disease should be diagnosed and treated early to prevent or delay end-stage renal disease.\nPrognosis\nPrognosis depends on the nature and severity of the kidney disease. Patients with minor kidney problems have normal life expectancy.\n\n                            Last update: \n                            October 2018\n\n\n                            - Expert reviewer(s): \n                            Dr Amin BARAKAT"}
{"Disease Name": "Hypophosphatasia", "Disease Definition": "A rare, genetic metabolic disorder characterized by reduced activity of unfractionated serum alkaline phosphatase (ALP) and various symptoms from life-threatening, severely impaired mineralization at birth to musculo-skeletal pain in adulthood.", "ORPHA ID": 436, "Summary": "Epidemiology\nExact prevalence and incidence data for hypophosphatasia (HPP) are not available. In North and West Europe, the birth prevalence of severe forms of the disease (perinatal lethal and infantile forms) has been estimated to be 1/300 000. Because of possible dominant autosomal inheritance, moderate forms of HPP are expected to be more frequent and are estimated to have a prevalence of 1/6300.\nClinical description\nSix different clinical forms of HPP have been described, although there is a continuum of severity. Perinatal lethal HPP involves significant hypomineralization and leads to hypercalcemia and respiratory insufficiency. Prenatal benign HPP involves prenatal skeletal manifestations that slowly resolve to become non-lethal. Infantile HPP is characterized by rickets developing between birth and six months of age. Childhood HPP ranges from low bone mineral density with unexplained fractures to rickets. Adult HPP involves early loss of adult dentition and stress fractures of the lower extremities in middle age. In the mildest form, adults may present with only unspecific signs like musculo-skeletal pain or osteoporosis. Lastly, odontoHPP includes premature exfoliation of primary teeth and/or severe dental caries.\nEtiology\nMore than 400 different mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The gene encodes alkaline phosphatase, tissue-nonspecific isozyme (TNSALP) involved in skeletal mineralization.\nDiagnostic methods\nThe diagnosis is based on laboratory testing and molecular genetic testing of the ALPL gene to detect causative mutations. Serum alkaline phosphatase (AP) activity is markedly reduced while 5'pyridoxal phosphate (PLP) in blood and urinary phosphoethanolamine (PEA) are increased but the latter is not pathognomonic. Ultrasound is used in prenatal and perinatal forms. Clinical examinations and radiographs help to establish the diagnosis in infantile, childhood and adult forms.\nDifferential diagnosis\nIn the prenatal context, the differential diagnosis includes osteogenesis imperfecta, campomelic dysplasia, hypophosphatemic rickets and achondrogenesis. The main differential diagnosis in other forms is osteogenesis imperfecta.\nAntenatal diagnosis\nPrenatal diagnosis can be performed through mutation analysis following chorionic villus sampling.\nGenetic counseling\nPerinatal and severe infantile HPP are typically inherited as autosomal recessive traits. Prenatal benign, moderate infantile, childhood HPP, adult HPP and odontohypophosphatasia can be inherited in an autosomal recessive or autosomal dominant manner, depending on the specific effect the gene mutation has on TNSALP activity. The less severe the disease, the more likely it is dominantly inherited. The range of inheritance patterns partially explains the clinical heterogeneity. In both autosomal recessive and dominant hypophosphatasia, de novo mutations are exceptional. In autosomal dominant hypophosphatasia, affected patients may have an affected parent but penetrance appears to be low. HPP displays highly variable expressivity. Genetic counseling is complicated by these factors but should be offered to affected families.\nManagement and treatment\nSupportive symptomatic treatment in childhood and adult forms includes non-steroidal anti-inflammatory drugs (children), teriparatide (adults) and orthopedic management. Dental monitoring and care are essential. Since its availability, enzyme replacement therapy plays an increasing role, especially in pediatric severe forms.\nPrognosis\nThe perinatal form is almost always fatal within days or weeks. Respiratory complications lead to high mortality rates in the infantile form. Life expectancy is not thought to be affected in childhood and adult forms or in odontohypophosphatasia.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Severine BACROT  - Dr Etienne MORNET"}
{"Disease Name": "Hypophosphatemic rickets", "Disease Definition": "A group of genetic, renal phosphate wasting disorders characterized by hypophosphatemia, rickets, and normal serum levels of calcium. Characteristic clinical features include slow growth/short stature, bone pain and bone deformities.", "ORPHA ID": 437, "Summary": ""}
{"Disease Name": "Hypopigmentation-punctate palmoplantar keratoderma syndrome", "Disease Definition": "A rare, genetic, epidermal disease characterized by punctate keratoderma on palms and soles associated with irregularly shaped hypopigmented macules (typically localized on the extremities). Ectopic calcification (e.g. early-onset calcific tendinopathy, calcinosis cutis) and pachyonychia may be occasionally associated.", "ORPHA ID": 324561, "Summary": ""}
{"Disease Name": "Hypoplasia of the mitral valve annulus", "Disease Definition": "A rare, congenital, mitral valve malformation characterized by hypoplastic annulus which usually appears within a complete mitral valve hypoplasia, causing mitral valve stenosis. Association with other cardiac malformation is common, including coarctation of the aorta, aortic valve stenosis, Shone complex and hypoplastic left heart syndrome.", "ORPHA ID": 99058, "Summary": ""}
{"Disease Name": "Hypoplasminogenemia", "Disease Definition": "A rare multi-system disease characterized by markedly impaired extracellular fibrinolysis leading to the formation of ligneous (fibrin-rich) pseudomembranes on mucosae.", "ORPHA ID": 722, "Summary": "Epidemiology\nWhilst epidemiological data is limited, the prevalence of hypoplasminogenemia (HPG) is estimated to be in the range of 1/625,000.\nClinical description\nOnset of clinical manifestations usually occurs in early infancy, but can occur at any age. Although not well understood, triggers of lesions may include microtrauma (dust, a foreign body), surgical procedures or local inflammation. The most common clinical manifestation of HPG are lesions of the conjunctivae (ligneous conjunctivitis (LC)) which initially appear as inflammation but progress to development of membranous lesions. Other sites of involvement include the oral cavity with gingival lesions (ligneous periodontitis), nose, sinuses, ears, throat and tonsils, gastrointestinal tract (duodenal ulcers, lesions in the small and large bowel), the respiratory tract (pseudomembranous laryngitis, trachea-bronchitis and consolidation or atelectasis), urinary tract, and the female genital tract (vaginitis, cervicitis, involvement of the fallopian tube, ovary and endometrium). The central nervous system (occlusive hydrocephalus, Dandy Walker malformation) and the skin (juvenile colloid milium) may also be affected, but are less common. HPG has been reported to effect wound healing. HPG is not a risk factor for thrombophilia.\nEtiology\nHPG is caused by homozygous or compound-heterozygous pathogenic variants in the gene PLG (6q26); encoding plasminogen (plg). In HPG, PLG mutations result in parallel reductions in both the level of immunoreactive plg and its functional activity.\nDiagnostic methods\nDiagnosis relies on recognition of the clinical manifestations and laboratory tests for plg activity and immunoreactive levels. Diagnosis can be confirmed by genetic testing.\nDifferential diagnosis\nWhilst infection of the affected area is most frequently the assumed diagnosis, the differential diagnosis is extensive and dependent on the area affected and includes polyps, allergies, cholesteatoma, hearing loss, Cowden's Disease, oral fibromas, gingival hypertrophy, reactive airway disease, pneumonia, gastroesophageal reflux disease, ulcers, inflammatory bowel disease, irritable bowel syndrome, kidney stones, endometriosis, polycystic ovarian disease, primary infertility, juvenile colloid milium, Ehlers Danlos (poor wound healing) as well as amyloidosis and lipoid proteinosis.\nAntenatal diagnosis\nPrenatal genetic diagnosis is possible if a couple has a prior affected child and the pathogenic genetic variants in both PLG genes have been identified. Identification of compound heterozygous or homozygous hypoplasminogenemia is not necessarily predictive of the development of symptoms or severity that may be experienced.\nGenetic counseling\nHPG is inherited in an autosomal recessive pattern. Siblings of individuals who have hypoplasminogenemia each have a 25% risk of inheriting the condition. Genetic counseling should be offered to families with an affected individual and at-risk couples. Individuals who are heterozygous or have dysplasminogenemia (plg activity is reduced, but immunoreactive levels are normal or slightly reduced) are asymptomatic.\nManagement and treatment\nManagement depends on the site(s) of involvement. Treatment strategies have been targeted mainly towards management of LC. The plg concentrate, ryplazim, was recently approved (June 2021, USA) and is administered intravenously as a replacement therapy for plasminogen and has been shown effective in treating both eye and systemic lesions. A currently unlicensed plg ophthalmologic concentrate has been utilized with reported success for eye lesions. In the absence of plg concentrate, treatment is with fresh frozen plasma. Other attempted systemic medications have included anticoagulants, immunosuppressants, hormone therapy, antihistamines, and antibiotics. Surgical interventions have been attempted, but in the absence of plg concentrate, typically result in rapid regrowth of lesions. Occlusive hydrocephalus is treated as standard. Other topical treatments for eye lesions may be used as an adjunctive to plg replacement.\nPrognosis\nWhere the conjunctivae is involved, the visual prognosis is typically moderate; although chronic lesions can lead to loss of vision. The prognosis for severe cases with multiorgan involvement can be quite poor.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Rebecca BIALAS  - Dr Amy SHAPIRO"}
{"Disease Name": "Hypoplastic left heart syndrome", "Disease Definition": "A rare, congenital, non-syndromic, heart malformation characterized by under development of the left-sided cardiac structures (including left ventricle, ascending aorta, aortic arch, and mitral and/or aortic valve) such that the left heart is unable to provide adequate systemic cardiac output.", "ORPHA ID": 2248, "Summary": "Epidemiology\nHypoplastic left heart syndrome (HLHS) has been reported to occur in 1/3,500 to 12,500 live births. A male to female predominance ratio of 1.5:1 is observed.\nClinical description\nNewborn infants with HLHS are generally born at full term. Initially appearing healthy, they are dependent upon the patent ductus arteriosus (PDA) for systemic blood flow. As the PDA closes, systemic perfusion decreases, resulting in hypoxemia, acidosis, and cardiogenic shock. Usually, no heart murmur (or a non-specific heart murmur) is detected. The second heart sound is loud and single because of aortic atresia. Often the liver is enlarged secondary to congestive heart failure. The spectrum of cardiac malformations can be distinguished by the status of the mitral and aortic valves. At the severe end of the spectrum is the aortic and mitral valve atresia (AA/MA) subtype that is associated with an absent or a slit-like left ventricle and diminutive aortic arch. The two other subtypes, aortic atresia with mitral stenosis (AA/MS), and aortic and mitral stenosis (AS/MS) subtype, have variable ventricular hypoplasia with a discrete left ventricular cavity.\nEtiology\nAs is the case of most congenital cardiac defects, the embryologic cause of the disease is not fully known.\nDiagnostic methods\nThe most useful diagnostic modality is the echocardiogram. Findings on echocardiogram include hypoplasia or atresia of the left ventricle, mitral valve, aortic valve, and ascending aorta.\nDifferential diagnosis\nDifferential diagnosis includes other left-sided obstructive lesions where the systemic circulation is dependent on ductal flow (critical aortic stenosis, coarctation of the aorta, interrupted aortic arch).\nAntenatal diagnosis\nAntenatal diagnosis is possible as the syndrome can be diagnosed by fetal echocardiography between 18 and 22 weeks of gestation.\nManagement and treatment\nInitially, ductal patency is maintained by continuous infusion of intravenous prostaglandin until surgery. Currently, there are two major surgical approaches: univentricular palliation or primary cardiac transplantation, the preference for selecting which option depending on the institutional experience and the availability of donor organs. Univentricular palliation is the most commonly used approach and involves a series of staged cardiac surgical procedures over a period of 2 years that ultimately result in separation of the systemic venous and arterial circulation. Stage I is typically performed in the first week of life, or when the neonate is stable, and techniques may include the Norwood procedure, the Sano modification or the hybrid procedure. Stage II is performed between 3 and 6 months of age and involves the bi-directional Glenn procedure. Stage III, the Fontan procedure, is performed between 2 and 5 years of age. In certain expert centers, fetal transcatheter intervention may be an option. Given the improvement in surgical outcomes, opting for comfort management only remains controversial.\nPrognosis\nIf left untreated, HLHS is universally fatal within a few days- weeks of life. Whilst surgical intervention supports survival through infancy and into early adulthood, the 5-year survival rate is approximately 65%. However, the significant mortality and morbidity associated with both surgical strategies merits discussions with the families regarding the initial decision relative to the treatment and long-term prognosis.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Ravi THIAGARAJAN"}
{"Disease Name": "Hypoplastic pancreas-intestinal atresia-hypoplastic gallbladder syndrome", "Disease Definition": "A rare, potentially fatal, genetic, visceral malformation syndrome characterized by neonatal diabetes, hypoplastic or annular pancreas, duodenal and jejunal atresia, as well as gallbladder aplasia or hypoplasia. Patients typically present intrauterine growth restriction, failure to thrive, malnutrition, intestinal malrotation, malabsorption, conjugated hyperbilirubinemia, acholia and infections. Cardiac anomalies may also be associated.", "ORPHA ID": 293864, "Summary": ""}
{"Disease Name": "Hypoplastic right heart syndrome", "Disease Definition": "A rare, cyanotic congenital heart malformation caused by underdevelopment of the right-sided heart structures (tricuspid valve, RV, pulmonary valve, and pulmonary artery) commonly associated with an atrial septal defect, ostium secundum type. Pulmonary blood flow is diminished and right-to-left shunting occurs at the atrial level, leading to dyspnea, fatigue, atrial arrhythmias, right-sided heart failure, hypoxemia, repeated miscarriages that were mostly due to hypoxemia and cyanosis. Two subtypes of HRHS have been characterized: pulmonary atresia-intact ventricular septum and right ventricular hypoplasia.", "ORPHA ID": 98723, "Summary": ""}
{"Disease Name": "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome", "Disease Definition": "This syndrome is characterized by the association of severe nasal hypoplasia, hypoplasia of the eyes, hyposmia, hypogeusia and hypogonadotropic hypogonadism.", "ORPHA ID": 2250, "Summary": "Epidemiology\nIt has been described in two males.\nClinical description\nAdditional features included bilateral inguinal hernias, undescended testes, and impaired vision with cataracts and colobomata.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "Hypospadias-intellectual disability, Goldblatt type syndrome", "Disease Definition": "A very rare multiple congenital anomalies syndrome described in three brothers of one South-African family, and characterized by hypospadias and intellectual deficit, in association with microcephaly, craniofacial dysmorphism, joint laxity and beaked nails.", "ORPHA ID": 2261, "Summary": ""}
{"Disease Name": "Hypothalamic adipsic hypernatraemia syndrome", "Disease Definition": "A rare endocrine disease characterized by severe chronic hypernatremic dehydration caused by decreased intake of water based on impaired thirst perception, due to a selective defect in hypothalamic osmoregulation of thirst. Structural hypothalamic lesions are absent and arginine vasopressin secretion is normal.", "ORPHA ID": 443101, "Summary": ""}
{"Disease Name": "Hypothalamic hamartomas with gelastic seizures", "Disease Definition": "Hypothalamic hamartomas with gelastic seizures is a rare cerebral malformation with epilepsy syndrome characterized by early-onset gelastic (i.e. ictal laughter) or dacrystic (i.e., ictal crying) seizures due to non-neoplastic developmental malformation - hypothalamic hamartomas. In many patients, seizures progress to other seizure types including focal and generalized seizures, with concomitant cognitive decline and behavioral disorders. Some patients also present a precocious puberty.", "ORPHA ID": 86906, "Summary": ""}
{"Disease Name": "Hypothyroidism due to deficient transcription factors involved in pituitary development or function", "Disease Definition": "Hypothyroidism due to mutations in transcription factors involved in pituitary development or function is a type of central congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth, characterized by low levels of thyroid hormones caused by disorders in the development or function of the pituitary.", "ORPHA ID": 226307, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe clinical manifestations can be subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment hypothyroidism results in severe intellectual deficit and short stature. Clinical manifestations may often include signs of hypopituitarism including septo-optic dysplasia or cleft lip and/or palate among others.\nEtiology\nThe hypothyroidism is caused by mutations in genes regulating pituitary gland development including HESX1, LHX3, LHX4, POU1F1 and PROP1 (3p21.2-p21.1, 9q34.3, 1q25, 3p11 and 5q) .\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Hypothyroidism due to TSH receptor mutations", "Disease Definition": "A type of primary congenital hypothyroidism, a permanent thyroid hormone deficiency that is present from birth due to thyroid resistance to TSH.", "ORPHA ID": 90673, "Summary": "Epidemiology\nResistance to TSH occurs in about 5% of cases of permanent congenital hypothyroidism.\nClinical description\nClinical manifestations are those of other forms of congenital hypothyroidism (CH; see this term). Goiter is always absent.\nEtiology\nMutations in the TSH receptor gene (TSHR; 14q31) result in resistance to TSH, which causes a reduction in thyroid hormone production. Mutations in TSHR may also cause thyroid hypoplasia (see this term).\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Hypotonia with lactic acidemia and hyperammonemia", "Disease Definition": "This syndrome is characterised by severe hypotonia, lactic academia and congenital hyperammonaemia.", "ORPHA ID": 137908, "Summary": "Epidemiology\nIt has been described in three newborns born to consanguineous parents.\nClinical description\nUltrasound examination during the 36th week of pregnancy revealed generalised oedema. Hypertrophic cardiomyopathy and tubulopathy developed within the first week of life and the infants died within the first month. The activities of enzymes in the mitochondrial respiratory chain were reduced in the muscles of the patients.\nEtiology\nMutations were identified in the MRPS22 gene, encoding a mitochondrial ribosomal protein.\n\n                            Last update: \n                            April 2008"}
{"Disease Name": "Hypotonia-cystinuria syndrome", "Disease Definition": "A rare, genetic disorder of amino acid absorption and transport, characterized by generalized hypotonia at birth, neonatal/infantile failure to thrive (followed by hyperphagia and rapid weight gain in late childhood), cystinuria type 1, nephrolithiasis, growth retardation due to growth hormone deficiency, and minor facial dysmorphism. Dysmorphic features mainly include dolichocephaly and ptosis. Nephrolithiasis occurs at variable ages.", "ORPHA ID": 163690, "Summary": ""}
{"Disease Name": "Hypotonia-failure to thrive-microcephaly syndrome", "Disease Definition": "Leukotriene C4 synthase deficiency is an extremely rare fatal neurometabolic developmental disorder characterized clinically by muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.", "ORPHA ID": 79507, "Summary": ""}
{"Disease Name": "Hypotonia-speech impairment-severe cognitive delay syndrome", "Disease Definition": "Hypotonia-speech impairment-severe cognitive delay syndrome is a rare, genetic neurodegenerative disorder characterized by severe, persistent hypotonia (presenting at birth or in early infancy), severe global developmental delay (with poor or absent speech, difficulty or inability to roll, sit or walk), profound intellectual disability, and failure to thrive. Additional manifestations include microcephaly, progressive peripheral spasticity, bilateral strabismus and nystagmus, constipation, and variable dysmorphic facial features (including plagiocephaly, broad forehead, small nose, low-set ears, micrognathia and open mouth with tented upper lip).", "ORPHA ID": 371364, "Summary": ""}
{"Disease Name": "Hypotrichosis simplex of the scalp", "Disease Definition": "Hypotrichosis simplex of the scalp (HSS) is characterized by diffuse progressive hair loss that is confined to the scalp.", "ORPHA ID": 90368, "Summary": "Epidemiology\nPrevalence is unknown but HSS has been described in multiple members (males and females) of several large families.\nClinical description\nProgressive hair loss generally begins during the first decade of life and most patients are completely bald by the third decade of life. In contrast to the generalized form of hypotrichosis simplex (see this term), body, axillary and facial hair, as well as the eyebrows and eye lashes are unaffected in HSS. There are no anomalies of the skin, nails and teeth.\nEtiology\nThe causative gene CDSN (encoding the keratinocyte adhesion molecule, corneodesmosin) has been mapped to chromosome 6p21.3.\nGenetic counseling\nHSS is transmitted in an autosomal dominant manner.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Regina BETZ"}
{"Disease Name": "Hypotrichosis simplex", "Disease Definition": "Hypotrichosis simplex (HS) or hereditary hypotrichosis simplex (HHS) is characterized by reduced pilosity over the scalp and body (with sparse, thin, and short hair) in the absence of other anomalies.", "ORPHA ID": 55654, "Summary": "Epidemiology\nPrevalence is unknown but numerous large pedigrees with several affected members have been described. Both men and women are equally affected.\nClinical description\nHair loss is diffuse and progressive and usually begins during early childhood. Body hair may also be sparse with variable involvement of the eyebrows, eyelashes, and pubic and axillary hair. There are no anomalies of the skin, nails or teeth. A scalp-limited form, hypotrichosis simplex of the scalp (see this term) has also been reported with mutations in the corneodesmosin (CDSN) gene.\nEtiology\nBoth autosomal dominant and recessive modes of transmission have been reported for HHS.Autosomal dominant HHS affecting both scalp and body hair has been reported in one Italian and two Pakistani families as due to mutations in the APCDD1 gene mapped to 18p11.22. Three clinically similar forms of localized autosomal recessive hypotrichosis (LAH1, LAH2 and LAH3) have been identified within the last years. The locus for LAH1 (involving mainly the hair of the scalp, chest, arms and legs) has been mapped to 18q12.1 and mutations in the desmoglein-4 (DSG4) gene have been identified. The locus for LAH2 (characterized by sparse or absent scalp, axillary and body hair, and sparse eyebrows and eyelashes) has been mapped to 3q27.3 and mutations in the lipase-H (LIPH) gene have been identified. The locus for LAH3 (characterized by progressive loss of scalp hair, sparse body hair, and normal eyebrows, eyelashes, and pubic and axillary hair) has been mapped to 13q14.11-q21.32 and mutations have been identified in a G protein-coupled receptor gene (P2RY5). These receptors belong to the group of lipophosphatidic acid (LPA) receptors and are therefore designated as LPAR6.\nManagement and treatment\nThere is no treatment for hypotrichosis simplex available to date.\n\n                            Last update: \n                            June 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Regina BETZ"}
{"Disease Name": "Hypotrichosis with juvenile macular degeneration", "Disease Definition": "Hypotrichosis with juvenile macular degeneration (HJMD) is a very rare syndrome characterized by sparse and short hair from birth followed by progressive macular degeneration leading to blindness.", "ORPHA ID": 1573, "Summary": "Epidemiology\nPrevalence is unknown but approximately 50 patients have been described since the first characterization of the syndrome in 1935.\nClinical description\nHJMD patients present with short and sparse scalp hair since birth or first months of life, with no subsequent growth during life. A decade later, during the first to third decades of life, visual acuity decreases because of progressive macular degeneration, leading in many cases to blindness between the second and fourth decades of life. HJMD is sometimes associated with limb anomalies, in which case it is termed Ectodermal dysplasia, Ectrodactyly, and Macular dystrophy (EEM; see this term). Many patients display fair hair complexion as compared with their healthy siblings. The hair phenotype does not improve significantly with age, even though diffuse alopecia in infancy can evolve towards short and sparse hair in puberty.\nEtiology\nHJMD is caused by mutations in the CDH3 gene (16q22.1), encoding P-cadherin. P-cadherin is part of adherens junctions in various epithelia including the hair follicular epithelium. Moreover, P-cadherin is expressed in the retinal pigment epithelium.\nDiagnostic methods\nDiagnosis is based on the combined occurrence of hypotrichosis with characteristic degenerative changes and pigmentary abnormalities of the macula on fundoscopy. Where available, electrophysiologic studies can confirm abnormal function of the posterior pole. Additional tests of lesser diagnostic value include (1) histopathologic examination of scalp biopsies, revealing mostly vellus and catagen hair follicles with significantly reduced number of terminal hair follicles; (2) light microscopy and scanning electron microscopy of hair which can demonstrate various structural abnormalities including pseudomonilethrix, pili torti, longitudinal ridging, scaling and folding of the hair shaft.\nDifferential diagnosis\nDifferential diagnosis includes EEM syndrome, also caused by CDH3 mutations.\nAntenatal diagnosis\nDNA-based prenatal diagnosis and genetic counseling are available provided the underlying mutation is known.\nGenetic counseling\nAs HJMD is an autosomal recessive disease, risk of recurrence is 25%.\nManagement and treatment\nNo curative or palliative options exist for HJMD. However, educational measures can be implemented and psychological support should be provided once HJMD is diagnosed.\nPrognosis\nThe most severe complication of HJMD is progressive macular degeneration leading to blindness between the second and fourth decades of life. Life expectancy is normal but quality of life can be reduced because of blindness and psychological impact due to the hair phenotype.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Liat SAMUELOV  - Pr Eli SPRECHER"}
{"Disease Name": "Hypotrichosis-deafness syndrome", "Disease Definition": "A syndromic genetic deafness characterized by erythrokeratoderma, hypotrichosis, nail dystrophy and sensorineural hearing loss. Erythema, recurrent skin infections and mucositis have also been associated.", "ORPHA ID": 330029, "Summary": ""}
{"Disease Name": "Hypotrichosis-intellectual disability, Lopes type", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by hypotrichosis of scalp and eyebrows, finger syndactyly, intellectual disability and early eruption of teeth. Facial dysmorphism (i.e. round face with prominent forehead, cheeks and ears, and upward-slanting palpebral fissures), hypoplasia of median and distal phalanges, and kyphosis are additionally observed features. There have been no further descriptions in the literature since 1996.", "ORPHA ID": 2266, "Summary": ""}
{"Disease Name": "Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome", "Disease Definition": "An extremely rare syndromic lymphedema disorder characterized by early-onset hypotrichosis, childhood-onset lymphedema, and variable telangiectasia, particularly of the palms.", "ORPHA ID": 69735, "Summary": ""}
{"Disease Name": "Hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome", "Disease Definition": "Hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome is an extremely rare ectodermal dysplasia syndrome characterized by hypotrichosis universalis with mild to severe scarring alopecia, acro-osteolysis, onychogryphosis, thin and tapered fingertips, periodontitis and caries leading to premature teeth loss, linear or reticular palmoplantar keratoderma and erythematous, scaling, psoriasis-like skin lesions on arms and legs. Lingua plicata and ventricular tachycardia have also been observed.", "ORPHA ID": 307936, "Summary": ""}
{"Disease Name": "Hypoxanthine guanine phosphoribosyltransferase partial deficiency", "Disease Definition": "Kelley-Seegmiller syndrome (KSS) is the mildest form of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (see this term), a hereditary disorder of purine metabolism, and is associated with uric acid overproduction (UAO) leading to urolithiasis, and early-onset gout.", "ORPHA ID": 79233, "Summary": "Epidemiology\nThe exact prevalence is unknown but is probably underestimated due to misdiagnosis. KSS may represent about 15% of HPRT deficient patients.\nClinical description\nAge of onset is usually in infancy but can also be in adulthood (up to 30 years). Males are generally affected and heterozygous females are carriers (usually asymptomatic). Patients are normal at birth. The first manifestation is the presence of orange crystals in diapers. Urolithiasis, uric acid nephropathy, urinary infections and renal obstruction are often the presenting symptoms. Gout may appear after puberty with acute arthritis or tophi. In contrast to Lesch-Nyhan syndrome (LNS; see this term), dystonia may be mild or even absent. Patients have normal intelligence associated with various degrees of attention deficit. Compulsive self-injurious behavior is absent.\nEtiology\nThe disease is caused by partial HPRT deficiency due to mutations in the HPRT1 gene (Xq26). Inheritance is X-linked recessive. UAO may be due to deficient recycling of purine bases with increased synthesis of purine nucleotides leading to hyperuricemia that increases the risk of UA crystal precipitation in tissues to form tophi, in joints leading to inflammatory processes and gouty arthritis, and renal UA excretion causing urolithiasis.\nDiagnostic methods\nDiagnosis may be suspected when nephrolithiasis and/or obstructive nephropathy occur and is based on biochemical, enzymatic and molecular tests. Hyperuricemia and UAO are detectable in serum and urine. Plasmatic levels and urinary excretion of urate, hypoxanthine, and, to a lesser extent, xanthine are elevated. HPRT activity in hemolysate ranges from 0.5% to 10%.\nDifferential diagnosis\nDifferential diagnosis includes glucose 6-phosphate dehydrogenase deficiency, Lesch-Nyhan syndrome and phosphoribosylpyrophosphate (PRPP) synthetase superactivity (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is usually not required.\nManagement and treatment\nUAO, nephrolithiasis, gouty arthritis and tophi can be managed with allopurinol, urine alkalinization (sodium bicarbonate or citrate) and generous hydration. Doses must be carefully adjusted to avoid xanthine lithiasis.\nPrognosis\nWith appropriated treatment renal function remains stable and patients have a normal life expectancy.\n\n                            Last update: \n                            April 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Juan GARCÍA PUIG  - Dr Rosa TORRES JIMÉNEZ"}
{"Disease Name": "Hypoxanthine-guanine phosphoribosyltransferase deficiency", "Disease Definition": "Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a hereditary disorder of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of the enzyme deficiency.", "ORPHA ID": 206428, "Summary": "Epidemiology\nPrevalence of HPRT deficiency is unknown but estimated prevalence for Lesch-Nyhan syndrome (LNS; see this term) is estimated between 1/380,000 and 1/235,000 live births. Males are generally affected and heterozygous females are carriers (usually asymptomatic).\nClinical description\nOnset occurs during infancy. Two forms of the disease have been described: LNS, the most severe form, with a complete enzyme deficiency, and Lesch-Nyhan variants with partial HPRT deficiency. LNS is characterized by uric acid overproduction-related symptoms associated with urolithiasis and gout, severe neurological manifestations, hematological disturbances, and compulsive self-injurious behaviour. LNS patients have a limited life expectancy. In the less severely affected LNS variants, also termed Kelley-Seegmiller syndrome (KSS; see this term), uric acid overproduction-related symptoms are prominent, neurological manifestations are usually unapparent, compulsive self-injurious behaviour is absent and patients have a normal life expectancy.\nEtiology\nInheritance is X-linked recessive and HPRT deficiency results from mutations in the HPRT1 gene (Xq26).\n\n                            Last update: \n                            April 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Juan GARCÍA PUIG  - Dr Rosa TORRES JIMÉNEZ"}
{"Disease Name": "Iatrogenic botulism", "Disease Definition": "Iatrogenic botulism is the most recent man-made form of botulism (see this term), a rare acquired neuromuscular junction disease with descending flaccid paralysis caused by botulinum neurotoxins (BoNTs), and it may occur as an adverse event after therapeutic or cosmetic use.", "ORPHA ID": 254509, "Summary": "Epidemiology\nPrevalence is unknown. As of 2008, 180 cases occurring between 1997 and 2006 have been reported to the FDA, including 87 hospitalized cases and 16 deaths.\nClinical description\nClinical manifestations are similar to other forms of botulism, with symmetrical cranial nerve palsies followed by descending, symmetric flaccid paralysis of voluntary muscles, which may progress to respiratory compromise and death.\nEtiology\nAfter injection, the toxin is absorbed into the blood stream and distributed throughout the body, causing the typical manifestations of botulism. Therapeutic BoNT injections are a first-line treatment for hemifacial spasm and focal dystonia, such as cervical dystonia and blepharospasm (see these terms). They can also be proposed to treat strabismus and other oculomotor disorders, focal spasticity (spastic foot, upper and lower limb spasticity), overactive bladder and autonomic disorders such as hyperhidrosis, Frey's syndrome and sialorrhea. BoNT injections may have a potential antinociceptive effect. Injected doses, that may be relatively high mostly in the treatment of lower limb spasticity, have caused events reported as adverse reactions including limited botulism-related symptoms (ptosis, diplopia, dysphagia), rare systemic events (flu-like syndrome, generalized weakness and respiratory distress) and occasional deaths following the use of BoNT types A and B. Doses recommended for cosmetic treatment are too low to cause systemic disease, but injection of unlicensed, highly concentrated botulinum toxin may cause severe botulism. All cases of botulism should be reported to the appropriate government agency.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Michel POPOFF"}
{"Disease Name": "Iatrogenic Creutzfeldt-Jakob disease", "Disease Definition": "A rare acquired human prion disease characterized by progressive, invariably fatal neurodegeneration resulting from accidental transmission of CJD prions in the course of medical procedures or treatments (treatment with human pituitary growth hormone or gonadotrophin, human dura mater or corneal graft, exposure to contaminated neurosurgical instruments). Patients present rapidly progressive cognitive impairment, as well as myoclonus, visual or cerebellar problems, pyramidal or extrapyramidal features, and/or akinetic mutism. EEG examination may show characteristic generalized periodic sharp wave complexes. Neuropathologic analysis reveals spongiform change, neuronal loss and gliosis, and deposition of abnormal prion protein.", "ORPHA ID": 576379, "Summary": ""}
{"Disease Name": "ICF syndrome", "Disease Definition": "A rare autosomal recessive syndrome with combined immunodeficiency characterized by the clinical triad of immunodeficiency, centromeric instability and facial anomalies (abbreviated ICF syndrome). The immunodeficiency is with panhypogammaglobulinemia, and a lack of memory (CD19+CD27+) B cells in the peripheral blood, although B and T-cell counts are normal. Anomalies and rearrangements associated with DNA hypomethylation in the vicinity of the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16 and sometimes 9, in mitogen-stimulated lymphocytes, is a hallmark of the syndrome. The typical facial anomalies include hypertelorism, low-set ears, epicanthus and macroglossia.", "ORPHA ID": 2268, "Summary": "Epidemiology\nICF has been described in about 100 patients worldwide.\nClinical description\nRecurrent infections are the presenting symptom, usually in early childhood. Autoimmune manifestations have been described. Other variable symptoms of this probably under-diagnosed syndrome include delayed developmental milestones with growth delay, failure to thrive, and global developmental delay, with various degrees of cognitive impairment.\nEtiology\nThe syndrome is caused by homozygote or heterozygote mutations in the DNA methyltransferase 3B (DNMT3B; ICF1), the zinc finger and BTB domain containing 24 (ZBTB24; ICF2), the cell division cycle-associated 7 (CDCA7; ICF3), the helicase lymphoid specific (HELLS; ICF4) genes. More recently, variants in the ubiquitin like with PHD and ring finger domains 1 gene (UHRF1) have been associated with one ICF patient. Loss of DNA methylation at satellite repeats embedded in the juxta-centromeric heterochromatin in the 1qh, 9qh, and 16qh, regions is a hallmark of ICF patients and is associated with whole-arm deletions, chromatid and chromosome breaks, stretching (decondensation), and multiradial chromosome junctions in mitogen-stimulated lymphocytes. DNA hypomethylation at centromeric satellite repeats (alpha-satellite), at subtelomeres and a set of unique genes are linked to the genotype of the patients.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation, mostly on recurrent infections and immunologic abnormalities (very low memory B cells). Molecular investigations based on cytogenetic analysis and gene panel sequencing enable to confirm the diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes other syndromic combined immunodeficiencies.\nAntenatal diagnosis\nPrenatal diagnosis is available for this disorder.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling is proposed to family with ICF syndrome. At-risk couples (both individuals are carriers of a disease-causing mutation) have a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment includes regular infusions of immunoglobulins, mostly intravenously, and antibacterial prophylaxis. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for ICF patients.\nPrognosis\nHSCT can cure the immunodeficiency of patients with ICF syndrome. Very few cases have been reported (less than 10 cases) and only for patients with mutations in the DNMT3B gene (ICF1). Long-term follow-up studies are limited.\n\n                            Last update: \n                            December 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Capucine PICARD  - Dr Guillaume VELASCO"}
{"Disease Name": "Ichthyosis follicularis-alopecia-photophobia syndrome", "Disease Definition": "Ichthyosis follicularis - alopecia - photophobia (IFAP) is a rare genetic disorder characterized by the triad of ichthyosis follicularis, alopecia, and photophobia from birth.", "ORPHA ID": 2273, "Summary": "Epidemiology\nPrevalence is unknown. Approximately 40 cases have been reported to date. IFAP primarily affects male subjects. Female carriers may develop some clinical features.\nClinical description\nAll patients present with congenital follicular ichthyosis, alopecia involving the scalp, eyebrows and eyelashes, and photophobia (in the first year of life, infancy or early childhood). Ichthyosis follicularis is characterized by widespread non-inflammatory thorn-like follicular projections. Hyperkeratotic papules are most pronounced over the extensor extremities and scalp and are distributed symmetrically. Non-cicatricial complete body alopecia is also a classical feature. Variable degrees of a collodion membrane may be present in newborns. Psoriasiform plaques, angular cheilitis, periungueal inflammation, dystrophic nails, hypohidrosis and atopic eczema can be present. The palms and soles are generally unaffected. Superficial corneal ulceration and vascularization may lead to progressive corneal scarring. Male patients have relentless progression of corneal vascularization and loss of vision. Atopic keratoconjunctival inflammation, chronic tearing, cataract, horizontal nystagmus, astigmatism and myopia have been reported. In a few cases, mild to severe intellectual disability, short stature, microcephaly, seizures, dysmorphic features (frontal bossing, choanal atresia, large ears), cleft hands, intestinal anomalies (omphalocele, Hirschsprung disease or congenital aganglionic megacolon (see these terms), small intestine stenosis, inguinal hernia), as well as renal, cardiac and vertebral anomalies can be present. Recurrent infections are common. External genitalia are generally normal with a few cases of cryptorchidism and one with hypospadias. Affected or carrier females may have milder symptoms (cutaneous hyperkeratotic lesions that follow the lines of Blaschko, asymmetric distribution of body hair, patchy alopecia).\nEtiology\nThe disorder is caused by mutations in the MBTPS2 gene (Xp22.12-p22.11) leading to impaired cholesterol homeostasis and response to endoplasmic reticulum stress.\nDiagnostic methods\nDiagnosis is based on the clinical features and on testing of the MBTPS2 gene.\nDifferential diagnosis\nDifferential diagnosis includes dermotrichic syndrome, hereditary mucoepithelial dysplasia, keratitis-ichthyosis-deafness (KID syndrome) and keratosis follicularis spinulosa decalvans (see these terms).\nAntenatal diagnosis\nIFAP cannot be detected prenatally by ultrasound.\nGenetic counseling\nIf the mutation has been identified in a carrier mother, prenatal diagnosis can be proposed. Transmission is X-linked recessive. The mutation might also arise de novo. A few cases of autosomal dominant inheritance have been reported.\nManagement and treatment\nFollicular hyperkeratosis can be treated using topical keratolytics, emollients and urea preparations. A moderate response to acitretin therapy has been found in some patients. Intensive lubrication of the ocular surface is essential. Corneal vascularization does not respond to topical corticosteroids.\nPrognosis\nPrognosis is variable. Some patients die in the neonatal period while others have normal life expectancy. However, in most patients, progressive loss of vision leads to loss of autonomy. Cardiopulmonary complications are the main cause of death.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Pr André MEGARBANE  - Dr Hala MEGARBANE"}
{"Disease Name": "Ichthyosis hystrix of Curth-Macklin", "Disease Definition": "Ichthyosis hystrix of Curth-Macklin (IHCM) is a rare type of keratinopathic ichthyosis (see this term) that is characterized by the presence of severe hyperkeratotic lesions and palmoplantar keratoderma (PPK, see this term).", "ORPHA ID": 79503, "Summary": "Epidemiology\nPrevalence is unknown. Six families and sporadic cases have been reported to date.\nClinical description\nThe skin is usually normal at birth. The disease starts in early childhood with severe hyperkeratosis of yellow-brown or grey color, and of spiky, cobblestone-like (hystrix) or verrucous appearance. Hyperkeratosis is often diffuse and more pronounced on extensor areas of the limbs, extremities and the trunk. Lesions may also be nevoid following the lines of Blaschko. Patients are also affected with striate or diffuse PPK. As the disease progresses, PPK worsens and results in deep bleeding, painful fissures and cracks. In severe cases, PPK can also lead to contractures, gangrene and loss of digits. The skin is malodorous and frequently infected. Nail dystrophy may be present. Contrary to other keratinopathic ichthyoses, no skin fragility/blister formation or erythroderma is present.\nEtiology\nIHCM results from heterozygous frameshift mutation in a section of the KRT1 gene encoding keratin 1 (K1). These mutations lead to an abnormal supramolecular organization of keratin intermediate filaments and may be related to defects in cytoplasmic trafficking and integrity of cellular structures such as organelles and nucleus.\nDiagnostic methods\nDiagnosis is based on clinical examination and on histological examination of skin lesion biopsies revealing papillomatous hyperplasia with hyperorthokeratosis and hypergranulosis. Electron microscopy shows keratin intermediate filaments forming continuous perinuclear shells, presence of perinuclear vacuoles and binucleate keratinocytes.\nDifferential diagnosis\nDifferential diagnosis includes other forms of keratinopathic ichthyosis such as epidermolytic ichthyosis, as well as epidermolytic palmoplantar keratoderma, erythrokeratodermia variabilis, and KID syndrome (see these terms).\nAntenatal diagnosis\nMolecular prenatal diagnosis is available for affected families.\nGenetic counseling\nTransmission is autosomal dominant but some sporadic cases have been reported. The risk for an affected parent to have an affected child is of 50%.\nManagement and treatment\nManagement is symptomatic and life-long. Oral and systemic keratolytics can improve localized hyperkeratotic lesions by exfoliating and increasing the moisture of the skin.\nPrognosis\nLife expectancy is normal. However, the unaesthetic and malodorous aspects of the skin, the pain and bleeding related to PPK, and infections lead to functional disabilities and a greatly reduced quality of life.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER"}
{"Disease Name": "Ichthyosis-alopecia-eclabion-ectropion-intellectual disability syndrome", "Disease Definition": "Ichthyosis-alopecia-eclabion-ectropion-intellectual disability syndrome is an ectodermal dysplasia syndrome characterized by severe generalized lamellar icthyosis at birth with alopecia, eclabium, ectropion and intellectual disability. Although similar to Sjögren-Larsson syndrome, this syndrome lacks the presence of neurologic or macular changes. There have been no further descriptions in the literature since 1987.", "ORPHA ID": 2269, "Summary": ""}
{"Disease Name": "Ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome", "Disease Definition": "Ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome is characterised by ichthyosis, hepatosplenomegaly and late-onset cerebellar ataxia. It has been described in two brothers. Transmission is either autosomal recessive or X-linked.", "ORPHA ID": 2274, "Summary": ""}
{"Disease Name": "Ichthyosis-hypotrichosis syndrome", "Disease Definition": "Ichthyosis-hypotrichosis syndrome is characterised by congenital ichthyosis and hypotrichosis. It has been described in three members of a consanguineous Arab Israeli family. The syndrome is transmitted as an autosomal recessive trait and is caused by a missense mutation in the ST14 gene, encoding the recently identified protease, matriptase. Analysis of skin samples from the patients suggests that this enzyme plays a role in epidermal desquamation.", "ORPHA ID": 91132, "Summary": ""}
{"Disease Name": "Ichthyosis-intellectual disability-dwarfism-renal impairment syndrome", "Disease Definition": "Ichthyosis-intellectual disability-dwarfism-renal impairment syndrome is characterised by nonbullous congenital ichthyosis, intellectual deficit, dwarfism and renal impairment. It has been described in four members of one Iranian family. Transmission is autosomal recessive.", "ORPHA ID": 2278, "Summary": ""}
{"Disease Name": "Ichthyosis-oral and digital anomalies syndrome", "Disease Definition": "Ichthyosis-oral and digital anomalies syndrome is characterised by ichthyosis, unusual facies (small mouth with a thin upper lip and lower lip with a midline groove) and digital anomalies (tapered fingers with a lack of distal flexion creases and wide spacing between the second and third fingers). It has been described in two sibs born to first cousin parents. Transmission appears to be autosomal recessive.", "ORPHA ID": 2272, "Summary": ""}
{"Disease Name": "Ichthyosis-prematurity syndrome", "Disease Definition": "A rare, syndromic congenital ichthyosis characterized by premature birth (at gestational weeks 30-32, in general) in addition to thick, caseous and desquamating epidermis, neonatal respiratory asphyxia, and persistent eosinophilia. After the perinatal period, a spontaneous improvement in the health of affected patients is observed and skin features (vernix caseosa-like scale) evolve into a mild presentation of flat follicular hyperkeratosis with atopy.", "ORPHA ID": 88621, "Summary": ""}
{"Disease Name": "Ichthyosis-short stature-brachydactyly-microspherophakia syndrome", "Disease Definition": "A rare, syndromic ichthyosis characterized by a collodion membrane at birth, generalized congenital ichthyosis, microspherophakia, myopia, ectopia lentis, short stature with brachydactyly and joint stiffness, and occasionally mitral valve dysplasia.", "ORPHA ID": 363992, "Summary": ""}
{"Disease Name": "Idiopathic achalasia", "Disease Definition": "Idiopathic achalasia (IA) is a primary esophageal motor disorder characterized by loss of esophageal peristalsis and insufficient lower esophageal sphincter (LES) relaxation in response to deglutition.", "ORPHA ID": 930, "Summary": "Epidemiology\nIA is a rare disease with an annual incidence of approximately 1/200,000 to 1/59,000 and a prevalence rate recently estimated to be 1/10,000. There is no gender predilection and the peak incidence occurs between 30 and 60 years of age. There is some suspicion of differences between ethnic groups.\nClinical description\nIA is characterized predominantly by dysphagia to solids and liquids, bland regurgitation often unresponsive to an adequate trial of proton pump inhibitor (PPI), and chest pain. Weight loss (usually between 5 and 10 kg) is present in most, but not all patients. Heartburn occurs in 27%-42% of IA patients. They are more likely to suffer from autoimmune disorders (diabetes mellitus, hypothyroidism, Sjögren syndrome, lupus erythematosus; see these terms).\nEtiology\nAlthough the precise etiology is unknown, it is often thought to be either autoimmune, viral immune, or neurodegenerative. Some familial cases have been reported, but the rarity of familial occurrence does not support the hypothesis that genetic inheritance is a significant etiologic factor. IA has been associated with viral infections and auto-antibodies against myenteric plexus have been found, but the causal relationship remains unclear.\nDiagnostic methods\nLack of response to proton pump inhibitor therapy in a patient initially diagnosed as gastroesophageal reflux disease (GERD) should raise suspicion for motility disorders such as IA, especially if dysphagia is an accompanying complaint. The diagnosis is based on history of the disease, radiography (barium esophagogram), and esophageal motility testing (esophageal manometry). Endoscopic assessment of the gastroesophageal junction and gastric cardia is necessary to rule out malignancy. Newer diagnostic modalities such as high resolution manometry (HRM) help in predicting treatment response in achalasia based on esophageal pressure topography patterns identifying three phenotypes of achlasia (I-III) and outcome studies suggest better treatment response with types I and II compared to type III.\nDifferential diagnosis\nA majority of patients are misdiagnosed as having reflux disease given regurgitation. The differential diagnosis of a patient with dysphagia and regurgitation includes GERD, esophageal spasm, pseudoachalasia (associated to malignancies), and possibly eosinophilic esophagitis (see this term).\nManagement and treatment\nAlthough IA cannot be permanently cured, excellent outcomes are achieved in over 90% of patients. Current medical and surgical therapeutic options (pneumatic dilation, surgical myotomy, and pharmacologic agents) aim at reducing the LES pressure and facilitating esophageal emptying by gravity and hydrostatic pressure of retained food and liquids. Either graded pneumatic dilatation (PD) or laparoscopic surgical myotomy with a partial fundoplication are recommended as initial therapy guided by patient age, gender, preference, and local institutional expertise. Botulinum toxin therapy is less effective than PD or surgical myotomy and is commonly reserved for patients who are not candidates for definitive therapies.\nPrognosis\nThe prognosis in IA patients is excellent. Most patients with IA who are appropriately treated have a normal life expectancy but the disease does recur and the patient may need intermittent treatment.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Dhyanesh PATEL  - Pr Michael VAEZI"}
{"Disease Name": "Idiopathic acute eosinophilic pneumonia", "Disease Definition": "Idiopathic acute eosinophilic pneumonia (IAEP) is an eosinophilic pneumonia of undetermined etiology that is characterized by acute febrile hypoxic respiratory failure associated with diffuse radiographic infiltrates and pulmonary eosinophilia, but without concurring allergy or infection.", "ORPHA ID": 724, "Summary": "Epidemiology\nThe prevalence of IAEP is still unknown but <100 cases have been reported to date. A recent study has described only 3 pediatric cases in a 5 year-time frame in France. Men are affected approximately twice as frequently as women.\nClinical description\nIAEP can occur at any age, even in previously healthy children, although most patients are between 20 and 40 years of age. IAEP presents itself as an acute pneumonia in previously healthy subjects and the clinical features include acute respiratory failure with fever, dry cough, progressive dyspnea, tachypnea and severe hypoxemia. Crackles on chest auscultation and marked chest wall retractions can be observed. Myalgia and abdominal pain may also be present.IAEP can be precipitated or exacerbated by smoking tobacco and cannabis.\nEtiology\nThe pathophysiology of IAEP is still not well understood. It appears to result from damage caused by eosinophils infiltrating the lung parenchyma and releasing toxic substances such as basic proteins, lipid mediators, and cytokines.\nDiagnostic methods\nDiagnostic criteria for IAEP are as follows: 1) acute onset of febrile illness (usually less than 7 days), 2) diffuse bilateral pulmonary infiltrates, 3) severe hypoxemic respiratory failure (with blood oxygen saturation <90% by pulse oximetry, or PaO2<60mmHg on room air or PaO2/FiO ≤300 mmHg), 4) lung eosinophilia (bronchoalveolar lavage [BAL] fluid eosinophilia >25% or predominance of eosinophils in lung biopsy), and 5) no known causes of acute eosinophilic lung (recent onset of tobacco smoking or exposure to inhaled dust). Chest radiographs show diffuse bilateral infiltrates, air space opacities, interstitial reticulo-nodular densities and/or pleural effusion. These interstitial infiltrates usually progress to extensive alveolar and interstitial infiltrates involving all lobes in several hours. Chest computed tomography (CT) scans show diffuse areas of ground-glass attenuation, alveolar infiltrates, poorly defined nodules and interlobular septal thickening.\nDifferential diagnosis\nDifferential diagnosis includes acute interstitial pneumonia (AIP), acute lung injury (ALI), acute respiratory distress syndrome (ARDS) (see these terms), severe community-acquired pneumonia, aspiration pneumonia, acute hypersensitivity pneumonitis and fungal or parasitic infections.\nManagement and treatment\nComplete clinical and radiological recovery without relapse may be achieved rapidly with corticosteroid therapy (between 2 and 12 weeks intravenous dosage followed by a switch to oral administration).In patients not properly treated, respiratory failure is observed, requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO).\nPrognosis\nPrognosis of IAEP is excellent as long as corticosteroid therapy is instituted promptly. Without the appropriate diagnosis and treatment, IAEP may be fatal.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Christophe DUBUS"}
{"Disease Name": "Idiopathic acute transverse myelitis", "Disease Definition": "A rare immune-mediated inflammatory demyelinating disorder of the spinal cord with motor, sensory and autonomic involvement.", "ORPHA ID": 139423, "Summary": "Epidemiology\nAnnual incidence is estimated at between 1/1,000,000 and 1/250,000 depending on the study. Onset may occur at any age and both sexes may be affected.\nClinical description\nThe spinal cord inflammation is focal and the signs and symptoms are usually bilateral and depend on the extent and site of the lesion, with the thoracic spinal cord being the most common localization. Progression to nadir occurs between 4 hours and 21 days after onset. Motor involvement is characterized by limb weakness, stiffness and muscle spasms. If the upper spinal cord is involved then respiratory function may be impaired. Back pain, paraesthesia, numbness and neuropathic pain are common sensory manifestations. Uncomfortable band-like sensations around the torso and radicular pain have also been reported. Autonomic anomalies include sexual dysfunction, urinary urge/retention and bowel urgency/retention. Autonomic dysreflexia (ADR), resulting in rapid onset of hypertension and bradycardia, is a complication seen in patients with spinal cord lesions at T6 or above and usually with severe myelitis.\nEtiology\nBy definition, the etiology of idiopathic acute transverse myelitis (ATM) is unknown. A history of viral illness (usually upper respiratory infection) often precedes onset of symptoms by three weeks and idiopathic ATM is believed to be associated with a late immune response against a recent microbial infection that inadvertently targets the spinal cord.\nDiagnostic methods\nThe diagnostic approach revolves around confirming the diagnosis of myelitis (MRI revealing transverse spinal cord lesions and swelling, with longitudinally extensive lesions in some cases), and excluding secondary causes (brain MRI, serology and analysis of cerebrospinal fluid to rule out secondary ATM; see this term), which may be associated with a relapsing disease course requiring preventative treatments.\nDifferential diagnosis\nAcute compressive lesions (such as metastases and epidural abscess) and infarction of the spinal cord should also be included in the differential diagnosis.\nManagement and treatment\nAcute treatment may include corticosteroid therapy and plasma exchange. The benefits of intravenous immunoglobulins and cyclophosphamide remain to be established. Long-term management is mainly symptomatic and should include rehabilitative therapy.\nPrognosis\nThe prognosis is variable and unpredictable. Recovery may begin between 2 and 12 weeks after the onset of symptoms. Full recovery (occurring in only a third of patients) may take years and permanent sequelae are frequent (moderate disability in one third of patients and severe disability in the remaining third).\n\n                            Last update: \n                            February 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Anu JACOB  - Dr Alison L JONES"}
{"Disease Name": "Idiopathic avascular necrosis", "Disease Definition": "A rare osteonecrosis characterized by bone necrosis due to disrupted blood supply in the absence of a known cause. Affected bones include the femoral head, talus, vertebral body, humerus, and scaphoid, among others. Patients may initially be asymptomatic but subsequently present with gradually developing refractory pain, swelling, and reduced range of motion. If left untreated, the condition may progress to bone collapse with secondary degeneration, fragmentation, and pathological fracture, as well as osteoarthritis.", "ORPHA ID": 399307, "Summary": ""}
{"Disease Name": "Idiopathic bilateral vestibulopathy", "Disease Definition": "Idiopathic bilateral vestibulopathy is a rare otorhinolaryngologic disease characterized by dysfunction of both peripheral labyrinths or of the eighth cranial nerves, which presents with persistent unsteadiness of gait (particularly in darkness, during eye closure or under impaired visual conditions, or when standing/walking on uneven, soft or wobbly ground) and oscillopsia associated with head movements. The disease may be progressive, presenting no episodes of vertigo, or sequential, presenting recurrent episodes of vertigo.", "ORPHA ID": 171684, "Summary": ""}
{"Disease Name": "Idiopathic bronchiectasis", "Disease Definition": "Idiopathic bronchiectasis (IB) is a progressive lung disease characterized by chronic dilation of the bronchi and destruction of the bronchial walls in the absence of any underlying cause (such as post infectious disease, aspiration, immunodeficiency, congenital abnormalities and ciliary anomalies).", "ORPHA ID": 60033, "Summary": ""}
{"Disease Name": "Idiopathic camptocormia", "Disease Definition": "Idiopathic camptocormia is a postural disease characterized by an anterior flexion of the torso (during walking or standing) that resolves in the supine position and that is caused by weakness of the lumbar paraspinal muscles (spinal extensors), due to massive fatty infiltrations of posterior spinal muscles, without an identifiable etiology.", "ORPHA ID": 1320, "Summary": ""}
{"Disease Name": "Idiopathic CD4 lymphocytopenia", "Disease Definition": "Idiopathic CD4 lymphocytopenia is a rare primary immunodeficiency disorder characterized by persistent CD4 T-cell lymphopenia (less than 300 cells/µL on multiple occasions) not associated with any other underlying primary or secondary immune deficiency. Patients typically present opportunistic infections (with cryptococcal, mycobacterial, candidal, varicella zoster virus infections and progressive multifocal leukoencephalopathy being the most prevalent), malignancies (mainly lymphoproliferative disorders), or autoimmune disorders. Some individuals are asymptomatic and incidentally diagnosed.", "ORPHA ID": 228000, "Summary": ""}
{"Disease Name": "Idiopathic chronic eosinophilic pneumonia", "Disease Definition": "A rare, severe, interstitial lung disease characterized by insidious onset with subacute or chronic non-specific respiratory manifestations (dyspnea, cough, wheezing) often associated with systemic manifestations (fatigue, malaise, weight loss) and a history of asthma (up to half of patients). Eosinophilia is present in most cases, usually in excess of 1000 cells/mm3.", "ORPHA ID": 2902, "Summary": ""}
{"Disease Name": "Idiopathic congenital hypothyroidism", "Disease Definition": "Idiopathic congenital hypothyroidism is a type of primary congenital hypothyroidism (see this term) whose cause and prevalence are unknown.", "ORPHA ID": 95717, "Summary": "Clinical description\nClinical manifestations are those of other forms of congenital hypothyroidism (CH; see this term). Goiter is always absent.\nDiagnostic methods\nUltrasound examination and thyroid scintigraphy show a thyroid gland of normal shape and size in the normal, eutopic location. Idiopathic congenital hypothyroidism can be diagnosed after exclusion of the known causes of CH.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Idiopathic copper-associated cirrhosis", "Disease Definition": "Idiopathic copper-associated cirrhosis is a rare copper-overload liver disease characterized by a rapidly progressive liver cirrhosis from the first few years of life leading to hepatic insufficiency and harboring a specific pathological aspect: pericellular fibrosis, inflammatory infiltration, hepatocyte necrosis, absence of steatosis, poor regeneration and histochemical copper staining.", "ORPHA ID": 209919, "Summary": ""}
{"Disease Name": "Idiopathic dropped head syndrome", "Disease Definition": "A rare acquired skeletal muscle disease characterized by severe weakness of the neck extensor muscles causing progressive reducible kyphosis of the cervical spine and the inability to hold the head up, in the absence of a known cause. Histological studies reveal a non-inflammatory myopathic picture. The clinical course is relatively benign, although cervical myelopathy may develop.", "ORPHA ID": 447881, "Summary": ""}
{"Disease Name": "Idiopathic ductopenia", "Disease Definition": "A rare biliary tract disease characterized by loss of interlobular bile ducts resulting in chronic cholestasis, without any known cause. Loss of less than 50% of interlobular bile ducts is associated with a mild disease course, while loss of the majority of ducts results in a severe form, potentially leading to cirrhosis and liver failure. Patients typically present as young or middle-aged adults with episodic jaundice, pruritus, and elevated liver enzymes.", "ORPHA ID": 480512, "Summary": ""}
{"Disease Name": "Idiopathic eosinophilic myositis", "Disease Definition": "A rare idiopathic inflammatory myopathy characterized by eosinophilic infiltration and inflammatory lesions of the skeletal muscle tissue, in the absence of an identifiable causative factor (e.g. parasitic infection, drug intake, systemic or malignant disease). Clinically patients may present focal or generalized muscle weakness and pain, difficulties to walk, motor clumsiness and/or mild bilateral Achilles tendon contracture , as well as elevated serum creatine kinase levels and peripheral blood and/or bone marrow hypereosinophilia.", "ORPHA ID": 247724, "Summary": ""}
{"Disease Name": "Idiopathic gastroparesis", "Disease Definition": "A rare idiopathic gastroesophageal disease characterized by delayed gastric emptying in the absence of mechanical obstruction of the gastric outlet. Patients present symptoms including nausea, vomiting, early satiety, postprandial fullness, bloating, abdominal pain and, in more severe cases, dehydration, electrolyte disturbances, weight loss and malnutrition.", "ORPHA ID": 558411, "Summary": ""}
{"Disease Name": "Idiopathic giant cell myocarditis", "Disease Definition": "A rare cardiomyopathy characterized by progressive myocarditis with diffuse infiltration of cardiac tissue by lymphocytes, macrophages, multinuclear giant cells, and myocardial necrosis. Clinical presentation includes rapidly progressive heart failure, ventricular arrhythmias, complete heart block, and sudden cardiac death. Some patients have associated autoimmune disorders.", "ORPHA ID": 329874, "Summary": ""}
{"Disease Name": "Idiopathic hemiconvulsion-hemiplegia syndrome", "Disease Definition": "A rare acute encephalopathy with inflammation-mediated status epilepticus characterized by infancy-onset of refractory unilateral, mainly clonic status epilepticus during or shortly after a febrile episode without evidence of central nervous system infection, followed by permanent or transient hemiplegia with a minimum duration of one week. The majority of children develop pharmaco-resistant epilepsy a few months later. Brain imaging shows edematous swelling of the affected hemisphere at the time of the initial status, followed by hemiatrophy that does not correlate with any vascular territory.", "ORPHA ID": 86908, "Summary": ""}
{"Disease Name": "Idiopathic hypercalciuria", "Disease Definition": "A rare renal disease characterized by persistent excess urinary calcium excretion in the absence of an underlying systemic disease and hypercalcemia. The condition leads to an increased risk for the formation of kidney stones and nephrocalcinosis, as well as reduced bone mineral density with increased incidence of fractures in some patients.", "ORPHA ID": 2197, "Summary": "Epidemiology\nPrevalence is estimated at 2.2-6.4% in the pediatric population and is the most common cause of calcium nephrolithiasis in childhood.\nClinical description\nIdiopathic hypercalciuria (IH) mainly presents in childhood with variable clinical symptoms including abdominal or back pain, cloudy urine (more evident at the first voiding of the day), sediment in urine collection, gross or microscopic hematuria, urinary tract infections, urinary urgency, incontinence or dysuria. Calcium kidney stones occur frequently as a result of supersaturation of calcium oxalate and calcium phosphate in urine, leading to the formation of mineral plaques in the renal papillary interstitium and subsequent growth of a calcium body. Excessive calcium excretion may also result in decreased bone mineral density and disturbance of bone mineralization.\nEtiology\nThe disorder can be caused by reduced tubular calcium reabsorption (renal IH) or by increased intestinal calcium absorption associated to a vitamin D receptor activation (absorptive IH), or as a result of both. Genetic susceptibility to absorptive IH is correlated to mutations on the ADCY10 gene (1q23.3-q24) and on the 4q33-qter segment, and a history of nephrolithiasis is frequently reported in first-degree relatives. Furthermore, pathological elevation of tissue vitamin D receptor (VDR) level is suggested as a molecular basis of IH, which may elevate intestinal calcium absorption and bone resorption, and decrease renal tubule calcium reabsorption. Environmental factors including dietary habits also influence the disease.\nDiagnostic methods\nDiagnosis is based on evidence of repeated hypercalciuria in the fasting or fed state, and in the absence of any underlying cause. Hypercalciuria is determined on 24-hour urine collection test, and is often associated with a calcium/creatinine ratio greater than 0.20 mg/mg. Kidney stones may be revealed by ultrasound and high resolution CT imaging of the urinary tract.\nDifferential diagnosis\nConditions in which urine calcium levels may be increased should be excluded, including hypercalcemia, bone metabolic diseases (e.g. primary hyperparathyroidism, Paget disease), renal tubular acidosis, metabolic acidosis, chronic renal failure, nephrocalcinosis of other origin, long-term immobilization, and drugs affecting bone metabolism (glucocorticoids, diuretics, vitamin D).\nGenetic counseling\nThe disease follows an autosomal dominant inheritance. Genetic counselling should be provided to family members and affected parents, informing them of the 50% risk of reoccurrence. Clinical variability is explained by dietary and other environmental factors.\nManagement and treatment\nTreatment is with dietary management ensuring daily calcium requirements (1,200 mg/day in adults or equivalent reference values for children ), preferably sourced from food, a reduced sodium intake (up to 1.5 g/day in adults or an equivalent quantity in children), moderation of animal protein, and a fluid intake of 3 to 3.5 liters daily depending on climate, lifestyle and working conditions. Thiazide diuretics and potassium citrate are commonly used to prevent persistent symptoms, recurrence of stone formation, development of nephrocalcinosis, and osteopenia and, when dietary adjustments fail, to decrease urinary calcium supersaturation. A urinary calcium: citrate ratio ≥ 0.25 is a risk marker for nephrolithiasis. Monitoring nutritional vitamin D deficiency is recommended but excessive supplementation should be avoided to prevent further excretion of urinary calcium.\nPrognosis\nThe prognosis of IH is usually favorable when treated appropriately. However, persistent hypercalciuria in children may decrease bone formation and lead to poor bone health in adulthood with osteopenia, osteoporosis and increased risks of fractures, whereas recurrent nephrolithiasis may result in progressive renal damage.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Gema ARICETA | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Idiopathic hypereosinophilic syndrome", "Disease Definition": "A rare hematologic disease characterized by eosinophilia without evidence of clonality persisting for at least six months, for which no underlying cause can be identified. The condition is associated with signs of organ damage and dysfunction. Clinical manifestations are highly variable, depending on the organ systems involved, and include rapidly developing, life-threatening cardiovascular or neurological complications.", "ORPHA ID": 3260, "Summary": ""}
{"Disease Name": "Idiopathic hypersomnia", "Disease Definition": "A rare neurologic disease characterized by an excessive daytime sleepiness with long and unrefreshing naps, and/or prolonged and undisturbed nocturnal sleep, impaired daytime alertness, and/or sleep inertia (ie, great difficulty in waking up after sleep) and where other causes have been excluded.", "ORPHA ID": 33208, "Summary": "Epidemiology\nThe prevalence estimates were initially based on the proportion of patients with idiopathic hypersomnia (IH) over those with narcolepsy in the sleep medicine population. The consensus currently estimates prevalence of IH in the range of 0.002%-0.010% in the general population. A higher frequency in women is reported.\nClinical description\nSymptoms frequently start during adolescence or young adulthood, but may occur at any age. Idiopathic hypersomnia with long sleep time is characterized by a prolonged (more than 10 hours) nocturnal sleep of good quality, and / or excessive daytime sleepiness with prolonged unrefreshing sleep episodes, and sometimes difficulty in awakening in the morning or after naps, with sleep inertia or drunkenness. Idiopathic hypersomnia without long sleep time is characterized by isolated excessive daytime sleepiness, with irresistible and more or less refreshing diurnal naps. Nocturnal sleep is normal or slightly prolonged but lasts less than 10 hours, and quality of awakening is often normal. Idiopathic hypersomnia is never associated with cataplexy (which would lead to a suspicion of narcolepsy type 1).\nEtiology\nEtiology is still unknown. There is no association with any particular HLA (human leukocyte antigen) marker or with a decrease in the orexin/hypocretin levels, as in narcolepsy type 1.\nDiagnostic methods\nDiagnosis is complex and must exclude other causes of sleepiness and document the excess of nighttime and daytime sleep. Definitive diagnosis is based on polysomnography completed with multiple sleep latency tests (MSLT), performed without any medication with an effect on sleep. These tests reveal a sleep of good quality and reveal a mean sleep latency of less than 8 min with a maximum of one episode of paradoxical sleep. In case of idiopathic hypersomnia with long sleep time, a 24h (or 32h) continuous sleep recording shows a nocturnal sleep episode of over 10 hours with a daytime nap of more than an hour, i.e. over 11 hours/ 24h (or over 19 hours/32h).\nDifferential diagnosis\nClinical examination (based on a clinical interview, a sleep diary or on actimetry) eliminates chronic insufficient sleep syndrome. Sleep recordings exclude narcolepsy, circadian rhythm disorders or fragmented night sleep due to motor or respiratory events. A psychological examination excludes hypersomnia of psychiatric origin (especially depressive symptoms). Finally, neuro-radiological tests, which are rarely performed, exclude cerebral lesions.\nGenetic counseling\nIH appears to be familial; however, there is no information on inheritance or penetrance.\nManagement and treatment\nTo date, no drug has authorisation for the treatment of patients affected with idiopathic hypersomnia worldwide; recommendations are based on expert opinion only. Stimulant drugs (i.e. modafinil, methylphenidate, pitolisant) have a good benefit risk ratio except for the post-awakening confusion (sleep inertia). Amphetamines are third-line therapies. Sodium oxybate could be effective on sleepiness and inertia (ongoing clinical trials).\nPrognosis\nThe disease has a negative social and professional impact. Spontaneous evolution of the disease is variable and may remain stable, resolve or evolve to narcolepsy type 2.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Lucie BARATEAU  - Pr Yves DAUVILLIERS"}
{"Disease Name": "Idiopathic intracranial hypertension", "Disease Definition": "Idiopathic intracranial hypertension is a neurological disorder characterized by isolated increased intracranial pressure manifesting with recurrent and persistent headaches, nausea, vomiting, progressive and transient obstruction of the visual field, papilledema. Visual loss can be irreversible.", "ORPHA ID": 238624, "Summary": ""}
{"Disease Name": "Idiopathic isolated micropenis", "Disease Definition": "A rare, non-syndromic, urogenital tract malformation characterized by an anatomically normal penis which has a stretched penile length of less than 2.5 SD for age, in the absence of any other abnormalities and with no known cause.", "ORPHA ID": 95707, "Summary": ""}
{"Disease Name": "Idiopathic juvenile osteoporosis", "Disease Definition": "Idiopathic juvenile osteoporosis (IJO) is a primary condition of bone demineralization that presents with pain in the back and extremities, walking difficulties, multiple fractures, and radiological evidence of osteoporosis.", "ORPHA ID": 85193, "Summary": "Epidemiology\nThe exact prevalence is unknown but several hundreds of cases have been reported in the literature so far.\nClinical description\nOnset usually occurs in the prepubertal period, between 8 and 12 years of age. The first sign of IJO is usually pain in the lower back, hips and feet. Knee and ankle pain, kyphosis, loss of height and a sunken chest may also be present. Low bone mineral density, vertebral collapse and metaphyseal compression fractures of the long bones are common.\nEtiology\nThe etiology of idiopathic juvenile osteoporosis remains unknown.\nDiagnostic methods\nDiagnosis is based on clinical presentation, skeletal X-rays and bone density tests (dual-energy X-ray absorptiometry, dual photon absorptiometry and quantitative computed tomography).\nDifferential diagnosis\nOsteogenesis imperfecta (see this term) is the main differential diagnosis.\nManagement and treatment\nManagement is aimed at protecting the spine and other bones from fracture. Physical therapy and exercise (avoiding weight-bearing activities), and other supportive measures are mandatory. There is no established treatment strategy. Treatments with calcium and/or vitamin D, fluoride, calcitonin, and bisphosphonates (in severe, long-lasting cases) have been reported with unequivocal efficacy.\nPrognosis\nThe disease is self-limiting with spontaneous resolution after the onset of puberty. Rarely, in more severe cases, permanent disability (kyphoscoliosis and rib deformity) can develop.\n\n                            Last update: \n                            April 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Pierre QUARTIER DIT MAIRE"}
{"Disease Name": "Idiopathic linear interstitial keratitis", "Disease Definition": "Idiopathic linear interstitial keratitis is a rare, acquired ocular disease characterized by migratory or non-migratory, horizontal, linear, stromal infiltrates that may heal spontaneously. Minimal vascularization and scarring may be observed but vision loss is not associated.", "ORPHA ID": 314017, "Summary": ""}
{"Disease Name": "Idiopathic localized lipodystrophy", "Disease Definition": "Idiopathic localized lipodystrophy is a rare, acquired, localized lipodystrophy characterized by asymptomatic, well-demarcated, depressed, lipoatrophic lesions of variable size, with normal overlying skin without antecedent inflammation or a known identifiable cause (autoimmune disease, drug injection, injury, etc).", "ORPHA ID": 90158, "Summary": ""}
{"Disease Name": "Idiopathic macular telangiectasia type 1", "Disease Definition": "Idiopathic macular telangiectasia type 1 is a rare, acquired, eye disease characterized by unilateral (rarely bilateral) abnormally dilated and tortuous capillaries around the fovea, associated with multiple arteriolar and venular aneurysms, lipid depositions, and intra-retinal cystoid degeneration. It leads to vision loss due to macular edema with hard exudates.", "ORPHA ID": 353344, "Summary": ""}
{"Disease Name": "Idiopathic macular telangiectasia type 3", "Disease Definition": "Idiopathic macular telangiectasia type 3 is a rare, acquired, eye disease characterized by progressive visual loss, due to bilateral juxtafoveolar capillary occlusions, capillary telangiectasia, and minimal exudation. It is associated with systemic or cerebral vascular occlusive disease.", "ORPHA ID": 353351, "Summary": ""}
{"Disease Name": "Idiopathic malabsorption due to bile acid synthesis defects", "Disease Definition": "A dirsorder that is due to increased acid bile synthesis is an intestinal disease of unknown etiology characterized by an overproduction of bile acids which leads to chronic watery diarrhea.", "ORPHA ID": 84065, "Summary": ""}
{"Disease Name": "Idiopathic neonatal atrial flutter", "Disease Definition": "Idiopathic neonatal atrial flutter (AFL) is a rare rhythm disorder, characterized by sustained tachycardia in newborns and infants with an atrial rate often at around 440 beats/minute (range 340-580). AFL may manifest as asymptomatic tachycardia, congestive heart failure or hydrops.", "ORPHA ID": 45452, "Summary": "Epidemiology\nAFL is rare with an approximate incidence of around 1/50,000 live births in Europe.\nClinical description\nAFL has a neonatal onset and the majority (72%) of patients present with symptoms within the first 48 h of life. Onset during the fetal period may be associated with hydrops fetalis and death. AFL manifests with tachycardia and congestive heart failure. AFL is sustained although conversion from atrial flutter to sinus rhythm may occur spontaneously (<24 hours). Some patients are asymptomatic and tachycardia may be noted on routine examination and monitoring.\nEtiology\nThe etiology of AFL is unknown but immaturity of the myocardium and the high pressure in the right atrium during the perinatal period may be factors that favor the appearance of atrial re-entry.\nDiagnostic methods\nThe diagnosis of AFL relies on surface electrocardiogram (ECG) which usually shows an atrial rate of around 440 beats/min, most often with 2:1 atrioventricular conduction (sometimes with variable AV conduction and an irregular ventricular rate of 125-280 beats/min), and saw tooth P waves in leads II, III, and aVF. The echocardiogram may show impaired ventricular function after prolonged tachycardia.\nDifferential diagnosis\nDifferential diagnosis includes multifocal atrial tachycardia (see this term) and other forms of supraventricular tachycardia.\nAntenatal diagnosis\nAFL may be diagnosed prenatally by fetal echocardiogram which will show an atrial rate of over 400 per minute and most often 2:1 AV conduction to give a ventricular rate of over 200 per minute.\nManagement and treatment\nThe first aim of treatment is the restoration of sinus rhythm. This is most easily achieved by transoesophageal overdrive pacing or synchronised low energy DC cardioversion using around 0.5-1 J/kg. The response to drug treatment is variable and unpredictable. Recurrence of atrial flutter in neonates is rare and prophylactic medication is usually not required. Sotalol is said to be an effective agent in the treatment of AFL in the fetus as it has excellent transplacental passage.\nPrognosis\nIn the absence of additional arrhythmias, infants with AFL have an excellent prognosis once in sinus rhythm, with a low risk of recurrence, and chronic anti arrhythmic therapy is unlikely to be necessary.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christopher WREN"}
{"Disease Name": "Idiopathic nephrotic syndrome", "Disease Definition": "A rare primary glomerular group of diseases characterized by the triad of edema, massive, or nephrotic-range, proteinuria and hypoalbuminemia, for which there is no known cause. Depending on response to treatment, disease is distinguished into steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS), with the latter being further divided, depending on occurrence, into familial or sporadic forms.", "ORPHA ID": 357502, "Summary": ""}
{"Disease Name": "Idiopathic non-lupus full-house nephropathy", "Disease Definition": "A rare idiopathic glomerular clinical syndrome characterized by diffuse renal lesions that are indistinguishable from the lesions observed in systemic lupus erythematosus (SLE) in the absence of circulating autoantibodies and other systemic features necessary to meet the classification criteria for SLE. Patients may present with nephrotic syndrome, abnormal urinary sediment, acute renal insufficiency, progressive glomerulonephritis, and hypertension. Some patients have been reported to develop a progression to SLE over time.", "ORPHA ID": 567544, "Summary": ""}
{"Disease Name": "Idiopathic optic perineuritis", "Disease Definition": "A rare ophthalmic disorder characterized by idiopathic orbital inflammation in which the specific target tissue is the optic nerve sheath. Patients typically present with ocular pain, pain on eye movement, visual symptoms with loss of vision progressing over several weeks, dyschromatopsia, and variable visual field defects. Orbital signs and symptoms may be present and include ptosis, ophthalmoplegia, and exophthalmos. Optic disc edema is observed in most cases. The condition is usually unilateral.", "ORPHA ID": 499107, "Summary": ""}
{"Disease Name": "Idiopathic panuveitis", "Disease Definition": "Idiopathic panuveitis is a rare inflammatory eye disease, of unknown etiology, characterized by generalized inflammation of the uvea (iris, ciliary body, choroid), retina and vitreous with consequent ciliary spasm and posterior synechiae formation, leading to acute or chronic, unilateral or bilateral visual impairment and ocular discomfort or pain. Patients present an increased risk of development of cataracts, secondary glaucoma, cystoid macular edema and/or retinal detachment. It could potentially result in vision loss.", "ORPHA ID": 280921, "Summary": ""}
{"Disease Name": "Idiopathic peliosis hepatis", "Disease Definition": "A rare vascular liver disease characterized by widespread or focal cystic dilatation of sinusoidal blood-filled spaces of the liver without any known cause. Lesions can vary in diameter between few millimeters and several centimeters. The condition may remain asymptomatic or manifest with complications including rupture and intraperitoneal hemorrhage, hepatomegaly, portal hypertension, cholestasis, and liver failure.", "ORPHA ID": 480524, "Summary": ""}
{"Disease Name": "Idiopathic phalangeal acro-osteolysis", "Disease Definition": "A rare bone disease characterized by bone resorption affecting the distal phalanx, most commonly the terminal tuft, in the absence of a known cause. Patients present with shortening of the affected fingers or toes, associated with nail abnormalities (dystrophic or hypertrophic nails) and skin changes (such as ulceration or pigment anomalies).", "ORPHA ID": 444316, "Summary": ""}
{"Disease Name": "Idiopathic pleuroparenchymal fibroelastosis", "Disease Definition": "A rare idiopathic interstitial pneumonia characterized by prominent subpleural and parenchymal fibroelastosis and pleural fibrosis, predominantly involving the upper lobes. Signs and symptoms include non-productive cough, dyspnea, and recurrent respiratory infections. Pneumothorax is a frequently reported complication. Pulmonary function test reveals a restrictive pattern and reduced diffusing capacity. Computed tomography shows pleural thickening with signs of fibrosis (traction bronchiectasis, architectural distortion, and loss of volume), and reticulation.", "ORPHA ID": 494428, "Summary": ""}
{"Disease Name": "Idiopathic posterior uveitis", "Disease Definition": "Idiopathic posterior uveitis is a rare, potentially sight-threatening, ocular disease, not attributed to any specific ocular or systemic cause, characterized by focal, multifocal or diffuse non-infectious inflammation in the posterior uvea (i.e. choroiditis, chorioretinitis, retinitis and neuroretinitis). Visual morbidity due to complications (including cystoid macular edema and choroidal neovascularization) has been reported.", "ORPHA ID": 280917, "Summary": ""}
{"Disease Name": "Idiopathic pulmonary arterial hypertension", "Disease Definition": "Idiopathic pulmonary arterial hypertension (IPAH) is a sporadic form of pulmonary arterial hypertension (PAH, see this term) characterized by elevated pulmonary arterial resistance leading to right heart failure. IPAH is progressive and potentially fatal and not associated with an underlying condition or family history of PAH.", "ORPHA ID": 275766, "Summary": "Epidemiology\nPrevalence of PAH, in all of its forms, is estimated at around 1/67,000. IPAH is one of the most commonly diagnosed forms.\nClinical description\nClinical manifestations of IPAH are similar to other forms of PAH regardless of its etiology. IPAH develop in adults and in rare cases in children; women are twice as likely as men to be affected. The diagnosis is often made in patients in their mid-forties. Initial symptoms include dyspnea, fatigue, syncope, chest pain, palpitations and pedal edema. Precordial signs include loud and palpable second heart sound, right ventricular heave, pulmonary ejection click and murmurs of pulmonary and tricuspid regurgitation. 70% of patients present heart failure (classed as New York heart association functional classification (NYHA FC) III or IV). More rarely, clubbing of digits and Raynaud phenomenon may be observed. Hemoptysis has also been reported.\nEtiology\nIPAH is caused by vascular remodeling of small pulmonary arteries due to unknown causes. Mutations in PAH predisposing genes are identified in about 15% to 20% of PAH patients initially considered to have an idiopathic form of the disease. IPAH patients carriers of a mutation in PAH predisposing gene have to be reclassified in ''heritable PAH'' (see this term). The main genetic risk factor of PAH is mutations in BMPR2gene (2q33). Mutations in ACVRL1>(12q13), ENG>(9q34), KCNK3 >(2p23),CAV1 (7q31), TBX4(17q21) have been identified in few cases.\nGenetic counseling\nGenetic counseling has to been proposed to all IPAH patients and mutations in PAH predisposing genes have to be searched. All PAH predisposing gene are transmitted in an autosomal dominant manner with an incomplete penetrance. In the cases of BMPR2 mutations, the penetrance is estimated to be 42% in female mutation carriers and 14% in male mutation carriers.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Barbara GIRERD  - Pr David MONTANI"}
{"Disease Name": "Idiopathic pulmonary artery dilatation", "Disease Definition": "Idiopathic pulmonary artery dilatation is a rare developmental defect during embryogenesis characterized by the dilatation of the main pulmonary artery, with or without dilatation of the right and left pulmonary artery branches, and not attributed to any other cardiac, pulmonary and/or arterial wall disease. It may present with exertional dyspnea, fatigue, cough, hemoptysis, palpitation and chest pain, but may also be asymptomatic. In serious cases, trachea constriction due to postural changes may lead to attacks of cyanosis with severe dyspnea. Sudden cardiac death has been reported in some cases.", "ORPHA ID": 1676, "Summary": ""}
{"Disease Name": "Idiopathic pulmonary fibrosis", "Disease Definition": "An interstitial lung disease with a poor prognosis, that is characterized by the progressive formation of scar tissue within the lungs in the absence of any known cause.", "ORPHA ID": 2032, "Summary": "Epidemiology\nIdiopathic pulmonary fibrosis (IPF) incidence appears to be increasing. Reported incidences range from 0.2 per 100.000 per year to 94 per 100.000 per year. The prevalence is estimated to be higher in men than in women.\nClinical description\nThe mean age at presentation is 66 years. IPF initially usually manifests with symptoms of breathlessness on exertion and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones. Clubbing is found in approximately 50% of IPF patients typically exertional dyspnea progresses over a period of months to years. In practice patients are often misdiagnosed.\nEtiology\nThe etiology is not yet completely understood. The current conceptual model is that environmental factors may cause microscopic damage in the lungs and that in susceptible people this may lead to a disturbed healing reaction that will result in an ongoing process of scar formation in the lung. This will ultimately lead to loss of lung function.\nDiagnostic methods\nIPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images. If these are non-conclusive a lung biopsy can be considered, though potential implications and associated risks should always be weighed and discussed. The diagnosis of IPF can be made by defined criteria that have been published in guidelines endorsed by several professional societies.\nDifferential diagnosis\nDifferential diagnosis includes other idiopathic interstitial pneumonias, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis + and other environmental (sometimes occupational) exposures. In a subgroup of patients with pulmonary fibrosis, despite thorough investigations, no definite diagnosis can be made and this group is than labeled as unclassifiable- pulmonary fibrosis.\nGenetic counseling\nIn patients that present one or more family members with pulmonary fibrosis, genetic counseling should be considered.\nManagement and treatment\nPharmacological management: Two medications, pirfenidone and nintedanib, are recommended in the current international guidelines for the treatment of IPF. These medication slow down disease progression, as measured by decline in forced vital capacity by approximately 50% and are safe. Besides these, multiple new molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medications. These non pharmacological management approaches aim to improve or maintain quality of life and sometimes also life longer. Preventative measures as smoking cessation, influenza and pneumococcal vaccination are recommended. Supplemental oxygen is recommended for patients with an oxyhemoglobin saturation of less than 88% and reduces exertional dyspnea and improves exercise capacity for patients. Pulmonary rehabilitation and measures aimed at symptom relieve improve health related quality of life for patients. In a subgroup of patient lung transplantation may be an option.\nPrognosis\nThe median survival without treatment is 2 to 5 years from the time of diagnosis.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr María MOLINA-MOLINA  - Dr M.S. [Marlies] WIJSENBEEK"}
{"Disease Name": "Idiopathic pulmonary hemosiderosis", "Disease Definition": "Idiopathic pulmonary hemosiderosis is a respiratory disease due to repeated episodes of diffuse alveolar hemorrhage without any underlying apparent cause, most often in children. Anemia, cough, and pulmonary infiltrates on chest radiographs are found in majority of the patients.", "ORPHA ID": 99931, "Summary": ""}
{"Disease Name": "Idiopathic recurrent pericarditis", "Disease Definition": "Idiopathic recurrent pericarditis is a rare autoinflammatory syndrome defined as recurrence of pericardial inflammation of unknown origin following the first episode of acute pericarditis and a symptom-free interval of 4-6 weeks or longer. Recurrent attacks of chest pain may be the sole presentation or the chest pain may be accompanied by pericardial friction rub, electrocardiographic or echocardiographic changes, pericardial effusion and increased C-reactive protein. Cardiac tamponade is a rare, life-threatening complication.", "ORPHA ID": 251307, "Summary": ""}
{"Disease Name": "Idiopathic recurrent stupor", "Disease Definition": "A rare neurologic disease characterized by unpredictable, transient and spontaneous unresponsiveness lasting from hours to days, with a frequency of three to seven attacks per year, in the absence of readily discernible toxic, metabolic or structural causes.", "ORPHA ID": 276174, "Summary": ""}
{"Disease Name": "Idiopathic spontaneous coronary artery dissection", "Disease Definition": "A rare vascular disease characterized by idiopathic detachment of the layers of the walls of coronary arteries, creating a false lumen which limits the main coronary flow, leading to myocardial ischemia. Clinical manifestations include acute coronary syndromes, especially ST-segment elevation myocardial infarction (STEMI), syncope, cardiogenic shock, or sudden cardiac death. The condition typically affects young women.", "ORPHA ID": 458718, "Summary": ""}
{"Disease Name": "Idiopathic steroid-resistant nephrotic syndrome", "Disease Definition": "A rare, idiopathic nephrotic syndrome characterized by the triad of proteinuria, hypoalbuminemia and edema in patients who do not respond, or only partially respond, to the initial trial of corticosteroids. Patients may be multidrug resistant or may be sensitive to second-line immunosuppressive therapy.", "ORPHA ID": 567548, "Summary": "Epidemiology\nThe annual incidence of idiopathic nephrotic syndrome is estimated at 1/34,000 children, although this varies according to ethnicity or the country of origin. Steroid-resistance is described in 2.1-27.3% of children with idiopathic nephrotic syndrome, with annual incidence estimated at 1/390,000. In most regions, there is a male predominance, although reported ratios vary between 1.0 and 3.8.\nClinical description\nChildren with nephrotic syndrome generally present with signs of edema, for instance with swollen eyes, abdomen, scrotum, and/or ankles. Evaluation by a pediatrician/pediatric nephrologist will confirm the diagnosis of idiopathic nephrotic syndrome. Some criteria may increase the chance of becoming steroid-resistant, such as hematuria, hypertension and/or acute kidney injury at presentation, as well as having a positive family history for kidney disease or signs of extra-renal manifestations. Histologically, children with steroid-resistant nephrotic syndrome (SRNS) present most frequently with focal segmental glomerulosclerosis, less frequently with diffuse mesangial sclerosis, and more rarely with minimal change disease.\nEtiology\nAfter exclusion of the genetic forms, SRNS may result from a circulating permeability factor; such a factor is still unidentified, but its presence may result in a relapse of nephrotic syndrome after kidney transplantation. SRNS can also be secondary to an infection (such as CMV or HIV) or an underlying kidney disease (such as IgA nephropathy, membranous nephropathy or a collagenopathy).\nDiagnostic methods\nSRNS is established when treatment with corticosteroids does not result in a full remission within 4-6 weeks. In such patients, it is essential to search for an underlying genetic cause, underlying kidney disease (by performing a kidney biopsy) and by excluding other causes of the SRNS (laboratory work up for i.e. sickle cell disease, HIV, SLE, HepB, malaria, parvovirus B19).\nDifferential diagnosis\nGenetic forms of SRNS should be excluded, as this has an important impact on subsequent therapies. Underlying kidney disease (membranous nephropathy, membranoproliferative glomerulonephritis, C3 glomerulopathy, IgA nephropathy, lupus nephritis, Alport syndrome/collagen IV glomerulopathy, amyloidosis, thrombotic microangiopathy), circulating permeability factor, infectious causes (cytomegalovirus (CMV), human immunodeficiency virus (HIV), hepatitis B, malaria, parvovirus B19, syphilis), sickle cell disease, and malignancy (mainly lymphoma) should also be excluded.\nManagement and treatment\nTreatment of a child with SRNS is based on reduction of proteinuria, immunosuppressive treatment, and supportive therapy. All children with SRNS should be treated with either an ACE inhibitor or an angiotensin-receptor blocker. Children in whom a genetic diagnosis is disproven and who have a GFR>30 ml/min/1.73m2, should receive immunosuppressive treatment, using calcineurin inhibitors, while corticosteroids are slowly tapered and discontinued. For current treatment schedules, please refer to international guidelines on treatment of SRNS. Supportive therapy consists of salt restriction and, on indication, diuretics to control edema. Albumin infusions are restricted to patients with symptomatic hypovolemia. Standard antibiotic prophylaxis is not recommended. Dysregulation of thyroid function, lipid levels, and calcium, magnesium, and vitamin D levels may occur, and should be treated accordingly. Thromboprophylaxis may be indicated in children with central venous catheters or with a history of thromboembolic events.\nPrognosis\nChildren with SRNS who respond to immunosuppressive treatment and reach complete remission may remain in remission, or exhibit a relapse-remitting course, which is usually steroid-sensitive. Multi-drug resistant SRNS cases generally do continue to kidney failure. There is a high risk of post-renal transplant relapse which may occur within a day after kidney transplantation.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Pr M.F. [Michiel] SCHREUDER | ERKNet* - Dr Marina VIVARELLI | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Idiopathic steroid-sensitive nephrotic syndrome with secondary steroid resistance", "Disease Definition": "A rare, idiopathic nephrotic syndrome characterized by pediatric onset of proteinuria, hypoalbuminemia and edema. Patients respond successfully to the initial standard course of corticosteroids, but are resistant to standard therapy for a subsequent relapse and following this relapse remain steroid-resistant.", "ORPHA ID": 567546, "Summary": ""}
{"Disease Name": "Idiopathic steroid-sensitive nephrotic syndrome", "Disease Definition": "A rare primary glomerulopathy of unknown cause characterized by edema, nephrotic-range proteinuria and hypoalbuminemia that responds to standard prednisone treatment within 4-6 weeks.", "ORPHA ID": 69061, "Summary": "Epidemiology\nThe annual incidence of idiopathic nephrotic syndrome varies by ethnicity and region ranging from 1/5,900-85,000 children, of which 70-98% are steroid sensitive. The disease is less frequently reported in adults. It has a male predominance (approximately 2:1) in young children.\nClinical description\nDisease onset can occur at any age, but mostly between 2 - 6 years, frequently preceded by an upper respiratory tract infection. Patients typically present with edema, mainly periorbital and of lower extremities. Anasarca may develop with pleural and pericardial effusion, ascites, abdominal pain (due to hypoperfusion) and cold extremities with hypotension. Intravascular volume depletion and oliguria are present, and concomitant factors, (sepsis, diarrhea, diuretic use) can lead to acute kidney injury. Proteinuria typically has a relapsing and remitting course of varying frequency, and can be steroid-dependent in certain cases (relapsing during steroid therapy or within 15 days of its discontinuation). Urinalysis reveals nephrotic-range proteinuria and blood chemistry results show reduced serum albumin and total protein, reduced total calcium with ionized calcium usually normal, markedly decreased IgG levels, and hyperlipidemia. Hemoconcentration leads to increased hematocrit levels and thrombocytosis. A state of hypercoagulability (due to hypovolemia, hyperdyslipidemia, thrombocytosis) leads to an increased risk of, usually venous, thrombosis.\nEtiology\nEtiology is thought to be immune-mediated, although exact mechanism leading to disruption of the glomerular filtration barrier and proteinuria is unknown.\nDiagnostic methods\nDiagnosis is based on clinical manifestations, laboratory findings, and response to prednisone. Although renal biopsy is usually not performed, it may be advisable in the presence of atypical features (e.g. onset age < 1 or > 12 years, gross hematuria, low serum complement C3, marked hypertension, renal failure without severe hypovolemia), if prolonged therapy with calcineurin inhibitors is required or if the patient's clinical course is particularly difficult. Renal biopsy will most frequently show minimal changes with a negative immunofluorescence (so-called minimal change disease), though occasionally it may show other pictures.\nDifferential diagnosis\nDifferential diagnoses include membranous nephropathy, IgA nephropathy, renal vasculitis, C3 glomerulopathy and post-infectious glomerulonephritis.\nManagement and treatment\nAt onset, management includes symptomatic care with, in severe cases, albumin infusions. In children, prednisone (60mg/m2/day) is the mainstay of therapy. If the patient presents frequent relapses or steroid-dependent disease, second-line steroid-sparing immunosuppression with various agents, including antiproliferatives, levamisole, calcineurin inhibitors, mycophenolate mofetil and, more recently, rituximab, is prescribed.\nPrognosis\nPrognosis is variable. After remission of the first episode, the risk of relapse is negligible in 30% of patients. Approximately 20%-30% progress to infrequent relapses (rarely more than 3-4 episodes in total) with prednisone alone. The remaining 40%-50%, mostly children < 5 years of age, have a frequently relapsing or steroid-dependent course. Rarely, patients with initially steroid-sensitive nephrotic syndrome develop secondary steroid resistance, leading to progressive renal failure. In forms that remain steroid-responsive, renal function is typically preserved. Long-term outcome is heavily influenced by side effects of protracted administration of steroids and second-line steroid-sparing agents. The disease tends to resolve following puberty, but a significant percentage, around 10-15% of patients, will continue to present this disease in adulthood.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Marina VIVARELLI | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Idiopathic syringomyelia", "Disease Definition": "Idiopathic syringomyelia is a rare, non-syndromic central nervous system malformation characterized by a longitudinally oriented fluid-filled cavity inside the spinal cord parenchyma or the central canal, without any readily identifiable cause. It is usually associated with pain, sensory and/or musculoskeletal disturbances, but it can also be an incidental and asymptomatic finding.", "ORPHA ID": 99858, "Summary": ""}
{"Disease Name": "Idiopathic trachyonychia", "Disease Definition": "A rare isolated nail anomaly characterized by brittle, thin, rough, opaque appearing nails with excessive longitudinal ridging. In a less severe form, the nails retain their luster and present with superficial ridging and multiple small geometric pits. In both varieties, superficial scaling of the nail plate and hyperkeratosis of the cuticles, as well as koilonychia and onychoschizia are observed. Any number of nails may be affected, and fingernails are more often affected than toenails. Spontaneous improvement of the condition may occur.", "ORPHA ID": 79153, "Summary": ""}
{"Disease Name": "Idiopathic uveal effusion syndrome", "Disease Definition": "A rare panuveitis characterized by uni- or bilateral abnormal fluid accumulation within the suprachoroidal space, resulting in internal choroidal elevation, in the absence of any known cause, such as decreased intraocular tension, intraocular tumor, intraocular inflammation or nanophtalmos. Patients typically present a protracted, relapsing-remitting course of visual acuity loss and fundus examination shows annular celio-choroidal detachment and shifting, serous retinal detachment.", "ORPHA ID": 209956, "Summary": ""}
{"Disease Name": "Idiopathic ventricular fibrillation, non Brugada type", "Disease Definition": "A rare, genetic, cardiac rhythm disease characterized by ventricular fibrillation in the absence of any structural or functional heart disease, or known repolarization abnormalities. The presence of J waves is associated with a higher risk of nocturnal ventricular fibrillation events and a higher risk of recurrence.", "ORPHA ID": 228140, "Summary": ""}
{"Disease Name": "Idiopathic/heritable pulmonary arterial hypertension", "Disease Definition": "A form of pulmonary arterial hypertension (PAH) characterized by elevated pulmonary arterial resistance leading to right heart failure; it is progressive and potentially fatal. The majority cases have an identifiable genetic cause, but a significant proportion are idiopathic.", "ORPHA ID": 422, "Summary": ""}
{"Disease Name": "IgA pemphigus", "Disease Definition": "A rare autoimmune bullous skin disease characterized by painful and pruritic vesiculopustular eruptions resulting from circulating IgA antibodies against keratinocyte cell surface components. The lesions are typically found at the periphery of erythematous annular plaques and favor intertriginous regions. Histologically and immunologically, IgA pemphigus can be subdivided into subcorneal pustular dermatosis and intraepidermal neutrophilic IgA dermatosis.", "ORPHA ID": 555905, "Summary": ""}
{"Disease Name": "IgG4-related aortitis", "Disease Definition": "A rare systemic autoimmune disease characterized by infiltrates of IgG4-positive plasma cells and lymphocytes in the adventitia of the aorta, resulting in thickening of perivascular tissue or formation of soft tissue masses surrounding the aorta and its major branches (potentially complicated by inflammatory aortic aneurysm), associated with elevated serum IgG4 levels. Preferential location is the infra-renal portion of the abdominal aorta. In addition, medium-sized blood vessels can be involved, and the condition may occur together with IgG4-related disease in other parts of the body. Clinical symptoms are unspecific and include chest or back pain and fever.", "ORPHA ID": 449400, "Summary": ""}
{"Disease Name": "IgG4-related dacryoadenitis and sialadenitis", "Disease Definition": "IgG4-related dacryoadenitis and sialoadenitis (Mikulicz disease) is an IgG4-related sclerosing disease (see this term) characterized by persistent, usually painless, bilateral enlargement of the lacrimal, parotid, and submandibular glands associated with elevated levels of serum immunoglobulin (Ig) G4 and with lymphocyte and IgG4-positive plasmacyte infiltration. It predominantly causes mouth and eye dryness but can also affect other organs such as the lungs, liver, and kidneys, and be accompanied by complications such as autoimmune pancreatitis (AIP), retroperitoneal fibrosis, and tubulointerstitial nephritis (see these terms).", "ORPHA ID": 79078, "Summary": ""}
{"Disease Name": "IgG4-related kidney disease", "Disease Definition": "A rare renal disease occurring in the setting of a systemic IgG4 related disease (IgG4-RD). The disorder is characterized by a fibrosing tubulointerstitial nephritis consisting of predominantly IgG4+ plasma cells with/without glomerulonephritis, retroperitoneal fibrosis and hydronephrosis.", "ORPHA ID": 449395, "Summary": "Epidemiology\nThe disease prevalence is unknown.\nClinical description\nThe clinical manifestations include tubulointerstitial nephritis (TIN) and membranous glomerulonephritis with or without TIN. Other glomerular disease is reported (IgA nephropathy, membranoproliferative glomerulonephritis, mesangioproliferative glomerulonephritis). Radiological abnormalities include mass lesions and diffusely enlarged kidneys. Presentation may be on routine imaging, with acute or chronic kidney disease, or with nephrosis depending on underlying lesion. Hydronephrosis may occur due to obstruction from IgG4-related retroperitoneal fibrosis.Other extra renal manifestations of IgG4-RD may also be present (e.g. salivary glands, hypophysis, hepatobiliary system, lungs).\nEtiology\nThe etiology is unknown.\nDiagnostic methods\nThe disease is diagnosed with characteristic imaging and renal biopsy findings (lymphocytic infiltration with predominantly IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis). Diagnostic criteria have been outlined.\nDifferential diagnosis\nThe differential diagnosis depends on presentation. For example, the differential for presentation with TIN includes: medications, autoimmune disease (e.g. Sjogren's syndrome, Sarcoid), malignancy (e.g. lymphoproliferative disease), and infection (e.g. Tuberculosis).\nManagement and treatment\nNot supported by randomized controlled trials. Lymphocytic infiltration is usually quickly responsive to steroids. Some patients require immunosuppressants such as Rituximab.\nPrognosis\nRelapse is common, and progressive renal impairment can occur, including the need for renal replacement therapy.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Rhys EVANS | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "IgG4-related mediastinitis", "Disease Definition": "A rare systemic autoimmune disease characterized by an aggressive fibroinflammatory process with infiltration of IgG4-positive plasma cells in the mediastinum, potentially resulting in compression and functional impairment of vital mediastinal structures, and associated with elevated serum IgG4. Clinical symptoms are unspecific and include pain or symptoms due to mass effect. The condition may occur together with IgG4-related disease in other parts of the body.", "ORPHA ID": 63999, "Summary": ""}
{"Disease Name": "IgG4-related mesenteritis", "Disease Definition": "Sclerosing mesenteritis (SM) is a rare pathological disease causing inflammation of the adipose tissue of the small bowel mesentery and is commonly associated with abdominal pain, diarrhea, nausea, weight loss, bloating and loss of appetite. The two subforms include mesenteric panniculitis (where inflammation and fatty necrosis are dominant features) and retractile mesenteritis (where fibrosis and retraction dominate).", "ORPHA ID": 238593, "Summary": ""}
{"Disease Name": "IgG4-related ophthalmic disease", "Disease Definition": "A rare, inflammatory eye disease characterized by IgG4-immunopositive lymphocyte and plasmacyte infiltration and collagenous fibrosis of affected tissue and elevated serum levels of IgG4. Clinical presentation includes mass lesion or swelling of the involved structures, commonly involving lacrimal gland and duct, infraorbital and supraorbital nerves, extraocular muscles and orbital soft tissues. A systemic involvement is common.", "ORPHA ID": 449563, "Summary": ""}
{"Disease Name": "IgG4-related pachymeningitis", "Disease Definition": "A rare, brain inflammatory disease characterized by thickening of the dura mater of the cranium or spine with at least two histiopatholgical features of IgG4-related disease: dense lymphoplasmacytic infiltrate, storiform fibrosis, and/or obliterative phlebitis. Patients typically have non-specific CSF findings, and might be without systemic involvement or serum IgG4 elevation. Clinical manifestation are caused by mechanical compression of nerve or vascular structure, leading to functional deficit, most commonly headache, cranial nerve palsies, vision problems and motor weakness.", "ORPHA ID": 449427, "Summary": ""}
{"Disease Name": "IgG4-related retroperitoneal fibrosis", "Disease Definition": "A rare systemic autoimmune disease characterized by mass-forming, potentially destructive inflammation and fibrosis in the soft tissues of the retroperitoneum, associated with elevation of serum IgG4 levels and infiltration of IgG4-positive plasma cells in at least one organ or site. Most frequent locations are peripheral to the abdominal aorta, as well as the iliac and renal arteries. Clinical symptoms are unspecific and include abdominal pain, back pain, and edema of the lower extremities. The condition may occur together with IgG4-related disease in other parts of the body.", "ORPHA ID": 49041, "Summary": ""}
{"Disease Name": "IgG4-related sclerosing cholangitis", "Disease Definition": "A rare systemic autoimmune disease characterized by cholestasis and diffuse cholangiographic abnormalities with circular and symmetrical bile duct wall thickening, and elevated serum IgG4 levels. Characteristic histopathological findings include dense infiltration of IgG4-positive plasma cells and extensive fibrosis in the bile duct wall. A marked response to steroid therapy is typical. Patients present with jaundice, cholangitis, pruritis, and sometimes associated findings of autoimmune pancreatitis, sialadenitis, and retroperitoneal fibrosis.", "ORPHA ID": 447764, "Summary": ""}
{"Disease Name": "IgG4-related submandibular gland disease", "Disease Definition": "A rare IgG4-related disease characterized by a benign tumor-like chronic inflammatory lesion of the submandibular gland. Histologic features are periductal fibrosis, acinar atrophy, obliterative phlebitis, dense lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells, and formation of lymphoid follicles. Lobular architecture is preserved. Patients most commonly present with unilateral, painless swelling of the submandibular gland. Serologic analysis reveals elevated IgG4 levels.", "ORPHA ID": 449432, "Summary": ""}
{"Disease Name": "IgG4-related systemic disease", "Disease Definition": "A rare systemic autoimmune disease characterized by mass-forming lesions with a lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells and storiform fibrosis, often displaying obliterative phlebitis, and usually accompanied by elevated serum IgG4. Almost any organ may be affected, with pancreas, salivary gland, and orbit being the most common. Multi-organ involvement (synchronously or metachronously) is typical. Many patients show lymphadenopathy, most often involving the mediastinal, intra-abdominal, axillary, and cervical nodes. Symptoms are usually attributable to the mass effect of the lesions.", "ORPHA ID": 596448, "Summary": ""}
{"Disease Name": "IgG4-related thyroid disease", "Disease Definition": "A fibroinflammatory disorder of the thyroid gland, occuring more frequently in females, characterized a large, hard thyroid mass, and presenting with pressure symptoms (breathing difficulties and dysphagia) or voice hoarseness and aphonia (impingement of recurrent laryngeal nerve). It can often be associated with extracervical fibroinflammatory disorders such as retroperitoneal fibrosis, primary scleroisng cholangitis and autoimmune diseases such as Hashimoto struma, Addison disease, and Biermer disease.", "ORPHA ID": 64744, "Summary": ""}
{"Disease Name": "IL21-related infantile inflammatory bowel disease", "Disease Definition": "A rare autosomal recessive primary immunodeficiency characterized by infancy onset of severe inflammatory bowel disease with life-threatening diarrhea and failure to thrive, oral aphthous ulcers, and recurrent severe upper and lower respiratory tract infections with finger clubbing. Laboratory examination reveals increased IgE and decreased IgG levels, as well as reduced numbers of circulating CD19+ B-cells including IgM+ naive and class-switched IgG memory B-cells, with a concomitant increase in transitional B-cells, while T-cell numbers and function are normal.", "ORPHA ID": 477661, "Summary": ""}
{"Disease Name": "Ileal neuroendocrine tumor", "Disease Definition": "Ileal neuroendocrine tumor is a rare, primary, malignant, epithelial neoplasm of the small intestine arising from enterochromaffin cells in the ileum (usually the terminal ileum). Clinical behavior depends on the histologic grade, but initially it is generally characterized by vague abdominal symptoms (cramping, bloating, diarrhea) with insidious onset, although sometimes it could present with signs of bowel obstruction/perforation or gastrointestinal bleeding. Diagnosis in advanced stages with regional or distant spread is common, but signs of carcinoid syndrome (flushing, sweating, diarrhea) are usually not apparent until hepatic metastasis has occurred.", "ORPHA ID": 100078, "Summary": ""}
{"Disease Name": "Ileal pouch anal anastomosis related faecal incontinence", "Disease Definition": "A rare intestinal disorder characterized by the inability to control the passage of rectal contents (feces, gas) through the anus following ileal pouch-anal anastomosis surgery. Fecal incontinence is usually more frequent during the night than during daytime. The condition generally worsens over time, with a significant negative impact on the quality of life of the patient.", "ORPHA ID": 238621, "Summary": ""}
{"Disease Name": "IMAGe syndrome", "Disease Definition": "A rare genetic disease characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (such as cryptorchidism, posterior hypospadias, and micropenis). Patients may present shortly after birth with severe adrenal insufficiency. Additional manifestations include postnatal growth failure and delayed bone age, mild developmental delay, macrocephaly, mild facial dysmorphism (with frontal bossing, wide nasal bridge, and small, low-set ears), epiphyseal dysplasia, and hypercalcemia/hypercalciuria, among others.", "ORPHA ID": 85173, "Summary": ""}
{"Disease Name": "Imerslund-Gräsbeck syndrome", "Disease Definition": "Imerslund-Grasbeck syndrome (IGS) or selective vitamin B12 (cobalamin) malabsorption with proteinuria is a rare autosomal recessive disorder characterized by vitamin B12 deficiency commonly resulting in megaloblastic anemia, which is responsive to parenteral vitamin B12 therapy and appears in childhood.", "ORPHA ID": 35858, "Summary": "Epidemiology\nThe syndrome was first described in Finland and Norway where the prevalence is about 1/200 000.\nClinical description\nOther manifestations include failure to thrive and grow, infections and neurological damage. Mild proteinuria (with no signs of kidney disease) is present in about half of the patients. Anatomical anomalies in the urinary tract were observed in some Norwegian patients. Vitamin B12 absorption tests show low absorption, not corrected by administration of intrinsic factor. The symptoms appear from 4 months (not immediately after birth as in transcobalamin deficiency) up to several years after birth.\nEtiology\nThe cause is a defect in the receptor of the vitamin B12-intrinsic factor complex of the ileal enterocyte. In most cases, the molecular basis of the selective malabsorption and proteinuria involves a mutation in one of two genes, cubilin (CUBN) on chromosome 10 or amnionless (AMN) on chromosome 14. Both the proteins are components of the intestinal receptor for the vitamin B12-intrinsic factor complex and the receptor mediating the tubular reabsorption of protein from the primary urine.\nManagement and treatment\nManagement includes life-long vitamin B12 injections, and with this regimen, the patients stay healthy for decades. However, the proteinuria persists. In diagnosing this disease, it is important to be aware that cobalamin deficiency affects enterocyte function; therefore, all tests suggesting general and cobalamin malabsorption should be repeated after abolishment of the deficiency.\n\n                            Last update: \n                            May 2006"}
{"Disease Name": "Iminoglycinuria", "Disease Definition": "A rare inborn error of metabolism characterized by elevated levels of imino acids (proline, hydroxyproline) and glycine in urine due to defective reabsorption in the kidney. The condition is considered benign and not associated with any specific clinical phenotype. Mode of inheritance is autosomal recessive.", "ORPHA ID": 42062, "Summary": ""}
{"Disease Name": "Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome", "Disease Definition": "A rare immune dysregulation disease with immunodeficiency characterized by severe, progressive infantile onset inflammatory bowel disease with pancolitis, perianal disease (ulceration, fistulae), recurrent respiratory, genitourinary and cutaneous infections, arthritis and a high risk of B-cell lymphoma.", "ORPHA ID": 238569, "Summary": ""}
{"Disease Name": "Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome", "Disease Definition": "A rare genetic immune disease characterized by early onset of recurrent bacterial, viral, and fungal infections, chronic inflammatory bowel disease, gastritis, and inflammatory polyarthritis. Patients present with diarrhea, vomiting, hepatosplenomegaly, mouth ulcers, perianal abscesses, chronic lung disease with bronchiectasis, and failure to thrive. Occurrence of a skin rash associated with lymphocytic vasculitis has also been reported. Immunologic abnormalities include variable T-cell lymphopenia, decreased natural killer cells, and decreased B-cells with variable hypogammaglobulinemia.", "ORPHA ID": 529977, "Summary": ""}
{"Disease Name": "Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome", "Disease Definition": "A rare immunodysregulatory disease characterized by refractory diarrhea, endocrinopathies, cutaneous involvement, and infections.", "ORPHA ID": 37042, "Summary": "Epidemiology\nImmune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX) syndrome prevalence is unknown. The disease has probably been underestimated, and milder clinical phenotypes surviving to adult life are being described.\nClinical description\nIPEX syndrome most commonly develops during the first few days or weeks of life and affects exclusively boys. It classically manifests with the sequential appearance of the triad of enteropathy, autoimmune disease (particularly Type I diabetes mellitus), and cutaneous involvement, but the clinical features and severity of the disease can vary considerably between individuals. Severe autoimmune enteropathy manifests with intractable secretory diarrhea leading to malabsorption, electrolyte disturbance and failure to thrive. Vomiting, ileus, gastritis or colitis can also be observed. Patients also present with autoimmune endocrinopathies, generally insulin-dependent diabetes mellitus (type 1 DM) often in infancy or early childhood, but also thryroiditis leading to hypothyroidism or hyperthyroidism. Skin involvement consists of a generalized pruriginous eruption resembling eczema, psoriasis, and/or atopic or exfoliative dermatitis. Less frequently, alopecia or onychodystrophy can be observed. Patients may develop autoimmune cytopenias, thrombocytopenia, hemolytic anemia and neutropenia. Autoimmune involvement may also lead to pneumonitis, hepatitis, nephritis, myositis, splenomegaly and/or lymphadenopathy. Local or systemic infections (e.g. pneumonia, Staphylococcus aureus infections, candidiasis) may occur but seem to be due to loss of skin and gut barriers, immunosuppressive therapies, and poor nutrition rather than a primary immunodeficiency. Neurological findings including peripheral neuropathy, myopathy and hypotonic are described.\nEtiology\nIPEX syndrome is caused by mutations in the FOXP3 gene (Xp11.23). This gene codes for a forkhead transcription factor which controls the development and function of CD4+ CD25+ regulatory T cells, a major lymphocyte population involved in self-tolerance and downregulation of immune responses.\nDiagnostic methods\nDiagnosis is based on clinical examination, family history, and laboratory findings revealing autoimmune enteropathy (anti-enterocyte, harmonin and villin autoantibodies), type 1 DM (antibodies against insulin, pancreatic islet cells, or anti-glutamate decarboxylase), thyroiditis (anti-thyroglobulin and anti-microsome peroxidase antibodies) and cytopenia (anti-platelets and anti-neutrophils antibodies, positive Coombs test). Molecular genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes Wiskott-Aldrich and Omenn syndromes, susceptibility to viral and mycobacterial infections, CD25 deficiency, IL10R deficiency, STAT5b deficiency, transient neonatal diabetes, severe combined immunodeficiency or intermediate forms of combined immunodeficiency, X-linked thrombocytopenia and pancreatic hypoplasia or agenesis.\nAntenatal diagnosis\nPrenatal diagnosis from chorionic villus samples is possible after determination of the fetal sex by karyotype analysis for families in which the disease-causing mutation has been identified.\nGenetic counseling\nTransmission is X-linked recessive. There is a 50% risk of transmission when the fetus is a male. 50% of females will be carriers.\nManagement and treatment\nThe only curative treatment for IPEX is hematopoietic stem cell transplantation (HSCT), which is much more successful when performed in the early stages of the disease. Supportive measures include monotherapy or combined immunosuppressive therapy with glucocorticoids (prednisone and methylprednisolone), cyclosporin A (CSA), tacrolimus, azathriopine, rapamycin, lifelong insulin and thyroid hormones supplementation in case of organ failure, topical CSA for skin manifestations, and parenteral nutrition for severe cases of enteropathy.\nPrognosis\nWithout timely diagnosis and treatment, the disease is usually fatal within the first 2 years of life in severe cases. Increasingly, patients survive into childhood when treated with appropriate immunosuppression. With HSCT, life expectancy is likely to be normal, and disease progression halted, although feeding difficulties may persist for many months post HSCT. Neurodevelopment is usually normal.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Immune hydrops fetalis", "Disease Definition": "Immune hydrops fetalis (IHF), a form of HF, describes the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities due to maternal rhesus (Rh) incompatibility.", "ORPHA ID": 364013, "Summary": "Epidemiology\nThe incidence of IHF has decreased greatly since the introduction of RhoD immune globulin in the 1960's and has wide regional variability. The incidence in the U.K. is estimated to be at about 1/3,000 births. IHF accounts for about 10-20% of all cases of HF.\nClinical description\nIHF presents during the gestational period (50% between 18-34 weeks of gestation, 50% between 34 weeks and term) and is characterized by the accumulation of fetal fluid manifesting as pericardial effusion, pleural effusion, ascites and subcutaneous edema in the fetus. The mother might notice decreased fetal movements prior to diagnosis. Fetal tachycardia, polyhydramnios and antenatal hemorrhage are often associated with HF. Mothers may develop massive anasarca, hypertension, and proteinuria (described as mirror syndrome). Death of the fetus is due to pulmonary hypoplasia and heart failure. Surviving newborns may present with respiratory distress, pale skin, jaundice, severe edema (mostly localized to the abdomen) and enlarged liver and spleen.\nEtiology\nIHF occurs when the mother's immune system causes a breakdown of red blood cells in the fetus (erythroblastosis fetalis). This results in destruction of fetal red blood cells by maternal IgG antibodies that cross the placenta. In feto-maternal Rh incompatibility, the maternal blood is Rh-negative and the fetal blood is Rh-positive. Rh alloimmunisation develops if maternal IgG antibodies cross the placenta, binding to antigens present on the fetal erythrocytes and causing hemolysis. Usually anti-D, anti-E, and antibodies directed against other Rh antigens comprise the majority of involved antibodies. The majority of the cases of Rh isoimmunisation lead to a mild to moderate fetal or neonatal hemolytic disease but about 20-25% of cases result in IHF.\nDiagnostic methods\nDiagnosis is usually by ultrasound during the 2nd to 3rd trimester of gestation. Ultrasound can detect fluid collections but if there is limited accumulation it may not be diagnosed. Having a placenta thickness of 5 mm or more, especially with a ''ground glass'' appearance on ultrasound may also be indicative of the presence of this condition. Maternal laboratory tests such as blood typing (to see if they are Rh negative), antibody screens for TORCHES-CLAP (Toxoplasma gondii; Rubella virus; Cytomegalovirus; Herpes simplex virus; Enterovirus; Syphilis; Chickenpox virus; Lyme disease; Aids; Parvovirus B19), hemoglobin electrophoresis, and an alpha-fetoprotein (AFP) test can also aid in diagnosing IHF.\nDifferential diagnosis\nThe many disorders associated with HF are differential diagnoses such as congestive heart failure, hepatitis B, Parvovirus B19 infection, hypercalcemia, hypernatremia, hypothrombinemia, hypothyroidism and diabetes (in mother) and neonatal hemochromatosis. A few conditions mimic full-blown HF such as obstructed or mature bowel, fetal abdominal cysts and an obstructed urinary system (in the end stages).\nAntenatal diagnosis\nPrenatal diagnosis is by ultrasound.\nManagement and treatment\nRh iso-immunization can usually be prevented by giving the mother an intramuscular injection of Rho(D) immune globulin. For those who develop IHF, intrauterine treatment can involve thoraco-amniotic drainage, antiarrhythmic drugs (ex. digoxin, sotalol, propranolol) to treat arrhythmia, and blood transfusion when anemia is present. If the fetus comes to term it should be delivered at a tertiary care center where the neonate can receive oxygen supplementation, medications for the kidneys and removal of excessive fluid from around the lungs and abdomen as necessary. Exchange transfusion or phototherapy can treat neonatal jaundice.\nPrognosis\nIn most cases, prognosis is poor with a perinatal mortality rate ranging from 55-98%, but it is influenced by numerous factors.\n\n                            Last update: \n                            December 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Carlo BELLINI"}
{"Disease Name": "Immune thrombocytopenia", "Disease Definition": "A rare autoimmune coagulation disorder characterized by isolated thrombocytopenia (a platelet count <100,000/microL), in the absence of any underlying disorder that may be associated with thrombocytopenia.", "ORPHA ID": 3002, "Summary": "Epidemiology\nThe annual incidence is estimated at between 1/25,600-37,000 in Europe, with a female to male ratio of 1.3:1. Although immune thrombocytopenia (ITP) can occur at any age, incidence shows an age-specific bimodal distribution for men with two incidence peaks observed in boys (under 18 years old) and among those older than 60 years of age.\nClinical description\nITP exposes to a risk of bleeding. It is defined as severe when the presence of bleeding symptoms at presentation is sufficient to warrant treatment or when the occurrence of new bleeding symptoms requires additional therapeutic intervention. It is asymptomatic in one-third of cases. Mucocutaneous hemorrhage with purpura is the most frequent clinical manifestation, usually occurring when the platelet count is below 30,000/microL. Severe visceral bleeding (hematuria, gastrointestinal hemorrhage or cerebromeningeal bleeding) is mainly observed when thrombocytopenia is below 10,000/microL and is rare, occurring mainly in elderly with comorbidities or in children in whom the disease is often self-limited; however, most children do not have severe bleeding problems despite very low platelet counts. Depending on the disease duration, ITP is classified into newly diagnosed, persistent (duration of 3-12 months) and chronic (duration of more than 12 months). Persistence or chronicity occurs in about 30 % of children compared with about 70% of adults.\nEtiology\nThe etiology is unknown. However, the disease origin is not genetic as familial cases are exceptional. Platelet destruction, mediated by autoantibodies mainly in the spleen, is associated both with impaired platelet production and with T-cell-mediated effects.\nDiagnostic methods\nA presumptive diagnosis is made when the history, physical examination, complete blood count and examination of the peripheral blood smear do not suggest other etiologies for the thrombocytopenia. There is no `gold standard' test that can reliably establish the diagnosis. A positive response to intravenous immunoglobulin (IVIg) and/or steroids is supportive of the diagnosis. In ITP the bone marrow is normal, and bone marrow aspiration is indicated mainly in patients over 60 years' of age, in case of anomalies of other cell lines, when thrombocytopenia is refractory to first-line treatments, or when other diagnoses are suspected such as myelodysplastic syndromes (MDS). In addition to the morphologic assessment, cytogenetic testing should be considered if an MDS is suspected.\nDifferential diagnosis\nThe differential diagnosis should include causes of secondary ITP (drug-induced), autoimmune diseases (such as systemic lupus erythematosus), HIV infection and hepatitis C. In elderly patients, MDS should be ruled out. In children, inherited thrombocytopenias are often misdiagnosed with ITP. ITP can be associated with genetic immunodeficiency syndromes (typically common variable immunodeficiency) and is observed mainly in children and young adults.\nManagement and treatment\nThe therapeutic strategy should be adapted both to the severity of the disease and to the patient's age. At diagnosis, children with mild or even moderate bleeding can be managed with monitoring. Treatment is rarely indicated in adults with platelet counts above 20 to 30x10exp9/L in the absence of bleeding. Corticosteroids (oral prednisone or short course of dexamethasone) are the standard first-line treatment. Use of intravenous immunoglobulins should be reserved for patients with severe bleeding (bleeding score could be used to help the physicians for IVIg indication) who are unresponsive to prednisone or for the rare patients with contra-indications to steroids. In case of chronic severe ITP, splenectomy has been used as the reference treatment for a long time. However, biologics (such as rituximab, eltrombopag, romiplostim) and even immunosuppressants (such as mycophenolate mofetil) can now be considered as an alternative to splenectomy as second-line treatment for patients refractory to first-line treatments. The respective place between these different second-line therapeutic options is still debated; ultimately, treatment should be personalized according to the patient's characteristics.\nPrognosis\nThe mortality rate is generally below 2%, but may exceed 10% in the rare patients refractory to first- and second-line treatments (including splenectomy).\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Bertrand GODEAU"}
{"Disease Name": "Immune-mediated necrotizing myopathy", "Disease Definition": "A rare form of idiopathic inflammatory myopathy characterized by acute or subacute, severe, symmetrical, proximal muscle weakness usually associated with muscle-specific antibodies (anti-HMGCR or anti-SRP). Histopathological characteristics include myocyte necrosis and regeneration without significant inflammation, and C5b-9 deposition on non-necrotic myofibers.", "ORPHA ID": 206569, "Summary": "Epidemiology\nThe incidence of idiopathic inflammatory myopathy as a whole ranges from 1.16 to 19/million/year and the prevalence ranges from 2.4 to 33.8 per 100 000 inhabitants. Although the prevalence and annual incidence are not known, immune-mediated necrotizing myopathy (IMNM) represents roughly 10% of the idiopathic inflammatory myopathies.\nClinical description\nAge of onset typically ranges from 30 to 70 years of age, although pediatric onset is possible. The main presenting feature of IMNM is subacute severe symmetrical proximal myopathy with a markedly elevated creatine kinase (CK) level. The main clinical symptom is upper and lower limb weakness causing difficulty in moving from a sitting position, climbing stairs, or lifting objects. The neck flexor, pharyngeal, and respiratory muscles may also be involved. Other manifestations include fatigue, weight loss, dysphagia and dyspnea. Interstitial lung disease and cardiac involvement have also been reported (especially in patients with anti-SRP antibodies).\nEtiology\nThe disease is thought to be related to an immune response possibly triggered by drug therapy (statins), viral infections, or cancer. The pathophysiological mechanisms are partially deciphered. A specific genetic background has been identified (HLA-DRB1*11:01 allele in adult patients with anti-HMGCR autoantibodies). The production of autoantibodies is a major feature of the disease. Several studies point toward a direct pathogenic role of these autoantibodies, potentially through the activation of the complement cascade.\nDiagnostic methods\nDiagnosis is based on the clinical picture with the presence of auto-antibodies (anti-SRP or anti-HMGCR) and/or a muscle biopsy showing minimal or no inflammatory infiltrates and marked muscle necrosis, unlike other inflammatory myopathies. Electromyography (EMG) shows myopathic findings. Creatine kinase (CK) levels are often more than 10 times above the upper limit of normal at the time of onset of muscle weakness. Magnetic resonance imaging (MRI) may show diffuse or patchy edema within muscles and damage-like muscle fatty replacement. Anti-SRP and anti-HMGCR autoantibodies are frequently associated with this condition. Currently, seronegative IMNM represents 20-30% of the cases.\nDifferential diagnosis\nDifferential diagnoses include other inflammatory myopathies. In children, the progressive form of the disease may mimic muscular dystrophy.\nManagement and treatment\nTreatment of the underlying cause, if identified, is essential (statin withdrawal, or malignancy). IMNM patients generally respond well to multiple-agent, long-term immunosuppressive therapies starting by high dose corticosteroids. The therapeutic strategy relies on an induction therapy combining high dose corticosteroids and other immunosuppressive agents (methotrexate, rituximab or intravenous immunoglobulins (IVIg)), followed by a maintenance therapy with the lowest tolerated dose of corticosteroids and the immunosuppressive agent. The maintenance therapy should be administered for at least 2 years in which there is well-controlled disease. Exercise is recommended to improve muscle strength. Response to therapy should be assessed clinically on the basis of muscle strength and biologically on CK levels.\nPrognosis\nIMNM is the most severe idiopathic inflammatory myopathy in terms of muscle damage, and relapses are frequent. Early age of onset is a poor prognosis factor for muscle strength recovery. There is an association with cancer risk in patients with seronegative IMNM and, to a lesser extent, in patients with anti-HMGCR IMNM.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE"}
{"Disease Name": "Immune-mediated thrombotic thrombocytopenic purpura", "Disease Definition": "A rare, non-hereditary thrombotic thrombocytopenic purpura (TTP), characterized by profound peripheral thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and single or multiple organ failure of variable severity.", "ORPHA ID": 93585, "Summary": "Epidemiology\nThe annual incidence of TTP is estimated at 0.25 to 1/250, 000. Immune-mediated TTP is much more common than congenital TTP, accounting for over 95% of all TTP cases, and has a 3:1 female-to-male ratio.\nClinical description\nDisease onset is typically sudden and occurs in adulthood (median age 40 years). Prodromic manifestations including fatigue, arthralgias, myalgias and abdominal and/or lumbar pain are frequently observed around the time of diagnosis. Thrombotic microangiopathy is associated with MAHA, consumptive peripheral thrombocytopenia and variable organ injury due to disseminated microvascular thrombosis. Manifestations due to cerebral (headache, confusion, seizure, focal deficiency, altered mental state and coma; 50-80% of cases), cardiac (infarction, congestive heart failure, arrhythmias, cardiogenic shock, and sudden cardiac arrest), and gastrointestinal (abdominal pain, nausea, vomiting, and diarrhea) involvement are observed. Renal involvement is usually mild. The disease course is variable. Patients may suffer from only one acute TTP episode; however, relapses have been reported in 30-40% of patients. Immune-mediated TTP is usually idiopathic but rarely may occur in association with a connective tissue disease (mostly systemic lupus erythematosus and Sjögren's syndrome), infections (typically HIV infection), or after ticlopidine intake. Patients with a history of immune-mediated TTP are at risk of a relapse during pregnancy.\nEtiology\nThe majority of cases of immune-mediated TTP are associated with the presence of autoantibodies directed against the von Willebrand factor-cleaving protease, ADAMTS13, resulting in a severe (< 10% of normal activity) ADAMTS13 deficiency. A trigger, including physical stress (surgery), infections, drug intake or a pregnancy, may precipitate the disease.\nDiagnostic methods\nBiological features are consistent with hemolysis (high reticulocyte count, indirect bilirubin and LDH levels and a low haptoglobin level). The direct antiglobulin test is negative whereas peripheral blood smear reveals schistocytes. A very low platelet count (≤ 30 000/mm3) and mild renal involvement (serum creatinine ≤ 200 µmol/L) can predict a severe acquired ADAMTS13 deficiency. A severe decrease in ADAMTS13 activity (< 10% normal levels) in the presence of anti-ADAMTS13 autoantibodies confirms diagnosis.\nDifferential diagnosis\nThe main differential diagnoses are congenital TTP and atypical hemolytic uremic syndrome as well as antiphospholipid syndrome, Evans syndrome, disseminated intravascular coagulation, cobalamin deficiency and, in pregnant patients, HELLP syndrome.\nManagement and treatment\nThe treatment of immune-mediated TTP is based on a triplet regimen of therapeutic plasma exchange (TPE; with 1.5 x plasma volume exchange), immunosuppression with corticosteroids and B-cell depletion (rituximab), and caplacizumab, an inhibitor of vWF-platelet interaction. This treatment should be initiated as soon as the clinical diagnosis of TTP is made or suspected and should be continued daily until remission. Steroids, in the absence of uncontrolled infection, are often used as adjuvant first line therapies. Thromboprophylaxis may be introduced when platelet count is above 50,000/mm3. Whilst exacerbations and refractory disease are rare with the triplet regimen, this can be managed with a more intensive treatment including twice-daily TPE. For patients in clinical remission but with a persistently undetectable ADAMTS13 activity, preemptive administrations of rituximab prevents relapse.\nPrognosis\nIn the absence of treatment, TTP is a rapidly fatal disease (mortality rate > 90%); however, the introduction of TPE has led to a decrease in the rate of mortality to 10-15%. With the recent addition of caplacizumab, mortality may further decrease to < 10%. Even with optimal management, neurological (attention deficit, memory loss) and physical (fatigue) sequelae may persist. A systematic long-term follow-up is required for all patients, due to the risk of relapse. Patients may also develop additional autoimmune diseases.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Paul COPPO"}
{"Disease Name": "Immunodeficiency by defective expression of MHC class I", "Disease Definition": "A rare autosomal recessive primary immunodeficiency characterized by severe reduction in the cell surface expression of HLA class I molecules, typically resulting in childhood-onset of chronic bacterial infections of the respiratory tract evolving to widespread bronchiectasis and respiratory insufficiency. Sterile necrotizing granulomatous skin lesions mainly involving the extremities and the mid-face may be observed in some patients. Severe viral infections do not occur as part of the condition. Atypical variants without respiratory or cutaneous manifestations, as well as asymptomatic individuals have been reported.", "ORPHA ID": 34592, "Summary": ""}
{"Disease Name": "Immunodeficiency by defective expression of MHC class II", "Disease Definition": "A rare autosomal recessive primary immunodeficiency characterized by absence of HLA class II molecules on the surface of immune cells, leading to severely impaired cellular and humoral immune response to foreign antigens, severe CD4+ T-cell lymphopenia, and hypogammaglobulinemia. The disease clinically manifests with early onset of severe and recurrent infections mainly of the respiratory and gastrointestinal tract, protracted diarrhea with failure to thrive, and autoimmune disease, and is frequently fatal in childhood.", "ORPHA ID": 572, "Summary": ""}
{"Disease Name": "Immunodeficiency due to a classical component pathway complement deficiency", "Disease Definition": "A rare primary immunodeficiency due to a deficiency in either complement components C1q, C1r, C1s, C2 or C4 characterized by increased susceptibility to bacterial infections, particularly with encapsulated bacteria, and increased risk for autoimmune disease. Most commonly, these include systemic lupus erythematosus (SLE), SLE-like disease, Henoch-Schonlein purpura, polymyositis and arthralgia. Disease severity is variable and dependent on the complement affected.", "ORPHA ID": 169147, "Summary": ""}
{"Disease Name": "Immunodeficiency due to a late component of complement deficiency", "Disease Definition": "Immunodeficiency due to a late component of complement deficiency is a primary immunodeficiency due to an anomaly in either complement components C5, C6, C7, C8 or C9 and is typically characterized by meningitis due to often recurrent meningococcal infections. The prognosis is generally favorable.", "ORPHA ID": 169150, "Summary": ""}
{"Disease Name": "Immunodeficiency due to CD25 deficiency", "Disease Definition": "A rare genetic primary immunodeficiency due to a defect in adaptive immunity characterized by severe immunodeficiency, presenting with profound susceptibility to viral, fungal and bacterial infections due to impaired CD25-mediated T-regulatory cell function, in association with severe autoimmune disease, such as alopecia universalis, erythrodermia, and autoimmune thyroiditis and enteropathy.", "ORPHA ID": 169100, "Summary": ""}
{"Disease Name": "Immunodeficiency due to ficolin3 deficiency", "Disease Definition": "Immunodeficiency due to ficolin3 deficiency is a rare, genetic, immunodeficiency due to a complement cascade protein anomaly characterized by low or undetectable serum ficolin3 levels, susceptibility to infections, and possibly autoimmunity. The presentation is variable, from perinatal necrotizing enterocolitis and recurrent skin infections with Staphylococcus aureus to childhood-onset recurrent pulmonary infections leading to brain abscesses and pulmonary fibrosis, to membranous nephropathy. In some patients, clinical consequences of ficolin3 deficiency were not clear.", "ORPHA ID": 331190, "Summary": ""}
{"Disease Name": "Immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency", "Disease Definition": "Interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency is an immunodeficiency associated with increased susceptibility to invasive infections caused by pyogenic bacteria.", "ORPHA ID": 70592, "Summary": "Epidemiology\nIt has been described in less than 15 patients from eight families with onset occurring during childhood.\nClinical description\nThe most common recurrent infections in these patients were caused by Streptococcus pneumoniae or Staphylococcus aureus, leading to a range of clinical manifestations such as pneumonia, septic arthritis, cellulitis, osteomyelitis, otitis media, meningitis and sinusitis. In contrast, the patients appeared to be resistant to infection caused by most other bacteria, parasites and viruses but fungal infections have been reported. Although routine immunological evaluations generally gave normal results, the patients displayed reduced inflammatory responses and neutropenia during infectious episodes.\nEtiology\nIRAK-4 deficiency is caused by mutations in the IRAK-4 gene (chromosome 12q12). IRAK-4 is a member of the IRAK protein kinase family and is involved in the toll-interleukin 1 (TIR) signalling pathway.\nDiagnostic methods\nIRAK-4 deficiency should be suspected in patients with a failure to sustain antibody responses and recurrent pyogenic bacterial infections. Diagnosis can be confirmed by detection of IRAK-4 gene mutations and through characterisation of the reduced response of blood cells and fibroblasts to stimulation with a large range of interleukin-1 receptor (IL-1R) and toll-like receptor (TLR) ligands and whole bacteria (S. aureus, Escherichia coli and Mycobacterium tuberculosis).\nManagement and treatment\nIntravenous immunoglobulin therapy (IVIG), antibiotic prophylaxis and administration of the heptavalent pneumococcal-conjugated vaccine have provided successful results in some cases.\nPrognosis\nThe prognosis for most patients is good, with infections becoming less frequent with age. However, bacterial meningitis has lead to death in a few cases, particularly when it occurred during infancy.\n\n                            Last update: \n                            November 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Alain FISCHER"}
{"Disease Name": "Immunodeficiency due to MASP-2 deficiency", "Disease Definition": "Immunodeficiency due to MASP-2 deficiency is a rare, genetic immunodeficiency due to a complement cascade protein anomaly characterized by low serum levels of MASP-2 and a variable susceptibility to bacterial infections (e.g. pulmonary tuberculosis, pneumococcal pneumonia, skin abscesses and sepsis), and autoimmune diseases (e.g. inflammatory lung disease, cystic fibrosis, systemic lupus erythematosus). In many cases it remains asymptomatic.", "ORPHA ID": 331187, "Summary": ""}
{"Disease Name": "Immunodeficiency due to selective anti-polysaccharide antibody deficiency", "Disease Definition": "A rare primary immunodeficiency characterized by normal immunoglobulin levels (including IgG sub-classes) but impaired polysaccharide responsiveness.", "ORPHA ID": 70593, "Summary": "Epidemiology\nAlthough the prevalence is not really known, >100 cases have been reported in the literature. The frequency ranges from 11-60% in selected patients with unexplained bacterial infections.\nClinical description\nThis condition can affect children > 2 years-old or adults, although most of the published cases are adults. Patients suffer from recurrent bacterial infections, mostly of the respiratory tract, such as bronchopulmonary infections (with or without bronchiectasis), recurrent bacterial sinusitis, or chronic rhinosinusitis. Sepsis and meningitis occur less frequently. Offending bacteria possess a polysaccharide capsule, such as pneumococci, Haemophilus influenzae (serotype b), meningococci and group B streptococci. Allergic manifestations are observed in half of the patients.\nEtiology\nThis immunodeficiency is likely heterogeneous with multiple causes. Higher prevalence in certain ethnic populations and familial cases suggest genetic factors are involved. Several hypotheses have been proposed concerning the cause of the disease, but the most likely is a defect in splenic marginal zone B cells (MZB), which is supported by the observed impaired polysaccharide antibody response in splenectomized patients.\nDiagnostic methods\nThe diagnosis is established by identifying deficient antibody response to polysaccharide antigens (usually unconjugated Streptococcus pneumoniae vaccine) contrasting with normal immunoglobulin (including the IgG subclasses) levels and unaffected antibody production to protein antigens (tetanus toxoid, diphtheria) and conjugate polysaccharides. The response to pneumococcal capsular polysaccharide is tested using the third-generation enzyme-linked immunosorbent assay adopted by the WHO. The results must be interpreted according to the guidelines issued in 2012 by the American Academy of Allergy, Asthma & Immunology (AAAAI) Working Group. A single serotype is considered to have normal response if the post-immunization antibody titer is > 1.3 μg/mL (considered to be protective) and/or achieves a 4-fold increase (relative to the preimmunization value). A 2-fold increase is considered acceptable if the initial titer was already > 1.3 μg/mL. A good immunization is defined if a normal response is observed for at least 50% (for children) to 70% (for adults) of the evaluated serotypes. As most children < 2 years old have a physiological defect in response to polysaccharide antigens, the diagnosis cannot be made before this age. Additionally, some patients also appear to be poor responders to conjugate polysaccharides. Anti-polysaccharide response cannot be evaluated in patients treated with steroids or immunosuppressants.\nDifferential diagnosis\nPracticians should exclude other primary immunodeficiencies also characterized by a defective response to polysaccharide antigens, mostly common variable immunodeficiency (CVID), the IgG2 and IgG3 deficiencies. A defect in antibody production to polysaccharides may also be associated with Wiskott-Aldrich syndrome.\nManagement and treatment\nAntibiotics should be given to both control and prevent infections as a prophylactic treatment when they are too frequent. Immunoglobulin substitution could also be of benefit whenever prophylactic antibiotherapy fails. Vaccinations with the conjugate antipneumococcal, antimeningococcal and anti-Haemophilus serotype b vaccines are also required.\nPrognosis\nUnder treatment, infections are generally well controlled. However, patients should be carefully followed-up since this condition could evolve into a more severe immunodeficiency (IgG subclass deficiency or CVID), particularly if the diagnosis is made during childhood.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Guillaume LEFEVRE"}
{"Disease Name": "Immunodeficiency with factor H anomaly", "Disease Definition": "A rare, genetic, primary immunodeficiency disease characterized by increased susceptibility to recurrent, usually severe, infections (particularly by  Neisseria meningitidis, Escherichia coli, and Haemophilus influenzae), renal impairment and/or autoimmune diseases, typically manifesting with otitis media, bronchitis, meningitis, and/or septicemia, as well as hematuria/proteinuria, asthma, nephrotic syndrome, hemolytic uremic syndrome, glomerulonephritis, and/or systemic lupus erythematosus. Laboratory serum analysis reveals, in addition to factor H deficiency, decreased complement factor B, properdin, complement C3 and terminal complement components.", "ORPHA ID": 200421, "Summary": ""}
{"Disease Name": "Immunodeficiency with factor I anomaly", "Disease Definition": "A rare, genetic, primary immunodeficiency disease characterized by increased susceptibility to recurrent, usually severe, infections (particularly by Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae), typically manifesting as otitis, sinusitis, bronchitis, pneumonia, and/or meningitis. Autoimmune disease (e.g. systemic lupus erythematosus, glomerulonephritis) and atypical hemolytic uremic syndrome may be associated. Laboratory serum analysis reveals, in addition to diminished or undetectable complement factor I, variably decreased complement C3, complement factor B and complement factor H.", "ORPHA ID": 200418, "Summary": ""}
{"Disease Name": "Immunoglobulin A nephropathy", "Disease Definition": "A rare glomerular disease, histologically characterized by glomerular mesangial deposits of IgA, often accompanied by IgG and complement C3 as well as mesangioproliferative changes, clinically mostly manifesting as oligosymptomatic glomerulonephritis, possibly infection-triggered macrohematuria and a variable course ranging from spontaneous remission to slow or rarely rapid progression to kidney failure.", "ORPHA ID": 34145, "Summary": "Epidemiology\nIn Europe, the annual incidence of IgA nephropathy (IgAN) is approximately 1/131,578, with a point prevalence of 1/3952. Higher prevalences are observed in Asia and lower prevalences in Africa. The male to female ratio is about 2:1 in Europeans. IgAN is rare in children younger than 10-12 years.\nClinical description\nIgAN typically runs an oligosymptomatic course with microscopic hematuria, variable degrees of proteinuria (but usually not the nephrotic syndrome), hypertension and slowly progressive decline of glomerular filtration rate (GFR). Consequently, the disease is often diagnosed by chance in younger adults undergoing medical work-up. Sometimes macrohematuria occurs within 1-2 days after the onset of an upper respiratory tract infection. If diagnosed very early, IgAN may spontaneously remit in up to 30% of the cases, whereas 25% slowly loose GFR. Of the patients coming to medical attention at later chronic kidney disease (CKD) stages, up to 100% progress to kidney failure over 20-30 years.\nEtiology\nIgAN is characterized by the deposition of IgA1 with a particular undergalactosylation pattern in the IgA1 hinge region (gd-IgA1). Deposition of gd-IgA1 with or without IgG directed at gd-IgA1 leads to complement activation, mesangial and other glomerular cell injury, followed by glomerulosclerosis and tubulointerstitial fibrosis. The origin of the B-cells producing undergalactosylated IgA1 may be the intestinal muscosa, pointing to the existence of a gut-kidney axis in IgAN, which is supported by genome-wide association studies.\nDiagnostic methods\nA diagnosis of IgAN can only be made by kidney biopsy. Findings include mesangial hypercellularity and matrix expansion, endocapillary proliferative changes, glomerulosclerosis and tubulointerstitial fibrosis. Glomerular crescents occur in up to 20% of all biopsies but are rarely extensive. The later very rare cases are characterized by kidney failure occurring within months to a few years.\nDifferential diagnosis\nSecondary causes of IgAN should be excluded. These include rheumatologic, celiac, and chronic inflammatory bowel disease, and infections (hepatitis B, hepatitis C). Other associations may be coincidental since glomerular IgA deposits can be frequently detected in autopsies even in patients with no known disease.\nManagement and treatment\nAll patients should receive optimized conservative therapy, targeting blood pressure, proteinuria, and life style (stop smoking, normalize body weight, dietary sodium and protein restrictions). Use of an ACE-inhibitor or angiotensin receptor blocker with systematic uptitration to the maximum allowed or tolerated dose is mandatory in patients with a proteinuria above 0.5 g/d. Patients should also receive a sodium-glucose cotransporter-2 (SGLT2) inhibitor. The value of high dose corticosteroids tapered over 6 months is controversial with some studies (in particular in Asian patients) reporting a delay of kidney failure by about 2.5 years, whereas recent European studies noted no benefit. All randomized trials noted a significant increase in serious adverse events with high dose corticosteroids, including infection-related mortality. In 2022 an enteric coated preparation of budesonide (nefecon) was licensed for IgAN. In 2023 this was followed by sparsentan, a dual angiotensin-II receptor and endothelin receptor-A blocker. Drugs in clinical testing include selective endothelin receptor-A blockers, B-cell proliferation and differentiation inhibitors (targeting APRIL and/or BAFF) and drugs targeting the complement system.\nPrognosis\nThe prognosis over 5-6 years can be estimated using the International IgAN Prediction Tool. Major prognostic parameters include the degree of proteinuria, GFR impairment at baseline, hypertension, nicotine consumption and obesity. However, in particular in younger adults with IgAN even low levels of proteinuria (i.e. <1 g/d) carry a high life-time risk of kidney failure.\n\n                            Last update: \n                            December 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Jürgen FLOEGE | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Immunoglobulin A vasculitis", "Disease Definition": "A rare, small-vessel vasculitis characterized by skin purpura, arthritis, abdominal and/or renal involvement, IgA tissue deposits (arterioles, capillaries, and venules) and circulating IgA immune complexes.", "ORPHA ID": 761, "Summary": "Epidemiology\nThe disease usually affects children and is rare in adults. Annual incidence in children is estimated at between 1/4,880 and 1/6,660, whereas it is estimated at around 1/1,000,000 in adults. The male-to-female ratio is 1.5:1.\nClinical description\nPatients present with vascular purpura that is usually symmetrical and primarily localized to the buttocks and legs. In adults it is more frequently complicated by necrotic or hemorrhagic bullous lesions. The lesions progressively regress, disappear after a few days and, in 80% of cases, never reappear. Patients also present with arthralgia, predominantly involving the knees and ankles. Abdominal pain is common and may be associated with life-threatening gastrointestinal bleeding. Renal involvement is more severe and frequent in adults. It usually consists of microscopic hematuria with varying degrees of proteinuria. Nephrotic syndrome, renal failure, and hypertension may also occur. Other manifestations are rare but may include headaches, seizures, paresis, orchiepididymitis, uretritis, pancreatitis, myositis, episcleritis, pulmonary bleeding and myocarditis.\nEtiology\nThe disease is associated with deposition of IgA-dominant immune complexes in arterioles, capillaries, and venules, but the exact etiology remains unknown. Several different viral or bacterial organisms, drugs, foods, and insect bites have been implicated as the initiating factors of the disease.\nDiagnostic methods\nThe diagnosis is based on clinical and histopathological findings. Examination of skin and kidney biopsies reveals tissue deposition of IgA with circulating IgA immune complexes.\nDifferential diagnosis\nDifferential diagnoses include other causes of purpura such as thrombopenia, hemopathy or infectious diseases. In adults, ANCA associated vasculitis, systemic lupus erythematosus, and mixed cryoglobulinemia should also be considered in the differential diagnosis.\nManagement and treatment\nThe treatment is symptomatic. The use of steroids and/or immunosuppressors is controversial but may be considered in case of severe gastrointestinal or renal manifestations. Renin-angiotensin-system blockers should be started as soon as the proteinuria/creatinine ratio is greater than 50 mg/mmol.\nPrognosis\nGastrointestinal or pulmonary bleeding can be life-threatening. The long term prognosis depends on the extent of the renal involvement. Long term follow-up studies of adult series show that end-stage renal failure may occur in up to one-third of patients.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Evangeline PILLEBOUT"}
{"Disease Name": "Immunoglobulin-mediated membranoproliferative glomerulonephritis", "Disease Definition": "A primary form of membranoproliferative glomerulonephritis (MPGN) characterized by deposition in the renal glomeruli of immunoglobulin with complement fractions, especially C3. Clinical presentation may range from nephrotic syndrome and acute kidney injury to asymptomatic proteinuria and hematuria.", "ORPHA ID": 329903, "Summary": "Epidemiology\nIt is amongst the rarest forms of glomerular disease; the annual incidence is unknown. Distribution between males and females tends to be equal, and presents at all ages, starting from early childhood.\nClinical description\nClinical features and severity are heterogenous, ranging from asymptomatic proteinuria which is noticed on routine urinalysis, to typical nephritic syndrome with mild proteinuria and hematuria, to a more acute presentation with nephrotic syndrome (edema, oligoanuria), hypertension and possibly acute renal failure. An infectious trigger, typically but not exclusively an upper respiratory tract infection, is frequently described, particularly in children presenting with macroscopic hematuria. Circulating complement evaluation shows frequently reduced C3, while C4 is usually normal.\nEtiology\nWhen a clear underlying etiology cannot be identified despite a thorough evaluation, Ig-mediated MPGN is considered primary or idiopathic. Variants in genes encoding for complement alternative pathway proteins and C3 nephritic factor are detected in 10%-25% and in 40%-54% of patients respectively.\nDiagnostic methods\nDiagnosis relies on renal biopsy, which shows features of MPGN with deposition of both immunoglobulins (IgG, IgA, IgM) and of complement (mainly C3, but also C1q, C4d). Upon histological diagnosis, secondary forms need to be excluded by screening for infection (mainly hepatitis B and C), autoimmune conditions (mainly systemic lupus erythematosus) and monoclonal gammopathies (especially in adults > 50 years of age). In primary forms, especially if circulating C3 is persistently reduced, screening for alternative pathway of complement dysregulation, both genetic and serological, should be performed in expert centers.\nDifferential diagnosis\nAt onset, this glomerular disease may resemble acute post-infectious glomerulonephritis, especially in children, which is a more frequent and self-limiting form of glomerulonephritis. Forms presenting with intra or post-infectious macrohematuria and proteinuria may resemble IgA nephropathy clinically, but the renal biopsy will give a different picture. The histological picture can also be found in secondary forms of MPGN, mostly due to infections, autoimmune conditions or monoclonal gammopathies.\nGenetic counseling\nThe forms of immunoglobulin-mediated MPGN with genetic mutations identified in genes encoding for alternative pathway regulator proteins are very rarely familial and disease pathogenesis is multifactorial. Therefore, genetic counseling may be useful but is not essential.\nManagement and treatment\nManagement is based on the severity of the presenting features. Due to the rarity of these conditions, expert advice should be sought both for appropriate treatment and for genetic and serological work-up. All patients with proteinuria should receive optimal conservative treatment with low-salt diet, renin-angiotensin system inhibitors and, when appropriate, lipid lowering agents. Although evidence is limited, immunosuppressive treatment is usually used when proteinuria and glomerular inflammation are present, using oral glucocorticoids and mycophenolate mofetil. Response is not always optimal. In the presence of intense inflammation with extracapillary proliferation or acute renal failure, more intense immunosuppression is attempted with anti-proliferative agents such as cyclophosphamide and intravenous boli of methylprednisolone. In patients with evidence of alternative pathway of complement dysregulation, particularly if the above approach has not been successful, the use of complement inhibitory agents may be reasonable. Treatment with these agents, particularly with eculizumab, has only proven effective in approximately one-third of patients. Further agents acting upstream, at the C3 convertase level, need to be investigated in clinical trials.\nPrognosis\nThough this disease is very heterogenous and can be extremely subtle with low-grade relapsing proteinuria, long-term prognosis in forms which do not respond to treatment is poor, leading not only to terminal renal failure but also to a consistent risk of relapse post-renal transplantation.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Erica DAINA | ERKNet* - Dr Marina VIVARELLI | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Immunotactoid glomerulopathy", "Disease Definition": "Immunotactoid glomerulopathy (ITG) is a very rare condition characterized by glomerular accumulation of microtubules in the mesangium and the glomerular basement membrane, that mainly presents with proteinuria, micro-hematuria, nephrotic syndrome, renal insufficiency and hematologic malignancy. ITG and non-amyloid fibrillary glomerulopathy (non-amyloid FGP, see this term) are often grouped together as pathogenetically related diseases.", "ORPHA ID": 97567, "Summary": "Epidemiology\nIn native renal biopsies, ITG comprises an estimated incidence of 0.06% of adult GN. The disease mainly affect Caucasian population and patients over 50 years old. Men are slightly more affected than women.\nClinical description\nITG may manifest with proteinuria (usually nephrotic), hematuria, renal insufficiency and hypertension. Patients present with edema, ascites, pleural effusion and have an elevated risk of blood clots and infection. ITG patients manifest at a high frequency with hypocomplementemia, dysproteinemia, monoclonal gammopathy, cryoglobulinemia and lymphoproliferative disorders (mainly B-cell lymphocytic leukemia or small lymphocytic non-Hodgkin's lymphoma).\nEtiology\nEtiopathology of ITG is unknown. It may arise spontaneously or be associated with lymphoproliferative disorders, hepatitis C virus infection, leukocytoclastic vasculitis and hypocomplementemia.\nDiagnostic methods\nDiagnosis of ITG is based on renal biopsy. Common histological patterns include those of membranoproliferative, diffuse proliferative or membranous glomerulopathy. The diagnosis is also based on the absence of reactivity with Congo red and other agents typically used for the histochemical demonstration of amyloid tissues (e.g. thioflavin T), as well as observation on light, fluorescence and electron microscopy. At the ultrastructural level, deposits consist of usually parallel, hollow microtubular structures (10-90 nm in diameter, often >30 nm), mainly composed of monoclonal immunoglobulin G and complement component 3 (C3). Other laboratory findings may include low serum albumin and an increase in creatinine and in blood cholesterol.\nDifferential diagnosis\nDifferential diagnosis of ITG includes simple cryoglobulinemia, systemic lupus erythematosus, amyloidosis and non-amyloid FGP (see these terms).\nManagement and treatment\nNo proven effective therapy has been reported for ITG so far. Diuretics (e.g. furosemide) and dietary/fluid restrictions may be recommended in order to reduce fluid retention and prevent the accumulation of salt in the blood. An angiotensin-converting enzyme inhibitor may be prescribed in case of mild renal damage and low levels of protein loss. A statin and blood-thinning medication may be required to reduce cholesterol and the risk of blood clotting respectively, in case of a heavier protein leak. In case of rapidly progressive GN, cyclophosphamide and high doses of steroids may be indicated. Finally, when the disease is associated with an underlying condition, effective therapy directed at this underlying disorder may have some beneficial effect on the renal disease.\nPrognosis\nThe overall course of ITG is usually slowly progressive, with about half of the patients developing end-stage renal disease over 2-4 years, requiring dialysis or renal transplantation. ITG recurrence in the transplanted kidney has been reported. A more extensive glomerular involvement or the presence of systemic involvement renders ITG prognosis poorer.\n\n                            Last update: \n                            March 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Laure Hélène NOEL"}
{"Disease Name": "Immunotactoid or fibrillary glomerulopathy", "Disease Definition": "Immunotactoid or fibrillary glomerulopathy is a group of very rare glomerular diseases, composed of immunotactoid glomerulopathy (ITG) and non-amyloid fibrillary glomerulopathy (non-amyloid FGP) (see these terms), that are characterized by mesangial deposition of monoclonal microtubular or polyclonal fibrillar deposits. Both present clinically with nephrotic range proteinuria, hematuria and renal insufficiency leading to renal failure in many cases. ITG is more likely to manifest with underlying lymphoproliferative disease, hypocomplementemia, dysproteinemia, monoclonal gammopathy or occult cryoglobulinemia. Non-amyloid FGP is 10 times more frequent than ITG.", "ORPHA ID": 91137, "Summary": ""}
{"Disease Name": "Imperforate oropharynx-costovertebral anomalies syndrome", "Disease Definition": "Imperforate oropharynx-costovertebral anomalies syndrome is a dysostosis with predominant vertebral and costal involvement characterized by oropharyngeal atresia, mild mandibulofacial dysostosis, auricular malformations, and costovertebral anomalies (hemivertebrae, block vertebra, partial fusion of the ribs, absent ribs). There have been no further descriptions in the literature since 1989.", "ORPHA ID": 2759, "Summary": ""}
{"Disease Name": "Incessant infant ventricular tachycardia", "Disease Definition": "Incessant infant ventricular tachycardia is a rare type of ventricular tachycardia (VT) characterized by the presence of tachycardia originating from the ventricles, observed for more than 10% of a 24 hour monitoring period. Patients are either asymptomatic or present congestive heart failure.", "ORPHA ID": 45453, "Summary": "Epidemiology\nThe incidence of incessant infant VT is estimated to be 1/333,300 live births in the United Kingdom. Males are more commonly affected than females.\nClinical description\nThis type of VT is diagnosed in infancy or early childhood, usually presenting at between 3 and 30 months of age. The rate of VT ranges from 170 to 440 (mean 260) beats/min occurring more than 10% of the day. The most common clinical presentation is VT with congestive heart failure.\nEtiology\nThe physiopathology of this type of VT is unknown but it has been suggested that microscopic tumors such as myocardial hamartomas, also known as histiocytoid cardiomyopathy (see this term), are responsible.\nDiagnostic methods\nThe electrocardiogram (ECG) usually shows a type of right bundle branch block morphology and a superior axis, predicting a tachycardia origin in the posterior or inferior left ventricle. There is usually clear evidence of ventriculo-atrial block with dissociated P waves, or capture beats or fusion beats. The finding of wide QRS tachycardia with retrograde block confirms the diagnosis of ventricular tachycardia. No structural abnormalities are found on the echocardiogram but there is often poor ventricular function at presentation.\nDifferential diagnosis\nThe differential diagnosis includes other types of ventricular tachycardia and supraventricular tachycardia with a wide QRS.\nManagement and treatment\nImmediate treatment involves control of tachycardia and general support or resuscitation as required. Intravenous lidocaine (1-2 mg/kg) will usually slow or stop the tachycardia leading to rapid symptomatic improvement. Intravenous amiodarone is an alternative. Direct current (DC) cardioversion is usually ineffective. Once sinus rhythm has been restored, drugs such as amiodarone and flecainide are usually effective in suppressing the arrhythmia, sometimes in combination with a beta-blocker. Digoxin and verapamil are best avoided as they may worsen the tachycardia and lead to cardiovascular collapse.\nPrognosis\nTachycardia usually resolves before the age of five years and drug treatment can be withdrawn. Late recurrence is unusual.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christopher WREN"}
{"Disease Name": "Inclusion body myopathy with Paget disease of bone and frontotemporal dementia", "Disease Definition": "Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is a multisystem degenerative genetic disorder characterized by adult-onset proximal and distal muscle weakness (clinically resembling limb-girdle muscular dystrophy; see this term); early-onset Paget disease of bone (see this term), manifesting with bone pain, deformity and enlargement of the long-bones; and premature frontotemporal dementia (see this term), manifesting first with dysnomia, dyscalculia and comprehension deficits followed by progressive aphasia, alexia, and agraphia. As the disease progresses, muscle weakness begins to affect the other limbs and respiratory muscles, ultimately resulting in respiratory or cardiac failure.", "ORPHA ID": 52430, "Summary": ""}
{"Disease Name": "Inclusion body myositis", "Disease Definition": "A rare degenerative inflammatory disorder of skeletal muscles characterized by late onset weakness, starting in either the quadriceps or finger flexors and slowly progressing to include other groups of limb muscles. Distinctive histopathological features include inflammatory and degenerative features.", "ORPHA ID": 611, "Summary": "Epidemiology\nInclusion body myositis (IBM) has a highly variable prevalence according to geographic, ethnic and age criteria. Prevalence in the general population ranges from 1/14,000-1,000,000 but a three-fold increase is observed when considering only a population over 50 years. Underdiagnosis may be an explanation for the high ethno-geographic variation. Male-to-female ratio is 2:1 on average (but varies between 0.5 to 6.5:1).\nClinical description\nIBM onset is over 50 years but the disease may also occur earlier, in the 4th decade. Compared to other idiopathic inflammatory myopathies, the clinical phenotype is characteristic with distal and asymmetrical muscle involvement, amyotrophy, and no extramuscular manifestations. First signs are weakness or even atrophy of the quadriceps or of the finger flexors, leading to difficulties in rising from chairs or ground, climbing stairs, gripping, lifting and using tools, and thereby provoking falls. Flexor digitorum profundus and flexor pollicis longus are more severely involved than the forearm extensor muscles, especially during early stages of the disease. With disease progression, other groups of muscles are also involved, such as the elbow flexors, the hip, knee or neck flexors, and the ankle dorsiflexors, leading to footdrop. Patients frequently have a mild weakness of facial muscles, except for the extraocular muscles. Dysphagia may occur in approximately 66% of patients in advanced stages of the disease and can be severe in some cases.\nEtiology\nEtiology of IBM is poorly understood. No causal gene has been identified but genes encoding the major histocompatibility complex (MHC), HLA-DR3 and 8.1 ancestral haplotypes (HLA-A1, B8, DRB1*0301), have been shown to correlate with IBM susceptibility. Ageing and environmental factors are also surmised to play a triggering role. Whether IBM is primarily an immuno-inflammatory disorder leading to muscle degeneration or a degenerative disorder leading to muscle inflammation is still under debate. The pathogenic role of anti-cN1A, which is detected in 30-50% of patients, is also debated as it is not specific to IBM and may be found in patients with other autoimmune diseases as well as in healthy controls.\nDiagnostic methods\nDiagnosis is based on physical examination (especially the detection of finger flexor weakness), age of presentation and a duration of symptoms over 6 months. Muscle biopsy identifies the inflammatory (diffuse MHC class I sarcolemmal overexpression, endomysial inflammatory infiltrates including CD8+ T cells, T cell invasion of non-necrotic muscle fibers) and degenerative features (rimmed vacuoles, P62 and/or TDP43 aggregates and, occasionally, an abnormally elevated number of COX-negative fibers). Laboratory findings are not specific as serum creatine kinase is only slightly raised in some cases. Electromyography only helps in confirming the myopathic origin of the weakness or atrophy. Magnetic resonance imaging (MRI) helps delineating the characteristic pattern of muscle involvement.\nDifferential diagnosis\nDifferential diagnosis may include other idiopathic inflammatory myopathies and, in early stages of the disease, arthritis or any motor neuron disease.\nManagement and treatment\nThere is no curative treatment for IBM, and patients usually do not respond to anti-inflammatory or immunosuppressant therapies. The standard of care involves symptomatic treatments including exercise therapy, ergotherapy, and orthotic appliance. However, clinical trials are ongoing for new therapeutic strategies, of note for sirolimus, an inhibitor of mTOR.\nPrognosis\nNo change in mean life expectancy has been observed. IBM patients present a progressive and continuous loss of muscle strength between 3.5-16.8% per year. There is a major impact of the disease on the daily activity. After 5 years, most patients require a walking aid and after 10, a wheelchair.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE"}
{"Disease Name": "Incomplete septal cirrhosis", "Disease Definition": "A histopathological form of portosinusoidal vascular disease characterized by the presence of incomplete, thin, perforated, or blind-ended septa, which intermittently delimit rudimentary nodules, although complete cirrhotic-type regenerative nodules are not seen. Isolated collagen bundles can also be observed within the parenchyma.", "ORPHA ID": 596941, "Summary": ""}
{"Disease Name": "Incontinentia pigmenti", "Disease Definition": "An X-linked syndromic muti-systemic ectodermal dysplasia presenting neonatally in females with a bullous rash along Blaschko's lines (BL) followed by verrucous plaques and hyperpigmented swirling patterns. It is further characterized by teeth abnormalities, alopecia, nail dystrophy and can affect the retinal and the central nervous system (CNS) microvasculature. It may have other aspects of ectodermal dysplasia such as sweat gland abnormalities. Germline pathogenic variants in males result in embryonic lethality.", "ORPHA ID": 464, "Summary": "Epidemiology\nThe birth prevalence is approximately 1/ 143,000. The female to male ratio is 20:1.\nClinical description\nThe disorder cutaneous findings typically present perinatally with an erythematous vesicular rash (bullous stage I) following BL: linear on extremities, swirled on trunk and head. Classically, Stage I evolves to a verrucous stage II characterized by wart-like plaques then to Stage III hyperpigmentation along BL that can persist to adulthood. This evolution varies and some adults report persistence of Stages I and II, usually with febrile illness, well into adulthood. These three stages are not sequential, as stage I rash can recur during febrile illness. The so-called Stage IV findings have hypopigmented, hairless regions following BL mostly evident on the lower extremities; however, it is possible that these areas of skin dysplasia may be present from an earlier age, but not visible until the growth of adult body hair. About 50% of IP symptoms are extracutaneous. Delayed dentition, missing, and/or malformed cone shaped teeth occur in most cases. Other manifestations include onycodystrophy, alopecia and a wide range of ophthalmologic abnormalities from primary microphthalmia, to reactive retinal neovascularization (RNV) conferring risk of retinal detachment. CNS abnormalities may comprise microcephaly and neonatal stroke that can result in seizures, neurocognitive and motor impairments. The majority (>60%) of patients are neurologically normal.\nEtiology\nIP is caused by familial (10-25%) or sporadic de novo (>50%) mutations of the NF-kappaB essential modulator gene IKBKG (formerly NEMO). In females, a common exon 4-10 deletion underlies 65% of cases, 8.6% have a sequence variant, and about 4% have a gene deletion.\nDiagnostic methods\nTypical skin lesions and genetic testing are sufficient for diagnosis. Leukocytosis and eosinophilia may be noted. Skin histology shows eosinophilic spongisostic bulles (stage I); hyperkeratotic and acanthotic epidermis with dyskeratotic keratinocytes (stage II) and loose dermal melanine deposits (stage III).\nDifferential diagnosis\nStage I may be misdiagnosed as bullous impetigo, inherited epidermolysis bullosa, herpes, or varicella. Differential diagnosis of stage II includes warts, molluscum contagiosum, and epidermal nevus syndrome. Any condition with 'linear and swirled' pigmentation overlaps with stage III. Stage IV resembles scarring, vitiligo, or other hypopigmentations with localized alopecia. Note that chromosomal mosaicism can manifest swirled and linear pigmentation abnormalities in both males and females. Additional reported differential diagnoses are Naegeli-Franceschetti-Jadassohn syndrome and Norrie's disease.\nAntenatal diagnosis\nFertility is normal except for the miscarriage of affected males. Genetic prenatal diagnosis is available.\nGenetic counseling\nIP is inherited X-linked dominantly. An affected woman has a 50% risk of having affected children. Live-born affected males should be checked for a 47,XXY karyotype.\nManagement and treatment\nTreatment is symptomatic, including standard management of blisters (not opening them and avoidance of trauma), topical treatment (medication, oatmeal baths) and addressing infections (as in cellulitis). Dental abnormalities should be managed by a pedodontist in combination with speech therapy and a pediatric nutritional program as needed. Appropriate specialists are required for RNV monitoring and treatment (cryotherapy and laser photocoagulation) and regular procedures should be followed if retinal detachment occurs. Early retinal angiograms may be indicated. Neurological involvement necessitates a pediatric neurologist, whereas developmental screening and additional complementary therapy may be recommended in cases with developmental delay.\nPrognosis\nLife expectancy is normal. Those without neonatal CNS abnormalities typically have normal physical and cognitive development.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Angela SCHEUERLE"}
{"Disease Name": "Indeterminate cell histiocytosis", "Disease Definition": "A rare neoplastic disease characterized by multiple, and on occasion single, asymptomatic, smooth, red-brown papulonodules located on the face, neck, trunk and/or extremities which present a nonepidermotrophic histiocytic infiltrate with immunohistochemical features of both Langerhans and non-Langerhans cells (i.e. immunopositive for S100 protein and CD1a in the absence of Birbeck granules and langerin expression).", "ORPHA ID": 158019, "Summary": ""}
{"Disease Name": "Indolent systemic mastocytosis", "Disease Definition": "A rare, usually benign, chronic, form of systemic mastocytosis (SM) characterized by an abnormal accumulation of neoplastic mast cells (MCs) mainly in the bone marrow (BM) but also in other organs or tissues such as preferably the skin.", "ORPHA ID": 98848, "Summary": "Epidemiology\nIndolent SM (ISM) represents 90% of all cases of SM for which the prevalence in Europe is estimated between 1/7,700 and 1/10,400.\nClinical description\nISM mainly affects adults and typically presents with skin lesions (ISM+), usually in the form of urticaria pigmentosa (UP), while only a few patients have no skin lesions (ISM-). In addition, ISM patients frequently suffer from MC mediator-related symptoms, including pruritus, flushing, syncope, headache and gastro-intestinal (GI) events (vomiting, diarrhea, abdominal pain). Isolated BM mastocytosis (BMM) is a provisional subcategory of ISM typically characterized by absence of cutaneous lesions of ISM and normal to slightly elevated basal tryptase levels. In most patients with BMM, the KIT D816V allele burden in the peripheral blood is low. A BM smear typically reveals small-sized clusters and aggregates of MCs. In both ISM and BMM, patients have a high risk to develop severe anaphylactic reactions to various exogenous substances (triggers/allergens) such as insect bites. Presentation of severe osteoporosis or even spontaneous fractures is also possible.\nEtiology\nAlthough the etiology of ISM is not fully understood, an activating mutation of KIT, usually KIT D816V, is found in the MCs of virtually all ISM cases. This mutation probably accounts for the abnormal accumulation of MCs in organ(s)/tissue(s). In some cases, the mutation is found primarily in the neoplastic MC compartment; in other cases, the mutation may be detected in other mature BM and peripheral blood cells such as basophils, eosinophils, neutrophils, as well as B- and T-lymphocytes. Furthermore, precursors of erythroid and myeloid cells as well as CD34+ progenitors may carry the KIT D816V mutation, suggesting the involvement of a pluripotent stem cell.\nDiagnostic methods\nSM diagnosis is established using the WHO consensus criteria and is subsequently categorized according to the presence of B-findings and C-findings. In ISM and BMM there are neither B-findings, nor C-findings.\nDifferential diagnosis\nDifferential diagnoses include all the other forms of SM as well as other causes of MC activation syndromes (MCAS): primary (clonal, but not fulfilling SM diagnostic criteria) MCAS; secondary MCAS where an IgE-dependent allergy or another reactive inflammatory disease process is present; and idiopathic MCAS where neither clonal MC nor an IgE-dependent allergy or another underlying condition/disease can be documented. Additional differential diagnoses include other forms of mastocytosis (pure cutaneous mastocytosis, mast cell sarcoma), endocrine disorders (adrenal tumors, VIPoma, gastrinoma), some gastrointestinal pathologies. In ISM-, the differential diagnosis is BMM. It should also be possible to distinguish Waldenström disease.\nManagement and treatment\nIndolent SM patients, as well as those with BMM, usually only require symptomatic treatments. The main objective is to reduce the symptoms of MC activation, such as pruritus, flushes and gastrointestinal cramps. In case of pruritus or skin manifestations, antihistamines H1 (anti-H1) are used. For GI tract manifestations, anti-H2 are effective and can be combined with anti-H1, with di-sodium cromoglycate or with leukotriene inhibitors. Corticoids can suppress antihistamines recalcitrant symptoms. Epinephrine is indicated for hypotension, which may be spontaneous or observed after an insect bite. Patients should be trained to self-administer injectable epinephrine. Of note, some SM patients may suffer from bee or wasp venom allergy. In these patients, specific immunotherapy should be administered lifelong to ensure protection. For patients with SM and osteoporosis, biphosphonates are recommended with adequate supplementation of calcium and vitamin D.\nPrognosis\nThe evolution of ISM and of BMM is slow and benign. The prognosis is generally good and life expectancy is similar to that of the general population. However, some of these patients may finally progress to SSM, SM-AHN, ASM or even MCL; multilineage KIT D816V involvement is probably the most important prognostic criterion for progression of ISM to more advanced SM subtypes.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Michel AROCK"}
{"Disease Name": "Indomethacin embryofetopathy", "Disease Definition": "Indomethacin embryofetopathy refers to the manifestations that may be observed in a fetus or newborn when the mother has taken indomethacin, a potent prostaglandin inhibitor and tocolytic agent that can cross placenta, during pregnancy. Reported adverse fetal/neonatal effects include decreased renal function resulting in oligohydramnios, closure of the ductus arteriosus, and delayed cardiovascular adaptation at birth. These effects are usually transient and reversible. Indomethacin may also be a risk factor for cerebral injury (periventricular leukomalacia) and necrotizing enterocolitisin preterm infants.", "ORPHA ID": 1909, "Summary": ""}
{"Disease Name": "Infant botulism", "Disease Definition": "A rare form of botulism, a rare acquired neuromuscular junction disease with descending flaccid paralysis caused by botulinum neurotoxins (BoNTs). It is due to intestinal colonization by Clostridium botulinum leading to toxin-mediated infection with toxemia.", "ORPHA ID": 178478, "Summary": "Epidemiology\nPrevalence is unknown. So far, at least 3,350 cases of infant botulism have been reported worldwide, except in Africa, and it is the most frequently occurring form of botulism in the USA and Argentina.\nClinical description\nThe disease affects infants between one and 52 weeks of age. Incubation is estimated between three and 30 days from the time of exposure to spores, although a case presenting after 38 hours has been reported. Clinical manifestations are similar to other forms of botulism (symmetrical cranial nerve palsy, followed by symmetrical descending flaccid motor paralysis), but infant botulism presentation is characterized by hypotonia, constipation, inability to suck and swallow, weak cry, ptosis, and poor head control. Fever is absent. The onset is subacute to acute and the disease may progress to generalized hypotonia (``floppy babies'') and respiratory failure. Cases of sudden infant death syndrome (SIDS) have been related to infant botulism. An initial presentation mimicking acute abdomen has also been reported.\nEtiology\nThe disease is due to temporary intestinal colonization by spores of C. botulinum type A, B, E, or very rarely by neurotoxigenic strains of C. baratii type F and C. butyricum type E, and in situ toxin production. The spores can reach the intestinal tract by inhalation, or via food. Environmental dust and honey have been identified as the vehicle of spores. Intestinal colonization by Clostridia is believed to occur because normal competitive microflora has not been fully established. After spore germination and toxinogenesis, the BoNT is absorbed into the blood stream and distributed throughout the body, causing the typical manifestations of botulism.\nDiagnostic methods\nDiagnosis is based on clinical presentation; the electromyography (EMG) pattern is characterized by brief, small, abundant motor-unit action potentials (BSAPs). Diagnosis is confirmed by detection of BoNTs in stools or serum or, more frequently, by isolation of BoNT-producing Clostridia in stools.\nDifferential diagnosis\nDifferential diagnosis includes sepsis, dehydration, electrolyte imbalance, intoxication and encephalitis; it also includes metabolic disorders, myopathies, Guillain-Barré syndrome (Miller-Fisher syndrome), infantile spinal muscular atrophy (SMA1), congenital myasthenic syndromes and poliomyelitis (see these terms).\nManagement and treatment\nManagement consists mostly of supportive care, such as respiratory and nutritional support, in an intensive care unit (ICU). Antitoxin therapy with a human-derived Botulinum Immune Globulin (BIG-IV, anti A, B) is available for infants. Antibiotics are not effective and not recommended as they may lead to lysis of vegetative cells of BoNT-producing Clostridia, increasing the amount of free toxin. Complications include respiratory arrest with resultant hypoxic encephalopathy and irreversible brain damage or death, cardiac arrest, inappropriate antidiuretic hormone secretion syndrome with hyponatremia, serum hyposmolality and urinary hyperosmolality, and acute otitis media related to Eustachian tube dysfunction.\nPrognosis\nPrognosis is good in the absence of complications and, with appropriate intensive care, the survival rate is nearly 100% with or without antitoxin therapy.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Lucia FENICIA"}
{"Disease Name": "Infantile apnea", "Disease Definition": "Infantile apnea is a cessation of respiratory air flow that may affect newborns or older children because of neurological impairment of the respiratory rhythm or obstruction of air flow through the air passages. The symptoms include cyanosis, pallor or bradycardia and snoring in case of obstructive apnea.", "ORPHA ID": 70590, "Summary": ""}
{"Disease Name": "Infantile bilateral striatal necrosis", "Disease Definition": "Infantile bilateral striatal necrosis (IBSN) comprises several syndromes of bilateral symmetric spongy degeneration of the caudate nucleaus, putamen and globus pallidus characterized by developmental regression, choreoathetosis and dystonia progressing to spastic quadriparesis. IBSN can be familial or sporadic (see these terms).", "ORPHA ID": 1576, "Summary": "Epidemiology\nThe prevalence of the sporadic form has been estimated at 1-9/1,000,000 and prevalence of the familial form has been estimated at less than 1/1,000,000.\nClinical description\nThe age of onset of familial IBSN varies between 7 months and 15 months, whereas sporadic IBSN can occur any time from the neonatal period through childhood and even in adolescence. Clinical features include choreoathetosis, dystonia, rigidity, spasticity, dysphagia, optic atrophy, intellectual deficit, developmental regression of motor and verbal skills, failure to thrive, myoclonus, quadriparesis, cerebellar ataxia and nystagmus. The familial form has an insidious onset and a slowly progressive downhill course, while the sporadic form is associated with abrupt neurologic dysfunction following an acute systemic febrile illness such as a mycoplasma, measles or streptococcus infection.\nEtiology\nAutosomal recessive IBSN is caused by mutation in the NUP62 gene (19q13.33) and mitochondrial IBSN is caused by mutation in the ATP synthase-6 gene (MTATP6).\nDiagnostic methods\nDiagnosis is based on clinical observation of choreoathetoid movements of the face, trunk and extremities and evidence of basal ganglia degeneration on CT and MRI images.\nDifferential diagnosis\nDifferential diagnoses include Wilson's disease, acute disseminated encephalomyelitis, neurodegeneration with brain iron accumulation, Leigh disease, juvenile Huntington chorea, methylmalonic aciduria, guanidinoacetate methyltransferase deficiency, glutaric acidemia I (see these terms), carbon monoxide intoxication, small vessel arteritis and trauma.\nAntenatal diagnosis\nAntenatal diagnosis and genetic counseling is offered to families of affected patients.\nGenetic counseling\nFamilial IBSN can be inherited as an autosomal recessive or mitochondrial disorder.\nManagement and treatment\nThere is no standard therapy for familial IBSN. Treatment with oral biotin has been observed to slow disease progress initially. Treatment for the sporadic form is based on treatment of the causal infection.\nPrognosis\nPrognosis for the familial form is usually poor with patients progressing to spastic quadriparesis followed by death, usually due to infection. For the sporadic form, prognosis is variable, with either gradual improvement in symptoms and complete recovery, observed after recovery from the infection, or severe neurological sequelae.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Rachel STRAUSSBERG"}
{"Disease Name": "Infantile cerebellar-retinal degeneration", "Disease Definition": "A rare, neurodegenerative disorder characterized by an early onset of truncal hypotonia, variable forms of seizures, athetosis, severe global developmental delay, intellectual disability and various ophthalmologic abnormalities, including strabismus, nystagmus, optic atrophy and retinal degeneration.", "ORPHA ID": 313850, "Summary": ""}
{"Disease Name": "Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly", "Disease Definition": "Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly is a rare, central nervous system malformation syndrome characterized by progressive microcephaly with profound motor delay and intellectual disability, associated with hypertonia, spasticity, clonus, and seizures, with brain imaging revealing severe cerebral and cerebellar atrophy, and poor myelination.", "ORPHA ID": 402364, "Summary": ""}
{"Disease Name": "Infantile choroidocerebral calcification syndrome", "Disease Definition": "A rare syndromic intellectual disability characterized by severe intellectual disability and calcification of the choroid plexus, associated with elevated cerebrospinal fluid protein concentration. Additional signs and symptoms include strabismus, increased deep tendon reflexes, and foot deformities, among others. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 1313, "Summary": ""}
{"Disease Name": "Infantile convulsions and choreoathetosis", "Disease Definition": "Infantile Convulsions and paroxysmal ChoreoAthetosis (ICCA) syndrome is a neurological condition characterized by the occurrence of seizures during the first year of life (Benign familial infantile epilepsy ; see this term) and choreoathetotic dyskinetic attacks during childhood or adolescence.", "ORPHA ID": 31709, "Summary": "Epidemiology\nThis disorder is rare but the exact prevalence is unknown.\nClinical description\nBenign familial infantile epilepsy begins at 3 to 12 months of age with a family history of the same type of seizures. Seizures are afebrile, partial or sometimes generalized, and normally disappear after the first year of life. During childhood or adolescence, affected individuals present with paroxysmal kinesigenic dyskinesia with frequent and recurrent episodic choreathetotic or dystonic movements that last less than 1 minute. The attacks are triggered by the initiation of voluntary movements or startle. The association with other paroxysmal disorders such as migraine, with or without aura, hemiplegic migraine, episodic ataxia and tics has also been described. Psychomotor development is normal.\nEtiology\nThe genetic loci of ICCA syndrome have been described on chromosomes 16p11.2-q12.1, 16q13-q22.1 and 3q29-29. Mutations in the Proline-rich transmembrane protein 2 (PRRT2) gene, located on 16p11.2, have recently been found in families affected by ICCA syndrome. This gene encodes a membrane protein that interacts with the presynaptic protein SNAP-25 but the mechanism leading to the disease remains unknown.\nDiagnostic methods\nThe diagnosis is mainly clinical, based on the appearance of infantile convulsions with benign evolution followed by kinesigenic dyskinesia attacks later on. Genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other paroxysmal dystonias such as paroxysmal exertion-induced dyskinesia and paroxysmal non-kinesigenic dyskinesia (see these terms) triggered by drugs or food intake (such as caffeine and alcohol).\nGenetic counseling\nICCA syndrome can present as sporadic or familial; in the latter case, it is transmitted as an autosomal dominant trait that can be variably expressed within the same family.\nManagement and treatment\nAntiepileptic drugs, mainly phenytoin or carbamazepine, are effective in controlling seizures and dyskinesia during the active phase of the disorder.\nPrognosis\nICCA has a good outcome. Without treatment, dyskinetic attacks tend to disappear during adulthood.\n\n                            Last update: \n                            July 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Federico VIGEVANO"}
{"Disease Name": "Infantile digital fibromatosis", "Disease Definition": "A rare, benign, superficial fibromatosis characterized by firm, pinkish to flesh-colored, solitary or multiple nodular growths, typically less than 2 cm in size. They occur on the dorsal or lateral aspect of fingers and toes and have a tendency to recur. Histology reveals bland intradermal spindle cells with spherical perinuclear inclusion bodies.", "ORPHA ID": 199267, "Summary": ""}
{"Disease Name": "Infantile dystonia-parkinsonism", "Disease Definition": "Infantile dystonia-parkinsonism (IPD) is an extremely rare inherited neurological syndrome that presents in early infancy with hypokinetic parkinsonism and dystonia and that can be fatal.", "ORPHA ID": 238455, "Summary": "Epidemiology\nThe prevalence is unknown. Only eight cases have been reported to date.\nClinical description\nThe disease presents soon after birth with irritability and feeding difficulties, followed by progressive parkinsonism (manifesting with resting tremor and bradykinesia), dystonia, axial hypotonia, limb hypertonicity and pyramidal tract signs. Clinically it can resemble cerebral palsy. Global developmental delay and impaired motor development occur during childhood, and patients can have trouble communicating. Treatment with L-dopa is ineffective, and death was reported in one case.\nEtiology\nIPD is caused by mutations in the SLC6A3 gene (5p15.33), which encodes a human dopamine transporter mediating the active reuptake of extracelluar dopamine. Mutations in this gene lead to a reduction in the level of mature dopamine transporter and therefore an impairment in dopaminergic neurotransmission.\nGenetic counseling\nIPD is inherited in an autosomal recessive manner. Genetic counseling is possible and is recommended.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "Infantile epileptic spasms syndrome", "Disease Definition": "A rare epilepsy syndrome characterized by onset of epileptic spasms in infants between 2 and 12 months of age, and rarely up to 24 months. Infants may have no antecedent history, or a history reflecting the underlying cause. The classical triad of epileptic spasms, hypsarrhythmia and developmental stagnation or regression is historically referred to as West syndrome.", "ORPHA ID": 3451, "Summary": "Epidemiology\nThe estimated birth prevalence is between 1/1,650-20,000. Both sexes are affected, with a higher incidence in males.\nClinical description\nEpileptic spasms are the typical type of seizures observed. They consist of brief tonic contractions of axial muscles, each typically lasting less than 3 seconds, which may be flexor, extensor or mixed. These usually occur in series or clusters, with increasing prominence of the motor features through the cluster, often over a period of minutes (though clusters may last 30 minutes or longer) and are often seen on awakening. Spasms may be symmetric or asymmetric and some might be subtle, with minor head nods, eye or chin movements. Prior to onset of spasms, development can be normal or abnormal depending on etiology. Developmental delay, arrest or regression is typically seen with the onset of spasms. Isolated regression in visual attention or altered social responsiveness may occur in the days or weeks preceding onset of spasms. Developmental plateauing and regression typically worsen without rapid, effective treatment. Infantile spasms syndrome may have different etiologies and can be a feature of other syndromes such as Down syndrome, tuberous sclerosis complex, inverted duplicated chromosome 15 syndrome, and rarely metabolic diseases.\nEtiology\nPathogenic variants in genes and chromosomal abnormalities have been associated with infantile spasms syndrome; amongst syndromes frequently featuring infantile spasms, they include STXBP1, TSC1, TSC2 and trisomy 21. Other common genetic etiologies include ARX, CDKL5, SPTAN1. Structural abnormalities include acquired antenatal and perinatal lesions and malformations of cortical development.\nDiagnostic methods\nDiagnosis is based on the presence of epileptic spasms, which may be witnessed in person or observed in home video and should be confirmed by electroencephalography (EEG) /video-EEG with electromyography (EMG). Interictal EEG shows either hypsarrhythmia that is observed in the awake and/or sleep recording, or focal and multifocal epileptic anomalies with a less disorganized background. The ictal recording is characterized by a fast activity that might precede a high amplitude, generalized sharp or slow wave followed or super-imposed by low amplitude. EMG helps to distinguish epileptic spasms from myoclonic seizures and tonic seizures. Neuroimaging is useful to determine the syndrome etiology: MRI is abnormal in half to two-thirds of children and can show either acquired or congenital focal, multifocal or diffuse lesions. Metabolic investigations exclude metabolic diseases. Genetic studies may include chromosomal microarray, gene panels or exomes and should be considered in all patients mainly those without a known acquired structural etiology.\nDifferential diagnosis\nBrief paroxysmal events which occur in clusters, both epileptic and non-epileptic, should be differentiated from epileptic spasms. These include myoclonic epilepsy in infancy, hyperekplexia, shuddering, infantile self-stimulation and gastro-esophageal reflux (Sandifer syndrome).\nGenetic counseling\nCounseling is important for subsequent pregnancies when a genetic etiology is identified. The pattern of inheritance depends on the etiology.\nManagement and treatment\nFirst line pharmacological treatment is vigabatrin or a combination of corticosteroids and vigabatrin. Treatment should be introduced as early as possible when the diagnosis is established. Early referral to a tertiary epilepsy center should be considered in order to identify candidates suitable for surgery.\nPrognosis\nInfantile Spasms syndrome may evolve to other epilepsy types or syndromes, including Lennox-Gastaut syndrome, or drug-resistant focal epilepsies. The majority of infants have a poor developmental outcome, regardless of seizure outcome. Severity of developmental delay relates predominantly to etiology and time to treatment from spasm onset. In a small subgroup, patients can have a full recovery with freedom from spasms and no cognitive impact.\n\n                            Last update: \n                            April 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Rima NABBOUT | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Infantile epileptic-dyskinetic encephalopathy", "Disease Definition": "A rare monogenic disease with epilepsy characterized by developmental delay and infantile spasms in the first months of life, followed by chorea and generalized dystonia and progressing to quadriplegic dyskinesia, recurrent status dystonicus, intractable focal epilepsy and severe intellectual disability.", "ORPHA ID": 364063, "Summary": ""}
{"Disease Name": "Infantile glycine encephalopathy", "Disease Definition": "Infantile glycine encephalopathy is a mild to severe form of glycine encephalopathy (GE; see this term), characterized by early hypotonia, developmental delay and seizures.", "ORPHA ID": 289860, "Summary": "Epidemiology\nThe prevalence of infantile glycine encephalopathy is not known. Infantile cases are less frequent than the classical neonatal form of GE (neonatal GE; see this term).\nClinical description\nPatients present with infantile-onset seizures and variable psychomotor delay after initially normal development, and often have a relatively long history of hypotonia. Seizures of any type are found in less than half of patients and some develop choreoathetosis. Developmental delay mostly affects language and behavioral problems are sometimes found including temper tantrums, irritability, aggressiveness and rage. Attention deficit-hyperactivity disorder (AD-HD) is also sometimes found. Patients do not have lethargy or coma in the neonatal period, unlike those with neonatal GE. The course may be mild or severe (50% of patients in each case).\nEtiology\nMutations in two genes are known to cause glycine encephalopathy: GLDC (9p22) and AMT (3p21.2-p21.1).\nGenetic counseling\nInfantile GE is inherited in an autosomal recessive manner.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                             Shigeo KURE"}
{"Disease Name": "Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder with complex I and IV deficiency characterized by hypertrophic cardiomyopathy, hepatic steatosis with elevated liver transaminases, exercise intolerance and muscle weakness. Neuro-opthalmological features (hemiplegic migraine, Leigh-like lesions on brain MRI, pigmentary retinopathy) have been reported later in life.", "ORPHA ID": 352563, "Summary": ""}
{"Disease Name": "Infantile hypophosphatasia", "Disease Definition": "A rare, severe, genetic form of hypophosphatasia (HPP) characterized by infantile rickets without elevated serum alkaline phosphatase (ALP) activity and a wide range of clinical manifestations due to hypomineralization.", "ORPHA ID": 247651, "Summary": "Epidemiology\nThe prevalence is not known. About 160 cases have been reported to date.\nClinical description\nIndividuals with infantile-HPP may be normal at birth. Clinical signs resembling rickets are generally found between birth and six months of age. Initial manifestations may include irritability, poor feeding, failure to thrive, hypotonia, and more rarely seizures. Other clinical features include growth failure, short stature, blue sclerae, bone hypomineralization (softening or thinning of the skull, rachitic ribs, scoliosis, thickening of wrists and ankles and bowing of long bones), craniosynostosis (possibly with increased intracranial pressure), lax ligaments, and hypercalciuria/hypercalcemia. Some patients have premature loss of deciduous teeth. Kidney damage (nephrocalcinosis due to hypercalciuria) is reported in some older infants. Severity is variable but many affected patients are at risk of respiratory failure due to rachitic deformities of the chest within the first year of life. There may be some clinical overlap with the moderate form, classed as childhood-onset HPP.\nEtiology\nLoss-of-function mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. Most patients with the infantile form have two ALPL mutations.\nDiagnostic methods\nDiagnosis is based on clinical examination, alkaline phosphatase assay and genetic testing.\nDifferential diagnosis\nThe main differential diagnosis is osteogenesis imperfecta.\nAntenatal diagnosis\nAlthough not typically picked up in ultrasound, there is evidence to suggest affected individuals may present prenatally with radiographic findings of limb bowing, limb shortening and/or skeletal hypomineralization. Genetic prenatal diagnosis may be offered to at risk pregnancies where the genetic mutation has been previously identified in an affected family member.\nGenetic counseling\nAn autosomal recessive pattern of inheritance is mostly reported. Few cases may be dominantly inherited. Genetic counseling should be offered to affected families. Currently, there is no identified geno-phenotype relationship and individuals inheriting a pathogenic mutation may express any form of HPP (perinatal lethal to odontoHPP).\nManagement and treatment\nAsfotase alfa is approved (Europe and USA) for enzyme replacement therapy (ERT) in patients with pediatric-onset hypophosphatasia and is associated with healing of the skeletal manifestations of hypophosphatasia as well as improved respiratory and motor function.\nPrognosis\nPrognosis depends on the organs affected and timely intervention. Currently there is no data on the long term prognosis when treated with ERT.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Severine BACROT  - Dr Etienne MORNET"}
{"Disease Name": "Infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by infantile hypotonia, congenital ophthalmic anomalies (including strabismus, esotropia, nystagmus, and central visual impairment), global developmental delay and intellectual disability, behavioral abnormalities, and movement disorder (such as dystonia, chorea, hyperkinesia, stereotypies). Mild facial dysmorphism and skeletal deformities have also been reported. EEG testing shows marked abnormalities in the absence of overt epileptic seizures.", "ORPHA ID": 522077, "Summary": ""}
{"Disease Name": "Infantile inflammatory bowel disease with neurological involvement", "Disease Definition": "A rare genetic disease characterized by infantile onset of severe inflammatory bowel disease manifesting with bloody diarrhea and failure to thrive, and central nervous system disease with global developmental delay and regression, impaired speech, hypotonia, hyperreflexia, and epilepsy. Brain imaging shows global cerebral atrophy, thin corpus callosum, delayed myelination, and posterior leukoencephalopathy. Cases with recurrent infections and impaired T-cell responses to stimulation, as well as decreased T-cell subsets, have been reported.", "ORPHA ID": 565788, "Summary": ""}
{"Disease Name": "Infantile LAD-like disease due to RAC2 deficiency", "Disease Definition": "Neutrophil immunodeficiency syndrome is a primary immunodeficiency characterized by neutrophilia with severe neutrophil dysfunction, leukocytosis, a predisposition to bacterial infections and poor wound healing, including an absence of pus in infected areas.", "ORPHA ID": 183707, "Summary": "Epidemiology\nPrevalence is unknown but, to date, two cases have been reported.\nClinical description\nNeutrophil immunodeficiency syndrome presents as similar to leukocyte-adhesion deficiency (LAD; see this term), however there is no evidence of deficiency in the CD11b/CD18 complex.\nEtiology\nThe disease is due to a point dominant negative mutation in the RAC2 gene causing decreased Rac2 protein expression and a defect in a signaling pathway controlling shape change/motility of neutrophils as well as assembly and activation of NADPH oxidase.\nGenetic counseling\nThe mode of transmission is unknown.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Daniel AMBRUSO"}
{"Disease Name": "Infantile mercury poisoning", "Disease Definition": "Infantile mercury poisoning is a rare intoxication affecting children, most commonly characterized by erythema of the hands, feet and nose, edematous, painful, pink to red, desquamating fingers and toes, bluish, cold and wet extremities, excessive sweating, irritability, photophobia, muscle weakness, diffuse hypotonia, paresthesia, hypertension and tachycardia, due to elemental, organic or inorganic mercury exposure. Additional manifestations include alopecia, loss of appetite, excessive salivation with red and swollen gums, tooth and nail loss and insomnia.", "ORPHA ID": 247165, "Summary": ""}
{"Disease Name": "Infantile multisystem neurologic-endocrine-pancreatic disease", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability characterized by global developmental delay, postnatal microcephaly, intellectual disability, ataxia, sensorineural hearing loss, and exocrine pancreatic insufficiency. More variable manifestations include hypotonia, growth retardation, peripheral demyelinating neuropathy, dysmorphic facial features, and additional endocrine abnormalities. Brain imaging may show progressive cerebellar atrophy in some patients.", "ORPHA ID": 456312, "Summary": ""}
{"Disease Name": "Infantile myofibromatosis", "Disease Definition": "A rare benign soft tissue tumor characterized by the development of nodules in the skin, striated muscles, bones, and in exceptional cases, visceral organs, leading to a broad spectrum of clinical symptoms. It contains myofibroblasts.", "ORPHA ID": 2591, "Summary": "Epidemiology\nThe estimated prevalence is 1/150,000 live births.\nClinical description\nInfantile myofibromatosis (IM) presents at birth or develops shortly thereafter, with 90% of cases occurring before the age of 2 years. IM is characterized by solitary or multiple nodules that are firm, flesh-colored to purple (''myofibroma''), and usually painless (except in case of compression of adjacent nerves). Tumors are located in the skin, subcutaneous tissue, striated muscles and in exceptional cases, visceral organs or bones. There are 4 patterns of clinical presentation: solitary (single lesion affecting the skin and/or muscles in the head, neck, or trunk (75% cases)); congenital multiple (multicentric limited to skin and muscles); congenital multiple with single visceral involvement; and congenital multiple with multiple visceral involvement (multiple lesions of skin and/or muscles, bones, lungs, heart and gastrointestinal tract). Rarely, prenatal diagnosis could be evoked.\nEtiology\nMost of these tumors are sporadic and isolated. Rare familial cases of IM have been described and 2 genes have been identified as disease causing:  PDGFRB and NOTCH3 which encode PDGFRB and NOTCH3 respectively. PDGFRB is a tyrosine kinase receptor for platelet derived growth factors which are mitogens for cells of mesenchymal origin. PDGFRB expression is up regulated by NOTCH3. This suggests that genetic defects in the 2 genes are involved in the same mechanism.\nDiagnostic methods\nDiagnosis is evoked partly on family history and physical examination at this age. Myofibromas are identified through ultrasound (mass with an anechoic center), MRI (low signal on T1-weighted imaging and high or low signal intensity areas on T2-weighted imaging) and less frequently CT (mass with peripheral enhancement and calcifications). Histopathology remains the gold standard for the diagnosis of IM. Biopsy reveals interlacing fascicles of spindle cells (myofibroblasts) in the periphery. Immunochemistry reveals vimentin and smooth muscle actin expression while vascular markers (S100 and CD34) are negative. In some cases, molecular tumor analysis could found a PDGFRB gene mutation.\nDifferential diagnosis\nDifferential diagnosis in case of solitary lesion includes hemangioma, lymphangioma, neurofibroma, infantile fibrosarcoma, Langerhans cell histiocytosis, inflammatory myofibroblastic tumor, desmoid tumors and dermoid or epidermoid tumors.\nAntenatal diagnosis\nPrenatal diagnosis is achieved by ultrasound examination and confirm by fetal MRI.\nGenetic counseling\nIM is mostly isolated and sporadic. In cases of familial and multifocal lesions, IM can be inherited as an autosomal recessive or dominant trait (incomplete penetrance and variable expressivity).\nManagement and treatment\nDue to the benignity of the lesion, therapies without long term effects are preferred. For lesions affecting the skin and/or muscles, treatment is not recommended and a wait-and-see policy is proposed (tendency towards spontaneous regression). Radical surgical excision is required if: vital organs are involved, lesions are in threatening sites, or lesions are symptomatic. In cases of incomplete resection, re-excision can be proposed later. Standard therapy is low dose weekly methotrexate and vinblastine and is indicated for multifocal progressive life threatening lesions. Other treatments such as conventional chemotherapy (vincristine, D-actinomycin, and cyclophosphamide) should be kept for patients with rapid symptomatic progression because of the long-term risks of secondary malignancy development. PDGFRB inhibitors have not already been studied in such disease.\nPrognosis\nIn the majority of cases, which lack visceral involvement, prognosis is excellent and spontaneous regression is often observed. On the other hand, the presence of visceral lesions is associated with a significantly poor outcome and a mortality rate of up to 70%, in the absence of therapy. Death is generally related to organ compression and cardiopulmonary and gastrointestinal involvement.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Christine BODEMER  - Dr Daniel ORBACH"}
{"Disease Name": "Infantile nephronophthisis", "Disease Definition": "A rare clinical variant of hereditary nephronophthisis characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before 3 years of age.", "ORPHA ID": 93591, "Summary": "Epidemiology\nThe prevalence of the infantile form is unknown. This rare kidney disorder affects both male and female; there is no difference in risk between ethnic groups.\nClinical description\nInfantile nephronophthisis can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with reduced kidney function beginning within 1 year after birth and progressing to ESRD before 3 years of age. The disease is characterized by severe hypertension, anemia, skeletal abnormalities and increased thirst and urination. Extra renal involvement may include hepatic fibrosis, recurrent bronchial infections, situs inversus and valvular or ventricular septal defects. Renal ultrasound findings include hyperechogenic kidneys with size ranging from reduced to enlarged. Histological findings include diffuse interstitial fibrosis, tubular atrophy, renal cortical microcysts, dilatation of proximal tubules and Bowman space, and absence of a thickened tubular basement membrane.\nEtiology\nMonogenic causal mutations have been identified in several genes involved in the Inversin compartment, which is localized at the proximal segment of the cilia. The most common pathogenic variants are found in the genes INVS (9q31.1) encoding Inversin, a protein that has a role in kidney development, and NPHP3 (3q22.1) encoding nephrocystin-3. Other pathogenic variants include NEK8  (17q11.2), TTC21B (2q24.3), ZNF423 (16q12.1), and CEP83 (12q22).\nDiagnostic methods\nThe diagnosis is either by renal biopsy or genetic testing. Investigational work-up may include blood tests for anemia, electrolyte imbalances and metabolic panel, and renal or abdominal ultrasound. Involvement of other organs should be investigated and may include an eye examination, neuroimaging, and a neurological examination.\nDifferential diagnosis\nDifferential diagnosis includes autosomal recessive polycystic kidney disease, early-onset autosomal dominant polycystic kidney disease, and renal hypodysplasia.\nAntenatal diagnosis\nAntenatal diagnosis is possible where a pathogenic variant has been identified in a family.\nGenetic counseling\nInheritance is autosomal recessive. Homozygous or compound heterozygous mutations can be present in the patient. The parents are obligate heterozygotes (carriers) for a pathogenic variation and are asymptomatic with no risk of developing the disorder. Each sib of an affected individual has 50% risk to be an asymptomatic carrier, 25% to be affected, and 25% to be unaffected and not a carrier. Doubtless the offspring of affected individuals will be obligate carriers for a nephronophthisis-related pathogenic variant.\nManagement and treatment\nThere is no specific therapy. The management is supportive to maintain fluid and metabolic balance including correction of water and electrolyte imbalances as well as anemia, hypertension and proteinuria treatment if necessary. The management of patients includes growth hormone therapy in children who meet the criteria for treatment. For the ESRD management, dialysis, and isolated kidney/combined liver-kidney transplant is necessary.\nPrognosis\nPatients progress to ESRD before the age of 3 years. Despite the risk of complications, transplant outcomes are excellent with no recurrence of tubular injury\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Davide MENEGHESSO | ERKNet* - Dr Luisa MURER | ERKNet* - Dr Susanna NEGRISOLO | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Infantile nephropathic cystinosis", "Disease Definition": "A subtype of cystinosis characterized by an accumulation of cystine in the organs and tissues, particularly in the kidneys and eyes, and that clinically manifests from infancy with renal Fanconi syndrome, photophobia, hypothyroidism, impaired growth and rickets, in addition to various other systemic effects. Progressive extra-renal manifestations include hypothyroidism, hypogonadism and male infertility, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension, muscle involvement with distal muscle weakness and atrophy, pharyngeal and oral dysfunction, swallowing difficulties, cerebral involvement with hypotonia, speech and walking difficulties, and cerebellar syndrome.", "ORPHA ID": 411629, "Summary": ""}
{"Disease Name": "Infantile neuroaxonal dystrophy", "Disease Definition": "Infantile neuroaxonal dystrophy/atypical neuroaxonal dystrophy (INAD/atypical NAD) is a type of neurodegeneration with brain iron accumulation (NBIA; see this term) characterized by psychomotor delay and regression, increasing neurological involvement with symmetrical pyramidal tract signs and spastic tetraplegia. INAD may be classic or atypical and patients present with symptoms anywhere along a continuum between the two.", "ORPHA ID": 35069, "Summary": "Epidemiology\nPrevalence is unknown, but more than 150 cases have been described, of which the majority are classic INAD.\nClinical description\nClassic INAD usually presents between ages six months and three years with psychomotor delay and regression, delayed walking or gait disturbance. It is characterized by early truncal hypotonia progressing to tetraparesis (usually spastic but can be areflexic) and dementia. Visual signs, including strabismus, pendular nystagmus, uncoordinated eye movements, optic atrophy and failing vision are generally early and prominent. Seizures occur in a minority. Onset of atypical NAD is usually in early childhood but can be as late as the late teens and progression is slower. As a result of slower progression patients may present with speech delay and neurobehavioral disturbances including impulsivity, poor attention span and emotional lability. Tetraparesis occurs late in the disease and is not necessarily preceded by truncal hypotonia and patients are more likely to have progressive dystonia and dysarthria. Optic atrophy, nystagmus and seizures occur as in classic INAD.\nEtiology\nINAD is caused by mutations in the PLA2G6 gene (22q13.1). The mutations alter phospholipid metabolism and often lead to abnormal iron accumulation in the basal ganglia.\nDiagnostic methods\nThe majority of patients with INAD and atypical NAD develop cerebellar atrophy appreciable on MRI at a relatively early age. This, in the presence of high brain iron or optic atrophy, suggests the diagnosis. Genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include infantile neuronal ceroid-lipofuscinosis, ataxia-telangectasia, and hereditary ataxia (see these terms), although cerebellar atrophy usually presents later for these disorders, other forms of NBIA, including pantothenate kinase-associated neurodegeneration (PKAN; see this term) which is characterized by an ``eye of the tiger'' sign not observed in INAD, infantile GM2 gangliosidosis, Niemann-Pick disease type C, autism and Menkes disease (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible if the disease causing mutations in the family are known.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment is palliative and includes pharmacologic treatment of spasticity and seizures, oral or intrathecal baclofen for those with significant dystonia, physiotherapeutic treatment of spasticity and measures such as gastric feeding tube or tracheostomy to prevent aspiration pneumonia. Iron chelation therapy is not currently recommended.\nPrognosis\nThe progression of classic INAD is usually rapid and many children never learn to walk. Severe spasticity, progressive cognitive decline and visual impairment can result in a vegetative state. Many affected patients do not survive beyond their first decade, but some survive into their teens or later. The life span of atypical NAD is not known but is expected to be longer than that observed in classic INAD.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Allison GREGORY  - Pr Susan HAYFLICK"}
{"Disease Name": "Infantile neurovisceral acid sphingomyelinase deficiency", "Disease Definition": "A rare, autosomal recessive, acid sphingomyelinase deficiency characterized clinically by onset in infancy or early childhood with failure to thrive, hepatosplenomegaly, interstitial lung disease and rapidly progressive neurodegenerative disorders.", "ORPHA ID": 77292, "Summary": "Epidemiology\nThe birth prevalence of acid sphingomyelinase deficiency (combined both Niemann-Pick disease (NPD) types A and B) is estimated between 1/167,000-250,000 in Europe. Niemann-Pick disease type A (NPD-A) is more prevalent in the Ashkenazi Jewish population, where the estimated birth rate is estimated at 1/33,000.\nClinical description\nThe first symptom in NPD-A is hepatosplenomegaly, usually noted in the first few months of life. Other non-neurological findings include feeding problems, failure to thrive, gastrointestinal complaints (e.g., constipation, diarrhea, and vomiting), recurrent respiratory infections, persistently elevated transaminases, and irritability. Early neurological manifestations include muscular hypotonia, weakness and feeding difficulties. Affected infants have decreased linear growth and body weight. By 6 months of age, global development delay becomes evident and regression of developmental milestones is noted. With advancing age, the loss of motor function and the deterioration of intellectual capabilities are progressively debilitating. A classic cherry-red spot of the macula of the retina is eventually present in all affected children after 6 months of age. Interstitial lung disease results in frequent respiratory infections and often respiratory failure. Osteoporosis is common, presumably due to infiltration and poor nutrition.\nEtiology\nNPDA is caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene (locus 11p15.4), leading to decreased activity of acid sphingomyelinase (ASM), which results in lysosomal accumulation of sphingomyelin (SM) and secondary increases in the concentrations of cholesterol and other lipids.\nDiagnostic methods\nThe diagnosis of NPD-A is established by detection of biallelic pathogenic variants in SMPD1 and/or residual acid sphingomyelinase enzyme activity (in peripheral blood lymphocytes, cultured skin fibroblasts or dry blood spots (DBS)). The de-acylated form of sphingomyelin (lyso-SPM) is increased in NPD-A and could be measured in plasma and DBS. Bone marrow examination reveals the histochemical characteristic, ''Niemann-Pick'' foam cells.\nDifferential diagnosis\nDifferential diagnoses include other lysosomal storage diseases such as Gaucher disease, GM1-and GM2-gangliosidosis, Niemann-Pick disease type C, lysosomal acid lipase deficiency, hematologic malignancy, and primary hepatic disease (e.g., fatty liver, autoimmune, chronic hepatitis B-related, cryptogenic cirrhosis).\nAntenatal diagnosis\nPrenatal diagnosis for pregnancies at increased risk is possible by testing of ASM enzyme activity or by DNA analysis if both SMPD1 pathogenic variants in the family are known.\nGenetic counseling\nNPD-A is inherited in an autosomal recessive manner. Genetic counseling should be offered to at-risk couples informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nCurrently, only supportive care is available for patients with NPD-A. The disease is best managed by an interprofessional team that includes a gastroenterologist, endocrinologist, neurologist, and geneticist. Also, family care, nursing support, and social support are an integral part of the management.\nPrognosis\nThe clinical course is characterized by a brief period of normal development followed by a severe neurodegenerative course and death in the first 5 years of life.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Ekaterina ZAKHAROVA"}
{"Disease Name": "Infantile onset panniculitis with uveitis and systemic granulomatosis", "Disease Definition": "A rare granulomatous autoinflammatroy syndrome characterized by infantile-onset, widespread, chronic, recurrent, progressive, lobular panniculitis associated with panuveitis, arthritis and severe systemic granulomatous inflammation.", "ORPHA ID": 251304, "Summary": ""}
{"Disease Name": "Infantile osteopetrosis with neuroaxonal dysplasia", "Disease Definition": "This syndrome is characterized by osteopetrosis, agenesis of the corpus callosum, cerebral atrophy and a small hippocampus.", "ORPHA ID": 85179, "Summary": "Epidemiology\nIt has been described in a brother and a sister born to nonconsanguineous Caucasian parents.\nClinical description\nThe children died at the ages of 1 and 9 months, respectively. Several additional cases combining axonal dystrophy and osteopetrosis have been described.\nEtiology\nThe etiology remains unclear.\nGenetic counseling\nAutosomal recessive inheritance has been suggested.\n\n                            Last update: \n                            March 2009"}
{"Disease Name": "Infantile Refsum disease", "Disease Definition": "Infantile Refsum disease (IRD) is the mildest variant of the peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD- ZSS; see this term), characterized by hypotonia, retinitis pigmentosa, developmental delay, sensorineural hearing loss and liver dysfunction. Phenotypic overlap is seen between IRD and neonatal adrenoleukodystrophy (NALD) (see this term).", "ORPHA ID": 772, "Summary": "Epidemiology\nThe birth prevalence of PBD-ZSS is estimated to be around 1/50,000 in North America and 1/500,000 in Japan. More than ½ of patients with PBD-ZSS have the NALD-IRD forms.\nClinical description\nIRD has an onset at birth or early infancy but manifestations may be subtle enough that diagnosis is not until adulthood. In infancy, symptoms may include nystagmus, hypotonia, sensorineural hearing loss, growth retardation, mild facial dysmorphism, and hepatomegaly. Hepatic dysfunction is first displayed in infants with jaundice and later in some with episodes of intracranial bleeding due to coagulopathy. In childhood, progressive retinitis pigmentosa, developmental deficits and hypotonia are seen. Most achieve motor milestones, though delayed, and communicate in a few words or signs. Osteoporosis and fractures can occur in the less mobile. Adrenal insufficiency and renal calcium oxalate stones can present in older children. Leukodystrophy with loss of previously acquired skills can occur at any age and may stabilize, or progress and be fatal. Atypical presentations (visual and hearing loss with preservation of intellect and cerebellar ataxia with/without peripheral neuropathy) have been described.\nEtiology\nPBD-ZSS is caused by mutations in one of 13 PEX genes encoding peroxins. Mutations in these genes lead to abnormal peroxisome biogenesis.\nDiagnostic methods\nIRD is suspected on physical exam and definitively confirmed with biochemical evaluation. Plasma very-long-chain fatty acid (VLCFA) levels indicate defects in peroxisomal fatty acid metabolism with elevated plasma concentrations of C26:0 and C26:1 and elevated ratios of C24/C22 and C26/C22. Erythrocyte membrane concentrations of plasmalogens C16 and C18 are usually reduced, but can be normal. Plasma pipecolic acid levels and bile acid intermediates (THCH and DHCA) are increased. Occasionally, VLCFA levels and enzymatic assays in fibroblasts can be within the normal range, requiring additional assessment in expert laboratories. Sequence analysis of the 13 PEX genes can be performed. MRI can be used to identify myelin changes.\nDifferential diagnosis\nThe main differential diagnoses include Usher syndrome I and II, other PBD-ZSS disorders (see these terms), single enzyme defects in peroxisome fatty acid beta-oxidation, and disorders that feature severe hypotonia, neonatal seizures, liver dysfunction or leukodystrophy. IRD should not be confused with adult Refsum disease (see this term).\nAntenatal diagnosis\nPrenatal screening of cultured amniocytes and chorionic villus sampling for VLCFA and plasmalogen synthesis is possible. If both disease causing alleles in parents have been identified, prenatal diagnosis can be performed as well as preimplantation genetic diagnosis.\nGenetic counseling\nIRD is inherited autosomal recessively, so genetic counseling is possible.\nManagement and treatment\nThere is no cure for IRD. Cataracts should be removed in early infancy and glasses used. Hearing aids should be provided to those with hearing impairment and cochlear implants considered when hearing loss is profound. Hepatic coagulopathy can be treated with vitamin K supplementation and liver function may improve with primary bile acid therapy. A gastrostomy tube may be necessary to allow for adequate calorie intake. Foods rich in phytanic acid (such as cow's milk) should be restricted. Standard epileptic drugs are used for seizures. Lifelong follow up monitors changes in hearing, vision and liver function.\nPrognosis\nGreat variation is seen with respect to life expectancy, medical complications and preservation of neurological function. Many patients survive childhood, and survival to adulthood is possible.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nancy BRAVERMAN"}
{"Disease Name": "Infantile spasms-broad thumbs syndrome", "Disease Definition": "Infantile spasms-broad thumbs syndrome is a rare neurologic disorder characterized by profound developmental delay, facial dysmorphism (i.e. microcephaly, large anterior fontanel, hypertelorism, downslanting palpebral fissures, beaked nose, micrognathia), broad thumbs and flexion and/or extension spasms. Bilateral cataracts, hypertrophic cardiomyopathy and hydrocele have also been reported. EEG shows hypsarrhythmic features and MRI may reveal partial agenesis of the corpus callosum, mild brain atrophy and/or ventriculomegaly. There have been no further descriptions in the literature since 1990.", "ORPHA ID": 3173, "Summary": ""}
{"Disease Name": "Infantile spasms-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome", "Disease Definition": "A rare, genetic disorder of thiamine metabolism and transport characterized by infantile spasms progressing to symptomatic generalized or partial seizures, severe global developmental delay, progressive brain atrophy, and bilateral thalamic and basal ganglia lesions.", "ORPHA ID": 263410, "Summary": ""}
{"Disease Name": "Infantile systemic hyalinosis", "Disease Definition": "Infantile systemic hyalinosis (ISH) is a very rare disorder belonging to the heterogeneous group of genetic fibromatoses and is characterized by progressive joint contractures, skin abnormalities, severe chronic pain and widespread deposition of hyaline material in many tissues such as the skin, skeletal muscle, cardiac muscle, gastrointestinal tract, lymph nodes, spleen, thyroid, and adrenal glands.", "ORPHA ID": 2176, "Summary": "Epidemiology\nLess than 20 cases have been described in the literature so far.\nClinical description\nThe clinical features are evident either at birth or within the first six months of life. Intrauterine growth retardation and reduced fetal movements have been described in some ISH patients. The main clinical features are painful swollen joint contractures, significant discomfort on handling and reduction of spontaneous movement. Dermal abnormalities include diminished skin elasticity, generalized skin thickening with hyperpigmentation over prominences, small pearly papules (predominantly on the face, scalp, and neck), massive gingival hypertrophy, and fleshy nodules in the perianal region. Susceptibility to infections and intractable diarrhea are common findings. Failure to thrive is characteristic. Osteopenia is often present and results in increased susceptibility to bone fractures. Children with ISH are intellectually normal.\nEtiology\nISH is caused by mutations in anthrax toxin receptor 2 gene (ANTRX2) on chromosome 4q21. Mutations in the same gene cause juvenile hyaline fibromatosis, a similar but milder disease (see this term).\nDiagnostic methods\nDiagnosis is clinical and can be further supported by histological evidence of deposition of amorphous hyaline material in the skin or mucosae.\nDifferential diagnosis\nJuvenile hyaline fibromatosis, Winchester syndrome, lipoid proteinosis (Urbach-Wiethe disease) and mucopolysaccharidosis type II (Hunter's syndrome) should be considered in the differential diagnosis (see these terms).\nGenetic counseling\nISH is transmitted as an autosomal recessive trait.\nManagement and treatment\nThere is no specific treatment for ISH. Physical therapy and nutritional support improve the quality of life of the patients.\nPrognosis\nISH has a progressive course that may lead to death within the first two years of life, mostly due to recurrent respiratory infections and severe diarrhea. In patients that live until adulthood, mobility remains severely restricted by joint contractures.\n\n                            Last update: \n                            June 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Luciano MERLINI"}
{"Disease Name": "Infantile-onset ascending hereditary spastic paralysis", "Disease Definition": "Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a very rare motor neuron disease characterized by severe spasticity of the lower limbs in early life, progression of spasticity to the upper limbs in late childhood, and dysarthria.", "ORPHA ID": 293168, "Summary": "Epidemiology\nThe prevalence and incidence of IAHSP are not known. 17 families accounting for at least 30 cases have been reported to date. The disorder has been described in various ethnic groups.\nClinical description\nAffected patients are normal at birth and early development is mostly unremarkable. They then develop spastic paraplegia, increased reflexes and sustained lower limb stiffness in the first two years of life. By 7 to 8 years of age they also develop progressive weakness and spasticity extending to the upper limbs. Other signs include dysarthria, dysphagia (sometimes with drooling), and slow eye movements. Most become wheel-chair bound by late childhood or early adolescence and some patients have feeding difficulties (swallowing liquids) starting in the second decade. Subsequently, the disease progresses to severe spastic tetraparesis and a pseudobulbar syndrome may be observed. Cognitive function is generally preserved.\nEtiology\nIAHSP appears to be caused by mutations in the ALS2 gene (2q33-q35) encoding alsin, a protein that is abundant in motor neurons. Mutations in this gene are not found in all families with members affected by the disease. Other genes or loci have not been identified to date.\nDiagnostic methods\nDiagnosis is based on the characteristic features of the disorder and on ascending progression. Electrophysiological studies show severe dysfunction of motor evoked potentials. Somatosensory evoked potentials, electromyography and nerve conduction velocities are normal. Magnetic resonance imaging (MRI) is normal in affected children but brain changes are found in older patients. The diagnosis can be confirmed by molecular genetic testing.\nDifferential diagnosis\nDifferential diagnoses include the allelic disorders juvenile primary lateral sclerosis and juvenile amyotrophic lateral sclerosis (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies is possible if the disease-causing mutations have been identified in the family.\nGenetic counseling\nIAHSP is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes and are therefore asymptomatic carriers. Genetic counseling should be provided to affected families.\nManagement and treatment\nThere is currently no specific treatment. Management primarily involves physical and occupational therapy to promote mobility and independence.\nPrognosis\nThe vital prognosis is good with long-term survival in most cases. Quality of life, however, is affected by progressive neurological manifestations and loss of independence.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI"}
{"Disease Name": "Infantile-onset autosomal recessive nonprogressive cerebellar ataxia", "Disease Definition": "A rare, genetic, autosomal recessive cerebellar ataxia disease characterized by nonprogressive cerebellar ataxia, with onset in infancy, manifesting with delayed motor and speech development, gait ataxia, dysmetria, hypotonia, increased deep tendon reflexes, and dysarthria. Additional variable manifestations include moderate nystagmus on lateral gaze, mild spasticity, intention tremor, short stature and pes planus. Brain imaging reveals cerebellar vermis atrophy.", "ORPHA ID": 284332, "Summary": ""}
{"Disease Name": "Infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome", "Disease Definition": "A rare neurologic disease characterized by axonal sensorimotor neuropathy, progressive optic atrophy, cognitive deficit, bulbar dysfunction, seizures, and early hypotonia and feeding difficulties. Additional possible features include dystonia, scoliosis, joint contractures, ocular anomalies, and urogenital anomalies. Brain MRI reveals variable degrees of cerebral atrophy. The disease is fatal in childhood due to respiratory failure.", "ORPHA ID": 457205, "Summary": ""}
{"Disease Name": "Infantile-onset generalized dyskinesia with orofacial involvement", "Disease Definition": "A rare hyperkinetic movement disorder characterized by delayed motor development and infantile onset of axial hypotonia and a generalized hyperkinetic movement disorder, principally with dyskinesia of the limbs and trunk, and facial involvement including orolingual dyskinesia, drooling, and dysarthria. Variable hyperkinetic movements may include a jerky quality, intermittent chorea and ballismus. Brain imaging is normal and cognitive performance is typically preserved.", "ORPHA ID": 494526, "Summary": ""}
{"Disease Name": "Infantile-onset mesial temporal lobe epilepsy with severe cognitive regression", "Disease Definition": "Infantile-onset mesial temporal lobe epilepsy with severe cognitive regression is a rare monogenic disease with infantile-onset pharmacoresistant focal seizures of mesial temporal lobe onset manifesting with unresponsiveness, hypertonia and automatisms and cognitive regression soon after seizure onset leading to severe intellectual disability with behavioral abnormalities.", "ORPHA ID": 391316, "Summary": ""}
{"Disease Name": "Infantile-onset periodic fever-panniculitis-dermatosis syndrome", "Disease Definition": "A rare genetic autoinflammatory syndrome characterized by early-onset of repeated episodes of fever, nodular neutrophil-rich panniculitis, arthralgia, and lipodystrophy. Additional reported features include diarrhea, failure to thrive, lymphadenopathy, and vasculitis. Laboratory examination may reveal elevated serum C-reactive protein and leukocytosis with neutrophilia in the absence of infection.", "ORPHA ID": 500062, "Summary": ""}
{"Disease Name": "Infantile-onset pulmonary alveolar proteinosis-hypogammaglobulinemia", "Disease Definition": "A rare genetic respiratory disease characterized by infantile onset of pulmonary alveolar proteinosis with hypogammaglobulinemia. Patients have normal respiratory function at birth, but subsequently develop recurrent, mainly viral, infections and progressive respiratory failure, often leading to death in infancy or early childhood. Additional reported features include leukocytosis and splenomegaly.", "ORPHA ID": 572428, "Summary": ""}
{"Disease Name": "Infantile-onset spinocerebellar ataxia", "Disease Definition": "Infantile-onset spinocerebellar ataxia (IOSCA) is a hereditary neurological disorder with early and severe involvement of both the peripheral and central nervous systems. It has only been described in Finnish families.", "ORPHA ID": 1186, "Summary": "Epidemiology\nSo far, 24 cases have been reported. In Finland, IOSCA has a population carrier frequency of more than 1:230.\nClinical description\nIOSCA is characterized by very early ataxia, athetosis and reduced tendon reflexes (between 9 and 18 months of age). Ophthalmoplegia and sensorineural hearing loss are diagnosed in childhood. Other features, such as optic atrophy and sensory neuropathy with progressive loss of myelinated fibers in the sural nerve, appear later in the disease course. Hypogonadism may occur in females. Some patients show intellectual deficit. Epilepsy is a late manifestation and seizures may be life-threatening.\nEtiology\nIOSCA is caused by mutations in the C10orf2 gene (10q24) encoding the mitochondrial helicase Twinkle. The c.1523A>G (p.Y508C) causative mutation has been postulated to be a founder mutation. Twenty-one of the reported patients were homozygous for this mutation, and three were compound heterozygotes: c.952G>A/c.1523A>G (two patients) and c.1523A>G/c.1287C>T (one patient). The mutations lead to mtDNA depletion in the brain and the liver, but not in the muscle.\nDiagnostic methods\nThe diagnosis is based on clinical and pathological findings. Studies of sural nerve biopsies reveal an early and rapidly progressive axonal neuropathy. Neuroimaging studies revealing cerebellar atrophy and genetic testing for the c.1523A>G mutation may also help to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include early-onset cerebellar ataxias with sensory axonal neuropathy and epileptic encephalopathy, mitochondrial disorders with axonal neuropathy (such as Friedreich ataxia), progressive external ophthalmoplegia (PEO), juvenile- or adult-onset mitochondrial recessive ataxia syndrome (MIRAS), and POLG-related disorders (see theseterms).\nAntenatal diagnosis\nPrenatal testing may be available for families in which the disease-causing mutations have already been identified.\nGenetic counseling\nIOSCA is inherited in an autosomal recessive manner. Genetic counseling is an important clinical tool for preventing new cases, especially for couples with an affected first child: the risk of having an affected child in further pregnancies is 25%.\nManagement and treatment\nIOSCA patients are often managed by a multidisciplinary team, involving a pediatrician, neurologist, psychiatrist, orthopedic surgeon, physical and occupational therapists, genetic counselor, and social worker. Treatment is symptomatic and may include: (1) hearing aids, speech therapy and sign language for deafness; (2) physical therapy, orthotic devices and orthopedic surgery for sensory axonal neuropathy; (3) walking aids, a wheelchair, physiotherapy and occupational therapy for ataxia; (4) antiepileptic drugs for seizures and (5) antipsychotics and antidepressants for psychiatric symptoms.\nPrognosis\nPrognosis is unfavorable. Patients are wheelchair-bound by adolescence. Early death is common due to severe seizures. The clinical course seems to be more rapid and severe (with death during infancy) in c.952G>A/ c.1523A>G compound heterozygotes.\n\n                            Last update: \n                            April 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen ESPINÓS  - Pr Francesc PALAU"}
{"Disease Name": "Infantile-onset X-linked spinal muscular atrophy", "Disease Definition": "A rare form of spinal muscular atrophy characterized by the neonatal onset of severe hypotonia, areflexia, profound weakness, multiple congenital contractures, facial dysmorphic features (myopathic face with open, tent-shaped mouth), cryptorchidism, and mild skeletal abnormalities (i.e. kyphosis, scoliosis), that is often preceded by polyhydramnios and reduced fetal movements in utero and followed by bone fractures shortly after birth. Muscle weakness is progressive and chest muscle involvement eventually leads to ventilatory insufficiency and respiratory failure.", "ORPHA ID": 1145, "Summary": ""}
{"Disease Name": "Infection-related hemolytic uremic syndrome", "Disease Definition": "A rare type of hemolytic uremic syndrome (HUS) characterized by the triad of hemolytic anemia due to generalized thrombotic microangiopathy, thrombocytopenia, and acute kidney injury, and most commonly occurring after acute gastroenteritis due to Shiga toxin-producing enterohemorrhagic Escherichia coli or Shigella dysenteriae. Other infectious causes of HUS include Streptococcus pneumoniae, HIV, Mycoplasma pneumoniae, Histoplasmosis, and Coxsackie virus.", "ORPHA ID": 544482, "Summary": ""}
{"Disease Name": "Infectious anterior uveitis", "Disease Definition": "A rare ophthalmic disorder characterized by inflammation primarily of the anterior part of the uvea (iris and ciliary body), due to an infectious etiology. Clinical symptoms are pain, redness, photophobia, and variable visual loss. Signs on examination include presence of inflammatory cells in the anterior chamber and anterior vitreous, keratic precipitates, hypopyon, iris nodules, posterior synechiae, and miosis, among others.", "ORPHA ID": 279922, "Summary": ""}
{"Disease Name": "Infectious epithelial keratitis", "Disease Definition": "Infectious epithelial keratitis is a rare, potentially sight-threatening, acquired ocular disease chracterized by corneal epithelium inflammation resulting from viral (mainly Herpes Simplex virus), bacterial, fungic or protist infection, manifesting with variable symptoms, such as conjunctival hyperemia, lacrimation, rapid onset of pain, blurred vision and/or photophobia, depending on the causative agent.", "ORPHA ID": 137593, "Summary": ""}
{"Disease Name": "Infectious panuveitis", "Disease Definition": "A rare ophthalmic disorder characterized by generalized inflammation of all parts of the uveal tract (iris, ciliary body, and choroid), simultaneously involving adjacent vitreous and retina, without any predominant site of inflammation, due to viral, bacterial, fungal, or parasitic infections. Clinical symptoms include pain, photophobia, redness, blurring of vision, and floaters. Signs on examination are lid edema, ciliary injection, chemosis, keratic precipitates, cells in the anterior chamber, hypopyon, iris nodules and neovascularization, posterior synechiae, macular edema, vitreous and retinal hemorrhage, and retinal detachment, among others. Complications may result in visual loss.", "ORPHA ID": 279925, "Summary": ""}
{"Disease Name": "Infectious posterior uveitis", "Disease Definition": "A rare ophthalmic disorder characterized by inflammation of the posterior uveal tract (retina and choroid), due to an infectious etiology. Presenting symptoms are decreased visual acuity, visual field defects, floaters, photopsia, photophobia, and occasionally pain. Signs on examination include conjunctival injection, keratic precipitates, retrolental cells, inflammatory infiltrates on the retina, macular edema, and peripheral retinal neovascularization, among others. Complications (such as cataracts, band keratopathy, glaucoma, cystoid macula edema, and retinal detachment) may lead to permanent vision loss.", "ORPHA ID": 279919, "Summary": ""}
{"Disease Name": "Infective dermatitis associated with HTLV-1", "Disease Definition": "Infective dermatitis associated with HTLV-1 is a rare and severe chronic disease characterized by recurrent chronic eczema (with erythematous, scaly and crusted lesions) mainly affecting seborrheic areas (e.g. scalp, forehead, eyelids, paranasal and periauricular skin, neck, axillae, and groin), a generalized fine papular rash, chronic nasal discharge with crusting of the anterior nares, and non-virulent Staphylococcus aureus or beta-hemolytic Streptococcus infections, thought to be a result of HTLV-1-induced immunosuppression. Lymphadenopathy, anemia, mild to moderate pruritus and increased incidence of other infections (e.g. crusted scabies) have also been reported in some patients. Patients may subsequently develop other HTLV-1 associated conditions such as adult T-cell leukemia/lymphoma and tropical spastic paraparesis (see these terms).", "ORPHA ID": 289347, "Summary": ""}
{"Disease Name": "Infective endocarditis", "Disease Definition": "A rare bacterial infectious disease characterized by infection of a native or prosthetic heart valve, the endocardial surface, or an indwelling cardiac device. Main causative agents are Gram-positive bacteria, most commonly Staphylococcus and Streptococcus species. Signs and symptoms include high fever or prolonged subfebrile state, excessive sweating, malaise, asthenia, arthralgia, myalgia, weight loss, headache, nausea, dyspnea, cough, heart murmurs, and petechiae of the skin. The most common complications are embolism in different organs and ischemic stroke, sepsis, heart failure, and renal failure.", "ORPHA ID": 570762, "Summary": ""}
{"Disease Name": "Inferior vena cava interruption without azygos continuation", "Disease Definition": "A rare congenital anomaly of the inferior vena cava characterized by complete interruption of the vessel in which no direct continuity exists between the inferior vena cava and the azygos/hemiazygos system. Clinical manifestations depend on the variant drainage patterns or collaterals and include lower extremity deep vein thrombosis, thromboembolic attacks, leg swelling and pain, lower extremity varices, abdominal pain, intraabdominal varices, and hematochezia, among others. Additional venous abnormalities or cardiac malformations are frequently present.", "ORPHA ID": 99123, "Summary": ""}
{"Disease Name": "Inflammatory bowel disease-recurrent sinopulmonary infections syndrome", "Disease Definition": "A rare genetic immune disease characterized by recurrent sinopulmonary infections and autoimmune enterocolopathy, manifesting as frequent episodes of intractable diarrhea with abdominal pain and fever, accompanied by eczematous rashes, due to deficits in components of innate and adaptive immunity. Immunologic abnormalities include IgG subclass deficiency, impaired antigen-induced lymphocyte proliferation, reduced cytokine production by CD8+ T lymphocytes, and decreased numbers of natural killer cells.", "ORPHA ID": 529980, "Summary": ""}
{"Disease Name": "Inflammatory myofibroblastic tumor", "Disease Definition": "Inflammatory myofibroblastic tumor is a rare neoplastic lesion of the submucosal stroma, which can develop in any organ, often occurring in the lung, mesentery, omentum and the retroperitoneal region. It is histologically heterogenous, composed of spindle-shaped cells, myofibroblasts and inflammatory cells. It is usually benign, however local invasion, recurrence, malignant transformation with vascular invasion and metastases may occur. The presentation is nonspecific and depends on the organ involved. Some patients may present with paraneoplastic syndrome (fever, malaise, weight loss, anemia, thrombocytosis) or symptoms related to compression of adjacent organs, such as bowel obstruction.", "ORPHA ID": 178342, "Summary": ""}
{"Disease Name": "Inflammatory myopathy with abundant macrophages", "Disease Definition": "A rare idiopathic inflammatory myopathy characterized by diffuse destructive infiltration of CD68+ macrophages into the fascia rather than muscle fibers in muscle biopsies, proximal muscle weakness and myalgia with or without scaly dermatomyositis-like or atypical non-dermatomyositis-like skin lesions, elevation of creatine kinase levels and thickening of muscle fascia in muscle MRI.", "ORPHA ID": 247718, "Summary": ""}
{"Disease Name": "Inflammatory pseudotumor of the liver", "Disease Definition": "A rare benign liver tumor characterized by a prominent inflammatory infiltrate and often mimicking a malignant liver neoplasm. The tumor is frequently solitary with a predilection for the right lobe; however, multiple lesions are possible. There are two clinicopathological subtypes: fibrohistiocytic inflammatory pseudotumor of the liver and lymphoplasmacytic inflammatory pseudotumor of the liver. Patients present with non-specific clinical symptoms such as abdominal pain or discomfort, fever, and weight loss. The condition may be associated with other chronic inflammatory or autoimmune diseases.", "ORPHA ID": 90003, "Summary": ""}
{"Disease Name": "Infundibulo-neurohypophysitis", "Disease Definition": "A type of primary hypophysitis characterized by an inflammation of the posterior pituitary and the stalk. The major clinical manifestation is diabetes insipidus with polyuria and polydipsia. Less frequent symptoms are headaches, adrenal insufficiency, hyperprolactinemia and hypogonadism.", "ORPHA ID": 238305, "Summary": ""}
{"Disease Name": "Inhalational anthrax", "Disease Definition": "Inhalational anthrax is a rare acute systemic infection caused by the inhalation of Bacillus anthracis spores (e.g. through infected animal products, bioterrorism) and characterized by an initial stage where patients present with non specific symptoms (fever, cough, chills, fatigue) that is followed by an acute phase during which hemorrhagic mediastinitis occurs that can progress into meningitis, gastrointestinal involvement, and refractory shock, that can be fatal, if left untreated.", "ORPHA ID": 247257, "Summary": ""}
{"Disease Name": "Inhalational botulism", "Disease Definition": "Inhalational botulism is a man-made form of botulism (see this term), a rare acquired neuromuscular junction disease with descending flaccid paralysis caused by botulinum neurotoxins (BoNTs).", "ORPHA ID": 254504, "Summary": "Epidemiology\nPrevalence is unknown. So far, nearly 10 cases have been reported worldwide.\nClinical description\nClinical manifestations are similar to other forms of botulism, with symmetrical cranial nerve palsies followed by descending, symmetric flaccid paralysis of voluntary muscles, which may progress to respiratory compromise and death.\nEtiology\nThe disease results from accidental or intentional release of aerosolized BoNTs. After inhalation, the toxin is absorbed into the blood stream and distributed throughout the body, causing the typical manifestations of botulism. The time to onset of inhalational botulism cannot be stated with certainty as few cases are known or because of repeated exposure. Accidental cases were initially reported in three laboratory workers and more recently in illicit drug users after intranasal use of cocaine, through sinusitis and possible sinus colonization and toxicogenesis, or through direct absorption by the nasal mucosa of preformed toxin in contaminated street cocaine. Deliberate dissemination of BoNTs by aerosol could produce an outbreak of inhalational botulism in a large number of simultaneous cases with a common geographic factor, but without common dietary exposure and, possibly, with an unusual BoNT type (e.g. type C, D, F, G). All cases of botulism should be reported to the appropriate government agency.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Michel POPOFF"}
{"Disease Name": "Inherited acute myeloid leukemia", "Disease Definition": "Inherited acute myeloid leukemia (AML) is a rare, malignant hematopologic disease characterized by clonal proliferation of myeloid blasts, primarily involving the bone marrow, in association with congenital disorders (e.g. Fanconi anemia, dyskeratosis congenita, Bloom syndrome, Down syndrome, congenital neutropenia, neurofibromatosis, etc.) and genetic defects predisposing to AML. Patients present with signs and symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement (gingivitis, splenomegaly, etc.). Depending on the underlying genetic defect, there may be additional cancer risks and other health problems present.", "ORPHA ID": 319465, "Summary": ""}
{"Disease Name": "Inherited arrhythmogenic cardiomyopathy", "Disease Definition": "A heart muscle disease that consists in progressive dystrophy of primarily the right ventricular myocardium with fibro-fatty replacement and ventricular dilation, and that is clinically characterized by ventricular arrhythmias and a risk of sudden cardiac death.", "ORPHA ID": 247, "Summary": "Epidemiology\nArrhythmogenic right ventricular cardiomyopathy (ARVC) has a reported prevalence of 1/2,500 to 1/5,000.\nClinical description\nARVC has a variable clinical picture. ARVC can be asymptomatic, or present, usually during adolescence, with ventricular arrhythmias with palpitations, chest pain, dizziness, fatigue, or syncope. All patients are at risk of sudden death, particularly during exertion. Although predominantly a disease of the right ventricle, ARVC may also involve the left ventricle (ARVC left dominant form) or both (ARVC biventricular form), the latter leading in later stages to progressive biventricular failure. ARVC can be associated with palmoplantar keratoderma and woolly hair, the so-called cardio cutaneous syndromes (Naxos disease and Carvajal syndromes, see these terms).\nEtiology\nARVC results from a fibro-fatty replacement of myocardium. It is believed to be a disease of desmosomes with impaired cell-to-cell contact and signaling Mutations have been observed in genes encoding for proteins of the cardiac desmosomes (JUP;  DSP;  PKP2;  DSG2; and  DSC2). However, in a minority of patients, mutations in non-desmosomal genes (TGFβ3;  TMEM43/LUMA; DES; CTNNA3; PLN; LMNA; TTN) have also been detected. Variable penetrance is found, suggesting a role for additional genetic or environmental modifiers. Compound/digenic heterozygosity is identified in up to 25% of mutation carriers and seems an additional risk factor. Recent investigations point to a role of the canonical Wnt signaling pathway in the pathogenesis of ARVC.\nDiagnostic methods\nDiagnosis is based on a scoring system taking into account right ventricle structural and functional abnormalities (dilatation, akinesia, dyskinesia, aneurysms) detected by echocardiography, MRI and angiography; electrocardiographic features (inverted T waves in right precordial leads, epsilon waves and late potentials by signal averaged ECG (SAECG), left bundle branch block ventricular tachycardia, >500 ventricular extrasystoles per 24 h); tissue characterization at endomyocardial biopsy (fibro-fatty replacement of myocardium); and family history. Contrast enhanced MRI substantially enhances the diagnostic sensitivity, particularly in left ventricle variants, while electroanatomic mapping is superior in detecting early RV involvement.\nDifferential diagnosis\nDifferential diagnosis includes idiopathic RV outflow tract tachycardia, myocarditis, sarcoidosis and congenital heart diseases (see these terms).\nAntenatal diagnosis\nAlthough prenatal diagnosis through amniocentesis is feasible, it is subject to ethical and legal considerations.\nGenetic counseling\nIn more than half of the patients, the disease is familial, primarily autosomal dominant with variable penetrance and polymorphic expressivity. Naxos disease and Carvajal syndrome show an autosomal recessive mode of inheritance. The success rate of genotyping depends on several factors (such as cohort location and ethnicity) and hence requires specialized counseling.\nManagement and treatment\nRisk stratification remains largely empiric and therapeutic interventions include antiarrhythmic drugs like beta-blockers, sotalol and amiodarone, catheter ablation, implantable cardioverter-defibrillator. In refractory congestive heart failure or untreatable ventricular arrhythmias, heart transplantation can be also considered. Since effort is a trigger for disease progression and arrhythmias, competitive sport and moderate to high intense physical activity should be avoided.\nPrognosis\nThe disease progression is variable. Risk factors for sudden death include a history of aborted sudden death, syncope, young age, decreased left ventricular function, and marked decrease in right ventricular function.\n\n                            Last update: \n                            December 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Cristina BASSO  - Dr Domenico CORRADO  - Pr Kalliopi PILICHOU  - Pr Gaetano THIENE"}
{"Disease Name": "Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations", "Disease Definition": "Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations is a rare cancer-predisposing syndrome, associated with the D1 subgroup of Fanconi anemia (FA), characterized by progressive bone marrow failure, cardiac, brain, intestinal or skeletal abnormalities and predisposition to various malignancies. Bone marrow suppression and the incidence of developmental abnormalities are less frequent than in other FA, but cancer risk is very high with the spectrum of childhood cancers including Wilms tumor, brain tumor (often medulloblastoma) and ALL/AML.", "ORPHA ID": 319462, "Summary": ""}
{"Disease Name": "Inherited congenital spastic tetraplegia", "Disease Definition": "Inherited congenital spastic tetraplegia is a rare, genetic, neurological disease characterized by non-progressive, variable spastic quadriparesis in multiple members of a family, in the absence of additional factors complicating pregnancy or birth (e.g. perinatal asphyxia, congenital infection). Additional clinical features include congenital hypotonia, intellectual disability, and developmental delay. Dysphagia, dysarthria, exotropia, nystagmus, seizures and brain atrophy with ventriculomegaly may be also present.", "ORPHA ID": 210141, "Summary": ""}
{"Disease Name": "Inherited Creutzfeldt-Jakob disease", "Disease Definition": "A rare form of genetic prion disease characterized by typical CJD features (rapidly progressive dementia, personality/behavioral changes, psychiatric disorders, myoclonus, and ataxia) with a genetic cause and sometimes a family history of dementia.", "ORPHA ID": 282166, "Summary": ""}
{"Disease Name": "Inherited epidermodysplasia verruciformis", "Disease Definition": "Epidermodysplasia verruciformis (EV) is a rare inherited genodermatosis characterized by chronic infection with human papillomavirus (HPV) leading to polymorphous cutaneous lesions and high risk of developing non melanoma skin cancer.", "ORPHA ID": 302, "Summary": "Epidemiology\nThe exact prevalence of EV is unknown; more than 200 cases have been reported in the literature so far.\nClinical description\nThe disease usually manifests during infancy (7.5% of cases), childhood (61.5% of cases) or puberty (22% of cases) with a progressive development of hyperpigmented or hypopigmented flat wart-like papules, irregular reddish brown plaques, seborrheic keratosis-like lesions and pityriasis versicolor-like macules on the trunk, neck, face, dorsal hands and feet (sun-exposed skin). Various HPV subtypes (HPV5 and HPV8 are found in 80% of cases) can be detected in the cutaneous lesions. Thirty to 60% of patients develop non-melanoma skin cancers, especially squamous cell carcinomas (SCC), during the fourth or fifth decades of life, mainly on sun-exposed areas. Black-skinned patients have a much lower incidence of skin cancer. Most SCC remain local; metastases are uncommon.\nEtiology\nEV can be caused by loss-of-function mutations in either of the 2 adjacent genes EVER1/TMC6 or EVER2/TMC8 (17q25.3) coding for membrane proteins that form a complex with the Zinc transporter protein ZnT-1 in the endoplasmic reticulum (ER) membrane of keratinocytes. The mutations in these genes lead to susceptibility to infection with specific HPV subtypes belonging to the beta genus, including HPV5, 8, 9, 12, 14, 15, 17, 19-25, 36-38, 47 and 49, which are ubiquitous and harmless to healthy individuals.\nDiagnostic methods\nDiagnosis is based on clinical and histological findings. Skin biopsy shows verruca plana-like lesions with mild hyperkeratosis, hypergranulosis and acanthosis of the epidermis. Keratinocytes of the upper epidermal layers are enlarged with perinuclear vacuolization and a typical blue-gray pallor. HPVs can be detected in keratinocytes using in situ hybridization or immunohistochemistry with anti-HPV antibodies.\nDifferential diagnosis\nDifferential diagnosis includes squamous cell carcinoma, acrokeratosis verruciformis (see these terms), tinea versicolor, and generalized verrucosis of other origin. In addition, an acquired epidermodysplasia verruciformis-like syndrome has been described in patients with impaired cell-mediated immunity, mainly HIV-infected subjects.\nGenetic counseling\nIn most cases, transmission is autosomal recessive but sex-linked and autosomal dominant inheritance patterns have also been reported.\nManagement and treatment\nAlthough permanent cure of EV cannot be achieved by any therapy at present, described treatment modalities include cryotherapy, topical imiquimod and 5-fluorouracil, systemic retinoids, interferon alpha, and 5-aminolevulinic acid photodynamic therapy. Surgical excision is the treatment of choice for SCC. Preventive measures, in particular sun exposure avoidance and photoprotection, are crucial for proper management.\nPrognosis\nPrognosis is favorable since skin tumors appear progressively and metastases are uncommon.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "Inherited epidermolysis bullosa", "Disease Definition": "Inherited epidermolysis bullosa (EB) encompasses a number of disorders characterized by recurrent blister formation as the result of structural fragility within the skin and selected other tissues.", "ORPHA ID": 79361, "Summary": "Epidemiology\nAll types and subtypes of EB are rare; the overall incidence and prevalence of the disease in the United States are approximately 1/53,000 live births and 1/125,000, respectively, and similar estimates have been obtained in some European countries. EB affects individuals from all ethnic origins and there is no gender predilection.\nClinical description\nClinical manifestations range widely, from localized blistering of the hands and feet to generalized blistering of the skin and oral cavity, and injury to many internal organs. Four major types of inherited EB have been defined: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), each with numerous subtypes, and Kindler syndrome (see these terms). These forms differ not only phenotypically and genotypically but more importantly by the site of ultrastructural disruption or cleavage.\nEtiology\nEach EB subtype is known to arise from mutations within the genes coding for several different proteins, each of which is intimately involved in the maintenance of keratinocyte structural stability or adhesion of the keratinocyte to the underlying dermis.\nDiagnostic methods\nEB is best diagnosed and subclassified by the collective findings obtained via detailed personal and family history, in concert with the results of immunofluorescence antigenic mapping, transmission electron microscopy, and in some cases, by DNA analysis.\nDifferential diagnosis\nExtensive differential diagnosis is not usually required in EB.\nAntenatal diagnosis\nMolecular prenatal diagnosis may be available if the disease-causing mutation in the family has been identified.\nGenetic counseling\nEB is inherited in either an autosomal dominant or autosomal recessive manner, depending on the EB type and subtype. Genetic counseling should be offered to affected families.\nManagement and treatment\nOptimal patient management requires a multidisciplinary approach, and revolves around the protection of susceptible tissues against trauma, use of sophisticated wound care dressings, aggressive nutritional support, and early medical or surgical interventions to correct the extracutaneous complications, whenever possible.\nPrognosis\nPrognosis varies considerably and is based on both EB subtype and the overall health of the patient.\n\n                            Last update: \n                            June 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Jo-David FINE"}
{"Disease Name": "Inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency", "Disease Definition": "Inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency is a rare, genetic, chronic, primary adrenal insufficiency disorder, due to partial loss-of-function CYP11A1 mutations, characterized by early-onset adrenal insufficiency without associated abnormal external male genitalia. Patients present with signs of adrenal crisis, including electrolite abnormalities, severe weakness, recurrent vomiting and seizures. Ultrasound reveals absent (or very small) adrenal glands.", "ORPHA ID": 289548, "Summary": ""}
{"Disease Name": "Inherited isolated arrhythmogenic cardiomyopathy", "Disease Definition": "Familial isolated arrhythmogenic right ventricular dysplasia (ARVC) is the familial autosomal dominant form of ARVC (see this term), a heart muscle disease characterized by life-threatening ventricular arrhythmias with left bundle branch block configuration that may manifest with palpitations, ventricular tachycardia, syncope and sudden fatal attacks, and that is due to dystrophy and fibro-fatty replacement of the right ventricular myocardium that may lead to right ventricular aneurysms.", "ORPHA ID": 217656, "Summary": ""}
{"Disease Name": "Iniencephaly", "Disease Definition": "Iniencephaly is a rare form of neural tube defect in which a malformation of the cervico-occipital junction is associated with a malformation of the central nervous system.", "ORPHA ID": 63259, "Summary": "Epidemiology\nIncidence is estimated at between 1/1,000 and 1/100,000 live births, depending on the geographical area, and more female infants are affected (male:female sex ratio: 1:3 to 1:9).\nClinical description\nThe cardinal features are occipital bone defect, partial or total absence of cervicothoracic vertebrae, fetal retroflexion of the head and characteristic absence of the neck. It is associated with malformations of the central nervous (spina bifida and/or anencephaly), gastrointestinal (omphalocele) and cardiovascular systems.\nEtiology\nAs with other neural tube defects, it is thought to be of multifactorial origin.\nAntenatal diagnosis\nAntenatal diagnosis is possible by ultrasonographic monitoring.\nPrognosis\nPrognosis is poor and iniencephaly is almost always lethal.\n\n                            Last update: \n                            January 2010"}
{"Disease Name": "Insulin autoimmune syndrome", "Disease Definition": "A rare endocrine disease characterized by hyperinsulinemic hypoglycemia associated with the presence of autoantibodies to endogenous insulin without previous exposure to exogenous insulin. Patients usually present in adulthood with postprandial, fasting-, or exercise-induced hypoglycemia, often with pronounced neuroglycopenic symptoms. Laboratory investigations reveal markedly elevated serum insulin, as well as increased C-peptide and proinsulin. The condition may be associated with other autoimmune diseases, monoclonal gammopathy, and/or recent exposure to certain medications.", "ORPHA ID": 411593, "Summary": ""}
{"Disease Name": "Insulin-resistance syndrome type A", "Disease Definition": "Type A insulin-resistance syndrome belongs to the group of extreme insulin-resistance syndromes (which includes leprechaunism, the lipodystrophies, Rabson-Mendenhall syndrome and type B insulin resistance syndrome; see these terms) and is characterized by the triad of hyperinsulinemia, acanthosis nigricans (skin lesions associated with insulin resistance), and signs of hyperandrogenism in females without lipodystrophy and who are not overweight.", "ORPHA ID": 2297, "Summary": "Epidemiology\nIt is a rare disorder of unknown prevalence.\nClinical description\nIt is generally diagnosed in young women with marked signs of hyperandrogenism, but insulin resistance and acanthosis nigricans may be observed in men and in childhood. Acromegaloid facies or muscular cramps are sometimes associated. Hyperinsulinemia, a biological marker for insulin resistance, is often associated with glucose tolerance defects over the course of the disease, and diabetes progressively sets in. Hyperandrogenism (associated with polycystic ovarian syndrome (see this term) or ovarian hyperthecoses) leads to fertility problems.\nEtiology\nIn some cases, the syndrome is caused by heterozygous mutations in the insulin receptor gene (INSR; 19p13.3-p13.2), affecting the region encoding the tyrosine kinase domain. Cases associated with homozygous mutations affecting the insulin-binding domain of the receptor have also been reported. However, only 15 to 20% of female patients with hyperandrogenism, insulin resistance and acanthosis nigricans present mutations in the insulin receptor gene. When such mutations are not found, the disease is of unknown cause and may be considered as an HAIR-AN syndrome (see this term).\nDifferential diagnosis\nThe differential diagnosis includes the other forms of extreme insulin-resistance, in particular the lipodystrophy syndromes (see these terms), in which the reparation anomaly of the adipose tissue may be clinically minor. The differential diagnosis with type B insulin resistance syndrome is based on the lack of insulin anti-receptor auto-antibodies in patients with the type A syndrome.\nGenetic counseling\nTransmission is autosomal dominant.\nManagement and treatment\nThe treatment consists of dietary changes and/or drugs (metformin, glitazones, or other antidiabetic drugs) to reduce the insulin resistance and treat the diabetes.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Corinne VIGOUROUX"}
{"Disease Name": "Insulin-resistance syndrome type B", "Disease Definition": "A rare genetic disease that belongs to the group of extreme insulin-resistance syndromes and is due to autoantibodies directed against insulin receptor.", "ORPHA ID": 2298, "Summary": "Epidemiology\nInsulin-resistance syndrome type B is a rare disorder that mainly affects middle-aged adults, predominantly females. The prevalence is unknown.\nClinical description\nThe disease may occur in the context of other autoimmune phenomena or well-characterized autoimmune diseases (mainly systemic lupus erythematosus). The onset of the disease is usually characterized by the appearance of a rapidly progressive, severely insulin-resistant diabetes with acanthosis nigricans (the typical skin lesion associated with insulin resistance), weight loss, and hirsutism in females. Hypoglycemia can occur during the course of the disease, or, more rarely, can be the only metabolic manifestation, and may be extremely severe. Unlike most insulin resistance syndromes, type B insulin resistance is not associated with hypertriglyceridemia.\nEtiology\nThe syndrome is associated with the presence of serum auto-antibodies directed against the insulin receptor.\nDiagnostic methods\nThe diagnosis is based on the clinical picture and results of laboratory tests. The detection of anti-insulin receptor auto-antibodies in the serum is rarely performed for routine diagnosis, so that the diagnosis is usually based on probabilistic arguments.\nDifferential diagnosis\nThe differential diagnosis include other insulin resistance syndromes and/or hypoglycemia due to other causes.\nManagement and treatment\nImmunosuppressive combination therapies including rituximab were shown effective to induce remission in most cases and should be followed by maintenance immunosuppressive therapy. Non specific therapies should be associated to reverse the hypercatabolic state and treat hyperglycemia (large amount of insulin) and/or hypoglycemia (diet, adaptation of insulin therapy, steroids).\nPrognosis\nPrognosis depends on the course of the underlying autoimmune disease, and is unfavorable in cases with hypoglycemia (reported to lead to death in 50% of cases).\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Corinne VIGOUROUX"}
{"Disease Name": "Insulinoma", "Disease Definition": "A form of functioning pancreatic neuroendocrine tumor characterized most commonly by a solitary, small pancreatic lesion that causes hyperinsulinemic hypoglycemia.", "ORPHA ID": 97279, "Summary": "Epidemiology\nThe incidence in the general population is 1/250,000-1,000,000 (but higher in autopsy studies). There is a slight female predominance. It is the most common endogenous cause of hyperinsulinemic hypoglycemia. Malignant insulinoma has an incidence 0.01/100,000 in Europe.\nClinical description\nInsulinoma can present at any age but the median age of diagnosis is in the fifth decade of life. It manifests with various autonomic and neuroglycopenic symptoms such as tremor, palpitations, weakness, diaphoresis, hyperphagia, visual disturbances, confusion, behavioral and personality changes, seizures and coma. Symptoms occur more often during times of fasting, exercise or with a delay in meals. 20-40% of patients are overweight. Insulinomas are malignant in only 7-10% of cases and the most common sites of metastasis are the liver and lymph nodes. Extra-pancreatic insulinoma is most commonly found in the duodenal wall but is extremely rare. The tumor can also rarely be non-functioning.\nEtiology\nThe etiology is unknown in most sporadic cases but somatic YY1 (14q32.2) variants are associated with insulinoma in some cases. Insulinoma originates in the islet beta cells that are equally distributed throughout the pancreas. When functioning, the tumor manifests with hypersecretion of insulin and consequently causes hypoglycemia.\nDiagnostic methods\nDiagnosis is suspected on the presence of Whipple's triad (hypoglycemia with blood glucose levels of < 50 mg/dL, neuroglycopenic symptoms, and immediate relief of symptoms following the administration of glucose) and confirmed by biological testing, including a 72 hour fasting test (measuring levels of insulin, C-peptide and proinsulin during hypoglycemia). The insulin/C-peptide ratio is > 1.0 in patients with insulinoma. Localization of insulinoma can be achieved by imaging techniques such as transabdominal ultrasound, computed tomography and magnetic resonance imaging, as well as by endoscopic ultrasonography (EUS), angiography, and arterial stimulation venous sampling. Occult insulinoma can be located by dotatate or Glucagon-like peptide-1 analog positron emission tomography.\nDifferential diagnosis\nMalignant insulinomas can be associated with multiple endocrine neoplasia type 1 (MEN1). Other differential diagnoses include other causes of hypoglycemia such as diffuse hepatic disease, Addison disease, and alcoholism, but insulin is not elevated in these conditions. Type B insulin resistance and insulin autoimmune syndrome also need to be considered.\nGenetic counseling\nWith the exception of insulinoma in MEN1, insulinoma is not hereditary.\nManagement and treatment\nSurgical resection is the standard treatment for a benign insulinoma and is often curative. Enucleation, partial or middle pancreatomy, laparoscopic resection and radical resection are all options for benign insulinomas. Octreotide, a somatostatin analogue, can be given pre-operatively as it may be successful in controlling blood glucose levels (not necessary in most cases). Malignant insulinomas require aggressive surgical resection (extended pancreatic and liver resection) along with aggressive secondary treatments (i.e. chemoembolization, radiofrequency ablation). In those with unresectable tumors, octreotide should be administered and glucose monitored regularly, and mammalian target of rapamycin (mTOR) inhibitors are particularly effective in controlling hypoglycemia. Sunitinib malate can be used for malignant insulinomas.\nPrognosis\nIn most cases, insulinomas are benign, and surgical resection is curative. The reported 10-year survival rate of those with a malignant insulinoma, however, is 29%.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Run YU"}
{"Disease Name": "Intellectual disability, Birk-Barel type", "Disease Definition": "Intellectual disability, Birk-Barel type is a rare, genetic, syndromic intellectual disability characterized by congenital central hypotonia, developmental delay, moderate to severe intellectual disability and subtle dysmorphic features which evolve over time (dolichocephaly, myopathic facies, ptosis, short and broad philtrum, tented upper lip vermillion, palatal anomalies, mild micro- and/or retrognathia). Patients present reduced facial movements, lethargy, weak cry, transient neonatal hypoglycemia, severe feeding difficulties and failure to thrive. Dysphagia, particularly of solid food, asthenic body build, joint contractures and scoliosis are additional features.", "ORPHA ID": 166108, "Summary": ""}
{"Disease Name": "Intellectual disability, Buenos-Aires type", "Disease Definition": "Intellectual disability, Buenos-Aires type is a rare intellectual disability syndrome characterized by growth retardation, microcephaly, characteristic facial features (including narrow forehead, bushy eyebrows, hypertelorism, small, downward-slanting palpebral fissures with blepharoptosis, malformed and low-set ears, broad straight nose, thin upper lip, and a wide, tented mouth), developmental delay, intellectual disability, speech disorder, and multiple organ malformations (e.g. ventricular septal defect, megaloureter, dilated renal pelvis). Additional manifestations reported include neurocutaneous lesions (including palmoplantar hyperkeratosis), internal hydrocephalus, and bilateral partial soft-tissue syndactyly of second and third toe.", "ORPHA ID": 3079, "Summary": ""}
{"Disease Name": "Intellectual disability, Wolff type", "Disease Definition": "Intellectual disability, Wolff type is a rare intellectual disability syndrome characterized by severe intellectual disability, characteristic facial features (low anterior hairline, upward slanting palpebral fissures, ocular hypertelorism, broad, bulbous nose, large ears with helix incompletely developed, thick lips, and micrognathia) and additional anomalies including peripheral joint contractures, delayed skeletal maturation, bilateral cleft lip and palate, strabismus, terminal hypoplasia of fingers, hypospadias, and bilateral inguinal hernias.", "ORPHA ID": 3080, "Summary": ""}
{"Disease Name": "Intellectual disability-alacrima-achalasia syndrome", "Disease Definition": "Intellectual disability-alacrima-achalasia syndrome is a rare, genetic intellectual disability syndrome characterized by delayed motor and cognitive development, absence or severe delay in speech development, intellectual disability, and alacrima. Achalasia/dysphagia and mild autonomic dysfunction (i.e. anisocoria) have also been reported in some patients. The phenotype is similar to the one observed in autosomal recessive Triple A syndrome, but differs by the presence of intellectual disability in all affected individuals.", "ORPHA ID": 289483, "Summary": ""}
{"Disease Name": "Intellectual disability-autism-speech apraxia-craniofacial dysmorphism syndrome", "Disease Definition": "A rare, syndromic intellectual disability characterized by developmental delay, speech apraxia, autism with stereotypies, intellectual disability and unspecific dysmorphic facial features. Seizures or isolated EEG abnormalities may also be associated.", "ORPHA ID": 529965, "Summary": ""}
{"Disease Name": "Intellectual disability-balding-patella luxation-acromicria syndrome", "Disease Definition": "Intellectual disability-balding-patella luxation-acromicria syndrome is characterised by severe intellectual deficit, patella luxations, acromicria, hypogonadism, facial dysmorphism (including midface hypoplasia and premature frontotemporal balding). It has been described in three unrelated males.", "ORPHA ID": 3041, "Summary": ""}
{"Disease Name": "Intellectual disability-brachydactyly-Pierre Robin syndrome", "Disease Definition": "Intellectual disability-brachydactyly-Pierre Robin syndrome is a rare developmental defect during embryogenesis syndrome characterized by mild to moderate intellectual disability and phsychomotor delay, Robin sequence (incl. severe micrognathia and soft palate cleft) and distinct dysmorphic facial features (e.g. synophris, short palpebral fissures, hypertelorism, small, low-set, and posteriorly angulated ears, bulbous nose, long/flat philtrum, and bow-shaped upper lip). Skeletal anomalies, such as brachydactyly, clinodactyly, small hands and feet, and oral manifestations (e.g. bifid, short tongue, oligodontia) are also associated. Additional features reported include microcephaly, capillary hemangiomas on face and scalp, ventricular septal defect, corneal clouding, nystagmus and profound sensorineural deafness.", "ORPHA ID": 364577, "Summary": ""}
{"Disease Name": "Intellectual disability-cardiac anomalies-short stature-joint laxity syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by intrauterine and postnatal growth restriction, global developmental delay, intellectual disability, and dysmorphic facial features (such as broad nasal root, anteverted nares, long philtrum, low-set and posteriorly rotated ears, and short neck). Additional reported manifestations are microcephaly, short stature, vertebral abnormalities, joint laxity, ocular, cardiac, and renal defects, and minor limb anomalies. Brain imaging may show hypoplastic corpus callosum, delayed myelination, and cerebral atrophy.", "ORPHA ID": 508498, "Summary": ""}
{"Disease Name": "Intellectual disability-cataracts-calcified pinnae-myopathy syndrome", "Disease Definition": "Intellectual disability-cataracts-calcified pinnae-myopathy syndrome is a rare, genetic intellectual disability syndrome characterized by macrocephaly, hypotonia, dysmorphic facial features (wide forehead, ptosis, downslanting palpebral fissures, enlarged and calcified external ears, large jaw), sparse body hair, tall stature, and intellectual disability. Hearing loss, insulin-resistant diabetes, and progressive distal muscle wasting (leading to joint contractures) have also been reported in adulthood. Rare manifestations include behavioral abnormalities (aggression and restlessness), hypothyroidism, cerebral calcification, ataxia, and peripheral neuropathy.", "ORPHA ID": 3042, "Summary": ""}
{"Disease Name": "Intellectual disability-coarse face-macrocephaly-cerebellar hypotrophy syndrome", "Disease Definition": "A rare, genetic, central nervous system malformation syndrome characterized by early-onset, progressive, severe cerebellar ataxia associated with progressive, moderate to severe intellectual disability, global developmental delay, progressively coarsening facial features, relative macrocephaly and absence of seizures. Sensorineural hearing loss may be associated. Neuroimaging reveals cerebellar atrophy/hypoplasia.", "ORPHA ID": 397709, "Summary": ""}
{"Disease Name": "Intellectual disability-developmental delay-contractures syndrome", "Disease Definition": "Intellectual disability-developmental delay-contractures syndrome, formerly known as Wieacker-Wolff syndrome, is a severe X-linked recessive neurodevelopmental disorder characterized by severe contractures (arthrogryposis; see this term) and intellectual disability.", "ORPHA ID": 3454, "Summary": "Epidemiology\nPrevalence and incidence rates are not known. The syndrome has been reported in 5 families to date, with fewer than 30 affected individuals described. Affected patients are male, while carrier females are often asymptomatic. Cases have been reported from Germany, France, the Netherlands, Australia, and the United States.\nClinical description\nThe syndrome is characterized by an association of arthrogryposis multiplexa congenita and intellectual disability. Affected patients are born with severe contractures (arthrogryposis) and muscle weakness causing respiratory distress. Intellectual disability and delayed motor development are found in all patients. Facial weakness (ptosis) and bulbar weakness (feeding difficulty), characteristic dysmorphic facial features (possibly including long flat philtrum, low-set ears, high-arched palate, and carp-shaped mouth), and skeletal abnormalities (camptodactyly, hip dislocation, scoliosis, kyphosis, lordosis and pes equinovarus) have been reported. Other neurological signs may include spasticity and seizures. Heterozygous female carriers may also be affected, but to a lesser degree (intellectual disability, distal muscle weakness, camptodactyly, joint contractures, and pes equinovarus).\nEtiology\nIntellectual disability-developmental delay-contractures syndrome is caused by mutations in the ZC4H2 gene (Xq11.1) that is presumed to play a role in neuronal function during fetal growth.\nGenetic counseling\nThe disorder follows an X-linked recessive pattern on inheritance. Simplex cases are also found. Genetic counseling should be provided to affected families.\n\n                            Last update: \n                            January 2015"}
{"Disease Name": "Intellectual disability-dysmorphism-hypogonadism-diabetes mellitus syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder characterized by mild to moderate intellectual disability, facial dysmorphism (including a long face, deep-set eyes, narrow-based, broad nose with nostril colobomata, mandibular prognathism), hypergonadotrophic hypogonadism, eunuchoid habitus, diabetes mellitus type 1, and epilepsy. There have been no further descriptions in the literature since 1990.", "ORPHA ID": 3044, "Summary": ""}
{"Disease Name": "Intellectual disability-epilepsy-extrapyramidal syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by hypotonia, delayed motor development, dyskinesia of the limbs, intellectual disability with impaired speech development, seizures, autistic features, stereotypic movements, and sleep disturbance. Onset of symptoms is in infancy. Bilateral abnormalities in the putamen on brain MRI have been reported in some patients.", "ORPHA ID": 468620, "Summary": ""}
{"Disease Name": "Intellectual disability-expressive aphasia-facial dysmorphism syndrome", "Disease Definition": "A rare genetic syndromic intellectual disability characterized by moderate to severe intellectual deficiency, language deficit (completely absent or significantly impaired speech), and distinctive facial dysmorphism (long face, straight eyebrows, and, less frequently, low-set ears and café-au-lait spots). Additional, variably observed features include motor delays, behavioral difficulties, and seizures.", "ORPHA ID": 436151, "Summary": ""}
{"Disease Name": "Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency", "Disease Definition": "A rare, syndromic intellectual disability characterized by intellectual disability of various severity, hypotonia, feeding difficulties, dysmorphic features, autism and behavioral issues. Growth retardation, congenital heart anomalies, gastrointestinal and genitourinary defects have been rarely associated.", "ORPHA ID": 404440, "Summary": ""}
{"Disease Name": "Intellectual disability-facial dysmorphism-hand anomalies syndrome", "Disease Definition": "Intellectual disability-facial dysmorphism-hand anomalies syndrome is a rare syndromic intellectual disability disorder characterized by moderate intellectual disability, variable hand abnormalities (including brachydactyly, cutaneous and osseous syndactyly), and facial dysmorphism that includes short palpebral fissures, bulbous nasal tip, thin upper and lower vermilion and broad, pointed chin. Other features, including obesity, microcephaly, short stature and a grimacing smile may be observed.", "ORPHA ID": 370010, "Summary": ""}
{"Disease Name": "Intellectual disability-hyperkinetic movement-truncal ataxia syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disease characterized by global developmental delay, microcephaly, mild to moderate intellectual disability, truncal ataxia, trunk and limb, or generalized, choreiform movements, and elevated serum creatine kinase levels. Variably associated features include mild cerebral atrophy, muscular weakness or hypotonia in early childhood, and/or seizures. Ocular abnormalities (e.g. exophoria, anisometropia, amblyopia) have been reported.", "ORPHA ID": 369847, "Summary": ""}
{"Disease Name": "Intellectual disability-hypoplastic corpus callosum-preauricular tag syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by psychomotor and growth delay, severe intellectual disability, microcephaly, and hypoplastic corpus callosum. Additional reported manifestations include increased muscle tonus, seizures, cardiac anomalies, recurrent bronchopneumonia, camptodactyly, preauricular skin tag, and dysmorphic facial features (such as broad forehead, hypertelorism, flat nasal bridge, anteverted nostrils, and prominent ears), among others.", "ORPHA ID": 1495, "Summary": ""}
{"Disease Name": "Intellectual disability-hypotonia-brachycephaly-pyloric stenosis-cryptorchidism syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by craniofacial dysmorphism (brachycephaly resulting from craniosynostosis, frontal bossing, downslanting palpebral fissures, large and low-set ears, depressed nasal bridge, high-arched, wide palate, thin upper lip), impaired neurological development with intellectual disability, hypotonia, pyloric stenosis, pectus excavatum, bilateral cryptorchidism and short stature.", "ORPHA ID": 314575, "Summary": ""}
{"Disease Name": "Intellectual disability-macrocephaly-hypotonia-behavioral abnormalities syndrome", "Disease Definition": "A rare, syndromic intellectual disability characterized by hypotonia, global developmental delay, limited or absent speech, intellectual disability, macrocephaly, mild dysmorphic features, seizures and autism spectrum disorder. Associated ophthalmologic, heart, skeletal and central nervous system anomalies have been reported.", "ORPHA ID": 457279, "Summary": ""}
{"Disease Name": "Intellectual disability-muscle weakness-short stature-facial dysmorphism syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, developmental delay, delayed bone age, short stature, generalized muscle weakness, and dysmorphic facial features (such as high arched eyebrows, downslanting palpebral fissures, prominent nose, and narrow palate and mouth). Additional reported manifestations include blue sclerae, ophthalmoplegia, and intention tremor. Brain imaging may show white matter abnormalities.", "ORPHA ID": 457365, "Summary": ""}
{"Disease Name": "Intellectual disability-myopathy-short stature-endocrine defect syndrome", "Disease Definition": "Intellectual disability-myopathy-short stature-endocrine defect syndrome is a rare congenital myopathy syndrome characterized by nonprogressive myopathy (manifesting with mild facial and generalized weakness, bilateral ptosis, and severe lumbar lordosis), severe intellectual disability, short stature, and sexual infantilism (due to hypogonadotropic hypogonadism). The presence of a small pituitary fossa was also noted. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 3068, "Summary": ""}
{"Disease Name": "Intellectual disability-obesity-brain malformations-facial dysmorphism syndrome", "Disease Definition": "Intellectual disability-obesity-brain malformations-facial dysmorphism syndrome is a rare, syndromic intellectual disability primarily characterized by moderate to severe intellectual disability, true-to-relative microcephaly and brain abnormalities including a thin corpus callosum, cerebellar hypoplasia, cerebral white matter hypoplasia and multi-focal hyperintensity of cerebral white matter on MRI. Obesity and distinctive craniofacial dysmorphism (including brachycephaly, round face, straight eyebrows, synophrys, hypertelorism, epicanthus, wide and depressed nasal bridge, protruding ears with uplifted lobe, downslanting corners of the mouth) are additional features.", "ORPHA ID": 352530, "Summary": ""}
{"Disease Name": "Intellectual disability-obesity-prognathism-eye and skin anomalies syndrome", "Disease Definition": "Intellectual disability-obesity-prognathism-eye and skin anomalies syndrome is a rare, genetic, syndromic intellectual disability disorder characterized by mild to profound intellectual disability, delayed speech, obesity, ocular anomalies (blepharophimosis, blepharoptosis, hyperopic astigmatism, decreased visual acuity, strabismus, abducens nerve palsy, and/or accommodative esotropia), and dermal manifestations, such as chronic atopic dermatitis. Associated craniofacial dysmorphism includes macrocephaly, maxillary hypoplasia, mandibular prognathism, and crowding of teeth.", "ORPHA ID": 397973, "Summary": ""}
{"Disease Name": "Intellectual disability-polydactyly-uncombable hair syndrome", "Disease Definition": "Intellectual disability-polydactyly-uncombable hair syndrome is a multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, postaxial polydactyly, phalangeal hypoplasia, 2-3 toe syndactyly, uncombable hair and facial dysmorphism (including frontal bossing, hypotelorism, narrow palpebral fissures, nasal bridge and lips, prominent nasal root, large abnormal ears with prominent antihelix, poorly folded helix, underdeveloped lobule and antitragus, and micrognathia evolving into prognatism). Cryptorchidism, conductive hearing loss and progressive thoracic kyphosis were also reported.", "ORPHA ID": 3082, "Summary": ""}
{"Disease Name": "Intellectual disability-seizures-abnormal gait-facial dysmorphism syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, seizures, abnormal gait, and craniofacial dysmorphism (including coarse features, depressed nasal bridge, anteverted nares, broad nasal tip, prominent maxilla and upper lip, wide mouth, abnormal gingiva, and widely spaced teeth). Additional reported manifestations are ocular anomalies, cardiac defects, gastrointestinal problems, and autistic features. Brain imaging may show thin corpus callosum, white matter abnormalities, or dilated ventricles.", "ORPHA ID": 513456, "Summary": ""}
{"Disease Name": "Intellectual disability-seizures-hypophosphatasia-ophthalmic-skeletal anomalies syndrome", "Disease Definition": "A rare congenital disorder of glycosylation characterized by neonatal hypotonia, global development delay, developmental regress and severe to profound intellectual disability, infantile onset seizures that are initially associated with febrile episodes with subsequent transition to unprovoked seizures, impaired vision with esotropia and nystagmus, progressive cerebral and cerebellar atrophy, skeletal abnormalities (including brachycephaly, scoliosis, slender long bones, delayed bone age, pectus excavatum and osteopenia), inverted nipples and dysmorphic features including high and narrow forehead, frontal bossing, short nose, depressed nasal bridge, anteverted nares, high palate and wide open mouth consistent with facial hypotonia. Other features may include cardiac abnormalities (such as patent ductus arteriosus, atrial septal defects), urogenital abnormalities (such as nephrocalcinosis, urolithiasis), and low plasma concentration of alkaline phosphatase.", "ORPHA ID": 369837, "Summary": ""}
{"Disease Name": "Intellectual disability-seizures-macrocephaly-obesity syndrome", "Disease Definition": "Intellectual disability-seizures-macrocephaly-obesity syndrome is a rare syndromic obesity due to complex chromosomal rearrangement characterized by development delay and intellectual disability, childhood-onset obesity, seizures, poor coordination and broad-based gait, macrocephaly and mild dysmorphic features (such as narrow palpebral fissures, malar hypoplasia and thin upper lips), eczema, ocular abnormalities and a social personality.", "ORPHA ID": 369950, "Summary": ""}
{"Disease Name": "Intellectual disability-short stature-hypertelorism syndrome", "Disease Definition": "Intellectual disability-short stature-hypertelorism syndrome is a rare genetic syndromic intellectual disability characterized by short stature, mild to moderate intellectual disability, craniofacial dysmorphism (prominent broad 'square' forehead, hypertelorism, depressed nasal bridge, broad nasal tip and anteverted nares) and early hypotonia, typically present until infancy. There have been no further descriptions in the literature since 1991.", "ORPHA ID": 3074, "Summary": ""}
{"Disease Name": "Intellectual disability-spasticity-ectrodactyly syndrome", "Disease Definition": "Intellectual disability-spasticity-ectrodactyly syndrome is a rare intellectual disability syndrome characterized by severe intellectual disability, spastic paraplegia (with wasting of the lower limbs) and distal transverse defects of the limbs (e.g. ectrodactyly, syndactyly, clinodactyly of the hands and/or feet).", "ORPHA ID": 1891, "Summary": ""}
{"Disease Name": "Intellectual disability-strabismus syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder characterized by moderate to severe intellectual disability and esotropia. Other associated features may include growth failure (underweight, failure to thrive, short stature), microcephaly, tone abnormalities (hypotonia, spasticity), epilepsy, behavioral problems (hyperactivity, aggressiveness), and/or abnormal brain morphology, including arachnoid cyst, cerebral atrophy, mild ventriculomegaly, abnormal CNS myelination or corpus callosum agenesis.", "ORPHA ID": 363528, "Summary": ""}
{"Disease Name": "Interatrial communication", "Disease Definition": "A congenital cardiac malformation characterized by a communication between the atrial chambers of the heart.", "ORPHA ID": 1478, "Summary": "Epidemiology\nOverall, openings between the atrial chambers account for about 6 to 8% of all congenitally malformed hearts. As a group, the prevalence at birth is between 6 to 9/10000; however, this is likely an underestimated due to the asymptomatic nature of the disease. The female-to-male ratio is 2-4:1.\nClinical description\nThere are four types of defects, named according to their position relative to the atrial septum. The ostium secundum defect is the most common type, accounting for three-quarters of all cases, located to the region of the oval fossa, most commonly due to a deficiency of the primary atrial septum (septum primum) but deficiency of the septum secundum (superior interatrial fold) may also contribute. The ostium primum defect, which accounts for one-sixth of defects, is in reality an atrioventricular septal defect, with shunting exclusively at atrial level. Only these two defects are true atrial septal defects. The sinus venosus defect (one-tenth of cases) is a hole outside the confines of the oval fossa, through which a caval vein and/or pulmonary vein(s) override the atrial septum or the septum secundum (superior interatrial fold) producing an interatrial or anomalous veno-atrial communication.The rarest defect, the coronary sinus defect, is a communication between the left atrium and the coronary sinus allowing interatrial communication through the orifice of the coronary sinus, and is due to absence or partial unroofing of the coronary sinus. Interatrial communications are most often asymptomatic in childhood but clinical manifestations can include: rapid breathing, shortness of breath, fatigue, sweating, palpitations, frequent respiratory infections, and poor growth. Symptoms often manifest by the age of 30 to 40 years. Adults with interatrial communications are at increased risk of developing pulmonary arterial hypertension, heart failure, arrhythmias, and stroke. About one third of affected children have an associated hereditary syndrome, such as Down's syndrome, Alagille syndrome, Holt-Oram syndrome, Ellis-van Creveld syndrome, or Noonan syndrome.\nEtiology\nSeveral susceptibility genes have been identified.\nDiagnostic methods\nThe defect is most often suspected during a physical examination. Cardiac auscultation reveals a systolic outflow murmur. Echocardiography, chest X-ray and electrocardiogram, and cardiac catheterization may help the diagnosis, although the latter technique is now rarely required for diagnostic purposes.\nDifferential diagnosis\nDifferential diagnosis includes other congenital cardiac anomalies that result in left-to-right shunt at the atrial level, including partial atrioventricular septal defect and anomalous pulmonary venous return.\nAntenatal diagnosis\nA significant defect may be diagnosed during fetal life, although prenatal diagnosis is difficult as interatrial communication is an integral part of fetal circulation.\nGenetic counseling\nMost defects occur sporadically as a result of spontaneous genetic mutations, but hereditary forms have been reported. Familial secundum defects can be associated with mutations in transcription factors NKX2.5 (5q34), GATA4 (8p23.1), TBX6 (16p11.2), along with conduction disorders such as atrioventricular block.\nManagement and treatment\nClosure of the defect is recommended if left-to-right shunt is important with right ventricular overload and dilatation. Transcatheter device closure is nowadays the treatment of choice for secundum defects beyond the infant period. For other types of interatrial communications, and in large secundum defects with deficient rims, open-heart surgery is indicated, and is complication-free in the majority of cases. Whatever the technique used, closure of the defect is rarely indicated before the age of 3 years. Large defects should be closed before the second decade of life.\nPrognosis\nSmall-to-moderate defects may be asymptomatic and life expectancy is not reduced. In some children, small openings may close spontaneously (occurring in up to four-fifths of cases with small openings in the first 18 months of life). In some patients with large defects, Eisenmenger reaction can occur after the first decade of life.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Lucile HOUYEL"}
{"Disease Name": "Interdigitating dendritic cell sarcoma", "Disease Definition": "A rare dendritic cell tumor characterized by a neoplasm composed of spindle to ovoid cells with phenotypic features similar to those of interdigitating dendritic cells. Solitary lymph node involvement is common, although extranodal localization (in particular skin and soft tissue) has also been reported. Patients usually present with an asymptomatic mass, sometimes with systemic symptoms such as fatigue, fever, and night sweats. Generalized lymphadenopathy, splenomegaly, or hepatomegaly may be seen in rare cases. The clinical course is generally aggressive.", "ORPHA ID": 86900, "Summary": ""}
{"Disease Name": "Intermediate atrioventricular septal defect", "Disease Definition": "A rare congenital non-syndromic heart malformation characterized by a common atrioventricular junction with a single atrioventricular valve ring, accompanied by an ostium primum type atrial septal defect and a small ventricular septal defect.", "ORPHA ID": 576242, "Summary": ""}
{"Disease Name": "Intermediate DEND syndrome", "Disease Definition": "A rare genetic neonatal diabetes mellitus syndrome characterized by neonatal insulin-dependent diabetes mellitus, mild motor, speech or cognitive delay, and absence of epilepsy. Is it a less severe form of DEND syndrome.", "ORPHA ID": 99989, "Summary": ""}
{"Disease Name": "Intermediate epidermolysis bullosa simplex with cardiomyopathy", "Disease Definition": "A rare, inherited, epidermolysis bullosa characterized by aplasia cutis congenita on the extremities, leaving behind hypopigmentation and atrophy in a whirled pattern. Generalized blistering persists during childhood and heals with cutaneous and follicular atrophy, linear and stellate scars, and hypopigmentation. Skin fragility decreases with adulthood. Adult patients exhibit dyspigmentation and atrophy of the skin, scars, follicular atrophoderma, sparse body hair, progressive diffuse alopecia of the scalp, diffuse palmoplantar keratoderma, and nail changes. Dilative cardiomyopathy with heart failure complicates the disease course in young adulthood or later and may have lethal outcome. Ultra-structurally, intraepidermal splitting appears at the level of the basal keratinocytes, above the hemidesmosomes.", "ORPHA ID": 508529, "Summary": ""}
{"Disease Name": "Intermediate generalized junctional epidermolysis bullosa", "Disease Definition": "A form of junctional epidermolysis bullosa (JEB) characterized by generalized skin blistering, atrophic scarring, nail dystrophy or nail absence, and enamel hypoplasia, with extracutaneous involvement.", "ORPHA ID": 79402, "Summary": "Epidemiology\nPrevalence of intermediate junctional epidermolysis bullosa (intermediate JEB) is unknown.\nClinical description\nThe condition is clinically apparent at birth. Skin blistering is generalized and healing can occur either with atrophic scars, sometimes accompanied by hypopigmentation or hyperpigmentation or, less commonly, with the formation of exuberant granulation tissue. Nail dystrophy or loss is a constant feature, and focal palmoplantar keratoderma can develop over time. Progressive and permanent hair loss is frequently present, affecting the scalp, eyelashes and eyebrows; pubic and axillary hair are scant or do not fully develop. Mucosal lesions mainly affect the oral and nasal cavity, although there is considerable individual variability. Ocular involvement has been reported in some patients and comprises corneal erosions and scars, and, rarely, ectropion. The teeth regularly show enamel hypoplasia, leading to severe caries. Chronic anemia of multifactorial etiology, although of varying severity, is frequent and may be associated with a growth delay.\nEtiology\nIntermediate JEB is caused by mutations in the COL17A1 (10q24.3), ITGB4 (17q25.1), LAMA3 (18q11.2), LAMB3 (1q32) and LAMC2 (1q25-q31) genes.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and confirmed by immunofluorescence mapping or transmission electron microscopy and genetic testing.\nDifferential diagnosis\nThe differential diagnosis includes other forms of EB. In the neonatal period, aplasia cutis congenita, herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, linear IgA bullous dermatosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, bullous impetigo, and staphylococcal scalded skin syndrome may need to be considered.\nAntenatal diagnosis\nAntenatal diagnosis can be recommended in families with this subtype depending on the degree of severity.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement is preventive: protective padding of the skin reduces blistering and careful wound care prevents secondary infection and reduces scarring. Oral hygiene is important for management of caries. A dietitian should evaluate nutritional requirements. Ocular, gastrointestinal, urinary and renal manifestations require specific treatment.\nPrognosis\nAlthough intermediate JEB is less severe than other forms of JEB, death can occur in infancy and childhood due to sepsis, failure to thrive and respiratory failure. Adult patients have an increased risk of developing squamous cell carcinomas in particular on the lower extremities, in areas of chronic blistering, long-standing erosions, or atrophic scarring.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Cristina HAS | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Intermediate maple syrup urine disease", "Disease Definition": "Intermediate maple syrup urine disease (intermediate MSUD) is a milder form of MSUD (see this term) characterized by persistently raised branched-chain amino acids (BCAAs) and ketoacids, but fewer or no acute episodes of decompensation.", "ORPHA ID": 268162, "Summary": "Epidemiology\nThe estimated birth prevalence of MSUD is 1/ 150,000. Around 30% of cases are believed to be of the intermediate type.\nClinical description\nSymptom onset of intermediate MSUD varies between the early months and the early years of childhood. Infants may have feeding problems, poor growth, maple syrup odor in urine and developmental delay. Older children usually present with learning difficulties. Like classic MSUD (see this term), catabolic stress can result in acute decompensation with anorexia, vomiting, ataxia (in infants/toddlers), cognitive impairment, sleep disturbances, hallucinations, hyperactivity, mood swings, acute dystonia, choreoathetosis (in adults), stupor, coma and cerebral edema, if untreated.\nEtiology\nMSUD is due to mutations in genes encoding 3 of the 4 subunits of the branched chain 2-ketoacid dehydrogenase (BCKAD) complex. The genes are BCKDHA (19q13.1-q13.2), encoding E1a, BCKDHB (6q14.1), encoding E1b, and DBT (1p31), encoding E2 respectively. Mutations lead to accumulation of BCAAs (especially leucine) and branched-chain alpha-ketoacids. In intermediate MSUD mutations in BCKDHB and DBT predominate. A mutation in the PPM1K gene (4q22.1) was found in one case.\nDiagnostic methods\nIntermediate MSUD can be diagnosed by tandem mass spectrometry newborn screening. Otherwise, plasma amino acid analysis is diagnostic. Plasma leucine levels are increased while isoleucine and valine levels may be normal or increased. Patients have 3-30% BCKAD activity so their levels of plasma BCAAs are not as high as those seen in classic MSUD (see this term). Molecular genetic testing can identify a disease causing mutation, equally confirming diagnosis.\nDifferential diagnosis\nDifferential diagnoses of the presenting symptoms include other inborn errors of intermediary metabolism such as NAGS deficiency, ornithine transcarbamylase deficiency, argininosuccinic aciduria (and other urea cycle defects), neonatal glycine encephalopathy, propionic acidemia, methylmalonic acidemia, and beta-ketothiolase deficiency (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease-causing mutation.\nGenetic counseling\nIntermediate MSUD is inherited autosomal recessively and genetic counseling is possible.\nManagement and treatment\nTreatment of intermediate MSUD is similar to classic MSUD. Infants require high calorie BCAA-free formulas, dietary leucine restriction and close outpatient monitoring at a metabolic clinic. Management of acute decompensation requires aggressive enhancement of protein anabolism using glucose plus insulin, intravenous lipids, plasma amino acid monitoring, and isoleucine and valine supplements. Patients must adhere to a strict life-long diet to avoid episodes of acute decompensation. Special monitoring during pregnancy is vital.\nPrognosis\nWith early diagnosis and appropriate therapy the prognosis is good, but because the disorder is mild, diagnostic delay is common and some neurological damage may be sustained.\n\n                            Last update: \n                            April 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Bridget WILCKEN"}
{"Disease Name": "Intermediate nemaline myopathy", "Disease Definition": "Intermediate nemaline myopathy is a type of nemaline myopathy (NM; see this term) that shows features of typical NM (see this term) in neonates with a more severe progression.", "ORPHA ID": 171433, "Summary": "Epidemiology\nThe annual incidence of NM has been estimated at 1/50,000 live births, and intermediate NM might represent 20% of all cases.\nClinical description\nNeonates with intermediate NM present with spontaneous anti-gravity movements and active respiratory muscles, but with a progressive generalized weakness which prevents achievement of gross motor milestones or leads to loss of ambulation and/or independent respiration by age 11 years. Children often develop joint contractures.\nEtiology\nThe ACTA1 (1q42.13), NEB (2q22) or TPM3 (1q21.2) genes have been associated with intermediate NM.\nGenetic counseling\nThe transmission pattern of the disease is autosomal recessive or dominant.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Monique RYAN"}
{"Disease Name": "Intermediate osteopetrosis", "Disease Definition": "A rare, genetic primary bone dysplasia with increased bone density characterized by susceptibility to fractures after minor trauma, anemia, and characteristic skeletal radiographic changes, such as sandwich vertebra, bone-within-bone appearance, Erlenmeyer-shaped femoral metaphysis, and mild osteosclerosis of the skull base. Dental anomalies and visual impairment secondary to optic nerve compression have been rarely described.", "ORPHA ID": 210110, "Summary": ""}
{"Disease Name": "Intermediate uveitis", "Disease Definition": "A rare ophthalmic disorder characterized by intraocular inflammation primarily localized to the vitreous and peripheral retina. It incorporates pars planitis, posterior cyclitis, and hyalitis. Patients present with painless floaters, decreased or blurred vision, less frequently with pain, redness, and photophobia. On examination, snow banking, vitreous snowballs, peripheral retinal vascular sheathing, vitreous cells, and vitreous haze can be seen. Complications include epiretinal membrane formation, cataract formation, cystoid macular edema, or band keratopathy, among others. The condition may be idiopathic or occur in the context of infectious or systemic diseases.", "ORPHA ID": 279914, "Summary": ""}
{"Disease Name": "Intermittent hydrarthrosis", "Disease Definition": "A rare rheumatologic disease characterized by recurrent self-remitting episodes of acute monoarticular arthritis, often with a fixed periodicity, typically affecting the knee or another large joint, which develops an effusion over 12 to 24 hours with only mild to moderate pain and minimal signs of inflammation. Attacks last three to five days and may parallel menses in females. Systemic symptoms are absent, and no joint damage occurs.", "ORPHA ID": 329967, "Summary": ""}
{"Disease Name": "Intermittent maple syrup urine disease", "Disease Definition": "Intermittent maple syrup urine disease (intermittent MSUD) is a mild form of MSUD (see this term) where patients (when well) are asymptomatic with normal levels of branched-chain amino acids (BCAAs) but with catabolic stress are at risk of acute decompensation with ketoacidosis, which can lead to cerebral edema and coma if untreated.", "ORPHA ID": 268173, "Summary": "Epidemiology\nMSUD has an estimated incidence of 1/150,000 live births. There is no data to suggest what number of patients has intermittent MSUD but it is probably underdiagnosed.\nClinical description\nUnlike classic MSUD (see this term), patients with intermittent MSUD show normal growth and intellectual development during infancy and childhood. They may develop symptoms (mainly in childhood) with any catabolic stress (i.e. fasting, dehydration, fever, infections or pregnancy (in adults)). These precipitating factors can lead to a potentially fatal episode of acute decompensation with anorexia, nausea, vomiting, lethargy, ataxia (in infants/toddlers), cognitive impairment, sleep disturbances, hallucinations, hyperactivity, mood swings, acute dystonia, and choreoathetosis (in adults), that can progress to stupor, coma and cerebral edema. Intelligence and development are not usually affected by these episodes.\nEtiology\nMSUD is due to mutations in genes encoding 3 of the 4 subunits of the branched-chain 2-ketoacid dehydrogenase (BCKAD) complex. The genes are BCKDHA (19q13.1-q13.2), encoding E1a, BCKDHB (6q14.1), encoding E1b, and DBT (1p31), encoding E2 respectively. Mutations lead to an accumulation of BCAAs (especially leucine) and branched-chain alpha-ketoacids. In intermittent MSUD, mutations in DBT may predominate.\nDiagnostic methods\nIntermittent MSUD may be missed on tandem mass spectrometry newborn screening. BCAA levels are usually normal or only slightly elevated, except during times of physiological stress when the biochemical profile is similar to classic MSUD. Ketonuria and gas chromatography-mass spectrometry can also identify branched-chain alpha ketoacids (BCKAs) in the urine during decompensation only.\nDifferential diagnosis\nDifferential diagnoses of the presenting symptoms may include other inborn errors of intermediary metabolism such as NAGS deficiency, ornithine transcarbamylase deficiency, argininosuccinic aciduria (and other urea cycle defects), neonatal glycine encephalopathy, propionic acidemia and beta-ketothiolase deficiency (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease-causing mutation.\nGenetic counseling\nInheritance is autosomal recessive and genetic counseling is possible.\nManagement and treatment\nPatients with intermittent MSUD tolerate a normal intake of leucine and treatment is not necessary. However, they need regular review at a metabolic clinic and a management strategy to avoid acute decompensation including a high-energy, low-protein diet during illness. Management of acute decompensation requires aggressive enhancement of protein anabolism which may include using glucose plus insulin, intravenous lipids, plasma amino acid monitoring, and isoleucine and valine supplements.\nPrognosis\nThe prognosis is good if metabolic control is maintained during times of stress and any episodes of acute decompensation are immediately treated.\n\n                            Last update: \n                            April 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Bridget WILCKEN"}
{"Disease Name": "Internal carotid absence", "Disease Definition": "Internal carotid artery (ICA) agenesis (uni or bilateral) is a developmental defect that may be asymptomatic or lead to cerebrovascular lesions. It is a rare malformation, with only around hundred cases reported in the literature. When symptoms are present, they are caused by cerebrovascular insufficiency, compression of the brain by vessels that dilate to compensate for the absence of the ICA, or the presence of an aneurysm. Associated intracranial aneurysms occur in 25 to 35% of patients and are often responsible for intracranial hemorrhage, which may present as the initial symptom. The absence of the ICA is the result of either agenesis or aplasia. The term agenesis is used when both the ICA and its bony canal are absent, whereas there is some evidence of carotid canals in cases of aplasia. The absence of the ICA can be detected by angiography or by computerised tomography.", "ORPHA ID": 981, "Summary": ""}
{"Disease Name": "Interstitial cystitis", "Disease Definition": "A rare non-infectious, chronic and most often progressive disease of the urinary bladder. It is characterized by varying combinations and extent of pain, urinary frequency (pollakisuria), nocturia and urgency. Interstitial cystitis (IC) has a broad intersection with Bladder Pain Syndrome (BPS) and Overactive Bladder (OAB).", "ORPHA ID": 37202, "Summary": "Epidemiology\nPrevalence of IC/BPS is approximately 1/200-2,000- for females and 1/2,450-12,500 for males. The prevalence of IC alone is less than 1/2,000. The estimated number of unreported cases might be much higher. Women are more affected than men (ratio 9:1).\nClinical description\nIC is characterized by a permanent or intermittent unpleasant sensation (pain, pressure, bladder spasms) in the pelvic (or vulvar, suprapubic, pubic, vaginal, perineal, scrotal or urethral) region of more than 6 month duration, often with worsening during bladder filling. Limited bladder capacity is frequent but not a mandatory precondition. Frequency, nocturia and urgency are often associated with IC. Two types of IC can be distinguished: Hunner-Type and Non-Hunner-Type IC.\nEtiology\nThe exact etiology of the disorder is unknown and might be multifactorial. Possible factors are urothelial alterations with an increased permeability of urine components, preceding infections (including history of bacterial cystitis), hormonal, vascular or neurological abnormalities, trauma, inflammation or autoimmune diseases. Other risk factors may include pelvic surgery, changes in microbiome, reduced microcirculation, histamine intolerance, dysfunction of the pelvic floor, endometriosis, genetic factors and psychological factors.\nDiagnostic methods\nIC is a diagnosis of exclusion. Diagnosis is based on the patient's history, questionnaires, pain protocol, bladder diary and physical examination including a pain mapping and urinalysis. Additional examinations include ultrasound, uroflowmetry, urethrocystoscopy, flow-electromyography and urodynamics, provocation tests (e.g. KCl test), hydrodistension of the bladder and bladder biopsy under anesthesia combined with a standardized counting for mast cells. A stool test may also helpful.\nDifferential diagnosis\nDifferential diagnoses include a long list of diseases of the musculoskeletal system and connective tissue, gastrointestinal diseases, gynecological diseases, neurological disorders, psychological disorders and urological diseases.\nManagement and treatment\nTreatment is most often symptomatic, and ranges from non-invasive behavioral treatment to oral medication, complementary medicine, intravesical therapy (instillation), transurethral procedures, invasive / surgical interventions and rehabilitation measures. A phased approach is recommended and the therapy should be individualized. Cystectomy and urinary diversion is an ultima ratio, although with excellent results in pain control in patients with IC.\nPrognosis\nIC is a debilitating disease and extremely affects the quality of life including physical, psychological, domestic, social, sexual and occupational aspects. IC is a chronically-recurring or chronically-progressive disease. Most often IC results in a bladder with very low capacity, high frequency and intolerable pain.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Thomas BSCHLEIPFER"}
{"Disease Name": "Interstitial granulomatous dermatitis with arthritis", "Disease Definition": "Interstitial granulomatous dermatitis with arthritis is a rare rheumatologic disease characterized by the occurrence of inflammatory arthritis in association with large, erythematous, symmetrical cutaneous lesions (ranging from typical, but infrequent, cord-like lesions on the flanks to more common violaceous plaques on the trunk and limbs) featuring a typical histologic infiltrate mainly constituted of histiocytes.", "ORPHA ID": 79099, "Summary": ""}
{"Disease Name": "Interstitial lung disease due to ABCA3 deficiency", "Disease Definition": "A rare genetic respiratory disease characterized by a variable clinical outcome ranging from a fatal respiratory distress syndrome in the neonatal period to chronic interstitial lung disease developing in infancy or childhood with chronic cough, rapid breathing, shortness of breath and recurrent pulmonary infections. Clinical manifestations of respiratory failure include grunting, intercostal retractions, nasal flaring, cyanosis, and progressive dyspnea.", "ORPHA ID": 440402, "Summary": ""}
{"Disease Name": "Interstitial lung disease due to SP-C deficiency", "Disease Definition": "A rare genetic interstitial lung disease characterized by diffuse lung disease of variable phenotype ranging from severe respiratory insufficiency in infancy to asymptomatic adults, due to surfactant protein C deficiency. Typical presentation in infancy includes dyspnea, cough, wheezing, and gradual cyanosis, with or without failure to thrive. Radiological findings include diffuse ground-glass opacities in neonates, later interstitial thickening associated with lung hyperinflation, intraparenchymal/subpleural cysts, honeycombing, subpleural nodules, or bronchiectasis. Infiltrates and air leaks are frequent complications.", "ORPHA ID": 440392, "Summary": ""}
{"Disease Name": "Interstitial lung disease-nephrotic syndrome-epidermolysis bullosa syndrome", "Disease Definition": "A life-threatening multiorgan disorder which develops in the first months of life, presenting with respiratory distress and proteinuria in the nephrotic range, and leading to severe interstitial lung disease and renal failure. Some patients additionally display cutaneous alterations, ranging from blistering and skin erosions to an epidermolysis bullosa-like phenotype, with toe nail dystrophy and sparse hair.", "ORPHA ID": 306504, "Summary": ""}
{"Disease Name": "Interventricular septum aneurysm", "Disease Definition": "Interventricular septum aneurysm is a rare, non-syndromic, congenital heart malformation characterized by the presence of a congenital aneurysm of the membranous portion of the interventricular septum. Patients may be asymptomatic or may present with ventricular or supraventricular tachycardia, fatigue, exertional dyspnea, palpitations, and cardiac murmur. Ventricular septal defects and conduction defects, such as first-degree atrio-ventricular block or incomplete right bundle branch block, may also be also associated.", "ORPHA ID": 99092, "Summary": ""}
{"Disease Name": "Intestinal botulism", "Disease Definition": "A rare form of botulism, a rare acquired neuromuscular junction disease with descending flaccid paralysis caused by botulinum neurotoxins (BoNTs), and is due to intestinal colonization by Clostridium botulinum leading to toxin-mediated infection with toxemia. The disease affects infants (infant botulism) and very rarely adults (adult intestinal botulism).", "ORPHA ID": 178481, "Summary": "Epidemiology\nPrevalence of intestinal botulism is unknown. So far, nearly 3,400 cases have been reported worldwide, mainly in infants (about 3,350 cases versus 20 cases in adults).\nClinical description\nClinical manifestations are similar to other forms of botulism, in particular those of foodborne botulism (see this term), except for the lack of gastrointestinal symptoms (nausea, vomiting and diarrhea).\nEtiology\nThe disease is caused by botulinum neurotoxins (BoNTs), produced by C. botulinum type A,B,E, or very rarely by neurotoxigenic strains of C. baratii type F and C. butyricum type E, that can temporarily colonize the intestinal tract. Colonization in adults is generally associated with anatomical abnormalities of the gastrointestinal tract or alteration of protective endogenous microflora by broad-spectrum antibiotics following inflammatory intestinal disease or surgery. Colonization in infants is believed to occur because normal competitive microflora has not been fully established. After spore germination and toxinogenesis, the toxin is absorbed into the blood stream and distributed throughout the body, causing the typical manifestations of botulism.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Lucia FENICIA"}
{"Disease Name": "Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency", "Disease Definition": "Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency is an extremely rare, autosomal recessive, gastroenterological disorder reported in three families so far that is characterized by meconium ileus without any further stigmata of cystic fibrosis (see this term) including pulmonary or pancreatic manifestations. Two of the reported patients developed chronic diarrhea in infancy. Homozygous mutations in the GUCY2C gene (12p12) leading to marked reduction or absence of enzymatic activity of guanylate cyclase 2C were found in the affected patients. The disease was reported to show partial penetrance.", "ORPHA ID": 314376, "Summary": ""}
{"Disease Name": "Intractable diarrhea of infancy", "Disease Definition": "Intractable diarrhea of infancy (IDI) is a heterogeneous syndrome that includes several diseases with different etiologies. Provisional classification of IDI, according to villous atrophy and based on immunohistological criteria, distinguishes two clearly different groups of IDI: 1) Immune-mediated: characterised by a mononuclear cell infiltration of the lamina propria and considered as being related to T cell activation. 2) The second histological pattern includes early onset severe intractable diarrhea histologically characterised by villous atrophy with low or without mononuclear cell infiltration of the lamina propria but specific histological abnormalities involving the epithelium.", "ORPHA ID": 73014, "Summary": "Clinical description\nBased on recent advances in the genetics of autoimmune enteropathy as well as the pathophysiology and clinical presentation, autoimmune enteropathy can be classified into three different types: the classical form of autoimmune enteropathy, identical to the so-called immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX) syndrome (autoimmune enteropathy type 1); autoimmune enteropathy type 2 (without extra-intestinal manifestations) and autoimmune enteropathy type 3 (in girls). Microvillus inclusion disease (MVID) and Intestinal epithelial dysplasia (IED), also known as tufting enteropathy, are congenital enteropathies presenting with villous atrophy and are thought to be related to abnormal enterocytes. Another form of IDI that should be considered in a different way from the two other groups is so-called 'phenotypic diarrhoea'' or 'syndromatic diarrhoea''. This form of IDI presents with severe early onset diarrhea resisting bowel rest, non-specific villous atrophy and very characteristic extra-digestive (facial and hair dysmorphy) manifestations.\nDiagnostic methods\nClinically, IDI may be easy to diagnose on the basis of the symptoms onset, clinical presentation and associated disorders. Histopathological analysis confirms the diagnosis.\nPrognosis\nInfants with IDI remain dependent on parenteralnutrition for months, years and, in most cases, forever because of the permanent intestinal failure associated with the high rate of digestive loss. As long-term parenteral nutrition is associated with complications and/or poor quality of life, alternative treatments, such as intestinal transplantation, have to be considered.\n\n                            Last update: \n                            March 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Olivier GOULET"}
{"Disease Name": "Intractable diarrhea-choanal atresia-eye anomalies syndrome", "Disease Definition": "Intractable diarrhea-choanal atresia-eye anomalies syndrome is characterised by the association of intractable diarrhoea of infancy with choanal atresia. Short stature, a prominent and broad nasal bridge, micrognathia, single palmar creases, chronic corneal inflammation, cytopenia, and abnormal hair texture were also reported. So far, the syndrome has been described in three children from the same family. The absence of intellectual deficit and immune deficiency allow this syndrome to be distinguished from other forms of intractable diarrhoea of infancy described previously.", "ORPHA ID": 137622, "Summary": ""}
{"Disease Name": "Intraductal papillary mucinous carcinoma of pancreas", "Disease Definition": "Intraductal papillary mucinous carcinoma of pancreas is a rare epithelial tumor of pancreas characterized by malignant, mucin-producing cystic mass, originating from the pancreatic ductal system, associated with local invasion and metastatic spread, composed of mucin-producing, columnar epithelial cells covering the dilated pancreatic ducts with a papillary structure. The presenting symptoms are non-specific and include abdominal pain, pancreatitis, steatorrhea, jaundice and diabetes. Many patients are asymptomatic at the time of diagnosis.", "ORPHA ID": 424058, "Summary": ""}
{"Disease Name": "Intraductal tubulopapillary neoplasm of pancreas", "Disease Definition": "A rare epithelial tumor of pancreas characterized by a solid, nodular mass growing within dilated pancreatic ducts, histologically composed of nodules of back-to-back tubular glands forming large cribriform structures, with high-grade dysplasia and ductal differentiation. There is no overt production of mucin. About half of the tumors occur in the head of the pancreas, one third involve the gland diffusely. Patients present with nonspecific symptoms including abdominal pain, vomiting, weight loss, steatorrhea, and diabetes mellitus, while obstructive jaundice is uncommon. This tumor type accounts for less than 1% of exocrine neoplasms and 3% of intraductal neoplasms of the pancreas.", "ORPHA ID": 580572, "Summary": ""}
{"Disease Name": "Intrahepatic cholestasis of pregnancy", "Disease Definition": "Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder characterized by (i) pruritus with onset in the second or third trimester of pregnancy, (ii) elevated serum aminotransferases and bile acid levels, and (iii) spontaneous relief of signs and symptoms within two to three weeks after delivery.", "ORPHA ID": 69665, "Summary": "Epidemiology\nICP is observed in 0.4-1% of pregnancies in most regions of Central and Western Europe and in North America. In Chile and Bolivia, as well as Scandinavia and the Baltic states, roughly 5-15% and 1-2%, respectively, of pregnancies are associated with ICP.\nClinical description\nIntrahepatic cholestasis of pregnancy increases the risk of preterm delivery (19-60%), meconium staining of amniotic fluid (27%), fetal bradycardia (14%), fetal distress (22-41%), and fetal loss (0.4-4.1%), particularly when associated with fasting serum bile acid levels >40 micromol/L.\nEtiology\nGenetic and hormonal factors, as well as environmental effects, may contribute to the pathogenesis of ICP.\nManagement and treatment\nThe hydrophilic bile acid, ursodeoxycholic acid (10-20 mg/kg/d), is today regarded as the first line treatment for intrahepatic cholestasis of pregnancy. Induction of delivery is recommended in the 38th week when lung maturity has been established.\n\n                            Last update: \n                            May 2007\n\n\n                            - Expert reviewer(s): \n                            Pr U.H.W. [Ulrich] BEUERS  - Pr Thomas PUSL"}
{"Disease Name": "Intraneural perineurioma", "Disease Definition": "Intraneural perineurioma is a rare tumor of cranial and spinal nerves arising from peripheral nerve sheath and composed exclusively or predominantly of cells showing perineurial differentiation. It presents as a localized, tubular or fusiform enlargement of a nerve or nerve segment, usually in the extremities or the trunk, associated with a motor-predominant mononeuropathy including slow, painless, gradual loss of motor function in the involved nerve trunk with muscle weakness and atrophy and, rarely, sensory dysfunction. Cranial nerve involvement is rare.", "ORPHA ID": 100003, "Summary": ""}
{"Disease Name": "Intraocular medulloepithelioma", "Disease Definition": "Intraocular medulloepithelioma is a rare eye tumor characterized by a white, gray or yellow-colored cystic mass that arises from the primitive neuroectodermal, nonpigmented epithelium of the ciliary body, or occasionally from the optic nerve, optic disc, retina or iris. Typically it has a benign clinical course with good prognosis and generally presents with childhood onset of poor vision and pain, glaucoma, and/or cataract. Leukocoria, exotropia, exophthalmos, strabismus, epiphora, change in eye color, hyphema, and raised intraocular pressure are also remarkable manifestations.", "ORPHA ID": 268139, "Summary": ""}
{"Disease Name": "Intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome", "Disease Definition": "A rare genetic disease characterized by the presence of multiple café-au-lait macules and elevated rates of sister chromatid exchange demonstrated on cytogenetic testing. Pre- and postnatal growth deficiency with short stature, microcephaly, mild developmental delay, cardiomyopathy, and symptomatic gastro-esophageal reflux have also been described, while malar rash is typically absent.", "ORPHA ID": 508512, "Summary": ""}
{"Disease Name": "Intrauterine growth restriction-short stature-early adult-onset diabetes syndrome", "Disease Definition": "A rare genetic endocrine disease characterized by intrauterine growth restriction, failure of an adolescent growth spurt with proportional adult short stature, insulin resistance, and early adulthood-onset diabetes. Minimal subluxation of the fifth metacarpal-phalangeal joint has been reported, while metaphyseal dysplasia is absent. Testicular volume is low, but fertility is normal. There is no evidence of primary adrenal insufficiency.", "ORPHA ID": 436144, "Summary": ""}
{"Disease Name": "Intravascular large B-cell lymphoma", "Disease Definition": "Intravascular large B-cell lymphoma (IVLBCL) is a very rare form of diffuse large B-cell lymphoma (see this term) characterized by the selective growth of lymphoma cells within the lumina of small blood vessels (especially the capillaries) that most often presents with a wide range of clinical manifestations (as potentially any tissue can be involved), with patients from Western countries more frequently manifesting with neurological and cutaneous symptoms while patients from Asian countries more frequently displaying hepatosplenomegaly and thrombocytopenia. IVLBCL is characterized by an absence of lymphadenopathy, an aggressive clinical course and a poor prognosis.", "ORPHA ID": 98839, "Summary": ""}
{"Disease Name": "Invasive infections due to vancomycin-resistant enterococci", "Disease Definition": "A rare bacterial infectious disease characterized by invasive infection with vancomycin-resistant enterococci (VRE), typically after VRE colonization of the gastrointestinal tract or the skin in healthcare settings. Invasive infection most commonly occurs in immunocompromised individuals and patients with breaches in normal defensive barriers (such as intravascular lines or urinary catheters). Patients may develop urinary tract infection, bacteremia, and endocarditis, as well as infections of the abdomen, pelvis, biliary tract, and wounds. Less frequent infection sites include the bone, joints, and meninges, among others.", "ORPHA ID": 90078, "Summary": ""}
{"Disease Name": "Invasive mole", "Disease Definition": "A form of gestational trophoblastic neoplasia similar to a hydatidiform mole but with deep invasion into the myometrium and histologically characterized by hyperplasia of trophoblasts, generalized cystic degeneration of chorionic villi and the presence of molar villi in the myometrium and/ or uterine blood vessels. Indicative signs include persistent unexplained metrorrhagia or secondary increase, stagnation, or non-normalization at 6 months of total serum chorionic gonadotropin (hCG) levels after evacuation of a hydatidiform mole. Metastases (in the lungs or vagina) may be observed.", "ORPHA ID": 99925, "Summary": ""}
{"Disease Name": "Invasive non-typhoidal salmonellosis", "Disease Definition": "Invasive non-typhoidal salmonellosis is a rare, bacterial, infectious disease caused by extraintestinal infection of non-typhoidal serotypes of  Salmonella enterica  in patients with underlying HIV infection, malaria or malignancy. It has a high mortality rate and patients typically present with fever, pallor and respiratory signs (cough, tachypnea, pneumonia). Gastrointestinal manifestations (diarrhea, vomit, abdominal pain) are not common. Occasionally, organ abscesses, septic shock and meningitis may be observed.", "ORPHA ID": 324648, "Summary": ""}
{"Disease Name": "Inverse Klippel-Trénaunay syndrome", "Disease Definition": "A rare vascular anomaly characterized by the association of capillary and venous malformations with hypotrophy or shortening of an affected limb due to alterations in bones, muscles, or subcutaneous tissues. In most cases, at least one of the findings is noted shortly after birth, while the other components become evident later in infancy.", "ORPHA ID": 329324, "Summary": ""}
{"Disease Name": "Inverse Marcus-Gunn phenomenon", "Disease Definition": "Inverse Marcus-Gunn phenomenon is a rare congenital synkinesis where jaw opening by the pterygoid muscle (during eating or yawning) causes eyelid drooping from inhibition of the oculomotor nerve to the levator palpebrae superioris. Familial occurrence has been reported.", "ORPHA ID": 98951, "Summary": ""}
{"Disease Name": "Inverted duplicated chromosome 15 syndrome", "Disease Definition": "A rare, complex chromosomal duplication/inversion in the region 15q11.2-q13.1 characterized by early central hypotonia, global developmental delay and intellectual deficit, autistic behavior, and seizures.", "ORPHA ID": 3306, "Summary": "Epidemiology\nPrevalence at birth is estimated at 1 in 30,000 but may be an underestimate. In patients with developmental concerns (developmental delay, intellectual disability, or autism spectrum disorder) or multiple congenital anomalies, the prevalence of partial tetrasomy of chromosome 15 is estimated to range between 1/253-584. There is an observed male predilection of 2:1.\nClinical description\nPresentation is typically with neonatal hypotonia, feeding difficulties and gross motor delay. Global developmental delay is typical in early childhood with speech and language particularly affected. Expressive language is absent or very poor and often echolalic. Comprehension is very limited and contextual. Intention to communicate is absent or very limited. Most children and adults have moderate to severe intellectual disability. The distinct behavioral disorder manifesting in children and adolescents has been widely described as autistic or autistic-like. Seizures occur in over half of affected individuals, with onset typically between 6 months and 9 years, and may include infantile spasms and myoclonic, tonic-clonic, tonic, atonic, atypical absences, and focal seizures. Various EEG (electroencephalography) abnormalities have been described. Muscle hypotonia is observed in almost all individuals, associated, in most cases, with joint hyperextensibility and drooling. Facial dysmorphism is absent or subtle, and major malformations are rare.\nEtiology\nChromosome region 15q11q13, known for its instability, is highly susceptible to clinically relevant genomic rearrangements, such as supernumerary marker chromosomes formed by the inverted duplication of proximal chromosome 15 (Inv dup(15)). It results in tetrasomy 15p and partial tetrasomy 15q. Large rearrangements, containing the Prader-Willi/Angelman syndrome critical region (PWS/ASCR), are responsible for the inv dup(15)/isodicentric 15 (idic(15)) phenotype.\nDiagnostic methods\nDiagnosis is established by standard cytogenetic and FISH (fluorescence in situ hybridization) analysis, using probes both from proximal chromosome 15 and from the PWS/ASCR. Microsatellite analysis on parental DNA or methylation analysis on the proband DNA are also needed to detect the parent-of-origin of the inv dup(15) chromosome. Array CGH (comparative genomic hybridization) has been shown to be a powerful approach for identifying and detecting both the increases in copy number of the 15q11.2q13.1 region and its extent, as well as atypical forms of idic(15).\nDifferential diagnosis\nThe possible occurrence of double supernumerary isodicentric chromosomes derived from chromosome 15, resulting in partial hexasomy of the maternally inherited PWS/ASCR, should be considered in the differential diagnosis. Mitochondrial encephalomyopathy, Rett and Angelman syndromes, and CDKL5 mutations should also be considered in the differential diagnosis.\nAntenatal diagnosis\nDue to possible maternal germline mosaicism, antenatal diagnosis maybe considered where there is an affected sibling.\nGenetic counseling\nGenetic counseling may be proposed due to possible maternal germline mosaicism but large rearrangements involving the PWS/ASCR and idic(15) are nearly always sporadic.\nManagement and treatment\nManagement of inv dup(15)/idic(15) includes a comprehensive neurophysiologic and developmental evaluation.\nPrognosis\nLife expectancy is not significantly reduced. Many adults have a severe intellectual disability with poor social interaction, and are unable to manage full self-care. Most live at home with their original family and a minority in a sheltered environment.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Agatino BATTAGLIA"}
{"Disease Name": "IRF2BPL-related regressive neurodevelopmental disorder-dystonia-seizures syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by childhood onset of severe global neurodevelopmental regression with eventual loss of independent walking and loss of language and fine and gross motor skills, and development of severe dysphagia requiring tube feeding, seizures, cerebellar syndrome, dystonia, and other neurologic manifestations. Brain imaging shows progressive cerebral and/or cerebellar atrophy in most cases. A less severe phenotype associated with missense mutations shows no regression or movement abnormalities, ambulation is preserved, and brain imaging is normal.", "ORPHA ID": 597623, "Summary": ""}
{"Disease Name": "IRIDA syndrome", "Disease Definition": "IRIDA (Iron-refractory iron deficiency anemia) syndrome is a rare autosomal recessive iron metabolism disorder characterized by iron deficiency anemia (hypochromic, microcytic) that is often unresponsive to oral iron intake and partially responsive to parenteral iron treatment.", "ORPHA ID": 209981, "Summary": "Epidemiology\n50 patients from 32 families of different ethnic origin have been described to date; however, it is likely that this condition is underdiagnosed.\nClinical description\nMost IRIDA patients have no major clinical signs, except for pallor, and have normal growth and development. The degree of anemia is mostly mild and more pronounced during childhood. If anemia is severe, they may present with weakness, fatigue, dizziness and exercise-induced dyspnea. Laboratory tests show hypochromic, microcytic anemia with very low serum iron and transferrin saturation levels and normal/high serum hepcidin values. Serum ferritin levels are mostly within the normal range, or even slightly elevated after intravenous iron treatment.\nEtiology\nIRIDA syndrome is due to mutations the TMPRSS6 gene encoding Matriptase 2, a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis.\nDiagnostic methods\nLaboratory tests show hypochromic, microcytic anemia with very low serum iron and transferrin saturation levels and normal/high serum hepcidin values. Serum ferritin levels are mostly within the normal range, or even slightly elevated after intravenous iron treatment. Molecular testing confirms the diagnosis.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            May 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Mayka SÁNCHEZ FERNÁNDEZ"}
{"Disease Name": "Iridocorneal endothelial syndrome", "Disease Definition": "Iridocorneal endothelial (ICE) syndrome describes a group of progressive corneal proliferative endotheliopathies comprised of Chandler’s syndrome, Cogan-Reese syndrome and essential iris atrophy (see these terms), affecting mainly young adult females and characterized by iris holes and atrophy, papillary distortion, anterior synechiae, corneal edema and often with secondary glaucoma and corneal decompensation as complications", "ORPHA ID": 64734, "Summary": ""}
{"Disease Name": "IRVAN syndrome", "Disease Definition": "A rare retinal vasculopathy disease characterized by idiopathic retinal vasculitis (IRV), aneurysmal dilations (A) at arteriolar bifurcations, and neuroretinitis (N), which if untreated progresses to peripheral capillary non-perfusion, retinal neovascularization, and macular exudation, leading to severe, bilateral vision loss.", "ORPHA ID": 209943, "Summary": ""}
{"Disease Name": "Isaacs syndrome", "Disease Definition": "Isaac's syndrome is an immune-mediated peripheral motor neuron disorder characterized by continuous muscle fiber activity at rest resulting in muscle stiffness, cramps, myokymia, and pseudomyotonia.", "ORPHA ID": 84142, "Summary": "Epidemiology\nPrevalence is unknown but 100 -200 cases have been reported so far.\nClinical description\nThe age of disease onset ranges from infancy to the sixth decade, with a peak incidence between forty and sixty. Isaac's syndrome is characterized by continuous muscle fiber activity at rest (even during sleep), resulting in cramps, muscle stiffness and weakness, pseudomyotonia, muscle twitching (visible myokymia), and fasciculation. Hyperhidrosis, muscle hypertrophy and hyporeflexia are also observed. Stiffness without severe pain is more remarkable in the distal than proximal muscles. In 20% of cases Isaac's syndrome is associated with malignancy (thymoma and small cell lung cancer) (see these terms). It is mainly associated with myasthenia gravis (see this term), but has incidentally been associated with other immune mediated diseases such as chronic inflammatory demyelinating polyneuropathy (CIDP), rheumatoid arthritis, Guillain-Barré syndrome, and systemic lupus erythematosus (see these terms). Some patients may present with a variant form known as Morvan syndrome (see this term) which is characterized by muscle activity and excessive perspiration and neurological findings with symptoms including personality changes, hallucinations, mood swings and sleeping disorders.\nEtiology\nThe etiology for this disorder remains unknown. However, a role for the voltage-gated potassium channel complex (VGKC) in terminal nerve fibers has been implicated by the discovery of VGKC-complex antibodies. These antibodies are not against VGKC itself, but against Caspr2 and to a lesser extent in neuromyotonia against LGI1. These antibodies down-regulate VGKC leading to repeated action potentials. The precise meaning of increased levels of VGKC-complex antibodies without Caspr2 or LGI1 antibodies is currently controversial, as is the use of immunotherapy in this specific group.\nDiagnostic methods\nDiagnosis of Isaac's syndrome relies on history, physical findings, and electromyography (EMG). Typical findings are doublet, triplet or multiplet ('myokymic') motor unit discharges and fasciculations. 35-40% of patients have elevated levels of anti-VGKC-complex antibodies, which is more frequent in Morvan syndrome than in Isaac's syndrome.\nDifferential diagnosis\nDifferential diagnosis includes hereditary neuromyotonia or myokymia (with/without episodic ataxia) syndromes, cramp-fasciculation syndrome, motor neuron diseases (progressive spinal muscle atrophy, neuropathy, amyotrophic lateral sclerosis (ALS) (see this term), intoxication (gold, mercury, toluene, insecticides) and tetanus (see this term).\nManagement and treatment\nPeripheral nerve hyperexcitability in Isaacs' syndrome can be treated with membrane-stabilizing drugs such as phenytoin, valproic acid, carbamazepine or lamotrigine, alone or in combination if necessary. If response is insufficient, oral corticosteroid (prednisolone) may be prescribed. The addition of non-steroid immunosuppressive drugs such as azathioprine and methotrexate may also be considered. Daily treatment with acetazolamide may improve twitching/writhing movements and eliminate episodes of loss of tone. Plasma exchange or intravenous immunoglobulin is indicated for severe neuromyotonia and for patients with Morvan's syndrome. In the paraneoplastic form, treatment of malignancy is warranted.\nPrognosis\nThere is no cure for Isaac's syndrome although it is not fatal. Morvan's syndrome has a more severe course and can be fatal. The long-term prognosis for individuals with paraneoplastic Isaac's syndrome is dependent on the tumor course.\n\n                            Last update: \n                            July 2013\n\n\n                            - Expert reviewer(s): \n                            Dr M.J. [Maarten] TITULAER"}
{"Disease Name": "Isobutyryl-CoA dehydrogenase deficiency", "Disease Definition": "Isobutyryl-CoA dehydrogenase deficiency is an inborn error of valine metabolism. The prevalence is unknown. Only one symptomatic patient (with anaemia, failure to thrive, dilated cardiomyopathy and plasma carnitine deficiency) has been described so far, but several series of patients have been identified through newborn screening programs relying on detection of increased C(4)-carnitine levels by tandem mass spectrometry. The disorder is caused by mutations in the ACAD8 gene (11q25).", "ORPHA ID": 79159, "Summary": ""}
{"Disease Name": "Isochromosomy Yp", "Disease Definition": "A rare sex-chromosome anomaly characterized by various clinical presentations including normal healthy fertile males, male phenotype with infertility, and males with ambiguous genitalia or incomplete masculinization.", "ORPHA ID": 98797, "Summary": ""}
{"Disease Name": "Isochromosomy Yq", "Disease Definition": "A rare sex-chromosome anomaly with a variable phenotype including a female phenotype with sexual development delay, streak gonads, short stature and Turner syndrome features, and a male phenotype with infertility due to azoospermia.", "ORPHA ID": 98798, "Summary": ""}
{"Disease Name": "Isolated absence of both forearm and hand", "Disease Definition": "Congenital absence of both forearm and hand is a rare developmental defect during embryogenesis characterized by unilateral or bilateral arrest of proximal to distal development of the upper limb, leading to a transverse deficiency with absence of the forearm, wrist and hand. A short below-the-elbow amputation is most commonly observed and the residual limb is usually well cushioned, with rudimentary nubbins or dumpling possibly found on the end.", "ORPHA ID": 294979, "Summary": ""}
{"Disease Name": "Isolated absence of both lower leg and foot", "Disease Definition": "Congenital absence of both lower leg and foot is a rare, non-syndromic, terminal transverse limb reduction defect characterized by unilateral or bilateral absence of both the tibia and the fibula, as well as the distal elements composing the foot.", "ORPHA ID": 294981, "Summary": ""}
{"Disease Name": "Isolated absence of thigh and lower leg with foot present", "Disease Definition": "Congenital absence of thigh and lower leg with foot present is a rare, non-syndromic, intercalary limb reduction defect characterized by unilateral or bilateral absence of femoral and tibio-fibular components, with the presence of intact foot elements.", "ORPHA ID": 294977, "Summary": ""}
{"Disease Name": "Isolated absence of upper arm and forearm with hand present", "Disease Definition": "A rare congenital limb malformation characterized by absence or marked shortening of the proximal to mid portion of an upper limb, while the hand is normal or nearly normal. The condition may be unilateral or bilateral, and occur sporadically or as part of a malformation syndrome.", "ORPHA ID": 294975, "Summary": ""}
{"Disease Name": "Isolated absence/hypoplasia of fingers excluding thumb, unilateral", "Disease Definition": "Congenital absence/hypoplasia of fingers excluding thumb, unilateral is a rare, non-syndromic, terminal transverse limb reduction defect characterized by unilateral absence of the terminal portions of digits 2 to 5, with a mildly hypoplastic thumb and small nail remnants on the digital stumps. Metacarpal bones may be variably reduced.", "ORPHA ID": 973, "Summary": ""}
{"Disease Name": "Isolated acheiria", "Disease Definition": "A rare non-syndromic limb reduction defect characterized by the congenital total absence of the hand and wrist with no bony elements distal to the radius or ulna. The malformation can be unilateral or bilateral.", "ORPHA ID": 294983, "Summary": ""}
{"Disease Name": "Isolated acheiropodia", "Disease Definition": "An extremely rare developmental disorder characterized by bilateral, congenital and complete amputation of the distal extremities (amputation of distal epiphysis of the humerus, distal portion of the tibial diaphysis, aplasia of the radius, ulna, fibula) and aplasia of hands and feet (aplasia of carpal, metacarpal, tarsal, metatarsal and phalangeal bones). Rarely, an ectopic bone can be found at the distal end of the humerus. No other systemic manifestations have been reported and the disorder follows an autosomal recessive pattern of inheritance.", "ORPHA ID": 931, "Summary": ""}
{"Disease Name": "Isolated agammaglobulinemia", "Disease Definition": "Isolated agammaglobulinemia (IA) is the non-syndromic form of agammaglobulinemia, a primary immunodeficiency disease, and is characterized by deficient gamma globulins and associated predisposition to frequent and recurrent infections from infancy.", "ORPHA ID": 229717, "Summary": "Epidemiology\nPrevalence is estimated to be about 1/250,000 to 1/500/000. Isolated agammaglobulinemia has been reported worldwide in all ethnic groups.\nClinical description\nTwo forms of IA have been described based on the pattern of inheritance of the genetic defects underlying the disorder: X-linked agammaglobulinemia (XLA) which represents approximately 85% of the affected patients, and autosomal agammaglobulinemia (see these terms) which includes recessive and dominant cases but is far less frequent. The clinical signs of the two forms are very similar and include recurrent bacterial infections (otitis media, pneumonia, and sinusitis), diarrhea and skin infections with onset in infancy. Late-onset agammaglobulinemia is known as common variable immunodeficiency (CVID; see this term).\nEtiology\nDefects in B lymphocyte development and maturation appear to underlie agammaglobulinemia. Mutations in seven genes have been reported to be related to IA: BTK (Xq21.33-q22), BLNK (10q23.2-q23.33), CD79A (19q13.2), CD79B (17q23), IGHM(14q32.33), IGLL1 (22q11.23), PIK3R1 (5q13.1) and TCF3 (19p13.3).\nGenetic counseling\nX-linked, autosomal recessive and autosomal dominant cases are reported.\n\n                            Last update: \n                            December 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Marie Ellen CONLEY"}
{"Disease Name": "Isolated agenesis of gallbladder", "Disease Definition": "A rare biliary tract disease characterized by congenital absence of the gallbladder and cystic duct. The majority of patients are asymptomatic. Possible clinical manifestations include abdominal pain and tenderness in the right upper quadrant, nausea, vomiting, fatty food intolerance, and jaundice. Frequency of choledocholithiasis is increased significantly.", "ORPHA ID": 440987, "Summary": ""}
{"Disease Name": "Isolated amelia of lower limb", "Disease Definition": "A rare, non-syndromic limb reduction defect characterized by complete or near-complete congenital absence of one (unilateral) or both (bilateral) of the lower extremities, occurring due to an intrauterine insult during the very early stages of embryonic development. It may be an isolated anomaly, but is more commonly observed in combination with multiple other congenital malformations.", "ORPHA ID": 294969, "Summary": ""}
{"Disease Name": "Isolated amelia of upper limb", "Disease Definition": "A rare, non-syndromic limb reduction defect characterized by complete or near-complete congenital absence of one (unilateral) or both (bilateral) of the upper extremities, occurring due to an intrauterine insult during the very early stages of embryonic development. It may be an isolated anomaly, but is more commonly observed in combination with multiple other congenital malformations.", "ORPHA ID": 294967, "Summary": ""}
{"Disease Name": "Isolated amyelia", "Disease Definition": "A rare central nervous system malformation characterized by congenital absence of the spinal cord, usually associated with segmental bony spinal anomalies. Neurologic deficits depend on the affected segments and the functioning of the residual spinal cord. Typically, the spinal cord appears normal above the defect and bulky, thickened, and low-lying caudally. Clinical presentation includes varying degrees of motor weakness (associated with deformities of the lower limbs) and neurogenic bladder dysfunction.", "ORPHA ID": 268868, "Summary": ""}
{"Disease Name": "Isolated anencephaly/exencephaly", "Disease Definition": "A neural tube defect. This malformation is characterized by the total or partial absence of the cranial vault and the covering skin, the brain being missing or reduced to a small mass. Most cases are stillborn, although some infants have been reported to survive for a few hours or even a few days.", "ORPHA ID": 1048, "Summary": "Epidemiology\nIts prevalence at birth ranges from 1 in 5000 to 1 in 2000. The prevalence at birth displays an unequal geographical distribution, with especially high rates in the British Isles, China, Mexico and Turkey. This may be attributed to the genetic backgrounds of the populations and to dietary habits.\nEtiology\nAutopsy findings reveal that anencephaly is in most cases associated with absence of adrenal glands. Anencephaly is likely to be multifactorial, the result of gene-environment interactions. Folic acid and zinc deficiencies, as well as maternal obesity, have been shown to be risk factors.\nAntenatal diagnosis\nPrenatal diagnosis can be made easily by ultrasonography in the first trimester of pregnancy when the cranial vault is not yet apparent.\nGenetic counseling\nFamilial cases with a seemingly autosomal recessive mode of inheritance have been described but most cases are sporadic.\nManagement and treatment\nPrevention of recurrence for subsequent pregnancies should include prescription of 4 mg/day of folic acid, to be started before pregnancy and continued until the second missed period. For subsequent pregnancies there is also an increased risk of spina bifida.\n\n                            Last update: \n                            March 2006"}
{"Disease Name": "Isolated aniridia", "Disease Definition": "Isolated aniridia is a congenital bilateral ocular malformation characterized by the complete or partial absence of the iris.", "ORPHA ID": 250923, "Summary": "Epidemiology\nThe annual incidence is estimated at 1/ 64,000- 1/ 96,000.\nClinical description\nIsolated aniridia can occur in association with a range of other ocular anomalies including cataract, glaucoma (usually occurring during adolescence), corneal pannus, optic nerve hypoplasia, absence of macular reflex, ectopia lentis, nystagmus, and photophobia, all of which generally result in poor vision.\nEtiology\nAniridia is due to mutations in the PAX6 gene (11p13) encoding a transcriptional regulator involved in oculogenesis. PAX6 mutations result in alterations in corneal cytokeratin expression, cell adhesion and glycoconjugate expression.\nDiagnostic methods\nDiagnosis is based on ophthalmological examination and is confirmed by mutation detection of the PAX6 gene.\nAntenatal diagnosis\nAntenatal diagnosis is only possible when the underlying genetic defect is known. It is performed by invasive procedures like chorionic villus sampling (CVS) or amniocentesis and molecular analysis of fetal DNA.\nGenetic counseling\nAniridia is inherited in an autosomal dominant manner with high penetrance and variable expression. About two-thirds of affected children have an affected parent and one-third of cases occur in sporadic form.\nManagement and treatment\nA regular follow-up is necessary. Intraocular pressure should be measured yearly for detection of glaucoma. Keratolimbal allograft (a stem cell transplantation technique) has been evaluated as a treatment of the aniridic keratopathy, which is a major cause of vision loss in aniridia patients. Glaucoma drainage is used to treat secondary angle closure glaucoma.\nPrognosis\nAniridia results in poor vision, the mean visual acuity being around 0,19 in young adulthood.\n\n                            Last update: \n                            March 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Michael PETERSEN"}
{"Disease Name": "Isolated ankyloblepharon filiforme adnatum", "Disease Definition": "Isolated ankyloblepharon filiforme adnatum (AFA) is characterised by the presence of single or multiple thin bands of connective tissue between the upper and lower eyelids, preventing full opening of the eye. Several cases have been reported. It can occur sporadically or following an autosomal dominant transmission pattern. In some cases, AFA can be associated with other disorders, such as trisomy 18. The bands should be removed to avoid amblyopia and this can easily be performed in the neonatal period by cutting with tissue scissors.", "ORPHA ID": 91397, "Summary": ""}
{"Disease Name": "Isolated anterior cervical hypertrichosis", "Disease Definition": "A rare form of localised hypertrichosis characterized by hair growth near the laryngeal prominence during childhood.", "ORPHA ID": 3387, "Summary": ""}
{"Disease Name": "Isolated apodia", "Disease Definition": "A rare non-syndromic limb reduction defect characterized by congenital total absence of the foot and ankle with no bony elements distal to the tibia or fibula, while the lower leg, including the epiphysis of the tibia and fibula, is present. The malformation can be unilateral or bilateral.", "ORPHA ID": 294986, "Summary": ""}
{"Disease Name": "Isolated arhinencephaly", "Disease Definition": "Isolated arhinencephaly is a rare non-syndromic central nervous system malformation defined by the agenesis of the olfactory bulbs and tracts and characterized by complete congenital anosmia.", "ORPHA ID": 268936, "Summary": ""}
{"Disease Name": "Isolated arrhinia", "Disease Definition": "An extremely rare, major congenital malformation consisting of an absence of the nose ranging from hyporrhinia (absence of external nasal structures) to total arrhinia (absence of external nose, nasal airways, olfactory bulbs, or olfactory nerve) often causing respiratory distress and requiring surgical correction. Arrhinia can be bilateral or unilateral (hemiarrhinia). Associated anomalies include ocular features (hypertelorism, microphthalmia, eyelid coloboma), facial clefts, midline defects and microtia.", "ORPHA ID": 1134, "Summary": ""}
{"Disease Name": "Isolated asymptomatic elevation of creatine phosphokinase", "Disease Definition": "A rare neurologic biological anomaly characterized by persistent elevation of the serum creatine phosphokinase (CK) without any clinical, neurophysical or histopathological evidence of neuromuscular disease using the available laboratory procedures. It is usually an incidental finding, diagnosed after exclusion of other possible causes of elevated CK levels.", "ORPHA ID": 206599, "Summary": ""}
{"Disease Name": "Isolated ATP synthase deficiency", "Disease Definition": "Isolated ATP synthase deficiency is a rare, genetic, mitochondrial oxidative phosphorylation disorder that may present with a wide range of symptoms (including muscular hypotonia, hypertrophic cardiomyopathy, psychomotor delay, encephalopathy, peripheral neuropathy, lactic acidosis, 3-methylglutaconic aciduria) and clinical syndromes (including NARP and MILS).", "ORPHA ID": 254913, "Summary": ""}
{"Disease Name": "Isolated autosomal dominant hypomagnesemia, Glaudemans type", "Disease Definition": "Isolated autosomal dominant hypomagnesemia, Glaudemans type (IADHG) is a form of familial primary hypomagnesemia (FPH, see this term), characterized by low serum magnesium (Mg) values but normal urinary Mg values. The typical clinical features are recurrent muscle cramps, episodes of tetany, tremor, and muscle weakness, especially in distal limbs. The disease is potentially fatal.", "ORPHA ID": 199326, "Summary": "Epidemiology\nIADHG has only been described in one large Brazilian kindred with 46 family members, of whom 21 were affected.\nClinical description\nOnset of IADHG is typically in infancy. Clinical manifestations consist of recurrent and severe muscle cramps, episodes of tetany, tremor, and muscle weakness, especially in distal limbs. Additional features include facial myokymia, arythmias, severe muscle spasms and muscular pain.\nEtiology\nIADHG is caused by a N255D mutation in the KCNA1 gene (12p13), which encodes the voltage-gated potassium channel Kv1.1 (expressed in the kidney, where it colocalized with TRPM6 in apical membrane of distal convoluted tubule). Mutations in KCNA1 result in a nonfunctional channel protein, with a dominant negative effect on wild-type Kv1.1 channel function, which is involved in the maintenance of membrane voltage and optimal function of the TRPM6 channel.\nDiagnostic methods\nDiagnosis relies on laboratory findings showing low serum Mg levels, while serum potassium (K) and calcium (Ca) levels and urinary Ca excretion are not affected. Diagnosis is confirmed by genetic screening of KCNA1.\nDifferential diagnosis\nDifferential diagnosis includes the other forms of FPH and episodic ataxia type 1 (see these terms).\nGenetic counseling\nTransmission is autosomal dominant. Genetic counseling may be proposed and the recurrence risk is 50%.\nManagement and treatment\nManagement is mainly symptomatic and involves a daily dose of magnesium chloride. During manifestations, intravenous or intramuscular administration of magnesium sulfate is preferred.\nPrognosis\nPrognosis highly depends on rapidity of diagnosis and treatment, as the disease can be fatal following tetany attacks.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Rosa VARGAS-POUSSOU"}
{"Disease Name": "Isolated bilateral hemispheric cerebellar hypoplasia", "Disease Definition": "Isolated bilateral hemispheric cerebellar hypoplasia is a rare cerebellar malformation characterized by hypoplasia of both cerebellar hemispheres with no other cerebellar/cerebral anomaly or other associated clinical feature. Affected patients present with mild hypotonia with motor delay, mild cognitive impairment, language delay, visuospatial and verbal memory deficits, dysdiadochokinesis, intentional tremor, and possible presence of emotional fragility and mild depression.", "ORPHA ID": 269221, "Summary": ""}
{"Disease Name": "Isolated biliary atresia", "Disease Definition": "A rare, biliary tract disease characterized by progressive obliterative cholangiopathy of the intra- and extrahepatic bile ducts, occuring in the embryonic/ perinatal period, leading to severe and persistent neonatal jaundice and acholic stool.", "ORPHA ID": 30391, "Summary": "Epidemiology\nBiliary atresia (BA) prevalence at birth is 1/ 15,000-19,000 in Europe and North America.\nClinical description\nDiagnosis is mostly made at 2-6 weeks of age, presenting with cholestasis, jaundice, acholia and possibly choluria and hepatomegaly, and sometimes vitamin K deficiency induced bleedings. Conjugated hyperbilirubinemia associated with an increase in γ-glutamyltransferase (GGT) are biochemical signs of the disease. The pathology is characterized by an ongoing inflammatory process of the entire biliary tree, although the disease is defined as an irreversible closure/ atresia of the extrahepatic bile ducts. In 10-20% of cases, biliary atresia is associated with other malformations (syndromic biliary atresia).\nEtiology\nThe etiology is yet to be explained, but it is believed that it can be the result of the interaction of genetic, environmental, immune, and infectious factors, individually or in combination.\nDiagnostic methods\nPreoperative evaluation may include abdominal ultrasound, hepatobiliary scintigraphy, percutaneous liver biopsy, endoscopic retrograde cholangiopancreatography, and magnetic resonance cholangiopancreatography (MRCP). However, the definitive diagnosis is confirmed only by cholangiography.\nDifferential diagnosis\nThe differential diagnosis include other causes of neonatal cholestasis, for example infections, Alagille syndrome, alpha-1-antitrypsin deficiency, progressive familiar intrahepatic cholestasis (PFIC) and hormonal deficiencies.\nAntenatal diagnosis\nSigns of biliary atresia on prenatal ultrasonography has rarely been reported.\nGenetic counseling\nThe disease is not yet identified to be hereditary. The genetic counseling is therefore not possible.\nManagement and treatment\nKasai portoenterostomy is the gold standard treatment, consisting in total extraction of the hilar fibrosis and subsequent biliary-enteric anastomosis, with favorable results in a maximum of 50% of cases, in which there is total restitution of the biliary drainage and normalization of total bilirubin levels.\nPrognosis\nThe main prognostic factors to short- and long-term survival after surgery include age at surgery, type of biliary atresia, and experience of the center. Out of the possible complications, the most common are cholangitis, portal hypertension, and ongoing deterioration of the liver function with cirrhosis, leading to end-stage failure. Early liver transplantation is required in about 50% of the cases. Very long term survival with native liver decreases to about 25%.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Björn FISCHLER | RARE-LIVER* - Pr Claus PETERSEN | RARE-LIVER*\n\n\n                                * European Reference Network"}
{"Disease Name": "Isolated blepharochalasis", "Disease Definition": "A rare palpebral disorder characterized by recurrent episodes of painless eyelid edema. It usually occurs bilaterally, typically affects the upper eyelids, and may manifest as a hypertrophic form resulting in orbital fat herniation through a weakened orbital septum, or an atrophic form with atrophy of redundant eyelid skin and superior nasal fat pads. Additional findings are formation of pseudoepicanthal folds, lacrimal gland prolapse, or ptosis.", "ORPHA ID": 519390, "Summary": ""}
{"Disease Name": "Isolated bone marrow mastocytosis", "Disease Definition": "A rare subtype of indolent systemic mastocytosis characterized by isolated bone marrow involvement without skin lesions, low burden of neoplastic mast cells, and often normal or near normal serum tryptase levels. The KIT D816V mutation is present in the majority of cases.", "ORPHA ID": 158778, "Summary": ""}
{"Disease Name": "Isolated cerebellar agenesis", "Disease Definition": "A rare non-syndromic central nervous system malformation characterized by complete or near-complete absence of the cerebellum with a normal sized posterior fossa, possibly accompanied by hypoplasia of the brainstem. The clinical picture is highly variable, but typically includes ataxia, dysarthria, tremor, dysmetria, dysdiadochokinesia, and oculomotor abnormalities, in addition to impaired mental, motor, and language development and intellectual disability.", "ORPHA ID": 1398, "Summary": ""}
{"Disease Name": "Isolated cerebellar vermis agenesis", "Disease Definition": "A rare, congenital, cerebellar malformation disorder characterized by complete or partial cerebellar vermis agenesis, with no other associated malformations or anomalies. Patients may be asymptomatic, although psychomotor delay, hypotonia and incoordination are usually associated. Additional variable manifestations include intellectual disability, oculomotor abnormalities (such as nystagmus, impaired smooth pursuit, impaired saccades, strabismus, ptosis, and oculomotor apraxia), retinopathy, abnormal visual evoked potentials, ataxia, episodic hyperpnea, and delayed gait acquisition, as well as delayed speech and language development.", "ORPHA ID": 269203, "Summary": ""}
{"Disease Name": "Isolated cerebellar vermis hypoplasia", "Disease Definition": "Isolated cerebellar vermis hypoplasia is a rare, non-syndromic cerebellar malformation characterized by an underdeveloped cerebellar vermis. Patients may present a variable phenotype ranging from normal neurodevelopment to motor and/or language delay, variable degrees of cognitive impairment, hypotonia, equilibrium disturbances, static/dynamic ataxia, oculomotor abnormalities, epilepsy and/or clumsiness. Behavioral disorders such as attention deficit hyperactivity disorder and generalized anxiety have also been reported. Brain MRI may reveal diffuse or selective (mostly posterior) vermian cerebellar hypoplasia and EEG may show focal paroxysms.", "ORPHA ID": 199630, "Summary": ""}
{"Disease Name": "Isolated childhood apraxia of speech", "Disease Definition": "A rare neurologic disease characterized by impaired ability to execute complex coordinated movements underlying the production of speech, leading to highly unintelligible speech in the absence of muscular or sensory deficits.", "ORPHA ID": 209908, "Summary": "Epidemiology\nThe exact prevalence of isolated childhood apraxia of speech (CAS) is unknown. Regarding CAS due to FOXP2 variants, approximately 35 individuals from 11 families with intragenic, pathogenic variants have been described in the literature so far. Moreover, a few individuals with speech and language disorders and larger deletions on chromosome 7 including FOXP2 or other structural variants in or next to FOXP2 have been reported.\nClinical description\nCAS is characterized by the impairment of the precision and consistency of movements underlying speech in the absence of neuromuscular deficits. Initial signs may include absence of babbling or delay of first words during infancy. Additional manifestations including dysarthria, oral motor dyspraxia, receptive and expressive language impairment, impairment of reading and spelling, global developmental delay, autistic features, and minor facial dysmorphism have been described occasionally for patients with CAS due to FOXP2 variants.\nEtiology\nThe disorder may be idiopathic or due to FOXP2 (7q31.1) haploinsufficiency. FOXP2 (7q31.1) encodes forkhead box protein P2, a member of the forkhead box family of transcription factors. Usually, heterozygous missense variants within the forkhead domain or truncating variants are identified but also larger deletions containing FOXP2 or structural aberrations disrupting FOXP2 have been reported.\nDiagnostic methods\nDiagnosis is usually by targeted analysis upon clinical suspicion or by more unbiased approaches such as chromosomal microarray analysis (deletions including FOXP2), multigene panel or exome sequencing.\nDifferential diagnosis\nDifferential diagnosis includes syndromic disorders with overlapping, prominent speech and language impairment and a variety of additional clinical aspects (e. g. intellectual disability, epilepsy, growth phenotypes, malformations) and includes 7q31 microdeletion syndrome, 16p11.2 microdeletion syndrome, 7q11.23 duplication syndrome, KANSL1-related intellectual disability syndrome, and GRIN2A-related disorders. CAS, although mostly not isolated, can also occur secondary to intrauterine stroke, infections, or trauma.\nAntenatal diagnosis\nIn principle possible, if the underlying pathogenic variant in the family is known.\nGenetic counseling\nRecurrence risk for siblings of an affected individual depends on the underlying cause of CAS. Recurrence risk for CAS due to FOXP2 alterations is low if the pathogenic variant occurred de novo and 50 % if it is inherited from one of the parents. Genetic counseling should be offered.\nManagement and treatment\nA multidisciplinary team including a speech and language pathologist, a pediatrician, an occupational therapist, and a neuropsychologist is required for evaluation of the phenotypic extent and to determine the individual treatment plan. Augmentative and alternative communication (use of sign language, picture boards or computers) may be useful in some cases.\nPrognosis\nPrognosis depends on the underlying cause of CAS. It is usually good in the context of intragenic FOXP2 variants, as clinical aspects are limited to speech and language impairment in most cases. However, learning disabilities or behavioral abnormalities may additionally occur. Though speech development and intelligibility usually improve over time, a lifelong speech and language impairment might be present.\n\n                            Last update: \n                            May 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Melissa RIEGER | ITHACA* - Pr Christiane ZWEIER \n\n\n                                * European Reference Network"}
{"Disease Name": "Isolated cleft lip", "Disease Definition": "Isolated cleft lip is a fissure type embryopathy extending from the upper lip to the nasal base.", "ORPHA ID": 199302, "Summary": "Epidemiology\nThe annual incidence is 1/4,000 to 1/10,000 births with major variation occurring between geographic locations and ethnic groups. Cleft lip is twice as common in boys as girls and is seen more frequently on the left side.\nClinical description\nThe cleft is paramedian and located at the level of the philtrum. It presents as a cutaneous, muscular and mucosal interruption from the lip to the nasal base, associated with nostril and nasal septum deformations. Clinical forms range from a simple notch in the upper lip to a complete cleft lip with an opening at the base of the nostril without reaching as far as the gum (alveolar ridge).\nEtiology\nThis embryopathy appears between the 5th and 12th week of pregnancy due to a failure in the fusion of the frontal processes (fronto-nasal process, medial and lateral nasal processes, maxillary process). Cleft lip is an isolated, non-syndromic anomaly in 70% of cases. The remaining 30% of cases are seen in at least 300 syndromes where cleft lip is just one of the featured anomalies. Non-syndromic clefts are possibly caused by a combination of genetic and environmental factors. Factors such as the exposure to teratogenic substances during pregnancy (alcohol, tobacco or drugs) can have an influence on genetic susceptibility.\nDiagnostic methods\nThe diagnosis is clinical.\nDifferential diagnosis\nThe presence of associated malformations allows for differentiation between isolated and syndromic forms.\nAntenatal diagnosis\nAntenatal diagnosis is often possible with a prenatal ultrasound. The case is submitted to a multidisciplinary center for prenatal diagnosis in order to establish if it is an isolated anomaly.\nManagement and treatment\nManagement requires multidisciplinary medical and surgical intervention from birth until the end of development. It involves primary surgery sometimes followed by secondary maxillo-facial and plastic surgery. An initial treatment timeline is established during the neonatal period. Secondary management is adapted to the child's age and based on morphological and functional problems that may arise during growth and development. Breathing difficulties can occur due to the nostril anomaly and the deviation of the vomer, of the nasal septum and to the turbinate hypertrophy. Secondary surgery of the nose can be performed to improve appearance and function.\nPrognosis\nPrognosis is dependent on the quality of initial management and the regular follow-up by an experienced interdisciplinary team until the child is fully grown. Cleft lip can have functional (morphological, respiratory), esthetic and psychological consequences that require management in a specialized health center.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Isolated complex I deficiency", "Disease Definition": "Isolated complex I deficiency is a rare inborn error of metabolism due to mutations in nuclear or mitochondrial genes encoding subunits or assembly factors of the human mitochondrial complex I (NADH: ubiquinone oxidoreductase) and is characterized by a wide range of manifestations including marked and often fatal lactic acidosis, cardiomyopathy, leukoencephalopathy, pure myopathy and hepatopathy with tubulopathy. Among the numerous clinical phenotypes observed are Leigh syndrome, Leber hereditary optic neuropathy and MELAS syndrome (see these terms).", "ORPHA ID": 2609, "Summary": ""}
{"Disease Name": "Isolated complex III deficiency", "Disease Definition": "Isolated complex III deficiency is a rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by a wide spectrum of clinical manifestations ranging from isolated myopathy or transient hepatopathy to severe multisystem disorder (that may include hypotonia, failure to thrive, psychomotor delay, cardiomyopathy, encephalopathy, renal tubulopathy, hearing impairment, lactic acidosis, hypoglycemia and other signs and symptoms).", "ORPHA ID": 1460, "Summary": ""}
{"Disease Name": "Isolated congenital adermatoglyphia", "Disease Definition": "Isolated congenital adermatoglyphia is a rare, genetic developmental defect during embryogenesis disorder characterized by the lack of epidermal ridges on the palms and soles, resulting in the absence of fingerprints, with no other associated manifestations. It is associated with a reduced number of sweat gland openings and reduced transpiration of palms and soles.", "ORPHA ID": 289465, "Summary": ""}
{"Disease Name": "Isolated congenital alacrima", "Disease Definition": "Congenital alacrima is characterised by deficient lacrimation (ranging from a complete absence of tears to hyposecretion of tears) that is present from birth.", "ORPHA ID": 91416, "Summary": "Epidemiology\nPrevalence is unknown.\nGenetic counseling\nTransmission is usually autosomal recessive, but dominant transmission has also been described.\nManagement and treatment\nArtificial tears are the first treatment option, needed to avoid corneal sequelae.\n\n                            Last update: \n                            April 2007"}
{"Disease Name": "Isolated congenital anonychia", "Disease Definition": "Isolated congenital anonychia is characterized by nail abnormalities ranging from onychodystrophy (dystrophic nails) to anonychia (absence of nails). Onychodystrophy-anonychia has been described in at least four generations of a family with male-to-male transmission, suggesting autosomal dominant transmission. Anonychia has been described in approximately less than 20 cases; it is likely to be transmitted as an autosomal recessive trait. Total anonychia congenita, in which all the fingernails and toenails are absent, may have an autosomal dominant inheritance pattern.", "ORPHA ID": 79143, "Summary": ""}
{"Disease Name": "Isolated congenital anosmia", "Disease Definition": "A rare otorhinolaryngologic disease characterized by total or partial anosmia at birth. The anosmia is caused by a defect in the development of the olfactory bulbs or by replacement of the olfactory epithelium by respiratory epithelium. Isolated congenital anosmia is found in some parents of individuals with Kallman syndrome.", "ORPHA ID": 88620, "Summary": ""}
{"Disease Name": "Isolated congenital auditory ossicle malformation", "Disease Definition": "Isolated congenital auditory ossicle malformation is a rare, congenital, middle ear anomaly characterized by, usually unilateral and sporadic, variations in the number, size and/or configuration of the ossicles, with no tympanic membrane and external ear abnormalities and no history of trauma or infection. Patients frequently present late, after schooling has started, with non-progressive, conductive hearing loss often associated with speech delay and poor school performance.", "ORPHA ID": 162526, "Summary": ""}
{"Disease Name": "Isolated congenital breast hypoplasia/aplasia", "Disease Definition": "A rare breast malformation characterized by congenital absence of breast and nipple (amastia), or nipple or mammary gland (athelia or amazia, respectively). It can be unilateral or bilateral and may occur as an isolated malformation or be associated with a syndrome or cluster of other anomalies.", "ORPHA ID": 180188, "Summary": ""}
{"Disease Name": "Isolated congenital ectropion", "Disease Definition": "Isolated congenital ectropion is a rare ocular disease characterized by congenital, unilateral or bilateral, lower or upper eyelid malposition with eversion of the margin due to a vertical shortage of skin, leading to exposure of the conjunctiva and sometimes the cornea. Chronic epiphora and exposure keratitis may be observed in severe cases.", "ORPHA ID": 99171, "Summary": ""}
{"Disease Name": "Isolated congenital entropion", "Disease Definition": "A rare eyelid malposition disorder characterized by congenital abnormal inversion of the eyelid towards the globe, potentially causing mechanical irritation of the ocular surface by the eyelashes, which may lead to corneal abrasion and scarring with visual impairment. Typical initial symptoms are foreign body sensation, redness, tearing, and ocular discharge.", "ORPHA ID": 519386, "Summary": ""}
{"Disease Name": "Isolated congenital hepatic fibrosis", "Disease Definition": "A rare parenchymal liver disease characterized by progressive fibrosis of the portal tracts due to arrest of maturation of the ductal plate of the intrahepatic bile ducts. Clinically, it may manifest as a portal hypertensive, cholangitic, mixed, or latent form. Onset of symptoms is mostly in adolescence or young adulthood. Hepatocellular function is relatively well preserved.", "ORPHA ID": 485426, "Summary": ""}
{"Disease Name": "Isolated congenital hypoglossia/aglossia", "Disease Definition": "A rare head and neck malformation characterized by congenital partial (hypoglossia) or total (aglossia) absence of the tongue. Patients present feeding and respiratory difficulties, as well as delayed speech development and slurred speech. Taste perception is not severely compromised. Associated features include a characteristic facies due to mandibular transverse arch deficiency, oligodontia, and malocclusion, among others.", "ORPHA ID": 141152, "Summary": ""}
{"Disease Name": "Isolated congenital hypogonadotropic hypogonadism", "Disease Definition": "A rare, genetic pituitary hormone deficiency characterized by gonadotropin (Gn) deficiency with low sex steroid levels associated with low levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH). This disorder may be associated with a normal (normosmic) or impaired sense of smell (Kallmann syndrome).", "ORPHA ID": 238666, "Summary": "Epidemiology\nExact prevalence is unknown but is estimated to be between 1/5,000 and 1/10, 000.\nClinical description\nCongenital hypogonadotrophic hypogonadism (CHH) is isolated when the deficiency is restricted to the gonadotrope axis. Diagnosis is typically during adolescence due to the absence or incomplete pubertal development although it may be suspected at birth in males with micropenis (often associated with cryptorchidism). Later diagnosis during adulthood is possible, but less frequent, as a result of infertility. Isolated CHH can be associated with normal sense of smell (normosmic CHH) or anosmia/hyposmia with hypoplasia or aplasia of the olfactory bulbs (Kallmann syndrome). Untreated adult males exhibit absent or reduced virilization and usually have decreased bone density and muscle mass, decreased testicular volume (< 4 mL), erectile dysfunction, diminished libido and infertility. Untreated adult females almost always experience primary amenorrhea with absent, little or even normal pubic hair and breast development. Kallmann syndrome may be associated with addition anomalies including sensorineural deafness, renal agenesis and midline defects.\nEtiology\nIsolated CHH is the result of the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), the master hormone regulating the reproductive axis. This is frequently due to failure of GnRH neurons in the hypothalamus to differentiate, develop (Kallmann syndrome) or secrete GnRH. In a subgroup of patients, the defect is due to GnRH resistance in pituitary gonadotropic cells (e.g. loss of function mutations in the GnRH receptor). Many genes have been implicated in the pathogenesis.\nDiagnostic methods\nDiagnosis is based on clinical evaluation of the hypogonadism and hormone testing to confirm gonadotropin deficiencies (FSH and LH) caused by GnRH deficiency. Laboratory tests should be performed either in the first six months of life or after 12-13 years of age. Further investigations may include familial and patient history, tests for anosmia and hearing loss, and MRI for identifying olfactory bulb and/or sulcus anomalies. However, the current increased use of next generation sequencing (targeted exome) in clinical practice allows the identification of causative genes without necessarily completing an exhaustive search for associated signs.\nDifferential diagnosis\nDifferential diagnoses should include other causes of micropenis and cryptorchidism at birth (syndromic or isolated), transitory hypogonatorphic-hypogonadism (associated with constitutional delay of growth and puberty), functional hypogonatorphic-hypogonadism associated with caloric restriction or undernutrition, hypothyroidism, and secondary causes of HH (hypothalamic-pituitary tumors / adenomas or infiltrations (iron overload), surgical or radiation therapy-induced sequelae, as well as other endocrine diseases).\nAntenatal diagnosis\nFetal ultrasound monitoring of anomalies associated with Kallmann syndrome may be useful but genetic prenatal diagnosis is generally not considered because of the good prognosis and the usual absence of major disability.\nGenetic counseling\nThe inheritance patterns of congenital hypogonadotropic hypogonadism vary and include X-linked recessive, autosomal recessive, autosomal dominant, oligogenic as well as sporadic forms. Genetic counseling should be offered accordingly.\nManagement and treatment\nCHH is one of the rare treatable causes of male infertility. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the possible psychological effects. In most cases, fertility can be induced using specialized treatment regimens, best deployed in a reference center, and patients typically require life-long treatment and monitoring in order to maintain sexual function and secondary sexual characteristics, although ~10-20% of patients exhibit a spontaneous recovery of reproductive function and some men seem to sustain reversal of the disease after discontinuation of hormonal therapy.\nPrognosis\nThe prognosis is generally good, with the outcome for fertility depending, particularly in affected males, on the severity of the sex hormone deficiency and the age of initiation of treatment. Rare cases of complete resolution have been described.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Jacques YOUNG"}
{"Disease Name": "Isolated congenital laryngeal web", "Disease Definition": "A rare laryngeal malformation characterized by a membrane-like structure of variable thickness that extends across the laryngeal lumen, between the vocal cords.", "ORPHA ID": 2374, "Summary": "Epidemiology\nThe worldwide prevalence is unknown. Congenital laryngeal web represents fewer than 5% of congenital laryngeal anomalies.\nClinical description\nManifestations may appear at any age (mostly with hoarse or weak voice) but onset usually occurs during infancy (respiratory distress, stridor and an unusual cry). Clinical manifestations and their severity vary with the extent of obstruction and glottic involvement. Webs are categorized in the Cohen classification on the basis of glottic involvement. Type 1 are thin webs with <35% of glottic involvement. Type 2 are webs with 35-50% of glottic involvement. Type 3 are webs with 50-75% of glottic involvement and subglottic stenosis due to anterior cricoid cartilage extension; type 4 are webs with 75-90% of glottic involvement and subglottic stenosis due to anterior cricoid cartilage extension. Other larynx anomalies, such as laryngeal cleft and congenital subglottic stenosis, may be associated with this malformation.\nEtiology\nThe malformation is a result of anomalous embryologic development of the larynx, stemming from incomplete resorption of the epithelial layer that normally obliterates the developing laryngeal opening at about the sixth week of gestation. This layer is usually completely eliminated by the tenth week. Since resorption proceeds from the dorsal to the ventral side, laryngeal webs are anteriorly located, leaving a posterior lumen. Although no gene was been specifically identified as the cause for this malformation, over half of the patients present with a syndromic form of the disease caused by a chromosome 22q11.2 deletion. Other genetic syndromes may also be associated with this malformation.\nDiagnostic methods\nDiagnosis of congenital laryngeal web is based on clinical signs (dysphonia, respiratory distress) and laryngeal endoscopy. A significant part of the patients presents with comorbidities such as chromosomal and cardiovascular anomalies. Patients should undergo genetic screening, which must include testing for a chromosome 22q11 deletion, and a thorough cardiovascular evaluation, which should include imaging of the aortic arch.\nDifferential diagnosis\nApart from syndromic forms linked to 22q11.2 deletion syndrome, the differential diagnosis includes laryngeal congenital complex stenosis, laryngeal papillomatosis, and subglottic cysts.\nGenetic counseling\nGenetic counseling with testing for 22q11 deletion is highly recommended. The mode of inheritance is autosomal dominant and families should be informed that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nThe primary goals of treatment are to provide a patent airway and to achieve a good voice quality. However, vocal cords have a tendency for restenosis, fibrosis and granulation tissue formation after a surgical procedure and notably at their anterior part, where the web is usually located. The management and treatments range from surveillance (for small and thin web with no effect on ventilation and no or light dysphonia) to endoscopic section with cold instruments or laser. A laser should be used carefully because of the alleged extra scarring the burns induce, increasing the risk of restenosis. Good voice quality is mainly achieved in patients with thin, membranous, uncomplicated webs. Treatment for thick webs, with or without associated congenital subglottic stenosis, remains unsatisfactory. Thick webs can be assimilated to congenital laryngeal stenosis, and therefore treated by endoscopic section but above all laryngoplasty by external approach and stenting.\nPrognosis\nThe laryngeal prognosis is usually good even if the dysphonia may not disappear totally over time.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Nicolas LEBOULANGER | ERN CRANIO* - Dr Roman LUSCAN | ERN CRANIO* - Dr Briac THIERRY | ERN CRANIO*\n\n\n                                * European Reference Network"}
{"Disease Name": "Isolated congenital megalocornea", "Disease Definition": "Isolated congenital megalocornea is a genetic, non-syndromic developmental defect of the anterior eye segment characterized by bilateral enlargement of the corneal diameter (>12.5 mm) and a deep anterior eye chamber, without an elevation in intraocular pressure. It can manifest with mild to moderate myopia as well as photophobia and iridodonesis (due to iris hypoplasia). Associated complications include lens dislocation, retinal detachment, presenile cataract development, and secondary glaucoma.", "ORPHA ID": 91489, "Summary": ""}
{"Disease Name": "Isolated congenital microcephaly", "Disease Definition": "A rare neurological disorder characterized by a reduced head circumference at birth with no gross anomalies of brain structure. It can be an isolated finding or it can be associated with seizures, developmental delay, intellectual disability, balance disturbances, hearing loss or vision problems.", "ORPHA ID": 199642, "Summary": ""}
{"Disease Name": "Isolated congenital nasal pyriform aperture stenosis", "Disease Definition": "A rare otorhinolaryngological malformation characterized by narrowing of the pyriform aperture (i. e. < 8 to 10 mm in a full-term infant) due to an overgrowth of the nasal process of the maxilla, resulting in potentially lethal nasal airway obstruction in the newborn. Depending on the degree of obstruction, clinical signs and symptoms include inspiratory stridor, respiratory distress, cyanosis, sternal retraction, ribcage asymmetry, and feeding difficulties.", "ORPHA ID": 162516, "Summary": ""}
{"Disease Name": "Isolated congenital onychodysplasia", "Disease Definition": "A rare isolated nail anomaly characterized by congenital unilateral or bilateral nail dysplasia (including micronychia, polyonychia, anonychia, hemionychrogryphosis, and malalignment) commonly involving the index fingers and/or other fingers or also toes, frequently associated with bony anomalies of the affected digits (such as Y-shaped bifurcation of the distal phalanx, brachymesophalangy, or syndactyly). The condition can be sporadic or familial.", "ORPHA ID": 79144, "Summary": ""}
{"Disease Name": "Isolated congenital radial head dislocation", "Disease Definition": "A rare congenital limb malformation characterized by mostly posterior, less frequently also anterior or lateral dislocation of the radial head from its position in the humeroradial joint. It is bilateral in the majority of cases and can occur as an isolated feature or in association with other congenital malformations and as part of a number of syndromes. The defect may at first cause only mild symptoms such as pain and limitation of flexion of the elbow, but may eventually lead to joint instability, dysplastic changes of the radial head, and arthritis.", "ORPHA ID": 295032, "Summary": ""}
{"Disease Name": "Isolated congenital sclerocornea", "Disease Definition": "A rare corneal disorder characterized by non-inflammatory, non-progressive, bilateral ingrowth of vascularized, opaque scleral tissue into the peripheral cornea, obliterating the corneoscleral limbus and scleral sulcus. The condition is not associated with other ocular abnormalities.", "ORPHA ID": 91490, "Summary": ""}
{"Disease Name": "Isolated congenital syngnathia", "Disease Definition": "Isolated congenital syngnathia is a very rare developmental defect during embryogenesis disorder characterized by varying degrees of congenital fusion (ranging from simple mucosal adhesions to extensive bony fusion) of mandible to maxilla that is not associated with any other malformations. Patients present with mouth opening limitation (which could range from severe to minimal restriction) that typically results in feeding, swallowing and/or respiratory difficulties which may lead to failure to thrive, malnutrition and/or temporomandibular joint ankylosis.", "ORPHA ID": 141214, "Summary": ""}
{"Disease Name": "Isolated corpus callosum agenesis", "Disease Definition": "A rare non-syndromic cerebral malformation characterized by congenital partial or complete absence of the corpus callosum. Patients are often asymptomatic but may also present with intellectual disability, visual impairment, delayed speech development, seizures, feeding difficulties, impaired hand-eye coordination, and behavioral abnormalities. Patients may have a normal intelligence quotient while exhibiting specific cognitive deficits, such as reduced interhemispheric transfer of sensorimotor information, reduced cognitive processing speed, and deficits in complex reasoning and novel problem-solving.", "ORPHA ID": 200, "Summary": ""}
{"Disease Name": "Isolated cryptophthalmia", "Disease Definition": "A rare congenital abnormality in which the eyelids are absent and skin covers the ocular bulb, which is often microphthalmic. A few cases of complete bilateral crytophthalmia have been described.", "ORPHA ID": 91396, "Summary": ""}
{"Disease Name": "Isolated cytochrome C oxidase deficiency", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder characterized by a highly variable clinical phenotype, including a benign infantile mitochondrial type affecting mainly the skeletal muscle, a lethal infantile mitochondrial myopathy linked to severe metabolic acidosis and mitochondrial dysfunction in skeletal muscle and often also in heart, Leigh syndrome, which causes severe, early-onset, progressive, and fatal encephalopathy, and French-Canadian type Leigh syndrome, which affects mostly the skeletal muscle, but also brain and liver.", "ORPHA ID": 254905, "Summary": ""}
{"Disease Name": "Isolated Dandy-Walker malformation", "Disease Definition": "A rare non-syndromic central nervous system malformation characterized by the association of three signs: hydrocephalus, partial or complete absence of the cerebellar vermis, and posterior fossa cyst contiguous with the fourth ventricle, presenting early in life with hydrocephalus, bulging occiput and posterior fossa signs such as cranial nerve palsies, nystagmus and ataxia.", "ORPHA ID": 217, "Summary": ""}
{"Disease Name": "Isolated delta-storage pool disease", "Disease Definition": "Isolated delta-storage pool disease is a rare, isolated, constitutional thrombocytopenia disorder characterized by defective formation and/or malfunction of platelet dense granules, as well as melanosomes in skin cells, resulting in variable manifestations ranging from mild bleeding and easy bruising to moderate mucous/cutaneous hemorrhagic diathesis and bleeding complications after surgery.", "ORPHA ID": 248340, "Summary": ""}
{"Disease Name": "Isolated distal symphalangism", "Disease Definition": "Distal symphalangism is a very rare bone disorder characterized by ankylosis of the distal interphalangeal joints of the hands and/or feet.", "ORPHA ID": 3248, "Summary": ""}
{"Disease Name": "Isolated distichiasis", "Disease Definition": "Isolated distichiasis is a rare congenital eyelid anomaly characterized by an accessory row of eyelashes (that may be partial or complete) posterior to the normal row of cilia, at or close to the meibomian gland orifices, that is not associated with any other condition, and that may lead to ocular irritation and corneal damage if left untreated.", "ORPHA ID": 99177, "Summary": ""}
{"Disease Name": "Isolated ectopia lentis", "Disease Definition": "Isolated ectopia lentis (IEL) is a rare, clinically variable, eye disorder characterized by dislocation of the lens, often causing significant reduction in visual acuity.", "ORPHA ID": 1885, "Summary": "Epidemiology\nThe prevalence of IEL is not known. About 90 cases have been reported to date, primarily in Europeans.\nClinical description\nPatients with IEL are found to have dislocation of the lens, which may present at any age, but may be present from birth. Dislocation of the lens can be very mild leading to late diagnosis. In more severe cases, the anomaly is generally detected earlier with a greater impact on visual acuity. Lens dislocation may be progressive. Some patients are also found to have displacement of the pupils, usually in the opposite direction to lens displacement (known as ectopia lentis et pupillae). Other findings include congenital abnormalities of the iris, spherophakia, enlarged iris processes leading to abnormal iridocorneal angle, iridodonesis, lens coloboma, refractive errors (hyperopia, myopia, astigmatism), and early-onset cataract. They may develop amblyopia. Increased intraocular pressure (20%-25% of cases), retinal detachment and glaucoma may also befound. Ocular findings vary widely within families, and between the eyes in an affected individual. Visual acuity is variable depending on the severity of ocular anomalies and complications, ranging from light perception to 20/20 vision. IEL does not involve systemic abnormalities.\nEtiology\nDislocation of the lens is the result of a loss of zonular fibers. Recessive mutations in the ADAMTSL4 (1q21.2) gene and dominant mutations in FBN1 gene (15q21.1) have been reported to cause IEL. Mutations in the former are thought to be the most important cause of this condition in Europeans. The exact function of these genes has not been clearly established. ADAMTSL4 mutations appear to manifest as a more severe, earlier onset condition than FBN1 mutations.\nDiagnostic methods\nDiagnosis is based on typical ocular findings through ophthalmologic examination and can be confirmed by molecular genetic testing of the causative genes.\nDifferential diagnosis\nPatients with IEL by definition do not have associated systemic abnormalities, although cardiac and skeletal examinations should be performed to help exclude Marfan syndrome (diagnosed according to the Ghent criteria) (see this term). Ectopia lentis is also a feature of homocystinuria, sulfite oxidase deficiency, Weill-Marchesani syndrome, aniridia, and Knobloch syndrome (see these terms), as well as pseudoexfoliation.\nAntenatal diagnosis\nPrenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutations in the family have been identified.\nGenetic counseling\nADAMTSL4-related IEL is inherited in an autosomal recessive manner. FBN1-related IEL follows an autosomal dominant pattern of inheritance.\nManagement and treatment\nVisual acuity, refractive error, and intraocular pressure should be monitored regularly in affected patients. The primary aim of treatment in children is to prevent amblyopia through early correction of refractive errors. Surgical intervention may be considered by experienced ophthalmic surgeons. Lensectomy may be considered in patients with cataracts, in cases where the ectopic lens affects vision significantly. Treatment of the resulting aphakia may be with contact lenses. Alternatively, an intraocular lens (IOL) may be inserted in the anterior chamber, and sutured or glued into the posterior chamber or into the capsule, if it has been preserved during surgery. Complications include loss of accommodation, secondary glaucoma, and retinal detachment. A standard approach should be adopted in cases of retinal detachment. All patients found to have mutations in FBN1 should have regular cardiac examinations.\nPrognosis\nVisual prognosis depends on the degree of lens dislocation, the age of onset, age of treatment and complications.\n\n                            Last update: \n                            July 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Aman CHANDRA"}
{"Disease Name": "Isolated encephalocele", "Disease Definition": "A rare, neural tube closure defect characterized by partial lacking of bone fusion, resulting in sac-like protrusions of the brain and the membranes that cover it through the openings in the skull. Protruding tissue may be located on any part of the head, but most often affects the occipital area. Depending in the size and location, encephalocele are often associated with neurological problems including intellectual disability, seizures, vision impairment, ataxia, and hydrocephalus.", "ORPHA ID": 199647, "Summary": ""}
{"Disease Name": "Isolated epispadias", "Disease Definition": "A congenital genitourinary malformation belonging to the spectrum of the exstrophy-epispadias complex (EEC) and is characterized in males by an ectopic meatus or a mucosal strip in place of the urethra on the penile dorsum and in females by bifid clitoris and a variable cleft of the urethra.", "ORPHA ID": 93928, "Summary": "Epidemiology\nThe prevalence at birth for the EEC is reported at 1/10,000. As epispadias (E), classic bladder exstrophy (CEB) and cloacal exstrophy (EC) are now recognized clinical variants of the same spectrum, accurate epidemiological data on E/EC/CEB are no longer available. The malformation is likely underdiagnosed in females but the adjusted male-to-female ratio is estimated at 1.4:1.\nClinical description\nEpispadias is usually recognized at birth, but the most distal forms, presenting with only minor clinical anomalies, maybe overlooked at birth, particularly in females. Epispadias in males can be classified as either penopubic, penile or glanular depending on the location of the meatus. Dorsal chordee is observed in all cases, although the degree varies. In females, epispadias can be severe (with a cleft involving the whole urethra and the bladder neck, together with bladder mucosal prolapse), intermediate, or mild (with a gaping meatus). The abdominal wall, rectus and umbilicus are normal and pelvic and pelvic floor anomalies are mild or absent. Urinary incontinence is the main clinical symptom in both sexes, ranging from urine permanently dripping through the meatus in severe forms, to involuntary urine loss with stress (coughing and strenuous effort) in milder forms. Urinary incontinence may not be observed in patients with the most distal forms of epispadias.\nEtiology\nEpispadias results from an anomaly during early embryologic development associated with abnormal partitioning of the cloacal membrane causing displacement of the genital tubercle and resulting in nonclosure of the urethral plate and an abnormal dorsal urethral location. The underlying cause remains unknown: both genetic and environmental factors are likely to play a role.\nDiagnostic methods\nDiagnosis is usually clinical. During follow-up, imaging studies (such as cystoscopy voiding cystography and urodynamics) are useful to determine the extent of the malformation.\nDifferential diagnosis\nThe typical clinical picture does not generally implicate any further differential diagnosis; however, epispadias is also a feature of the whole EEC spectrum (see this term).\nAntenatal diagnosis\nPrenatal diagnosis by ultrasound examination is very rare in patients with isolated epispadias due to the minor ultrasound features.\nManagement and treatment\nManagement is surgical, aiming for adequate cosmetic and functional genital reconstruction and, if necessary, achieving urinary continence. Several surgical approaches have been described for correction of epispadias in males involving meticulous partial or complete disassembly of the penis to allow correction of the dorsal chordee, urethral reconstruction for micturition and semen transport, glandular reconstruction and penile skin closure. Readaptation of the external sphincter and pelvic floor musculature or a complete bladder neck procedure may be required to achieve urinary continence. In females, genital reconstruction includes tubularization and correct placement of the distal urethra, as well as longitudinal closure of the cleft to fuse the labia and bifid clitoris, and, if necessary, skin and tissue reconstruction of the mons pubis area. After reconstructive surgery of the penis, adequate cosmetic and functional outcome can be expected. If a bladder neck procedure was necessary, continence rates are about 80% during childhood. In females, the genital defect is judged to be minor, mostly resulting in excellent cosmetic outcomes. In puberty, genital and reproductive function constitute increasingly important issues for both sexes.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Anne-Karoline EBERT  - Dr Michaël LUDWIG  - Pr Heiko REUTTER  - Pr Wolfgang RÖSCH"}
{"Disease Name": "Isolated femoral agenesis/hypoplasia", "Disease Definition": "Congenital short femur is a rare malformation of variable severity ranging from mild hypoplasia to complete absence of the femur.", "ORPHA ID": 1987, "Summary": ""}
{"Disease Name": "Isolated fibular hemimelia", "Disease Definition": "A rare congenital limb malformation characterized by complete or partial absence of the fibula bone combined with dysplasia and hypoplasia of the tibia and dysplasia, hypoplasia or aplasia of parts of the foot.", "ORPHA ID": 93323, "Summary": "Epidemiology\nFibular hemimelia incidence is reported to be between 1/50,000 and 1/135,000 births. A slight male preponderance has been reported in some studies, whereas other reports describe an equal sex distribution.\nClinical description\nUnilateral involvement is found in most cases. Bilateral fibular hemimelia is rare. Fibular hemimelia may vary from partial absence of the fibula with mild shortening and a relatively normal-appearing limb, to absence of the fibula with severe shortening and pro-curvatum of the tibia, knee joint instability and foot and ankle deformity. The foot frequently shows deficiency of the lateral rays with or without tarsal coalitions, and an equinovalgus position. Clubfoot-type fibular hemimelia presents with a clubfoot-like foot deformity. Shortening of the leg results from a constant growth inhibition that allows for prediction of leg length discrepancy at maturity. In many cases, fibular hemimelia is associated with congenital femoral deficiency of the femur (CFD), which can be very mild with only mild shortening and distal femur valgus. Most cases do not show any additional anomalies or other birth defects. In rare cases other skeletal anomalies (craniosynostosis, syndactyly, brachydactyly, oligodactyly and ectrodactyly) may be present. Fibular hemimelia can also be found in generalized skeletal dysplasias and dysostoses. Very rarely, fibular hemimelia is associated with non-skeletal malformations (eye abnormalities such as anterior chamber anomalies or anophthalmia, cardiac anomalies, renal dysplasia, thrombocytopenia, thoracoabdominal schisis, spina bifida).\nEtiology\nThe etiology is unclear. The deformity is probably due to disruptions during the critical period of embryonic limb development, between 4th and 7th week of gestation. A somatic gene mutation has been suggested.\nDiagnostic methods\nDiagnosis is based on clinical examination and X-rays.\nDifferential diagnosis\nDifferential diagnoses include skeletal dysplasias and dysostoses with asymmetrical involvement of the lower limbs such as femoral-facial syndrome.\nAntenatal diagnosis\nPrenatal diagnosis of fibular hemimelia has been reported. The rate of true positive prenatal diagnosis is depending on the severity of shortening and the presence of foot anomalies like absent rays or clubfoot.\nGenetic counseling\nMost cases are sporadic. A family history has been reported in a small percentage of cases with an autosomal dominant pattern of inheritance and incomplete penetrance.\nManagement and treatment\nManagement requires a multidisciplinary approach (genetic counselors, pediatric orthopedic surgeons,). Orthopedic treatment aims at correcting the leg length discrepancy, and, in bilateral cases, correcting the asymmetrical dwarfism. However, the functional outcome in more severe cases is primarily depending on correction and management of the deformities and anomalies at the knee and foot and ankle. In less severe cases with minimal hypoplasia of the fibula and a stable knee and foot and ankle, simple bone lengthening is used to equalize limb length. In moderate to severe fibular hemimelia, limb lengthening needs to be combined with a correction of the complex deformities at the foot and ankle. If instability at the knee joint is clinically significant it also needs to be addressed with reconstructive procedures. Very rarely, for cases with most severe shortening and a non-functional foot, amputation with prosthetic fitting in early childhood may be considered. However, even then tibial procurvatum and knee flexion contracture need to be addressed.\nPrognosis\nFibular hemimelia is usually a benign condition, although severe cases might need multiple surgeries throughout childhood. The functional result mostly depends on the status or quality of reconstruction of the knee and foot and ankle. In case of syndromic presentation, prognosis depends on the nature of the associated anomalies.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Sebastian FARR  - Pr Christof RADLER"}
{"Disease Name": "Isolated focal cortical dysplasia", "Disease Definition": "Isolated focal cortical dysplasia is a rare, genetic, non-syndromic cerebral malformation due to abnormal neuronal migration disorder characterized by variable-sized, focalized malformations located in any part(s) of the cerebral cortex, which manifests with drug-resistant epilepsy (usually leading to intellectual disability) and behavioral disturbances. Abnormal MRI findings (e.g. abnormal white and/or grey matter signal, blurred gray-white matter junction, localized volume loss, cortical thickening, abnormal gyral pattern, abnormal hippocampus) and variable histopathologic patterns are associated.", "ORPHA ID": 65683, "Summary": ""}
{"Disease Name": "Isolated focal non-epidermolytic palmoplantar keratoderma", "Disease Definition": "A rare hereditary palmoplantar keratoderma characterized by focal hyperkeratotic lesions on the palms and soles. Histopathologic examination reveals prominent hyperkeratosis, thickened stratum spinosum with reduced stratum granulosum, disadhesion of cells in the suprabasal layers, elongation of rete ridges, and sparse lymphocyte infiltration in the dermis.", "ORPHA ID": 448264, "Summary": ""}
{"Disease Name": "Isolated follicle stimulating hormone deficiency", "Disease Definition": "A rare congenital hypogonadotropic hypogonadism characterized by hypogonadism due to selective deficiency of follicle stimulating hormone (FSH). Clinical manifestations are primary amenorrhea, absent or incomplete breast development, and infertility in women, and small testes, azoospermia, and infertility in men. Luteinizing hormone is elevated in the gonadotropin-releasing hormone stimulation test, while the FSH response is impaired.", "ORPHA ID": 52901, "Summary": ""}
{"Disease Name": "Isolated foveal hypoplasia", "Disease Definition": "A rare macular disorder characterized mostly by a variable degree of decreased visual acuity, jerk or pendular nystagmus, and typical ocular findings at imaging. The disease is usually bilateral. Rarely, nystagmus can be absent. Locally, the disease is characterized by underdeveloped foveal pit, absence of foveal pigmentation and/or foveal avascular zone, and persistence of inner retinal layers at the fovea, in absence of concomitant ocular or systemic pathology.", "ORPHA ID": 519398, "Summary": ""}
{"Disease Name": "Isolated generalized anhidrosis with normal sweat glands", "Disease Definition": "A rare genetic skin disease characterized by congenital generalized anhidrosis resulting in severe heat intolerance, due to functionally impaired eccrine sweat production. Skin biopsy reveals normal morphology and number of sweat glands. Dental, hair, nail, or other skin or extracutaneous anomalies are absent.", "ORPHA ID": 468666, "Summary": ""}
{"Disease Name": "Isolated glycerol kinase deficiency", "Disease Definition": "Isolated glycerol kinase deficiency (GKD) is a very rare X-linked disorder of glycerol metabolism characterized biochemically by elevated plasma and urine glycerol levels, and clinically by variable neurometabolic manifestations, depending on the age of onset, and varying from a life-threatening childhood metabolic crisis to an asymptomatic adult form (infantile GKD, juvenile GKD, and adult GKD (see these terms)).", "ORPHA ID": 408, "Summary": ""}
{"Disease Name": "Isolated hemihyperplasia", "Disease Definition": "Isolated hemihyperplasia is a rare overgrowth syndrome characterized by an asymmetric regional body overgrowth, involving at least one limb, and associated with an increased risk of developing embryonal tumors, principally nephroblastoma (see this term) and hepoblastoma.", "ORPHA ID": 2128, "Summary": ""}
{"Disease Name": "Isolated hereditary congenital facial paralysis", "Disease Definition": "Isolated hereditary congenital facial paralysis (IHCFP) is an extremely rare neurological disorder presumed to result from maldevelopment of the facial nucleus and/or cranial nerve and has been reported in fewer than 10 families to date. It manifests as non-progressive, isolated, unilateral or bilateral, symmetrical or asymmetrical facial palsy. Involvement of the branches of the facial nerve can be unequal.", "ORPHA ID": 306527, "Summary": ""}
{"Disease Name": "Isolated humeral agenesis/hypoplasia", "Disease Definition": "Humeral agenesis/hypoplasia is a rare, non-syndromic limb reduction defect characterized by the unilateral or bilateral presence of a short arm with completely absent or underdeveloped humerus, frequently associated with ulnar and/or radial malformations. Patients may present with the appearance of the forearm directly attached to the shoulder, no articulation at the shoulder joint, impossible passive extension of the arm beyond the mid-axillary line, no elbow joints, bowing of the radius, a short ulna and/or ulnar/radial deviation of the hand at the wrist.", "ORPHA ID": 294973, "Summary": ""}
{"Disease Name": "Isolated humero-radial synostosis", "Disease Definition": "Humero-radial synostosis is a rare, genetic, congenital joint formation defect disorder characterized by uni- or bilateral fusion of the humerus and radius bones at the elbow level, with or without associated ulnar and carpal/metacarpal deficiency, leading to loss of elbow motion and, in many cases, functional arm incapacity. Bowing of radius may be additionally present.", "ORPHA ID": 3265, "Summary": ""}
{"Disease Name": "Isolated humero-radio-ulnar synostosis", "Disease Definition": "Humero-radio-ulnar synostosis is an extremely rare, genetic, congenital joint formation defect disorder characterized by uni- or bilateral fusion of the humerus, radius and ulnar bones, leading to loss of elbow motion and, in most, functional arm incapacity. It may appear as distal humeral bifurcation with absent elbow joint and shortened arm length on imaging. Hand abnormalities, namely oligoectrosyndactyly, may be associated.", "ORPHA ID": 3266, "Summary": ""}
{"Disease Name": "Isolated humero-ulnar synostosis", "Disease Definition": "A rare joint formation defect characterized by a bony connection between the humerus and the ulna, resulting in fixed flexion of the forearm, usually near 90°. The condition may be associated with upper limb hypoplasia. It may be sporadic or familial and occur uni- or bilaterally.", "ORPHA ID": 94056, "Summary": ""}
{"Disease Name": "Isolated hyperchlorhidrosis", "Disease Definition": "A rare genetic skin disease characterized by excessive salt wasting in sweat, leading to hyponatremic dehydration, hyperkalemia, and poor feeding and slow weight gain in infancy. Laboratory examination shows hyponatremia, hyperkalemia, increased aldosterone, and increased sweat chloride concentrations.", "ORPHA ID": 542657, "Summary": ""}
{"Disease Name": "Isolated hyperphalangy", "Disease Definition": "Hyperphalangy is a congenital, non-syndromic limb malformation characterized by the presence of an accessory phalanx between metacarpal/metatarsal and proximal phalanx, or between any two other phalanges of a digit, excluding the thumb. Hypherphalangy is almost always bilateral and patients present no more than five digits and no other skeletal anomalies.", "ORPHA ID": 295002, "Summary": ""}
{"Disease Name": "Isolated hypoplasia of thumb", "Disease Definition": "A rare congenital malformation characterized by underdevelopment of the thumb, ranging from a slight decrease in thumb size to complete absence of the thumb. The malformation may occur isolated, combined to other defects of the hand or upper limb, or as part of a multiple congenital anomaly syndrome.", "ORPHA ID": 294988, "Summary": ""}
{"Disease Name": "Isolated iridoschisis", "Disease Definition": "A rare disorder of the anterior segment of the eye characterized by spontaneous separation of the anterior layer of the iris stroma from the posterior stroma and muscle layers. The anterior layer then splits into strands, and the free ends float freely in the anterior chamber. The condition usually affects patients in the seventh decade of life and is often associated with glaucoma. It may begin on one side but is typically a bilateral disease. The inferior part of the iris is most commonly involved.", "ORPHA ID": 519392, "Summary": ""}
{"Disease Name": "Isolated Klippel-Feil syndrome", "Disease Definition": "Klippel-Feil Syndrome is characterised by improper segmentation of cervical segments resulting in congenitally fused cervical vertebrae.", "ORPHA ID": 2345, "Summary": "Epidemiology\nThe prevalence has been estimated at 1 in 50,000.\nClinical description\nThe syndrome was first reported in 1912 by Maurice Klippel and André Feil and is often associated with the classic clinical triad of manifestations consisting of a low posterior hairline, short neck, and limited neck range of motion. However, subsequent studies have shown that only 34% to 74% of patients present with such findings. The phenotypic expression of Klippel-Feil syndrome is variable, occurring with or without extraskeletal manifestations or any additional spinal abnormalities.\nEtiology\nThe syndrome is caused by failure of cervical segmentation in the early stages of pregnancy but the exact aetiology and mode of inheritance remain unknown.\nDiagnostic methods\nLateral neutral and flexion-extension as well as anteroposterior plain cervical radiographs demonstrating congenitally fused vertebrae are diagnostic. Magnetic resonance imaging and computed tomography can assist in the diagnosis and be used to evaluate for associated abnormalities.\nDifferential diagnosis\nDifferential diagnosis should include a surgical history of spinal fusion, ankylosing spondylitis, juvenile rheumatoid arthritis, fibrodysplasia ossificans progressiva (see these terms), and active or \"burned out'' osteomyelitis.\nManagement and treatment\nTreatment is based on the management of commonly associated symptoms, which include neck pain, radiculopathy, and/or myelopathy. The mainstay of treatment for patients with predominantly neck pain is conservative, non-operative measures. Radiculopathy secondary to nerve root impingement is also managed initially with conservative interventions and in selected cases may include spinal injections. Myelopathy due to spinal cord compression is typically attributed to congenital cervical stenosis, but may be exacerbated secondary to spinal cord compression from a combination of vertebral osteophyte and/or soft tissue compression. Patients with extensive congenital cervical fusion and/or excessive motion at a non-fused motion segment are regarded as being at high-risk for spinal cord injury and should alter daily activities to limit such potential injury. Surgical intervention may be warranted for specific cases where excessive cervical or craniovertebral motion is deemed potentially unstable and is associated with an increased risk of spinal cord injury.\nPrognosis\nThe prognosis is variable.\n\n                            Last update: \n                            June 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Dino SAMARTZIS  - Pr Francis SHEN"}
{"Disease Name": "Isolated lissencephaly type 1 without known genetic defects", "Disease Definition": "Isolated lissencephaly type 1 without known genetic defects belongs to the genetically heterogeneous group, classic lissencephaly (see this term). It is a diagnosis of exclusion, when neither associated malformations nor family history are present, and in the absence of mutations of genes known to be involved in classic lissencephaly. Clinically patients present with the common features of classic lissencephaly such as developmental delay, intellectual disability, and seizures.", "ORPHA ID": 1084, "Summary": ""}
{"Disease Name": "Isolated megalopapilla", "Disease Definition": "A rare ophthalmic disorder characterized by an abnormally large optic disc (greater than 2.1 mm in diameter). The anomaly is usually bilateral with otherwise normal configuration of the disc, and typically associated with an increased cup-to-disc ratio, a round or horizontal oval optic cup, and an intact, pale-appearing neuroretinal rim. In a less frequent variant, a unilateral, anomalous superior excavation obliterates part of the adjacent neuroretinal rim. In general, visual acuity and visual fields are normal, except for an enlarged blind spot. Ciliary arteries are more common in megalopapilla.", "ORPHA ID": 519402, "Summary": ""}
{"Disease Name": "Isolated melanotic schwannoma", "Disease Definition": "A rare nervous system tumor characterized by cells phenotypically representing Schwann cells but containing melanosomes and expressing melanoma markers. The entity occurs as a non-psammomatous (typically affecting spinal nerves) or a psammomatous (also involving nerves of the intestinal tract and heart) variant. About 50% of psammomatous tumors are associated with Carney complex. Slightly over 10% of melanotic schwannomas follow a malignant course.", "ORPHA ID": 590539, "Summary": ""}
{"Disease Name": "Isolated mesenteric vein thrombosis", "Disease Definition": "A rare intestinal disease characterized by isolated thrombosis of the mesenteric veins without involvement of the splenic or portal veins, potentially causing mesenteric ischemia. It may be primary/idiopathic or due to one or more local or systemic predisposing conditions, and may be acute/subacute or chronic, the latter being used for patients with symptoms lasting longer than 4 weeks but without bowel infarction, or patients without recent symptoms, where the thrombosis is an incidental finding. Symptoms depend on the extent and severity of thrombosis and often involve prolonged nonspecific abdominal complaints.", "ORPHA ID": 583861, "Summary": ""}
{"Disease Name": "Isolated microphthalmia-anophthalmia-coloboma", "Disease Definition": "A non-syndromic group of structural developmental eye defects characterized by the variable combination of microphthalmia, ocular coloboma, and anophthalmia, either unilaterally or bilaterally, with no other associated ocular conditions in the affected/contralateral eye, and no systemic anomalies.", "ORPHA ID": 2542, "Summary": "Epidemiology\nThe prevalence of microphthalmia is 1:7,000, anophthalmia is 1:30,000 and coloboma is 1:5,000 live births, with combined prevalence 3-30:100,000 births. Associated malformations affect 32-93% of the patients. There is no clear predilection for ethnicity or gender.\nClinical description\nMicrophthalmia-anophthalmia-coloboma (MAC) consists of phenotypic continuum of congenital eye defects that are manifest at birth. In some cases, such as retinal coloboma or mild microphthalmia, detection may occur later in life. True anophthalmia is the abortion of eye development at the developing optic vesicle stage (3-4 weeks gestation) leading to absence of the eye, optic nerve and chiasm. Commonly clinical anophthalmia (also referred to as severe microphthalmia) occurs, where a small cystic remnant is detectable on pathology/imaging. Nanophthalmos and posterior microphthalmia, are rare subsets of microphthalmia, where overall the eye is structurally normal but it has a reduced axial length of <20 mm with high hypermetropia. Ocular coloboma may involve the inferonasal aspect of the eye, including the iris, ciliary body, zonules, retina, retinal pigment epithelium (RPE), choroid and/or optic disc.\nEtiology\nMAC has a complex etiology, with monogenic, chromosomal and environmental causes. SOX2, OTX2 and STRA6 variants account for 75% of bilateral anophthalmia/severe microphthalmia. Chromosomal abnormalities account for 20-30% of MAC. Environmental factors associated with anophthalmia include maternally-acquired infections, smoking and antenatal exposure to certain medications. Maternal vitamin A deficiency, alcohol abuse and use of teratogenic drugs during pregnancy have been linked to coloboma and microphthalmia.\nDiagnostic methods\nPostnatal diagnosis can be made through clinical examination, with confirmation of true/clinical anophthalmia through MRI brain and orbit imaging. Molecular diagnosis can be made through genetic testing, such as array comparative genomic hybridization (aCGH) or whole exome/genome sequencing.\nDifferential diagnosis\nDifferential diagnoses includes aniridia, anterior segment dysgenesis, congenital corneal opacity, sclerocornea, cryptophthalmos, cyclopia and congenital cystic eye. MAC may also occur as part of various syndromes, and thus examination by specialists for the presence of systemic features (e.g. associated neurological or pituitary defects) is recommended. Genetic diagnosis may aid the identification of potential systemic anomalies.\nAntenatal diagnosis\nPrenatal diagnosis of anophthalmia or microphthalmia may be made through 2D or 3D ultrasonography during the second trimester (or 12 weeks post-conception with a transvaginal ultrasound) or fetal magnetic resonance imaging to visualize the orbit.\nGenetic counseling\nGenetic counselling can be challenging due to the range of known genetic causes and phenotypic variability. Prediction of inheritance pattern is often difficult, due to de novo changes, mosaicism and non-penetrance. If a genetic diagnosis is established, informed family planning advice can be provided including prenatal and preimplantation diagnosis.\nManagement and treatment\nThere is no treatment for MAC patients. They should be managed by a multidisciplinary team of specialists, including ophthalmologists, pediatricians and clinical geneticists. If there is visual potential, children should be monitored to maximize vision by correcting refractive error or squints, and preventing amblyopia. Fundus examinations are required in patients with chorioretinal coloboma as it is associated with a risk of retinal detachment. Low vision should be supported using visual aids. Significant microphthalmic or anophthalmic eyes may undergo socket expansion using enlarging cosmetic shells/conformers to minimize facial deformity.\nPrognosis\nIsolated MAC are structural birth defects with no treatment available.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                             Philippa HARDING  - Dr Mariya MOOSAJEE"}
{"Disease Name": "Isolated microspherophakia", "Disease Definition": "A rare disorder of the anterior segment of the eye characterized by the presence of an unusually small and spherical lens with increased anteroposterior thickness, and visibility of the lens equator on full mydriasis. The condition is typically bilateral and may be associated with lens dislocation or subluxation, lenticular myopia, and secondary angle-closure glaucoma.", "ORPHA ID": 519396, "Summary": ""}
{"Disease Name": "Isolated nail clubbing", "Disease Definition": "Isolated congenital digital clubbing is a rare genodermatosis disorder characterized by enlargement of the terminal segments of fingers and toes with thickened nails without any other abnormality.", "ORPHA ID": 217059, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nIsolated congenital digital clubbing is often painless and usually symmetrical and bilateral. Sometimes, some fingers or toes are spared, but the thumbs are almost always involved.\nEtiology\nIt results from proliferation of the connective tissues between the nail matrix and the distal phalanx and abnormal function of the nail matrix. The condition can be caused by autosomal recessive mutation of the HPGD gene (4q34-q35), but autosomal dominant forms without a known genetic cause have also been reported.\n\n                            Last update: \n                            March 2010"}
{"Disease Name": "Isolated neonatal sclerosing cholangitis", "Disease Definition": "Isolated neonatal sclerosing cholangitis is a rare, genetic, biliary tract disease characterized by severe neonatal-onset cholangiopathy with patent bile ducts and absence of ichthyosiform skin lesions. Patients present with jaundice, acholic stools, hepatosplenomegaly and high serum gamma-glutamyltransferase activity. Liver histology shows portal fibrosis, ductular proliferation, hepatocellular metallothionein deposits, and intralobular bile-pigment accumulations. Some patients may also have renal disease.", "ORPHA ID": 480556, "Summary": ""}
{"Disease Name": "Isolated optic neuritis", "Disease Definition": "A rare inflammatory optic neuropathy characterized by isolated episodes (either single or recurrent) of optic neuritis not associated with other neurological or systemic disease. Patients typically present with subacute unilateral loss of vision progressing over several days to two weeks, periocular pain and pain on eye movement (which may precede the onset of visual symptoms), light flashes on eye movement, abnormal color vision, reduced contrast sensitivity, and relative afferent pupillary defect. The optic disc appears swollen in many patients, and uveitis may be associated and can be present for years before the onset of optic neuritis.", "ORPHA ID": 499096, "Summary": ""}
{"Disease Name": "Isolated osteopoikilosis", "Disease Definition": "A rare primary bone dysplasia characterized by multiple, small, round to ovoid osteosclerotic foci with a predilection for the epiphyses and metaphyses of long tubular bones as well as the pelvis, scapula, carpal, and tarsal bones. The condition is usually clinically silent and discovered only incidentally, although some patients may experience mild articular pain with or without joint effusion. Bone strength is normal.", "ORPHA ID": 166119, "Summary": ""}
{"Disease Name": "Isolated partial vaginal agenesis", "Disease Definition": "A rare, non-syndromic urogenital tract malformation characterized by the absence of a vagina or the presence of a vaginal dimple shorter than 5 cm. It is often associated with uterine agenesis, hematocolpos or primary amenorrhea and dyspareunia. Ovaries and fallopian tubes are normal.", "ORPHA ID": 96269, "Summary": ""}
{"Disease Name": "Isolated patella aplasia/hypoplasia", "Disease Definition": "Isolated patella aplasia-hypoplasia is an extremely rare genetic condition characterized by congenital absence or marked reduction of the patellar bone described in only a few families to date.", "ORPHA ID": 86789, "Summary": ""}
{"Disease Name": "Isolated permanent neonatal diabetes mellitus", "Disease Definition": "Permanent neonatal diabetes mellitus (PNDM) is a monogenic form of neonatal diabetes (NDM, see this term) characterized by persistent hyperglycemia within the first 12 months of life in general, requiring continuous insulin treatment.", "ORPHA ID": 99885, "Summary": "Epidemiology\nThe incidence of NDM is estimated to be 1/95,000 to 1/150,000 live births. About 50% of NDM cases are permanent (PNDM) and 50% transient (TNDM, see this term). The condition has been reported in all ethnic groups and affects male and female infants equally.\nClinical description\nThe median age of onset of PNDM is nine weeks. Initial clinical manifestations include hyperglycemia, glycosuria, intrauterine growth retardation, osmotic polyuria, severe dehydration, and failure to gain weight. The subsequent course of the disease depends on the genetic defect underlying DM. Most patients display some degree of developmental coordination disorder (including visual-spatial dyspraxia). Manifestations depend on the type of gene mutation involved. In KCNJ11 and ABCC8-related cases, patients usually present before three months of age with symptomatic hyperglycemia, and often ketoacidosis. Approximately 25% of patients with mutations in the KCNJ11 gene have associated neurological findings, including developmental delay and epilepsy (DEND syndrome, see this term) or a milder form of DEND without seizures and with less severe developmental delay (intermediate DEND, see this term). In INS-related cases, patients present with marked hyperglycemia or diabetic ketoacidosis usually at nine weeks, but some at a much later age. GCK-related PNDM patients have permanent insulin-dependent diabetes from the first day of life. Homozygous PDX1 mutations or mutations in other genes such as GATA6, PTF1A or HNF1B are related to rare cases of pancreatic hypoplasia with severe insulin deficiency and possibly exocrine pancreatic insufficiency. Two groups can be distinguished based on pancreatic involvement: patients with abnormal pancreas development and children with a normal pancreas. Long-term complications include developmental delay, microalbuminuria, and retinopathy.\nEtiology\nMutations in 10 genes have been associated with PNDM: KCNJ11 (34% of cases), ABCC8 (24%), INS (13%), GCK (4%), PDX1 (<1%), GATA6, PTF1A, HNF1B, RFX6 and MNX1. These last five genes may be associated with syndromic forms. The genetic defects result in partial or complete insulin deficiency, and for the last six in possible pancreatic hypoplasia.\nDiagnostic methods\nDiagnosis of PNDM is made in infants under 12 months of age with persistent hyperglycemia (plasma glucose concentration >150-200 mg/dl). Molecular genetic testing of the implicated genes confirms the diagnosis and guides management.\nDifferential diagnosis\nDifferential diagnoses include type 1 diabetes mellitus, transient neonatal diabetes mellitus (TNDM), IPEX syndrome, and Wolcott-Rallison syndrome (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies is available for most forms of PNDM provided that the disease-causing mutation has been identified in the family.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant or autosomal recessive depending on the gene. Genetic counseling should be provided to affected families.\nManagement and treatment\nImmediate treatment involves rehydration and administration of intravenous insulin. Insulin can rapidly be switched to subcutaneously administered preparations. The aim is to control hyperglycemia and to enable catch-up growth. In those with KCNJ11 or ABCC8 mutations, a complete neurological assessment is recommended. Patients with activating mutations in these two genes can be treated long-term with oral sulfonylureas (currently in research protocols as no market authorization has yet been granted in this indication), and others with long-term insulin therapy.\nPrognosis\nAppropriate early treatment significantly reduces the risk of long-term complications.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Michel POLAK"}
{"Disease Name": "Isolated Pierre Robin syndrome", "Disease Definition": "A rare, congenital head and neck malformation characterized by the association of retrognathia and glossoptosis, with or without cleft palate, and respiratory obstruction.", "ORPHA ID": 718, "Summary": "Epidemiology\nThe prevalence of this syndrome has been estimated at 1 in 10 000 births. However, precise values are difficult to obtain because historically the definition varied and studies often included cases which occurred as part of a recognised syndrome.\nClinical description\n.Isolated Pierre Robin sequence (PRS), occurring without any other associated malformation, constitutes about 50% of cases presenting with these orofacial malformations. At birth and during the first weeks of life, the main troubles are functional and include upper airway obstruction, difficulties in respiration, poor sucking and swallowing, reflux, oesophageal motor anomalies, and vagal syncope.\nEtiology\nThis condition is referred to as a sequence because the posterior cleft palate is a secondary defect associated with abnormal mandibular development and glossoptosis. Mandibular hypoplasia, occurring early in gestation, causes the tongue to be maintained high-up in the oral cavity, preventing normal fusion of the palatal shelves (secondary palate). The mandibular growth defect can be either the consequence of antenatal orofacial hypomobility (usually related to a brainstem dysfunction, or from peripheral origin), or the consequence of a primary growth defect from tissue origin (bone, connective tissue). Molecular identification of isolated PRS is rare. Only mutations in regulatory elements upstream from SOX9 were identified in families with PRS.\nDiagnostic methods\nPierre-Robin sequence is usually diagnosed at birth based on clinical presentation. It is more and more often evoked during prenatal life.\nDifferential diagnosis\nPRS often occurs as part of a complex malformation syndrome. The nature of these anomalies is heterogeneous but they are most commonly collagenopathies, first arch anomalies, various chromosomal disorders (including microdeletion 22q11), phenocopy syndromes associated with toxic agents (alcohol, sodium valproate) and other more complicated associations.\nAntenatal diagnosis\nPrenatal diagnosis is possible if the retrognathia is detected on the strict profile of the fetus at ultrasound. Several angle measures may help discern retrognathia, leading to screening of the cleft palate and the tongue position (posterior and high-up in the oral cavity). An excess of amniotic fluid is a good diagnostic indicator.\nGenetic counseling\nThe majority of cases occur sporadically; however, approximately 10% cases are familial (mainly dominant). Genetic counselling is subtle and should be offered to all families, even in the event of sporadic cases, by expert teams.\nManagement and treatment\nMost of the time, respiratory and feeding problems resolves during the first year of life. The growth of the mandible leads to correction of retrognathia and tongue position within the first years. In cases of mandibulofacial dysostosis, surgery of the mandible may be necessary. The cleft palate is corrected by surgical intervention (one or two steps) before the age of one year. However, the persistent risk of otitis, transmission hearing loss and phonation difficulties necessitate follow-up by an ear, nose and throat specialist, and speech therapist.\nPrognosis\nFor patients with isolated PRS, the prognosis is very favourable.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Véronique ABADIE"}
{"Disease Name": "Isolated polycystic liver disease", "Disease Definition": "Isolated polycystic liver disease (PCLD) is a genetic disorder characterized by the appearance of numerous cysts spread throughout the liver and that in most cases is described as autosomal dominant polycystic liver disease (ADPCLD).", "ORPHA ID": 2924, "Summary": "Epidemiology\nThe prevalence of ADPCLD is 1/100, 000.\nClinical description\nWomen are predominantly affected and have a larger number of cysts than affected males. Cysts are undetectable early in life and usually appear after the age of 40 years. Their number and size increases with age. Symptoms depend on the mass (compression effect) and can include abdominal distension, gastro-esophageal reflux, early satiety, dyspnea, decreased mobility and back pain due to hepatomegaly. Some patients are asymptomatic. Other complications (intracystic hemorrhage or infection, torsion or rupture of cysts) can cause acute abdominal pain. Liver function is usually normal. There is no portal hypertension. Extrahepatic manifestations are very rare and may include intracranial aneurysms (usually small sized and at a low risk of rupture) and mitral leaflet abnormalities. In rare cases hepatomegaly can lead to malnutrition which can be lethal.\nEtiology\nLiver cysts result from overgrowth of biliary epithelium or from dilatation of peribiliary glands. Some cases occur sporadically, but most are inherited as an autosomal dominant trait (ADPCLD). ADPCLD is caused in 1/3-1/2 of cases by mutations in the PRKCSH or SEC63 genes. As not all cases of PCLD have a mutation in one of these genes, other not yet discovered genes and modes of transmission may exist.\nDiagnostic methods\nUltrasound, computed tomography (CT) and magnetic resonance imaging (MRI) is used for diagnosis. Among patients at risk (belonging to a family known to be affected), diagnostic criteria include more than one cyst in patients below the age of 40 years, and more than three cysts in those over 40. For patients with no known affected relatives, the usual criterion is more than 20 cysts.\nDifferential diagnosis\nDifferential diagnoses include multiple liver cysts, found in association with autosomal dominant polycystic kidney disease (ADPKD; see this term), but PCLD is genetically distinct from ADPKD with liver cysts. Simple liver cysts are also a differential diagnosis. Caroli disease (see this term), characterized by cysts communicating with the biliary tract, is differentiated by using imaging with contrast agents specifically excreted into the bile.\nManagement and treatment\nMost patients are asymptomatic and do not require treatment. For those with symptoms, management depends on the extent, distribution, and anatomy of the cysts and may include percutaneous cyst aspiration, alcohol sclerosis, cyst fenestration, partial hepatectomy, and even liver transplantation (in rare cases where the massively enlarged liver considerably alters the quality of life). Any form of estrogen therapy should be stopped immediately. Recently, lanreotide and long acting octreotide (somatostatin analogues) have been shown to be safe and effective treatments for PCLD that reduce moderate polycystic liver volume and prevent its growth.\nPrognosis\nMost patients with PCLD have good prognosis and do not require treatment.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Dominique VALLA"}
{"Disease Name": "Isolated posterior meningocele", "Disease Definition": "Posterior meningocele is a rare neural tube closure defect characterized by the herniation of a cerebrospinal fluid-filled sac, that is lined by dura and arachnoid mater, through a posterior spina bifida and covered by a layer of skin of variable thickness, which may be dysplastic or ulcerated. The spinal cord and nerves are generally not included and function normally, although sometimes a tethered cord may be associated. They are most commonly located in the lumbar or sacral region.", "ORPHA ID": 268810, "Summary": ""}
{"Disease Name": "Isolated pseudoarthrosis of the limbs", "Disease Definition": "A rare, genetic, non-syndromic limb malformation characterized by delayed union or non-union of a long bone, resulting in formation of a false joint, with abnormal mobility and angulation at the pseudoarthrosis site, which manifests with progressive anterolateral forearm or leg bowing, limb shortening, and non-healing fractures. Typical histopathological findings include fibromatosis-like proliferation in the soft tissues with cystic or dysplastic lesions. Neurofibromatosis and osteofibrous dysplasia are frequently associated.", "ORPHA ID": 157808, "Summary": ""}
{"Disease Name": "Isolated pulmonary capillaritis", "Disease Definition": "Isolated pauciimmune pulmonary capillaritis is a small vessel vasculitis restricted to the lungs that may induce diffuse alveolar hemorrhage with dyspnea, anemia, chest pain, hemoptysis, bilateral and diffuse alveolar infiltrates at chest X-rays, without any underlying systemic disease. ANCA are frequently positive but could be negative.", "ORPHA ID": 264691, "Summary": ""}
{"Disease Name": "Isolated radial hemimelia", "Disease Definition": "A rare congenital limb malformation characterized by partial or total absence of the radius.", "ORPHA ID": 93321, "Summary": "Epidemiology\nThe disorder occurs in 1/5,000-30,000 live births, and is slightly more common in males than in females (sex ratio of 3:2).\nClinical description\nThe disorder is bilateral in 60% of cases and the right side is more commonly involved than the left. The degree of malformation varies greatly. In mild cases, only a minor shortening of the radius is present. In the most severe cases in contrast, the radius is completely absent (including presence of aberrant muscles, nerves, tendons, ligaments and blood vessels). The disorder is thus characterized by varying degree of deficiencies of the radius, carpal bones, and the thumb that produces radial deviation of the hand and marked shortening of the forearm. There may also be underdevelopment or absence of the thumb, and malformation of the elbow joint with restricted motion. Radial longitudinal deficiency is frequently (67%) associated with other congenital anomalies or syndromes, including chromosomal anomalies (trisomy 13, 18 and 21), Holt-Oram syndrome, Roberts syndrome, Rothmund-Thomson syndrome, thrombocytopenia-absent radius (TAR) syndrome, Townes-Brocks syndrome, VACTERL association and Fanconi anemia.\nEtiology\nThe etiology remains unknown. The deformities are believed to develop early in pregnancy, between the 26th and 52th day of gestation. The disorder is being caused by reduction in FGF function.\nDiagnostic methods\nDiagnosis is based on clinical examination and X-rays. In utero, prenatal ultrasound may potentially detect this malformation and thus be a valuable imaging modality for early diagnosis.\nAntenatal diagnosis\nPrenatal diagnosis is possible using ultrasound, 3D-ultrasound or fetal magnetic resonance imaging.\nGenetic counseling\nApproximately 5-10% of cases are familial. Routine genetic counseling is recommended for these cases.\nManagement and treatment\nManagement aims at reducing the functional deficit. Initial therapy consists of straightening of the hand and stabilization of the wrist by serial splinting or casting that should be undertaken shortly after birth. Various surgical methods of correction have been described, such as soft tissue releases with or without ulnar osteotomy, soft tissue distraction to distalize the hand, centralization and radialization, pollicization, microvascular epiphyseal transfer and forearm lengthening.\nPrognosis\nThe prognosis is generally good. If an early individualized treatment plan is followed a good clinical outcome can be achieved. However, the more extensive the radial longitudinal deficiency type, the more impaired is the finger function and mobility.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Sebastian FARR  - Pr Christof RADLER"}
{"Disease Name": "Isolated radio-ulnar synostosis", "Disease Definition": "Congenital radioulnar synostosis is a rare bone disorder that may be isolated or associated with other disorders and that is characterized by failure of segmentation of the radius and ulna during embryological development, causing limited rotational movements of the forearm, which may lead to difficulties with some activities of daily living.", "ORPHA ID": 3269, "Summary": ""}
{"Disease Name": "Isolated right ventricular hypoplasia", "Disease Definition": "Isolated right ventricular hypoplasia (IRVH) is a rare congenital heart malformation (see this term) characterized by underdevelopment of the right ventricle associated with patent foramen ovale or interauricular communication (see these terms) and normally developed tricuspid and pulmonary valves. IRVH manifests with severe cyanosis, congestive heart failure, and in severe cases, death in early infancy.", "ORPHA ID": 439, "Summary": ""}
{"Disease Name": "Isolated sedoheptulokinase deficiency", "Disease Definition": "A rare, hereditary disorder of pentose phosphate metabolism characterized by increased urine levels of sedoheptulose and erythritol, and low-to-normal excretion of sedoheptulose-7P. Clinical presentation of this disorder is currently unclear.", "ORPHA ID": 440713, "Summary": ""}
{"Disease Name": "Isolated splenic vein thrombosis", "Disease Definition": "A rare gastroenterologic disease characterized by isolated thrombotic obstruction of the splenic vein, typically due to pancreatic disorders, in particular acute or chronic pancreatitis or pancreatic neoplasms. It is the main cause of left-sided portal hypertension. Patients may be asymptomatic or present with abdominal pain, gastrointestinal bleeding, nausea, and vomiting, as well as signs of portal hypertension.", "ORPHA ID": 583856, "Summary": ""}
{"Disease Name": "Isolated splenogonadal fusion", "Disease Definition": "A rare, non-syndromic visceral malformation characterized by an abnormal, continuous or discontinuous attachment of the spleen to the gonad, epididymis or vas. Continuous type has a direct connection between spleen and the gonad, whereas discontinuous type indicates gonadal tissue fused with an accessory spleen or ectopic spleen tissue without connection to the principal spleen. Males typically present with a scrotal mass or as an incidental finding during the management of cryptorchidism, testicular tumors or inguinal hernia. In females this is usually an incidental finding during laparotomy.", "ORPHA ID": 457083, "Summary": ""}
{"Disease Name": "Isolated split hand-split foot malformation", "Disease Definition": "A rare, congenital, bone development disorder characterized by a spectrum of terminal limb malformations including hypoplasia/absence of central rays of the hands and feet (that can occur in one to all four digits), variable degrees of median clefts of the hands and/or feet, aplasia and syndactyly, with a wide range of severity ranging from malformed central finger/toe to a lobster claw-like appearance of the hands and feet. It can occur as an isolated malformation or it can be a feature in various syndromes.", "ORPHA ID": 2440, "Summary": ""}
{"Disease Name": "Isolated sternocostoclavicular hyperostosis", "Disease Definition": "Isolated sternocostoclavicular hyperostosis is a rare rheumatologic disease characterized by predominantly bilateral, chronic, sterile inflammation and progressive sclerosis and hyperostosis of the sternocostoclavicular joint, with adjacent soft tissue ossification, in the absence of other joint involvement. It presents as recurrent episodes of pain, edema and/or erythema of the sternoclavicular region. Palmoplantar pustulosis may be additionally observed in some cases.", "ORPHA ID": 178311, "Summary": ""}
{"Disease Name": "Isolated succinate-CoQ reductase deficiency", "Disease Definition": "A rare, mitochondrial oxidative phosphorylation disorder characterized by a highly variable phenotype. The severe, multisystemic disease involves brain, heart, muscles, liver, kidneys, and eyes and results in death in infancy. Mildly affected individuals have only isolated cardiac or muscle involvement in the adulthood. Histochemical and biochemical analysis reveals a global reduction of succinate dehydrogenase activity.", "ORPHA ID": 3208, "Summary": ""}
{"Disease Name": "Isolated tetra-amelia", "Disease Definition": "A rare, non-syndromic, limb reduction defect characterized by the partial or complete absence of all four limbs. Sometimes, other malformations may be associated.", "ORPHA ID": 294971, "Summary": ""}
{"Disease Name": "Isolated thyroid-stimulating hormone deficiency", "Disease Definition": "A type of central congenital hypothyroidism, a permanent thyroid deficiency that is present from birth, characterized by low levels of thyroid hormones due to a deficiency in TSH synthesis.", "ORPHA ID": 90674, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe clinical manifestations are often subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age.\nEtiology\nIsolated TSH deficiency is transmitted in an autosomal recessive manner and is caused by mutations in the TSHB subunit gene (1p13).\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Isolated tibial hemimelia", "Disease Definition": "A rare congenital limb formation characterized by partial or complete absence of the tibia with a relatively intact fibula.", "ORPHA ID": 93322, "Summary": "Epidemiology\nTibial hemimelia incidence is reported to be 1/1,000,000.\nClinical description\nThe disorder presents with a shortened lower limb and deformities at the knee, foot and ankle. The fibula is always present and may be quite normally formed or dysplastic, might be migrated proximally or can be hypertrophied to match a hypoplastic tibia. The tibia can be shortened, partially absent or completely absent. The quadriceps muscle and patella may be normally formed, deficient or absent, which is an important factor regarding reconstruction. Similarly, the cruciate and collateral ligaments may be present or absent. The knee may fully extend or have a flexion contracture or dislocation. The foot can show duplication or deficiency of the medial rays and can be in equinus or equino-varus. Tibial hemimelia is found bilateral in approximately 30%. The degree of dysplasia and type may vary significantly between sides. Unilateral cases have a leg length discrepancy. Various classifications are published, with early classification based on radiographic appearance, while later included the status of knee motion and also the cartilaginous anlage. The most recent classification additionally focuses on prognosis and treatment. Associated anomalies include congenital femoral deficiency, bifid femur, radial dysplasia, lobster claw deformity, hand syndactyly, polydactyly, triphalagism, missing fingers or toes, hip dysplasia, hip dislocation, hemivertebrae and myelomeningocele. The disorder is associated with several syndromes. Werner's syndrome, Gollop-Wolfgang, chromosome 8q deletion, Langer-Giedion syndrome or type II tricho-rhino-phalangeal syndrome (TRPS II) may also be responsible for the disorder.\nEtiology\nThe etiology is unknown.\nDiagnostic methods\nDiagnosis is based on clinical and radiological findings.\nAntenatal diagnosis\nPrenatal diagnosis using ultrasound is possible.\nGenetic counseling\nAlthough the majority of cases with tibial hemimelia are sporadic, affected families with possible autosomal dominant or autosomal recessive inheritance have been reported.\nManagement and treatment\nSurgical correction is generally possible for most subtypes. However, in cases with absent patella and/or no quadriceps function a through-knee amputation is usually recommended. The functional result after reconstruction mostly depends on knee stability and the position of the foot. Reconstruction of more severe types includes multiple surgeries and residual knee-instability requiring bracing might persist. Reconstruction versus amputation must be discussed with the family. Associated ray duplications on the foot need to be addressed.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Sebastian FARR  - Pr Christof RADLER"}
{"Disease Name": "Isolated tibio-fibular synostosis", "Disease Definition": "Tibio-fibular synostosis is a rare, non-syndromic limb malformation characterized by fusion of the proximal or distal tibial and fibular metaphysis and/or diaphysis, frequently associated with distal positioning of the proximal tibiofibular joint, leg length discrepancy, bowing of the fibula, and valgus deformity of the knee.", "ORPHA ID": 295028, "Summary": ""}
{"Disease Name": "Isolated tracheoesophageal fistula", "Disease Definition": "A rare, congenital, esophageal malformation characterized by the presence of an abnormal connection between the esophagus and the trachea (typically occurring in the lower cervical or upper thoracic area and taking an oblique path upward to trachea), without concomitant esophageal atresia. Depending on the size of the lumen, presentation varies from neonatal episodes of choking and cyanosis on feeding to subtle symptoms of wheezing and recurrent respiratory infections in childhood or early adulthood.", "ORPHA ID": 454750, "Summary": ""}
{"Disease Name": "Isolated ulnar hemimelia", "Disease Definition": "A rare congenital limb malformation characterized by complete or partial absence of the ulna.", "ORPHA ID": 93320, "Summary": "Epidemiology\nUlnar longitudinal deficiency incidence is estimated at 1/25,000-100,000 live births, with a male to female ratio of 3:2. The prevalence is unknown.\nClinical description\nThe disorder is reported to be unilateral in about 70% of cases, and is mostly right-sided and incomplete. The most common feature is the shortening of the entire upper limb and mainly the forearm, radial bowing and tendency of the hand to drift to the ulnar side of the wrist. Other skeletal upper limb anomalies such as humeroradial synostosis, congenital radial head dislocation, carpal or metacarpal coalition, and digital abnormalities such as syndactylies or thumb malformations are frequently seen. In total, 90% of cases have missing fingers. In rare cases (type 0), missing finger rays are the only clinical feature. The disorder is mostly non-syndromic and may be associated with scoliosis, fibular hemimelia, proximal focal femoral deficiency and phocomelia. The patients may be asymptomatic in the presence of isolated mild ulnar deficiency. Cases of prominent ulnar deficiency accompanied by complex upper limb abnormalities leading to severe disability may however also be observed. The disability caused by the disorder and associated anomalies may lead to severe functional limitations of daily life activities in childhood necessitating surgical correction early in life.\nEtiology\nThe ulnar longitudinal deficiency is caused by an interruption of the sonic hedgehog (SHH) pathway, which is responsible for the development of ulnar-sided forearm structures during embryogenesis. The deformity is believed to develop between the 4th and 7th week of gestation.\nDiagnostic methods\nDiagnosis is based on clinical examination and X-rays. In utero, prenatal ultrasound may potentially detect this malformation and thus be a valuable imaging modality for early diagnosis.\nDifferential diagnosis\nThe differential diagnosis should include focal fibrocartilaginous dysplasia, dyschondrogenesis, congenital pseudarthrosis of the ulna, Nievergelt syndrome and embryofetopathy due to maternal diabetes mellitus.\nAntenatal diagnosis\nPrenatal diagnosis is possible using ultrasound, 3D-ultrasound or fetal magnetic resonance imaging.\nGenetic counseling\nMost of the reported cases are sporadic but a few familial cases have been described.\nManagement and treatment\nManagement should be highly individualized. The timing and procedure to be performed may be dictated by the age of the patient, bilaterality, and the extent of the hand malformations and forearm stability. Nonsurgical management approaches may rarely be sufficient. Different surgical approaches including syndactyly separation, thumb metacarpal rotation osteotomy, pollicization, ulnar anlage resection, one-bone forearm creation, and humeral derotational osteotomy are possible.\nPrognosis\nPatients with ulnar longitudinal deficiency may have limited motion, function and strength, but in general, the limb and hand will function as supportive limb. The severity of the disorder and the presence or absence of the accompanying skeletal anomalies determine the time of presentation and the clinical course.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Sebastian FARR  - Pr Christof RADLER"}
{"Disease Name": "Isolated unilateral hemispheric cerebellar hypoplasia", "Disease Definition": "Isolated unilateral hemispheric cerebellar hypoplasia is a rare, non-syndromic cerebellar malformation characterized by loss of volume in the right or left cerebellar hemisphere, with intact vermis and no other neurological anomalies (i.e. normal cerebral hemispheres, fourth ventricle, pons, medulla and midbrain). Patients may be asymptomatic or may present developmental and speech delay, hypotonia, abnormal ocular movements, persistent headaches and/or peripheral vertigo and ataxia. Neurological examination is otherwise normal.", "ORPHA ID": 269218, "Summary": ""}
{"Disease Name": "Isosporiasis", "Disease Definition": "Isosporiasis (also known as cystoisosporiasis) is an exclusively human parasitosis occurring mainly in the tropics and subtropics, due to infection with Isospora belli (through ingestion of contaminated food), that is frequently asymptomatic or that can cause fever and diarrhea, but that is usually a self-limiting condition in the immunocompetent. HIV-positive individuals are particularly at risk of suffering from symptomatic isosporiasis and can manifest with a more severe clinical course of chronic diarrhea and severe weight loss.", "ORPHA ID": 472, "Summary": ""}
{"Disease Name": "Isotretinoin syndrome", "Disease Definition": "A rare tetrogenic embryofetopathy due to exposure to isotretinoin, an oral synthetic vitamin A derivative, which is used to treat severe recalcitrant cystic acne. Exposure to isotretinoin during the first trimester of pregnancy has been associated with an increased risk of spontaneous abortions and severe birth defects including serious craniofacial (microcephaly, asymmetric crying facies, microphthalmia, developmental abnormalities of the external ear, ocular hypertelorism), cardio vascular (conotruncal heart defects, aortic arch abnormalities), and central nervous system (hydrocephalus, microcephaly, lissencephaly, Dandy-Walker malformation, cognitive deficit) anomalies and thymic aplasia.", "ORPHA ID": 2305, "Summary": ""}
{"Disease Name": "Isotretinoin-like syndrome", "Disease Definition": "Isotretinoin-like syndrome is a phenocopy of the isotretinoin embryopathy.", "ORPHA ID": 2306, "Summary": "Epidemiology\nIt has been described in six male patients, three of them being sibs born to nonconsanguineous parents.\nClinical description\nIt is characterized by the same anomalies as those described after maternal treatment with the drug isotretinoin (a vitamin A analog used for treatment of acne): malformations of the face (small, malformed, or missing ears, micrognathia, cleft palate), conotruncal heart defects, aortic arch anomalies, and central nervous system anomalies (hydrocephalus and posterior fossa abnormalities).\nEtiology\nThe etiology is unknown.\nDiagnostic methods\nDiagnosis may be suspected in patients with a conotruncal heart and ear anomalies. Computed tomography of the temporal bone may reveal agenesis of the external auditory canals and bilateral ossicular chain abnormalities.\nAntenatal diagnosis\nPrenatal diagnosis may be performed by ultrasonography with careful examination of facial and cardiac structures.\nGenetic counseling\nAs the syndrome has only been reported in males, X-linked recessive inheritance is possible, but autosomal recessive inheritance cannot be ruled out.\nPrognosis\nSurvival may be influenced by the severity of the heart defect and no data are available on long term prognosis.\n\n                            Last update: \n                            October 2006"}
{"Disease Name": "Isovaleric acidemia", "Disease Definition": "A rare, autosomal recessive, organic aciduria that is characterized by variable clinical presentation ranging from acute neonatal onset of metabolic decompensation to later onset of chronic, non-specific manifestations including failure to thrive and/or developmental delay. All patients are prone to intermittent, acute metabolic decompensation. During metabolic episodes, urine analysis demonstrates elevated isovaleric acid derivatives.", "ORPHA ID": 33, "Summary": "Epidemiology\nAccurate data on the prevalence is not readily available. Best estimates come from newborn screening studies that estimate prevalence at birth between 1/50,000-150,000.\nClinical description\nPatients present along a spectrum. Acute, neonatal presentation is characterized by onset in the first two weeks of life with vomiting, seizures, and lethargy, progressing to coma. Metabolic acidosis with an increased anion gap is apparent on laboratory evaluation. Hyperammonemia may occur. Later onset is relatively non-specific with failure to thrive and/or developmental delay. Patients who survived an early acute presentation are subsequently indistinguishable from those with the chronic phenotype. All patients are prone to intermittent acute episodes of decompensation with minor illnesses. Childhood onset metabolic acidosis is typically brought on by prolonged fasting, increased intake of protein-rich food or infections, and can be fatal if not treated immediately. The characteristic smell of isovaleric acid may be present, and is likened to sweaty feet/body sweat. Though severe developmental delay and neurologic sequelae are present in some patients, they are likely related to severe biochemical presentations.\nEtiology\nIsovaleric acidemia (IVA) is caused by mutations in the IVD gene (15q15.1) encoding the enzyme isovaleryl-CoA dehydrogenase (IVDH) resulting in accumulation of isovaleric acid and its derivatives. Asymptomatic patients with specific mutations have been reported, especially when identified through newborn screening.\nDiagnostic methods\nWhere implemented, diagnosis is through newborn blood spot screening. Otherwise, in symptomatic individuals diagnosis is suspected based on the clinical presentation. Metabolite or molecular genetic testing confirms diagnosis. Characteristic urine metabolites includes elevated N‐isovalerylglycine, N‐isovalerylcarnitine and 3‐hydroxyisovaleric acid. Isovalerylcarnitine (''C5 carnitine'') is elevated in blood. The urine organic acids may normalize when a patient is well.\nDifferential diagnosis\nIn acutely decompensating patients, the differential diagnosis includes other organic acidemias (including lactic acidosis), urea cycle defects, and sepsis. On newborn screening, ''C5-carnitine'' may also indicate 2-methylbutyryl-CoA dehydrogenase deficiency; urine organic acids and molecular testing readily differenciate the two disorders.\nAntenatal diagnosis\nPrenatal genetic testing is possible when the mutation of a proband has previously been determined.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive; genetic counseling is recommended for affected families. The risk of disease transmission at each pregnancy is 25% when the parents are proven or obligate carriers.\nManagement and treatment\nLifelong management is with a low protein diet. Children diagnosed with IVA should be referred to a metabolic dietician who can tailor the diet to support normal growth and development. Supplementing with artificial protein restricted in leucine may be required. L-carnitine and glycine may be prescribed to clear excess isovaleric acid. Emergency treatment in times of metabolic stress (including illness and fasting) is with an anabolic diet. Reducing, but not eliminating, natural protein in the diet for 12-24 hours may help, but only if additional other calories can be given to promote anabolism.\nPrognosis\nPrognosis for patients diagnosed by newborn screening is excellent with the potential for normal neurodevelopmental outcome with appropriate metabolic management. Patients who present symptomatically can have significant neurologic sequelae including neurodevelopmental delay, especially if acidosis and hyperammonemia are severe.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jerry VOCKLEY"}
{"Disease Name": "ISPD-related limb-girdle muscular dystrophy R20", "Disease Definition": "A rare subtype of autosomal recessive limb-girdle muscular dystrophy disorder characterized by infantile to childhood-onset of slowly progressive, principally proximal, shoulder and/or pelvic-girdle muscular weakness that typically presents with positive Gowers' sign and is associated with elevated creatine kinase levels, hyporeflexia, joint and achilles tendon contractures, and muscle hypertrophy, usually of the thighs, calves and/or tongue. Other highly variable features include cerebellar, cardiac and ocular abnormalities.", "ORPHA ID": 352479, "Summary": ""}
{"Disease Name": "ITM2B amyloidosis", "Disease Definition": "A rare, neurodegenerative disease characterized by progressive dementia and ataxia, widespread cerebral amyloid angiopathy and parenchymal amyloid deposition. Two subtypes have been identified, ABri amyloidosis and ADan amyloidosis.", "ORPHA ID": 439254, "Summary": ""}
{"Disease Name": "ITPA-related lethal infantile neurological disorder with cataract and cardiac involvement", "Disease Definition": "A rare, genetic, neurometabolic disease characterized by early onset encephalopathy with progressive microcephaly, severe global development delay, seizures, hypotonia, feeding difficulties, variable cardiac abnormalities, and cataracts. Brain MRI shows distinct pattern with high T2 signal and restricted diffusion in the posterior limb of the internal capsule in combination with delayed myelination and progressive cerebral atrophy. The disease is typically fatal.", "ORPHA ID": 457375, "Summary": ""}
{"Disease Name": "IVIC syndrome", "Disease Definition": "IVIC syndrome is a very rare genetic malformation syndrome characterized by upper limb anomalies (radial ray defects, carpal bone fusion), extraocular motor disturbances, and congenital bilateral non-progressive mixed hearing loss.", "ORPHA ID": 2307, "Summary": "Epidemiology\nPrevalence of IVIC is not known. To date, four affected families from Venezuela, Italy, Hungary, and Turkey (discordant monozygotic twins) have been described.\nClinical description\nAsymmetrical upper limbs are a characteristic clinical manifestation. Thumb involvement is the most typical clinical manifestation and can range from absence or hypoplasia to the presence of a triphalangic thumb. Other upper limb anomalies include radial ray defects and carpal bone fusion. Upper limbs may be severely malformed. Extraocular motor disturbances and hearing loss of variable severity have also been reported. Some affected individuals have been reported to have mild thrombocytopenia, leukocytosis, shoulder girdle hypoplasia, cardiac involvement, kidney malrotation, intermediate anorectal malformation (see this term), or rectovaginal fistula. The clinical presentation is highly variable but lower limbs are normal. There have been reports of sudden death.\nEtiology\nThe syndrome has been linked to mutations in the SALL4 gene (20q13.2) encoding a transcription factor involved in the maintenance and self-renewal of embryonic and hematopoietic stem cells. Okihiro syndrome (see this term) is a disorder allelic to IVIC syndrome.\nGenetic counseling\nIVIC syndrome is inherited in an autosomal dominant manner. Genetic counseling should be offered to affected families, informing them of the 50% risk of offspring inheriting the disease-causing mutation and therefore being affected with the syndrome.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanni NERI"}
{"Disease Name": "Jackson-Weiss syndrome", "Disease Definition": "Jackson-Weiss syndrome (JWS) is a rare genetic disorder characterized by foot malformations (tarsal and metatarsal fusions; short, broad, medially deviated great toes) and in some patients craniosynostosis with facial anomalies. Hands are normal in affected patients.", "ORPHA ID": 1540, "Summary": ""}
{"Disease Name": "Jacobsen syndrome", "Disease Definition": "A rare genetic disorder caused by deletions in the long arm of chromosome 11 (11q) and mainly characterized by craniofacial dysmorphism, congenital heart disease, intellectual disability, Paris Trousseau bleeding disorder, structural kidney defects and immunodeficiency.", "ORPHA ID": 2308, "Summary": "Epidemiology\nWhilst prevalence of Jacobsen syndrome is unknown, the birth prevalence has been suggested at 1/50,000-100,000 in the United States, with a female/male ratio of 2:1.\nClinical description\nJacobsen syndrome is contiguous gene disorder, characterized by craniofacial dysmorphism (skull deformities, hypertelorism, ptosis, coloboma, downslanting palpebral fissures, epicanthal folds, a broad nasal bridge, short nose, V-shaped mouth, and small, low-set and posteriorly rotated ears), craniosynostosis, eye abnormalities, congenital heart disease, intellectual disability, behavioral problems including ADHD and autism, seizures, Paris-Trousseau bleeding disorder, structural kidney defects and other urogenital anomalies including undescended testes in males, chronic constipation, pyloric stenosis, and immunodeficiency.\nEtiology\nThe syndrome is caused by deletion of one copy of the long arm of chromosome 11 (11q). Most of the deletions are terminal, i.e. extending to the end of the chromosome. The deletion size ranges from ~7 to ~16Mb, with the proximal breakpoint within or telomeric to subband 11q23.3 and the deletion usually extending to the telomere. Interstitial deletions in this region and terminal deletions less than 7Mb can cause a ''partial Jacobsen syndrome'' phenotype. In a minority of cases the breakpoint is at the FRA11B fragile site. There are a few reported cases of mosaicism for the deletion, which may lessen the severity of the clinical phenotype.\nDiagnostic methods\nDiagnosis is based on clinical findings and confirmed by array comparative genomic hybridization, and/or FISH.\nDifferential diagnosis\nDifferential diagnoses may include the Turner and Noonan syndromes, as well as acquired thrombocytopenia due to sepsis.\nAntenatal diagnosis\nPrenatal diagnosis of 11q deletion is possible through array comparative genomic hybridization analysis of genomic DNA from amniocytes or chorionic villus samples. Deletions can also potentially be detected by non-invasive prenatal testing from a maternal blood sample, although the reliability of this test for Jacobsen syndrome is unknown.\nGenetic counseling\nAbout 90% of cases are de novo. The remainder are inherited from an affected parent, either from one carrying a balanced translocation (giving rise to an unbalanced translocation in the offspring) or from a parent carrying a terminal 11q deletion. Genetic counseling is not possible.\nManagement and treatment\nManagement is multi-disciplinary and requires evaluation by a pediatrician, pediatric cardiologist, neurologist, hematologist, allergy/immunologist, endocrinologist and ophthalmologist. Additional subspecialty evaluations might include neurosurgery, urology, and nephrology. Follow-up with subspecialists varies between individuals, depending on need. Most individuals with JS have intellectual disability (ranging from mild learning disabilities to severe intellectual disability) and behavioral problems, requiring care by a pediatrician specializing in behavioral/developmental disabilities. Psychological and psychiatric care may also be warranted. Cardiac malformations can be severe and require heart surgery in the neonatal period. Newborns with Jacobsen syndrome may also have feeding difficulties requiring tube feeding. Special attention should be devoted to hematological problems.\nPrognosis\nHistorically, the most common causes of death in people with JS have been from congenital heart disease, bleeding and immunodeficiency. Early diagnosis of the syndrome can lead to lifesaving interventions including the need for prophylactic platelet transfusions at times of risk to prevent bleeding, prophylactic antibiotic or IVIG infusions to prevent life-threatening infections, early medical or surgical intervention for complex congenital heart defects, and brain imaging to identify potential life-threatening brain aneurysms. Intellectual disability can range from mild to severe. For patients who survive the neonatal period and infancy, the life expectancy remains unknown.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Paul GROSSFELD"}
{"Disease Name": "Jalili syndrome", "Disease Definition": "Jalili syndrome is characterized by the association of amelogenesis imperfecta (AI; see this term) and cone-rod retinal dystrophy (CORD; see this term).", "ORPHA ID": 1873, "Summary": "Epidemiology\nIt has been described in only one family with 29 affected individuals.\nClinical description\nAI is a generic term for an inherited group of dental diseases in which the common clinical feature is an abnormality of tooth enamel. The enamel may be thin but normal, and/or hypomineralized. CORD is a rare retinal disorder that leads to an initial loss of central vision, color vision and photophobia before the age of 10 years with subsequent night blindness and visual field restriction.\nEtiology\nMutations in the CNNM4 gene (2q11.2), which is implicated in metal ion transport, have been identified in several families.\nGenetic counseling\nJalili syndrome is transmitted in an autosomal recessive manner.\n\n                            Last update: \n                            April 2009"}
{"Disease Name": "Japanese encephalitis", "Disease Definition": "Japanese encephalitis is an arboviral disease (i.e. a disease due to a virus transmitted by an arthropod).", "ORPHA ID": 79139, "Summary": "Epidemiology\nThe estimated annual incidence of the disease is 1/160 000 but it is 20 times higher in endemic areas. It mainly occurs in rural areas of China, Korea and Japan, in sub-tropical regions of Asia, and in some regions of Oceania. Imported cases are exceptional. The disease is symptomatic in 1-20/1000 infections, and children and young adults are predominantly affected.\nClinical description\nAfter an incubation period of four to 14 days, infected individuals present with signs ranging from moderate with a headache and low-grade fever to more severe infection with high fever, meningeal syndrome (neck stiffness, vomiting), disorientation and sometimes tremors or coma.\nEtiology\nThe disease is caused by a flavivirus spread by wild birds, amplified by domestic pigs, and transmitted to humans mainly by a mosquito of the genus Culex.\nManagement and treatment\nThere is no specific treatment, but intensive supportive therapy should be provided. A vaccine is available, but its prescription should be adapted to each case and depends on the risks of transmission when travelling to endemic areas (length of the stay, transmission season, visits to rural areas).\nPrognosis\nThe disease, when it is symptomatic, can leave neurological sequelae and leads to death in 25 to 30% of the cases.\n\n                            Last update: \n                            September 2006"}
{"Disease Name": "Jawad syndrome", "Disease Definition": "Jawad syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by congenital microcephaly wih facial dysmorphism (sloping forehead, prominent nose, mild retrognathia), moderate to severe, non-progressive intellectual disability and symmetrical digital malformations of variable degree, including brachydactyly of the fifth fingers with single flexion crease, clinodactyly, syndactyly, polydactyly and hallux valgus. Congenital anonychia and white café au lait-like spots on the skin of hands and feet are also associated.", "ORPHA ID": 313795, "Summary": ""}
{"Disease Name": "Jejunal neuroendocrine tumor", "Disease Definition": "Jejunal neuroendocrine tumor is a rare, primary, malignant, epithelial neoplasm of the small intestine arising from enterochromaffin cells in the jejunum. Clinical behavior depends on the histologic grade, but initially it is generally characterized by vague abdominal symptoms (cramping, bloating, diarrhea) with insidious onset, although sometimes it could present with signs of bowel obstruction/perforation or gastrointestinal bleeding. Diagnosis in advanced stages with regional or distant spread is common, but signs of carcinoid syndrome (flushing, sweating, diarrhea) are usually not apparent until hepatic metastasis has occurred.", "ORPHA ID": 100077, "Summary": ""}
{"Disease Name": "Jervell and Lange-Nielsen syndrome", "Disease Definition": "A rare, severe, familial long QT syndrome characterized by congenital profound bilateral sensorineural hearing loss, a long QT interval on electrocardiogram and life-threatening ventricular tachyarrhythmias.", "ORPHA ID": 90647, "Summary": "Epidemiology\nThe disease is very rare. Prevalence is unknown and varies depending on the population studied (1/100,000-1/1,000,000) but is more common in countries in which consanguineous marriage is frequent.\nClinical description\nAlmost 50% of patients become symptomatic before age of 3 years. The typical presentation of Jervell and Lange-Nielsen syndrome (JLNS) is a congenitally deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. Deafness is congenital, bilateral, profound and sensorineural. The QT interval is usually markedly prolonged (>500 ms) and associated with tachyarrhythmias (including ventricular tachycardia, episodes of Torsades de Pointes (TdP) ventricular tachycardia and ventricular fibrillation) that may cause syncope or sudden death. It is one of the most severe forms of LQTS. Patients become symptomatic much earlier than in any other LQTS form, with the exception of calmodulin-related LQTS. Almost 90% of patients have cardiac events triggered by intense or sudden emotion, competitive sports, fright or jumping into cold water.\nEtiology\nThe disease is caused by homozygous or compound heterozygous mutations in either the KCNQ1 gene (locus LQT1; 11p15.5) or the KCNE1 gene (locus LQT5; 21q22.1-q22.2) and is inherited in an autosomal recessive manner.\nDiagnostic methods\nDiagnosis is based on the presence of congenital sensorineural deafness, long QT intervals and disease-causing mutations in either KCNQ1 or KCNE1. Molecular genetic testing is clinically available.\nDifferential diagnosis\nDifferential diagnosis for hearing loss includes other forms of syndromic and nonsyndromic congenital and acquired disorders associated with sensorineural hearing loss. Differential diagnosis for cardiac events includes other forms of LQTS, electrolyte abnormalities (hypokalemia, hypomagnesemia, and hypocalcemia), orthostatic hypotension, vasovagal syncope, and drug-induced LQTS.\nAntenatal diagnosis\nPrenatal testing and preimplantation genetic diagnosis may be available for families in which the disease-causing mutation is known.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive, and genetic counseling is recommended. The risk of offspring inheriting the disease is 25% where both parents are heterozygous carriers of the mutation. Parents may have Romano-Ward syndrome, but typically this is very mild.\nManagement and treatment\nHearing loss in JLNS benefits from cochlear implantation. The main goal in management of JLNS is prevention of syncope, cardiac arrest and sudden death. The therapeutic approach is complicated by the early age at which most of the patients become symptomatic. As the efficacy of beta-blockers in JLNS while good is not complete, an implantable cardioverter defibrillator (ICD) should be seriously considered and, if necessary, left cardiac sympathetic denervation (LCSD). However, even with additional therapies (pacemakers, ICDs, and LCSD), more than 50% of patients experience additional symptoms and are at risk of sudden death. Family members should be trained in cardiopulmonary resuscitation as up to 95% of patients with JLNS have a cardiac event before adulthood.\nPrognosis\nMore than half of untreated children die before 15 years of age.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Peter SCHWARTZ"}
{"Disease Name": "Jessner lymphocytic infiltration of the skin", "Disease Definition": "A rare chronic benign cutaneous disease characterized by asymptomatic non-scaly erythematous papules or plaques on the face and neck.", "ORPHA ID": 33314, "Summary": "Epidemiology\nJessner lymphocytic infiltration of the skin (JLIS) is rare, but the exact prevalence is unknown. There is no sex or ethnic predominance. It usually occurs in adults between 30 and 50 years of age. Few cases are reported in childhood.\nClinical description\nCutaneous lesions are mainly localized on the malar region of the face, neck, shoulders, upper back, arms, and hands (sun-exposed skin). Their diameter usually varies between 1 cm and 3 cm. They consist of annular, pink or red papules, sometimes resulting in plaques. No follicular plugging or atrophy appears on the surface of the lesions. The lesions may be singular (approximately 15% of cases) or multiple. When multiple, they are often grouped with an arciform disposition. The lesions may have a chronic waxing and waning course, or more rarely, remain unchanged for several weeks. Onset or exacerbation of the lesions may occur after sun exposure. In general, the lesions are asymptomatic, but they may be sometimes associated with a burning sensation or pruritus. They frequently spontaneously disappear, without resulting scars.\nEtiology\nJLIS is an inflammatory disease of unknown etiology caused by an accumulation of T cells within the dermis of the skin. There may be a genetic/hereditary component due to multiple reported familial cases. A history of photosensitivity may be associated with the disease. Drug induced JLIS have been described as a reaction to ustekinumab, etanercept, leflunomide, glatiramer acetate, duloxetine and ACE inhibitors. Association with cutaneous B cell lymphoma, Borrelia burgdorferi infection and immune reconstitution syndrome in HIV has been reported.\nDiagnostic methods\nDiagnosis may be only clinical. Histology reveals nodular perivascular or periadnexal lymphocytes, and dermal infiltration under a normal or only slightly modified epidermis. Infiltrate consists predominantly of reactive CD8+ T cells, with a few CD4+ T cells and B cells. Clusters of plasmacytoid dendritic cells (CD123+) mostly accumulated in the deep vascular plexus, have been described in JLIS as well with identical pattern in lupus erythematous tumidus. Mild mucin deposition may be seen in the dermis. Direct immunofluorescence analyses are usually negative (absence of lupus band test).\nDifferential diagnosis\nDifferential diagnoses include rosacea, granuloma annulare, granuloma faciale, cutaneous B-cell lymphomas or pseudolymphoma and idiopathic photodermatoses such as polymorphic light eruption. The differential diagnosis with lupus erythematosus tumidus is much more difficult and some recent studies suggest JLIS cannot be separated from lupus tumidus.\nManagement and treatment\nTreatment of JLIS is not mandatory in all cases. Topical and intralesional corticosteroids are first line therapies. In cases in which photosensitivity is relevant antimalarial drugs (chloroquine and hydroxychloroquine) are generally effective. Multiple therapies have been used even if data on efficacy are scarce, including topical calcineurin inhibitors, auranofin, methotrexate, etretinate, proquazone, thalidomide, and even pulsed dye laser and photodynamic therapy. Photoprotection is advised. Remission, exacerbation or spontaneous resolution may occur.\nPrognosis\nThe overall prognosis is favorable and no systemic involvement has been reported so far.\n\n                            Last update: \n                            June 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Giampiero GIROLOMONI"}
{"Disease Name": "Jeune syndrome", "Disease Definition": "Jeune syndrome, also called asphyxiating thoracic dystrophy, is a short-rib dysplasia characterized by a narrow thorax, short limbs and radiological skeletal abnormalities including 'trident' aspect of the acetabula and metaphyseal changes.", "ORPHA ID": 474, "Summary": "Epidemiology\nAnnual incidence at birth is unknown but is estimated to be 1-5/500,000.\nClinical description\nThe syndrome is recognizable during the antenatal period or at birth. In rare cases, postaxial polydactyly may also be present. The narrow thorax may cause neonatal respiratory failure, and may be associated with persistent respiratory manifestations. Some cases are severe while others have a benign course. The growth rate is variable but may be almost normal. Hepatic and renal failure has been reported in rare cases (liver fibrosis or nephronophthisis) occurring at any age. Retinal pigmentary degeneration could also be observed. Intellectual development is normal.\nEtiology\nThe molecular basis of the syndrome has been partially elucidated indicating involvement of the IFT80 (3q25.33), DYNC2H1 (11q22.3), WDR19 (4p14) and TTC21B (2q24.3) genes, each encoding an intraflagellar transport protein, which confirms that Jeune syndrome belongs to the ciliopathies group. Mutations in other genes may also be implicated in the disease and remain to be identified.\nDiagnostic methods\nThe diagnosis is based on radiologic findings: ribs are short and the pelvis has an abnormal morphology, with a horizontal acetabular roof and a trident aspect formed by a median protrusion and two lateral spurs. Hands are normal or short with possible cone-shaped epiphyses in the phalanges.\nDifferential diagnosis\nDifferential diagnosis should include thoracolaryngopelvic dysplasia, Ellis-van Creveld syndrome, Sensenbrenner syndrome and paternal uniparental disomy of chromosome 14 (see these terms).\nAntenatal diagnosis\nMolecular diagnosis must be confirmed in the proband before proposing prenatal molecular testing. In other cases, only a careful antenatal ultrasound examination can detect the disease.\nGenetic counseling\nThe syndrome is transmitted as an autosomal recessive trait. The recurrence risk is 25% for every pregnancy after the birth of an affected child.\nManagement and treatment\nTreatment consists of management of respiratory infections, which may lead to severe complications. Renal and hepatic function should be monitored regularly, and retinal examination performed.\nPrognosis\nPrognosis is highly variable depending of the visceral associated diseases, and the risk of severe respiratory complications decreases after 2 years of age.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Geneviève BAUJAT"}
{"Disease Name": "Johanson-Blizzard syndrome", "Disease Definition": "Johanson-Blizzard syndrome (JBS) is a multiple congenital anomaly characterized by exocrine pancreatic insufficiency, hypoplasia/aplasia of the nasal alae, hypodontia, sensorineural hearing loss, growth retardation, anal and urogenital malformations, and variable intellectual disability.", "ORPHA ID": 2315, "Summary": "Epidemiology\nThe prevalence of JBS in Europe has been estimated to be around 1/250,000 live births.\nClinical description\nOnset of symptoms is usually during infancy with hallmark features being aplasia/hypoplasia of nasal alae and pancreatic exocrine insufficiency (presenting in the newborn or young infant with failure to thrive, oily stools and fat-soluble vitamin malabsorption). Additional features include dental anomalies (oligodontia/hypodontia (see these terms) of permanent teeth; >90%), sensorineural hearing loss (~75%), scalp defects (aplasia cutis congenital; ~65%), short stature (~60%), hypothyroidism (~40%), microcephaly (~35%), intrauterine growth restriction (~30%), genitourinary malformations (~30%; cryptorchidism, micropenis, hypospadias, clitoral hypertrophy/clitoromegaly, uterovaginal anomalies, hydronephrosis), congenital heart defects (25%; atrial and ventricular septal defects, patent arterial duct, tetralogy of Fallot, hypertrophic cardiomyopathy; see these terms), and imperforate anus (~20%). A presumably high risk for diabetes mellitus development during adolescence or adulthood has been reported. Developmental and intellectual delays of variable degree are present in ~60% of cases. Other frequent minor signs include abnormal frontal hair pattern (upsweep), lacrimal duct anomalies, severe facial clefting (cleft lip/palate) and lower eyelid coloboma. Less common features are natal teeth, tethered spinal cord, poly-/syndactyly of the feet, prostate aplasia, gastroesophageal reflux, cholestatic liver disease, café au-lait spots, growth hormone deficiency, hypopituitarism, brain malformations (e.g. arhinencephaly), situs inversus, and osseous malformations (left hip dislocation).\nEtiology\nMost cases of JBS are caused by mutations of UBR1 gene (15q13) which encodes a protein highly expressed in pancreatic acinar cells. UBR1 deficiency may contribute to gradual destruction of previously formed acinar cells starting prenatally, thereby leading to pancreatic enzymes deficiency.\nDiagnostic methods\nDiagnosis is based on identification of the pathognomonic combination of congenital or infantile exocrine pancreatic insufficiency (fecal fat quantification; fecal elastase; C-triglyceride breath test) with other characteristic anomalies such as aplasia/hypoplasia alae nasi. Diagnosis is confirmed by genetic screening of UBR1.\nDifferential diagnosis\nDifferential diagnosis includes cystic fibrosis, Shwachman-Diamond syndrome, Pearson Marrow-Pancreas syndrome, partial pancreatic agenesis (for congenital exocrine pancreatic insufficiency), oculodentodigital dysplasia (for hypoplasia of the alae nasi) and Adams-Oliver syndrome (for aplasia cutis congenita) (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is suspected by a beak-like nose (due to aplasia/hypoplasia of nasal alae) and a dilated sigmoid colon suggestive of imperforate anus at 21 weeks of gestation. Molecular testing of UBR1 confirms the diagnosis.\nGenetic counseling\nTransmission is autosomal recessive. Inter- rather than intrafamilial variability have been described.\nManagement and treatment\nTreatment includes oral administration of exogenous pancreatic enzymes and nutritional support (high-calorie diet with 30-40% calories from fat, lipase, fat-soluble vitamins and mineral supplementation) for pancreatic insufficiency; thyroid hormone substitution; surgery for anorectal and genitourinary malformations; hearing aids for deafness; insulin for diabetes mellitus; early intervention programs and specific education for patients with intellectual disabilities; and dental implantation during the teenage years. Facial malformations may be corrected by plastic surgery.\nPrognosis\nPancreatic insufficiency and complications of severe malnutrition (e.g. severe hypoproteinemia, vitamin deficiency, immunodeficiency) may lead to death in infancy or early childhood. For patients managed appropriately, survival into adulthood is the rule.\n\n                            Last update: \n                            July 2016\n\n\n                            - Expert reviewer(s): \n                            Pr Martin ZENKER"}
{"Disease Name": "Johnson neuroectodermal syndrome", "Disease Definition": "Johnson neuroectodermal syndrome is characterised by alopecia, anosmia or hyposmia, conductive deafness with malformed ears and microtia and/or atresia of the external auditory canal, and hypogonadotropic hypogonadism.", "ORPHA ID": 2316, "Summary": "Epidemiology\nSo far, less than 30 cases have been described in the literature.\nClinical description\nOther variable features include a congenital heart defect, facial asymmetry, intellectual deficit, cleft palate, choanal stenosis and an increased tendency for dental caries.\nEtiology\nThe aetiology is unknown but the combination of developmental anomalies present in patients with this syndrome is suggestive of an embryological defect in the formation of the neuroectodermal derivatives of cephalic neural crest.\nGenetic counseling\nThe syndrome is transmitted as an autosomal dominant trait.\n\n                            Last update: \n                            October 2006"}
{"Disease Name": "Joubert syndrome and related disorders", "Disease Definition": "Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomaly syndromes in which the mandatory feature is the ``molar tooth sign'' (MTS), a complex midbrain-hindbrain malformation recognizable on brain imaging. The MTS is characterized by cerebellar vermis hypodysplasia, thickening and malorientation of the superior cerebellar peduncles and abnormally deep interpeduncular fossa.", "ORPHA ID": 140874, "Summary": "Epidemiology\nThe prevalence of JSRD at birth has been estimated to be between 1/80,000 and 1/100,000 live births, although this frequency is probably underestimated.\nClinical description\nThe neurological features of JSRD include neonatal hypotonia, developmental delay, which is particularly related to language and motor skills, mild to severe intellectual disability, ataxia, and abnormal eye movements including oculomotor apraxia and primary position nystagmus. A subset of patients present neonatal breathing abnormalities, that are characterized by episodes of apnea and hyperpnea starting shortly after birth and improving with age. These neurological manifestations may occur alone or be variably associated with multiorgan features, mainly retinal dystrophy, nephronophthisis, hepatic fibrosis and polydactyly, with both inter- and intra-familial variability. Depending on the associated multiorgan involvement, JSRD is classified in six clinical subgroups: Pure JS; JS with ocular defect; JS with renal defect; JS with oculorenal defect; JS with hepatic defect; and JS with orofaciodigital defect (see these terms).\nEtiology\nTwelve causative genes have been identified to date, all encoding proteins that are part of the primary cilium or its apparatus, making JSRD part of the expanding group of diseases called ``ciliopathies''.\nDiagnostic methods\nThe diagnosis of JSRD should be suspected in all infants presenting with hypotonia, abnormal eye movements and developmental delay, especially if breathing abnormalities are also present. In children, the diagnosis is suspected in presence of neurological signs suggestive of cerebellar involvement (ataxia, developmental delay, intellectual disability, abnormal eye movements) variably associated with involvement of other organs. Brain magnetic resonance imaging is necessary and sufficient to confirm or exclude the diagnosis of JSRD based on the detection of the MTS. This should be followed by a specific diagnostic protocol to assess the potential multiorgan involvement.\nDifferential diagnosis\nDifferential diagnosis must consider in particular the other ciliopathies (such as nephronophthisis, Senior-Loken syndrome, and Bardet-Biedl syndrome; see these terms), distinct cerebellar and brainstem congenital defects and disorders with cerebro-oculo-renal manifestations.\nAntenatal diagnosis\nMutational analysis of causative genes is available in few laboratories worldwide on a diagnostic or research basis. The identification of the molecular defect in at-risk couples enables early prenatal genetic testing, whereas fetal brain neuroimaging may remain uninformative until the end of the second trimester of pregnancy.\nGenetic counseling\nWith the exception of rare X-linked recessive cases, JSRDs are transmitted in an autosomal recessive manner.\nManagement and treatment\nOptimal management requires a multidisciplinary approach, with particular attention to respiratory and feeding problems in neonates and infants, while cognitive and behavioral assessments are recommended to provide young patients with adequate neuropsychological support and rehabilitation.\nPrognosis\nAfter the first months of life, when prognosis is primarily linked to the extent and severity of breathing abnormalities, global prognosis varies considerably among JSRD subgroups, depending on the extent and severity of organ involvement.\n\n                            Last update: \n                            July 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE"}
{"Disease Name": "Joubert syndrome with hepatic defect", "Disease Definition": "Joubert syndrome with hepatic defect is a very rare subtype of Joubert syndrome and related disorders (JSRD, see this term) characterized by the neurological features of JS associated with congenital hepatic fibrosis (CHF).", "ORPHA ID": 1454, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe age of onset and severity of hepatic manifestations are variable. Some patients may also present chorioretinal or optic nerve colobomas and nephronophthisis (NPH), but these are not mandatory features.\nEtiology\nOver 70% of cases are due to mutations in the TMEM67 gene (8q22.1).\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            July 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE"}
{"Disease Name": "Joubert syndrome with Jeune asphyxiating thoracic dystrophy", "Disease Definition": "A rare genetic developmental defect during embryogenesis characterized by the association of the classic features of Joubert syndrome (congenital midbrain-hindbrain malformations causing hypotonia, abnormal breathing and eye movements, ataxia and cognitive impairment) together with the skeletal anomalies of Jeune asphyxiating thoracic dystrophy (short ribs, long and narrow thorax causing respiratory failure, short-limbs, short stature, and polydactyly). Additional variable manifestations include cystic kidneys, liver fibrosis, and retinal dystrophy.", "ORPHA ID": 397715, "Summary": ""}
{"Disease Name": "Joubert syndrome with ocular defect", "Disease Definition": "Joubert syndrome with ocular defect is, along with pure JS, the most frequent subtype of Joubert syndrome and related disorders (JSRD, see these terms) characterized by the neurological features of JS associated with retinal dystrophy.", "ORPHA ID": 220493, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nAge of onset and severity of retinal involvement are variable, ranging from congenital blindness in patients with Leber congenital amaurosis (LCA, see this term) to progressive retinopathy with partial conservation of vision.\nEtiology\nTo date, the most frequently mutated gene in this subtype is AHI1 (6q23.2), which accounts for about 20% of cases, following autosomal recessive inheritance.\n\n                            Last update: \n                            July 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE"}
{"Disease Name": "Joubert syndrome with oculorenal defect", "Disease Definition": "A rare subtype of Joubert syndrome (JS) and related disorders (JSRD) characterized by the neurological features of JS associated with both renal and ocular disease.", "ORPHA ID": 2318, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nPatients present retinal involvement (manifesting with either Leber congenital amaurosis (LCA, see this term), or progressive retinal dystrophy) and nephronophthisis (NPH, usually juvenile). Retinal involvement is present at birth (LCA) or may manifest later in life. Juvenile NPH usually becomes clinically symptomatic towards the late first decade or the early second decade of life.\nEtiology\nAbout 50% of patients carry mutations in the CEP290 gene (12q21.33), transmitted in an autosomal recessive manner.\n\n                            Last update: \n                            July 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE"}
{"Disease Name": "Joubert syndrome with renal defect", "Disease Definition": "Joubert syndrome with renal defect is a rare subtype of Joubert syndrome and related disorders (JSRD, see this term) characterized by the neurological features of JS associated with renal disease, in the absence of retinopathy.", "ORPHA ID": 220497, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nIn most cases, renal disease manifests as juvenile nephronophthisis, with onset of clinical symptoms in the late first/early second decade of life, although in rare cases there may be infantile NPH, with onset in the first years of life.\nEtiology\nThe most commonly mutated genes in this subtype are NPHP1 (2q13) and RPGRIP1L (16q12.2) with autosomal recessive inheritance.\n\n                            Last update: \n                            July 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE"}
{"Disease Name": "Joubert syndrome", "Disease Definition": "A rare, autosomal recessive congenital cerebellar ataxia characterized by congenital malformation of the brainstem and agenesis or hypoplasia of the cerebellar vermis leading to an abnormal respiratory pattern, nystagmus, hypotonia, ataxia, and delay in achieving motor milestones.", "ORPHA ID": 475, "Summary": "Epidemiology\nPrevalence is estimated at approximately 1/100,000.\nClinical description\nDisease onset is antenatal, although clinical presentation is typically in the neonatal period with irregular breathing pattern (episodic tachypnea and/or apnea), and nystagmus. During infancy, hypotonia may appear. Cerebellar ataxia (staggering gait and imbalance) may develop later. Delayed acquisition of motor milestones is common. Cognitive abilities are variable, ranging from severe intellectual deficit to normal intelligence. Neuro-ophthalmologic examination may show oculomotor apraxia. In some cases, seizures occur. Careful examination of the face often shows a characteristic appearance: large head, prominent forehead, high rounded eyebrows, epicanthal folds, ptosis (occasionally), an upturned nose with prominent nostrils, an open mouth (which tends to have an oval shape early on, a 'rhomboid' appearance later, and finally can appear triangular with downturned angles), tongue protrusion and rhythmic tongue motions, and occasionally low-set and tilted ears. Other features sometimes present in Joubert syndrome include retinal dystrophy, hepatopathy, nephronophthisis, and polydactyly.\nEtiology\nJS is due to dysfunction of the primary, non-motile cilium found in most cells. The syndrome is genetically heterogeneous with numerous genes and two loci on chromosomes 9q34 (INPP5E) and 11p12-q13 (TMEM216) associated with the disease so far. Most of these genes encode proteins that constitute the primary cilium or the regulatory proteins and transcription factors involved in its development and function.\nDiagnostic methods\nDiagnosis is based on the main clinical features (hypotonia, ataxia, development delay and oculomotor apraxia), which must be accompanied by the presence of a neuroradiological hallmark, designated as the ''molar tooth sign'' (MTS) on magnetic resonance imaging (MRI). MTS results from hypoplasia of the cerebellar vermis and midbrain-hindbrain malformations. Moreover the clinical distinct sign is oculomotor apraxia.\nDifferential diagnosis\nDifferential diagnoses include Joubert syndrome-related disorders (JSRD), cerebellar vermis malformations without the MTS (which include Dandy-Walker malformation), X-linked cerebellar hypoplasia, ataxia with oculomotor apraxia types 1 and 2 (AOA1, AOA2), congenital disorders of glycosylation (CDG), 3-C syndrome, pontocerebellar hypoplasias/atrophies, orofaciodigital syndromes II and III, and Meckel-Gruber syndrome.\nAntenatal diagnosis\nAntenatal diagnosis is feasible through genetic testing where both disease-causing mutations have been previously identified in an affected family member. Imaging studies can suggest the disease (fetal ultrasonography and MRI) but cannot be use to conduct any antenatal diagnosis.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling is recommended for families with an affected child; the recurrence risk for future offspring is 25%.\nManagement and treatment\nManagement is symptomatic and should be multidisciplinary. Education programs, physical, occupational, and speech therapy may improve the hypotonia and reduce the delay in achieving motor milestones. In general, the neurological disability and amaurosis are not progressive. Particularly relevant is the detection of nephronophthisis (NPH) which leads to chronic kidney disease which occurs in about 30% of subjects with all genetic types (with higher risk for mutations in the following genes: CEP290 (12q21.32), RPGRIP1L ( 16q12.2), TMEM216 (11q13.1), TMEM67 (8q22.1), NPHP4 (1p36.31; 1 case), AHI1 (6q23.3). Another aspect that may determine progressivity is the association with a liver disease, and particularly a liver fibrosis that may need liver transplantation.\nPrognosis\nPrognosis is favorable for moderate forms of the disease. In patients with nephronophthisis (NPH), end stage renal disease occurs in the second decade of life. Management of patients with more severe forms should be carried out by a specialized reference center. Liver disease does not recur in the transplanted liver.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI  - Pr Enza Maria VALENTE"}
{"Disease Name": "Juberg-Hayward syndrome", "Disease Definition": "Juberg-Hayward syndrome is a polymalformative syndrome that associates multiple skeletal anomalies with microcephaly, facial dysmorphism, urogenital anomalies and intellectual deficit.", "ORPHA ID": 2319, "Summary": ""}
{"Disease Name": "Junctional epidermolysis bullosa inversa", "Disease Definition": "A rare intermediate form of junctional epidermolysis bullosa characterized by congenital blistering and erosions confined to intertriginous skin sites, the esophagus, groin, and perineum. Blistering is usually severe and lesions may heal with atrophic scarring and milia formation. Extracutaneous manifestations include nail dystrophy, enamel hypoplasia and dental caries, oral, esophageal and vaginal blisters and erosions.", "ORPHA ID": 79405, "Summary": ""}
{"Disease Name": "Junctional epidermolysis bullosa with pyloric atresia", "Disease Definition": "A severe form of junctional epidermolysis bullosa (JEB) characterized by generalized blistering at birth and congenital atresia of the pylorus and rarely of other portions of the gastrointestinal tract.", "ORPHA ID": 79403, "Summary": "Epidemiology\nPrevalence of junctional epidermolyis bullosa-pyloric atresia syndrome (JEB-PA) is unknown. More than 100 cases have been reported worldwide.\nClinical description\nSkin manifestations include severe blistering, atrophic scarring, and nail dystrophy. Congenital absence of skin (aplasia cutis congenita) is common, and ear anomalies are also relatively common. The manifestations of pyloric atresia include intractable vomiting, abdomen distension, and an absence of stools. Patients present oral cavity involvement and, if they survive, enamel hypoplasia. Other extracutaneous manifestations include involvement of the respiratory, gastrointestinal and genitourinary tracts. In particular, genitourinary malformations and acquired genitourinary abnormalities (polypoid bladder wall lesions, hemorrhagic cystitis, urethral strictures) are relatively frequent and characteristic. Growth delay and anemia, secondary to the extensive cutaneous and mucosal lesions, are common. Polyhydramnios, secondary to pyloric atresia, is usually present in pregnancies with an affected fetus. Some patients with an identical presentation have been found to have intraepidermal rather than intra-lamina lucida blister formation, necessitating their inclusion under the rarer subtypes of EB simplex (EBS; epidermolytic) severe with pyloric atresia rather than under junctional EB. These patients might have mutations in the intracellular domain of integrin beta4, or plectin deficiency.\nEtiology\nThe condition is caused by biallelic mutations in either of the genes encoding the two subunits of alpha6-beta4 integrin, ITGA6 (2q31.1) and ITGB4 (17q11-qter).\nDiagnostic methods\nDiagnosis in neonates is suspected based on clinical findings of skin fragility and gastric outlet obstruction demonstrated by X-rays without contrast. In addition to the finding of a cleavage plane located within the lamina lucida of the cutaneous basement membrane zone by immunofluorescence antigen mapping and/or transmission electron microscopy, a negative or highly reduced immunofluorescence staining for integrin alpha6beta4 is typical of JEB-PA. Genetic testing should be the gold standard, in order to differentiate from EBS with pyloric atresia, particularly if immunofluorescence mapping and/or transmission electron microscopy are not available/feasible.\nDifferential diagnosis\nThe main differential diagnosis is of EBS with pyloric atresia.\nAntenatal diagnosis\nDiagnosis may be suspected on ultrasound findings of polyhydramnios, secondary to pyloric atresia, with high levels of alpha-feto-protein (> 20 times normal values). Prenatal diagnosis by genetic testing should be offered to the family.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nPyloric atresia must be corrected surgically in the first days of life; without this, the disorder is lethal in the neonatal period. Multidisciplinary management with hospitalization in neonatal intensive care is required. Patients should be monitored and treated for water-electrolyte balance, failure to thrive, anemia, infectious and respiratory complications, etc. Pain management is also extremely important in these patients and often requires opioids. Skin management is based on the avoidance of blistering by meticulous protective padding of the skin, avoidance of trauma in daily life, lancing and draining of new blisters, and prevention of secondary infection by careful wound care.\nPrognosis\nJEB-PA leads in most cases to early death within the first months of life. Prognosis depends predominantly on the prompt surgical correction of pyloric atresia. Amongst patients in whom this is successful, a minority show mild skin involvement or a gradual improvement of blistering lesions, allowing the recanalized patient to reach a normal life span.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Michela BRENA | ERN-Skin* - Dr Sophie GUEZ | ERN-Skin* - Dr Gianluca TADINI | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Junctional epidermolysis bullosa", "Disease Definition": "A group of inherited epidermolysis bullosa characterized by involvement of the skin and mucous membranes, and is defined by the formation of blistering lesions between the epidermis and the dermis at the lamina lucida level of the cutaneous basement membrane zone and by healing of lesions with atrophy and/or exuberant granulation tissue formation.", "ORPHA ID": 305, "Summary": "Epidemiology\nJunctional epidermolysis bullosa (JEB) is the less common, but frequently early lethal form of EB. Point prevalence is generally below 1/1,000,000 worldwide except in the Netherlands where it is estimated at 1/475,000. Prevalence at birth ranges from 1/110,000-455,000 worldwide.\nClinical description\nOnset is usually at birth with the exception of late-onset JEB. Several JEB subtypes have been described based on clinical features. All subtypes are characterized by the presence of enamel hypoplasia manifesting as localized or more extensive thimble-like pitting of some or all of the tooth surfaces. Blistering is usually associated with atrophic scarring or with exuberant granulation tissue formation and nail dystrophy. Additional skin findings may include congenital aplasia cutis and progressive hair loss. Mucosal involvement is constant, although of variable severity, and can affect the gastrointestinal, respiratory and genitourinary tracts and the eyes. Pyloric atresia is the hallmark of the JEB with pyloric atresia subtype. JEB is divided in the following subtypes: severe JEB, intermediate JEB, localized JEB, JEB with pyloric atresia (JEB-PA), JEB inversa, late-onset JEB, laryngo-onycho-cutaneous syndrome (LOC) syndrome and JEB with interstitial lung disease and nephrotic syndrome.\nEtiology\nJEB is caused by mutations in various genes, including COL17A1 (10q25.1), ITGA6 (2q31.1), ITGB4 (17q25.1), LAMA3 (18q11.2), LAMB3 (1q32.2), LAMC2 (1q25.3) and ITGA3 (17q21.33).\nDiagnostic methods\nDiagnosis is based on determination of the level within which blisters develop on skin biopsy samples following minor traction to the skin. The recommended techniques are immunofluorescence antigen mapping and transmission electron microscopy. In JEB, the blister cleavage plane is localized within the lamina lucida of the cutaneous basement membrane zone. Subtypes are then defined on the basis of immunofluorescence and electron microscopic findings, and clinical presentation. Genetic testing should be always performed, as it is necessary for antenatal diagnosis.\nDifferential diagnosis\nDiagnosis is usually straightforward with little need for extensive differential diagnosis. However, in the neonatal period, in utero Herpes simplex infection may need to be considered, especially if there is no family history of blistering disease or if the clinical findings are very atypical for EB. The differential diagnosis in neonates may include inherited or acquired skin disorders with a similar presentation.\nAntenatal diagnosis\nPrenatal diagnosis should always be offered to families at risk of having a child with severe JEB.\nGenetic counseling\nInheritance is autosomal recessive. Parents of a child with JEB are obligate carriers of the pathogenic variants. For each pregnancy of the parents, the risk of having an affected child is 25%.\nManagement and treatment\nPatients affected by most JEB forms require hospitalization in neonatal intensive care because of the severity skin lesions and extracutaneous manifestations, and should be monitored and treated for water-electrolyte balance, failure to thrive, anemia, infectious and respiratory complications, etc. Pain management is also extremely important in these patients and often requires opioids. Subsequently, patient management should involve a multidisciplinary team, to ensure coordinated care. Skin management is based on the avoidance of blistering by meticulous protective padding of the skin, avoidance of trauma in daily life, lancing and draining of new blisters, and prevention of secondary infection by careful wound care.\nPrognosis\nPatients with JEB, particularly those with severe subtypes (severe JEB, JEB-PA and JEB with interstitial lung disease and nephrotic syndrome) are at major risk of death during the first few years of life.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Cristina HAS | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Jung syndrome", "Disease Definition": "A rare, congenital malformation syndrome characterized by the association of anterior ocular chamber cleavage disorder with developmental delay, short stature and congenital hypothyroidism. Additional manifestations include cerebellar hypoplasia, tracheal stenosis, narrow external auditory meatus, and hip dislocation. There have been no further description in the literature since 1995.", "ORPHA ID": 2321, "Summary": ""}
{"Disease Name": "Juvenile absence epilepsy", "Disease Definition": "Juvenile absence epilepsy (JAE) is a genetic epilepsy with onset occurring around puberty. JAE is characterized by sporadic occurrence of absence seizures, frequently associated with a long-life prevalence of generalized tonic-clonic seizures (GTCS) and sporadic myoclonic jerks.", "ORPHA ID": 1941, "Summary": "Epidemiology\nThe incidence of JAE is still unknown but it accounts for approximately 2-3% of patients with adult epilepsy in general, and about 8-10% of patients with genetic generalized epilepsy (GGE). No sex predominance has been observed.\nClinical description\nJAE is characterized by sporadic occurrence of absence seizures (only one or a few absences daily; 100% of cases), frequently associated with a long-life prevalence of generalized tonic-clonic seizures (GTCS; 80%) and sporadic myoclonic jerks (20%). The seizures onset is typically between 9 and 13 years of age and it manifests as a ''staring spell'' that can be accompanied by atonic postures such as drooping of the head and/or automatisms such as lip smacking. GTCS and myoclonic seizures often occur 1-10 years after the absence seizure onset. Patients with JAE usually develop normally, although uncontrolled absence seizures may have an impact on their ability to learn at school.\nEtiology\nThe exact etiology of JAE is still elusive. However, genetic mutations for voltage-gated sodium channels (CACNB4 gene (2q22-q23)), potassium channels (CLCN2 gene (3q27.1)), and EFHC1 (6p12.3) may be involved in a subset of patients. Moreover, different mutations have been found in genes for GABA receptors (ligand ion channels), specifically in the GABRA1 gene (5q34).\nDiagnostic methods\nDiagnosis relies on the clinical features and on electroencephalogram (EEG) recorded awake and during sleep, that displays a generalized 3-4 Hz spike-and-slow-wave complexes.\nDifferential diagnosis\nDifferential diagnosis includes childhood absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome (see these terms).\nGenetic counseling\nThe transmission is still unknown although an increased risk for first degree related parents to develop JME may exist.\nManagement and treatment\nThe antiepileptic drugs of choice are valproic acid (VPA) and lamotrigine (LTG). In cases where VPA deals with only partial seizure control, add-on of LTG (GTCS) or ethosuximide (absence seizures) can be beneficial.\nPrognosis\nPrognosis of JAE is usually favorable with good therapy responsiveness. Generally, seizure freedom can be achieved with antiepileptic medication in 62-84% of all patients with JAE. However, the occurrence of GTCS predicts a worse prognosis.\n\n                            Last update: \n                            November 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Gabrielle RUDOLF"}
{"Disease Name": "Juvenile amyotrophic lateral sclerosis", "Disease Definition": "Juvenile amyotrophic lateral sclerosis (JALS) is a very rare severe motor neuron disease characterized by progressive upper and lower motor neuron degeneration causing facial spasticity, dysarthria, and gait disorders with onset before 25 years of age.", "ORPHA ID": 300605, "Summary": "Epidemiology\nThe prevalence and incidence of JALS are not known. A small number of cases have been reported to date. The disorder has been described in various ethnic groups.\nClinical description\nOnset is during childhood with a mean age of 6.5 years and a reported range of 3 to 20 years. Patients then develop motor neuron degeneration leading to facial muscle spasticity, spastic dysarthria, and spastic gait. Some patients are reported to have uncontrolled laughter and weeping (pseudobulbar syndrome). Mild atrophy of the legs and hands are observed in some cases. Bladder dysfunction and sensory disturbances are also found. The disease is usually slowly progressive and some patients have been reported to have become bedridden by 12 to 50 years of age.\nEtiology\nMutations in the following genes have been found in patients presenting with JALS: ALS2 (2q33-q35), and rarely SIGMAR1 (9p13.3), SPG11 (15q13-q15) and FUS (16p11.2). Mutations in the latter gene are sporadic and appear to be associated with a severe and aggressive course.\nDiagnostic methods\nDiagnosis is based on the clinical findings. Motor evoked potential studies show absent or reduced action potentials, electromyography demonstrates signs of denervation, while nerve conduction velocities are normal. Magnetic resonance imaging (MRI) scans of the brain and spinal cord are normal.\nDifferential diagnosis\nDifferential diagnoses include juvenile primary lateral sclerosis and, to a lesser extent, infantile-onset ascending hereditary spastic paralysis (see these terms).\nGenetic counseling\nCases related to the ALS2 and SIGMAR1 genes have an autosomal recessive pattern of inheritance. Genetic counseling should be provided to affected families.\nManagement and treatment\nThere is currently no specific treatment. Management primarily involves physical and occupational therapy to promote mobility and independence.\nPrognosis\nPrognosis is guarded and quality of life severely affected by the clinical manifestations of the disease.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI"}
{"Disease Name": "Juvenile cataract-microcornea-renal glucosuria syndrome", "Disease Definition": "A rare autosomal dominant association characterized clinically by juvenile cataract associated with bilateral microcornea, and renal glucosuria without other renal tubular defects.", "ORPHA ID": 247794, "Summary": ""}
{"Disease Name": "Juvenile dermatomyositis", "Disease Definition": "An early-onset form of dermatomyositis (DM), a systemic, autoimmune inflammatory muscle disorder with vasculopathy, characterized by proximal and symmetrical muscle weakness, evocative skin lesions, and systemic manifestations. Vasculopathy occurs in the skin, muscle (mainly in the perifascicular area), and sometimes in the intestinal tissue.", "ORPHA ID": 93672, "Summary": "Epidemiology\nJuvenile dermatomyositis (JDM) is the most common idiopathic inflammatory myopathy of childhood, with an annual incidence of 1/250,000-500,000 children. Females are affected more frequently than males (2-5:1 ratio).\nClinical description\nOnset of juvenile dermatomyositis (JM) is on average between 5 to 14 years of age. Patients commonly have the signs of DM, i.e symmetrical proximal muscle weakness and erythematous rash (heliotrope rash, Gottron papules, erythema in sun-exposed areas), that is sometimes pruritic, along with cutaneous vasculitis and ulcerations, calcinosis of soft tissue (20-40%), and vasculopathy affecting the digestive tract (with bowel ischemia and/or infarction, abdominal pain, and melena). Muscle weakness variably impairs physical function. Commonly reported signs also include myalgia and arthralgia. Other associated extramuscular features include dysphagia, sometimes dysphonia, hoarseness, pneumonitis, cardiac manifestations (conduction defects, myocarditis, dilated cardiomyopathy), Raynaud's phenomenon and inflammatory arthritis. Specific clinical and histological characteristics are described according to myositis-specific antibody presence. Calcinosis is associated with a younger age at disease onset and positivity for anti-NXP2 antibody. Macrophage activation syndrome, a severe sometimes life-threatening condition, is described in some children. Unlike adult-onset DM, there is no association between malignancy and anti-TIF1-γ antibody positivity. The rare reported malignancies include lymphoma and leukemia.\nEtiology\nThe pathogenesis of JDM has been partially elucidated and is associated with certain HLA regions (different associations compared to adult onset DM) as well as several triggers such as infections. The interferon (IFN) pathways play a key role, especially type I IFNs and an IFN signature has been detected in muscle fibers, and endothelial cells.\nDiagnostic methods\nDiagnosis is based on the clinical signs and magnetic resonance imaging (MRI) of muscle. Muscle and skin involvements should be evaluated with specific standardized tools. Muscle biopsy and electromyographic testing may also be used, especially in case of atypical JDM. Muscle enzymes (creatine kinase) may be elevated. In JDM, 65% of the patients have myositis-specific antibodies with different prevalence compared to adult onset DM (20-25% with anti-TIF1-γ, 18-20% with anti-NXP2, 4-10% with anti-Mi2). Lung and cardiac involvement should be assessed at diagnosis.\nDifferential diagnosis\nDifferential diagnosis in JDM may include mitochondrial myopathies, infectious myopathies, other forms of inflammatory myopathies, particularly autoimmune necrotizing myopathy, as well as Duchenne muscular dystrophy or Becker muscular dystrophy, systemic lupus erythematosus, and juvenile idiopathic arthritis. Monogenic interferonopathies, such as proteasome-associated autoinflammatory syndrome and STING-associated vasculopathy with onset in infancy syndrome, may mimic JDM.\nManagement and treatment\nThe aim of treatment is to reduce long-term morbidity and to restore physical function. High-dose corticosteroids are the mainstay of treatment, with dose tapering after a few weeks of therapy depending on patient response. Methotrexate may also be used, and for severe disease, intravenous methylprednisolone (IVMP). In case of refractory disease, other immunosuppressive treatments may be prescribed. Physical therapy is important to maintain or restore muscle strength. Topical corticosteroids and tacrolimus have been used to treat skin manifestations. Patients should avoid direct UV light and use high-factor sunscreen. There is no validated treatment for calcinosis.\nPrognosis\nThe course of JDM is highly variable: 30-50% patients go into remission within 2 to 3 years, whilst others have a cyclic course marked by relapse or an ulcerative or chronic disease course. Treatment is generally effective, with very low mortality rates (less than 4%). The disorder may however be associated with significant morbidity (calcinosis, persistent muscle weakness, skin and muscle atrophy).\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE"}
{"Disease Name": "Juvenile glaucoma", "Disease Definition": "A rare primary early-onset glaucoma characterized by early onset, severe elevation of intra ocular pressure of rapid progression, leading to optic nerve excavation and, when untreated, substantial visual impairment.", "ORPHA ID": 98977, "Summary": "Epidemiology\nThe disorder is estimated to occur in 0,32/100 000 individuals before the age of 20 years.\nClinical description\nJuvenile glaucoma (JG) typically presents between the ages of 5 to 18 years, but it can appear later. Patients are initially asymptomatic and are often discovered incidentally on a routine examination. JG is generally bilateral; there can be a marked asymmetry between the two eyes. The intraocular pressure increases progressively leading to optic nerve excavation and eventually, substantial visual impairment and field loss.\nEtiology\nJG is caused by impaired outflow of aqueous humor through the trabecular meshwork and into the Schlemm canal. Mutation in MYOC (1q23-q24) genes have been found in patients with JG. MYOC gene codes for the glycoprotein myocilin that is found in the trabecular meshwork and ocular tissue and mutations are disease-causing.\nDiagnostic methods\nThe diagnosis is suspected with the presence of clinical features such as increased intraocular pressure and optic nerve excavation. On gonioscopy the angle appears normal. Typical features of primary congenital glaucoma such as corneal edema and Haab's striae are not present. The refraction test reveals myopia. Typical glaucomatous field defects can be documented. Optic nerve head shows glaucomatous optic neuropathy.\nDifferential diagnosis\nDifferential diagnoses include other forms of open angle glaucoma that can occur at any age, late recognized congenital glaucoma, steroid induced glaucoma, traumatic glaucoma and inflammatory glaucoma.\nGenetic counseling\nTransmission is autosomal dominant with high penetrance. Genetic testing can be used to identify family members at risk of developing JG. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nMedical therapy (carbonic anhydrase inhibitors, beta blockers, prostaglandin analogues) is often useful in the treatment of JG. When the condition becomes unresponsive to medications, angle surgery (goniotomy, trabeculotomy), filtration surgery (trabeculectomy), LASER treatment (angle laser surgery or cyclodiode laser therapy) and/or aqueous shunt devices can be considered.\nPrognosis\nPrognosis is good in patients diagnosed and treated early. Without treatment, the evolution towards blindness is possible.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Pascal DUREAU  - Dr Emmanuel MARCIANO"}
{"Disease Name": "Juvenile Huntington disease", "Disease Definition": "Juvenile Huntington disease (JHD) is a form of Huntington disease (HD; see this term), characterized by onset of signs and symptoms before 20 years of age.", "ORPHA ID": 248111, "Summary": "Epidemiology\nExact prevalence of the juvenile form is not known, but is estimated to be about 1/166,000. JHD is reported in 6% of the total cases of HD, which has a prevalence of 1/10,000.\nClinical description\nBehavioral disturbances and learning difficulties at school are often the first signs. Motor behavior is often hypokinetic and bradykinetic with dystonic components. Dementia is present in the early stage of the disease. Chorea, the classical sign of HD, is rarely seen in the 1st decade and only appears in the 2nd decade. Seizures, ataxia and weight loss are common.\nEtiology\nHD is caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4 (4p16.3) in the huntingtin gene, HTT. In juvenile Huntington disease, the CAG repeat length is over 55 in most cases. The length of the repeat determines about 70% of the variance in age at onset but gives no indication of initial symptoms, course, or duration of illness. In 75% of patients with JHD, the father is the affected parent.\nDiagnostic methods\nDiagnosis is based on clinical manifestations in an individual with a parent with proven HD, and is confirmed by DNA testing. Premanifest testing has been codified in the Guidelines of the International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group, and is not performed in at-risk patients below the age of 18.\nDifferential diagnosis\nDifferential diagnoses of JHD are young-onset type 2 spinocerebellar ataxia (SCA2: 12q) with chorea, dystonia, and dementia, and dentatorubral pallidoluysian atrophy (DRPLA: 12p) with chorea and myoclonic epilepsy, but also SCA3 (14q) with rigidity, ataxia, and dystonia and SCA17 (6q) with psychiatric features and dementia (see these terms). Other causes of chorea including general internal disorders or iatrogenic drug-induced disorders must also be considered. Sydenham chorea and post-streptococcal chorea are is still present in many parts of the world.\nManagement and treatment\nNo cure is currently available. Management should be multidisciplinary and is based on treating manifestations with a view to improving quality of life. Chorea should be treated with dopamine receptor blocking (risperidone, tiapride, pimozide) or depleting agents (tetrabenazine). None of these drugs are officially approved for use in children but are prescribed off-label as treatment of the main symptoms of the disease. Attempts have been made to treat hypokinesia with a number of antiparkinsonian drugs, but without success. Paramedical care with speech, occupational, and physical therapy with psychological support for the patient and family are recommended.\nPrognosis\nThe progression of the disease leads to complete dependency in daily life, which results in patients requiring full-time care, and finally death. The mean disease duration is comparable or slightly shorter than adult HD. The most common cause of death is pneumonia.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Pr R.A.C. [Raymund] ROOS"}
{"Disease Name": "Juvenile hyaline fibromatosis", "Disease Definition": "A rare hyaline fibromatosis syndrome characterized by papulo-nodular skin lesions (especially around the head and neck), soft tissue masses, gingival hypertrophy, joint contractures, and osteolytic bone lesions in variable degrees. Joint contractures may cripple patients and delay normal motor development if occuring in infancy. Severe gingival hyperplasia can interfere with eating and delay dentition. Histopathology analysis of involved tissues reveals cords of spindle-shaped cells embedded in an amorphous, hyaline material.", "ORPHA ID": 2028, "Summary": ""}
{"Disease Name": "Juvenile idiopathic arthritis", "Disease Definition": "A rare, heterogeneous group of rheumatologic diseases characterized by arthritis which has an onset before 16 years of age, persists for more than 6 weeks, and is of unknown origin.", "ORPHA ID": 92, "Summary": ""}
{"Disease Name": "Juvenile myasthenia gravis", "Disease Definition": "Juvenile myasthenia gravis (MG; see this term) is a rare form of MG, an autoimmune disorder of the neuromuscular junction resulting in ocular manifestations or generalized weakness, with onset before 18 years of age.", "ORPHA ID": 391497, "Summary": "Epidemiology\nThe exact prevalence and incidence of juvenile MG are not known. Estimated incidence has been reported at 1/1,000,000 to 1/200,000. The disorder is uncommon in Europe and North America (10% to 15% of cases of myasthenia gravis; see this term). In the Asian population, a much higher proportion of cases (up to 50%) with mainly ocular manifestations occurs in children below 15 years of age.\nClinical description\nOnset may be prepubertal (before 12 years of age) or postpubertal (over 12 years). The hallmark of MG is fatigable muscle weakness. Initial presentation may be acute or subacute, and the course is usually chronic with remission and relapses. Prepubertal children more commonly have the ocular presentation (fatigable ptosis, ophthalmoplegia, and diplopia) while postpubertal patients more often develop generalized weakness. The proportion of patients having only ocular symptoms is higher than in adult MG, particularly in the prepubertal group in which half of cases are purely ocular. In generalized cases, manifestations include facial weakness, dysarthria, and dysphagia. In severe cases (myasthenic crisis), respiratory muscle involvement may be life-threatening and require respiratory support. Thymoma (see this term) development is rare in juvenile MG.\nEtiology\nThe exact pathogenesis is not known but MG is related to circulating antibodies to various muscle receptors, including, in most of patients, acetylcholine receptor (AChR) and, rarely, muscle-specific receptor tyrosine kinase (MuSK). The thymus is thought to trigger antibody production in the form with anti-AChR antibodies. In the prepubertal form, there is a high rate of the MG form with no antibodies detectable (30-50%). It is currently unknown whether anti-LRP4 antibodies could be found in these patients. The disorder can also be drug-induced.\nDiagnostic methods\nThe diagnosis is primarily clinical and is suspected on the basis of fatigable muscle weakness. Specific serum antibody tests, including acetylcholine antibody test, are diagnostic. Other tests that support diagnosis include repetitive nerve stimulation and single-fiber electromyography. Edrophonium testing has been used and involves administration of this short-acting cholinesterase inhibitor intravenously. The test is positive if there is a rapid but transient improvement in a monitored clinical sign (usually ptosis). Computed tomography (CT) or magnetic resonance imaging (MRI) should be used to screen for thymoma.\nDifferential diagnosis\nCongenital myasthenic syndrome (CMS; see this term) should be considered in case of seronegativity.\nManagement and treatment\nAcetylcholinesterase inhibitors (pyridostigmine) are recommended as first-line treatment in juvenile MG and may be sufficient in ocular forms. Corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, and cyclophosphamide have been used in children with refractory MG, but adverse effects limit their usefulness. Plasmapheresis and intravenous immunoglobulin (IVIg) can also be used, mainly in severe exacerbation or myasthenic crisis, and pre- or postoperatively in the context of thymectomy. Thymectomy has been recommended for the treatment of generalized juvenile MG in patients not responding to anticholinesterase treatment, nor immunomodulatory or immunosuppressive treatments. Age at thymectomy is debated.\nPrognosis\nSevere cases may be life-threatening, but the prognosis is generally very good. In the prepuberal form, there is a higher rate of remission in patients with the ocular form.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Sonia BERRIH-AKNIN  - Pr Bruno EYMARD"}
{"Disease Name": "Juvenile myelomonocytic leukemia", "Disease Definition": "A rare myelodysplastic/myeloproliferative neoplasm characterized by a proliferation primarily of granulocytic and monocytic lineages with infiltration of the liver and spleen, among other organs. Blasts and promonocytes account for less than 20% of white blood cells in peripheral blood and bone marrow. Erythroid and megakaryocytic abnormalities are often present. BCR-ABL1 fusion is absent, while somatic mutations in genes of the RAS pathway or monosomy 7 may be found. The condition may also occur in the context of neurofibromatosis type 1 or Noonan syndrome-like disorder. Children of less than three years are predominantly affected, with a clear male preponderance. Most patients present with constitutional symptoms, signs of infection, and hepatosplenomegaly.", "ORPHA ID": 86834, "Summary": ""}
{"Disease Name": "Juvenile myoclonic epilepsy", "Disease Definition": "Juvenile myoclonic epilepsy is the most common hereditary idiopathic generalized epilepsy syndrome and is characterized by myoclonic jerks of the upper limbs on awakening, generalized tonic-clonic seizures manifesting during adolescence and triggered by sleep deprivation, alcohol intake, and cognitive activities, and typical absence seizures (30% of cases).", "ORPHA ID": 307, "Summary": ""}
{"Disease Name": "Juvenile nasopharyngeal angiofibroma", "Disease Definition": "Juvenile nasopharyngeal angiofibroma (JNA) is a rare and benign but locally aggressive fibrovascular tumor arising from the posterolateral wall of the nasopharynx, which affects mainly young and adolescent males (onset usually occurring between 7-19 years of age) and that presents as a mass in the nasopharynx and nasal cavity, leading to manifestations such as nasal obstruction, epistaxis, profound facial swelling, proptosis or diplopia. Although slowly progressive, it has a high rate of recurrence and sometimes invades adjacent structures.", "ORPHA ID": 289596, "Summary": ""}
{"Disease Name": "Juvenile nephropathic cystinosis", "Disease Definition": "A subtype of cystinosis characterized by an accumulation of cystine in different organs and tissues, particularly in the kidneys and eyes, and that clinically manifests between childhood and adolescence with a slowly progressive proximal tubulopathy and/or proteinuria, and photophobia. Extra-renal manifestations (e.g. hypothyroidism, insulin-dependent diabetes, hepatosplenomegaly, muscular and cerebral involvement) are less severe than in the infantile form of the disease.", "ORPHA ID": 411634, "Summary": ""}
{"Disease Name": "Juvenile overlap myositis", "Disease Definition": "A rare juvenile idiopathic inflammatory myopathy characterized by the association of inflammatory myositis (manifesting with acral erythema, progressive weakness of the limbs, pain, general fatigue, moodiness or crankiness) with clinical and/or laboratory features of other autoimmune diseases (e.g. systemic lupus erythematosus, localized scleroderma, diabetes). Cardiac involvement has been reported in some patients.", "ORPHA ID": 329894, "Summary": ""}
{"Disease Name": "Juvenile Paget disease", "Disease Definition": "Juvenile Paget disease is a very rare form of Paget disease of the bone characterized by a general increase in bone turnover with increased bone resorption and deposition, resulting in cortical and trabecular thickening, and clinically presenting as progressive skeletal deformities, growth impairment, fractures, vertebral collapse, skull enlargement and sensorineural hearing loss.", "ORPHA ID": 2801, "Summary": ""}
{"Disease Name": "Juvenile polymyositis", "Disease Definition": "A rare type of juvenile idiopathic inflammatory myopathy (IIM) characterized by an onset before 18 years of age of chronic skeletal muscle inflammation, manifesting as progressive, proximal and distal muscle weakness and atrophy.", "ORPHA ID": 93568, "Summary": ""}
{"Disease Name": "Juvenile polyposis of infancy", "Disease Definition": "Juvenile polyposis of infancy (JPI) is the most severe form of juvenile gastrointestinal polyposis (see this term) and is characterized by pancolonic hamartomatous polyposis from stomach to rectum, diagnosed in the first two years of life.", "ORPHA ID": 79076, "Summary": "Epidemiology\nPrevalence is unknown but only 11 cases have been described in the literature so far.\nClinical description\nThe digestive phenotype is severe and life-threatening, with gastrointestinal bleeding, diarrhea, inanition and exudative enteropathy. Early death has been reported and the risk of cancer in surviving children has not yet been clearly established. Signs of the Cowden or Bannayan-Riley-Ruvalcaba (BRRS) syndromes (see these terms) such as macrocephaly, lipomas, and hemangioblastomas can be observed. Dysmorphic signs, such as a large forehead, hypertelorism, down-slanting palpebral fissures, a flat nasal bridge, low-set ears, and a small mouth and chin, have also been described. Mild intellectual deficit has been reported in some cases. Recently, a less severe form of JPI has been described in several patients with early-onset gastrointestinal tract juvenile polyps but with a mild digestive phenotype.\nEtiology\nThe majority of cases are caused by a large deletion in the chromosome 10q23 region, encompassing the PTEN and BMPR1A genes. The hypothesis is that the severe digestive phenotype results from a cooperative effect of the deletion of each gene. However, this hypothesis is under debate as the patients with the mild digestive phenotype were also found to harbor a deletion of the PTEN and BMPR1A genes.\nDiagnostic methods\nDiagnosis may be suspected on the basis of the clinical picture and digestive endoscopy investigation but is confirmed by detection of the 10q23 deletion. This deletion is rarely detected through karyotype analysis, and FISH or Array-CGH, followed by semiquantitative PCR methods (QMPSF, MLPA, MP/LC), are required to define the length and the location of the deletions.\nDifferential diagnosis\nThe differential diagnosis should include the allelic disorders Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, which are caused by mutations in the PTEN gene, as well as familial adenomatous polyposis and Peutz-Jeghers syndrome (see these terms).\nGenetic counseling\nJPI appears to be sporadic.\nManagement and treatment\nManagement revolves around colonoscopy with endoscopic polypectomy. Early endoscopic polypectomy may reduce morbidity by reducing the risk of the cancer, bleeding, or intestinal obstruction.\nPrognosis\nHowever, as JPI is life-threatening and colectomy is generally necessary in infancy, the prognosis during infancy is severe and the survival rate is generally low. The prognosis for surviving children depends on the risk of gastrointestinal tract cancer.\n\n                            Last update: \n                            December 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Capucine DELNATTE  - Pr Damien SANLAVILLE  - Pr Dominique STOPPA-LYONNET"}
{"Disease Name": "Juvenile polyposis syndrome", "Disease Definition": "A rare condition characterized by the presence of juvenile hamartomatous polyps in the gastrointestinal (GI) tract.", "ORPHA ID": 2929, "Summary": "Epidemiology\nAnnual incidence is estimated at between 1/100,000 and 1/15,000.\nClinical description\nPolyps may develop at any age from infancy through to adulthood, with most affected individuals presenting polyps by adolescence/early adulthood. A diagnosis of JIP is made on the basis of one or several of the following findings: the presence of more than five juvenile polyps in the colon and/or rectum; the presence of juvenile polyposis throughout the digestive tract, including the stomach; the presence of any number of juvenile polyps in association with a family history of JIP. Several types of JIP have been described, including three forms that differ on the basis of the location of the polyps (generalized juvenile polyposis of the upper and lower GI tract, juvenile polyposis coli and juvenile polyposis of the stomach) and a more severe infantile form, juvenile polyposis of infancy (see this term). Regardless of the subtype, the clinical signs of JIP are isolated rectal bleeding, anemia, abdominal pain, intussusceptions and diarrhea. Rectal prolapse and spontaneous anal elimination of polyps have been noted in juvenile polyposis coli and generalized juvenile polyposis. Other associated signs may include growth delay and edema.\nEtiology\nJIP is transmitted in an autosomal dominant manner and mutations in the SMAD4 (18q21.1) and BMPR1A (10q22.3) genes have been associated with the disease. However, no genetic anomalies have been identified so far in around 60% of the cases. A few genotype-phenotype correlations have been established: the frequency of gastric polyposis is higher in SMAD4 carriers than in BMPR1A carriers and the association of JPS with hereditary hemorrhagic telangiectasia (juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome) is observed in just under a quarter of SMAD4 mutation carriers.\nDiagnostic methods\nDiagnosis is based on the clinical findings, family history, endoscopic findings and histological analysis of the polyps. Molecular genetic testing may also be useful for confirming the diagnosis in carriers of SMAD4 and BMPR1A gene mutations.\nDifferential diagnosis\nThe differential diagnosis should include other syndromes associated with polyposis including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, familial adenomatous polyposis and Peutz-Jeghers syndrome (see these terms).\nManagement and treatment\nManagement should involve routine colonoscopy and if the number of polyps remains low endoscopic polypectomy is the gold standard for treatment. Due to the risk of cancer and polyposis extension, surgical colectomy associated with protectomy and ileoanal anastomosis may also be proposed.\nPrognosis\nThe prognosis of JIP is based on the risk of developing GI or pancreatic cancer after 20 years of age. The cumulative risk for developing cancer in patients with JIP is 20% at the age of 35 years and 68% after the age of 60 years. The risk of cancer is higher among individuals with generalized juvenile polyposis.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Frédérique SAUVAT"}
{"Disease Name": "Juvenile primary lateral sclerosis", "Disease Definition": "A very rare motor neuron disease characterized by progressive upper motor neuron dysfunction leading to loss of the ability to walk with wheelchair dependence, and subsequently, loss of motor speech production.", "ORPHA ID": 247604, "Summary": "Epidemiology\nThe prevalence and incidence of JPLS are not known. A very small number of cases have been reported to date with this condition. The disorder has been described in various ethnic groups.\nClinical description\nAffected patients are usually normal at birth and have normal early development. During the second year of life, they lose the ability to walk (some patients never walk due to early severe spasticity) and then develop slowly progressive upper motor neuron disorders including pseudobulbar palsy and spastic quadriplegia. Other signs include clumsiness, muscle weakness and balance difficulties. Patients generally become wheelchair dependent by adolescence. Between 2 and 10 years of age, motor speech production is lost causing dysarthria, dysphagia and drooling. Cognitive function is generally not affected.\nEtiology\nMutations in the ALS2 gene (2q33-q35) encoding alsin, a protein that is abundant in motor neurons, and less commonly mutations in the ERLIN2 gene (8p11.2) have been reported.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical signs and can be confirmed by molecular genetic testing. Electromyography, nerve conduction velocities, visual evoked potentials, and brain stem auditory evoked potentials are all normal, while transcranial magnetic stimulation shows no motor evoked potentials. Computed tomography (CT) and magnetic resonance imaging (MRI) scans of the brain and spinal cord are normal.\nDifferential diagnosis\nDifferential diagnoses include the allelic disorders juvenile amyotrophic lateral sclerosis and infantile-onset ascending hereditary spastic paralysis (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies is possible if the disease-causing mutations have been identified in the family.\nGenetic counseling\nJPLS is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes and are therefore asymptomatic carriers. Genetic counseling should be provided to affected families.\nManagement and treatment\nManagement primarily involves physical and occupational therapy to promote mobility and independence.\nPrognosis\nThe prognosis is guarded, with the clinical signs having a major impact on quality of life.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI"}
{"Disease Name": "Juvenile temporal arteritis", "Disease Definition": "A rare vasculitis characterized by mostly unilateral inflammation of the temporal artery affecting patients up to fifty years of age. Patients typically present with a lump in the temporal region or a prominent temporal artery and often have headaches. Males are more frequently affected than females, and major systemic symptoms, ocular complications, and a biological inflammatory syndrome are usually absent, although peripheral blood eosinophilia may be seen. Histopathological analysis shows arteritis predominantly of the intima with possible extension to the perivascular tissue. The presence of granuloma, giant cells or fibrinoid necrosis is rare. Clinical relapses after one episode are uncommon.", "ORPHA ID": 26137, "Summary": ""}
{"Disease Name": "Juvenile xanthogranuloma", "Disease Definition": "Juvenile xanthogranuloma is the most common type of non-Langerhans cell histiocytosis (see this term) characterized by the occurrence of one or more reddish or yellowish self-limiting and benign papules or nodules of several millimeters in diameter, usually appearing on the head and neck (but sometimes on the extremities and trunk) during the first year of life (or rarely in adulthood) and usually regressing spontaneously. Extracutaneous involvement has also been reported, involving most commonly the eye (uveal tract) but with other locations including the central nervous system, lung, liver, bones and endocrine glands, and may be associated with considerable morbidity.", "ORPHA ID": 158000, "Summary": ""}
{"Disease Name": "Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome", "Disease Definition": "A rare genetic disease characterized by juvenile-onset insulin-dependent diabetes mellitus associated with central and peripheral nervous system abnormalities with variable onset between infancy and adolescence. Neurological manifestations include combined cerebellar and afferent ataxia, sensorineural hearing loss, pyramidal tract signs, and demyelinating sensorimotor peripheral neuropathy. Hypothyroidism has been reported in some patients. Brain imaging may show generalized cerebral atrophy.", "ORPHA ID": 445062, "Summary": ""}
{"Disease Name": "Juxtaposition of the atrial appendages", "Disease Definition": "Juxtaposition of the atrial appendages is a rare atrial appendage anomaly when both appendages are located on the left or the right side of the great arteries. It is asymptomatic and is usually diagnosed incidentally, but is frequently associated with other congenital heart diseases.", "ORPHA ID": 99100, "Summary": ""}
{"Disease Name": "Kabuki syndrome", "Disease Definition": "A rare multiple congenital anomalies/neurodevelopmental disorder characterized by five major features: intellectual disability (typically mild to moderate), visceral malformations (frequently congenital heart defects), persistence of fetal fingertip pads, post-natal short stature, skeletal anomalies (brachymesophalangy, brachydactyly V, spinal column abnormalities and fifth digit clinodactyly) and specific facial features (arched and broad eyebrows, long palpebral fissures, eversion of the lower eyelid, large prominent, cupped ears, depressed nasal tip and short columella). Various additional features are frequently observed.", "ORPHA ID": 2322, "Summary": "Epidemiology\nThe prevalence of Kabuki syndrome (KS) is estimated at 1/32000 birth and seems a frequent etiology in malformed fetus.\nClinical description\nPresentation is typically with neonatal/infantile hypotonia and feeding difficulties (affecting more than 70%). KS associates developmental delay and intellectual disability in 90% of patients. Intellectual disability is frequently mild to moderate; however, the spectrum ranges from normal intellect to severe disability. Verbal language acquisition and memory are usually better than visuospatial or processing speed. Individuals with KS usually achieve walking and language milestones. Heart malformations are observed in around 50% of patients. Kidney malformations, deafness, and seizures of different types are observed in 20%. Immune deficiency and recurrent infection are frequent. Autoimmune features increase with age affecting around 20% of the adults with KS. Scoliosis and patellar luxation require frequent screening and should be monitored carefully at puberty. Missing teeth are frequently observed. Obesity could arise from the age of 5 and requires monitoring. Growth hormone deficiency is observed in 25-30%. Premature thelarche occurs in 30% of females.\nEtiology\nKS is usually due to de novo pathogenic variants in about 70% of patients fulfilling the diagnostic criteria. For the majority of patients (56% to 75%), KS is due to mutations in KMT2D (12q13.12) and for the minority of patients (5%), KS is due to mutations in KDM6A (xp11.2).\nDiagnostic methods\nDiagnosis is evoked on clinical examination, and confirmed using genetic studies.\nDifferential diagnosis\nDifferential diagnosis includes CHARGE, 3MC, and Hardikar syndromes, KAT6B-related disorders, and other genetic disorders involving chromatin regulation.\nAntenatal diagnosis\nFor parents of an index individual, detection of KS by amniocentesis in subsequent pregnancies should be discussed. KS could be identified using exome sequencing during pregnancy screening for malformative syndromes.\nGenetic counseling\nTransmission of KMT2D-related KS is autosomal dominant; however, in most situations, the pathogenic variants arise de novo and thus the risk of sibling recurrence is low. The estimated recurrence risk to siblings is 1% based on the possibility of parental germline mosaicism. Transmission of KDM6A-related KS is X-linked with males slightly more affected than females.\nManagement and treatment\nManagement requires a lifelong multidisciplinary approach. Regular follow-up by a clinical geneticist, pediatrician, psychologist/psychiatrist, speech therapist, physiotherapist and ophthalmologist will have a major impact. Feeding difficulties may require tube feeding (nasogastric or gastrostomy). Developmental assessments are required in order to tailor medical services to each individual's needs. Other specialists can be required, such as a cardiologist, gastroenterologist, nephrologist, immunologist, ENT (ear, nose and throat) or stomatologist. Special attention is need for fine graphomotor and visuals difficulties.\nPrognosis\nThe prognosis is usually good. A specific survey is required for autoimmune and kidney problems. Autonomy may be limited and affected individuals will sometimes require life-long support from caregivers.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr David GENEVIEVE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Kagami-Ogata syndrome", "Disease Definition": "Kagami-Ogata syndrome is a rare genetic disease characterized by polyhydramnios (mostly due to placentomegaly), fetal macrosomia, abdominal wall defects, skeletal abnormalities (including bell-shaped thorax, coat-hanger appearance of the ribs and decreased mid to wide thorax diameter ratio in infancy), feeding difficulties and impaired swallowing, dysmorphic features (hairy forehead, full cheeks, protruding philtrum, micrognathia), developmental delay and intellectual disability. Additional features may include kyphoskoliosis, joint contractures, diastasis recti, muscular hypotonia. There is increased risk of hepatoblastoma.", "ORPHA ID": 254519, "Summary": ""}
{"Disease Name": "Kallmann syndrome-heart disease syndrome", "Disease Definition": "Kallmann syndrome with cardiopathy is characterised by hypogonadotropic hypogonadism associated with gonadotropin-releasing hormone (GnRH) deficiency, anosmia or hyposmia (with hypoplasia or aplasia of the olfactory bulbs) and complex congenital cardiac malformations (double-outlet right ventricle, dilated cardiomyopathy, right aortic arch). It represents a distinct clinical entity from Kallmann syndrome.", "ORPHA ID": 2326, "Summary": "Epidemiology\nLess than 10 cases have been described so far.\nEtiology\nThe aetiology is unknown but both autosomal recessive and dominant modes of inheritance, de novo mutations and a teratogenic origin have been suggested.\n\n                            Last update: \n                            September 2007"}
{"Disease Name": "Kallmann syndrome", "Disease Definition": "Kallmann syndrome (KS) is a developmental genetic disorder characterized by the association of congenital hypogonadotropic hypogonadism (CHH) due to gonadotropin-releasing hormone (GnRH) deficiency, and anosmia or hyposmia (with hypoplasia or aplasia of the olfactory bulbs).", "ORPHA ID": 478, "Summary": "Epidemiology\nThe prevalence is estimated at 1/8,000 males and 1/40,000 females, but is probably underestimated.\nClinical description\nMost cases are diagnosed at the time of puberty due to lack of sexual development, but KS may also be suspected in infancy in males with cryptorchidism, micropenis or associated non reproductive signs. The main clinical features consist of the absence of complete spontaneous puberty and a partial or total impairment of the sense of smell (anosmia) in both sexes. Untreated adult males usually have decreased bone density and muscle mass, decreased testicular volume (< 4 mL), erectile dysfunction, diminished libido and infertility. Untreated adult females almost always experience primary amenorrhea with absent, little or normal breast development. Rare presentations include unilateral (occasionally bilateral and lethal at birth) renal agenesis, hearing impairment, cleft lip or palate, dental agenesis or bimanual synkinesis persisting beyond childhood.\nEtiology\nKS is caused by impaired development of the olfactory system and disrupted embryonic migration of the GnRH-synthesizing neurons from the olfactory epithelium to the hypothalamic region of the brain. The majority of reported cases are sporadic but familial forms have been described. Causative genes include: KAL1 (Xp22.32), in the X-linked recessive form, FGFR1 (8p12), FGF8 (10q25-q26), CHD7 (8q12.2) and SOX10 (22q13.1) in the AD form, and PROKR2 (20p12.3) and PROK2 (3p21.1), in both the AR and oligogenic forms. More evidence is needed to determine if other genes (ex: SEMA3A), presumably involved in KS, are indeed causal.\nDiagnostic methods\nDiagnostic methods consist of hormone evaluation (sex steroids, gonadal peptides and pituitary gonadotropin dosage), as well as evaluation of the sense of smell (olfactometry). Morphological analysis of the olfactory bulbs by MRI can be useful, especially in young children. Genetic testing can identify a disease causing mutation, and is mandatory before starting infertility treatment.\nDifferential diagnosis\nDifferential diagnoses include isolated congenital gonadotropin deficiency and CHARGE syndrome (see these terms).\nAntenatal diagnosis\nIn a familial context of FGFR1, FGF8, KAL1, or CHD7 mutations, bone abnormalities, cleft lip/palate, renal agenesis, or multiple developmental defects can be found in the fetus by ultrasonography.\nGenetic counseling\nGenetic counseling should be adapted to each family, taking into account the potential mode of inheritance (AD/AR, X-linked, or presumably oligogenic) and the great variability in clinical expression, even within the same family, as well as the risk, in sporadic cases, of neomutations.\nManagement and treatment\nHormonal replacement therapy is used to induce puberty, and later, fertility. Testosterone esters are usually used and sometimes human chorionic gonadotropin (hCG) injections in combination with follicle-stimulating hormone (FSH) or in monotherapy are given to males to achieve normal virilization and increased testicular volume. In adults combined gonadotropin therapy is mandatory to stimulate spermatogenesis. In females, estrogen is administered to induce breast development and genital development along with progestin to establish endometrial cyclicity. Pulsatile GnRH administration or exogenous gonadotropins are used to induce folliculogenesis and ovulation and therefore to restore fertility. There is currently no treatment for anosmia.\nPrognosis\nKS is not a life threatening disease. With hormonal treatment, pubertal feminization or virilization occurs in all patients. Fertility, when desired, is achieved in most cases but cryptorchidism has a poor prognosis in males.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jean-Pierre HARDELIN  - Pr Jacques YOUNG"}
{"Disease Name": "Kandori fleck retina", "Disease Definition": "Kandori fleck retina is a rare, genetic retinal dystrophy disorder characterized by irregular, sharply defined, yellowish-white lesions of variable size that are distributed mainly in the nasal equatorial region of the retina, with a tendency to confluence, that are not associated with any vascular or optic nerve abnormalities. They frequently manifest as mild and stationary night blindness.", "ORPHA ID": 99179, "Summary": ""}
{"Disease Name": "Kaposi sarcoma", "Disease Definition": "A rare vascular tumor that is characterized by human herpes virus 8 (HHV-8)-induced endothelial inflammatory neoplasm that develops with various clinically distinct settings, manifesting mostly as cutaneous lesions, or mucosal or visceral involvement.", "ORPHA ID": 33276, "Summary": "Epidemiology\nMore than 100 million people worldwide are infected with HHV-8, with a heterogeneous geographic distribution (high in Africa and the Mediterranean). Only a very small proportion of those infected with HHV-8 develop KS. Incidence in Europe is reported to be about 1/300,000.\nClinical description\nHHV-8 infection is asymptomatic in the vast majority of cases. In some clinical contexts, the risk of developing Kaposi sarcoma (KS) is much higher, giving rise to four subtypes: Classic KS, African endemic KS, iatrogenic immunodepression KS, and AIDS-related KS. Cases affecting otherwise healthy people with no manifest immunological deficit except ''immunosenescence'' are known as classic KS (mostly reported in the Mediterranean basin) and African endemic KS (reported in sub-Saharan Africa) which affects primarily children and middle-aged men. Iatrogenic KS is mostly found in recipients of solid organs. Lastly, AIDS-related KS affects mainly homosexual men. A fifth subtype has been recently identified affecting non HIV infected homosexual men. Skin lesions manifest as solitary, localized or disseminated patches, or macular/papular eruptions, which progress to nodular plaques or lesions on any area of the skin. Progression is highly variable with lesions at different stages possibly occurring in the same individual. Lymph node and visceral involvement may be found in some forms especially iatrogenic and AIDS-KS. The oral cavity and the gastrointestinal tract (GI) are frequently affected. Pulmonary involvement is less common but may be life-threatening. Lymphedema of the face, genitalia and lower extremities may be found especially in classic and endemic KS. Some rare patients do not present skin lesions.\nEtiology\nAll known forms of KS are caused by HHV-8 infection. The exact routes of HHV-8 transmission are currently unknown but both sexual and non-sexual modes are suspected. The highest levels of HHV-8 shedding are found in saliva.\nDiagnostic methods\nKS is usually diagnosed on the basis of disseminated skin lesions, sometimes with lymph node and visceral involvement. Skin biopsy reveals neoangiogenesis and proliferating spindle-shaped cells, admixed with a variable chronic inflammatory infiltrate. Immunohistochemistry using monoclonal antibody against latent protein of HHV-8 is useful to differentiate KS from other angioproliferative tumors. Imaging techniques may be required to identify systemic disease but there is no consensus on systematic explorations.\nDifferential diagnosis\nThe differential diagnosis may include bacillary angiomatosis, hemosiderotic hemangioma, fibrous histiocytoma, interstitial granuloma annulare, arteriovenous malformations, and pyogenic granuloma.\nManagement and treatment\nNo specific treatment recommendations have been established. Treatment depends on the KS type and presence of localized or systemic involvement. The main aim of treatment is to restore immunity. Rapamycin or everolimus can be used in organ transplant recipients, and discontinuation or reduction of immunosuppressive therapy is recommended. Antiretroviral therapy should be systematically prescribed in KS-AIDS to prevent or reduce lesions. For localized lesions, radiotherapy, topical gels (alitretinoin), intralesional injections (vinblastine or bleomycin), surgery, or cryotherapy can be used. Visceral involvement generally requires systemic therapy with antiproliferative agents (taxanes and liposomal anthracyclins or interferon alpha 2b). Use of steroids should be avoided in patients with KS.\nPrognosis\nKS ranges from an indolent disorder to an aggressive disease with significant morbidity and mortality. It is generally not life-threatening in most forms, but may have major psychosocial implications and significant impact on quality of life.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Nicolas DUPIN"}
{"Disease Name": "Kaposiform hemangioendothelioma", "Disease Definition": "A rare low-grade malignant cutaneous or visceral vascular tumour that may be associated with severe thrombopaenia with consumption coagulopathy (Kasabach-Merritt syndrome) in pediatric patients.", "ORPHA ID": 2122, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nKaposiform haemangioendothelioma may develop at any age, but is most common during infancy. Congenital forms have also been described. Depending on the initial site of development, the vascular tumours present as sensitive blue-purple infiltrated plaques, palpable masses or as a tumour compression syndrome (retroperitoneal, severe cervical or mediastinal forms). The majority of reported cases concern the complicated visceral forms. Superficial forms appear to be less common. Cutaneous forms show clinical similarities to tufted angiomas, or graft on to diffuse lymphatic malformations (lymphangiomas). Osseous and regional lymph node involvement has been reported but metastasis does not appear to be a feature of this disease.\nEtiology\nThe etiology is unknown.\nDiagnostic methods\nThe diagnosis is based on the results of histological studies (after definition of the boundaries by magnetic resonance imaging, MRI), which reveal nodules and dense nests of fusiform cells with slight cellular atypia and mitotic activity, frequent slit-like vascular spaces and positive immunostaining for the D2-40 lymphatic marker.\nDifferential diagnosis\nThe differential diagnoses include Kaposi's sarcoma and tufted angioma. The clinical similarities with tufted angioma, the association of both conditions with Kasabach-Merritt syndrome and the histological features of these syndromes have led to the suggestion that kaposiform haemangioendothelioma and tufted angioma are part of the same clinical spectrum of vascular tumours.\nAntenatal diagnosis\nPrenatal diagnosis is possible for voluminous forms of kaposiform haemangioendothelioma through detection of highly vascularised masses on foetal ultrasound, followed by foetal MRI. However, precise diagnosis of the tumour type can only be made by biopsy after the birth.\nManagement and treatment\nTreatment depends of the form of disease present: treatment of non-complicated cutaneous forms differs from that for forms associated with Kasabach-Merritt syndrome. Non-complicated cutaneous forms presenting as relatively small lesions may be treated by local corticotherapy, whereas diffuse invalidating forms may require alpha 2b-interferon therapy or vincristine administration. Therapeutic options for forms associated with Kasabach-Merritt syndrome include pharmacological treatment (systemic corticotherapy, vincristine, alpha 2b-interferon, polychemotherapy and a combination of ticlopidine, asprin and pentoxyphilline), embolisation, surgical excision and radiotherapy.\nPrognosis\nThe prognosis depends on the chronicity of the lesions and extent of the complications (severity of the form present and association with Kasabach-Merritt syndrome).\n\n                            Last update: \n                            September 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Odile ENJOLRAS"}
{"Disease Name": "Kaposiform lymphangiomatosis", "Disease Definition": "A rare vascular anomaly or angioma characterized by multifocal malformed lymphatic channels lined by clusters or sheets of spindled lymphatic endothelial cells with a predilection for the thoracic cavity, but also involving extra-thoracic locations, especially bones and spleen. Typical clinical signs and symptoms are pericardial and pleural effusions, cough, dyspnea, bleeding, and fractures secondary to bone involvement. Prognosis is generally poor due to the progressive nature of the condition.", "ORPHA ID": 464329, "Summary": ""}
{"Disease Name": "Kapur-Toriello syndrome", "Disease Definition": "Kapur-Toriello syndrome is an extremely rare syndrome characterized by facial dysmorphism, severe intellectual deficiency, cardiac and intestinal anomalies, and growth retardation.", "ORPHA ID": 2328, "Summary": "Epidemiology\nOnly four cases have been reported in the literature, in three unrelated families.\nClinical description\nDysmorphic features include bilateral cleft lip and palate, bulbous nasal tip and eye anomalies.\nGenetic counseling\nThe condition seems to be inherited as an autosomal recessive trait.\n\n                            Last update: \n                            February 2010"}
{"Disease Name": "Karsch-Neugebauer syndrome", "Disease Definition": "Karsch-Neugebauer syndrome is a rare syndrome characterized by split-hand and split-foot deformity and ocular abnormalities, mainly a congenital nystagmus.", "ORPHA ID": 2329, "Summary": "Epidemiology\nTen cases from four families have been reported in the literature.\nClinical description\nIn some cases the hands are monodactylous. The affected patients have normal mental development.\nGenetic counseling\nThe condition seems to be autosomal dominant with a relatively high proportion of gonadal mosaicism.\n\n                            Last update: \n                            September 2010"}
{"Disease Name": "Karyomegalic interstitial nephritis", "Disease Definition": "A rare, genetic renal disease characterized by slowly progressive, chronic, tubulointerstitial nephritis, leading to end-stage renal disease before the age of 50 years, manifesting with mild proteinuria, glucosuria and, occasionally, urinary sediment abnormalities (mainly hematuria). Mild extrarenal manifestations, such as recurrent upper respiratory tract infections and abnormal liver function tests, may be associated. Renal biopsy reveals severe, chronic, interstitial fibrosis and tubular changes, as well as hallmark karyomegalic tubular epithelial cells which line the proximal and distal tubules and have enlarged, hyperchromatic nuclei.", "ORPHA ID": 401996, "Summary": ""}
{"Disease Name": "Kasabach-Merritt phenomenon", "Disease Definition": "A rare hemorrhagic disorder characterized by potentially life-threatening thrombocytopenia, microangiopathic hemolytic anemia, and consumptive coagulopathy in the context of kaposiform hemangioendothelioma or tufted angioma.", "ORPHA ID": 2330, "Summary": ""}
{"Disease Name": "Kawasaki disease", "Disease Definition": "A rare inflammatory disease characterized by an acute febrile, systemic, self-limiting, medium-vessel vasculitis primarily affecting children. It often causes acute coronary arteritis which is associated with coronary arterial aneurysms (CAA) that may be life threatening when untreated.", "ORPHA ID": 2331, "Summary": "Epidemiology\nAlthough it has been reported worldwide, Kawasaki disease (KD) is over-expressed among Asian populations. In Europe, the annual incidence for children under 5 years of age ranges between 1/6,500-20,500. The disease is the most common cause of acquired heart disease in children in developed countries.\nClinical description\nMedian age of onset is 2 years (with 75% of patients being under 5 years old). Fever (greater than 39 degrees C) that persists for greater than 5 days when untreated is a constant feature. Children are usually very irritable. Additional typical manifestations of KD include extremity changes (erythema and edema of palms and soles that desquamate after 2-3 weeks, usually seen in the subacute phase), polymorphic skin rash (maculopapular, urticarial, or scarlatiniform rash), lymphadenopathy (cervical, often unilateral, greater than 1.5 cm diameter), non-exudative bilateral conjunctivitis, and involvement of lips and oral mucosa (erythema, strawberry tongue, lip fissures). CAA is a life threatening complication that usually occurs in the subacute phase (6 to 8 weeks after onset) in 20-35% of untreated children. The regression of giant CAA (greater than 8 mm) is very unlikely, while minor dilations are usually transient. Atypical manifestations include myocarditis pericarditis, valvular regurgitation, hepatitis, diarrhea, abdominal pains, hydrops of gallbladder, arthralgia, arthritis, myalgia, aseptic meningitis, sensorineural hearing loss, urethritis and sterile pyuria. KD is a risk factor for ischemic heart disease in adulthood.\nEtiology\nEtiology is unknown but several pathogenic theories have been proposed (e.g. infection by a toxin-secreting microorganism and a superantigen-driven process). Genetics appear to play a major role, and the disease is much more common in Asian populations. Genome-wide studies have identified single nucleotide polymorphisms which would confer increased susceptibility to the disease and to its complications.\nDiagnostic methods\nDiagnosis is clinical. Complete KD is defined by fever and 4/5 of the standard clinical criteria (extremity changes, polymorphous rash, conjunctival injection, changes in lips and oral cavity, and cervical lymphadenopathy greater than 1.5 cm diameter). Incomplete KD can be diagnosed in case of prolonged fever, 2-3/5 standard criteria, and specific signs of coronary disease, particularly CAA when other causes of coronary vasculitis are excluded. Laboratory findings (elevated inflammatory markers and liver enzymes, neutrophilia and thrombocytosis), though non-specific, are supportive. At diagnosis, patients must be investigated for coronary involvement via transthoracic echocardiography.\nDifferential diagnosis\nDifferential diagnosis includes autoimmune and autoinflammatory diseases (e.g. systemic-onset JIA), bacterial infections (i.e. bacterial toxic shock syndrome, leptospirosis, adenophlegmon), viral infections (i.e. measles, enterovirus, Epstein-Barr virus), and toxin or drug reactions.\nManagement and treatment\nEarly administration of intravenous immunoglobulin (IVIg) reduces the rate of coronary abnormalities to less than 5% of patients. IVIg is administrated at a single dose of 2 g/kg before the 10th day of onset, or even later if persistent inflammation. In case of treatment failure, IVIg readministration, corticosteroids, anakinra and infliximab may be considered as second line treatments. Aspirin (30-50 mg/kg/day) are usually given in the febrile phase, followed by low (antiplatelet) doses (3-5 mg/day) for 6-8 weeks. Following diagnosis, coronary involvement is monitored at 2 weeks and 6-8 weeks by transthoracic echocardiography.\nPrognosis\nNon-complicated cases resolve without sequelae, while patients with persistent CAA are at risk for major cardiovascular events and their long-term outcome may be complicated by premature ischemic heart disease.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Rolando CIMAZ  - Dr Caroline GALEOTTI  - Dr Teresa GIANI  - Pr Isabelle KONE-PAUT"}
{"Disease Name": "KBG syndrome", "Disease Definition": "A rare congenital malformation syndrome characterized by a typical facial dysmorphism, macrodontia of the permanent upper central incisors, short stature, skeletal anomalies, developmental delay and behavioral abnormalities.", "ORPHA ID": 2332, "Summary": "Epidemiology\nThe prevalence is unknown. More than 150 cases have been reported to date. ANKRD11 is one of the most frequently muted gene in patients with neurodevelopmental disorders diagnosed by whole exome sequencing.\nClinical description\nKBG syndrome (KBGS) manifests in childhood with global developmental delay with short stature, mild-to-moderate intellectual disability, characteristic facies, macrodontia of the permanent upper central incisors and skeletal anomalies. Behavioral disturbances including hyperactivity, aggressiveness, attention deficit and autism spectrum disorders are recognized as constant clinical features. Developmental delay includes delayed motor milestones and markedly delayed speech and is almost always present in all patients. Characteristic facial dysmorphism is prominent in about half of the patients, consisting of triangular face, wide eyebrows with mild synophrys, hypertelorism, prominent ears and nasal bridge with bulbous nasal tip, long flat philtrum and thin upper lip. The hallmark feature, macrodontia, is observed in about 80% of cases; additional dental findings include oligo- or hypodontia, premature teeth loss in adults and enamel hypoplasia. Height below the 10th centile is observed in about two-thirds of cases. The most frequent skeletal anomalies are brachydactyly and fifth finger clinodactyly. Seizures, feeding difficulties, recurrent otitis media/hearing loss, palatal abnormalities and precocious puberty are notable additional features associated with KBGS.\nEtiology\nKBGS is caused by loss-of function alterations (pathogenic variants and copy number variations) affecting the ANKRD11 gene (16q24.3) which encodes ankyrin repeat domain-containing protein 11. The extent of ANKRD11 functions is yet to be determined, but it has been shown to be a crucial chromatin regulator that controls histone acetylation and gene expression during neural development.\nDiagnostic methods\nDiagnosis is based on clinical evaluation; there is no consensus on diagnostic criteria. The diagnosis is established by cytogenetic and molecular studies including a-CGH (array-comparative genome hybridization), targeted sequencing, gene panel, whole exome or genome sequencing.\nDifferential diagnosis\nDifferential diagnosis includes Cornelia de Lange syndrome, cleidocranial dysplasia, Robinow syndrome and 22q11.2 deletion syndrome.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. Most cases occur sporadically due to de novo mutations. Intra-familial variability of the phenotype has been noted in familial cases.\nManagement and treatment\nManagement is symptom-based and requires a multidisciplinary approach. At diagnosis, systematic echocardiogram, palatal assessment, vision, hearing and dental assessment, pediatric assessment for developmental delay, autism spectrum disorders and behavioral anomalies are recommended. Additional investigations depends on the clinical presentation. Management and follow-up include educational support, surveillance of growth and puberty, screening for hearing loss (otitis media), educational and speech therapy, and treatment of seizures when needed.\nPrognosis\nDespite the history of developmental delay, many patients grow into autonomous adults.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Nicole PHILIP | ITHACA* - Dr Florence RICCARDI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "KCNQ2-related epileptic encephalopathy", "Disease Definition": "KCNQ2-related epileptic encephalopathy is a severe form of neonatal epilepsy that usually manifests in newborns during the first week of life with seizures (that affect alternatively both sides of the body), often accompanied by clonic jerking or more complex motor behavior, as well as signs of encephalopathy such as diffuse hypotonia, limb spasticity, lack of visual fixation and tracking and mild to moderate intellectual deficiency. The severity can range from controlled to intractable seizures and mild/moderate to severe intellectual disability.", "ORPHA ID": 439218, "Summary": ""}
{"Disease Name": "KDM5C-related syndromic X-linked intellectual disability", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by mild to severe intellectual deficit associated with variable clinical manifestations including spasticity, cryptorchidism, maxillary hypoplasia, alopecia areata, epilepsy, short stature, impaired speech, and behavioral problems.", "ORPHA ID": 85279, "Summary": ""}
{"Disease Name": "Kearns-Sayre syndrome", "Disease Definition": "A rare inborn error of metabolism that is characterized by progressive external ophthalmoplegia (PEO), pigmentary retinitis and an onset before the age of 20 years. Common additional features include deafness, cerebellar ataxia and heart block.", "ORPHA ID": 480, "Summary": "Epidemiology\nKearns-Sayre syndrome (KSS) exact prevalence is unknown, but has been estimated at 1/125,000.\nClinical description\nThe disease often presents in childhood with the hallmark ocular symptoms of ptosis, pigmentary retinopathy and PEO, followed by the progressive occurrence of several other signs, depending on the tissue distribution of the molecular anomaly. The most frequently associated features include bilateral sensorineural deafness, heart involvement (cardiomyopathy, cardiac conduction defect), central nervous system involvement (cerebellar ataxia, dysarthria, bilateral facial weakness, intellectual deficit), skeletal muscle myopathy, intestinal disorders, endocrine disorders (delayed puberty, hypoparathyroidism, diabetes), and renal failure. The disease progresses slowly, over decades, with new symptoms appearing and previous symptoms slowly worsening. A very few cases of Pearson syndrome have progressed into KSS.\nEtiology\nKSS is caused by deletions of large portions of mitochondrial DNA (mtDNA), resulting in the loss of genes involved in the oxidative phosphorylation pathway. Deletions are heteroplasmic (i.e. a single cell can harbor both deleted and normal DNA molecules). Symptoms only appear if the proportion of abnormal DNA is high. The abnormal DNA threshold depends on the organ (e.g. about 60% for the skeletal striated muscle). Exceptional cases of KSS may be observed in the absence of a typical single large mtDNA deletion. They may be due either to point mutations located in the mtDNA encompassing tRNA genes or in nuclear genes involved in mtDNA maintenance (i.e. RRM2B).\nDiagnostic methods\nClinical diagnostic criteria of the disorder include the triad of progressive external ophthalmoplegia, pigmentary retinopathy, and onset before 20 years of age, plus at least one of the followings: heart block, cerebellar symptoms, or cerebrospinal fluid protein levels above 100 mg/dl. Apart from clinical features, muscle pathology and molecular genetic analysis can play a great role in the diagnostic workup. Muscle pathology showed ragged-red fibers (RRF), ragged-blue fibers (RBF), or cytochrome c-oxidase (COX)-negative fibers in almost all patients. Diagnosis can be confirmed by the detection of a large deletion of mtDNA (1.3-10 kb) in a clinically or morphologically affected tissue (usually skeletal muscle).\nDifferential diagnosis\nDifferential diagnoses include any disease caused by large mtDNA deletions or with an overlapping clinical picture, such as Pearson syndrome or maternally-inherited progressive external ophthalmoplegia.\nAntenatal diagnosis\nPrenatal diagnosis is usually not performed.\nGenetic counseling\nMost cases of KSS are sporadic. Deletions of mtDNA are only exceptionally transmitted from one generation to the next. Men do not transmit their mtDNA to their offspring. The risk of a woman, carrying a large size mtDNA deletion, transmitting the deletion to her child has been estimated to be less than 4%. The exceptional cases of KSS due to causes other than a large size mtDNA deletion follow the transmission associated with the gene involved (maternal transmission in the case of mtDNA point mutations or autosomal recessive in the case of nuclear gene mutations).\nManagement and treatment\nTreatment of KSS is supportive. Regular follow-up with a cardiologist is recommended. In those with high-grade heart block, a permanent pacemaker/implantable cardioverter-defibrillator device may be suggested and improves the prognosis. Hearing aids may be given to those with sensorineural deafness. Supplementation with coenzyme Q10 has been beneficial in some cases. Ophthalmologic manifestations may be treated by surgery but there is a high risk of recurrence and possible ocular complications.\nPrognosis\nThe prognosis essentially depends on the number of organs involved and, in each of them, on the proportion of the abnormal mtDNA. In the majority of cases, life expectancy can be normal with appropriate support.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Josef FINSTERER"}
{"Disease Name": "Keipert syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by facial dysmorphism (hypertelorism, broad and high nasal bridge, depressed nasal ridge, short columella, underdeveloped maxilla, and prominent cupid-bow upper lip vermillion), mild to severe congenital sensorineural hearing loss, and skeletal abnormalities consisting of brachytelephalangy and broad thumbs and halluces with large, rounded epiphyses. Additional manifestations that have been reported include pulmonary valve stenosis, voice hoarseness and renal agenesis.", "ORPHA ID": 2662, "Summary": ""}
{"Disease Name": "Kennedy disease", "Disease Definition": "Kennedy's disease, also known as bulbospinal muscular atrophy (BSMA), is a rare X-linked recessive motor neuron disease characterized by proximal and bulbar muscle wasting.", "ORPHA ID": 481, "Summary": "Epidemiology\nThe prevalence of BSMA is 1/30,000 male births. The incidence is 1/526,315 males/year.\nClinical description\nDisease onset occurs between 30-60 years of age. Initial clinical manifestations include tremor, muscle cramps, muscle twitching, fatigue and slurred speech. With disease progression patients additionally develop weakness and wasting of the limb and bulbar muscles, manifesting as dysarthria, dysphonia, hanging jaw, tongue wasting, chewing difficulty and impaired mobility. Intellectual decline is minimal to none. In the terminal stages of the disease some patients may be unable to swallow or breathe. Non-neurological manifestations include gynecomastia, hypogonadism (leading to infertility and impotence) and in rare cases Dupuytren's contracture, or groin hernia.\nEtiology\nBSMA is caused by an unstable expansion of a CAG triplet repeat (40-62 repeats) in exon 1 of the androgen receptor (AR) gene on chromosome Xq11-12. The abnormally increased repetition of this CAG triplet leads to an expanded stretch of glutamines within the androgen-receptor (AR). Polyglutamine-expansion results in misfolding and proteolysis of the mutated AR, rendering it insensitive to androgen hormones. In the nucleus AR fragments are produced, which aggregate and these aggregates are believed to cause dysregulation of the transcription of various other proteins and consecutively lead to motor neuron degeneration. Without a sufficient number of motor neurons, initiation and maintenance of muscle contractions can no longer occur, leading to progressive muscle wasting. Recently, a BSMA phenotype with distal predominance of limb weakness and wasting has been reported, caused by mutations in a subunit of the dynactin 1 DCTN1 gene.\nDiagnostic methods\nDiagnosis is established upon medical history, clinical examination, elevated creatine-kinase, testosterone, progesterone, follicle-stimulating hormone, luteinizing hormone, reduced nerve conduction velocities or reduced nerve action potential amplitudes, acute or chronic denervation and re-innervation on electromyography and documentation of the mutation.\nDifferential diagnosis\nDifferential diagnoses include hereditary spastic paraplegia, spinocerebellar ataxia (see these terms), other motor neuron diseases, myopathies, neuropathies, lead or aluminum poisoning, and cervical spondylosis.\nAntenatal diagnosis\nAntenatal diagnosis is possible for mothers carrying the mutation.\nGenetic counseling\nFemale mutation carriers usually do not manifest clinically but have a 50% risk to transmit the mutation to their male and female offspring. Affected males do not transmit the disease but 100% of their daughters become mutation carriers.\nManagement and treatment\nSymptomatic treatment includes physiotherapy and rehabilitation, agents against tremor and muscle cramps and hormone therapy or surgical treatment of gynecomastia. Recently, treatment of patients with the anti-testosterone leuprorelin was found to be beneficial. In advanced stages of the disease, tube feeding or ventilatory support may be indicated.\nPrognosis\nDisease progression is slow with only one third of patients requiring a wheelchair 20 years after diagnosis. Prognosis of BSMA is usually fair with only a small decrease in life expectancy.\n\n                            Last update: \n                            July 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Josef FINSTERER"}
{"Disease Name": "Kenny-Caffey syndrome", "Disease Definition": "A rare primary bone dysplasia syndrome characterized by growth retardation with proportionate short stature, cortical thickening and medullary stenosis of the long bones, delayed anterior fontanelle closure, hypocalcemia due to congenital hypoparathyroidism and facial dysmorphism, including prominent forehead, microphthalmia, and micrognathia. Additional manifestations include ocular and dental anomalies (e.g. corneal opacity, hyperopia, optic atrophy, tortuous retinal vessels, dental caries, enamel defects) and, occasionally, hypoplastic nails and neonatal liver disease. Inheritance may be autosomal dominant or autosomal recessive, with more severe growth retardation, small hands and feet, intellectual disability, microcephaly and recurrent bacterial infections being observed in the latter.", "ORPHA ID": 2333, "Summary": ""}
{"Disease Name": "Keppen-Lubinsky syndrome", "Disease Definition": "A rare, genetic, primary lipodystrophy syndrome characterized by severe developmental delay and intellectual disability, hypertonia, hyperreflexia, microcephaly, tightly adherent skin, an aged appearance, severe generalized lipodystrophy, and distinct facial dysmorphism which includes large prominent eyes, narrow nasal bridge, tented upper lip vermilion, an open mouth, and high-arched palate. Laboratory analysis of serum and urine are normal.", "ORPHA ID": 435628, "Summary": ""}
{"Disease Name": "Keratinopathic ichthyosis", "Disease Definition": "A group of rare inherited non-syndromic ichthyoses characterized by mutations in keratin genes. Mutations in KRT1 and KRT10 cause most cases of epidermolytic ichthyosis (EI), as well as congenital reticular ichthyosiform erythroderma (CRIE). EI manifests at birth with generalized blistering, which later transforms into hyperkeratosis. Severe palmoplantar involvement is suggestive of the presence of a KRT1 mutation. CRIE patients present at birth with erythroderma and scaling, often with a collodion membrane, and gradually develop confetti-like clear areas of normal skin. KRT2 mutations are associated with superficial epidermolytic ichthyosis (SEI), which is clinically similar to EI, but generally milder and more localized.", "ORPHA ID": 281103, "Summary": ""}
{"Disease Name": "Keratocystic odontogenic tumor", "Disease Definition": "A rare odontogenic tumor characterized by an unilocular or multilocular cyst most commonly located in the posterior body and lower ramus of the mandible, often surrounding the crown of the third molar. Histopathologically, the lesion shows a lining of parakeratinized stratified squamous epithelium with palisading hyperchromatic basal cells. Patients may be asymptomatic or present with local infection and/or signs and symptoms of mass effect. Recurrence is rare after complete surgical removal. Some patients have multiple cysts (metachronous or synchronous), especially in the context of nevoid basal cell carcinoma syndrome (Gorlin syndrome).", "ORPHA ID": 447777, "Summary": ""}
{"Disease Name": "Keratoderma hereditarium mutilans with ichthyosis", "Disease Definition": "A rare diffuse, mutilating, hereditary palmoplantar keratoderma characterized by severe, honeycomb-pattern palmoplantar keratosis and pseudoainhum of the digits leading to autoamputation, associated with mild to moderate congenital sensorineural hearing loss. Additional features include stellate keratosis on the extensor surfaces of the fingers, feet, elbows and knees. Alopecia, onychogryphosis, nail dystrophy or clubbing, spastic paraplegia and myopathy may also be associated.", "ORPHA ID": 79395, "Summary": ""}
{"Disease Name": "Keratoderma hereditarium mutilans", "Disease Definition": "Keratoderma hereditarium mutilans is a rare, diffuse, mutilating, hereditary palmoplantar keratoderma disorder characterized by severe, honeycomb-pattern palmoplantar keratosis and pseudoainhum of the digits leading to autoamputation, associated with mild to moderate congenital sensorineural hearing loss. Additional features include stellate keratosis on the extensor surfaces of the fingers, feet, elbows and knees. Alopecia, onychogryphosis, nail dystrophy or clubbing, spastic paraplegia and myopathy may also be associated.", "ORPHA ID": 494, "Summary": ""}
{"Disease Name": "Keratolytic winter erythema", "Disease Definition": "Keratolytic winter erythema is a rare epidermal disease, characterized by recurrent centrifugal palmoplantar peeling and erythema presenting seasonal variation (cold weather). Skin lesions may spread to the dorsum of hands and feet and to the interdigital spaces. Lower legs, knees and thighs may also be involved. Episodes may be preceded by itch and hyperhidrosis. Skin biopsy reveals an epidermal spongiosis with clefting in the stratum corneum, followed by regrowth. Keratolytic winter erythema follows an autosomal dominant mode of transmission.", "ORPHA ID": 50943, "Summary": ""}
{"Disease Name": "Keratosis follicularis spinulosa decalvans", "Disease Definition": "Keratosis follicularis spinulosa decalvans is a rare genodermatosis occurring during infancy or childhood, predominantly affecting males, and characterized by diffuse follicular hyperkeratosis associated with progressive cicatricial alopecia of the scalp, eyebrows and eyelashes. Additional findings can include photophobia, corneal dystrophy, facial erythema, and/or palmoplantar keratoderma.", "ORPHA ID": 2340, "Summary": ""}
{"Disease Name": "Keratosis follicularis-dwarfism-cerebral atrophy syndrome", "Disease Definition": "A rare, genetic, developmental defect during embryogenesis syndrome characterized by generalized keratosis follicularis, severe proportionate dwarfism and cerebral atrophy. Alopecia (of scalp, eyebrows and eyelashes) and microcephaly are additionally observed features. Intellectual disability, inguinal hernia and epilepsy may also be associated. There have been no further descriptions in the literature since 1974.", "ORPHA ID": 2339, "Summary": ""}
{"Disease Name": "Keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome", "Disease Definition": "Keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome is an inherited epidermal disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules on the flexural side of large joints (cord-like distribution around wrists, in antecubital and popliteal folds), hyperkeratotic plaques (on neck, axillae, elbows, wrists, and knees), mild ichthyosiform scaling, and sclerotic constrictions around fingers that present flexural deformities.", "ORPHA ID": 281201, "Summary": ""}
{"Disease Name": "Keratosis palmaris et plantaris-clinodactyly syndrome", "Disease Definition": "Keratosis palmaris et plantaris-clinodactyly syndrome is characterised by the association of palmoplantar keratosis with clinodactyly of the fifth finger. Less than 20 cases have been described in the literature so far, and the majority of reported patients were of Mexican origin. Transmission is autosomal dominant.", "ORPHA ID": 86919, "Summary": ""}
{"Disease Name": "Kerion celsi", "Disease Definition": "A rare inflammatory and suppurating type of tinea capitis, a skin infection caused by Trichophyton or Microsporum fungi, that predominantly affects the scalp and that is characterized by the development of painful crusty lesions covered with follicular pustules and surrounded by erythematous alopecic areas, that can later evolve into abscesses and leave permanent cicatricial alopecia. Lesions can be associated with regional lymphadenopathy.", "ORPHA ID": 499, "Summary": ""}
{"Disease Name": "Ketamine-induced biliary dilatation", "Disease Definition": "Ketamine-induced biliary dilatation is an acquired biliary tract disease caused by the abusive consumption of ketamine, which results in the fusiform dilatation of the common bile ducts (CBD) without obstructive lesions or dilatation of the intrahepatic biliary ducts. Possible manifestations of the underlying cholangiopathy include epigastric pain and impaired liver function. Severity of CBD dilatation appears to correlate with the duration of ketamine consumption and the condition has been reported to be reversible in abstinent patients.", "ORPHA ID": 293807, "Summary": ""}
{"Disease Name": "Ketoacidosis due to monocarboxylate transporter-1 deficiency", "Disease Definition": "A rare disorder of ketone body transport characterized by recurrent episodes of ketoacidosis provoked by fasting or infections in the first years of life. The episodes are typically preceded by poor feeding and vomiting and are associated with dehydration, in severe cases also with decreased consciousness and insufficient respiratory drive. Hypoglycemia is observed only infrequently. Patients with homozygous mutations tend to present at a younger age, have more profound ketoacidosis, and may show mild to moderate developmental delay in addition.", "ORPHA ID": 438075, "Summary": ""}
{"Disease Name": "Keutel syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by diffuse cartilage calcification, brachytelephalangism, peripheral pulmonary artery stenoses and facial dysmorphism. Vascular calcification has been reported in some cases.", "ORPHA ID": 85202, "Summary": "Epidemiology\nMore than 40 cases have been reported in the literature so far, with the majority of patients being diagnosed during childhood or earlier.\nClinical description\nThe abnormal calcification principally involves the cartilage of the ears, nose, larynx and the tracheobronchial tree. Epiphyseal stippling of the long bones and calcification of the spinal column vertebrae have also been reported. The facial dysmorphism is characterized by maxillary and midface hypoplasia (broad and depressed nasal bridge with small alae nasi). Other associated features may include hearing loss and recurrent otitis and/or sinusitis, mild intellectual deficit, seizures/epilepsy, frequent respiratory infections, nasal speech and short stature. Patients may show vascular calcification, cerebral calcification, moyamoya and arterial stenosis. Additional findings of white matter anomalies, encephalomalacia, optic nerve atrophy, and lax and doughy skin with prominent skin folds were reported in one affected family.\nEtiology\nThe syndrome is caused by mutations in the gene encoding the matrix Gla protein (MGP, located at 12p13.1-p12.3).\nDiagnostic methods\nDiagnosis is usually suspected on the basis of the clinical presentation and radiographic examination, with abnormal cartilage calcification and brachytelephalangism being the cardinal signs of the syndrome. The diagnosis can be confirmed by gene mutation analysis.\nDifferential diagnosis\nThe principle differential diagnosis is X-linked recessive chondrodysplasia punctata, but abnormal calcification has also been observed in children with warfarin embryopathy and in those with combined vitamin K-dependent coagulation factor deficiency.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment is symptomatic and may involve angiographic dilatation for peripheral pulmonary artery stenosis and bronchodilating agents to relieve dyspnea and wheezing.\nPrognosis\nThe prognosis for most patients is good, but life expectancy depends on the extent of the pulmonary involvement.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                             Kyoungmi BAK  - Pr Monzur MURSHED"}
{"Disease Name": "KID syndrome", "Disease Definition": "A rare congenital ectodermal disorder characterized by vascularizing keratitis, hyperkeratotic skin lesions and hearing loss.", "ORPHA ID": 477, "Summary": "Epidemiology\nLess than 100 cases have been described so far.\nClinical description\nPatients usually present at birth with generalized erythema and ichthyosiform scaling. The skin manifestations are progressive with erythrokeratoderma characterized by well-demarcated erythematous and keratotic plaques with a verrucous appearance predominantly located on the face, scalp, ears, elbows and knees. Other skin changes include deep furrows around the mouth, palmoplantar hyperkeratosis (PPHK) with leather grain-like keratoderma, follicular HK on the trunk, and spiky HK (hystrix-like ichthyosis) in some cases. The skin lesions are prone to infection and rare fatal cases of severe recurrent infections with septicemia have been reported. Nail dystrophy, alopecia, and sparse or absent eyebrows and eyelashes are also frequent. KID/HID patients have an increased susceptibility for squamous cell and tongue carcinomas. Hearing loss is congenital, usually sensorineural and is often profound. Ocular findings may be absent in some patients but when present onset usually occurs during childhood or adolescence with photophobia, punctate keratitis and progressive corneal vascularization leading to vision loss. The combined vision and hearing loss may lead to severe developmental delay. Cerebellar and neuromuscular defects have been reported in a few cases.\nEtiology\nKID/HID syndrome is caused by mutations involving the N-terminus and first extracellular loop of the GJB2 gene (13q11-q12), encoding connexin-26. One patient with KID and atrichia had a mutation in the GJB6 gene (13q12) encoding connexin-30.\nDiagnostic methods\nDiagnosis is suspected on the basis of dermatological, ophthalmological and hearing evaluation. Histological findings are nonspecific, revealing acanthosis and orthokeratotic HK. MRI may also be indicated to detect cerebellar anomalies. The diagnosis may be confirmed by molecular analysis.\nDifferential diagnosis\nDifferential diagnoses should include diseases belonging to the erythrokeratoderma group, as well as Clouston syndrome and keratosis follicularis spinulosa decalvans (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis may be offered to families of an index case (generalized form or mosaicism) in which the disease-causing mutation has been identified.\nGenetic counseling\nMost of the reported cases were sporadic, but familial cases with autosomal dominant inheritance have been reported. A few cases of KID syndrome caused by parental germline mosaicism for the GJB2 gene have also been described. Genetic counseling should be proposed to affected families as the risk of transmission from an affected parent is 50%. Segmental skin lesions may correspond to somatic and germline mosaicism, and should be considered as a risk factor for transmission of a generalized form.\nManagement and treatment\nManagement is symptomatic only. The use of systemic retinoids is controversial in patients with KID/HID and several authors have recommended limiting the treatment of the skin manifestations to application of topical therapies (bland emollients and topical keratolytics). KID/HID patients should undergo regular surveillance for mucosal carcinomas. Careful ophthalmological and ORL follow-up should be recommended and patients should be included in developmental programs for combined hearing and vision loss. Cochlear implants have been shown to be beneficial in some cases.\nPrognosis\nThe prognosis for patients with KID/HID syndrome is variable and, although cases with a fatal outcome are rare, the cutaneous manifestations persist and are generally severe with recurrent infections and an increased risk of mucosal carcinomas. The combined hearing and vision loss may lead to significant developmental delay.\n\n                            Last update: \n                            April 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Alain HOVNANIAN"}
{"Disease Name": "Kidney tubulopathy-dilated cardiomyopathy syndrome", "Disease Definition": "A rare renal disease characterised by hypokalaemic metabolic alkalosis secondary to a tubulopathy, hypomagnesaemia with hypermagnesuria, severe hypercalciuria and dilated cardiomyopathy.", "ORPHA ID": 73224, "Summary": ""}
{"Disease Name": "Kienbock disease", "Disease Definition": "Kienbock disease is a rare bone disorder of unknown etiology characterized clinically by osteonecrosis of the carpal lunate, eventually leading to collapse of the lunate bone impacting wrist function.", "ORPHA ID": 97332, "Summary": ""}
{"Disease Name": "Kikuchi-Fujimoto disease", "Disease Definition": "A rare systemic disease characterized by subacute, necrotizing, regional lymphadenopathy with tenderness, usually accompanied with mild fever, night sweats, myalgia, leukopenia and anemia. Less frequent symptoms include weight loss, nausea, vomiting and sore throat. It is a self-limiting benign disease that usually recedes within six months, even without drug treatment.", "ORPHA ID": 50918, "Summary": "Epidemiology\nKikuchi-Fujimoto disease is an extremely rare disease known to have a worldwide distribution, with higher prevalence among Japanese and other Asian populations. It is found in both sexes, with female predominance, albeit sex ratio has been found close to 1:1 in some reports and male predominance was observed in Asian pediatric populations.\nClinical description\nKikuchi-Fujimoto disease is self-limiting, with acute to subacute course evolving during several weeks. It usually affects young adults (< 40 years old), but can occur in any age group. Patients most commonly present with posterior cervical lymphadenopathy, frequently with concomitant involvement of axillary and/or supraclavicular lymph nodes. Affected lymph nodes are tender and painful. Lymphadenopathy is most commonly associated with fever; other infrequent symptoms include weight loss, nausea and vomiting, weakness, headache, arthralgia, night sweats, upper respiratory symptoms, and sore throat. Hepatomegaly and splenomegaly rarely occur.\nEtiology\nTwo competing theories exist to explain the etiology of this disease: infectious or autoimmune origin. The prevailing explanation for Kikuchi-Fujimoto disease is that a viral, bacterial or other infectious agent triggers an inflammatory process in susceptible individuals. The co-occurrence of different autoimmune diseases, including systemic lupus erythematosus (most commonly), relapsing polychondritis, Sjögren-Larsson syndrome, systemic sclerosis or antiphospholipid syndrome, is suggestive of an alteration of the immune system in these patients. The chronology of co-occurrence was found to be variable; autoimmune disease may appear before, during, or after the course of Kikuchi-Fujimoto disease.\nDiagnostic methods\nDiagnosis is based on the histological analysis and immunohistochemistry of biopsies from affected lymph nodes, essential for the exclusion of other clinically similar entities (i.e. lymphoma, metastasis or tuberculous adenitis). Histological landmarks include follicular hyperplasia with paracortical infiltration of histiocytes and lymphocytes, absence of neutrophils and eosinophils (in the proliferative stage), and necrotic foci with a high degree of karyorrhexis (in the necrotizing stage).\nDifferential diagnosis\nThe differential diagnosis includes infectious lymphadenitis of different etiologies, autoimmune lymphadenopathy (primarily systemic lupus erythematosus) and non-Hodgkin lymphoma.\nManagement and treatment\nTreatment is symptomatic and includes antipyretics, analgesics, nonsteroidal anti-inflammatory drugs and, rarely, corticosteroids. Patients with Kikuchi-Fujimoto disease should be followed up for several years to monitor the possible development of systemic lupus erythematosus and other autoimmune diseases.\nPrognosis\nSpontaneous recovery occurs in 1 to 6 months, but recurrences (3-4%) and fatal cases have been reported.\n\n                            Last update: \n                            June 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Massimo FUSCONI  - Dr Fabiana ZACCARELLI"}
{"Disease Name": "Kimura disease", "Disease Definition": "Kimura disease is a benign and chronic inflammatory disorder of unknown etiology, occurring mainly in Asian countries (very rarely in Western countries) and predominantly affecting young men, that usually presents with solitary or multiple non-tender subcutaneous masses in the head and neck region (in particular the preauricular and submandibular area) and/or generalized painless lymphadenopathy, often with salivary gland involvement. Characteristic laboratory findings include blood eosinophilia and markedly elevated serum immunoglobulin E (IgE) levels. It is often associated with autoinflammatory disorders (i.e. ulcerative colitis, bronchial asthma) and a co-existing renal disease.", "ORPHA ID": 482, "Summary": ""}
{"Disease Name": "Kindler epidermolysis bullosa", "Disease Definition": "A rare inherited epidermolysis bullosa (EB) characterized by skin fragility and blistering at birth followed by development of photosensitivity and progressive poikilodermatous skin changes.", "ORPHA ID": 2908, "Summary": "Epidemiology\nKindler epidermolysis bullosa (KEB) is the fourth major type of EB, after EB simplex, junctional EB and dystrophic EB. The exact prevalence is unknown. More than 250 cases have been reported to date.\nClinical description\nThe disease usually manifests at birth with trauma-induced skin blistering that is more prominent on extremities and tends to regress with age, becoming rare in adulthood. Healing of blisters occurs with minimal scarring. With age, additional skin findings are observed: (i) in most patients, photosensitivity with erythema and photo-induced blisters is obvious since early childhood and often diminishes after adolescence, (ii) progressive skin poikiloderma (atrophy, telangiectases, and reticular pigmentation) manifests from childhood and is predominantly localized to the face and neck, and (iii) skin atrophy is localized to hands and feet in the first years of life but becomes generalized by adolescence. Blisters also affect the mucosae. In the oral cavity, chronic gingivitis and periodontitis are frequent and prominent features in adulthood. Esophageal strictures, causing dysphagia and requiring repeated dilatations, frequently develop in adulthood. Anal (bleeding, stenosis), urogenital (urethral bleeding, meatal stenosis), and ocular (ectropion) involvement has also been described. The frequency of these manifestations increases with age. An additional frequent feature is digit webbing/partial pseudosyndactyly. Laryngeal and intestinal involvement, the latter manifesting with severe colitis, are rare. Other features may include: skin xerosis and fine scaling, palmoplantar hyperkeratosis, milia formation, nail dystrophy, constricting bands of pseudoainhum type, and orogenital leukokeratosis. Finally, KEB patients present an increased susceptibility to the development of squamous cell carcinomas (SCC).\nEtiology\nKindler epidermolysis bullosa is caused by loss-of-function mutations in the kindlin-1 gene (FERMT1; 20p12.3) causing the defective expression of the fermitin family homologue 1 (kindlin-1), a component of cell adhesive focal contacts.\nDiagnostic methods\nDiagnosis is based on clinical examination and determination by biopsy of the level within which blisters develop following minor traction. Immunofluorescence antigen mapping and transmission electron microscopy of blistered skin samples show single or multiple cleavage planes at the level of the cutaneous basement membrane zone as well as an extensive reduplication of the lamina densa. Blister formation can occur below the lamina densa, within the lamina lucida or within basal keratinocytes. The diagnosis is confirmed by molecular genetic testing, particularly during the first years of life.\nDifferential diagnosis\nThe differential diagnosis includes all forms of inherited EB, in particular dystrophic EB and EB simplex with mottled pigmentation, as well as congenital diseases with photosensitivity and poikiloderma, such as Rothmund-Thomson syndrome, Bloom syndrome, dyskeratosis congenita, poikiloderma with neutropenia or xeroderma pigmentosum.\nAntenatal diagnosis\nAntenatal diagnosis can be performed in families at risk of having a child with KEB where the disease-causing genetic variant has been previously identified in an affected family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement is based on the avoidance of blistering by protective padding of the skin. Skin moisturizers should be applied to reduce xerosis and skin fissures. Preventive measures should also be adopted for photosensitivity. Careful and early care of the oral mucosa is mandatory to preserve dentition. Esophageal strictures can be treated by balloon dilatation with fluoroscopic guidance. Early diagnosis of SCC (skin and mucosal membranes) requires a rigorous and regular follow-up from young adulthood onwards.\nPrognosis\nIn the majority of cases, life expectancy is normal. However, there are reports of patients with fatal aggressive SCC and, in a case series, skin cancer affected 70% of the patients older than 45 years.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Cristina HAS | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "King-Denborough syndrome", "Disease Definition": "King-Denborough syndrome is a rare genetic non-dystrophic myopathy characterized by the triad of congenital myopathy, dysmorphic features and susceptibility to malignant hyperthermia. Patients present with a wide phenotypic range, including delayed motor development, muscle weakness and fatigability, ptosis and facies myopathica (with or without creatine kinase elevations), skeletal abnormalities (e.g. short stature, scoliosis, kyphosis, lumbar lordosis and pectus carinatum/excavatum), mild dysmorphic facial features (e.g. hypertelorism, down-slanting palpebral fissures, epicanthic folds, low set ears, micrognathia), webbing of the neck, cryptorchidism, and a susceptibility to malignant hyperthermia and/or rhabdomyolysis due to intensive physical strain, viral infection or statin use.", "ORPHA ID": 99741, "Summary": ""}
{"Disease Name": "Klatskin tumor", "Disease Definition": "Klatskin tumor is an extra-hepatic cholangiocarcinoma (CCA, see this term) arising in the junction of the main right or left hepatic ducts to form the common hepatic duct.", "ORPHA ID": 99978, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nKlatskin tumors occur in the hepatic duct bifurcation, usually presenting in the 5th to 7th decade of life and are seen slightly more frequently in males (1.3:1 male to female ratio). Patients are usually asymptomatic until advanced stages of the disease where jaundice is the principle manifestation. Abdominal pain, weight loss and malaise are other manifestations experienced by some patients. Metastasis to regional lymph nodes is frequent. It can spread from the pericholedochal nodes in the hepatoduodenal ligament to the posteriorsuperior area around the pancreatic head, common hepatic artery and portal vein.\nEtiology\nIn 90% of cases Klatskin tumors occur sporadically but certain risk factors have been associated with the disease. Risk factors include primary sclerosing cholangitis (see this term), secondary sclerosing cholangitis, chronic typhoid carriage, parasitic infections (with Opisthochis viverrini and Clonorchis sinensis), exposure to thorotrast (x-ray contrast medium) and choledochal cysts, all of which cause chronic biliary inflammation.\nDiagnostic methods\nDiagnosis is suspected on clinical and laboratory findings. Serum carbohydrate antigen (CA) 19-9 is a glycoprotein tumor marker found to be elevated in most cases of Klatskin tumors. Increased levels of alkaline phosphate (ALP), conjugated bilirubin and gamma-glutamyl transpeptidase (GGT) are also noted. Abdominal imaging, visualization of the biliary tree and biopsies of the lesion are necessary to make the diagnosis. Endosonography (EUS) guided fine needle aspiration (FNA) of hilar lymph nodes is the most useful tool in the diagnosis and staging of Klatskin tumors. Brush cytology and percutaneous biopsies have a low sensitivity for diagnosis. Ultrasound, and contrast enhanced helical computerized computed tomography (CT) can be used in visualizing the extent of disease.\nDifferential diagnosis\nAutoimmune cholangitis and primary biliary non-Hodgkin's lymphoma are differential diagnoses of Klatskin tumors.\nManagement and treatment\nRelief of biliary blockage and resection of disease are the main goals of treatment. As Klatskin tumors are typically resistant to chemotherapy and radiotherapy, surgical resection of the tumor is the only curative treatment but it is not always an option in those patients with widespread metastasis. Surgical resection involves a liver resection with caudate lobectomy in order to achieve a higher chance of negative resection margins. Palliative treatment involves the placement of plastic or metallic biliary stents. Percutaneous transhepatic catheters provide the best access for palliation of inoperable Klatskin tumors. Unresectable Klatskin tumors are treated with radiotherapy and/or chemotherapy. Gemcitabine combined with cisplatin therapy has been recognized as a standard treatment for unresectable biliary tract cancers including Klatskin tumors.\nPrognosis\nAs Klatskin tumors are often only discovered at an advanced stage, the prognosis is quite poor with five year survival rates after surgery ranging from 25-30% and 0% in unresectable tumors.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Junji FURUSE"}
{"Disease Name": "Kleefstra syndrome", "Disease Definition": "A rare genetic, intellectual disability syndrome characterized by intellectual disability, childhood hypotonia, severe expressive speech delay, autism spectrum disorder, and a distinctive facial appearance with a spectrum of additional clinical features.", "ORPHA ID": 261494, "Summary": "Epidemiology\nThe prevalence is unknown. However, based on genomic wide studies, it is estimated to be around 1 in 500 individuals with a neurodevelopmental disorder.\nClinical description\nPatients with Kleefstra syndrome (KS) have a distinctive facial appearance comprised of brachy-microcephaly, midface hypoplasia, unusual eyebrow shape, synophrys, cupid bow upper lip, full-everted lower lip, protruding tongue and prognathism. With age, facial features become more coarse. Dental anomalies, like retention of primary dentition, are observed. Birth weight is normal but half of children go on to suffer from obesity. Childhood hypotonia causes motor delay, but most children walk independently by age 2 or 3 years. Most patients have moderate to severe intellectual disability with expressive speech delay and little speech development (nonverbal communication is possible). Additional features include congenital heart malformations (interauricular communication, ventricular septal defects, bicuspid aortic valve, pulmonary valve stenosis), genital defects in males (hypospadias, cryptorchidism, micropenis), renal defects (hydronephrosis, chronic renal insufficiency, renal cysts, vesico-ureteral reflux), epilepsy, recurrent infections, severe constipation and hearing problems. In adolescence/adulthood behavioral problems (aggressive/emotional outbursts, attention deficit problems, self-mutilation and severe sleep disturbances) can occur, these often coincide with regression. Autistic-like behavior can be noted earlier in some children.\nEtiology\nThe majority of the clinical features in KS can be attributed to loss of function of EHMT1, either due to a point mutation or a microdeletion in the chromosome region 9q34.3, leading to the loss of the entire gene. This gene encodes an enzyme that modifies histone function and is essential for normal development. Whilst there is not a clear gene-phenotype, correlation, individuals with an intragenic EHMT1 pathogenic variant or a small (<1Mb) 9q34.3 deletion have similar clinical findings whereas the phenotype of individuals with a relatively larger 9q34.3 deletion (i.e. ≥1Mb) appears to be more severe with a more pronounced intellectual disability and more comorbidities. Pulmonary infections and aspiration difficulties in particular appear to be more severe in individuals with a larger 9q34.3 defect. A similar phenotype is reported in patients with a loss of function mutation in the gene KMT2C (7q36.1).\nDiagnostic methods\nDiagnosis of KS is determined by the presence of the characteristic clinical features and molecular genetic testing. Most cases will be identified by unbiased genetic testing, including chromosomal microarray, intellectual disability gene panels, whole exome or whole genome sequencing. Targeted genetic testing is possible.\nDifferential diagnosis\nDifferential diagnoses include Down, Pitt-Hopkins, Smith-Magenis, Angelman, Rett and 2q23.1 microdeletion syndromes.\nAntenatal diagnosis\nAntenatal diagnosis is offered to unaffected parents of a child with KS, especially in case of parental mosaicism of the pathogenic variant or in case of balanced chromosomal rearrangements in one of the parents.\nGenetic counseling\nMost reported cases have been de novo but familial recurrence has been observed. KS has a theoretical autosomal dominant transmission, but the majority of patients do not reproduce.\nManagement and treatment\nTreatment requires a multidisciplinary team, specializing in patients with intellectual deficiencies. Special education and vocational training along with speech therapy, physical and occupational therapy and sensory integration therapy are recommended from an early age. Standard treatment is necessary for those with renal, cardiac and urologic issues and for hearing loss. Psychiatric care along with behavioral intervention therapy may be needed. Cardiac screening (for the presence of arrhythmias) as well as intestinal and renal/urologic monitoring is recommended. Medical follow-up is life-long.\nPrognosis\nThe prognosis of KS is variable but in most cases it is not a life-threatening disease. Prognosis is mainly based on the incidence and severity of comorbidities that can occur with KS.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr T. [Tjitske] KLEEFSTRA | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Kleine-Levin syndrome", "Disease Definition": "Kleine-Levin syndrome (KLS) is a rare neurological disorder of unknown origin characterised by relapsing-remitting episodes of hypersomnia in association with cognitive and behavioural disturbances.", "ORPHA ID": 33543, "Summary": "Epidemiology\nIt affects around 1/500 000 individuals. Patients are mostly male (68-78% of cases) and adolescents (81% of patients), with a mean age of onset of 15 years (range 4-82 years).\nClinical description\nThe first episode is triggered by an infection in 72% of patients. Patients experience 7-19 neurological episodes with a duration of 10-13 days/episode and relapses every 3.5 months. One third of patients have episodes lasting longer than one month. Episodes recur more quickly in patients with childhood onset. During episodes, all patients have hypersomnia (with sleep periods lasting 15-21 hours per day), cognitive impairment (apathy, confusion, slowness and amnesia) and a specific feeling of derealization (a dream-like state with altered perception). Less frequently, patients experience hyperphagia (66% of patients), hypersexuality (53% of patients, principally men), anxiety, compulsive or mood disorders and depression (53% of patients, predominantly women). Sleep, vigilance, mood, and eating habits are similar to those of controls between episodes. The median disease course is 8-14 years, but tends to be longer in men, in patients with hypersexuality, and when onset occurs after 20 years of age.\nEtiology\nSusceptibility factors include perinatal and developmental problems. Familial clustering occurs in 5% of cases with multiplex families and similar symptoms. An association of KLS with HLA-DQ2 positivity was found in a small series but not replicated in larger independent sample groups. There is no family history of neuropsychiatric disorders. In 10% of cases, KLS arises secondary to various genetic, inflammatory, vascular or paraneoplastic conditions. In these cases the patients are older and have more frequent and longer episodes, but clinical symptoms, disease course and treatment response are similar to those of primary cases.\nDiagnostic methods\nStructural brain imaging, cerebrospinal fluid and serological inflammatory markers are unremarkable. EEG slowing is noted in 70% of cases during episodes, without epileptic activity. Sleep structure varies from harmonious hypersomnia to hypoarousal with low sleep efficiency. Functional brain imaging (brain scintigraphy or TEP scan) frequently show hypoperfusion/hypometabolism, mainly focused in the thalamic, hypothalamic and frontotemporal associative areas, especially when compared to images obtained between episodes. Reduced metabolism at the parietotemporal junction is marked during episodes, correlates with the intensity of derealization and persists during asymptomatic periods.\nDifferential diagnosis\nThe disorder should mainly be differentiated from epilepsy, migraine with aura, and bipolar disorder.\nManagement and treatment\nThe prevention of episodes is mainly based on lithium therapy, combined with regular sleep-wake habits, as well as avoidance of alcohol intake and infections. Lithium therapy stops episodes in 37% patients (vs. 3.4% if no treatment is given) and reduces the frequency/duration of episodes in 46% of other patients. The treatment is usually given to patients with frequent, prolonged or very severe episodes. Patients with rare (e.g., 1/y) episodes may not need any treatment. Antiepileptics (valproate, carbamazepine, lamotrigine) have marginal benefits. During episodes, patients feel better resting at home under parental supervision, unless psychotic or depressive symptoms require hospitalization. Stimulants are not effective. Trials of IV steroids may help terminate long episodes in around 40% of patients.\nPrognosis\nThe prognosis is generally good, with most patients presenting less frequent and less severe episodes with advancing age and disappearance of the syndrome around 30-35 y old. During asymptomatic periods, around 20-30% of patients have mild difficulties focusing or remembering. Persistent psychiatric disorders occur in a minority of patients.\n\n                            Last update: \n                            September 2018\n\n\n                            - Expert reviewer(s): \n                            Pr Isabelle ARNULF"}
{"Disease Name": "KLHL9-related early-onset distal myopathy", "Disease Definition": "KLHL9-related early-onset distal myopathy is a rare, genetic distal myopathy characterized by slowly progressive distal limb muscle weakness and atrophy (beginning with anterior tibial muscle involvement followed by the intrinsic hand muscles) in association with reduced sensation in a stocking-glove distribution. Patients present with high stepping gait, ankle areflexia and contractures in the first to second decade of life, associated with marked ankle extensor muscle atrophy; later proximal muscle involvement is moderate and ambulation is preserved throughout the life.", "ORPHA ID": 399081, "Summary": ""}
{"Disease Name": "Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome", "Disease Definition": "A rare genetic disease characterized by the association of Klippel-Feil anomaly (fusion of the cervical spine), myopathy, hypotonia, short stature, microcephaly, and facial dysmorphism (including low-set ears, bulbous nose, long philtrum, high-arched palate, and low posterior hairline, among others). Cardiac abnormalities and various skeletal anomalies (such as pectus excavatum or clinodactyly) have also been reported.", "ORPHA ID": 447974, "Summary": ""}
{"Disease Name": "Klippel-Trénaunay syndrome", "Disease Definition": "A rare congenital complex vascular malformation syndrome characterized by capillary malformations manifesting as wine stains and venous varicosities typically prominent along the lateral aspect of the lower extremities, associated with overgrowth of a limb (most commonly a leg, less frequently other regions of the body), involving bone and/or soft tissues. The diagnosis is usually made in presence of at least two of these three features. Lymphatic malformations are also observed, while arteriovenous fistulas are absent. Patients present recurrent painful thrombophlebitis, venous thrombosis, and sudden venous hemorrhage.", "ORPHA ID": 90308, "Summary": "Epidemiology\nThe prevalence of Klippel-Trénaunay syndrome (KTS) is unknown. KTS is one of the overgrowth syndromes associated with a PIK3CA variant, also known as PROS (for PIK3CA-related overgrowth spectrum), which affects over 500 patients in France.\nClinical description\nClinical diagnosis is based on a clinical triad combining: planar angioma(s), truncal venous/lymphatic-venous slow-flow malformation, and soft tissues and bone hypertrophy in the area affected by vascular dysplasia. The existence of an incontinence of marginal venous system with very slow or even stagnant flow, leading to a risk of thrombosis (mostly superficial, less frequent in deep veins) with embolic potential and pain, coexisting with a deep venous system that may be dysplasic, are characteristic features. Blood stagnation can lead to coagulation activation and even chronic localized intravascular coagulation. Lymphatic malformations can be macro- or microcystic, the latter being at risk of inflammation.\nEtiology\nThe syndrome is due to heterozygous post-zygotic mosaic variation in the PIK3CA gene, occurring in early embryogenesis. It has to be noted that not all KTS appear to result from PIK3CA mosaic variation.\nDiagnostic methods\nDiagnosis must be confirmed by identification of a PIK3CA mosaic variation on affected tissue (most often skin) without culture, using high-depth high-throughput sequencing.\nDifferential diagnosis\nThe differential diagnosis includes: Parkes-Weber syndrome which is due to variants of the RASA1 and EPHB4 genes, and characterized by high-flow vascular malformations with arteriovenous fistula; CLOVES syndrome; other PROS syndromes and PTEN-related overgrowth disorders.\nAntenatal diagnosis\nThe diagnosis may be suspected during pregnancy in the presence of segmental hypertrophy. Prognosis will be based on the extent of vascular malformations. A negative amniocentesis does not exclude the diagnosis.\nGenetic counseling\nThe risk for siblings of a proband with a PIK3CA mosaic variant is the same as in the general population if the parents are not variant carriers. Prenatal diagnosis is therefore not particularly recommended.\nManagement and treatment\nBecause of the multisystemic involvement, patient management requires multi-disciplinary care by expert teams, with at least one annual physical examination, and further investigations may be needed based on clinical presentation. Screening for Wilms tumor is not needed when the risk is less than 5%. Therapeutic management consists of preventing and treating complications: medical management of inflammatory or painful flare-ups, thromboembolic complications, superficial or non-disabling vascular malformations, correction of lower limb length discrepancy, and of a possibly associated scoliosis. Acute painful episodes due to the presence of phleboliths in venous malformations are relieved by anti-inflammatory drugs or even heparin rather than analgesics. Compression of vascular deformities of the limbs is often unavoidable. Some vascular malformations can be managed by interventional radiology, thus avoiding the need for surgery. Laser treatment may be required for superficial vascular malformations. Alpelisib, a PI3K pathway inhibitor, is currently proposed in therapeutic trials or on a compassionate basis, according to a therapeutic protocol. This treatment improves quality of life, reduces hypertrophy and vascular symptoms, and avoids the need for surgery.\nPrognosis\nThe clinical presentation of the disease can be highly variable. Treatment with alpelisib changes the prognosis when a PIK3CA variant was identified.\n\n                            Last update: \n                            January 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Laurent GUIBAUD | ERN CRANIO* - Pr Laurence OLIVIER-FAIVRE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Klüver-Bucy syndrome", "Disease Definition": "A rare neurologic disease characterized by visual agnosia, hyperorality (strong tendency to examine objects orally), hypermetamorphosis (described as the irresistible impulse to notice and react to everything within sight), hypersexuality, changes in dietary habits and hyperphagia, placidity, and amnesia, due to bilateral lesions of the temporal lobe including the hippocampus and amygdala.", "ORPHA ID": 157823, "Summary": ""}
{"Disease Name": "Kniest dysplasia", "Disease Definition": "Kniest dysplasia is a severe type II collagenopathy characterized by a short trunk and limbs, prominent joints and midface hypoplasia (round face with a flat nasal root).", "ORPHA ID": 485, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe disease is apparent from birth. Cleft palate (sometimes associated with Pierre-Robin syndrome, see this term), kyphoscoliosis, premature osteoarthritis, severe myopia and deafness are common findings. Stature varies but is often severely affected. Intelligence is usually normal.\nEtiology\nThe disease is caused by mutations in the COL2A1 gene (12q13.11-q13.2) encoding type II collagen.\nDiagnostic methods\nDiagnosis is made on the basis of radiologic features including large and deformed epiphyses, absence of the femoral head, enlargement of the superior metaphysis of the femur, platyspondyly and other vertebral malformations. Pathological studies of the cartilage reveal the presence of intracytoplasmic inclusions in chondrocytes and a highly vacuolated matrix.\nDifferential diagnosis\nForms of spondyloepiphyseal dysplasia and metatropic dysplasia (see these terms) constitute the principle differential diagnoses. In young patients, clinical and radiological features overlap with those of OSMED (see this term), but in the latter myopia is absent.\nAntenatal diagnosis\nMolecular prenatal diagnosis is possible for families in which the disease-causing mutation has already been identified. Micromelia may be detected during the second trimester of the pregnancy and fetal CT scan may be a useful tool for diagnosis.\nGenetic counseling\nThe disease is transmitted as an autosomal dominant trait. Most cases are due to de novo heterozygous COL1A2 mutations but affected parents should be informed of a recurrence risk of 50%.\nManagement and treatment\nManagement is supportive only.\nPrognosis\nPrognosis depends on the extent of the joint malformations and vertebral anomalies\n\n                            Last update: \n                            September 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Knobloch syndrome", "Disease Definition": "A rare systemic disorder characterized by vitreoretinal and macular degeneration, as well as occipital encephalocele.", "ORPHA ID": 1571, "Summary": "Epidemiology\nThe exact prevalence of Knobloch syndrome (KS) is unknown but less than 100 cases have been reported in the literature so far.\nClinical description\nKS is characterized by early-onset severe myopia (usually becoming apparent in the first year of life), vitreoretinal degeneration with retinal detachment, macular abnormalities, and midline encephalocele (mainly in the occipital region). Predisposition to hydrocephalus is frequent. Ocular abnormalities vary and may include congenital cataract, iris abnormalities, and lens subluxation. Numerous extraocular abnormalities have been described: a single umbilical artery, pyloric stenosis, a flat nasal bridge, midface hypoplasia, bilateral epicanthic folds, abnormal lymphatic vessels in the lung, patent ductus arteriosus, cardiac dextroversion, generalized hyperextensibility of the joints, unusual palmar creases, and unilateral duplication of the renal collecting system. Structural brain defects, epilepsy and cognitive abnormalities have also been frequently reported. However, the full phenotypic spectrum is yet to be defined.\nEtiology\nThe syndrome is caused by inactivating mutations in the collagen XVIII/endostatin gene (COL18A1; 21q22.3) which is highly expressed throughout the human eye. As a mutational hot-spot the c.4063_4064delCT is the most common mutation detected in Knobloch syndrome to date. İn one reported family the locus remains unmapped.\nDiagnostic methods\nDiagnosis is based on ocular abnormalities and occipital encephalocele (detected by computed tomography and magnetic resonance imaging). Magnetic resonance imaging of the brain would also help to detect associated developmental brain abnormalities. Sequencing of (COL18A1) gene.\nDifferential diagnosis\nThe differential diagnosis should include the following syndromes with or without encephalocele: Stickler, Wagner, Marshall, Meckel, and Walker-Warburg syndromes.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement of the ocular manifestations requires referral to an ophthalmologist specialist in retinopathies. Treatment modalities include retinal reattachment surgery, prophylactic treatment of the vitreoretinal pathology and photodynamic therapy. Encephalocele should be treated by surgical methods, aiming to restore normal anatomy with repair of the defective dura, bone and skin.\nPrognosis\nThe eye findings in KS are severe and progressive, and regularly lead to bilateral blindness at a young age.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Ahmet CAGLAYAN"}
{"Disease Name": "Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome", "Disease Definition": "A rare, syndromic genetic deafness disease characterized by symmetric or asymmetric knuckle pads (typically located on the distal and interphalangeal joints), leukonychia, diffuse palmoplantar keratoderma, and congenital, mild to moderate sensorineural deafness.", "ORPHA ID": 2698, "Summary": ""}
{"Disease Name": "Kommerell diverticulum", "Disease Definition": "Kommerell diverticulum (KD) is a developmental anomaly of the aortic arch characterized by a diverticulum at the proximal descending aorta of left or right arch configuration that gives rise to an aberrant subclavian artery. KD is primarily asymptomatic but may become symptomatic secondary to dilatation of KD, atheroma and fibrotic changes in paratracheal or paraesophageal tissue, presenting with signs of tracheal compression (more common in children), esophageal compression (dysphagia lusoria; more common in patients with a right sided aortic arch), chest pain, or blood pressure difference in the upper limbs. KD may also predispose toward aortic dissection or rupture.", "ORPHA ID": 99077, "Summary": ""}
{"Disease Name": "Koolen-De Vries syndrome", "Disease Definition": "A rare multisystem disorder characterized by neonatal/childhood hypotonia, mild to moderate developmental delay or intellectual disability, epilepsy, dysmorphic facial features, hypermetropia, congenital heart anomalies, congenital renal/urologic anomalies, musculoskeletal problems, and a friendly/amiable disposition.", "ORPHA ID": 96169, "Summary": "Epidemiology\nThe prevalence of this disorder is unknown; however, the prevalence of the 17q21.31 deletion is approximately 1/55,000 individuals. The prevalence of single nucleotide variants (SNVs) in KANSL1 cannot be ascertained with precision owing to the limited number of cases identified thus far. Males and females are affected equally.\nClinical description\nHypotonia is most evident between the neonatal period and infancy with poor sucking and slow feeding, but may persist throughout life. Feeding difficulties may require hospitalization and/or nasogastric tube feeding in some neonates. Tracheo/Laryngomalacia is a common feature. Global psychomotor developmental delay is noted in all individuals from an early age, although the level of developmental delay varies significantly. The majority of individuals with Koolen-de Vries syndrome (KdVS) function in the mild to moderate range of intellectual disability. Oral hypotonia and apraxia in infancy and preschool, associated with severely delayed speech development is one of the hall marks of KdVS. A history of epilepsy is noted in ~30-50% of all cases and other neurological problems may also be present. The facial dysmorphism is characterized by upslanted palpebral fissures, blepharophimosis, epicanthal folds, ptosis, a pear-shaped nose with bulbous nasal tip, and large / protruding ears. Short stature, pectus excavatum, spine anomalies, dislocation of the hip(s), long slender fingers and slender lower limbs, and positional deformities of the hands/feet have been reported. Other features include heart defects (bicuspid aortic valve, atrial and ventricular septal defects), kidney and urologic anomalies, and cryptorchidism.\nEtiology\nKdVS is typically a sporadic disorder caused either by a 17q21.31 deletion encompassing the KAT8 regulatory NSL complex subunit 1 (KANSL1) gene or a mutation of the KANSL1 gene.\nDiagnostic methods\nMolecular genetic testing approaches can include a combination of chromosomal microarray (CMA), a multigene panel, and comprehensive genomic testing (exome sequencing, exome array, genome sequencing). In individuals with normal CMA results, targeted Sanger sequencing of the KANSL1-gene testing can be considered based on the clinical findings.\nDifferential diagnosis\nDifferential diagnoses include Prader-Willi syndrome in the neonatal period and 22q11.2 deletion syndrome, fragile X syndrome, Angelman syndrome and blepharophimosis-intellectual disability syndrome, SBBYS type in older patients.\nAntenatal diagnosis\nAlmost all cases correspond to a single occurrence in a family, but prenatal testing can be offered for at risk pregnancies.\nGenetic counseling\nGenetic counseling should be proposed to parents of affected individuals. Whilst almost all affected individuals represent simplex cases (i.e., a single affected individuals in the family) with a very small risk of sibling recurrence, the pattern of inheritance is autosomal dominant and thus the risk to offspring of affected individuals inheriting KdVS is 50%\nManagement and treatment\nAffected individuals should have routine examinations by the primary care physician and pediatrician. Cardiac investigations, and kidney and urologic evaluations are warranted. Speech production requires intensive motor speech treatment in preschool years and language development requires focused intervention and augmentative (sign language) or alternative (communication device) support until oral speech and language develops. Regular check up by a dermatologist can be considered in case of multiple nevi. Referral to other specialists is indicated if neurological or other systemic problems are suspected.\nPrognosis\nLongitudinal data are insufficient to determine life expectancy, although survival into adulthood is typical, autonomy is likely to be limited and affected individuals will probably require life-long support from caregivers.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Dr D.A. [David] KOOLEN"}
{"Disease Name": "Kosaki overgrowth syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by postnatal tall stature with long hands and feet, scoliosis, distinctive dysmorphic facial features (prominent forehead, proptosis, downslanting palpebral fissures, broad nasal bridge, thin upper lip, and pointed chin), hyperelastic, thin, and fragile skin, lipodystrophy, and variable intellectual disability and neurological deterioration. Additional reported manifestations include craniosynostosis, camptodactyly, progressive flexion contractures, joint dislocation, and cerebrovascular complications, among others. Brain MRI may show extensive periventricular white matter lesions and other anomalies.", "ORPHA ID": 477831, "Summary": ""}
{"Disease Name": "Kostmann syndrome", "Disease Definition": "Kostmann syndrome is a rare, severe, congenital neutropenia disorder characterized by a lack of mature neutrophils (absolute neutrophil counts less than 500 cells/mm3) associated with frequent, recurrent bacterial infections (e.g. otitis media, pneumonia, sinusitis, urinary tract infections, abscesses of skin and/or liver) and increased promyelocytes in the bone marrow. Periodontal disease, as well as neurological symptoms, such as cognitive impairment, severe neurodegeneration and epilepsy, have been reported in some patients.", "ORPHA ID": 99749, "Summary": ""}
{"Disease Name": "Kousseff syndrome", "Disease Definition": "A rare syndromic central nervous system malformation characterized by the association of conotruncal heart defects, myelomeningocele and craniofacial dysmorphism similar to that seen in monosomy 22q11.", "ORPHA ID": 2351, "Summary": ""}
{"Disease Name": "Krabbe disease", "Disease Definition": "A rare lysosomal disorder that affects the white matter of the central and peripheral nervous systems characterized by neurodegeneration with severity depending on the age of onset (infantile, late-infantile, juvenile, adolescent and adulthood).", "ORPHA ID": 487, "Summary": "Epidemiology\nIt has an estimated prevalence of 1/100,000 in the Northern European population (higher in certain populations) and a worldwide incidence of 1/100,000-1/250,000 live births. The infantile form is the most common form and accounts for 85-90% of cases in the Northern European population. Later-onset forms may be more common in other populations.\nClinical description\nThe infantile form has an onset at 2-6 months of age and is divided into 3 stages. In the first stage, symptoms include irritability, stiffness, poor head control, feeding difficulties, intermittent thumb clasp, episodes of increased temperature, and developmental delay. In the second stage, hypertonic episodes occur with opisthotonus, myoclonic seizures, developmental regression, fisting and vision deficits. In the third stage, hypotonia, blindness and deafness occur. Patients progress into a vegetative state and usually die before the age of 2-3 years, generally due to respiratory infections. In the late infantile/juvenile (1-16 years) and adult (>16 years) forms, the presenting symptoms vary greatly and progression is variable (generally slower in older patients). Patients with late infantile /juvenile onset most resemble infantile patients, while the first signs in adult forms are often weakness, gait disturbances (spastic paraparesis or ataxia), burning paresthesias, hemiplegia, and/or vision loss, with or without peripheral neuropathy. Cognitive regression is variable and often absent in adult forms. In the later-onset forms the disease progresses at a slower rate than infantile patients with some adults living until the sixth decade with mild symptoms.\nEtiology\nThe disease is due to mutations in the  GALC gene (14q31) encoding the lysosomal enzyme galactocerebrosidase (GALC), that catabolizes the hydrolysis of galactose from galactocerebroside and galactosylsphingosine (psychosine). The accumulation of cytotoxic psychosine leads to apoptosis of oligodendrocytes and demyelination of the CNS and PNS. Rarely, infantile Krabbe disease is caused by a mutation in the PSAP gene (10q21-q22), encoding prosaposin which is necessary for GALC activity.\nDiagnostic methods\nDiagnosis is suspected by the clinical picture, slow nerve conduction velocity, abnormal electroencephalogram, and brain MRI revealing white matter abnormalities (demyelination, gliosis, late-stage cerebral atrophy, cerebral calcifications). It is established by enzymatic assays in leukocytes or cultured fibroblasts that reveal, in almost all cases, a deficiency of GALC activity. Biopsy of nervous tissues is not indicated for diagnosis. Mutation analysis is sometimes done to confirm the diagnosis. Newborn screening (NBS) may be available in certain regions; however additional studies are required after an initial positive test.\nDifferential diagnosis\nDifferential diagnosis includes metachromatic leukodystrophy, GM1 gangliosidosis, GM2 gangliosidosis, Canavan disease, encephalopathy due to prosaposin deficiency, X-linked adrenoleukodystrophy, Pelizaeus-Merzbacher disease and Alexander disease.\nAntenatal diagnosis\nAntenatal diagnosis (enzymatic assay or mutation analysis) is possible for at-risk families. If the disease-causing mutations in the family are known, pre-implantation genetic diagnosis is also possible.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% chance of having an affected child.\nManagement and treatment\nTreatment is currently limited to hematopoietic stem cell transplantation in pre-symptomatic infantile patients and mildly affected late-onset patients. It has been shown to slow the progression of the disease. Most individuals predicted to have infantile Krabbe disease and treated before 4 weeks of age can live into the second decade with mostly preserved cognitive functioning, but with difficulty in walking and in expressive language.\nPrognosis\nSteady neurodegeneration and early death within two to three years occur in most infantile cases. In late infantile/juvenile patients, the disease is generally fatal 2-7 years after the symptoms begin. Adult-onset patients can survive many years after symptoms present.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Paola LUZI  - Pr David WENGER"}
{"Disease Name": "KRT1-related diffuse nonepidermolytic keratoderma", "Disease Definition": "A rare, genetic, isolated diffuse palmoplantar keratoderma characterized by diffuse, mild to thick, finely demarcated hyperkeratosis of palms and soles. Additional clinical findings include knuckle pad-like keratoses on fingers, hyperkeratosis of umbilicus and areolae, diffuse dry skin, hyperhidrosis, hangnails and frequent fungal infections. Histological examination of lesions reveals orthokeratotic hyperkeratosis, acanthosis, hypergranulosis, and mild lymphocyte infiltrations in the upper dermis with no evidence of epidermolysis.", "ORPHA ID": 530838, "Summary": ""}
{"Disease Name": "Kufor-Rakeb syndrome", "Disease Definition": "Kufor-Rakeb syndrome (KRS) is a rare genetic neurodegenerative disorder characterized by juvenile Parkinsonism, pyramidal degeneration (dystonia), supranuclear palsy, and cognitive impairment.", "ORPHA ID": 306674, "Summary": ""}
{"Disease Name": "Kuru", "Disease Definition": "A rare acquired human prion disease characterized by rapidly progressive, fatal neurodegeneration, caused by the consumption of prion-containing tissue in endocannibalistic funeral rituals in Papua New Guinea until the late 1950s. After a decades-long asymptomatic period and a non-specific prodromal phase with headaches and arthralgia, the most prominent neurological feature is ataxia, in addition to other symptoms involving the cerebellum, brain stem, mid-brain, hypothalamus, and cerebral cortex, and emotional changes including inappropriate euphoria and compulsive laughter, or depression and apprehension. The last reported patient died in 2005 with an incubation period extending over four decades.", "ORPHA ID": 454745, "Summary": ""}
{"Disease Name": "Kuskokwim syndrome", "Disease Definition": "A very rare congenital contracture disorder, reported exclusively in Yup'ik Eskimos of the Kuskokwim River delta region of Alaska, characterized by multiple contractures of large joints (predominantly the knees and ankles) that present at birth or during childhood but are lifelong; deformities of the spine, pelvis and feet; and sometimes proximally or distally displaced patellae and muscle atrophy in the limbs with contractures. Additional radiological features include mild vertebral wedging, elongation of the vertebral pedicle, and clubbing of the distal clavicle. An autosomal recessive pattern of inheritance has been suggested.", "ORPHA ID": 1149, "Summary": ""}
{"Disease Name": "Kyasanur forest disease", "Disease Definition": "A rare infectious disease caused by the kyasanura forest disease virus and clinically characterized by an initial fever, headache and myalgia that can progress to a hemorrhagic disease and that in some cases is followed by a second phase characterized by neurological manifestations.", "ORPHA ID": 319254, "Summary": ""}
{"Disease Name": "Kyphomelic dysplasia", "Disease Definition": "A rare primary bone dysplasia characterized, radiologically, by short, stubby long bones, severely angulated femurs and lesser bowing of other long bones (mild, moderate or no bowing), short and wide iliac wings with horizontal acetabular roofs, platyspondyly and a narrow thorax, clinically manifesting with severe, disproportionate short stature. Regression of femora angulation is observed with advancing age.", "ORPHA ID": 1801, "Summary": ""}
{"Disease Name": "Kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome", "Disease Definition": "A rare complex hereditary spastic paraplegia characterized by neonatal to infantile onset of progressive spasticity in the lower limbs, hyperreflexia, tip-toe walking, pes equinus, and delayed motor developmental milestones. Kyphoscoliosis becomes evident in older patients, and most patients show atrophy of the lateral aspects of the tongue. Additional signs may include intellectual disability, language impairment, and moderate upper limb involvement.", "ORPHA ID": 496689, "Summary": ""}
{"Disease Name": "Kyphoscoliotic Ehlers-Danlos syndrome due to FKBP22 deficiency", "Disease Definition": "A rare subtype of kyphoscoliotic Ehlers-Danlos syndrome characterized by congenital muscle hypotonia, congenital or early-onset kyphoscoliosis (progressive or non-progressive), and generalized joint hypermobility with dislocations/subluxations (in particular of the shoulders, hips, and knees). Additional common features are skin hyperextensibility, easy bruising of the skin, rupture/aneurysm of a medium-sized artery, osteopenia/osteoporosis, blue sclerae, umbilical or inguinal hernia, chest deformity, marfanoid habitus, talipes equinovarus, and refractive errors. Subtype-specific manifestations include congenital hearing impairment (sensorineural, conductive, or mixed), follicular hyperkeratosis, muscle atrophy, and bladder diverticula. Molecular testing is obligatory to confirm the diagnosis.", "ORPHA ID": 300179, "Summary": ""}
{"Disease Name": "Kyphoscoliotic Ehlers-Danlos syndrome due to lysyl hydroxylase 1 deficiency", "Disease Definition": "A rare subtype of kyphoscoliotic Ehlers-Danlos syndrome characterized by congenital muscle hypotonia, congenital or early-onset kyphoscoliosis (progressive or non-progressive), and generalized joint hypermobility with dislocations/subluxations (in particular of the shoulders, hips, and knees). Additional common features are skin hyperextensibility, easy bruising of the skin, rupture/aneurysm of a medium-sized artery, osteopenia/osteoporosis, blue sclerae, umbilical or inguinal hernia, chest deformity, marfanoid habitus, talipes equinovarus, and refractive errors. Subtype-specific manifestations include skin fragility, atrophic scarring, scleral/ocular fragility/rupture, microcornea, and facial dysmorphology (like low‐set ears, epicanthal folds, down‐slanting palpebral fissures, high palate). Molecular testing is obligatory to confirm the diagnosis.", "ORPHA ID": 1900, "Summary": ""}
{"Disease Name": "Kyphoscoliotic Ehlers-Danlos syndrome", "Disease Definition": "A rare systemic disease for which two subtypes exist, either related to the gene PLOD1 or FKBP22, and for which the clinically overlapping characteristics include congenital muscle hypotonia, congenital or early-onset kyphoscoliosis (progressive or non-progressive), and generalized joint hypermobility with dislocations/subluxations (in particular of the shoulders, hips, and knees). Additional features which may occur in both subtypes are skin hyperextensibility, easy bruising of the skin, rupture/aneurysm of a medium-sized artery, osteopenia/osteoporosis, blue sclerae, umbilical or inguinal hernia, chest deformity, marfanoid habitus, talipes equinovarus, and refractive errors. Gene-specific features, with variable presentation, are additionally observed in each subtype.", "ORPHA ID": 536545, "Summary": ""}
{"Disease Name": "Kyphosis-lateral tongue atrophy-myofibrillar myopathy syndrome", "Disease Definition": "A rare genetic skeletal muscle disease characterized by neonatal to childhood onset of slowly progressive muscle weakness and atrophy primarily affecting the lower limbs, joint contractures, kyphosis or lordosis of the spine, lateral tongue atrophy, and pes equinus. Progression to upper limb involvement, facial weakness, language impairment, intellectual disability, and behavioral abnormalities have been reported in addition. Muscle biopsy shows myopathic changes with increased fiber size variation, internalized nuclei, fiber atrophy, as well as rod structures and core targetoid defects.", "ORPHA ID": 496686, "Summary": ""}
{"Disease Name": "L-2-hydroxyglutaric aciduria", "Disease Definition": "L-2-hydroxyglutaric aciduria is a primarily neurological form of 2-hydroxyglutaric aciduria (see this term) characterized by psychomotor retardation, cerebellar ataxia and variable macrocephaly or epilepsy.", "ORPHA ID": 79314, "Summary": "Epidemiology\nExact prevalence and incidence of this disorder are not known but about 140 cases have been reported to date. The disorder appears to be pan-ethnic with cases reported worldwide.\nClinical description\nOnset is often insidious in the first year of life. Presenting symptoms include motor retardation and epilepsy. The disease course is progressive leading to mental deterioration such as speech difficulties and motor deficits such as loss of independent walking. Most reported patients had macrocephaly. Other signs include hypotonia in the early stages and spasticity later in the course of the disease, extrapyramidal symptoms and behavioral disorders. An increased incidence of brain tumors has also been reported.\nEtiology\nL-2-hydroxyglutaric aciduria is thought to be caused by mutations in the L2HGDH gene (14q22.1) L-encoding mitochondrial 2-hydroxyglutarate dehydrogenase. More than 70 different mutations have been identified to date. However, several affected families did not have identifiable mutations in this gene.\nDiagnostic methods\nUrinary organic acid screening reveals a massive increase of 2HG, and subsequent chiral differentiation is needed establish the biochemical diagnosis of L-2-hydroxyglutaric aciduria. Diagnosis may be delayed due to the slowly progressive course of the disorder and is based on magnetic resonance imaging (MRI) or computed tomography (CT) findings, biochemical testing, and mutational analysis of the L2HGDH gene. MRI and CT findings are typically subcortical and paraventricular hyperintensities. Varying degrees of subcortical leukoencephalopathy and cerebellar atrophy have been observed.\nDifferential diagnosis\nUrinary organic acid screening does not allow differentiation between L-2-hydroxygluratic acid and D-2-hydroxyglurac acid. Therefore, this differentiation has to be performed subsequently by a specialized laboratory.\nAntenatal diagnosis\nPrenatal diagnosis can be performed by mutational analysis and by the measurement of L-2-hydroxyglutaric acid in amniotic fluid.\nGenetic counseling\nL-2-hydroxyglutaric aciduria follows an autosomal recessive pattern of inheritance.\nManagement and treatment\nThere is currently no specific treatment for L-2-hydroxyglutaric aciduria. Supportive and symptomatic measures are therefore recommended.\nPrognosis\nPrognosis is poor but most patients reach adulthood.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Pr G.S. [Gajja] SALOMONS  - Dr E.A. [Eduard] STRUYS"}
{"Disease Name": "L-Arginine:glycine amidinotransferase deficiency", "Disease Definition": "L-Arginine:glycine amidinotransferase (AGAT) deficiency is a very rare type of creatine deficiency sydrome characterized by global developmental delay, intellectual disability, and myopathy.", "ORPHA ID": 35704, "Summary": "Epidemiology\nLess than 20 patients have been described with AGAT deficiency to date.\nClinical description\nAGAT deficiency is characterized by global developmental delay, appearing in infancy, which can be associated with language impairment and autistic behavior in some, as well as a mild to moderate intellectual disability. Progressive muscle weakness and fatigability have been reported in older patients. Seizures and failure to thrive have also been described. If creatine supplementation is administered early enough, psychomotor delay may be avoided.\nEtiology\nAGAT deficiency is caused by mutations in the L-arginine:glycine amidinotransferase gene (GATM) located to chromosome 15q15.1. This gene encodes AGAT, which converts arginine and glycine to ornithine and guanidinoacetate in the creatine cycle pathway.\nGenetic counseling\nAGAT deficiency is transmitted in an autosomal recessive manner and genetic counseling is possible.\n\n                            Last update: \n                            December 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Sylvia STOCKLER"}
{"Disease Name": "L-ferritin deficiency", "Disease Definition": "A rare genetic hematologic disease characterized by decreased or undetectable serum L-ferritin with otherwise normal laboratory parameters. Clinical signs and symptoms include generalized seizures, atypical restless leg syndrome, mild neuropsychologic impairment, and progressive hair loss. Asymptomatic cases have also been reported.", "ORPHA ID": 440731, "Summary": ""}
{"Disease Name": "L1 syndrome", "Disease Definition": "A rare, congenital X-linked developmental disorder characterized by hydrocephalus of varying degrees of severity, intellectual deficit, spasticity of the legs, and adducted thumbs. The syndrome represents a spectrum of disorders including: X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA syndrome, X-linked complicated hereditary spastic paraplegia type 1, and X-linked complicated corpus callosum agenesis.", "ORPHA ID": 275543, "Summary": "Epidemiology\nL1 syndrome primarily affects males. HSAS is the most common genetic form of congenital hydrocephalus, with a prevalence of approximately 1/30,000. The prevalence and incidence of the other disorders in the spectrum are not known.\nClinical description\nPresentation is commonly in the antenatal or neonatal period but, depending on the severity of condition, may present later in life with developmental delay and other neurological features such as spasticity. Affected males have varying degrees of hydrocephalus (frequently present in the prenatal period) ranging from subclinical to severe. Intellectual deficit ranges from mild to severe. Patients develop generalized hypotonia and spasticity of the legs at an early age and the condition appears to progress over time, leading to leg muscle atrophy causing a shuffling gait. Adducted thumbs are a characteristic feature of the syndrome, present in about 50% of cases. Some patients also experience seizures. A small number of patients (< 20) have been reported to have a combination of L1 syndrome and Hirschsprung disease. Female carriers may have minor features such as adducted thumbs or mild intellectual deficit but they rarely have the severe manifestations of the syndrome.\nEtiology\nL1 syndrome is caused by mutations in the L1CAM gene (Xq28) encoding the L1 cell adhesion molecule that is expressed mainly in the developing nervous system. More than 240 different mutations have been reported to date, possibly explaining the wide clinical spectrum. About 7% of mutations have been reported to occur de novo.\nDiagnostic methods\nDiagnosis in male patients is made on the basis of the characteristic clinical and neuropathologic findings and a family history consistent with X-linked transmission. Bilateral absence of the pyramids (corticospinal tract) detected by magnetic resonance imaging (MRI) or autopsy is practically a pathognomonic feature of the syndrome. The diagnosis can be confirmed by molecular genetic testing of the L1CAM gene.\nDifferential diagnosis\nThe differential diagnosis is broad. Other hydrocephalus and spastic paraplegia disorders should be ruled out. A pediatric/neurologic/clinical genetics work-up enables diagnosis of the possible individual diseases.\nAntenatal diagnosis\nPrenatal testing can be performed in female carriers if an L1CAM disease-causing mutation has been identified in a family member. Genetic counseling is important; fetal gender determination can be part of the prenatal workup. Fetal cells, obtained by chorionic villus sampling or by amniocentesis, can be studied for the known disease-causing mutation. Girls may be affected, and ultrasound at 20 weeks is recommended in female fetuses. Normal fetal ultrasound at 20 weeks does not however rule out the disorder: absence of hydrocephalus at this stage does not guarantee that a male fetus is not affected.\nGenetic counseling\nL1 syndrome is inherited in an X-linked manner. Genetic counseling should be provided to affected families. For carrier females, there is a 50% chance that male offspring will be affected; for female offspring there is 50% risk of inheriting the mutation. Carrier females may be asymptomatic or express a milder phenotype.\nManagement and treatment\nTreatment requires a multidisciplinary team including specialists in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics. Shunting of cerebrospinal fluid (CSF) can be carried out to lower intracranial pressure. Corrective surgery for adducted thumbs is not indicated. Monitoring should include developmental progress and neurological symptoms.\nPrognosis\nHydrocephalus may result in stillbirth or death in early infancy. Prognosis is dependent on the severity of the manifestations.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr C.T.R.M. [Connie] STUMPEL | ITHACA* - Dr Y.J. [Yvonne] VOS \n\n\n                                * European Reference Network"}
{"Disease Name": "La Crosse encephalitis", "Disease Definition": "An acute arboviral infection caused by the La Crosse bunyavirus transmitted by an infected mosquito, usually observed in infants, children or adolescents (6 months to 16 years), and characterized by the onset of flulike symptoms such as fever, chills, nausea, vomiting, headache, and abdominal pain, followed by the onset of encephalitis characterized by somnolence, obtundation, and even seizures, focal neurologic signs (asymmetrical reflexes or Babinski signs), paralysis or even coma. CE can leave sequelae such as residual epilepsy and neurocognitive deficits.", "ORPHA ID": 83483, "Summary": ""}
{"Disease Name": "Lacrimoauriculodentodigital syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by hypoplasia, aplasia or atresia of the lacrimal system, anomalies of the ears with sensorineural or mixed hearing loss, hypoplasia, aplasia or atresia of the salivary glands, dental anomalies, and digital malformations. Patients present obstruction of the nasal lacrimal ducts that can lead to epiphora, and chronic conjunctivitis due to alacrimia. Aplasia or hypoplasia of the salivary glands lead to dry mouth and early onset of severe dental caries. Dental features include late tooth eruption, small and peg-shaped lateral maxillary incisors and mild enamel dysplasia. The digital features are variable and include fifth finger clinodactyly, duplication of the distal phalanx of the thumb, triphalangeal thumb, and/or syndactyly. Unilateral radial aplasia and radial-ulnar synostosis have also been reported in association.", "ORPHA ID": 2363, "Summary": ""}
{"Disease Name": "Lafora disease", "Disease Definition": "A rare, inherited, severe, progressive myoclonic epilepsy characterized by myoclonus and/or generalized seizures, visual hallucinations (partial occipital seizures), and progressive neurological decline.", "ORPHA ID": 501, "Summary": "Epidemiology\nThe prevalence varies: LD is seen worldwide but is more common in geographic isolates and areas with a high degree of inbreeding. In Western countries, prevalence is estimated to be below 1/1,000,000.\nClinical description\nOnset occurs during adolescence, with generalised tonic-clonic or clonic-tonic-clonic seizures, action and resting myoclonus, negative myoclonus, and focal occipital seizures with transient amaurosis. The course is marked by prominent and rapid cognitive deterioration (the primary symptoms of which may precede the motor anomalies), and by the progressive increase in intensity of the seizures and myoclonus.\nEtiology\nLD is genetically heterogeneous. Mutations/deletions of the EPM2A gene, localised in 1995 to 6q24 (product: laforin), are found in 80% of cases. The less common EPM2B variant is localised on 6p22 (product: malin). However, these two localisations do not account for all cases of LD.\nDiagnostic methods\nThe diagnosis of LD may be suspected on the basis of the family history, age at onset, typical appearance of symptoms, rapid worsening of cognitive function and detection of fairly typical electroencephalogram (EEG) features. It can easily be confirmed by axillary skin biopsy with detection of Lafora bodies (polyglucosan aggregates) in the sweat duct cells. Other biopsies, such as brain biopsy, are generally not necessary. Molecular biology is useful for diagnosis but the genetic heterogeneity does not allow LD to be excluded when none of the known mutations are detected.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counselling and prenatal diagnosis are theoretically possible when the genetic anomaly has been documented in an affected member of the family.\nManagement and treatment\nThe treatment of LD with antiepileptic and antimyoclonic drugs remains purely symptomatic. Drugs that may aggravate myoclonus must be avoided. Psychological and social management is of utmost importance in LD.\nPrognosis\nDeath occurs 4 to 10 years after onset in typical forms.\n\n                            Last update: \n                            February 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Pierre GENTON"}
{"Disease Name": "Laing distal myopathy", "Disease Definition": "A rare autosomal dominant distal myopathy characterized by preferential weakness of the great toe, ankle dorsiflexor, finger extensor and neck flexor. Progression is slow with variations in age of onset, severity, weakness, cardiac, and respiratory involvement.", "ORPHA ID": 59135, "Summary": "Epidemiology\nWorldwide prevalence is unknown. A founder variant in La Safor region (Spain) causes a local prevalence of 1/5,000. De novo variants cause 30% of cases.\nClinical description\nOnset is usually from 4-5 years to the early 20s but may be in the 50s. The disease initially involves the dorsiflexors of the ankles and great toes, with foot drop causing high step walking and tripping, then spreads to finger extensors. Some patients present with neck flexion weakness. Mild involvement of the face (particularly the orbicularis oculi and oris) is frequent. Proximal and axial weakness may develop with variable severity and progression ranging from loss of ambulation in the 4th decade to symptomless old age. Exercise myalgia and backpain are occasional complaints. Atypical congenital or childhood forms with spinal rigidity, bent spine, dropped head or scapuloperoneal distribution may occur. Cleft palate, scoliosis, pes cavus, tendon contractions and calf hypertrophy may present. Cardiopathy occurs in one third of patients. Respiratory involvement is less common.\nEtiology\nThe disease is caused by missense, deletion and insertion pathogenic variants (PVs) of the MYH7 gene (14q11), in the beta-myosin heavy chain rod domain. PVs alter the heptad amino acid repeat forming the coiled coil tail, or change its charge, hindering thick filament assembly and perturbing interaction with other sarcomeric proteins. Recent findings indicate altered myosin head function despite the PVs being in the myosin tail.\nDiagnostic methods\nDiagnosis is based on molecular genetic testing (exome, gene panel or Sanger sequencing). Serum creatine kinase concentration is normal to mildly increased. Electromyography demonstrates myopathy but occasional neurogenic features may mislead diagnosis. Muscle MRI grades muscle impairment and confirms the pattern of involvement with constant fatty replacement of anterior lower leg muscles and variable extension to other muscles independent of disease duration. Muscle pathology includes nonspecific myopathic/dystrophic features, type I fiber predominance and atrophy, cores or minicores, sarcoplasmic inclusions, occasional rimmed vacuoles and ragged-red fibres. Abundant fibers express both fast and slow myosin. Electron-microscopy shows focal sarcomeric disorganization, granular electrodense deposits like reducing bodies or lipofuscin material, aberrant mitochondria, and disorganized triads.\nDifferential diagnosis\nDifferential diagnosis is broad including: congenital myopathies and cardiomyopathies (RYR1 or MYH7-related); muscular dystrophies (due to PVs in LMNA/B, FHL1, SELENON, DUX4); Udd, Markesbery-Griggs, and Welander distal myopathies; GNE myopathy; distal nebulin myopathy; and neuropathy.\nAntenatal diagnosis\nPrenatal diagnosis may be performed using standard methods of preimplantation genetic testing or chorionic villus sampling and analysis.\nGenetic counseling\nTransmission is autosomal dominant. PV carriers have a 50% chance of transmitting it to their offspring.\nManagement and treatment\nManagement includes physiotherapy and lightweight ankle splinting for footdrop. Orthopedic and surgical management should be considered for scoliosis, rigid spine and tendon contractions. Annual neurologic evaluation, monitoring (electrocardiogram and echocardiogram) for cardiac involvement and spirometry for respiratory complications are recommended. There is no disease modifying therapy.\nPrognosis\nLife expectancy is normal for typical Laing distal myopathy. Patients with cardiac, spinal and respiratory complications should be evaluated accordingly.\n\n                            Last update: \n                            June 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Nigel LAING  - Pr Phillipa LAMONT  - Dr Nuria MUELAS  - Pr Juan Jesús VILCHEZ PADILLA"}
{"Disease Name": "LAMA5-related multisystemic syndrome", "Disease Definition": "A rare genetic systemic or rheumatologic disease characterized by infantile onset of skin anomalies (such as delayed wound healing with atrophic scars and mild alopecia with dry and brittle hair), retinal rod degeneration with night blindness, degenerative myopathy with muscle weakness, myalgia, and cramps, osteoarthritis, joint laxity, prolapse of internal organs, floating kidney syndrome, malabsorption syndrome, and hypothyroidism. The phenotype has been reported to be more severe in women than in men.", "ORPHA ID": 521450, "Summary": ""}
{"Disease Name": "Lamb-Shaffer syndrome", "Disease Definition": "A rare genetic syndromic intellectual disability characterized by global developmental delay and speech delay, variable degrees of intellectual disability, and dysmorphic facial features (such as frontal bossing, epicanthal folds, strabismus, depressed nasal bridge, short philtrum, auricular abnormalities, micrognathia, or crowded teeth, among others). Additional reported manifestations are behavioral problems (stereotypies, aggression, anxiety, autism spectrum disorder), skeletal anomalies (scoliosis, pectus carinatum, clinodactyly of fingers and toes, among others), and seizures.", "ORPHA ID": 530983, "Summary": "Epidemiology\nLamb-Shaffer syndrome (LAMSHF) is a rare disorder reported in less than 100 patients worldwide. The prevalence is not known.\nClinical description\nIn most cases, pregnancy and delivery are unremarkable and the neonatal period is uneventful. Developmental delay (delayed independent walking and speech) and truncal hypotonia during infancy are the usual first manifestations. In older children, mild-to-moderate intellectual disability is the main clinical feature, with some patients having either more severe or milder cognitive impairment. Behavioral disturbances are frequent, including autism spectrum disorder, stereotypies, isolation, tantrums and hyperactivity. Seizures may occur but epilepsy is relatively infrequent (<10%). Height, weight and occipitofrontal circumference are within normal ranges. Mild dysmorphological features are noted in most patients, including broad/full nasal tip, thin upper lip or full lips, small jaw or chin, strabismus, long face and/or epicanthus. Optic atrophy is a rare feature. Malformations of organs are infrequent, skeletal malformations mainly involve the spine (scoliosis, thoracic kyphosis, fused cervical vertebrae).\nEtiology\nLAMSHF is an autosomal dominant disorder caused by haplo-insufficiency of the SOX5 gene (12p12.1) due to either a 12p12.1 microdeletion encompassing the gene or heterozygous point variants. Points variants are either truncating variants or missense variants affecting functional domains of the protein.\nDiagnostic methods\nLAMSHF diagnosis may be suspected on clinical presentation and confirmed by micro-array analysis (SOX5 deletion) or sequencing of SOX5 (gene panel, exome sequencing, genome sequencing).\nDifferential diagnosis\nMany differential diagnoses may be considered, i.e. developmental disorders with mild-to-moderate intellectual disability and mild morphological features.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe disorder is autosomal dominant and whilst most cases arise sporadically, parental mosaicism is not exceptional. Genetic counseling should be offered to i) couples with an affected child informing them that there is a risk of having another affected child, ii) affected individuals informing them that there is a 50% risk of transmission.\nManagement and treatment\nThere is no specific treatment for LAMSHF. Management of patients requires medical and social care as for other patients with intellectual disability, including special schooling, speech therapy, etc.\nPrognosis\nLife expectancy of individuals with LAMSHF does not seem to be affected. The functional prognosis depends on the severity of intellectual disability.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Cyril MIGNOT | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Lambert syndrome", "Disease Definition": "A very rare syndrome described in four sibs of one French family and characterized by branchial dysplasia (malar hypoplasia, macrostomia, preauricular tags and meatal atresia), club feet, inguinal herniae and cholestasis due to paucity of interlobular bile ducts and intellectual deficit.", "ORPHA ID": 1296, "Summary": ""}
{"Disease Name": "Lambert-Eaton myasthenic syndrome", "Disease Definition": "Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune, presynaptic disorder of neuromuscular transmission characterized by fluctuating muscle weakness and autonomic dysfunction frequently associated with small-cell lung cancer (SCLC).", "ORPHA ID": 43393, "Summary": "Epidemiology\nThe prevalence is estimated to be between 1/250,000- 1/333,300 worldwide.\nClinical description\nThe age of onset is typically over 40 years old, although it may occur at any age. LEMS is characterized by the clinical triad of proximal muscle weakness, autonomic disturbance, and depressed tendon reflexes. Tumors, mostly SCLC (see this term), are present in fifty to sixty percent of LEMS patients. Cerebellar ataxia can occur, in which case it is almost always accompanied by SCLC.\nEtiology\nAround 90% of LEMS patients have pathogenic antibodies against the presynaptic P/Q-type voltage-gate calcium channel (VGCC). Dysfunction or decrease in number of these channels inhibits release of acetylcholine from the presynaptic endplate, resulting in impaired neuromuscular transmission and muscle weakness.\nDiagnostic methods\nIn addition to the classical clinical triad (although all three features are not always present), the diagnosis of LEMS is based on the detection of VGCC antibodies by using radioimmunoprecipitation assays and/or typical abnormalities of the repetitive nerve stimulation (RNS) test: a low amplitude compound muscle action potential (CMAP), a decremental response to low rate stimulation, and an incremental response to high rate stimulation or after brief exercise (postexercise facilitation). Abnormal single fiber EMG (SFEMG) can confirm a disorder of the neuromuscular junction, but is non-specific.The diagnosis of LEMS almost invariably precedes the discovery of SCLC.\nDifferential diagnosis\nIn 60% of LEMS patients, a different diagnosis was initially made such as myasthenia gravis (MG), inclusion body myositis, Guillain-Barré syndrome (GBS), amyotrophic lateral sclerosis (ALS) (see these terms), lumbar canal stenosis, early-phase Parkinson's disease and lower body parkinsonism.\nManagement and treatment\nThere is no cure for LEMS and treatment is mainly symptomatic. This includes 3, 4-diaminopyridine phosphate (DAP) which is usually well tolerated and effective. In some patients, the combination of pyridostigmine with 3,4-DAP has been suggested to have an additional positive effect. If symptomatic treatment is insufficient, immunosuppressive therapy with prednisone, alone or in combination with azathioprine, can achieve long-term control of the disorder. Plasmapheresis and high dose administration of intravenous immunoglobulins (IVIGs) have a short effect. An effective treatment against any tumor present is mandatory, both to control the tumor and to improve the clinical symptoms of LEMS.\nPrognosis\nIn general, LEMS responds well to symptomatic and immunosuppressive treatments. However, LEMS can affect every day activities and quality of life of individual patients. Life expectancy depends on the presence of lung cancer. Without cancer, the life expectancy is considered normal. As SCLC (see this term) is a very aggressive cancer, prognosis of patients with LEMS and SCLC is often rather poor. Median survival is 17-24 months, although the amount of patients with long-standing remission or cured is approximately 20% (compared to <2% of patients with a SCLC without LEMS).\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr M.J. [Maarten] TITULAER"}
{"Disease Name": "Lamellar ichthyosis", "Disease Definition": "A rare autosomal recessive congenital ichthyosis characterized by the presence of large scales all over the body without significant erythroderma.", "ORPHA ID": 313, "Summary": "Epidemiology\nIt is the most common variant of autosomal recessive congenital ichthyosis (ARCI). Prevalence in Europe is estimated at approximately 1/100,000-1/300,000 individuals.\nClinical description\nNewborns are often encased in a collodion membrane (taut, shiny, translucent membrane appearing as an extra skin layer) with ectropion and eclabium. Once the membrane has been shed (after one to two weeks), scales covering the whole body become apparent. In classic lamellar ichthyosis (LI), scales are large, dark and plate-like. Milder forms with lighter and thinner scales are possible. Contrarily to congenital ichthyosiform erythroderma (CIE), there is no significant erythroderma. Nevertheless, LI and CIE are the two extremities of the same spectrum, with many patients exhibiting intermediate phenotypes. Furthermore, patients' phenotypes may change over time or under treatment. Skin is usually itchy or painful (with cracks), mobility can be reduced due to skin stiffness over the joints, and cutaneous barrier function is impaired, which can result in increased transepidermal water loss and a proneness to dehydration. Other associated features include: persistent ectropion and associated eye complications (keratitis, corneal scarring), nail dystrophy, scarring alopecia, palmoplantar keratoderma, failure to thrive, short stature, hypohidrosis with heat intolerance, and impaired hearing (due to the accumulation of scales in the external ear).\nEtiology\nLI is a genetically heterogeneous disease within the disease spectrum of autosomal recessive congenital ichthyosis (ARCI) generally due to mutations in the genes TGM1, ABCA12, ALOX12B, and NIPAL4. Most mutations are found in the TGM1 gene encoding transglutaminase 1, involved in the formation of the epidermal cornified cell envelope. ABCA12 encodes an ATP-binding cassette (ABC) transporter, involved in lipid transport, ALOX12B and NIPAL4 encode arachidonate 12(R)-lipoxygenase and ichthyn respectively and are involved in lipid metabolism. There is no clear genotype-phenotype correlation. There also exists an autosomal dominant lamellar ichthyosis with palmoplantar keratoderma due to mutations in ASPRV1, which encodes a protease involved in Filaggrin processing.\nDiagnostic methods\nThe diagnosis is based on the clinical appearance of the skin and can be confirmed by genetic testing. Histological features include orthohyperkeratosis, a normal to slightly widened stratum granulosum, acanthosis, and papillomatosis of the epidermis. Immunohistochemistry using antibodies directed against transglutaminase 1 or transglutaminase 1 enzyme activity measurement is available in some centers. Molecular testing (such as gene panel diagnosis) is possible in national reference laboratories.\nDifferential diagnosis\nDifferential diagnosis includes syndromic forms of ichthyosis, recessive X-linked ichthyosis and semidominant ichthyosis vulgaris, and CIE in case of erythroderma.\nAntenatal diagnosis\nPrenatal diagnosis is based on DNA analysis of amniocentesis and chorion villus sampling materials.\nGenetic counseling\nGenetic counseling should be offered to the affected families.\nManagement and treatment\nNewborns presenting with collodion baby are usually admitted to a neonatal intensive care unit for 2 to 4 weeks. In later life, management is based on daily applications of emollients and/or keratolytics. Oral retinoids are useful in severe forms. Acitretin is the only retinoid approved by the European Medical Agency (EMA). Usually dosages of 0.5 mg/kg/day are sufficient. Doses should be maintained as low as 10-25 mg/day.\nPrognosis\nPrognosis is variable. During the neonatal period, there is a risk of sepsis and electrolyte imbalance. The disease often remains stable throughout life, with periods of exacerbation. Life expectancy is normal after the somewhat critical neonatal period. LI has a strong impact on quality of life due to altered physical appearance, troublesome symptoms, and the many constraints due to the disease and its treatment.\n\n                            Last update: \n                            December 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Kira SÜßMUTH | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Laminin subunit alpha 2-related congenital muscular dystrophy", "Disease Definition": "Congenital muscular dystrophy type 1A (MCD1A) belongs to a group of neuromuscular disorders with onset at birth or infancy characterized by hypotonia, muscle weakness and muscle wasting.", "ORPHA ID": 258, "Summary": "Epidemiology\nMCD1A represents 30-40% of congenital muscular dystrophies, with some regional variation. Prevalence is estimated at 1/30,000.\nClinical description\nThe disease presents at birth or in the first few months of life with hypotonia and muscle weakness in the limbs and trunk. Respiratory and feeding disorders can also occur. Motor development is delayed and limited (sitting or standing is only possible with help). Infants present with early rigidity of the vertebral column, scoliosis, and respiratory insufficiency. There is facial involvement with a typical elongated myopathic face and ocular ophthalmoplegia disorders can appear later. Epileptic attacks are possible, although they occur in less than a third of patients. Intellectual development is normal.\nEtiology\nMCD1A is caused by mutations in the LAMA2 gene coding for the alpha-2 laminin chain.\nDiagnostic methods\nDiagnosis is based on muscular biopsy, as merosin deficiency can be detected in the muscle and skin. MRI reveals diffuse abnormalities in brain white matter, typically sparing the corpus callosum, capsula interna and cerebellum. In the initial phase of the disease there is a four-fold increase in levels of serous creatine kinase.\nDifferential diagnosis\nDifferential diagnoses include other forms of congenital muscular dystrophy, linked particularly with glycosylation and alpha-dystroglycan anomalies, as well as congenital structural myopathies (central core disease, multi-minicore myopathy, centronuclear myopathy), of which the causative genes have been identified in the majority of cases (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible in the ninth week by chorionic villus sampling for evidence of merosin deficiency, and by evidence of mutation in the LAMA2 gene.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to families.\nManagement and treatment\nTreatment is symptomatic. It consists of a multidisciplinary approach, including physiotherapists, occupational therapists and speech-language therapists, with the objective of optimizing each patient's abilities. Seizures or other neurological complications require specific treatment.\nPrognosis\nThe prognosis of these muscular dystrophies is very severe as a large proportion of affected children do not reach adolescence. Currently, the prognosis can only be improved by attentive multidisciplinary (particularly orthopedic and respiratory) management.\n\n                            Last update: \n                            April 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Michel FARDEAU"}
{"Disease Name": "Laminin subunit alpha 2-related limb-girdle muscular dystrophy R23", "Disease Definition": "A rare autosomal recessive limb-girdle muscular dystrophy characterized by childhood to adult onset of slowly progressive limb girdle muscular weakness, often accompanied by calf hypertrophy, and moderately elevated creatine kinase levels. Patients remain ambulatory but may variably present mild intellectual disability, seizures, migraine, or cardiopulmonary involvement. Occurrence of dilated cardiomyopathy has been reported. Brain MRI typically shows hyperintensity in T2-weighted sequences. Muscle biopsy commonly reveals dystrophic features.", "ORPHA ID": 565837, "Summary": ""}
{"Disease Name": "Landau-Kleffner syndrome", "Disease Definition": "Landau-Kleffner syndrome (LKS) is an age-related epileptic encephalopathy where developmental regression occurs mainly in the language domain and the electroencephalographic (EEG) abnormalities are mainly localized around the temporal-parietal regions. The term acquired epileptic aphasia describes the main features of this condition.", "ORPHA ID": 98818, "Summary": "Epidemiology\nThe prevalence is difficult to estimate because of heterogeneous definitions. The male-to-female ratio is 2:1.\nClinical description\nLKS only affects children and adolescents. The age of onset is thought to range from the ages of 2-8 years. Acquired aphasia in previously normal children is the defining feature of this disorder and it usually presents as verbal auditory agnosia. Expressive aphasia follows the receptive aphasia and spontaneous speech becomes limited. Behavioral problems such as attention deficits, hyperactivity, impulsivity, and distractibility often accompany the language regression. Seizures occur in 2/3 of patients and are generally easy to control and remit spontaneously before adolescence. Approximately 1/3 of patients do not have seizures. Seizure types observed include partial motor (most common), generalized clonic and atypical absence. The disease course is progressive with spontaneous fluctuations in severity over time.\nEtiology\nThe exact etiology is unknown. Structural brain lesions are very infrequent in LKS patients. Genetic factors may be involved, with GRIN2A (16p13.2) mutations appearing to be causal.\nDiagnostic methods\nDiagnosis is based on clinical (acquired aphasia) and EEG findings. EEG findings include bilateral centro-temporal, posterior temporal, and parieto-occipital spikes during wakefulness that become much more diffuse and intense during non-rapid eye movement (non-REM) sleep, leading in occasions to electrical status epilepticus in sleep (ESES). ESES is characterized by marked potentiation of epileptiform discharges during the transition from wakefulness to sleep leading to (near-) continuous, bilateral or occasionally lateralized slow spikes and waves that occur during a significant proportion of non-REM sleep. The pattern of ESES in LKS is unilateral or bilateral. A reduction of volume in language development areas of the brain may be observed with MRI volumetric analysis. As of now it is not routine clinical practice to perform genetic tests for GRIN2A in LKS, but testing is available in certain specialized centers.\nDifferential diagnosis\nThe differential diagnosis includes any epileptic syndrome with sleep potentiation of epileptiform activity such as continuous spikes and waves during sleep, Panayiotopoulos and Gastaut types of benign childhood occipital epilepsy and rolandic epilepsy (see these terms). It is important to rule out a hearing defect and/or autism that may present initially in a similar way.\nGenetic counseling\nAn autosomal dominant transmission has been proposed in families with a GRIN2A mutation.\nManagement and treatment\nIn those with seizures, several antiepileptic drugs (AEDs) are often effective and seizure control is generally not an issue. Corticosteroids have also been linked to improvements or at least stabilization of language abilities. Subpial transections, a surgical approach that seeks to disrupt the epileptic network while preserving eloquent cortex, have been successful in selected cases. Carbamazepine, oxcarbacepine, phenytoin and phenobarbital are generally avoided due to a risk of exacerbation of epileptiform discharges of ESES. Follow-up with an audiologist is recommended and special education may be necessary.\nPrognosis\nThe prognosis is good in regards to seizures as they are easy to control and remit spontaneously around puberty. Language outcome is characterized by a variable improvement with treatment and/or at around puberty, but without ever returning to the pre-disease state.\n\n                            Last update: \n                            April 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Tobias LODDENKEMPER  - Dr Iván SÁNCHEZ FERNÁNDEZ"}
{"Disease Name": "Langer mesomelic dysplasia", "Disease Definition": "A rare, genetic skeletal dysplasia characterized by severe disproportionate short stature with mesomelic and rhizomelic shortening of the upper and lower limbs.", "ORPHA ID": 2632, "Summary": "Epidemiology\nThe exact prevalence is unknown. More than 100 cases have been described in the literature to date, with most of the patients being reported from populations with a high level of consanguinity.\nClinical description\nLanger mesomelic dysplasia (LMD) is a more severe form of Léri-Weill dyschondrosteosis (LWD) and presents at birth with a severely shortened long bones of the limbs (involving both the middle and proximal segments), deformity of the humeral head, angulation of the radial shaft, carpal distortion, a short femoral neck, and absence or hypoplasia of the proximal half of the fibula. Mild hypoplasia of the mandible has been reported in some cases. In contrast to LWD, Madelung deformity is not typically present in LMD. Associated malformations are rare and intellect is normal in almost all reported LMD cases.\nEtiology\nLMD is inherited in a pseudoautosomal recessive manner and is associated with homozygous or compound heterozygous mutations and deletions of the Short stature HomeobOX (SHOX) gene (which maps to the pseudoautosomal region 1 (PAR1) of the sex chromosomes; Xp22.33 and Yp11.32) or of the upstream or downstream PAR1 (where SHOX enhancer elements are located). LMD is part of a spectrum of disorders (ranging from the most severe, LMD, to LWD, isolated Madelung deformity and so-called idiopathic short stature), all associated with SHOX/PAR1 anomalies. The prevalence of SHOX/PAR1 mutations is estimated at 1/1000.\nDiagnostic methods\nDiagnosis of LMD may be suspected on the basis of the clinical and radiologic findings and can be confirmed by molecular analysis (preferably multiplex ligation-dependent probe amplification for PAR1 deletions and DNA sequencing for point mutations, small deletions and insertions of SHOX).\nDifferential diagnosis\nDuring the antenatal period differential diagnosis includes femur-fibula-ulna complex and the Reinhardt-Pfeiffer mesomelic dysplasia.\nAntenatal diagnosis\nLMD may be suspected by ultrasound at 20 weeks of gestation. Prenatal genetic testing is available; however, requests for testing for these disorders are uncommon but are more frequent for LMD.\nGenetic counseling\nGenetic counseling should be proposed and families should be informed that SHOX/PAR1 anomalies are inherited in a pseudoautosomal dominant manner. Each child of an individual with LWD has a 50% risk of inheriting the mutation. If both parents have LWD, the offspring have a 50% risk of having LWD, a 25% risk of having LMD, and a 25% risk of having neither condition. All children of an individual with LMD and an unaffected parent will present with LWD.\nManagement and treatment\nThere is no effective treatment for LMD. The symptomatic medical management of children with LMD begins at birth and continues into adulthood. Careful monitoring of height, weight, and head circumference is essential.\nPrognosis\nThe short stature and limb deformities are severe but life expectancy is normal.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Karen HEATH"}
{"Disease Name": "Langerhans cell histiocytosis", "Disease Definition": "A rare systemic disease characterized by the accumulation (usually organized in granulomas) of macrophage, bearing the features of Langerhans cells in various tissues.", "ORPHA ID": 389, "Summary": "Epidemiology\nIts prevalence is estimated at 1-2/100,000. More than 60% of the cases occur before age of 2. But the disease may be diagnosed in adults.\nClinical description\nBone is the most frequently affected organ (80% of cases), followed by the skin (35% of cases) and then the pituitary gland (25% of cases). However, involvement of these organs does not affect the vital prognosis. Involvement of the hematopoietic system (cytopenia), lungs and liver is much less common (15-20% of cases) but results in more severe disease. The aggressive nature of the hematological forms in young children, the long-term sequelae associated with lung and liver (sclerosing cholangitis) involvement, and the neurodegenerative manifestations (2-5% of cases) make LCH a severe disease. The disease may occur as one or several crises. It may result in aesthetic or functional sequelae with variable expression depending on the sites involved (deafness, respiratory or hepatic failure, diabetes insipidus, growth hormone deficiency, and cerebellar syndrome). In adults, the clinical picture is characterized by isolated lung disease, with a strong association with smoking.\nEtiology\nThe origin of the LCH lesions, originally thought to be neoplastic proliferation of Langerhans cells, was found to instead be similar to proliferation of immature myeloid precursors, with activation of one gene of the MAPK/ERK pathway (most frequently BRAF) involving the macrophagic cells.\nDiagnostic methods\nDiagnosis of LCH usually relies on histological and immunohistochemical analysis of the affected tissues. A thoracic CT scan showing typical radiological findings may allow diagnosis in adults with isolated lung involvement.\nDifferential diagnosis\nA large range of alternative diagnoses may be considered, depending on the associated clinical picture and radiological findings.\nManagement and treatment\nThe choice of therapeutic approach depends on the extent of disease, determined by routine examinations (clinical examination, hemogram, liver function tests, and bone and chest radiographs). Local treatment is usually effective for forms limited to one organ. In children, treatment of the systemic forms relies on the combination of corticosteroids and vinblastine. Smoking cessation is necessary for adults with lung involvement. Second-line treatments are available in specialized centers for patients with progressive disease. Given the polymorphic and chronic nature of the disease, management of LCH should be multidisciplinary. Treatment protocols for adult forms of the disease are less well established than those for patients with childhood onset. Long-term follow-up is needed for detection and management of later-onset sequelae.\nPrognosis\nThe vital prognosis is not usually affected in childhood forms, except in cases with hematological involvement resistant to first-line therapies.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Jean DONADIEU"}
{"Disease Name": "Langerhans cell sarcoma", "Disease Definition": "A rare dendritic cell tumor characterized by an aggressive, high-grade neoplasm derived from Langerhans cells, most commonly extranodal and multifocal, involving the skin and underlying soft tissue, as well as lung, liver, spleen, and bone. Primary nodal involvement is seen in a minority of patients. Immune-phenotyping and the presence of Birbeck granules on ultrastructural examination reveal the Langerhans cell derivation of the neoplastic cells. Prognosis is generally poor.", "ORPHA ID": 86897, "Summary": ""}
{"Disease Name": "Large congenital melanocytic nevus", "Disease Definition": "A rare skin hamartoma characterized by at least one pigmented skin lesion present at birth of more than 20 cm (large congenital melanocytic nevus; LCMN) or 40 cm (giant; GCMN) projected adult diameter. The primary lesion is composed of mutated melanocytes and often locally disorganized epidermal annexes or dermis, and presents with an elevated risk of malignant transformation to melanoma or, more rarely, other neoplasms in skin or central nervous system.", "ORPHA ID": 626, "Summary": "Epidemiology\nLCMN has a prevalence of about 1/20,000, while GCMN is estimated to occur in 1/50,000 to 1/500,000 births, becoming increasingly rare as more body surface is implicated. It is present in all ethnic groups examined to date and in both genders, with a slight female predominance.\nClinical description\nCMN develop during pregnancy as at least one darkly colored, circumscribed area of the skin sometimes covered with dense hair or proliferative nodules, often accompanied by multiple small satellite nevi at birth or pigmenting during early childhood (tardive nevi). Three or more ''multiple medium CMN'' present a total surface, when summed, similar to that of other LCMN but are more frequently associated with complications. The term ''CMN syndrome'' covers these additional neurological (epilepsy, hydrocephalus, neurocutaneous or diffuse leptomeningeal melanocytosis, spinal meningeal cysts or tethered spinal cord) or endocrine symptoms. All LCMN/GCMN patients present an elevated risk of pediatric melanoma and other neuroectodermal tumors of varying severity (rhabdomyosarcoma, schwannoma, malignant peripheral nerve sheath tumor, lipoma, neurofibroma).\nEtiology\nCMN are disorders of embryonic neural crest development caused by somatic mutations in genes involved in the MAP kinase signaling pathway. Multiple and L/GCMN are often associated with NRAS mutations while BRAF mutations are more frequent in small to medium CMN. BRAF-mutated GCMN may be linked to higher frequency of co-morbidities (vascular malformations or benign proliferative nodules). No strict phenotype-genotype relationship has been confirmed, and further genetic heterogeneity is supported by rare reports of other activating mutations, fusion events or duplications in these and other pathway genes.\nDiagnostic methods\nDiagnosis is clinical, based on size, delimitation, depth and location of the lesions. Magnetic resonance imaging (MRI) and neurological evaluations are also performed in order to screen for complications. Pigmentation is darkest at the epidermal surface, in contrast to dermal (''blue'') nevi. When malignant transformation is suspected, biopsy is necessary.\nDifferential diagnosis\nDifferential diagnoses include Becker nevus syndrome, malignant melanoma, neurofibroma, nevus of Ota, Spitz nevus, blue nevus, epidermal nevus and congenital smooth muscle hamartoma.\nAntenatal diagnosis\nReported cases of antenatal diagnosis are unusual.\nGenetic counseling\nCMN is nearly always sporadic despite rare familial reports (in siblings and cousins).\nManagement and treatment\nRegular periodic dermatological follow-up is necessary. In some cases, excision may be advisable by an experienced plastic surgeon. Dermabrasion, curettage and laser treatments are inferior to full-thickness removal or to simple surveillance. Neurological involvement requires a multidisciplinary approach. Psychological support should be proposed to affected patients and families.\nPrognosis\nMost patients have normal lives. The incidence of complications increases with nevus size. Malignant transformation may occur at any age with no correlation to sun exposure, in approximately 2-3% of multiple and LCMN patients, and up to 5% of GCMN patients. Prophylactic surgery is not known to reduce cancer risk.\n\n                            Last update: \n                            August 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Heather ETCHEVERS"}
{"Disease Name": "Laron syndrome with immunodeficiency", "Disease Definition": "This syndrome is characterized by severe growth retardation associated with immunodeficiency.", "ORPHA ID": 220465, "Summary": "Epidemiology\nLess than 10 cases have been described in literature.\nClinical description\nThe patients present typical clinical and biochemical features of Laron syndrome such as post-natal growth retardation, delayed bone age and facial dysmorphism (prominent forehead, hypoplastic nasal bridge), and low serum IGF-1 concentrations with normal or high GH concentrations. Immunodeficiency is characterized by moderate lymphopenia which leads to recurrent infections of the skin and respiratory tract. Severe chronic lung disease, chronic diarrhea, juvenile idiopathic arthritis (see these terms), generalized eczema, pulmonary infections and respiratory distress have already been described.\nEtiology\nThe syndrome is due to mutation in the signal transducer and activator of transcription 5b gene (STAT5b). Transmission is autosomal recessive. There have been reports of STAT5b mutations resulting in Laron symptoms but not associated with immunodeficiency.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Juliane LEGER"}
{"Disease Name": "Laron syndrome", "Disease Definition": "Laron syndrome is a congenital disorder characterized by marked short stature associated with normal or high serum growth hormone (GH) and low serum insulin-like growth factor-1 (IGF-I) levels which fail to rise after exogenous GH administration.", "ORPHA ID": 633, "Summary": "Epidemiology\nThe disease has been described in more than 250 cases and is more frequent in Semitic or Mediterranean populations. Males and females are equally affected.\nClinical description\nIntrauterine growth and birth size are usually normal. Postnatal growth is slowed and generally disproportional with delayed bone age; adult stature ranges from -3 to -12 SD. Motor development is delayed because of diminished muscle mass. Newborns often present with hypoglycemia and a micropenis. Puberty is often delayed. Facial dysmorphism is common and includes protruding and high forehead, shallow orbits, hypoplastic nasal bridge and small chin. Sparse hair may be observed in infancy. Relative obesity, delayed tooth eruption, high-pitched voice, thin bones and skin, and decreased sweating are often present. Patients occasionally have blue sclera and hip degeneration.\nEtiology\nThe disease is due to mutations in the GHR gene (5p14-p12). Mutations affecting the extracellular domain of the growth hormone receptor result in low growth hormone binding protein levels (GHBP, structurally identical to the extracellular domain of GHR) and defective IGF-I production. A Laron syndrome-like phenotype has been described which is associated with immunodeficiency and is due to gene dysfunction of the signal transducer and activator of transcription 5b (STAT5b deficiency; see this term). A mutation in STAT5B has also been observed in a patient suffering from typical Laron syndrome.\nDiagnostic methods\nDiagnosis is based on clinical and biological findings. Hormonal tests reveal normal or increased level of GH and low IGF-1 levels, which fail to rise after exogenous GH administration. GHBP levels are low in cases with mutations in the extracellular domain of the GHR and normal in cases with mutations in the intracellular domain. Genetic tests should be performed to make a precise etiological diagnosis.\nDifferential diagnosis\nThe differential diagnosis should include severe growth hormone deficiency (GHD) and growth delay due to IGF-I resistance (see this term), as well as secondary IGF-I deficiency mostly due to nutritional problems or chronic pediatric diseases.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be proposed to parents of an affected individual before any further pregnancy, informing them of the risks and the available diagnostic methods.\nManagement and treatment\nManagement aims at improving growth and includes treatment with daily subcutaneous injections of mecasermin, recombinant human IGF-I, and diet with adequate caloric intake. Frequent feeding is necessary in order to avoid hypoglycemia. In August 2005, mecasermin was granted EC orphan drug designation. There is no treatment that cures or prevents the disease.\nPrognosis\nPrognosis seems good but with age, patients may develop obesity, hypercholesterolemia and have increased risk of fractures due to osteopenia.\n\n                            Last update: \n                            November 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Juliane LEGER"}
{"Disease Name": "Larsen syndrome", "Disease Definition": "An orofacial clefting syndrome characterized by congenital dislocation of large joints, foot deformities, cervical spine dysplasia, scoliosis, spatula-shaped distal phalanges and distinctive craniofacial abnormalities, including cleft palate.", "ORPHA ID": 503, "Summary": "Epidemiology\nLarsen syndrome (LS) birth prevalence is estimated to be less than 1 in 100,000 in Europe.\nClinical description\nPrimary clinical characteristics of LS are congenital dislocations of hip, knee and elbow joints with equinovarus or equinovalgus foot deformities (club feet). Other frequent manifestations include spinal deformities such as scoliosis and cervical spine kyphosis, sometimes associated with cervical myelopathy and short, broad, spatula-shaped distal phalanges with the thumb almost always affected. Recurrent craniofacial abnormalities include a prominent forehead, depressed nasal bridge, flattened midface and ocular hypertelorism. Midline cleft palate and conductive hearing loss have also commonly been reported.\nEtiology\nThe syndrome is due to missense mutations or small in frame deletions in the FLNB gene (localized to 3p14.3) that encodes cytoskeletal protein filamin B.\nDiagnostic methods\nDiagnosis is established by clinical assessment, and skeletal X-rays displaying, amongst other factors, supernumerary carpal and tarsal bone ossification centers and is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes other more severe and lethal FLNB-related disorders: atelosteogenesis type I, atelosteogenesis type III and boomerang dysplasia as well as otopalatodigital syndrome type I and spondyloepiphyseal dysplasia, CHST3 type; chondrodysplasia with joint dislocations, gPAPP type; Larsen-like syndrome, B3GAT3 type; Reunion island's Larsen syndrome and Desbuquois syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is available for those with a family history of LS.\nGenetic counseling\nLS is transmitted in an autosomal dominant manner. The autosomal recessive cases reported in the past may perhaps correspond to parental germline mosaicism, but are more likely to represent more recently defined recessive syndromes with similar but still distinct presentations. Genetic counseling should be proposed to individuals having the disease causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nManagement should be adapted to each patient and may involve orthopedic treatment and monitoring, surgical procedures, especially for hip dislocation, and physiotherapy. In case of hearing loss, a multidisciplinary team with pediatric expertise is recommended. It is essential that all infants with a clinical diagnosis of LS have their cervical spine evaluated as soon as practicable after birth to exclude life threatening cervical spine instability.\nPrognosis\nLS does not affect life expectancy.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Stephen ROBERTSON  - Dr Emma WADE"}
{"Disease Name": "Larsen-like osseous dysplasia-short stature syndrome", "Disease Definition": "Larsen-like osseous dysplasia-short stature syndrome is a rare primary bone dysplasia characterized by a Larsen-like phenotype including multiple, congenital, large joint dislocations, craniofacial abnormalities (i.e. macrocephaly, flat occiput, prominent forehead, hypertelorism, low-set, malformed ears, flat nose, cleft palate), spinal abnormalities, cylindrical fingers, and talipes equinovarus, as well as growth retardation (resulting in short stature) and delayed bone age. Other reported clinical manifestations include severe developmental delay, hypotonia, clinodactyly, congenital heart defect and renal dysplasia.", "ORPHA ID": 2370, "Summary": ""}
{"Disease Name": "Larsen-like syndrome, B3GAT3 type", "Disease Definition": "Larsen-like syndrome, B3GAT3 type is a rare, genetic, primary bone dysplasia characterized by laxity, dislocations and contractures of the joints, short stature, foot deformities (e.g. clubfeet), broad tips of fingers and toes, short neck, dysmorphic facial features (hypertelorism, downslanting palpebral fissures, upturned nose with anteverted nares, high arched palate) and various cardiac malformations. Severe disease is associated with multiple fractures, osteopenia, arachnodactyly and blue sclerae. A broad spectrum of additional features, including scoliosis, radio-ulnar synostosis, mild developmental delay, and various eye disorders (glaucoma, amblyopia, hyperopia, astigmatism, ptosis), are also reported.", "ORPHA ID": 284139, "Summary": ""}
{"Disease Name": "Laryngeal abductor paralysis-intellectual disability syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by congenital and permanent vocal cord paralysis causing severe congenital laryngeal stridor, associated with intellectual disability in male patients. Other presenting symptoms may include weak cry, cough, cyanosis, neonatal asphyxia, feeding difficulty, aspiration, and bronchiectasis. Microcephaly, tone abnormalities, visual and hearing impairment may also be associated features.", "ORPHA ID": 2375, "Summary": ""}
{"Disease Name": "Laryngeal neuroendocrine tumor", "Disease Definition": "A rare head and neck tumor characterized by an epithelial neoplasm with evidence of neuroendocrine differentiation, typically located in the supraglottic larynx. The tumor can be well, moderately, or poorly differentiated, the latter group being subdivided into small cell or large cell neuroendocrine carcinomas. There is a strong association with tobacco use. Patients present with hoarseness, dysphagia, sore throat, airway obstruction, hemoptysis, and rarely a paraneoplastic syndrome due to aberrant hormone production. Poorly differentiated tumors are highly aggressive with high rates of regional and distant metastasis.", "ORPHA ID": 100083, "Summary": ""}
{"Disease Name": "Laryngo-onycho-cutaneous syndrome", "Disease Definition": "LOC syndrome is a subtype of junctional epidermolysis bullosa (JEB, see this term) characterized by an altered cry in the neonatal period and by aberrant production of granulation tissue in particular affecting the upper airway tract, conjunctiva and periungual/subungual sites.", "ORPHA ID": 2407, "Summary": "Epidemiology\nPrevalence is unknown. Fewer than 50 cases have been reported to date, mostly in consanguineous families from the Punjabi region of Pakistan and India.\nClinical description\nThe condition is present at birth. Characteristic cutaneous findings are transient blisters leaving slowly healing erosions with exuberant granulation tissue formation, mainly localized to the head and neck, hands, feet, elbows and knees. Extracutaneous manifestations are always observed: the progressive laryngeal involvement frequently leads to fatal respiratory obstruction in infancy, and the chronic conjunctival lesions cause symblepharon formation, and also total palpebral occlusion and blindness. Enamel hypoplasia is also always present and nail dystrophies are common.\nEtiology\nThe condition is associated with mutations in the alpha-3 chain of laminin-332 (LAMA3).\nGenetic counseling\nLOC syndrome follows an autosomal recessive pattern of inheritance.\nPrognosis\nPrognosis is poor.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "Laryngocele", "Disease Definition": "A rare congenital laryngeal anomaly characterized by an abnormal dilation of the laryngeal saccule that is filled with air, maintains communication with the laryngeal lumen, and is either confined to the false vocal fold or extends upward, protruding through the thyrohyoid membrane to the neck. Symptoms may include cough, hoarseness, stridor, sore throat and uni- or bilateral swelling of the neck. Blockage of the laryngocele neck can result isn laryngomucocele, and forms laryngopyocele when infected.", "ORPHA ID": 2372, "Summary": ""}
{"Disease Name": "Laryngotracheoesophageal cleft type 0", "Disease Definition": "Laryngo-tracheo-esophageal cleft (LC) type 0 is a congenital respiratory tract anomaly characterized by a submucosal laryngo-tracheo-esophageal cleft with minor symptoms or an asymptomatic course.", "ORPHA ID": 280205, "Summary": "Epidemiology\nPrevalence of this form of LC is difficult to ascertain because of the mild or asymptomatic nature of the condition, but it is thought to be rare.\nClinical description\nSubjects with type 0 LC may have no obvious symptoms or mild symptoms such as occasional aspirations. Syndromic associations may be present.\nEtiology\nThe causes underlying development of this anomaly are unknown.\nDiagnostic methods\nThe anomaly is often detected during endoscopy indicated for other reasons.\nManagement and treatment\nNo specific treatment is required.\n\n                            Last update: \n                            November 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER"}
{"Disease Name": "Laryngotracheoesophageal cleft type 1", "Disease Definition": "A congenital respiratory tract anomaly characterized by a supraglottic, interarytenoid cleft above the vocal folds with moderate respiratory symptoms.", "ORPHA ID": 93938, "Summary": "Epidemiology\nPrevalence of this form of LC is difficult to ascertain because of the moderate nature of the condition, but it is thought to be rare.\nClinical description\nClinical signs include stridor, a toneless or hoarse cry, swallowing disorders such as aspirations, cough, dyspnea, cyanosis during feeding and gastro-esophageal reflux.\nEtiology\nThe causes underlying development of this anomaly are unknown.\nManagement and treatment\nIn children with mildly symptomatic type 1 LC, management includes maintaining adequate ventilation, feeding with thickened food, treatment of gastro-esophageal reflux, and maintaining a postprandial upright position. Children with moderate symptoms may also benefit from nasogastric tube feeding. Treatment initially involves conservative measures such as anti-reflux therapy, thickened feeds, and maneuvers during feeding to prevent aspiration. In cases of failure of a conservative approach, surgical correction of the cleft, using an endoscopic treatment approach, is recommended.\n\n                            Last update: \n                            November 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER"}
{"Disease Name": "Laryngotracheoesophageal cleft type 2", "Disease Definition": "A congenital respiratory tract anomaly characterized by a cleft extending below the vocal folds into the cricoid cartilage, with swallowing disorders and lung infections.", "ORPHA ID": 93939, "Summary": "Epidemiology\nPrevalence of this form of LC is unknown, but it is thought to be rare.\nClinical description\nPatients most often have aspirations and severe respiratory and swallowing disorders. Dyspnea and stridor are also possible.\nEtiology\nThe causes underlying development of this anomaly are unknown.\nManagement and treatment\nManagement includes anti-reflux treatment and nasogastric tube feeding. Treatment involves surgical correction of the cleft, often using an endoscopic treatment approach.\n\n                            Last update: \n                            November 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER"}
{"Disease Name": "Laryngotracheoesophageal cleft type 3", "Disease Definition": "A congenital respiratory tract anomaly characterized by a cleft extending through the cricoid cartilage, sometimes into the cervical trachea, with severe swallowing disorders, lung infections and pulmonary damage.", "ORPHA ID": 93940, "Summary": "Epidemiology\nPrevalence of this form of LC is unknown, but it is thought to be very rare. To date, about 30 cases have been reported in the literature. .\nClinical description\nPatients have constant aspirations and severe respiratory and swallowing disorders with a high risk of pulmonary infection.\nEtiology\nThe causes underlying development of this anomaly are unknown.\nManagement and treatment\nParenteral nutrition may be required temporarily in patients with high-grade LCs due to the high risk of aspirations. High-grade LCs often require a mid- to long-term gastrostomy, often with fundoplication. Treatment involves surgical correction of the cleft, often requiring an external approach.\nPrognosis\nThe prognosis in this type of LC is poor.\n\n                            Last update: \n                            November 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER"}
{"Disease Name": "Laryngotracheoesophageal cleft type 4", "Disease Definition": "A serious congenital respiratory tract anomaly characterized by a cleft extending into the thoracic trachea and possibly down to the carina, with respiratory distress.", "ORPHA ID": 93941, "Summary": "Epidemiology\nPrevalence of this form of LC is difficult to ascertain because of the extremely poor prognosis and death before diagnosis, but it is thought to be very rare. Fewer than 20 cases have been reported in the literature to date.\nClinical description\nPatients have constant aspirations and serious life-threatening respiratory and swallowing disorders, often associated with other severe cardiopulmonary malformations.\nEtiology\nThe causes underlying development of this anomaly are unknown.\nManagement and treatment\nParenteral nutrition may be required temporarily in patients with high-grade LCs due to the high risk of aspirations. High-grade LCs often require a mid- to long-term gastrostomy, often with fundoplication. Gastric division with a proximal drainage tube and distal gastrotomy have also been proposed. Treatment involves surgical correction of the cleft, often requiring an external cervical and/or thoracic approach, sometimes with cardiopulmonary bypass.\nPrognosis\nThe prognosis in this type of LC is very poor.\n\n                            Last update: \n                            November 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER"}
{"Disease Name": "Laryngotracheoesophageal cleft", "Disease Definition": "A laryngo-tracheo-esophageal cleft (LC) is a congenital malformation characterized by an abnormal, posterior, sagittal communication between the larynx and the pharynx, possibly extending downward between the trachea and the esophagus.", "ORPHA ID": 2004, "Summary": "Epidemiology\nThe estimated annual incidence of LC is 1/10,000 to 1/20,000 live births, accounting for 0.2% to 1.5% of congenital malformations of the larynx. These incidence rates may however be underestimated due to difficulty in diagnosing minor forms and a high mortality rate in severe forms. A slightly higher incidence has been reported in boys than in girls. No specific geographic distribution has been found.\nClinical description\nDepending on the severity of the malformation, patients may present with stridor, hoarse cry, swallowing difficulties, aspirations, cough, dyspnea and cyanosis through to early respiratory distress. Five types of laryngo-tracheo-esophageal cleft have been described based on the downward extension of the cleft, which typically correlates with the severity of symptoms: Type 0 laryngo-tracheo-esophageal cleft to Type 4 laryngo-tracheo-esophageal cleft (see these terms). LC is often associated with other congenital abnormalities/anomalies (16% to 68%), mainly involving the gastro-intestinal tract, which include laryngomalacia, tracheo-bronchial dyskinesia, tracheo-bronchomalacia (mostly in types 3 and 4), and gastro-esophageal reflux disease (GERD). The syndromes most frequently associated with an LC are Opitz/BBB syndrome, Pallister Hall syndrome, VACTERL/VATER association, and CHARGE syndrome (see these terms).\nEtiology\nLaryngeal clefts result from failure of fusion of the posterior cricoid lamina and abnormal development of the tracheo-esophageal septum. The causes of the embryological developmental anomalies leading to LC are not known but are thought to be multifactorial.\nDiagnostic methods\nThe age of diagnosis depends mainly on the severity of the clinical symptoms and therefore on the extent of the LC. Diagnosis is made either based on clinical manifestations or on investigations, such as endoscopy, X-ray, CT scan, performed for other conditions.\nDifferential diagnosis\nDifferential diagnoses include tracheo-bronchial fistula, gastro-esophageal reflux disease and neurological swallowing disorders, as well as laryngomalacia and laryngeal palsy.\nAntenatal diagnosis\nPrenatal diagnosis of LC has never been reported, although associated anomalies may be detected on fetal ultrasonography.\nGenetic counseling\nLC appears to be mostly sporadic although some familial cases with suspected autosomal dominant transmission have been reported.\nManagement and treatment\nOnce the cleft is diagnosed, it is essential to determine its length to orient the management and treatment approach. Management involves maintenance of satisfactory ventilation, prevention of secondary pulmonary complications as a result of repeated aspirations, and adequate feeding. Endotracheal intubation may be required for respiratory distress in severe cases. Treatment requires endoscopic or external surgery to close the cleft. Surgery should be performed as early as possible to avoid complications related to aspiration and gastric reflux, except in type 0 and type 1 cases in which conservative measures must first be attempted.\nPrognosis\nThe prognosis is variable depending on the severity of the LC and associated malformations. Early diagnosis and appropriate treatment and management help to reduce mortality and morbidity.\n\n                            Last update: \n                            November 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Noël GARABEDIAN  - Pr Nicolas LEBOULANGER"}
{"Disease Name": "Larynx atresia", "Disease Definition": "A rare larynx anomaly characterized by complete absence of the laryngeal lumen resulting in congenital upper airway obstruction syndrome which, without fetal or neonatal intervention, is incompatible with life. Fetal sonography shows a dilated trachea, hyperechoic lungs, pleural effusion, minimal fetal abdominal ascites or hydrops, and amniotic fluid abnormalities.", "ORPHA ID": 1202, "Summary": ""}
{"Disease Name": "Lassa fever", "Disease Definition": "Lassa fever (LF) is a potentially severe viral hemorrhagic disease caused by Lassa virus and characterized by initial fever and malaise followed by gastrointestinal symptoms and, in severe cases, bleeding, shock and multi-organ system failure.", "ORPHA ID": 99824, "Summary": "Epidemiology\nLF is endemic in West Africa. Lack of surveillance prohibits accurate estimates of incidence, but estimates range up to 300,000-500,000 infections and 5,000-10,000 cases of LF per year. Up to 80% of infections are thought to be asymptomatic or mild.\nClinical description\nAfter an incubation period of 1-3 weeks (range 3-21 days), patients typically present with the insidious onset of non-specific signs and symptoms including fever, sore throat, malaise, headache, chest pain and myalgia/arthralgia, followed rapidly by gastrointestinal manifestations (vomiting, diarrhea, abdominal pain) and, in some cases, rash. In the second week, severe cases develop neck and facial swelling, bleeding (usually from the nose and mouth), neurologic involvement, shock and multi-organ system failure. Mild-to-moderate leukopenia and thrombocytopenia are often present. Deafness is a sequelae in up to 30% of survivors.\nEtiology\nOver 25 different viruses cause viral hemorrhagic fever. LF is caused by Lassa virus, a member of the virus family Arenaviridae. Lassa virus is maintained in nature in the multimammate rat (Mastomys natalensis) and humans are infected through exposure to this rodent's excreta. Human-to-human transmission occurs through direct contact with blood or bodily fluids of infected persons.\nDiagnostic methods\nCommon diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories.\nDifferential diagnosis\nLF is difficult to distinguish from a host of other febrile illnesses, at least during its onset. Other viral hemorrhagic fevers need to be excluded, as well as malaria, typhoid fever, leptospirosis, rickettsial infection (see these terms), and meningococcemia.\nManagement and treatment\nPatients should be isolated and viral hemorrhagic fever precautions (face shields, surgical masks, double gloves, surgical gowns, and aprons) should be used to prevent nosocomial transmission. The nucleoside analogue drug ribavirin should be administered intravenously. Oral ribavirin may also be effective but is less so than the IV form. Otherwise, treatment generally follows the guidelines for severe septicemia. Anti-malarials and broad spectrum antibiotics should be considered until the diagnosis of LF can be confirmed. Persons who had unprotected contact with someone with LF should be monitored and post-exposure treatment with oral ribavirin considered.\nPrognosis\nThe case-fatality rate in hospitalized patients is typically 15-20%. Shock, bleeding, neurological manifestations, high viremia, aspartate aminotransferase (AST > 150 IU/L) and pregnancy confer a poor prognosis.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Daniel BAUSCH  -  Andrew BENNETT"}
{"Disease Name": "Late-onset citrullinemia type I", "Disease Definition": "A form of citrullinemia type I characterized clinically by adult onset of symptoms including variable hyperammonemia and less striking neurological findings which may include intense headache, scotomas, migraine-like episodes, ataxia, slurred speech, lethargy and drowsiness. Serious increased intracranial pressure may occur.", "ORPHA ID": 247573, "Summary": ""}
{"Disease Name": "Late-onset distal myopathy, Markesbery-Griggs type", "Disease Definition": "A rare, genetic, non-dystrophic myofibrillar myopathy disorder characterized by late-adult onset of distal and/or proximal limb muscle weakness with initial involvement of posterior lower leg muscles, medial gastrocnemius and soleus. Patients present with ankle weakness followed by weakness of finger and wrist extensors and later on of proximal muscles. Ambulation is usually preserved. Late-onset associated cardiomyopathy and/or neuropathy has been reported in a minority of cases.", "ORPHA ID": 98912, "Summary": ""}
{"Disease Name": "Late-onset familial hypoaldosteronism", "Disease Definition": "A rare form of familial hypoaldosteronism characterized by adult onset of subnormal plasma aldosterone with elevated plasma renin activity, hyperkalemia, metabolic acidosis, and hypotension. Signs and symptoms are typically mild, and affected individuals may be clinically asymptomatic and diagnosed only after biochemical screening.", "ORPHA ID": 556037, "Summary": ""}
{"Disease Name": "Late-onset focal dermal elastosis", "Disease Definition": "Late-onset focal dermal elastosis is a rare, acquired, dermis elastic tissue disorder characterized by a pseudoxanthoma elasticum-like papular eruption consisting of multiple, slowly progressive, asymptomatic, 2-5 mm, white to yellowish, non-follicular papules (that tend to form cobblestone plaques) predominantly distributed over the neck, axillae and flexural areas, with no systemic involvement. Skin biopsy reveals a focal increase of normal-appearing elastic tissue in the reticular dermis with no calcium deposits.", "ORPHA ID": 228227, "Summary": ""}
{"Disease Name": "Late-onset isolated ACTH deficiency", "Disease Definition": "Late-onset isolated ACTH deficiency is a rare, acquired, pituitary hormone deficiency characterized by secondary adrenal insufficiency, with normal secretion of anterior pituitary hormones, except for ACTH. Patients present with weakness, fatigue, weight loss, anorexia, vomiting/nausea, hypoglycemia, and abnormally low serum ACTH and cortisol levels. Association with autoimmune disease such as Hashimoto's thyroiditis has been described.", "ORPHA ID": 199299, "Summary": ""}
{"Disease Name": "Late-onset junctional epidermolysis bullosa", "Disease Definition": "A form of junctional epidermolysis bullosa characterized by onset in childhood or young adulthood of blistering that first occurs around nails, accompanied by nail dystrophy and shedding, and then affects the hands and feet and, to a lesser extent, the elbows, and knees. Lesions heal with atrophic scarring. Other manifestations include disappearance of dermatoglyphs and palmoplantar hyperhidrosis. Extracutaneous involvement is restricted to soft tissue abnormalities of the oral cavity and enamel defects with development of caries.", "ORPHA ID": 79406, "Summary": ""}
{"Disease Name": "Late-onset localized junctional epidermolysis bullosa-intellectual disability syndrome", "Disease Definition": "A rare junctional epidermolysis bullosa subtype characterized by late-onset blistering surrounded by erythema and localized on the anterior aspect of the lower legs, associated with dystrophic toenails, tooth enamel defects and mild to severe intellectual disability. Lens subluxation and mild facial dysmorphism (with short midface, prognatism and thin upper lip vermilion) are additional reported features. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 231556, "Summary": ""}
{"Disease Name": "Late-onset retinal degeneration", "Disease Definition": "Late-onset retinal degeneration is an inherited retinal dystrophy characterized by delayed dark adaptation and nyctalopia and drusen deposits presenting in adulthood, followed by cone and rod degeneration that presents in the sixth decade of life, which leads to central vision loss. Anterior segment features such as peripupillary iris transillumination defects and abnormally long anterior zonular insertions are also observed. Choroidal neovascularization and glaucoma may occur in the late stages of the disease.", "ORPHA ID": 67042, "Summary": ""}
{"Disease Name": "Lateral meningocele syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by multiple lateral meningoceles, distinctive facial dysmorphism (including hypertelorism, downslanting palpebral fissures, posteriorly rotated ears, micrognathia, and high, narrow palate, among others), and skeletal abnormalities (e. g. vertebral anomalies, wormian bones, short stature, and scoliosis). Multiple additional features may present, such as conductive hearing impairment, hypotonia, and connective tissue and urogenital abnormalities. Cognition is usually normal.", "ORPHA ID": 2789, "Summary": ""}
{"Disease Name": "Lathosterolosis", "Disease Definition": "Lathosterolosis is an extremely rare inborn error of sterol biosynthesis characterized by facial dysmorphism, congenital anomalies (including limb and kidney anomalies), failure to thrive, developmental delay and liver disease.", "ORPHA ID": 46059, "Summary": "Epidemiology\nOnly 4 cases have been reported in the literature to date.\nClinical description\nMicrocephaly is present at birth along with hypotonia, failure to thrive and facial dysmorphic features such as bitemporal narrowing, ptosis, puffy cheeks, and micrognathia. Limb anomalies that have been reported include postaxial polydactyly of upper or lower limbs (mainly feet), bilateral syndactyly between the 2nd and 3rd or 2nd and 4th toes and bilateral club feet. Developmental delay and learning disability starting in early childhood have been noted in all patients. Additional anomalies have also been reported such as corneal clouding, cataract, conductive hearing loss, gingival hypertrophy, ambiguous genitalia, horseshoe kidney (see this term) and neurological manifestations (i.e. myoclonus). Liver disease seen in patients ranges from hypertransaminasemia to progressive cholestasis and can lead to end stage hepatic disease, occurring in childhood.\nEtiology\nLathosterolosis is due to mutations in the SC5D gene (11q23.3). A mutation in this gene leads to a deficiency in 3-beta-hydroxysteroid-delta-5-desaturase, which is necessary in the conversion of lathosterol into 7-dehydrocholesterol. This prevents the synthesis of cholesterol, which among other functions acts as a structural lipid, a precursor for bile acids and steroid hormones, and is necessary for the maturation of hedgehog morphogens during embryonic development.\nDiagnostic methods\nDiagnosis is based on clinical and biochemical findings. An elevation of lathosterol by gas chromatography/mass spectroscopy (GC/MS) is noted in both skin fibroblasts and plasma. The levels of 7-dehydrocholesterol and cholesterol are normal or low. Molecular genetic testing revealing mutations in the SC5D gene confirms the diagnosis.\nDifferential diagnosis\nThe main differential diagnosis is Smith-Lemli-Opitz syndrome (see this term) that shares many clinical features with lathosterolosis but that can be excluded with biochemical and genetic testing.\nAntenatal diagnosis\nPrenatal diagnosis is feasible if the mutations are known but it has never been performed given the rarity of the disease.\nGenetic counseling\nLathosterolosis is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and they therefore have a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment involves cholesterol supplementation and reduction of 7-hydrocholesterol. Simvastin, a 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitor, has been proven to be beneficial in normalizing the lathosterol level in one patient. Liver transplantation was successful in normalizing liver function and cholesterol levels in a patient who had developed end stage liver disease. Moreover, it appeared to improve neurocognitive functions. Regular opthalmological evalutations and ultrasound monitoring of the liver are recommended.\nPrognosis\nThe prognosis is poor but treatment appears to prolong life and arrest progression of neurological damage.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Nicola BRUNETTI PIERRI  - Pr Giancarlo PARENTI"}
{"Disease Name": "Lattice corneal dystrophy type I", "Disease Definition": "Type I lattice corneal dystrophy (LCDI) is a frequent form of stromal corneal dystrophy (see this term) characterized by a network of delicate interdigitating branching filamentous opacities within the cornea with progressive visual impairment and no systemic manifestations.", "ORPHA ID": 98964, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is unknown. It is one of the more common forms in Western countries but has been reported worldwide.\nClinical description\nLesions mostly develop bilaterally towards the end of the 1st decade of life, but may develop in middle age, or rarely in infancy. LCDI is slowly progressive and usually results in substantial discomfort and visual impairment before the 6th decade. Corneal sensation is often diminished.\nEtiology\nMost cases of LCDI are caused by mutations in the multifunctional TGFBI gene (5q31).\nDiagnostic methods\nThe interwoven linear opaque filaments have some resemblance to nerves, but may not be observed in all affected members of families with the condition. Recurrent corneal erosions may precede the corneal opacities and even appear in individuals lacking recognizable stromal disease. Amyloid deposits are found throughout the corneal stroma. Linear and other shaped opaque areas accumulate particularly within the central corneal stroma, while the peripheral cornea remains relatively transparent.\nGenetic counseling\nAn autosomal dominant pattern of inheritance has been reported.\nManagement and treatment\nA corneal graft may be necessary by 20 years of age, but is usually not indicated until after the 4th decade. The outcome of penetrating keratoplasty (PK) is excellent, but amyloid may deposit in the grafted donor tissue after 2 to 14 years.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Laubry-Pezzi syndrome", "Disease Definition": "Laubry-Pezzi syndrome is a rare, non-syndromic, congenital heart malformation characterized by the prolapse of an aortic valve cusp into a subjacent ventricular septal defect due to Venturi effect, resulting in aortic regurgitation. Patients typically present with symptoms of progressive aortic valve insufficiency, such as shortness of breath, heart palpitations, chest pain and exercise intolerance.", "ORPHA ID": 99094, "Summary": ""}
{"Disease Name": "Laurence-Moon syndrome", "Disease Definition": "A very rare genetic multisystemic disorder characterized by progressive neurological, ophthalmologic and endocrine manifestations leading to severe handicap.", "ORPHA ID": 2377, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nThe neurological manifestations include peripheral neuropathy, spastic paraplegia and cerebellar ataxia. The symptoms progressively worsen for patients over time. The ophthalmologic manifestations are caused by chorioretinal dystrophy presenting widespread chorioretinal atrophy (thinning of the retina, loss of retinal architecture and choroid vessels) under fundus observation. The onset of visual impairment ranges widely from 1 year old to 60 years old. Hypogenitalism is present at birth due to hypogonadotrophic hypogonadism with primary amenorrhea, small penis and testes, or absence of pubic hair/breast development. Related growth delay during adolescence can also occur.\nEtiology\nLikely pathogenic or pathogenic variants in the PNPLA6 gene have been identified in patients with Laurence-Moon syndrome (LMS). The PNPLA6 gene codes for the patatin-like phospholipase domain-containing protein 6, also called neuropathy target esterase (NTE), a 1375 amino acids long protein (UniProt accession number: Q8IY17). The protein is composed of 5 domains including a single pass transmembrane domain (N-terminus), 3 cyclic nucleotide-binding domains (cNMP) and a NEST domain (NTE-esterase domain) at the C-terminus. The protein is a serine hydrolase that functions as a phospholipase B by catalyzing the deacylation of glycerophospholipids. It has also been shown to have a strong lysophospholipase activity. Altogether it plays a major role in phospholipid homeostasis, membrane trafficking, and axonal integrity in cells. Previously, the terms Laurence-Moon-Biedl syndrome or Laurence-Moon-Bardet-Biedl syndrome were used for this disease. However, the association Laurence-Moon/Bardet-Bield is no longer relevant given the different underlying gene mechanisms. It should be underlined that this condition is now clearly considered as part of the continuous spectrum of PNPLA6-related disorders linked to NTE activity. Recent evidence seems to inversely correlate the level of NTE activity with disease severity and tissue onset.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and confirmed by genetic testing including sequencing of the PNPLA6 gene (by direct Sanger sequencing or panel/exome next generation sequencing).\nDifferential diagnosis\nThe main differential diagnoses are the other PNPLA6-related disorders such as autosomal recessive spastic paraplegia type 39, cerebellar ataxia-hypogonadism syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome and trichomegaly-retina pigmentary degeneration-dwarfism syndrome that share all or a subset of the clinical manifestations, sometimes with a different age of onset.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant(s) have previously been identified in an affected family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment is only symptomatic and depends on the severity of the neurological manifestations. Optical aids can be provided to manage visual impairment.\nPrognosis\nData on prognosis is limited for patients with PNPLA6-related disorders but recent evidence has shown a highly dependent relation between the NTE activity and severity of the disease and/or tissue onset.\n\n                            Last update: \n                            April 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Hélène DOLLFUS | ERN-EYE* - Dr Jean MULLER | ERN-EYE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Laurin-Sandrow syndrome", "Disease Definition": "Laurin-Sandrow syndrome (LSS) is characterised by complete polysyndactyly of the hands, mirror feet and nose anomalies (hypoplasia of the nasal alae and short columella), often associated with ulnar and/or fibular duplication (and sometimes tibial agenesis). It has been described in less than 20 cases. Some cases with the same clinical signs but without nasal defects have also been reported, and may represent the same entity. The etiology of LSS is unknown. Different modes of inheritance have been suggested.", "ORPHA ID": 2378, "Summary": ""}
{"Disease Name": "LCAT deficiency", "Disease Definition": "LCAT (lecithin-cholesterol acyltransferase) deficiency is a rare lipoprotein metabolism disorder characterized clinically by corneal opacities, and sometimes renal failure and hemolytic anemia, and biochemically by severely reduced HDL cholesterol.", "ORPHA ID": 650, "Summary": "Epidemiology\nPrevalence of LCAT deficiency is unknown. About 125 cases have been reported to date worldwide. Most cases were reported in Europe, Japan and Canada.\nClinical description\nAge of onset is variable but most patients are diagnosed during adulthood. Two familial forms of LCAT deficiency have been reported: familial LCAT deficiency (FLD, see this term) characterized by corneal opacities, anemia and renal insufficiency, and Fish-eye disease (FED, see this term) characterized by corneal opacities and sometimes atherosclerosis.\nEtiology\nLCAT deficiency is caused by deficient or absent catalytic activity of the LCAT enzyme, which catalyzes the formation of cholesterol esters in lipoproteins and is encoded by the LCAT gene (16q22.1). Accumulation of unesterified cholesterol in the body, e.g. in the cornea, erythrocytes and kidneys, is thought to underlie the clinical manifestations. To date, more than 85 mutations in the LCAT gene have been identified. LCAT deficiency follows an autosomal recessive pattern of inheritance.\n\n                            Last update: \n                            March 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Laura CALABRESI  - Pr Guido FRANCESCHINI"}
{"Disease Name": "Lead poisoning", "Disease Definition": "Lead poisoning is defined as acute or chronic exposure to lead resulting in lead accumulation (blood lead concentration (BLC) >5 ug/dL) that can affect every organ system in the body and to which children are more susceptible. Clinical manifestations depend on the amount and duration of exposure and include abdominal pain, colic, constipation, lead line on gingival tissue, arthralgia, myalgia, peripheral neuropathy, fatigue, irritability, anemia, chronic nephropathy and hypertension. In children, even low levels of exposure (BLC <5 ug/dL) is reported to lead to irreversible effects such as loss of cognition, shortening of attention span, alteration of behavior, dyslexia, attention deficit disorder, hypertension, renal impairment, immunotoxicity and toxicity to the reproductive organs.", "ORPHA ID": 330015, "Summary": ""}
{"Disease Name": "Leber congenital amaurosis", "Disease Definition": "Leber congenital amaurosis (LCA) is a retinal dystrophy defined by blindness and responses to electrophysiological stimulation (Ganzfeld electroretinogram (ERG)) below threshold, associated with severe visual impairment within the first year of life.", "ORPHA ID": 65, "Summary": "Epidemiology\nThe prevalence of LCA is 1/50,000 - 1/33,000 live births and accounts for 5% of all retinal dystrophies and 20% of blindness in school age children.\nClinical description\nLCA is characterized by severely reduced visual acuity (less or equal 20/400) or blindness within in the first year of life. Sluggish pupillary responses, roving eye movement, photophobia, high hyperopia, nystagmus, convergent strabismus, or keratoconus may occur depending on the genetic cause. The Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing is pathognomonic. LCA may be associated with mutations in genes linked to syndromes presenting with neurodevelopmental delay, intellectual disability, oculomotor apraxia-type behavior (difficulty moving the eye) and renal dysfunction.\nEtiology\nTo date, mutations in genes encoding retina specific proteins have been reported to cause LCA. This includes GUCY2D (17p13.1), CEP290 (12q21.33), RPGRIP1 (14q11.2), RDH12 (14q24.1), SPATA7 (14q31.3), AIPL1 (17p13.1), RD3 (1q32.3), CRB1 (1q31-q32.1), CRX (19q13.3), IMPDH1 (7q31.3-q32), IQCB1 (3q21.1), KCNJ13 (2q37), LCA5 (6q14), NMNAT1 (1p36.22), and TULP1 (6p21.3). These mutations cause severe functional impairment or are mostly related to retinal dystrophies. Mutations in CRX or IMPDH1 genes may cause an early and severe onset disease. Patients with GUCY2D mutations present with very slow progressive morphological degeneration and a mostly functional defect.\nDiagnostic methods\nDiagnosis relies on clinical observation which shows a pupillary response that may be sluggish or near-absent in early life; on funduscopy findings revealing attenuation of retinal vessels along with variable signs of retinal degeneration (from almost unremarkable to an overall granulated appearance). Diagnosis is confirmed by sedated ERG close to or below threshold. Molecular diagnosis is indispensable and may be performed using an arrayed primer extension (APEX) chip (tests a subset of known mutations in known LCA genes; diagnosis achieved in 50-70% of cases) and next generation sequencing (NGS) (covering the whole sequence of the known reported genes; this is the preferable method covering up to 90% of patients). Confirmation of identified mutations and segregation analysis in the parents by Sanger sequencing is the final step.\nDifferential diagnosis\nDifferential diagnosis includes retinitis pigmentosa, Alström syndrome, Joubert syndrome, Stargardt disease, Senior-Loken syndrome, Conorenal syndrome and infantile neuronal ceroid lipofuscinosis. Cortical blindness is a frequent misdiagnosis when there is limited access to functional testing or high resolution morphological examination.\nAntenatal diagnosis\nPrenatal diagnosis may be offered by specialized laboratories for at-risk couples with identified disease-causing mutations.\nGenetic counseling\nLCA is typically an autosomal recessive inherited disease. Rarely, mutations within CRX or IMPDH1 genes are inherited in an autosomal dominant manner that may overlap with the diagnosis of LCA.\nManagement and treatment\nCurrently LCA is an incurable disease. Treatment is mainly supportive and includes correction of refractive error and use of low-vision aids. Repeated poking and pressing on the eyes should be discouraged. Periodic ophthalmic evaluation and assessment of the presence of amblyopia, glaucoma, or cataract should be achieved. Therapies are presently being investigated, including gene therapy (particularly for RPGRIP and CEP290) and optogenetics (genetic targeting of light-sensing molecules to residual cells in a degenerate retina).\nPrognosis\nVision commonly declines with age until complete blindness is observed most often latest by the third or fourth decade of life.\n\n                            Last update: \n                            July 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Birgit LORENZ  - Dr Markus PREISING"}
{"Disease Name": "Leber hereditary optic neuropathy", "Disease Definition": "A rare hereditary optic neuropathy characterized by sudden onset, painless central vision loss, loss of retinal ganglion cells and optic atrophy.", "ORPHA ID": 104, "Summary": "Epidemiology\nThe prevalence of the disease is estimated at 1/27,000 - 1/54,000 in Europe. Lower prevalence is reported in Australia (1 in 113,300) and in Serbia (1/526,000). The disease predominantly affects males, who are 4-5 times more likely to be affected and to lose vision.\nClinical description\nWhilst carriers may remain asymptomatic, there may be recognizable changes on ophthalmological examination. Clinical onset of Leber hereditary optic neuropathy (LHON) is typically in young adulthood (age 18-30) and is divided into subacute (< 6 months from onset) and dynamic (6-12 months) stages. Typically, onset is with sudden, painless central vision loss that can occur in both eyes simultaneously or sequentially with vision loss in the second eye occurring weeks to months after the first eye. Visual loss generally stabilizes within 4 to 6 months. However, many patients will continue to show expansion of their central scotoma, producing a more profound level of blindness over a period of years (chronic stage). Extraocular symptoms (motor disorders, dystonia, postural tremor and cerebellar ataxia) are uncommon, but when present are known as Leber plus disease.\nEtiology\nLHON is caused by mutations in the mitochondrial DNA (mtDNA). Over 90% have been identified to occur at nucleotide positions 3460, 11778 or 14484, respectively corresponding to the mtDNA respiratory chain complex I subunit genes MT-ND1, MT-ND4, and MT-ND6. Other genetic or epigenetic factors may have an effect on the development of this disease; in addition, the gene NDUFS2 (1q23.3) may be associated with a LHON-like phenotype.\nDiagnostic methods\nThe diagnosis is based on patient and family history, in addition to an ophthalmologic examination and genetic testing for mtDNA. Baseline examination should include visual acuity, color vision, fundus examination, visual fields, and optical coherence tomography (OCT) imaging. Swelling of the optic nerve head, vascular tortuosity, peripapillary telangiectasia, microangiopathy and central scotomas on visual field testing are all signs of LHON. OCT confirms the swelling of the retinal nerve fiber layer. Red-green dyschromatopsia during color vision testing, and pseudopapilledema during fluorescein angiography are also observed. Snellen vision acuities of 20/200 or worse are typical.\nDifferential diagnosis\nDifferential diagnosis includes optic neuritis, autosomal dominant optic atrophy (DOA), Wolfram syndrome, metabolic optic neuropathies (toxic, nutritional, and combinations), chiasmal tumors, and anterior ischemic optic neuropathy.\nAntenatal diagnosis\nThe prenatal presence of mtDNA pathogenic variant for LHON does not predict occurrence of disease, age of onset, or vision loss.\nGenetic counseling\nLHON is a maternally-inherited disease. Female carriers will pass the mutation to all their children, while male carriers will not pass the mutation to any children. Genetic counseling is recommended for affected families, though it is complicated by incomplete penetrance of pathogenic variants. Although, extremely rare, inheritance is autosomal recessive for NDUFS2.\nManagement and treatment\nLow-vision aids are the primary supportive care offered to patients. It is important that patients avoid toxic exposures such as alcohol, smoke (tobacco and environmental) and certain antibiotics that interfere with mitochondrial oxidative phosphorylation. Several compounds have shown positive results in moderating the visual loss. Idebenone (approved in the USA and Europe), shows a modest visual improvement after one year, and should be started as soon as possible in patients presenting within subacute and dynamic stages of disease (< 12 months). There is insufficient evidence at this time for treatment in chronic stage patients. Multiple clinical trials for other compounds and gene therapies are ongoing; notably EPI-743 has demonstrated efficacy in a small open label study for LHON.\nPrognosis\nThe age of symptom onset and the causative mutation are factors that determine the disease outcome. Younger patients have a more favorable prognosis. Some patients, especially with the 14484 mutation, show spontaneous partial recovery 1-2 years after onset; whilst visual field improvement is usually incomplete, the recovery in visual acuity can be dramatic. In 30 to 50 % of male carriers and 80 to 90 % of female carriers, blindness will not ensue. Complete blindness is rare.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Elise MA  - Pr Alfredo SADUN"}
{"Disease Name": "Leber plus disease", "Disease Definition": "A rare inherited mitochondrial disease characterized by the clinical features of Leber hereditary optic neuropathy in combination with other systemic or neurological abnormalities. These abnormalities include: postural tremor, motor disorder, multiple sclerosis-like syndrome, spinal cord disease, skeletal changes, Parkinsonism with dystonia, anarthria, motor and sensory peripheral neuropathy, spasticity, mild encephalopathy, and cardiac arrhythmias.", "ORPHA ID": 99718, "Summary": ""}
{"Disease Name": "Ledderhose disease", "Disease Definition": "A rare, benign, superficial fibromatosis disease characterized by single or multiple, uni- or bilateral, slow-growing, round, firm nodules typically located on the medial portion of the plantar aponeurosis, with no calcification. Patients are often asymptomatic or may present with foot pain, difficulty to walk or stand and, rarely, toe contractures. Histopathology reveals dense fibrocellular tissue with parallel and nodular arrays of fibrocytes and fibrillar collagen with a distinctive cork-screw morphology and no atypia.", "ORPHA ID": 199251, "Summary": ""}
{"Disease Name": "Left sided atrial isomerism", "Disease Definition": "A rare cardiac malformation characterized by both atrial appendages having the morphology of the left atrial appendage. It is associated with other anomalies of the heart, systemic and pulmonary veins, and other organ systems, including the gastrointestinal, respiratory, and genitourinary tract, as well as the spleen and immune system.", "ORPHA ID": 566862, "Summary": ""}
{"Disease Name": "Left ventricular noncompaction", "Disease Definition": "A rare cardiomyopathy characterized anatomically by prominent left ventricular trabeculae and deep intratrabecular recesses causing progressive systolic and diastolic dysfunction, conduction abnormalities, and occasionally thromboembolic events.", "ORPHA ID": 54260, "Summary": ""}
{"Disease Name": "Legg-Calvé-Perthes disease", "Disease Definition": "A rare disorder characterized by uni- or bilateral avascular necrosis (AVN) of the femoral head in children.", "ORPHA ID": 2380, "Summary": "Epidemiology\nReported annual incidences vary greatly, from 1/250,000 in Hong Kong and 1/18,000 in the UK, to 1/3,500 in the Faroe Islands. Legg-Calvé-Perthes disease (LCPD) affects children between 2 and 12 years of age, but it is more prevalent among children of 5-6 years, and more common in boys.\nClinical description\nThe initial symptoms are usually a limping gait, pain in the hip, thigh or knee, and a reduced range of hip motion. Later in the disease course, leg length discrepancy, as well as atrophy of musculature around the hip can be observed. The active phase of the disease can last for several years, and during this phase the femoral head becomes partially or completely necrotic and gradually deformed. This is followed by new bone formation (re-ossification) in the epiphysis and eventual healing. The final deformity can vary from a nearly normal joint configuration to an extensive deformation with severe flattening and subluxation of the femoral head, broadening of the femoral neck, and a deformed and dysplastic acetabulum, which in turn can lead to early-onset osteoarthritis.\nEtiology\nThe etiology of LCPD remains obscure. It is generally accepted that one or more infarctions of the femoral head due to interruption of vascular supply eventually cause the deformity, however, there are several theories concerning the cause of this interruption. Several contributory factors have also been suggested: delayed skeletal maturity, impaired and disproportionate growth, short stature, low birth weight, social and economic deprivation and trauma, as well as an association with congenital anomalies. It has also been proposed that coagulation system disorders could cause thrombophilia and/or hypofibrinolysis and lead to thrombotic venous occlusion with subsequent AVN of the femoral head in children. Mutations in the COL2A1 gene (12q12-q13.2) have recently been identified in familial cases of AVN of the femoral head (see this term) and LCPD.\nDiagnostic methods\nDiagnosis is made by conventional radiography in frontal and lateral projections. Scintigraphy and ultrasound can be of value in selected cases and MRI can be useful in the early stages of the disease to distinguish LCPD from other hip disorders.\nDifferential diagnosis\nDifferential diagnoses include Meyers dysplasia, multiple epiphyseal dysplasia and spondyloepiphyseal dysplasia (see these terms).\nManagement and treatment\nThe main aim of treatment is to contain the femoral head within the acetabulum, either using an abduction brace or through surgical interventions (femoral or pelvic osteotomy). A recent study suggested that femoral osteotomy gives significantly better results than treatment with braces (specifically the Scottish Rite abduction orthosis).\nPrognosis\nPrognosis is variable and several factors are of prognostic importance, such as the extent of femoral head necrosis and residual deformity. The more deformed the femoral head is during healing, the greater the risk of osteoarthritis later in life. Total hip replacement in early adulthood may be required in some cases. A younger age at diagnosis is generally accepted to be associated with a better outcome.\n\n                            Last update: \n                            March 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Ola WIIG"}
{"Disease Name": "Legionnaires disease", "Disease Definition": "A rare form of Legionellosis characterized by a severe, potentially fatal, pneumonia.", "ORPHA ID": 549, "Summary": "Epidemiology\nThe annual notification rate in 2009 from 25 EU Member States amounted to approximately 1/90,000. In France the annual incidence is around 1/50,000.\nClinical description\nLD has an incubation period of 2-10 days with fatigue and weakness often being the first signs of the disease. It manifests as pneumonia characterized by fever, cough, sputum production and shortness of breath. Other symptoms can include diarrhea, myalgia, headaches, confusion/delirium and nausea. LD is most severe in elderly and immunocompromised people (due to immunosuppressive therapy, especially with corticosteroids, transplants, hematologic malignancy or cancer), who are an ever-increasing risk group for infection. Other risk factors for LD include cigarette smoking, age over 50, male gender, diabetes, and chronic heart, lung or kidney disease.\nEtiology\nLD is caused by Legionella pneumophila (most commonly serogroup 1), a bacteria found in water and wet soil. Humans are infected by inhaling aerosols containing the bacteria, most commonly from showers, hot tubs, saunas or other bathing facilities. The same bacteria are responsible for Pontiac fever (PF; see this term) a mild form of LD. LD occurs sporadically and in outbreaks, with the sporadic form accounting for 65 to 80% of cases. Outbreaks are predominantly linked to contaminated aerosols from wet cooling systems or occur in hospitals, nursing homes or hotels.\nDiagnostic methods\nEU case definitions have been agreed upon associating clinical and laboratory criteria for case confirmation. Any person with pneumonia and one of the following criteria: isolation of Legionella spp.  from respiratory secretions or any normally sterile site, detection of L. pneumophila antigen in urine or L. pneumophila serogroup 1-specific antibody response, are given a diagnosis of LD. Detection of Legionella spp.  nucleic acid in a clinical specimen has been added as criteria for probable cases.\nDifferential diagnosis\nThe disease has no particular clinical features that clearly distinguish it from other types of pneumonia. Other bacterial (Streptococcus pneumonia, Staphylococcus aureus and Haemophilus influenza) or viral infections that cause pneumonia need to be ruled out.\nManagement and treatment\nTreatment involves antibiotics (usually macrolides and quinolones). Hospitalization is often required. Ventilatory support may be necessary in those with serious breathing difficulties. Legionella surveillance programs are based on notification of cases at a national and European level and on legislation for controlling the development of the bacteria in the aquatic environment.\nPrognosis\nIn most cases, LD is treated and cured with antibiotics but in those with compromised immune systems or underlying health conditions the prognosis can be poor. The overall case fatality rate is around 10-15%.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Sophie JARRAUD"}
{"Disease Name": "Legius syndrome", "Disease Definition": "Legius syndrome, also known as NF1-like syndrome, is a rare, genetic skin pigmentation disorder characterized by multiple café-au-lait macules with or without axillary or inguinal freckling.", "ORPHA ID": 137605, "Summary": "Epidemiology\nThe prevalence of Legius syndrome is not known. Fewer than 200 cases have been reported to date. Prevalence may be higher than expected due to misdiagnosis of cases as neurofibromatosis type 1 (NF1, see this term). The incidence of NF1 is reported to be 1/3000, and about 2% of patients fulfilling diagnostic criteria for NF1 are found to have the genetic mutation underlying Legius syndrome (SPRED1).\nClinical description\nThe clinical presentation of Legius syndrome is very similar to that of NF1. Patients typically present with multiple café-au-lait spots sometimes associated with intertriginous freckling, but lack Lisch nodules, optic pathway gliomas, bone abnormalities, neurofibromas or other tumor manifestations. The number of café-au-lait macules tends to increase with age during childhood. Other less common manifestations include short stature, macrocephaly, Noonan-like facies, pectus excavatum/carinatum, lipomas, hypopigmented macules, vascular lesions, learning disabilities, attention deficit/hyperactivity disorder (ADHD), and developmental delay.\nEtiology\nLegius syndrome is caused by heterozygous inactivating mutations in the SPRED1 gene (15q14), involved in regulation of the RAS-MAPK signal transduction pathway. Nearly 100 different mutations in this gene have been identified. The proportion of cases related to de novo mutations is not yet known. No genotype-phenotype correlations have been found.\nDiagnostic methods\nAbout 50% of patients with Legius syndrome fulfill the diagnostic criteria for NF1, but they have a far milder phenotype compared to NF1 patients. Diagnosis based solely on the presence of clinical features is difficult, given the overlap with other disorders characterized by multiple café-au-lait spots. The presence of characteristic clinical signs in parents of affected individuals is supportive of diagnosis. However, molecular genetic testing is required to confirm the diagnosis and testing is available on a clinical basis.\nDifferential diagnosis\nLegius syndrome is differentiated from NF1 by the absence of the non-pigmentary clinical manifestations seen in this disorder (i.e. Lisch nodules, neurofibromas, optic glioma, bone abnormalities). Correct diagnosis is essential because of the differences in prognosis and long-term monitoring between Legius syndrome and NF1. Other disorders to consider include Noonan syndrome, Noonan syndrome with lentigines (LEOPARD syndrome), and McCune-Albright syndrome (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible and requires prior identification of the disease-causing mutation in the family.\nGenetic counseling\nLegius syndrome follows an autosomal dominant pattern of inheritance. Genetic counseling should be provided to affected families.\nManagement and treatment\nDrug therapy should be considered for the behavioral manifestations of the disorder (ADHD). Physical, speech, and occupational therapy is recommended for those with developmental delay and educational support for those with learning difficulties.\nPrognosis\nGiven the current knowledge of disease manifestations and complications, the prognosis for patients with Legius syndrome is considered to be very good.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Eric LEGIUS"}
{"Disease Name": "Leigh syndrome", "Disease Definition": "A progressive neurological disease defined by specific neuropathological features associating brainstem and basal ganglia lesions.", "ORPHA ID": 506, "Summary": "Epidemiology\nIts prevalence at birth has been estimated at approximately 1 in 36 000.\nClinical description\nTypical onset of symptoms occurs before the age of 12 months but, in rare cases, the disease may manifest during adolescence or even early adulthood. Loss of motor milestones, hypotonia with poor head control, recurrent vomiting, and a movement disorder are common initial symptoms. Pyramidal and extrapyramidal signs, nystagmus, breathing disorders, ophthalmoplegia and peripheral neuropathy are often noted later. Epilepsy is relatively uncommon.\nEtiology\nLeigh syndrome has multiple causes, all of which imply a defect in aerobic energy production, ranging from the pyruvate dehydrogenase complex to the oxidative phosphorylation pathway. Most mutations are located in the nuclear genome. The genes identified to-date encode either one of the subunits of the pyruvate dehydrogenase (PDH) complex, one of the subunits of respiratory complexes I or II, or a protein involved in the assembly of respiratory complex IV. Between 10 and 30% of individuals with Leigh syndrome carry mitochondrial DNA mutations, the most common of which are the 8993T>G or 8993T>C mutations in the MTATP6 gene encoding a subunit of ATP synthase. These individuals are often referred to as having maternally inherited Leigh syndrome (MILS). They harbor very high proportions (above 95%) of the mitochondrial DNA mutation. Lower proportions of this mutation are associated with a milder phenotype such as the NARP syndrome (Neurogenic Ataxia and Retinitis Pigmentosa). The genetic cause of a number of cases of Leigh syndrome remains unknown, despite the presence of a specific biochemical defect in some of the cases.\nDiagnostic methods\nDiagnosis of the syndrome relies on brain imaging showing the specific topology of the lesions in the brainstem and basal ganglia, often in association with leucodystrophy and cerebral atrophy. Lactate levels are constantly increased in cerebrospinal fluid, and often in the blood. The etiological diagnosis relies on biochemical investigations looking for the underlying defect in energy production. Pyruvate dehydrogenase is assayed in leucocytes or in cultured skin fibroblasts, whereas oxidative phosphorylation is more completely analyzed in muscle or liver.\nAntenatal diagnosis\nPrenatal diagnosis may be possible in cases with a known genetic anomaly in a nuclear gene. It is much more difficult when the alteration involves a mitochondrial DNA gene due to heteroplasmy (coexistence of mitochondria with altered genome and normal mitochondria). When only the biochemical defect has been identified, prenatal diagnosis is made complex by potential technical difficulties in biochemical analysis of amniocytes, as well as the possibility that these cells do not express the defect detected in skin fibroblasts.\nGenetic counseling\nIn the majority of cases, Leigh syndrome is transmitted in an autosomal recessive manner. However, PDH defects due to subunit E1alpha anomalies are X-linked and the mitochondrial DNA alterations are maternally transmitted. Genetic counseling depends on the identification of the cause of the disease.\nManagement and treatment\nThere is no specific treatment for Leigh disease. Several different vitamins or cofactors, including vitamin B1 (thiamine), vitamin B2 (riboflavin) and coenzyme Q10, have been proposed and may be tried systematically. Their efficacy depends upon the underlying defect. A ketogenic diet has been proposed for patients with pyruvate dehydrogenase deficiency.\nPrognosis\nThe prognosis of Leigh syndrome is poor, with a life expectancy reduced to only a few years for most patients.\n\n                            Last update: \n                            July 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Anne LOMBES"}
{"Disease Name": "Leiomyosarcoma of small intestine", "Disease Definition": "Small bowel leiomyosarcoma is a rare type of small bowel malignancy, originating in the smooth muscle cells within the muscularis propria or the muscularis mucosa, most often found in the jejunum, and presenting with gastrointestinal bleeding and anemia and sometimes with other non-specific symptoms such as vomiting, nausea, abdominal pain and weakness and spreading to regional lymph nodes in 14% of cases.", "ORPHA ID": 104076, "Summary": ""}
{"Disease Name": "Leiomyosarcoma of the cervix uteri", "Disease Definition": "Leiomyosarcoma of the cervix uteri is a rare, malignant mesenchymal tumor of smooth muscle origin, macroscopically appearing as a large, poorly circumscribed mass, often protruding from the cervical canal or expanding it circumferentially. The most common presenting symptoms are vaginal discharge or bleeding, pain in the lower abdomen and a bulky cervical mass. There is a reported tendency to metastatsize hematogenously, especially to the lungs, peritoneum, bones and the liver.", "ORPHA ID": 213807, "Summary": ""}
{"Disease Name": "Leiomyosarcoma of the corpus uteri", "Disease Definition": "Leiomyosarcoma of the corpus uteri is a rare, malignant, mesenchymal tumor of smooth muscle origin characterized, histologically, by spindle and/or pleomorphic cells, often forming disorganized fascicles, with tumor cell necrosis and, macroscopically, by a large, soft, usually intramural mass with irregular borders and necrotic and hemorrhagic areas, located in the uterus. Presenting signs and symptoms typically include dysfunctional vaginal bleeding, vaginal discharge, palpable pelvic mass and/or pelvic pain/pressure. Changes in bowel habits, frequent or painful urination and hematuria may also be associated.", "ORPHA ID": 213625, "Summary": ""}
{"Disease Name": "Leiomyosarcoma", "Disease Definition": "A rare soft tissue sarcoma characterized by a malignant space-occupying lesion most commonly located in the retroperitoneum or the inferior vena cava, but also other soft tissues, and composed of cells showing distinct features of smooth muscle cells. The tumor presents with mass effect depending on the location. It is capable of both local recurrence and distant metastasis, while lymph node metastasis is rare. Prognosis largely depends on tumor location and size.", "ORPHA ID": 64720, "Summary": ""}
{"Disease Name": "Leishmaniasis", "Disease Definition": "A parasitic disease caused by different species of the genus Leishmania, transmitted through the bite of hematophagous female phlebotomine sand flies. The clinical spectrum ranges from asymptomatic to clinically overt disease which can remain localized to the skin or disseminate to the upper oral and respiratory mucous membranes or throughout the reticulo-endothelial system. Three main clinical syndromes have been described: visceral (or Kala-Azar; with fever, weight loss, hepatosplenomegaly), cutaneous, and mucocutaneous leishmaniasis (cutaneous or mucocutaneous ulceration).", "ORPHA ID": 507, "Summary": ""}
{"Disease Name": "Lelis syndrome", "Disease Definition": "Lelis syndrome is characterised by the association of ectodermal dysplasia (hypotrichosis and hypohidrosis) with acanthosis nigricans.", "ORPHA ID": 140936, "Summary": "Epidemiology\nSo far, only eight cases have been described in the literature.\nClinical description\nOther clinical features may include palmoplantar hyperkeratosis, nail dystrophy, intellectual deficit and hypodontia.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            July 2008"}
{"Disease Name": "Lemierre syndrome", "Disease Definition": "Lemierre syndrome is a rare, potentially lethal, oropharyngeal infectious disease occurring in immunocompetent adolescents and young adults that is mainly due to Fusobacterium necrophorum and that is characterized by septic thrombophlebitis of the internal jugular vein that leads to septic, usually pulmonary, embolism, associated with ENT (ear, nose, and throat) infection that manifests with fever, neck pain, and tonsillopharyngitis.", "ORPHA ID": 137839, "Summary": ""}
{"Disease Name": "Lennox-Gastaut syndrome", "Disease Definition": "A rare, severe early-onset developmental epileptic encephalopathy characterized by the triad of intellectual impairment, multiple seizure types, and typical electroencephalography (EEG) abnormalities.", "ORPHA ID": 2382, "Summary": "Epidemiology\nThe incidence of Lennox-Gastaut syndrome (LGS) is estimated at 0.1 to 0.28 per 100,000 people per year, the lifetime prevalence at the age of ten years amounts to 0.26 per 1000 children. Although rare, it represents 1-10% of childhood epilepsies, and 1-2% of all epilepsy patients. Males are slightly more affected.\nClinical description\nCharacteristic seizure types include atypical absences and tonic seizures during sleep, but atonic seizures during wakefulness, myoclonic, tonic-clonic, and focal seizures as well as non-convulsive status epilepticus commonly occur. Tonic, myoclonic, or atonic seizures can lead to sudden falls (drop attacks). The interictal EEG typically shows slow spike-wave complexes (< 3/s), paroxysmal fast rhythms (10-20/s) during non-REM (rapid eye movement) sleep, and a slowing of the background activity. The disease begins mostly between 3 and 5 years of age and the full triad develops over time. In more than half of the patients, intellectual impairment is present at disease-onset and worsens over time. Behavioral problems are commonly observed and may complicate the treatment.\nEtiology\nThe etiology is heterogeneous including prenatal or perinatal infarctions, central nervous system infections, metabolic disorders, traumatic lesions, and cortical malformations. Genetic de-novo mutations are increasingly identified, such as in GABRB3 (15q12), CHD2 (15q26.1) DNM1 (9q34.11), SCN1A (2q24.3), MAPK10 (4q21.3), CUX2 (12q24.11-q24.12), and CACNA1A (19p13.13). LGS can evolve from early epileptic encephalopathies like West syndrome. In about one fourth of cases, the etiology remains unclear.\nDiagnostic methods\nThe presence of typical clinical features and EEG abnormalities confirms the diagnosis. Magnetic resonance imaging identifies structural abnormalities in more than two thirds of the patients. Genetic testing helps to distinguish between LGS and other disease entities and should be performed in selected cases (e.g. suspected tuberous sclerosis complex, late infantile neuronal ceroid lipofuscinosis, ring chromosome 20 syndrome).\nDifferential diagnosis\nIn principle, all epilepsies with frequent and brief motor seizures occurring in childhood may be considered; the most relevant differential diagnoses include myoclonic atonic epilepsy, Dravet syndrome, and focal epilepsies with secondary bilateral synchrony.\nGenetic counseling\nIf a monogenetic etiology is suspected, genetic counseling is recommended.\nManagement and treatment\nSeizures in LGS are difficult to treat and the treatment should aim to improve the quality of life and reduce the burden of seizures with falls. Sodium valproate is recommended as a first line anti-seizure medicine. Randomized controlled trials with lamotrigine, felbamate, clobazam have demonstrated efficacy in all seizure types. The use of felbamate is limited by adverse side effects. Topiramate, rufinamide, and cannabidiol proved effective in reducing drop attacks. Other anti-seizures medicines levetiracetam, zonisamide, perampanel as well as a ketogenic diet, vagus nerve stimulation, corpus callosotomy, and resective brain surgery in candidate cases, should be considered. In some cases, seizure worsening was reported with carbamazepine, lacosamide, oxcarbazepine, phenytoin, and vigabatrin.\nPrognosis\nThe prognosis of children with LGS is poor. 80-90% of the patients have recurrent seizures and the mortality rate is 14 times higher than in the general population, mainly due to epilepsy-related events (e.g. status epilepticus, sudden unexpected death in epilepsy). Cognitive and behavioral problems are present in nearly all affected individuals. The severity of the disease has a significant impact on family members.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Alexis ARZIMANOGLOU | EpiCARE* - Pr Rima NABBOUT | EpiCARE* - Pr Rainer SURGES | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Lenz-Majewski hyperostotic dwarfism", "Disease Definition": "An extremely rare syndrome associating dwarfism, characteristic facial appearance, cutis laxa and progressive bone sclerosis.", "ORPHA ID": 2658, "Summary": "Epidemiology\nNine cases have been reported in the literature.\nClinical description\nMarked hypertelorism and broad forehead are noted in all patients as well as large ears. Loose and wrinkled atrophic skin with prominent veins is also apparent, giving the patient a progeroid appearance. Increasing generalized osteosclerosis of tubular bones, vertebrae and cranial bones is a characteristic feature. Cutaneous syndactyly of 2nd to 5th fingers was observed in all patients, as well as brachydactyly (see this term) and proximal symphalangism (see this term). All patients have moderate to severe intellectual deficit.\nGenetic counseling\nThe elevated age of some patient's fathers of the reported families is suggestive of an autosomal dominant de novo mutation.\n\n                            Last update: \n                            March 2010"}
{"Disease Name": "Leprechaunism", "Disease Definition": "Leprechaunism is a congenital form of extreme insulin resistance (a group of syndromes that also includes Rabson-Mensenhall syndrome, type A insulin-resistance syndrome, and acquired type B insulin-resistance syndrome; see these terms) characterized by intrauterine and mainly postnatal severe growth retardation.", "ORPHA ID": 508, "Summary": "Epidemiology\nIt is a very rare condition with less than 1 case in every million births.\nClinical description\nLeprechaunism is associated with a characteristic dysmorphic facies (resembling that of the 'leprechauns' in Irish folk traditions), atrophic subcutaneous adipose tissue (lipoatrophy) and muscular hypotrophy. Signs of virilization are often observed in young girls. Biologically, episodes of hypo- and hyperglycemia are observed along with marked hyperinsulinemia due to an extreme resistance to insulin.\nEtiology\nThe syndrome is associated with homozygous or compound heterozygous mutations in the insulin receptor gene (INSR; 19p13.3-p13.2).\nDiagnostic methods\nA positive diagnosis requires identification of one mutation in each allele of this gene.\nDifferential diagnosis\nThe differential diagnosis should include the other forms of extreme insulin resistance.\nGenetic counseling\nThe disorder is transmitted as an autosomal recessive trait.\nManagement and treatment\nTreatment with recombinant insulin-like growth factor 1 (IGF1) may be considered. A combination treatment with insulin-like growth factor binding protein 3 (IGF-BP3) resulted in an increased lifespan in one case.\nPrognosis\nPrognosis is uncertain, growth is severely affected and life expectancy rarely exceeds a few months.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Jacqueline CAPEAU"}
{"Disease Name": "Leprosy", "Disease Definition": "A chronic infectious disease affecting primarily the skin and peripheral nervous system.", "ORPHA ID": 548, "Summary": "Epidemiology\nWorldwide annual incidence is estimated at 250,000 cases, with a large majority in India and Brazil.\nClinical description\nA wide clinical spectrum has been described from a polar tuberculoid (localized) form (TT) to a polar lepromatous (disseminated) one (LL). Borderline forms exist: borderline tuberculoid, borderline borderline and borderline lepromatous (BT, BB, BL). Tuberculoid leprosy (TLep) or paucibacillary form includes TT and BT and lepromatous leprosy (LLep) or multibacillary form includes LL, BL and BB. The incubation time ranges from several months to more than 20 years and does not exceed 5 years in TLep. After contact with Mycobacterium leprae, only 5% of patients develop the disease, almost all with cutaneous lesions and variably severe peripheral neuropathy. In TLep, initially a few large lesions are found (1 to 10). They appear as well demarcated hypopigmented, macules or erythematous plaques. A characteristic loss of sensation at the skin lesion is always present. In LLep, the cutaneous lesions are numerous (10 to 100 or more), normoesthesic, poorly demarcated hypopigmented macules or erythematous papules or nodules and sometimes plaques and may induce diffuse infiltration causing a leonine facies. Mucosas are affected leading in severe cases to nasal destruction, and corneal or laryngeal impairment. Visceral involvement (adenopathies, hepato-splenomegaly or orchiepididymitis) may be present. Neural involvement affects especially the ulnar, median, radial, external popliteal and tibial posterior nerves, with a greater risk in TLep than LLep of distal (hands and feet) anesthesia, palsy (foot drop or clawed hands) and amyotrophy. About 40% of patients may develop 2 types of reactional states: 1) reversal reaction (RR; inflammation of the skin lesions and severe acute neuritis) or down-grading reaction (increased number of lesions) and 2) erythema nodosum leprosum (ENL; vasculitis with painful and eruptive erythematous nodules, fever, neuritis and joint swelling) or Lucio's phenomenon (granulomatous vasculitis with painful necrotic macules).\nEtiology\nThe disease is caused by M. leprae, a mycobacterium for which the main reservoir is humans and some species of armadillos. Recently M. lepromatosis was identified as causing some LLep cases. Possible predisposing genetic factors have been found.\nDiagnostic methods\nDiagnosis is based on clinical, histopathological and bacteriological findings. Skin biopsy is used to determine the form. Examination of slit skin smears enables quantitative evaluation of the bacterial load, usually low or nil in TLep and always high in LLep. PCR assays in tissue may accurately detect M. leprae's 16s rRNA in LLep cases and gene mutations inducing antibiotic resistance. It is generally negative in TLep and only gives a qualitative score.\nDifferential diagnosis\nDifferential diagnosis includes hypochromic eczematides, annular granuloma, annular erythema, dermatophyties and annular sarcoidosis in TLep, and pityriasis versicolor, post-inflammatory hypomelanosis, hypochromic or papulo-nodular sarcoidosis, Kaposi sarcoma, syphilis, lymphoma, cutaneous leukemia in LLep.\nManagement and treatment\nThere are 2 treatment groups: paucibacillary (PB; up to 5 skin lesions) and multibacillary (MB; more than 5). The recommended therapy combines 2 antibiotics (for PB) or 3 (for MB): rifampicin, dapsone and clofazimine. In some cases, other drugs can be used (ofloxacin, minocycline, clarithromycin). Treatment duration is 6 months for PB and at least 1 year for MB. Reactional states can be treated with systemic corticosteroids and sometimes surgical neurolysis for RR, and thalidomide, corticosteroids or pentoxifylline for ENL.\nPrognosis\nPrognosis is favorable when antibacillary and anti-reactional treatments are rapidly instituted. If not, the disease may lead to definitive neurological disabilities.\n\n                            Last update: \n                            September 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Béatrice FLAGEUL"}
{"Disease Name": "Leptospirosis", "Disease Definition": "An anthropozoonosis, rare in Europe, clinically characterized by an initial presentation of flu-like symptoms rapidly progressing into life-threatening multisystem failure (notably hepatonephritis) caused by spiral-shaped bacteria belonging to the genus Leptospira. Leptospirosis is a widespread zoonosis with a worldwide distribution and has emerged as a major public health problem in developing countries in South-East Asia and South America.", "ORPHA ID": 509, "Summary": "Epidemiology\nEstimations from the World Health Organization (WHO) indicate that over 1 million cases of leptospirosis are thought to occur each year, with a mortality rate ranging from 5 to 20% depending on the country. However, the incidence in Europe is much lower with, for example, 600-700 cases in France which is the country with the highest incidence in Europe.\nClinical description\nInitial signs of infection include fever associated with shivering and pain (myalgia, headaches and abdominal pain). The disease progresses over several days with severity varying from flu-like symptoms to rapidly life-threatening multisystem failure, with the most characteristic manifestation being hepatonephritis. Marked jaundice, renal insufficiency, neurologic signs, respiratory involvement, myocarditis, painful hepatomegaly with splenomegaly, and bleeding may also occur. Laboratory investigations reveal polynuclear hyperleucocytosis, cholestasis that is in some cases severe and isolated (without or with only limited cytolysis), and occasionally rhabdomyolysis and thrombopenia.\nEtiology\nAnimal hosts (generally rodents) excrete leptospires in their urine. Humans become infected through skin or mucosal contact with contaminated soft water. The incubation period lasts around 10 days.\nDiagnostic methods\nThe diagnosis relies on PCR results and serology. PCR analysis of blood or urine samples can be used to detect leptospire DNA and allows early diagnosis within the first week following disease onset. Antibodies can become detectable by the 6th to 10th day of the onset of symptoms by IgM ELISA or microscopic agglutination test (MAT). However, leptospirosis is often diagnosed late due to its wide spectrum of symptoms ranging from a flu-like syndrome to renal failure.\nDifferential diagnosis\nThe symptoms mimic the clinical presentations of many other diseases, including dengue fever and malaria.\nManagement and treatment\nLeptospira remain sensitive to penicillin G and therefore treatment is based on administration of antibiotics. Antibiotic therapy is beneficial but must be administered in the early stage of the disease. Disease prevention revolves around eradication of rodents and the use of proper precautions. In some countries, such as France, a vaccine is also available but is reserved for those in at-risk professions, such as sewerage workers.\nPrognosis\nLeptospirosis may lead to pulmonary hemorrhages and irreversible multiple organ failure and death in 5 to 20% of cases.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Mathieu PICARDEAU"}
{"Disease Name": "Leri pleonosteosis", "Disease Definition": "Leri pleonosteosis is characterized by broadening and deformity of the thumbs and great toes in a valgus position (a 'spade-shaped' appearance), flexion contracture of the interphalangeal joints, generalized limitation of joint mobility, short stature, and often mongoloid facies. Additional malformations include genu recurvatum, enlargement of the posterior neural arches of the cervical vertebrae, and thickening of the palmar and forearm fasciae. A few multigenerational families have been reported so far. The disease is inherited in an autosomal dominant manner.", "ORPHA ID": 2900, "Summary": ""}
{"Disease Name": "Lesch-Nyhan syndrome", "Disease Definition": "Lesch-Nyhan syndrome (LNS) is the most severe form of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (see this term), a hereditary disorder of purine metabolism, and is associated with uric acid overproduction (UAO), neurological troubles, and behavioral problems.", "ORPHA ID": 510, "Summary": "Epidemiology\nEstimated prevalence at birth is between 1/380,000 and 1/235,000 live births. Males are generally affected and heterozygous females are carriers (usually asymptomatic).\nClinical description\nPatients are normal at birth. Psychomotor delay becomes evident within 3 to 6 months with a delay in head support and sitting, hypotonia and athetoid movements. Sandy urine in diapers or crystalluria with urinary tract obstruction are common forms of presentation. Patients have severe action dystonia with baseline hypotonia that may lead to an inability to stand up and walk, and involuntary movements (choreoathetosis and ballismus) associated with voluntary movements increased by stress but not evident at rest. Dysarthria, dysphagia, and opisthotonus are frequent. Spasticity, hyperreflexia and extensor plantar reflex appear later. Patients usually show mild to moderate intellectual deficit. Obsessive-compulsive self-mutilation (lip biting or finger chewing) can appear as soon as teeth are present, does not result from lack of sensation and may be associated with or aggravated by psychological stress. Aggressive behavior (i.e. spitting, abusive language) may be directed against family and friends. Megaloblastic anemia is frequent and may be severe. Microcytic anemia may occur. UAO may result in joint inflammation, gouty arthritis and urolithiasis. Renal failure or acidosis occur rarely.\nEtiology\nLNS is caused by complete HPRT deficiency due to mutations in the HPRT1 gene (Xq26). UAO is due to deficient recycling and enhanced synthesis of purine bases. Megaloblastic anemia is supposed to be due to increased folic acid consumption but it does not respond to folic supplementation. The cause of neurological and behavioral symptoms is unknown. Several neurotransmitter disorders and a toxic effect of hypoxanthine excess have been advocated.\nDiagnostic methods\nDiagnosis is suspected when psychomotor delay occurs in a patient with elevated UA in blood and urine. Undetectable HPRT enzyme activity in peripheral blood or in intact cells (erythrocyte, fibroblast) and molecular genetic testing confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include cerebral palsy, other causes of intellectual deficit, dystonia and self-injury including autism, Tourette syndrome, Cornelia de Lange syndrome (see these terms), idiopathic intellectual deficit, and severe psychiatric disorders.\nAntenatal diagnosis\nPrenatal diagnosis by amniocentesis or chorionic villus sampling is possible if the mutation has been identified in the family.\nGenetic counseling\nInheritance is X-linked recessive and genetic counseling is essential.\nManagement and treatment\nUAO is managed with allopurinol, urine alkalinization, and hydration. Doses must be adjusted to avoid xanthine urolithiasis. There is no treatment for the neurological dysfunction. Spasticity and dystonia can be managed with benzodiazepines (diazepam, alprazolam) and gamma-aminobutyric acid inhibitors (baclofen, tizanidine). Physical rehabilitation (i.e. management of dysarthria and dysphagia), devices to enable hand control, walking aids, and posture management to prevent deformities are recommended. Self-injury requires physical restraints, behavioral and pharmaceutical treatment (gabapentin, carbamazepine).\nPrognosis\nPatients may die from aspiration pneumonia or complications from chronic nephrolithiasis and renal failure. With optimal care, few patients live beyond 40 years and most are confined to a wheelchair.\n\n                            Last update: \n                            April 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Juan GARCÍA PUIG  - Dr Rosa TORRES JIMÉNEZ"}
{"Disease Name": "Lethal acantholytic erosive disorder", "Disease Definition": "Lethal acantholytic epidermolysis bullosa is a suprabasal subtype of epidermolysis bullosa simplex (EBS, see this term) characterized by generalized oozing erosions, usually in the absence of blisters.", "ORPHA ID": 158687, "Summary": "Epidemiology\nPrevalence is unknown but 3 cases have been reported to date.\nClinical description\nOnset of the disease is at birth. Erosions are associated with absent nails, universal alopecia, and, in one patient, neonatal teeth. Extracutaneous involvement is always present, involving erosions of the soft tissues of the oral cavity, and gastrointestinal, genitourinary and respiratory tract abnormalities. Cardiomyopathy has been reported in one case.\nEtiology\nThis form of EBS is due to mutations in the DSP (6p24) gene encoding desmoplakin. A homozygous nonsense mutation in the JUP gene (17q21) has been reported in a patient with a very similar phenotype.\nGenetic counseling\nTransmission is autosomal recessive.\nPrognosis\nIn reported cases, death occurred within the first month of life from multiorgan failure secondary to huge transcutaneous fluid loss or airway obstruction due to mucosal sloughing.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "Lethal arteriopathy syndrome due to fibulin-4 deficiency", "Disease Definition": "A rare, genetic, vascular disorder characterized by severe aneurysmal dilatation, elongation, and tortuosity of the thoracic aorta, its branches and pulmonary arteries with stenosis at various typical locations, typically resulting in infantile demise. Variable associated features may include cutis laxa, long philtrum with thin vermillion border, hypertelorism, sagging cheeks, arachnodactyly, joint laxity and pectus deformities.", "ORPHA ID": 314718, "Summary": ""}
{"Disease Name": "Lethal ataxia with deafness and optic atrophy", "Disease Definition": "Lethal ataxia with deafness and optic atrophy (also known as Arts syndrome) is characterized by intellectual deficit, early-onset hypotonia, ataxia, delayed motor development, hearing impairment and loss of vision due to optic atrophy.", "ORPHA ID": 1187, "Summary": "Epidemiology\nIt was initially described in 12 male members from five generations of a Dutch family. Arts syndrome has also been described in one Australian family.\nClinical description\nOther manifestations included floppiness, susceptibility to infections, and later, flaccid tetraplegia and areflexia.\nEtiology\nIt is caused by missense mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1) localized to Xq22.1-q24, leading to impaired purine biosynthesis.\nGenetic counseling\nArts syndrome is transmitted as an X-linked recessive trait.\nManagement and treatment\nTreatment with S-adenosylmethionine may be beneficial and is currently under evaluation.\nPrognosis\nThe disease has a fatal course during childhood (the majority of patients die before the age of 5 years) due to the high susceptibility of the patients to infections, especially of the upper respiratory tract.\n\n                            Last update: \n                            September 2008"}
{"Disease Name": "Lethal brain and heart developmental defects", "Disease Definition": "A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by early intrauterine growth retardation, generalized edema, craniofacial dysmorphism (such as microcephaly, brachycephaly, frontal bossing, hypertelorism, short palpebral fissures, or absent nasal bone), cerebellar hypoplasia, sex reversal in male fetuses, congenital heart defects (including septal and valve defects and cardiomegaly), and late fetal loss.", "ORPHA ID": 580933, "Summary": ""}
{"Disease Name": "Lethal congenital contracture syndrome type 1", "Disease Definition": "Lethal congenital contracture syndrome type 1 is a rare, genetic arthrogryposis syndrome characterized by total fetal akinesia (detectable since the 13th week of gestation) accompanied by hydrops, micrognathia, pulmonary hypoplasia, pterygia and multiple joint contractures (usually flexion contractures in the elbows and extension in the knees), leading invariably to death before the 32nd week of gestation. Lack of anterior horn motoneurons, severe atrophy of the ventral spinal cord and severe skeletal muscle hypoplasia are characteristic neuropathological findings, with no evidence of other organ structural anomalies.", "ORPHA ID": 1486, "Summary": ""}
{"Disease Name": "Lethal congenital contracture syndrome type 2", "Disease Definition": "Lethal congenital contracture syndrome type 2 is a rare arthrogryposis syndrome characterized by multiple congenital contactures (typically extended elbows and flexed knees), micrognathia, anterior horn cell degeneration, skeletal muscle atrophy (mainly in the lower limbs), presence of a markedly distended urinary bladder and absence of hydrops, pterygia and bone fractures. Other craniofacial (e.g. cleft palate, facial palsy) and ocular (e.g. anisocoria, retinal detachment) anomalies may be additionally observed. The disease is usually neonatally lethal however, survival into adolescence has been reported.", "ORPHA ID": 137776, "Summary": ""}
{"Disease Name": "Lethal congenital contracture syndrome type 3", "Disease Definition": "Lethal congenital contracture syndrome type 3 is a rare arthrogryposis syndrome characterized by clinical features identical to Lethal congenital contracture syndrome type 2 (i.e. multiple congenital contactures (typically extended elbows and flexed knees), micrognathia, anterior horn cells degeneration, skeletal muscle atrophy (mainly in the lower limbs), in the absence of hydrops, pterygia or bone fractures), but without bladder enlargement.", "ORPHA ID": 137783, "Summary": ""}
{"Disease Name": "Lethal congenital contracture syndrome", "Disease Definition": "A group of rare arthrogryposis syndromes characterized by fetal akinesia, multiple congenital contractures, anterior horn cell degeneration, skeletal muscle atrophy, and other features, depending on the subtype. All types are lethal in the fetal or neonatal period.", "ORPHA ID": 294965, "Summary": ""}
{"Disease Name": "Lethal faciocardiomelic dysplasia", "Disease Definition": "An extremely rare polymalformative syndrome.", "ORPHA ID": 1972, "Summary": "Epidemiology\nIt was described only once, in 1975, in 3 affected males in a sibship of 13, from second-cousin parents.\nClinical description\nPatients were all of low birth weight, had microretrognathia, microstomia, and microglossia, hypoplasia of the radius and ulna with radial deviation of the hands, simian creases and hypoplasia of fingers I and V, hypoplasia of the fibula and tibia with talipes and wide space between toes I and II, and severe malformation of the left heart which may have been responsible for death of all 3 in the first week or so of life.\n\n                            Last update: \n                            December 2011"}
{"Disease Name": "Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome", "Disease Definition": "A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by mid-gestation lethality and features of a ciliopathy. Clinical manifestations include hydrocephalus, cerebellar vermis hypoplasia, corpus callosum agenesis, duodenal atresia, gastrointestinal malrotation, bilateral renal hypoplasia, and dysmorphic craniofacial features (such as microcephaly, hypertelorism, low-set ears, prominent nose, short columella, cleft palate, micrognathia, and wide mouth).", "ORPHA ID": 444069, "Summary": ""}
{"Disease Name": "Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome", "Disease Definition": "Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome is a rare, genetic developmental defect during embryogenesis malformation syndrome characterized by intrauterine growth restriction, flexion arthrogryposis of all joints, severe microcephaly, renal cystic dysplasia/agenesis/hypoplasia and complex malformations of the brain (cerebral and cerebellar hypoplasia, vermis, corpus callosum and/or occipital lobe agenesis, with or without arhinencephaly), as well as of the genitourinary tract (ureteral agenesis/hypoplasia, uterine hypoplasia and/or vaginal atresia), leading to fetal demise.", "ORPHA ID": 439897, "Summary": ""}
{"Disease Name": "Lethal hemolytic anemia-genital anomalies syndrome", "Disease Definition": "A rare genetic disease characterized by lethal non-spherocytic, non-immune hemolytic anemia, in association with abnormalities of the external genitalia (such as micropenis and hypospadias). Reported dysmorphic features include flat occiput, dimpled earlobes, deep plantar creases, and increased space between the first and second toes. There have been no further descriptions in the literature since 1995.", "ORPHA ID": 1046, "Summary": ""}
{"Disease Name": "Lethal hydranencephaly-diaphragmatic hernia syndrome", "Disease Definition": "Lethal hydranencephaly-diaphragmatic hernia syndrome is a rare, genetic, lethal, multiple congenital anomalies syndrome characterized by hydranencephaly and diaphragmatic hernia, as well as macrocephaly, a widely open anterior fontanel, scaphoid abdomen and hypotonia. Additionally, congenital heart defects, polyhydramnios and pulmonary hypertension have also been associated.", "ORPHA ID": 480528, "Summary": ""}
{"Disease Name": "Lethal infantile mitochondrial myopathy", "Disease Definition": "Lethal infantile mitochondrial myopathy is a rare mitochondrial oxidative phosphorylation disorder characterized by progressive generalized hypotonia, progressive external ophthalmoplegia and severe lactic acidosis, which results in early fatality (days to months after birth). Patients may present with lethargy and areflexia and may associate additional features, such as cardiomyopathy, renal dysfunction, liver involvement and seizures.", "ORPHA ID": 254857, "Summary": ""}
{"Disease Name": "Lethal intrauterine growth restriction-cortical malformation-congenital contractures syndrome", "Disease Definition": "A rare and fatal central nervous system malformation occurring during embryogenesis, presenting prenatally with holoprosencephaly and fetal hypokinesia as major features. Other manifestations include microcephaly, multiple contractures and intrauterine growth restriction. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 2570, "Summary": ""}
{"Disease Name": "Lethal Kniest-like dysplasia", "Disease Definition": "A rare, lethal, congenital, chondrodysplasia disorder characterized by dumbbell-shaped long bones with markedly shortened diaphyses and metaphyseal irregularities associated with a 'Swiss cheese' appearance of the cartilage matrix, as well as distinctive changes in the growth plate and resting cartilage, resulting in death in the neonatal period. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 2347, "Summary": ""}
{"Disease Name": "Lethal Larsen-like syndrome", "Disease Definition": "A rare developmental defect with connective tissue involvement characterized by multiple joint dislocations, flattened facial appearance, abnormal palmar creases, laryngotracheomalacia, and pulmonary hypoplasia. Additional signs may include a bifid tongue, micrognathia, non-immune hydrops fetalis, and brain dysplasia. The disease is lethal shortly after birth due to respiratory insufficiency.", "ORPHA ID": 2371, "Summary": ""}
{"Disease Name": "Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome", "Disease Definition": "Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome is rare, genetic, neurometabolic disease characterized by global developmental delay, severe hypotonia, seizures, cataracts, cardiomyopathy (including left or bi-ventricular hypertrophy, dilated cardiomyopathy) and left ventricular non-compaction, typically resulting in infantile or early-childhood death. Patients usually present metabolic lactic acidosis, failure to thrive, head lag, respiratory problems and decrease in respiratory chain complex activity. Highly variable cerebral abnormalities have been reported and include microcephaly, prominent extra-axial cerebrospinal fluid spaces, diffuse neuronal loss and cortical/white matter gliosis.", "ORPHA ID": 478049, "Summary": ""}
{"Disease Name": "Lethal multiple pterygium syndrome", "Disease Definition": "A rare genetic multiple pterygium syndrome characterized by intrauterine growth retardation, fetal akinesia, multiple joint contractures causing severe arthrogryposis and pterygia (webbing) across multiple joints. Cystic hygroma and/or fetal hydrops are almost invariably present.", "ORPHA ID": 33108, "Summary": "Epidemiology\nTo date, less than 50 fetuses have been reported in 28 families. Of these cases, approximately 60% were male and 40% were female. Half of the families had affected males only, including five with multiple affected males.\nClinical description\nLethal multiple pterygium syndrome (LMPS) is characterized by growth deficiency of prenatal onset, pterygia present in multiple areas (chin to sternum, cervical, axillary, humero-ulnar, crural, popliteal and the ankles) and flexion contractures giving rise to severe arthrogryposis. Subcutaneous edema varies from mildly edematous skin to fetal hydrops with cystic hygroma, lung hypoplasia, and oligo or polyhydramnios. Facial anomalies include hypertelorism, down-slanting palpebral fissures, epicanthic folds, flat nasal root, microretrognathism, microstomia, low-set malformed ears and cleft palate. Other anomalies include a small chest, reduced muscle bulk, cryptorchidism, central nervous system abnormalities (in particular cerebellar hypoplasia, ventricular dilatation and polymicrogyria), hypoplastic dermal ridges and creases, and less frequently a mid-forehead hemangioma, intestinal malrotation, cardiac hypoplasia, diaphragmatic hernia, obstructive uropathy, rocker bottom feet, microcephaly and/or cerebellar and pontine hypoplasia.\nEtiology\nCausal mutations have been identified in subunits of the acetylcholine receptor encoded by CHRNA1  (2q31.1), CHRND (2q37.1), CHRNG (2q37.1), as well as in the nebulin gene (NEB, 2q23.3), and the ryanodine receptor (RYR1, 19q13.2).\nDiagnostic methods\nDiagnosis is suspected based on characteristic clinical features and ultrasound findings observed during routine pregnancy examination (for more details see the section on antenatal diagnosis).\nDifferential diagnosis\nDifferential diagnoses include other disorders which present with prenatal ultrasound features of reduced or absent fetal movements in association with an abnormal fetal posture and other arthrogrypotic conditions. These may include fetal akinesia deformation sequence (FADS), Bartsocas-Papas syndrome, Escobar variant multiple pterygium syndrome, arthrogryposis multiplex congenita, and maternal myasthenia gravis, as well as trisomy 18, severe neural tube defects, caudal regression sequence and vertebral anomalies, limb body wall complex, fetal neck masses, fetal hypoxia, constriction rings syndrome and fetal constraint.\nAntenatal diagnosis\nFetal akinesia may be detected as early as 12 weeks. Prenatal ultrasound findings with LMPS include intrauterine growth retardation, flexion contractures of the limbs, multiple pterygia, cystic hygroma, fetal hydrops, hypoplastic lungs, a cleft palate and other structural abnormalities. Additional findings of hypoplastic skeletal development may help in distinguishing LMPS from other conditions with FADS, and detailed ultrasound scans and fetal MRI may identify a central nervous system abnormality which may be a feature in LMPS or suggest an alternative etiology. Molecular prenatal genetic testing can be undertaken if early scans are inconclusive and the mutation has been identified. LMPS should also be considered in patients with a history of recurrent mid-trimester losses.\nGenetic counseling\nThe inheritance is autosomal recessive. The sibling recurrence risk is 25%. X-linked inheritance has also rarely been reported and is also suggested by the excess of males with LMPS.\nManagement and treatment\nAs the condition is lethal, termination of the pregnancy may be proposed.\nPrognosis\nLMPS is typically fatal during the second or third trimester.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Julie VOGT"}
{"Disease Name": "Lethal neonatal spasticity-epileptic encephalopathy syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by neonatal onset of rigidity and intractable seizures, with episodic jerking already beginning in utero. Affected infants have small heads, remain visually inattentive, do not feed independently, and make no developmental progress. Frequent spontaneous apnea and bradycardia usually culminate in cardiopulmonary arrest and death in infancy, although some cases were described with a milder clinical course and survival into childhood.", "ORPHA ID": 435845, "Summary": ""}
{"Disease Name": "Lethal occipital encephalocele-skeletal dysplasia syndrome", "Disease Definition": "Lethal occipital encephalocele-skeletal dysplasia syndrome is a rare, genetic, bone development disorder characterized by occipital and parietal bone hypoplasia leading to occipital encephalocele, calvarial mineralization defects, craniosynostosis, radiohumeral fusions, oligodactyly and other skeletal anomalies (arachnodactyly, terminal phalangeal aplasia of the thumbs, bilateral absence of the great toes, pronounced bilateral angulation of femora, shortened limbs, advanced osseous maturation). Fetal death in utero is associated.", "ORPHA ID": 293925, "Summary": ""}
{"Disease Name": "Lethal omphalocele-cleft palate syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by the association of omphalocele and cleft palate. Other reported features include cleft lip, bifid uvula, bilateral talipes equinovarus, bicornuate uterus, and hydrocephalus internus. The condition is lethal in infancy.", "ORPHA ID": 2736, "Summary": ""}
{"Disease Name": "Lethal polymalformative syndrome, Boissel type", "Disease Definition": "A rare, genetic, lethal, multiple congenital anomalies/dysmorphic syndrome characterized by failure to thrive, severe developmental delay, severe postanatal microcephaly, frequent congenital cardiac defects and characteristic facial dysmorphysm (including coarse face with anteverted nostrils, thin vermillion, prominent alveolar ridge and retro- or micrognatia). Additional common features include neurologic abnormalities (hyper-/hypotonia, sensorineural deafness, hydrocephalus, cerebral atrophy, seizures), as well as brachydactyly, cutis marmorata and genital anomalies.", "ORPHA ID": 210144, "Summary": ""}
{"Disease Name": "Lethal recessive chondrodysplasia", "Disease Definition": "Lethal recessive chondrodysplasia is an extremely rare lethal form of chondrodysplasia characterized by severe micromelic dwarfism, short and incurved limbs with normal hands and feet, facial dysmorphism (disproportionately large skull, frontal prominence, slightly flattened nasal bridge and short neck), muscular hypotonia, hyperlaxity of the extremities, and a narrow thorax. Most patients die of respiratory distress during the first hours or weeks of life. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 1423, "Summary": ""}
{"Disease Name": "Leukocyte adhesion deficiency type I", "Disease Definition": "Leukocyte adhesion deficiency type I (LAD-I) is a form of LAD (see this term) characterized by life-threatening, recurrent bacterial infections.", "ORPHA ID": 99842, "Summary": "Epidemiology\nLAD-I affects 1 individual per million.\nClinical description\nUsually the first signs occur in infancy or early childhood. Patients present recurrent, life-threatening bacterial infections of the skin, mouth, and respiratory tract. Delayed umbilical cord separation is common. Skin infections may evolve into large ulcers. Severe periodontitis is often present later in life and leads to early tooth loss. A lack of swelling, redness, heat, or pus is observed in the area of infection.\nEtiology\nLAD-I is caused by mutations in the ITGB2 gene (21q22.3), encoding the beta-2-integrin, CD18, which is essential for firm adhesion of leukocytes to the endothelium. Severity of the disease correlates with the degree of CD18 deficiency.\nDiagnostic methods\nDiagnosis is based on complete blood counts revealing neutrophilic leukocytosis. Flow cytometric analyses reveal reduced CD18 expression on leukocytes. Genetic analyses of mutations in the ITGB2 gene confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include IRAK-4 deficiency, autosomal dominant hyper IgE syndrome, chronic granulomatous disease, other primary immunodeficiencies (see these terms) and a leukemoid reaction.\nAntenatal diagnosis\nAntenatal diagnosis is possible through biochemical or molecular analysis of chorionic villus cells or amniocytes in affected families for which the mutation has been identified. Flow cytometry can be performed at 20 weeks of gestation.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nManagement should focus on controlling infections and includes antibiotics. Hematopoietic cell transplantation represents the only cure for LAD-I, but gene therapy may be available in the future.\nPrognosis\nPrognosis depends on the severity of the disease. Without hematopoietic stem cell transplantation, death in patients with severe LAD-I occurs from infection within the first 2 years of life, whereas patients with a moderate form of the disease have abetter chance of surviving into adulthood. Survival rate after bone marrow transplantation is 75%.\n\n                            Last update: \n                            May 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Amos ETZIONI"}
{"Disease Name": "Leukocyte adhesion deficiency type II", "Disease Definition": "Leukocyte adhesion deficiency type II (LAD-II) is a form of LAD (see this term) characterized by recurrent bacterial infections, severe growth delay and severe intellectual deficit.", "ORPHA ID": 99843, "Summary": "Epidemiology\nLAD-II is extremely rare: less than 10 cases have been reported so far.\nClinical description\nThe first signs usually occur in infancy or early childhood. Patients present recurrent bacterial infections, severe growth delay resulting in short stature, and severe intellectual deficit. Patients have the Bombay phenotype (they do not express the H antigen). Facial dysmorphism is common, characterized mainly by a depressed nasal bridge. Severe periodontitis is often present later in life and leads to early tooth loss. In adulthood, intellectual deficit and growth retardation, rather than infections, dominate the clinical picture.\nEtiology\nLAD-II is a carbohydrate-deficient glycoprotein syndrome (CDG syndrome; see this term) and is therefore also referred to as CDG IIc. It results from mutations in the SLC35C1 gene (11p11.2), encoding the guanosine 5'-diphosphate (GDP)-fucose transporter localized in the Golgi apparatus. This is a specific fucose transporter that translocates GDP-fucose from the cytosol to the Golgi where it is used as a substrate for fucosylation.\nDiagnostic methods\nDiagnosis is based on clinical findings and complete blood counts revealing leukocytosis with neutrophilia. Blood typing is essential to look for the Bombay blood group, which is present in all patients with LAD-II and is extremely rare in the general population. Final diagnosis is based on genetic analysis.\nDifferential diagnosis\nThere is no differential diagnosis as the clinical symptoms of recurrent infections, leukocytosis, the Bombay blood group, and severe growth and intellectual deficit are unique to LAD-II.\nAntenatal diagnosis\nAntenatal diagnosis through biochemical or molecular analysis of chorionic villus cells or amniocytes is possible in families for which the mutation has been identified.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nManagement should focus on controlling infections and includes antibiotics. Fucose replacement may improve phagocytic function in some cases.\nPrognosis\nInfections in LAD-II are rarely life-threatening and thus patients may live to adulthood.\n\n                            Last update: \n                            May 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Amos ETZIONI"}
{"Disease Name": "Leukocyte adhesion deficiency type III", "Disease Definition": "Leukocyte adhesion deficiency type III (LAD-III) is a form of LAD (see this term) characterized by both severe bacterial infections and a severe bleeding disorder.", "ORPHA ID": 99844, "Summary": "Epidemiology\nLAD-III is extremely rare: only 17 patients have been reported so far.\nClinical description\nUsually the first signs occur in infancy or early childhood. Patients present LAD-I life-threatening infections and a Glanzmann thrombasthenia-like bleeding disorder (see these terms). A lack of pus is observed in infected areas.\nEtiology\nLAD-III is caused by mutations in the FERMT3 gene (11q13.1), which encodes kindlin-3 in hematopoietic cells. The FERMT3 mutations lead to an activation defect of all beta-integrins.\nDiagnostic methods\nDiagnosis is based on clinical findings and complete blood counts revealing leukocytosis with neutrophilia. Platelet aggregation assays and genetic analysis confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include LAD-I, Glanzmann thrombasthenia (see these terms), and leukemoid reaction. Antenatal diagnosis may be confirmed through biochemical or molecular analysis of chorionic villus cells.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nManagement should focus on controlling infections and includes symptomatic treatment with antibiotics and blood transfusions. Bone marrow transplantation is the only available curative treatment option.\nPrognosis\nPrognosis is poor and death occurs in early infancy if bone marrow transplantation is not performed.\n\n                            Last update: \n                            May 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Amos ETZIONI"}
{"Disease Name": "Leukocyte adhesion deficiency", "Disease Definition": "Leukocyte adhesion deficiency (LAD) is a primary immunodeficiency characterized by defects in the leukocyte adhesion process, marked leukocytosis and recurrent infections.", "ORPHA ID": 2968, "Summary": "Epidemiology\nPrevalence is unknown, but less than 350 cases have been reported so far.\nClinical description\nUsually the first signs occur in infancy or early childhood. Three distinct defects in the leukocyte adhesion cascade have been defined leading to three distinct entities. LAD-I (see this term) is characterized by life-threatening, recurrent bacterial infections. LAD-II (see this term) presents with leukocytosis, recurrent infections, severe growth delay and intellectual deficit. LAD-III (see this term; also called LAD-I variant) is characterized by both severe bacterial infections and a severe bleeding disorder.\nEtiology\nLAD results from an impaired step in the inflammatory process, namely, the migration of leukocytes from the blood vessels to sites of infection, which requires adhesion of leukocytes to the endothelium. LAD-I is caused by mutations in the ITGB2 gene (21q22.3), encoding the beta-2-integrin CD18. LAD-II results from mutations in the SLC35C1 gene (11p11.2), encoding the guanosine 5'-diphosphate (GDP)-fucose transporter. LAD-III is caused by mutations in the FERMT3 gene (11q13.1), encoding kindlin-3 in hematopoietic cells.\nDiagnostic methods\nDiagnosis is based on the clinical symptoms and on a complete blood count revealing neutrophilia. In LAD-I and LAD-II, flow cytometry should be performed for CD18 and CD15 respectively. In LAD-III, platelet aggregation assays should be performed. In all cases, a genetic analysis confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include IRAK-4 deficiency, autosomal dominant hyper IgE syndrome, chronic granulomatous disease (see these terms), neutrophil dysfunction and a leukemoid reaction.\nAntenatal diagnosis\nAntenatal diagnosis is feasible by genetic analysis of chorionic villus samples.\nGenetic counseling\nIn all cases, transmission is autosomal recessive. Genetic counseling should always be offered to the patients and their families.\nManagement and treatment\nManagement depends on the type of LAD. Treatment should focus on controlling infections and includes antibiotics and, in many cases, bone marrow transplantation. Without hematopoietic stem cell transplantation, patients with severe LAD-I and LAD-III usually die from infection within the first 2 years of life.\nPrognosis\nThe survival rate in patients with LAD-I who undergo bone marrow transplantation is 75%. Some patients with LAD-II survive to adulthood.\n\n                            Last update: \n                            May 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Amos ETZIONI"}
{"Disease Name": "Leukoencephalopathy with bilateral anterior temporal lobe cysts", "Disease Definition": "A rare, nonprogressive, neurological disorder marked by intellectual deficit, spasticity and motor retardation associated with characteristic MRI findings of anterior bilateral temporal lobe cysts and multilobar leukoencephalopathy. So far, around 30 cases have been reported in the literature. Onset occurs in the first few months of life. Sensorineural deafness and microcephaly have also been reported. The etiology is unknown but an autosomal recessive mode of inheritance has been suggested.", "ORPHA ID": 139444, "Summary": ""}
{"Disease Name": "Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome", "Disease Definition": "This disease is characterised by progressive cerebellar ataxia with pyramidal and spinal cord dysfunction, associated with distinctive MRI anomalies and increased lactate in the abnormal white matter.", "ORPHA ID": 137898, "Summary": "Epidemiology\nSo far, 38 cases have been reported.\nClinical description\nOnset occurs in early childhood. Epilepsy and cognitive decline have also been described.\nEtiology\nThe syndrome is caused by mutations in the DARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase.\nDiagnostic methods\nMRI reveals inhomogeneous periventricular and deep white matter anomalies, with involvement of the cerebellar connections, the entire length of the pyramidal and sensory tracts.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            April 2008"}
{"Disease Name": "Leukoencephalopathy with calcifications and cysts", "Disease Definition": "A rare genetic cerebral small vessel disease characterized by leukoencephalopathy and cerebral calcification and cysts due to diffuse cerebral microangiopathy resulting in microcystic and macrocystic parenchymal degeneration. The condition can present at any age from early childhood to late adulthood and manifests as a progressive cerebral degeneration. Symptoms are variable, but restricted to the central nervous systems, and include, among others, slowing of cognitive performance, seizures, and movement disorder with a combination of pyramidal, extrapyramidal, and cerebellar features.", "ORPHA ID": 542310, "Summary": ""}
{"Disease Name": "Leukoencephalopathy with mild cerebellar ataxia and white matter edema", "Disease Definition": "A rare neurologic disease characterized by a specific pattern of white matter abnormalities on brain imaging (magnetic resonance imaging, MRI), as well as mild ataxia, headaches, mild visual impairment, learning difficulties and cases of male infertility.", "ORPHA ID": 363540, "Summary": ""}
{"Disease Name": "Leukoencephalopathy-dystonia-motor neuropathy syndrome", "Disease Definition": "Leukoencephalopathy-dystonia-motor neuropathy syndrome is a peroxisomal neurodegenerative disorder characterized by spasmodic torticollis, dystonic head tremor, intention tremor, nystagmus, hyposmia, and hypergonadotrophic hypogonadism with azoospermia. Slight cerebellar signs (left-sided intention tremor, balance and gait impairment) are also noted. Magnetic resonance imaging (MRI) shows bilateral hyperintense signals in the thalamus, butterfly-like lesions in the pons, and lesions in the occipital region, whereas nerve conduction studies of the lower extremities shows a predominantly motor and slight sensory neuropathy.", "ORPHA ID": 163684, "Summary": ""}
{"Disease Name": "Leukoencephalopathy-palmoplantar keratoderma syndrome", "Disease Definition": "Leukoencephalopathy-palmoplantar keratoderma syndrome is a rare, genetic epidermal disease characterized by early childhood-onset of punctate palmoplantar keratoderma in association with adult-onset leukoencephalopathy manifested by progressive tetrapyramidal syndrome and cognitive deterioration.", "ORPHA ID": 2386, "Summary": ""}
{"Disease Name": "Leukoencephalopathy-spondyloepimetaphyseal dysplasia syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by the association of hypomyelinating leukodystrophy with spondylometaphyseal dysplasia. Patients present in infancy with absent or delayed ability to walk independently, slowly progressive motor deterioration, spasticity, ataxia, proximal weakness, and joint contractures. Additional manifestations include mild cognitive impairment, short stature, scoliosis, enlarged and deformed joints, dysarthria, nystagmus, visual defects, and mildly dysmorphic features, among others. Mode of inheritance is X-linked recessive.", "ORPHA ID": 83629, "Summary": ""}
{"Disease Name": "Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome", "Disease Definition": "A rare, genetic neurological disorder defined by early-onset of neurologic symptoms, biphasic clinical course, unique MRI features (incl. extensive, symmetrical, deep white matter abnormalities), and increased lactate in body fluids. The severe form is characterized by delayed psychomotor development, seizures, early-onset hypotonia, and persistently increased lactate levels. The mild form usually presents with irritability, psychomotor regression after six months of age, and temporary high lactate levels, with overall clinical improvement from the second year onward.", "ORPHA ID": 314051, "Summary": ""}
{"Disease Name": "Leukomelanoderma-infantilism-intellectual disability-hypodontia-hypotrichosis syndrome", "Disease Definition": "Leukomelanoderma-infantilism-intellectual disability-hypodontia-hypotrichosis syndrome is a rare ectodermal dysplasia syndrome characterized by congenital generalized melanoleukoderma, hypodontia and hypotrichosis associated with infantilism, intellectual disability and growth delay. There have been no further descriptions in the literature since 1961.", "ORPHA ID": 1816, "Summary": ""}
{"Disease Name": "Leukonychia totalis-acanthosis-nigricans-like lesions-abnormal hair syndrome", "Disease Definition": "Leukonychia totalis-acanthosis-nigricans-like lesions-abnormal hair syndrome is a rare, syndromic nail anomaly disorder characterized by the association of leukonychia totalis with acanthosis-nigricans-like lesions (occurring in the neck, axillae and abdomen regions) and hair dysplasia, manifesting with dry, brittle hair which presents an irregular pattern of complete or incomplete twists and an irregular surface with londitudinal furrows on electronic microscopy.", "ORPHA ID": 210133, "Summary": ""}
{"Disease Name": "Leukonychia totalis", "Disease Definition": "Leukonychia totalis is a rare nail anomaly disorder characterized by complete white discoloration of the nails. Patients typically present white, chalky nails as an isolated finding, although other cutaneous or systemic manifestations could also be present.", "ORPHA ID": 2387, "Summary": ""}
{"Disease Name": "Levocardia", "Disease Definition": "A rare, congenital, non-syndromic, developmental defect during embryogenesis characterized by the heart located in the normal (levo) position associated with abdominal viscera located in the dextro position. Cardiac (e.g. interrupted inferior vena cava with azygous continuation) and/or splenic (asplenia, polysplenia) anomalies, as well as intestinal malrotation, are frequently associated.", "ORPHA ID": 95854, "Summary": ""}
{"Disease Name": "Lewis-Sumner syndrome", "Disease Definition": "A rare acquired demyelinating polyneuropathy characterized by asymmetrical distal weakness of the upper or lower extremities and motor dysfunction with adult onset. It is considered to be a variant of chronic inflammatory demyelinating polyneuropathy.", "ORPHA ID": 48162, "Summary": ""}
{"Disease Name": "Leydig cell hypoplasia", "Disease Definition": "A rare 46,XY difference of sex development due to impaired androgen production characterized by impaired normal male sexual development. The severity of the disorder varies and can manifest in its severe form with complete 46,XY male pseudohermaphroditism, including low testosterone and high luteinizing hormone levels, absent development of secondary male sex characteristics and lack of breast development. Patients with the milder form can have a wider range of phenotypes, ranging from micropenis to severe hypospadias.", "ORPHA ID": 755, "Summary": ""}
{"Disease Name": "Lhermitte-Duclos disease", "Disease Definition": "A rare developmental defect during embryogenesis characterized by abnormal development and enlargement of the cerebellum, and an increased intracranial pressure. The tumors can be characterized by the abnormal growth of ganglion cells that regulate activities in the cerebellum.", "ORPHA ID": 65285, "Summary": "Epidemiology\nApproximately 230 cases of Lhermitte-Duclos disease (LDD) have been reported in literature to date, there is no sex or race preference. It typically presents between ages of 30-50, although it may occur in infants and adults over age of 60.\nClinical description\nIt manifests, most commonly in the third and fourth decades of life, with headache, nausea, cerebellar dysfunction, occlusive hydrocephalus, ataxia, visual disturbances and other cranial nerve palsies. Various associated abnormalities may be present (megalencephaly, microgyria, hydromyelia, polydactyly, partial gigantism, macroglossia). Co-existing conditions include Cowden syndrome.\nEtiology\nThe etiology is uncertain; germline mutations in tumor suppressor gene PTEN have been identified in some patients with LDD.\nDiagnostic methods\nDiagnosis of LDD is confirmed by magnetic resonance imaging (MRI) and genetic testing for germline PTEN pathogenic variant.\nDifferential diagnosis\nDifferential diagnosis include Cowden syndrome as LDD can co-manifest along with Cowden syndrome features.\nAntenatal diagnosis\nAntenatal diagnosis is possible if the pathogenic variant has previously been identified in the family, but was never described in the literature.\nGenetic counseling\nThis is an autosomal dominant condition which may occur sporadically or in a familial form. Genetic counseling should be offered to at-risk family members to inform them of the 50% risk of transmission for each pregnancy.\nManagement and treatment\nManagement includes decompressive surgical intervention.\nPrognosis\nThere is no data regarding the prognosis of this disease.\n\n                            Last update: \n                            December 2023\n\n\n                            - Expert reviewer(s): \n                             Manasadevi KARTHIKEYAN  - Dr Joanne NGEOW"}
{"Disease Name": "Li-Fraumeni syndrome", "Disease Definition": "A rare, inherited, cancer predisposition syndrome characterized by the early-onset of multiple primary cancers including breast cancer, soft tissue and bone sarcomas, brain tumors, adrenal cortical carcinoma (ACC), leukemias, and other cancers.", "ORPHA ID": 524, "Summary": "Epidemiology\nMore than 400 families with Li-Fraumeni (LFS) have been reported in the literature. The estimated prevalence of pathogenic and likely pathogenic germline TP53 mutations is not well defined but has been estimated to range between 1/3,555-5,476.\nClinical description\nThe core cancers in Li-Fraumeni syndrome (LFS) are early-onset breast cancer, ACC, soft tissue sarcomas, osteosarcomas, and brain tumors. Also seen in LFS are leukemias, lymphomas, colorectal cancer, and many other cancers. People with LFS have about a 50% increased risk of developing a second cancer.\nEtiology\nLFS is caused by germline mutations in the tumor suppressor gene TP53 (17p13.1) in the majority of families with classic LFS. This gene encodes the tumor antigen p53 protein involved in many cellular processes such as DNA repair, growth arrest and apoptosis. 7-20% of TP53 mutations are estimated to be de novo. No other gene has been associated with LFS thus far.\nDiagnostic methods\nDiagnosis is confirmed by genetic testing and identification of a TP53 mutation. Individuals may also be clinically diagnosed with LFS if they meet classic LFS criteria which include: (1) a person with a sarcoma diagnosed before age 45 years and (2) a first-degree relative with any cancer diagnosed before age 45 years and (3) a first- or second degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age. The Chompret criteria may also be used to identify individuals for whom TP53 testing is indicated: (1) an individual with a tumor belonging to the LFS tumor spectrum before age 46 years and a first- or second-degree relative with an LFS tumor (except multiple breast cancer tumors or breast cancer before 56 years of age); (2) an individual with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum , with the first occurring before 46 years of age; (3) an individual with ACC or CPC, or anaplastic embryonal rhabdomyosarcoma regardless of family history; or (4) an individual with breast cancer before 31 years of age.\nDifferential diagnosis\nDifferential diagnoses include hereditary breast and ovarian cancer syndrome, CHEK2 cancer susceptibility syndrome, and constitutional mismatch repair deficiency syndrome.\nAntenatal diagnosis\nPrenatal and preimplantation genetic diagnoses are available for families with a TP53 mutation.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant; the risk of inheriting the mutation from a carrier is 50%. The lifetime risk of cancer in LFS is estimated to be about 70% for men and over 90% for women, although these may be overestimates. The age-related cancer risks are estimated at 22% between 0-15 years, 51% between 16-50 years, and 27% between 51-80 years. Genetic counseling is recommended to inform individuals of issues related to genetic testing, cancer risks, medical surveillance, and psychosocial and family impact.\nManagement and treatment\nManagement of LFS-related cancers generally follows standard treatment protocols, with minimizing radiation when possible. Mastectomies are recommended over lumpectomies for the treatment of breast cancer. Prophylactic mastectomy can also be offered to those with a known TP53 mutation for risk reduction. Regular surveillance (adapted from the ''Toronto protocol'') is recommended for individuals with TP53 mutations, and incorporate screening with biochemical and imaging modalities. Complete physical exams and ultrasound of the abdomen and pelvis is recommended every 3-4 months from birth until age 18. Children and adults are advised to have annual whole-body and brain magnetic resonance imaging (MRI). Women are recommended to have clinical breast exams every 6-12 months, an annual breast MRI from age 20 and an annual mammogram from age 30. For other cancer risks, physical exam is recommended every 6-12 months from age 18 years, with annual dermatologic exam. Colonoscopy and upper endoscopy are recommended every 2-5 years from age 25 (or 5 years before the earliest colon cancer in the family). Other screening may also be recommended.\nPrognosis\nPrognosis depends on the type and severity of cancers developed. Patients followed on the Toronto screening protocol were reported to have higher 5-year survival rates.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Junne KAMIHARA  -  Katherine SCHNEIDER"}
{"Disease Name": "Lichen amyloidosis", "Disease Definition": "Lichen amyloidosis is a rare chronic form of cutaneous amyloidosis (see this term), a skin disease characterized by the accumulation of amyloid deposits in the dermis, clinically characterized by the development of pruritic, often pigmented, hyperkeratotic papules on trunk and extremities, especially on the shins, and histologically by the deposition of amyloid or amyloid-like proteins in the papillary dermis.", "ORPHA ID": 49804, "Summary": ""}
{"Disease Name": "Lichen planopilaris", "Disease Definition": "A rare cutaneous variant of lichen planus which affects hair follicles. It may occur on its own or in association with more common forms of lichen planus, usually classical type and/or oral lichen planus.", "ORPHA ID": 525, "Summary": "Epidemiology\nThe prevalence is unknown. LPP is more frequent in women than in men.\nClinical description\nThe disease manifests in adulthood (40-60 years of age), with some rare cases in childhood. Patients present with peri-follicular inflammation and hair loss. They may be asymptomatic or have itch or discomfort. The scalp is the commonest area affected but any hair bearing skin may be affected, like for example the axillae or the pubic area. Perifollicular erythema, scales, and/or keratotic plugs are seen at the edge of the affected area. Single or multiple lesions of scarring alopecia lacking follicular orifices are typical. Two other variants of LPP can be observed: frontal fibrosing alopecia (FFA), and Lassueur-Graham-Little syndrome (see these terms). In FFA, there is symmetrical, progressive anterior hairline loss of the scalp associated with eyebrow loss. The Lassueur-Graham-Little syndrome constitutes a combination of lichen planus follicularis of the scalp with follicular keratosis and noncicatricial alopecia of the axillae and pubes.\nEtiology\nEtiology is unknown but LPP is thought to be an autoimmune disorder in which T-lymphocytes attack and destroy keratinocytes expressing unknown target antigens. Triggering factors could be pharmacologic agents, contact sensitizers or infectious agents.\nDiagnostic methods\nDiagnosis is based on clinical and histopathological findings. Biopsy of an inflammatory lesion shows a band-like perifollicular lymphocytic infiltrate at the level of the isthmus and infundibulum. There may be vacuolar changes of the basal layer and follicular plugging. In more advanced lesions, perifollicular fibrosis and replacement of hair follicles by fibrosis are found. Diagnosis is difficult in the later stages when inflammation disappears.\nDifferential diagnosis\nDifferential diagnosis includes discoid lupus erythematosus (DLE), folliculitis decalvans, mucous membrane pemphigoid (see these terms), seborrheic dermatitis, alopecia areata, and central centrifugal cicatricial alopecia (CCCA).\nManagement and treatment\nThere is no long-term effective treatment for LPP. Current treatments aim at slowing down progression of hair loss and reduction of symptoms. Topical, intralesional and oral corticosteroids are the mainstay of treatment. Unfortunately, relapse is common. Other options for treatment include hydroxychloroquinine, ciclosporin and methotrexate.\nPrognosis\nLPP can progress slowly or rapidly. Some cases may spontaneously resolve but others are progressive.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Susan COOPER"}
{"Disease Name": "Lichen planus pemphigoides", "Disease Definition": "Lichen planus (LP) pemphigoides is a rare cross-over syndrome between lichen planus and bullous pemphigoid (see these terms).", "ORPHA ID": 254478, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nLP pemphigoides affects primarily adult men in middle age (40-50 years of age), but several cases have been reported in children. It is quite distinct from bullous lichen planus (see this term), both clinically and pathologically. In lichen planus pemphigoides, bullous lesions arise in both normal skin and skin affected by lichenoid lesions, whereas in bullous lichen planus, the blisters only develop on lichenoid papules. The bullae in LP pemphigoides can be hemorrhagic or clear, and have a predilection for acral sites.\nEtiology\nEpitope spreading seems to account for the pathogenesis of lichen planus pemphigoides, whereby damage to the basal layer in LP lesions exposes a basement membrane antigen (e.g. BP180 epitope) leading to the development of circulating antibodies. Occurrence of LP pemphigoides has been reported following the use of several medications including cinnarizine, angiotensin-converting enzyme (ACE) inhibitors (ramipril and captopril), simvastatin and anti-tuberculous drugs, and also following Psoralen and Ultraviolet A Light (PUVA) therapy.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Stephanie ARNOLD  - Dr Susan COOPER"}
{"Disease Name": "Lichen planus pigmentosus", "Disease Definition": "Lichen planus (LP) pigmentosus is a rare variant of cutaneous lichen planus (see this term) characterized by the presence of hyperpigmented lichenoid lesions in sun-exposed or flexural areas of the body.", "ORPHA ID": 254463, "Summary": "Epidemiology\nLP pigmentosus is a rare disease in Europe but it is common in Indian populations and in the Middle East. The overall prevalence is unknown. There is no difference in distribution between males and females.\nClinical description\nThe disease usually appears in the third and fourth decade of life. The lesions are asymptomatic or mildly pruritic. Skin changes are dark brown or slate grey macules or papules with, in most cases, a diffuse pigmentation pattern. They most commonly affect the face, neck and upper limbs. Predominantly a intertriginous disease, usually in the axillae and groin (described mostly in Caucasians), it has also been termed as lichen planus pigmentosus inversus. The scalp, nails or mucosa are not affected. LP pigmentosus can exist in association with typical LP lesions.\nEtiology\nEtiology is unknown but various factors (e.g. viral infections and certain topical agents including mustard oil, amla oil and henna hair dyes) can trigger the disease. One case has been reported in association with Bazex syndrome (see this term).\nDiagnostic methods\nHistological features of LP pigmentosus are similar but milder than classic LP, with a lichenoid interface reaction, vacuolar change and apoptotic keratinocytes. Melanin incontinence is prominent, and may be the only feature of older lesions; it may extend deeper into the dermis than typical post-inflammatory pigmentation.\nPrognosis\nLichen planus pigmentosa seems to follow a chronic progressive course.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Stephanie ARNOLD  - Dr Susan COOPER"}
{"Disease Name": "Lichtenstein syndrome", "Disease Definition": "A rare genetic disease characterized by frequent infections associated with neutropenia and IgA deficiency, in combination with osteoporosis and skeletal anomalies, such as posterior spinal arch fusion defect, metacarpal subluxation, syndactyly, and camptodactyly. Reported dysmorphic features include synophrys, anteverted nostrils, and single palmar crease. There have been no further descriptions in the literature since 1972.", "ORPHA ID": 2390, "Summary": ""}
{"Disease Name": "Liddle syndrome", "Disease Definition": "A rare genetic form of low-renin hypertension characterized by hypertension associated with decreased plasma levels of potassium and aldosterone.", "ORPHA ID": 526, "Summary": "Epidemiology\nLiddle syndrome prevalence is unknown. The condition is considered rare with less than 80 families reported worldwide.\nClinical description\nThe disease can be clinically heterogeneous, ranging from mild to severe. Most patients are diagnosed in young adulthood, although the diagnosis may be made as early as in infancy, especially when family screening of an affected patient is performed. The typical clinical features are resistance to treatment with conventional anti-hypertensives, salt-sensitive arterial hypertension, hypokalemia and metabolic alkalosis often associated with a family history of early-onset hypertension and sudden death. Associated manifestations of hypokalemia may include muscular weakness, polyuria/polydipsia. Sudden death due to stroke or myocardial infarction or associated with malignant arrhythmias elicited by severe hypokalemia has been reported. Mild forms with essential normal plasma electrolytes have also been reported.\nEtiology\nLiddle syndrome is due to gain-of-function mutations in the genes SCNN1A (16p13), SCNN1B (16p12.2-p12.1) and SCNN1G (16p12.2), encoding, respectively, the alpha, beta and gamma subunits of the epithelial sodium channel (ENaC), a key protein involved in sodium reabsorption in the distal renal tubules. Physiologically, ENaC channel abundance is regulated by aldosterone. The gain-of-function mutations causing Liddle syndrome impair the retrieval from the apical membrane and subsequent degradation of ENaC by the ubiquitin proteasome pathway. The prolonged tenancy of mutated ENaC in the membrane results in increased sodium reabsorption independent of aldosterone with consequent hypertension.\nDiagnostic methods\nDiagnosis is suspected by the detection of hypertension, associated with hypokalemic alkalosis and suppressed renin and aldosterone, especially in the presence of a relevant family history. It can be confirmed by genetic testing.\nDifferential diagnosis\nLiddle syndrome needs to be distinguished from other forms of hypertension with hypokalemic alkalosis. The suppressed renin and aldosterone levels separate it from primary and secondary forms of hyperaldosteronism, such as Conn syndrome or renovascular hypertension. A family history consistent with dominant inheritance, a urine steroid profile and genetic testing can separate it from apparent mineralocorticoid excess and glucocorticoid remediable hypertension.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant, the risk to offspring of inheriting the mutation from an affected parent is 50%. Given the variable phenotype reported in some families, genetic screening should be performed in first-degree relatives of a mutation carrier.\nManagement and treatment\nTreatment is based on administration of potassium-sparing diuretics, such as amiloride or triamterene, which act by blocking ENaC activity. This results in reduction of blood pressure and correction of hypokalemia and metabolic alkalosis. Conventional antihypertensive therapies are not effective. Patients must also follow a low sodium diet.\nPrognosis\nWith adequate treatment, prognosis is good. Without treatment, cardiovascular and renal complications usually occur.\n\n                            Last update: \n                            May 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Detlef BÖCKENHAUER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "LIG4 syndrome", "Disease Definition": "LIG4 syndrome is a hereditary disorder associated with impaired DNA double-strand break repair mechanisms and characterized by microcephaly, unusual facial features, growth and developmental delay, skin anomalies, and pancytopenia, which is associated with combined immunodeficiency (CID).", "ORPHA ID": 99812, "Summary": "Epidemiology\nPrevalence is unknown. To date, at least 12 patients have been reported.\nClinical description\nLIG4 syndrome presents in childhood with microcephaly, unusual facial features that have been described as ''bird-like'' (beak-like nose and micrognathia), growth and developmental delay, skin anomalies including photosensitivity and psoriatic-like lesions, and pancytopenia. The disease is associated with immunodeficiency. Some patients have been reported as having telangiectasias, leukemia, lymphoma, bone marrow abnormalities, and type 2 diabetes. One patient presented with features of Omenn syndrome (see this term).\nEtiology\nLIG4 syndrome is caused by mutations in the LIG4 gene (13q22-q34). The resulting defect of DNA ligase IV, a component of the classical non-homologous end-joining (NHEJ) pathway, affects the major mechanism of DNA double-strand break repair.\nDiagnostic methods\nDiagnosis is based on evidence of the characteristic clinical signs of LIG4 syndrome, particularly the ''bird-like'' facial features, and low T and B cells. Diagnosis is confirmed on the basis of molecular genetic analysis and the evidence of radiosensitivity of cell lines. Chromosome 7/14 translocations are also common.\nDifferential diagnosis\nDifferential diagnoses include other rare DNA damage response diseases such as Seckel syndrome, Nijmegen breakage syndrome (NBS), Cernunnos-XLF deficiency and Fanconi anemia (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis can be performed by chorionic villus sampling in families with previously affected members.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nSupportive treatment is with prophylactic antibiotics and anti-virals. Hematopoietic stem cell transplantation may be indicated in some patients using modified conditioning regimens without radiotherapy.\nPrognosis\nLifespan is generally limited with an increased incidence of leukemia or lymphoma.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Light and heavy chain deposition disease", "Disease Definition": "A rare non-amyloid monoclonal immunoglobulin deposition disease characterized by secretion of abnormal light and heavy chains, which are deposited in tissues and cause organ dysfunction, but do not form amyloid beta-pleated sheets or contain an amyloid P component. The condition most frequently occurs in association with multiple myeloma. The kidneys are most commonly affected (clinically manifesting as nephrotic syndrome and renal failure), but liver, heart, peripheral nerves, blood vessels, and joints may also be involved.", "ORPHA ID": 93557, "Summary": ""}
{"Disease Name": "Light chain deposition disease", "Disease Definition": "A rare non-amyloid monoclonal immunoglobulin deposition disease characterized by deposition of abnormal immunoglobulin light chains in the kidneys, resulting in nephrotic syndrome and renal failure. Symptomatic extrarenal deposition is uncommon, although hepatic, cardiac, and neural deposits have been reported. The condition frequently occurs in association with multiple myeloma or in patients with M protein and marrow plasma cells at monoclonal gammopathy of undetermined significance levels.", "ORPHA ID": 93558, "Summary": ""}
{"Disease Name": "Limb body wall complex", "Disease Definition": "Limb body wall complex (LBWC) is characterized by severe multiple congenital anomalies in the fetus with exencephaly/encephalocele, thoraco- and/or abdominoschisis (anterior body wall defects) and limb defects, with or without facial clefts.", "ORPHA ID": 2369, "Summary": "Epidemiology\nApproximately 250 cases have been reported in the literature so far.\nClinical description\nClinical manifestations vary widely and include limb defects and visceral malformations (95% of cases), spinal abnormalities, absent diaphragm, bowel atresia and renal agenesis. LBWC generally presents as a short umbilical cord, abdominal placental attachment, persistence of an extraembryonic celom, anorectal malformations, urogenital abnormalities, lumbosacral meningomyelocele and kyphoscoliosis. A spectrum of LBWC manifestations is included in the amniotic band sequence (see this term), presenting mostly with craniofacial defects, facial clefts, amniotic bands and/or adhesions. At present, it remains unclear whether these two entities represent a single disorder.\nEtiology\nThe etiology of LBWC remains unknown. Karyotypes have been reported as normal and no correlations with gender, parental age and teratogenic agents have been found. The principal theories are an extrinsic origin by early amniotic rupture, or a vascular origin due to an early vascular accident during embryological development. Single cases of familial occurrence have been documented.\nDiagnostic methods\nDiagnosis is based on the presenting features.\nDifferential diagnosis\nLBWC should be differentiated from gastroschisis (see this term), which has better prognosis.\nAntenatal diagnosis\nEarly antenatal diagnosis is feasible by ultrasound examination and may be followed by medical termination of the pregnancy.\nPrognosis\nLBWC is fatal, with death occurring antenatally or early in the neonatal period.\n\n                            Last update: \n                            March 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Didier LACOMBE"}
{"Disease Name": "Limb-girdle muscular dystrophy due to POMK deficiency", "Disease Definition": "Limb-girdle muscular dystrophy due to POMK deficiency is a form of limb-girdle muscular dystrophy presenting in infancy with muscle weakness and delayed motor development (eventually learning to walk at 18 months of age) followed by progressive proximal weakness, pseudohypertrophy of calf muscles, mild facial weakness, and borderline intelligence.", "ORPHA ID": 445110, "Summary": ""}
{"Disease Name": "Limb-girdle muscular dystrophy", "Disease Definition": "Limb-girdle muscular dystrophy (LGMD) is a heterogeneous group of muscular dystrophies characterized by proximal weakness affecting the pelvic and shoulder girdles. Cardiac and respiratory impairment may be observed in certain forms of LGMD.", "ORPHA ID": 263, "Summary": "Epidemiology\nThe estimated prevalence for all forms of LGMD ranges from 1/44,000 to 1/123,000.\nClinical description\nLGMD ranges from severe forms with onset in the first decade and rapid progression (resembling Duchenne muscular dystrophy) to milder forms with late onset and slower progression (similar to Becker muscular dystrophy). LGMD is characterized by weakness and wasting predominantly of the limb musculature (proximal greater than distal). The initial presentations are usually weakness of the hip and proximal leg muscles. Affected individuals usually have normal early motor and intellectual milestones and show a positive Gowers' sign. Cardiac involvement in the form of dilated or hypertrophic cardiomyopathy and dysrhythmias are present in LGMD 2C-F, 2I, 2W, 2X, 1B, and 1E. At some stage, when upper arm muscles are involved, all subtypes may also have respiratory muscle weakness with nocturnal hypoventilation, in particular type 2I where it is noted from an earlier stage. Additional clinical features include a waddling gait, muscle pain during exercise, hypertrophy of the deltoids and quadriceps, and muscle wasting, affecting either the pelvis and/or shoulder girdle. The facial muscles are usually spared or involved only minimally.\nEtiology\nLGMD is caused by mutations in more than 25 genes which encode numerous components of the myofiber, contractile apparatus, nuclear lamina, sarcolemma or the cytoplasm.\nDiagnostic methods\nDiagnosis of LGMD involves physical examination and muscle biopsy, which reveals fiber size variation including (non specific) fiber hypertrophy, scattered degenerating and regenerating muscle fibers, and a mild increase in perimysial tissue. Serum creatine-kinase can be normal or mildly to grossly elevated. Diagnosis of a specific LGMD subtype can be achieved by biochemical protein testing performed on muscle biopsies, followed by confirmation with genetic testing. Genetic testing, using panels, is becoming more readily available and can confirm diagnosis.\nDifferential diagnosis\nThe differential diagnosis of LGMD includes facioscapulohumeral muscular dystrophy, Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, polymyositis, myotonic, myofibrillar, distal and metabolic myopathy, collagen 6-related disorders and dermatomyosistis.\nAntenatal diagnosis\nPrenatal diagnosis is available when a causative gene in a family is known.\nGenetic counseling\nThere are at least 30 different genetic forms of LGMD, among which the type 1 LGMDs (LGMD1) are inherited in an autosomal dominant manner and the type 2 LGMDs (LGMD2) are inherited in an autosomal recessive manner. Genetic counseling should be offered to families according to the mode of inheritance.\nManagement and treatment\nTreatment of LGMD remains palliative and supportive and includes weight control to avoid obesity, physical therapy and stretching exercises to promote mobility and prevent contractures, use of mechanical aids to help ambulation and mobility, surgical intervention for orthopedic complications, use of respiratory aids when indicated, monitoring for cardiomyopathy in LGMD types with cardiac involvement, and social as well as emotional support and stimulation.\nPrognosis\nThe clinical course of LGMD is typically progressive, although it is highly variable and is dependent on the severity of the individual genetic mutation. In most childhood onset forms of LGMD (in particular the rapidly progressive forms), ambulation is achieved but is invariably lost in later years. In other forms of LGMD, ambulation can be maintained and wheelchair assistance needed only later in life.\n\n                            Last update: \n                            April 2017\n\n\n                            - Expert reviewer(s): \n                            Dr A.J. [Anneke] VAN DER KOOI"}
{"Disease Name": "Limb-mammary syndrome", "Disease Definition": "A rare, genetic, ectodermal dysplasia syndrome characterized by severe hand/foot anomalies, breast and/or nipple hypoplasia, and ectodermal dysplasia (principally teeth and nail anomalies). Cleft lip/palate may be variably present.", "ORPHA ID": 69085, "Summary": ""}
{"Disease Name": "Limbal stem cell deficiency", "Disease Definition": "A rare corneal disorder characterized by dysfunction and/or insufficient quantity of corneal limbal stem cells, leading to impaired self-renewal of the corneal epithelium and resulting in epithelial breakdown, corneal conjunctivalization and neovascularization, chronic inflammation, persistent epithelial defects, and scarring. Patients usually present with ocular redness, decreased vision, photophobia, foreign body sensation, tearing, and pain. The condition may be genetic, idiopathic, or acquired (in the context of inflammation, infection, trauma, or ocular surface tumors).", "ORPHA ID": 171673, "Summary": ""}
{"Disease Name": "Limited cutaneous systemic sclerosis", "Disease Definition": "Limited cutaneous systemic sclerosis (lcSSc) is a subtype of systemic sclerosis (SSc; see this term) characterized by the association of Raynaud's phenomenon with skin fibrosis limited to the hands, face, feet and forearms.", "ORPHA ID": 220402, "Summary": "Epidemiology\nThe prevalence is estimated at about 1/12,500 adults. Women are predominantly affected (F/M sex ratio around 4:1).\nClinical description\nWomen are predominantly affected (F/M sex ratio around 4:1). The disease usually manifests at between 40 and 50 years of age. Raynaud's phenomenon is the most common and often the first sign of the disease. The other signs usually appear some years later. Skin involvement is limited to the hands, face, feet and forearms. Skin tautness is absent in the chest, abdomen, back, or thighs. Telangiectasias and sclerodactyly with a risk of digital ulcers are observed. Esophageal dysmotility is common, and provokes gastroesophageal reflux and sometimes dysphagia. About 30-40% of the patients have lung fibrosis on computed tomography (CT) scan and about 10% have pulmonary arterial hypertension. In some early stages of the disease, cutaneous involvement is not yet present; as a consequence the disease is called limited SSc. In rare situations, cutaneous involvement never occurs; as a consequence, the disease is called SSc sine scleroderma. CREST syndrome (see this term) is usually considered a synonym of limited cutaneous SSc but it is rather a subtype with more frequent and more extended telangiectasias.\nEtiology\nThe exact cause of limited cutaneous SSc is unknown. The disease originates from an autoimmune reaction which leads to overproduction of collagen. In some cases, the condition is associated with exposure to chemicals (including silica, solvents and hydrocarbons).\nDiagnostic methods\nDiagnosis is based on typical clinical manifestations and on evidence of specific microangiopathy with giant loops on nailfold capillaroscopy. Blood tests show a high incidence of anticentromere antibodies (ACA). The extent of the disease should be evaluated by CT, electrocardiogram, echocardiography, radiography of the hands and esophageal and gastric fibroscopy if needed.\nDifferential diagnosis\nDifferential diagnoses include Sharp syndrome, systemic lupus erythematosus, antiphospholipid syndrome, and polyarteritis nodosa (see these terms).\nManagement and treatment\nManagement is mostly symptomatic. Raynaud's phenomenon can be treated with calcium channel blockers. Proton pomp inhibitors are given for gastric reflux. Patients require regular clinical follow-up with early pulmonary function tests and echocardiography. Low doses of corticosteroids with immunosuppressive agents are needed in cases with progressive lung fibrosis. Pulmonary vasodilators are given in case of pulmonary arterial hypertension.\nPrognosis\nThe prognosis of limited cutaneous SSc is relatively good with a long-lasting disease duration (10-year survival rate is about 80 to 90%). However, pulmonary arterial hypertension may be a complication of the disease (in about 10% of cases) and may lead to a more severe prognosis. Severe lung fibrosis may occur in some patients.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Eric HACHULLA"}
{"Disease Name": "Limited systemic sclerosis", "Disease Definition": "Limited systemic sclerosis (lSSc) (or SSc sine scleroderma) is a subset of systemic sclerosis (SSc; see this term) characterized by organ involvement in the absence of fibrosis of the skin.", "ORPHA ID": 220407, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nPatients do not have skin fibrosis but only Raynaud's phenomenon, and are at risk of organ involvement (fibrosis and vascular obliteration of lungs, heart, digestive tract). They can later present with esophageal dysmotility which provokes gastroesophageal reflux and sometimes dysphagia, and can also suffer from lung fibrosis and pulmonary arterial hypertension.\nEtiology\nThe exact cause of lSSc is unknown. The disease originates from an autoimmune reaction which leads to overproduction of collagen. In some cases, SSc is associated with exposure to chemicals (silica, solvents, hydrocarbons, etc.).\nDiagnostic methods\nDiagnosis can be difficult due to the absence of skin involvement. Nailfold capillaroscopy shows a SSc pattern and blood tests show a high incidence of anti-centromere antibodies.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Eric HACHULLA"}
{"Disease Name": "Linear and whorled nevoid hypermelanosis", "Disease Definition": "A rare hyperpigmentation of the skin disease characterized by the congenital to infantile-onset of bilateral, diffuse (occasionally localized), reticulate (swirls and streaks), macular hyperpigmentation following the lines of Blaschko, typically involving the trunk, limbs, head and neck (but sparing palms, soles and mucosa), without preceding inflammation, blistering or atrophy. Occasionally, extracutaneous abnormalities, including autism, seizures, cardiac defects, skeletal abnormalities and developmental delay, may be associated. Histologically, basal and/or suprabasal melanosis, without pigment incontinence, is observed.", "ORPHA ID": 79150, "Summary": ""}
{"Disease Name": "Linear atrophoderma of Moulin", "Disease Definition": "Linear atrophoderma of Moulin (LAM) is characterized by mildly atrophic and hyperpigmented band-like lesions that follow the lines of Blaschko on the trunk or limbs. Since its initial description in 1992, less than 30 cases have been reported in the literature. Onset occurs during childhood or adolescence and the disease is non-progressive. There is no prior inflammation or subsequent scleroderma. The aetiology is unknown but as LAM follows the lines of Blaschko it has been suggested that the disease is caused by mosaicism of a predisposing gene.", "ORPHA ID": 140933, "Summary": ""}
{"Disease Name": "Linear focal elastosis", "Disease Definition": "Linear focal elastosis is a rare, acquired, dermis elastic tissue disorder characterized by asymptomatic, palpable, hypertrophic or atrophic, yellowish or red, indurated, horizontal, striae-like linear plaques distributed symmetrically across the mid and lower back. No systemic involvement has been described. Skin biopsy reveals a focal increase in abnormal elastic tissue with abundant, wavy, fragmented and aggregated, basophilic elastic fibers in the reticular dermis.", "ORPHA ID": 228236, "Summary": ""}
{"Disease Name": "Linear hypopigmentation and craniofacial asymmetry with acral, ocular and brain anomalies", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by linear hypopigmentation and hypotrichosis following the lines of Blaschko, symmetric or asymmetric facial dysmorphism, and body asymmetry, in association with ocular, dental, and acral anomalies. Reported manifestations include microphthalmia, strabismus, myopia, oligodontia, microdontia, conical teeth, abnormal enamel, brachydactyly, syndactyly, and broad first toe, as well as dysmorphic facial features such as downslanting palpebral fissures, broad nasal bridge, malar hypoplasia, and microstomia. Brain imaging may show cystic leukoencephalopathy and ventricular dilation.", "ORPHA ID": 589608, "Summary": ""}
{"Disease Name": "Linear IgA dermatosis", "Disease Definition": "A rare, acquired autoimmune bullous skin disease characterized by annular, grouped blisters on the skin and, frequently, mucous membranes with linear deposition of immunoglobulin A along the basement membrane zone (BMZ).", "ORPHA ID": 46488, "Summary": "Epidemiology\nThe estimated incidence varies worldwide, ranging between 0.2-1/1000,000.\nClinical description\nLinear IgA dermatosis (LAD) has two forms: the infantile/childhood form and the adult form. In children, presentation is characterized by annular, tense blisters with new lesions appearing at the periphery of older lesions, giving the ''string of pearls'' appearance. Sites of predilection include the face, lower trunk, perineum, and perioral region. Childhood onset is typically before 5 years of age, rarely affects neonates, and tends to resolve spontaneously before puberty. The adult form typically involves severe pruritus with variable lesions, which may consist of annular papules, vesicles, tense bullae, erythema, urticarial plaques, and/or erosions. Scarring is possible. Sites of predilection include the face, extension faces of the limbs, large body folds, buttocks and trunk. LAD can occur at any age, however there is an increased risk of chronic disease in those less than 70 years of age. Mucous membrane involvement occurs in up to 80% of affected children and 70% of affected adults and can affect oral, nasal, pharyngeal, or esophageal mucosa. Drug induced LAD tends to be more severe than the spontaneous form. Lesions occur between 1 and 30 days after treatment and can result in toxic epidermal necrolysis that can be fatal. The disease is associated with ulcerative colitis prior to LAD onset, and with an increased risk of developing lymphoproliferative diseases.\nEtiology\nSpontaneous LAD is mediated by IgA autoimmunity which targets heterogeneous antigens of either the lamina lucida or sublamina densa of the BMZ. LAD can also be triggered by various drugs including vancomycin, beta lactam antibiotics, captopril, or non-steroidal anti-inflammatory drugs. Infections and malignancies have also been suspected as possible factors triggers in LAD.\nDiagnostic methods\nHistology analysis on skin biopsy typically demonstrates features of subepidermal blisters with a prominent neutrophilic infiltrate and linear and positive direct immunofluorescence microscopy demonstrates continuous deposition of IgA in the BMZ and/or IgG and C3. Indirect immunofluorescence microscopy on patients's sera demonstrates that circulating IgA anti-basement membrane binds the epidermal side of 1 M NACL split human skin.\nDifferential diagnosis\nDifferential diagnosis includes bullous pemphigoid, dermatitis herpetiformis, mucous membrane pemphigoid, lichen planus, lichenoid drug reaction, contact allergy, and other causes of toxic epidermal necrolysis.\nManagement and treatment\nDapsone and sulfapyridine (or sulfasalazine) as are the preferred therapeutics in combination with topical corticosteroids and general supportive care for skin lesions. Systemic corticosteroids may be used in severe cases. Erythromycin, colchicine, flucloxacillin, intravenous immunoglobulin, azathioprine, mycophenolic acid, and immunoadsorption have been also used in unresponsive patients. Some severe cases have been treated with rituximab. In case of drug induced LAD, the culprit drug is withdrawn and a short course of corticosteroids may be considered.\nPrognosis\nPrognosis is generally better for children, who frequently have spontaneous resolution and long-term remission. The prognosis is variable in adults who may have complete remission or suffer chronic disease either with permanent lesions or relapse.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Marion CASTEL | ERN-Skin* - Pr Pascal JOLY | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Linear lichen planus", "Disease Definition": "Linear lichen planus (LLP), also referred to as Blaschkoid LP, is a rare type of lichen planus characterized by a linear distribution of lichenoid lesions along the lines of Blaschko, which are embryonic pathways of skin development.", "ORPHA ID": 254379, "Summary": "Epidemiology\nThe prevalence is unknown. Less than 0.5% of patients with LP present with Blaschkoid LP. Cases have been more commonly reported in children, however LLP does occur in adults.\nClinical description\nLesions appear as pruritic, violaceous papules in a linear distribution, usually on the limbs, but also anywhere on the body. It follows a Blaschkoid, not dermatomal, pattern of distribution. It can be superimposed on the more typical non-segmental and randomly-distributed lesions of classic LP. Histology is that of classical papulosquamous lichen planus. A very rare LLP variant, called zosteriform LP, has also been observed and is characterized by a segmental zosteriform distribution of lichenoid lesions. Zosteriform LP may appear as a Koebner phenomenon following herpes zoster infection.\nEtiology\nEtiology of LLP is unknown, however it has been associated with metastatic carcinoma, HIV infection and hepatitis C infection. It is thought that LLP arises due to an abnormal keratinocyte clone that is only unmasked after the initiating event for lichen planus.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Stephanie ARNOLD  - Dr Susan COOPER"}
{"Disease Name": "Linear nevus sebaceus syndrome", "Disease Definition": "A rare nevus syndrome characterized by the association of an nevus sebaceous with a broad spectrum of abnormalities that affect many organ systems, most commonly the eye, skeletal and central nervous system.", "ORPHA ID": 2612, "Summary": "Epidemiology\nThe incidence of epidermal nevus (EN) (isolated finding or as a syndrome) is estimated at 1-3/1,000 live births, with nevus sebaceous (NS) estimated at half of the total. Nevus sebaceous syndrome (NSS) is rare; the exact prevalence and incidence in the general population is unknown.\nClinical description\nNSS is the association of NS with extracutaneous manifestations. NS presents typically at birth as hairless yellow-pink, salmon-colored Blaschkoid plaque(s), but nevi may not appear clinically until later in infancy or early childhood. NS are found on the head and neck in two-thirds of cases, and large extensive nevi or a centrofacial location is more associated with NSS. In puberty, NS thicken and can become verrucous in appearance. Later in life, benign neoplasms may grow within the NS; rarely do malignant neoplasms grow, and the risk specifically for basal cell carcinoma is less than 1%. Central nervous system (CNS) findings are the most common extracutaneous anomalies, notably intellectual disability (nearly 80%) and seizures (57%, generalized tonic, tonic-clonic, focal motor, infantile spasms). While structural brain anomalies may occur (hemiatrophy, vascular anomalies, hemimegalencephaly, gyral or posterior fossa abnormalities), 75% of patients with CNS findings have normal imaging. Many other organ systems may also be involved in this syndrome, most commonly ophthalmologic (strabismus, lipodermoids, retinal anomalies, coloboma, cataracts, corneal vascularization) and skeletal (frontal bossing, skeletal hypoplasia, scoliosis and kyphoscoliosis, vitamin D-resistant rickets, hypophosphatemia). Other rare findings have included endocrine, cardiovascular and urogenital systems and oral anomalies (including rare neoplasms of ameloblastoma ,odontoma, giant cell granuloma).\nEtiology\nNSS is a sporadic disease. EN syndromes are the result of post-zygotic mutations. Mutations in KRAS, HRAS , and NRAS have been described in both isolated NS and NSS. Mutations in these same genes are seen in keratinocytic EN (KEN).\nDiagnostic methods\nEvaluation should include prenatal, developmental, and family histories. Cutaneous examination should evaluate all skin including areas covered by hair, mucosa, eyes (especially the conjunctiva, sclerae, and extra-ocular eye movements). Careful neurologic and ophthalmologic exams should be performed. Any child with NS on the head or neck and developmental delay should have brain imaging. Skeletal exam should evaluate for kyphoscoliosis, gait and limb length. Skin biopsies and relevant laboratory studies (serum/urine calcium and phosphate, liver and renal function tests) as appropriate. Referral to specialists guided by the above is recommended.\nDifferential diagnosis\nDifferential diagnosis includes cutaneous-skeletal hypophosphatemia syndrome, nevus comedonicus syndrome, Becker nevus syndrome, phakomatosis pigmentokeratotica, CHILD syndrome, the spectrum of PIK3CA-related overgrowth syndrome, SOLAMEN (segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome), and CLOVES syndrome.\nGenetic counseling\nNSS occurs sporadically due to a postzygotic mutation. They do not appear to be heritable, as the severity of the mutations are thought to be incompatible with life when present in the germline.\nManagement and treatment\nNSS management is individualized and multidisciplinary based on the involved organ systems and degree of impairment. NS are no longer prophylactically excised in infancy, given low risk of malignant potential. In puberty, patients may opt for removal of the thickened lesions for cosmetic reasons. Biopsy is recommended for any growths that may occur within lesions. Tissue should be sent to an experienced dermatopathologist to prevent misdiagnosis of basal cell carcinoma.\nPrognosis\nThe prognosis depends on the severity of the clinical manifestations and the extent of the multisystem involvement.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Sarah ASCH  - Dr Jeffrey SUGARMAN"}
{"Disease Name": "Linear verrucous nevus syndrome", "Disease Definition": "A rare skin disease characterized by a hamartomatous epidermal lesion presenting as a linear array of verrucous, hyperkeratotic papules that often coalesce into plaques and are formed along the lines of Blaschko. The condition is associated with involvement of other organ systems, mainly brain, eye, and skeletal system. It is the result of mosaic post-zygotic mutations and most commonly presents at birth, but may occur anytime during childhood, rarely also in adulthood.", "ORPHA ID": 2611, "Summary": ""}
{"Disease Name": "LIPE-related familial partial lipodystrophy", "Disease Definition": "A rare, genetic lipodystrophy characterized by abnormal subcutaneous fat distribution, resulting in excess accumulation of fat in the face, neck, shoulders, axillae, trunk and pubic region, and loss of subcutaneous fat from the lower extremities. Variable common additional features are progressive adult onset myopathy, insulin resistance, diabetes, hypertriglyceridemia, hepatic steatosis, and vitiligo.", "ORPHA ID": 435660, "Summary": ""}
{"Disease Name": "Lipoblastoma", "Disease Definition": "A rare soft tissue tumor characterized by a lobulated, localized (lipoblastoma) or diffuse (lipoblastomatosis) lesion resembling fetal adipose tissue, composed of mature and immature adipocytes. It is most commonly found during the first years of life and presents as a slowly growing, well circumscribed mass, which may compress adjacent structures, depending on the location. Malignant transformation or metastasis does not occur, while recurrences are described especially in lipoblastomatosis.", "ORPHA ID": 247762, "Summary": ""}
{"Disease Name": "Lipodystrophy due to peptidic growth factors deficiency", "Disease Definition": "A rare genetic lipodystrophy characterized by loss of subcutaneous fat layers on the limbs, lipodystrophy in the face and trunk and scleroderma-like skin disorders (thickened skin on the palms and soles and skin pigment changes on the limbs and trunk). Additional clinical signs include joint contractures, reduced relative body weight, a bird-like facial appearance with a beaked nose, micrognathia and insulin-resistant diabetes mellitus.", "ORPHA ID": 1979, "Summary": ""}
{"Disease Name": "Lipodystrophy-intellectual disability-deafness syndrome", "Disease Definition": "A rare form of genetic lipodystrophy, reported in 3 patients from one family to date, characterized by generalized congenital lipodystrophy, low birth weight, progressive sensorineural deafness occurring in childhood, intellectual deficit, progressive osteopenia, delayed skeletal maturation, skeletal abnormalities described as slender, undermineralized tubular bones, and dense metaphyseal striations in the distal femur, ulna and radius of older patients. Autosomal recessive inheritance has been suggested.", "ORPHA ID": 50811, "Summary": ""}
{"Disease Name": "Lipoic acid synthetase deficiency", "Disease Definition": "A rare neurometabolic disease characterized by a neonatal onset of seizures (often intractable), muscular hypotonia, feeding difficulties (poor sucking and/or swallowing) and mild to severe psychomotor delay, associated with nonketotic hyperglycinemia typically revealed by biochemical analysis. Respiratory problems (apnea, acute respiratory acidosis), lethargy, hearing loss, microcephaly and spasticity with pyramidal signs may also be associated.", "ORPHA ID": 401859, "Summary": ""}
{"Disease Name": "Lipoid proteinosis", "Disease Definition": "Lipoid proteinosis (LP) is a rare genodermatosis characterized clinically by mucocutaneous lesions, hoarseness developing in early childhood and, at times, neurological complications.", "ORPHA ID": 530, "Summary": "Epidemiology\nIncidence and prevalence are not known. More than 300 cases (ages 6 to 67 years) have been reported worldwide. Most patients are of European ancestry (Dutch or German). A founder effect is reported among large kindreds in South Africa. Many cases are also reported from the Middle East and India. The disease is more commonly seen in consanguineous unions.\nClinical description\nA wide range of clinical signs is noted and disease severity is variable, while the course is usually slowly progressive. The usual presenting manifestation is a hoarse cry due to laryngeal infiltration at birth or in infancy. Subsequently, skin and mucous membrane changes develop in the first two years of life. Crusted lesions initially appear on the face and extremities and heal with scarring. Waxy, thickened and at times verrucous skin lesions may affect the face, eyelids, axillae, knees and scrotum. Eyelid beading (moniliform blepharosis) is a hallmark feature but occurs later in childhood. Patchy or diffuse hair loss may be present. The oral mucosa is often involved with cobblestone lips, tongue or gingiva, impaired tongue mobility causing speech problems, and transient swelling and ulceration of the lips and tongue. Oligodontia (see this term) may be present. Respiratory tract infiltration may cause upper respiratory tract infections, hoarseness or aphonia, dysphagia, and airway obstruction. Dystonia, seizures, behavioral changes, learning difficulties and short stature have been reported in affected children. Less commonly, the disease manifests in adulthood with subtle skin findings and possible complications due to visceral deposition. Heterozygous carriers are generally asymptomatic but may have a mild presentation including abnormal dentition.\nEtiology\nLP is caused by deposition of an amorphous hyaline material in the skin, mucosa, and viscera. Causative loss-of-function mutations have been found in the ECM1 gene (1q21) encoding extracellular matrix protein 1, which has a role in physiology and homeostasis of the skin and many other tissues.\nDiagnostic methods\nDiagnosis is based on the clinical signs (particularly hoarseness and skin manifestations). Histological findings on biopsy of affected cutaneous or mucosal sites show periodic acid-Schiff-positive deposition of amorphous hyaline material in the papillary dermis which confirms the diagnosis. Cranial magnetic resonance imaging or computed tomography reveals bean-shaped intracerebral calcifications in the temporal lobe (in up to 75% of patients). Molecular genetic testing confirms the diagnosis.\nDifferential diagnosis\nThe main differential diagnoses are hydroa vacciniforme and autosomal erythropoietic protoporphyria, but also include leprosy, lichen amyloidosis (see these terms), and xanthomas.\nAntenatal diagnosis\nIf a family member is affected by the disease and the gene mutation has been confirmed, prenatal diagnosis is possible.\nGenetic counseling\nLP is inherited in an autosomal recessive manner. Genetic counseling should be provided to affected families.\nManagement and treatment\nThere is currently no known effective curative treatment and no standard treatment approach. D-penicillamine, oral dimethyl sulfoxide, acitretin, topical corticosteroids, and carbon dioxide laser have been used with varying degrees of success. Treatment of LP with acitretin has shown some efficacy for hoarseness after use over a long period, but there has been variable success in treating the skin lesions.\nPrognosis\nThe prognosis is generally favorable. Fatal outcomes are uncommon, but the disease may strongly impact quality of life.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Bernice KRAFCHIK  - Dr Irene LARA-CORRALES"}
{"Disease Name": "Lipoprotein glomerulopathy", "Disease Definition": "A rare genetic renal disease characterized by the formation of intraglomerular lipoprotein thrombi due to lipid deposition in severely dilated glomerular capillaries. Laboratory examination reveals abnormal serum lipid profiles, in particular markedly elevated apolipoprotein E. Clinical manifestations include proteinuria or nephrotic syndrome with hypertension and potential progression to chronic renal failure. Systemic complications of dyslipidemia are not observed.", "ORPHA ID": 329481, "Summary": ""}
{"Disease Name": "Liposarcoma", "Disease Definition": "Liposarcoma (LS), a type of soft tissue sarcoma, describes a group of lipomatous tumors of varying severity ranging from slow-growing to aggressive and metastatic. Liposarcomas are most often located in the lower extremities or retroperitoneum, but they can also occur in the upper extremities, neck, peritoneal cavity, spermatic cord, breast, vulva and axilla.", "ORPHA ID": 69078, "Summary": "Epidemiology\nLiposarcomas account for approximately 15-20% of all soft tissue sarcomas. The incidence is approximately 1 per 100, 000 persons/years.\nClinical description\nThey can affect all age groups but are most frequently seen in middle-aged and older adults. Liposarcomas are classified into 4 biological groups (encompassing five histological subtypes): well-differentiated (WDLS), dedifferentiated (DDLS), myxoid /round cell (MRCLS) and pleomorphic (PLS) (see these terms).\nEtiology\nThe etiology is unknown but many chromosomal aberrations are found in liposarcomas.\nPrognosis\nThe prognosis is dependent on the specific subtype, size, stage and location of the disease.\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Samuel SINGER"}
{"Disease Name": "Lipoyl transferase 1 deficiency", "Disease Definition": "A rare inborn error of metabolism disorder, with a highly variable phenotype, typically characterized by neonatal to infancy-onset of seizures, psychomotor delay, and abnormal muscle tone that may include hypo- and/or hypertonia, resulting in generalized weakness, dystonic movements, and/or progressive respiratory distress, associated with severe lactic acidosis and elevated lactate, ketoglutarate and 2-oxoacids in urine. Additional manifestations may include dehydration, vomiting, signs of liver dysfunction, extrapyramidal signs, spastic tetraparesis, brisk deep tendon reflexes, speech impairment, swallowing difficulties, and pulmonary hypertension.", "ORPHA ID": 401862, "Summary": ""}
{"Disease Name": "Lipoyl transferase 2 deficiency", "Disease Definition": "A rare inborn error of metabolism characterized by severe neonatal encephalopathy with EEG abnormalities, increased serum lactate, little or no psychomotor development, and sometimes death in infancy. Brain imaging may show cortical atrophy, enlarged ventricles, delayed myelination, and white matter abnormalities, among others.", "ORPHA ID": 447795, "Summary": ""}
{"Disease Name": "Lisch epithelial corneal dystrophy", "Disease Definition": "Lisch epithelial corneal dystrophy (LECD) is a very rare form of superficial corneal dystrophy characterized by feather-shaped opacities and microcysts in the corneal epithelium arranged in a band-shaped and sometimes whorled pattern, occasionally with impaired vision.", "ORPHA ID": 98955, "Summary": "Epidemiology\nExact prevalence of this form of corneal dystrophy is not known but very few cases have been reported to date. LECD has been documented in one German family and in rare sporadic cases in Germany and the USA.\nClinical description\nLesions generally develop in childhood. Epithelial opacities are slowly progressive and painless blurred vision sometimes occurs after 60 years of age.\nEtiology\nThe exact cause is unknown but appears to be genetic. The gene related to Lisch epithelial corneal dystrophy has been mapped to the short arm of the X chromosome (Xp22.3).\nGenetic counseling\nAn X-linked recessive pattern of inheritance has been reported.\nManagement and treatment\nThe pathologic corneal epithelium can be removed if the symptoms demand such a treatment.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Lissencephaly due to LIS1 mutation", "Disease Definition": "Lissencephaly due to LIS1 mutation is a cerebral malformation with epilepsy characterized predominantly by posterior isolated lissencephaly with developmental delay, intellectual disability and epilepsy that usually evolves from West syndrome to Lennox-Gastaut syndrome. Additional features include muscular hypotonia, acquired microcephaly, failure to thrive and poor control of airways leading to aspiration pneumonia.", "ORPHA ID": 95232, "Summary": ""}
{"Disease Name": "Lissencephaly due to TUBA1A mutation", "Disease Definition": "Lissencephaly (LIS) due to TUBA1A mutation is a congenital cortical development anomaly due to abnormal neuronal migration involving neocortical and hippocampal lamination, corpus callosum, cerebellum and brainstem. A large clinical spectrum can be observed, from children with severe epilepsy and intellectual and motor deficit to cases with severe cerebral dysgenesis in the antenatal period leading to pregnancy termination due to the severity of the prognosis.", "ORPHA ID": 171680, "Summary": ""}
{"Disease Name": "Lissencephaly syndrome, Norman-Roberts type", "Disease Definition": "Lissencephaly syndrome, Norman-Roberts type is characterised by the association of lissencephaly type I with craniofacial anomalies (severe microcephaly, a low sloping forehead, a broad and prominent nasal bridge and widely set eyes) and postnatal growth retardation.", "ORPHA ID": 89844, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nSevere intellectual deficit, spasticity and epilepsy are also present.\nEtiology\nMutations in the RELN gene (7q22) have been identified in some patients.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            March 2008"}
{"Disease Name": "Lissencephaly type 1 due to doublecortin gene mutation", "Disease Definition": "Type 1 lissencephaly due to doublecortin (DCX) gene mutations is a semi-dominant X-linked disease characterised by intellectual deficiency and seizures that are more severe in male patients.", "ORPHA ID": 2148, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nBoys presenting with lissencephaly show an abnormally thick cortex with very few gyri (pachygyria) or even none (agyria). Clinical manifestations include swallowing and feeding difficulties, abnormal muscular tone, seizures and severe to profound psychomotor retardation. Female patients display a less severe malformation referred to as ''doublecortex'' or subcortical laminar heterotopia (SCLH) and present with clinical signs of variable severity ranging from mild epilepsy, beginning in childhood or adolescence with difficulties at school, to refractory epileptic seizures and severe intellectual deficiency.\nEtiology\nThe condition is caused by doublecortin (DCX, located at Xq22.3-q23) gene mutations. These mutations lead to a specific defect of neuronal migration during embryogenesis, affecting all the neurons in males (lissencephaly) or only a population of neurons in heterozygous females, explaining why affected females display the less severe SCLH malformation. The DCX gene is linked to 50% of the cases of agyria, 33% of frontal pachygyria cases and 75% of SCLH cases. There is no correlation between the type of mutation and the severity of the disease. The group of type I lissencephalies includes Miller-Dieker syndrome and isolated lissencephalies linked to a deletion or point mutation in the LIS1 gene located on chromosome 17 (see these terms). In contrast to lissencephaly resulting from mutations in DCX, these types of lissencephaly are never familial.\nDiagnostic methods\nThe diagnosis of subcortical laminar heterotopia and lissencephaly relies on magnetic resonance imaging (MRI). There seems to be a correlation between the degree of pachygyria of the cortex, widening of the ventricles, and thickness of laminar heterotopia on the one hand, and early onset of attacks and severity of intellectual deficiency on the other hand.\nDifferential diagnosis\nSCLH should be distinguished from periventricular nodular heterotopia (see this term), which is also observed in girls, and is caused by a mutation in the filamin A gene, also located on the X chromosome. The clinical picture is milder with later onset and moderate epilepsy occurring in the young adult.\nGenetic counseling\nThe molecular diagnosis of SCLH and lissencephaly is useful for genetic counselling and potential early antenal diagnosis of this very severe epileptogenic encephalopathy, before the stage when gyri normally appear (15 weeks of amenorrhea). If the mother carries the mutation, her risk of having a child with the mutation is 50%. Even when the mutation fails to be detected in the mother's blood, a risk nevertheless exists for future pregnancies, due to germinal mosaicism (5% to 10% of the cases).\nManagement and treatment\nAntiepileptic medication generally succeeds in controlling epilepsy, although in some cases seizures do not completely resolve despite the use of several drugs. A gastric catheter or even a gastrotomy may be necessary to prevent complications linked to swallowing and feeding difficulties (malnutrition, regurgitation-induced pneumopathy). Orthopaedic problems (hip luxation, progressive scoliosis) can be prevented by posture correction and use of a surgical corset, which allow surgery to be delayed or avoided.\nPrognosis\nThe prognosis depends on the degree of cerebral involvement. Lissencephaly is a severe disease, potentially associated with multiple impairments. The prognosis of SCLH is more variable, and depends on the severity of learning difficulties and epilepsy.\n\n                            Last update: \n                            January 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Vincent DES PORTES"}
{"Disease Name": "Lissencephaly type 3-familial fetal akinesia sequence syndrome", "Disease Definition": "Lissencephaly type 3-familial fetal akinesia sequence syndrome is characterised by the association of microencephaly, agenesis of the corpus callosum, brainstem hypoplasia, cystic cerebellum and foetal akinesia sequence. Less than 10 cases have been described so far. The syndrome is transmitted as an autosomal recessive trait and may be an allelic variant of Neu-Laxova syndrome and lissencephaly type III with metacarpal bone dysplasia (see these terms).", "ORPHA ID": 86821, "Summary": ""}
{"Disease Name": "Lissencephaly type 3-metacarpal bone dysplasia syndrome", "Disease Definition": "A rare syndromic form of lissencephaly characterized by severe microcephaly, agyria, agenesis of the corpus callosum, cerebellar hypoplasia, facial dysmorphology and epiphyseal stippling of the metacarpal bones. The syndrome may be an allelic variant of Neu-Laxova syndrome and Lissencephaly type III with cystic dilations of the cerebellum and foetal akinesia sequence.", "ORPHA ID": 86822, "Summary": ""}
{"Disease Name": "Lissencephaly with cerebellar hypoplasia type A", "Disease Definition": "A rare, genetic, lissencephaly with cerebellar hypoplasia subtype characterized by classical lissencephaly with thickened cortical gray matter (with either no discernable gradient, a predominantly posterior gradient, or a predominantly anterior gradient) associated with variable, predominantly midline, cerebellar hypoplasia.", "ORPHA ID": 100011, "Summary": ""}
{"Disease Name": "Lissencephaly with cerebellar hypoplasia type B", "Disease Definition": "A rare form of lissencephaly with cerebellar hypoplasia characterized by subtle microcephaly, hypotonia and neurological and cognitive development delay. Hippocampal malformation is a characteristic imaging feature of this disorder.", "ORPHA ID": 100012, "Summary": ""}
{"Disease Name": "Lissencephaly with cerebellar hypoplasia type C", "Disease Definition": "A severe form of lissencephaly with cerebellar hypoplasia characterized by severe microcephaly, cleft palate, and severe cerebellar and brainstem hypoplasia leading to neonatal death.", "ORPHA ID": 100013, "Summary": ""}
{"Disease Name": "Lissencephaly with cerebellar hypoplasia type D", "Disease Definition": "A rare form of lissencephaly with cerebellar hypoplasia characterized by pronounced microcephaly (≤ -3 SD), intellectual disability, spastic diplegia and moderate to severe cerebellar hypoplasia involving both vermis and hemispheres.", "ORPHA ID": 100014, "Summary": ""}
{"Disease Name": "Lissencephaly with cerebellar hypoplasia type E", "Disease Definition": "A rare, genetic, lissencephaly with cerebellar hypoplasia subtype characterized by the presence of lissencephaly with an abrupt transition, near the boundary between the frontal and parietal cortex, from frontal agyria to posterior gyral simplification, associated with cerebellar hypoplasia which predominantly affects the midline vermis.", "ORPHA ID": 100015, "Summary": ""}
{"Disease Name": "Lissencephaly with cerebellar hypoplasia type F", "Disease Definition": "A severe form of lissencephaly with cerebellar hypoplasia, characterized by a microcephaly of at least - 3 SD and a thick cortex associated with complete absence of the corpus callosum.", "ORPHA ID": 100016, "Summary": ""}
{"Disease Name": "Lissencephaly with cerebellar hypoplasia", "Disease Definition": "Lissencephaly with cerebellar hypoplasia (LCH) is a variant form of lissencephaly and involves a heterogeneous group of cortical malformations without severe congenital microcephaly (>-3 SD). LCH is characterized by cerebellar underdevelopment ranging from vermian hypoplasia to total aplasia with classical or cobblestone lissencephaly. The phenotypic features of LCH include small head circumference (between -2 and -3 standard deviations (SD) forage) at birth and postnatally, moderate to severe intellectual disability, hypotonia and spasticity. Seizures are often observed and infantile spasms have been reported in some rare cases. LCH has been classified into six subgroups according to neuroradiographic properties and are classified LCH type A to F.", "ORPHA ID": 86823, "Summary": ""}
{"Disease Name": "Listeriosis", "Disease Definition": "A rare bacterial infectious disease caused by the foodborne pathogen Listeria monocytogenes, characterized by a febrile gastroenteritis, which is usually mild and self-limiting in otherwise healthy persons, but can progress to severe illness in at-risk groups like pregnant women, elderly people, immunocompromised people, and neonates. Complications include sepsis, meningitis, and encephalitis. Listeriosis during pregnancy usually occurs during the third trimester and may lead to preterm labor, miscarriage, stillbirth, or intrauterine infection of the unborn child.", "ORPHA ID": 533, "Summary": ""}
{"Disease Name": "Livedoid vasculopathy", "Disease Definition": "A rare vascular skin disease characterized by recurrent focal non-inflammatory thrombosis of dermal venulae, predominantly of the lower extremities, resulting in a cutaneous response manifested as pruritus and painful papules and erythematous plaques. The lesions evolve into hemorrhagic vesicles or bullae, which rupture and turn into painful ulcers merging into reticulate, confluent, geometric, and painful ulcerations. During a period of a few months, the ulcerations change to porcelain-white atrophic scars with punctate telangiectasia (so-called atrophie blanche). In active disease, lesions in different stages coexist.", "ORPHA ID": 542643, "Summary": ""}
{"Disease Name": "Liver adenomatosis", "Disease Definition": "A rare neoplastic disease characterized by the presence of ten or more hepatocellular adenomas in a background of normal appearing hepatic parenchyma. The majority of reported cases are female. There is no association with steroid use. The condition is considered benign, although the risk of complications (such as malignant transformation or spontaneous rupture with intraperitoneal hemorrhage) is much higher than in isolated hepatic adenoma. Hepatocellular carcinoma develops in less than 10% of cases.", "ORPHA ID": 566841, "Summary": ""}
{"Disease Name": "LMNA-related cardiocutaneous progeria syndrome", "Disease Definition": "LMNA-related cardiocutaneous progeria syndrome is a rare, genetic, premature aging syndrome characterized by adulthood-onset cutaneous manifestations that result in a prematurely aged appearance (i.e. premature thinning and graying of scalp hair, loss of subcutaneous fat, tightening of skin) associated with prominent cardiovascular manifestations, such as accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. Patients present loss of eyebrows and eyelashes in childhood and have a predisposition to develop malignancies.", "ORPHA ID": 363618, "Summary": ""}
{"Disease Name": "Lobar holoprosencephaly", "Disease Definition": "A form of holoprosencephaly characterized by separation of the right and left cerebral hemispheres and lateral ventricules with some continuity only across the frontal neocortex, especially rostrally and ventrally. Craniofacial features are variable may include ocular hypotelorism, midline cleft lip (complete or partial) and/or flat nose amongst other features.", "ORPHA ID": 93924, "Summary": ""}
{"Disease Name": "Localized dystrophic epidermolysis bullosa, acral form", "Disease Definition": "A form of localized dystrophic epidermolysis bullosa characterized by trauma-induced blistering confined primarily to the hands and feet. Healing of blisters is associated with milia formation, atrophic scarring and dystrophic nails. There is no extracutaneous involvement.", "ORPHA ID": 158673, "Summary": ""}
{"Disease Name": "Localized dystrophic epidermolysis bullosa, nails only", "Disease Definition": "A form of localized dystrophic epidermolysis bullosa characterized by dystrophic nails in the absence of blistering. The nail deformity is often limited to toenails which can appear thickened and shortened, or may be absent. No other cutaneous or extracutaneous symptoms are observed.", "ORPHA ID": 158676, "Summary": ""}
{"Disease Name": "Localized dystrophic epidermolysis bullosa, pretibial form", "Disease Definition": "A form of localized dystrophic epidermolysis bullosa characterized by the development of blisters, erosions, and lichenoid lesions predominantly in the anterior lower legs (pretibial areas and feet), the hands and nails. Individual lesions, which tend to be papular or plaque-like, are often violaceous. Pruritus is possible. Healing of blisters is associated with hypertrophic scarring and milia formation. Dystrophy of both fingernails and toenails is characteristic.", "ORPHA ID": 79410, "Summary": ""}
{"Disease Name": "Localized dystrophic epidermolysis bullosa", "Disease Definition": "A localized form of dystrophic epidermolysis bullosa characterized by blisters confined primarily to the hands and feet (acral form) or to the pretibial region (pretibial form). Nail dystrophy or loss is common and may be an isolated finding (nail only form).", "ORPHA ID": 595356, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nThe disorder manifests at birth or during infancy with trauma-induced blisters but in some cases may be delayed until the adolescence. Blisters are limited to the extremities or the anterior lower legs. Healing of blisters is associated with milia formation, atrophic scarring and dystrophic nails. There is no extracutaneous involvement. Individual lesions, which tend to be papular or plaque-like, are often violaceous, suggesting the clinical diagnosis of lichen planus. Some patients complain of pruritus. Dystrophy of both fingernails and toenails is characteristic.\nEtiology\nThe disorder is caused by mutations within the type VII collagen gene (COL7A1; 3p21.31). Mutations in this gene lead to an alteration in function of collagen VII. This impairs its assembly into anchoring fibrils that anchor the basement membrane to the underlying dermis.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and confirmed by genetic testing. Immunofluorescence antigen mapping and/or transmission electron microscopy on skin samples may show only discrete changes.\nDifferential diagnosis\nThe differential diagnosis includes localized subtypes of epidermolysis bullosa simplex or junctional EB and lichen planus.\nAntenatal diagnosis\nAntenatal diagnosis is not recommended.\nGenetic counseling\nThe disorder can be autosomal dominant or recessive. Genetic counseling will depend on the type of inheritance or if the disease occurs sporadically. The nail only form is usually autosomal dominant.\nManagement and treatment\nManagement is preventive: protective padding of the skin and appropriate lifestyle measures reduce blistering, and careful wound care prevents secondary infection and reduces scarring.\nPrognosis\nPrognosis is very good, life expectancy is not influenced by this form of EB.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Cristina HAS | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Localized epidermolysis bullosa simplex", "Disease Definition": "Localized epidermolysis bullosa simplex, formerly known as EBS, Weber-Cockayne, is a basal subtype of epidermolysis bullosa simplex (EBS, see this term). The disease is characterized by blisters occurring mainly on the palms and soles, exacerbated by warm weather.", "ORPHA ID": 79400, "Summary": "Epidemiology\nReported prevalence ranges from 1/318,000 for localized EBS in the United States to 1/35,000 for localized EBS and non-Dowling-Meara generalized EBS (combined) in Scotland. About two-thirds of EBS patients have the localized basal form.\nClinical description\nOnset is usually in late infancy or early childhood. The usual distribution of blisters in these patients is on the palms and soles, although other skin surfaces may also blister if subjected to significant trauma. Milia and scarring are rare in localized EBS, and dystrophic nails are uncommon. Focal keratoderma of the palms and soles may occur by adulthood in some patients. The only common extracutaneous finding in localized EBS, i.e. localized intraoral erosions or blisters, tends to be asymptomatic, occurs in about one third of patients, and is usually seen only during infancy.\nEtiology\nLocalized EBS is caused by dominant negative mutations within either the KRT5 (12q13.13) or KRT14 (17q12-q21) genes, encoding keratin 5 and keratin 14, respectively.\nGenetic counseling\nTransmission is autosomal dominant and sporadic cases are frequent.\nPrognosis\nAlthough the disease can be disabling, life-expectancy is normal.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "Localized junctional epidermolysis bullosa", "Disease Definition": "A form of junctional epidermolysis bullosa characterized by neonatal onset of localized blistering, and dystrophic or absent nails. Skin blistering is mainly confined to hands, feet, lower legs and face. Additional findings may include dental enamel hypoplasia and an increased incidence of caries.", "ORPHA ID": 251393, "Summary": ""}
{"Disease Name": "Localized lichen myxedematosus with mixed features of different subtypes", "Disease Definition": "Localized lichen myxedematosus (LM) with mixed features of different subtypes is a form of atypical lichen myxedematosus (see this term), characterized by mixed features of the 5 subtypes of localized LM which are: discrete papular LM, acral persistent papular mucinosis, self-healing papular mucinosis, papular mucinosis of infancy, and nodular LM (see these terms).", "ORPHA ID": 90398, "Summary": "Epidemiology\nLocalized LM with mixed features of different subtypes is a rare disease and to date only a few cases have been described in the literature.\nClinical description\nThe disease affects middle age adults and manifests with mixed features of the 5 subtypes of localized LM (discrete papular LM, acral persistent papular mucinosis, self-healing papular mucinosis, papular mucinosis of infancy, and nodular LM). One case is reported as having features of both acral persistent papular mucinosis and self-healing juvenile cutaneous mucinosis (see this term) with carpal tunnel syndrome.\nEtiology\nAs all primitive mucinosis, the pathogenesis of localized LM with mixed features of different subtypes is still unknown.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Elisa CINOTTI  - Pr Franco RONGIOLETTI"}
{"Disease Name": "Localized lichen myxedematosus with monoclonal gammopathy or systemic symptoms", "Disease Definition": "Localized lichen myxedematosus with monoclonal gammopathy or systemic symptoms is a form of atypical lichen myxedematosus (see this term), characterized by the appearance of several 2-4 mm erythematous waxy papules confined to a few sites that may be associated with either an immunoglobulin A (IgA) nephropathy in patients with acral persistent papular mucinosis; discrete papular lichen myxedematosus (see these terms); a scleromyxedema-like involvement, with dysphagia, hoarseness, pulmonary involvement, and carpal tunnel syndrome; myositis without skin sclerosis; or paraproteinemia.", "ORPHA ID": 90399, "Summary": ""}
{"Disease Name": "Localized lichen myxedematosus", "Disease Definition": "A group of skin diseases characterized by the development of papules, nodules and/or plaques with mucin deposits and a variable degree of fibrosis in the absence of thyroid disease. The group comprises five sub-forms: nodular lichen myxedematosus, discrete papular lichen myxedematosus, papular mucinosis of infancy, acral persistent papular mucinosis and self-healing papular mucinosis.", "ORPHA ID": 86795, "Summary": ""}
{"Disease Name": "Localized lipodystrophy", "Disease Definition": "A rare group of acquired lipodystrophies that are characterized by loss of subcutaneous tissue from generally small regions of the body, either single or multiple areas, and are not typically associated with metabolic complications. Some cases may involve lipohypertrophy (insulin). This group includes pressure-induced localized lipoatrophy, drug-induced localized lipodystrophy, panniculitis- induced localized lipodystrophy, centrifugal lipodystrophy, and idiopathic localized lipodystrophy.", "ORPHA ID": 79088, "Summary": "Epidemiology\nThe term covers a heterogeneous group of conditions for which the prevalence varies according to the cause.\nClinical description\nLocalized lipohypertrophy involves small body areas, manifesting as either a soft bump or a depression in the soft tissue, and are not usually accompanied by a metabolic syndrome. They are most frequently observed in association with repeated mechanical microtraumatism (pressure induced localized lipoatrophy) such as drug injection, but may also be seen as the sequelae of an inflammation (panniculitis-induced localized lipodystrophy). Drug-induced localized lipodystrophy is often observed in diabetes associated with steroid or antiretroviral treatment leading to possible android obesity, and sometimes a lipoatrophy of Bichat balls under antiretroviral drugs. Centrifugal lipodystrophy is characterized by fat loss spread in a centrifugal pattern from abdomen and groin area and is associated with peripheral panniculitis. It begins in infancy, stops spreading between the ages of 3 and 8 and then in most cases, resolves by itself. Panniculitis-induced localized lipodystrophy is characterized by an initial development of panniculitis followed by localized fat loss when these lesions heal. The disease is associated with serum ANA and anti dsDNA antibodies, patients may also have concurrent autoimmune diseases. Localized lipoatrophy is not painful but can induce discomfort, especially when they are localized in a support zone such as the bottom, or dressing difficulties or aesthetic prejudice.\nEtiology\nLocalized lipodystrophy is generally iatrogenic and secondary to medication injections (somatostatin analogs, pegvisomant, insulin), vaccines or repetitive pressure trauma. In addition certain medications can induce localized lipodystrophy such as steroids or antiretroviral treatment, or it can be triggered by panniculitis (such as nodular non-suppurative panniculitis, Weber-Christian syndrome). The etiology for idiopathic localized lipodystrophy and centrifugal localized lipodystrophy remains unknown.\nDifferential diagnosis\nDifferential diagnoses may include scleroderma, idiopathic dermal atrophy, idiopathic atrophoderma of Pasini and Pierini, and Gowers panatrophy.\nAntenatal diagnosis\nNot applicable.\nGenetic counseling\nNot applicable.\nManagement and treatment\nTreatment should revolve around elimination of the cause whenever possible: modification of the injection technique or plastic surgery if necessary. Localized lipodystrophy associated with insulin therapy usually resolves in a few weeks after changing the site of injection and modification of the length of the needle.\nPrognosis\nThe prognosis depends on the cause but is more severe in case of panniculitis.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Marie-Christine VANTYGHEM"}
{"Disease Name": "Localized pagetoid reticulosis", "Disease Definition": "A rare variant of mycosis fungoides (MF), a form of cutaneous T-cell lymphoma, characterized by the presence of localized patches or plaques with epidermal hyperplasia and intraepidermal proliferation of neoplastic T-cells, usually involving one extremity.", "ORPHA ID": 178517, "Summary": "Epidemiology\nThe annual incidence of MF and its variants is estimated at between 1/350,000 and 1/110,000, with localized pagetoid reticulosis accounting for less than 2% of MF cases. Exact data on the male to female ratio are unavailable.\nClinical description\nOnset usually occurs in the 4th to 5th decade of life, but younger patients may be affected in rare cases. Patients present with solitary psoriasiform or hyperkeratotic patches or plaques. Extracutaneous involvement is exceptional in the solitary variant, but rarely the disease may progress to \"conventional\" MF.\nEtiology\nThe etiology remains unknown.\nDiagnostic methods\nThe diagnosis is based on clinical presentation and is confirmed by a skin biopsy. Histological findings reveal a hyperplastic epidermis with marked infiltration by atypical \"haloed\" lymphocytes that have medium-sized, pleomorphic nuclei. Immunohistology shows either a memory T-helper (CD3+, CD4+, CD8-) or a T-cytotoxic (CD3+, CD4-, CD8+) phenotype. CD30 may be positive.\nDifferential diagnosis\nThe differential diagnosis includes other epidermotropic lymphomas, such as CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (aggressive cutaneous T-cell lymphoma: see this term).\nManagement and treatment\nRadiotherapy and surgical excision are the main treatment options. Topical steroids may also be effective.\nPrognosis\nLocalized pagetoid reticulosis is slowly progressive. Prognosis is favorable: disease-related death has never been reported in these patients.\n\n                            Last update: \n                            June 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Lorenzo CERRONI"}
{"Disease Name": "Localized scleroderma", "Disease Definition": "A rare skin disease characterized by inflammatory and sclerosing disease affecting the skin and underlying connective tissues (subcutaneous tissue, fascia, muscle or bone). It causes cutaneous patches or bands of skin inflammation and thickness affecting the head, neck region, trunk and extremities.", "ORPHA ID": 90289, "Summary": "Epidemiology\nThe incidence of localized scleroderma has been estimated at 1/37,000-625,000 people per year depending on the country. Women are predominantly affected (F/M sex ratio around 3:1). The mean age at diagnosis ranges from 8 to 47 years. In two-thirds of cases, it occurs in adults. Localized scleroderma is called ''juvenile'' when occurring in childhood (peak incidence between 7 and 11 years).\nClinical description\nLocalized scleroderma is classified into several subtypes (there is no consensual classification) that include limited (circumscribed or plaque morphea), generalized (≥4 lesions and/or ≥2-3 anatomical sites) or pansclerotic morphea, and linear morphea. Linear morphea tends to affect children and adolescents, while plaque morphea is more common in adults. However, both can coexist in the same patient (mixed morphea). First, areas of hard and dry skin develop in the hands, arms, face, or leg in an ipsilateral fashion. Then, plaques that spread centrifugally or wide strips (linear scleroderma) appear. Plaques are round or oval, often with a white appearance and a violaceous border. Linear scleroderma mainly develops on the face, thorax, arms, and legs. In the case of facial involvement, some strips developing on the forehead may be hollow and lead to a sabre-cut appearance (termed ''en coup de sabre''). Linear scleroderma tends to involve the underlying fat and muscles and may lead to muscle atrophy, ophthalmologic or neurological disorders such as headaches, seizures or uveitis. Localized scleroderma can result in major facial or limb asymmetry, flexion contractures, and disability. Raynaud's phenomenon is usually absent. It is important to note that localized scleroderma does not evolve into systemic sclerosis (rarely, systemic sclerosis and localized scleroderma can co-exist).\nEtiology\nThe exact cause of localized scleroderma is unknown. The disease originates from a combination of genetic predisposition and environmental factors, implies vascular and autoimmune pathways which lead to localized overproduction of extracellular matrix (collagen).\nDiagnostic methods\nDiagnosis is based on clinical presentation. A skin biopsy may help to confirm the diagnosis by revealing abnormal accumulation of collagen, thickening of the vessel walls, and the presence of inflammatory infiltrates in the papillary dermis and around the vessels. Blood tests are usually normal. Some patients may have antinuclear antibodies excluding systemic sclerosis-associated specificities (anti-topoisomerase, anti-centromere or anti-RNA polymerase III antibodies).\nDifferential diagnosis\nThe differential diagnosis includes (but is not limited to): lichen sclerosus, granuloma annulare, erythema chronicum migrans, drug-induced dermatitis, eosinophilic fasciitis or systemic sclerosis, especially in case of generalized/pansclerotic morphea.\nManagement and treatment\nManagement is symptomatic and includes the use of topical steroids, tacrolimus, vitamin D derivates or imiquimod for morphea lesions, and systemic steroids, methotrexate or phototherapy for linear scleroderma of the neck and extremities with potential functional/esthetic consequences, or for generalized morphea. Treatment should be initiated promptly to prevent irreversible tissue damage. Physical therapy may be helpful to limit cutaneous indurations and muscle retraction.\nPrognosis\nPrognosis is usually favorable within 5 years but some patients may present with chronic disease and recurrences. Localized scleroderma is only rarely life threatening but can severely affect quality of life, particularly in children. Linear lesions tend to persist longer than plaque lesions.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Vincent SOBANSKI"}
{"Disease Name": "Locked-in syndrome", "Disease Definition": "A rare neurologic disease characterized by severe paralysis of the limbs and the oral structures causing the person to be completely dependent on help in all activities of daily living and communication, while having preserved cognition. Most commonly, the term locked-in syndrome (LIS) is used when the condition is caused by acquired brain injury (as in this text), but sometimes also when referring to the advanced stage of certain neurodegenerative disorders.", "ORPHA ID": 2406, "Summary": "Epidemiology\nLIS is a very rare condition. No prevalence studies have been published. A study published in 1986 identified 139 cases in the literature. A recent (2023) national population-based study from Norway reported 16 cases living with LIS in a population of approximately 5.425 million (1 out of 339,000 individuals).\nClinical description\nLIS can be classified into 3 categories: classic, where patients are quadriplegic and anarthric with preserved consciousness and upper eyelid and vertical eye movements; incomplete, where patients have limited voluntary movements in addition to vertical eye movements; total, where patients show complete immobility including eye movements.\nEtiology\nThe most common cause of LIS is vascular lesions; trauma, infection, myelinolysis, polyneuropathy and demyelination are rare etiologies.\nDiagnostic methods\nDiagnosis is based on clinical features. The presence of cognitive abilities and willingness to communicate is frequently noticed by patient's relatives or caregivers. Eye movement response to verbal commands should systematically be searched for in apparent vegetative state cases. Unambiguous but limited signs of consciousness (voluntary eye movements or blinking), fluctuations of vigilance and cognitive or sensory deficits lead to diagnostic difficulties. A normal and reactive EEG rhythm should alert the physician but is not sufficient to disentangle LIS from unconscious patients. Brain imaging (ideally MRI) usually shows isolated lesions of the ventral portion of the pons or midbrain, but cerebral lesions outside the brain stem might occur in as much as 80% of the cases.\nDifferential diagnosis\nDifferential diagnoses include coma, vegetative state/unresponsive wakefulness and minimally conscious states.\nManagement and treatment\nInitial management is based on respiratory assistance, gastrostomy and prevention of any immobility, dysphagia and incontinence complications. It is important to establish a mode of communication; eye movements are preferred rather than blinking. As the individual is completely dependent on help, one needs to assure the patient feels safe. Rehabilitation should start in the acute phase and be continued throughout the subacute stage. Cornerstones are chest physiotherapy, recovery of independent swallowing and continence, and motor rehabilitation. Motor progress should be accurately monitored as even small movements might be used for interaction by switches etc. Often, communication methods can be gradually refined as a number of technical solutions are available. Brain-computer interfaces (BCI) are of growing help to provide more direct and spontaneous ways of communication.\nPrognosis\nIn the acute phase, patients may rarely experience a transient LIS, while some patients do not survive. Further prognosis varies. Usually some motor improvement occurs. Almost 9 out of 10 patients who are ''locked in'' for at least 6 weeks remain highly dependent on help while 1 in 20 experiences complete motor recovery. Young age at onset and early intensive rehabilitation are probably favorable prognostic factors. LIS caused by a non-vascular brain injury seems to have better motor recovery.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Frank BECKER"}
{"Disease Name": "Loeffler endocarditis", "Disease Definition": "A rare restrictive cardiomyopathy characterized by hypereosinophilia and fibrous thickening of the endocardium, with usually large thrombi against the ventricle walls, that can lead to cardiovascular complications such as heart failure and thromboembolism. It manifests with symptoms like edema, fatigue and shortness of breath. It is usually secondary to eosinophil-associated tissue damage and is associated with idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, carcinoma, or lymphoma.", "ORPHA ID": 75566, "Summary": ""}
{"Disease Name": "Loeys-Dietz syndrome", "Disease Definition": "Loeys-Dietz syndrome is a rare genetic connective tissue disorder characterized by a broad spectrum of craniofacial, vascular and skeletal manifestations with four genetic subtypes described forming a clinical continuum.", "ORPHA ID": 60030, "Summary": ""}
{"Disease Name": "Logopenic progressive aphasia", "Disease Definition": "Logopenic progressive aphasia (lv-PPA) is a form of primary progressive aphasia (PPA; see this term), characterized by impaired single-word retrieval and naming and impaired repetition with spared single-word comprehension and object knowledge.", "ORPHA ID": 250831, "Summary": ""}
{"Disease Name": "Loiasis", "Disease Definition": "Loiasis is a form of filariasis (see this term), caused by the parasitic worm Loa loa, endemic to the forest and savannah regions of Central and Western Africa. Loiasis may either be asymptomatic or manifest as a large, transient area of localized, non-erythematous subcutaneous edema (Calabar swellings), adult worm migration through the sub-conjunctiva (''African eye worm'') and pruritus. Generalized itching, hives, muscle pains, arthralgias, fatigue, and adult worms visibly migrating under the surface of the skin may be observed. Severe complications such as encephalopathy have been reported in highly infected individuals receiving ivermectin during mass drug administration programs for the control of onchocerciasis and lymphatic filariasis (see these terms).", "ORPHA ID": 2404, "Summary": ""}
{"Disease Name": "Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency", "Disease Definition": "A mitochondrial disorder of long chain fatty acid oxidation characterized in most patients by onset in infancy/ early childhood of hypoketotic hypoglycemia, metabolic acidosis, liver disease, hypotonia and, frequently, cardiac involvement with arrhythmias and/or cardiomyopathy.", "ORPHA ID": 5, "Summary": "Epidemiology\nThe worldwide birth prevalence is estimated at 1/250,000. However around the Baltic Sea the frequency is higher; birth prevalence is predicted to be 1/120,000 in Poland and 1/20,000 in the Pomeranian district.\nClinical description\nMost patients display a severe phenotype that presents in infancy, usually from the neonatal period up until 12 months of age. The disease manifests as hypoketotic hypoglycemia, metabolic acidosis, hypotonia, liver involvement with hepatic encephalopathy, cardiomyopathy and arrhythmias. Clinical presentation is frequently preceded by fasting and/or intercurrent illness and often presents with hypoketotic hypoglycemia. Chronic peripheral neuropathy and pigmentary retinopathy develop over time in many surviving patients. Rarer presentations of LCHADD are sudden cardiac arrest or sudden infant death. HELLP syndrome (see this term) often occurs in pregnant women carrying a fetus affected with LCHADD.\nEtiology\nLCHADD is caused by the isolated deficiency of long chain 3-hydroxyacyl-CoA dehydrogenase, an enzyme of the mitochondrial trifunctional protein complex (TFP). TFP is a heterooctamer of 4 alpha and 4 beta subunits. LCHADD is due to mutations in the HADHA gene (2p23) which encodes for the alpha subunit of TFP. The majority of patients with LCHADD of European origin are homozygous for the common LCHADD alpha-subunit mutation 1528G>C, that is located at the catalytic site of the LCHAD domain.\nDiagnostic methods\nUrine organic acids show a C6-C14 (hydroxy) dicarboxylic aciduria. Blood acylcarnitine analysis shows increased long chain hydroxyacylcarnitine species (C14-OH, C16-OH, C18-OH, and C18:1-OH). Confirmation is by molecular analysis of the HADHA gene that frequently demonstrates homozygocity for the 1528G>C mutation. Enzyme analysis of cultured fibroblasts or lymphocytes shows isolated deficiency of long chain 3-hydroxyacyl-CoA dehydrogenase activity. Newborn screening for LCHADD is available in Austria, Czech Republic, Denmark, Germany, Hungary, Iceland, Netherlands and Portugal.\nDifferential diagnosis\nMitochondrial trifunctional protein deficiency (TFPD; see this term) is clinically indistinguishable from LCHADD. Some patients present as sudden infant death so this also needs to be excluded.\nAntenatal diagnosis\nPrenatal diagnosis is by molecular analysis for established mutation(s) within the family and/or by measuring enzyme activity in chorionic villi samples.\nGenetic counseling\nLCHADD is inherited autosomal recessively and genetic counseling is available.\nManagement and treatment\nTreatment involves strict adherence to a low fat diet with restriction of long chain fatty acid intake and substitution with medium chain fatty acids and avoidance of fasting as well as limitation of exercise or exposure to environmental extremes. An emergency regimen should be available for all patients and medical attention should be sought at the first sign of any decompensation. Treatment is lifelong.\nPrognosis\nThe prognosis for clinically detected LCHADD patients was generally poor but due to early detection and current treatments, it is improving, with a significant number of patients surviving into adulthood.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Simon OLPIN"}
{"Disease Name": "Longitudinal vaginal septum", "Disease Definition": "A rare vaginal malformation characterized by the presence of a complete or incomplete septum dividing the vagina into two parallel cavities, resulting from failure of reabsorption of the midline uterine septum between the two fused Müllerian ducts during embryogenesis. Patients are often asymptomatic, but may present with menorrhagia, dysmenorrhea, dyspareunia, infertility, or spontaneous abortion. The condition may occur as an isolated malformation or in association with other Müllerian duct anomalies (such as septate uterus or uterus didelphys) or renal abnormalities.", "ORPHA ID": 180157, "Summary": ""}
{"Disease Name": "Loose anagen syndrome", "Disease Definition": "Loose anagen syndrome is a rare benign hair disorder affecting predominantly blond females in childhood and characterized by the presence of hair that can be easily and painlessly pulled out. Most of the hair is in the anagen phase and lacks an external epithelial sheath. Hair grows back quickly and the condition improves spontaneously with aging. Loose anagen hair can be associated with other anomalies, such as coloboma.", "ORPHA ID": 168, "Summary": ""}
{"Disease Name": "Low phospholipid-associated cholelithiasis", "Disease Definition": "A rare genetic hepatic disease characterized by low biliary phospholipid concentration with symptomatic and recurring cholelithiasis which develops before the age of 40 years.", "ORPHA ID": 69663, "Summary": "Epidemiology\nThis syndrome is infrequent and corresponds to a small subgroup of patients with symptomatic gallstone disease.\nClinical description\nPatients with LPAC syndrome present typically with the following main features: age less than 40 years at onset of symptoms, recurrence of biliary symptoms after cholecystectomy, intrahepatic hyperechoic foci or sludge or microlithiasis along the biliary tree.\nEtiology\nA defect in ABCB4 function causes the production of bile with low phospholipid content, increased lithogenicity and high detergent properties leading to bile duct luminal membrane injuries and resulting in cholestasis with increased serum gamma-glutamyltransferase (GGT) activity.\nDiagnostic methods\nIntrahepatic gallstones may be detected by ultrasonography (US), computing tomography (CT), abdominal scan or magnetic resonance cholangiopancreatography. Intrahepatic hyperechogenic foci along the biliary tree may be detected by US, and hepatic bile composition (phospholipid content) may be determined by duodenoscopy.\nManagement and treatment\nIn all cases where ABCB4 genotyping confirms the diagnosis of LPAC syndrome in young adults, long-term curative or prophylactic therapy with ursodeoxycholic acid (UDCA) should be initiated early to prevent the occurrence or recurrence of the syndrome and its complications. Cholecystectomy is indicated in the case of symptomatic gallstones. Biliary drainage or partial hepatectomy may be indicated in the case of symptomatic intrahepatic bile duct dilatations filled with gallstones. Patients with end-stage liver disease may be candidates for liver transplantation.\n\n                            Last update: \n                            July 2007"}
{"Disease Name": "Low-flow priapism", "Disease Definition": "A rare urogenital condition characterized by a persistent unwanted painful erection that lasts more than 4 hours, caused by obstruction of the normal drainage of blood from the erectile tissues, leading to ischemia. It may be due to hematological diseases, metabolic or neurological disorders, and some erectile dysfunction medications. If the condition continues for several days, abnormal thickening and scarring of the erectile tissue may develop, causing permanent erectile dysfunction.", "ORPHA ID": 140949, "Summary": ""}
{"Disease Name": "Low-grade neuroendocrine tumor of the corpus uteri", "Disease Definition": "Low-grade neuroendocrine tumor of the corpus uteri is an extremely rare uterine cancer typically characterized by a well demarcated, solid, frequently pedunculated tumor originating from neuroendocrine cells scattered within the endometrium, often associated with ectopic hormone production. Patients usually present with vaginal bleeding or discharge and a pelvic mass with a polypoid tumor sometimes protruding through the cervical canal. Symptoms related to ectopic hormone production (flushing, sweating, diarrhea, bronchospasm) may also develop.", "ORPHA ID": 213736, "Summary": ""}
{"Disease Name": "Lowe-Kohn-Cohen syndrome", "Disease Definition": "Lowe-Kohn-Cohen syndrome is an extremely rare anorectal malformation syndrome characterized by imperforate anus, closed ano-perineal fistula, preauricular skin tag and absent renal abnormalities and pre-axial limb deformities. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 2408, "Summary": ""}
{"Disease Name": "Lower limb hypertrophy", "Disease Definition": "A rare, genetic, non-syndromic developmental defect during embryogenesis disorder characterized by uni- or bilateral overgrowth of lower limbs involving bones and/or soft tissues and resulting in an abnormal increase in leg length and/or width. Hypertrophy presents either as a proportionate overgrowth of entire limb or involves only the proximal or distal parts of it. Phenotype ranges from mild hypertrophy without functional disability to massively hypertrophied limb with knee flexion and ankle equinus contractures and macrodystrophia lipomatosa. Patients may also present vascular abnormalities (e.g. cutaneous angiomas, varicose veins) and myalgia.", "ORPHA ID": 295051, "Summary": ""}
{"Disease Name": "Lower limb malformation-hypospadias syndrome", "Disease Definition": "Lower limb malformation-hypospadias syndrome is a rare developmental defect during embryogenesis characterized by severe, uni- or bilateral lower limb malformations (incl. tibial hypoplasia, split and rocker bottom-shaped feet, and oligosyndactyly), normal upper limbs and hypospadias. Additional dysmorphic features (e.g. short neck and low-set, large ears), atrial septal defect, ureteropelvic junction stenosis and slight septation of the spleen, have also been reported. There have been no further descriptions in the literature since 1977.", "ORPHA ID": 2487, "Summary": ""}
{"Disease Name": "Lower lip fistula", "Disease Definition": "A rare otorhinolaryngological malformation characterized by congenital, typically bilateral and paramedian, symmetric or asymmetric fistulae in the lower lip, which are lined by labial mucosa. The malformation is usually asymptomatic, although it may communicate with accessory salivary glands and then result in secretion of saliva from the opening. Infections may also occur.", "ORPHA ID": 141064, "Summary": ""}
{"Disease Name": "Lower motor neuron syndrome with late-adult onset", "Disease Definition": "A rare, genetic, motor neuron disease characterized by slowly progressive, predominantly proximal, muscular weakness and atrophy which typically manifests with muscle cramps, fasciculations, decreased/absent deep tendon reflexes, hand tremor, and elevated serum creatine kinase at onset and later associates with reduced walking ability and impaired vibration sensation.", "ORPHA ID": 276435, "Summary": "Epidemiology\nMore than 97 patients have been described with Lower motor neuron syndrome with late-adult onset to date, all originating from Finland, where the point prevalence estimate rises to 1/8,000 in northern Karelia.\nClinical description\nThe main early signs generally present after 30 to 40 years of age, and usually include muscle cramps, fasciculations, decreased/absent deep tendon reflexes, elevated serum creatine kinase, and hand tremor. Disease progresses slowly and leads to muscular weakness and mild to moderate atrophy (predominantly affecting the proximal lower limbs, although occasional distal upper limb and abdominal involvement has also been reported). Impaired vibration sensation in the lower limbs may occur later in life, and some patients may develop mild dysphagia. Additional signs and symptoms include myalgia, and fatty degenerative replacement predominantly in the calves and hamstrings muscles. Respiratory functions are usually normal and there are no upper motor neuron signs.\nEtiology\nThe disease is caused by a pathogenic mutation (p.G66V) in the CHCHD10 gene (22q11.2), encoding a mitochondrial, coiled-coil-helix-coiled-coil-helix protein of unknown function. CHCHD10 is involved in oxidative phosphorylation and possibly takes part in mitochondrial complex function (particularly complex IV), and in maintaining mitochondrial DNA. The exact pathogenic mechanism of this mutation remains poorly understood.\nDiagnostic methods\nDiagnosis is based on clinical and electromyographic evaluation showing prominent fasciculations and chronic denervation in all limbs and possibly in the trunk, as well as evidence of neurogenic changes on muscle biopsy. Diagnosis is confirmed by identification of a causative mutation on the CHCHD10 gene.\nDifferential diagnosis\nThe disorder must be differentiated from other neuromuscular diseases, including autosomal dominant adult-onset proximal spinal muscular atrophy and amyotrophic lateral sclerosis (ALS), due to significant genetic and/or clinical overlap.\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with a known disease causing mutation.\nGenetic counseling\nThe disease follows an autosomal dominant pattern of inheritance. Genetic counseling should be provided to affected families, informing them of the 50% risk of transmission in future pregnancies.\nManagement and treatment\nDisease management is mainly symptomatic, as no specific treatment is available to date.\nPrognosis\nThe disease has a relatively mild course, as most patients remain ambulatory for several decades after disease onset and present a normal life expectancy.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Manu JOKELA"}
{"Disease Name": "Lown-Ganong-Levine syndrome", "Disease Definition": "Lown-Ganong-Levine syndrome is an extremely rare conduction disorder characterized by a short PR interval (less than or equal to 120 ms) with normal QRS complex on electrocardiogram associated with the occurrence of episodes of atrial tachyarrythmias (e.g. atrial fibrillation, atrial tachycardia).", "ORPHA ID": 844, "Summary": ""}
{"Disease Name": "Lowry-MacLean syndrome", "Disease Definition": "Lowry-MacLean syndrome is a very rare syndrome characterized by microcephaly, craniosynostosis, glaucoma, growth failure and visceral malformations.", "ORPHA ID": 2409, "Summary": "Epidemiology\nOnly three cases have been reported in the literature in three unrelated families.\nClinical description\nDysmorphic features include trigonocephaly, exotropia, cleft palate, beaked nose and low-set ears. All the affected patients have associated congenital visceral malformations including congenital heart defects, diaphragmatic hernia, genital or cerebral abnormalities.\nGenetic counseling\nThe demonstration of congenital glaucoma, hallmark of the syndrome, in the father of an affected patient, supports autosomal dominant inheritance.\nPrognosis\nPrognosis is poor.\n\n                            Last update: \n                            January 2010"}
{"Disease Name": "Lowry-Wood syndrome", "Disease Definition": "A rare disorder characterized by the association of epiphyseal dysplasia, short stature, microcephaly and, in the first reported cases, congenital nystagmus. So far, less than 10 cases have been described in the literature. Variable degrees of intellectual deficit have also been reported. Other occasional features include retinitis pigmentosa and coxa vara. Transmission appears to be autosomal recessive.", "ORPHA ID": 1824, "Summary": ""}
{"Disease Name": "LRP5-related primary osteoporosis", "Disease Definition": "A rare primary bone dysplasia characterized by reduced bone mineral density (defined as a Z score below -2.0), vertebral compression fractures, and recurrent peripheral fractures caused by low-impact trauma, leading to bone pain and impaired mobility. Patients typically become symptomatic in childhood or adolescence.", "ORPHA ID": 498481, "Summary": ""}
{"Disease Name": "Lujan-Fryns syndrome", "Disease Definition": "The Lujan-Fryns syndrome or X-linked mental retardation (XLMR) with marfanoid habitus syndrome is a syndromic X-linked form of intellectual disability, associated with tall, marfanoid stature, distinct facial dysmorphism and behavioral problems.", "ORPHA ID": 776, "Summary": "Epidemiology\nThe syndrome affects predominantly males. The prevalence in the general population is not known.\nClinical description\nPatients present tall stature, long hyper-extensible fingers and toes, short halluces and long second toes. Patients have mild to moderate intellectual disability. Craniofacial features include long forehead, long narrow face, maxillary hypoplasia, small mandible, long nose with high and narrow nasal bridge, short and deep philtrum, thin upper lip and highly arched palate. The marfanoid stature becomes evident after puberty. In adulthood, patients are tall but height is in the normal range. A hypernasal voice and generalized hypotonia are often present. Secondary sexual development and testicular size are normal. Behavioral features include emotional instability, hyperactivity and shyness. Psychiatric disorders such as psychotic disturbances with hallucinatory visions and sounds, and schizophrenia can be present.\nEtiology\nThe Lujan-Fryns syndrome is a developmental disorder of genetic origin. In the original Lujan family, a novel missense mutation in the mediator complex subunit 12, MED12 gene (Xq13) was found as the cause of Lujan-Fryns syndrome. Defects in this gene also cause FG syndrome (see this term). In some cases, mutations in the UPF3B gene (Xq25-q26) and in the ZDHHC9 gene (Xq26.1) have been reported in XLMR with marfanoid habitus.\nDiagnostic methods\nDiagnosis is based on the clinical manifestations and can be confirmed by the presence of the missense mutation in the MED12 gene. However, the frequency of the presence of a mutation in patients with the clinical diagnosis of Lujan-Fryns syndrome is not known.\nDifferential diagnosis\nDifferential diagnosis includes the fragile X syndrome (molecular analysis of the FMR-1 gene), Marfan syndrome (cardiac and ophthalmologic examination) (see these terms), and homocystinuria (biochemical analysis). Lujan-Fryns syndrome should be considered in the differential diagnosis of schizophrenia.\nAntenatal diagnosis\nThere is currently no specific prenatal test for this condition. However, prenatal diagnosis for at-risk pregnancies first requires identification of the mutations in the family. Molecular analysis of the MED12 gene in chorionic villus samples is possible.\nGenetic counseling\nGenetic counseling, based on the X-linked mode of inheritance, should be offered to patients with a prior identified MED12 gene mutation.\nManagement and treatment\nThere is no specific treatment for this condition. Patients require specialized education and psychological follow-up. Psychiatric disorders (psychosis) should be diagnosed as early as possible.\nPrognosis\nData on life expectancy are not available as most reports describe patients in adolescence and young adulthood. Special attention should be given to comorbidity and behavioral problems.\n\n                            Last update: \n                            January 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Griet VAN BUGGENHOUT"}
{"Disease Name": "Lujo hemorrhagic fever", "Disease Definition": "Lujo hemorrhagic fever, caused by the Lujo virus (a newly discovered Old World arenavirus) is a zoonotic disease from Zambia, Africa, whose reservoir is unknown and is characterized by fever and hemorrhagic manifestations with an extremely high fatality rate of 80% (in the 5 reported cases to date) and a moderate to high level of nosocomial transmission.", "ORPHA ID": 319213, "Summary": ""}
{"Disease Name": "LUMBAR syndrome", "Disease Definition": "A disorder defining by the association of Perineal hemangioma, External genitalia malformations, Lipomyelomeningocele, Vesicorenal abnormalities, Imperforate anus, and Skin tag. Eleven cases have been reported.", "ORPHA ID": 83628, "Summary": ""}
{"Disease Name": "Lung agenesis-heart defect-thumb anomalies syndrome", "Disease Definition": "A rare genetic disease characterized by the association of unilateral complete or partial lung agenesis, complex congenital cardiac anomalies such as atrial septal defect, total anomalous pulmonary venous return, or patent ductus arteriosus, and ipsilateral or bilateral thumb abnormalities. Presence of facial dysmorphism and other malformative features has also been reported.", "ORPHA ID": 1120, "Summary": ""}
{"Disease Name": "Lung fibrosis-immunodeficiency-46,XX gonadal dysgenesis syndrome", "Disease Definition": "Lung fibrosis-immunodeficiency-46,XX gonadal dysgenesis syndrome is characterised by immune deficiency, gonadal dysgenesis and fatal lung fibrosis. So far, it has been described in two sisters born to consanguineous parents. Both karyotypes were normal female (46,XX). No genetic anomalies could be identified by comparative genome hybridization analysis of their genomes or by analysis of genes known to be associated with these types of anomalies.", "ORPHA ID": 137631, "Summary": ""}
{"Disease Name": "Lupus erythematosus panniculitis", "Disease Definition": "A rare form of chronic cutaneous lupus erythematosus characterized by recurrent, indurated, erythematous plaques and subcutaneous nodules with normal overlying epidermis, occurring predominantly on the face, upper arms, trunk, buttocks, and thighs. The lesions can ulcerate and lead to scarring. Histological findings include lobular lymphocytic panniculitis, hyaline fat necrosis, mucin deposition, and calcification. The condition may be associated with discoid or systemic lupus erythematosus.", "ORPHA ID": 90285, "Summary": ""}
{"Disease Name": "Lupus erythematosus tumidus", "Disease Definition": "A rare form of chronic cutaneous lupus erythematosus characterized by extreme photosensitivity with intermittent formation of erythematous, edematous, urticarial-like, smooth plaques on sun-exposed skin areas. The lesions heal without scarring. The course of the disease is benign, and development of systemic lupus erythematosus is infrequent. Most patients do not have lupus-related autoantibodies. Skin biopsy shows a perivascular and periadnexal lymphocytic infiltrate and increased dermal mucin deposition without involvement of the dermoepidermal junction.", "ORPHA ID": 90283, "Summary": ""}
{"Disease Name": "Luscan-Lumish syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by a variable phenotype including macrocephaly, postnatal overgrowth, advanced carpal ossification, obesity, speech delay, intellectual disability, autism spectrum disorders, and behavioral difficulties with aggressive outbursts, and variable facial dysmorphism. Seizures, structural abnormalities of the brain, as well as a variety of other manifestations such as recurrent otitis media, joint hypermobility, hirsutism, or naevi have also been reported.", "ORPHA ID": 597738, "Summary": ""}
{"Disease Name": "Lyme disease", "Disease Definition": "Lyme disease (named after the towns in the USA where the disease was first identified) is a bacterial infection caused by Borrelia burgdorferi.", "ORPHA ID": 91546, "Summary": "Epidemiology\nIncidence is variable and is estimated at 1-70/20,000 in Europe.\nClinical description\nThe clinical manifestations can be divided into three stages. Onset of the initial stage occurs between three days and one month after being bitten by an infected tick (generally the patient is aware of the bite) and is marked by erythema migrans, a characteristic cutaneous lesion that appears over time at various sites of the body. The second stage is characterized by dissemination to the central nervous system (resulting in facial paralysis, encephalitis etc.), joints, skin, heart and eye. The third (chronic) stage of the disease is characterized by joint, neurologic and cutaneous manifestations.\nEtiology\nThe disease is transmitted to humans by bites from contaminated ticks (Ixodes) but rodents, birds and lizards are the main hosts.\nDiagnostic methods\nDiagnosis relies on recognition of the clinical picture during the initial stage of the disease, detection of  Borrelia burgdorferi through analysis of cultures, PCR and detection of  Borrelia burgdorferi DNA, or through elevations in antibody levels in patients in the second and third stages of the disease.\nPrognosis\nTreatment revolves around administration of antibiotics (amoxicillin and cyclines); with the treatment being more effective the earlier the antibiotics are administered. Prevention revolves around eradication of the ticks and on individuals taking protective measures against tick bites when visiting at-risk zones.\n\n                            Last update: \n                            April 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Muriel CORNET  - Dr Elisabeth FERQUEL"}
{"Disease Name": "Lymphangioleiomyomatosis", "Disease Definition": "A rare, multiple cystic lung disease characterized by progressive cystic destruction of the lung and lymphatic abnormalities, frequently associated with renal angiomyolipomas (AMLs).", "ORPHA ID": 538, "Summary": "Epidemiology\nSporadic lymphangioleiomyomatosis (LAM) affects around 1/129 000 - 385 000 adult women in Europe. However, LAM may occur as a feature of tuberous sclerosis complex (TSC) and is present in up to 30-40% of adult TSC cases. Sporadic LAM affects almost exclusively females.\nClinical description\nDefining manifestations of the disease are respiratory and include progressive dyspnea, pneumothorax and chylothorax. LAM may lead to chronic respiratory failure. A common extra-pulmonary manifestation is a high incidence of AMLs, mostly localized to the kidneys and usually asymptomatic (hemorrhage is rare). Chylous ascites, abdominal and thoracic lymphadenopathy and lymphangioleiomyomas (especially retroperitoneal) can be observed. Symptoms may worsen during pregnancy.\nEtiology\nSporadic LAM is due to somatic mutations in the tuberous sclerosis genes TSC2 and/or TSC1, that encode the major signaling proteins tuberin and hamartin. Mutations result in excessive proliferation of LAM cells. In contrast, TSC is due to germline mutations.\nDiagnostic methods\nFor a definite LAM diagnosis, a high resolution computed tomography (HRCT) scan shows typical lung cysts with diffuse distribution and may be associated together with one of the following: TSC; a lung biopsy showing cysts and abnormal immature smooth muscle-like cells (LAM cells); AMLs in the kidney; thoracic or abdominal chylous effusion; lymphangioleiomyoma; elevation of serum level of vascular endothelial growth factor D (VEGF-D) greater than 800 mg/L. The diagnosis of LAM is possible when only characteristic lung cysts are present.\nDifferential diagnosis\nThe two main differential diagnoses are adult pulmonary Langerhans cell histiocytosis and emphysema. Less frequent differential diagnoses include hypersensitivity pneumonitis, light chain-deposition disease, Birt-Hogg-Dubé syndrome and Sjögren syndrome.\nGenetic counseling\nSporadic LAM is not inherited. In contrast, TSC may be inherited or result from de novo germline mutations of TSC1 or TSC2.\nManagement and treatment\nLAM patients who develop respiratory symptoms should have periodic pulmonary function testing. Management of air flow obstruction is essential and a quarter of patients respond to inhaled bronchodilators. Patients should be informed of the risk of pneumothorax. Pleurodesis may be performed at first pneumothorax to prevent increased risk of recurrent pneumothorax. Surgical pleurodesis is often necessary for a recurrent pneumothorax or chylothorax. Single/bilateral lung transplantation is performed when other options have proven unsuccessful. The mTOR inhibitor sirolimus may be used in expert centers to stabilize or improve pulmonary function in cases with altered lung function (forced expiratory volume in one second [FEV1] < 70% of predicted value) or declining lung function (FEV1 decline > 90 mL/year). Asymptomatic AMLs < 4cm in diameter do not usually need to be treated but should be monitored. AMLs > 4 cm or with microaneurysms > 0.5 cm or bleeding risk should be treated by selective arterial embolization, sirolimus or everolimus therapy, or nephron sparing surgery. Estrogen therapy should be avoided.\nPrognosis\nDisease progression rate and severity is highly variable. The main predictor of prognosis is the rate of decline in pulmonary function.\n\n                            Last update: \n                            May 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Vincent COTTIN | ERN-LUNG*\n\n\n                                * European Reference Network"}
{"Disease Name": "Lymphatic filariasis", "Disease Definition": "Lymphatic filariasis (LF) is a severe form of filariasis (see this term), caused by the parasitic worms Wuchereria bancrofti, Brugia malayi and Brugia timori, and the most common cause of acquired lymphedema worldwide. LF is endemic to tropical and subtropical regions. The vast majority of infected patients are asymptomatic but it can also cause a variety of clinical manifestations, including limb lymphedema, genital anomalies (hydrocele, chylocele), elephantiasis in later stages of the disease (frequently in the lower extremities), and tropical pulmonary eosinophilia (nocturnal paroxysmal cough and wheezing, weight loss, low-grade fever, adenopathy, and pronounced blood eosinophilia). Renal involvement (hematuria, proteinuria, nephritic syndrome, glomerulonephritis), and mono-arthritis of the knee or ankle joint have also been reported.", "ORPHA ID": 2035, "Summary": ""}
{"Disease Name": "Lymphedema-atrial septal defects-facial changes syndrome", "Disease Definition": "Lymphedema-atrial septal defects-facial changes syndrome is characterised by congenital lymphoedema of the lower limbs, atrial septal defect and a characteristic facies (a round face with a prominent forehead, a flat nasal bridge with a broad nasal tip, epicanthal folds, a thin upper lip and a cleft chin). It has been described in two brothers and a sister. Transmission appears to be autosomal recessive.", "ORPHA ID": 86915, "Summary": ""}
{"Disease Name": "Lymphedema-cerebral arteriovenous anomaly-primary pulmonary hypertension syndrome", "Disease Definition": "Lymphedema-cerebral arteriovenous anomaly syndrome is characterised by the variable association of a cerebrovascular malformation, foot lymphoedema and primary pulmonary hypertension. It has been described in a woman and four of her children. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 86914, "Summary": ""}
{"Disease Name": "Lymphedema-distichiasis syndrome", "Disease Definition": "A rare autosomal dominant syndromic lymphedema characterized by lower-limb lymphedema and varying degrees of abnormal growth of eyelashes from the orifices of the Meibomian glands (distichiasis), with occasional associated manifestations.", "ORPHA ID": 33001, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nLymphedema-distichiasis syndrome is characterized by primary lower limb lymphedema (with or without genital edema in males) usually starting in childhood or puberty (but in some cases later or, occasionally, at birth) and associated with distichiasis (extra eyelashes growing from the Meibomian gland orifices in the inner eyelid). Ptosis of the eyelid(s) is frequent. Other associated manifestations can include: heart abnormalities, cleft palate (with or without Pierre Robin sequence), renal malformations, varicose veins and extradural cysts. Distichiasis may lead to infection (styes), congenital ectropion, photophobia corneal abrasion or ulceration.\nEtiology\nThe causative gene is FOXC2 (previously referred to as MFH1, located at 16q24.3), coding for transcription factor FOXC2.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation with the presence of 'extra' eyelashes arising from the inner eyelid, ptosis and lower limb lymphedema; although the latter may not present until later in childhood or adolescence. The condition can usually be confirmed by genetic testing.\nDifferential diagnosis\nThe differential diagnosis includes other conditions presenting with late onset (i.e. not congenital) lymphedema of the lower limbs. This includes Meige disease, Noonan syndrome, Emberger syndrome (part of the GATA2 deficiency spectrum) and CELSR-related lymphedema.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. The nuchal translucency, visible by sonograph, is often slightly increased (3mm to 4.5mm). The fetus may develop fetal hydrops in the second trimester. There may be congenital heart disease and or congenital renal malformations.\nGenetic counseling\nThe disorder is autosomal dominant. Although the condition is usually inherited from an affected parent, some cases occur sporadically. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nThe standard treatment for the lower limb (and genital) lymphedema are made-to-measure compression garments with the option of intensive bandaging for moderate to severe swelling. Skin care is necessary to prevent infections. Every newly diagnosed patient should have a renal ultrasound and echocardiogram to exclude congenital malformations. They should also be examined for a cleft of the hard or soft palate. The distichiasis is often problematic, and they may require to be plucked or even electrolysis. If severe, they may require lamellar eyelid division and cryotherapy to the posterior lamella.\nPrognosis\nThe severity may vary even within families. A normal life span is expected but there is a high mortality with the rare complication of fetal hydrops. Approximately 7% will have congenital heart disease but it is not usually severe. There is a high morbidity associated with recurrent cellulitis of the edematous limbs.\n\n                            Last update: \n                            June 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Kristiana GORDON | VASCERN* - Pr Sahar MANSOUR | VASCERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Lymphedema-posterior choanal atresia syndrome", "Disease Definition": "A rare genetic disease characterized by choanal atresia and early onset of lymphedema of the lower extremities. Additional reported features include facial dysmorphism (hypertelorism, broad forehead, smooth philtrum, unilateral low-set ear, and high-arched palate), hypoplastic nipples, and pectus excavatum.", "ORPHA ID": 99141, "Summary": ""}
{"Disease Name": "Lymphoepithelial-like carcinoma", "Disease Definition": "Lymphoepithelial-like carcinoma is a rare, malignant epithelial tumor, composed of undifferentiated epithelial cells with dense lymphoid stroma, mimicking lymphoepithelioma. It often shows association with Epstein-Barr virus infection and can develop in various organs, such as the nasopharynx, stomach, skin, breast and lungs, among others. The presenting symptoms, as well as the radiologic features, are usually nonspecific and depend on the affected site and organ.", "ORPHA ID": 289682, "Summary": ""}
{"Disease Name": "Lymphoid interstitial pneumonia", "Disease Definition": "A rare idiopathic interstitial pneumonia characterized by a diffuse, dense, polyclonal lymphoid cell infiltration of the pulmonary interstitium and air spaces, with high prevalence in patients with immune dysregulation. Presenting symptoms are non-specific and include dyspnea and cough. The clinical course is highly variable, ranging from spontaneous resolution to progressive, fatal respiratory failure.", "ORPHA ID": 79128, "Summary": ""}
{"Disease Name": "Lymphomatoid granulomatosis", "Disease Definition": "Lymphomatoid granulomatosis (LYG) is a very rare Epstein-Barr virus (EBV)-driven lymphoproliferative disease most commonly occurring in adults (in the fourth to sixth decade of life) and commonly affecting the lungs (with presentations varying from small bilateral pulmonary nodules to large necrotic and sometimes cavitating lesions), skin, central nervous system, and kidneys, but only very rarely affecting the lymph nodes and spleen. The symptoms associated with LYG depend on the site of disease involvement but mainly include cough, dyspnea or chest pain (in those with pulmonary involvement) and constitutional symptoms such as weight loss and fever.", "ORPHA ID": 86869, "Summary": ""}
{"Disease Name": "Lymphomatoid papulosis", "Disease Definition": "Lymphomatoid papulosis (LyP) is a rare cutaneous condition characterized by chronic, recurrent, and self-regressing papulonodular skin eruptions. It belongs to the spectrum of primary cutaneous CD30+ lymphoproliferative disorders, along with primary cutaneous anaplastic large cell lymphoma (primary C-ALCL; see this term) with which it shares overlapping clinical and histopathologic features.", "ORPHA ID": 98842, "Summary": "Epidemiology\nExact prevalence is unknown.\nClinical description\nLyP lesions develop at any age, more frequently during adulthood (mean age 45 years), as erythematous papules and nodules of less than 1.5-2 cm, grouped in clusters or disseminated throughout the body. Lesions may become necrotic in the center, show pigmentation and leave scarring. They spontaneously regress within 4 to 8 weeks but new lesions can occur at any time. Patients with LyP are at an increased risk of developing cutaneous or nodal lymphoid malignancies such as classic mycosis fungoides, ALCL, and Hodgkin lymphoma (see these terms).\nEtiology\nEtiology is unknown. In some reports, a correlation has been found between the use of immunosuppressive medication (e.g. anti-tumor necrosis factor (TNF) agents) for the treatment of chronic inflammatory diseases and the occurrence of LyP.\nDiagnostic methods\nDiagnosis is based on physical examination and medical history, and is confirmed by histopathologic and immunohistochemical evaluation of skin biopsies. Five histologic sub-types have been defined: type A (wedge-shaped mixed infiltrate with CD30+ tumor cells and inflammatory cells), type B (epidermotropic CD30+ T-cell infiltrate resembling MF), type C (sheets of CD30+ large atypical lymphoid cells), type D (CD30+ and CD8+ lymphocytes with cytotoxic TIA-1 staining resembling Berti's lymphoma), and type E (angiocentric and angiodestructive CD30+ T-cell infiltrate). In case of extracutaneous disease, no imagery techniques are recommended for LyP except pulmonary radiography.\nDifferential diagnosis\nDifferential diagnosis includes classical mycosis fungoides, primaryC-ALCL, diffuse large B cell lymphoma, Hodgkin lymphoma (see these terms), metastatic melanoma, and squamous cell carcinoma of the skin.\nManagement and treatment\nTreatment includes use of topical steroids in the initial stages of the disease which, in cases with an increase in the number of lesions, is combined with or followed by phototherapy (psoralen-UVA light therapy [PUVA]) or oral low-dose methotrexate (MTX). Treatment does not guarantee total regression of lesions and relapses are common with the use of lower doses or the discontinuation of treatment. Interferon alfa-2a can be used as an alternative to MTX treatment.\nPrognosis\nPrognosis is good, with a normal life expectancy, even if the disease is chronic with recurring lesions and an increased risk of developing second lymphoid neoplasms (4-25% of patients). Complications due to long-term treatment may also appear and include a higher incidence of non-melanoma skin cancer (due to PUVA) or hepatic fibrosis (due to MTX).\n\n                            Last update: \n                            April 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Martine BAGOT"}
{"Disease Name": "Lymphoplasmacytic inflammatory pseudotumor of the liver", "Disease Definition": "A subtype of inflammatory pseudotumor of the liver characterized by a benign, well-circumscribed tumor with diffuse lymphoplasmacytic infiltration with histological features of IgG4-related disease (numerous IgG4-positive plasma cells, prominent eosinophils, stromal fibrosis, fibroblastic proliferations and, frequently, obliterative phlebitis), and that is likely located around the hepatic hilum. Most often it is discovered as an incidental finding.", "ORPHA ID": 555437, "Summary": ""}
{"Disease Name": "Lymphoplasmacytic lymphoma without IgM production", "Disease Definition": "A rare B-cell non-Hodgkin lymphoma characterized by the presence of small B-lymphocytes, plasmacytoid lymphocytes, and plasma cells, and either non-secreting or secreting IgG or IgA paraproteins. The disease usually involves the bone marrow, sometimes also the spleen or lymph nodes. Patients typically present with symptoms related to anemia. Hyperviscosity, autoimmune phenomena, and B symptoms may also be observed. Mortality is higher as compared to Waldenström macroglobulinemia.", "ORPHA ID": 443159, "Summary": ""}
{"Disease Name": "Lynch syndrome", "Disease Definition": "A rare form of hereditary nonpolyposis colon cancer (HNPCC) characterized by predisposition to a wide variety of cancers, including neoplasms of the digestive tract, urinary tract, endometrium, ovary, brain, and prostate, as well as sebaceous skin tumors. LS-associated tumors are typically characterized by the presence of microsatellite instability (MSI) and loss of expression of MMR proteins in tumor tissue.", "ORPHA ID": 144, "Summary": "Epidemiology\nThe population prevalence of germline pathogenic variants in the MMR genes has been estimated at 1:279. Cancer type incidences vary with the affected gene, sex, and population. LS accounts for approximately 3% of colorectal (CRC) and endometrial cancers (EC).\nClinical description\nLS-associated cancer usually occurs in adulthood, at earlier ages compared to the general population. CRC is the predominant LS-associated cancer; it has an increased risk of being synchronous or metachronous and is typically located in the proximal colon; symptoms include abdominal pain, iron deficiency or signs of colonic obstruction. EC is the most prevalent LS-associated cancer in women and manifests with pelvic pain and menorrhea. Other cancers include ovarian, stomach, hepatobiliary tract, pancreas, breast, small intestine, urinary tract, prostate, brain (mainly glioblastoma) and skin cancers (sebaceous adenomas/carcinomas/epitheliomas and keratoacanthomas). Muir-Torre and Turcot syndromes were terms used to describe patients with skin neoplasia, or with tumors of the colon and central nervous system, respectively.\nEtiology\nLS is caused by heterozygous pathogenic germline variants affecting DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2). Other variants involve C-terminal deletions of EPCAM leading to methylation of the adjacent MSH2 promoter in epithelial tissue. Rarely, LS is due to constitutional inactivation of MLH1 by epimutation.\nDiagnostic methods\nAmsterdam/revised Bethesda criteria fail to identify up to 50% of LS patients. MSI analysis and/or immunohistochemical analysis of MMR protein expression in CRC and EC is recommended for all patients. Universal or age-dependent somatic and/or germline genetic testing of these patients is undergoing evaluation. Cascade testing should follow the identification of an individual with a MMR pathogenic mutation.\nDifferential diagnosis\nDifferential diagnosis includes several forms of attenuated polyposis, particularly recessive tumor syndromes associated with germline biallelic pathogenic variants in MUTYH, NTHL1, MBD4, or MSH3, polymerase proofreading-related adenomatous polyposis, constitutional MMR deficiency, and other cancer predisposition syndromes such as PTEN hamartoma tumor or Li-Fraumeni syndrome. Unexplained cases might be classified as Lynch-like syndrome or familial CRC type X, depending on the status of the MMR system in the tumors.\nAntenatal diagnosis\nPrenatal and preimplantation genetic diagnoses are possible if a pathogenic variant has been identified in a parent.\nGenetic counseling\nLS follows an autosomal dominant mode of inheritance with incomplete penetrance. The inheritance pattern of MLH1 epimutations is variable, presumably reflecting their mechanistic basis. Genetic counseling should be offered to affected individuals and their relatives to inform them of the increased risk of cancer. Each child of an individual with LS has a 50% chance of inheriting the variant.\nManagement and treatment\nDue to the high risk of synchronous or metachronous tumors, patients should be included in surveillance programs consisting of colonoscopy with removal of precancerous polyps, and transvaginal ultrasound examination and endometrial biopsy (with yearly education on EC and ovarian cancer) for women, every 1-2 years starting at the age of 20-25 years. Full colectomy should be considered in LS-CRC patients. Screening may start at an earlier age depending on family history. Aspirin decreases the risk of CRC. Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be proposed to women after childbearing age. Treatments supporting anti-tumoral immune response show great success against MSI-high tumors.\nPrognosis\nEarly diagnosis and surveillance significantly reduce morbidity and mortality. LS-associated tumors tend to have a better prognosis at similar stage compared with microsatellite stable tumors.\n\n                            Last update: \n                            September 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Stefan ARETZ | ERN GENTURIS* - Dr Marta PINEDA RÍU | ERN GENTURIS* - Dr Laura VALLE | ERN GENTURIS*\n\n\n                                * European Reference Network"}
{"Disease Name": "Lysinuric protein intolerance", "Disease Definition": "A rare disorder of amino acid absorption and transport characterized by a secondary urea cycle disorder with failure to thrive, hepatosplenomegaly, and a wide range of clinical manifestations including hematological (macrophagic activation syndrome or hemophagocytic lymphohistiocytosis, HLH), immune, digestive, renal, pulmonary and/or bones involvement.", "ORPHA ID": 470, "Summary": "Epidemiology\nLysinuric protein intolerance (LPI) is mainly found in Japan and Finland where the prevalence is approximately 1/60,000. More than 200 cases have been reported in the literature.\nClinical description\nThe metabolic disturbance in LPI causes increased renal excretion and reduced absorption from intestine of dibasic amino acids and orotic aciduria. Patients affected by LPI may present with nausea and vomiting after protein ingestion, diarrhea, failure to thrive, hepatosplenomegaly, bone marrow abnormalities, osteopenia, episodes of hyperammoniaemic coma, altered immune response, autoimmune manifestations, cytopenias associated with macrophagic activation syndrome, chronic renal disease, and lung involvement (interstitial lung disease due to alveolar proteinosis).\nEtiology\nIt is caused by defective dibasic amino acids transport at the basolateral membrane of epithelial cells in the kidney and intestine. LPI is caused by at least 69 affecting-function variants in the gene coding for solute carrier family 7A member 7 (SLC7A7) located at chromosome 14q11.2, with no clear genotype-phenotype correlation found so far.\nDiagnostic methods\nDiagnosis requires amino acid assays in plasma and urine where increased urinary excretion and low plasma concentration of lysine, arginine, and ornithine indicate positive diagnosis, but these signs may vary over time. Macrophagic activation syndrome is a constant finding, with hepatosplenomegaly, hyperferritinemia and elevated LDH. Identification of biallelic pathogenic variants (by single-gene testing or multigene panel depending on the clinical findings) can help confirm the diagnosis.\nDifferential diagnosis\nThe differential diagnoses include other causes of hyperammonemia, lysosomal storage diseases, other causes of macrophage activation syndrome, and some autoimmune disorders such as systemic lupus erythematosus.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nAcute hyperammonemic manifestations are treated by intravenous administration of nitrogen-scavenger drugs, dextrose infusion and/or extra-renal depuration following the usual guidelines for hyperammonemia management. Due to HLH, intravenous lipids should be avoided. Long term treatment revolves around protein-restricted diet (1-1.5 g/kg/day in children and 0.5-0.8 g/kg/day in adults) and supplement of citrulline (<100 mg/kg/day), and monitoring of biochemical markers. The complication of pulmonary alveolar proteinosis has been reported to be successfully treated by whole lung lavage.\nPrognosis\nPrognosis varies depending on early identification of the disease, hyperammonemia and pulmonary complications. Pulmonary involvement represents a major cause of impaired clinical course and fatal outcome. In adulthood, chronic kidney failure is common, and may require dialysis followed by renal transplantation. Long-term outcomes are also related to the unpredictable risk of occurrence of autoimmune and/or dysimmune manifestations, independent from the metabolic management.\n\n                            Last update: \n                            January 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Juliette BOUCHEREAU | MetabERN* - Pr Manuel SCHIFF \n\n\n                                * European Reference Network"}
{"Disease Name": "Lysosomal acid lipase deficiency", "Disease Definition": "A rare, progressive metabolic liver disease due to marked to complete lysosomal acid lipase deficiency and characterized by dyslipidemia and massive lipid accumulation leading to hepatomegaly and liver dysfunction, splenomegaly, accelerated atherosclerosis.", "ORPHA ID": 275761, "Summary": "Epidemiology\nBased on allele frequency, worldwide birth prevalence is estimated at 1/177,000; however, birth prevalence is lower in populations with Finnish, Ashkenazi Jewish, and South or East Asian ancestry.\nClinical description\nPresentation is along a clinical continuum with variable rates of progression and severity. The early-onset, rapidly progressive form, Wolman disease, presents in the neonatal or infantile period with non-specific symptoms of massive hepatosplenomegaly, liver failure, diarrhea/steatorrhea and vomiting, resulting in malabsorption, and cachexia. Adrenal calcifications occur in approximately half of infants. The later onset form, cholesteryl ester storage disease (CESD), presents between childhood and adulthood with a more variable clinical course that ranges from insidious to symptomatic. Progressive lysosomal lipid accumulation leads to the characteristic liver pathology and dysfunction (including hepatomegaly, liver fibrosis and/or cirrhosis, and elevated serum transaminases), dyslipidemia (elevated serum LDL-cholesterol and triglycerides, with normal to low HDL-cholesterol concentrations), premature atherosclerosis, splenomegaly and, eventually, end-stage liver failure. Secondary complications are variable and may include portal hypertension, ascites, cachexia, esophageal varices, gastrointestinal bleeding, coronary artery disease, aneurysm, stroke, anemia and thrombocytopenia. Approximately one-third of children experience severe gastrointestinal symptoms, including frequent diarrhoea, vomiting, abdominal pain, malabsorption and steatorrhoea.\nEtiology\nThe disease is due to mutations in the gene LIPA (10q23.2-q23.3) encoding the enzyme lysosomal acid lipase (LAL). LAL hydrolyzes cholesteryl esters and triglycerides, and thus LAL deficiency results in gradual accumulation of these lipids in the liver, spleen, and other organs. The variable phenotype is due to the amount of residual LAL activity, less than 1% for Wolman disease and between 1-12% for CESD.\nDiagnostic methods\nThe disease is suspected on clinical presentation of hepatomegaly, elevated transaminases, total cholesterol, low-density lipoprotein, and triglycerides, and low high-density lipoprotein. Liver biopsy shows microvesicular steatosis and/or fibrosis or cirrhosis. Immunostaining for lysosomal fat accumulation may facilitate diagnosis. Confirmation is by assessment of LAL activity on dry blood spot testing or in leukocytes and/or presence of a LIPA gene mutation.\nDifferential diagnosis\nDifferential diagnosis includes familial hypercholesterolemia, non-alcoholic fatty liver disease, cryptogenic cirrhosis, and combined hyperlipidemia, as well as other lysosomal storage disorders.\nAntenatal diagnosis\nPrenatal molecular genetic testing is possible in affected families.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive and genetic counseling is recommended. The sibling recurrence risk is 25%.\nManagement and treatment\nSupportive measures include statins and cholestyramine to cholesterol, and liver transplant for end-stage liver failure. Patients should follow a diet low in cholesterol and triglycerides, and nutritional status should be monitored. Magnetic resonance imaging to assess liver and spleen volumes may be useful. Enzyme replacement therapy (ERT) with the enzyme sebelipase alfa (authorized in Europe and the US) is available; however, the long-term clinical efficacy is yet to be determined. In infants with severe disease, ERT improves 1-year survival rates. In patients with later-onset disease, ERT reduces alanine aminotransferase levels and liver fat content, and improves the lipid parameters. Anemia and thrombocytopenia should be treated with standard approaches.\nPrognosis\nIn Wolman disease, patients rarely survive beyond infancy. In CESD, the prognosis and life expectancy is variable depending on the severity of the disease and timely diagnosis. The long-term prognosis with ERT is, as yet, unknown.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Barbara BURTON"}
{"Disease Name": "Lysosomal acid phosphatase deficiency", "Disease Definition": "A rare lysosomal disease characterized by intermittent vomiting, hypotonia, lethargy, opisthotonos, and fatal outcome in early infancy, associated with deficient acid phosphatase in lysosomes. There have been no further descriptions in the literature since 1971.", "ORPHA ID": 35121, "Summary": ""}
{"Disease Name": "Léri-Weill dyschondrosteosis", "Disease Definition": "A rare, genetic skeletal dysplasia marked by disproportionate short stature and the characteristic Madelung wrist deformity.", "ORPHA ID": 240, "Summary": "Epidemiology\nPrevalence of Léri-Weill dyschondrosteosis (LWD) is unknown.\nClinical description\nThe characteristics of mesomelic disproportion of the limbs and Madelung deformity may develop over time, presenting anywhere from birth to adolescence. The wrist deformity is bilateral and is characterized by shortened and bowed radii and ulnae leading to dorsal dislocation of the distal ulna and limited mobility of the wrist and elbow. Expression is variable but the clinical features are generally more severe in females. Male patients show an athletic body habitus due to muscular hypertrophy, without any underlying muscle disorder. Intelligence is normal.\nEtiology\nIn around 70% of cases, LWD is caused by haploinsufficiency of the short stature homeobox (SHOX) gene, which maps to the pseudoautosomal region 1 (PAR1) of the sexual chromosomes (Xp22.33 and Yp11.32). Haploinsufficiency results from heterozygous mutations and deletions of SHOX, or of the enhancer regions located upstream and downstream of SHOX, in the PAR1. The molecular defect remains unknown in the remaining 30% of LWD cases. SHOX-associated LWD is part of a spectrum of disorders (ranging from the most severe Langer mesomelic dysplasia (LMD) to LWD to short stature, all associated with SHOX/PAR1 anomalies. The prevalence of SHOX/PAR1 mutations is estimated at 1/1000.\nDiagnostic methods\nDiagnosis of LWD may be suspected on the basis of the clinical and radiologic findings and can be confirmed by molecular analysis (preferably multiplex ligation-dependent probe amplification for PAR1 deletions and DNA sequencing for point mutations, small deletions and insertions of SHOX).\nDifferential diagnosis\nDifferential diagnoses should include the other SHOX-related haploinsufficiency disorders and related conditions such as Turner syndrome and distal monosomy Xp.\nAntenatal diagnosis\nPrenatal genetic testing is available; however, requests for testing for these disorders are uncommon but are more frequent for LMD. LWD may be suspected by ultrasound at 20 weeks of gestation on presentation of short limbs.\nGenetic counseling\nLWD is inherited in a pseudoautosomal dominant manner with each child of an affected individual having a 50% risk of inheriting the mutation. If both parents have LWD, the offspring will have a 50% risk of having LWD, a 25% risk of having LMD, and a 25% risk of having neither condition.\nManagement and treatment\nManagement should include regular surveillance with biannual height evaluations and annual wrist radiographs. Treatment options include administration of recombinant human growth hormone (rhGH) to improve final adult height; or concurrent use of rhGH and gonadotrophin-releasing hormone agonist (GnRHa) to prevent the blunted pubertal growth spurt caused by the presence of estrogen. Molecular genetic testing of at-risk family members ensures early treatment with rhGH therapy to improve growth. Wrist splints, supports and ergonomic devices may reduce wrist discomfort. In some cases, surgical intervention (physiolysis of the ulnar aspect of the distal radius and excision of the Vickers ligament) is required in mid-to-late childhood and may decrease pain and restore wrist function.\nPrognosis\nThe quality of life is good for individuals with LWD. Pain may worsen with age due to arthritis in the joint. Individuals with LMD have problems associated with their severe short stature and severely shortened arms.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Karen HEATH"}
{"Disease Name": "Machado-Joseph disease type 1", "Disease Definition": "Machado-Joseph disease type 1 is a rare, usually severe subtype of Machado-Joseph disease (SCA3/MJD, see this term) characterized by the presence of marked pyramidal and extrapyramidal signs.", "ORPHA ID": 276238, "Summary": "Epidemiology\nThe prevalence of this form of MJD is not known. It accounts for 13% of all SCA3 cases.\nClinical description\nOnset is generally early (mean of 24 years) and symptoms progress rapidly. MJD Type 1 patients generally present with cerebellar signs and external progressive ophthalmoplegia with variable degrees of pyramidal manifestations (spasticity, hyperreflexia). Patients also have extrapyramidal signs including dystonia.\nEtiology\nThe disease is caused by CAG repeat expansion mutations in the ATXN3 gene (14q21). Patients with this subtype of SCA3 tend to have larger CAG expansions than those with other subtypes.\nGenetic counseling\nMJD follows an autosomal dominant pattern of inheritance.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Machado-Joseph disease type 2", "Disease Definition": "Machado-Joseph disease type 2 is a subtype of Machado-Joseph disease (SCA3/MJD, see this term) with intermediate severity characterized by an intermediate age of onset, cerebellar ataxia and external progressive ophthalmoplegia, with variable pyramidal and extrapyramidal signs.", "ORPHA ID": 276241, "Summary": "Epidemiology\nThe prevalence of this form of MJD is not known. It is the most frequent form of SCA3 and accounts for 57% of all SCA3 cases.\nClinical description\nPatients develop the disease in middle adulthood (mean age 40 years). If present, extrapyramidal and peripheral manifestations are mild. Some patients progress within 5 to 10 years to type 1 MJD (see this term) if significant extrapyramidal signs develop, or type 3 MJD (see this term) if significant peripheral signs appear.\nEtiology\nThe disease is caused by CAG repeat expansion mutations in the ATXN3 gene (14q21).\nGenetic counseling\nMJD follows an autosomal dominant pattern of inheritance.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Machado-Joseph disease type 3", "Disease Definition": "Machado-Joseph disease type 3 is a subtype of Machado-Joseph disease (SCA3/MJD, see this term) of milder severity characterized by late onset, slower progression, and peripheral amyotrophy.", "ORPHA ID": 276244, "Summary": "Epidemiology\nThe prevalence of this form of MJD is not known. It accounts for 30% of all SCA3 cases.\nClinical description\nThe mean age of onset is 46 years and signs include cerebellar ataxia and external progressive ophthalmoplegia along with peripheral amyotrophy, with or without mild pyramidal and extrapyramidal features.\nEtiology\nThe disease is caused by CAG repeat expansion mutations in the ATXN3 gene (14q21).\nGenetic counseling\nMJD follows an autosomal dominant pattern of inheritance.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Macrocephaly-developmental delay syndrome", "Disease Definition": "Macrocephaly-developmental delay syndrome is a rare, intellectual disability syndrome characterized by macrocephaly, mild dysmorphic features (frontal bossing, long face, hooded eye lids with small, downslanting palpebral fissures, broad nasal bridge, and prominent chin), global neurodevelopmental delay, behavioral abnormalities (e.g. anxiety, stereotyped movements) and absence or generalized tonic-clonic seizures. Additional features reported in some patients include craniosynostosis, fifth finger clinodactyly, recurrent pneumonia, and hepatosplenomegaly.", "ORPHA ID": 397612, "Summary": ""}
{"Disease Name": "Macrocephaly-intellectual disability-autism syndrome", "Disease Definition": "A rare, genetic, neurological disease characterized by association of macrocephaly, dysmorphic facial features and psychomotor delay leading to intellectual disability and autism spectrum disorder. Facial dysmorphism may include frontal bossing, hypertelorism, midface hypoplasia, depressed nasal bridge, short nose, and long philtrum.", "ORPHA ID": 210548, "Summary": ""}
{"Disease Name": "Macrocephaly-intellectual disability-left ventricular non compaction syndrome", "Disease Definition": "Macrocephaly-intellectual disability-left ventricular non compaction syndrome is a rare, genetic, syndromic intellectual disability characterized by motor and cognitive developmental delay with language impairment, macrocephaly, hypotonia, dysmorphic facial features (including long face, slanting palpebral fissures and prominent, flattened nose) and left ventricular noncompaction cardiomyopathy. Patients also present skeletal abnormalities (e.g. scoliosis, finger clinodactyly, pes planus), slender build and shy behavior. Strabismus and various neurological signs (including ataxia, tremor and hyperreflexia) may be associated, as well as epilepsy, autism and MRI findings showing a small cerebellum and abnormalities of the corpus callosum. A phenotypic variant with no cardiac involvement has been reported.", "ORPHA ID": 466791, "Summary": ""}
{"Disease Name": "Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability, characterized by macrocephaly, intellectual disability, seizures, dysmorphic facial features (including tall forehead, downslanting palpebral fissures, hypertelorism, depressed nasal bridge, and macrostomia), megalencephaly, and small thorax. Other reported features are umbilical hernia, muscular hypotonia, global developmental delay, autistic behavior, and café-au-lait spots, among others.", "ORPHA ID": 457485, "Summary": ""}
{"Disease Name": "Macrocephaly-short stature-paraplegia syndrome", "Disease Definition": "A rare, syndromic intellectual disability characterized by macrocephaly, short stature, intellectual disability, variable degree of spastic paraplegia, central nervous system malformations (hydrocephalus, Dandy-Walker malformation), and dysmorphic features, such as high and broad forehead, midface hypoplasia, and small and broad hands and feet. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 2427, "Summary": ""}
{"Disease Name": "Macrocephaly-spastic paraplegia-dysmorphism syndrome", "Disease Definition": "Macrocephaly-spastic paraplegia-dysmorphism syndrome is a rare syndrome of multiple congenital anomalies characterized by macrocephaly (of post-natal onset) with large anterior fontanelle, progressive complex spastic paraplegia, dysmorphic facial features (broad and high forehead, deeply set eyes, short philtrum with thin upper lip, large mouth and prominent incisors), seizures, and intellectual deficit of varying severity. Inheritance appears to be autosomal recessive.", "ORPHA ID": 2429, "Summary": ""}
{"Disease Name": "Macrocystic lymphatic malformation", "Disease Definition": "A rare common cystic lymphatic malformation characterized by a benign cystic lesion composed of dilated lymphatic channels. Macrocystic lesions consist of cysts larger than 1 cm in diameter. They usually present at birth or during the first years of life and most often occur in the head and neck region but may affect any site. Symptoms depend on the location and extent of the lesion. Infection, trauma, or intracystic hemorrhage can lead to lesional expansion. Malignant transformation does not occur.", "ORPHA ID": 79489, "Summary": ""}
{"Disease Name": "Macrodactyly of fingers", "Disease Definition": "A rare non-syndromic limb overgrowth characterized by isolated congenital enlargement of some or all tissue elements of one or more digits of the hand, typically within a peripheral nerve territory, with the nerve itself being elongated, as well as increased in diameter. The index finger is most commonly affected. If two or more digits are involved, these are always adjacent. The enlargement may be progressive with disproportionate or static with proportionate growth and can be unilateral or bilateral. Patients may experience pain and reduced range of motion.", "ORPHA ID": 295044, "Summary": ""}
{"Disease Name": "Macrodactyly of toes", "Disease Definition": "A rare non-syndromic limb overgrowth characterized by isolated congenital enlargement of some or all tissue elements of one or more digits of a foot. Enlargement may be progressive with disproportionate or static with proportionate growth and can be unilateral or bilateral. It typically occurs within a peripheral nerve territory, with the nerve itself being elongated, as well as increased in diameter.", "ORPHA ID": 295047, "Summary": ""}
{"Disease Name": "Macrophage activation syndrome", "Disease Definition": "A rare hemophagocytic syndrome characterized by excessive activation and proliferation of macrophages and T cells occurring in the context of a variety of diseases, including infections, neoplasms, rheumatic disorders, and leading to sudden onset of persistent fever, lymphadenopathy, and hepatosplenomegaly. Complications include profound depression of one or more blood cell lines with coagulopathy and pancytopenia, and impaired liver and renal function. Bone marrow examination reveals numerous well differentiated macrophages actively phagocytosing hematopoietic elements.", "ORPHA ID": 158061, "Summary": ""}
{"Disease Name": "Macrophagic myofasciitis", "Disease Definition": "A rare acquired skeletal muscle disease characterized by infiltration of the epimysium, perimysium, and perifascicular endomysium by macrophages with crystal inclusions composed of aluminum salts at the site of a previous vaccination (most commonly the deltoid muscle). Muscle necrosis is typically absent. Patients may present with myalgias, arthralgias, muscle weakness, chronic fatigue, asthenia, fever, and cognitive dysfunction. Signs and symptoms usually develop slowly over several months.", "ORPHA ID": 592, "Summary": ""}
{"Disease Name": "Macrosomia-microphthalmia-cleft palate syndrome", "Disease Definition": "Macrosomia-microphthalmia-cleft palate syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by early macrosomia, bilateral severe microphthalmia and a protuberant abdomen with hepatomegaly. Additional reported features include brachycephaly, large fontanelles, prominent forehead, upturned nose and median cleft palate. Cyanotic apneic spells and overwhelming infection lead to death within the first 6 months of life. There have been no further descriptions in the literature since 1989.", "ORPHA ID": 2432, "Summary": ""}
{"Disease Name": "Macrostomia-preauricular tags-external ophthalmoplegia syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by macrostomia or abnormal mouth contour, preauricular tags or pits, and uni- or bilateral ptosis due to external ophthalmoplegia. This syndrome belongs to the oculoauriculovertebral spectrum, a developmental disorder affecting the structures derived from the first and second branchial arches.", "ORPHA ID": 83619, "Summary": ""}
{"Disease Name": "Macrothrombocytopenia with mitral valve insufficiency", "Disease Definition": "Macrothrombocytopenia with mitral valve insufficiency is a rare hemorrhagic disorder due to a platelet anomaly characterized by dysfunctional platelets of abnormally large size, moderate thrombocytopenia, prolonged bleeding time and mild bleeding diathesis (ecchymoses and epistaxis), associated with mitral valve insufficiency.", "ORPHA ID": 220448, "Summary": ""}
{"Disease Name": "Macular amyloidosis", "Disease Definition": "Macular amyloidosis (MA) is a rare chronic form of cutaneous amyloidosis (see this term), a skin disease characterized by the accumulation of amyloid deposits in the dermis, clinically characterized by pruritic hyperkeratotic gray-brown macules that give a rippled or reticulated pattern of pigmentation usually in the upper back and extensor sites of arms, forearms and legs, and histologically by the deposition of amyloid in the upper dermis and close to the basal cell layer of the epidermis. MA is commonly associated with other skin diseases, such as atopic dermatitis.", "ORPHA ID": 137814, "Summary": ""}
{"Disease Name": "Macular coloboma-cleft palate-hallux valgus syndrome", "Disease Definition": "Macular coloboma-cleft palate-hallux valgus syndrome is characterised by the association of bilateral macular coloboma, cleft palate, and hallux valgus. It has been described in a brother and sister. Pelvic, limb and digital anomalies were also reported. Transmission is autosomal recessive.", "ORPHA ID": 91494, "Summary": ""}
{"Disease Name": "Macular corneal dystrophy", "Disease Definition": "Macular corneal dystrophy (MCD) is a rare, severe form of stromal corneal dystrophy (see this term) characterized by bilateral ill-defined cloudy regions within a hazy stroma, and eventually severe visual impairment.", "ORPHA ID": 98969, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is not known. Cases of MCD have been identified worldwide. The condition is most prevalent in India, Saudi Arabia, Iceland and parts of the USA.\nClinical description\nWhitish opacities in the cornea usually appear during adolescence but may develop in early infancy, or as late as the 6th decade of life. The non-transparent areas progressively merge as the entire corneal stroma becomes cloudy, causing severe visual impairment usually before the 5th decade. The bilateral corneal opacities progressively extend through the entire thickness of the central and peripheral corneal stroma. The corneal stroma is thinner than normal.\nEtiology\nMost cases of MCD are caused by mutations in the CHST6 gene (16q22) encoding a protein involved in the production of keratan sulfate, which plays a role in the maintenance of corneal transparency. More than 125 mutations in this gene have been identified to date.\nDiagnostic methods\nMCD is characterized histopathologically by intracytoplasmic accumulations of non-sulfated keratan sulfate within the keratocytes and corneal endothelium, sparing the corneal epithelium. MCD is classified as a corneal stromal dystrophy but also involves the Descemet membrane and the corneal endothelium.\nDifferential diagnosis\nThe clinical features of MCD are similar to the corneal involvement found in the systemic mucopolysaccharidoses, such as mucopolysaccharidosis type IH and IS and the mucolipidoses (see these terms).\nGenetic counseling\nAn autosomal recessive mode of inheritance has been shown in most cases, but some cases are of unknown etiology.\nManagement and treatment\nSince the condition affects the entire corneal stroma, Descemet membrane and corneal endothelium, lamellar keratoplasty does not excise all damaged tissue. Corneal transplantation may therefore be needed. Vision can be restored by corneal grafting but opacities may recur in the graft after many years.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Maculopapular cutaneous mastocytosis", "Disease Definition": "Maculopapular cutaneous mastocytosis (MCM) is a form of cutaneous mastocytosis (CM; see this term) characterized by the presence of multiple hyperpigmented macules, papules or nodules associated with abnormal accumulation of mast cells in the skin.", "ORPHA ID": 79457, "Summary": "Epidemiology\nMCM is the most common form of CM (accounting for up to 90% of cases) but the prevalence in the general population is unknown. Incidence has been estimated at between 1/1000 and 1/125 births. This entity is most commonly reported among the Caucasian population and affects both sexes, although a slight male predominance (1.7-1.8:1) has been reported in cases with early onset.\nClinical description\nThe majority of patients present in infancy or childhood but onset may also occur in adulthood. As lesions vary in aspect, several subvariants have been described in the past (plaque form, typical form, telangiectatic form, and nodular form) but are all now grouped under the same entity. The plaque or papular form presents with orange/yellow papules or plaques often appearing during the first few months of life. Typical or classic forms have a more widespread, symmetrical distribution of round or oval red/brown macules. The telangiectatic form (telangiectasia macularis eruptiva perstans; TMEP) is a disputed entity described as a rare variant occurring in adults and characterized by the presence of red/brown telangiectatic macules. The nodular form is rare. In MCM, the size and number of lesions is variable, typically ranging in size from 1 mm to over 1 cm and in number from 10-1000 lesions. MCM may appear on all regions of the body but the trunk and extremities are most frequently involved. The palms and soles are usually spared. Darier's sign, dermographism and pruritus are additional features of MCM. Extensive mechanical manipulation and other factors that trigger mast cell degranulation (non-steroidal anti-inflammatory drugs, physical stimuli, emotional stress, insect venom and certain foods) may lead to systemic symptoms such as flushing, headache, dyspnea, wheezing, rhinorrhea, nausea, vomiting, diarrhea, and syncope.\nEtiology\nMutations in the KIT gene (4q11-q12) have been identified in patients with MCM. However, this mutation is rare in the pediatric population and the etiology and pathogenesis of MCM in these cases remains to be determined. MCM generally occurs sporadically but rare familial cases have been reported.\nDiagnostic methods\nDiagnosis in children is based on the clinical appearance of the lesions and the positive Darier's sign. Occasionally (generally in cases with presentation after 5 years of age), a skin biopsy may be required for confirmation of the diagnosis. In adults, a bone marrow examination should be performed to exclude the diagnosis of SM.\nDifferential diagnosis\nThe diagnosis is usually straightforward but misdiagnosis as chronic urticaria or idiopathic anaphylaxis has been reported.\nManagement and treatment\nTrigger factors should be avoided and symptomatic management includes administration of antihistamines, topical steroids and mast cell membrane stabilizers. PUVA or UVA1 therapy may also be used for adolescents or adults who do not respond to other forms of treatment.\nPrognosis\nThe prognosis is good, especially for patients with childhood onset below the age of 5 years, with improvement (around 50% of cases) or complete resolution (30% of cases) of symptoms by adolescence. In contrast, spontaneous resolution is rare in patients with adult-onset forms of the disease and there is a higher risk of systemic involvement.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Pr A.P. [Arnold] ORANJE"}
{"Disease Name": "Madras motor neuron disease", "Disease Definition": "Madras motor neuron disease (MMND) is characterized by weakness and atrophy of limbs, multiple lower cranial nerve palsies and sensorineural hearing loss.", "ORPHA ID": 137867, "Summary": "Epidemiology\nLess than 200 cases have be reported to date, predominantly from Southern India. Isolated MMND cases have been reported from Thailand and Italy.\nClinical description\nOnset occurs at a young age (often before the age of 15), with a slight male preponderance or equal sex distribution. Parental consanguinity has been reported in some cases. Main clinical features include thin habitus, wasting and weakness predominantly of the distal limb muscles, involvement of facial and bulbar muscles, and pyramidal dysfunction. Multiple cranial nerve palsies particularly involve the 7th, and the 9th to 12th cranial nerves. Hearing impairment was described in all patients. Optic atrophy is reported in some patients.\nEtiology\nThe etiopathogenesis of MMND remains unknown. The majority of cases are sporadic. A few familial cases have been reported, but the mode of inheritance is yet to be determined. Inflammation and/or environmental factors may play a role in the etiology of MMND.\nDiagnostic methods\nDiagnosis is clinical and is supported by the association of benign focal atrophy of the extremities with hearing impairment. Neuroimaging studies may help to distinguish MMND from other motor neuron diseases.\nDifferential diagnosis\nDifferential diagnoses include amyotrophic lateral sclerosis, spinocerebellar ataxia syndromes, Brown-Vialetto-Van Laere syndrome, progressive muscular atrophy, post-polio progressive muscular atrophy, and spinal muscular atrophy (see these terms).\nManagement and treatment\nCurrently, there is no cure for MMND. Management should involve a multidisciplinary team (neurologists, physical therapists, occupational therapists, palliative care specialists, specialist nurses and psychologists) and should focus on the relief of symptoms. Symptomatic treatment and supportive care can help patients to maintain their daily living activities. Patients should be offered hearing aids.\nPrognosis\nThe disease shows a slowly progressive but benign course. Most of the reported patients survived for over 30 years after the onset of the disease.\n\n                            Last update: \n                            April 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Luciano MERLINI"}
{"Disease Name": "Maffucci syndrome", "Disease Definition": "A rare disorder characterized by multiple enchondromatosis associated with multiple (dark, irregularly shaped) hemangiomas. Less commonly, lymphangiomas are also reported.", "ORPHA ID": 163634, "Summary": "Epidemiology\nAbout 250 cases worldwide have been reported in the literature so far. The disease affects both males and females.\nClinical description\nSymptoms are present usually in childhood, but may occur at birth, during infancy or, rarely, at a later age. Vascular anomalies are diagnosed a median of 2 years after the enchondromas. Because of this, it may be misdiagnosed as Ollier disease. Moreover, fewer than 15% of patients with Maffuci syndrome are diagnosed with vascular anomalies before the age of 1 year. Enchondromas are commonly found in the bones of the hands and feet, as well as the femur, tibia, fibula, and pelvis, rarely the humerus, ribs, and skull. Lesions are asymmetrically distributed and may be uni- or bilateral. This asymmetric distribution may result in bones deformities which include asymmetrical growth, limb length inequality or angular deformity (genu varum or genu valgum). Functional impairment and deformities may cause fractures in some patients. Soft tissue, visceral, or cutaneous hemangiomas manifest as blue subcutaneous nodules. Rarely, lymphangiomas or phlebectasias may be found. Hemangiomas can be uni- or bilateral and are generally asymmetric with wide distribution and reported locations including the leptomeninges, eyes, pharynx, tongue, trachea, and intestines. The disease course tends to be slow, with bone and skin abnormalities resolving in the second or third decade of life. There is however a risk of malignant progression from enchondromas to chondrosarcoma in adulthood. Hemangiomas can also become malignant in about 8.5% of cases. Other reported malignancies include pancreatic and hepatic adenocarcinoma, mesenchymal ovarian tumors, as well as glioma, astrocytoma, and sarcomas.\nEtiology\nSomatic mutations in IDH1 (2q34) and IDH2 (15q26.1) have been identified in affected tissue (enchondromas or spindle cell hemangiomata) of most tested patients. No familial case has been reported.\nDiagnostic methods\nThe diagnosis is based on the characteristic occurrence of enchondromas and hemangiomas. As in Ollier disease, diagnosis of enchondromas is based on clinical and conventional radiological evaluations. Enchondromas appear as radiolucent defects that originate in the metaphyses.\nDifferential diagnosis\nOllier disease is the main differential diagnosis.\nManagement and treatment\nManagement and treatment aim to relieve symptoms and are not indicated in asymptomatic patients. Regular examinations by an orthopedic surgeon and dermatologist to evaluate changes in the skin and bone lesions are mandatory. Annual monitoring of malignant transformation is recommended. No specific therapy exists to treat the disease. Surgery is at present the only option when complications occur.\nPrognosis\nDepending on the extent of skeletal involvement, Maffucci syndrome may result in severe deformities with functional and quality of life repercussions. Life span depends on malignant transformation but is otherwise normal. Prognosis is difficult assess because of wide clinical expression and variability, and low prevalence of the disease.\n\n                            Last update: \n                            May 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Luca SANGIORGI | ERN BOND*\n\n\n                                * European Reference Network"}
{"Disease Name": "MAGEL2-related Prader-Willi-like syndrome", "Disease Definition": "A rare Prader-Willi-like syndrome characterized by arthrogryposis, including contractures of the proximal and distal interphalangeal joints, and autism spectrum disorder due to MAGEL2 mutation. Overlapping phenotypes with Prader-Willi syndrome include hypotonia, feeding difficulties, weigth gain, developmental delay, intellectual disability and hypogonadism. Minority of patients manifest hyperphagia and morbid obesity in contrast to patients with Prader-Willi syndrome.", "ORPHA ID": 398069, "Summary": ""}
{"Disease Name": "MAGIC syndrome", "Disease Definition": "A rare autoinflammatory syndrome characterized by the presence of features of relapsing polychondritis and Behçet's disease in the same individual. This includes cartilage inflammation of the ears, nose, throat, and rib cage, as well as recurrent oral and genital ulcers, respectively. Patients may also present ocular involvement (in particular anterior uveitis or scleritis), arthritis, fever, colitis, thrombophlebitis, central nervous system vasculitis, or, in rare cases, arterial aneurysms. Symptoms of polychondritis occur secondary to those of Behçet's disease in the vast majority of cases.", "ORPHA ID": 324972, "Summary": ""}
{"Disease Name": "Majeed syndrome", "Disease Definition": "Majeed syndrome is a rare genetic multisystemic disorder characterized by chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, which may be accompanied by neutrophilic dermatosis.", "ORPHA ID": 77297, "Summary": "Epidemiology\nThe syndrome is extremely rare. Fourteen cases born into consanguineous families, from the Middle East, India and Spain have been reported.\nClinical description\nOnset is generally within the first two years of life although it may present later in childhood (range 1 month to 8 years) as bone pain. Chronic recurrent multifocal osteomyelitis (CRMO) associated with Majeed syndrome is typically more severe than that of non-syndromic CRMO, and is more persistent, with short remissions and more frequent exacerbations. It can be associated with fever, joint pain, delayed bone age, growth failure, short adult stature, and development of flexion contractures. Patients also have a hypochromic, microcytic anemia with dyserythropoiesis present on 11 of 11 bone marrow biopsies. In half of the cases, the anemia is mild with the remainder requiring one or more transfusions for anemia. The inflammatory neutrophilic dermatosis Sweet syndrome has been reported in two patients with Majeed syndrome. Other reported manifestations include failure to thrive, hepatomegaly, neutropenia, and transient cholestatic jaundice. The course is chronic and the syndrome may have a significant impact on quality of life.\nEtiology\nMajeed syndrome is caused by a mutation in LPIN2 (18p11.31), which encodes phosphatidate phosphatase LPIN2 (Lipin-2), important in lipid metabolism. Recent studies have shown that Lipin-2 is a negative regulator of the NLRP3 inflammasome.\nDiagnostic methods\nThe diagnosis is based on the typical clinical manifestations and on molecular genetic testing of the causative gene mutation. Osteomyelitis can be diagnosed on skeletal radiographs but may require magnetic resonance imaging (MRI). Bone, bone marrow and skin biopsies may also be needed.\nDifferential diagnosis\nDifferential diagnoses include Caffey disease, SAPHO syndrome, non-syndromic CRMO, deficiency of the interleukin-1 receptor antagonist (DIRA) and immune deficiency.\nAntenatal diagnosis\nPrenatal diagnosis is possible in affected families when a disease causing mutation has been identified.\nGenetic counseling\nMajeed syndrome follows an autosomal recessive pattern of inheritance. Genetic counseling can inform parents with an affected child of their 25 % risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment is empiric. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main treatment options for non-syndromic CRMO, but are not likely to control bone inflammation in Majeed syndrome patients. Corticosteroids may also be used to control CRMO and inflammatory dermatosis, but have a multitude of side effects that limit their use for long term treatment. Methotrexate with or without pamidronate has been utilized in a few cases with mild to moderate improvement reported. TNF inhibitors were used in 2 children without significant benefit. IL-1 beta inhibition looks more promising with resolution of clinical symptoms, normalization of blood inflammatory markers and normalization of radiologic bone lesions in 4 of 4 patients treated.\nPrognosis\nThe prognosis has generally been poor because of progressive bone and hematological manifestations, however, outcomes have improved with more aggressive treatments. There is limited information on long-term outcomes in patients treated with IL-1 beta inhibitors but short-term follow-up has shown sustained clinical response to this biologic class.\n\n                            Last update: \n                            August 2017\n\n\n                            - Expert reviewer(s): \n                            Dr Polly FERGUSON"}
{"Disease Name": "Mal de débarquement", "Disease Definition": "Mal de débarquement (MdD) is a rare otorhinolaryngological disease characterized by a persistent sensation of motion such as rocking, swaying, tumbling and/or bobbing following a period of exposure to passive movement, usually an ocean cruise or other types of water, train, automobile or air travel and less commonly other movements (like sleeping on a waterbed). Onset may be spontaneous in some patients. Manifestations begin shortly after the stimulus, persist for 6 months to years and may be associated with anxiety, fatigue and impaired cognition. Symptoms are often accentuated when in an enclosed space or when attempting to be motionless (sitting, lying down or standing in a stationary position) and are relieved when in passive motion such as in a moving car, airplane or train.", "ORPHA ID": 210272, "Summary": ""}
{"Disease Name": "Mal de Meleda", "Disease Definition": "A rare diffuse palmoplantar keratoderma characterized by symmetric palmoplantar hyperkeratosis that progressively extends to the dorsal surfaces of hands and feet (transgrediens). The disease can be associated to hyperhidrosis, lichenoid plaques and perioral erythema.", "ORPHA ID": 87503, "Summary": "Epidemiology\nThe estimated worldwide prevalence is 1:100,000. About 300 patients with a molecularly confirmed pathogenic variants are described in the literature. Most of these patients were from Mediterranean countries in Europe, North Africa, the Middle East, and South Asia.\nClinical description\nOnset is in the first months of life. The first symptom is erythema on the palms and soles, rapidly followed by diffuse, yellowish hyperkeratosis. Keratoderma of the dorsal surface of the distal phalanges gradually extends (sometimes in a glove/stocking-like manner) to the dorsa of the hands and feet, affecting the wrists and ankles in the majority of cases. In most patients, transgressive keratoderma also affects the apparence of the ulnar forearms. Keratoderma on the palms and soles is usually surrounded by a red, erythrodermic scale. Hyperconvexity of the nails and conical terminal phalanges are constant features of the disease, mainly in adult patients. In older patients, contractures of the hands and fingers and sclerodactyly (whitish, conical, sclerodermiform phalanges) are common. Hyperhidrosis, pseudoainhum and brachydactyly can be observed in some patients. Other features include perioral erythema, lichenoid plaques on the knees and the elbows, and nail abnormalities.\nEtiology\nMal de Meleda (MDM) is caused by biallelic mutations in the gene SLURP1 (chromosome 8q24). SLURP1 mediates keratinocyte apoptosis and down-regulates tumor necrosis factors-induced inflammation. The variants are mostly missense and nonsense mutations, or, to a lesser extent, splicing substitutions or small deletions. A case of large deletion was also described in the literature. Less than 30 different pathogenic variants with an allele frequency of less than 0,001 each are described in the databases.\nDiagnostic methods\nThe diagnosis is based on the evaluation of clinical signs and confirmed by multiplex ligation-dependent probe amplification (MLPA), quantitative PCR or DNA sequencing (e.g. Sanger sequencing, NGS).\nDifferential diagnosis\nDifferential diagnosis includes diffuse palmoplantar keratodermas such as Papillon-Lefevre-Syndrome, Greither disease, epidermolytic palmoplantar keratoderma, non-epidermolytic palmoplantar keratoderma, and palmoplantar keratodermas, Nagashima type. It also includes mild forms of pachyonychia congenita, and Vohwinkel syndrome with ichthyosis.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nMDM is an autosomal recessive transmitted disease with full penetrance. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment recommendations include systemic retinoids, oral retinoid acid or oral acitretin (20 mg/day), topical antimicrobial and keratolytic therapy.\nPrognosis\nThe progressive nature of the lesions in MDM can lead to severe functional handicap with reduced mobility of hands and feet.\n\n                            Last update: \n                            March 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Judith FISCHER | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Malakoplakia", "Disease Definition": "Malakoplakia is a chronic multisystem granulomatous inflammatory disease characterized by the presence of single or multiple soft plaques on various organs of the body.", "ORPHA ID": 556, "Summary": "Epidemiology\nPrevalence is unknown but more than 700 cases have been described in the literature.\nClinical description\nMalakoplakia can occur in all ages, with a mean age at diagnosis of 50 years old and a female predominance. Pediatric cases are rare. It is most common in immunodeficient patients with a history of diabetes, transplantation, lymphoma, steroid therapy or alcoholism. In the majority of cases (60-80%), malakoplakia affects the urinary tract (bladder, kidney, and ureters) and cases of locoregional extension have been reported (retroperitoneal region and lymph nodes). Other organs can also be involved, with the gastrointestinal system (left colon, sigmoid, rectum, stomach) being the second most common site (15%). Other sites include the genital tract, skin, neck, tongue, lungs, and central nervous system. Patients are either asymptomatic or present with clinical symptoms that are non specific (fever, pain) and that vary depending on the organ involved. In case of urinary tract involvement, patients generally present with chronic urinary tract infections and symptoms such as urinary urgency, hesitancy, intermittent dysuria, hematuria, and proteinuria. In case of gastrointestinal involvement, patients can present with symptoms such as recurrent diarrhea, dyspepsia, abdominal pain, and hemorrhage. In case of malakoplakia of the female genital tract, patients usually present with vaginal bleeding. Cutaneous malakoplakia presents as papules or ulcerations on various locations (abdomen, face, perianal region) associated with rash and itching. Malakoplakia can also be associated with other granulomatous diseases such as sarcoidosis and tuberculosis, and with carcinomas (prostate and colorectal carcinomas).\nEtiology\nMalakoplakia seems to be due to an impaired response to bacterial infection. Macrophages and monocytes show a defective phagolysosomal activity: they phagocytose bacteria but are unable to digest them completely. Partially digested bacteria accumulate in the cytoplasm and lead to a granulomatous reaction of the immune cells. It has been suggested that the defective phagolysosomal activity could be due to a decrease in the concentration of intracellular cyclic guanosine monophosphate (cGMP).\nDiagnostic methods\nThe diagnosis of malakoplakia is difficult due to the absence of specific clinical symptoms and no specific characterization in imaging. Diagnosis is based on endoscopy which reveals the presence of vascularized yellowish or white polypoid nodules or plaques. The diagnosis is confirmed by biopsy of the affected tissue. Histological examination reveals the presence of von Hansemann cells (histiocytes with small nuclei and granular acidophilic cytoplasm) with Michaelis-Gutmann bodies (periodic acid-Schiff and von Kossa positive calcific inclusions). This lesion is pathognomonic for malakoplakia. Michaelis-Gutmann bodies probably correspond to partially digested calcified bacterial inclusions.\nDifferential diagnosis\nDepending on the organ involved, differential diagnoses include primary or metastatic malignancies, inflammatory diseases (sarcoidosis, Crohn's disease; see these terms), infections (tuberculosis, Whipple disease; see these terms), and cutaneous fungal infections.\nManagement and treatment\nTreatment consists in antibiotherapy that uses intracellular molecules (fluoroquinolones, trimethroprim-sulfametoxazol). Currently, the duration of therapy is still not standardized. In pseudo-tumoral cases, surgical removal of the lesions is required.\nPrognosis\nPrognosis is usually good. However, recurrences and complications may occur over the years such as renal failure in case of urinary tract involvement.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Maïté DAROUX"}
{"Disease Name": "Malan overgrowth syndrome", "Disease Definition": "A rare multisystemic genetic disorder characterized by a characteristic facial features with macrocephaly, overgrowth in infancy, intellectual disability and behavioral problems including anxieties and aggressiveness.", "ORPHA ID": 420179, "Summary": "Epidemiology\nApproximatively 80 patients have been reported in the literature to date.\nClinical description\nMalan syndrome is an overgrowth disorder characterized by postnatal overgrowth (in infancy and childhood), developmental delay, moderate to severe intellectual disability and unusual behavior (i.e. anxieties, noise sensitivity, hetero/auto-aggressive behavior). It is worth noting that overgrowth is less marked in adulthood. The most characteristic facial features include macrocephaly, long, triangular face, prominent forehead, depressed nasal bridge, deeply set eyes, downslanting palpebral fissures, short nose with anteverted nares, small mouth with an everted lower lip and a prominent chin. Additional variable manifestations comprise musculoskeletal abnormalities with slender habitus, scoliosis and pectus excavatum as well as long hands. Visual problems are frequent, especially strabismus, myopia, hypermetropia, nystagmus and underdeveloped optic nerves. Structural brain imaging abnormalities (i.e. enlarged ventricles, hypoplasia of the corpus callosum, cortical dysplasia and periventricular nodular heterotopia) have also been reported. Some patients have seizures and/or electroencephalogram abnormalities. The increased prevalence of epilepsy in individuals with deletions of NFIX may be explained by the presence of a contiguous gene disorder.\nEtiology\nNFIX (Nuclear factor I X) haploinsufficiency is responsible for this syndrome and may be the result of heterozygous loss-of-function variants in the NFIX (Nuclear Factor I X (19p13.13) gene or 19p13 microdeletions encompassing the gene NFIX.\nDiagnostic methods\nMalan syndrome is a clinically recognizable overgrowth syndrome. The diagnosis is based on the major clinical findings including postnatal overgrowth, facial dysmorphism with macrocephaly, intellectual disability and behaviorally anxiety. The genetic diagnosis is established by identification of a heterozygous pathogenic variant in NFIX or a deletion encompassing this gene. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and/or comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, genome sequencing).\nDifferential diagnosis\nThe differential diagnoses include Sotos syndrome, Weaver syndrome and Marfan or Marfan-like syndromes. In case of large 19p13 deletions, other clinical signs are reported corresponding to the 19p13.13 microdeletion syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is possible if the disease-causing variant has been identified in the family. The recent implementation of prenatal whole exome sequencing could lead to molecular diagnostics during pregnancy.\nGenetic counseling\nMalan syndrome is inherited in an autosomal dominant manner. In the majority of cases, the pathogenic variants or deletions occur de novo. In this situation, the risk to sibs of the proband is very low due to a possible germinal mosaicism (<1%). In the rare familial cases, there is a 50% risk of transmitting the disease from an affected individual to offspring.\nManagement and treatment\nManagement of Malan syndrome requires a multidisciplinary approach with appropriate medical specialists for intellectual disability, seizures, musculoskeletal and ocular abnormalities. Special education training along with behavioral intervention therapy may also be required.\nPrognosis\nMalan syndrome has significant impact on quality of life.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Valérie CORMIER-DAIRE  - Dr Valérie MALAN | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Malaria", "Disease Definition": "A life-threatening parasitic disease caused by Plasmodium (P. ) parasites that are transmitted by Anophles mosquito bites to humans and is typically clinically characterized by attacks of fever, headache, chills and vomiting.", "ORPHA ID": 673, "Summary": ""}
{"Disease Name": "Male hypergonadotropic hypogonadism-intellectual disability-skeletal anomalies syndrome", "Disease Definition": "This syndrome is characterized by hypergonadotropic hypogonadism, intellectual deficit, congenital skeletal anomalies involving the cervical spine and superior ribs, and diabetes mellitus.", "ORPHA ID": 2234, "Summary": "Epidemiology\nIt has been described in two brothers.\nClinical description\nTesticular biopsy revealed germinal aplasia and complete seminiferous tubular fibrosis.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "Male infertility due to globozoospermia", "Disease Definition": "Male infertility due to globozoospermia is a male infertility due to sperm disorder characterized by the presence, in sperm, of a large majority of round-headed spermatozoa that lack the acrosome and have an aberrant nuclear membrane and midpiece defects. The acrosomeless spermatozoa is not able to penetrate the zona pellucida and thus fertilization failures, even with intracytoplasmic sperm injection, are frequent.", "ORPHA ID": 171709, "Summary": ""}
{"Disease Name": "Male infertility due to large-headed multiflagellar polyploid spermatozoa", "Disease Definition": "A rare male infertility due to a sperm disorder characterized by the presence, in sperm, of a very high percentage of spermatozoa with enlarged head, irregular head shape, multiple flagella, and abnormal midpiece and acrosome. It is generally associated with severe oligoasthenozoospermia and a high rate of sperm chromosomal abnormalities (polyploidy, aneuploidy).", "ORPHA ID": 137893, "Summary": ""}
{"Disease Name": "Male infertility with azoospermia or oligozoospermia due to single gene mutation", "Disease Definition": "A rare, genetic male infertility due to a sperm disorder characterized by the absence of a measurable amount of spermatozoa in the ejaculate (azoospermia), or a number of sperm in the ejaculate inferior to 15 million/mL (oligozoospermia), resulting from a mutation in a single gene known to cause azoo- or oligo-spermia. Sperm morphology may be normal.", "ORPHA ID": 399805, "Summary": ""}
{"Disease Name": "Male infertility with teratozoospermia due to single gene mutation", "Disease Definition": "Male infertility with teratozoospermia due to single gene mutation is a rare, genetic male infertility due to sperm disorder characterized by the presence of spermatozoa with abnormal morphology, such as macrozoospermia or globozoospermia, in over 85% of sperm, resulting from mutation in a single gene known to cause teratozoospermia. It is a heterogeneous group that includes a wide range of abnormal sperm phenotypes affecting, solely or simultaneously, head, neck, midpiece, and/or tail.", "ORPHA ID": 399808, "Summary": ""}
{"Disease Name": "Malignancy diagnosed during pregnancy", "Disease Definition": "A rare condition characterized by the occurrence and/or diagnosis of a malignancy during pregnancy. The most frequently diagnosed neoplasms are gynecologic tumors, especially cervical cancer, followed by hematologic malignancies. Patient management should be carried out by a multidisciplinary team of specialists.", "ORPHA ID": 289385, "Summary": ""}
{"Disease Name": "Malignant atrophic papulosis", "Disease Definition": "Malignant atrophic papulosis (MAP) is a rare, chronic, thrombo-obliterative vasculopathy characterized by papular skin lesions with central porcelain-white atrophy and a surrounding teleangiectatic rim. Systemic lesions may affect the gastrointestinal tract and the central nervous system (CNS) and are potentially lethal.", "ORPHA ID": 679, "Summary": "Epidemiology\nLess than 200 cases have been described in the literature.\nClinical description\nMAP onset occurs in adults aged 20-50 with skin lesions that appear initially as small erythematous papules, predominantly on the trunk and the upper extremities. Over several days, the center of the lesions sinks and develops a characteristic morphology: 0.5-1 cm wide papules with an atrophic porcelain-white center and an erythematous, teleangiectatic rim. This condition is chronic and lesions persist over years, often throughout life. Face, scalp, palms of hands and soles of feet are rarely involved. In the systemic variant, which may develop simultaneously or even years after cutaneous symptoms, patients may present with multiple limited infarcts of the intestine, with abdominal pain, bleeding and diarrhea, and/or of the CNS, with cerebrovascular accidents (in rare cases, medullary). It may more rarely manifest as pericarditis or in other organs such as the lungs, presenting as pleuritis. Ocular involvement, which affects the eyelids, conjuctiva, retina, sclera and the choroid plexus, as well as the development of diplopia and ophthalmoplegia (as secondary side effects of the neurologic involvement), has also been described.\nEtiology\nThe etiopathogenesis of the disease remains unknown. Hypotheses implicating vasculitis, coagulopathy or a primary dysfunction of endothelial cells have been proposed. Many patients have been reported to have defects in blood coagulation.\nDiagnostic methods\nDiagnosis is based primarily on the cutaneous clinical picture that is nearly pathognomonic. In early stages, histology of lesions may reveal a superficial and deep perivascular lymphocytic infiltration with distinct mucin deposition. Later a wedge-shaped connective tissue necrosis in the deep dermis, due to a thrombotic occlusion of the small arteries and sparse lymphocytes, occurs. More developed lesions show prominent changes in the dermoepidermal junction, with atrophy of the epidermis and an area of sclerosis in the papillary dermis.\nDifferential diagnosis\nThe histology of early lesions resembles cutaneous lupus erythematosus (see this term). More developed lesions can imitate lichen sclerosus (see this term).\nGenetic counseling\nA genetic predisposition with an autosomal dominant trait has been suggested.\nManagement and treatment\nTherapeutic efforts with anticoagulants and compounds that facilitate blood perfusion, such as acetylosalicylic acid, pentoxifylline, dipyridamole, ticlodipine and heparin have achieved a partial regression of skin lesions in some individual cases. As all patients may potentially develop the systemic, life-threatening variant, an annual follow-up is mandatory. A clinical inspection of the skin should be combined with additional examinations including brain magnetic resonance tomography, gastroscopy, colonoscopy, X-ray of the chest and abdominal ultrasound, in order to assess the long-term prognosis. No effective treatment for the systemic manifestations has been established, however, subcutaneous treprostinil has been tested successfully in one case with intestinal and CNS manifestations.\nPrognosis\nIdiopathic, monosymptomatic, cutaneous presentations are benign, however, systemic manifestations can develop years after the occurrence of skin lesions. Systemic manifestations are progressive and may lead to serious complications: bowel perforation and peritonitis as well as thrombosis of the cerebral arteries or massive cerebral hemorrhage, meningitis, encephalitis, radiculopathy and myelitis which have been reported to be lethal in around 50% of patients within 2-3 years.\n\n                            Last update: \n                            April 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Christos ZOUBOULIS"}
{"Disease Name": "Malignant epithelial tumor of salivary glands", "Disease Definition": "A rare neoplastic disease characterized by the presence of a tumor located in the parotid, sublingual, submandibular and/or minor salivary glands, which presents with a wide spectrum of clinical features depending on the location, size and type of salivary gland involved, ranging from clinically asymptomatic, slow-growing, painless mass(es), that may or may not be fixed to underlying skin or muscles, to rapidly growing mass(es) associated with pain, facial weakness/nerve palsy, otorrhoea, dysphagia, palatal/parapharyngeal fullness, nasal obstruction/bleeding, voice hoarseness/change, dyspnea, trismus, palate bone erosion, telangiectasia, mucosal/skin ulceration and/or cervical adenopathy.", "ORPHA ID": 276145, "Summary": ""}
{"Disease Name": "Malignant germ cell tumor of ovary", "Disease Definition": "Malignant germ cell tumor of ovary is a rare ovarian cancer arising from germ cells in the ovary, frequently unilateral at diagnosis which characteristically presents during adolescence with pelvic mass, fever, vaginal bleeding and acute abdomen.", "ORPHA ID": 35807, "Summary": "Epidemiology\nThe annual incidence is 1/200000 females in Europe. Ovarian germ-cell tumors represent 15-20% of all ovarian tumors, 3% of which are malignant.\nClinical description\nMalignant germ cell tumor of ovary is almost always unilateral at diagnosis (except malignant dysgerminomatous germ cell tumor, which can be bilateral in 10 to 15% cases). It usually presents during adolescence with symptoms of abdominal pain, pelvic mass, fever and vaginal bleeding. In about 10% of tumors the mass may grow rapidly, resulting in acute abdomen due to capsular distension, necrosis, hemorrhage, rupture or torsion. Certain subtypes may occasionally be associated with isosexual precocity, dysgenetic gonads, virilization, hyperthyroidism or carcinoid syndrome. Malignant germ cell tumor of ovary comprises the following histological subtypes: malignant dysgerminomatous germ cell tumor (most frequent form), malignant non dysgerminomatous germ cell tumor (yolk sac tumor, embryonal carcinoma, mixed germ cell tumor), primary non-gestational choriocarcinoma of ovary and malignant teratoma of ovary.\nEtiology\nThey are rapidly growing neoplasms that arise from germ cells in the ovary.\nDiagnostic methods\nDiagnosis relies on clinical findings, serum tumor markers and imaging. Imaging includes pelvic ultrasonography and computed tomography of abdomen and pelvis (if extra ovarian metastasis is suspected) and chest X-ray (to detect metastasis to lung and mediastinum). Dosage of human chorionic gonadotropin (hCG), lactate dehydrogenase (LDH) and alpha fetoprotein (alpha-FP) also contribute to the diagnosis, the prognosis and follow-up of the disease. 12 p isochromosome (i(12p)) and chromosome 12 over-representation are observed, in non teratomatous ovarian germ cell tumors while pure teratomas lack i(12p). Diagnosis is only confirmed histologically after laparotomy or laparoscopy.\nDifferential diagnosis\nDifferential diagnoses include the less common malignant ovarian sex cord-stromal tumor, small cell carcinomas of the ovary (see these terms) and ovarian involvement of non-gonadal tumors.\nManagement and treatment\nMalignant germ cell tumor of ovary shows excellent sensitivity to platinum. Young women with tumor confined to a single ovary are treated with fertility sparing surgery (unilateral salphingo-oopherectomy with preservation of uterus and contralateral ovary), followed by careful surgical staging with appropriate adjuvant chemotherapy usually comprising of bleomycin, etoposide and cisplatin for stage I tumor (except pure dysgerminoma). In women with advanced disease, preservation of reproductive function is still possible particularly if the contralateral ovary is normal. Paclitaxel and ifosfamide can also be used in case of relapse or resistance to cisplatin.\nPrognosis\nWhen treated promptly and appropriately, these tumors have excellent prognosis with return of normal menstrual function and fertility rates and no increase in teratogenicity.\n\n                            Last update: \n                            September 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Mojgan DEVOUASSOUX  - Pr Isabelle RAY-COQUARD"}
{"Disease Name": "Malignant germ cell tumor of the cervix uteri", "Disease Definition": "Malignant germ cell tumor of the cervix uteri is an extremely rare uterine neoplasm characterized by a usually polypoid, friable tumor deriving from primordial germ cells located in the uterine cervix. Presentation is non-specific and often includes abnormal vaginal bleeding and/or discharge, a cervical mass protruding from the vagina, abdominal and/or pelvic pain or, less commonly, difficulty passing stool and perianal pain. Various histological subtypes (incl. dysgerminoma, yolk sac tumor, choriocarcinoma and malignant teratoma) are reported.", "ORPHA ID": 213837, "Summary": ""}
{"Disease Name": "Malignant germ cell tumor of the corpus uteri", "Disease Definition": "Malignant germ cell tumor of the corpus uteri is an extremely rare uterine neoplasm characterized by a typically polypoid mass deriving from primordial germ cells localized in the endometrium. Presentation is non-specific and often includes abnormal vaginal bleeding and/or discharge, a mass protruding from the vagina, abdominal and/or pelvic pain or, less commonly, difficulty passing stool and perianal pain. The malignant teratoma and yolk sac tumor histological subtypes are the most common.", "ORPHA ID": 213751, "Summary": ""}
{"Disease Name": "Malignant germ cell tumor of the vagina", "Disease Definition": "Malignant germ cell tumor of the vagina is an extremely rare, malignant, vulvovaginal neoplasm, deriving from primordial germ cells in the vagina, typically characterized by painless bloody vaginal discharge and a polypoid mass which protrudes from the vagina. Serum alpha-fetoprotein is usually elevated and rapid progression, local agression and early metastasis to liver and lungs is reported.", "ORPHA ID": 206489, "Summary": ""}
{"Disease Name": "Malignant granulosa cell tumor of the ovary", "Disease Definition": "A rare malignant sex cord stromal tumor of ovary arising from the granulosa cells of the ovary, which occurs in peri and post menopausal women, and that presents with abnormal vaginal bleeding, abdominal pain and distension. The tumor is frequently unilateral, estrogen secreting, and has a slow natural history and a tendency to relapse long after the initial diagnosis.", "ORPHA ID": 99915, "Summary": ""}
{"Disease Name": "Malignant hyperthermia of anesthesia", "Disease Definition": "Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, to stresses such as vigorous exercise and heat.", "ORPHA ID": 423, "Summary": "Epidemiology\nThe incidence of MH reactions ranges from 1/5000 to 1/50,000-100,000 anesthesias. However, the genetic prevalence of the genetic abnormalities may be as great as 1/400 individuals. A significant male preponderance has been reported.\nClinical description\nClinical symptoms of MH are highly variable, ranging from self limiting courses with mild or moderate symptoms to fulminant MH crises. The classic signs of MH include marked hyperthermia, tachycardia, supraventricular and ventricular arrhythmia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, isolated masseter spasm or generalized muscle rigidity and rhabdomyolysis, all of which are related to a hypermetabolic response. In untreated patients, multiorgan failure (including acute renal failure) and circulatory collapse are the end-stage of the disease.\nEtiology\nIn most cases, MH is caused by a defect in the ryanodine receptor. Over 400 variants have been identified in the ryanodine receptor gene (RYR1), located on chromosome 19q13.1, and at least 34 are causal for MH. The pathophysiologic changes of MH are due to an uncontrolled rise in myoplasmic calcium, which activates biochemical processes related to muscle activation. As a result of ATP depletion, muscle membrane integrity is compromised, leading to hyperkalemia and rhabdomyolysis. MH events are mainly triggered by volatile anesthetics and succinylcholine. Extremely rarely stresses such as exercise, emotion and heat may trigger a reaction.\nDiagnostic methods\nAn early diagnostic clue is elevation of end-expired carbon dioxide. Arterial blood gas analyses reveal a combination of respiratory and metabolic acidosis with negative base excess, lactemia, hypercapnia, and hypoxemia. Diagnostic testing relies on assessing the in-vitro contracture response of biopsied muscle to halothane and caffeine. Other drugs such as ryanodine and 4-chloro-m-cresol have also been used but are not part of a standard protocol. A diagnosis of MH is given when contracture forces exceed the given threshold after exposure to these substances. Elucidation of the genetic changes has led to the introduction, on a limited basis so far, of genetic testing for susceptibility to MH. As the sensitivity of genetic testing increases, molecular genetics will be increasing useful for identifying those at risk.\nDifferential diagnosis\nThe differential diagnosis of a fulminant MH crisis includes sporadic pheochromocytoma, serotonin syndrome, neuroleptic malignant syndrome (see these terms), anaphylactic reaction, thyroid crisis and sepsis.\nGenetic counseling\nMH is inherited autosomal dominantly. Genetic counseling is possible in families with a known disease causing mutation.\nManagement and treatment\nDantrolene sodium is a specific antagonist of the pathophysiologic changes in MH and should be available wherever general anesthesia is administered. When MH is suspected, administration of triggering agents should be ceased immediately and anesthesia continued with intravenous propofol, opiods and/or sedatives. During an MH crisis, dantrolene should be administered at a dosage of 2.5 mg/kg, every 5-10 minutes until patient is stabilized. Volume resuscitation and administration of vasopressors might be needed to stabilize hemodynamics. Cooling (with cold intravenous fluids, topical ice or special cooling blankets) is essential as high temperatures exacerbate an established MH reaction.\nPrognosis\nThe syndrome is likely to be fatal if untreated but thanks to the dramatic progress in understanding the clinical manifestations and pathophysiology of the syndrome, the mortality from MH has dropped from over 80%, thirty years ago, to less than 5% at present.\n\n                            Last update: \n                            February 2015\n\n\n                            - Expert reviewer(s): \n                             Teresa BULGER  - Dr Neil POLLOCK  - Dr Henry ROSENBERG  -  Anja SCHIEMANN  - Dr Kathryn STOWELL"}
{"Disease Name": "Malignant melanoma of the mucosa", "Disease Definition": "A rare, aggressive, neoplastic disease characterized by the presence of a melanocyte tumor that develops in any mucosal membrane. Clinical manifestations vary depending on the site of occurrence.", "ORPHA ID": 168999, "Summary": ""}
{"Disease Name": "Malignant migrating focal seizures of infancy", "Disease Definition": "A rare epileptic and developmental encephalopathy characterized by seizure onset during the first months of life, focal seizures arising independently in both hemispheres, marked drug resistance, and severe, long-term cognitive disability.", "ORPHA ID": 293181, "Summary": "Epidemiology\nThe estimated prevalence of Epilepsy of infancy with migrating focal seizures (EIMFS) is approximately 1/900,000 children. Both sexes are equally affected.\nClinical description\nSeizures start during the first 6 months of life, typically in the neonatal period. Seizures are initially infrequent and consist of focal motor, tonic or clonic seizures, showing in some patients as subtle seizures reported as behavioral arrest with minor motor signs, and prominent autonomic features. Seizure frequency rapidly increases and status epilepticus is common. At onset, focal seizures arise independently in both hemispheres and can migrate from one region to another. Seizures show a marked drug resistance. Neurological status progressively deteriorates with worsening seizures and leads to progressive hypotonia, loss of visual contact, and lack or regression of psychomotor achievements. Most patients develop microcephaly by 1 year of age.\nEtiology\nThe genetic etiology is variable. 70% of children have an identified genetic etiology. Half of them present gain-of-function mutations affecting the KCNT1 gene, located on 9q34.4. In other cases, the genes involved may include SCN2A (2q24.3), KCNQ2 (20q13.33), PLCB1 (20p12.3), TBC1D24 (16p13.3),PIGA (Xp22.2), SCN1A (2q24.3), SLC25A22 (11p15.5), and SLC12A5 (20q13.12). The following genes have been reported in single cases: GABRA1, GABRB1, ATP1A3, CDKL5, and ITPA.\nDiagnostic methods\nDiagnosis is based on clinical and electroencephalographic (EEG) findings. The EEG background can be normal at onset; however, diffuse slowing of the background occurs with time. At onset, seizures may be subtle and video-EEG recordings are necessary to identify the seizures and the ictal EEG pattern. This is characterized by rhythmic theta discharges that affect different cortical regions consecutively in the same single seizure event giving the eponym ''migrating'' to EIMFS. Multifocal discharges appear with time in all cases. Rarely hypsarrhythmia is reported. Brain magnetic resonance imaging (MRI) is usually normal at onset and may show diffuse brain atrophy as the condition progresses. Delayed myelination with white matter hyperintensity on MRI and decreased N-acetyl aspartate on magnetic resonance spectroscopy are often reported early during the first months of the disease onset. Molecular genetic testing should be proposed in order to identify the causal pathogenic variant.\nDifferential diagnosis\nDifferential diagnosis includes other epileptic and developmental encephalopathies starting during the neonatal period, in particular when multifocal seizures and EEG abnormalities are present.\nAntenatal diagnosis\nPrenatal genetic diagnosis can be performed in families with a known mutation.\nGenetic counseling\nIn the majority of patients, KCNT1 mutations arise de novo. In a few families with a known KCNT1 mutation, inheritance is autosomal dominant with variable penetrance and expressivity. Genetic counselling is highly recommended in all patients with known genetic etiology. According to the gene involved, the disorder may be autosomal dominant, autosomal recessive, or X-linked.\nManagement and treatment\nSeizures are often difficult to treat and may continue into adulthood despite anti-seizures medications. Currently, there is no anti-seizures medication that has been proven to be more efficient to reduce seizure frequency and duration. Overtreatment should be avoided and follow-up by a reference center recommended.\nPrognosis\nPrognosis is poor with on-going drug resistant seizures, severe neurological disability, acquired microcephaly and reduced life expectancy, although a milder evolution has been reported in a few children. Some patients are also affected by severe gastrointestinal dysmotility and movement disorder.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Giulia BARCIA | EpiCARE* - Dr Amy MC TAGUE  - Pr Rima NABBOUT | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Malignant mixed Müllerian tumor of the ovary", "Disease Definition": "Malignant mixed Müllerian tumor of the ovary is a rare and very aggressive neoplasm presenting most commonly in postmenopausal women and is composed of adenocarcinomatous and sarcomatous elements and, depending on the types of these elements, can be classified as homologous or heterologous. It often has a poor prognosis.", "ORPHA ID": 213512, "Summary": ""}
{"Disease Name": "Malignant non-dysgerminomatous germ cell tumor of ovary", "Disease Definition": "Malignant non-dysgerminomatous germ cell tumor of ovary is a rare malignant germ cell tumor of ovary (see this term) arising from germ cells in the ovary, frequently unilateral at diagnosis, usually presenting during adolescence with pelvic mass, fever, vaginal bleeding and acute abdomen, with certain subtypes being occasionally associated with isosexual precocity, virilization, hyperthyroidism or carcinoid syndrome (see this term). Histologically they comprise the following: embryonal carcinoma, Yolk sac tumor, polyembryoma and mixed germ cell tumor.", "ORPHA ID": 206538, "Summary": ""}
{"Disease Name": "Malignant peripheral nerve sheath tumor with perineurial differentiation", "Disease Definition": "Malignant peripheral nerve sheath tumor with perineurial differentiation is a rare soft tissue sarcoma composed predominantly of spindle-shaped neoplastic cells showing perineurial differentiation and displaying abundant cellular pleomorphism or anaplasia, frequent mitoses, tumor necrosis and high metastatic potential. It often presents as a soft, painless, solid mass in subcutaneous tissues of the trunk or limbs, but tumors have also been described in the facial area, mediastinum, retroperitoneum, pancreas, paravertebral column and the pelvic soft tissues. Frequent local recurrence and distant metastatic spread has been reported.", "ORPHA ID": 252128, "Summary": ""}
{"Disease Name": "Malignant peripheral nerve sheath tumor", "Disease Definition": "Malignant peripheral nerve sheath tumor (MPNST) is a rare and often aggressive soft tissue sarcoma occurring in a wide range of anatomical sites.", "ORPHA ID": 3148, "Summary": "Epidemiology\nExact prevalence and incidence are unknown. Incidence of MPNST in the general population has been reported to be 1/100,000. MPNSTs account for about 5 to 10% of all soft tissue sarcomas. The sex ratio is about equal. Incidence among neurofibromatosis type 1 patients (NF1; see this term) is reported to be approximately 5 to 10%.\nClinical description\nThe age of occurrence is highly variable but most cases are reported in adults (typically between 20 and 50 years of age). In most cases, tumors arise in major nerve trunks such as the sciatic nerve or in the brachial plexus and sacral plexus. They are highly variable in appearance and commonly present as a rapidly enlarging palpable mass that is sometimes painful, with associated neurologic deficits such as radicular pain, paresthesia, and motor weakness. Tumors are fusiform to globular in shape, usually well circumscribed, and can be white to yellow and soft or firm. They occur most commonly in the trunk, head, neck and proximal extremities. Very rare anatomical sites include the brain, breast, posterior mediastinum, bladder, adrenal gland and skin. Tumors are often aggressive and high-grade, with the tendency to recur or to metastasize. MPNSTs can occur sporadically or in patients with NF1. They occur either de novo or from a preexisting neurofibroma or rarely from a schwannoma.\nEtiology\nThe etiology is unknown. Identified gene alterations include loss of the NF1 (17q11.2) and TP53 tumor suppressor gene (17p13.1). About 10% of tumors are associated with prior therapeutic or environmental radiation exposure.\nDiagnostic methods\nHistopathological examination is needed for definitive diagnosis. Biopsy usually reveals MPNST to be an infiltrative neoplasm with a varied range of cell morphologies (spindle, rounded or fusiform cells), with cellular fascicles which alternate with myxoid regions (marbled pattern). Diagnosis may be challenging because there are no specific immunohistochemical or molecular markers. Radiological imaging is used to determine the site and extension of the tumor.\nDifferential diagnosis\nOther malignant neoplasms to include in the differential diagnosis include synovial sarcoma, fibrosarcoma, undifferentiated pleomorphic sarcoma, angiosarcoma (see these terms), melanoma, and myoepithelial tumors.\nManagement and treatment\nTotal surgical resection is the mainstay of treatment. If removal is not possible, excision combined with high-dose radiation therapy may be used. Local Radiotherapy may be beneficial, but appears to have little effect on long-term survival. Chemotherapy is generally not effective.\nPrognosis\nPrognosis is generally poor and depends on the size of the tumor and success of treatment. A less favorable prognosis is associated with large tumors, NF1-associated cases, and truncal localization. The recurrence rate is reported to be as high as 40% and approximately two thirds of cases metastasize (lungs and bone). Five-year survival rate is reported to be 26% to 60%, and 10-year survival to be around 45%.\n\n                            Last update: \n                            August 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Khin THWAY"}
{"Disease Name": "Malignant peritoneal mesothelioma", "Disease Definition": "Malignant peritoneal mesothelioma is a primary peritoneal malignancy occurring in the lining cells (mesothelium) of the peritoneal cavity.", "ORPHA ID": 168811, "Summary": "Epidemiology\nPeritoneal mesothelioma accounts for 10 to 30% of all malignant mesotheliomas. The annual incidence is approximately 1/500,000 in France but reaches 1/200,000 in some parts of Europe (Italy). Men are predominantly affected.\nClinical description\nThe tumors are usually diagnosed in late adulthood (median age: 55 years). Typical presenting features are abdominal distention, abdominal pain, presence of an abdominal mass, impaired general state, weight loss, and ascites. Dyspnea, coagulation disorders, edema of the lower limbs and intestinal occlusion may be observed.\nEtiology\nThe relationship between peritoneal mesothelioma and asbestos exposure is unclear, especially in women, and has not been established unlike in malignant pleural mesothelioma. Other causes have been reported such as exposure to erionite, viral infection and vaccine products and/or genetic factors.\nDiagnostic methods\nDiagnosis is based on imaging techniques, such as ultrasound and chest-abdominal-pelvic computed tomography (CAP-CT). Diagnosis is confirmed histologically on tissue biopsy and by relevant immunostaining results (positive for calretinin and negative for carcinoembryonic antigen (CEA)), and should be performed by two experts.\nDifferential diagnosis\nDifferential diagnosis includes peritoneal carcinomatosis secondary to colorectal or gastric cancer and primary peritoneal carcinoma (see this term).\nManagement and treatment\nTreatment strategies require a multidisciplinary approach and must be discussed by a panel of physicians in a specialized center. There are currently no validated recommendations on clinical management and no cytotoxic agents have been granted a European Marketing Authorization (MA) in this indication. Currently proposed treatment with curative intent involves a combination of cytoreductive surgery (visceral resections and peritonectomy procedures) with hyperthermic intraperitoneal chemotherapy (HIPEC) (off-label use) in specific patients (young, good general status, low tumor volume). Systemic chemotherapy (off-label use) is sometimes used in palliative treatment.\nPrognosis\nWith palliative treatment (systemic chemotherapy), median survival does not reach 1 to 2 years. Following cytoreductive surgery and HIPEC, median survival of more than 50 months, and 5-year survival of more than 50% may be obtained.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Olivier GLEHEN"}
{"Disease Name": "Malignant Sertoli-Leydig cell tumor of the ovary", "Disease Definition": "A rare malignant sex cord stromal tumor of ovary occuring typically in young women and characterized by manifestations of androgen excess (hirsutism, hair loss, amenorrhea, or oligomenorrhea), when functional.", "ORPHA ID": 99916, "Summary": ""}
{"Disease Name": "Malignant sex cord stromal tumor of ovary", "Disease Definition": "Malignant sex cord stromal tumor (SCST) of ovary is a rare ovarian cancer (see this term) arising from granulosa, theca, sertoli and leydig cells or stromal fibroblasts, occurring at any age and presenting with abdominal or pelvic mass, and characterized (with the exception of fibroma) by the production of sex steroids resulting in manifestations of hormone excess, with a relatively favorable prognosis.", "ORPHA ID": 35808, "Summary": "Epidemiology\nAge related incidence rate was found to be 1 per 500,000 women. Sex cord stromal tumors constitute about 5% of ovarian malignancies.\nClinical description\nMalignant SCST of ovary may occur at any age but usually occurs in child bearing or post menopausal age groups, presenting with manifestations of mass effect (abdominal pain or distention, gastrointestinal symptoms, or abdominal mass) and/or signs of sex hormone production (isosexual precocity including breast swelling and vaginal bleeding, primary or secondary amenorrhea, and/or virilization). Malignant SCST of ovary comprises the following 4 histological forms: gynandroblastoma; malignant granulosa cell tumor of ovary; malignant Sertoli-Leydig cell tumor of ovary; and malignant steroid cell tumor of ovary, not otherwise specified (see these terms).\nEtiology\nMutations in the DICER1 (14q32.13) gene have been found to be a susceptibility factor for SCST, particularly in malignant Sertoli-Leydig cell tumor of ovary.\nDiagnostic methods\nDiagnosis is based on clinical features, particularly hormonal manifestations, and is supported by imaging (ultrasonogram, computed tomography) and tumor markers. Malignant granulosa cell tumor of ovary produces inhibin A and B which is helpful in diagnosis and follow-up. A FOXL2 mutation (3q23) has been found in most malignant granulosa cell tumors of the ovary, in adults. Chromosomal abnormalities have been recently detected among granulosa cell tumors and they include trisomy 12, monosomy 22 and chromosome 6 deletion. Diagnosis is confirmed by histological examination.\nDifferential diagnosis\nDifferential diagnoses include the more common malignant ovarian germ cell tumor of ovary, small cell carcinoma of the ovary (see this term) and ovarian metastasis of non-gonadal tumors. Malignant SCST of ovary is also found in association with enchondromatosis, Peutz Jeghers syndrome (see these terms) and Maffuci syndrome.\nManagement and treatment\nSurgery is performed for staging, histological confirmation and debulking. Total abdominal hysterectomy and bilateral salphingo-oopherectomy is often the initial management. Fertility sparing surgery is offered to patients with localized disease. In the absence of significant infiltration, preservation of the uterus along with the contralateral tube and ovary is attempted in children. Adjuvant chemotherapy is given to patients with advanced tumors.\nPrognosis\nHormonal symptoms lead to earlier diagnosis and hence a better prognosis in many malignant SCST tumors of ovary. Initial stage at diagnosis is the main prognostic factor. Histological type, presence of atypia and mitotic rate are other important prognostic factors. Stage, tumor size and presence of residual tumor after surgery influence the risk of recurrence\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Mojgan DEVOUASSOUX  - Pr Isabelle RAY-COQUARD"}
{"Disease Name": "Malignant teratoma of ovary", "Disease Definition": "A rare ovarian germ cell tumor characterized by a unilateral large adnexal mass containing variable amounts of immature embryonal-type tissues (mostly in the form of neuroectodermal tubules and rosettes, sometimes with a component of cellular mitotically active glia), admixed with ectodermal and endodermal elements with varying degrees of maturation. Patients typically present in their first three decades of life with signs and symptoms related to mass effect. The tumor is often associated with the occurrence of innumerable miliary nodules of mature glia in the peritoneum (gliomatosis peritonei) and abdominal lymph nodes.", "ORPHA ID": 398987, "Summary": ""}
{"Disease Name": "Malignant triton tumor", "Disease Definition": "Malignant triton tumor (MTT) is a rare aggressive subtype of malignant peripheral nerve sheath tumor (MPNST; see this term) characterized histopathologically by focal rhabdomyoblastic differentiation.", "ORPHA ID": 252212, "Summary": "Epidemiology\nIncidence of malignant triton tumors is not known. MTT accounts for about 5% of all MPNSTs. There appears to be an equal sex distribution.\nClinical description\nMost cases are reported in adults (mean age of about 30 years) but patients of all ages have been described. It is estimated that between 40% and 70% of cases occur in patients with neurofibromatosis type 1 (see this term), with an earlier age of onset and predominantly in male subjects. The remaining cases are sporadic and occur at a later age. MTT generally arises from a peripheral nerve in the head, neck, extremities or trunk. Rare localizations include the brain, buttock, viscera, mediastinum and retroperitoneum. Exceedingly rare intracranial MTT, not associated with a cranial nerve, has been reported. MTT is defined histologically as a malignant peripheral nerve sheath tumor with additional rhabdomyoblastic differentiation. Prognosis is generally very poor since MTT is aggressive, with a poorer prognosis than classical MPNST, and is often difficult to completely resect. Local recurrence and distant metastases are common. 5-year survival for MTT is reported to be about 10-14%.\nEtiology\nThe pathogenesis of MTTs has not been elucidated.\n\n                            Last update: \n                            August 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Khin THWAY"}
{"Disease Name": "Malonic aciduria", "Disease Definition": "Malonic aciduria is a metabolic disorder caused by deficiency of malonyl-CoA decarboxylase (MCD).", "ORPHA ID": 943, "Summary": "Epidemiology\nIt is a very rare disorder that has been described in less than 20 patients.\nClinical description\nThis condition usually presents in early childhood and the manifestations are variable. The majority of patients are developmentally delayed with other features that include hypotonia, seizures, hypoglycaemia, metabolic acidosis, cardiomyopathy and diarrhoea.\nEtiology\nThe disease is caused by mutations in the malonyl-CoA decarboxylase gene (MLYCD, chromosome 16q24) and is inherited as an autosomal recessive trait. The MCD enzyme is involved in the degradation of malonyl-CoA and it appears that inhibition of fatty acid synthesis as a result of malonyl-CoA accumulation is responsible for at least some of the clinical manifestations of the disorder.\nDiagnostic methods\nThe diagnosis of malonic aciduria can be made by detecting elevated levels of organic acids (in particular malonic and methylmalonic acid) in the urine and high levels of malonylcarnitine in the blood. The diagnosis is confirmed by demonstrating reduced enzyme activity in cultured skin fibroblasts. Identification of the MLYCD gene mutation may also be useful for diagnosis and for genetic counselling.\nAntenatal diagnosis\nScreening of newborns may be possible through detection of elevated blood levels of malonylcarnitine using electrospray ionisation tandem mass spectrometry (ESI-MS/MS). Prenatal screening is theoretically possible through enzyme or DNA analysis of amniocytes or chorionic villus samples.\nManagement and treatment\nThe principle treatment is dietary, with patients being recommended to follow a low fat/high carbohydrate diet. Carnitine supplements may also be recommended.\nPrognosis\nThe prognosis for patients is variable but the disease can be lethal in the neonatal period.\n\n                            Last update: \n                            December 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Pascale DE LONLAY"}
{"Disease Name": "Malposition of a coronary ostium", "Disease Definition": "A rare coronary artery congenital malformation characterized by displacement of one of the coronary arteries, originating closer to the aortic root or to the commissural area. The anomaly is considered to be asymptomatic, however, it may impose surgical difficulties during aortic root surgery.", "ORPHA ID": 99090, "Summary": ""}
{"Disease Name": "MALT lymphoma", "Disease Definition": "MALT (mucosa-associated lymphoid tissue) lymphoma is a rare form of malignant non-Hodgkin lymphoma (see this term) that affects B cells and grows at the expense of lymphoid tissue associated with mucous membranes, but also occurs, more rarely, in lymph nodes.", "ORPHA ID": 52417, "Summary": "Epidemiology\nIt accounts for about 5% of non-Hodgkin lymphoma diagnosed annually. Annual incidence is estimated at about 1/313,000.\nClinical description\nThe disease mainly affects adults over 60 years of age (median age 65 years) with a slight female predominance. It is very rare in children. MALT lymphoma can develop in the gastrointestinal tract (especially in the stomach), lungs and glands (lacrimal, thyroid and breast). The main symptoms are nonspecific and include fatigue, fever, nausea, constipation, weight loss and anemia. Other symptoms depend on the affected organs: abdominal pain in cases with gastric involvement, recurrent respiratory infections in cases with pulmonary involvement and visual impairment in cases with lacrimal gland involvement. In general, patients do not have lymphadenopathy.\nEtiology\nIn most cases, MALT lymphoma is secondary to autoimmune disease or chronic infection. There is a well-established link between chronic Helicobacter pylori infection and gastric MALT lymphoma. In 40% of cases of gastric lymphoma associated with H. pylori infection and in 53% of cases of MALT lymphoma not associated with H. pylori infection, MALT lymphoma is associated with a translocation t(11;18)(q21;q21) leading to the fusion of two genes, BIRC3 and MALT1, implicated in apoptosis regulation.\nDiagnostic methods\nDiagnosis is based on histology of the lesion, as in all lymphomas, a complete blood count and biochemical analysis. Endoscopic examination is required for gastrointestinal or pulmonary lymphoma. MRI and CT scanning are required to determine the stage of the disease. Bone marrow biopsy is also performed.\nDifferential diagnosis\nDifferential diagnoses include B cell lymphomas, diffuse large B cell lymphomas, all other non-Hodgkin lymphomas (see these terms), and infection with H. pylori.\nManagement and treatment\nIn cases with localized gastric involvement that are due to H. pylori, antibiotic therapy often results in regression of the lymphoma. In other cases, chemotherapy (chlorambucil, cyclophosphamide, or fludarabine) is required. Radiotherapy may be considered in cases of conjunctival lymphomas and in recurrent cases of localized forms, particularly gastric forms. Conjunctival MALT lymphoma is treated with interferon alpha-2a.\nPrognosis\nThese lymphomas evolve slowly. When the lymphoma is isolated, the 10yr-survival rate after treatment is around 75%.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Vincent RIBRAG"}
{"Disease Name": "Mammary-digital-nail syndrome", "Disease Definition": "Mammary-digital-nail syndrome is a syndromic limb malformation characterized by congenital onychodystrophy/anonychia, brachydactyly of the fifth finger, digitalization of the thumbs, with absence or hypoplasia of the distal phalanges of the hands and feet in association with juvenile hypertrophy of the breast with gigantomastia in peripubertal females.", "ORPHA ID": 238744, "Summary": ""}
{"Disease Name": "MAN1B1-CDG", "Disease Definition": "MAN1B1-CDG is a form of congenital disorders of N-linked glycosylation characterized by intellectual disability, delayed motor development, hypotonia and truncal obesity. Additional features include slight facial dysmorphism (hypertelorism, downslanting palpebral fissures, large, low-set ears, hypoplastic nasolabial fold, thin upper lip), hypermobility of the joints and skin laxity. The disease is caused by mutations in the gene MAN1B1 (9q34.3).", "ORPHA ID": 397941, "Summary": ""}
{"Disease Name": "Mandibular arteriovenous malformation", "Disease Definition": "Mandibular arteriovenous malformation is a rare vascular anomaly characterized by an abnormal connection of the arterial and venous vasculature, without capillary connections, in the mandibular area, commonly presenting with minor gingival bleeding, dental loosening, lower lip numbness, facial deformity and malocclusion. This usually high-flow vascular malformation may also present with potentially life-threatening, spontaneous, or tooth extraction-induced, hemorrhagic shock.", "ORPHA ID": 141174, "Summary": ""}
{"Disease Name": "Mandibular hypoplasia-deafness-progeroid features-lipodystrophy syndrome", "Disease Definition": "A rare, genetic, premature aging disease characterized by sensorineural deafness, generalized lack of subcutaneous fatty tissue (although with increased truncal deposition) noted from childhood, scleroderma, and facial dysmorphism which includes prominent eyes, a beaked nose, small mouth, crowded teeth and mandibular hypoplasia. Other associated features include growth delay, joint contractures, telangiectasia, hypogonadism (with lack of breast development in females), cryptorchidism, skeletal muscle atrophy, hypertriglyceridemia and diabetes mellitus/insulin resistance.", "ORPHA ID": 363649, "Summary": ""}
{"Disease Name": "Mandibuloacral dysplasia", "Disease Definition": "Mandibuloacral dysplasia (MAD) is a rare genetic bone disorder characterized by growth delay, postnatal development of craniofacial anomalies including mandibular hypoplasia, progressive acral osteolysis, mottled or patchy pigmentation, skin atrophy, and partial or generalized lipodystrophy.", "ORPHA ID": 2457, "Summary": ""}
{"Disease Name": "Mandibulofacial dysostosis with alopecia", "Disease Definition": "A rare mandibulofacial dysostosis characterized by the association with scalp alopecia and sparse eyebrows and eyelashes. Craniofacial dysmorphic features include zygomatic and mandibular dysplasia or hypoplasia, cleft palate, micrognathia, dental anomalies, auricular dysmorphism, and eyelid anomalies, among others. Patients may experience limited jaw mobility, glossoptosis, upper airway obstruction, and conductive hearing loss.", "ORPHA ID": 443995, "Summary": ""}
{"Disease Name": "Mandibulofacial dysostosis-macroblepharon-macrostomia syndrome", "Disease Definition": "Mandibulofacial dysostosis-macroblepharon-macrostomia syndrome is a rare developmental defect during embryogenesis disorder characterized by macroblepharon, ectropion, and facial dysmorphism which includes severe hypertelorism, downslanting palpebral fissures, posteriorly rotated ears, broad nasal bridge, long and smooth philtrum, and macrostomia with thin upper lip vermilion border. Other features may include large fontanelles, prominent metopic ridge, thick eyebrows, mild synophrys, increased density of upper eyelashes, anterverted nares, abnormal dentition and capillary hemangioma.", "ORPHA ID": 357158, "Summary": ""}
{"Disease Name": "Mandibulofacial dysostosis-microcephaly syndrome", "Disease Definition": "A rare genetic, multiple congenital malformation syndrome characterized by malar and mandibular hypoplasia, microcephaly, ear malformations with associated conductive hearing loss, distinctive facial dysmorphism (with significantly overlap to Treacher Collins syndrome), developmental delay, and intellectual disability.", "ORPHA ID": 79113, "Summary": "Epidemiology\nMore than 100 cases have been reported to date in various ethnic groups.\nClinical description\nMandibulofacial dysostosis-microcephaly syndrome (MFDM) has a wide range of manifestations. Affected patients have malar and mandibular hypoplasia, sometimes with upper airway compromise at birth. Congenital or postnatal-onset microcephaly is found in 90 % of patients (rarely associated with epilepsy). Microcephaly is congenital in two thirds of patients and secondary (postnatal) in about one third. Patients also have preauricular skin tags, microtia or malformations of the pinna, auditory canal, and/or the middle ear (ossicles and semi-circular canals) causing hearing loss (HL) in more than 70 % of cases. HL is generally conductive (about 80 % of patients) and occasionally sensorineural or mixed. Esophageal atresia or tracheo-esophageal fistula is also found occasionally. MFDM also includes a distinctive facial appearance with prominent metopic ridge, up- or down-slanting palpebral fissures, prominent glabella, broad nasal bridge, bulbous nasal tip, and everted lower lip. Associated craniofacial malformations may include cleft palate, choanal atresia and facial asymmetry. Short stature is found in about 30 % of patients. Mild to severe developmental delay is very common and includes delayed walking and speech. Almost all affected individuals have intellectual disability that is mostly mild or moderate, and sometimes severe. Other major extracranial malformations may also be found and include congenital heart malformations (e.g. atrial and ventricular septal defects, tetralogy of Fallot, patent arterial duct, and aortic arch defects), cryptorchidism, clinodactyly, and thumb abnormalities.\nEtiology\nMFDM is caused by heterozygous, mostly de novo, mutations in the EFTUD2 gene (17q21.31), encoding 116 kDa U5 small nuclear ribonucleoprotein component. A range of deletions and rearrangements, as well as pathogenic missense, nonsense, splice, and frameshift mutations, have been identified.\nDiagnostic methods\nThe diagnosis can be challenging but is generally based on the constellation of clinical manifestations and confirmed by molecular genetic testing revealing a mutation in the EFTUD2 gene.\nDifferential diagnosis\nThe differential diagnosis includes Treacher Collins, Nager and CHARGE syndromes and oculo-auriculo-vertebral spectrum.\nAntenatal diagnosis\nPrenatal testing for at-risk pregnancies is possible when the mutation has been identified in the family.\nGenetic counseling\nMFDM follows an autosomal dominant pattern of inheritance, although most mutations occur de novo. Genetic counseling should be offered to affected individuals, informing them of the 50% chance of offspring inheriting the disease-causing mutation and therefore being affected with the syndrome. The syndrome displays high penetrance but variable expressivity. Gonadal mosaicism has been reported.\nManagement and treatment\nIntubation and/or tracheostomy may be required in some affected infants at birth. Craniofacial manifestations should be treated on a case-by-case basis and managed by a multidisciplinary team. Occupational, physical, and speech therapies should be provided, along with standard measures for hearing loss and possible cardiac defects.\nPrognosis\nThe prognosis in MFDM is generally good. Life expectancy is normal in the absence of severe congenital anomalies. Feeding is a significant problem during infancy. The functional repercussions of the syndrome are highly variable with some patients being intellectually normal, some living semi-independently and employed, and some being nonverbal and in need of significant assistance.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Dagmar WIECZOREK | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Manganese poisoning", "Disease Definition": "A rare disorder due to toxic effects characterized by a progressive, permanent affliction of the extrapyramidal system with the globus pallidus and striatum as primary targets of neurotoxic effects. Symptoms include headache, insomnia, memory loss, emotional instability, hyperreflexia, dystonia, tremor, speech disturbances, and gait abnormalities. Individual factors like age, gender, genetics, and pre-existing medical conditions appear to have a profound impact on manganese toxicity.", "ORPHA ID": 306682, "Summary": ""}
{"Disease Name": "Mansonelliasis", "Disease Definition": "A form of filariasis, distributed throughout sub-Saharan Africa as well as in some locations of Central and South America and the Caribbean, caused by the parasitic worms Mansonella perstans and Mansonella ozzardi. The disease is often asymptomatic but may also cause fever, vertigo, myalgias, arthralgias and a sensation of coldness in the legs. Additional features include neuropsychiatric symptoms, skin rash, pruritus, nodules containing adult worms (in the conjunctiva or eyelids), lymphadenopathy, recurrent lymphedema in the limbs and face (resembling the Calabar swellings of loasis), severe abdominal pain and endocrine disturbances.", "ORPHA ID": 2459, "Summary": ""}
{"Disease Name": "Mantle cell lymphoma", "Disease Definition": "Mantle cell lymphoma is a rare form of malignant non-Hodgkin lymphoma (see this term) affecting B lymphocytes in the lymph nodes in a region called the ``mantle zone''.", "ORPHA ID": 52416, "Summary": "Epidemiology\nIt accounts for 2-10% of lymphomas. Prevalence is estimated at about 1/25,000.\nClinical description\nMantle cell lymphoma affects middle-aged adults, especially around 65 years (range 35-85 years) with males affected more than females (ratio M/F: 4:1). At diagnosis, most patients present with a disseminated form of the disease. Mantle cell lymphoma is often associated with generalized adenopathy (90% of cases), gastrointestinal disorders (60% of cases) and bone marrow involvement (55-80% of cases). Fever and impaired general condition (fatigue, loss of appetite and weight loss) may occur.\nEtiology\nMantle cell lymphoma is caused by a chromosomal translocation t(11;14) (q13;q32), which juxtaposes the CCND1 gene to the gene encoding for heavy chain immunoglobulins, leading to abnormally high expression of cyclin D1, a cell cycle regulator, in the nucleus of lymphoma cells.\nDiagnostic methods\nDiagnosis is based on lymph node biopsy revealing the presence of tumor cells. Phenotypic immunohistochemical analysis as well as evidence of abnormal expression of cyclin D1 (or the translocation t(11;14) by FISH or conventional cytogenetics) is necessary to confirm the diagnosis. Analysis of the stage of the disease is done with imaging (ultrasound, CT scanning and MRI) as well as bone marrow analysis (biopsy). Endoscopic examination should be used to detect intestinal involvement.\nDifferential diagnosis\nDifferential diagnoses include follicular lymphoma (see this term) and other forms of lymphoma.\nManagement and treatment\nTreatment of mantel cell lymphoma includes intensive chemotherapy combined with monoclonal antibodies. In younger patients, autologous stem cell transplantation is currently suggested. Torisel (chemotherapy) is a product that has received European market authorization as an orphan drug for refractory or relapsing disease. Rare localized forms of the disease may benefit from radiotherapy.\nPrognosis\nFew patients (30%) have a complete response to current treatments. The median overall survival time reported in the literature is 3-5 years.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Vincent RIBRAG"}
{"Disease Name": "Maple syrup urine disease", "Disease Definition": "A rare inherited disorder of branched-chain amino acid metabolism classically characterized by poor feeding, lethargy, vomiting and a maple syrup odor in the cerumen (and later in urine) noted soon after birth, followed by progressive encephalopathy and central respiratory failure if untreated. The four overlapping phenotypic subtypes are: classic, intermediate, intermittent and thiamine-responsive MSUD.", "ORPHA ID": 511, "Summary": "Epidemiology\nThe estimated prevalence is around 1/150,000 live births, from published and unpublished newborn screening data.\nClinical description\nClassic MSUD presents in the first days of life with poor feeding and drowsiness followed by a worsening encephalopathy with lethargy, intermittent apnea, stereotypic movements (\"fencing\" and ''bicycling\") and opisthotonus. Coma and central respiratory failure supervene 7 to 10 days after birth. The only abnormality in biochemistry is ketosis. Intermediate MSUD clinically resembles classic MSUD but it can have a later onset and less severe symptoms. Intermittent MSUD patients are asymptomatic at birth but may suffer episodes of acute decompensation or develop neurological symptoms and developmental delay during childhood. Thiamin-responsive MSUD is clinically similar to intermediate MSUD with thiamin therapy improving dietary leucine tolerance.\nEtiology\nMSUD is due to mutations in the genes encoding subunits E1a, E1b, and E2 of the branched chain 2-ketoacid dehydrogenase (BCKAD) complex, involved in the second enzymatic step in the degradation of the branched chain amino acids (BCAAs): leucine, isoleucine and valine. BCKAD has four subunits: E1a, E1b, E2, and E3, which are encoded by the genes BCKDHA (19q13.1-q13.2), BCKDHB (6q14.1), DBT (1p31) and DLD (7q31-q32) respectively. Mutations in these genes lead to the accumulation of BCAAs (especially leucine) and their branched-chain alpha-ketoacids. Mutations in the E3 subunit gene (DLD) are not associated with MSUD but lead to pyruvate dehydrogenase E3 deficiency (see this term). A mutation in the PPM1K gene (4q22.1) has been reported in a single case of mild intermediate MSUD.\nGenetic counseling\nMSUD follows an autosomal recessive inheritance pattern and genetic counseling is possible.\n\n                            Last update: \n                            April 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Bridget WILCKEN"}
{"Disease Name": "Marburg acute multiple sclerosis", "Disease Definition": "Marburg acute multiple sclerosis is a rare variant of multiple sclerosis characterized by a rapidly progressive, aggressive form of multiple sclerosis with numerous large multifocal demyelinating lesions in deep white matter on cerebral MRI that usually leads to severe disability or death within weeks to months without remission. A relapsing form of multiple sclerosis is observed in surviving patients.", "ORPHA ID": 228157, "Summary": ""}
{"Disease Name": "Marburg hemorrhagic fever", "Disease Definition": "Marburg hemorrhagic fever (MHF), caused by Marburg virus, is a severe viral hemorrhagic disease characterized by initial fever and malaise followed by gastrointestinal symptoms, bleeding, shock, and multi-organ system failure.", "ORPHA ID": 99826, "Summary": "Epidemiology\nMHF is endemic to Central Africa and is generally recognized in sporadic small outbreaks (<50 cases), although one large (>250 cases) nosocomial outbreak occurred in Angola in 2004-2005. Less than 500 cases have been reported to date.\nClinical description\nAfter an incubation period of about 8 days (range 3-21 days), patients typically present with the abrupt onset of non-specific signs and symptoms including fever, malaise, headache, chest pain and myalgia/arthralgia, followed rapidly by gastrointestinal manifestations (vomiting, diarrhea, abdominal pain) and, in some cases, a maculopapular skin rash. Severe cases develop bleeding (sub-conjunctival hemorrhage, epistaxis, bleeding from the mouth and rectum, oozing from venipuncture sites), neurologic involvement (disorientation, convulsions, coma), shock and multi-organ system failure. Mild-to-moderate leukopenia and thrombocytopenia are often present and disseminated intravascular coagulation (DIC) commonly develops, best indicated by the presence of D-dimers.\nEtiology\nOver 25 different viruses cause viral hemorrhagic fever. Marburg virus is a member of the virus family Filoviridae, along with Ebola virus. Numerous strains have been identified, putatively with different degrees of lethality. Accumulating evidence implicates fruit bats as the Marburg virus reservoir, with primary human infection presumably from unwitting contact with bat excreta or saliva. Entry into caves and mines where fruit bats roost is a risk factor. Infection has also rarely occurred through contact with tissues of wild monkeys, presumably also infected through bat exposure. Human-to-human transmission occurs through direct contact with blood or bodily fluids of infected persons.\nDiagnostic methods\nCommon diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories.\nDifferential diagnosis\nMHF is difficult to distinguish from a host of other febrile illnesses, at least early in the course of disease. Other viral hemorrhagic fevers need to be excluded, especially Ebola hemorrhagic fever, as well as malaria, typhoid fever, leptospirosis, rickettsial infection, plague (see these terms), bacterial dysenteryand meningococcemia.\nManagement and treatment\nPatients should be isolated and viral hemorrhagic fever precautions (face shields, surgical masks, double gloves, surgical gowns and aprons) should be used to prevent nosocomial transmission. As there is presently no antiviral drug available for MHF, treatment is supportive, following the guidelines for treatment of severe septicemia. Persons who have unprotected contact with someone with MHF should be monitored.\nPrognosis\nCase-fatality rates are typically over 80%, although it was only 22% in one outbreak in Europe stemming from imported monkeys. Shock, bleeding, neurological manifestations, high viremia, aspartate aminotransferase (AST) > 150 IU/L, and pregnancy confer a poor prognosis. Convalescence may last up to a year but survivors usually have no lasting sequelae.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Daniel BAUSCH  -  Andrew BENNETT"}
{"Disease Name": "Marchiafava-Bignami disease", "Disease Definition": "A rare neurologic disease most prominently characterized by progressive demyelination and necrosis of the corpus callosum. It is in most cases associated with chronic alcoholism and malnutrition. Speed of onset and clinical presentation are very variable with a range of possible symptoms, including dementia, seizures, gait abnormalities, dysarthria, aphasia, athetosis, as well as stupor and coma.", "ORPHA ID": 221074, "Summary": ""}
{"Disease Name": "Marcus-Gunn syndrome", "Disease Definition": "A rare ophthalmic disorder characterized by congenital ptosis associated with pterygoid-levator synkinesis (also called jaw-winking).", "ORPHA ID": 91412, "Summary": "Epidemiology\nThe syndrome is responsible for 2-6% of congenital ptoses.\nClinical description\nSeverity of the ptosis and jaw-winking is highly variable. The ptosis is corrected by the opening of the mouth or lateral movements of the lower jaw. The synkinesis can be linked with Duane retraction syndrome and other various strabismus patterns. Amblyopia is also a frequent association. Anisometropia is occasionally reported.\nEtiology\nThe etiology is still unclear and two main hypotheses have been proposed. The first hypothesis suggests the presence of an aberrant connection between the mandibular division of the trigeminal nerve and the oculomotor nerve, possibly provoked in utero. An ephaptic mechanism has been postulated: it would be a persistent phenomenon, determining a stereotyped, well reproducible, and stable movement. The second hypothesis proposes the unmasking of a primitive pathway, due to a neural misdirection in the brainstem, and an electric stimulus of the ipsilateral pterygoid nerve is known to determine a retraction of the upper eyelid in 20% of normal subjects.\nDiagnostic methods\nDiagnosis is made based on clinical presentation.\nDifferential diagnosis\nInverse Marcus Gunn phenomenon and Marin-Amat syndrome present as eyelid drooping on jaw opening. The first is a congenital condition in which the eyelid levator muscle is inhibited, while Marin-Amat syndrome occurs after facial paralysis and represents patients with a connection between the orbicularis oculi and not with levator muscle.\nGenetic counseling\nMarcus-Gunn syndrome is mainly sporadic, although familial cases with an irregular autosomal dominant inheritance have been reported.\nManagement and treatment\nIf only mild ptosis and mild jaw winking are present, no intervention is recommended. A moderate ptosis can be corrected with levator muscle advancement, but results in worsening of the aberrant movement. Candidates for this surgery are young adults with moderate ptosis that have learned how to minimize abnormal movements and can control mild synkinesis. Levator resection appears to be inadequate to correct severe ptosis (with high rates of ptosis recurrence) despite a good levator function and should not be performed. If there is severe ptosis and severe jaw-winking, levator excision associated with frontalis suspension or frontalis flap is the treatment of choice. Bilateral treatment yields more satisfactory cosmetic results. Unilateral treatment should be limited to patients with associated anomalies of the affected eye whom are reluctant to accept bilateral procedures.\nPrognosis\nPrognosis is usually good if an adequate treatment is planned. Occasionally, ptosis seems to improve with time, although there is no evidence that this really happens. A possibility is that, as time passes, the patient recognizes which movements are responsible for the synkinesis and learns how to control it.\n\n                            Last update: \n                            May 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Francesco QUARANTA LEONI"}
{"Disease Name": "Marden-Walker syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by multiple joint contractures (arthrogryposis), a mask-like face with blepharophimosis, micrognathia, high-arched or cleft palate, low-set ears, decreased muscular bulk, kyphoscoliosis and arachnodactyly.", "ORPHA ID": 2461, "Summary": "Epidemiology\nThe prevalence is still unknown but to date between 30-50 cases have been described in the world literature.\nClinical description\nThe typical age of onset lies in the neonatal or infancy period and clinically Marden-Walker syndrome (MWS) is characterized by postnatal growth retardation and multiple joint contractures associated with restricted mobility of the joints. Facial dysmorphism includes a mask-like and asymmetric face along with blepharophimosis, low-set ears, high arched or cleft palate, micrognathia, short neck, and decreased muscular bulk. Other common features are kyphoscoliosis, pectus excavatum or carinatum, limited motor function in the shoulder, elbow and wrist joints and arachnodactyly and camptodactyly. Congenital talipes equinovarus, absent deep tendon reflexes and limbs with hypoplastic muscles are generally observed. Hypospadias with bilateral inguinal hernia may be observed. Minor cerebral malformations, cardiovascular or renal anomalies and intellectual deficit have also been described.\nEtiology\nThe underlying pathological mechanism of MWS has not yet been clearly established, but it is assumed that it is a developmental disorder of the central nervous system. In two patients, pathological variants in PIEZO2 (18p11.22-p11.21) have been identified.\nDiagnostic methods\nThe diagnosis of MWS is based on the minimal criteria (postnatal growth retardation, severe developmental retardation, multiple joint contractures, a 'mask-like' face with blepharophimosis, micrognathia, high-arched or cleft palate, low-set ears and (kyphoscoliosis). Magnetic resonance imaging (MRI) of the head and an echocardiography may reveal cerebral malformations and cardiovascular abnormalities respectively. Kyphosis is diagnosed using X-ray imaging.\nDifferential diagnosis\nDifferential diagnosis includes trisomy 13 and 18, Smith-Lemli-Opitz syndrome, Zellweger syndrome, spinal cord injury, amyoplasia congenita, infantile spinal muscular atrophy, Moebius syndrome, congenital hypomyelinating neuropathy, blepharophimosis-intellectual deficit syndromes, Van den Ende-Gupta syndrome, Freeman-Sheldon syndrome, Schwartz-Jampel syndrome (same clinical presentation but MWS lacks myotonia), infantile neuronal degeneration and focal infantile spinal muscular atrophy.\nAntenatal diagnosis\nPrenatal diagnosis of MWS in a fetus with a previously affected sibling may be achieved by finding intrauterine growth retardation and renal cystic disease. Moreover, arthrogryposis can be viewed antenatally on ultrasound from the second trimester onwards. Ultrasonographic examination may also indicate an oligohydramnios. The finding of the latter should encourage a more detailed ultrasonographic examination, as ankylosed joints can be detected in utero.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\nManagement and treatment\nThe treatment of MWS is symptomatic with multidisciplinary management. Conservative orthopedic treatment and physiotherapy are indicated.\nPrognosis\nIntellectual deficit observed in MWS remains severe but contracture is not progressive and decreases with advancing age and physiotherapy. The long term prognosis is limited in many patients due to complications e.g. skeletal deformities, lung infections and gastrointestinal problems.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Gnanavelu INJETI  - Dr Amar TAKSANDE"}
{"Disease Name": "Marfan syndrome", "Disease Definition": "Marfan syndrome is a systemic disease of connective tissue characterized by a variable combination of cardiovascular, musculo-skeletal, ophthalmic and pulmonary manifestations.", "ORPHA ID": 558, "Summary": "Epidemiology\nThe prevalence is estimated at 1/5,000 and there is no difference between sexes.\nClinical description\nSymptoms can appear at any age and vary greatly between individuals even within the same family. Cardiovascular involvement is characterized by 1) progressive dilation of the aorta accompanied by an increased risk of aortic dissection, which affects prognosis; the aortic dilation can result in a leaky aortic valve; and 2) mitral insufficiency, which can be complicated by arythmias, endocarditis or cardiac insufficiency. Skeletal involvement is often the first sign of the disease and can include dolichostenomelia (excessive length of extremities), large size, arachnodactyly, joint hypermobility, scoliotic deformations, acetabulum protrusion, thoracic deformity (pectus carinatum or pectus excavatum), dolichocephaly of the anteroposterior axis, micrognathism or malar hypoplasia. Ophthalmic involvement results in axile myopia, which can lead to retinal detachment and lens displacement (ectopia or luxation are characteristic signs). Ocular complications, particularly lens ectopia, can lead to blindness. Cutaneous signs (vergetures), a risk of pneumothorax and dural ectasia can also occur.\nEtiology\nIn the vast majority of cases, Marfan syndrome is caused by mutations of the FBN1 gene (15q21), which codes for fibrilline-1, a protein essential for connective tissues. Frontier forms have been identified that are secondary to mutations in the TGFBR2 gene located on chromosome 3, which codes for a TGF-beta receptor.\nDiagnostic methods\nDiagnosis is based on clinical signs and family history. However, as a result of the widely variable clinical picture, the diagnosis can be difficult to establish. International diagnostic criteria (Ghent criteria) based on major and/or minor clinical signs have been established to aid diagnosis.\nDifferential diagnosis\nDifferential diagnoses include MASS syndrome, Shprintzen-Goldberg syndrome, mitral valve prolapse, Ehlers-Danlos syndrome and other diseases that present with aortic aneurysm such as Loeys-Dietz syndrome (see these terms).\nAntenatal diagnosis\nPrenatal genetic diagnosis is possible for families in which the causal mutation has been identified.\nGenetic counseling\nTransmission is autosomal dominant. An affected individual has a 50% risk of transmitting the mutation responsible for the disease. Some sporadic cases have been reported.\nManagement and treatment\nManagement should be multidisciplinary with consultations from different specialists including cardiologists, geneticists, rheumatologists, ophthalmologists, pediatricians and radiologists. Management should aim to limit aortic dilation (beta-blockers and a reduction in sport activities) and regularly monitor the aorta (annual echocardiograms) in order to allow the aortic root to be replaced before dissection occurs. Surgery can be offered for skeletal anomalies (vertebral column stabilization in the case of scoliosis or reparation of thoracic deformities) and ocular anomalies (laser treatment or replacement of a dislocated lens). Treatment is otherwise symptomatic.\nPrognosis\nPrognosis depends on the degree of aortic involvement. With regular follow-up and adequate management, patients now have a life expectancy close to that of the general population. Over the last 30 years that life expectancy has increased by 30 years.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Guillaume JONDEAU"}
{"Disease Name": "Marfanoid habitus-autosomal recessive intellectual disability syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, psychomotor retardation, flat face and some features resembling Marfan syndrome, such as tall stature, dolichostenomelia, arm span larger than height, arachnodactyly of hands and feet, little subcutaneous fat, and muscle hypotonia. There have been no further descriptions in the literature since 1984.", "ORPHA ID": 2463, "Summary": ""}
{"Disease Name": "Marfanoid habitus-inguinal hernia-advanced bone age syndrome", "Disease Definition": "A rare developmental defect with connective tissue involvement disorder characterized by tall stature, inguinal hernia, facial dysmorphism (including a long, triangular face, prominent forehead, telecanthus, downslanting palpebral fissures, bilateral ptosis, everted lower eyelids, large ears, long nose, full, everted vermilions, narrow and high arched palate, dental crowding), and radiologic evidence of advanced bone age. Additional manifestations include hyperextensible joints, long digits, mild muscle weakness, myopia, and foot deformities (i.e. hallux valgus, talipes equinovarus).", "ORPHA ID": 314041, "Summary": ""}
{"Disease Name": "Marfanoid syndrome, De Silva type", "Disease Definition": "A rare syndromic intestinal malformation characterized by the association of marfanoid features (including marfanoid habitus, severe myopia, retinal detachment, and mitral valve prolapse) with visceral diverticula (inguinal and/or femoral hernia and diverticula of the large and small bowel or urinary bladder). Some patients also had diaphragmatic eventration. There have been no further descriptions in the literature since 1996.", "ORPHA ID": 2464, "Summary": ""}
{"Disease Name": "Marie Unna hereditary hypotrichosis", "Disease Definition": "A rare autosomal dominant hair loss disorder characterized by the absence or scarcity of scalp hair, eyebrows, and eyelashes at birth; coarse and wiry hair during childhood; and progressive hair loss beginning around puberty.", "ORPHA ID": 444, "Summary": "Epidemiology\nPrevalence and incidence are unknown. To date, approximately 30 families and sporadic cases with a molecular diagnosis have been reported in the literature.\nClinical description\nAffected individuals of both sexes are typically born with an absence or scarcity of scalp hair, eyelashes, and eyebrows. During early childhood the scalp hair becomes coarse and wiry. Loss of scalp hair begins around puberty in a pattern resembling that of androgenetic alopecia and progresses to almost total alopecia. Body, axillary, and pubic hair is sparse or absent as is beard hair in men and adolescent boys. No other ectodermal abnormalities are observed.\nEtiology\nThe disorder is due to mutations in U2HR, an inhibitory upstream open reading frame of the HR gene located to 8p21.2, causing a gain of function of HR. Worldwide, about 20 different U2HR mutations have been identified in more than 30 affected families and sporadic cases. Recently, a missense mutation in EPS8L3, located on chromosome 1p13.2, was identified in a Chinese family; however, there are currently no other reports of this mutation.\nDiagnostic methods\nDiagnosis depends on clinical and microscopic examination and can be confirmed by mutational analysis of U2HR. Scanning electron microscopic study of the hair reveals irregular twisting, longitudinal ridging and cuticle peeling. Scalp biopsy shows a marked reduction in the number of follicles with follicular fibrosis. However, the small number of biopsies analyzed makes it difficult to obtain an objective impression.\nDifferential diagnosis\nDifferential diagnoses include hypotrichosis simplex, loose anagen syndrome, uncombable hair syndrome, ectodermal dysplasia syndromes, congenital atrichia, androgenetic alopecia and alopecia areata.\nGenetic counseling\nTransmission is autosomal dominant. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nNo curative treatment exists.\nPrognosis\nLife expectancy is normal but quality of life can be reduced due to the psychological impact related to the hair phenotype.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Regina BETZ"}
{"Disease Name": "Marinesco-Sjögren syndrome", "Disease Definition": "A rare autosomal recessive disorder characterized by cerebellar ataxia, early-onset bilateral cataracts, chronic myopathy; additional features are delayed motor development and variable intellectual disability, hypergonadotrophic hypogonadism and delayed puberty, and short stature.", "ORPHA ID": 559, "Summary": "Epidemiology\nPrevalence is not known, most likely in the 1-9/1,000,000 range. The estimated worldwide carrier frequency is 1:700, and in Finland it is 1:96. Disease onset occurs in infancy.\nClinical description\nHypotonia is usually present in early infancy, and muscle weakness is noticed during the first decade. Truncal ataxia, dysdiadochokinesia, nystagmus and dysarthria appear later. Cataracts can develop rapidly. Less constant features are skeletal deformities, somatic growth delay, and hypergonadotropic hypogonadism. Developmental milestones are often delayed and cognition varies from normal to severe intellectual disability. Cerebellar atrophy is observed on magnetic resonance imaging in all patients. Serum creatine kinase levels are usually only slightly or moderately elevated. Electromyography shows myopathic features. Electron microscopy of a muscle biopsy typically shows vacuolar myopathy and characteristic perinuclear membrane-like structures.\nEtiology\nMarinesco-Sjögren syndrome is caused by biallelic pathogenic variants in the SIL1 gene. Most of pathogenic variants are missense, but frameshift, nonsense and splice site variants have also been reported. SIL1 (nucleotide exchange factor SIL1) is present in the endoplasmic reticulum and plays a role as a co-chaperon in protein translocation into the endoplasmic reticulum, protein folding, control of degradation of misfolded proteins and response to cell stress. As a consequence, mutations in SIL1 lead to disturbance in proper folding of proteins and subsequently cell destruction.\nDiagnostic methods\nDiagnosis is based on typical clinical findings and/or biallelic pathogenic variants in the SIL1 gene. Ophthalmologic examination should be performed to detect cataract. Magnetic resonance imaging allows investigation of cerebellar atrophy particularly involving the vermis. Electron microscopy shows findings specific to Marinesco-Sjögren syndrome in muscle biopsy, while light microscopy does not.\nDifferential diagnosis\nDifferential diagnosis includes congenital cataracts-facial dysmorphism-neuropathy syndrome, congenital muscular dystrophy with cataracts and intellectual disability due to INPP5K gene variant, autosomal recessive spastic paraplegia type 46, autosomal recessive cerebellar ataxia with late-onset spasticity, ADan amyloidosis and dysequilibrium syndrome.\nAntenatal diagnosis\nPreimplantation or prenatal diagnosis are possible where the pathogenic variants have previously been identified in the index case and the parents.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant). The risk of recurrence of having an affected child is 25% at each pregnancy.\nManagement and treatment\nTreatment is symptomatic. Cataracts often require surgical removal to preserve vision. Hormonal replacement therapy may be needed if hypogonadism is present. Physical and occupational therapy are crucial.\nPrognosis\nPatients can survive to old age, with varying disability.\n\n                            Last update: \n                            December 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Dídac CASAS-ALBA | ITHACA* - Pr Francesc PALAU | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Marshall syndrome", "Disease Definition": "A malformation syndrome that is characterized by facial dysmorphism, severe hypoplasia of the nasal bones and frontal sinuses, ocular involvement, early-onset hearing loss, skeletal and anhidrotic ectodermal anomalies and short stature with spondyloepiphyseal dysplasia and early-onset osteoarthritis.", "ORPHA ID": 560, "Summary": ""}
{"Disease Name": "Marshall-Smith syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies syndrome characterized by abnormal bone maturation with skeletal anomalies, airway obstructions, failure to thrive, developmental delay, moderate to severe intellectual disability and characteristic facial features with macrocephaly, prominent forehead, shallow orbits, proptosis and blue sclerae.", "ORPHA ID": 561, "Summary": "Epidemiology\nLess than 60 cases have been reported in the literature to date.\nClinical description\nMarshall-Smith syndrome was originally considered as an overgrowth condition based on advanced bone maturation. It is characterized by a dysostosis with skeletal anomalies including progressive kyphoscoliosis, postnatal failure to thrive in weight, short stature, and osteopenia with fractures. Wide bullet-shaped phalanges as well as large hands and feet are observed. Neonates and infants usually manifest with feeding difficulties and upper airway obstruction with respiratory distress due to glossoptosis, laryngomalacia and/or choanal stenosis. The majority of patients die in the neonatal period or early infancy from respiratory compromise. Respiratory infections are frequent. Patients surviving infancy also have developmental delay, moderate to severe intellectual disability and behavioral abnormalities such as anxiety and stereotyped movements. Brain MRI may show corpus callosum anomalies, macrogyria, pachygyria, delayed myelination, ventricular dilatation, hydrocephalus and periventricular leukomalacia. Characteristic facial features include high forehead, proptosis, blue sclerae, midface hypoplasia, short nose, depressed nasal bridge, anteverted nostrils and retrognathia. Vision impairment may occur as a result of optic nerve hypoplasia. Hypertrichosis, umbilical hernia, connective tissue, endocrine and cardiovascular anomalies may be associated. In a single case a concomitant Wilms tumor had developed, otherwise an increased risk of neoplasm development is not known.\nEtiology\nMarshall-Smith syndrome is cause by heterozygous de novo variants in the NFIX (Nuclear Factor I X; 19p13.13) gene. NFIX variants escape nonsense-mediated mRNA decay leading to abnormal proteins with an abnormal C-terminus (dominant-negative mechanism). The NFIX gene acts as the transcription factor in the nuclear factor I family, and is implicated in replication, signal transduction, and transcriptional processes, with, currently not fully elucidated mechanisms.\nDiagnostic methods\nThe syndrome is clinically recognizable. The genetic diagnosis is established by identification of a heterozygous pathogenic variant in the NFIX gene. Most of the variants have been identified in exons 6-10 of the gene.\nDifferential diagnosis\nThe differential diagnoses for Marshall-Smith syndrome are Sotos syndrome, Malan overgrowth syndrome, Weaver syndrome, and bone fragility disorders. Radiological findings distinguish them based on skeletal findings.\nAntenatal diagnosis\nPrenatal diagnosis is possible if the disease-causing variant has been identified in the family. The recent implementation of prenatal whole exome sequencing could lead to molecular diagnostics during pregnancy.\nGenetic counseling\nMarshall-Smith syndrome is inherited in an autosomal dominant manner. All known pathogenic variants have occurred de novo, and in these cases the risk to sibs of the proband is very low due to a possible germinal mosaicism (<1%).\nManagement and treatment\nManagement of Marshall-Smith syndrome required a multidisciplinary approach with appropriate specialists. Patients need symptomatic treatment for airway obstruction, respiratory infections, and feeding difficulties, as well as specific management for bone fragility.\nPrognosis\nThe prognosis is poor and most patients will die in the neonatal period or early infancy due to respiratory compromise. A few cases of prolonged survival have been reported in patients without respiratory complications.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Valérie CORMIER-DAIRE  - Dr Valérie MALAN | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Martinique crinkled retinal pigment epitheliopathy", "Disease Definition": "A rare, genetic retinal disease characterized by characteristic \"dried-out soil\" fundus pattern due to diffuse deep white lines in the macula, to the level of the retinal pigment epithelium, which is slightly elevated and rippled. Macular exudation may be associated, and Bruch's membrane may be affected too. Occasionally, peripheral nummular pigmentary changes may be observed, associated with blindness. The lesions enlarge with time, with a preferential macular extension and confluence. Complications may include polypoidal choroidal vasculopathy, choroidal neovascularization or atrophic fibrous macular scarring that can lead to reduced visual acuity over time.", "ORPHA ID": 466718, "Summary": ""}
{"Disease Name": "MASA syndrome", "Disease Definition": "A X-linked, clinical subtype of L1 syndrome, characterized by mild to moderate intellectual disability, delayed development of speech, hypotonia progressing to spasticity or spastic paraplegia, adducted thumbs, and mild to moderate distension of the cerebral ventricles.", "ORPHA ID": 2466, "Summary": ""}
{"Disease Name": "Mast cell leukemia", "Disease Definition": "A very rare malignant systemic mastocytosis (SM) characterized by a huge infiltration of bone marrow, and often of blood, by abnormal mast cells (MC) which frequently manifests with organ dysfunction (liver, spleen, peritoneum, bones, and marrow).", "ORPHA ID": 98851, "Summary": "Epidemiology\nIt is extremely rare (less than 1% of cases of SM).\nClinical description\nMast cell leukemia (MCL) is a hematological disease that may occur at any age and is characterized by a massive infiltration of bone marrow by abnormal mast cells (at least 20% MC on BM smears). In patients suffering from the classical variant of MCL, circulating MC are also found. However, in a substantial number of patients with MCL, the leukemic spread into the peripheral blood is less extensive or is even absent. When MCs comprise less than 10% of all circulating blood leukocytes, the disease is termed aleukemic MCL. In a majority of patients, cutaneous lesions are absent. In most patients with MCL, signs and symptoms of organ damage, so-called C Findings, are present, and qualify the disease as acute MCL (aMCL). Patients with aMCL have a very poor prognosis with a median survival of less than 6 months, due to multiple organ failures caused by massive infiltration by MCs and/or to anaphylactic shock. Presentation is with organ dysfunction related to mast cell invasion (C-findings) and the intense release of mediators resulting in syncope, recurrent flushing, diarrhea, pain and organomegaly. C-findings include bone marrow (BM) dysfunction, palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension, skeletal involvement with large osteolytic lesions and/or pathological fractures, palpable splenomegaly with hypersplenism and malabsorption with ascites. However, a subvariant of MCL, termed chronic MCL (cMCL), is defined by at least 20% MCs on BM smears and absence of C-Findings. MC in BM smears of cMCL patients appear more mature than those in BM smears of aMCL patients. Patients with cMCL have longer median survival as compared to those with acute MCL. However, in patients with chronic MCL in whom one or more C-Findings develop, the diagnosis changes from chronic to acute MCL.\nEtiology\nIn the few cases that have been studied, activating mutations of the gene KIT (D816V, D816Y, G820V), chromosome location 4q12, have been found in malignant mast cells, however, various chromosomal anomalies have also been noted.\nDiagnostic methods\nDiagnosis is based on the histological and cytological analysis of bone marrow samples. Cytological analysis reveals a proportion of bone marrow mast cells over 20%. In most cases of mast cell leukemia, bone marrow mast cells with an atypical appearance, immature with a bi or multi-lobed core or, sometimes, a blast-like morphological appearance. Abnormal mast cells are present in the blood in most cases, with a proportion greater than 10% of circulating white blood cells. Additional tests include measurement of serum tryptase (above 20 ng/mL, with values sometimes exceeding 1,000 ng/mL), searching for mutations of KIT and phenotyping bone marrow mast cells.\nDifferential diagnosis\nDifferential diagnoses include all other acute leukemias and rare cases of basophilic leukemia.\nManagement and treatment\nManagement includes chemotheraphy, with or without interferon alpha or cladribine. For MCL patients with rapid progression and those who are resistant against 2CdA or midostaurin, poly-chemotherapy (protocols otherwise used for high-risk AML) is usually recommended. In patients who are young and fit and have a suitable donor, stem cell transplantation (SCT) should be considered after successful debulking. The outcome after allogeneic SCT is better for those prepared with ablative conditioning compared with less-intensive (nonmyeloablative) conditioning. In cases with splenomegaly with hypersplenism, splenectomy is indicated. Hydroxyurea is a palliative treatment.\nPrognosis\nThe prognosis in acute MCL is very poor and survival time is several months. In chronic MCL, the clinical course is unpredictable. Some of these patients have an indolent course for several months or even years. Other patients progress to acute MCL within a short time. In most cases reported so far, progression to acute MCL was seen.\n\n                            Last update: \n                            May 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Michel AROCK"}
{"Disease Name": "Mast cell sarcoma", "Disease Definition": "Mast cell sarcoma is a rare, neoplastic disease characterized by locally destructive sarcoma-like growth of a solitary mass, composed of atypical mast cells, and without systemic involvement. It can affect any organ and the symptoms depend on the location. Cells are medium to large, pleomorphic or epithelioid, with oval, bilobed or multilobulated nuclei, sometimes prominent multinucleated giant cells. The disease closely resembles other neoplasms and may share associated markers, however the tumor is positive for mast cell tryptase.", "ORPHA ID": 66661, "Summary": ""}
{"Disease Name": "Maternal hyperthermia-induced birth defects", "Disease Definition": "A rare maternal disease-related embryofetopathy characterized by variable developmental anomalies of the fetus due to teratogenic effect of elevated maternal body temperature (resulting from febrile illness or hot environment exposure). Reported developmental anomalies include neural tube defects (spina bifida, ecephalocele, anencephaly), cardiac defects (transposition of great vessels), urogenital defects (hypospadias), abdominal wall defects, cleft lip/palate, eye defects (cataract, coloboma) or various minor anomalies (e.g., bifid uvula, preauricular pit or tag). Consensus regarding cause-effect relationship has not been reached.", "ORPHA ID": 2216, "Summary": ""}
{"Disease Name": "Maternal phenylketonuria", "Disease Definition": "A rare disorder of phenylalanine (Phe) metabolism, an inborn error of amino acid metabolism, characterized by the development of microcephaly, growth retardation, congenital heart disease, facial dysmorphism and intellectual disability in non-phenylketonuric offspring of mothers with excess blood Phe concentrations.", "ORPHA ID": 2209, "Summary": "Epidemiology\nThe incidence of maternal phenylketonuria (PKU) in Europe is not known. Increased survival and improved health among females with treated PKU, thanks to neonatal screening, has increased the number of potential pregnancies with a risk of elevated maternal blood Phe.\nClinical description\nHyperphenylalaninemia is classified by blood Phe concentrations of more than 1,200 micromol/L (classic PKU) or less than 600 micromol/L (mild hyperphenylalaninemia), between 600 and 1,200 micromol/L as mild PKU. Maternal phenylketonuria syndrome has been shown to result in intrauterine and postnatal growth retardation with associated low birth weight, microcephaly, and intellectual disability in the offspring. Congenital heart malformation is also found and may include double-chambered right ventricle, tetralogy of Fallot, and ventricular septal defects. In severe cases, facial dysmorphism may also occur with various features reported including receding forehead, ptosis or fused eyes, strabismus, dysplastic ear helices, high palate, underdeveloped philtrum, anteverted nostrils, broad flat nasal bridge, deviated nasal septum, and micrognathia. Optimal maternal blood Phe concentrations should be strictly maintained throughout pregnancy to reduce the risk of these abnormalities. This can be achieved by minimal dietary Phe intake, along with tyrosine-enriched supplements. Studies have also shown that dietary treatment to control blood Phe concentrations can prevent the disorder if started before conception.\nEtiology\nAbnormally high maternal blood Phe concentrations underlie the clinical effects found in children with this disorder. PKU and hyperphenylalaninemia are caused by mutations in the PAH gene (12q22-q24.2).\nDiagnostic methods\nThe diagnosis is based on clinical observation, blood Phe analysis and genetic test to evaluate the presence of the PAH variant.\nGenetic counseling\nPhenylketonuria is transmitted in an autosomal recessive manner. Children of affected parents will therefore mostly (75%) be heterozygous carriers or non-carriers of the defect.\nManagement and treatment\nMaternal PKU is managed by a strict low-Phe diet (commonly ≤ 6 g/day natural protein is tolerated in the early stages of pregnancy but PHE amount is dependent on PKU severity), together with a Phe-free L-amino acid supplement and sufficient energy intake to ensure adequate maternal weight gain during pregnancy. The protein equivalent from amino acid and natural protein should supply ≥ 70 g/ day protein. Nausea and vomiting during the early phases of pregnancy is common and may lead to inadequate intake of amino acid and energy and subsequently unsatisfactory blood Phe control.\nPrognosis\nPrognosis is favorable if blood Phe concentrations are kept strictly below 360 micromol/L before and during the entire pregnancy.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Nenad BLAU"}
{"Disease Name": "Maternal riboflavin deficiency", "Disease Definition": "Maternal riboflavin deficiency is a rare, genetic disorder of metabolite absorption or transport characterized by persistently decreased riboflavin serum levels due to a primary genetic defect in the mother and which leads to clinical and biochemical findings consistent with a secondary, life-threatening, transient multiple acyl-CoA dehydrogenase deficiency (MADD) in the newborn. The mother usually presents hyperemesis gravidarum in the absence of other features of riboflavin deficiency, such as skin lesions, jaundice, pruritus, sore mucous membranes, visual disturbances.", "ORPHA ID": 411712, "Summary": ""}
{"Disease Name": "Maternal uniparental disomy of chromosome 1", "Disease Definition": "Maternal uniparental disomy of chromosome 1 is an uniparental disomy of maternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only mother is a carrier.", "ORPHA ID": 251009, "Summary": ""}
{"Disease Name": "Maternal uniparental disomy of chromosome 13", "Disease Definition": "Maternal uniparental disomy of chromosome 13 is an uniparental disomy of maternal origin that most likely do not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only mother is a carrier.", "ORPHA ID": 97678, "Summary": ""}
{"Disease Name": "Maternal uniparental disomy of chromosome 16", "Disease Definition": "Maternal uniparental disomy of chromosome 16 is a uniparental disomy of maternal origin which might be associated with intrauterine growth retardation and an elevated risk of congenital malformations. Healthy carriers have also been reported. In addition, cases of homozygosity for a recessive disease mutation for which the mother was a carrier have been described, and specific phenotype depends on the inherited disorder.", "ORPHA ID": 96185, "Summary": ""}
{"Disease Name": "Maternal uniparental disomy of chromosome 2", "Disease Definition": "Maternal uniparental disomy of chromosome 2 is an uniparental disomy of maternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only mother is a carrier.", "ORPHA ID": 96179, "Summary": ""}
{"Disease Name": "Maternal uniparental disomy of chromosome 20", "Disease Definition": "Maternal uniparental disomy of chromosome 20 (UPD 20) is a very rare chromosomal anomaly in which both copies of chromosome 20 are inherited from the mother. The main feature described is prenatal and postnatal growth retardation. Microcephaly, minor dysmorphic features and psychomotor developmental delay have been occasionally reported. Maternal UPD20 is most often ascertained by a mosaic trisomy 20 pregnancy.", "ORPHA ID": 96186, "Summary": ""}
{"Disease Name": "Maternal uniparental disomy of chromosome 21", "Disease Definition": "A uniparental disomy of maternal origin that does not seem to have an adverse impact on the phenotype of an individual. There is a possibility of homozygosity for a recessive disease mutation for which the mother is a carrier and specific phenotype depends on the inherited disorder.", "ORPHA ID": 96187, "Summary": ""}
{"Disease Name": "Maternal uniparental disomy of chromosome 22", "Disease Definition": "Maternal uniparental disomy of chromosome 22 is a uniparental disomy of maternal origin that does not seem to have an adverse impact on the phenotype of an individual. There is a possibility of homozygosity for a recessive disease mutation for which the mother is a carrier and specific phenotype depends on the inherited disorder.", "ORPHA ID": 96188, "Summary": ""}
{"Disease Name": "Maternal uniparental disomy of chromosome 4", "Disease Definition": "Maternal uniparental disomy of chromosome 4 is an uniparental disomy of maternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only mother is a carrier.", "ORPHA ID": 96180, "Summary": ""}
{"Disease Name": "Maternal uniparental disomy of chromosome 6", "Disease Definition": "Maternal uniparental disomy of chromosome 6 is an uniparental disomy of maternal origin characterized by intrauterine growth retardation. Homozygosity for a recessive disease mutation for which only a mother is a carrier may lead to other phenotypes.", "ORPHA ID": 96181, "Summary": ""}
{"Disease Name": "Maternal uniparental disomy of chromosome 9", "Disease Definition": "Maternal uniparental disomy of chromosome 9 is a uniparental disomy of maternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only mother is a carrier.", "ORPHA ID": 96183, "Summary": ""}
{"Disease Name": "Maternal uniparental disomy of chromosome X", "Disease Definition": "A uniparental disomy of maternal origin that does not seem to have an adverse impact on the phenotype of an individual. There is a possibility of homozygosity for a recessive disease mutation for which the mother is a carrier and specific phenotype depends on the inherited disorder.", "ORPHA ID": 261519, "Summary": ""}
{"Disease Name": "Matthew-Wood syndrome", "Disease Definition": "A rare, genetic congenital malformation syndrome characterized by bilateral anopthalmia (or less commonly microphthalmia) in association with a variable combination of the following: pulmonary hypoplasia or agenesis, congenital diaphragmatic hernia or eventration, and variable cardiovascular defects (congenital heart defects and/or pulmonary artery atresia). Intellectual disability is noted in surviving patients. Other variable malformations affecting different organ systems, as well as facial dysmorphism, may be observed.", "ORPHA ID": 2470, "Summary": ""}
{"Disease Name": "Maxillary arteriovenous malformation", "Disease Definition": "Maxillary arteriovenous malformation is a rare vascular anomaly characterized by an abnormal connection of the arterial and venous vasculature, without capillary connections, in the maxillofacial area, usually presenting with chronic, intermittent, and potentially life-threatening, hemorrhage. Association with infection, pain, pressure, pulsation, swelling, facial asymmetry, headache, ocular pain, tinnitus, otalgia, epistaxis, toothache and/or teeth mobility and compressibility into their sockets is possible, although it may also be asymptomatic.", "ORPHA ID": 141171, "Summary": ""}
{"Disease Name": "Maxillonasal dysplasia", "Disease Definition": "A rare developmental anomaly characterized by midfacial hypoplasia affecting primarily the anterior part of the maxilla (premaxilla) and the nasal complex.", "ORPHA ID": 1248, "Summary": "Epidemiology\nMaxillonasal dysplasia (also called Binder syndrome) occurs in less than 1/10,000 birth but is probably underdiagnosed.\nClinical description\nAffected individuals have very specific facial features that are easy to recognize. The central face is underdeveloped (midfacial hypoplasia), with an abnormally flat reduced nose, small crescent-shaped nostrils and a very short columella. The nasomaxillary angle is increased because of the missing anterior nasal spine, giving a ''heel of axe'' appearance at the lip-columella junction. The philtrum of the upper lip may be bow shaped, but without convergence to columella, demonstrating the non-adhesion of the orbicularis muscle to the anterior nasal spine. The anterior maxilla is underdeveloped with frequent lateral incisors anomalies ranging from small dystrophies to a total absence. These dental particularities lead to anterior malocclusion (class III) whereas the posterior occlusion remains normal. Fingers anomalies (such as hypoplasia of distal phalanges) can be present when the malformation is associated to a chondrodysplasia punctata.\nEtiology\nThe etiology and pathogenesis of maxillonasal dysplasia remains uncertain.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation. The absence of anterior nasal spine on radiological exam is pathognomonic of Binder.\nDifferential diagnosis\nPhenocopies of maxillonasal dysplasia have been described in children exposed in utero to phenytoin or to vitamin K deficiency, being induced either by drug (anticoagulants) or by biliary lithiasis. Some authors consider maxillonasal dysplasia as an allelic form of chondrodysplasia punctata. Others suggest that it does not represent a distinct disease entity or syndrome, but rather is a nonspecific abnormality of the nasomaxillary regions. Holoproencephaly and arhinencephaly are the two main differential diagnosis, but there is no brain anomaly or olfactory deficit in maxillonasal dysplasia.\nAntenatal diagnosis\nMaxillonasal dysplasia can be suspected during second semester routine ultrasound. Nasal hypoplasia, flat nasofrontal angle, and midface hypoplasia are specific indicators.\nManagement and treatment\nSurgery is the main treatment of the syndrome when required. Since the degree of malformation varies significantly between patients, surgical correction must be tailored individually. It can consist in orthognathic surgery and nose reconstruction. Orthodontic treatments and prosthodontic rehabilitations can also be performed.\nPrognosis\nFacial prognosis depends on the degree of malformation. Maxillonasal dysplasia can have a negative impact on quality of life.\n\n                            Last update: \n                            April 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Joël FERRI  - Dr Adeline KERBRAT"}
{"Disease Name": "Mayer-Rokitansky-Küster-Hauser syndrome type 1", "Disease Definition": "Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome type 1, a form of MRKH syndrome (see this term), is an isolated form of congenital aplasia of the uterus and 2/3 of the vagina occurring in otherwise phenotypically normal females.", "ORPHA ID": 247775, "Summary": "Epidemiology\nMRKH syndrome (including type 1 and type 2) has a worldwide prevalence of 1/4500 live female births. The rate of MRKH syndrome type 1 varies largely between different cohorts reported, therefore an accurate incidence of this type is not possible.\nClinical description\nMRKH syndrome type 1 is most often diagnosed in adolescence as the first symptom is most commonly a primary amenorrhea in young women presenting with otherwise normal development of secondary sexual characteristics and normal external genitalia. Patients lack the uterus and the upper 2/3 of the vagina. Because of this, difficulties with sexual intercourse have been reported. Pelvic pain can be reported in those with uterine remnants. As the uterus is missing or not functional, women cannot bear children. However, the ovaries are normal and functional.\nEtiology\nThe exact etiology of MRKH syndrome remains largely unknown. Initially, MRKH syndrome was considered to be of sporadic occurrence, suggesting the involvement of non-genetic or environmental factors. However, no link between an environmental cause and MRKH syndrome has ever been established. It is now clear that MRKH syndrome has a genetic origin, through increasing family descriptions and numerous genetic studies already completed. The latter have led to reveal several chromosomal abnormalities associated with the disease, such as small interstitial duplications in 1q21.1 and in Xpter-p22.32, or deletions in 4q34-qter, 8p23.1, 10p14, 16p11.2, 17q12, 22q11.21 and Xq21.31. These genomic rearrangements affect numerous genes. Putative candidate genes have been described, such as  HNF1B  (17q12), LHX1 (17q12), SHOX (Xp22.33 and Yp11.32), TBX6 (16p11.2), and ITIH5 (10p14). The phenotype-genotype correlations however, have not been established.\nGenetic counseling\nMRKH syndrome (type 1 or type 2) was thought to be purely sporadic but in familial cases it seems to be inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. Genetic counseling can be beneficial in these familial cases.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Karine MORCEL"}
{"Disease Name": "Mayer-Rokitansky-Küster-Hauser syndrome type 2", "Disease Definition": "A form of Mayer-Rokitansky-Küster-Hauser syndrome, characterized by congenital aplasia of the uterus and upper two-thirds of the vagina that is associated with at least one other malformation such as renal, vertebral, or, less commonly, auditory and cardiac defects.", "ORPHA ID": 2578, "Summary": "Epidemiology\nMRKH syndrome has an estimated worldwide incidence of 1/4500 live female births. The prevalence of MRKH syndrome type 2 is unknown.\nClinical description\nMRKH syndrome type 2 is most often diagnosed in adolescence as the first symptom is most commonly a primary amenorrhea in young women presenting with otherwise normal development of secondary sexual characteristics and normal external genitalia. Patients lack the uterus and the upper 2/3 of the vagina. Because of this, difficulties with sexual intercourse have been reported. Pelvic pain can be reported in those with uterine remnants. As the uterus is missing or not functional, women cannot bear children but ovaries are normal and functional. Other associated malformations seen in MRKH type 2 include upper urinary tract malformations (40% of cases), unilateral renal agenesis (23-28%; see this term), ectopia of one or both kidneys (17%; see this term), renal hypoplasia (4%), horseshoe kidney and hydronephrosis. Skeletal abnormalities, mainly of the spine and less frequently in the face and limbs, are also reported. Spinal malformations encountered include scoliosis, isolated vertebral anomalies (asymmetric, fused or wedged vertebrae), isolated Klippel-Feil syndrome and/or Sprengel deformity (see these terms), rib malformation or agenesis, and spina bifida (see this term). Face and limb malformations are mainly brachymesophalangy, ectrodactyly, duplicated thumb, absent radius, atrio-digital dysplasia (Holt-Oram-like syndrome) and facial asymmetry. Hearing impairment, due to middle ear malformations or sensorineural defects, is seen in 10-25% of cases. Heart malformations are very rare but include valvular pulmonary stenosis, Tetralogy of Fallot (see these terms) Holt-Oram or velocardiofacial-like syndromes, aorto-pulmonary window or atrial septal defects.\nEtiology\nThe exact etiology of MRKH syndrome remains largely unknown, even if the spectrum of malformation encountered suggests a developmental defect of the intermediate mesoderm during embryogenesis (by the end of the 4th week of fetal life), leading to an alteration of the blastema of the cervicothoracic somites and the pronephric ducts. Initially, MRKH syndrome was considered to be of sporadic occurrence, suggesting the involvement of non-genetic or environmental factors. However, no link between an environmental cause and MRKH syndrome has ever been established. It is now clear that MRKH syndrome has a genetic origin, through increasing family descriptions and numerous genetic studies already completed. The latter have led to reveal several chromosomal abnormalities associated with the disease, such as small interstitial duplications in 1q21.1 and in Xpter-p22.32, or deletions in 4q34-qter, 8p23.1, 10p14, 16p11.2, 17q12, 22q11.21 and Xq21.31. These genomic rearrangements affect numerous genes. Putative candidate genes have been described, such as HNF1B (17q12), LHX1 (17q12), SHOX (Xp22.33 and Yp11.32), TBX6 ( 16p11.2), and ITIH5 (10p14). The phenotype-genotype correlations however, cannot be established.\nGenetic counseling\nMRKH syndrome (type 1 or type 2) was thought to be purely sporadic but in familial cases it seems to be inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. Genetic counseling can be beneficial in these familial cases.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Karine MORCEL"}
{"Disease Name": "Mayer-Rokitansky-Küster-Hauser syndrome", "Disease Definition": "A rare spectrum of Mullerian duct anomalies characterized by congenital aplasia of the uterus and upper two-thirds of the vagina in otherwise phenotypically normal females. It can be classified as either Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome type 1 (corresponding to isolated utero-vaginal aplasia) or MRKH syndrome type 2 (utero-vaginal aplasia associated with other malformations).", "ORPHA ID": 3109, "Summary": "Epidemiology\nMRKH syndrome has a worldwide incidence of 1/4500 live female births.\nClinical description\nMRKH syndrome is most often diagnosed in adolescence as the first symptom is usually a primary amenorrhea in young women presenting otherwise with normal development of secondary sexual characteristics and normal external genitalia. MRKH syndrome type 1 and 2 patients lack the uterus and the upper 2/3 of the vagina leading to difficulties with sexual intercourse in some. Pelvic pain can be reported in those with uterine remnants. As the uterus is missing or not functional, women cannot bear children, but ovaries are normal and functional. Other associated malformations seen in MRKH type 2 include kidney abnormalities (40% of cases), skeletal abnormalities (20-25%), hearing impairment (10%), and, more rarely, heart defects.\nEtiology\nThe exact etiology is largely unknown, even if the spectrum of malformations encountered suggests a developmental defect of the intermediate mesoderm during embryogenesis (by the end of the 4th week of fetal life), leading to an alteration of the blastema of the cervicothoracic somites and the pronephric ducts. It is now clear that MRKH syndrome has a genetic origin through increasing family descriptions and numerous genetic studies already completed. These latter have led to reveal several chromosomal abnormalities associated with the disease and several putative candidate genes have been described.\nDiagnostic methods\nThe karyotype of MRKH patients is always 46, XX. Hormone levels are normal, showing normal and functional ovaries without hyperandrogenism. Transabdominal ultrasonography must be the first investigation in evaluating patients with suspected utero-vaginal aplasia. MRI can be performed to clearly visualize the malformation. A full check-up (renal ultrasonography, spine radiography, heart echography, audiogram) must be undertaken to search for any associated malformations.\nDifferential diagnosis\nDifferential diagnosis includes isolated vaginal atresia, which is found in various syndromes such as McKusick-Kaufman syndrome, androgen insensitivity syndrome, Mullerian aplasia and hyperandrogenism, and renal-genital-middle ear anomalies (see these terms).\nGenetic counseling\nMRKH syndrome was thought to be purely sporadic but familial cases seem to be inherited autosomal dominantly with incomplete penetrance and variable expressivity, and in these cases genetic counseling can be beneficial.\nManagement and treatment\nThe medical care of MRKH patients requires the coordinated efforts of pediatricians, gynecologists, surgeons, endocrinologists and psychologists. Treatment consisting in creating a neovagina must be offered to patients only when they are ready to start sexual activity and when emotionally mature (around 17-21 years). Frank's (nonsurgical) method requires the application of vaginal dilators on the vaginal dimple for at least 20 minutes/day for several months. If unsuccessful, various surgical procedures can be performed to create a neovagina. Clinical follow-up and regular intercourse are essential components to a successful outcome. Psychological support and counseling is strongly recommended for affected women and should provide patients with future fertility options (in vitro fertilization of one's own oocytes followed by surrogate pregnancy or adoption). For the associated malformations in MRKH type 2, specific medical care is directed toward the anomalies.\nPrognosis\nMRKH syndrome is not a life threatening disease. With treatment, sexual relationships are possible and fertility options are available.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Karine MORCEL"}
{"Disease Name": "Mazabraud syndrome", "Disease Definition": "Mazabraud syndrome is a rare primary bone dysplasia (see this term) characterized by the association of fibrous dysplasia with intramuscular myxomas. Fibrous dysplasia (usually polyostotic, sometimes monostotic) occurs during the growth period and can be asymptomatic or can present with pain, skeletal deformities or fractures while intramuscular myxoma, associated with polyostotic fibrous dysplasia (see this term) is usually multifocal, typically occuring in the vicinity of skeletal lesions, and presents in adulthood as a painless soft-tissue mass (most commonly in the thigh). Although it is a benign condition, local recurrences of myxomas after incomplete excision and malignant transformation of a fibrous dysplastic lesion into osteogenic sarcoma have been reported.", "ORPHA ID": 57782, "Summary": ""}
{"Disease Name": "McCune-Albright syndrome", "Disease Definition": "A rare mosaic syndrome characterized by the combination of two or more of the following: fibrous dysplasia of bone (FD), hyperpigmented macules, and hyperfunctioning endocrinopathies (precocious puberty, hyperthyroidism, growth hormone excess, endogenous Cushing syndrome).", "ORPHA ID": 562, "Summary": "Epidemiology\nIt is a rare disease with an estimated prevalence of between 1/100,000 and 1/1,000,000.\nClinical description\nFD can involve a single or multiple skeletal sites and can present with a limp, pain, pathologic fracture, or craniofacial asymmetry. Scoliosis is common and may be progressive. In addition to precocious puberty (vaginal bleeding or spotting and early development of breast tissue in girls, testicular and penile enlargement and precocious sexual behavior in boys), other hyperfunctioning endocrinopathies may occur including hyperthyroidism, growth hormone excess, Cushing syndrome, and hypophosphatemia due to renal phosphate loss. Hyperpigmented macules usually appear in the neonatal period.\nEtiology\nThe disease results from somatic variants of the GNAS gene, specifically in the cAMP-regulating protein, Gs alpha. The extent of the disease is determined by the proliferation, migration and survival of the cell in which the mutation spontaneously occurred during embryonic development.\nDiagnostic methods\nDiagnosis of McCune-Albright syndrome (MAS) is usually established on clinical grounds, based on the presence of two or more characteristic features. The evaluation of patients with MAS should be guided by knowledge of the spectrum of tissues that may be involved, with specific testing for each. Genetic testing is possible, but is not routinely available.\nDifferential diagnosis\nDifferential diagnoses include neurofibromatosis, osteofibrous dysplasia, non-ossifying fibromas, idiopathic central precocious puberty, and ovarian neoplasm.\nManagement and treatment\nTreatment is dictated by the tissues affected, and the extent to which they are affected. Some forms of surgical interventions may be indicated for treatment of craniofacial and skeletal abnormalities associated with FD (progressive visual disturbance, severe pain, severe disfigurement), as well as in the management of MAS-associated endocrinopathies and malignancies. Bisphosphonates may be helpful for treatment of bone pain. Strengthening exercises are recommended to help maintain the musculature around the FD bone and minimize the risk of fracture. Treatment of all endocrinopathies is required.\nPrognosis\nMorbidity is proportional to the number and extent of tissues involved. Longevity is generally not affected. MAS is rarely associated with malignancy. Malignant transformation of FD lesions occurs in probably less than 1% MAS patients.\n\n                            Last update: \n                            June 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Alison BOYCE  - Dr Michael COLLINS"}
{"Disease Name": "McDonough syndrome", "Disease Definition": "McDonough syndrome is a rare, multiple congenital anomalies/dysmorphic syndrome characterized by facial dysmorphsim (prominent superciliary arcs, synophrys, strabismus, large, anteverted ears, large nose, malocclusion of teeth), delayed psychomotor development, intellectual disability and congenital heart defects (e.g. pulmonic stenosis, patent ductus arteriosus, atrial septal defect). Additional features include thorax deformation (pectus excavatum/carinatum), kyphoscoliosis, diastasis recti and cryptorchidism. There have been no further descriptions in the literature since 1984.", "ORPHA ID": 2471, "Summary": ""}
{"Disease Name": "McKusick-Kaufman syndrome", "Disease Definition": "A rare, genetic multiple congenital anomalies syndrome characterized by genitourinary malformations (hydrometrocolpos in females and in males, glanular hypospadias and prominent scrotal raphe) , postaxial polydactyly that may affect only one or several limbs, and to a lesser extent cardiac defects. Hydrometrocolpos is due to either a congenital obstruction, imperforate hymen or vaginal atressia, and causes a palpable mass and possibly hydronephrosis. Other anomalies occasionally reported include choanal atresia, pituitary dysplasia, esophageal atresia and distal tracheoesophageal fistula, Hirschsprung disease, vertebral anomalies, and hydrops fetalis. The disorder is allelic with Bardet-Biedl, and as some phenotypic overlap has been observed, patients should be reevaluated in later childhood for retinistis pigmentosas and other signs of Bardet-Biedl syndrome.", "ORPHA ID": 2473, "Summary": ""}
{"Disease Name": "McLeod neuroacanthocytosis syndrome", "Disease Definition": "McLeod neuroacanthocytosis syndrome (MLS) is a form of neuroacanthocytosis (see this term) and is characterized clinically by a Huntington's disease-like phenotype with an involuntary hyperkinetic movement disorder, psychiatric manifestations and cognitive alterations, and biochemically by absence of the Kx antigen and by weak expression of the Kell antigens.", "ORPHA ID": 59306, "Summary": "Epidemiology\nPrevalence and incidence are not known, but the disorder is very rare and a few hundred cases are suspected worldwide. MLS has been described in Europe, North and South America, and Japan without obvious clustering. The disease primarily affects males; female carriers rarely develop a neurological syndrome.\nClinical description\nOnset of neurological symptoms is at 25-60 years of age and disease duration may be more than 30 years. About 1/3 of patients present with chorea indistinguishable from that observed in Huntington disease (see this term), and most patients will develop chorea during the course of the disease. Additional involuntary movements include facial dyskinesias, vocalizations and rarely feeding dystonia. Psychiatric manifestations including depression, schizophrenia-like psychosis and obsessive compulsive disorder (OCD) are frequent and may appear many years prior to the movement disorders. A subset of patients develops cognitive deficits, particularly in later disease stages. Generalized seizures and muscle weakness (rarely severe) and atrophy occur in about 1/2 of patients. MLS myopathy may predispose some to rhabdomyolysis, particular with neuroleptic medication use. Neuromuscular signs include sensorimotor axonal neuropathy, neurogenic muscle atrophy and variable additional myopathy. About 60% of patients develop cardiomyopathy manifesting with atrial fibrillation, malignant arrhythmias or dilated cardiomyopathy. Cardiac complications are a frequent cause of death. Some female heterozygote carriers show CNS manifestations related to MLS as well as corresponding neuropathological changes. MLS may be part of a ''contiguous gene syndrome'' on the X chromosome including chronic granulomatous disease, Duchenne muscular dystrophy or X-linked retinitis pigmentosa (see these terms).\nEtiology\nMLS is caused by mutations of the XK gene (Xp21.1) encoding the XK protein, which includes the Kx erythrocyte antigen. Most pathogenic mutations are nonsense mutations or deletions predicting an absent or shortened XK protein lacking the Kell protein binding site.\nDiagnostic methods\nDiagnosis may be challenging. CK levels are almost always elevated. The procedure of choice is determination of absent Kx antigen and reduced Kell antigens on erythrocytes in males, and fluorescence absorbent cell sorting with Kell antigens in female heterozygotes. Analysis of the XK gene revealing a mutation confirms the diagnosis.\nDifferential diagnosis\nThe differential diagnoses depend on the presenting symptoms and include chorea-acanthocytosis, Huntington disease, Huntington disease-like disorders, and Tourette's syndrome (see these terms).\nAntenatal diagnosis\nRoutine methods for prenatal testing can be applied.\nGenetic counseling\nMLS is an X-linked disorder and genetic counseling is recommended. Affected males will pass on the mutant X chromosome to their daughters, whose sons will have a 1:2 risk of developing MLS and whose daughters will have a 1:2 risk of being carriers.\nManagement and treatment\nSo far, no curative or disease-modifying treatments are available and management is symptomatic. MLS patients and asymptomatic carriers of the McLeod blood group phenotype should undergo cardiologic evaluation due to serious cardiac complications.\nPrognosis\nMLS is relentlessly progressive and the prognosis is poor. Sudden death may be due to seizures, possibly autonomic dysfunction, and sudden cardiac death. There may be gradual generalized weakness with fatal aspiration pneumonia or systemic infections.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Hans JUNG"}
{"Disease Name": "Meacham syndrome", "Disease Definition": "Meacham syndrome is a multiple malformation syndrome characterized by congenital diaphragmatic abnormalities, genital defects and cardiac malformations.", "ORPHA ID": 3097, "Summary": "Epidemiology\nLess than 15 patients have been reported worldwide.\nClinical description\nAmbiguous or female external genitalia are present in individuals with 46,XY karyotype. The genital abnormalities are variable and may include a true double vagina or septate vagina, absent uterus, abnormal male gonads in the presence of normal external female genitalia or male pseudohermaphroditism with abnormal internal female genitalia. Complex cyanotic congenital heart defects, (hypoplastic right lungs, anomalous pulmonary venous return and abnormalities of the diaphragm) are frequent. One patient with rhabdomyomatous dysplasia of the lungs has been reported.\nEtiology\nMutations in the WT1 gene have been identified in some patients with Meacham syndrome. Mutations in the same gene have previously been detected in patients with Denys-Drash syndrome (see this term).\nDiagnostic methods\nDiagnosis is based on the clinical findings. The occurrence of a true double vagina should lead the clinician to careful pulmonary and cardiac evaluation.\nDifferential diagnosis\nThe main differential diagnosis comprises Denys-Drash syndrome, an allelic disorder with overlapping clinical features. Beckwith-Wiedemann, Simpson-Golabi-Behmel and Perlman syndromes should also be considered (see these terms).\nManagement and treatment\nManagement is supportive.\nPrognosis\nAll patients reported to date died in early childhood.\n\n                            Last update: \n                            December 2008"}
{"Disease Name": "Meckel syndrome", "Disease Definition": "A rare, lethal, genetic, multiple congenital anomaly disorder characterized by the triad of brain malformation (mainly occipital encephalocele), large polycystic kidneys, and polydactyly, as well as associated abnormalities that may include cleft lip/palate, cardiac and genital anomalies, central nervous system (CNS) malformations, liver fibrosis, and bone dysplasia.", "ORPHA ID": 564, "Summary": "Epidemiology\nPrevalence is estimated at 1/38,500 births in Europe. However, birth prevalence is higher in specific populations such as in Finland (1/9,000), Kuwaiti Bedouin populations (1/3,500), Gujarati Indians (1/1,300), and in Qatar (1/5,000). No gender predilection is reported.\nClinical description\nFetuses affected by Meckel syndrome (MKS) survive only a few days to a few weeks at the most, or die in utero. The main CNS features include occipital encephalocele, hydrocephalus, anencephaly, holoprosencephaly, as well as Dandy-Walker. Large polycystic kidneys with cystic dysplasia are a constant feature of Meckel syndrome. Hepatic dysgenesis and liver fibrosis are frequent. Polydactyly may affect all four extremities and is typically postaxial (80%) or very rarely preaxial. Affected individuals have pulmonary hypoplasia secondary to oligohydramnios. Cleft lip and palate, microphthalmia and micrognathia may be observed. Cardiac malformations may include atrial septal defect, aorta coarctation, patent arterial duct, and valvular pulmonary stenosis. Incomplete development of internal and external genitalia, and cryptorchidism in males are common.\nEtiology\nDefective ciliary biology underlies MKS. Mutations in many different cilia-related genes have been associated with this disorder, often in the context of consanguineous unions. Most of these genes are also responsible for Joubert syndrome, leading to the concept that MKS is the extreme lethal phenotype of Joubert syndrome.\nDiagnostic methods\nDiagnosis may be made on fetal ultrasonography showing occipital encephalocele and dysplastic kidneys. Two of the three major malformations or two other anomalies along with one classical feature are sufficient for diagnosis of MKS. Autopsy may also be required. The disorder is often detected before the 14th gestational week. Molecular genetic testing can be used to confirm the diagnosis or to guide genetic counseling.\nDifferential diagnosis\nDifferential diagnoses include trisomy 13, Bardet-Biedl syndrome, Hydrolethalus, and Smith-Lemli-Opitz Syndrome.\nAntenatal diagnosis\nPrenatal diagnosis by ultrasonography is possible starting from 12 weeks of pregnancy. Encephalocele, cystic kidneys and polydactyly may be detected.\nGenetic counseling\nMKS is inherited in an autosomal recessive manner. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nNo treatment is currently available for Meckel syndrome which has a constantly fatal outcome.\nPrognosis\nMKS is lethal in utero or in the very early neonatal period with pulmonary hypoplasia and kidney failure as the main causes of early demise.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Tania ATTIE-BITACH | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Meconium aspiration syndrome", "Disease Definition": "Meconium aspiration syndrome is a pulmonary complication appearing in newborns with a meconium-stained amniotic fluid. Aspirated meconium can interfere with normal breathing by several mechanisms including airway obstruction, chemical irritation, infection and surfactant inactivation and induces more or less severe signs of respiratory distress at birth.", "ORPHA ID": 70588, "Summary": ""}
{"Disease Name": "Medial condensing osteitis of the clavicle", "Disease Definition": "A rare bone disease characterized by benign, usually unilateral, sclerosis of the inferomedial third of the clavicle. Patients present with localized swelling and persistent pain. Typical radiographic findings are expansion of the medial end of the clavicle with increased radio-density and signs of bone remodeling.", "ORPHA ID": 57196, "Summary": ""}
{"Disease Name": "Median cleft lip/mandible", "Disease Definition": "A rare median facial cleft characterized by median cleft of the lower lip (ranging in extent from a notch in the vermilion to a complete cleft involving the tongue, lower lip, and chin, and extending to the cervical region), median cleft of the mandible (ranging from notching to a complete cleft), and anomaly of the tongue including bifid tongue and tongue tie. Associated features in severe cases may include absent hyoid, thyroid cartilage, and manubrium sterni, as well as atrophic neck muscles.", "ORPHA ID": 2006, "Summary": ""}
{"Disease Name": "Median cleft of the upper lip and maxilla", "Disease Definition": "A rare median facial cleft characterized by a midline vertical cleft through the upper lip and premaxillary bone, which is highly variable in its extent and may also involve the nasal septum and central nervous system. Depending on the severity of the defect, associated manifestations include atrophy of midline structures, hypo-/hypertelorism, monophthalmia, proboscis, nasal deformity, median alveolar cleft, and short upper frenulum.", "ORPHA ID": 141239, "Summary": ""}
{"Disease Name": "Median nodule of the upper lip", "Disease Definition": "A rare familial facial anomaly characterized by a nodule beneath the vermilion border of the upper lip that tapered into the frenulum. The lesion is soft, easily compressible and asymptomatic. It can be wide (up to 8 mm) or flat and less prominent. Regression of the nodule by age has been reported. There have been no further descriptions in the literature since 1994.", "ORPHA ID": 2699, "Summary": ""}
{"Disease Name": "Medich giant platelet syndrome", "Disease Definition": "Medich giant platelet syndrome (MGPS) is a platelet granule disorder characterized by thrombocytopenia with giant platelets resulting in easy bleeding.", "ORPHA ID": 370127, "Summary": ""}
{"Disease Name": "Medium chain acyl-CoA dehydrogenase deficiency", "Disease Definition": "Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is an inborn error of mitochondrial fatty acid oxidation characterized by a rapidly progressive metabolic crisis, often presenting as hypoketotic hypoglycemia, lethargy, vomiting, seizures and coma, which can be fatal in the absence of emergency medical intervention.", "ORPHA ID": 42, "Summary": "Epidemiology\nThe estimated birth prevalence of MCADD is thought to range from 1/4,900 to 1/27,000 in Caucasian populations and is highest in individuals of Northern European descent. The worldwide birth prevalence is 1/14,600.\nClinical description\nMCADD usually presents 3 to 24 months after birth in previously healthy infants. However, neonatal presentations are well described as are those in adults, given sufficient metabolic stress (such as significant alcohol ingestion). Nevertheless, many affected individuals remain asymptomatic throughout life. Typically hypoketotic hypoglycemia, lethargy and vomiting are triggered by an infection, fasting or surgery. Some patients, however, can present with a progressive metabolic crisis despite ketosis and normal blood glucose. Rarely patients may present in crisis with ''paradoxically'' gross ketosis. During a crisis, a patient may manifest with lethargy, emesis, respiratory arrest, seizures, hepatomegaly and rapid progression to cardiac arrest unless emergency treatment is implemented. Potential brain injury occurring during these episodes can lead to an increased risk of long term neurological damage. Sudden unexplained death can sometimes be the first manifestation of this disease. Historically, about 25% of undiagnosed patients die during their first presentation of a crisis.\nEtiology\nMCADD is caused by mutations in the ACADM gene (1p31) which encodes the mitochondrial MCAD protein. The most prevalent mutation, c.985A>G, (K329E), p.(Lys329Glu), accounted for about 80% of clinical disease prior to newborn screening programs but many more individuals are now being identified with other ACADM mutations.\nDiagnostic methods\nDiagnosis is through the identification of a characteristic abnormal pattern in dried blood spots or plasma of acylcarnitines species (increased C6, C8 and increased ratio of C8/C10 with abnormal urine organic acid findings of C6 to C10 dicarboxylic acids, hexanoylglycine and suberylglycine). Final confirmation is by mutation analysis. MCADD is now included in newborn screening programs in many European countries such as the UK, Germany, the Netherlands, Portugal and Spain.\nDifferential diagnosis\nDifferential diagnosis includes other disorders of mitochondrial fatty acid oxidation including multiple acyl-CoA dehydrogenase deficiency (MADD) (see this term).\nGenetic counseling\nMCADD is inherited autosomal recessively. Genetic counseling is possible.\nManagement and treatment\nStrict avoidance of fasting is the primary objective. Medium chain triglycerides should be avoided but no other special dietary restrictions are required. Guidelines are available for the safe interval time between feeds for infants and young children. The use of low dose carnitine supplementation in patients who develop a low blood carnitine status remains controversial. In symptomatic patients, simple carbohydrates are given by mouth (glucose tablets) or intravenously until blood glucose level is maintained at above 5 mmol/L. During intercurrent infections, an emergency regimen should be made available. Immediate medical attention is needed in case of decompensation. Artificial sweeteners should be avoided.\nPrognosis\nThe prognosis is excellent in diagnosed patients who avoid fasting and who are managed appropriately during an intercurrent illness/ metabolic crisis.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Simon OLPIN"}
{"Disease Name": "MEDNIK syndrome", "Disease Definition": "A rare disorder of copper metabolism characterized by intellectual deficit, enteropathy, sensorineural hearing loss, peripheral neuropathy, lamellar and erythrodermic ichthyosis, and keratodermia.", "ORPHA ID": 171851, "Summary": ""}
{"Disease Name": "Medullary sponge kidney", "Disease Definition": "A rare renal tract malformation characterized by dilated malformation of the medullary collecting ducts (typically bilateral), and associated with stone formation, renal colic, hematuria, urinary tract infection, nephrocalcinosis, calcium nephrolithiasis, pyelonephritis, hypercalciuria and hypocitraturia. The disease is associated with abnormal distal tubular functions.", "ORPHA ID": 1309, "Summary": "Epidemiology\nPrevalence of medullary sponge kidney (MSK) in the general population is unknown; rough estimations suggest a prevalence of 1/2,000-20,000. However, it is much higher, up to 20%, in recurrent renal calcium stone formers. MSK affects males and females equally.\nClinical description\nThe majority of patients with MSK are asymptomatic; diagnosis of symptomatic patients typically occurs between 30 to 50 years of age, though the range is wider. The major clinical manifestations are kidney stones, hematuria, and urinary tract infections. Clinical manifestations including hypercalciuria, impaired urine acidification, and hyperparathyroidism may contribute to decreased bone density, leading to osteopenia and osteoporosis that is observed in some MSK patients. Medullary ectasias vary between 1 to 7 mm in size and are frequently without stones. Stones are primarily composed of calcium phosphate and calcium oxalate, and typically recur every two years. Flank pain can occur in the presence or absence of stones, can be acute resembling renal colic. Chronic pain is rare, but can lead to significant disability. Hematuria can occur in the presence or absence of stones, can be microscopic or gross, singular or recurrent, and is typically painless unless clots lead to ureteral obstruction or it is associated with nephrolithiasis. Abnormal tubular functions observed include defective urinary concentrations, incomplete and overt distal tubular acidosis, and hypocitraturia. Occurrence in children is rare but typically manifests with severe bone-related consequences of distal renal tubular acidosis (failure to thrive, short stature and rickets-like symptoms). MSK may be associated with developmental anomalies and tumors, such as Wilms tumor, horseshoe kidney, contralateral congenital small kidney, Beckwith-Wiedemann syndrome, and congenital hemihypertrophy.\nEtiology\nWhilst no disease-causing gene mutations have been identified, MSK may be associated with GDNF variants. In addition, HNF1B variants are associated with a spectrum of kidney disorders and two family members with an MSK phenotype have been identified with HNF1B mutations.\nDiagnostic methods\nUrography was the cornerstone of MSK diagnosis, and reveals dilated papillary collecting ducts with collection of contrast medium appearing as striations or bouquets of flowers. These features can also be disclosed by multidetector computed tomography (CT) urography. MRI and Ultrasound do not have the required specificity to diagnose MSK.\nDifferential diagnosis\nThe differential diagnosis is essentially that of medullary nephrocalcinosis and other causes of multiple medullary cysts such as autosomal dominant interstitial kidney disease and autosomal dominant polycystic disease.\nGenetic counseling\nTypically, the disease is sporadic; however, family clustering of MSK has been observed and, in certain cases, is suggestive of autosomal dominant inheritance.\nManagement and treatment\nTreatment with potassium citrate is effective in reducing calciuria and stone recurrence rate. A diet with a high intake of water, vegetables and fruit, and low in sodium and proteins, is recommended. Thiazides are suggested where calciuria does not improve. Whilst small stones can pass spontaneously, in recurring stone formers and selected symptomatic patients, pain can be controlled with laser papillotomy. Renal autotransplantation with pyelovesicostomy, a last resort in intractable, chronic painful stone disease, has also been reported in one MSK patient.\nPrognosis\nLong term prognosis is excellent.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanni GAMBARO"}
{"Disease Name": "Medullary thyroid carcinoma", "Disease Definition": "Medullary thyroid carcinoma (MTC) is developed from thyroid C cells that secrete calcitonin (CT).", "ORPHA ID": 1332, "Summary": "Epidemiology\nMTC represents 5-10% of thyroid cancers with a 1-2% incidence in nodular thyroid diseases. Estimated prevalence in the general population is 1/14,300.\nDiagnostic methods\nDiagnosis is usually made in the presence of a solitary nodule often associated with nodal metastasis and confirmed by a high basal CT level which represents its biological marker. MTC may present as a sporadic form, and in about 30% of cases, as a familial form as a part of multiple endocrine neoplasia (see this term); a dominant inherited disease related to germline mutation of the protooncogene RET. Both biological (CT) and genetic (RET) markers allows optimal diagnosis and treatment of MTC; the former allowing screening and early diagnosis of MTC by routine CT measurements in nodular thyroid diseases that require adequate and complete surgery required to be performed. The former leads to the diagnosis of familial MTC and to the identification of at-risk subjects on whom early or prophylactic surgery may be performed.\nManagement and treatment\nTreatment of MTC is based on complete surgical resection, including total thyroidectomy along with central and laterocervical nodal dissection. For locally advanced or metastatic MTC, complete cervical surgery is required and needs to be combined with other systemic treatments; as chemotherapy is not very efficient, radioimmunotherapy and RET target gene therapy (mainly tyrosine kinase inhibitors) appear as possible valuable therapeutic options for the future.\nPrognosis\nTen-year survival is about 80% when patients are not surgically cured and reaches 95% when the biological marker CT is normalized after surgery.\n\n                            Last update: \n                            November 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Bernard CONTE-DEVOLX  - Pr Patricia NICCOLI"}
{"Disease Name": "Medulloblastoma with extensive nodularity", "Disease Definition": "Medulloblastoma with extensive nodularity (MBEN) is a histological variant of medulloblastoma (see this term), an embryonic malignancy, most often located in the inferior medullary velum and then growing into the fourth ventricle, and presenting in infants and young children with symptoms of increased intracranial pressure such as headache, listlessness, vomiting, diplopia and papilledema. It is often associated with Gorlin syndrome (see this term) and has a relatively good prognosis.", "ORPHA ID": 251858, "Summary": ""}
{"Disease Name": "Medulloblastoma", "Disease Definition": "A rare embryonic tumor of the neuroepithelial tissue characterized clinically by increased intracranial pressure and cerebellar dysfunction, with the most common presenting symptoms being headache, vomiting, and ataxia. The disease can be classified according to histological (classic, anaplastic, large-cell, or desmoplatic medulloblastoma, or medulloblastoma with extensive nodularity) and molecular criteria (WNT-activated, sonic-hedgehog-activated, group 3, group 4).", "ORPHA ID": 616, "Summary": "Epidemiology\nMedulloblastoma (MB) is the most common malignant brain tumor in childhood. Annual incidence varies according to age a group, and is estimated in the USA at 0.47/100,000 in children (0-14 years of age), 0.11/100,000 in adolescents and young adults, 0.02/100,000 in adults (over 40 years of age). Males are more affected than females.\nClinical description\nAge of disease onset is variable and can occur in patients ranging in age from the newborn period to adulthood (peak age at presentation is children 3-6 years, with only 25% of patients being between 15 and 44 years). The most common presenting symptoms are headache, vomiting, and ataxia. Additional features that may be observed include lethargy, motor or cranial nerve impairment, gaze palsy, visual impairment due to hydrocephalia, vertigo/hearing loss, behavioral changes/irritability, and extracranial pain (e.g. back pain in those with spinal metastases). Around 30% of pediatric cases present with metastases at diagnosis. Most metastases occur within the central nervous system by seeding via the cerebrospinal fluid (cranial or spinal), while spread to extracranial organs (e.g. bone marrow, liver, lungs) is very rare at diagnosis. In a minority of patients, MB is associated with Gorlin syndrome, familial adenomatous polyposis (FAP; the association of FAP and MB is referred to as the Turcot syndrome with polyposis) or with Li-Fraumeni Syndrome. Increased susceptibility to certain tumors (neuroblastoma), hematological malignancies (acute lymphoblastic leukemia, acute myeloid leukemia) or disorders caused by mutations in genes encoding components of the RAS signaling pathway (Noonan syndrome or neurofibromatosis-Noonan syndrome) have been reported in MB.\nEtiology\nTo date, the exact etiology of MB is still unknown but genomic data has identified multiple candidate genes that contribute to the pathogenesis of different subgroups of MB. This includes inhibitors of the sonic hedgehog pathway SUFU (10q24.32), Ptch1 (9q22.32), the RNA helicase DDX3X (Xp11.3-p11.23), chromatin regulators KDM6A (Xp11.2) and N-CoR complex genes BCOR (Xp11.4), and the Parkinson's disease genes KMT2D (12q13.12), SMARCA4 (19p13.3), MYC (8q24.21), MYCN (2p24.3), and TP53 (17p13.1).\nDiagnostic methods\nMB occurs in the vermis and 20% occurs in the hemispheres of the cerebellum. WNT-activated MB may arise from the dorsal brainstem. Histologically, MB is characterized by small, round cells that stain blue with haematoxylin spectrum and appearance ranges from tumors with extensive nodularity to those with large cell/anaplastic features. Apart from classical MB, four histological variants of MB are recognized: anaplastic MB, large cell MB, MB with extensive nodularity, and desmoplastic/nodular MB. Four different molecular subgroups (WNT-activated, sonic-hedgehog-activated, group 3, group 4) have been identified.\nDifferential diagnosis\nDifferential diagnosis includes other brain tumors (ependymoma, glial tumor, atypical teratoid rhabdoid tumor; see these terms) and other causes of cerebellar alterations (infectious or cystic lesions, hemorrhages).\nGenetic counseling\nGenetic counseling is indicated in specific constellations, e.g. in sonic hedgehog-activated MB (Gorlin-syndrome, Li-Fraumeni-Syndrome, BRCA2), CTNNB1-negative WNT-activated MB (Turcot-syndrome).\nManagement and treatment\nInitially, patients need to be checked for increased intracranial pressure, which if present, needs to be controlled either by medication (e.g. steroids) or by neurosurgical drainage (e.g. external drainage). The postoperative treatment depends on age, histological and molecular subgroup, and result of staging assessments (cranial and spinal MRI, assessment of lumbar cerebrospinal fluid if lumbar puncture is not contraindicated). In children older than 3-5 years, combinations of chemotherapy and craniospinal irradiation are applied. In younger children, brain sparing therapies avoiding irradiation can be administered in very specific constellations.\nPrognosis\nThe overall survival rates are now 80% in standard risk patients, and 30-60 % in high-risk patients. Relapse occurs in nearly 75% of pediatric cases within 2 years.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Stefan RUTKOWSKI"}
{"Disease Name": "Meesmann corneal dystrophy", "Disease Definition": "Meesmann corneal dystrophy (MECD) is a rare form of superficial corneal dystrophy characterized by distinct tiny bubble-like, round-to-oval punctate bilateral opacities in the central corneal epithelium, and to a lesser extent in the peripheral cornea, with little impact on vision.", "ORPHA ID": 98954, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is not known as a registry of affected cases does not exist. Numerous cases have been reported from Denmark, Germany, Japan, USA, Saudi Arabia and Poland.\nClinical description\nLesions develop during infancy. MECD often remains asymptomatic until middle age, when intermittent, mild ocular irritation, photophobia, transient blurred vision, and irregular astigmatism develop. The condition persists throughout life. In severe cases, subepithelial scarring produces a slight grayish central corneal opacification. Corneal sensitivity is normal.\nEtiology\nMeesmann corneal dystrophy is caused by a mutation in one of a pair of genes, KRT3 (12q13.13) or KRT12 (17q11-q1) that encode the two units of cytokeratin in the corneal epithelium. Stocker-Holt corneal dystrophy is a variant of MECD caused by a p. Arg19Leu amino acid change in cytokeratin 12.\nDiagnostic methods\nLight microscopy reveals intraepithelial cysts and the epithelium may be thickened and disorganized. Histopathologically, MECD is characterized by intraepithelial cysts at different levels in the corneal epithelium, which is irregular in thickness.\nDifferential diagnosis\nSuspected cases of MECD should be differentiated from other disorders of the corneal epithelium, such as vapor spray keratitis, mild epithelial edema and the bleb pattern of epithelial basement membrane dystrophy. MECD and Lisch epithelial corneal dystrophy (LECD, see this term) have clinical similarities but are easily distinguished from one another by the different modes of inheritance, i.e. autosomal dominant versus X-linked recessive.\nGenetic counseling\nMECD has an autosomal dominant pattern of inheritance.\nManagement and treatment\nRemoval of the abnormal corneal epithelium has been used to treat MECD, but this approach is not curative as the dystrophy recurs in the regenerated epithelium.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Mega-cisterna magna", "Disease Definition": "A rare, non-syndromic, posterior fossa malformation characterized by a cisterna magna that measures above 15 mm in length, 5 mm in height and 20 mm in width (or greater than 10 mm in fetuses) associated with a normal cerebellar vermis and absence of hydrocephalus. The majority of patients are asymptomatic; however, variable neurodevelopmental outcomes, including delayed speech and language development, motor development delay, visiospatial perception difficulties, and attention problems, has been observed in some patients.", "ORPHA ID": 97252, "Summary": ""}
{"Disease Name": "Megaconial congenital muscular dystrophy", "Disease Definition": "A rare, genetic, skeletal muscle disease characterized by an early-onset hypotonia, muscle weakness, global developmental delay with intellectual disability, and cardiomyopathy. Congenital structural heart defects and ichthyosiform cutaneous lesions have also been associated. Muscle biopsy shows characteristic enlarged mitochondria located at the periphery of muscle fibers.", "ORPHA ID": 280671, "Summary": ""}
{"Disease Name": "Megacystis-megaureter syndrome", "Disease Definition": "Megacystic-megaureter syndrome is an urinary tract malformation characterized by the presence of a massive primary non-obstructive vesicoureteral reflux and a large capacity, smooth, thin walled bladder due to the continual recycling of refluxed urine. Recurrent urinary infections are commonly associated with this condition.", "ORPHA ID": 238637, "Summary": ""}
{"Disease Name": "Megacystis-microcolon-intestinal hypoperistalsis syndrome", "Disease Definition": "Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare congenital disease characterized by massive abdominal distension caused by a largely dilated non-obstructed urinary bladder (megacystis), microcolon and decreased or absent intestinal peristalsis.", "ORPHA ID": 2241, "Summary": "Epidemiology\nMMIHS prevalence is unknown but the disease has been reported in 230 patients, of which 71% are females.\nClinical description\nEnlarged and nonobstructed bladder is the first manifestation of MMIHS and can be detected prenatally. It results in abdominal distension, which is an early constant finding. Usual clinical presentation is similar to other neonatal intestinal obstructions: bile stained vomiting and failure to pass meconium. Patients show various visceral anomalies of the digestive tract including microcolon, malrotation of the gut, intestinal generalized hypo- or aperistalsis and short bowel. Along with the severe megacystis, malformations of the urinary tract with renal dysplasia (see this term), hydronephrosis, ureteral dilatation and hydroureter are frequently described. Undescended testis or bilateral streak gonads, cardiac anomalies, umbilical hernia or omphalocele have been reported in some cases.\nEtiology\nEtiology of MMIHS is unknown but various hypotheses have been proposed to describe the pathogenesis including genetic, neurogenic, myogenic and hormonal origin. The 15q11.2 region might be associated with MMIHS.\nDiagnostic methods\nPostnatally, MMIHS is mainly diagnosed by clinical presentation and supportive radiological and surgical findings. Histologically, vacuolar degeneration in the center of smooth muscle of the bowel and bladder has been described.\nDifferential diagnosis\nThis disorder should not be mistaken for a milder and autosomal dominant disorder, called chronic idiopathic intestinal pseudo-obstruction, in which megacystis is also present, or for prune belly syndrome (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis of MMIHS is mostly based on fetal ultrasound, revealing enlarged urinary bladder and hydronephrosis. Recent reports have proposed prenatal magnetic resonance imaging (MRI) in combination with analysis of enzymatic changes to contribute to prenatal diagnosis of MMIHS. The enlarged bladder can be observed from the second trimester and polyhydramnios from the third.\nGenetic counseling\nMMIHS has been suggested to have an autosomal recessive inheritance pattern so genetic counseling remains difficult, to date.\nManagement and treatment\nThere is no curative treatment for MMIHS. Various surgical interventions including gastrostomy, jejunostomy and vesicostomy have been reported and have been generally unsuccessful in most patients. Several multivisceral transplantations have also been reported. In the majority of patients total parenteral nutrition is required.\nPrognosis\nSurvival in MMIHS seems to have improved, thanks to more specialized care, innovations in parenteral nutrition, and introduction of multivisceral transplantation. However, prognosis and life expectancy of this generally fatal disease remains poor. Death is mainly caused by sepsis, malnutrition or multiple organ failure.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Prem PURI"}
{"Disease Name": "Megakaryoblastic acute myeloid leukemia with t(1;22)(p13;q13)", "Disease Definition": "Megakaryoblastic acute myeloid leukemia with t(1;22)(p13;q13) is a rare subtype of acute myeloid leukemia with recurrent cytogenetic abnormalities characterized by clonal proliferation of myeloid blasts with predominantly megakaryoblastic differentiation in the bone marrow and blood, often with extensive infiltration of the abdominal organs. It occurs typically in infants and usually presents with hepatosplenomegaly, anemia, thrombocytopenia and nonspecific symptoms related to ineffective hematopoiesis (fatigue, bleeding and bruising, recurrent infections). Myelofibrosis and fibrosis of other infiltrated organs is also characteristic of this disease.", "ORPHA ID": 402023, "Summary": ""}
{"Disease Name": "Megalencephalic leukoencephalopathy with subcortical cysts", "Disease Definition": "A form of leukodystrophy that is characterized by infantile-onset macrocephaly, often with mild neurologic signs at presentation (such as mild motor delay), which worsen with time, leading to poor ambulation, falls, ataxia, spasticity, increasing seizures and cognitive decline. Brain magnetic resonance imaging reveals diffusely abnormal and mildly swollen white matter as well as subcortical cysts in the anterior temporal and frontoparietal regions.", "ORPHA ID": 2478, "Summary": ""}
{"Disease Name": "Megalencephaly-capillary malformation-polymicrogyria syndrome", "Disease Definition": "A rare developmental defect during embryogenesis that is characterized by growth dysregulation with overgrowth of the brain and multiple somatic tissues, with capillary skin malformations, megalencephaly (MEG) or hemimegalencephaly (HMEG), cortical brain abnormalities (in particular polymicrogyria), typical facial dysmorphisms, abnormalities of somatic growth with asymmetry of the body and brain, developmental delay and digital anomalies.", "ORPHA ID": 60040, "Summary": "Epidemiology\nOver 200 patients have been reported without sex predominance.\nClinical description\nSymptoms are usually recognizable at birth. Their severity varies widely among patients. Megalencephaly is a major clinical feature (MEG: occipitofrontal circumference [OFC] greater than or equal to 3 SD above the mean), which sometimes progresses to hydrocephaly, malformations of cortical development with polymicrogyria and Chiari malformation. Cutaneous capillary anomalies are often scattered over the limbs, palms, soles and trunk, are frequently pink/red and are aggravated by crying and emotions. Facial dysmorphism is observed with frontal bossing, full cheeks, prominent lips and nevus flammeus of the nose and/or philtrum and upper lip. There is a delay in speech and motor skills. Patients may present neurological symptoms, mainly neonatal hypotonia, and, less frequently, seizures. Additional clinical manifestations include prenatal overgrowth, limb asymmetry, joint laxity, soft skin and thick, ''doughy'' subcutaneous tissue, postaxial polydactyly and/or syndactyly of toes 2-3 or fingers 3-4. Some patients develop neoplasias (risk of tumor development estimated at 2-3%). There is a slight increased risk for congenital heart defects and/or cardiac rhythm abnormalities. Adult OFCs range from +2 to +10 SDs above the mean.\nEtiology\nSomatic mutations of the PIK3CA gene (3q26), with evidence of postzygotic mosaicism, were found in several patients. Two individuals had a de novo germline pathogenic variant in PIK3CA. The gene PIK3CA encodes the alpha catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase. PIK3CA mutations are found in several benign overgrowth syndromes, collectively known as PIK3CA-related overgrowth spectrum (PROS). The mutational spectrum in children with the disorder is broader than other PIK3CA-related overgrowth disorders.\nDiagnostic methods\nThe disorder can be diagnosed based on clinical findings in individuals with classic features of MEG or HMEG (major finding 1) associated with neurologic findings of hypotonia, seizures, and mild to severe intellectual disability and characteristic capillary malformations (major finding 2) with focal or generalized somatic overgrowth.. Mosaic mutations of the PIK3CA gene were mainly identified with the advent of massively parallel or next-generation sequencing (NGS) methods. that facilitate detection of low-frequency variation. The level of mosaicism is often lowest in blood‐derived DNA, and higher in saliva and fibroblast‐derived DNA: multiple tissue samples should be tested, prioritizing samples other than blood.\nDifferential diagnosis\nDifferential diagnoses include Hemimegalencephaly (HMEG), Megalencephaly - polymicrogyria - post-axial polydactyly - hydrocephalus (MPPH), Klippel-Trénaunay syndrome (KTS), Beckwith-Wiedemann syndrome (BWS), PTEN-related overgrowth disorders.\nAntenatal diagnosis\nFindings of prenatal ultrasound include marked fetal overgrowth and progressive macrocephaly in the absence of maternal hyperglycemia or fetal hyperinsulinemia, ventriculomegaly, hydrocephalus, frontal bossing, polydactyly, limb asymmetry, polyhydramnios, hydrops fetalis and pleural effusions.\nGenetic counseling\nThe risk to sibs of a proband with somatic mosaicism for a pathogenic variant in PIK3CA would be expected to be the same as in the general population. However, low-level germline mosaicism may theoretically be present in a parent of a very rare child with a germline PIK3CA pathogenic variant.\nManagement and treatment\nManagement requires a multidisciplinary approach (involving pediatrician, neurologist, ophthalmologist, cardiologist, orthopedist, physiatrist, ENT, and dermatologist). Neurologic complications (obstructive hydrocephalus, increased intracranial pressure, cerebellar tonsillar ectopia or Chiari malformation; epilepsy in those with HMEG) may warrant neurosurgical intervention. Regular surveillance is recommended (brain MRI in the first 8 years of life, kidney ultrasound for Wilms tumor screening in the first 8 years of life). However, tumor risk in the disorder appears to be lower than in BWS.\nPrognosis\nPrognosis depends on the severity of symptoms. Early death, due to complex cardiac heart disease and arrhythmia, has been reported in rare occasions.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Livia GARAVELLI"}
{"Disease Name": "Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome", "Disease Definition": "A rare syndrome with a central nervous system malformation as a major feature characterized by macrocephaly, megalencephaly, bilateral perisylvian polymicrogyria, variable degrees of ventriculomegaly/hydrocephalus, developmental delay and intellectual disability, oromotor dysfunction, hypotonia, seizures, and dysmorphic facial features (such as frontal bossing, low-set ears, a flat nasal bridge, and high-arched palate). Postaxial polydactyly of one or more extremities is also common.", "ORPHA ID": 83473, "Summary": ""}
{"Disease Name": "Megalencephaly-severe kyphoscoliosis-overgrowth syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by overgrowth and macrocephaly with megalencephaly apparent at birth, global developmental delay, intellectual disability, and dysmorphic facial features (including frontal bossing, long face, sparse eyebrows, hypertelorism, downslanting palpebral fissures, and prognathism). Patients may exhibit tall stature with dolichostenomelia, arachnodactyly, kyphoscoliosis, and joint laxity, as well as neurologic manifestations, such as hypotonia, gait ataxia, or seizures. Brain imaging may show increased white matter volume, thick corpus callosum, or small cerebellum.", "ORPHA ID": 457359, "Summary": ""}
{"Disease Name": "Megalencephaly", "Disease Definition": "A rare central nervous system malformation characterized by an abnormally large brain, accompanied by abnormal head circumference measurements evident at birth or developing over the first years of life. The condition can be unilateral or bilateral and affects males more often than females. There is no typical pattern of symptoms, but mental retardation, seizures, and other neurologic abnormalities have been reported.", "ORPHA ID": 2477, "Summary": ""}
{"Disease Name": "Megalocornea-intellectual disability syndrome", "Disease Definition": "Megalocornea-intellectual disability syndrome is a rare intellectual disability syndrome most commonly characterized by megalocornea, congenital hypotonia, varying degrees of intellectual disability, psychomotor/developmental delay, seizures, and mild facial dysmorphism (including round face, frontal bossing, antimongoloid slant of the eyes, epicanthal folds, large low set ears, broad nasal base, anteverted nostrils, and long upper lip). Interfamilial and intrafamilial clinical variability has been reported.", "ORPHA ID": 2479, "Summary": ""}
{"Disease Name": "MEGDEL syndrome", "Disease Definition": "MEGDEL syndrome is a rare, genetic, neurometabolic disorder characterized by neonatal hypoglycemia, features of sepsis that are not linked to infection, development of feeding problems, failure to thrive, transient liver dysfunction, and truncal hypotonia followed by dystonia and spasticity which results in psychomotor development arrest and/or regression. Progressive sensorineural deafness, intellectual disability and absent speech are also associated. Laboratory tests demonstrate 3-methylglutaconic aciduria and temporary elevated serum lactate and transaminases.", "ORPHA ID": 352328, "Summary": ""}
{"Disease Name": "MEHMO syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by mild to profound intellectual disability, microcephaly, growth delay, and hypogenitalism. Obesity, early-onset diabetes and epilepsy are more variably present.", "ORPHA ID": 85282, "Summary": "Epidemiology\nTo date, a total of 22 patients from 11 unrelated families, of all origins, have been reported in the literature with pathogenic variants in EIF2S3. Only male patients are affected while carrier females are asymptomatic.\nClinical description\nThe phenotype is heterogeneous ranging from a severe, complete phenotype, which is associated to a recurrent frameshift variant (p.(Ile465Serfs*4), to a less severe and/or incomplete phenotype associated with various missense variants. Patients with missense variants present with inconstant features including developmental delay (90%), growth retardation (83%), microcephaly (83%), and more variably epilepsy (33%), and obesity (33%). Endocrinopathy including low growth hormone level, hypopituitarism and hypogonadism was described in 66%. Although intellectual disability is common in patients with missense variants, its severity varied from mild to moderate or severe, while all patients with the frameshift variant shared severe to profound intellectual disability. Early-onset diabetes is a recurrent feature found in patients with the recurrent frameshift variant, while hypoglycaemia and glucose dysregulation are not constant in patients with EIF2S3 missense variant.\nEtiology\nMEHMO syndrome is caused by pathogenic variants in EIF2S3 (Xp22.11). The gene encodes the gamma subunit of the eukaryotic translation initiation factor-2, eIF2, essential for protein translation. Families with a recurrent frameshift variant p.(Ile465Serfs*4) in EIF2S3 exhibit a severe, full phenotype of MEHMO syndrome. The majority of patients with missense variants exhibit a less severe and/or incomplete phenotype.\nDiagnostic methods\nThe diagnosis is usually found by next generation sequencing (e,g Whole Exome Sequencing).\nDifferential diagnosis\nDifferential diagnosis includes Wolcott-Rallison syndrome caused by pathogenic variants in EIF2AK3; primary microcephaly-mild intellectual disability-young-onset diabetes syndrome caused by TRMT10A or PPP1R15B; primary microcephaly-epilepsy-permanent neonatal diabetes syndrome caused by IER3IP1 pathogenic variants.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is X-linked recessive. Genetic counseling should be offered to at-risk couples (where the mother is a healthy carrier of a disease-causing variant) informing them that there is a 50% risk of having an affected male child at each pregnancy. Intrafamilial phenotypic variation is observed, most particularly concerning EIF2S3 missense variants.\nManagement and treatment\nMultidisciplinary care is needed for this multisystemic disorder; initially including neonatal care, and then with regular pediatric, endocrinology and neuropediatric follow-up. Regular glycemic controls are suggested.\nPrognosis\nThe prognosis depends on the severity of the syndrome. Patients with missense variants usually have a normal lifespan while severely affected patients (in particular with the recurrent frameshift variant p.(Ile465Serfs*4)) could present a poor life prognosis.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Stéphanie MOORTGAT | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Meige disease", "Disease Definition": "Meige disease is a frequent form of late-onset, primary lymphedema characterized by lower limb lymphedema typically developing during puberty.", "ORPHA ID": 90186, "Summary": ""}
{"Disease Name": "Meigs syndrome", "Disease Definition": "Meigs syndrome is a rare neoplastic disease characterized by the clinical triad of benign ovarian tumor (typically, ovarian fibroma or fibroma-like tumor), hydrothorax and ascites, which resolve after tumor resection. Patients usually present with dyspnea, pelvic mass with or without a tender, distended abdomen and/or weight loss.", "ORPHA ID": 314451, "Summary": ""}
{"Disease Name": "Melanoma and neural system tumor syndrome", "Disease Definition": "Melanoma and neural system tumor syndrome is an extremely rare tumor association characterized by dual predisposition to melanoma and neural system tumors (typically astrocytoma; see this term).", "ORPHA ID": 252206, "Summary": "Epidemiology\nPrevalence and incidence rates are not known. Fewer than 20 affected families have been reported to date. Cases have been reported from France, Italy, the UK and the USA.\nClinical description\nIn reported families, affected individuals had cutaneous melanoma in association with dysplastic nevi, astrocytoma, benign or malignant peripheral nerve sheath tumor, neurofibroma, medulloblastoma, glioblastoma multiforme, ependymoma, glioma, and meningioma (see these terms). In some cases, melanoma was described first followed by nervous system tumors, and in other cases, melanoma was a secondary cancer.\nEtiology\nThe etiology of this tumor association is unknown. Genetic mutations or germline deletions are thought to underlie this cancer susceptibility syndrome.\nGenetic counseling\nMale-to-male transmission was reported in one family but inheritance patterns are not clearly characterized. The increased risk appears to be found in both first- and second-degree relatives.\n\n                            Last update: \n                            March 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Monica RODOLFO"}
{"Disease Name": "Melanoma of soft tissue", "Disease Definition": "A rare soft tissue tumor characterized by a slowly growing mass typically involving tendons and aponeuroses of the extremities, composed of polygonal or spindle-shaped cells with melanocytic differentiation. The tumor typically affects young adults, who often present with pain or tenderness at the tumor site. Prognosis is poor with high recurrence rates and frequent metastasis, especially to lymph nodes, lung, and bones.", "ORPHA ID": 97338, "Summary": ""}
{"Disease Name": "MELAS", "Disease Definition": "A rare neurometabolic genetic disorder which is progressive and multisystemic due to mitochondrial dysfunction and that is characterized by encephalomyopathy, lactic acidosis, and stroke-like episodes.", "ORPHA ID": 550, "Summary": "Epidemiology\nPrecise prevalence and incidence data are not available. Estimated prevalence has been reported about 0.2/100,000 in Japan. It is one of the most frequent mitochondrial disorders, which are estimated to affect 1/10,000 people. Males and females are affected equally.\nClinical description\nMELAS is a multi-organ disease with protean manifestations. MELAS symptoms usually occur before 20 years, but can develop at any age. The hallmark feature is stroke-like episodes causing vomiting, headache, or epilepsy followed by loss of consciousness, frequently hemiparesis, hemianopia, and cortical blindness. Patients may have a history of developmental delay, short stature, learning disabilities before occurrence of stroke. Lactic acidosis is another systematic manifestation. Myopathy presents as hypotonia, exercise intolerance, and weakness. Other manifestations may include endocrinopathy (diabetes, mostly type 2 and occasionally type 1, hypo- or hyperthyroidism), polyneuropathy, cardiomyopathy, sensorineural hearing loss and intestinal pseudo-obstruction. Psychiatric manifestations include loss of appetite, depression, anxiety, psychosis, bipolar disorder, dementia, autism spectrum disorders, and rarely behavioral disturbances. Nephrotic syndrome is a rare manifestation. Dermatological involvement includes purpura, hirsutism, and erythema. The course is often progressive, with gradual cognitive decline, disability, and early demise.\nEtiology\nThe exact pathogenesis has not been fully elucidated. Energy depletion due to mitochondrial dysfunction underlies the clinical manifestations. Among mutations in 19 mitochondrial genes so far identified , the 3243A>G mutation in the mitochondrial tRNA Leu(UUR) gene (MT-TL1) is most frequent (approximately 80%). These mutations lead to mitochondrial tRNA dysfunction, causing disturbances in mitochondrial protein synthesis.\nDiagnostic methods\nDiagnosis of MELAS is made based on a combination of the characteristic clinical features, laboratory findings indicative of mitochondrial dysfunction, and genetic testing. Diagnostic laboratory findings include demonstration of lactic acidosis, brain imaging during stroke not conforming to the vascular territory, muscle biopsy showing ragged red fibers, and respiratory chain analysis showing multiple partial defects. The diagnosis can be confirmed by molecular genetic testing. It is of note that the genetic test results alone cannot predict the diagnosis, because of variable phenotypes caused by the mutation (m.3243A-to-G), ranging from severe MELAS to diabetes, or deafness, or even asymptomatic.\nDifferential diagnosis\nVarious diseases causing juvenile-onset acute ischemic stroke need to be distinguished. In patients with migraine, epilepsy, or encephalitis MELAS should be ruled out. Further differential diagnoses are other mitochondrial disorders that share clinical manifestations with MELAS.\nAntenatal diagnosis\nPrenatal diagnosis, though possible, is difficult due to heterogeneity in the proportion of mutations between tissues.\nGenetic counseling\nMELAS is inherited in a mitochondrial manner, through maternal inheritance and rarely as de novo mutations. Genetic counseling is challenging due to heteroplasmy.\nManagement and treatment\nThere is currently no recommended treatment for MELAS syndrome. Agents that have been used albeit with insufficient evidence include arginine, taurine, citrulline, carnitine, creatine monohydrate, idebenone, dichloroacetate, coenzyme Q10, menadione, phylloquinone, ascorbic acid, riboflavin, and nicotinamide. Endocrine, cardiac, gastrointestinal, psychiatric, renal, and dermatological manifestations are managed with standard symptomatic measures. Progressive encephalomyopathy should be closely monitored.\nPrognosis\nMELAS progresses over years with accumulation of neurological deficits and exhibits high morbidity and mortality.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Yoshihide SUNADA"}
{"Disease Name": "Melhem-Fahl syndrome", "Disease Definition": "Melhem-Fahl syndrome was described in two siblings born to consanguineous parents in 1985 and was characterized by the presence of 15 dorsal vertebrae and rib pairs. No other cases have been documented since the initial report.", "ORPHA ID": 2482, "Summary": ""}
{"Disease Name": "Melioidosis", "Disease Definition": "A tropical infectious disease caused by the Gram-negative bacterium Burkholderia pseudomallei, which is present in soil and water in tropical countries. Melioidosis can present itself in many ways, including pneumonia, sepsis and abscess formation.", "ORPHA ID": 31202, "Summary": "Epidemiology\nMelioidosis is present throughout the tropics and highly endemic in (Southeast) Asia and Australia. The disease is increasingly reported in African and South American countries. Melioidosis has a male predominance and may occur in any age group, but is more frequent between 40 and 60 years of age.\nClinical description\nThe incubation period varies from days to months or years. Melioidosis has a spectrum of clinical manifestations ranging from local skin infection to pneumonia, sepsis and abscess formation. Less frequent manifestations include involvement of the central nervous system or the musculoskeletal apparatus. Melioidosis presents as an acute disease in the majority of cases, characterized by respiratory infections and septicemia. It can also present as a chronic infection characterized by subacute tuberculosis-like lesions or non-healing skin infections.\nEtiology\nMelioidosis is caused by the Gram-negative bacterium Burkholderia pseudomallei, which is present in soil and water in tropical countries. Rice fields are associated with the presence of B. pseudomallei. The bacterium can enter the body via inoculation, inhalation or ingestion. Risk factors include diabetes, chronic kidney, lung and liver disease and alcohol abuse.\nDiagnostic methods\nThe gold standard for diagnosis is culture and identification of B. pseudomallei from patient samples (of blood, sputum, urine and wounds). Ideally, suspected isolates are confirmed using PCR or sequencing methods. Currently available antibody tests, such as the indirect hemagglutination assay, are less reliable, but can provide information about exposure to the bacterium. Imaging is important to assess the extent of disease.\nDifferential diagnosis\nDifferential diagnosis includes tuberculosis, pneumonia, and other infectious diseases such as plague, typhoid fever and syphilis.\nManagement and treatment\nPatients are treated with an initial intensive phase of antibiotics with ceftazidime or carbapenem (i.e. meropenem or imipenem) followed by a longer eradication phase with preferably cotrimoxazole.\nPrognosis\nThe mortality varies and is dependent on available diagnostics and therapeutic options. The reported mortality is around 40% in low- and middle-income countries, while in Australia the mortality is almost 5%. Early recognition and adequate treatment are key. Relapses can occur.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                             J. [Jelmer] SAVELKOEL  - Pr W.J. [Joost] WIERSINGA"}
{"Disease Name": "Melkersson-Rosenthal syndrome", "Disease Definition": "A rare orofacial granulomatosis characterized by the triad of recurrent or persistent orofacial edema (facial and lip edemas), fissured tongue, and relapsing, unilateral or bilateral peripheral facial nerve paralysis. Most cases present with partial symptoms. Typical age of onset is in childhood or adolescence. Histological examination shows non-caseating epithelioid cell granulomas and lymphedema.", "ORPHA ID": 2483, "Summary": ""}
{"Disease Name": "Melnick-Needles syndrome", "Disease Definition": "Melnick-Needles syndrome (MNS) belongs to the otopalatodigital syndrome spectrum disorder and is associated with a short stature, facial dysmorphism, osseous abnormalities involving the majority of the axial and appendicular skeleton resulting in impaired speech and masticatory problems.", "ORPHA ID": 2484, "Summary": "Epidemiology\nTo date, less than 70 cases with MNS have been documented. MNS is a disorder essentially limited to females as it is lethal in males. Survivorship in males is possible due to mosaicism.\nClinical description\nMNS is a congenital disorder characterized by a short stature, facial dysmorphism (small facies with prominent forehead, full cheeks, retrognathia, marked micrognathia), impaired speech, masticatory problems, and bowing of the arms and lower legs. Eye and ear abnormalities include bilateral exophthalmus, strabismus, blue sclera, conductive deafness and large pinna. Kyphoscoliosis is common. Mitral and tricuspid valve prolapse, bowel malrotation, hydronephrosis, and joint subluxation may be observed. Severe mandibular hypoplasia can cause upper airway restriction, obstructive sleep apnea syndrome and pneumonia and occasionally respiratory failure. Complete atrioventricular canal, prune belly syndrome and omphalocele have been reported in lethally affected males. Intelligence is normal. In females, the syndrome presents with bone dysplasia and facial dysmorphism. Males born to affected mothers show a lethal course of the disease in the embryonic or perinatal period.\nEtiology\nMNS is caused by gain of function mutations in the gene FLNA (Xq28) that encodes the actin-binding cytoskeletal protein filamin A. Several lines of evidence suggest that filamin participates in the remodeling of the cytoskeleton during development by integrating cell signaling events with subsequent alterations in cellular shape and motility. MNS is allelic with 4 other skeletal dysplasias (otopalatodigital syndrome type 1 and 2 (OPD1 and OPD2, respectively), terminal osseous dysplasia - pigmentary defects (TOD) and frontometaphyseal dysplasia (FMD).\nGenetic counseling\nMNS is inherited in an X-linked dominant manner. Male-to-male transmission has not been reported. The risk of transmitting the mutation in each pregnancy is 50%; males inheriting the mutation will be affected while females who inherit the mutation are less severely affected.\n\n                            Last update: \n                            May 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Stephen ROBERTSON"}
{"Disease Name": "Melorheostosis with osteopoikilosis", "Disease Definition": "Melorheostosis with osteopoikilosis is a rare sclerosing bone dysplasia, combining the clinical and radiological features of melorheostosis and osteopoikilosis (see these terms), that has been reported in some families with osteopoikilosis and that is characterized by a variable presentation of limb pain and deformities.", "ORPHA ID": 1879, "Summary": "Epidemiology\nLess than 5 families have been reported in the literature to date.\nClinical description\nAs osteopoikilosis is a benign, usually asymptomatic condition, the clinical signs are primarily those of melorheostosis that can manifest with joint contractures, pain, stiffness, limited joint functions, limb-length discrepancy and deformity.\nEtiology\nThe combination of melorheostosis with osteopoikilosis may be an unusual complication of familial osteopoikilosis. Osteopoikilosis is caused by a germline mutation in the LEMD3 gene (12q14). A germline mutation in the LEMD3 gene may predispose individuals with osteopoikilosis to develop melorheostosis. However, the exact pathogenesis is currently unknown.\nGenetic counseling\nOsteopoikilosis is inherited autosomal dominantly. There are no reports of parent to child transmission of melorheostosis. Genetic counseling is possible.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Geert MORTIER"}
{"Disease Name": "Melorheostosis", "Disease Definition": "Melorheostosis is a rare connective tissue disorder characterized by a sclerosing bone dysplasia, usually limited to one side of the body (rarely bilateral), that manifests with pain, stiffness, joint contractures and deformities.", "ORPHA ID": 2485, "Summary": "Epidemiology\nThe estimated prevalence is of 1/1,100,000. More than 400 cases have been reported to date.\nClinical description\nThe disease usually presents in early childhood, and is frequently diagnosed before the age of 20, but can occur at any age. Patients can range from asymptomatic to those with joint contractures and/or chronic pain. The long bones of the extremities are most commonly affected and monostotic, polyostotic or monomelic presentations can occur. Usually, the initial manifestations are pain (from dull to sharp and penetrating), stiffness, limitation of joint movement or joint deformity. Pain is present in almost all cases and is usually aggravated by activity but it is rarely constant. Soft tissue fibrosis around the affected limb can also be noted. Other common associated manifestations include edema, hyperpigmented skin patches, circumscribed and linear scleroderma, vascular tumors and malformations. Limb shortening is rarely observed.\nEtiology\nEtiology of melorheostosis is unknown and it is considered a sporadic disease probably due to somatic mosaicism for a genetic defect. The pathology is essentially that of abnormal proliferation of compact haversian bone distorting the contour of bone periosteal and endosteal surfaces.\nDiagnostic methods\nDiagnosis is mainly based on conventional radiography. On plain radiographs, melorheostosis presents as linear lesions of increased bone density along the major axis (shafts or diaphyses) of the tubular bones. Lesions result in an increased thickness of the cortices and can expand to the external surface of the bones, giving the appearance of dripping wax along a candle. When there is polyostotic involvement, the linear lesions are typically continuous along the same side of the affected limb and ''jump'' across the joints. Soft tissue calcification and even ectopic ossification may be seen. Magnetic resonance imaging contributes to the assessment of soft tissue lesions. Radioisotope bone scanning can help distinguish melorheostosis from other bone lesions. Biopsy shows variable degrees of bone marrow fibrosis, along with markedly irregular bone with mixed areas of lamellar and woven bone. A mix of osteocartilagenous, fibrovascular, and adipose tissue is seen in the soft tissue masses.\nDifferential diagnosis\nThe main differential diagnoses include bone tumors generating dense bone such as osteosarcoma, as well as osteopathia striata, osteopoikilosis, myositis ossificans progressiva (see these terms) and osteoma. Rarely, in families with osteopoikilosis or Buschke-Ollendorf syndrome, patients with melorheostosis may be present (as seen in melorheostosis with osteopoikilosis) (see these terms).\nGenetic counseling\nMelorheostosis is a sporadic disorder. There are no reports of parent to child transmission. For a parent with isolated melorheostosis, the risk of having an affected child is very low.\nManagement and treatment\nThere is no curative treatment for melorheostosis. Management aims to relieve pain, correct deformity and restore movement of the affected limb(s). Bisphosphonates (pamidronate and etidronate) and most recently zoledronate have been shown to improve symptoms in some but not all patients (but further studies are needed). Physical therapy, serial casting, braces, manipulations, nerve blocks and sympathectomies are other conservative options. Surgical options include limb and tendon lengthening, fasciotomies, capsulotomies, osteotomies, excision of fibrous tissue and/or hyperostosis, contralateral epiphysiodesis, arthrodesis, callotasis and amputation. Surgical treatments are best performed after skeletal maturity is reached but deformities can recur.\nPrognosis\nMelorheostosis is not life-threatening but can greatly affect quality of life due to chronic pain that can worsen or reappear, even after surgery.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Geert MORTIER"}
{"Disease Name": "MEND syndrome", "Disease Definition": "A rare, genetic, syndromic, sterol biosynthesis disorder affecting males characterized by skin manifestations, including collodion membrane, ichthyosis, and patchy hypopigmentary lesions, associated with severe neurological involvement (e.g. intellectual disability, delayed psychomotor development, seizures, hydrocephalus, cerebellar/corpus callosum hypoplasia, Dandy-Walker malformation, hypotonia) and craniofacial dysmorphism (large anterior fontanelle, telecanthus, hypertelorism, microphthalmia, prominent nasal bridge, low-set ears, micrognathia, cleft palate). 2,3 toe syndactyly, polydactyly, and kyphosis, as well as ophthalmic, cardiac and urogenital anomalies may also be associated.", "ORPHA ID": 401973, "Summary": ""}
{"Disease Name": "Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency", "Disease Definition": "Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete interferon gamma receptor 1 (IFN-gammaR1) deficiency is a genetic variant of MSMD (see this term) characterized by a complete deficiency in IFN-gammaR1, leading to impaired IFN-gamma immunity and, consequently, to severe and often fatal infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).", "ORPHA ID": 99898, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nSevere and often fatal BCG and EM infections begin in early childhood (before the age of 3) as a complete deficiency displays complete clinical penetrance in childhood. The most common pathogens include Mycobacterium fortuitum,  Mycobacterium chelonae, Mycobacterium smegmatis and Mycobacterium peregrinum. Infection is disseminated and can involve soft tissue, bone marrow, lungs, skin, bones and lymph nodes. Manifestations include fever, weight loss, hepatosplenomegaly, lymphadenopathies and lepromatous-like lesions. Salmonellosis has been reported in 5% of patients. Other infections caused by cytomegalovirus, Listeria monocytogenes and human herpes virus 8 have been reported in a single case.\nEtiology\nMSMD due to complete IFN-gammaR1 deficiency is caused by mutations in the  IFNGR1 gene on chromosome 6q23-q24. This gene encodes the IFN-gamma receptor ligand binding chain and a mutation leads to the halt of IFN-gammaR1 at the cell surface. More than 21 causal mutations have been identified to date, with most of them being homozygous. Two forms of clinically indistinguishable complete IFN-gammaR1 deficiency have been identified: with or without the expression of cell surface receptors.\nDiagnostic methods\nDiagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA, after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. High plasma concentrations of IFN-gamma suggest a complete IFN-gammaR deficiency. Leukocytes and fibroblasts from patients with this immunodeficiency do not respond to IFN-gamma in vitro. Histology of lymph nodes shows ill defined and poorly differentiated lepromatous-like multibacillary granulomas with few giant cells. Genetic testing reveals mutations in IFNGR1.\nDifferential diagnosis\nDifferential diagnoses include other genetic etiologies of MSMD, especially complete IFN-gammaR2 deficiency (see these terms). Chronic granulomatous disease, cystic fibrosis and severe combined immunodeficiency (see these terms) should also be excluded.\nAntenatal diagnosis\nAs this variant is often fatal, antenatal diagnosis is offered to families with a known IFNGR1 mutation.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling is possible.\nManagement and treatment\nThe only curative option for MSMD due to AR complete IFN-gammaR1 deficiency is hematopoietic stem cell transplantation (HSCT). As there is a high risk for rejection with this procedure, treatment with IFN-gamma-depleted antibodies to lower pre-transplantation IFN-gamma levels will favor a more positive outcome. Due to a lack of specific receptors, IFN-gamma treatment is not indicated. BCG vaccination should be avoided in those with a known IFNGR1 mutation.\nPrognosis\nPrognosis is poor with most patients not living past 10 years of age.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency", "Disease Definition": "Mendelian susceptibily to mycobacterial diseases (MSMD) due to complete interferon gamma receptor 2 (IFN-gammaR2) deficiency is a genetic variant of MSMD (see this term) characterized by a complete deficiency in IFN-gammaR2, leading to an undetectable response to IFN-gamma, and consequently, to severe and often fatal infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).", "ORPHA ID": 319547, "Summary": "Epidemiology\nThe prevalence is unknown. Only ten children have been identified to date.\nClinical description\nSevere and often fatal BCG and EM infections begin in early childhood (before the age of 3). The most common pathogens seen in patients include Mycobacterium fortuitum, Mycobacterium bovis BCG, Mycobacterium abscessus and Mycobacterium avium. Infections are disseminated and can involve soft tissue, bone marrow, lungs, skin, bones and lymph nodes. Infections manifest with fever, weight loss, hepatosplenomegaly and lymphadenopathies and can be fatal.\nEtiology\nThis disease is caused by mutations in IFNGR2 on chromosome 21q22.1-22.2 which encodes the IFN-gamma receptor signal transducing chain, essential for IFN-gamma mediated immunity. Two clinically indistinguishable forms have been reportedly defined by the presence or absence of protein expression on the cell surface.\nDiagnostic methods\nDiagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA, after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. Leukocytes and fibroblasts from patients with this immunodeficiency do not respond to IFN-gamma in vitro. Genetic testing reveals mutations in IFNGR2.\nDifferential diagnosis\nDifferential diagnosis includes the other variants of MSMD, especially complete IFN-gammaR1 deficiency (see this term). Chronic granulomatous disease, cystic fibrosis and severe combined immunodeficiency (see these terms) should also be excluded.\nAntenatal diagnosis\nAs this disease is often fatal, antenatal diagnosis is offered to families with a known IFNGR2 mutation.\nGenetic counseling\nMSMD due to complete IFN-gammaR2 deficiency is inherited autosomal recessively and genetic counseling is recommended.\nManagement and treatment\nThe only curative option for MSMD due to complete IFN-gammaR2 deficiency is hematopoietic stem cell transplantation (HSCT). Due to a lack of specific receptors, IFN-gamma treatment is not indicated. BCG vaccination should be avoided in those with a known IFNGR2 mutation.\nPrognosis\nPrognosis is poor with most patients not living past 10 years of age.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency", "Disease Definition": "Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete interleukin-12 subunit beta (IL12B) deficiency is a genetic variant of MSMD (see this term) characterized by mild bacillus Calmette-Guérin (BCG) infections and recurrent Salmonella infections.", "ORPHA ID": 319558, "Summary": "Epidemiology\nThe prevalence is unknown. Mutations have been found in 49 patients from 30 kindreds originating from India, Iran, Pakistan, Saudi Arabia and Tunisia.\nClinical description\nThe disease presents in early childhood. BCG is the most common infection encountered, usually after receiving the vaccination. Non-typhoidal Salmonella infections are also seen in half of all cases. A few other infections have been reported, including chronic mucocutaneous candidiasis (CMC), nocardiosis, and klebsiellosis. An incomplete clinical penetrance is observed in this immunodeficiency.\nEtiology\nMSMD due to complete IL12B deficiency is caused by homozygous mutations in the IL12B gene on chromosome 5q31.1-q33.1 which encodes for the IL-12p40 subunit. There are 9 different IL12B mutant alleles identified, including 2 small insertions, 3 small deletions, 2 splice site mutations, 1 large deletion and 1 nonsense mutation.\nDiagnostic methods\nDiagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. The patients lack detectable IL-12p70, IL-12p40 and produce low levels of IFN-gamma. Genetic testing reveals mutations in IL12B.\nDifferential diagnosis\nDifferential diagnoses include other genetic forms of MSMD, especially MSMD due to complete IL12RB1 deficiency (see this term).\nAntenatal diagnosis\nThis immunodeficiency is not severe and antenatal diagnosis is not necessary.\nGenetic counseling\nMSMD due to complete IL12B deficiency is inherited in an autosomal recessive manner. Genetic counseling is possible for families where a IL12B mutation is known.\nManagement and treatment\nBCG vaccination should be avoided in patients with this disease. Treatment involves prolonged antimicrobial therapy along with recombinant IFN-gamma to control infections, which is successful in most cases. Hematopoietic stem cell (HST) transplantation is not recommended.\nPrognosis\nPatients with this immunodeficiency usually have a good prognosis.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency", "Disease Definition": "Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete interleukin-12 receptor subunit beta-1 (IL12RB1) deficiency is a genetic variant of MSMD (see this term) characterized by mild bacillus Calmette-Guérin (BCG) infections and recurrent Salmonella infections.", "ORPHA ID": 319552, "Summary": "Epidemiology\nThe prevalence is unknown. Over 140 cases have been reported in the world.\nClinical description\nDisease onset usually occurs in patients before the age of 12 with the appearance of BCG disease, usually after receiving the vaccination. Over half of patients with this variant experience an additional infection with non-typhoidal Salmonella. Severe tuberculosis caused by Mycobacterium tuberculosis has been reported in several unrelated patients, providing the first documented evidence of a mendelian predisposition to tuberculosis. Other infections with Paracoccidiodes brasiliensis, Leishmania and Klebsiella have been reported in a single patient. Some patients also suffer from Candida infections. Most genetically affected siblings of index cases are asymptomatic, indicating low penetrance for case definition phenotypes.\nEtiology\nMSMD due to complete IL12RB1 deficiency is caused by mutations in the IL12RB1 gene (19p13.1) subunit that encodes for the IL-12R-beta1 chain. These mutations impair the IL-12/IL-23 pathway essential for production of IFN-beta and the resulting immunity against Salmonella and BCG infections. Two clinically indistinguishable forms have been reported defined by the presence or absence of protein expression on the cell surface.\nDiagnostic methods\nDiagnosis is made by laboratory analysis. In general, there is no expression of IL12RB1 at the surface of activated T-lymphocytes and NK cells. For the moment, only one mutation of IL12 RB1 leads to residual expression of the receptor on the cell surface. Low IFN-gamma levels are measured by ELISA after whole blood activation by BCG and BCG+IL-12. Genetic testing reveals mutations in IL12RB1. Impaired development of the Th17 cells is demonstrated in patients with this immunodeficiency.\nDifferential diagnosis\nOther genetic etiologies of MSMD should be excluded.\nAntenatal diagnosis\nThis immunodeficiency is not severe and antenatal diagnosis is not necessary.\nGenetic counseling\nMSMD due to complete IL12RB1 deficiency is inherited in an autosomal recessive manner so genetic counseling is possible.\nManagement and treatment\nBCG vaccination should be avoided in those with a known mutation in the IL12RB1 gene. Treatment is usually attained from long term antimicrobial therapy combined with recombinant IFN-gamma. For those who have localized splenic/mesenteric lesions with poor drug penetration, surgical removal is indicated.\nPrognosis\nWith proper treatment the prognosis is usually good with most patients reaching adulthood.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency", "Disease Definition": "Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete ISG15 deficiency is a genetic variant of MSMD (see this term) characterized by Bacille Calmette-Guérin (BCG) infections.", "ORPHA ID": 319563, "Summary": "Epidemiology\nThe prevalence is unknown. In 2012, three patients were reported from two unrelated kindreds from Turkey and Iran.\nClinical description\nPatients are described to have BCG infections. Patients of 12 or 15 years of age were reported to have been infected in the past with many other viruses but with no unusually severe consequences reported.\nEtiology\nMSMD due to complete ISG15 deficiency is caused by mutations in the ISG15 gene (1p36.33), which encodes an IFN-alpha/beta inducible, ubiquitin-like intracellular protein. These mutations impair ISG15 secretion by leukocytes, a molecule which plays an essential role as an IFN-gamma-inducing secreted molecule needed for optimal antimycobacterial immunity.\nDiagnostic methods\nDiagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. Similarly to patients with an IL12RB1 deficiency, patients with an ISG15 deficiency produce small amounts of IFN-gamma whereas they produce normal amounts of IL12p40 and IL12p70. Genetic testing reveals mutations in ISG15.\nDifferential diagnosis\nOther etiologies of MSMD, especially MSMD due to complete IL12RB1 deficiency (see this term), should be excluded.\nAntenatal diagnosis\nThis immunodeficiency is not severe and antenatal diagnosis is not necessary.\nGenetic counseling\nMSMD due to complete ISG15 deficiency is inherited in an autosomal recessive manner and genetic counseling is possible.\nManagement and treatment\nBCG vaccination should be avoided in those with a known ISG15 mutation. Treatment usually involves long term antimicrobial therapy combined with recombinant IFN-gamma.\nPrognosis\nWith proper treatment the prognosis is presumed to be good.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency", "Disease Definition": "Mendelian susceptibility to mycobacterial diseases (MSMD) due to partial IRF8 (interferon regulatory factor 8) deficiency is a rare genetic variant of MSMD (see this term) characterized by a selective susceptibility to relatively mild infections with bacillus Calmette-Guérin (BCG)..", "ORPHA ID": 319600, "Summary": "Epidemiology\nThe prevalence is unknown. Only 2 cases in the world have been described to date.\nClinical description\nThe first infections occur after vaccination with BCG and before the age of 2. They are relatively mild with manifestations of fever and lymphadenopathy. No other infectious diseases have been reported.\nEtiology\nMSMD due to a partial IRF8 deficiency is caused by heterozygous mutations in the IRF8 gene on chromosome 16q24.1 which encodes IRF8, a protein essential for the development of dendritic cells and the differentiation of macrophages and granulocytes. Mutations in the IRF8 gene impairs IL-12 secretion by monocytes and dendritic cells.\nGenetic counseling\nMSMD due to a partial IRF8 deficiency is inherited in an autosomal dominant manner so genetic counseling is possible.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency", "Disease Definition": "Mendelian susceptibility to mycobacterial diseases (MSMD) due to partial STAT1 (signal transducer and activator of transcription 1) deficiency is a genetic variant of MSMD (see this term) characterized by a partial defect in the interferon (IFN)-gamma pathway, leading to mild mycobacterial infections.", "ORPHA ID": 319595, "Summary": "Epidemiology\nThe prevalence is unknown. In 2001, two patients from unrelated kindreds were described and they suffered only mild MSMD. Since 2001, up to six other kindreds have been described to have a partial dominant STAT1 deficiency associated with MSMD.\nClinical description\nFirst infections occur after the age of 3, most commonly with weakly virulent Mycobacterium bovis BCG and Mycobacterium avium complex or with the more virulent Mycobacterium tuberculosis. Clinical penetrance is incomplete and some patients are asymptomatic while others have very mild clinical manifestations. None of the patients identified to date developed severe viral illness.\nEtiology\nMSMD due to partial STAT1 deficiency is due to heterozygous mutations in the STAT1 gene on chromosome 2q32.2-q32.3 encoding the signal transducer and activator of transcription 1. Two distinct forms have been described: one affecting phosphorylation and the other impairing DNA-binding activity.\nGenetic counseling\nTransmission is autosomal dominant and genetic counseling is possible.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Mendelian susceptibility to mycobacterial diseases", "Disease Definition": "Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare immunodeficiency syndrome, characterized by a narrow vulnerability to poorly virulent mycobacteria, such as bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria (EM), and defined by severe, recurrent infections, either disseminated or localized.", "ORPHA ID": 748, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nMSMD due to autosomal recessive (AR) complete interferon gamma receptor 1 (IFN-gammaR1) and receptor 2 (IFN-gammaR2) deficiencies (see these terms), the most serious variants, develop in early childhood with first infections generally occurring around the age of 3. Serious, disseminated infections with BCG and EM are observed and can involve soft tissue, bone marrow, lungs, skin, bones and lymph nodes. Other infections with Salmonella spp., Listeria monocytogenes and viruses have been reported. MSMD due to partial IFN-gammaR1, partial IFN-gammaR2, complete IL-12R-beta1, complete IL12B, complete ISG15, partial STAT1 and partial IRF8 deficiencies and MSMD due to partial X-linked recessive (XR) mutations (see these terms) are usually less severe. They have minor symptoms and some occur after the age of 3 to adulthood. Patients are vulnerable to Mycobacterium tuberculosis. Severe diseases caused by non-typhoidal Salmonella species have been reported in half of patients, especially in those with IL-12R-beta1 or IL12B deficiencies.\nEtiology\nOnly about half of patients with MSMD have an identified genetic etiology. Nine genes are known to be responsible for MSMD. Seven of them are inherited autosomally (IFNGR1, IFNGR2, STAT1, IL12B , IL12RB1 and more recently IRF8 and ISG15) and 2 are X-linked (IKBKG  and CYBB). MSMD is heterogeneous and thought to be mendelian based on the large number of consanguineous and/or multiplex kindred identified and/or X-linked heritance. The genetic defects impair IL-12 dependent IFN-gamma immunity. The high allelic heterogeneity results in 17 genetic disorders according to the mode of transmission, impact on function, association of a lack of protein expression or expression of an abnormal protein, and the specific function affected. Molecular and cellular mechanisms remain largely unknown.\nDiagnostic methods\nDiagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA, after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. High plasma concentrations of IFN-gamma suggest a complete IFN-gammaR deficiency. Mutational analysis is necessary to identify the exact causative genes involved.\nDifferential diagnosis\nChronic granulomatous disease, cystic fibrosis and severe combined immunodeficiency should be excluded as well as complete defects in IRF8 or STAT1 and TyK2 (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis can be offered to those families with the often fatal complete IFNGR deficiencies.\nGenetic counseling\nMSMD can be inherited in an AD, AR or X-linked manner. Genetic counseling is possible when a specific mutation is identified within a family.\nManagement and treatment\nBCG vaccination should be avoided in those with MSMD. Patients with IL-12B, IL-12R-beta1 or ISG15 deficiencies and partial IFN-gammaR, IRF8 and STAT1 deficiencies respond well to antibiotic therapy and can also be treated with IFN-g therapy. Abdominal lymph node resection may be needed in some cases. Hematopoietic stem cell transplantation (HSCT) should be considered in those with complete IFN-gammaR1 and IFN-gammaR2 deficiencies but rates of rejection are high, probably due to high levels of IFN-gamma detected in the serum of these patients.\nPrognosis\nPrognosis depends on the specific mutation involved and the corresponding associated disorder. Some cases are fatal while others resolve with antibiotic therapy.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "Meningeal melanocytoma", "Disease Definition": "A rare nervous system tumor characterized by a benign pigmented space-occupying lesion derived from leptomeningeal melanocytes. Symptoms typically show insidious onset and are related to the mass effect on adjacent tissues. Depending on the location of the tumor, they include focal neurological deficits, increased intracranial pressure, seizures, and spinal cord compression, among others. Although the tumor may behave aggressively, prognosis is good after complete surgical resection.", "ORPHA ID": 252046, "Summary": ""}
{"Disease Name": "Meningioma", "Disease Definition": "A rare, mostly benign, neoplastic disease characterized by a primary tumor of the meninges, usually located intracranially (~90%) but spinal meningiomas occur as well. Clinical symptoms relate to the location of the tumor and may include seizures, focal neurological deficits (sensory-motor or visual symptoms, cranial nerve dysfunction), vascular complications (occlusion of cerebral blood vessels, deep venous thrombosis, pulmonary embolism), chronically increased intracranial pressure neurocognitive impairment and/or loss of bladder/anus sphincter control.", "ORPHA ID": 2495, "Summary": "Epidemiology\nIn adults, intracranial meningiomas represent approximately 30% of central nervous system tumors. The male to female ratio is 1:3.5.\nClinical description\nWhilst meningioma may appear at any age, it is predominantly diagnosed between the third and sixth decade of life. Meningiomas typically appear as oval or hemispheric lesions with broad dural attachment. They most frequently occur supratentorially at the calvaria or skull base meninges, along the falx and in the parafalcine location, but can also be found attached to the tentorium, in the cerebello-pontine angle, within the optic nerve sheath, intraventricularly, or in the spinal canal. Lesions are classified into grade I (benign, most frequent), II (atypical), III (malignant) based on local invasiveness, cellular features and mitotic activity. Osseous destruction is indicative of atypical or malignant meningioma. Hyperostosis of adjacent skull bone is highly suggestive of benign meningioma. There are 15 immunohistological subtypes; features are subtype dependent but typically include whorl formation, nuclear pseudo-inclusions, pseudo-syncytial growth, and strong somatostatin-receptor subtype 2 (SSTR2) and epithelial membrane antigen expression.\nEtiology\nThe tumor most likely originates from arachnoid meningothelial cells. Several frequently mutated genes have been detected in meningiomas and include NF2, AKT1, SMO, PIK3CA, BAP1, TERT (promoter), SUFU, SMARCE1, and TRAF7.\nDiagnostic methods\nThe radiological diagnosis is made using contrast-enhanced MRI. Contrast-enhanced CT may also be used and is valuable for the detection of calcification within the tumor, hyperostosis of adjacent bone, and intraosseous tumor growth, especially in skull-base meningiomas. PET-based imaging using SSTR ligands is a helpful additional diagnostic tool and can be used to discriminate the lesion from healthy tissue or other entities. If imaging strongly suggests meningioma, histological verification is not mandatory; however, exclusion of rare differential diagnoses such as metastasis is recommended. Moreover, current diagnostic methods are not able to predict tumor grade which may have therapeutic implications.\nDifferential diagnosis\nThe main differential diagnoses include other intracranial lesions, such as dural metastases, primary glial tumors that extend into the subarachnoid space, hematopoietic neoplasms (such as extra-axial non-Hodgkin lymphoma), pituitary neoplasms (e.g. adenomas or craniopharyngiomas), as well as inflammatory (rheumatoid arthritis, Wegener's granulomatosis, extra-axial neurosarcoidosis) and infectious diseases (tuberculosis, syphilitic gumma).\nGenetic counseling\nGenetic counseling should be considered for patients with multiple meningioma, particularly in combination with ependymoma or schwannoma (NF2-related), and multiple spinal clear-cell meningioma (SMARCE1-related).\nManagement and treatment\nIf treatment is required, surgery is the first option. Adjuvant therapies, mainly radiotherapy, may be required if location of the tumor is challenging, in case of significant residual disease or for grade III lesions. So far, there is no clear postoperative guideline for grade II meningiomas. Current systemic therapies have shown little or no response. Asymptomatic lesions (typically diagnosed incidentally) may be managed with observation and long-term follow-up with MRI until either symptoms develop, sustained growth occurs, or concerns of entrapment on sensitive structures arises.\nPrognosis\nTumor grade and extent of resection (based on Simpson grading) are the most important predictors of progression-free survival. For completely resected grade I lesions, the risk of tumor recurrence is low. However, meningiomas may confer an aggressive clinical course with multiple recurrences and, infrequently, metastases to other organs. Of note, long-term sequelae (e.g. impairment of neurocognitive functioning and quality of life) following treatment have been reported.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Christine JUNGK  - Dr Felix SAHM"}
{"Disease Name": "Meningococcal meningitis", "Disease Definition": "Meningococcal meningitis is an acute bacterial disease caused by Neisseria meningitides that presents usually, but not always, with a rash (non blanching petechial or purpuric rash), progressively developing signs of meningitis (fever, vomiting, headache, photophobia, and neck stiffness) and later leading to confusion, delirium and drowsiness. Neck stiffness and photophobia are often absent in infants and young children who may manifest nonspecific signs such as irritability, inconsolable crying, poor feeding, and a bulging fontanel. Meningococcal meningitis may also present as part of early or late onset sepsis in neonates. The disease is potentially fatal. Surviving patients may develop neurological sequelae that include sensorineural hearing loss, seizures, spasticity, attention deficits and intellectual disability.", "ORPHA ID": 33475, "Summary": ""}
{"Disease Name": "Menke-Hennekam syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by variable intellectual disability, developmental delay, autistic behavior, short stature, and microcephaly. Additional variable manifestations include feeding problems, vision and hearing impairments, recurrent upper airway infections, and epilepsy. Reported malformations are cryptorchidism and cerebral anomalies. Dysmorphic facial features include short and upslanted palpebral fissures, ptosis, telecanthus, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum.", "ORPHA ID": 592574, "Summary": ""}
{"Disease Name": "Menkes disease", "Disease Definition": "A rare congenital disorder of copper metabolism with severe multisystemic manifestations that are primarily characterized by progressive neurodegeneration and marked connective tissue anomalies. A pathognomonic feature is the typical sparse, abnormal steely hair.", "ORPHA ID": 565, "Summary": "Epidemiology\nPrevalence at birth is estimated at 1/300,000 and 1/360,000 in Europe and Japan, respectivley. In Australia, the birth prevalence is much higher (1/50,000-100,000), likely due to a founder effect. The disorder is X-linked and thus primarily affects males.\nClinical description\nMenkes disease (MD) manifests in the neonatal period. Most patients are born at term with appropriate birth measurements. Cephalohematomas and spontaneous fractures are occasionally observed at birth. In the early neonatal period, patients may present with prolonged jaundice, hypothermia, hypoglycemia and feeding difficulties. Pectus excavatum and umbilical and inguinal hernias have also been reported. Unusual sparse and dull scalp hair is often the initial observation at the age of 1-2 months. Characteristically, the hair appears hypopigmented/depigmented, resembles steel wool and is friable, especially in the areas of the scalp subjected to friction. Additional symptoms are failure to thrive, poor eating, vomiting, and diarrhea. The appearance of pale skin, frontal or occipital bossing, micrognathia and pudgy cheeks may be observed. Patients develop gradual motor dysfunction and seizures. Muscular hypotonia in early life is replaced later-on by spasticity and weakness of the extremities. The clinical course is usually severe. Variable forms exist with occipital horn syndrome (OHS) being the mildest recognized form, which further presents with prominent bony exostoses and bladder diverticula.\nEtiology\nMD is caused by pathogenic variants in ATP7A (Xq21.1) encoding a membrane bound copper-transport protein (Cu2+-transporting ATPase-alpha polypeptide). To date, about 300 different variants in this gene have been reported. There is no obvious correlation between the variants and the clinical course.\nDiagnostic methods\nInitial diagnosis is based on clinical features (typical hair changes associated with hypotonia and delayed neuromotor development) and supported by demonstration of reduced levels of serum copper and ceruloplasmin. However, in the neonatal period these markers should be interpreted with caution, as their levels are also low in healthy newborns. In this period, plasma catecholamine analysis (ratio of DOPA to dihydroxyphenylglycol), indicative of dopamine beta-hydroxylase deficiency, may be used as a diagnostic test when the clinical diagnosis suggests MD. Although not specific, other laboratory investigations are useful to complete the clinical work up, these include light microscopy (for hair), radiological imaging (for generalized osteoporosis, metaphyseal flaring and spurs in the long bones, diaphyseal periosteal reaction and thickening, and Wormian bones in the cranial sutures), and arteriography (arterial tortuosity, especially of the intracranial arteries). Definitive diagnosis is based on molecular genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes Ehlers-Danlos syndrome, Marfan syndrome, cutis laxa syndromes, mitochondrial disorders, osteogenesis imperfecta and child abuse.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member and the preferred situation is to determine the carrier status of the mother prior to pregnancy and prenatal diagnosis.\nGenetic counseling\nTransmission is X-linked recessive. Genetic counseling should be offered to couples where the mother is a carrier of a pathogenic variant, informing them that the risk for a male fetus to be affected is 50% at each pregnancy. In rare cases, a female fetus may be affected (manifesting heterozygote) and this possibility should also be considered during genetic counselling. Similarly, germ-line mosaicism has been described and, although probably infrequent, it should also be discussed when counselling non-carrier mothers of singleton cases.\nManagement and treatment\nTreatment is mainly symptomatic. Early parenteral copper-histidine supplementation may modify disease progression and some symptoms by providing extra copper to tissue and to copper-dependent enzymes. Oral administration of copper is ineffective as it is trapped in the intestines.\nPrognosis\nPrognosis is poor and patients usually die in early childhood. However, careful medical care, and possibly copper administration, may extend life span.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Bert CALLEWAERT | ERN-Skin* - Pr Zeynep TÜMER | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Menstrual cycle-dependent periodic fever", "Disease Definition": "A rare anomaly of puberty or/and menstrual cycle characterized by recurrent fevers (higher than 38 degrees Celsius) associated with the luteal phase of the menstrual cycle in women.", "ORPHA ID": 498251, "Summary": ""}
{"Disease Name": "MEPAN syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by childhood-onset dystonia with distinctive MRI changes in the basal ganglia, and optic atrophy developing either immediately or within a few years after the appearance of dystonia. Additional symptoms include chorea and other movement disorders, dysarthria, or nystagmus, among others. Motor disability progresses gradually, while cognitive function is relatively spared.", "ORPHA ID": 508093, "Summary": ""}
{"Disease Name": "Mercury poisoning", "Disease Definition": "Mercury poisoning is caused mainly through ingestion or inhalation of any of the 3 forms of mercury, elemental, organic, and inorganic. Exposure to elemental mercury affects the pulmonary (inhalation of mercury vapors causes coughing, chills, fever, shortness of breath), dermatological (mild swelling, vesiculation, scaling, irritation, urticaria, erythema and allergic contact dermatitis accompanied by pain), and peripheral and central nervous (CNS) systems (depression, paranoia, extreme irritability, hallucinations, inability to concentrate, memory loss, hands, head, lips, tongue, jaw and eyelids tremors, weight loss, perpetually low body temperature, drowsiness, headaches, insomnia, fatigue). Exposure to inorganic mercury generally causes development of a metallic taste, local oropharyngeal pain, nausea, vomiting, bloody diarrhea, colic abdominal pain, renal dysfunction and, neurologic abnormalities; while that to organic mercury can lead to delayed neurotoxicity.", "ORPHA ID": 330021, "Summary": ""}
{"Disease Name": "MERRF", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder characterized by myoclonic seizures, ataxia, generalized epilepsy, muscle weakness and ragged red fibers in the muscle biopsy.", "ORPHA ID": 551, "Summary": "Epidemiology\nThe prevalence in the general population of Europe ranges between 1/256,000-67,000 in the adult population, and the birth prevalence is reported at 1/202,000 in Sweden.\nClinical description\nPatients usually present during adolescence or early adulthood with myoclonic epilepsy, sometimes with neurosensory deafness, optic atrophy, short stature or peripheral neuropathy. A few cases have been associated with lipomatosis, cardiomyopathy, pigmentary retinopathy, ophthalmoparesis and/or pyramidal signs. The disease is progressive with worsening of the epilepsy and onset of additional symptoms including ataxia, deafness, muscle weakness, and dementia. Magnetic resonance imaging of the brain may show cortical atrophy, cerebellar atrophy, basal ganglia calcifications and leucodystrophy. Clinical manifestations may vary greatly between patients from the same family and between families.\nEtiology\nMERRF syndrome is caused by mutations in the mitochondrial DNA. Over 80% of individuals with MERRF syndrome carry the m.8344A>G mutation in the lysine transfer RNA (tRNA Lys) gene (MTTK). Other mutations have been found in other transfer RNA genes or in the MTND5 gene. They may be associated with MERRF/MELAS overlap syndrome, in which affected individuals also suffer from stroke-like episodes.\nDiagnostic methods\nThe diagnosis of MERRF syndrome relies on the demonstration of abnormal lactate accumulation in blood or, more often, in the cerebrospinal fluid or MRI brain spectroscopy, and on the muscle biopsy, which reveals the presence of cytochrome c oxidase negative muscle fibers and ragged red fibers. Biochemical analysis of muscle often shows cytochrome c oxidase deficiency or combined respiratory chain defect. Genetic testing usually shows heteroplasmic (coexistence of the mutant form with a residual population of wild type mitochondrial DNA) variant in the mitochondrial DNA. The proportion of the mutation may differ considerably between tissues. However, in MERRF syndrome, this proportion is most often very high (above 90%) in every tissue and the mutation may therefore be easily investigated in blood.\nDifferential diagnosis\nThe differential diagnosis comprises other syndromes characterized by progressive myoclonic epilepsy and ataxia including Unverricht-Lundborg disease, Lafora disease, neuronal ceroid lipofuscinosis, and sialidosis.\nAntenatal diagnosis\nThe possibility of heterogeneous proportions of the mutation between tissues theoretically hampers prenatal diagnosis.\nGenetic counseling\nThe heteroplasmy makes genetic counseling very arduous in MERRF syndrome. Mitochondrial DNA mutations are transmitted through maternal inheritance. An affected man cannot transmit the disease. The mutation will be transmitted along the maternal lineage but its proportion is unpredictable. Although higher proportions of the mutation in the blood of the mother result in a higher risk of having a child with severe phenotype, there are many examples of extreme segregation of the mutation from mother to child, which prevent efficient genetic counseling at an individual level.\nManagement and treatment\nAs with other mitochondrial encephalomyopathies, there is no specific treatment for MERRF syndrome. Seizures can be treated with conventional anticonvulsant therapies but valporic acid should be avoided (mainly if the cause of the mitochondrial epilepsy is a patnogenic variant in POLG gene) or administered with care. In the absence of proper clinical trials, it is difficult to evaluate the effect of proposed supportive treatment such as coenzyme Q10 and its analogue idebenone, carnitine, etc.\nPrognosis\nThe prognosis for patients with MERRF syndrome is globally poor because of the progressive nature of the disease. However, the severity varies greatly and some patients, mainly those with non-cerebral presenting symptoms, may have a prolonged survival with relatively little handicap.\n\n                            Last update: \n                            January 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Michelangelo MANCUSO | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "Mesial temporal lobe epilepsy with hippocampal sclerosis", "Disease Definition": "Mesial temporal lobe epilepsy with hippocampal sclerosis is a rare epilepsy syndrome defined by seizures originating in limbic areas of the mesial temporal lobe, particularly in the hippocampus, amygdala, and in the parahippocampal gyrus and its connections, and hippocampal sclerosis, usually unilateral or assymetric. It is frequently associated with an initial precipitating event, such as febrile seizures, hypoxia, intracranial infection or head trauma, most often occurring in the first five years of life, followed by a latent period without seizures. Typical seizures consist of a characteristic aura that is frequently a rising epigastric sensation associated with emotional disturbances, illusions, and autonomic symptoms (widened pupils, palpitations), progressive impairment of consciousness, oro-alimentary automatisms (lip smacking, chewing, licking, tooth grinding), behavioral arrest, head deviation, dystonic postures, hand and verbal automatisms. Seizures are followed by postictal dysfunction. Initially, seizures are easily controlled with antiepileptic drugs, later they frequently become refractory and associated with progressive behavioral changes and memory deficits.", "ORPHA ID": 99701, "Summary": ""}
{"Disease Name": "Mesoaxial synostotic syndactyly with phalangeal reduction", "Disease Definition": "A rare non-syndromic syndactyly characterized by mesoaxial reduction of fingers, complete syndactyly of the 3rd and 4th fingers with synostoses of the corresponding metacarpals and associated single phalanges, malformed thumbs, and hypoplasia and clinodactyly of the 5th finger. Preaxial webbing of toes with terminal phalangeal hypoplasia of all toes has been reported in association.", "ORPHA ID": 157801, "Summary": ""}
{"Disease Name": "Mesocardia", "Disease Definition": "A rare, congenital non-syndromic heart malformation characterized by an atypical location of the heart in a central position in the thorax, with the apex in the midline of the thorax. Atria are usually situs solitus, whereas ventricles may be situs inversus. Various congenital heart anomalies and visceral situs inversus have also been associated.", "ORPHA ID": 95443, "Summary": ""}
{"Disease Name": "Mesomelia-synostoses syndrome", "Disease Definition": "A rare syndromic osteochondrodysplasia characterized by progressive mesomelia and bony fusions in the extremities, distinctive facial gestalt, and soft palate anomalies.", "ORPHA ID": 2496, "Summary": "Epidemiology\nTo date, less than 10 patients have been reported.\nClinical description\nIn contrast to other mesomelic dysplasias, Mesomelia-synostoses syndrome (MSS) has a slowly progressive clinical course, at least until skeletal growth ceases. Symmetric acral synostoses and extra-skeletal involvement are distinguishing features. Craniofacial phenotype includes downslanted palpebral fissures, eyelid ptosis, telecanthus, soft palate hypoplasia and absent or hypoplastic uvula with hypernasal speech, and tall and mildly retruded chin. Skeletal anomalies comprise short stature, progressive non-inflammatory movement restriction of large and small joints, mesomelic bowing and shortening in upper and lower limbs, congenital or postnatal joint deformities (clino- and camptodactyly of fingers and toes, ulnar deviation of the wrists, radial head subluxation, genu valgum, pes equinus), and apparent postaxial brachydactyly of fingers and toes with sparing of the first two rays. MSS patients may present with complex congenital heart defects, congenital hydronephrosis, short umbilical cord and redundant skin on the umbilical stump, myopia, short sublingual frenulum and progressive hearing loss. Cognitive development is normal. Radiological anomalies include shortening of metacarpals and metatarsals II-III to V, synostoses between the bases of these bones or between metacarpals and metatarsals II to V and adjacent carpal/tarsal bones, partial fusion of carpal and tarsal bones, and mild medial bowing of distal femur.\nEtiology\nNon-recurrent deletions of two contiguous genes in 8q13.2q13.3, SULF1 and SLCO5A1, ranging in size from 582 to 738 Kb, have been found in six patients. Monoallelic expression of SULF1 without microdeletion has been reported in one patient. The exact mechanism that causes MSS is currently unclear, but it is likely that other genetic or epigenetic alterations besides the haploinsufficiency of one of the two genes contribute to the MSS phenotype.\nDiagnostic methods\nDiagnosis is based upon clinical and radiological findings. Copy-number losses involving SULF1 and SLCO5A1 may be detected by molecular analyses (e.g. genomic arrays).\nDifferential diagnosis\nRadiologically, Kantaputra type mesomelic dysplasia shows very similar acral anomalies. Other rare mesomelic dysplasias (e.g. Langer or Fryns type mesomelic dysplasia) are not associated with synostoses. Syndromes with synostoses (e.g. Nievergelt syndrome, multiple synostoses or proximal symphalangism syndromes, Osebold-Remondini syndrome) show different patterns of associated anomalies.\nAntenatal diagnosis\nBoth invasive prenatal diagnosis or preimplantation genetic diagnosis of 8q13 microdeletion are available for at-risk couples. Fetal ultrasound may reveal hypoplastic radii and ulnae, brachydactyly, unusual gaps between fingers or toes, clubfoot, micrognathia, and congenital heart defect or hydronephrosis, if present.\nGenetic counseling\nMSS is transmitted as an autosomal dominant trait. When a parent is affected, recurrence risk is 50%.\nManagement and treatment\nEarly diagnosis allows for more effective care: the progressive nature of skeletal and joint involvement deserves regular follow-up and treatment by orthopedic and rehabilitation specialists. Cardiac surgery or surgical correction of palatal anomalies and speech therapy may be needed.\nPrognosis\nLife expectancy is unknown, but clinical manifestations appear to remain stable in adulthood.\n\n                            Last update: \n                            December 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Andrea DARDIS | MetabERN* - Dr Alessandro SPINELLI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Mesomelic dwarfism, Reinhardt-Pfeiffer type", "Disease Definition": "A rare disorder characterized by disproportionate short stature from birth with dysplasia of the ulna and fibula.", "ORPHA ID": 2634, "Summary": "Epidemiology\nPrevalence is unknown but only a few families have been described in the literature so far.\nClinical description\nCurvatures of the forearm, radial head luxation, and tibial anomalies have also been described.\nEtiology\nThe syndrome is transmitted in an autosomal dominant manner and cases of this dysplasia have been described in families with Langer mesomelic dwarfism and Léri-Weill dyschondrosteosis (see these terms) leading to the suggestion that this dysplasia, type Reinhardt-Pfeiffer may also be associated with haploinsufficiency of the short stature homeobox (SHOX; Xp22.33 and Yp11.32) gene or anomalies of the downstream pseudoautosomal region 1 (PAR1) where SHOX enhancer elements are located.\n\n                            Last update: \n                            October 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Mesomelic dwarfism-cleft palate-camptodactyly syndrome", "Disease Definition": "A rare syndrome characterised by mesomelic shortening and bowing of the limbs, camptodactyly, skin dimpling and cleft palate with retrognathia and mandibular hypoplasia. It has been described in a brother and sister born to consanguineous parents. Transmission is autosomal recessive.", "ORPHA ID": 2631, "Summary": ""}
{"Disease Name": "Mesomelic dysplasia, Kantaputra type", "Disease Definition": "Mesomelic dysplasia Kantaputra type (MDK) is a rare skeletal disease characterized by symmetric shortening of the middle segments of limbs and short stature.", "ORPHA ID": 1836, "Summary": "Epidemiology\nIt has been described in five families.\nClinical description\nIn the upper limbs, the ulnae are very short, and the radii are bowed. The distal humerus has a dumbbell shape. The hands show progressive flexion contractures of the proximal interphalangeal joints. In the lower limbs, feet are fixed in plantar flexion so that the patients walk on their toetips. The prominent distal fibula on the ventral aspect is common and considered a hallmark. Fibula, talus and calcaneus are small and fibulo-calcaneal synostosis is a characteristic feature. Carpal and tarsal synostoses are observed in some individuals. All affected patients have normal craniofacial features and intelligence.\nEtiology\nUsing microarray-based comparative genomic hybridization (array-CGH), two microduplications have been identified on chromosome 2 (2q31.1-q31.2), separated by a segment of normal copy number. The more centromeric duplication encompasses the HOXD cluster and it is proposed that duplications cause dysregulation of HOXD gene expression.\nGenetic counseling\nIn all families, the condition is transmitted as an autosomal dominant trait.\n\n                            Last update: \n                            November 2010"}
{"Disease Name": "Mesomelic dysplasia, Nievergelt type", "Disease Definition": "A rare primary bone dysplasia characterized by severe mesomelic shortness particularly of the lower limbs with distinctive triangular or rhomboid-shaped tibiae and fibulae, accompanied by bony protuberances and skin dimples. Additional manifestations include radioulnar synostosis, dislocation of the radial head, abnormalities of the hands (such as oligosyndactyly or fusiform-shaped fingers) and feet (pes equinovarus, synostoses of tarsals/metatarsals and phalanges), and dysmorphic facial features.", "ORPHA ID": 2633, "Summary": ""}
{"Disease Name": "Mesomelic dysplasia, Savarirayan type", "Disease Definition": "Mesomelic dysplasia, Savarirayan type is characterised by severely hypoplastic and triangular-shaped tibiae, and absence of the fibulae. So far, two sporadic cases have been described. Moderate mesomelia of the upper limbs, proximal widening of the ulnas, pelvic anomalies and marked bilateral glenoid hypoplasia were also reported.", "ORPHA ID": 85170, "Summary": ""}
{"Disease Name": "Metabolic myopathy due to lactate transporter defect", "Disease Definition": "Metabolic myopathy due to lactate transporter defect is a rare metabolic myopathy characterized by muscle cramping and/or stiffness after exercise (especially during heat exposure), post-exertional rhabdomyolysis and myoglobinuria, and elevation of serum creatine kinase.", "ORPHA ID": 171690, "Summary": ""}
{"Disease Name": "Metachondromatosis", "Disease Definition": "Metachondromatosis (MC) is a rare disorder characterized by the presence of both multiple enchondromas and osteochondroma-like lesions.", "ORPHA ID": 2499, "Summary": "Epidemiology\nThe prevalence is unknown and fewer than 40 cases have been reported.\nClinical description\nThe first signs of MC occur during the first decade of life. Most frequently, osteochondromas occur in the hands and feet, predominantly in digits and toes, and enchondromas involve the iliac crests and metaphyses of long bones. Osteochondromas are small and point towards the adjacent growth plate. MC does not lead to shortening or bowing of the long bones, joint deformity, or subluxation. The lesions spontaneously decrease in size or regress.\nEtiology\nLoss-of-function mutations, including deletions, non-sense mutations and splice sites mutations, of the PTPN11 gene (12q24) have been linked to MC in several families.\nDiagnostic methods\nDiagnosis is based on clinical signs, radiographic findings and familial history. The radiographic features are osteochondromas at the metaphyses of the short tubular bones (hands and feet) pointing towards the joints and coexisting with enchondromas.\nDifferential diagnosis\nThe differential diagnosis should include hereditary multiple osteochondromas (MO; see this term) in which the long bones are predominantly affected and the lesions point away from the joint/growth plate and may result in shortening or deformity of the affected bones. Other diseases to be considered include the non-hereditary conditions Ollier disease and Maffucci syndrome (in which multiple enchondromas are found in the medulla of the bone and are predominantly unilateral), and dysplasia epiphysealis hemimelica (DEH; characterized by a cartilaginous overgrowth mainly located in the lower extremities on one side of the body) (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is technically feasible.\nGenetic counseling\nMC has an autosomal dominant mode of inheritance. Genetic counseling may be proposed to the patients and their families.\nManagement and treatment\nFor severe malalignment of the fingers/toes, surgical intervention can be considered to remove osteochondromas.\nPrognosis\nNo malignant transformation has been reported so far. Clinical course is unpredictable as there may be simultaneous growth of some of the lesions and regression of others. Nerve paralysis or vascular complications (avascular necrosis of the femoral head; see this term) may occur.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Pr J.V.M.G. [Judith] BOVÉE  -  Christianne REIJNDERS"}
{"Disease Name": "Metachromatic leukodystrophy, adult form", "Disease Definition": "A subtype of Metachromatic leukodystrophy characterized by progressive psychomotor regression with an insidious onset after the age of 16 years, most often beginning with intellectual and behavioral changes, such as memory deficits or emotional instability. The clinical picture is dominated by gradual cognitive, later also motor, decline, taking a protracted course with periods of waxing and waning. Decerebration and death occur within decades after disease onset.", "ORPHA ID": 309271, "Summary": ""}
{"Disease Name": "Metachromatic leukodystrophy, juvenile form", "Disease Definition": "A subtype of Metachromatic leukodystrophy characterized by progressive psychomotor regression with an onset between 30 months and 16 years of age, often beginning with behavioral abnormalities or deterioration of school performance. Further manifestations are ataxia, gait disturbances, reduced deep tendon reflexes, spasticity, seizures, paralysis, dementia, and loss of speech, vision, and hearing, eventually resulting in complete loss of motor and cognitive skills, and decerebration. The rate of deterioration is variable with possible survival up to the third decade of life.", "ORPHA ID": 309263, "Summary": ""}
{"Disease Name": "Metachromatic leukodystrophy, late infantile form", "Disease Definition": "A subtype of Metachromatic leukodystrophy characterized by rapidly progressive psychomotor regression with an onset before 30 months of age after a period of apparently normal development. Manifestations developing during the course of the disease are impaired feeding and swallowing due to pseudobulbar palsies, seizures, painful spasms, muscle weakness, ataxia, paralysis, dementia, and loss of speech, vision, and hearing, quickly resulting in complete loss of motor and cognitive skills, and decerebration. Death occurs within the first decade of life.", "ORPHA ID": 309256, "Summary": ""}
{"Disease Name": "Metachromatic leukodystrophy", "Disease Definition": "A rare lysosomal disease characterized by accumulation of sulfatides in the central and peripheral nervous system due to deficiency of the enzyme arylsulfatase A, leading to demyelination. Three clinical subtypes can be distinguished based on the age of onset: late infantile, juvenile, and adult. Lead symptoms are deterioration in motor or cognitive function or behavioral problems, depending on the subtype, all eventually culminating in a decerebrated state and death after a highly variable disease course and duration. Mode of inheritance is autosomal recessive.", "ORPHA ID": 512, "Summary": ""}
{"Disease Name": "Metaphyseal anadysplasia", "Disease Definition": "A rare form of metaphyseal dysplasia characterized by short stature, rhizomelic micromelia and a mild varus deformity of the legs evident from the first months of life, that is associated with radiological features of severe metaphyseal changes (irregularities, widening and marginal blurring) in long bones, most prominent in proximal femurs, and generalized osteopenia, and that usually spontaneously resolves by the age of three years. Severe autosomal dominant and milder recessive variants have been observed.", "ORPHA ID": 1040, "Summary": ""}
{"Disease Name": "Metaphyseal chondrodysplasia, Jansen type", "Disease Definition": "A rare autosomal dominant skeletal dysplasia characterized by short-limbed short stature (due to severe metaphyseal changes that are often discovered in childhood by imaging), waddling gait, bowed legs, contracture deformities of the joints, short hands with clubbed fingers, clinodactyly, prominent upper face and small mandible, as well as chronic parathyroid hormone-independent hypercalcemia, hypercalciuria, and mild hypophosphatemia.", "ORPHA ID": 33067, "Summary": ""}
{"Disease Name": "Metaphyseal chondrodysplasia, Kaitila type", "Disease Definition": "Metaphyseal chondrodysplasia, Kaitila type is a rare multiple metaphyseal dysplasia disease characterized by disproportionate short stature, short limbs and digits, tracheobronchial malacia and progressive thoracolumbar scoliosis. Radiographic imaging shows progression from marked metaphyseal dysplasia of tubular bones in childhood to short and broad bones with mild dysplasia of the joints in adulthood. There have been no further descriptions in the literature since 1982.", "ORPHA ID": 166038, "Summary": ""}
{"Disease Name": "Metaphyseal chondrodysplasia, Rosenberg type", "Disease Definition": "Ulna metaphyseal dysplasia syndrome is a rare primary bone dysplasia characterized by dysplasia of the distal ulnar metaphyses, as well as metacarpal/metatarsal dysplasia and metaphyseal changes resembling enchondromata. Patients usually present bony swelling of the wrists with or without pain (knees and ankles may also be affected). Other variably associated features include platyspondyly, skeletal development delay, short stature and coxa valga.", "ORPHA ID": 1837, "Summary": ""}
{"Disease Name": "Metaphyseal chondrodysplasia, Schmid type", "Disease Definition": "Schmid metaphyseal chondrodysplasia is a rare disorder characterized by moderately short stature with short limbs, coxa vara, bowlegs and an abnormal gait.", "ORPHA ID": 174, "Summary": "Epidemiology\nPrevalence is unknown.\nEtiology\nThe disorder is caused by mutations in the COL10A1 (6q21-q22) gene encoding the collagen alpha-1(X) chain.\nDiagnostic methods\nThe condition is usually diagnosed during the second or third year of life. Diagnosis relies on detection of the metaphyseal lesions at radiography.\nDifferential diagnosis\nHypochondroplasia (see this term) and sequelae from rickets are the principle differential diagnoses. Other metaphyseal dysplasias (such as cartilage-hair hypoplasia or Jansen type metaphyseal chondrodysplasia; see these terms) can be excluded as they are associated with very short stature and other features.\nAntenatal diagnosis\nPrenatal diagnosis should not be proposed for this disease.\nGenetic counseling\nSchmid metaphyseal chondrodysplasia is transmitted in an autosomal dominant manner. Genetic counseling may be recommended with a 50% risk of recurrence.\nManagement and treatment\nOrthopedic correction is the only possible treatment.\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Metaphyseal chondrodysplasia, Spahr type", "Disease Definition": "A rare, genetic, primary bone dysplasia disease characterized by usually moderate, postnatal short stature, progressive genu vara deformity, a waddling gait, and radiological signs of metaphyseal dysplasia (i.e. irregular, sclerotic and widened metaphyses), in the absence of biochemical abnormalities suggestive of rickets disease. Intermittent knee pain, lordosis, and delayed motor development may also occasionally be associated.", "ORPHA ID": 2501, "Summary": ""}
{"Disease Name": "Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria", "Disease Definition": "Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria is an extremely rare genetic disorder characterized by the unique association of enchondromatosis with D-2 hydroxyglutaric aciduria (see these terms). Clinical features include enchondromatosis (with short stature, severe metaphyseal dysplasia and mild vertebral involvement), elevated levels of urinary 2-hydroxyglutaric acid and mild developmental delay.", "ORPHA ID": 99646, "Summary": ""}
{"Disease Name": "Metaphyseal dysostosis-intellectual disability-conductive deafness syndrome", "Disease Definition": "Metaphyseal dysostosis-intellectual disability-conductive deafness syndrome is characterised by metaphyseal dysplasia, short-limb dwarfism, mild intellectual deficit and conductive hearing loss, associated with repeated episodes of otitis media in childhood. It has been described in three brothers born to consanguineous Sicilian parents. Variable manifestations included hyperopia and strabismus. The mode of inheritance is autosomal recessive.", "ORPHA ID": 2502, "Summary": ""}
{"Disease Name": "Metaphyseal dysplasia, Braun-Tinschert type", "Disease Definition": "Metaphyseal dysplasia, Braun-Tinschert type is characterised by metapyhseal undermodeling with broadening of the long bones and femora with an 'Erlenmeyer flask'' appearance, expansion and bowing of the radii with severe varus deformity and flat exostoses of the long bones at the metadiaphyseal junctions.", "ORPHA ID": 85188, "Summary": "Epidemiology\nIt has been described in four German families originating from the same town in Bohemia and in a 7-year-old Japanese girl.\nDifferential diagnosis\nErlenmeyer flask deformity is also a prominent feature of the autosomal recessive Pyle type of metaphyseal dysplasia (see this term). The two conditions can be distinguished by the mode of inheritance and by the presence of the marked varus deformity of the distal part of the radii in Braun-Tinschert metaphyseal dysplasia.\nGenetic counseling\nTransmission of metaphyseal dysplasia, Braun-Tinschert type is autosomal dominant.\n\n                            Last update: \n                            June 2007"}
{"Disease Name": "Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome", "Disease Definition": "Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome is characterized by metaphyseal dysplasia associated with short stature and facial dysmorphism (a beaked nose, short philtrum, thin lips, maxillary hypoplasia, dystrophic yellowish teeth) and acral anomalies (short fifth metacarpals and/or short middle phalanges of fingers two and five). It has been described in several members spanning four generations of a French-Canadian family. The syndrome is likely to be transmitted as an autosomal dominant trait.", "ORPHA ID": 2504, "Summary": ""}
{"Disease Name": "Metaplastic carcinoma of the breast", "Disease Definition": "Metaplastic carcinoma of the breast is a rare, aggressive subtype of invasive breast carcinoma characterized by rapid growth, relatively large tumor size and a tendency to metastasize to distant organs, particularly the lungs, with relatively less frequent involvement of the axillary lymph nodes. Histologically, the tumor shows high-grade cellularity and heterologous differentiation, including chondroid, osseous, pleomorphic/sarcomatoid, spindled, and squamous elements. Patients usually present with a fast-growing, large, well-circumscribed, mobile lump in the breast, which can become painful and involve the chest wall and the skin, leading to ulceration.", "ORPHA ID": 213531, "Summary": ""}
{"Disease Name": "Metatropic dysplasia", "Disease Definition": "Metatropic dysplasia (MTD) is a rare spondyloepimetaphyseal dysplasia characterized by a long trunk and short limbs in infancy followed by severe and progressive kyphoscoliosis causing a reversal in proportions during childhood (short trunk and long limbs) and a final short stature in adulthood.", "ORPHA ID": 2635, "Summary": "Epidemiology\nThe prevalence is unknown. Approximately 81 cases have been reported in the literature to date.\nClinical description\nThe phenotypic spectrum of MTD is variable with severe cases being lethal in utero, or shortly after birth, and others having only milder skeletal changes. Infants present at birth with a long trunk and short limbs. Craniofacial abnormalities can also be noted and include a prominent forehead, midface hypoplasia, and a squared-off jaw. Some are born with an elongation of the coccyx and rarely reported additional findings include sensorineural hearing loss. Rapidly progressive kyphoscoliosis appears during childhood and a reversal in proportions is seen with a shortening of the trunk and relatively long extremities. Kyphoscoliosis can lead to thorax deformities and to a decrease in pulmonary function and respiratory distress that can be fatal. The small joints are usually hypermobile while contractures of the large joints are not uncommon and are usually progressive. Severe kyphoscoliosis and possible atlantoaxial instability can lead to myelopathy. Adults reach an average height of 107-135 cm. Intelligence is normal.\nEtiology\nMTD is due to mutations in the transient receptor potential vanilloid 4 (TRPV4) gene (12q24.1) encoding a polymodal Ca2+ permeable cation channel found in a variety of tissues. Mutations in this gene cause an increase in calcium in the chondrocytes and consequently disrupted endochondral ossification and the clinical manifestations of MTD.\nDiagnostic methods\nDiagnosis is based on clinical and radiological findings. Radiological findings include short diaphyses with wide metaphyses, marked platyspondyly, precocious calcification of hyoid and cricoid cartilage, halberd shaped pelvis, severe hypoplasia of the anterior part of the first cervical vertebrae and squared-off, irregular calcaneal bones. Radiological manifestations change at different ages. Molecular genetic testing can identify a mutation in the TRPV4 gene, confirming diagnosis.\nDifferential diagnosis\nDifferential diagnoses include mucopolysaccharidosis type IV and other types of spondylometaphyseal dysplasia, in particular spondylometaphyseal dysplasia, Kozlowski type (see these terms), an allelic disorder that shows important overlap with mild MD cases.\nAntenatal diagnosis\nPrenatal diagnosis is possible through genetic testing and prenatal assessment (with a 3D computed tomography scan or ultrasound) and should be offered when a mutation in the family is known.\nGenetic counseling\nMTD is inherited autosomal dominantly and genetic counseling is possible. Parents with MTD have a 50% risk of passing the disease on to their offspring. Many cases occur de novo, but in families with no history of the disease, germline mosaicism cannot be excluded.\nManagement and treatment\nTreatment is targeted at possibly avoiding the progression of skeletal deformity and maintaining pulmonary function. Standard practice includes bracing until skeletal maturity is reached. A conservative approach is usually preferred, but surgical procedures (i.e. corrective spine surgery with posterior fusion) can be successful in some cases in halting deformity. Preoperative evaluation of pulmonary function is mandatory before any invasive procedure is considered. Regular follow-up should monitor for any breathing difficulties or signs of myelopathy. A tracheostomy and long-term ventilatory support may be necessary in severe cases.\nPrognosis\nThe prognosis varies on the severity of the disease. Life expectancy is not usually affected unless there are respiratory complications.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Elena ANDREUCCI"}
{"Disease Name": "Methanol poisoning", "Disease Definition": "Methanol poisoning is a rare poisoning resulting in elevated anion gap metabolic acidosis, due to the alcohol dehydrogenase (ADH)-mediated production of formic acid (which is poisonous to the central nervous system), and characterized by dizziness, nausea, vomiting, confusion, metabolic acidosis, visual disturbances (which if left untreated can lead to blindness), coma, and death (due to respiratory failure).", "ORPHA ID": 31825, "Summary": ""}
{"Disease Name": "Methimazole embryofetopathy", "Disease Definition": "A teratogenic embryofetopathy that results from maternal exposition to methimazole (MMI; or the parent compound carbimazole) in the first trimester of pregnancy. MMI is an antithyroid thionamide drug used for the treatment of Graves' disease. In the infant, MMI may result in choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, congenital heart disease (such as ventricular septal defect), renal system malformations and aplasia cutis. Additional features that may be observed include facial dysmorphism (short upslanting palpebral fissures, a broad nasal bridge with a small nose and a broad forehead) and athelia/hypothelia.", "ORPHA ID": 1923, "Summary": ""}
{"Disease Name": "Methionine adenosyltransferase I/III deficiency", "Disease Definition": "A rare inborn error of metabolism characterized by persistently elevated serum methionine levels. Half of patients reported with MAT I/III deficiency, notably those with hypermethioninemia below 800 µM, have no CNS abnormalities and are clinically asymptomatic. However, individuals with higher levels might show evidence of central nervous system abnormalities, most notably hypo- or demyelination on brain MRI, as well as developmental delay and intellectual disability. Bad breath or a strong smell of urine and sweat may be noted in some patients.", "ORPHA ID": 168598, "Summary": ""}
{"Disease Name": "Methotrexate toxicity", "Disease Definition": "A rare intoxication characterized by acute renal tubular toxicity due to crystallization of methotrexate in the renal tubular lumen (which in turn leads to impaired methotrexate clearance and further deterioration of renal function and exacerbation of non-renal adverse events), myelosuppression with pancytopenia, gastrointestinal mucositis, maculopapular skin rash, chemical conjunctivitis, hepatotoxicity (reversible chemical hepatitis and hyperbilirubinemia), pulmonary toxicity, and, in severe cases, multiorgan failure. Central nervous system involvement, including headaches, seizures, and stroke-like symptoms, may also be observed.", "ORPHA ID": 565782, "Summary": ""}
{"Disease Name": "Methotrexate-associated lymphoproliferative disorders", "Disease Definition": "Methotrexate-associated lymphoproliferative disorders are rare immunodeficiency-associated lymphoproliferative diseases characterized by lymphoid proliferation or lymphomas (large B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, reactive lymphadenitis and a polymorphic post-transplant lymphoproliferative disorder) that develop in patients with different autoimmune diseases treated with methotrexate. Swelling is the predominant manifestation of the disease and regression after methotrexate withdrawal is observed in a significant proportion of patients.", "ORPHA ID": 86904, "Summary": ""}
{"Disease Name": "Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency", "Disease Definition": "Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency is a rare inborn error of metabolism disease characterized by mild to moderate, persistent elevation of methylmalonic acid in plasma, urine and cerebrospinal fluid. Clinical presentation may include acute metabolic decompensation with metabolic acidosis (presenting with vomiting, dehydration, confusion, hallucinations), nonspecific neurological symptoms, or may also be asymptomatic.", "ORPHA ID": 308425, "Summary": ""}
{"Disease Name": "Methylmalonic acidemia with homocystinuria type cblF", "Disease Definition": "cblF type methylmalonic acidemia with homocystinuria is a form of methylmalonic acidemia with homocystinuria (see this term), an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures.", "ORPHA ID": 79284, "Summary": "Epidemiology\nTo date, 15 cases have been reported.\nClinical description\ncblF type methylmalonic acidemia with homocystinuria has a variable age of onset (from birth to 11 years of age) and manifestations also vary and can include development delay, feeding difficulties, signs of megaloblastic anemia (pallor, fatigue, anorexia), hypotonia, stomatitis and skin rashes.\nEtiology\nThe disorder is caused by mutations in the LMBRD1 gene (6q13) and is transmitted in an autosomal recessive manner.\n\n                            Last update: \n                            March 2012\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Methylmalonic acidemia with homocystinuria, type cblC", "Disease Definition": "cblC type methylmalonic acidemia with homocystinuria is a form of methylmalonic acidemia with homocystinuria (see this term), an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures.", "ORPHA ID": 79282, "Summary": "Epidemiology\nTo date, over 500 cases of cblC have been reported, making it the most frequent type of methylmalonic acidemia with homocystinuria.\nClinical description\nThe disease typically presents with failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly, a salt-and-pepper retinopathy, and signs of megaloblastic anemia (pallor, fatigue, anorexia). Severe brain abnormalities including hydrocephalus, white matter abnormalities, cerebral atrophy, and unusual basal ganglia lesions are common. Onset of the disorder can be early (infantile) or late (juvenile or adult), with the late-onset form characterized by ataxia, dementia and psychosis.\nEtiology\ncblC type methylmalonic acidemia with homocystinuria is caused by mutations in the MMACHC gene (1p36.3) and is transmitted in an autosomal recessive manner.\n\n                            Last update: \n                            March 2012\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Methylmalonic acidemia with homocystinuria, type cblD", "Disease Definition": "cblD type methylmalonic acidemia with homocystinuria is a form of methylmalonic acidemia with homocystinuria (see this term), an inborn error of vitamin B12 (cobalamin) metabolism characterized by variable biochemical, neurological and hematological manifestations.", "ORPHA ID": 79283, "Summary": "Epidemiology\nTo date, 17 cases of cblD have been reported (6 classic cblD, 5 cblDv1 and 6 cblDv2).\nClinical description\nThree different presentations have been described: the classic form with combined methylmalonic aciduria and homocystinuria; cblD variant 1 (cblDv1) with isolated homocystinuria; and cblD variant 2 (cblDv2) with isolated methylmalonic aciduria. Clinical presentation is extremely variable. The disorder can present from early infancy to late childhood. Presenting signs are variable depending on which aspect(s) of cobalamin metabolism are affected and can include developmental delay, severe learning difficulties, seizures, movement and gait abnormalities, behavioral problems and signs of megaloblastic anemia (pallor, fatigue, anorexia).\nEtiology\nThe causal gene for cblD is MMADHC (2q23.2) and the disorder is transmitted in an autosomal recessive manner.\n\n                            Last update: \n                            March 2012\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Methylmalonic acidemia with homocystinuria", "Disease Definition": "A rare inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures. There are four complementation classes of cobalamin defects (cblC, cblD, cblF and cblJ) that are responsible for methylmalonic acidemia - homocystinuria (methylmalonic acidemia - homocystinuria cblC, cblD cblF and cblJ).", "ORPHA ID": 26, "Summary": "Epidemiology\nAnnual incidence in the USA, based on the California newborn screening program, has been estimated at 1/67,000 (for the cblC form). cblC is the most frequent type (over 550 cases). To date, rare cases of cblD (6 cases), cblF (15 cases) and cblJ (3 cases) have been reported.\nClinical description\nOnset of the disorder can be between early infancy to adulthood. Patients with methylmalonic acidemia with homocystinuria of all types can present with developmental delay, signs of megaloblastic anemia (pallor, fatigue, and anorexia), lethargy and seizures. In addition, patients with cblC present with acute neurological deterioration, retinal deterioration, microcephaly and severe brain abnormalities including hydrocephalus, white matter abnormalities and unusual basal ganglia lesions. Patients with cblD present with severe learning difficulties, behavioral problems and movement and gait abnormalities and patients with cblF and cblJ present with feeding difficulties, hypotonia, stomatitis, mild facial dysmorphism, cardiac malformations, and skin rashes. Patients who become symptomatic beyond infancy may present with ataxia, dementia or psychosis.\nEtiology\nMethylmalonic acidemia - homocystinuria is caused by anomalies in the synthesis of both adenosylcobalamin (AdoCbl) and of methylcobalamin (MeCbl) resulting from genetic defects in the cbl complementation classes C, D, F and J. CblC is caused by mutations in the MMACHC gene (1p36.3), cblD by mutations in the MMADHC gene (2q23.2), cblF by mutations in the LMBRD1 gene (6q13) and cblJ by mutations in the ABCD4 gene.\nDiagnostic methods\nMeasurement of organic acids and amino acids, in particular evidence of increased total plasma homocysteine (tHcy), is suggestive of the disease. Diagnosis is confirmed by complementation analysis of cultured patient fibroblasts or by identification of mutations in the MMACHC, MMADHC, LMBRD1 or ABCD4 genes.\nDifferential diagnosis\nDifferential diagnoses include acquired vitamin B12 deficiency, vitamin B12-responsive methylmalonic aciduria, and homocystinuria without methylmalonic aciduria (see these terms). The combination of methylmalonic aciduria, homocystinuria and normal serum cobalamin concentrations is required to distinguish patients.\nAntenatal diagnosis\nAntenatal diagnosis is possible by measurement of methylmalonate and homocysteine in amniotic fluid and maternal urine at mid-trimester and by studies of cobalamin metabolism in cultured amniotic fluid cells. Molecular diagnosis is possible when the affected gene and the mutation(s) segregating in the family are known. Prenatal therapy (treating the mother with hydroxycobalamin during pregnancy) has been reported in two cases with apparent success.\nGenetic counseling\nAll four forms of the disorder are transmitted in an autosomal recessive manner. Genetic counseling should be provided to affected families.\nManagement and treatment\nPatients are treated with intramuscular injections of hydroxycobalamin, oral betaine, and folic acid. Good metabolic control and correction of hematologic problems can sometimes be achieved with this treatment but most patients continue to have signs of motor and language delay, intellectual deficit and abnormal ophthalmologic findings. Early diagnosis and treatment are important.\nPrognosis\nPrognosis is better in patients with later-onset disease.\n\n                            Last update: \n                            May 2013\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Methylmalonic acidemia without homocystinuria", "Disease Definition": "Methylmalonic acidemia is an inborn error of vitamin B12 metabolism characterized by gastrointestinal and neurometabolic manifestations resulting from decreased function of the mitochondrial enzyme methylmalonyl-CoA mutase.", "ORPHA ID": 293355, "Summary": "Epidemiology\nPrevalence of methylmalonic acidemia has been estimated at 1/48,000 to 1/61,000 in North America, and at 1/26,000 in China (these values may include patients with methylmalonic acidemia with homocystinuria; see this term).\nClinical description\nClinical signs include lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and muscle hypotonia, as well as developmental delay, intellectual deficit, hepatomegaly and coma. Long-term consequences of the disorder include neurological damage due to metabolic stroke affecting the brain stem, and end stage renal failure. The disease can either be responsive or unresponsive to treatment with vitamin B12 (vitamin B12-responsive or unresponsive methylmalonic acidemia; see these terms). Patients with mut0 or cblB tend to be more severely affected than patients with cblA, cblDv2 or mut-.\nEtiology\nVitamin B12-responsive methylmalonic acidemia is caused by defects in the synthesis of adenosylcobalamin (AdoCbl) that result from genetic defects in cobalamin metabolism (cblA, cblB or cblD variant 2 [cblDv2]). Vitamin B12-unresponsive methylmalonic acidemia is caused by complete (mut0) or partial (mut-) deficiency in the activity of the mitochondrial enzyme methylmalonyl-CoA mutase. cblA is caused by mutations in the MMAA gene (4q31.1-2), cblB by mutations in the MMAB gene (12q24.1), cblDv2 by mutations in the MMADHC gene (2q23.2), and mut0 and mut- by mutations in the MUT gene (6p21), and all are transmitted in an autosomal recessive manner. The previously reported cblH disorder is now known to be cblDv2.\n\n                            Last update: \n                            March 2012\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Methylmalonic aciduria due to transcobalamin receptor defect", "Disease Definition": "Methylmalonic aciduria due to transcobalamin receptor defect is a rare metabolite absorption and transport disorder characterized by a moderate increase of methylmalonic acid (MMA) in the blood and urine due to decreased cellular uptake of cobalamin resulting from decreased transcobalamin receptor function. Patients are usually asymptomatic however, screening reveals increased C3-acylcarnitine and MMA in plasma. Serum homocysteine levels may vary from normal to moderately elevated and retinal vascular occlusive disease, resulting in severe visual loss, has been reported.", "ORPHA ID": 280183, "Summary": ""}
{"Disease Name": "Mevalonate kinase deficiency", "Disease Definition": "A rare inborn error of metabolism characterized by a spectrum of presentation ranging from hyperimmunoglobulinemia D with periodic fever (HIDS) to mevalonic aciduria.", "ORPHA ID": 309025, "Summary": "Epidemiology\nSome 300 cases of mevalonate kinase deficiency (MKD) have been reported worldwide. Many cases are probably not diagnosed, implying that prevalence may be higher than expected. Males and females are affected equally.\nClinical description\nAll patients suffer from recurrent inflammatory episodes with fever, pain, diarrhea, skin eruptions, and headache. Patients with the more severe phenotype, mevalonic aciduria (MVA), can also exhibit developmental, neurological and ophthalmological involvement. MKD develops antenatally, during infancy, or in childhood and covers a clinical spectrum ranging from a relatively mild periodic fever disorder to a lethal metabolic disease. There are two types of MKD depending on the severity of the clinical manifestations: Hyperimmunoglobinemia D syndrome (HIDS) with periodic episodes of fever lasting 3 to 7 days, and MVA which includes dysmorphic features, failure to thrive, developmental delay, progressive ataxia, psychomotor delay, progressive ocular manifestations, short stature, and myopathy later in life.\nEtiology\nMKD is caused by mutations in the MVK gene (12q24), which encodes mevalonate kinase involved in cholesterol and isoprenoid production. The exact pathogenesis is currently unclear. Enzyme deficiency results in impaired cholesterol biosynthesis and increased production of inflammatory mediators. The residual enzyme activity is correlated with the severity of the manifestations with HIDS patients having a residual activity between 1.8% and 28%, while MVA patients have enzyme activities below 0.5%. However, overlap between both phenotypes may occur. No clear genotype-phenotype correlations have been identified.\nGenetic counseling\nMKD follows an autosomal recessive pattern of inheritance.\n\n                            Last update: \n                            February 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Joost FRENKEL  - Dr Jerold JEYARATNAM"}
{"Disease Name": "Mevalonic aciduria", "Disease Definition": "A rare, severe form of mevalonate kinase deficiency (MKD) characterized by dysmorphic features, failure to thrive, psychomotor delay, ocular involvement, hypotonia, progressive ataxia, myopathy, and recurrent inflammatory episodes.", "ORPHA ID": 29, "Summary": "Epidemiology\nThe exact prevalence and incidence of MVA are not known. Fewer than 50 patients have been reported to date. A small proportion of patients with MKD have mevalonic aciduria (MVA), while most cases correspond to the milder phenotype known as Hyperimmunoglobinemia D with periodic fever (HIDS).\nClinical description\nOnset of MVA is usually during infancy and in some severe cases antenatally. The clinical presentation is variable with cases of severe disease with significantly reduced life expectancy to milder cases with no effect on life expectancy. Infants may be born with shortened limbs and dysmorphic features (dolichocephaly, microcephaly, frontal bossing, a triangular-shaped face, down-slanting eyelids, and dysplastic or low-set ears. Affected patients may also present with marked failure to thrive, and recurrent episodes of fever (that may be fatal in infancy) possibly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal pain, vomiting, diarrhea, arthralgia, myalgia, mouth ulcers, and skin eruptions. During childhood, patients may show failure to thrive, developmental delay and progressive ataxia; in later childhood or adolescence they may develop progressive ocular disorders such as uveitis, blue sclera, retinitis pigmentosa, or cataracts. Short stature and myopathy are reported in older patients.\nEtiology\nMVA is caused by mutations in the MVK gene (12q24). MVK encodes mevalonate kinase, which is involved in cholesterol and isoprenoid production. In patients with the severe form of MKD, enzyme deficiency is nearly complete causing the severe manifestations of the disorder. Severity usually depends on the degree of residual enzyme activity.\nGenetic counseling\nMKD follows an autosomal recessive pattern of inheritance. Genetic counseling should be proposed to affected families.\nManagement and treatment\nInflammatory attacks can often be controlled with interleukin-1 blocking agents such as canakinumab or anakinra. Severely affected patients have been seen to improve significantly upon allogeneic hematopoietic stem cell transplantation.\n\n                            Last update: \n                            February 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Joost FRENKEL  - Dr Jerold JEYARATNAM"}
{"Disease Name": "MGAT2-CDG", "Disease Definition": "A rare form of disorder of protein N-glycosylation characterized by facial dysmorphism (large, posteriorly rotated ears with prominent antihelices, convex nasal ridge, open mouth, large and crowded teeth), stereotypic hand movements, seizures, and varying degrees of developmental delay. A bleeding tendency is also observed and this results from diminished platelet aggregation. The disease is caused by loss-of-function mutations in the gene MGAT2 (14q21).", "ORPHA ID": 79329, "Summary": ""}
{"Disease Name": "Micro syndrome", "Disease Definition": "Micro syndrome is an autosomal recessive disorder caracterised by ocular and neurodevelopmental defects and by microgenitalia. It presents with severe intellectual disability, microcephaly, congenital cataract, microcornea, microphthalmia, agenesis/hypoplasia of the corpus callosum, and hypogenitalism.", "ORPHA ID": 2510, "Summary": "Epidemiology\nSince its initial description, 26 cases of Micro syndrome have been reported in the literature.\nClinical description\nWith exception of the ophthalmologic features, the clinical and dysmorphic findings are either unapparent or subtle in the early postnatal period.\nEtiology\nMutations in RAB3GAP, a gene showing linkage to a region of homozygosity at 2q21.3, have been identified in some families. The RAB3GAP gene encodes a member of the Rab3 protein family, which is involved in regulated exocytosis of neurotransmitters and hormones. It has been suggested that the hypogenitalism is hypothalamic in origin, and that the ocular and neurodevelopmental defects result from abnormal neurotransmitter vesicular transport and exocytosis.\nDiagnostic methods\nOcular findings are the most reliable diagnostic signs of Micro syndrome, especially during infancy. Pathognomonic ophthalmologic findings include microphthalmia, microcornea, cataract, atonic pupils, mild optic atrophy, and severe cortical vision impairment.\nDifferential diagnosis\nMicro syndrome should be considered in any infant with congenital cataract.\nManagement and treatment\nThere is no specific treatment for Micro syndrome and the management is symptomatic. The conventional approach used for congenital cataract should be recommended.\n\n                            Last update: \n                            January 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Pinar AGRAS  - Dr Murat DERBENT"}
{"Disease Name": "Microbrachycephaly-ptosis-cleft lip syndrome", "Disease Definition": "Microbrachycephaly-ptosis-cleft lip syndrome is characterised by the association of intellectual deficit, microbrachycephaly, hypotelorism, palpebral ptosis, a thin/long face, cleft lip, and anomalies of the lumbar vertebra, sacrum and pelvis. It has been described in two Brazilian sisters. Transmission appears to be autosomal recessive.", "ORPHA ID": 2511, "Summary": ""}
{"Disease Name": "Microcephalic cortical malformations-short stature due to RTTN deficiency", "Disease Definition": "A rare, genetic, neurodevelopmental disorder with primordial microcephaly characterized by primary microcephaly, moderate to severe intellectual disability, and global developmental delay. Variable brain malformations are common ranging from simplified gyration, to cortical malformations such as pachygyria, polymicrogyria, reduced sulcation and midline defects. Craniofacial dysmorphism (e.g. sloping forehead, high and broad nasal bridge) are related to the primary microcephaly. Short stature is frequently observed, and may be severe.", "ORPHA ID": 468631, "Summary": "Epidemiology\nTo date, approximately 30 cases with identified RTTN mutations have been reported in the scientific and medical literature. Males and females are equally affected.\nClinical description\nPresentation can be in utero or at birth with congenital microcephaly. Cortical malformations are common with a broad spectrum ranging from polymicrogyria-like dysgyric cortex to severe congenital microcephaly with large interhemispheric cysts. The cortical malformation is often predominant in frontal regions, suggesting elective underdevelopment of frontal lobes. The neurological problems include severe cognitive, motor and speech delay and only rarely seizures. The clinical severity correlates with the extension of the migration disorder and with the extent of microcephaly. Variable congenital anomalies occur, including eye anomalies (microphthalmia, abnormal orbitae, ankyloblepharon, optic hypoplasia), pituitary failure (growth and endocrine anomalies), urogenital malformations (cryptorchidism, micropenis, double uterus), kidney defect (agenesis, ectopy, pyelocaliectasis), skeletal anomalies (kyphoscoliosis, hip dysplasia), and heart defects. Short stature is variable and can be severe.\nEtiology\nGermline biallelic variants in RTTN (18q22.2) are responsible for the disease.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and confirmed by genetic testing: exome sequencing or panel-based exome sequencing.\nDifferential diagnosis\nDifferential diagnosis is of other causes of autosomal-recessive non-syndromic primary microcephaly with primary dwarfism or short stature.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive; genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nSupportive care includes physical therapy to manage the complications of spasticity, occupational therapy, and speech therapy based on individual needs. Nutritional needs commonly require nasogastric tube feeding, followed eventually by gastrostomy tube placement. Seizures are treated with antiepileptic drugs based on the specific seizure type.\nPrognosis\nThe prognosis of these severe neurodevelopmental diseases is poor, with multiple disabilities and the subsequent complications (respiratory, nutritional, orthopedic) in almost all cases. For patients with severe cortical malformations (lissencephalies, polymicrogyria-like cortical dysplasia), it is usually appropriate to discuss the level of care to be provided in the event of a severe intercurrent illness. No data are available on the quality of life or life expectancy of patients with RTTN mutations.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Nadia BAHI-BUISSON | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Microcephalic osteodysplastic dysplasia, Saul-Wilson type", "Disease Definition": "Microcephalic osteodysplastic dysplasia, Saul-Wilson type is a skeletal dysplasia characterized by a distinct facial phenotype, short stature, brachydactyly, clubfoot deformities, cataracts, and microcephaly. It has been described in four patients. Facial features include frontal bossing with a depression over the metopic suture, a narrow nasal root with a beaked nose, and midfacial hypoplasia with prominent eyes. Characteristic radiographic findings are observed (irregularities of the vertebral bodies, hypoplasia of the odontoid process, short phalanges, coning several epiphyses etc.).", "ORPHA ID": 85172, "Summary": ""}
{"Disease Name": "Microcephalic osteodysplastic primordial dwarfism type II", "Disease Definition": "A rare bone disease and a form of microcephalic primordial dwarfism characterized by severe pre- and postnatal growth retardation, with marked microcephaly in proportion to body size, skeletal dysplasia, abnormal dentition, insulin resistance, and increased risk for cerebrovascular disease.", "ORPHA ID": 2637, "Summary": "Epidemiology\nMicrocephalic osteodysplastic primordial dwarfism type II (MOPDII) is one of the most common forms of microcephalic primordial dwarfism (MPD) and accounts for more than 150 cases worldwide.\nClinical description\nMOPDII is congenital, with a perinatal and infancy onset. It is characterized by severe pre- and postnatal growth retardation, with proportionate severe microcephaly, skeletal dysplasia, abnormal dentition, an increased risk for cerebrovascular disease (aneurysms and Moya Moya disease in 19%-52% of cases) and insulin resistance. Intrauterine growth restriction (IUGR) is common. The average length, weight, and head occipitofrontal circumference (OFC) at birth are respectively 7.0, 3.9, and 4.6 SDs below the population mean (after correcting for gestational age <37 weeks). Head growth appears to stop by 18 months of age giving rise to the appearance of progressive microcephaly. At maturity, the average height, weight, and OFC are respectively 10.3, 14.3, and 8.5 SDs below the population mean. Skeletal dysplasia with progressive scoliosis, radial head dislocation and coxa vara may be seen. Distinct craniofacial features include prominent, small pinnae with attached lobes; small, dysplastic and poorly rooted, opalescent dentition and sparse hair. Further hallmarks of MOPD II include high-pitched nasal voice, areas of hypo- and hyperpigmentation (with café-au-lait spots), poikiloderma, acanthosis nigricans, and truncal obesity in adolescence and adulthood. A disorder initially named primordial short stature-microdontia-opalescent and rootless teeth was originally and mistakenly reported to have distinct MOPD, but it is now recognized to be the same entity as MOPD II.\nEtiology\nMOPD II is caused by mutations in PCNT (21q22.3), encoding pericentrin, which anchors a wide range of centrosomal proteins and protein complexes during cell division. Disruption of pericentrin is thought to cause mitotic spindle defects, and impaired cell proliferation. A role in ATR DNA damage dependent signaling has also been proposed.\nDiagnostic methods\nDiagnosis relies on clinical features, radiographic examinations of bone age that usually show disharmonic maturation of centers and a retarded bone age. Diagnosis is confirmed by genetic screening of PCNT. Some individuals have elevated platelet counts.\nDifferential diagnosis\nDifferential diagnosis includes Meier-Gorlin syndrome, LIG4 syndrome, XRCC4 deficiency, Seckel syndrome, MOPD types I and III, SHORT syndrome, Schimke immuno-osseous dysplasia, and Dubowitz syndrome.\nAntenatal diagnosis\nPregnancies with affected children are often complicated by the observation of IUGR. Early age of delivery is noted. C-sections may be performed at earlier ages due to the IUGR. Prenatal diagnosis is possible if the causative mutation(s) in PCNT have been identified in the carrier parents.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement is mainly symptomatic. Screening for CNS vascular abnormalities with brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) is recommended at diagnosis and every 12 to 18 months. Yearly screening for signs of insulin resistance including a lipid profile should be performed (beginning at grade school age), as well as monitoring for anemia, platelet counts, and hip and spine anomalies.\nPrognosis\nLife expectancy is generally decreased, but individuals live into their 30s. Many complications arise, but most can be handled by adapting modern medical techniques to the diminutive size. Vascular anomalies are a common complication. They may involve neurovasculature in childhood, and renal and coronary arteries in adulthood, the latter of which may be life-threatening.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Michael BOBER  -  Angela DUKER"}
{"Disease Name": "Microcephalic osteodysplastic primordial dwarfism types I and III", "Disease Definition": "A rare, severe, primary bone dysplasia characterized by intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, skeletal dysplasia, low-birth weight and brain anomalies.", "ORPHA ID": 2636, "Summary": "Epidemiology\nLess than 60 cases have been described in the literature so far.\nClinical description\nThe facial dysmorphism is characterized by a round face, metopic ridge, small anterior fontanelle, a sloping forehead, prominent occiput, protruding eyes, prominent nose, small dysplastic ears and micrognathia. The neck is short. Sparse hair and eyebrows, and dry skin are frequently observed. Skeletal anomalies include short limbs, brachydactyly, flexion contractures markedly delayed epiphyseal ossification and, more variably, dislocation of the hips and elbows. The most frequent neurological manifestations are intellectual deficit and seizures, and reported brain anomalies include brain hypoplasia, lissencephaly or pachygyria, hypoplastic frontal lobes, arachnoid cysts, agenesis of the corpus callosum or and mild cerebellar vermis hypoplasia. Cardiac anomalies and retinal dystrophy are more variably reported.\nEtiology\nCaused by bi-allelic mutations of RNU4ATAC (2q14.2), a gene encoding a small nuclear RNA involved in minor (U12) splicing. Mutations in the same gene also cause Roifman syndrome in which there are many overlapping features but Roifman is distinguished by immunodeficiency.\nDiagnostic methods\nDiagnosis is made on the basis of the clinical and radiological phenotype including marked growth retardation and microcephaly, severe brain anomalies and common radiological bone features including delayed epiphyseal ossification, short and bowed tubular bones, enlarged metaphyses, elongated clavicles, mild platyspondyly, cleft vertebral arches, short fingers and toes and small iliac wings.\nDifferential diagnosis\nThe differential diagnosis should include MOPD type 2 and other syndromes associated with primordial dwarfism, such as Seckel syndrome and microcephalic primordial dwarfism due to RTTN deficiency.\nAntenatal diagnosis\nPrenatal diagnosis, by ultrasonography showing brain anomalies, IUGR and short distal limb at around 20 weeks of gestation, has been reported in affected families.\nGenetic counseling\nMOPD type I/III is transmitted as an autosomal recessive trait. Genetic counseling should be offered to at risk families (where each parent is an unaffected carrier) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment is supportive only. Particular attention should be provided to growth and psychomotor development. Medical care and management should be provided according to malformations and intellectual deficiency. Great attention should be paid to apparently mild medical events (fever, drowsiness), especially in the first three years of life.\nPrognosis\nThe prognosis is poor with most of the reported patients dying either in utero or unexpectedly as a result of a fever or an apparently mild medical event within the first 3 years of life. Several RNU4ATAC mutations appear to be compatible with prolonged survival, sometimes until adulthood.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Patrick EDERY | ITHACA* - Dr Audrey PUTOUX \n\n\n                                * European Reference Network"}
{"Disease Name": "Microcephalic primordial dwarfism due to ZNF335 deficiency", "Disease Definition": "Microcephalic primordial dwarfism due to ZNF335 deficiency is characterized by severe antenatal microencephaly, simplified gyration, agenesis of the corpus callosum, absence of basal ganglia (very rare), pontocerebellar atrophy and involvement of the white matter with secondary cerebral atrophy. Congenital cataract, choanal atresia, multiple arthrogryposis and spastic tetraparesis can occur.", "ORPHA ID": 329228, "Summary": ""}
{"Disease Name": "Microcephalic primordial dwarfism, Dauber type", "Disease Definition": "Microcephalic primordial dwarfism, Dauber type is a rare, genetic developmental defect during embryogenesis characterized by severe pre- and postnatal growth retardation, severe microcephaly, severe developmental delay and intelletual disability, severe adult short stature and facial dysmorphism (incl. hypotelorism, small ears, prominent nose). Other reported features include skeletal anomalies (Madelung deformity, clinodactyly, mild lumbar scoliosis, bilateral hip dysplasia) and seizures. Absence of thelarche and menarche is also associated.", "ORPHA ID": 319675, "Summary": ""}
{"Disease Name": "Microcephalic primordial dwarfism, Montreal type", "Disease Definition": "A rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by severe short stature and craniofacial dysmorphism (microcephaly, narrow face with flat cheeks, ptosis, prominent nose with a convex ridge, low-set ears with small or absent lobes, high-arched/cleft palate, micrognathia), associated with premature graying and loss of scalp hair, redundant, dry and wrinkled skin of the palms, premature senility and varying degrees of intellectual disability. Cryptorchidism and skeletal anomalies may also be observed. There have been no further descriptions in the literature since 1970.", "ORPHA ID": 2617, "Summary": ""}
{"Disease Name": "Microcephalic primordial dwarfism, Toriello type", "Disease Definition": "A rare disorder characterised by growth retardation with prenatal onset, cataracts, microcephaly, intellectual deficit, immune deficiency, delayed ossification and enamel hypoplasia. It has been described in two siblings. Transmission is autosomal recessive.", "ORPHA ID": 2643, "Summary": ""}
{"Disease Name": "Microcephalic primordial dwarfism-insulin resistance syndrome", "Disease Definition": "A rare genetic disease characterized by severe pre- and postnatal growth failure with short stature and microcephaly, facial dysmorphism (including a small jaw and prominent midface), severe insulin resistance, fatty liver, and hypertriglyceridemia developing in childhood, and primary gonadal failure. Mild global learning difficulties and acanthosis nigricans have also been reported.", "ORPHA ID": 436182, "Summary": ""}
{"Disease Name": "Microcephaly-albinism-digital anomalies syndrome", "Disease Definition": "Microcephaly - albinism - digital anomalies syndrome is a very rare syndrome associating microcephaly, micrognathia, oculocutaneous albinism, hypoplasia of the distal phalanx of fingers and agenesia of the distal end of the right big toe.", "ORPHA ID": 2513, "Summary": "Epidemiology\nIt has been described in two sibs.\nClinical description\nBoth brother and sister had psychomotor retardation and died in the course of a respiratory infection.\nGenetic counseling\nThe reported cases suggest that the condition is hereditary, and is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Microcephaly-brachydactyly-kyphoscoliosis syndrome", "Disease Definition": "Microcephaly-brachydactyly-kyphoscoliosis syndrome is characterized by profound intellectual deficit in association with microcephaly, short stature, brachydactyly type D, a flattened occiput, downslanting palpebral fissures, low-set large ears, a broad prominent nose and kyphoscoliosis. It has been described in three sisters. The disorder is likely to be transmitted as an autosomal recessive trait.", "ORPHA ID": 3433, "Summary": ""}
{"Disease Name": "Microcephaly-brain defect-spasticity-hypernatremia syndrome", "Disease Definition": "Microcephaly-brain defect-spasticity-hypernatremia syndrome is a rare congenital genetic syndrome with a central nervous system malformation as a major feature characterized by microcephaly, hypertonia, developmental delay and cognitive impairment, swallowing difficulty, hypernatremia, and hypoplasia of the frontal parts and fusion of the lateral ventricles on brain MRI. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 2523, "Summary": ""}
{"Disease Name": "Microcephaly-capillary malformation syndrome", "Disease Definition": "Microcephaly-capillary malformation syndrome is a rare, genetic vascular anomaly characterized by severe congenital microcephaly, poor somatic growth, diffuse multiple capillary malformations on the skin, intractable epilepsy, profound global developmental delay, spastic quadriparesis and hypoplastic distal phalanges.", "ORPHA ID": 294016, "Summary": ""}
{"Disease Name": "Microcephaly-cardiac defect-lung malsegmentation syndrome", "Disease Definition": "Microcephaly - cardiac defect - lung malsegmentation syndrome is a very rare syndrome characterized by the combination of microcephaly, heart defects, renal hypoplasia, lung segmentation defects and cleft palate.", "ORPHA ID": 2516, "Summary": "Epidemiology\nIt has been described in three female sibs (including a fetus).\nClinical description\nDysmorphic features were not characteristic.\nGenetic counseling\nThe condition seems to be hereditary, and transmitted as an autosomal recessive trait.\nPrognosis\nPrognosis is poor and all infants died in infancy.\n\n                            Last update: \n                            July 2010"}
{"Disease Name": "Microcephaly-cardiomyopathy syndrome", "Disease Definition": "Microcephaly-cardiomyopathy syndrome is characterised by severe intellectual deficit, microcephaly and dilated cardiomyopathy. Hand and foot anomalies have also been reported. The syndrome has been described in three individuals. Transmission is autosomal recessive.", "ORPHA ID": 2515, "Summary": ""}
{"Disease Name": "Microcephaly-cerebellar hypoplasia-cardiac conduction defect syndrome", "Disease Definition": "Microcephaly-cerebellar hypoplasia-cardiac conduction defect syndrome is a rare, genetic congenital anomalies/dysmorphic syndrome characterized by growth failure, global developmental delay, profound intellectual disability, autistic behaviors, acquired second-degree heart block with bradycardia and vasomotor instability. Hands and feet present with long fusiform fingers, campto-clinodactyly and crowded toes while craniofacial dysmorphism includes microcephaly, broad forehead, thin eyebrows, upslanting palpebral fissures, large ears with prominent antihelix, prominent nose, long philtrum, thin upper lip vermillion and prominent lower lip. Neurological signs include hypotonia, brisk reflexes, dystonic-like movements and truncal ataxia and imaging shows cerebellar hypoplasia and simplified gyral pattern.", "ORPHA ID": 329332, "Summary": ""}
{"Disease Name": "Microcephaly-cervical spine fusion anomalies syndrome", "Disease Definition": "Microcephaly-cervical spine fusion anomalies syndrome is characterized by microcephaly, facial dysmorphism (beaked nose, low-set ears, downslanting palpebral fissures, micrognathia), mild intellectual deficit, short stature, and cervical spine fusion anomalies producing spinal cord compression. It has been described in two brothers born to consanguineous parents. Transmission is likely to be autosomal recessive.", "ORPHA ID": 2522, "Summary": ""}
{"Disease Name": "Microcephaly-cleft palate-abnormal retinal pigmentation syndrome", "Disease Definition": "Microcephaly-cleft palate-abnormal retinal pigmentation syndrome is a rare orofacial clefting syndrome characterized by microcephaly, cleft of the secondary palate and other variable abnormalities, including abnormal retinal pigmentation, facial dysmorphism with hypotelorism and maxillary hypoplasia. Goiter, camptodactyly, abnormal dermatoglyphics and mild intellectual disability may also be associated. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 2521, "Summary": ""}
{"Disease Name": "Microcephaly-complex motor and sensory axonal neuropathy syndrome", "Disease Definition": "Microcephaly-complex motor and sensory axonal neuropathy syndrome is an extremely rare subtype of hereditary motor and sensory neuropathy characterized by severe, rapidly-progressing, distal, symmetric polyneuropathy and microcephaly (which can be evident in utero) with intact cognition. Clinically it presents with delayed motor development, hypotonia, absent or reduced deep tendon reflexes, progressive muscle wasting and weakness and scoliosis.", "ORPHA ID": 423894, "Summary": ""}
{"Disease Name": "Microcephaly-congenital cataract-psoriasiform dermatitis syndrome", "Disease Definition": "A rare sterol biosynthesis disorder characterized by microcephaly, bilateral congenital cataract, mild developmental delay, growth delay with short stature, psoriasiform dermatitis of variable severity, and immune dysregulation. Behavioral disorder, joint contractures, and arthralgia have also been described.", "ORPHA ID": 488168, "Summary": ""}
{"Disease Name": "Microcephaly-corpus callosum and cerebellar vermis hypoplasia-facial dysmorphism-intellectual disability syndrom", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and moderate to severe intellectual disability, as well as variable other manifestations, such as macro- or microcephaly, epilepsy, hypotonia, behavioral problems, stereotypic movements, and facial dysmorphism (including arched eyebrows, long palpebral fissures, prominent nasal bridge, upturned nose, dysplastic ears, and broad mouth), among others. Brain imaging may show cerebellar anomalies, hypoplastic corpus callosum, enlarged ventricles, polymicrogyria, or white matter abnormalities.", "ORPHA ID": 500159, "Summary": ""}
{"Disease Name": "Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by variable degrees of developmental delay and intellectual disability with poor or absent speech, hypotonia, hypoplastic or absent corpus callosum, and facial dysmorphism (such as long face, frontal bossing, hypertelorism, downslanting palpebral fissures, and tented upper lip). Additional reported features include microcephaly, seizures, gait ataxia, scoliosis, and syndactyly of fingers, among others.", "ORPHA ID": 457284, "Summary": ""}
{"Disease Name": "Microcephaly-deafness-intellectual disability syndrome", "Disease Definition": "Microcephaly-deafness-intellectual disability syndrome is characterised by microcephaly, deafness, intellectual deficit and facial dysmorphism (facial asymmetry, prominent glabella, low-set and cup-shaped ears, protruding lower lip, micrognathia). It has been described in a mother and her son. The mode of inheritance is probably autosomal dominant.", "ORPHA ID": 2533, "Summary": ""}
{"Disease Name": "Microcephaly-facial dysmorphism-ocular anomalies-multiple congenital anomalies syndrome", "Disease Definition": "A rare genetic disease characterized by a highly variable phenotype comprising ocular anomalies (congenital glaucoma, myopia, retinal detachment, and/or Axenfeld-Rieger anomaly), congenital hypothyroidism, hearing loss, microcephaly, dental defects, kidney anomalies, cerebrovascular anomalies, and distal limb anomalies. Dysmorphic facial features may include square face with prominent jaw, broad flat nasal bridge, short philtrum, and prominent ears.", "ORPHA ID": 521445, "Summary": ""}
{"Disease Name": "Microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type", "Disease Definition": "Microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type is a rare syndrome with cardiac malformations (see this term), characterized by prenatal-onset growth retardation (low birth weight and short stature), hypotonia, developmental delay and intellectual disability associated with microcephaly and craniofacial (low anterior hairline, hypotelorism, thick lips with carp-shaped mouth, high-arched palate, low-set ears), cardiac (conotruncal heart malformations such as tetralogy of Fallot; see these terms) and skeletal (hypoplastic thumbs and first metacarpals) abnormalities.", "ORPHA ID": 217026, "Summary": ""}
{"Disease Name": "Microcephaly-glomerulonephritis-marfanoid habitus syndrome", "Disease Definition": "A rare intellectual disability syndrome characterized by intellectual deficit, marfanoid habitus, microcephaly, and glomerulonephritis. There have been no further reports since 1992.", "ORPHA ID": 2172, "Summary": ""}
{"Disease Name": "Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome", "Disease Definition": "A rare genetic disease characterized by microcephaly, global developmental delay, intellectual disability, abnormal muscle tone, and sensorineural hearing impairment. Additional variable manifestations include epilepsy, cortical visual impairment, gastrointestinal disturbances, growth restriction, scoliosis, as well as immunodeficiency and thrombocytopenia. Brain imaging may show cerebral atrophy, thin corpus callosum, and hypomyelination.", "ORPHA ID": 457351, "Summary": ""}
{"Disease Name": "Microcephaly-lymphedema-chorioretinopathy syndrome", "Disease Definition": "Microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) is a rare autosomal dominant condition characterized by variable expression of microcephaly, ocular disorders including chorioretinopathy, congenital lymphedema of the lower limbs, and mild to moderate intellectual disability.", "ORPHA ID": 2526, "Summary": "Epidemiology\nThe exact prevalence of MCLID is not known but the disorder is thought to be rare. Approximately 50 families with clinical features of the syndrome have been described to date with mutations in the KIF11 gene reported in 25 families worldwide. Males and females appear to be affected equally.\nClinical description\nMCLID presents with variable expression of the main clinical features (microcephaly, chorioretinopathy, lymphedema and intellectual disability). The microcephaly is primary, and the severity is variable even within families. Mild to moderate learning difficulties are common. A characteristic facial phenotype including upslanting palpebral fissures, broad nose with rounded tip, anteverted nares, long philtrum with thin upper lip, and prominent chin and ears is well recognized. The ocular features include choroidal atrophy and non-progressive dysplasia. Hypermetropic astigmatism, myopic astigmatism, retinal folds, and microphthalmia are also observed. Lymphedema when present, is generally congenital, bilateral and confined to the dorsa of the feet, and resembles the lymphedema seen in Milroy disease (see this term). Congenital heart defects and epilepsy may be rare features of the syndrome.\nEtiology\nThere is likely to be genetic heterogeneity. However, a significant proportion of cases are caused by mutations in the kinesin family member 11 (KIF11) gene (10q24.1). KIF11 encodes EG5, a homotetramer kinesin motor, likely to be important for the development and maintenance of retinal and lymphatic structures. Individuals with pathogenic mutations in KIF11 have been reported without clinical features of the syndrome demonstrating reduced penetrance.\nGenetic counseling\nInheritance is autosomal dominant with variable expression and reduced penetrance.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Gabriela JONES  - Pr Sahar MANSOUR  - Dr Pia OSTERGAARD"}
{"Disease Name": "Microcephaly-microcornea syndrome, Seemanova type", "Disease Definition": "Microcephaly-microcornea syndrome, Seemanova type is characterised by microcephaly and brachycephaly, eye anomalies (microphthalmia, microcornea, congenital cataract), hypogenitalism, severe intellectual deficit, growth retardation and progressive spasticity. It has been described in two patients (a male and his sister's son). Both patients also presented with facial dysmorphism, including upslanting palpebral fissures, epicanthal folds, highly arched palate, microstomia, and retrognathia. This syndrome is transmitted as an X-linked trait.", "ORPHA ID": 2528, "Summary": ""}
{"Disease Name": "Microcephaly-micromelia syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by severe intrauterine growth retardation, profound microcephaly, dysmorphic craniofacial features (such as craniosynostosis and distinctive facial appearance with short palpebral fissures, broad and beaked nose, microstomia, micrognathia, low-set ears, and short neck), and variable malformations of the limbs, especially the arms. Cardiac, gastrointestinal, and genitourinary anomalies have also been reported. Brain imaging shows gray and white matter abnormalities and hypoplastic or absent corpus callosum. The disease is commonly fatal in the fetal to neonatal period due to respiratory failure.", "ORPHA ID": 572768, "Summary": ""}
{"Disease Name": "Microcephaly-polymicrogyria-corpus callosum agenesis syndrome", "Disease Definition": "Microcephaly-polymicrogyria-corpus callosum agenesis syndrome is a rare, genetic, central nervous system malformation syndrome characterized by marked prenatal-onset microcephaly, severe motor delay with hypotonia, bilateral polymicrogyria, corpus callosum agenesis, ventricular dilation, small cerebellum and early lethality.", "ORPHA ID": 171703, "Summary": ""}
{"Disease Name": "Microcephaly-seizures-intellectual disability-heart disease syndrome", "Disease Definition": "A rare, multiple congenital anomalies/dysmorphic syndrome characterized by microcephaly, intellectual disability, seizures, and congenital heart defects (e.g. atrial/ventricular septal defect, hypoplastic aortic arch with persistent ductus arteriosus). Additional manifestations include mild hypothyroidism, skeletal abnormalities, micropenis, delayed psychomotor development, dysmorphic facial features (including epicanthus, depressed nasal bridge, prominent antitragus), and pulmonary vascular occlusive disease. There have been no further descriptions in the literature since 1989.", "ORPHA ID": 2519, "Summary": ""}
{"Disease Name": "Microcephaly-short stature-intellectual disability-facial dysmorphism syndrome", "Disease Definition": "Microcephaly-short stature-intellectual disability-facial dysmorphism syndrome is a rare genetic malformation syndrome with short stature characterized by postnatal microcephaly, failure to thrive and short stature, global developmental delay and intellectual disability, hypotonia, dysmorphic features (short nose, depressed nasal bridge, low set ears, short neck, clinodactyly and cutaneous syndactyly of T2-3 at birth and broad forehead, midface retrusion, epicanthal folds, laterally sparse eyebrows, short nose, long philtrum, widely spaced teeth, micrognathia and coarsening of facial features later in life). Other associated features include postnatal transient generalized edema, myopia, strabismus, hypothyroidism.", "ORPHA ID": 423306, "Summary": ""}
{"Disease Name": "Microcephaly-short stature-limb abnormalities syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies syndrome characterized by severe microcephaly, intrauterine growth retardation, short stature and variable limb anomalies such as radial ray defects, short limbs, absent/hypoplastic patellae, syndactyly, brachydactyly and hypoplastic carpal or metacarpal bones. Craniofacial dysmorphism is characterized by long and broad nose, microstomia and micrognathia. Intellectual disability is mild when present. Cases with extremely severe phenotype with very short limbs and poor lung development are perinatally lethal.", "ORPHA ID": 572773, "Summary": ""}
{"Disease Name": "Microcephaly-thin corpus callosum-intellectual disability syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disease characterized by progressive postnatal microcephaly and global developmental delay, as well as moderate to profound intellectual disability, difficulty or inability to walk, pyramidal signs (including spasticity, hyperreflexia and extensor plantar response) and thin corpus callosum revealed by brain imaging. Ophthalmologic signs (including nystagmus, strabismus and abnormal retinal pigmentation), foot deformity and genital anomalies may also be associated.", "ORPHA ID": 397951, "Summary": ""}
{"Disease Name": "Microcornea-glaucoma-absent frontal sinuses syndrome", "Disease Definition": "A rare developmental defect during embryogenesis syndrome characterized by the association of microcornea, glaucoma and frontal sinus hypoplasia. Thick palmar skin and torus palatinus have also been reported. There have been no further descriptions in the literature since 1995.", "ORPHA ID": 2536, "Summary": ""}
{"Disease Name": "Microcornea-myopic chorioretinal atrophy-telecanthus syndrome", "Disease Definition": "A rare syndromic chorioretinal dystrophy characterized by childhood onset of mild to severe myopia with microcornea and chorioretinal atrophy, typically associated with telecanthus and posteriorly rotated ears. Other variable features include early-onset cataracts, ectopia lentis, ecotpia pupilae and retinal detachment.", "ORPHA ID": 369970, "Summary": ""}
{"Disease Name": "Microcornea-posterior megalolenticonus-persistent fetal vasculature-coloboma syndrome", "Disease Definition": "A rare developmental defect of the eye characterized by bilateral microcornea, posterior megalolenticonus, persistent fetal vasculature (extending from the posterior pole of the lens to the optic disc) and posterior chorioretinal coloboma.", "ORPHA ID": 231736, "Summary": ""}
{"Disease Name": "Microcystic lymphatic malformation", "Disease Definition": "A rare common cystic lymphatic malformation characterized by a benign cystic lesion composed of dilated lymphatic channels. Microcystic lesions consist of cysts smaller than 1 cm in diameter. They usually present at birth or during the first years of life and most often occur in the head and neck region but may affect any site. Symptoms depend on the location and extent of the lesion. Infection, trauma, or intracystic hemorrhage can lead to lesional expansion. Malignant transformation does not occur.", "ORPHA ID": 79490, "Summary": ""}
{"Disease Name": "Microcystic stromal tumor", "Disease Definition": "A rare benign ovarian stromal tumor characterized by a stromal neoplasm with variable microcystic morphology, low mitotic activity, and diffuse nuclear beta-catenin and cyclin D1 immunoreactivity, while inhibin and calretinin are not expressed. Patients most commonly present with symptoms of a unilateral pelvic mass. Hormonal manifestations are usually absent. The tumor may be associated with familial adenomatous polyposis.", "ORPHA ID": 569248, "Summary": ""}
{"Disease Name": "Microcytic anemia with liver iron overload", "Disease Definition": "A congenital hypochromic microcytic anemia with progressive liver iron overload paradoxically associated with normal to moderately elevated serum ferritin levels has been described in three unrelated patients.", "ORPHA ID": 83642, "Summary": "Etiology\nThis syndrome is due to mutations in  DMT1 which codes for a transporter mediating the uptake of iron from the intestinal lumen in cytosol of duodenal enterocytes.\nManagement and treatment\nAnemia poorly responds to oral iron treatment.\n\n                            Last update: \n                            October 2006"}
{"Disease Name": "Microduplication Xp11.22p11.23 syndrome", "Disease Definition": "Familial and de novo recurrent Xp11.22-p11.23 microduplication has been recently identified in males and females.", "ORPHA ID": 217377, "Summary": "Epidemiology\nTo date, twelve patients have been described.\nClinical description\nAll patients show moderate to severe intellectual deficit and speech delay. Seizures, early puberty and lower-extremity anomalies, including pes planus or cavus, 5th toe hypoplasia, and syndactyly, are common. A peculiar electroencephalographic (EEG) pattern characterized by rolandic-like spikes and/or continuous spike wave during slow sleep (CSWS) exists in childhood.\nEtiology\nThe microduplication was identified by microarray-based comparative genomic hybridization (aCGH). Most affected females show preferential activation of the duplicated X chromosome. Duplications are mediated by nonallelic homologous recombination (NAHR) or Alu-mediated recombination.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "Microform holoprosencephaly", "Disease Definition": "A benign form of holoprosencephaly characterized by midline defects without the typical HPE defect in brain cleavage and which can variably manifest with microcephaly, hypotelorism, midline cleft lip and/or flat nose, choanal stenosis, pyriform sinus stenosis, coloboma as well as a single median maxillary incisor.", "ORPHA ID": 280200, "Summary": ""}
{"Disease Name": "Microgastria-limb reduction defect syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by congenital microgastria and a uni- or bilateral limb reduction defect, that can include absent or hypoplastic thumbs, radius, ulna and/or amelia. Association with other variable abnormalities, including intestinal malrotation, asplenia, dysplastic kidneys, hypoplastic lungs, dysplastic corpus collosum, and abnormal genitalia, has been reported.", "ORPHA ID": 2538, "Summary": ""}
{"Disease Name": "Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability characterized by mild global developmental delay, intellectual disability or learning difficulties, behavioral problems (like autistic, hyperactive, or aggressive behavior), variable dysmorphic craniofacial features, and abnormalities of the fingers (brachydactyly, tapering fingers, prominent interphalangeal joints). Additional manifestations are highly variable and include recurrent infections and skeletal anomalies, among others.", "ORPHA ID": 476126, "Summary": ""}
{"Disease Name": "Microlissencephaly-micromelia syndrome", "Disease Definition": "Microlissencephaly-micromelia syndrome is a syndrome of abnormal cortical development, characterized by severe prenatal polyhydramnios, postnatal microcephaly, lissencephaly, upper limb micromelia, dysmorphic facies (coarse face, hypertrichosis, and short nose with long philtrum), intractable seizures, and early death. Hypoparathyroidism was noted in one case.", "ORPHA ID": 50810, "Summary": ""}
{"Disease Name": "Microlissencephaly", "Disease Definition": "Microlissencephaly describes a heterogenous group of a rare cortical malformations characterized by lissencephaly in combination with severe congenital microcephaly, presenting with spasticity, severe developmental delay, and seizures and with survival varying from days to years.", "ORPHA ID": 1083, "Summary": ""}
{"Disease Name": "Microphthalmia with brain and digit anomalies", "Disease Definition": "Microphthalmia with brain and digit anomalies is characterised by anophthalmia or microphthalmia, retinal dystrophy, and/or myopia, associated in some cases with cerebral anomalies. It has been described in two families. Polydactyly may also be present. Linkage analysis allowed identification of mutations in the  BMP4 gene, which has already been shown to play a role in eye development.", "ORPHA ID": 139471, "Summary": ""}
{"Disease Name": "Microphthalmia with limb anomalies", "Disease Definition": "A rare developmental disorder characterized by bilateral microphthalmia or anophthalmia, synostosis, syndactyly, oligodactyly and/or polydactyly.", "ORPHA ID": 1106, "Summary": "Epidemiology\nThe prevalence is unknown but more than 35 cases have been reported to date, mainly from consanguineous parents.\nClinical description\nThe disease presents at birth with unilateral, or more often, bilateral anophthalmia or microphthalmia and numerous limb anomalies (including synostosis, syndactyly, oligodactyly, polydactyly and long bone hypoplasia). Typically patients have clinical anophthalmia/severe microphthalmia with little/no vision. The most common limb anomalies are synostosis of the fourth and fifth metacarpals, a short 5th finger and only 4 toes bilaterally. Developmental milestones (such as responsive smile) are often delayed and most patients have moderate to severe intellectual deficiencies. Facial features can include flattened midface, sparse eyelashes, short palpebral fissures, high palate and cleft lip. Renal (horseshoe kidney), venous and vertebral anomalies have also been reported in rare cases. Early postnatal/perinatal death has occurred in several cases.\nEtiology\nThe majority of cases are caused by mutations in the SPARC-related modular calcium binding protein 1 SMOC1 gene (14q24.1) which may be involved in the regulation of bone morphogenetic proteins. The existence of other causative genes is possible but they have not yet been discovered. The FNBP4 gene (11q12.1) was identified in a case with a phenotype similar to OAS but further studies are necessary to conclude if it is indeed causative of OAS.\nDiagnostic methods\nDiagnosis is based on the presence of characteristic clinical findings. Computed tomography (CT) scans and magnetic resonance imaging (MRI) can also be helpful in identifying the presence or absence of the globe, optic nerve and extra ocular muscles. Identifying a mutation in the SMOC1 gene confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses include isolated cryptophthalmia and other forms of syndromic microphthalmia such as microphthalmia, Lenz type, oculofaciocardiodental syndrome and anophthalmia/microphthalmia-esophageal atresia (see these terms).\nAntenatal diagnosis\nPrenatal testing via CVS or amniocentesis is possible if the causative mutation in a family has been identified. Ultrasound can also be utilized to identify the limb anomalies associated with OAS.\nGenetic counseling\nThe disease is inherited autosomal recessively so genetic counseling is possible in affected families and can help in informing parents of the recurrence risk of OAS in subsequent pregnancies. If both parents are carriers there is a 25% risk with each pregnancy of having an affected child.\nManagement and treatment\nThere is no cure for OAS. Treatment for anophthalmia/microphthalmia may be discussed with an oculoplastic surgeon and ocularist. For anophthalmia, expansion of the eyelids, socket and orbital bones is recommended as soon as possible after birth and is done via conformer therapy by an ocularist or by oculoplastic surgery using hydrogel socket expanders followed by orbital implants or dermis-fat grafts. This can help patients with achieving a more typical appearance by preventing facial deformity. Those with some vision (if the microphthalmia is not severe) may benefit from visual aids. Some limb abnormalities may also be surgically corrected to help the patient gain mobility or function, therefore orthopedic evaluation is necessary. All individuals with OAS should receive evaluation by a vision teacher and special education may be necessary.\nPrognosis\nLittle is known about the prognosis given the rarity but quality of life is usually affected due to intellectual disability, visual impairment and limb anomalies.\n\n                            Last update: \n                            December 2013\n\n\n                            - Expert reviewer(s): \n                             Tanya BARDAKJIAN  - Dr Adele SCHNEIDER"}
{"Disease Name": "Microphthalmia with linear skin defects syndrome", "Disease Definition": "A rare X-linked, syndromic eye disorder characterized by ocular defects (microphthalmia, orbital cysts, corneal opacities) and linear skin dysplasia of the neck, head, and chin. Additional findings may include agenesis of corpus callosum, sclerocornea, chorioretinal abnormalities, hydrocephalus, seizures, intellectual deficit, and nail dystrophy.", "ORPHA ID": 2556, "Summary": ""}
{"Disease Name": "Microphthalmia, Lenz type", "Disease Definition": "A rare X-linked inherited form of syndromic microphthalmia characterized by unilateral or bilateral microphthalmia (and/or clinical anophthalmia) with or without coloboma in addition to a range of extraocular manifestations such as microcephaly, malformed ears, dental abnormalities (i.e. irregular shape of incisors), skeletal anomalies (duplicated thumbs, syndactyly, clinodactyly, camptodactyly), urogenital anomalies (hypospadias, cryptorchidism, renal dysgenesis, hydroureter) and mild to severe intellectual disability. It is allelic to two disorders: oculofaciocardiodental syndrome and premature aging appearance-developmental delay-cardiac arrhythmia syndrome.", "ORPHA ID": 568, "Summary": ""}
{"Disease Name": "Microphthalmia-ankyloblepharon-intellectual disability syndrome", "Disease Definition": "Microphthalmia-ankyloblepharon-intellectual disability syndrome is characterized by microphthalmia, ankyloblepharon and intellectual deficit. It has been described in seven male patients from two generations of a Northern Ireland family. The causative gene is localized to the Xq27-q28 region. The syndrome is transmitted as an X-linked recessive trait.", "ORPHA ID": 85275, "Summary": ""}
{"Disease Name": "Microphthalmia-brain atrophy syndrome", "Disease Definition": "A rare genetic neurodegenerative disorder characterized by congenital microphthalmia, sunken eyes, blindness, microcephaly, severe intellectual disability, progressive spasticity, and seizures. Psychomotor development is normal in the first 6-8 months of life and thereafter declines rapidly and continuously. Brain MRI reveals progressive and extensive degenerative changes, especially cortex, cerebellum, brainstem, and corpus callosum atrophy, with complete loss of cerebral white matter.", "ORPHA ID": 77299, "Summary": ""}
{"Disease Name": "Microphthalmia-microtia-fetal akinesia syndrome", "Disease Definition": "A rare lethal multiple congenital anomalies/dysmorphic syndrome characterized by the association of fetal akinesia sequence, bilateral microphthalmia, microtia, and persistent truncus arteriosus. Additional dysmorphic features include prominent forehead, small nose, micrognathia, as well as camptodactyly and symphalangism. Contractures of large joints and micropenis have also been reported.", "ORPHA ID": 2547, "Summary": ""}
{"Disease Name": "Microphthalmia-retinitis pigmentosa-foveoschisis-optic disc drusen syndrome", "Disease Definition": "Microphthalmia-retinitis pigmentosa-foveoschisis-optic disc drusen syndrome is a rare, genetic, non-syndromic developmental defect of the eye disorder characterized by the association of posterior microphthalmia, retinal dystrophy compatible with retinitis pigmentosa, localized foveal schisis and optic disc drusen. Patients present high hyperopia, usually adult-onset progressive nyctalopia and reduced visual acuity, and, on occasion, acute-angle glaucoma.", "ORPHA ID": 251279, "Summary": ""}
{"Disease Name": "Microscopic polyangiitis", "Disease Definition": "A rare inflammatory, necrotizing, systemic vasculitis that affects predominantly small vessels (i.e. small arteries, arterioles, capillaries, venules) in multiple organs, including the kidney, the lungs, the skin and the peripheral nerves.", "ORPHA ID": 727, "Summary": "Epidemiology\nMicroscopic polyangiitis (MPA) has a prevalence of 1/40,000 adults in France. Pediatric-onset MPA (<10 years of age) is uncommon.\nClinical description\nMPA affects small vessels (more rarely medium-sized arteries) in any organ, resulting in a wide variety of non-specific symptoms. The early clinical manifestations are indicative of systemic inflammation: fever, arthralgias, myalgias, fatigue, and/or loss of appetite. As the disease progresses, 90% of patients show renal involvement with pauci-immune necrotizing and crescentic glomerulonephritis that can have a rapidly progressive course if not treated promptly. Pulmonary involvement (alveolar hemorrhage) is frequent and manifests with symptoms such as dyspnea, cough or hemoptysis. The most severe manifestation is combined pulmonary and renal disease (pulmonary-renal syndrome). Gastro-intestinal involvement can present with abdominal pain, nausea, or vomiting, and can be life-threatening in case of peritonitis, ischemia or perforation. Neurological (mainly mononeuritis multiplex), dermatologic (mainly leukocytoclastic angiitis), musculoskeletal (arthralgias, myalgias) and ocular involvement (e.g. episcleritis, retinal vasculitis, uveitis) are also observed. Cardiovascular involvement (e.g. pericarditis, cardiac insufficiency) is rare.\nEtiology\nMPA is an antineutrophil cytoplasmic autoantibodies (ANCA)-associated auto-immune disease with little or no immune complex deposition. Evidence indicates that ANCA can activate neutrophils and monocytes, and cause them to attack vessel walls.\nDiagnostic methods\nDiagnosis can be difficult and is essentially made by exclusion of other diseases. Detection of ANCA is a useful serologic marker. Generally, 60% of patients have myeloperoxidase (MPO)-ANCA, 30% proteinase 3 (PR3)-ANCA and 10% are ANCA-negative. Blood tests can reveal elevated C-reactive protein, leukocytosis, and anemia. Urine tests can show proteinuria, hematuria, and leukocyturia. Renal, pulmonary and skin biopsy can support the diagnosis. Pathologically, MPA is characterized by segmental vascular necrosis with infiltration of neutrophils and monocytes, often with leukocytoclasia and accumulation of fibrin.\nDifferential diagnosis\nThe differential diagnosis includes granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (distinguished from MPA by the presence of necrotizing granulomatous inflammation in the absence or presence of asthma, respectively), Henoch-Schönlein purpura and cryoglobulinemic vasculitis (distinguished from MPA by IgA-dominant and cryoglobulin immune deposits, respectively), and polyarteritis nodosa.\nManagement and treatment\nTreatment consists of two phases: induction of remission and maintenance of remission. The first-line induction therapy consists of oral or intravenous administration of high dose corticosteroids with immunosuppressive treatment (e.g. cyclophosphamide, or rituximab) in severe cases. Milder forms can be treated with glucocorticoids alone. Maintenance treatment consists of semestral infusions of rituximab. Relapses are treated with increased or reinstituted immunosuppression. In case of renal failure, dialysis and/or renal transplantation are appropriate.\nPrognosis\nWith early diagnosis and treatment, prognosis is improved. Induction of remission occurs in 90% of patients. Optimum treatment reduces relapses (10% of patients have a relapse within 2 years of remission). Five-year patient survival has significantly improved during the last decade.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Xavier PUECHAL  - Pr Benjamin TERRIER"}
{"Disease Name": "Microspherophakia-metaphyseal dysplasia syndrome", "Disease Definition": "Microspherophakia - metaphyseal dysplasia is a very rare syndrome associating bone dysplasia with micromelic dwarfism and eye defects.", "ORPHA ID": 2551, "Summary": "Epidemiology\nIt has been reported in a father and his son.\nClinical description\nBone dysplasia is characterized by diaphyseal thickening of the long bones, metaphyseal deformation and epiphyseal irregularities. Eye defects consisted of myopia, microspherophakia, lens coloboma and luxation, and retinal detachment. The affected patients have normal mental development.\nEtiology\nThe condition is most probably hereditary, transmitted as an autosomal dominant trait.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "Microsporidiosis", "Disease Definition": "Microsporidiosis is a parasitosis caused by microsporidia (protozoan parasites).", "ORPHA ID": 2552, "Summary": "Epidemiology\nThe annual incidence of microsporidiosis is unknown and the geographical distribution of microsporidia remains to be defined. Immunodeficient patients (individuals with HIV, and patients who have undergone a bone marrow or organ transplant) are the main target.\nClinical description\nThe infection results in chronic diarrhea that leads to severe weight loss.\nEtiology\nMicrosporidia are unicellular eukaryotic parasites without mitochondria and are responsible for opportunistic infections. Microsporidia are strictly intracellular parasites. The initial proliferative asexual stage (merogony) is followed by a disseminating stage (sporogony) that leads to spore development. Small spores (1 to 3 µm depending on the species) represent the most resistant and disseminating form and are characterized by a polar filament, which allows them to perforate the cell wall and inject nuclear material. They develop mainly in intestinal cells but may also develop in adipocytes, epithelium cells and blood cells. Several genera have been reported in humans, among which Encephalitozoon and Enterocytozoon are the most common. Contamination probably occurs after ingesting spores contained in water or food. Direct interhuman contamination is also likely.\nDiagnostic methods\nDiagnosis is based on the identification of spores through laboratory testing.\nDifferential diagnosis\nDifferential diagnoses include the other genera of microsporidia.\nManagement and treatment\nTreatment with albendazole is well tolerated and successful, except for patients with Enterocytozoon bieneusi infections, for which only fumagillin is effective but hematotoxic.\nPrognosis\nThe prognosis may be severe in immunodeficient patients.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Annick DATRY"}
{"Disease Name": "Microtia-eye coloboma-imperforation of the nasolacrimal duct syndrome", "Disease Definition": "This syndrome is characterised by the association of microtia, eye coloboma, and imperforation of the nasolacrimal duct.", "ORPHA ID": 139450, "Summary": "Epidemiology\nSo far, it has been described in only one family.\nEtiology\nThe phenotype is associated with the presence of five copies of a copy-number-variable region (CNV) localised to 4pter. This is the first example of an amplified CNV being associated with a Mendelian disorder.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            May 2008"}
{"Disease Name": "Microtia", "Disease Definition": "A congenital malformation of the external ear, seen more frequently in males, that occurs sporadically or is inherited, that is characterized by unilateral (79-93% of cases, 60% of which involve the right ear) or bilateral small and abnormally shaped auricles and that is often associated with atresia or stenosis of the ear canal, attention deficit disorders and delayed language development. The variation in auricle size ranges from grade I, where the auricle is simply smaller than normal, to grade IV, also known as anotia, where there is a complete absence of the external ear and of the auditory canal.", "ORPHA ID": 83463, "Summary": ""}
{"Disease Name": "Microtriplication 11q24.1", "Disease Definition": "Microtriplication 11q24.1 is an extremely rare partial autosomal tetrasomy, resulting from a partial triplication of the long arm of chromosome 11, characterized by intellectual disability (with severe verbal impairment), short stature with small extremities, keratoconus and distinctive facial features (round, course face, upward slanting palpebral fissures, mild synophris, large nose with thick ala nasi and triangular tip, large mouth with broad lips, short and smooth philtrum, large protruded chin, ears with adherent lobules). Additionally, patients are overweight and present hypercholesterolemia.", "ORPHA ID": 289522, "Summary": ""}
{"Disease Name": "Microvillus inclusion disease", "Disease Definition": "Microvillus inclusion disease (MVID) is a very rare and severe intestinal disease characterized by intractable neonatal secretory diarrhea persisting at bowel rest and specific histological features of the intestinal epithelium.", "ORPHA ID": 2290, "Summary": "Epidemiology\nPrevalence data are not available. Less than 200 cases have been reported to date. There is a male predominance, with a sex ratio of 1.5:1.\nClinical description\nTwo clinical forms of MVID have been described: an early-onset form, developing within hours or days of birth, and a late-onset form, occurring in the first months of life. In both, intractable, watery diarrhea is profuse and leads to severe metabolic acidosis, dehydration, malabsorption and failure to thrive. Total parenteral nutrition is necessary, however, in some later-onset cases, partial oral absorption has been described. The intestinal insufficiency is progressively life-threatening in the absence of rapid, appropriate hydroelectrolytic and nutritional compensation. Developmental delays may be present and rare associated anomalies (e.g. inguinal hernia, renal dysplasia) have been reported. Long-term parenteral nutrition may be complicated with specific liver cholestasis. Atypical forms of MVID, without detectable microvillus inclusions and less severe course, have been described.\nEtiology\nMVID is caused by mutations in the MYO5B gene (18q) resulting in perturbation of intestinal epithelial cell apical polarity. Disorganized microvilli impair the absorptive capacity of the enterocytes. A variant of the disorder, without microvillous inclusion vesicles, is caused by loss-of-function mutations in the syntaxin 3 (STX3) gene (11q12.1), and when associated with hemophagocytic lymphohistiocytosis, can also be caused by mutation of STXBP2 (19p13.2) gene. Some patients do not display mutations in any identified gene.\nDiagnostic methods\nThe diagnosis is suspected based on clinical manifestations and is confirmed by histological analysis of small bowel biopsies showing villous atrophy and abnormal periodic acid-Schiff stain (PAS)-positive inclusion material in intestinal epithelium, without crypt hyperplasia. Electronic microscopy reveals microvillous atrophy and in most cases, microvillous inclusion vesicles in the cytoplasm of enterocytes. Molecular genetic testing has become essential to confirm the diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes rare congenital enteropathies such as autoimmune enteropathy, chloride diarrhea, congenital sodium diarrhea, and congenital tufting enteropathy.\nAntenatal diagnosis\nAs MVID is a rare disease with no specific and systematic prenatal signs. Prenatal diagnosis is possible only if the specific gene mutation has been identified in an affected member of the family.\nGenetic counseling\nThe inheritance pattern of MVID is autosomal recessive (parents of an affected individual have a probability of 25 % to transmit the causal mutation to their offspring). Genetic counseling should be offered to affected families in order to provide more information about this genetic condition, its risk of recurrence and the necessity/availability of prenatal diagnosis.\nManagement and treatment\nTo date, there is no curative therapy for MVID. Treatment involves total parenteral nutrition, intestinal transplantation (when long-term parenteral nutrition is no longer possible) and, when required, associated liver transplantation.\nPrognosis\nDue to the severity and precocity of the symptoms, as well as the long-term parenteral nutrition's complications, prognosis for MVID is generally poor. Causes of death include severe dehydration and metabolic imbalance, malnutrition, and sepsis.\n\n                            Last update: \n                            October 2017\n\n\n                            - Expert reviewer(s): \n                            Pr Olivier GOULET  - Dr Julie SALOMON"}
{"Disease Name": "Micturation-induced seizures", "Disease Definition": "Micturation-induced seizures is a rare neurologic disease characterized by tonic posturing or clonic movements triggered by micturition, with bilateral or unilateral involvement of the extremities and with or without loss of consciousness. Developmental delay is reported in some cases.", "ORPHA ID": 166430, "Summary": ""}
{"Disease Name": "Mid-dermal elastolysis", "Disease Definition": "A rare, acquired, dermis elastic tissue disease characterized by asymptomatic, well-demarcated, symmetric patches and/or plaques of finely wrinkled skin arranged parallel to skin cleavage lines (type I), associated with perifollicular papular protrusions (type II) or with persistent reticular erythema (type III), occurring predominantly on the shoulders, trunk, back, and proximal extremities, associating, on histopathology, a selective loss of elastic tissue in the midreticular dermis. Erythema and/or urticaria may or may not precede wrinkly lesions.", "ORPHA ID": 228299, "Summary": ""}
{"Disease Name": "Middle aortic syndrome", "Disease Definition": "A rare vascular anomaly characterized by the segmental narrowing of the abdominal and/or distal descending thoracic aorta, with varying involvement of the visceral and renal arteries, that commonly presents in children and young adults with early onset and refractory hypertension, abdominal angina, and lower-limb claudication, that can lead to life-threatening complications associated with severe hypertension (i.e. myocardial infarction, heart failure, aortic rupture, renal insufficiency and intracranial hemorrhage). It may be due to various congenital or acquired causes, but it is most often secondary to an acquired inflammatory disease (i.e. Takayasu arteritis or giant cell arteritis).", "ORPHA ID": 1456, "Summary": ""}
{"Disease Name": "Middle ear neuroendocrine tumor", "Disease Definition": "Middle ear neuroendocrine tumor is a rare, otorhinolaryngologic tumor characterized by a mixed glandular and non-glandular histological features and positive immunostaining for pancytokeratin, vimentin, synaptophysin and islet-1 protein. Common signs and symptoms are hearing loss, mass, pain, discharge, equilibrium disturbances, tinnitus and nerve paralysis.", "ORPHA ID": 100084, "Summary": ""}
{"Disease Name": "Middle East respiratory syndrome", "Disease Definition": "A rare infectious disease caused by Middle East respiratory syndrome coronavirus (MERS‐CoV) and characterized by a spectrum of illness, ranging from mild upper respiratory symptoms to rapidly progressive lower respiratory infection/pneumonia potentially leading to acute respiratory distress syndrome (ARDS), multi-system organ failure, and death. Presenting signs and symptoms typically include fever, cough, shortness of breath, chills, dyspnea, myalgia, abdominal pain, nausea, vomiting, and diarrhea.", "ORPHA ID": 576074, "Summary": ""}
{"Disease Name": "Midline cervical cleft", "Disease Definition": "A rare neck malformation characterized by a congenital vertical atrophic and usually erythematous skin defect of variable length, lacking adnexal elements and located along the midline of the anterior neck. It typically presents with a superior skin tag, a midline subcutaneous fibrous cord which is often longer than the overlying skin defect, and an inferior blind sinus from which mucus can be expressed. The length of the defect increases with patients' age. Likewise, the fibrous cord becomes more prominent with age, potentially leading to restriction of neck extension if the malformation is left untreated. Other possible complications include microgenia, exostosis, torticollis, or infection.", "ORPHA ID": 141288, "Summary": ""}
{"Disease Name": "Midline interhemispheric variant of holoprosencephaly", "Disease Definition": "Midline interhemispheric variant of holoprosencephaly (MIH) or syntelencephaly is a form of holoprosencephaly (HPE; see this term) characterized by non-separation of the posterior frontal and parietal lobes, normally-formed callosal genu and splenium, absence of the callosal body, normally-separated hypothalamus and lentiform nucleus, and frequent heterotopic gray matter.", "ORPHA ID": 93926, "Summary": "Epidemiology\nAbout 2% to 15% of HPE patients have MIH type.\nClinical description\nPatients have rather mild dysmorphic facial features such as ocular hypotelorism, flat or narrow nasal bridge or a relatively normal facial appearance.\nEtiology\nMIH has mainly been reported in patients with ZIC2 (13q32) mutations.\nPrognosis\nPrognosis is better than in classical forms of HPE.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Sandra MERCIER  - Pr Sylvie ODENT"}
{"Disease Name": "Mietens syndrome", "Disease Definition": "Mietens syndrome is a very rare syndrome consisting of corneal opacity, nystagmus, strabismus, flexion contracture of the elbows with dislocation of the head of the radius and abnormally short ulnae and radii.", "ORPHA ID": 2557, "Summary": "Epidemiology\nTo date, only nine cases have been reported.\nClinical description\nOcular findings are striking. Dysmorphic features are not characteristic except for a small pinched nose and a depressed nasal root. Intellectual deficit and growth delay are observed in the majority of patients.\nGenetic counseling\nAn autosomal recessive pattern of inheritance is probable.\n\n                            Last update: \n                            July 2010"}
{"Disease Name": "Mikati-Najjar-Sahli syndrome", "Disease Definition": "Mikati-Najjar-Sahli syndrome is characterized by microcephaly, hypergonadotropic hypogonadism, short stature and facial dysmorphism (a narrow forehead, hypertrophy and fusion of the eyebrows, micrognathia and pinnae abnormalities).", "ORPHA ID": 2558, "Summary": "Epidemiology\nIt has been described in five siblings (three males and two females) born to consanguineous parents.\nClinical description\nAdditional congenital anomalies present in some of the patients included cubitus valgus and genu valgum. Early tooth loss was also reported.\nGenetic counseling\nThe mode of transmission appears to be autosomal recessive.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "Mild Canavan disease", "Disease Definition": "Mild Canavan disease (CD) is a neurodegenerative disorder characterized by mild speech delay or motor development.", "ORPHA ID": 314918, "Summary": "Epidemiology\nMild CD has been identified in only a few cases. The majority of patients with Canavan disease have the severe form (see this term). In contrast to the severe CD, most mild CD patients are not from Ashkenazi Jewish descent.\nClinical description\nMild CD usually presents in childhood with mild developmental delay or problems with speech or motor development. Head circumference is usually normal. Retinitis pigmentosa (see this term) may be present. .\nEtiology\nCD is caused by mutation in the ASPA gene (17p13.3), coding for the aspartoacylase enzyme. Mild CD is associated with heterozygous genotypes comprising a mild mutation and a severe one. Mild mutations include Y288C, R71H, P257R, I143T, and Y231C.\nDiagnostic methods\nThe brain MRI usually demonstrates an increased signal intensity in the basal ganglia and the urine level of N-acetyl-L-aspartic acid (NAA) is slightly elevated. Mutation screening can be performed for molecular diagnosis.\nPrognosis\nPrognosis is good and children often attend normal school but may need speech therapy or a tutor. Life expectancy is normal.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Kimberlee MATALON  - Dr Reuben MATALON"}
{"Disease Name": "Mild hemophilia A", "Disease Definition": "A mild form of hemophilia A characterized by a small deficiency of factor VIII (biological activity between 5 and 40 IU/dL) leading to abnormal bleeding as a result of minor injuries or following surgery or tooth extraction. Spontaneous hemorrhages do not occur. Patients may be also labeled as having mild hemophilia A if they have a FVIII >40 IU/dL and a DNA change in the F8 gene and one of the following: (i) a family member with the same DNA change and FVIII of <40 IU/dL, and the DNA change is found in <1% of the population; and (ii) the international databases list the DNA change as being associated with hemophilia A and <40 IU/dL FVIII. The condition may affect males and female carriers of disease-causing mutations.", "ORPHA ID": 169808, "Summary": ""}
{"Disease Name": "Mild hemophilia B", "Disease Definition": "A mild form of hemophilia B characterized by a small deficiency of factor IX (biological activity between 5 and 40 IU/dL) leading to abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction. Spontaneous hemorrhages do not occur. The condition may affect males and female carriers of disease-causing mutations.", "ORPHA ID": 169799, "Summary": ""}
{"Disease Name": "Mild hyperphenylalaninemia", "Disease Definition": "A rare form of phenylketonuria, an inborn error of amino acid metabolism, characterized by blood phenylalanine (Phe) concentrations of 120-600 micromol/L with or without clinical manifestations of impaired cognitive function, and behavioral and developmental disorders.", "ORPHA ID": 79651, "Summary": ""}
{"Disease Name": "Mild phenylketonuria", "Disease Definition": "A mild to moderate form of phenylketouria (PKU), an inborn error of amino acid metabolism, characterized by blood phenylalanine concentrations of 600-1,200 micromol/L and manifests with reduced cognitive function and behavioral and developmental disorders. Dietary phenylalanine tolerance is 400-600 mg/day.", "ORPHA ID": 79253, "Summary": ""}
{"Disease Name": "Mild phosphoribosylpyrophosphate synthetase superactivity", "Disease Definition": "A mild form of phosphoribosylpyrophosphate (PRPP) synthetase superactivity, an X-linked disorder of purine metabolism, characterized by adolescent or early adult-onset hyperuricemia and hyperuricosuria, leading to urolithiasis and gout.", "ORPHA ID": 411536, "Summary": "Epidemiology\nPRPP synthetase superactivity is a rare disorder with 30 families described in the literature. The mild form accounts for approximately 75% of cases. The disorder predominantly affects males.\nClinical description\nMild PRPP synthetase superactivity typically manifests in late adolescence or early adulthood, but may manifest earlier, with uric acid crystalluria and urinary stones (kidney and/or bladder), followed by the development of gouty arthritis and eventually renal failure as a result of obstructive uropathy from uric acid crystal deposition. This form is not associated with any neurodevelopmental anomalies.\nEtiology\nThe disease is due to overactivity of PRPP synthetase 1 (PRS-I), an enzyme that catalyzes the synthesis of PRPP, a cofactor involved in the synthesis of purine and pyrimidine nucleotides. PRS-I overactivity results in overproduction of purine nucleotides and uric acid (a waste product of purine breakdown). The exact molecular mechanism leading to the mild form is not yet well understood, but it seems to be linked to increased rates of transcription of the gene PRSP1 (Xq22.3) encoding PRS-I .\nDiagnostic methods\nDiagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by a PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes.\nDifferential diagnosis\nDifferential diagnosis includes other causes urinary stones and gout.\nAntenatal diagnosis\nPrenatal genetic testing in male fetuses may be possible if the mutation has been previously identified in the family.\nGenetic counseling\nAlthough no genetic mutation has been identified in this mild form, the pattern of inheritance is thought to be X-linked with complete penetrance in males. Females are not typically affected, but some females may show a mild clinical presentation.\nManagement and treatment\nHyperuricemia and hyperuricosuria are treated with: allopurinol or febuxostat to reduce uric acid formation and thus serum urate and urinary uric acid. A high daily fluid intake is recommended; and, as needed, potassium citrate to alkalinize the urine. Dietary recommendations include emphasis on low-fat dairy and complex carbohydrate-containing foods.\nPrognosis\nSevere gout can lead to renal impairment, if not properly treated.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Arjan DE BROUWER"}
{"Disease Name": "Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis", "Disease Definition": "Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis is a type 2 collagen-related bone disorder characterized by precocious, generalized osteoarthritis (with onset as early as childhood) and mild, dysplastic spinal changes (flattening of vertebrae, irregular endplates and wedge-shaped deformities) resulting in a mildly short trunk.", "ORPHA ID": 93279, "Summary": ""}
{"Disease Name": "Miller Fisher syndrome", "Disease Definition": "A rare acquired peripheral neuropathy characterized by acute ophthalmoplegia, ataxia, and areflexia, typically manifesting with diplopia and unsteady gait, and generalized areflexia.", "ORPHA ID": 98919, "Summary": "Epidemiology\nAnnual incidence is estimated at 1/333,333.\nClinical description\nMiller Fisher syndrome (MFS) is characterized by the clinical triad of acute onset of gait ataxia, areflexia, and ophthalmoplegia. Acute onset of external ophthalmoplegia is a cardinal feature of MFS. Facial and bulbar nerve palsies have also been reported.\nEtiology\nIn the majority of cases, MFS occurs following upper respiratory tract or gastrointestinal infections. Although the exact pathological mechanism is not fully understood, MFS is associated with the presence of antiganglioside antibodies (primarily, anti-GQ1b).\nDiagnostic methods\nDiagnosis is based on the clinical findings, patient history, cerebrospinal fluid (CSF) analysis (revealing raised protein levels), detection of anti-GQ1b IgG antibodies (not present in all patients), brain MRI studies are usually unremarkable, and electromyography is normal.\nDifferential diagnosis\nThe clinical picture in MFS shows clinical overlap with Bickerstaff brainstem encephalitis (BBE), which is also associated with raised titers of anti-GQ1b antibodies, leading to the suggestion that BBE and MFS represent variable manifestations of the same clinical spectrum.\nManagement and treatment\nIf the severity is high (inability to walk, or complete ophthalmoplegia), management is based on immunotherapy with intravenous immunoglobulin (IVIg) or plasma exchange. In mild cases, spontaneous recovery is expected.\nPrognosis\nMFS is generally self-limiting and patients recover within a few months, however, cases of progression to respiratory failure have been reported in MFS patients with features of both MFS and other forms of GBS (MFS/GBS overlap syndrome).\n\n                            Last update: \n                            November 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Satoshi KUWABARA"}
{"Disease Name": "Miller-Dieker syndrome", "Disease Definition": "Miller-Dieker Syndrome (MDS) is a contiguous gene deletion syndrome of chromosome 17p13.3, characterised by classical lissencephaly (lissencephaly type 1) and distinct facial features. Additional congenital malformations can be part of the condition.", "ORPHA ID": 531, "Summary": "Epidemiology\nMDS is undoubtedly a rare condition with a reported estimate of 1 cases per 100 000 live births, although incidence and prevalence are probably higher.\nClinical description\nChildren with MDS present with severe developmental delay, usually have epilepsy, and feeding problems are common. The lissencephaly represents the severe end of the spectrum with generalized agyria, or agyria and some frontal pachygyria.\nEtiology\nVisible and submicroscopic deletions of 17p13.3, including the LIS1 gene, are found in almost 100% of patients.\nManagement and treatment\nManagement of children with MDS is symptomatic. To avoid the complications of feeding and swallowing problems (poor nutritional state, aspiration pneumonia), nasogastric tubes and gastrostomies (a more long-term solution) can be utilised. Seizure control is important.\n\n                            Last update: \n                            April 2005\n\n\n                            - Expert reviewer(s): \n                            Pr Daniela PILZ"}
{"Disease Name": "Mills syndrome", "Disease Definition": "A rare, acquired motor neuron disease characterized by a slowly progressive, unilateral, ascending or descending hemiplegia, associated to unilateral or asymmetrical pyramidal signs and no sensory loss. It is a diagnosis of exclusion and controversy exists regarding whether the presence of bulbar symptoms, sphincter disturbances, fasciculations or cognitive manifestations characterize the disease.", "ORPHA ID": 94091, "Summary": ""}
{"Disease Name": "Milroy disease", "Disease Definition": "Milroy disease is a frequent form of primary lymphedema (see this term) characterized generally by painless, chronic lower-limb lymphedema found at birth or developing in the early neonatal period.", "ORPHA ID": 79452, "Summary": ""}
{"Disease Name": "Minimal pigment oculocutaneous albinism type 1", "Disease Definition": "An extremely rare form of Oculocutaneous albinism type 1 with minimal pigment present, characterized by blond hair (white at birth), variable iris transillumination (blue irides at birth followed by minimal development of pigment during the first decade of life), visual acuity ranging from 20/80-20/200 and white skin, with or without skin nevi.", "ORPHA ID": 352734, "Summary": ""}
{"Disease Name": "MIRAGE syndrome", "Disease Definition": "A rare genetic disease characterized by pre- and postnatal growth restriction, developmental delay, adrenal hypoplasia, genital abnormalities (such as microphallus, hypospadias, or cryptorchidism), thrombocytopenia and/or anemia, recurrent severe invasive infections, and enteropathy with chronic diarrhea. Myelodysplastic syndrome and dysmorphic features (including downslanting palpebral fissures, low-set and posteriorly rotated ears, anteverted nares, camptodactyly, and arachnodactyly, among others) may also be observed.", "ORPHA ID": 494433, "Summary": ""}
{"Disease Name": "Mirizzi syndrome", "Disease Definition": "A rare biliary tract disease characterized by external compression and subsequent obstruction of an extrahepatic biliary duct by one or more gallstones in the cystic duct or the gallbladder. Patients may present with acute or chronic cholecystitis with right upper abdominal pain, nausea, and vomiting, jaundice, or cholangitis. Cholecystobiliary or -enteric fistulae can arise due to chronic inflammation and ulceration.", "ORPHA ID": 521219, "Summary": ""}
{"Disease Name": "Mirror polydactyly-vertebral segmentation-limbs defects syndrome", "Disease Definition": "A rare disorder characterized by mirror polydactyly, vertebral hypersegmentation and severe congenital limb deficiencies. Duodenal atresia and absent thymus were also reported. So far, it has been described in four unrelated infants identified through a congenital malformation screening program carried out in Spain. The prevalence was estimated at around 1 in 330,000. The etiology is unknown but it was suggested that the syndrome is caused by defective expression of a developmental control gene.", "ORPHA ID": 3004, "Summary": ""}
{"Disease Name": "Mirror-image polydactyly", "Disease Definition": "A rare non-syndromic limb malformation characterized by a hand or foot with more than five digits that has a recognizable anterior/posterior axis of symmetry, either with a hallux- or thumb-like structure or an interdigital space in the middle. The most lateral digits on each side typically resemble fifth fingers or toes. The malformation may be unilateral or bilateral and may occur in isolation or in association with other congenital anomalies.", "ORPHA ID": 498494, "Summary": ""}
{"Disease Name": "MiT family translocation renal cell carcinoma", "Disease Definition": "MiT family translocation renal cell carcinoma (t-RCC) is a rare subtype of renal cell carcinoma with recurrent genetic abnormalities, harboring rearrangements of the TFE3 (Xp11 t-RCC) or TFEB [t(6;11) t-RCC] genes. The t(6;11) t-RCC has distinctive histologic features of biphasic appearance with larger epitheloid and smaller eosinophilic cells. The symptoms are usually non-specific and include hematuria, flank pain, palpable abdominal mass and/or systemic symptoms of anemia, fatigue and fever.", "ORPHA ID": 319308, "Summary": ""}
{"Disease Name": "MITF-related melanoma and renal cell carcinoma predisposition syndrome", "Disease Definition": "MITF-related melanoma and renal cell carcinoma predisposition syndrome is an inherited cancer-predisposing syndrome due to a gain-of-function germline mutation in the MITF gene, associated with a higher incidence of amelanotic and nodular melanoma, multiple primary melanomas and increase in nevus number and size. It may also predispose to co-occurring melanoma and renal cell carcinoma and to pancreatic cancer.", "ORPHA ID": 293822, "Summary": ""}
{"Disease Name": "Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria", "Disease Definition": "A rare mitochondrial DNA depletion syndrome characterized by neonatal or infantile onset of global developmental delay, hypotonia, failure to thrive, progressive neurologic decline, sensorineural deafness, and movement disorder. Seizures, external ophthalmoplegia, polyneuropathy, cardiomyopathy, and renal tubular dysfunction have also been reported. Brain imaging may show T2-weighted hyperintensities in the basal ganglia, and laboratory examination may reveal lactic acidosis and mild methylmalonic aciduria.", "ORPHA ID": 1933, "Summary": ""}
{"Disease Name": "Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy", "Disease Definition": "A rare mitochondrial DNA depletion syndrome characterized by neonatal or infantile onset of hypotonia, failure to thrive, global developmental delay, and persistent lactic acidosis. The disease course is variable and ranges from intractable diarrhea and respiratory failure with fatal outcome in early infancy to a milder phenotype with survival into childhood. Additional reported features include sensorineural hearing loss, microcephaly, seizures, pigmentary retinopathy, and renal tubulopathy.", "ORPHA ID": 255235, "Summary": ""}
{"Disease Name": "Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies", "Disease Definition": "A rare mitochondrial DNA depletion syndrome characterized by congenital or early-onset lactic acidosis, hypotonia, and severe global developmental delay with feeding difficulties and failure to thrive. It is frequently associated with variable dysmorphic facial features. Additional manifestations include seizures, movement disorders, and cardiac and ophthalmologic anomalies, among others. Brain imaging may show generalized atrophy and white matter abnormalities.", "ORPHA ID": 369897, "Summary": ""}
{"Disease Name": "Mitochondrial DNA depletion syndrome, encephalomyopathic form", "Disease Definition": "Mitochondrial DNA depletion syndrome, encephalomyopathic form is a group of mitochondrial DNA maintenance syndrome diseases characterized by predominantly neuromuscular manifestations with typically infantile onset of hypotonia, lactic acidosis, psychomotor delay, progressive hyperkinetic-dystonic movement disorders, external ophtalmoplegia, sensosineural hearing loss, generalized seizures and variable renal tubular dysfunction. It may be associated with a broad range of other clinical features.", "ORPHA ID": 254803, "Summary": ""}
{"Disease Name": "Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency", "Disease Definition": "A rare immune disease characterized by severely reduced mitochondrial DNA content due to DGUOK deficiency typically manifesting with early-onset liver dysfunction, psychomotor delay, hypotonia, rotary nystagmus that develops into opsoclonus, lactic acidosis and hypoglycemia.", "ORPHA ID": 279934, "Summary": "Epidemiology\nPrevalence of Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency (DGUOK-MDS) is unknown. However, more than 100 cases of MDS have been described, DGUOK deficiency being one of the most common causes of hepatocerebral form of mitochondrial DNA depletion syndromes.\nClinical description\nIn most cases, DGUOK-MDS presents as a multi-organ disease in the first week of life with hypoglycemia and lactic acidosis followed by development of hepatic and neuromuscular dysfunction within weeks of birth. Neuromuscular manifestations include hypotonia, psychomotor delay which progresses to developmental regression, typical rotary nystagmus developing into opsoclonus, and severe myopathy. Liver involvement includes jaundice, cholestasis (usually intrahepatic), hepatomegaly, and elevated serum transaminases, conjugated bilirubinemia and ferritin. Hepatic dysfunction frequently progresses to neonatal- or infantile-onset liver failure with coagulopathy, ascites, and edema. In a minority of cases, patients initially present isolated liver disease (with onset in infancy or early childhood). Development of mild hypotonia and renal involvement in these latter patients may be observed.\nEtiology\nDGUOK-MDS results from mitochondrial DNA depletion resulting from biallelic mutations in the DGUOK (2p13.1) gene, which codes for mitochondrial deoxyguanosine kinase involved in the mitochondrial nucleotide synthesis. The mitochondrial DNA deletion leads to insufficient production of key subunits of mitochondrial respiratory chain complexes causing insufient energy production. The reasons for tissue-specific clinical expression of the disease are not yet understood.\nDiagnostic methods\nDiagnosis is suggested by the clinicopathological correlation of hepatoencephalopathic signs and symptoms with the finding of reduced mitochondrial DNA copy numbers in liver or muscle (typically >20% of control in liver). It is confirmed by the presence of biallelic pathogenic mutations in the DGUOK gene. Elevated serum concentration of tyrosine or phenylalanine on newborn screening is suggestive of the disease and should prompt further examination. Respiratory chain enzyme assays in liver reveal a combined deficiency of complex I, III, and IV. Liver histology typically shows microvesicular cholestasis while electron microscopy usually reveals increased number of mitochondria with abnormal cristae.\nDifferential diagnosis\nDifferential diagnosis includes the other hepatocerebral mitochondrial depletion syndromes, namely due to mutations in the POLG, MPV17 or TWNK genes.\nAntenatal diagnosis\nPrenatal testing is possible if pathogenic variants have been previously identified in the family.\nGenetic counseling\nDGUOK-MDS is inherited in an autosomal recessive manner. Parents of an affected child should be informed of the 25% risk of disease recurrence among future offspring.\nManagement and treatment\nTreatment is mostly directed towards providing symptomatic management, as currently no efficacious treatment exists. Diet modulation (e.g. fractional meals, nocturnal enteric nutrition, uncooked cornstarch and formulas with enriched medium-chain triglyceride content), as well as cofactor supplementation, may be beneficial. Liver transplantation is usually reserved for patients with isolated liver disease, as in patients with multi-organ involvement transplantation provides no survival benefit.\nPrognosis\nPrognosis is generally poor. Vital prognosis is typically engaged before four years of age.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Ayman EL-HATTAB"}
{"Disease Name": "Mitochondrial DNA depletion syndrome, hepatocerebrorenal form", "Disease Definition": "A rare, genetic, mitochondrial DNA depletion syndrome characterized by neonatal or early-infantile onset hepatopathy (manifesting with hepatomegaly, cholestasis, increased transaminases, coagulopathy, hypoalbuminemia, ascites, and/or liver failure), associated with renal tubulopathy and progressive neurodegenerative manifestations, which include muscular atrophy, hyporeflexia, ataxia, sensory neuropathy, epilepsy, sensorineural hearing impairment, psychomotor regression, athetosis, nystagmus, and/or ophthalmoplegia. Patients typically present with recurrent vomiting, severe failure to thrive, feeding difficulties, and fasting hypoglycemia.", "ORPHA ID": 363534, "Summary": ""}
{"Disease Name": "Mitochondrial DNA depletion syndrome, myopathic form", "Disease Definition": "A rare mitochondrial DNA depletion syndrome characterized by muscle weakness, and progressive, generalized hypotonia due to depletion of mtDNA in skeletal muscles. Clinical progression ranges from rapid and early fatal course due to respiratory failure, to slowly progressive myopathy over the course of childhood or even early adulthood.", "ORPHA ID": 254875, "Summary": ""}
{"Disease Name": "Mitochondrial DNA depletion syndrome", "Disease Definition": "A clinically heterogeneous group of mitochondrial disorders characterized by a reduction of the mitochondrial DNA copy number in affected tissues without mutations or rearrangements in the mitochondrial DNA. It is phenotypically heterogeneous, and can affect a specific organ or a combination of organs, with the main presentations described being either hepatocerebral (i.e. hepatic dysfunction, psychomotor delay), myopathic (i.e. hypotonia, muscle weakness, bulbar weakness), encephalomyopathic (i.e. hypotonia, muscle weakness, psychomotor delay) or neurogastrointestinal (i.e gastrointestinal dysmotility, peripheral neuropathy). Additional phenotypes include fatal infantile lactic acidosis with methylmalonic aciduria, spastic ataxia (early-onset spastic ataxia-neuropathy syndrome), and Alpers syndrome.", "ORPHA ID": 35698, "Summary": ""}
{"Disease Name": "Mitochondrial DNA-associated Leigh syndrome", "Disease Definition": "Maternally inherited Leigh syndrome is a rare subtype of Leigh syndrome (see this term) characterized clinically by encephalopathy, lactic acidosis, seizures, cardiomyopathy, respiratory disorders and developmental delay, with onset in infancy or early childhood, and resulting from maternally-inherited mutations in mitochondrial DNA.", "ORPHA ID": 255210, "Summary": ""}
{"Disease Name": "Mitochondrial DNA-related cardiomyopathy and hearing loss", "Disease Definition": "A rare mitochondrial disease that has a heterogeneous clinical presentation characterized by the association of progressive sensorineural hearing loss with hypertrophic cardiomyopathy and, in the majority of cases, encephalomyopathy symptoms such as ataxia, slurred speech, progressive external opthalmoparesis (PEO), muscle weakness, myalgia, and exercise intolerance.", "ORPHA ID": 1349, "Summary": ""}
{"Disease Name": "Mitochondrial DNA-related dystonia", "Disease Definition": "Maternally-inherited mitochondrial dystonia is a rare neurological mitochondrial DNA-related disorder characterized clinically by progressive pediatric-onset dystonia with variable degrees of severity.", "ORPHA ID": 254851, "Summary": ""}
{"Disease Name": "Mitochondrial DNA-related mitochondrial myopathy", "Disease Definition": "A group of rare mitochondrial oxidative phosphorylation disorders due to mitochondrial DNA anomalies characterized by progressive, most commonly proximal, myopathy with variable degrees of weakness, exercise-induced muscle pain, and fatigue. Progressive external ophthalmoplegia is often observed. Additional features include neurological signs and symptoms (such as seizures, stroke-like episodes, or developmental delay), cardiomyopathy, involvement of liver, kidneys, and gastrointestinal tract, and diabetes. Lactic acidosis is frequently present, while recurrent rhabdomyolysis and myoglobinuria are rare. Muscle biopsy may reveal the presence of ragged-red fibers and a mosaic pattern of cytochrome c oxidase-negative fibers.", "ORPHA ID": 254788, "Summary": ""}
{"Disease Name": "Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder with complex I and IV deficiency characterized by lactic acidosis, hypotonia, hypertrophic cardiomyopathy and global developmental delay. Other clinical features include feeding difficulties, failure to thrive, seizures, optic atrophy and ataxia.", "ORPHA ID": 314637, "Summary": ""}
{"Disease Name": "Mitochondrial membrane protein-associated neurodegeneration", "Disease Definition": "A rare neurodegenerative disorder characterized by iron accumulation in specific regions of the brain, usually the basal ganglia, and associated with slowly progressive pyramidal (spasticity) and extrapyramidal (dystonia) signs, motor axonal neuropathy, optic atrophy, cognitive decline, and neuropsychiatric abnormalities.", "ORPHA ID": 289560, "Summary": "Epidemiology\nMitochondrial membrane protein-associated neurodegeneration (MPAN) is an extremely rare disease with an estimated worldwide prevalence of about 1/1,000,000. MPAN accounts for approximately 6-10% of cases neurodegeneration with brain iron accumulation (NBIA) cases, with less than 80 cases reported to date.\nClinical description\nMPAN usually manifests during childhood (mean age: 10 years), but cases during adolescence or adulthood have been reported too. It presents with gait difficulty, dysarthria and bilateral optic atrophy. Early upper motor neuron signs (pyramidal signs, e.g. spasticity) are constant findings and are later followed by signs of lower motor neuron dysfunction (deep tendon reflex loss, muscular weakness and atrophy). Progressive dystonia, parkinsonism, cognitive decline, and neuropsychiatric symptoms are present in more than half of the patients. Weight loss and bowel and/or bladder dysfunction are common.\nEtiology\nMPAN is caused by mutations in the chromosome 19 open reading frame 12 gene (C19orf12 ; 19q13.11). A founder mutation (c.204_214del11 (p.Gly69ArgfsX10)) has been described in Eastern Europe. The function of C19orf12 remains uncertain, but it may be involved in mitochondrial function, lipid homeostasis and coenzyme A metabolism.\nDiagnostic methods\nDiagnosis is based on neuroimaging that shows evidence of iron deposits mainly in the globus pallidus and substantia nigra, often with unique T2-hyperintense streaking between the hypointense internal globus pallidus and external globus pallidus. Ophthalmologic examinations and evoked visual potentials are important to identify optic atrophy. Neuropathologic examination shows axonal spheroids, Lewy bodies and hyperphosphorylated tau-containing inclusions. Mutation analysis of the C19orf12 gene confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other NBIAs, more particularly fatty acid hydroxylase-associated neurodegeneration and PLA2G6-associated neurodegeneration. Spasticity, more prominent than dystonia, optic atrophy, motor neuropathy, and a slowly progressive course with cognitive decline help to differentiate MPAN from the other NBIAs.\nAntenatal diagnosis\nPrenatal diagnosis may be available for families in which disease-causing mutations have been identified in a previous affected sib.\nGenetic counseling\nMPAN is an autosomal recessive disorder. It is more common in consanguineous families or families of the same origin (i.e. both parents from the same small town). Parents of a patient with MPAN are obligate carriers. The risk of having an affected child in further pregnancies is of 25%.\nManagement and treatment\nThere is currently no curative treatment. Management strategies focus on the medical and surgical palliation of symptoms. Follow-up by a multidisciplinary team formed by neurologists, geneticists, ophthalmologists, physiotherapists, occupational therapists, speech and language therapists, orthopedic surgeons, and neurosurgeons is essential.\nPrognosis\nThe progression of MPAN is usually slow and may lead to loss of independent ambulation due to spasticity, dystonia and parkinsonism; limited communication due to dysarthria and cognitive decline; and severe dementia. Life expectancy is variable. Premature death may occur due to secondary complications such as aspiration pneumonia.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen ESPINÓS"}
{"Disease Name": "Mitochondrial myopathy and sideroblastic anemia", "Disease Definition": "Mitochondrial myopathy and sideroblastic anemia belongs to the heterogeneous family of metabolic myopathies. It is characterised by progressive exercise intolerance manifesting in childhood, onset of sideroblastic anaemia around adolescence, lactic acidaemia, and mitochondrial myopathy.", "ORPHA ID": 2598, "Summary": "Epidemiology\nLess than 10 cases have been described so far.\nEtiology\nA 656C-->T mutation in the nuclear pseudouridine synthase 1 gene (PUS1), localised to 12q24.33, has recently been identified in some patients. Deficient pseudouridylation of mitochondrial tRNAs may be responsible for the oxidative phosphorylation disorder.\nDiagnostic methods\nMuscle biopsy demonstrates low activity of complexes 1 and 4 of the respiratory chain and paracrystalline inclusions can be revealed in most mitochondria by electron microscopy.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            June 2006"}
{"Disease Name": "Mitochondrial myopathy with reversible cytochrome C oxidase deficiency", "Disease Definition": "A rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by a potentially life-threatening, severe myopathy manifesting in the neonatal to early infantile period, followed by marked, spontaneous improvement of muscular function by early childhood. Associated biochemical findings include lactic acidosis and a transient, marked decrease in respiratory chain activity.", "ORPHA ID": 254864, "Summary": ""}
{"Disease Name": "Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome", "Disease Definition": "A rare mitochondrial myopathy characterized by motor developmental delay (in infancy), growth impairment and mostly proximal muscle weakness caused by a muscular dystrophy. Muscle biopsy presents myopathic abnormalities and decreased mtDNA content. Electromyography (EMG) shows a myopathic process and serum creatine kinase is increased. The disease is also characterized by early onset non-progressive cerebellar atrophy (particularly cerebellar vermis and hemispheres), corticospinal tract dysfunction, and global or partial cerebral atrophy on brain MRI. Additionally, some patients presented with cognitive deficiencies, skeletal abnormalities, tremors, and retinopathy.", "ORPHA ID": 502423, "Summary": "Epidemiology\nApproximately 30 cases have been reported worldwide.\nClinical description\nOnset generally occurs in newborns, children or adolescents. First symptoms are often observed during the postnatal period: ataxia (secondary to cerebellar atrophy) and proximal muscle weakness. The condition of patients progressively deteriorates during childhood with delayed motor (delayed walking between 2 and 8 years old) and cognitive development. Although cognitive capacities might be normal, most of the children present learning difficulties and intellectual disabilities. In early adolescence, patients show decreased height and weight compared to the average, with an inability to perform complex motor movements. Other symptoms include dysmetria, tremor, dysarthria, adiadochokinesia, and skeletal abnormalities. Pigmentary retinopathy is rarely reported. In patients carrying a dominant mutation, these clinical signs appear later (late adolescence or adulthood).\nEtiology\nThe disease is caused by biallelic mutations in the MSTO1 gene located on chromosome 1q22 with autosomal recessive inheritance. Only one family was described with an apparently autosomal dominant inheritance (mutation c.22 G > A p.Val8Met). MSTO1 encodes for a mitochondrial fusion protein, localized in the cytoplasm and on the outer membrane of the mitochondria. The mutation inactivates the protein leading to a fragmented mitochondrial network.\nDiagnostic methods\nDiagnosis relies primarily on clinical presentation of cerebellar ataxia and mitochondrial myopathy. MRI shows hypotrophy or damage to the cerebellum. Electromyography confirms the muscular involvement. Muscle biopsies show marked variation in fiber size, with severe atrophy of type I fibers and decreased mtDNA content. Levels of the biomarker creatine kinase, fibroblast growth factor 21 or growth/differentiation factor-15 are increased. Despite the mitochondrial origin, diagnostic criteria based on oxygen consumption or respiratory chain complex activities are not informative for these patients. Cognitive capacities tests support the diagnosis. Sequencing of the MSTO1 gene confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses include Marinesco-Sjögren syndrome, alpha-dystroglycanopathies, Kearns-Sayre syndrome, mitochondrial myopathies, neurogenic muscle weakness-ataxia-retinitis pigmentosa (NARP) syndrome, some hereditary spastic paraplegia (AP5Z1 gene mutations), Leigh syndrome, PMM2-congenital glycosylation disorder, and Pelizaeus-Merzbacher-like 1 disease.\nAntenatal diagnosis\nPrenatal diagnosis is possible when MSTO1 variants have been previously identified in the family.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples informing them of the 25% risk of having an affected child at each pregnancy. In a very few cases, the pattern of inheritance is autosomal dominant. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nNo curative treatments have been identified. Physiotherapy remains the best long-term management for patients.\nPrognosis\nCerebellar atrophy progresses during childhood and stabilizes in early adolescence. After adolescence, the condition appears to stabilize. Above 50 years of age, prognostic data is limited.\n\n                            Last update: \n                            December 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Alessandra FERLINI  - Dr Marcella NERI"}
{"Disease Name": "Mitochondrial myopathy-lactic acidosis-deafness syndrome", "Disease Definition": "A rare metabolic myopathy presenting during childhood, and characterized clinically by growth failure, severe muscle weakness, and moderate sensorineural deafness and biochemically by metabolic acidosis, elevated serum pyruvate concentration, hyperalaninemia and hyperalaninuria. There have been no further descriptions in the literature since 1973.", "ORPHA ID": 2597, "Summary": ""}
{"Disease Name": "Mitochondrial neurogastrointestinal encephalomyopathy", "Disease Definition": "Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE) syndrome is characterized by the association of gastrointestinal dysmotility, peripheral neuropathy, chronic progressive external ophthalmoplegia and leukoencephalopathy.", "ORPHA ID": 298, "Summary": "Epidemiology\nSo far, just under 100 sporadic and familial cases have been reported.\nClinical description\nThe first clinical manifestations generally appear between the ages of 10 and 40 (most often before 20 years of age). The symptoms are progressive and the clinical picture is dominated by severe gastrointestinal disorders (cramping, vomiting, diarrhea, intestinal pseudo-obstruction, dysphagia and gastroparesis) due to abnormal bowel motility. Gastrointestinal disorders gradually progress to chronic pseudo-obstruction leading to cachexia. Neurological involvement includes chronic progressive ophthalmoplegia with or without ptosis, and sensorimotor peripheral neuropathy. Cerebral imaging often reveals subclinical leukodystrophy. Deafness, pigmentary retinopathy, and cerebellar involvement are less frequent findings and are not defining features of the syndrome. Patients are usually thin with short stature. Morphological studies of the muscles reveal the presence of a low proportion of muscle fibers with mitochondrial proliferation (ragged-red fibers) or cytochrome c oxidase deficiency.\nEtiology\nMNGIE syndrome is inherited in an autosomal recessive manner and is caused by mutations in the TYMP gene (22q13.32-qter), encoding a protein involved in thymidine phosphorylation. These mutations lead to total abolition of enzyme activity, thymidine and deoxyuridine accumulation in body fluids and tissues, and imbalanced mitochondrial DNA replication and repair leading to multiple deletions and sometimes partial depletion.\nDiagnostic methods\nDiagnosis is based on measurement of thymidine phosphorylase activity in leukocytes (absence of activity in symptomatic individuals and reduced activity in asymptomatic heterozygous individuals), and on genetic analysis.\nDifferential diagnosis\nDifferential diagnoses include similar disorders with phenotypes that overlap between MNGIE and MELAS, MERRF or progressive external ophthalmoplegia (PEO; see these terms), for example patients with prominent gastrointestinal symptoms and genetic alterations either in the mitochondrial DNA (such as the MT-TL1 or MT-TK genes with the m.3243A>G ``MELAS'' mutation or the m.8313G>A ``MERRF'' mutation) or in the nuclear POLG gene encoding DNA polymerase gamma (responsible for mitochondrial DNA replication and implicated in PEO).\nManagement and treatment\nManagement is mainly symptomatic, involving treatment of the chronic intestinal pseudo-obstruction. Thymidine and deoxyguanosine clearance appears to be an efficient approach. However, hemodialysis is not an effective treatment due to the rapid re-accumulation of compounds between sessions. Bone marrow transplantation has been performed on a few patients with promising results (stabilization of the disease course).\nPrognosis\nThe prognosis is unfavorable due to the severity of the digestive involvement with infections and the need for permanent parenteral nutrition.\n\n                            Last update: \n                            November 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Anne LOMBES"}
{"Disease Name": "Mitochondrial oxidative phosphorylation disorder due to nuclear DNA anomalies", "Disease Definition": "A group of clinically heterogeneous diseases, commonly defined by lack of cellular energy due to defects of oxidative phosphorylation (OXPHOS), resulting from pathogenic mutations in the nuclear DNA. Mitochondrial oxidative phosphorylation disorder due to nuclear DNA anomalies includes diseases classified according to defects in: genes encoding structural components of OXPHOS complexes (such as Leigh syndrome, coenzyme Q10 deficiency); genes encoding assembly factors of OXPHOS complexes (such as GRACILE syndrome); genes altering the stability of mitochondrial DNA (such as autosomal dominant progressive external ophthalmoplegia, mitochondrial DNA depletion syndrome); mitochondrial protein synthesis.", "ORPHA ID": 2443, "Summary": ""}
{"Disease Name": "Mitochondrial pyruvate carrier deficiency", "Disease Definition": "A rare pyruvate metabolism disorder characterized by neonatal onset of a mitochondrial encephalopathy with global developmental delay and the biochemical characteristics of lactic acidosis and increased serum pyruvate with normal lactate/pyruvate ratio. Additional reported manifestations include epilepsy, peripheral neuropathy, hypotonia, nystagmus, extensor plantar responses, hepatomegaly, and craniofacial dysmorphism (such as progressive microcephaly, epicanthus, long philtrum, and thin upper lip).", "ORPHA ID": 447784, "Summary": ""}
{"Disease Name": "Mitochondrial trifunctional protein deficiency", "Disease Definition": "A rare disorder of fatty acid oxidation characterized by a wide clinical spectrum ranging from severe neonatal manifestations including cardiomyopathy, hypoglycemia, metabolic acidosis, skeletal myopathy and neuropathy, liver disease and death to a mild phenotype with peripheral polyneuropathy, episodic rhabdomyolysis and pigmentary retinopathy..", "ORPHA ID": 746, "Summary": "Epidemiology\nTFPD has been reported in less than 100 cases in the literature.\nClinical description\nThe neonatal onset, severe form manifests as hepatic steatosis, cardiomyopathy, skeletal myopathy and neuropathy and is usually fatal. A moderately severe form, with onset usually from the neonatal period to 18 months of age, presents primarily with hypoketotic hypoglycemia and metabolic acidosis which is often precipitated by prolonged fasting and/or intercurrent illness. Both forms can manifest with neuropathy with or without cardiomyopathy and can be fatal. The mild form merges with the moderately severe infantile form and can present from a few months of age until adolescence as a peripheral polyneuropathy with episodic rhabdomyolysis triggered by prolonged fasting, illness, exercise or exposure to heat or cold. There is respiratory failure associated with the episodes of rhabdomyolysis. A pigmentary retinopathy may also develop over time. Very occasionally, adults presenting for the first time with a previously unrecognized disease are described.\nEtiology\nThe TFP, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids which are the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase (LCEH), and long-chain thiolase (LCTH) steps. The HADHA gene (2p23) encodes the LCEH and LCHAD enzymes and the HADHB gene (2p23) encodes the LCTH enzyme. Two mutations in either one of these two genes causes TFPD.\nDiagnostic methods\nUrine organic acids may show a C6-C14 (hydroxy) dicarboxylic aciduria, and blood acylcarnitine analysis often shows increased long chain hydroxyacyl carnitine species (C14-OH, C16-OH, C18-OH, C18:1-OH). Both urine and blood markers are less reliable and more variable than those seen in LCHAD deficiency (see this term). This is because defects in LCEH may block the formation of hydroxy-metabolites. Reduced enzyme activity in at least two (usually all 3) enzymes in cultured fibroblasts is seen. Molecular analysis confirming bi-allelic non-1528C>G mutations in the HADHA gene or bi-allelic mutations in the HADHBgene confirms diagnosis. Newborn screening is available in Austria, Czech Republic, Denmark, Germany, Hungary, Iceland, Netherlands and Portugal.\nDifferential diagnosis\nSudden infant death syndrome and isolated LCHAD deficiency (see this term) form part of the differential diagnosis. LCHAD deficiency is clinically indistinguishable from severe TFPD.\nAntenatal diagnosis\nPrenatal diagnosis is possible by analyzing enzyme activity in chorionic villi samples, once a deficiency of TFP has been established in the index case/family. Molecular analysis is the preferred option when two mutations have been identified in a family.\nGenetic counseling\nTFPD is an autosomal recessive disorder and genetic counseling is possible.\nManagement and treatment\nTreatment involves adherence to a low fat diet with restriction of long chain fatty acid intake and substitution with medium chain fatty acids. Fasting and exposure to environmental extremes must be strictly avoided and exercise should be limited.\nPrognosis\nPrognosis for the severe neonatal form of TFPD is very poor. The later onset mild form has a far more favorable prognosis.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Simon OLPIN"}
{"Disease Name": "Mitral atresia", "Disease Definition": "A rare congenital non-syndromic heart malformation characterized by an imperforate or absent mitral valve. In most cases, there is a univentricular atrioventricular connection to a dominant right ventricle via a tricuspid valve, and a hypoplastic left ventricle. Morphologic heterogeneity is considerable, and hemodynamic picture and clinical manifestation depend on the type and severity of associated cardiovascular anomalies (such as ventricular septal defect or aortic atresia).", "ORPHA ID": 1205, "Summary": ""}
{"Disease Name": "Mitral valve agenesis", "Disease Definition": "Mitral valve agenesis is a rare congenital heart malformation defined as an agenesis or severe hypoplasia of both mitral valve leaflets (complete agenesis) or one of the leaflets (partial agenesis). Complete mitral valve agenesis presents in the neonatal period with symptoms of severe mitral regurgitation and is rapidly fatal unless surgically treated. It is frequently associated with other heart malformations. Partial mitral valve agenesis may present at various ages, usually with symptoms of mitral regurgitation.", "ORPHA ID": 99062, "Summary": ""}
{"Disease Name": "Mixed autoinflammatory and autoimmune syndrome", "Disease Definition": "A group of systemic diseases characterized by mixed patterns of dysregulated innate and/or adaptive immune responses, leading to chronic activation of the immune system and tissue inflammation, which presents clincally with a wide range of variable, concomitant, autoimmune and autoinflammatory manifestations in various organ systems.", "ORPHA ID": 324933, "Summary": ""}
{"Disease Name": "Mixed connective tissue disease", "Disease Definition": "Mixed connective tissue disease (MCTD) is a rare connective tissue disorder combining clinical features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM) (see these terms) and/or rheumatoid arthritis (RA).", "ORPHA ID": 809, "Summary": "Epidemiology\nThe exact prevalence of MCTD is unknown, except in Japan where it is estimated at 1/37,000. MCTD is found in all ethnic groups with a female-to-male ratio of approximately 10:1.\nClinical description\nOnset usually occurs between 15 and 35 years old. Common clinical signs include Raynaud's phenomenon (see this term), arthralgia/arthritis, swollen hands/puffy fingers, sclerodactyly, and myositis. Some patients may also complain of esophageal hypomotility, lupus-like or dermatomyositis-like rashes, trigeminal neuralgia, pleuritis, pericarditis and/or pulmonary hypertension. Nonspecific constitutional symptoms such as fatigue, general malaise or low-grade fever (which should always prompt a careful search for infection) can also be observed during flares.\nEtiology\nThe exact cause of MCTD is still unknown, but abnormal B- and T-cell immune responses against apoptotically modified self-antigens may be observed in MCTD patients.\nDiagnostic methods\nMost patients have high titers (often >1:1000) of anti-U1-ribonucleoprotein (RNP) and anti-U1-70 kd autoantibodies. The diagnosis of MCTD relies on overlapping features of SLE, SSc, PM, or RA (or when additional overlapping features are present in patients with a well-defined connective tissue disease) and on blood test results indicating high titers of anti-U1-RNP antibodies with normal titers of other connective tissue disease antibodies (except anti-SSA and/or anti-SSB antibodies in cases with secondary Sjögren syndrome; see this term).\nDifferential diagnosis\nDifferential diagnoses include other connective tissue diseases such as SLE, SSc, PM and/or RA, and other systemic diseases such as sarcoidosis, periarteritis nodosa, or Still's disease (see these terms).\nManagement and treatment\nManagement of MCTD is similar to that of the various overlapping connective tissue diseases. NSAIDs, antimalarials, or low-dose corticosteroids are effective for the minor or mild disease while corticosteroids (approximately 0.5-1mg/kg/day) are effective for moderate to severe disease. Higher doses of corticosteroids and additional immunosuppressants may be administered in case of severe visceral involvement. Symptomatic treatment (eg: treatment of Raynaud's phenomenon) is also of major importance.\nPrognosis\nMCTD is a chronic relapsing-remitting disease. The overall 10-year survival rate of the disease is approximately 80%. In general, the prognosis is favorable but it is largely dependent on which visceral manifestations of MCTD predominate. Patients with features of SSc or PM are thought to have the worst prognosis, and pulmonary hypertension has been recognized as the most frequent disease-associated cause of death.\n\n                            Last update: \n                            October 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Zahir AMOURA  - Pr Laurent ARNAUD"}
{"Disease Name": "Mixed cryoglobulinemia type II", "Disease Definition": "A clinico-serological subtype of mixed cryoglobulinemia syndrome, an immune complex disorder, characterized by purpura, weakness and arthralgia and defined immunochemically by cryoglobulins composed of polyclonal IgGs (autoantigens) and monoclonal IgM (autoantibody).", "ORPHA ID": 93554, "Summary": ""}
{"Disease Name": "Mixed cryoglobulinemia type III", "Disease Definition": "A clinico-serological subtype of mixed cryoglobulinemia syndrome, is an immune complex disorder, characterized by purpura, weakness and arthralgia and defined immunochemically by cryoglobulins containing both polyclonal IgGs and polyclonal IgMs.", "ORPHA ID": 93555, "Summary": ""}
{"Disease Name": "Mixed cystic lymphatic malformation", "Disease Definition": "A rare common cystic lymphatic malformation characterized by a benign cystic lesion composed of dilated lymphatic channels. Mixed cystic lesions consist of cysts both larger (macrocystic) and smaller (microcystic) than 1 cm in diameter. They usually present at birth or during the first years of life and most often occur in the head and neck region but may affect any site. Symptoms depend on the location and extent of the lesion. Infection, trauma, or intracystic hemorrhage can lead to lesional expansion. Malignant transformation does not occur.", "ORPHA ID": 458792, "Summary": ""}
{"Disease Name": "Mixed germ cell tumor", "Disease Definition": "A rare germ cell tumor characterized by composition of two or more malignant germ cell components, the most common combination being dysgerminoma and yolk sac tumor. The tumors typically occur between childhood and young adulthood. They are usually located in the gonads, occasionally also in other regions. Clinical presentation corresponds to the individual germ cell components and the tumor location; manifestations may include abdominal pain, abdominal mass, and menstrual disorder in females, and a testicular mass in males. The most important prognostic factor is tumor stage.", "ORPHA ID": 180234, "Summary": ""}
{"Disease Name": "Mixed neuroendocrine and non-neuroendocrine neoplasm of pancreas", "Disease Definition": "A rare neuroendocrine neoplasm of pancreas characterized by morphologically recognizable neuroendocrine and non-neuroendocrine components, each constituting at least 30% of the tumor volume. Based on histopathology, mixed ductal- and mixed acinar-neuroendocrine carcinomas are distinguished. Patients usually present with unspecific symptoms related to tumor growth and/or metastasis, although occurrence of Zollinger-Ellison syndrome has been reported. Resectability of the tumor is the most important prognostic factor.", "ORPHA ID": 506112, "Summary": ""}
{"Disease Name": "Mixed phenotype acute leukemia", "Disease Definition": "A group of rare acute leukemias of ambiguous lineage characterized by the presence of separate populations of blasts of more than one lineage (bilineal), a single population of blasts coexpressing antigens of more than one lineage (biphenotypic), or a combination thereof. The diagnosis relies on immunophenotyping, the T-cell component being characterized by strong expression of cytoplasmic CD3, usually in the absence of surface CD3, the B-cell component expressing CD19, almost always together with CD10, cCD79a, CD22, or PAX5, while the most specific hallmark of the myeloid component is the presence of myeloperoxidase in the blast cytoplasm.", "ORPHA ID": 530995, "Summary": ""}
{"Disease Name": "Mixed sclerosing bone dystrophy with extra-skeletal manifestations", "Disease Definition": "A rare, genetic, primary bone dysplasia with increased bone density disorder characterized by bone abnormalities, including metaphyseal plaques, osteopathia striata, marked cranial sclerosis, and sclerosis of the ribs and long bones, as well as macrocephaly, cleft palate, hearing loss, developmental delay, and facial dysmorphism (hypertelorism, prominent forehead, wide nasal bridge). Hypotonia, tracheo-/laryngomalacia, and astigmatic myopia are also associated.", "ORPHA ID": 324364, "Summary": ""}
{"Disease Name": "Mixed-type autoimmune hemolytic anemia", "Disease Definition": "Mixed autoimmune hemolytic anemia is a type of autoimmune hemolytic anemia (AIHA; see this term) defined by the presence of both warm and cold autoantibodies, which have a deleterious effect on red blood cells at either body temperature or at lower temperatures.", "ORPHA ID": 90036, "Summary": "Epidemiology\nMixed AIHA occurs in less than 10% of cases of AIHA, whose annual incidence is between 1/35,000-1/80,000 in North America and Western Europe.\nClinical description\nMixed AIHA can occur at any age but is rare in children. Patients with mixed AIHA usually present with abrupt onset severe hemolysis and anemia.\nEtiology\nMixed AIHA can be idiopathic or secondary, mainly associated with systemic lupus erythematosus (SLE) and lymphoma.\nDiagnostic methods\nDiagnosis is based on clinical or laboratory evidence of hemolytic anemia and the detection of autoantibodies, usually both IgG and IgM, with the direct anti-globulin test (DAT) showing a pattern of IgG with complement C3, and the presence of cold agglutinins (IgM) in the serum at a significant titer.\nDifferential diagnosis\nErroneous diagnosis of mixed AIHA is sometimes made on the basis of inadequate serologic studies as a large proportion of patients with warm AIHA also have cold autoantibodies that are measured but are clinically insignificant. Unless a cold autoantibody with a high thermal amplitude (>30 degrees C) is observed in association with a warm autoantibody, a diagnosis of mixed AIHA is not warranted.\nManagement and treatment\nThe principles of management are comparable to that of warm AIHA (see this term), including corticosteroids and, if these are ineffective, splenectomy, but avoidance of cold must also be considered. Cautious transfusion is possible in cases with severe anemia. However, the best compatible or ``least incompatible'' packed red blood cell units must be identified by the blood centre to avoid post-transfusional hemolysis.\nPrognosis\nThe disease responds to corticosteroids, and may be followed by remission, but usually runs a chronic course with intermittent exacerbations.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Marc MICHEL"}
{"Disease Name": "Miyoshi myopathy", "Disease Definition": "A recessive distal myopathy characterized by weakness in the distal lower extremity posterior compartment (gastrocnemius and soleus muscles) and associated with difficulties in standing on tip toes.", "ORPHA ID": 45448, "Summary": "Epidemiology\nMiyoshi myopathy (MM) is the most common form of recessive distal myopathy in populations with founder mutations such as Libyan and Israeli Jewish population, Italian and Spanish populations.\nClinical description\nThe typical age of onset of MM lies between 15 and 30 years (median 19 years) and the disease is characterized by muscle atrophy usually symmetric especially of the calf muscles (soleus and gastrocnemius). Onset in the anterior tibial muscles has been rarely reported. Ankle muscle stretch reflexes are lost and difficulties for toe walking or climbing stairs are encountered. Exercise-induced myalgia and aching discomfort in the calves can be an early symptom. Anterior compartment muscles of the distal lower extremities eventually become weak as well. As the disease progresses, patients will develop proximal leg and arm weakness to varying degrees. Decrease in respiratory functions have been reported only in few patients with moderate to severe disease. Bulbar or symptoms have not been reported.\nEtiology\nMM is caused by mutations in the DYSF gene (2p13), which encodes dysferlin. The latter orchestrates skeletal muscle membrane repair and has also been associated with myogenesis, angiogenesis and microtubule dynamics.\nDiagnostic methods\nDiagnosis of MM relies on laboratory findings showing an elevated serum creatine kinase level (20 to 150 times the normal), muscle biopsy routine reveals dystrophic features. Western blotting may help in cases with uncertain immunohistochemistry findings. Magnetic resonance imaging (MRI) of calf muscles show typical fatty replacement. EMG reveals 'myopathic' motor units and recruitment patterns. Diagnosis is confirmed by the genetic screening of DYSF.\nDifferential diagnosis\nDifferential diagnosis includes autosomal recessive limb-girdle muscular dystrophy type 2L (LGMD2L), LGMD2B and qualitative or quantitative defects of caveolin-3.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\nManagement and treatment\nNo definitive treatments for MM exist and management is mainly supportive. To prolong survival and improve quality of life, weight control to avoid obesity, physical therapy and stretching exercises to promote mobility and use of mechanical aids to help ambulation and mobility are recommended.\nPrognosis\nProgression is variable with some patients remaining fairly stable with distal weakness, while others can have a more aggressive pattern involving both proximal and distal muscles. Patients may become wheelchair bound 10-30 years after onset of symptoms. Disease progression is usually related to disease duration rather than age of onset of symptoms.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Johanna PALMIO"}
{"Disease Name": "MME-related autosomal dominant Charcot Marie Tooth disease type 2", "Disease Definition": "A rare autosomal dominant hereditary axonal motor and sensory neuropathy characterized by adult onset of slowly progressive distal muscle weakness and atrophy, sensory impairment, and hyporeflexia beginning in the lower limbs. Progressive gait disturbance may lead to loss of independent ambulation in some patients at a higher age.", "ORPHA ID": 497757, "Summary": ""}
{"Disease Name": "MMEP syndrome", "Disease Definition": "The MMEP syndrome is a congenital syndromic form of split-hand/foot malformation (SHFM; see this term). It is characterized by microcephaly, microphthalmia, ectrodactyly of the lower limbs and prognathism. Intellectual deficit has been reported. MMEP syndrome is considered to be a very rare condition, although the exact prevalence remains unknown. The etiology is not completely understood. Disruption of the sorting nexin 3 gene (SNX3; 6q21) has been shown to play a causative role in MMEP, although this was not confirmed in recent studies.", "ORPHA ID": 3434, "Summary": ""}
{"Disease Name": "Moderate and severe traumatic brain injury", "Disease Definition": "A rare neurologic condition characterized by brain damage caused by an external mechanical force, with a Glasgow Coma Scale score of 9 to 12 in moderate traumatic brain injury (TBI), or 3 to 8 in severe TBI, respectively. TBI can be closed (with the dura mater remaining intact) or open (with penetration of the dura mater) and may lead to focal damage, such as cerebral contusion and hemorrhage, as well as diffuse axonal injury and secondary damage due to increased intracranial pressure. Signs and symptoms are highly variable, depending on the nature, severity, localization, and extent of the trauma.", "ORPHA ID": 90056, "Summary": ""}
{"Disease Name": "Moderate hemophilia A", "Disease Definition": "A moderately severe form of hemophilia A characterized by factor VIII deficiency (biological activity between 1 and 5 IU/dL) leading to abnormal bleeding as a result of minor injuries, or following trauma, surgery or tooth extraction. Spontaneous hemorrhages are rare. The condition primarily affects males but may also be observed in female carriers of disease-causing mutations.", "ORPHA ID": 169805, "Summary": ""}
{"Disease Name": "Moderate hemophilia B", "Disease Definition": "A moderately severe form of hemophilia B characterized by factor IX deficiency (biological activity 1-5 IU/dL) leading to abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction. Spontaneous hemorrhages are rare. The condition primarily affects males but may also be observed in female carriers of disease-causing mutations.", "ORPHA ID": 169796, "Summary": ""}
{"Disease Name": "MODY", "Disease Definition": "MODY (maturity-onset diabetes of the young) is a rare, familial, clinically and genetically heterogeneous form of diabetes characterized by young age of onset (generally 10-45 years of age) with maintenance of endogenous insulin production, lack of pancreatic beta-cell autoimmunity, absence of obesity and insulin resistance and extra-pancreatic manifestations in some subtypes.", "ORPHA ID": 552, "Summary": "Epidemiology\nMODY is the most common form of monogenic diabetes. Prevalence is estimated to be about 1/10,000 in adults and 1/23,000 in children. No specific ethnic predilection has been reported. It has been estimated that around 80% of cases are misdiagnosed as type 1 or type 2 diabetes, thus complicating prevalence and incidence estimations.\nClinical description\nThe clinical features of MODY vary depending on the genetic etiology. The most frequent subtypes are HNF1A-MODY (30-50%), GCK-MODY (30-50%), HNF4A-MODY (10%), and HNF1B-MODY (1-5%). The latter is also known as renal cysts and diabetes syndrome (see this term). At least 9 other genetic subtypes have been described but are very rare. Patients with HNF1A and HNF4A mutations have slowly progressing beta-cell dysfunction and respond well to treatment with low-dose sulfonylureas, which are recommended as first line therapy. Vascular complications of diabetes are observed with a similar frequency to type 1 or type 2 diabetes. Low C-Reactive Protein is seen in HNF1A-MODY and neonatal hypoglycaemia and macrosomia are reported in babies with HNF4A-MODY. GCK-MODY is characterized by asymptomatic non-progressing mild fasting hyperglycemia with low post-prandial glucose excursions from birth, is not associated with vascular complications and does not require treatment.\nEtiology\nMutations in at least 13 genes have been reported to be associated with a MODY phenotype: common causes (>5% of cases): HNF1A (12q24.31), GCK (7p15.3-p15.1), HNF4A (20q13.12); rare causes (about 1% of cases): KCNJ11 (11p15.1), ABCC8 (11p15.1), INS (11p15.5), HNF1B (17q12); and very rare (described in only a few families, genetic evidence not compelling for some): CEL (9q34.3),  PDX1 (13q12.1), NEUROD1 (2q32), PAX4 (7q32.1), KLF11 (2p25) and BLK (8p23-p22).\nGenetic counseling\nCriteria for genetic testing for MODY include diabetes onset in adolescence or young-adulthood, maintenance of endogenous insulin production, and usually a significant family history of diabetes. Subjects will also have absence of typical features of type 1 or type 2 diabetes. Although de novo mutations can arise, cascade screening of family members is essential to ensure that those with diabetes get the correct diagnostic label and those at risk of inheriting the mutation are tested for diabetes and/or consider predictive genetic testing.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Katharine OWEN"}
{"Disease Name": "Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome", "Disease Definition": "A rare syndromic neurological disorder characterized by the association of Möbius syndrome (congenital facial palsy with impaired ocular abduction) with peripheral axonal neuropathy and hypogonadotropic hypogonadism. There have been no further reports since 1996.", "ORPHA ID": 2560, "Summary": ""}
{"Disease Name": "Moebius syndrome", "Disease Definition": "A very rare congenital cranial dysinnervation disorder characterized by unilateral or bilateral non progressive congenital facial palsy (VII cranial nerve) with impairments of ocular abduction (VI cranial nerve). It can also be associated with other cranial nerves palsies, orofacial anomalies and limb defects.", "ORPHA ID": 570, "Summary": "Epidemiology\nEpidemiological data on Moebius syndrome (MBS) is limited. The prevalence at birth is estimated at 1/47,250 in the Netherlands. MBS occurs equally in both sexes.\nClinical description\nMBS is a non-progressive disease, present at birth, characterized by high clinical heterogeneity, with frequent asymmetrical presentations. The main feature of the disorder is the paralysis of the VII cranial nerve, responsible for the facial diplegia, often asymmetric and incomplete, sparing the lower face and platysma, resulting in a mask-like facial appearance. The ocular manifestations include alterations of ocular motility with uni- or bilateral abduction defects (esotropia is the most common), ectropion, epiphora and exposure keratopathy, ophthalmoplegia and ptosis. Feeding difficulties and drooling at birth and in infancy are common. Other associated manifestations, due to other cranial nerves deficiencies include: deafness, trigeminal nerve sensitivity disorders, dysphagia, dysphonia and tongue hypoplasia. MBS may be accompanied by hypotonia and global developmental delay with infants demonstrating motor, emotional and speech difficulties. Development tends to normalize at 3 years of age but weakness in hand-eye coordination persists. Minor facial anomalies may include small palpebral fissures, epicanthic folds, hypertelorism, bifid uvula, micrognathia, and microstomia. Clubfoot is described in about 45% of cases. Hand anomalies (syndactyly, brachydactyly, ectrodactyly) and agenesis of the pectoral muscle (Poland-Moebius syndrome) are associated occasionally.\nEtiology\nThe etiology of MBS is currently unknown. It is thought to involve abnormal development of the brainstem, intrauterine hypoxia, teratogen exposure (e.g. misoprostol or cocaine), genetically determined vascular rhombencephalic disturbances in development or an acquired ischemic event occurring after the fifth week of pregnancy. De novo mutations in the PLXND1 (3q21.3) and REV3L (6q22) genes involved in hindbrain development have been found in about 6% of cases.\nDiagnostic methods\nThe diagnosis of MBS is based exclusively on clinical criteria, although recent studies are beginning to document causative genetic patterns. MBS can be recognized and diagnosed early during the neonatal period with electromyographic examination and brain MRI. Key clinical findings include poor or absent sucking due to incomplete closure of the lips, lack of facial mimicking (especially while crying), fixed gaze, incomplete eyelid closure during sleep and ptosis.\nDifferential diagnosis\nDifferential diagnoses include Carey-Fineman-Ziter syndrome, Oro-Mandibular-Limb hypogenesis syndrome (OMLH), Moebius-like syndrome, hypoglossia-hypodactyly syndrome and glossopalatine ankylosis.\nAntenatal diagnosis\nPrenatal genetic diagnosis is possible if pathogenic mutations responsible for the disease have been identified in the family (very rare cases). Clubfeet may be detected by prenatal ultrasound but is non-specific.\nGenetic counseling\nMost of cases of MBS follows a sporadic pattern of occurrence. Familial cases represent about 2% of all affected individuals. Recurrence in siblings of affected individuals is therefore extremely rare.\nManagement and treatment\nTreatment and management are supportive and symptomatic. A multidisciplinary clinical approach is important in order to optimize the diagnosis, treatment and advice given to these patients. The microneurovascular transfer of a free-muscle transplant is the procedure of choice for facial paralysis and midfacial animation. Ocular manifestations are treated with standard methods. Rehabilitation therapy (physiotherapy, oral motor, psychomotor/speech therapy) must start soon as possible and adapted over time in response to functional assessments. Psychological aspects relate to the patient's facial appearance. Communication between affected infants and their parents should be taken into consideration.\nPrognosis\nPrognosis is strongly correlated with the degree of brainstem involvement. It is non-progressive. Most of cases with MBS have normal life expectancy; although in severe cases, early demise shortly after birth is possible.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Maria Francesca BEDESCHI | ITHACA* - Dr Odoardo PICCIOLINI \n\n\n                                * European Reference Network"}
{"Disease Name": "MOGS-CDG", "Disease Definition": "MOGS-CDG is a form of congenital disorders of N-linked glycosylation characterized by generalized hypotonia, craniofacial dysmorphism (prominent occiput, short palpebral fissures, long eyelashes, broad nose, high arched palate , retrognathia), hypoplastic genitalia, seizures, feeding difficulties, hypoventilation, severe hypogammaglobulinemia with generalized edema, and increased resistance to particular viral infections (particularly to enveloped viruses). The disease is caused by loss-of-function mutations in the gene  MOGS  (2p13.1).", "ORPHA ID": 79330, "Summary": ""}
{"Disease Name": "Mohr-Tranebjaerg syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by clinical manifestations commencing with early childhood onset hearing loss, followed by adolescent onset progressive dystonia or ataxia, visual impairment from early adulthood onwards and dementia from the 4th decade onwards.", "ORPHA ID": 52368, "Summary": "Epidemiology\nMohr-Tranebjaerg syndrome (MTS) prevalence is unknown. More than 90 cases (37 families) are known, but not all cases have been reported in the literature.\nClinical description\nThe onset of rapidly progressive prelingual or postlingual sensorineural hearing loss, the only typical symptom, occurs in early childhood (18 months). The audiological phenotype is characterized by auditory neuropathy, characterized by preserved OAE (oto- acoustic emissions,) abnormal ABR (Auditory brain stem response), very poor speech discrimination, worsening in noisy environment and questionable benefit of treatment with cochlear implants (very few cases reported). Neuropsychologic manifestations, such as personality changes, paranoia, and mild intellectual deficit may emerge at the same time. A slowly progressive movement disorder, appearing as gegenhalten (diffuse resistance to limb movement), dystonia (mostly generalized or focal) or ataxia develops from early adolescence and is associated with brisk tendon reflexes, ankle clonus and extensor plantar responses. Patients experience reduced visual acuity, photophobia, acquired color vision defect and central scotomas starting from about 20 years of age and leading to legal blindness at around age 30 to 40. Slowly progressive dementia develops from the 4th decade onwards. In those with a contiguous gene deletion syndrome (CGS), recurrent infections may be present. Carrier females may be mildly affected with mild hearing impairment and focal dystonia. Despite the X linked recessive inheritance of the disease, there are a few cases where the proband was a female with dystonia.\nEtiology\nMTS is caused by either a mutation in the TIMM8A gene (located to Xq22) or by a CGS at Xq22, resulting in a deafness-dystonia peptide 1 (DDP1) deficiency. If the CGS includes the Bruton agammaglobulinemia tyrosine kinase (BTK) gene, recurrent infections secondary to this X-linked agammaglobulinemia (XLA) are present.\nDiagnostic methods\nA combination of hearing impairment and recurrent infections due to XLA in a male patient should elicit sequencing of the TIMM8A gene. Neuroimaging is employed to verify the presence of cerebral atrophy. In cases of suspected CGS; testing for XLA is possible.\nDifferential diagnosis\nDifferential diagnosis includes MELAS syndrome; mitochondrial DNA depletion syndrome (encephalomyopathic form with methylmalonic aciduria); Arts syndrome; X-linked spinocerebellar ataxia type 3 and 4; McLeod neuroacanthocytosis syndrome; Usher syndrome type 1 and 2; Wolfram syndrome; autosomal recessive nonsyndromic sensorineural deafness type DFNB; Pendred syndrome; and other forms of dystonia or rarely Friedreich ataxia.\nAntenatal diagnosis\nPrenatal diagnosis may be proposed to affected couples or parents for further pregnancies.\nGenetic counseling\nThe pattern of inheritance is X-linked recessive and gentic counselling should be offerend to affected families. Where the female is a carrier, the risk to male offspring inheriting the disease is 50%, female offspring have a 50% risk of being carriers. Where a male is affected, female offspring are obligate carriers, and male offspring do not inherit the pathogenic mutation.\nManagement and treatment\nTreatment of MTS is symptomatic and evolves over time. Hearing aids are used with variable success. For mild hearing loss, a hearing device and cochlear implants are an option whereas hearing aids with visual clues are used in cases with more severe hearing loss. The management of the hearing impairment is challenged by the fact that it is an auditory neuropathy. Management of dystonia and ataxia includes treatment with GABA-agonists together with psycho-motor re-education and physical therapy. Other supportive measures include therapies for the deaf-blind, addressing progressive sensory deficits, such as tactile sign language. In those with secondary complications, intravenous immunoglobulin may prevent infections in XLA. Furthermore, live viral vaccines should be avoided in cases of XLA. In adulthood, regular neurological evaluation (assessment for dementia and/or psychiatric manifestations) should be maintained.\nPrognosis\nPrognosis is poor. The combination of deafness and blindness severely affects communication, while the ongoing movement disorder results in an increasingly unstable gait. Life expectancy is highly variable and can range from death in the teenage years (after a rapidly progressive dystonia) to those that live into their 60's.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Lisbeth TRANEBJAERG"}
{"Disease Name": "MOMO syndrome", "Disease Definition": "MOMO syndrome is a very rare genetic overgrowth/obesity syndrome (see this term) characterized by macrocephaly, obesity, mental (intellectual) disability and ocular abnormalities. Other frequent clinical signs include macrosomia, downslanting palpebral fissures, hypertelorism, broad nasal root, high and broad forehead and delay in bone maturation, in association with normal thyroid function and karyotype.", "ORPHA ID": 2563, "Summary": ""}
{"Disease Name": "Monilethrix", "Disease Definition": "A rare genodermatosis characterized by a hair shaft dysplasia resulting in hypotrichosis.", "ORPHA ID": 573, "Summary": "Epidemiology\nThe prevalence and incidence are not known.\nClinical description\nMonilethrix has an early onset in infancy. Alopecia, associated with follicular hyperkeratosis and perifollicular erythema, can involve only the occiput and the nape of the neck or, in severe forms, the entire scalp, the eyebrows and eyelashes, and secondary hair. Infants show a characteristic hair shaft dysplasia: dystrophic constrictions regularly separated by elliptical nodes of normal thickness, giving a beaded appearance of affected hair. The thin internodal region shows a high propensity to break. In some cases, nail dystrophy (koilonychia) on fingers and toes has been reported. This symptomatic triad (moniliform hair, follicular hyperkeratosis and nail dystrophy), when associated with other ectodermal defects, such as as neurological, dental, and ophthalmological alterations, constitute the ''moniliform hair syndrome''.\nEtiology\nFour genes have been associated with monilethrix: KRT81, KRT83 and KRT86, coding for the type II hair keratins Hb1, Hb3 and Hb6, and are responsible for the autosomal dominant form of the disease. An autosomal recessive form has also been described in a few families, caused by mutations in the DSG4 gene, coding for the desmoglein 4 protein, also involved in hypotrichosis simplex (see this term) that has clinical overlap with monilethrix.\nDiagnostic methods\nA trichogram shows the characteristic moniliform hairs. Trichoscopy is another approach to detect the characteristic hair shaft dysplasia of monilethrix. An electron microscopy-based diagnostic test is available.\nDifferential diagnosis\nDifferential diagnosis includes pseudomonilethrix that presents with diffuse alopecia or alopecia limited to the occipital area. However, using trichogram analysis, pseudomoniletrix hair does not present with dystrophic constrictions but with flattened irregular beading.\nGenetic counseling\nIn severe forms with alopecia and hyperkeratosis on the body, genetic counseling would be necessary.\nManagement and treatment\nTreatment is disappointing. The best measure is to avoid the mechanical action of combing and brushing. Depilation only achieves repopulation with normal looking hair for a short while. Temporary improvement has been described with daily doses of 125 mg of griseofulvin, zinc-sulfate, X-ray depilation, and topical application of retinoid acid. There have also been improvements with the application of minoxidil and tretinoin, and with the administration of 0.5-1 mg/kg/day of etretinate.\nPrognosis\nThe course of the localized form of monilethrix can be favorable with a reduction of hypotrichosis with time. In general, hypotrichosis improves with age, although remissions have been noted during puberty or pregnancy.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Francisco CAMACHO-MARTÍNEZ"}
{"Disease Name": "Monoamine oxidase A deficiency", "Disease Definition": "Monoamine oxidase-A deficiency is a very rare recessive X-linked biogenic amine metabolism disorder characterized clinically by mild intellectual deficit, impulsive aggressiveness, and sometimes violent behavior and presenting from childhood.", "ORPHA ID": 3057, "Summary": ""}
{"Disease Name": "Monoclonal mast cell activation syndrome", "Disease Definition": "A rare hematologic disease characterized by symptoms of mast cell activation in the absence of cutaneous findings, as well as absence of diagnostic criteria of systemic mastocytosis with tryptase levels of less than 20 ng/ml and normal to low burden of mast cells. Bone marrow biopsy reveals the presence of monoclonal mast cells carrying the KIT D816V mutation and/or expressing CD25. Patients present with recurrent episodes of flushing, headache, hypotension, abdominal cramping, nausea, diarrhea, cardiac arrhythmias, bronchoconstriction, and bleeding diathesis, among others.", "ORPHA ID": 529468, "Summary": ""}
{"Disease Name": "Monomelic amyotrophy", "Disease Definition": "Monomelic amyotrophy (MA) is a rare benign lower motor neuron disorder characterized by muscular weakness and wasting in the distal upper extremities during adolescence followed by a spontaneous halt in progression and a stabilization of symptoms.", "ORPHA ID": 65684, "Summary": "Epidemiology\nThe prevalence is unknown. It is seen mainly in Asian countries (particularly in Japan and India) with only a very few cases reported in Europe and the United States. A nation-wide survey conducted from 1996 to 1998 in Japan found 333 identified cases with the estimated prevalence being approximately 1/33, 300.\nClinical description\nMA is seen more frequently in males (male to female ratio of 20:1) with an age of onset in the second to third decade of life (ages 14-25). Muscle weakness and wasting begins in the hand or forearm on one side. There is no pain associated with this muscular atrophy, nor sensory changes. Progression is slow, usually over a 3-9 year time span, followed by a halt and stabilization of symptoms. Occasionally it can destabilize and continue progression after the age of 40. In rare cases it can progress to the opposite limb. Additional rare manifestations include worsening of symptoms with exposure to cold (cold paresis), muscle cramps, cold hands, irregular coarse tremor and/or contraction fasciculations. O'Sullivan-McLeod syndrome (see this term), considered to be a variant of MA, presents with weakness in the intrinsic hand muscles. It begins unilaterally but eventually spreads to the opposite limb with an asymmetrical distribution.\nEtiology\nThe exact etiology is unknown. One theory is that MA is caused by the anterior shift of the cervical dural sac, due to repeated neck flexion, leading to the compression of the anterior aspect of the spinal cord against the posterior margin of the vertebral body. Autoimmunity, toxins and infections have been proposed as possible causes, but more evidence is needed. Since there have been several familial cases of MA reported (<1% of MA patients), genetic susceptibility could also be a factor.\nDiagnostic methods\nDiagnosis is based on clinical imaging and electromyography findings. Magnetic resonance imaging (MRI) shows distinctive images of the anterior horn being compressed when a patient is in the maximum cervical anteflexion position (snake eyes sign). Atrophy in the lower cervical spinal cord is also visible. Nerve conduction tests show reduced compound muscle action potential of the median and ulnar nerves in the affected limb and F-wave studies show reduced frequency and prolonged minimum latency in these muscles.\nDifferential diagnosis\nPoliomyelitis, multifocal motor neuropathy with conduction block, syringomyelia (see these terms), anterior interosseous or deep ulnar neuropathy, cervical vertebral abnormalities, spinal cord tumors, brachial plexopathy and trauma must be excluded.\nManagement and treatment\nThere is no cure for MA. Treatment is conservative and with early detection aims to slow the progression of muscle wasting. A cervical collar worn in the early stages of disease has been shown to halt progress of the disease in some cases, as it prevents neck flexion. Muscle strengthening exercises and hand coordination training can also be helpful.\nPrognosis\nMA is not life threatening but can cause a social disability in those with a complete loss of hand function. Early intervention can minimize progression of disease.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Satoshi KUWABARA"}
{"Disease Name": "Mononen-Karnes-Senac syndrome", "Disease Definition": "Mononen-Karnes-Senac syndrome is characterized by skeletal dysplasia associated with finger malformations (brachydactyly with short and abducted thumbs, short index fingers, and markedly short and abducted great toes), variable mild short stature, and mild bowleg with overgrowth of the fibula. It has been described in two males, their mothers, and a maternal aunt. Females are less severely affected than males. X-linked dominant inheritance is suggested.", "ORPHA ID": 2565, "Summary": ""}
{"Disease Name": "Monosomy 13q14", "Disease Definition": "Monosomy 13q14 is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the long arm of chromosome 13, characterized by developmental delay, variable degrees of intellectual disability, retinoblastoma and craniofacial dysmorphism (incl. micro/dolichocephaly, high and broad forehead, prominent eyebrows, thick, anteverted ear lobes, short nose with a broad nasal bridge and bulbous tip, prominent philtrum, large mouth with thin upper lip and thick, everted lower lip). Other features reported include high birth weight, macrocephaly, pinealoma, hepatomegaly, inguinal hernia and cryptorchidism.", "ORPHA ID": 1587, "Summary": ""}
{"Disease Name": "Monosomy 13q34", "Disease Definition": "Monosomy 13q34 is a rare chromosomal anomaly syndrome, resulting from the partial deletion of the long arm of chromosome 13, principally characterized by global developmental delay, mild intellectual disability, obesity and mild craniofacial dysmorphism (microcephaly, wide rectangular forehead, downslanting palpebral fissures, mild ptosis, prominent nose with long nasal bridge and broad tip, small chin). Other variable reported features include congenital heart defects, hand and foot anomalies (e.g. polydactyly) and agenesis of the corpus callosum.", "ORPHA ID": 96168, "Summary": ""}
{"Disease Name": "Monosomy 18p", "Disease Definition": "Monosomy 18p refers to a chromosomal disorder resulting from the deletion of all or part of the short arm of chromosome 18.", "ORPHA ID": 1598, "Summary": "Epidemiology\nThe incidence is estimated to be about 1:50,000 live-born infants.\nClinical description\nIn the commonest form of the disorder, the dysmorphic syndrome is very moderate and non-specific. The main clinical features are short stature, round face with short philtrum, palpebral ptosis and large ears with detached pinnae. Intellectual deficiency is mild to moderate. A small subset of patients, about 10 to 15 percent of cases, present with severe brain/facial malformations evocative of holoprosencephaly spectrum disorders.\nEtiology\nIn two-thirds of the cases, the 18p- syndrome is due to a mere terminal deletion occurring de novo. In the remaining cases the following are possible: a de novo translocation with loss of 18p, missegregation of a parental translocation or inversion, or a ring chr18. Parental transmission of the 18p- syndrome has been reported.\nDiagnostic methods\nCytogenetic analysis is necessary to make a definite diagnosis.\nDifferential diagnosis\nDifferential diagnosis may include a wide number of syndromes with short stature and mild intellectual deficiency. In young children, deletion 18p syndrome may be vaguely evocative of either Turner syndrome or trisomy 21 (see these terms).\nAntenatal diagnosis\nDeletion 18p can be detected prenatally by amniocentesis or chorionic villus sampling and cytogenetic testing.\nGenetic counseling\nRecurrence risk for siblings is low for de novo deletions and translocations, but is significant if a parental rearrangement is present.\nManagement and treatment\nNo specific treatment exists but speech therapy and early educational programs may help to improve the performances of the children.\nPrognosis\nExcept for the patients with severe brain malformations, the life expectancy does not seem significantly reduced.\n\n                            Last update: \n                            February 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Catherine TURLEAU"}
{"Disease Name": "Monosomy 18q", "Disease Definition": "A partial deletion of the long arm of chromosome 18 characterized by highly variable phenotype, most commonly including hypotonia, developmental delay, short stature, growth hormone deficiency, hearing loss and external ear anomalies, intellectual disability, palatal defects, dysmorphic facial features, skeletal anomalies (foot deformities, tapering fingers, scoliosis) and mood disorders.", "ORPHA ID": 1600, "Summary": ""}
{"Disease Name": "Monosomy 22", "Disease Definition": "A rare autosomal anomaly syndrome, with a highly variable phenotype, typically characterized by short length, joint abnormalities (e.g. dysplasia, hyperextensibility, contractures, dislocation), congenital cardiac defects, and craniofacial dysmorphism (incl. microcephaly, a high, prominent, narrow and/or hairy forehead, epicanthus, upward-slanting and/or small palpebral fissures, broad, high or depressed nasal bridge and malformed ears). Delayed motor development and intellectual disability is observed in patients not presenting early demise.", "ORPHA ID": 96123, "Summary": ""}
{"Disease Name": "Monosomy 5p", "Disease Definition": "A rare developmental defect during embryogenesis, resulting from partial or total deletion of the short arm of chromosome 5, classically characterized by a high-pitched, monotone, cat-like cry (cri du chat) present since birth, associated with varying degrees of intellectual disability, developmental delay, microcephaly, and facial dysmorphism.", "ORPHA ID": 281, "Summary": "Epidemiology\nMonosomy 5p prevalence at birth ranges from 1/15,000 to 1/45,000, with females being slightly more affected than males.\nClinical description\nNewborns typically exhibit low birthweight and microcephaly, as well as asphyxia cyanotic crises, and impaired suction. The disorder shows high phenotypic variability that evolves over time. Craniofacial dysmorphism includes microcephaly, round face, broad nasal bridge, hypertelorism, epicanthic folds, strabismus, downward-slanting palpebral fissures, low-set ears, down-turned corners of mouth, high-arched palate, microretrognathia, and malocclusion. Psychomotor delay and intellectual disability usually become evident in the first year of life and recurrent respiratory and intestinal infections may be observed during infancy. Pre- and postnatal growth delay, with weight more affected than height, is reported. With increasing age, the following features develop: hypotonia changes to hypertonia, face becomes long and narrow and supraorbital arch prominent, dental malocclusions arise, palpebral fissures tend to become horizontal, and premature grey hair appears.\nEtiology\nThe disorder is due to a partial or total deletion of the short arm of chromosome 5, with the critical region located between 5p15.2 and 5p15.3. The deletion size may range from 0.5 to 40 Mb. Deletions may be terminal (most frequent), interstitial, or due to an unbalanced translocation. In approximately 80% of cases, the deletion is a de novo event.\nDiagnostic methods\nDiagnosis is suspected based on clinical characteristics, in particular the typical cry. Karyotype analysis can confirm the diagnosis. In doubtful cases, when there is conflict between the clinical suspicion and an apparently normal karyotype result, FISH analysis, quantitative PCR and/or CMA should be performed.\nDifferential diagnosis\nDifferential diagnosis includes Mowat-Wilson and Wolf-Hirschhorn syndromes, 1p36 monosomy, 17q21 microdeletion, and other chromosomal anomalies.\nAntenatal diagnosis\nPrenatal diagnosis is possible by ultrasonographic observation of structural abnormalities. Some cases present with cerebellar abnormalities. Chorionic villus sampling or amniocentesis, with karyotype, FISH or CMA analysis may reveal deletion of the critical region on chromosome 5p. However, in some cases, ultrasound can be normal. Noninvasive prenatal testing (NIPT) is currently commercially available in some countries and can be used as a screening method for some microdeletion syndromes, including Cri-du-chat syndrome. In families with an already known translocation involving 5p, preimplantation genetic testing for chromosomal structural rearrangement (PGT-SR) is possible.\nGenetic counseling\nGenetic counseling, including communication of risk of recurrence, family orientation, and anticipatory supervision for common complications, is possible for cases with a diagnosis of Cri-du-chat syndrome. Parents should be tested in order to rule out a balanced translocation. The recurrence risk for a de novo deletion is negligible.\nManagement and treatment\nNo specific treatment exists, however, rehabilitation, initiated early-on, has proven to be beneficial as it seems to improve prognosis and social adaptation. During the neonatal period, physical therapy should be started in the first week of life to help with any difficulty in swallowing and suction. Physical therapy, psychomotricity, and speech therapy are suggested for psychomotor and speech retardation. Patients often have sensorineural deafness; therefore, audiometric examinations should be routinely carried out. Malformations, including congenital heart disease and renal abnormalities, should be rule out as soon as the diagnosis is suspected. Periodic general check-up is recommended, including ENT, ophthalmological and dental assessments.\nPrognosis\nIt is reported a 10% mortality, with 75 - 90% of the cases within the first year of life. The type, size, and location of the deletion greatly influence the severity and prognosis of the disease, with patients with larger deletions typically being more severe. Early diagnosis greatly influences prognosis as early detection allows for the prompt implementation of therapeutic measures, thus improving the outcome of physical and psychomotor development and helping with social adaptation.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Kim CHONG  - Dr Rachel HONJO KAWAHIRA"}
{"Disease Name": "Monosomy 9p", "Disease Definition": "Monosomy 9p is a rare chromosomal anomaly characterized by psychomotor developmental delay, facial dysmorphism (trigonocephaly, midface hypoplasia, upslanting palpebral fissures, dysplastic small ears, flat nasal bridge with anteverted nostrils and long philtrum, micrognathia, choanal atresia, short neck), single umbilical artery, omphalocele, inguinal or umbilical hernia, genital abnormalities (hypospadia, cryptorchidism), muscular hypotonia and scoliosis.", "ORPHA ID": 261112, "Summary": ""}
{"Disease Name": "Monosomy 9q22.3", "Disease Definition": "Interstitial 9q22.3 microdeletion is associated with a phenotype including macrocephaly, overgrowth and trigonocephaly. Psychomotor delay, hyperactivity and distinctive facial features were also observed. It has been described in two unrelated children.", "ORPHA ID": 77301, "Summary": ""}
{"Disease Name": "Mooren ulcer", "Disease Definition": "A rare disorder of the anterior segment of the eye characterized by a unilateral or bilateral rapidly progressive, intractable, painful, ulcerative keratitis which initially affects the peripheral cornea and may spread circumferentially and then centrally. The destructive process involves stromal corneal tissue only, leaving the epithelium and endothelium largely unaffected. There is no involvement of the adjacent sclera. The condition can be complicated by glaucoma, cataract, and perforation.", "ORPHA ID": 519408, "Summary": ""}
{"Disease Name": "Morgagni-Stewart-Morel syndrome", "Disease Definition": "A rare cranial malformation characterized by hyperostosis frontalis interna, variably associated with metabolic and endocrine disorders (such as obesity, diabetes mellitus, and hirsutism, among others). Compression by calvarial thickening may lead to cerebral atrophy and present with cognitive impairment, neuropsychiatric symptoms, headaches, and epilepsy. The condition predominantly affects women.", "ORPHA ID": 77296, "Summary": ""}
{"Disease Name": "MORM syndrome", "Disease Definition": "A rare genetic syndromic intellectual disability characterized by language delay and mild to moderate intellectual disability associated with truncal obesity, congenital nonprogressive retinal dystrophy with poor night vision and reduced visual acuity, and micropenis in males. Cataracts may occur in the second or third decade of life.", "ORPHA ID": 75858, "Summary": ""}
{"Disease Name": "Morning glory disc anomaly", "Disease Definition": "A congenital optic disc anomaly characterized by a funnel shaped excavation of the posterior fundus that incorporates the optic disc. Clinically, the optic disc malformation resembles the morning glory flower. Morning glory disc anomaly (MGDA) is usually unilateral and often results in a decrease in best-corrected visual acuity (BCVA). MGDA can be isolated or associated with other ocular or non-ocular anomalies.", "ORPHA ID": 35737, "Summary": "Epidemiology\nThe overall prevalence of MGDA is unknown, but it is estimated at 1/38,500 among subjects between 2 and 19 years old in Sweden. More than 100 cases have been reported in the medical literature. The disease is thought to be more common in women than in men.\nClinical description\nMGDA often manifests early in childhood with strabismus of the affected eye. When the child is older and BCVA can be assessed, a substantial visual loss is noted (BCVA usually ranging between counting fingers and 20/200 in the affected eye). However, visual acuity is not always severely impaired, and can be close to normal. MGDA can be isolated or associated with other ocular anomalies in the same or contralateral eye (nystagmus, cataract, microphthalmia, glaucoma, coloboma of the crystalline lens, optic nerve drusen, aniridia, lid haemangioma, preretinal gliosis, peripheral retinal non-perfusion, serous retinal detachment, lenticonus, glioma or cyst of any optic pathway, acute retrobulbar optic neuritis, etc.). In younger patients, MGDA combined with persistent hyperplastic primary vitreous may indicate higher incidence of, and more severe associated complications. Associated facial dysmorphism (hypertelorism, dysplastic ears, cleft lip and palate, etc.), intracranial anomalies (basal encephalocele, other types of encephalocele, affected pituitary gland, corpus callosum agenesis, cerebral midline lipomas, etc.) and renal abnormalities (renal hypoplasia, chronic glomerulonephritis, hydronephrosis, etc.) have been reported, as well as several neurovascular and cardiac defects. MGDA can be associated with Moyamoya disease, PHACES syndrome, Aicardi syndrome, neurofibromatosis type 2, Arnold-Chiari malformation type I, CHARGE syndrome, Poland syndrome, among others. Bilateral cases are rare and might be correlated with a more severe systemic involvement.\nEtiology\nThe exact etiology is not fully understood, but the syndrome is related to poor development of the posterior sclera and lamina cribrosa during gestation. The PAX6 gene could be linked to the anomaly.\nDiagnostic methods\nThe diagnosis is based on clinical examination and relies on fundoscopy findings, showing an enlarged optic disc with peripapillary pigmentations, funnel shaped deep excavation, a radiating pattern of retinal blood vessels and a pale fluffy tuft of hyperplastic glial tissue overlying the optic disc. Optical coherence tomography, OCT may show a serous retinal detachment. Other MGDA-associated ocular anomalies, disorders elsewhere, e.g. cerebral malformations, systemic involvement and diseases, etc. should be ruled out.\nDifferential diagnosis\nThe differential diagnoses include optic disc colobomas, staphylomas and amblyopia.\nManagement and treatment\nThere is no curative treatment for the anomaly. However, associated amblyopia is usually treated by occlusion of the contralateral eye with good possibilities of some visual improvement. Strabismus can be corrected with surgery. Serous retinal detachment seems common, usually not requiring treatment but needing follow up. Vitrectomy with peripapillary photocoagulation and silicone oil tamponade may be required if a proliferative retinal detachment is associated with macular hole in children with MGDA. Associated somatic disorders/conditions, especially cranial malformations, cerebrovascular anomalies, cardiovascular anomalies, renal anomalies, endocrine and other systemic disease, etc. should be diagnosed and, if possible, treated accordingly.\nPrognosis\nThe visual loss is usually non-progressive but MGDA increases the risk of serous retinal detachment (30% of patients in some studies). Other reported complications include choroidal neovascularization.\n\n                            Last update: \n                            January 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Kristina TEÄR FAHNEHJELM"}
{"Disease Name": "Morvan syndrome", "Disease Definition": "Morvan syndrome is a rare, life-threatening, acquired neurologic disease characterized by neuromyotonia, dysautonomia and encephalopathy with severe insomnia. Signs involving central (e.g. hallucinations, confusion, amnesia, myoclonus), autonomic (e.g. variations in blood pressure, hyperhidrosis) and peripheral (e.g. painful cramps, myokymia) hyperactivity, as well as systemic manifestations (such as weight loss, pruritus, fever), are reported. Thymoma is present in some cases.", "ORPHA ID": 83467, "Summary": ""}
{"Disease Name": "Mosaic genome-wide paternal uniparental disomy", "Disease Definition": "A rare chromosomal anomaly characterized by a combination of paternal uniparental and biparental cell lineages, leading to variable clinical presentation that predominantly includes features of Beckwith-Wiedemann syndrome and increased risk of various tumors. In addition, features of Angelman syndrome and transient neonatal diabetes might be expected.", "ORPHA ID": 329813, "Summary": ""}
{"Disease Name": "Mosaic trisomy 1", "Disease Definition": "A rare autosomal trisomy, characterized by reduced fetal movements and intrauterine growth retardation, low birth weight, and multiple congenital anomalies. The latter include, amongst others, facial dysmorphism (like hypertelorism, cleft lip/palate, micrognathia, low hairline, and small, low-set, and posteriorly rotated ears), head circumference below average, deformities of the hands (camptodactyly) and feet, marked hypertrichosis, and anomalies of the brain, heart, and lungs. Lethality appears to depend on the degree of mosaicism.", "ORPHA ID": 1692, "Summary": ""}
{"Disease Name": "Mosaic trisomy 10", "Disease Definition": "Mosaic trisomy 10 is a rare chromosomal anomaly syndrome, with a highly variable phenotype, principally characterized by growth delay, craniofacial dysmorphism (incl. prominent forehead, hypertelorism, upslanting palpebral fissures, blepharophimosis, low-set malformed large ears, high arched palate, cleft lip/palate, retrognathia) and cardiac, renal and skeletal (e.g. radial ray defects, scoliosis) malformations, with death usually ocurring neonatally or in early infancy. Other reported features include central nervous system and ear anomalies, as well as facial clefts and anal atresia.", "ORPHA ID": 96063, "Summary": ""}
{"Disease Name": "Mosaic trisomy 12", "Disease Definition": "Mosaic trisomy 12 is a rare chromosomal anomaly syndrome, with a highly variable phenotype, principally characterized by developmental or growth delay, short stature, craniofacial dysmorphism (e.g. turricephaly, tall forehead, downslanting palpebral fissures, posteriorly rotated and low set ears, narrow palate), congenital heart defects (e.g. atrial septal defect, patent ductus arteriosus), hypotonia, and pigmentary dysplasia. Scoliosis, hearing loss, facial/body asymmetry, and intellectual disability have also been reported.", "ORPHA ID": 1698, "Summary": ""}
{"Disease Name": "Mosaic trisomy 14", "Disease Definition": "Mosaic trisomy 14 is a rare chromosomal anomaly disorder, with a highly variable phenotype, principally characterized by growth and developmental delay, intellectual disability, body asymmetry/hypotonia, congenital heart defects, genitourinary abnormalities (cryptorchidism, micropenis, large clitoris, labial swelling), and abnormal skin hyperpigmentation. Patients usually present with craniofacial dysmorphism such as microcephaly, abnormal palpebral fissure, hypertelorism, ear abnormalities, broad nose, low-set ears, micro/retro-gnathia, and cleft or highly arched palate.", "ORPHA ID": 1703, "Summary": ""}
{"Disease Name": "Mosaic trisomy 15", "Disease Definition": "Mosaic trisomy 15 is a rare chromosomal anomaly syndrome principally characterized by intrauterine growth restriction, congenital cardiac anomalies (incl. ventricular and atrial septal defects, patent ductus arteriosus) and craniofacial dysmorphism (incl. hypertelorism, downslanting palpebral fissures, wide nasal bridge). Patients also present brain (e.g. hypoplastic cerebellum, ventricular asymmetry), renal (e.g. small dysplastic kidneys), and/or genital (undescended testis, small penis, hypoplastic labia majora) anomalies. Digital and skin pigmentation abnormalities have also been reported.", "ORPHA ID": 1706, "Summary": ""}
{"Disease Name": "Mosaic trisomy 16", "Disease Definition": "Mosaic trisomy 16 is a rare chromosomal anomaly syndrome with a highly variable phenotype ranging from minor anomalies with normal development to intrauterine growth retardation, abnormal skin pigmentation, craniofacial and body asymmetry, cardiac (e.g. ventricular septal defect) and genital (e.g. hypospadias, cryptorchidism) anomalies, scoliosis and hearing loss to neonatal death. Additional features observed include skeletal malformations (e.g. clino/polydactyly, talipes), mild facial dysmorphism, and developmental delay.", "ORPHA ID": 1708, "Summary": ""}
{"Disease Name": "Mosaic trisomy 17", "Disease Definition": "Mosaic trisomy 17 is a rare chromosomal anomaly syndrome, with a highly variable clinical presentation, mostly characterized by growth delay, intellectual disability, body asymmetry with leg length differentiation, scoliosis, and congenital heart anomalies (e.g. ventricular septal defect). Prenatal ultrasound findings include intrauterine growth retardation, nuchal thickening brain anomalies (e.g. cerebellar hypoplasia), pleural effusion and single umbilical artery. Patients with no associated malformations have also been reported.", "ORPHA ID": 1711, "Summary": ""}
{"Disease Name": "Mosaic trisomy 2", "Disease Definition": "Mosaic trisomy 2 is a rare chromosomal anomaly syndrome, with a highly variable phenotype, principally characterized by intrauterine growth restriction, growth and motor delay, craniofacial dysmorphism (e.g. microcephaly, hypertelorism, micro/anophthalmia, midface hypoplasia, cleft lip/palate), congenital heart and neural tube defects, as well as various skeletal (e.g. scoliosis, radioulnar hypoplasia, preaxial polydactyly) and gastrointestinal (e.g. intestinal malrotation, Hirschsprung disease) anomalies. Central nervous system malformations (including ventriculomegaly, thin corpus callosum, spina bifida) have also been reported.", "ORPHA ID": 1723, "Summary": ""}
{"Disease Name": "Mosaic trisomy 20", "Disease Definition": "Mosaic trisomy 20 is a rare chromosomal anomaly syndrome with a highly variable phenotype ranging from normal (in the majority of cases) to a mild, subtle phenotype principally characterized by spinal abnormalities (i.e. stenosis, vertebral fusion, and kyphosis), hypotonia, lifelong constipation, sloped shoulders, skin pigmentation abnormalities (i.e. linear and whorled nevoid hypermelanosis) and significant learning disabilities despite normal intelligence. More severe phenotypes, with patients presenting psychomotor and speech delay, mild facial dysmorphism, cardiac (i.e. ventricular septal defect, dysplastic tricuspid mitral valve) and renal anomalies (e.g. horseshoe kidneys), have also been reported.", "ORPHA ID": 1724, "Summary": ""}
{"Disease Name": "Mosaic trisomy 22", "Disease Definition": "Mosaic trisomy 22 is a rare chromosomal anomaly syndrome, with a highly variable phenotype, principally characterized by prenatal and postnatal growth delay, mild to severe intellectual disability, hemiatrophy, webbed neck, ocular and cutaneous pigmentary anomalies, craniofacial dysmorphic features (e.g. microcephaly, upslanted palpebral fissures, ptosis, ear malformations, flat nasal bridge, micrognathia) and cardiac abnormalities (including ventricular and atrial septal defect, pulmonary or aortic stenosis). Hearing loss and limb malformations (e.g. cubitus valgus, syn/brachydactyly), as well as renal and genital anomalies, have also been reported.", "ORPHA ID": 96068, "Summary": ""}
{"Disease Name": "Mosaic trisomy 3", "Disease Definition": "Mosaic trisomy 3 is a rare chromosomal anomaly syndrome with high phenotypic variability ranging from a mild phenotype presenting joint pain and laxity, mild facial dysmorphism (e.g. long facies, prominent eyes, dysplastic ears, downturned corners of the mouth, micrognathia) and no developmental delays to more severe phenotypes including short stature, intellectual disability, severe developmental delays, additional craniofacial dysmorphic features (e.g. brachycephaly, high forehead, flat midface, short neck) and hearing impairment, as well as skeletal (e.g. pectus excavatum, scoliosis), ocular (e.g. coloboma) and cardiac abnormalities.", "ORPHA ID": 100071, "Summary": ""}
{"Disease Name": "Mosaic trisomy 4", "Disease Definition": "Mosaic Trisomy 4 is a rare autosomal anomaly, due to the presence of an extra copy of chromosome 4 in a fraction of all cells, with a variable phenotype characterized by intrauterine growth retardation, low birth weight/length/OFC, mild intellectual deficit, congenital heart defects, hypertrophic cardiomyopathy, dysmorphic features (asymmetry of the face, eyebrow anomalies, low-set, posteriorally rotated, dysplastic ears, micro-/retrognathia), characteristic thumb abnormalities (aplasia, hypoplasia) and skin abnormalities (hypo/hyperpigmentation). Delayed puberty may be associated.", "ORPHA ID": 96059, "Summary": ""}
{"Disease Name": "Mosaic trisomy 5", "Disease Definition": "Mosaic trisomy 5 is a rare chromosomal anomaly syndrome with a variable phenotype ranging from clinically normal to patients presenting intrauterine growth retardation, congenital heart anomalies (mainly ventricular septal defect), multiple dysmorphic features (e.g. hypertelorism, prominent nasal bridge) and other congenital anomalies (incl. eventration of diaphragm, agenesis of corpus callosum, cloverleaf skull, clinodactyly, anteriorly placed anus). Psychomotor development may be normal in spite of low growth parameters being associated.", "ORPHA ID": 96060, "Summary": ""}
{"Disease Name": "Mosaic trisomy 7", "Disease Definition": "Mosaic trisomy 7 is a rare chromosomal anomaly syndrome, with a highly variable phenotype, mostly characterized by blaschkolinear skin pigmentary dysplasia, body asymmetry, enamel dysplasia, and developmental and growth delay. Intellectual disability, facial dysmorphism (e.g. frontal bossing, abnormal palpebral fissures, strabismus, abnormally shaped ears, and micrognathia), and genital anomalies (e.g. undescended testes) have also been observed. It has been reported to be associated with maternal uniparental disomy of chromosome 7, resulting in a Silver-Russell syndrome phenotype. Cases with no associated malformations have also been reported.", "ORPHA ID": 1747, "Summary": ""}
{"Disease Name": "Mosaic trisomy 8", "Disease Definition": "A rare autosomal anomaly defined by the presence of three copies of chromosome 8 in some cells of the body, and clinically characterized by facial dysmorphism, typically deep palmar and plantar creases, mild intellectual deficit and joint, urinary, cardiac and skeletal anomalies.", "ORPHA ID": 96061, "Summary": "Epidemiology\nHistorically, the birth prevalence was estimated between 1/25,000-50,000 but supporting epidemiological studies are lacking. Males are more frequently affected than females (sex-ratio 4:1).\nClinical description\nFacial dysmorphic features are mild and include elongation of the skull (scaphocephaly), prominent forehead, hypertelorism, deeply set eyes (50%), bulbous upturned nose (60%), micrognathia (with everted lower lips), large dysplastic ears with prominent anthelices and large lobules. Additional features include: agenesis of the corpus callosum, highly arched or cleft palate (8%), short and broad neck, tall stature, elongated narrow chest, shoulders and pelvis. Urinary (hydronephrosis, ureteral reflux), and cardiac and large vessels abnormalities are frequent (40% and 25% respectively). Camptodactyly (70%), arthrogryposis of the joints (aggravating with time), deep palmar (in infants) and plantar furrows (75%), absent or hypoplastic patellae, vertebral malformations (65%: segmentation anomalies, costal anomalies, scoliosis), epilepsy, as well as corneal opacity and strabismus are also commonly observed. Most individuals present a mild-to-moderate intellectual disability (IQ between 50 and 75), with some patients having normal intelligence. Usually speech is more delayed than other developmental domains. There is no correlation between the percentage of trisomic cells and the severity of the intellectual disability.\nEtiology\nMosaic trisomy 8 is the result of a post-zygotic event (error in chromosome segregation during mitosis in a fetus having a normal karyotype or due to spontaneous correction of trisomy 8). Complete trisomy 8 is due to an error in chromosome segregation during meiosis and often results in miscarriage during the first trimester. When, exceptionally, the fetus survives, it presents the same phenotype as mosaic trisomy. Patients with isochromosome 8p (tetrasomy of the short arm (p) of chromosome 8) have the same phenotype as patients with trisomy 8p.\nDiagnostic methods\nDiagnosis is based on karyotype analysis or on detection of copy number variation by microarray or whole exome sequencing. In the latter case confirmation by karyotyping is recommended.\nDifferential diagnosis\nDifferential diagnosis includes non-specific syndromic intellectual disability.\nAntenatal diagnosis\nPrenatal ultrasound abnormalities (hydronephrosis, corpus callosum agenesis and increased nuchal fold) are occasionally observed. On the other hand, when mosaic trisomy 8 is detected without ultrasound abnormalities, this should be interpreted with care since confined placental mosaicism frequently occurs. Prenatal diagnosis should be considered in cases where one of the parents has a mosaic trisomy 8.\nGenetic counseling\nThe origin of the mosaic trisomy 8 is either post-zygotic non-disjunction, i.e. a mitotic error in the fetus, or meiotic non-disjunction resulting in a full trisomy 8 karyotype with subsequently trisomy rescue by mitotic loss of a chromosome 8. Almost all cases occur sporadically, but genetic counseling should be offered to parents and the individuals themselves.\nManagement and treatment\nManagement requires a multidisciplinary approach. In some cases, cardiac surgery may be proposed.\nPrognosis\nMosaic trisomy 8 seems to predispose to Wilms tumors, myelodysplasias and myeloid leukemia. Some mosaic trisomy 8 patients have had children. In absence of serious malformations, life expectancy is normal.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Pr C.M.A. [Conny] VAN RAVENSWAAIJ-ARTS | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Mosaic variegated aneuploidy syndrome", "Disease Definition": "Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal anomaly characterized by multiple mosaic aneuploidies that leads to a variety of phenotypic abnormalities and cancer predisposition.", "ORPHA ID": 1052, "Summary": "Epidemiology\nTo date, 41 cases of MVA have been described in the literature.\nClinical description\nThe most common clinical features are growth retardation of prenatal onset, microcephaly, developmental delay, structural central nervous system and ophthalmological anomalies (e.g. cataract, corneal opacities, microphthalmia and glaucoma), and mild dysmorphic features, including triangular facies, micrognathia, and epicanthic folds. Additional features include oligohydramnios, ventricular dilatation, Dandy-Walker malformation, fetal ascites, and increased nuchal translucency. Cancer occurs in approximately 1/3 of individuals. Wilms tumor, rhabdomyosarcoma, acute lymphoblastic leukemia, and granulosa cell malignant tumor of the ovary (see these terms) all occur before the age of 5 years. In one individual, carcinoma of the ampulla of Vater and of the colon occurred in adulthood.\nEtiology\nMVA is due to defective cell division, leading to aberrant disjunction of chromosomes during mitosis. This results in a high proportion (>10%) of aneuploid cells. Mutations of the BUB1B and CEP57 genes have been identified in individuals with MVA. BUB1B encodes BUBR1, a key protein in the mitotic spindle checkpoint. CEP57 is a centrosomal protein involved in nucleating and stabilizing microtubules. Individuals with BUB1B mutations have a high incidence of cancer (approximately 75%). No individual with a CEP57 mutation has thus far been diagnosed with cancer.\nDiagnostic methods\nDiagnosis of MVA is based on cytogenetic analysis showing variable aneuploidy.\nDifferential diagnosis\nAneuploidy can be a feature of chromosomal instability syndromes including Roberts syndrome, ataxia telangiectasia, xeroderma pigmentosum, Bloom syndrome, Werner syndrome and Nijmegen breakage syndrome. Microcephaly with chromosome instability can occur in Fanconi anemia (see these terms).\nAntenatal diagnosis\nPrenatal karyotype can be undertaken by chorionic villus sampling or amniocentesis. This allows prenatal diagnosis of familial recurrence or investigation of abnormal sonographic findings consistent with MVA.\nGenetic counseling\nMVA is inherited in an autosomal recessive manner. The parents of an affected child are obligate carriers. Recurrence risk to siblings is 25%. Carrier testing for at-risk family members of individuals with biallelic BUB1B or CEP57 mutations is possible.\nManagement and treatment\nClinical management depends on the affected individual's specific needs (e.g.: growth hormone therapy for the treatment of growth failure). Cases with a cytogenetic confirmation of MVA syndrome and/or demonstrated BUB1B mutations should be offered Wilms tumor surveillance with renal ultrasonography every three to four months until five years.\nPrognosis\nPrognosis is related to the nature of the malformations and the risk of malignancy.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Sandra HANKS  - Pr Nazneen RAHMAN  - Dr Katie SNAPE"}
{"Disease Name": "Mounier-Kühn syndrome", "Disease Definition": "A rare congenital respiratory disorder characterized by marked dilatation of the trachea and proximal bronchi that leads to impaired airway secretion clearance and recurrent lower respiratory tract infections.", "ORPHA ID": 3347, "Summary": "Epidemiology\nMounier-Kühn syndrome is a rare underdiagnosed condition of unknown prevalence. About 300 cases have been reported to date. The condition is more frequent in men.\nClinical description\nThe disorder may manifest at various ages but is usually diagnosed in young adults with recurrent bronchopulmonary infections (e.g. bronchitis, pneumonia), and tracheobronchial irritation of varying degrees of severity causing chronic dry or productive cough with purulent sputum production, dyspnea (occasionally on exertion) and hemoptysis. Progressive hoarseness has also been observed. Bronchial crackles and/or wheezing and finger clubbing are common. In mild cases, patients are asymptomatic or present only with chronic cough and have normal pulmonary function. In the rare severe cases, patients may suffer from pulmonary obstructive diseases such as bronchiectasis or bullous emphysema, and airflow obstruction that can lead to chronic respiratory failure.\nEtiology\nMounier-Kühn syndrome results from the atrophy of elastic fibers in the trachea and main bronchi which lead to thinning of the smooth muscle layer and subsequent tracheobroncheal flaccidity, dilatation and collapse. The etiologic mechanism remains unknown. Irritants like cigarette smoke and air pollution could act as irritating factors. The disease is sometimes associated with connective tissue diseases such as Ehlers-Danlos syndrome, Marfan syndrome and cutis laxa and might have a genetic origin; however no gene mutation has been identified to date.\nDiagnostic methods\nMounier-Kühn syndrome is diagnosed when the coronal and the sagittal diameters of the trachea, measured on plain chest radiography or computed tomography (CT), are greater than 25 mm and 27 mm, respectively in males, and greater than 21 mm and 23 mm in females. Fiberoptic bronchoscopy shows dilatation of the trachea and proximal bronchi, expiratory collapse in patients with tracheomalacia, and possible presence of diverticula on the posterior wall. Biopsies of bronchial and tracheal wall tissue show loss of elastic fibers but are usually unnecessary. Pulmonary function tests can be normal or show varying degrees of airflow obstruction and increased residual volume.\nDifferential diagnosis\nDifferential diagnosis includes lower respiratory tract infections like bronchitis and chronic obstructive pulmonary disease, ankylosing spondylitis, and Williams-Campbell syndrome.\nGenetic counseling\nThe disease is sporadic in most cases, although several familial cases have been described.\nManagement and treatment\nTreatment is symptomatic. Chest physiotherapy can be proposed to improve mucociliary clearance and antibiotics are administered for treatment of pulmonary infections. Some patients may benefit from non-invasive positive-pressure ventilation, also needed at night in severe cases. Insertion of a tracheal or tracheobronchial stent, with or without surgical tracheobronchoplasty, was shown to reduce airway collapsibility in some highly selected cases with tracheomalacia. Double lung transplantation has been successful in one case.\nPrognosis\nThe impact of this condition on life expectancy has not been evaluated. Complications include respiratory infections, tracheomalacia, pulmonary obstructive diseases, pneumothorax, and exceptionally lung fibrosis that can lead to chronic respiratory failure.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Vincent COTTIN  - Dr Mouhamad NASSER"}
{"Disease Name": "Mowat-Wilson syndrome", "Disease Definition": "A rare multiple congenital anomaly syndrome characterized by a distinct facial phenotype, intellectual disability, epilepsy, Hirschsprung disease (HSCR) and variable congenital malformations.", "ORPHA ID": 2152, "Summary": "Epidemiology\nPrevalence is estimated at 1/50,000-70,000 live births. Over 300 patients have been reported so far. It seems probable that Mowat-Wilson syndrome (MWS) is underdiagnosed, particularly in patients without HSCR.\nClinical description\nThe typical characteristic facies of MWS includes a high forehead, frontal bossing, large eyebrows that are medially flaring and sparse in the middle part, hypertelorism, deepset but large eyes, large and uplifted ear lobes with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth with M-shaped upper lip, and a prominent but narrow and triangular pointed chin. The facies becomes more pronounced with age. Associated HSCR causes constipation which frequently persists after surgery. Patients usually have moderate to severe intellectual disability. Speech is absent or limited to a few words, with onset at around 4 years. Seizures are common; all types of seizures (absence, generalized tonic-clonic seizures, myoclonic, and focal seizures) have been reported. Most subjects have a happy demeanor with frequent smiling and a sociable personality. Other associated congenital anomalies can include cerebral (agenesis of the corpus callosum), cardiac (patent ductus arteriosus, ventricular septal defect), respiratory (valvular pulmonary stenosis, pulmonary artery sling, with or without tracheal stenosis), genitourinary (hypospadias, cryptorchidism, vesicoureteral reflux and hydronephrosis), ocular (microphthalmia) and musculoskeletal (pes planus, calcaneovalgus). Asplenia is rare. Affected children tend to have a high pain threshold.\nEtiology\nMWS is caused by heterozygous variants in the zinc finger E-box-binding homeobox 2 gene, ZEB2 (2q22.3). To date, over 100 variants have been reported in patients with a typical phenotype; variants are usually whole/partial gene deletions or truncating mutations, suggesting that haploinsufficiency is the main pathological mechanism. Genotype-phenotype analysis shows that facial gestalt and delayed psychomotor development are constant clinical features, while the frequent and severe congenital malformations are variable. In a small number of patients, missense variants affecting a functional domain of the ZEB2 protein can lead to an atypical phenotype.\nDiagnostic methods\nDistinct facies is particularly important for the initial clinical diagnosis and provides the hallmark warranting ZEB2 mutational analysis in all cases, even in the absence of HSCR. Congenital malformations and seizures require early clinical investigations for which patients should be referred to the relevant specialists (including neonatologists and pediatricians).\nDifferential diagnosis\nDifferential diagnoses include Pitt-Hopkins, Goldberg-Shprintzen megacolon, Smith-Lemli-Opitz and Angelman syndromes.\nAntenatal diagnosis\nPrenatal diagnosis is available for subsequent pregnancies of parents with an affected child.\nGenetic counseling\nMWS is an autosomal dominant disorder; however, the majority of MWS cases reported are sporadic. Germinal mosaicism has been described and recurrence risk has been calculated at 2%.\nManagement and treatment\nCongenital heart disease and HSCR disease may require early surgery during the first days or months of life. Seizures are common and require standard therapy. Genitourinary anomalies may require surgery in the first few years of life. Psychomotor development is delayed in all patients and thus, rehabilitation (physical therapy, psychomotor and speech therapy) should be started as soon as possible. Musculoskeletal anomalies may require orthopedic intervention.\nPrognosis\nMortality and morbidity depend on the presence and severity of congenital anomalies. Patients have been reported to live into early adulthood but require assistance with activities of daily living.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Stefano Giuseppe CARAFFI | ITHACA* - Dr Livia GARAVELLI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome", "Disease Definition": "Moyamoya angiopathy - short stature - facial dysmorphism - hypergonadotropic hypogonadism is a very rare, hereditary, neurological, dysmorphic syndrome characterized by moyamoya disease, short stature of postnatal onset, and stereotyped facial dysmorphism.", "ORPHA ID": 280679, "Summary": "Epidemiology\nThe syndrome is extremely rare and has been reported in three unrelated families to date, with 10 affected individuals in several generations. These families are not from Japan or Asia, whereas in general the incidence of moyamoya disease (see this term) is highest in Japan and other Asian countries, in comparison with other parts of the world.\nClinical description\nAffected patients are all male (X-linked inheritance) and have moyamoya angiopathy (progressive stenosis of the terminal portion of the intracranial internal carotid arteries), short stature, hypergonadotropic hypogonadism, and other variable manifestations including stroke, hypertension, dilated cardiomyopathy (see this term), premature coronary heart disease, premature hair graying, azoospermia, and early bilateral acquired cataract. Moyamoya angiopathy causes cerebral infarcts or hemorrhage and acute neurological symptoms. Facial dysmorphism is characterized by hypertelorism, flared nares, long philtrum, and mild ptosis. Carrier females are not affected.\nEtiology\nThe genetic cause appears to involve Xq28 deletions removing MTCP1/CMC4and BRCC3 (Xq28) .The specific pathophysiological mechanisms underlying this disorder remain obscure, but appear to involve alteration in DNA repair.\nGenetic counseling\nReported cases are suggestive of a hereditary syndrome with an X-linked recessive pattern of inheritance.\n\n                            Last update: \n                            April 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Karin KLIJN"}
{"Disease Name": "Moyamoya disease with early-onset achalasia", "Disease Definition": "Moyamoya disease with early-onset achalasia is an exceedingly rare autosomal recessive neurological disorder reported only in a few families so far. It is characterized by the association of early onset achalasia (manifesting in infancy) with severe intracranial angiopathy that is consistent with moyamoya angiopathy in most cases (moyamoya disease; see this term). Other variable associated manifestations include hypertension, Raynaud phenomenon, and livedo reticularis.", "ORPHA ID": 401945, "Summary": ""}
{"Disease Name": "Moyamoya disease", "Disease Definition": "Moyamoya disease (MMD) is a rare intracranial arteriopathy involving progressive stenosis of the cerebral vasculature located at the base of the brain causing transient ischemic attacks or strokes.", "ORPHA ID": 2573, "Summary": "Epidemiology\nThe incidence of MMD is highest in Asian populations but MMD occurs in many other ethnic groups. The incidence ranges from 1/280,000 to 1/89,000 in Japan and China to1/1,100,000 in the US. The prevalence in Japan is estimated to be 1/30,000-1/9,500.\nClinical description\nThere are two peak incidence ages: young children (5-9 years) and adults (mid-40s). Involvement is usually bilateral but unilateral cases are reported. Disease manifestations are highly variable. Some affected individuals remain asymptomatic, some develop transient attacks, and others severe neurologic deficits as a result of infarcts or hemorrhage. Hemorrhage occurs less often in children. Other manifestations include headache, dizziness, seizures, and chorea. Some patients present intellectual disability. The course is also highly variable but generally progressive. The term MMD is used when there is no cause and Moyamoya syndrome (MMS) when the disease is associated with other diseases (sickle cell anemia, neurofibromatosis; see these terms).\nEtiology\nThe etiology of MMD is not currently known but is thought to be multifactorial with genetic determinants playing a role. In Japan, about 15% of patients have a family history. Mutations in the RNF213(17q25.3) gene have been found in some patients but their pathogenic role remains unclear. The intracranial vasculopathy associated with smooth muscle actin alpha 2 (ACTA2) (10q23.31) mutations has been referred to as MMS, but it has distinctive angiographic features, including dilatation of proximal ICAs, an abnormally straight course of intracranial arteries, and absence of typical moyamoya collateral vessels.\nDiagnostic methods\nThe diagnosis of MMD may be difficult because it is rare and because of the non-characteristic signs and symptoms. Diagnosis is suspected on the basis of the clinical presentation and imaging findings. Cerebral angiography is the standard confirmatory diagnostic method. Moyamoya disease involves in particular the supraclinoid internal carotid arteries and their proximal branches. The term moyamoya means \"puff of smoke\" in Japanese, in reference to the appearance of abnormal vascular collateral networks on angiography that develop adjacent to the stenotic vessels. Magnetic resonance angiography (MRA) can also be used.\nDifferential diagnosis\nMMD may develop in an isolated manner but can also be associated with other diseases when it is known as MMS: typical angiographic MMDfeatures associated with other diseases, e.g. sickle cell anemia, Down syndrome, neurofibromatosis type 1 (see these terms) and many others.\nGenetic counseling\nAutosomal dominant inheritance with incomplete penetrance has been described in affected Japanese families. Other suggested patterns include autosomal-recessive, X-linked-recessive, or multifactorial inheritance.\nManagement and treatment\nNo specific treatment to stop progression or reverse the intracranial arteriopathy is available for MMD. Drug therapy is mainly used to counter disease complications such as stroke and transient ischemic attacks, to alleviate symptoms, and to prevent cognitive deterioration. Physical, occupational and speech therapy may be needed after attacks. Surgical revascularization procedures to restore blood flow to the brain involving direct, indirect or combined techniques have also been used and appear to reduce the risk ofischemic stroke and possibly cognitive dysfunction. The indication and timing of surgery remains controversial.\nPrognosis\nEarly detection and appropriate treatment improve the long-term outcome. The prognosis depends on disease severity. Mortality rates are estimated at about 5% for adults and 2% for children. The main cause of death is hemorrhage.\n\n                            Last update: \n                            April 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Karin KLIJN"}
{"Disease Name": "Moynahan syndrome", "Disease Definition": "A rare, genetic, epilepsy syndrome characterized by congenital alopecia, early-onset epilepsy, intellectual disability and speech delay. Large stature, delayed bone development and abnormal electroencephalogram have also been associated.", "ORPHA ID": 2574, "Summary": ""}
{"Disease Name": "MPDU1-CDG", "Disease Definition": "A rare disorder of multiple-pathway glycosylation characterised by psychomotor delay, seizures, failure to thrive, cardiomyopathy, and ichthyosis-like cutaneous anomalies.", "ORPHA ID": 79323, "Summary": ""}
{"Disease Name": "MPI-CDG", "Disease Definition": "MPI-CDG is a form of congenital disorders of N-linked glycosylation, characterized by cyclic vomiting, profound hypoglycemia, failure to thrive, liver fibrosis, gastrointestinal complications (protein-losing enteropathy with hypoalbuminaemia, life-threatening intestinal bleeding of diffuse origin), and thrombotic events (protein C and S deficiency, low anti-thrombine III levels), whereas neurological development and cognitive capacity is usually normal. The clinical course is variable even within families. The disease is caused by loss of function of the gene MPI (15q24.1).", "ORPHA ID": 79319, "Summary": ""}
{"Disease Name": "MRCS syndrome", "Disease Definition": "MRCS syndrome is a rare, genetic retinal dystrophy disorder characterized by bilateral microcornea, rod-cone dystrophy, cataracts and posterior staphyloma, in the absence of other systemic features. Night blindness is typically the presenting manifestation and nystagmus, strabismus, astigmatism and angle closure glaucoma may be associated findings. Progressive visual acuity deterioration, due to pulverulent-like cataracts, results in poor vision ranging from no light perception to 20/400.", "ORPHA ID": 263347, "Summary": ""}
{"Disease Name": "MT-ATP6-related mitochondrial spastic paraplegia", "Disease Definition": "A rare complex hereditary spastic paraplegia characterized by adulthood-onset of slowly progressive, bilateral, mainly lower limb spasticity and distal weakness associated with lower limb pain, hyperreflexia, and reduced vibration sense. Axonal neuropathy is frequently observed on electromyography and nerve conduction examination.", "ORPHA ID": 320360, "Summary": ""}
{"Disease Name": "MTHFS-related developmental delay-microcephaly-short stature-epilepsy syndrome", "Disease Definition": "A rare, genetic, neurometabolic disease characterized by microcephaly, short stature, epilepsy, cerebral hypomyelination, severe global developmental delay, and progressive spasticity. Macrocytic anemia and hyperthermia have also been reported in association. Brain imaging reveals delayed myelination with minimal progression over time, mild cerebellar atrophy and/or thin corpus callosum.", "ORPHA ID": 597874, "Summary": ""}
{"Disease Name": "Mu-heavy chain disease", "Disease Definition": "A type of HCD characterized by the production of incomplete monoclonal mu-heavy chains without associated light chains. The clinical presentation resembles that of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).", "ORPHA ID": 100024, "Summary": "Epidemiology\nThe prevalence is unknown but the disease is extremely rare. Only about 35 cases have been reported in the world literature.\nClinical description\nThe age at diagnosis is usually between 50 and 60 years. The most common presenting symptoms are those of a lymphoproliferative malignancy although peripheral lymphadenopathy is less common than in CLL. Lytic bone lesions and osteoporosis have been reported in a few cases.\nEtiology\nThe cause of mu-HCD is unknown.\nDiagnostic methods\nThe diagnosis of mu-HCD is made by documentation of the abnormal heavy chain by immunofixation of serum and urine. Unlike alpha- and gamma-HCD, some patients with mu-HCD have increased free light chain secretion (Bence Jones proteinuria). Examination of the bone-marrow shows an increase in lymphocytes, plasma cells, or plasmacytoid lymphocytes.\nDifferential diagnosis\nThe differential diagnosis of mu-HCD includes all lymphoplasma-cell proliferative disorders. Without a suspicion for the disease, mu-HCD is difficult to diagnose. The finding of Bence Jones proteinuria in a patient with a lymphoproliferative disorder and vacuolated plasma cells in the bone marrow deserves further investigation for possible mu-HCD.\nManagement and treatment\nThere is no specific treatment for mu-HCD. If mu-HCD protein is found in the serum of an asymptomatic patient this should be followed closely for the development of a symptomatic lymphoplasma-cell proliferative disorder. Treatment of symptomatic patients with mu-HCD is similar to that employed in patients with CLL (eg, glucocorticoids, alkylating agents).\nPrognosis\nThe disease course and prognosis seen in mu-HCD is highly variable. The median survival from time of diagnosis is 24 months and ranges from < 1 month to 11 years.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Robert KYLE  - Dr Dietlind WAHNER-ROEDLER"}
{"Disease Name": "MUC1-related autosomal dominant tubulointerstitial kidney disease", "Disease Definition": "A rare autosomal dominant tubulointerstitial kidney (ADTKD) disease due to MUC1 mutations characterized clinically by a bland urinalysis (absence of blood or protein in the urine), and chronic kidney disease leading to end-stage kidney disease (ESKD) between 20 and 80 years.", "ORPHA ID": 88949, "Summary": "Epidemiology\nWhilst prevalence data is limited, prevalence is estimated at 1/1,400,000 in the USA and 1/250,000 in Ireland. The disease has equal prevalence among all studied racial groups and genders.\nClinical description\nChronic kidney disease usually is first evident in the early twenties. Patients will have slowly progressive loss of kidney function, between 1 and 3 ml/min/1.73m2/year. The mean age of ESKD is approximately 45 years of age, although this varies widely from 20 to over 70 years of age, even among family members with the same mutation. The reason for this variation in age of ESKD is unclear.\nEtiology\nADTKD-MUC1 is caused by frameshift mutations in the MUC1 gene, all of which result in the creation of the same frameshift protein. The most common mutation (responsible for approximately 95% of cases) is a cytosine duplication within a tract of seven cytosines. The protein deposits in the endoplasmic reticulum Golgi intermediate compartment (ERGIC) where it leads to cellular stress, early cell death, and progressive kidney failure.\nDiagnostic methods\nDiagnosis should be considered in families where a parent and child have chronic kidney disease, and urinalysis reveals no blood and little or no protein. De novo mutations may arise and are difficult to identify. Patients should first undergo multi-gene panel testing or whole exome sequencing for other mutations that cause ADTKD and then undergo specialized genetic testing for the MUC1 cytosine duplication, which is causative in 95% of cases of ADTKD-MUC1. This specific test is available in certain laboratories in Europe (see Orphanet Diagnostic Tests) and the USA. Multigene panels, whole exome, and whole genome sequencing do not detect this duplication. If negative, other causative mutations can be identified immunohistochemically in a research setting.\nDifferential diagnosis\nADTKD-UMOD is clinically very similar, distinguished only by the higher prevalence of gout. Most other conditions have other associated symptoms, but when these symptoms are less severe or not clinically noted, ADTKD-MUC1 should be considered. These include kidney disease related to DNAJB11, IFT140, or HNF1B, and, in rare cases, Alagille syndrome.\nAntenatal diagnosis\nDue to the difficulty in genetic testing for MUC1 variants, antenatal diagnosis is not currently available in the USA but is available in Europe.\nGenetic counseling\nThe disorder is autosomal dominant. Counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. Genetic testing in childhood is not advised as patients are asymptomatic and may not have symptoms of CKD for more than two decades. Relatives should be informed of their risk of ADTKD-MUC1, as the disease is often misdiagnosed, and reaching out to family members can prevent the need for kidney biopsy or inappropriate treatment.\nManagement and treatment\nThere are currently no specific therapies available. Sodium glucose-2 transport inhibitors (SGLT2 inhibitors) are indicated in chronic kidney disease and may be helpful in ADTKD. Patients with ADTKD-MUC1 are excellent transplant candidates, as the disease does not recur in the transplanted kidney and most patients do not have other comorbid conditions. The goal should be transplant without ever needing dialysis. Family members should be screened for the familial MUC1 mutation to see if they can donate. Major advances are occurring in kidney disease management, with placement of pig kidneys, CRISPR technology to treat genetic disorders, and advances in immunosuppression-free kidney transplantation.\nPrognosis\nPatients usually develop end-stage kidney disease at a mean age of 45 years, but there is wide inter- and intra-familial variation. Some family members may go on dialysis in their twenties, while other family members may not start dialysis until past 70 years of age. Survival post-transplant is comparable to the general ESKD transplant population.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Anthony BLEYER  - Pr Stanislav KMOCH"}
{"Disease Name": "Mucinous adenocarcinoma of ovary", "Disease Definition": "Mucinous adenocarcinoma of ovary is a rare, malignant epithelial tumor of the ovary characterized, macroscopically, by a large, usually unilateral tumor with smooth surface and evenly distributed cystic and solid areas and, histologically, by a complex papillary growth pattern with microscopic cystic glands and necrotic debris. Patients often present with pelvic pain and pressure, abdominal mass or gastrointestinal problems such as early satiety or bloating.", "ORPHA ID": 398961, "Summary": ""}
{"Disease Name": "Mucinous adenocarcinoma of the appendix", "Disease Definition": "Mucinous adenocarcinoma of the appendix is a very rare, slow growing, well-differentiated epithelial neoplasm of the appendix characterized by abundant mucin production. Clinically, it presents as acute appendicitis (with abdominal pain, fever, leukocytosis) or as pseudomyxoma peritonei (wide-spread presence of mucin within the peritoneal cavity), however some patients may be completely asymptomatic at the time of diagnosis. In many cases, a second gastrointestinal malignancy is present.", "ORPHA ID": 391723, "Summary": ""}
{"Disease Name": "Mucinous cystadenocarcinoma of the pancreas", "Disease Definition": "A rare, epithelial tumor of the pancreas characterized, histologically, by columnar, mucin-producing epithelium associated with ovarian-type subepithelial stroma, which does not communicate with the pancreatic ductal system, most frequently localized to the body or tail of the pancreas. Clinically, small tumors (<3 cm) are usually asymptomatic, while large tumors typically present obstructive jaundice, a palpable abdominal mass, and may associate portal hypertension, hemobilia and diabetes mellitus.", "ORPHA ID": 424053, "Summary": ""}
{"Disease Name": "Mucinous tubular and spindle cell renal carcinoma", "Disease Definition": "Mucinous tubular and spindle cell renal carcinoma is a rare subtype of renal cell carcinoma characterized, histologically, by tubular architecture and sheets of spindle cells embedded in a mucinous/myxoid stroma and, macroscopically, by a solid, generally well-circumscribed, partially encapsulated tumor of variable size, with a homogenously colored, bulging cut surface, occassionally containing areas of hemorrhage or necrosis, usually located in the cortex. Patients can present abdominal/flank pain, adbominal mass and/or hematuria, however most are asymptomatic and tumor is discovered incidentally. Indolent behavior is frequent and association with nephrolithiasis and end-stage kidney disease has been noted.", "ORPHA ID": 319322, "Summary": ""}
{"Disease Name": "Muckle-Wells syndrome", "Disease Definition": "Muckle-Wells syndrome (MWS) is an intermediate form of cryopyrin-associated periodic syndrome (CAPS; see this term) and is characterized by recurrent fever (with malaise and chills), recurrent urticaria-like skin rash, sensorineural deafness, general signs of inflammation (eye redness, headaches, arthralgia/myalgia) and potentially life-threatening secondary amyloidosis (AA type).", "ORPHA ID": 575, "Summary": "Epidemiology\nThe prevalence of MWS is unknown. However a French survey through genetic laboratories has reported 135 cases and estimated CAPS prevalence at 1/360,000.\nClinical description\nMWS onset is variable but patients usually present within the first few years of life with recurrent peak of fever (max of 39-40°C, starting generally in the evening (circadian pattern) and lasting a few hours, with a variable recurrence during a week. Intense general malaise and chills occur at the same time and lead to severe disability. Non-pruriginous urticarial rash (diffuse, erythematous, edematous plaques on a background of generalized, faintly erythematous patches) is a key feature of CAPS and is generally present with marked intensification during acute episodes. Progressive, high frequency, sensorineural deafness due at least in part to chronic inflammation of the cochlea begins in childhood (generally after the age of 10 years) resulting in complete deafness. Myalgia, arthralgias and distal edema are very common. With age, patients develop eythematous band over the hands as well as digital clubbing. Additional features include severe chronic fatigue, recurrent headaches, cognitive impairment, ocular involvement (conjunctivitis, uveitis, episcleritis), oral aphthosis, lymphadenopathy, thoracic and abdominal pain. Cold, fatigue, stress, or exercise are universal triggers of acute inflammation however acute attacks may appear unprovoked. Secondary amyloidosisis (see this term), revealed by persistent proteinuria, is a prominent feature affecting 25% of patients and can result in chronic renal insufficiency. Severe MWS cases, (MWS/CINCA) may display chronic meningitis, papillar edema with progressive optic atrophy. Failure to thrive and male sterility are common.\nEtiology\nMWS is due to dominant mutation in the NLRP3 (1q44) gene which encodes cryopyrin. This defect results in the gain of function of cryopyrin that ultimately leads to the increased secretion of the proinflammatory cytokine interleukin (IL)-1 beta and and dysregulated inflammation. Mutations in this gene may also cause two additional phenotypes of CAPS: familial cold urticaria (FCAS) and CINCA syndrome (see these terms), Patients carrying identical amino acid substitution may present with distinctly different clinical subtypes, suggesting that additional genetic and/or environmental modifying factors are important in disease expression. Somatic NLRP3 mosaicism could explain 30-60% of patients with negative conventional genetic testing. Some patients with a classical phenotype of MWS, FCAS or CINCA syndrome may not have mutations in NLRP3.\nGenetic counseling\nTransmission is autosomal dominant with variable expression within a family and from one family to another.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Isabelle KONE-PAUT"}
{"Disease Name": "Mucocutaneous venous malformations", "Disease Definition": "Mucocutaneous venous malformations (VMCMs) are hereditary vascular malformations characterized by the presence of small, multifocal, bluish-purple venous lesions involving the skin and mucosa.", "ORPHA ID": 2451, "Summary": "Epidemiology\nPrevalence is unknown but around 20 families have been identified so far.\nClinical description\nThe multifocal venous lesions are usually small (< 2cm in diameter), and are present at birth. They are soft and usually compressible and undergo proportionate growth with age. There is significant clinical variation with respect to the size, location and number of lesions, even between affected individuals from the same family. Classically, one individual in a given family has a large lesion. Small lesions are usually asymptomatic, whereas larger lesions can cause pain and invade subcutaneous muscle. New lesions appear with time. Patients with VMCMs have normal mental and physical development.\nEtiology\nVMCMs are associated with amino acid substitutions (R849W and Y897S) in the tyrosine-protein kinase endothelial cell receptor (TEK/TIE2; 9p21). Approximately 90% of individuals who have a mutation in the TEK gene develop mucocutaneous venous malformations by 20 years of age; conversely, approximately 10% of individuals with a TEK mutation are clinically unaffected.\nDiagnostic methods\nDiagnosis is based on clinical evaluation of the cutaneous lesions. Doppler ultrasound examination can be used to confirm slow blood flow, and MRI can be used to confirm the venous component and extent of the lesions. Ultrasound examination reveals saccular compressible venous-like cavities. Molecular genetic testing for confirmation of the diagnosis is available on a research basis.\nDifferential diagnosis\nThe differential diagnosis should include glomuvenous malformations (GVMs, which are deeper purple in color than VMCMs, painful on palpation, and more superficial than venous malformations; see this term) and Blue rubber bleb nevus syndrome (characterized by the association of cutaneous and mucosal venous-like lesions with gastrointestinal lesions; see this term).\nAntenatal diagnosis\nPrenatal diagnosis is feasible for affected families in which the disease-causing mutation has been identified, but is not widely available.\nGenetic counseling\nVMCMs are transmitted in an autosomal dominant manner with incomplete penetrance. Paradominant inheritance (presence of a germline mutation and a somatic mutation) appears to be involved in disease expression and may explain the variability in clinical phenotype. Genetic counseling should be provided for affected families, informing patients of a 50% risk of inheriting the disease-causing mutation and of the variability in clinical expression. There is no anticipation in reported families.\nManagement and treatment\nThe principle treatment approach is sclerotherapy, alone or in combination with plastic and reconstructive surgery depending on the size and location of the lesions. Ethanol (96%) for injection is the most commonly used sclerosing agent and obtained EU orphan drug designation in April 2005 for the treatment of congenital venous malformations. When D-dimers are elevated, indicating activation of coagulation, low-molecular-weight heparin can be used to treat the associated pain. Female patients should avoid using oral contraceptives with high estrogen levels.\nPrognosis\nThe prognosis for patients is good, malignant transformation has not been reported and the life expectancy for patients is not reduced.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence BOON  - Pr Miikka VIKKULA"}
{"Disease Name": "Mucolipidosis type II", "Disease Definition": "A rare, severe form of mucolipidosis characterized by growth retardation, skeletal abnormalities (dysostosis multiplex, craniosynostosis, contractures of the joints and osteopenia), facial dysmorphism, stiff skin, obstructive airway, cardiomegaly and severe global developmental delay.", "ORPHA ID": 576, "Summary": "Epidemiology\nMucolipidosis type II (MLII) and type III (MLIII) represent a continuum of clinical severity and reported data is either combined or reported separately; in all instances the data is over 10 years old. The combined birth prevalence is estimated between 1/ 37,000-455,000 worldwide, whereas the reported birth prevalence for MLII is estimated between 1/123,000-2,000,000 in Europe. A founder effect has been reported in Saguenay-Lac-St-Jean region of Quebec where birth prevalence is estimated at 1/6,000.\nClinical description\nMLII patients present prenatally (hydrops fetalis), directly after birth or within the first months of live with dysmorphic features, cardiac involvement, respiratory symptoms, dysostosis multiplex, severe growth abnormalities, transient neonatal hyperparathyroidism inducing rickets-like bone disease (not always present), clubfeet, hypotonia and global developmental delay; all symptoms gradually worsen over time. Facial dysmorphism includes a flat face, shallow orbits with proptotic eyes (due to craniosynostosis), depressed nasal bridge, prominent mouth and gingival hypertrophy. Coarsening of facial features is progressive. Spinal cord compression develops over time. Postnatal growth (both length and weight) usually stops in the second year of life and contractures develop in all joints. Most patients never walk. Cardiac involvement most commonly includes the thickening and insufficiency of the mitral or aortic valves. Breathing is noisy due to the progressive narrowing of airways, mucosal thickening and stiffening of all connective tissues which, along with cardiac involvement, leads to cardiorespiratory insufficiency.\nEtiology\nMLII is due to mutations in the GNPTAB gene (12q23.3), encoding the alpha and beta subunits of the N-acetylglucosamine phosphotransferase complex. Mutations in this gene lead to a failure of mannose-6-phosphate (MP6) synthesis, the marker on the oligomannosyl type glycan side chains of lysosomal enzymes, which targets the enzymes to the lysosomes. Without the MP6 signal, the enzymes are missorted into the extracellular space, leading to accumulation of the enzymes in the tissues.\nDiagnostic methods\nDiagnosis is based on clinical/radiographic examination as well as detection of elevated plasma lysosomal enzyme or decreased lysosomal enzyme activity. Radiographs reveal increasing osteopenia and dysostosis multiplex (diaphyseal widening and shortening of tubular bones, anterior-inferior hook configuration of first and/or second lumbar vertebra, and relatively long pubic and ischial bones). Lysosomal hydrolase levels in plasma and other body fluids are 5-20 times higher than normal. Molecular mutation screening of the GNPTAB gene confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses include Hurler syndrome, the infantile form of galactosialidosis, sialidosis type 2, infantile form of free sialic acid storage disease, and hypocalcemic rickets. Pacman dysplasia is in many instances the prenatal expression of MLII.\nAntenatal diagnosis\nAntenatal diagnosis is possible in chorionic villi by molecular testing.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThere is no cure for MLII and treatment is supportive. Interactive programs to stimulate cognitive development, as well as ''low-impact'' therapies (such as aqua therapy) and occupational and/or speech therapy may be beneficial. Attention should be given to overfeeding, which should be avoided. Gingivectomy may be considered in those with severe mouth pain and infections. Respiratory support and assisted ventilation may be necessary in some cases. Infants and toddlers should have regular follow-ups (every 3 months) to monitor cardiac and pulmonary functioning, and afterwards every year throughout early childhood.\nPrognosis\nThe prognosis is poor with a fatal outcome (most commonly due to cardiorespiratory insufficiency) most often occurring in early childhood.\n\n                            Last update: \n                            October 2021\n\n\n                            - Expert reviewer(s): \n                            Dr E. [Esmee] OUSSOREN | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Mucolipidosis type III alpha/beta", "Disease Definition": "Mucolipidosis III alpha/beta (MLIII alpha/beta) is a lysosomal disorder characterized by progressive slowing of the growth rate from early childhood, stiffness and pain in joints, gradual coarsening of facial features, moderate developmental delay and mild intellectual disability in most patients.", "ORPHA ID": 423461, "Summary": "Epidemiology\nPrevalence has been estimated at 1/53,000 live births in Portugal and 1/1, 250,000 live births in the Netherlands.\nClinical description\nInfants appear normal at birth. Onset is gradual and usually observed at around the age of 3 years with slowing of growth rate and apparent shoulder, hip and knee contractures. Dysmorphic facial features (full cheeks, depressed nasal bridge, prominent mouth and inconsistently mild gingival hypertrophy) are mild but coarsen with age. Otitis media is common in the young. Functional changes in hard and soft connective tissues result in a slowly progressive reduction in the range of motion in the shoulders, hips and knees. Gradual hardening of the cardiac valves, from childhood onwards, ultimately leads to cardiac insufficiency. Gait slows in childhood, becoming increasingly painful due to severe hip disease. Bone pain, even at rest, results from osteoporosis and osteolytic bone lesions. Moderate claw-like flexion deformity of the fingers and carpal tunnel syndrome are common complications. Bronchitis/bronchopneumonia is frequent in childhood and gradual restrictive lung disease becomes life-threatening in older patients. Mild intellectual disability has been reported in most patients. Death is often due to treatment-refractory cardiopulmonary failure.\nEtiology\nML III alpha/beta is due to mutations in the GNPTABgene (12q23.3), encoding the inactive alpha/beta precursor protein that generates the catalytically active alpha and beta subunits of N-acetylglucosamine-1-phosphotransferase (GNPT). The gamma subunit is encoded by the GNPTG gene (16p13.3) and mutations in this gene cause the milder MLIII gamma (see this term). In MLIII alpha/beta, at least one of the two mutations is hypomorphic, which results in the later onset and a less severe phenotype than ML II.\nDiagnostic methods\nDiagnosis is based on clinical and radiographic observations at the time of onset and is confirmed initially by assays of several lysosomal enzymes in plasma demonstrating increased activity (up to 10-fold) of almost all lysosomal hydrolases. In cultured fibroblasts, the activity of the same lysosomal enzymes is significantly decreased but not totally absent. Mutation screening of the GNPTAB gene provides the most formal and useful confirmation of the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include MLIII gamma; mucopolysaccharidosis type 1, 2, 4B, 6, and 7; free sialic acid storage disease, infantile form; multiple sulfatase deficiency; multiple epiphyseal dysplasia; progressive pseudorheumatoid arthropathy of childhood; chondrodysplasia punctata; and rheumatoid arthritis (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a patient with known disease-causing mutant genotype.\nGenetic counseling\nML III alpha/beta is inherited autosomal recessively and genetic counseling is offered accordingly.\nManagement and treatment\nThere is no cure for ML III alpha/beta and treatment is purely supportive. Myringotomy and tube placement may be recommended to those with recurrent otitis media. Low-impact physical therapy and tendon release procedures (for carpal tunnel features) can provide some relief. Analgesics and IV bisphosphonate can treat bone pain. Young children should be examined biannually. After the age of 6, yearly visits may suffice, but cardiac valve status must be monitored. Cognitive stimulation is of paramount importance in children with only minor intellectual disability. Careful weighing of risk and benefit is required when considering surgery.\nPrognosis\nPrognosis is generally poor, with the morbidity of late complications adversely affecting quality of life and limiting life expectancy. Occasionally patients may survive into mid-adulthood.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Jules LEROY"}
{"Disease Name": "Mucolipidosis type III gamma", "Disease Definition": "Mucolipidosis type III gamma (ML 3 gamma) is a very rare lysosomal disease, that has most often been observed in the Middle East, characterized by a progressive slowing of the growth rate in early childhood; stiffness and pain in shoulders, hips, and finger joints; a gradual, mild coarsening of facial features; and by a slower progression, milder clinical course and longer life expectancy than that seen in mucolipidosis type II and mucolipidosis type III alpha/beta. Cognitive function is normal or only slightly impaired and retinitis pigmentosa has been reported in a few patients. Many survive into early adulthood, but ultimately succumb to cardiorespiratory insufficiency.", "ORPHA ID": 423470, "Summary": ""}
{"Disease Name": "Mucolipidosis type III", "Disease Definition": "A rare lysosomal disease characterized by dysmorphic features and skeletal changes, restricted joint mobility, short stature, and hand deformities (such as claw hands, stiffness of hands, carpal tunnel syndrome, inability to make fists). Most patients have normal intellectual capacity and the clinical progression is less rapid than that of mucolipidosis type II (MLII).", "ORPHA ID": 577, "Summary": "Epidemiology\nMLII and mucolipidosis type III (MLIII) represent a spectrum of severity. The estimated combined prevalence at birth of MLII and MLIII is estimated between 1/ 37,000-455,000 worldwide. Whilst data is limited on MLIII, the prevalence at birth has been estimated at 1/1,250,000 in the Netherlands.\nClinical description\nIn MLIII, symptom onset is often in the first two decades of life and patients typically present with progressive hand deformities and restricted range of joint motion. For these symptoms, patients will often consult specialists such as rheumatologists and orthopedic or plastic surgeons. Progressive hip dysplasia may cause bone pain and leads to waddling gait. Other musculoskeletal problems like dysostosis multiplex, short stature, osteopenia, osteoarthritis, spinal cord compression and carpal tunnel syndrome are common in MLIII. Mild corneal clouding, cardiac valvular disease, mild coarsening of facial features, and mild intellectual disability are also possible.\nEtiology\nThere are two subtypes, the MLIII alpha/beta subtype due to pathogenic variants in GNPTAB (12q23.3) and the milder MLIII gamma subtype with pathogenic variants in GNPTG (16p13.3). These two genes encode for the activity of the enzyme N-acetylglucosamine-1-phosphotransferase, which is decreased in MLIII. This enzyme catalyzes the first step of the formation of mannose 6-phosphate (M6P) on specific lysosomal soluble hydrolases. MP6 is an essential targeting signal for the transport to the lysosomes and without this, the enzymes are missorted into the extracellular space and are not broken down within the lysosomes. This all leads to accumulation of the enzymes in connective tissues, cartilage, bones, ligaments, and other tissues.\nDiagnostic methods\nDiagnostic procedures include clinical/radiographical examination as well measurement of the activity of several lysosomal enzymes in plasma and/or fibroblasts, where these enzymes are elevated in plasma and decreased in fibroblasts. Radiographs reveal increasing osteopenia and dysostosis multiplex. In addition, GlcNAc-1-phophotransferase activity can be measured in fibroblasts. Finally, molecular analysis of GNPTAB (MLII and III α, β) or GNPTG (MLIII γ) can be performed.\nDifferential diagnosis\nDifferential diagnosis includes the different types of mucopolysaccharidosis and alpha-mannosidosis.\nAntenatal diagnosis\nAntenatal diagnosis is possible in chorionic villi by molecular testing.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThere are currently no curative or disease-modifying treatments available for MLIII. Musculoskeletal problems often requires surgical (orthopedic or plastic) interventions at a young age or pain and or/ anti-inflammatory medications. Bisphosphonate treatment in MLIII patients can decrease pain, increase bone density and improve mobility. However, long-term treatment with bisphosphonates is not to be recommended as this can induce femoral fractures.\nPrognosis\nThe MLIII α/ β subtype has a broad phenotypic range, from severely affected patients that die in childhood to milder affected patients displaying primarily skeletal symptoms, who survive into adulthood. Osteoarthritis is rapidly progressive in all patients (due to dysostosis multiplex and osteopenia) and results in cartilage destruction and bone lesions. All patients clinically suffer from bone and joint pain which has a great impact on the quality of life.\n\n                            Last update: \n                            October 2021\n\n\n                            - Expert reviewer(s): \n                            Dr E. [Esmee] OUSSOREN | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Mucolipidosis type IV", "Disease Definition": "A rare lysosomal storage disease characterized clinically by severe global development delay due to neuronal dysmyelination, hypotonia which gradually progresses to spasticity during childhood, speech deficits, progressive visual impairment (due to corneal clouding, retinal degeneration and optic atrophy), achlorhydria, with increased gastrin secretion and iron deficiency anemia, and kidney disease and failure, all in the absence of dysmorphic features.", "ORPHA ID": 578, "Summary": "Epidemiology\nMucolipidosis type IV (MLIV) is rare in the general population but is more prevalent among Ashkenazi Jews, among whom the prevalence at birth is 1/40 000.\nClinical description\nThe clinical spectrum of MLIV can range from severe to mild. MLIV patients typically have severe cognitive impairment, ocular abnormalities and achlorhydria with iron deficiency anemia. The most common presentation is of severe global developmental delay by the end of the first year of life and a progressive visual impairment during the first decade of life secondary to bilateral corneal opacities and retinal degeneration and resulting in blindness by adolescence. Development is usually limited to few or no words and poor hand use, and most patients do not achieve independent walking. Neurologic deficits (dys-/anarthria, slow chewing, eating and swallowing, spastic di- or quadriplegia, and hyperreflexive hypotonia) usually remain static during the first three decades of life, but in up to 15% neurologic deterioration may be observed. Brain MRI typically shows hypoplasia of the corpus callosum, signal abnormalities in the white matter, increased ferritin deposition in the thalamus and basal ganglia and (later in life) atrophy of the cerebellum. Progressive renal failure develops in the third decade of life. Strabismus and iron deficiency are present in about 50% of the patients. Milder manifestations or disproportionate affection of one of the organ systems may be observed. All of the MLIV patients have (asymptomatic) constitutive achlorhydria.\nEtiology\nMLIV is caused by biallelic mutations in the MCOLN1 (19p13.2) gene coding for mucolipin-1 protein, a nonselective cation channel which is distributed in the membranes of late endosomes and lysosomes in all tissues, with the highest expression in brain, kidney, liver, spleen, and heart. The exact pathophysiological mechanism is unknown, but is hypothesized that abnormal flux of calcium is probably the most important, resulting in disruption in sorting and/or transport of late endosomes/lysosomes. Two variants, c.406-2A>G and 6.4 kb del, account for 95% of pathogenic variants in individuals of Ashkenazi Jewish heritage.\nDiagnostic methods\nMLIV is suspected in the individuals with typical clinical findings and elevated plasma gastrin levels or polymorphic lysosomal inclusions in skin or conjunctival biopsy. Identification of biallelic pathogenic variants in MCOLN1 (19p13.2) confirms the diagnosis. Periodic Acid-Schiff staining of conjunctival cells reveals autofluorescent amorphous inclusions. Urine mucopolysaccharides, oligosaccharides and plasma lysosomal hydrolase assays are normal.\nDifferential diagnosis\nCorneal clouding may initially lead to suspicion of mucolipidoses and mucopolysaccharidoses but MLIV is distinguished by absence of dysmorphism. The developmental profile is different to GM1 gangliosidosis.\nAntenatal diagnosis\nPrenatal diagnosis is done by molecular testing.\nGenetic counseling\nMLIV is transmitted as an autosomal recessive trait. Parents of an affected child bear a 25% risk of disease recurrence among the future offspring.\nManagement and treatment\nNo specific treatment exists, and management is symptomatic and targeted towards the visual manifestations and the neurological problems (cognitive delay, spasticity and speech deficit). Physical therapy with special focus on spasticity and ataxia can improve motor function. A speech therapist can advise patients with swallowing problems. Iron supplementation is used to treat iron deficiency. Cataract or strabismus surgery is often necessary.\nPrognosis\nCompared to other mucolipidoses (I and II), MLIV patients have a prolonged survival.\n\n                            Last update: \n                            October 2021\n\n\n                            - Expert reviewer(s): \n                            Dr E. [Esmee] OUSSOREN | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Mucopolysaccharidosis type 1", "Disease Definition": "Mucopolysaccharidosis type 1 (MPS 1) is a rare lysosomal storage disease belonging to the group of mucopolysaccharidoses. There are three variants, differing widely in their severity, with Hurler syndrome being the most severe, Scheie syndrome the mildest and Hurler-Scheie syndrome giving an intermediate phenotype.", "ORPHA ID": 579, "Summary": "Epidemiology\nPrevalence is estimated at 1/100,000, with Hurler syndrome accounting for 57% of cases, Hurler-Scheie syndrome accounting for 23% of cases and Scheie syndrome accounting for 20% of cases.\nClinical description\nIn the severe form (Hurler syndrome or MPS I-H; see this term) skeletal deformities and a delay in motor and intellectual development are the leading symptoms. Onset occurs 6-8 months after birth. Other manifestations include corneal clouding, organomegaly, heart disease, short stature, hernias, facial dysmorphism and hirsutism. Radiological examination of the skeleton reveals the characteristic pattern of dysostosis multiplex. Hydrocephaly can occur after the age of two. Patients with the adult-onset form (Scheie syndrome or MPS I-S; see this term) are of almost normal height and do not show intellectual deficiency. Typical symptoms are stiff joints, corneal opacities, carpal tunnel syndrome and mild skeletal changes. Aortic valve disease can be present. Compression of the cervical spinal cord, caused by glycosaminoglycan infiltration of the dura, may lead to spastic paresis if not corrected by neurosurgical intervention. Patients with the intermediate form (Hurler-Scheie syndrome or MPS I-H/S; see this term) have normal or almost normal intelligence, but exhibit various degrees of physical impairment.\nEtiology\nThe different phenotypes are caused by allelic mutations in the alpha-L-iduronidase (IDUA) gene (localized to 4p16.3). The mutations result in complete deficiency of the enzyme in Hurler syndrome or partial function in Scheie syndrome, leading to lysosomal accumulation of dermatan sulfate (DS) and heparan sulfate (HS).\nDiagnostic methods\nEarly diagnosis is difficult as the first clinical signs are not specific (hernias, respiratory infections, etc.) but it is very important to allow early treatment. Biological diagnosis relies on detection of increased urinary excretion of DS and HS and the demonstration of the enzymatic deficiency (in plasma, leucocytes, fibroblasts, trophoblastic cells or amniocytes).\nDifferential diagnosis\nMucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; see this term) resembles mucopolysaccharidosis type I in many aspects, MPS VI patients, however, never have intellectual impairment. Mucopolysaccharidosis type II (see this term), an X-linked recessive disorder in which severe joint contractures are a characteristic symptom, also has many features in common with mucopolysaccharidosis type I.\nAntenatal diagnosis\nAntenatal diagnosis can be performed by enzyme assay or molecular genetics in families where the mutation has been identified.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling is recommended.\nManagement and treatment\nThe genotype should be established at diagnosis in all patients as this may aid in determining the therapeutic approach. Symptomatic treatment should be proposed by a multidisciplinary team. Hematopoietic stem cell transplantation has been shown to be useful in some patients. Treatment with the enzyme substitute (laronidase) obtained EU marketing authorization as an orphan drug in 2003. All patients including those who have not received a transplant or whose graft has failed may benefit significantly from enzyme replacement therapy (ERT). Given as weekly infusions, it leads to improvement of lung function and joint mobility.\nPrognosis\nEarly treatment slows progression of the disease. However, it is not effective against neurological lesions. Life expectancy is normal or only slightly affected in Scheie syndrome, but is reduced in Hurler syndrome, with death occurring before adolescence due to serious cardiovascular and respiratory complications.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Michael BECK"}
{"Disease Name": "Mucopolysaccharidosis type 2, attenuated form", "Disease Definition": "Mucopolysaccharidosis type 2, attenuated form (MPS2att), the less severe form of MPS2 (see this term), leads to a massive accumulation of glycosaminoglycans and a wide variety of symptoms including distinctive facies, short stature, cardiorespiratory and skeletal findings. It is differentiated from mucopolysaccharidosis type 2, severe form (see this term) by the absence of cognitive decline.", "ORPHA ID": 217093, "Summary": "Epidemiology\nPrevalence of MPS2 at birth in Europe is 1/166,000. The minority of these cases present with the attenuated form.\nClinical description\nMPS2att is clinically heterogeneous and its rate of progression is highly variable. Patients appear healthy at birth, with subtle initial symptoms appearing between 18 months and 4 years of age or even later, in particular umbilical or inguinal hernia. A distinctive facies (thickening of lips and nostrils, enlarged and protruding tongue), forms slowly and may first be observed at 2-4 years of age (often not evident until late). Swelling of the upper respiratory tract may be responsible for frequent infections, in particular otitis media; excessive snoring and sleep apnea; a distinctive hoarse voice and progressive loss of hearing. During early childhood growth is stunted and patients have a short stature with dysostosis multiplex and stiff joints that may make movement painful, hip dysplasia may also occur. Phalangeal joints are universally contracted resulting in claw-like hands; carpal tunnel syndrome is common. Spastic paresis due to spinal cord compression at the cranio-cervical region may also occur. Pressure exerted on the optic nerve may lead to loss of vision and retinal degeneration has also been reported in some cases. MPS2att patients, in general, have no cognitive impairments.\nEtiology\nMPS2 results from iduronate-2-sulfatase (I2S) deficiency, which leads to lysosomal accumulation of two specific mucopolysaccharides, dermatan sulfate and heparan sulfate. MPS2att, is typically associated with missense mutations of the causative gene IDS (Xq28), e.g.: c.1122C>T. In 12 cases of affected girls, skewed X inactivation led to MPS2.\nGenetic counseling\nMPS2 is the only MPS transmitted as an X-linked recessive trait; female carriers transmit the disorder to 50% of their sons.\nManagement and treatment\nExtensive palliative care is required, patients must be regularly evaluated by echocardiogram, respiratory function, hearing tests, eye exams, nerve conduction velocity tests, cranial and cervical MRI with or without lumbar puncture to assess cerebrospinal fluid pressure. Hernia repair, tonsillectomy and adenoidectomy may be required. Cardiac valve or hip replacement and carpal tunnel release may be necessary in MPS2att patients over time; patients should be considered for weekly intravenous enzyme replacement therapy with idursulfase (Elaprase) as early as possible.\nPrognosis\nIn general, if patients have no evidence of cognitive involvement by about 5 years of age, it is most likely that they will develop only the attenuated form of MPS2. Prognosis is highly variable. In most attenuated cases patients live into adulthood and require limited palliative care, however, it is impossible to predict outcomes due to the great variability of disease progression from patient to patient, even when siblings carry an identical mutation.\n\n                            Last update: \n                            September 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Barbara BURTON"}
{"Disease Name": "Mucopolysaccharidosis type 2, severe form", "Disease Definition": "Mucopolysaccharidosis type 2 (MPS2, see this term), severe form (MPS2S), is associated with a massive accumulation of glycosaminoglycans and a wide variety of symptoms including a rapidly progressive cognitive decline; it is most often fatal in the second or third decade.", "ORPHA ID": 217085, "Summary": "Epidemiology\nPrevalence of MPS2 at birth in Europe is 1/166,000, the severe form accounts for at least two-thirds of all cases.\nClinical description\nMPS2S presents with the spectrum of symptoms observed in all MSP2 (see this term) cases, often with an earlier presentation. MPS2S patients have a decrease in growth rate in early to mid-childhood, along with respiratory difficulties and a thickening of lips and nostrils as well as an enlarged and protruding tongue (distinctive facies), which may become evident between 2-4 years of age. Psychomotor milestones are delayed, and regression often occurs. Between the ages of 2-6 years patients begin to exhibit aggressive behavior and hyperactivity, often lacking any sense of danger as they follow a course of progressive cognitive decline. Vision may be affected, and progressive hearing loss occurs in most cases. Myocardial thickening and cardiac valve dysfunction are common. Approximately 60-80 % of patients with MPS2 have the severe form of the disease with neurological implications.\nEtiology\nMPS2 results from iduronate-2-sulfatase (I2S) deficiency, which leads to lysosomal accumulation of two specific mucopolysaccharides, dermatan sulfate and heparan sulfate. MPS2S appears to be associated with a complete absence of functional enzyme due to nonsense mutations or complete gene deletions or rearrangements. In most cases, however, prognosis cannot be established by genotype alone.\nDiagnostic methods\nDiagnosis is based on detection of increased levels of DS and HS in the urine and confirmed by the demonstration of the enzyme deficiency in the serum, leukocytes or fibroblasts, or in dried blood spot samples. Enzymatic activity of another sulfatase should also be assessed. Genetic testing is possible; sequencing must include the entire IDS gene including its promoter region.\nManagement and treatment\nRegular evaluation of patients should be followed by palliative care as is necessary. Cranial shunting to relieve hydrocephalus is often required. Weekly intravenous infusion with recombinant enzyme preparations has been shown to help with somatic symptoms. Intrathecal administration of enzyme replacement therapy holds promise to treat neurological aspects of MSP2; testing of such treatments is ongoing.\nPrognosis\nPrognosis is poor. MPS2S is most often fatal within the second or third decade of life, due to obstructive airway disease, infection, or cardiac failure due to valve dysfunction, pulmonary hypertension or cardiomyopathy.\n\n                            Last update: \n                            September 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Barbara BURTON"}
{"Disease Name": "Mucopolysaccharidosis type 2", "Disease Definition": "A lysosomal storage disease with multisystemic involvement leading to a massive accumulation of glycosaminoglycans and a wide variety of symptoms including distinctive coarse facial features, short stature, cardio-respiratory involvement and skeletal abnormalities. It manifests as a continuum varying from a severe form with neurodegeneration to an attenuated form without neuronal involvement.", "ORPHA ID": 580, "Summary": "Epidemiology\nMucopolysaccharidosis type 2 (MPS2) prevalence at birth in Europe is 1/166,000. It is an X-linked recessive disorder; very rare cases of female presentation have been reported.\nClinical description\nMPS2 patients appear healthy at birth, with initial symptoms appearing between 18 months and 4 years of age. Macrocephaly develops during infancy and infants initially grow at normal or above average rates. Initial manifestations include: frequent respiratory tract infections (in particular otitis media); umbilical and inguinal hernia; intractable diarrhea; hepatosplenomegaly; and skin lesions resembling an orange peel (on the shoulder, back and thighs). A distinctive facies with thickening of lips and nostrils as well as an enlarged and protruding tongue forms slowly and may become evident between 2-4 years of age, later in attenuated cases. Progression varies from a severe form (MPS2, severe form) with early psychomotor regression to an attenuated form (MPS2, attenuated form) which manifests without cognitive involvement.\nEtiology\nMPS2 results from iduronate-2-sulfatase (I2S) deficiency, which leads lysosomal accumulation of two specific mucopolysaccharides, dermatan sulfate (DS) and heparan sulfate (HS). The causative gene, IDS, is located on Xq28, approximately 320 mutations have been reported to cause MPS2.\nDiagnostic methods\nDiagnosis is based on clinical signs followed by the detection of increased levels of DS and HS in the urine and confirmed by the demonstration of the enzyme deficiency in the serum, leukocytes or fibroblasts, or in dried blood spot samples. Enzymatic activity of another sulfatase should also be assessed. Genetic testing requires searching for exonic or whole-gene deletions, for point mutations in IDS and its promoter region, and for recombination with the nearby pseudogene IDS2.\nDifferential diagnosis\nDifferential diagnoses include mucopolysaccharidosis type 1, 6, 7; sialidosis type 2; mucolipidosis type 2 and 3; and multiple sulfatase deficiency.\nAntenatal diagnosis\nPrenatal diagnosis by measuring IDS activity or by mutation analysis in chorionic villi or amniocytes is only performed for male fetuses.\nGenetic counseling\nWomen at risk of being a carrier should undergo genetic testing as MPS2 is X-linked recessive. Female carriers transmit the disorder to 50% of their sons; only 12 cases of affected girls have been described due to skewed X-inactivation.\nManagement and treatment\nAll patients should be considered for weekly intravenous enzyme replacement therapy (ERT) which has been shown to alleviate somatic symptoms. Cranial shunting should be performed to relieve cases of hydrocephalus. Hernia repair, tonsillectomy and adenoidectomy (to liberate the upper respiratory tract) and in some cases positive pressure ventilation or tracheostomy may be required. Cardiac valve or hip replacement and carpal tunnel release may be necessary over time. Extensive palliative care is required, patients must be regularly evaluated by echocardiogram, respiratory function, full radiologic examination to identify dysostosis multiplex, cranial and cervical MRI with or without lumbar puncture to assess cerebrospinal fluid pressure, hearing tests, eye exams and nerve conduction velocity tests.\nPrognosis\nPrognosis is highly variable. In the severe form (60-80% of cases) life expectancy is markedly reduced, death generally occurring before the age of 25 often as a result of cardio-respiratory complications. In the attenuated form, patients may survive into adulthood, sometimes even beyond the age of 60, and intellectual deficits are most often absent in these cases.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Barbara BURTON"}
{"Disease Name": "Mucopolysaccharidosis type 3", "Disease Definition": "A group of rare lysosomal storage diseases characterized by progressive neurocognitive decline, loss of functional abilities and premature death. There are four etiological subtypes of mucopolysaccharidosis type 3 (MPS III, Sanfilippo syndrome) called Sanfilippo syndrome type A, B, C, and D. Each subtype is caused by deficiency of a particular enzyme involved in the degradation of heparan sulfate leading to substrate accumulation and cellular dysfunction.", "ORPHA ID": 581, "Summary": "Epidemiology\nThe total number of patients with Sanfilippo syndrome is most likely underestimated due to delayed or missed diagnoses. The combined prevalence of Sanfilippo syndrome is estimated as 1:50,000 to 1:250,000 depending on the population studied. Sanfilippo syndrome type A is the most common subtype globally; however, the prevalence of subtypes can vary depending on the geographic region. Sanfilippo syndrome types C and D are much less common.\nClinical description\nThe age at onset, severity of symptoms and rate of disease progression vary greatly in Sanfilippo patients. The behavioral, cognitive, and physical findings present as a clinical spectrum from early-onset, rapidly progressive disease with death in late childhood and adolescence, to slower progressing forms that present in later childhood with survival into adulthood. After a period of normal development typical disease manifests between 1 and 4 years of age with mild global developmental or speech delay. Behavioral disturbances include but are not limited to hyperactivity, attention deficit, loss of impulse control, unawareness of dangerous situations, autistic-like behavior, hyperorality and unresponsiveness to discipline. Furthermore, patients frequently present with severe sleep disturbances. Physical manifestations are often less pronounced and might include musculoskeletal, respiratory, gastrointestinal, cardiovascular symptoms and hearing loss. In later stages of the disease patients show a decline in engagement with their environment, dementia, and progressive loss of motor function. Patients may develop seizures, dysphagia, and become fully bedridden.\nEtiology\nDeficiencies in one of the four enzymes required for heparan sulfate (HS) degradation are responsible for each of the subtypes: heparan-N-sulfatase for Sanfilippo syndrome type A (SGSH gene), alpha-N-acetylglucosaminidase for type B (NAGLU gene), alpha-glucosaminide N-acetyltransferase for type C (HGSNAT gene), and N-acetylglucosamine-6-sulfate sulfatase for type D (GNS gene). Numerous pathogenic variants have been identified in corresponding genes.\nDiagnostic methods\nIn individuals with clinical features suggestive of Sanfilippo syndrome confirmation of diagnosis requires at least two biochemical or genetic tests. Diagnosis is based on detection of increased levels of HS in urine, demonstration of one of the four enzyme deficiencies and/or evidence of pathogenic or likely pathogenic variants in the corresponding genes. For types A and D, the measurement of the activity of another sulfatase is compulsory for exclusion of multiple sulfatase deficiency.\nDifferential diagnosis\nSanfilippo syndrome should be included in the differential diagnosis of children with behavioural disorders, attention deficit syndrome and autism spectrum disorders. Furthermore, other neuropathic types of mucopolysaccharidoses (e.g. neuropathic Hunter syndrome) do present with a similar phenotype.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variants have previously been identified.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThere is currently no approved disease-modifying therapy for patients with Sanflippo syndrome. However, disease-specific therapies are being studied within clinical trials including but not limited to enzyme replacement therapies accessing the central nervous system as well as in vivo and ex vivo gene therapies. Patient care requires a multidisciplinary team with experience in the management of Sanfilippo syndrome focusing on supportive interventions to maintain function, optimize ability, and maximize quality of life. Consensus guidelines for clinical care are available.\nPrognosis\nThe prognosis is poor with death usually occurring within the second decade of life in severe cases (> 80% of cases). Patients with attenuated phenotypes have a more variable life span, in rare cases surviving into the seventh decade of life.\n\n                            Last update: \n                            June 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MUSCHOL | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Mucopolysaccharidosis type 4", "Disease Definition": "A rare lysosomal storage disease characterized by mild to severe spondylo-epiphyso-metaphyseal dysplasia, manifesting with disproportionate short stature (short neck and trunk), joint laxity, pectus carinatum, genum valgum, abnormal gait, tracheal narrowing, spinal abnormalities (kyphosis and scoliosis), respiratory impairment and valvular heart disease.", "ORPHA ID": 582, "Summary": "Epidemiology\nThe prevalence at birth varies worldwide between 1/240,000 - 7,600,000, the median worldwide prevalence at birth is approximately 1/1,500,000.\nClinical description\nClinically, the two forms of MPS, IVA and IVB, have similar skeletal manifestations; however, MPS IVA has a more severe phenotype. MPS IVA is generally diagnosed during the second year of life. Progressive skeletal and joint deformities lead to impairment in walking and daily activities, and include platyspondyly, kyphosis, scoliosis, pectus carinatum, genu valgum, long bone deformities, and joint hyperlaxity (neck, hands, fingers, hips, knees). A rapidly progressive growth failure, with arrest at around 3-5 years of age in severe cases, results in short stature. Potential nervous complications are secondary to skeletal deformations. From the age of 2 to 5 years, hypoplasia of the odontoid vertebra combined with joint hyperlaxity leads to an instability at the level of the first two cervical vertebrae, with a risk of spinal cord compression. Facial dysmorphism includes prominent forehead, large mandible, and short neck. Respiratory impairment, with heavy restriction of lung capacity, susceptibility to pneumonia, and tracheal obstruction/narrowing, is often indicated by life-threatening sleep apnea, cor pulmonale or anesthetic complications. Extra-skeletal manifestations include hepatomegaly, valvulopathies, hearing loss, corneal clouding and dental hypoplasia. Intelligence is normal. Patients typically have low endurance, debilitating fatigue, and pain. Many patients become wheelchair-dependent in their second decade.\nEtiology\nThe dysfunction and dysplasia is a result of body-wide accumulation of glycosaminoglycans (GAGs). MPS IVA is due to deficiency in the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS, 16q24.3) required for degradation of keratin sulfate (KS) and chondroitin 6-sulfate. MPS IVB is due to deficiency in beta-galactosidase (GLB1, 3p22.3) required for KS degradation.\nDiagnostic methods\nPreliminary investigations may include urinary analysis of GAGs; however, total urinary GAG level overlaps between MPS IV patients and age-matched controls. Urine KS and blood KS should be measured. Definitive diagnosis is by demonstration of enzymatic deficiency in plasma, serum, leukocytes or fibroblasts.\nDifferential diagnosis\nDifferential diagnosis includes MPS I, II, VI, and VII, spondyloepiphyseal dysplasia, Legg-Calve-Perthes disease, and GM1 gangliosidosis type 3 for MPS IVB.\nAntenatal diagnosis\nWhere the genetic mutation has previously been identified in a family member, prenatal diagnosis is possible through molecular analysis or enzyme measurements in trophoblasts or amniocytes.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive in both forms and genetic counseling should be offered to affected families. The risk of disease transmission is 25% where both parents are unaffected carriers.\nManagement and treatment\nThe treatment remains symptomatic (prosthesis, surgery, neck consolidation by vertebral fusion, tracheal vascular reconstruction for near-fatal tracheal obstruction, walking aids or wheelchair). Non-invasive assessment of airway obstruction at an early stage is critical. General anesthesia may be problematic due to intubation difficulties. Imaging of the cervical spine is commonly required. Clinical therapies include hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT), both of which lead to the partial restoration of the clinical phenotype but are not reported to improve skeletal manifestations. ERT with elosulfase alfa is approved for MPS IVA and may be associated with increased endurance and pulmonary function, and reduced urinary excretion of KS. HSCT has been used on over 30 MPS IVA patients, however, further studies are required to evaluate therapeutic efficacy. In MPS IVB, management and treatment remains supportive and surgical.\nPrognosis\nThe common causes of mortality are airway compromise and heart disease. Prognosis depends on disease severity and quality of care. Left untreated, MPS IVA patients do not generally survive beyond the third decade of life; with appropriate management, patients may survive beyond the age of 50 with some surviving over 70 years of age.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Shunji TOMATSU"}
{"Disease Name": "Mucopolysaccharidosis type 6", "Disease Definition": "Mucopolysaccharidosis type 6 (MPS 6) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B (ASB) leading to the accumulation of dermatan sulfate.", "ORPHA ID": 583, "Summary": "Epidemiology\nBirth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births.\nClinical description\nThe disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (GAG, generally >100 microgram/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 microgram/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS 6, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness.\nEtiology\nThe disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (ASB or N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation.\nDiagnostic methods\nDiagnosis generally requires evidence of clinical picture, ASB activity of less than 10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude mucosulfatidosis, see this term). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive.\nDifferential diagnosis\nIn addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS 1, 2, 4A, 7), sialidosis and mucolipidosis (see these terms).\nManagement and treatment\nBefore enzyme replacement therapy (ERT) with galsulfase (Naglazyme®), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile.\nPrognosis\nPrognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided.\n\n                            Last update: \n                            April 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Paul HARMATZ  - Dr Helen NICELY  - Dr Sean TURBEVILLE  - Dr Vassili VALAYANNOPOULOS"}
{"Disease Name": "Mucopolysaccharidosis type 7", "Disease Definition": "A rare, genetic lysosomal storage disease characterized by accumulation of glycosaminoglycans in connective tissue which results in progressive multisystem involvement with severity ranging from mild to severe. The most consistent features include musculoskeletal involvement (particularly dysostosis multiplex, joint restriction, thorax abnormalities, and short stature), limited vocabulary, intellectual disability, coarse facies with a short neck, pulmonary involvement (predominantly decreased pulmonary function), corneal clouding, and cardiac valve disease.", "ORPHA ID": 584, "Summary": "Epidemiology\nThe prevalence at birth is reported to range between 1/345,000 -5,000,000. However, the frequency of the disease may be underestimated as the most frequent presentation is the antenatal form, which remains underdiagnosed.\nClinical description\nSigns are extremely variable: there are prenatal forms with non-immune hydrops fetalis, and severe neonatal forms with dysmorphism, hernias, hepatosplenomegaly, club feet, dysostosis, small stature and severe hypotonia and neurological involvement that ultimately lead to profound intellectual deficit in patients who survive. At the other end of the spectrum, there are very mild cases that are discovered during adolescence or adulthood following presentation with thoracic kyphosis.\nEtiology\nMutations in the gene GUSB  (7q11.21) causes beta-D-glucuronidase deficiency, which leads to accumulation of several glycosaminoglycans (dermatan sulfate (DS), heparan sulfate (HS), and chondroitin sulfate (CS)) in lysosomes.\nDiagnostic methods\nDiagnosis is supported by x-ray evidence of dysostosis multiplex and detection of increased levels of urinary glycosaminoglycan (either CS alone or CS+HS+DS) excretion, although this sign may be absent in adult forms. Diagnosis is confirmed by demonstration of beta-D-glucuronidase deficiency in cultured leucocytes or fibroblasts. Pseudodeficient alleles make mild forms more difficult to identify and prenatal diagnosis difficult.\nDifferential diagnosis\nDifferential diagnosis includes other types of mucopolysaccharidosis (MPS) and oligosaccharidosis. The determination of enzymatic activity in leucocytes allows heterozygous individuals to be detected for the severe forms. When the two mutations have been identified in the index patient, the detection of heterozygous relatives can be performed accurately.\nAntenatal diagnosis\nDiagnosis is possible in forms with in utero presentation and may prevent recurrence of pregnancies leading to in utero death or late termination of the pregnancy. Prenatal diagnosis (by molecular analysis or measurement of enzyme activity in trophoblasts or amniocytes) can be offered to parents with an affected child. Parents should be made aware of the availability of enzyme replacement therapy (ERT).\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nERT with recombinant human beta-glucuronidase has been approved in Europe and the USA for MPS type 7, and has shown improvement in walking, lung function and hepatosplenomegaly in clinical trials. Still, multidisciplinary management allows adapted symptomatic treatment, which is essential for improving the quality of life of the patients. In late-onset forms, treatment is mainly orthopedic. Bone marrow transplantation has been successful in three of five patients.\nPrognosis\nPrognosis is typically poor for antenatal forms, often leading to death in utero. Neonatal and childhood forms typically have a very limited life expectancy, whereas milder forms have a prolonged survival. Whilst ERT is now available, long term outcome data are not yet available on the ERT treated patients.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Dr William SLY"}
{"Disease Name": "Mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders", "Disease Definition": "A rare genetic disease characterized by early-onset respiratory difficulties and frequent respiratory infections, congenital heart defects, dysostosis multiplex, hepatosplenomegaly, renal involvement, hematopoietic abnormalities, facial dysmorphism (coarse facial features, large forehead, synophrys, long eyelashes, broad nasal bridge, macroglossia, short neck, and low hairline), and global developmental delay. Laboratory examination shows increased urinary excretion of glycosaminoglycans and increased plasma heparan sulfate, but no lysosomal enzyme deficiency. The disease is usually fatal in the first years of life.", "ORPHA ID": 505248, "Summary": ""}
{"Disease Name": "Mucous membrane pemphigoid", "Disease Definition": "A rare autoimmune bullous skin disease characterized clinically by blistering of the mucous membranes followed by scarring, and immunologically characterized by IgG, IgA and/or C3 deposits on the epidermal basement membrane. The disease principally involves the oral mucosa, but may also affect ocular, pharyngolaryngeal, genital, and esophageal mucous membranes.", "ORPHA ID": 46486, "Summary": "Epidemiology\nAnnual incidence was estimated to be 1/500,000 to 1/770,000 in Germany and France. A slight female predominance is reported.\nClinical description\nThe average age of onset is 60-70 years. The disease is rare in children. Mucous membrane pemphigoid is a chronic disease with periods of more rapid evolution. The disease manifests as fragile bullous lesions that give way to superficial erosions. The principle sites affected are the oral (80-90% of cases), ocular (50-70% of cases), pharyngolaryngeal (8-20% of cases), genital (15% of cases) and esophageal mucous membranes. Some forms affect only one mucosal membrane, in particular the buccal (erosive gingivitis) or ocular mucosae. An exclusively cutaneous form has also been observed in some cases. The ocular manifestations are initially inflammatory but then lead to retractile scarring of the conjunctive membrane, associated with corneal metaplasia resulting in vision loss.\nEtiology\nWhilst the etiology is unknown, several different antigens are implicated in the auto-antibody response including BPAg1, BPAg2, integrin subunits alpha-6/beta-4, laminin 5 and 6, and type VII collagen.\nDiagnostic methods\nImmunological studies reveal the presence of auto-antibodies against several antigens such as PB180, the alpha Laminin-5 subunit and the beta subunit of the integrin alpha-6 beta-4 complex. Histologically, the cutaneous or mucosal blisters are subepithelial, without evidence of acantholysis, and are indistinguishable from those of bullous pemphigoid. Diagnosis can be confirmed by direct (DIF) or indirect immunofluorescence analysis. Immunoelectron microscopy can differentiate bullous from cicatricial pemphigoid by the precise location of immune deposits along the basement membrane.\nDifferential diagnosis\nDifferential diagnosis includes the full range of autoimmune bullous disorders. Pemphigus vulgaris is differentiated by the DIF pattern with a labelling of the intercellular substance. Bullous pemphigoid is characterized by a predominant cutaneous involvement. Epidermolysis bullosa acquisita is a difficult to differentiate and relies on ELISA (enzyme-linked immunosorbent assay) anti collagene VII, a different localization of immune deposits along the basement membrane zone as imaged by immunoelectron microscopy, or DIF on salt separated skin. Oral erosive lichen planus and recurrent aphtosis do not show any immune deposits on DIF.\nManagement and treatment\nManagement should be multidisciplinary with close follow-up in specialized centers, in particular for the management of the ocular manifestations. The choice of therapeutic strategy (anti-inflammatory drugs, immunosuppressive therapy, intravenous immunoglobulins or local treatments) depends in the severity of the ocular disease.\nPrognosis\nThe prognosis also revolves around the ocular manifestations, which may lead to blindness due to scarring of the conjunctive membrane and corneal metaplasia.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Christophe BEDANE"}
{"Disease Name": "Mueller-Weiss syndrome", "Disease Definition": "A rare bone disease characterized by spontaneous adult-onset tarsal navicular osteonecrosis. Patients present with chronic mid- and hindfoot pain, swelling and tenderness over the dorsomedial aspect of the midfoot, flattening of the medial longitudinal arch, and pes planovarus. Radiographic findings include comma-shaped deformity due to collapse of the lateral part of the navicular bone and medial or dorsal protrusion of a portion or the entire bone. The condition may be bilateral or asymmetric and associated with pathological fractures.", "ORPHA ID": 566943, "Summary": ""}
{"Disease Name": "Muenke syndrome", "Disease Definition": "Muenke syndrome is a syndromic craniosynostosis with significant phenotypic variability, usually characterized by coronal synostosis, midfacial retrusion, strabismus, hearing loss and developmental delay.", "ORPHA ID": 53271, "Summary": "Epidemiology\nBirth prevalence is estimated at approximately 1/30,000, accounting for about 8% of all craniosynostoses and over 25% of cases with an identified genetic cause.\nClinical description\nMuenke syndrome (MS) patients show a wide range of clinical findings, even within a single family. Most have coronal synostosis (more frequently bilateral), however, synostosis of other sutures, all sutures, macrocephaly without craniosynostosis, or a normal skull may be observed. Bilateral coronal synostosis usually results in brachycephaly (turribrachycephaly/cloverleaf skull are also possible) with temporal bossing and facial symmetry. Unilateral coronal synostosis results in plagiocephaly with facial asymmetry, frontal bossing, eyebrow elevation, anterior placement of the ear, and midface retrusion. Over 15% of mutation-positive individuals do not have premature fusion of the skull, but may or may not have other associated clinical findings. Craniofacial findings include: widely spaced eyes, ptosis or proptosis, strabismus, and high arched palate or cleft lip/palate. Over 70% of patients have some form of, usually mild, hearing loss (sensorineural being the most common, followed by conductive and mixed). Neurologic complications such as elevated intracranial pressure and hydrocephalus can occur, especially when two or more sutures are prematurely fused. Additional extracranial manifestations include: otitis media, brachydactyly, broad toes, broad thumbs, clinodactyly, developmental delay, intellectual disability (often mild), epilepsy, and/or increased risk for behavioral problems, including adaptive behavior.\nEtiology\nMS is due to a mutation in the FGFR3 gene (4p16.3), encoding fibroblast growth factor receptor 3, which is required for normal skeleton development.\nDiagnostic methods\nMolecular genetic testing identifying a p.Pro250Arg mutation in FGFR3 confirms diagnosis. Suture involvement and the presence of hydrocephalus can be visualized by radiography, 3D computed tomography, and MRI. Characteristic extracranial radiographic features include: fusion of the carpal and tarsal bones, short and broad (''thimble-like'') middle phalanges of the hands and feet, and epiphyseal coning.\nDifferential diagnosis\nDifferential diagnoses include other types of syndromic craniosynostosis such as Crouzon and Saethre-Chotzen syndromes and Pfeiffer syndrome type 1.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease-causing mutation. Prenatal ultrasound examination may be used as an adjunct to prenatal genetic testing.\nGenetic counseling\nInheritance is autosomal dominant and genetic counseling can inform a parent with MS of their 50% risk of passing on the pathogenic variant to future offspring.\nManagement and treatment\nManagement of MS should be multidisciplinary. Patients should be tested for hearing loss and be subsequently monitored, even if initial evaluation is normal. Developmental and behavioral assessments, eye exams, speech therapy and/or special education should be evaluated on a case-by-case basis. Surgical management is offered based on craniosynostosis severity. Typically, an initial craniosynostosis repair (usually at 3-6 months of age), that consists of fronto-orbital advancement and cranial vault remodeling, is performed. A secondary (or tertiary) transcranial repair, with or without extracranial contouring, may be needed. Endoscopic strip craniectomy is a newer and less invasive procedure, usually performed before the age of 3 months.\nPrognosis\nThe prognosis is variable. Good outcomes are observed if patients receive early surgical reconstruction (based on severity), as well as early and continued medical management of the neurologic, auditory, ocular, developmental and behavioral manifestations. Life-expectancy is normal.\n\n                            Last update: \n                            March 2017\n\n\n                            - Expert reviewer(s): \n                             Yonit. A ADDISSIE  - Dr Paul KRUSZKA  - Dr Maximilian MUENKE"}
{"Disease Name": "Mulibrey nanism", "Disease Definition": "A rare developmental defect during embryogenesis characterized by growth delay and multiorgan manifestations.", "ORPHA ID": 2576, "Summary": "Epidemiology\nThe exact prevalence is unknown. Worldwide, around 150 cases have been reported. Most cases described are from Finland where a birth prevalence of 1/37,000 has been reported.\nClinical description\nMulibrey nanism (MUL) manifests neonatally and during infancy. It is characterized by pre- and postnatal growth restriction, relative macrocephaly, thin extremities and typical craniofacial features (scaphocephaly, facial triangularity, broad forehead and low nasal bridge). Psychomotor development is mainly normal. Feeding difficulties are common in infants. Children are prone to respiratory problems. Characteristic features also include yellowish dots in the retinal mid peripheral region, a high-pitched voice and cutaneous naevi flammei. Radiologic findings include slender long bones with thick cortex, narrow medullary channel and fibrous dysplasia, J-shaped sella turcica and a small thoracic cage. A restrictive, perimyocardial heart disease is the most serious element of the disorder. Hepatomegaly and fatty liver are common. Insulin resistance is an important metabolic finding. More than 90% of the adults show abnormally high fasting insulin levels resulting in type 2 diabetes in half of the patients. Tumors have been detected in several internal organs. The most frequent malignant tumor is Wilms' tumor. Females are at high risk of developing ovarian fibrothecomas. Primary hypogonadism, both male and female, as well as infertility, are central clinical characteristics.\nEtiology\nMUL is caused by mutations in the TRIM37 gene (17q22) encoding the peroxisomal TRIM37 protein of unknown function. Worldwide, around 110 Finnish and 30 non-Finnish patients have a molecularly confirmed diagnosis. In Finland, one major founder mutation is seen in all patients with less than 10% of them being compound heterozygous combined with another mutation. Private mutations account for the non-Finnish cases. To date around 30 different disease associated mutations are known.\nDiagnostic methods\nThe diagnosis relies on the clinical signs. Major and minor signs for clinical diagnosis have been established. Molecular diagnostics does confirm the diagnosis. Molecular genetic testing for the two most common mutations of the TRIM37 gene is available in Finland. However, sequencing of the whole TRIM37 gene is necessary particularly for non-Finnish patients. The TRIM37 gene is usually well covered by exome sequencing and targeted next-generation sequencing (NGS)-based panels.\nDifferential diagnosis\nDifferential diagnosis includes dysmorphic growth disorders with prenatal onset growth failure, namely Silver-Russell syndrome and 3M-syndrome.\nAntenatal diagnosis\nPrenatal molecular genetic testing is possible but is rational only in families known to be affected with the disease.\nGenetic counseling\nMUL is an autosomal recessive disorder. A genetic counseling should be offered to affected couples.\nManagement and treatment\nEarly recognition and management of feeding-, respiratory- or cardiac problems are of major importance. Regular cardiovascular follow-up is central, as well as assessment of growth and puberty. Abdominal ultrasound is well-grounded as the risk for tumors, namely Wilms' tumor, and organ abnormalities is elevated. From adolescence, the glucose metabolism should be monitored, and females need regular gynecological follow-up.\nPrognosis\nThe severity of the heart disease is the main prognostic factor. The average survival is clearly shortened but a normal life span is not excluded.\n\n                            Last update: \n                            January 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Marita LIPSANEN-NYMAN"}
{"Disease Name": "Multicentric carpo-tarsal osteolysis with or without nephropathy", "Disease Definition": "A very rare syndrome characterized by progressive loss of bone, usually the capsal and tarsal bones, resulting in deformity and disability, as well as chronic renal failure in many cases. The bone and renal disorders are sometimes associated with intellectual deficit and facial abnormalities.", "ORPHA ID": 2774, "Summary": ""}
{"Disease Name": "Multicentric osteolysis-nodulosis-arthropathy spectrum", "Disease Definition": "A rare systemic or rheumatologic disease characterized by peripheral osteolysis (especially carpal and tarsal bones), interphalangeal joint erosions, subcutaneous fibrocollagenous nodules, facial dysmorphism, and a wide range of associated manifestations.", "ORPHA ID": 371428, "Summary": "Epidemiology\nMulticentric osteolysis-nodulosis-arthropathy (MONA) spectrum prevalence and incidence of MONA are not known. Fewer than 50 cases have been reported worldwide. Cases have been reported from Saudi Arabia, Italy, Turkey, Algeria, Morocco, the United States, and Korea.\nClinical description\nOnset is usually at preschool age (1-5 years) and the course of the disease is variable. Manifestations of the disorder include multiple peripheral osteolysis beginning at the carpal, tarsal, metacarpal/metatarsal-phalangeal and interphalangeal joints with subsequent generalization. The joint erosions lead to small hands and feet, arthropathy causing decreased range of motion, and progressive joint contractures. Some patients have been reported to have wide metacarpals and metatarsals, generalized osteoporosis of vertebrae, short stature, coarse face or facial dysmorphism (frontal bossing and hypertelorism), gum hypertrophy, corneal opacities, hyperpigmentation, hypertrichosis, and subcutaneous fibrocollagenous nodules. Associated cardiac malformations have been reported and included transposition of the great arteries, mitral valve prolapse, bicuspid aortic valve, and atrial and ventricular septal defects. Intrafamilial variability of manifestations is also found. Due to overlapping clinical features and the involvement of mutations in MMP2gene, Torg-Winchester syndrome and nodulosis-arthropathy-osteolysis (NAO) syndromes, that were originally reported separately, are now presumed to belong to the clinical spectrum of MONA (with other nomenclatures still being is use).\nEtiology\nMONA spectrum disorders are caused by mutations in the MMP2 gene (16q13-q21) or MMP14 gene (14q11-q12). The pathogenesis of the disorder remains unclear.\nDiagnostic methods\nThe diagnosis is based on the clinical manifestations of the disease and can be confirmed by molecular genetic testing.\nDifferential diagnosis\nThe main differential diagnoses are juvenile idiopathic arthritis and multicentric carpotarsal osteolysis.\nGenetic counseling\nMONA spectrum disorders follow an autosomal recessive pattern on inheritance. Many cases are reported in children from consanguineous unions. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 25% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no specific treatment for MONA spectrum. Management is primarily symptomatic. Some patients initially respond to non-steroidal anti-inflammatory drugs (NSAIDs).\nPrognosis\nThe progressive joint destruction leads to significant disability; many patients are wheelchair bound. However, life expectancy does not appear to be significantly affected.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Andreas ZANKL"}
{"Disease Name": "Multicentric reticulohistiocytosis", "Disease Definition": "A rare non-Langerhans cell histiocytosis characterized by the association of specific nodular skin lesions and destructive arthritis.", "ORPHA ID": 139436, "Summary": "Epidemiology\nPrevalence is unknown but around 200 cases have been reported in the literature so far.\nClinical description\nOnset is insidious, usually occurring at around 50 years of age. Multicentric reticulohistiocytosis (MRH) is a progressive disease, articular inflammation becomes more severe and, after periods of worsening and improving symptoms, incapacitating arthritis is a frequent feature. Multiple joints may be involved (mainly of the hands, wrists, shoulders, knees, hips and ankles). Joint symptoms oscillate and severe deforming arthritis, known as mutilating arthritis, is a prominent manifestation in between 11 and 45% of the cases, depending on the patient series. Similarly, cutaneous nodules appear and regress, with new eruptions developing over periods of many months, as the old ones become inactive, stabilize or disappear. The cutaneous nodules are either skin-colored or have a red/brown appearance and are usually asymptomatic. They are more frequent on the upper body, particularly the hands, and may also appear on mucosal surfaces. Internal organ involvement has also been reported. After a period of many years (usually 6 to 8), in the majority of cases, arthritis becomes quiescent and the mucocutaneous nodules stabilize or become smaller.\nEtiology\nThe etiology is unknown. MRH is believed to reflect a peculiar type of reactive inflammatory response to unknown stimuli with involvement of macrophages and T lymphocytes. An underlying malignancy has been described in around a quarter of patients.\nDiagnostic methods\nHistopathological and immunohistochemical studies (revealing the characteristic reticulohistiocytic granulomas mainly composed of CD68 positive cells) are diagnostic in most cases. Radiologic examinations should be performed in all patients.\nDifferential diagnosis\nThe differential diagnosis should include leprosy, rheumatoid arthritis, xanthogranulomas, lymphomas, sarcoidosis, Urbach-Wiethe disease, Farber disease and dermatomyositis (see these terms).\nManagement and treatment\nAt present, no satisfactory treatment is available. Some chemotherapeutical schemes, particularly those involving alkylating agents and specific therapies targeted towards the tumor necrosis factor (TNF) or its receptors may lead to some improvement. Systemic steroids are usually of only limited benefit.\nPrognosis\nPatients with MRH usually undergo spontaneous remission within a variable period of 6 to 8 years, however, sequelae (esthetic sequelae associated with the skin lesions and deforming sequelae associated with the arthritis) are frequent after cure. Death can occur due to internal organ involvement or as a result of the underlying malignancy.\n\n                            Last update: \n                            February 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Flavio LUZ  - Pr Marcia RAMOS-E-SILVA"}
{"Disease Name": "Multicystic dysplastic kidney", "Disease Definition": "A rare congenital anomaly of the kidney and urinary tract (CAKUT) in which one or both kidneys (unilateral or bilateral MCDK respectively) are large, distended by multiple cysts, and non-functional. Unilateral MCDK is typically asymptomatic if the other kidney is fully functional but may occasionally present with abdominal obstructive signs when the cysts become too large. Bilateral MCDK is considered a lethal entity and neonates present with features of the Potter sequence, severe pulmonary hypoplasia and severe renal failure, and generally die shortly after birth.", "ORPHA ID": 1851, "Summary": ""}
{"Disease Name": "Multifocal atrial tachycardia", "Disease Definition": "Multifocal atrial tachycardia is a rare supraventricular arrhythmia in neonates and young infants that is characterized by multiple P waves with varying P wave morphology and is usually asymptomatic.", "ORPHA ID": 3282, "Summary": "Epidemiology\nIt is a very rare condition occurring in around 1 per 150,000 live births.\nClinical description\n'The disease mainly affects newborn infants (or those younger than 6 months of age) with a normal heart and no other underlying illness. Most infants are asymptomatic but some may show shortness of breath or respiratory distress. Less often, the disorder may occur in children with heart malformations (such as hypertrophic cardiomyopathy, tetralogy of Fallot, or atrioventricular canal defect; see these terms) or in those having recently undergone an open-heart surgery. Very rarely, multifocal atrial tachycardia can be associated with other clinical features and be part of a syndrome, such as in Costello syndrome where it is associated with growth retardation, coarse facies, intellectual disability, and skin anomalies (see this term).'\nEtiology\nThe etiology is unknown.\nDiagnostic methods\nDiagnosis is made by surface electrocardiogram: atrial activity is polymorphic (at least 3 different morphologies of P waves with a discrete isoelectric baseline, and variable PP, RR, and PR intervals), rapid (atrial rates can increase up to 400 beats per minute), and irregular. Atrioventricular conduction is variable so that some P waves are not conducted. Rate-related QRS widening (aberrancy) is sometimes seen.\nDifferential diagnosis\nDifferential diagnosis includes most other types of tachycardia (e.g. nonsustained ventricular tachycardia, paroxysmal supraventricular tachycardia (PSVT)).\nManagement and treatment\nIf the ventricular rate is relatively normal and the infant is asymptomatic with normal heart function, no treatment may be necessary. Cardioversion is unsuccessful due to the fact that the arrhythmia is restarting all the time. A beta-blocker is probably the drug of choice, with an occasional patient with poor ventricular function needing treatment with amiodarone.\nPrognosis\nThe natural history of multifocal atrial tachycardia is spontaneous resolution within weeks or months. In those who require drug treatment, medication can be withdrawn after that time. The long term outlook is good, with no late recurrence.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christopher WREN"}
{"Disease Name": "Multifocal infantile hemangioma with extracutenous involvement", "Disease Definition": "Diffuse neonatal hemangiomatosis is a rare vascular tumor from unknown origin characterized by multiple, progressive, rapidly growing cutaneous hemangiomas (e.g. in the scalp, face, trunk and extremities) associated with widespread visceral hemangiomas in the liver, lungs, gastrointestinal tract, brain, and meninges.", "ORPHA ID": 2123, "Summary": ""}
{"Disease Name": "Multifocal lymphangioendotheliomatosis-thrombocytopenia syndrome", "Disease Definition": "A rare lymphatic system anomaly characterized by multifocal congenital and progressive vascular lesions of the skin, gastrointestinal tract, and occasionally other anatomic sites, causing potentially life-threatening thrombocytopenic coagulopathy. Macroscopically, the lesions appear as round to oval, red-brown plaques, as large as a few centimeters in diameter. Histopathologically, they consist of dilated, thin-walled vessels with variable endothelial hyperplasia, positive for lymphatic endothelial cell markers, and resembling benign lymphangioendothelioma.", "ORPHA ID": 464321, "Summary": ""}
{"Disease Name": "Multifocal motor neuropathy", "Disease Definition": "Multifocal motor neuropathy (MMN) is a rare acquired immune-mediatedneuropathy characterized clinically by a purely motor deficit with conduction block and asymmetric multifocal weakness, fasciculations, and cramping.", "ORPHA ID": 641, "Summary": ""}
{"Disease Name": "Multifocal pattern dystrophy simulating fundus flavimaculatus", "Disease Definition": "A rare, patterned dystrophy of the retinal pigment epithelium characterized by multiple yellowish irregular flecks scattered or interconnected around the macula, simulating what is observed in Stargardt disease, and usually asymptomatic until adulthood when patients present with a slowly progressive loss of vision that often only becomes apparent in old age.", "ORPHA ID": 99003, "Summary": ""}
{"Disease Name": "Multilocular cystic renal neoplasm of low malignant potential", "Disease Definition": "Multilocular cystic renal neoplasm of low malignant potential is a rare subtype of clear cell renal cell carcinoma with distinct pathological features of cysts lined by occasionally flattened cuboidal clear cells and septa containing aggregates of epithelial cells with clear cytoplasm, and excellent prognosis. The tumor usually presents as an asymptomatic, unilateral, solitary lesion, macroscopically consisting of numerous, fluid-filled, septated cysts of variable size. Rarely, the symptoms typically associated with renal tumors (flank pain, hematuria, palpable mass) may be present.", "ORPHA ID": 319287, "Summary": ""}
{"Disease Name": "Multiloculated renal cyst", "Disease Definition": "A rare benign renal tumor characterized by a typically unilateral, solitary, multiloculated cystic mass consisting of small, non-communicating cysts with flat, cuboidal, or hobnail epithelial lining, separated by fibrous septa which may have an ovarian stroma-like appearance or be paucicellular. The tumor is surrounded by a thick fibrous capsule and does not contain solid areas or necrosis. Patients may be asymptomatic or present with a palpable abdominal mass and/or abdominal or flank pain. Age distribution is bimodal, the typical age of onset being either below five or between 40 and 70 years of age.", "ORPHA ID": 97366, "Summary": ""}
{"Disease Name": "Multiminicore myopathy", "Disease Definition": "A rare hereditary neuromuscular disorder characterized by multiple cores on muscle biopsy and clinical features of a congenital myopathy.", "ORPHA ID": 598, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nMarked clinical variability corresponds to genetic heterogeneity: the most instantly recognizable classic phenotype characterized by spinal rigidity, early scoliosis and respiratory impairment is due to recessive mutations in the selenoprotein N (SEPN1) gene, whereas recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features comprising external ophthalmoplegia, distal weakness and wasting or predominant hip girdle involvement resembling central core disease (CCD). In the latter forms, there may also be a histopathologic continuum with CCD caused by dominant RYR1 mutations, reflecting the common genetic background.\nEtiology\nThe pathogenetic mechanisms of RYR1-related MmD are currently not well understood, but are likely to involve altered excitability and/or changes in calcium homeostasis. The presence of calcium-binding motifs within the selenoprotein N protein also suggests a possible role in calcium handling.\nDiagnostic methods\nThe diagnosis of MmD is based on the presence of suggestive clinical features and multiple cores on muscle biopsy. Muscle MRI may aid genetic testing as distinct patterns of selective muscle involvement can be detected depending on the genetic background. Mutational analysis of the RYR1 or the SEPN1 gene may provide genetic confirmation of the diagnosis.\nManagement and treatment\nManagement is mainly supportive and has to address the risk of marked respiratory impairment in SEPN1-related MmD and the possibility of susceptibility to malignant hyperthermia in RYR1-related forms.\nPrognosis\nIn the majority of patients, weakness is static or only slowly progressive, with the degree of respiratory impairment being the most important prognostic factor.\n\n                            Last update: \n                            July 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Heinz JUNGBLUTH"}
{"Disease Name": "Multinodular goiter-cystic kidney-polydactyly syndrome", "Disease Definition": "Multinodular goiter - cystic kidney - polydactyly syndrome is a very rare syndrome characterized by the association of multinodular goiter, cystic renal disease and digital anomalies.", "ORPHA ID": 2091, "Summary": "Epidemiology\nIt has been described in two sibs and one unrelated child.\nClinical description\nThe two sibs had digitalized thumbs and preaxial polydactyly, the third child had normal thumbs and postaxial polydactyly. Goiter and/or digitalized thumbs and/or polydactyly were present in other members of families.\nGenetic counseling\nThis syndrome seems to be transmitted as an autosomal dominant trait with variable expression and incomplete penetrance.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome", "Disease Definition": "A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by severe hydranencephaly and renal dysplasia or agenesis. Pregnancy is complicated by oligo- or anhydramnios, leading to features of Potter sequence (including typical facies and microretrognathia, limb contractures, talipes equinovarus, and pulmonary hypoplasia) in the fetus. Affected fetuses either die in utero or shortly after birth. Histology of the brain shows widespread presence of multinucleated neurons and glial cells.", "ORPHA ID": 500135, "Summary": ""}
{"Disease Name": "Multiple acyl-CoA dehydrogenase deficiency", "Disease Definition": "Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid and amino acid oxidation and is a clinically heterogeneous disorder ranging from a severe neonatal presentation with metabolic acidosis, cardiomyopathy and liver disease, to a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness, and respiratory failure.", "ORPHA ID": 26791, "Summary": "Epidemiology\nBirth prevalence is estimated at 1/200,000 but great variation is seen between countries/ethnicities.\nClinical description\nPatients with MADD fall into 3 broad clinical phenotypes: 1) neonatal onset with congenital anomalies, 2) neonatal onset without anomalies, (together called MADD-severe (S); see this term) and 3) mild and/or late onset (MADD-mild (M); see this term). The first group of MADD-S patients are often premature presenting with severe non-ketotic hypoglycemia, hypotonia, hepatomegaly and severe metabolic acidosis within the first 24 hours of life. They usually have dysplastic kidneys with multiple cysts and may also have facial dysmorphism (low-set ears, high forehead, hypertelorism and hypoplastic midface), rocker-bottom feet and anomalies of external genitalia. Death usually occurs within the first week of life. The second group of patients usually present within the first 24-48 hours of life with hypotonia, tachypnea, hepatomegaly, metabolic acidosis and hypoketotic hypoglycemia. Most die during the first week(s) of life but some have survived for several months, usually dying with severe cardiomyopathy. MADD-M patients show a broad clinical spectrum of disease ranging from onset of intermittent episodes of vomiting, metabolic acidosis and hypoketotic hypoglycaemia (+/- cardiac involvement) during the first few months of life to adolescent/adult presentation with acute Reye-like illness with ketoacidosis and lipid storage myopathy. The latter subgroup often responds to pharmacological doses of riboflavin (rr-MADD).\nEtiology\nMADD is caused by mutations in the ETFA (15q23-q25), ETFB (19q13.3-q13.4) and ETFDH (4q32-q35) genes which encode the alpha and beta subunits of electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase. Dysfunction of either of these two flavoproteins leads to compromised fatty acid oxidation..\nDiagnostic methods\nUrinary organic acid analysis usually displays various combinations of increased dicarboxylic acids, glutaric acid, ethylmalonic acid, 2-hydroxyglutarate, and glycine conjugates. Blood acylcarnitines show increased C4-C18 species although patients may be severely carnitine depleted, which may limit the degree of these abnormalities. Fibroblast fatty acid oxidation flux and fibroblast acylcarnitine analysis following incubation with palmitic acid is usually abnormal. Final confirmation is by mutation analysis. Newborn screening programs are available in Austria, Belgium, Hungary, Iceland, Portugal and Spain.\nDifferential diagnosis\nDifferential diagnosis includes autosomal resessive polycystic kindney disease; carnitine palmitoyl transferase II deficiency, neonatal form; Zellweger syndrome and sterol biosynthesis disorders (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible when 2 pathogenic mutations have been identified in the family.\nGenetic counseling\nMADD is an autosomal recessive disorder and genetic counseling is available.\nManagement and treatment\nTreatment for the more severe phenotypes involves restriction of both fat and protein and reliance on a high carbohydrate diet. Strict avoidance of fasting and of other precipitating stresses is essential. Emergency regimens should be available for any metabolic decompensation. Riboflavin supplementation of 100-400 mg/day is a very effective treatment for patients with rr-MADD as is CoQ10 supplementation in some. For moderately severe cases, 3-hydroxybutyrate has been used successfully, but further studies are still needed.\nPrognosis\nMADD-S is invariably fatal. Milder phenotypes have a more favorable prognosis.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Simon OLPIN"}
{"Disease Name": "Multiple benign circumferential skin creases on limbs", "Disease Definition": "A rare genetic disease characterized by benign circumferential skin creases, mainly on the limbs, due to folding of excess skin. The creases often improve spontaneously in childhood. Patients also exhibit variable degrees of intellectual disability, short stature, cleft palate, and facial dysmorphism (including epicanthal folds, microphthalmia, broad nasal bridge, low-set, posteriorly rotated ears, and microstomia, among others). Variable additional features have been reported, such as seizures, infantile hypotonia, hearing impairment, strabismus, and urogenital anomalies. Brain imaging may show hypoplastic corpus callosum or mildly dilated ventricles.", "ORPHA ID": 2505, "Summary": ""}
{"Disease Name": "Multiple carboxylase deficiency", "Disease Definition": "A group of inborn errors of biotin metabolism characterized by reduced activities of biotin-dependent enzymes resulting in a wide spectrum of symptoms, including feeding difficulty, breathing difficulties, lethargy, seizures, skin rash, alopecia, and developmental delay. This group includes biotinidase deficiency and biotin holocarboxylase synthetase deficiency.", "ORPHA ID": 148, "Summary": ""}
{"Disease Name": "Multiple congenital anomalies-hypotonia-seizures syndrome type 2", "Disease Definition": "A rare, genetic, lethal, neurometabolic malformation syndrome characterized by multiple, variable, congenital cardiac (systolic murmur, atrial septal defect), urinary (duplicated collecting system, vesicoureteral reflux) and central nervous system (thin corpus callosum, cerebellar hypoplasia) malformations associated with neonatal hypotonia, early-onset epileptic encephalopathy, and myoclonic seizures. Craniofacial dysmorphism (prominent occiput, enlarged fontanel, fused metopic suture, upslanted palpebral fissures, overfolded helix, depressed nasal bridge, anteverted nose, malar flattening, microstomy with downturned corners, Pierre-Robin sequence, high arched palate, short neck) and other manifestations (joint contractures, hyperreflexia, dysplastic nails, developmental delay) are also observed.", "ORPHA ID": 300496, "Summary": ""}
{"Disease Name": "Multiple congenital anomalies-hypotonia-seizures syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by severe global developmental delay, hypotonia, and early-onset seizures, associated with multiple congenital anomalies, such as cardiac (e.g. patent foramen ovale, atrial septal defect, patent ductus arteriosus), genitourinary (i.e. hydrocele, renal collecting system dilatation, hydroureter, hydronephrosis, hypertrophic trabecular urinary bladder) and gastrointestinal abnormalities (including gastroesophageal reflux, anal stenosis, imperforate anus, ano-vestibular fistula), as well as facial dysmorphism which includes coarse facies, a prominent occiput, bitemporal narrowing, epicanthal folds, hypertelorism, nystagmus/strabismus/wandering eyes, low-set, large ears with auricle abnormalities, depressed nasal bridge, upturned nose, long philtrum, large, open mouth with thin lips, high-arched palate, and micro/retrognathia.", "ORPHA ID": 280633, "Summary": ""}
{"Disease Name": "Multiple endocrine neoplasia type 1", "Disease Definition": "A rare inherited cancer syndrome, characterized by the development of multiple neuroendocrine tumors of the parathyroids, gastro-entero-pancreatic tract, and anterior pituitary gland, and less commonly the adrenal cortical gland, thymus and bronchi, with other non-endocrine tumors in some patients.", "ORPHA ID": 652, "Summary": "Epidemiology\nPrevalence of multiple endocrine neoplasia type 1 (MEN1) is estimated to range between 1/10,000-30,000. The sex ratio is equal.\nClinical description\nTumors can develop at any age with 95% of patients developing clinical symptoms by the 5th decade. Parathyroid tumors are the most common (95% of patients), followed by pancreatic islet tumors (40%) and anterior pituitary tumors (30%). Pancreatic neuroendocrine tumors include gastrinoma (50%), insulinoma (33%), glucagonoma (5%), vasoactive intestinal peptide (VIP)-oma, pancreatic polypeptide (PP)-oma and non-functioning tumors, and are associated with high levels of morbidity and mortality. Pituitary tumors include prolactinoma (66%), somatotrophinoma (25%), and ACTHomas (5%) and non-functioning adenomas (5%). The most common initial manifestation is primary hyperparathyroidism (PHPT; mean age onset in third decade of life), due to parathyroid hyperplasia and/or adenoma. PHPT can present with long periods of normal serum level of calcium (normocalcemic PHPT), that is often asymptomatic. When associated with hypercalcemia, and often also hypophosphatemia, PHPT can manifest clinical signs that may include nephrolithiasis, polyuria, polydipsia, constipation, fatigue, depression, confusion, anorexia, osteopenia and osteoporosis. Untreated PHPT can exacerbate over-secretion of gastrina from a concomitant gastrinoma and favor peptic ulcers. Gastrinomas lead to peptic ulcers in more than 50% of MEN 1 patients, and can be associated with Zollinger-Ellison syndrome.\nEtiology\nMEN1 is caused by germinal heterozygote inactivating mutations of the MEN1 gene (11q13) encoding the menin protein, a tumor suppressor.In many cases the genetic etiology remains unknown.\nDiagnostic methods\nMEN1 is clinically diagnosed in affected patients manifesting at least two of the main endocrine tumors (parathyroid, pituitary, and/or pancreatic) during their life. In these cases, the genetic testing is used and confirmed by the presence of a germinal mutation of the MEN1 gene.\nDifferential diagnosis\nThe differential diagnosis includes other types of MEN, mainly MEN2A and MEN4 (associated to the gene CDKN1B). Familial primary hyperparathyroidism should also be considered. Differential diagnosis with MEN4 is necessarily made by genetic testing.\nAntenatal diagnosis\nPrenatal diagnosis is possible, when one of the parent is carrier of a mutation of the MEN1.\nGenetic counseling\nMEN1 displays a high degree of penetrance; mutation carriers show up to 100% of disease penetrance after the age of 55. The inheritance pattern is autosomal dominant and genetic counseling should be provided to affected individuals and their families informing them that the risk of disease transmission is 50% from an individual with a pathogenic variant to their offspring.\nManagement and treatment\nAnnual life-long screening is recommended for all the carriers of a MEN1 mutations and individuals from affected families without an identified MEN1 mutations or who have not undergone the genetic test. Six-monthly screening is recommended for affected patients (CT, MRI, blood biochemistry). Treatment is prevalently by surgery based on approaches for each specific tumor. Some pharmacological therapies are available for treatment of hormone over-secretion and related symptoms; calcimimetic can be used to treat PHPT in patients in whom surgery had either failed or was contraindicated. Prior to surgery, bone anti-resorptive agents are used to reduce hypercalcemia and limit bone resorption. Dopamine agonists are used for prolactinoma. Somatostatin analogs for GH-secreting tumors and for controlling the secretory hyperfunction associated with carcinoid syndrome. Proton pump inhibitors or H2-receptor blockers reduce gastric acid output caused by gastrinomas.\nPrognosis\nMalignancy is the main risk patients (accounting for approximately 30% of deaths); however, untreated hormone over-secretion by functioning tumors can account for morbidity and mortality. Early diagnosis and treatment success are the main prognostic factors.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Maria Luisa BRANDI  - Dr Francesca GIUSTI  - Dr Francesca MARINI"}
{"Disease Name": "Multiple endocrine neoplasia type 2", "Disease Definition": "A rare multiple endocrine neoplasia (MEN) syndrome that is principally characterized by the association of medullary thyroid carcinoma (MTC) with other endocrine tumors. The variant MEN 2A is defined by MTC associated with pheochromocytoma and/or primary hyperparathyroidism (MEN2A); the variant MEN 2B is defined as an aggressive form of MTC in association with pheochromocytoma but without primary hyperparathyroidism.", "ORPHA ID": 653, "Summary": "Epidemiology\nThe total prevalence of all variants of multiple endocrine neoplasia type 2 (MEN2) is approximately 1/35,000. MEN2A, accounts for 95% of MEN2 cases.\nClinical description\nMEN2 can affect all age groups, with manifestations beginning in infancy to early childhood (MEN2B) or adulthood (MEN2A). Clinical manifestations are related to the tumors associated. MTC affects all forms of MEN2, is usually the first manifestation of the disease, and arises in the parafollicular cells of the thyroid. In MEN2A, MTC is associated in 50% of cases with pheochromocytoma (PCC) and in 20-30% with primary hyperparathyroidism (PHPT). PCC is almost always benign and is usually multicentric, bilateral, and confined to the adrenal gland. In classical MEN2A, PHPT is usually mild and between one to four parathyroid glands may be enlarged. MEN2A can also be associated with cutaneous lichen amyloidosis or Hirschsprung's disease (HD). In MEN2B, MTC often presents in infancy and is highly aggressive, metastasizing early to regional lymph nodes and beyond. Approximately 50% of patients with MEN2B develop PCC. They also have a unique physical appearance characterized by a typical facies (mucosal neuromas of the lips and tongue), ophthalmologic abnormalities (alacrima in infancy, thickened and everted eyelids, mild ptosis, and prominent corneal nerves), skeletal anomalies (marfanoid body habitus, narrow long facies, pes cavus, pectus excavatum, high-arched palate, scoliosis, hyperextensible joints and slipped capital femoral epiphyses), and a generalized ganglioneuromatosis throughout the aerodigestive tract.\nEtiology\nMEN2 is caused by a heterozygote germline activating mutation in the RET proto-oncogene (10q11.2), encoding a membrane tyrosine kinase receptor. The clinical subtypes depend on which functional domain the mutations affect.\nDiagnostic methods\nClinical diagnosis involves identification of MTC, PCC, and eventually PHPT. MTC is diagnosed by ultrasound (US) of the neck and serum levels of calcitonic (Ctn) and carcinoembryonic antigen (CEA). Screening of PCC consists of measuring metanephrines and normetanephrines from either free plasma or a 24-hour urine test. Adrenal imaging with CT or MRI is indicated in patients with positive biochemical results. A positive genetic test of RET confirms the clinical diagnosis in affected patients.\nDifferential diagnosis\nDifferential diagnoses include MTC, Hirschsprung disease and familial medullary thyroid carcinoma (FMTC). FMTC is also associated with germline RET variants but patients only manifest MTC.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the mutation has previously been identified in a family member.\nGenetic counseling\nMEN2 is an autosomal-dominant syndrome and individuals carrying the pathogenic variant have a 50% risk of transmitting the variant to each offspring, independent of sex. Approximately 75% of MEN2B cases are sporadic (with the RET mutation arising de novo), while 25% are familial.\nManagement and treatment\nRET mutation predicts the clinical phenotype and guides treatment. As recommended by the American thyroid association, management and treatment is stratified according to risk of aggressive MTC: highest risk (HST); high risk (H); moderate risk (MOD). All patients require evaluation of serum Ctn every 6 months for the first year, then annually if serum Ctn remains normal or undetectable. Annual US of the neck is indicated for both H and HST categories. Total thyroidectomy (TTX) should be performed when the serum Ctn level becomes elevated in MOD, and at or before 5 years of age (based on serum Ctn levels) for H and HST risk groups. Life-long thyroid hormone supplementation is needed after thyroid removal. The tyrosine kinase inhibitors, vandetanib and cabozantinib, are approved (in the USA and Europe) for the treatment of patients with advanced progressive MTC. MEN2A patients in the H and MOD risk groups should be simultaneously screened for PHPT and PCC. Only visibly enlarged parathyroids should be resected.\nPrognosis\nThe prognosis depends on the stage at which MTC is diagnosed and efficacy of initial surgical treatment. Early diagnosis and complete initial resection of tumors increases life expectancy.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Maria Luisa BRANDI  - Dr Francesca GIUSTI  - Dr Francesca MARINI"}
{"Disease Name": "Multiple endocrine neoplasia type 2A", "Disease Definition": "A form of multiple endocrine neoplasia type 2 (MEN2) syndrome characterized by medullary thyroid carcinoma in association with pheochromocytoma (one or both adrenal glands can be affected) and/or primary hyperparathyroidism (caused by parathyroid adenoma). Onset is typically later than in MEN2B, before 35 years of age. Diarrhea is the most frequent systemic symptom. Patients can develop Hirschsprung disease and, less frequently, cutaneous lichen amyloidosis or excessive production of adrenocorticotropic hormone.", "ORPHA ID": 247698, "Summary": ""}
{"Disease Name": "Multiple endocrine neoplasia type 2B", "Disease Definition": "A rare form of multiple endocrine neoplasia type 2 (MEN2) syndrome characterized by aggressive medullary thyroid carcinoma in association with other endocrine tumors, notably pheochromocytoma (one or both adrenal glands can be affected). Onset is typically in infancy or childhood and patients often have a typical facies (mucosal neuromas of the lips and tongue, and bumpy lips), ophthalmologic abnormalities (alacrima in infancy, thickened and everted eyelids, mild ptosis, and prominent corneal nerves), skeletal anomalies (marfanoid body habitus, narrow long facies, pes cavus, pectus excavatum, high-arched palate, scoliosis, hyperextensible joints and slipped capital femoral epiphyses), and a generalized ganglioneuromatosis throughout the aerodigestive tract. Chronic constipation, abdominal distension, diarrhea, or megacolon at birth are often the initial manifestations.", "ORPHA ID": 247709, "Summary": ""}
{"Disease Name": "Multiple endocrine neoplasia type 4", "Disease Definition": "Multiple endocrine neoplasia type 4 (MEN4) is a very rare form of MEN (see this term), an inherited cancer syndrome, characterized by parathyroid and anterior pituitary tumors, possibly associated with adrenal, renal, and reproductive organ tumors.", "ORPHA ID": 276152, "Summary": "Epidemiology\nThe prevalence of multiple endocrine neoplasia type 4 is unknown, but the syndrome is very rare. To date, 12 index cases have been reported. Prevalence is thought to be less than 1/million.\nClinical description\nMEN4 is a recently described MEN-like syndrome similar to MEN1 (see this term). Age of onset of tumors is variable. Patients have been reported to develop parathyroid tumors from fourth decade of life and pituitary tumors from the third decade. Affected patients develop parathyroid tumor with associated primary hyperparathyroidism (81%) and anterior pituitary tumors (42%). In MEN4 patients, various types of pituitary adenoma have been reported: Cushing disease, somatotropic adenoma, prolactinoma, and non-functioning pituitary adenoma (see these terms). Cases of gastric and bronchial carcinoid tumor or Zollinger-Ellison syndrome (see this term) have also been reported. Other associated tumors include reproductive organ tumors, peripheral neuroendocrine tumor of cervix uteri (see this term), and adrenal or renal tumors.\nEtiology\nMEN4 is caused by heterozygous inactivating mutations in the CDKN1B gene (12p13.1-p12) encoding p27, a cyclin-dependent kinase inhibitor that acts as a negative regulator of cell cycle progression. In MEN4, unlike in MEN1, CDKN1B acts as a non-conventional oncosuppressor gene and no loss of heterozygosity has been reported. The exact MEN4 tumorigenesis molecular mechanisms remain to be elucidated but it is suspected that the mutated allele could be responsible for the reduction of p27 protein localized in the nucleus and, thus, able to exert its role of negative regulator of cell cycle progression and cell growth.\nGenetic counseling\nMost cases are the result of autosomal dominant inheritance. Some cases of sporadic de novo occurrence are however reported. Genetic counseling should be provided to affected individuals and their families.\n\n                            Last update: \n                            April 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Maria Luisa BRANDI"}
{"Disease Name": "Multiple endocrine neoplasia", "Disease Definition": "Multiple endocrine neoplasia (MEN) is a group of rare inherited cancer syndromes characterized by the development of two or more endocrine gland tumors, sometimes with tumor development in other tissues or organs.", "ORPHA ID": 276161, "Summary": "Epidemiology\nThe overall prevalence and incidence of MEN are not known. The prevalence of MEN1 is estimated to be approximately 1/10,000 to 1/30,000, while the total prevalence of MEN2 variants is approximately 1/35,000. MEN4 is extremely rare. The incidence of MEN1 has been estimated from random postmortem studies to be 0.25%, and to be 1-18% in patients with primary hyperparathyroidism, 16 to 38% in patients with gastrinomas, and less than 3% in patients with pituitary tumors.\nClinical description\nMultiple endocrine neoplasia syndromes can develop in patients of all ages: from infants to elderly patients over 70 years of age. Manifestations vary depending on the affected endocrine glands. There are three types of MEN (multiple endocrine neoplasia types 1, 2, and 4; see these terms) based on the underlying genetic abnormalities, the endocrine glands involved and the clinical manifestations. Each type includes a different combination of pituitary, pancreatic, parathyroid, medullary, thyroid, and adrenal tumors. MEN1 is characterized by parathyroid, pituitary gland, and pancreatic tumors. MEN2 is divided into two subtypes: MEN2A characterized by medullary thyroid carcinoma (see this term) in combination with pheochromocytoma (see this term) and primary mild hyperparathyroidism; and MEN2B (formerly MEN3), a rare form, involving medullary thyroid carcinoma, pheochromocytoma, mucosal ganglioneuromas and marfanoid habitus. MEN4 involves the development of parathyroid and anterior pituitary tumors.\nEtiology\nMEN1 is caused by inactivating mutations in the MEN1 gene (11q13), and in some patients by mutations in the cyclin-dependent kinase inhibitor genes (CDKN1A, CDKN2B, CDKN2C). MEN2A and MEN2B are due to activating mutations in the RET gene (10q11.2), and MEN4 to inactivating mutations in the CDKN1B gene (12p13.1-p12). Patients with MEN1-like phenotypes (primary hyperparathyroidism associated with various tumors and lesions of the pituitary gland, pancreas, and duodenum) have also been found to have inactivating germline heterozygote mutation in CDKN1B.\nGenetic counseling\nMEN follows an autosomal dominant pattern of inheritance and some sporadic cases are reported. First-degree relatives have a 50% risk of developing the disorder, making appropriate genetic counseling very important in affected families. Biochemical and genetic screening may be suggested to family members.\n\n                            Last update: \n                            April 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Maria Luisa BRANDI"}
{"Disease Name": "Multiple epiphyseal dysplasia due to collagen 9 anomaly", "Disease Definition": "Multiple epiphyseal dysplasia due to collagen 9 anomaly is a rare primary bone dysplasia disorder characterized by normal or mild short stature, early-onset pain and/or stiffness of the joints (mainly affecting knees but also elbows, wrists, ankles and fingers, with relative sparing of the hips) and early degenerative joint disease. Other skeletal anomalies (incl. varus or valgus deformities, osteochondritis dissecans, abnormal carpal shape, free articular bodies) and mild myopathy have also been reported.", "ORPHA ID": 166002, "Summary": ""}
{"Disease Name": "Multiple epiphyseal dysplasia type 1", "Disease Definition": "Multiple epiphyseal dysplasia type 1 (MED 1) is a form of multiple epiphyseal dysplasia that is characterized by normal or mild short stature, pain in the hips and/or knees, progressive deformity of extremities and early-onset osteoarthrosis. Specific features to MED 1 include a more pronounced involvement of hip joints and gait abnormality and a shorter adult height. MED1 is allelic to pseudoachondroplasia with which it shares clinical and radiological features. The disease follows an autosomal dominant mode of transmission.", "ORPHA ID": 93308, "Summary": ""}
{"Disease Name": "Multiple epiphyseal dysplasia type 4", "Disease Definition": "Multiple epiphyseal dysplasia type 4 is a multiple epiphyseal dysplasia with a late-childhood onset, characterized by joint pain involving hips, knees, wrists, and fingers with occasional limitation of joint movements, deformity of hands, feet, and knees (club foot, clinodactyly, brachydactyly), scoliosis and slightly reduced adult height. Radiographs display flat epiphyses with early arthritis of the hip, and double-layered patella. Multiple epiphyseal dysplasia type 4 follows an autosomal recessive mode of transmission. The disease is allelic to diastrophic dwarfism, atelosteogenesis type 2 and achondrogenesis type 1B with whom it forms a clinical continuum.", "ORPHA ID": 93307, "Summary": ""}
{"Disease Name": "Multiple epiphyseal dysplasia type 5", "Disease Definition": "Multiple epiphyseal dysplasia type 5 is a multiple epiphyseal dysplasia characterized by an early-onset of pain and stiffness (involving knee and hip), progressive deformity of the extremities and precocious osteoarthritis associated with delayed and irregular ossification of epiphyses. Features specific to multiple epiphyseal dysplasia, type 5 include normal stature and lesser incidence of gait abnormalities. Radiographs reveal epiphyseal and metaphyseal irregularities. Multiple epiphyseal dysplasia type 5 follows an autosomal dominant mode of transmission.", "ORPHA ID": 93311, "Summary": ""}
{"Disease Name": "Multiple epiphyseal dysplasia, Lowry type", "Disease Definition": "Multiple epiphyseal dysplasia, Lowry type is a rare primary bone dysplasia characterized by small, flat epiphyses (esp. the capital femoral epiphyses), rhizomelic shortening of limbs, cleft of secondary palate, micrognathia, mild joint contractures and facial dysmorphism (incl. mildly upward-slanting palpebral fissures, hypertelorism, broad nasal tip). Additionally reported features include scoliosis, genu valgum, mild pectus excavatum, platyspondyly, dislocated radial heads, brachydactyly, hypoplastic fibulae and talipes equinovarus.", "ORPHA ID": 166016, "Summary": ""}
{"Disease Name": "Multiple epiphyseal dysplasia-macrocephaly-facial dysmorphism syndrome", "Disease Definition": "A rare primary bone dysplasia characterized by the association of multiple epiphyseal dysplasia with macrocephaly and dysmorphic facial features (such as frontal bossing, hypertelorism, flat malar region, low-set ears, and short neck). Patients are of normal stature and present with joint swelling and genu valgum. Additional reported manifestations include clinodactyly, spindle-shaped fingers, and pectus excavatum.", "ORPHA ID": 166024, "Summary": ""}
{"Disease Name": "Multiple epiphyseal dysplasia-miniepiphyses syndrome", "Disease Definition": "Multiple epiphyseal dysplasia, with miniepiphyses is a rare primary bone dysplasia disorder characterized by strikingly small secondary ossification centers (mini-epiphyses) in all or only some joints, resulting in severe bone dysplasia of the proximal femoral heads. Short stature, increased lumbar lordosis, genua vara and generalized joint laxity have also been reported.", "ORPHA ID": 166032, "Summary": ""}
{"Disease Name": "Multiple epiphyseal dysplasia-severe proximal femoral dysplasia syndrome", "Disease Definition": "Multiple epiphyseal dysplasia, with severe proximal femoral dysplasia is a rare primary bone dysplasia characterized by severe, early-onset dysplasia of the proximal femurs, with almost complete absence of the secondary ossification centers and abnormal development of the femoral necks (short and broad with irregular metaphyses). It is associated with gait abnormality, mild short stature, arthralgia, joint stiffness with limited mobility of the hips and irregular acetabula, and hip and knee pain. Coxa vara and mild spinal changes are also associated.", "ORPHA ID": 166029, "Summary": ""}
{"Disease Name": "Multiple epiphyseal dysplasia", "Disease Definition": "A rare group of primary bone dysplasia disorders characterized by the association of epiphyseal anomalies of long bones causing joint pain early in life, recurrent osteochondritis and early arthrosis. This group contains an heterogeneous group of diseases with variable expression. Common reported clinical signs include waddling gait and pain at onset, and moderate short stature. Some forms are mainly limited to the femoral epiphyses, while several other syndromes are characterized by the association of multiple epiphyseal dysplasia with other clinical manifestations such as myopia, deafness and facial dysmorphism. Diagnosis relies on identification of the radiological features.", "ORPHA ID": 251, "Summary": ""}
{"Disease Name": "Multiple intestinal atresia", "Disease Definition": "Multiple intestinal atresia is a rare form of intestinal atresia characterized by the presence of numerous atresic segments in the small bowel (duodenum) or large bowel and leading to symptoms of intestinal obstruction: vomiting, abdominal bloating and inability to pass meconium in newborns.", "ORPHA ID": 2300, "Summary": ""}
{"Disease Name": "Multiple mitochondrial dysfunctions syndrome type 1", "Disease Definition": "A rare mitochondrial disease characterized by failure to thrive, infantile encephalopathy, muscular hypotonia, global developmental delay and regression, pulmonary arterial hypertension, episodes of apnea and bradycardia, respiratory failure, hyperglycinemia, and lactic acidosis. Hypertrophic or dilated cardiomyopathy have also been reported. Brain imaging may show leukoencephalopathy involving variable regions. The disease is typically fatal in early infancy.", "ORPHA ID": 401869, "Summary": ""}
{"Disease Name": "Multiple mitochondrial dysfunctions syndrome type 2", "Disease Definition": "A rare mitochondrial disease characterized by infantile onset of severe regression after a period of normal development, epileptic encephalopathy, hypotonia, movement disorder, cardiomyopathy, hyperglycinemia, and lactic acidosis. Optic atrophy may also be present. Brain imaging findings are highly variable and include white matter abnormalities. The disease is typically fatal in infancy.", "ORPHA ID": 401874, "Summary": ""}
{"Disease Name": "Multiple mitochondrial dysfunctions syndrome type 3", "Disease Definition": "A rare neurometabolic disease, due to a lipoic acid biosynthesis defect, with a highly variable phenotype, typically characterized by early-onset acute or subacute developmental delay or regression frequently associated with feeding difficulties. Clinical severity is variable and may range from mild cases which present a later onset with slow neurological deterioration and general improvement over time to severe cases with clinical signs since birth and leading to early death. Associated manifestations include hypotonia, vision loss, respiratory failure, seizures, and intellectual disability. Brain magnetic resonance imaging frequently shows cavitating leukoencephalopathy with lesions in the periventricular/central white matter and parieto-occiîtal lobes.", "ORPHA ID": 363424, "Summary": ""}
{"Disease Name": "Multiple mitochondrial dysfunctions syndrome type 4", "Disease Definition": "A rare, severe, genetic, neurometabolic disease characterized by infantile-onset of progressive neurodevelopmental regression, optic atrophy with nystagmus and diffuse white matter disease. Affected individuals usually have central hypotonia that progresses to limb spasticity and hyperreflexia, eventually resulting in a vegetative state. Recurrent chest infections are frequently associated and seizures (usually generalized tonic-clonic) may occasionally be observed. Brain magnetic resonance imaging shows diffuse bilateral symmetric abnormalities in the cerebral periventricular white matter, with variable lesions in other areas but sparing the basal ganglia.", "ORPHA ID": 457406, "Summary": ""}
{"Disease Name": "Multiple mitochondrial dysfunctions syndrome type 5", "Disease Definition": "A rare mitochondrial disease characterized by early infantile onset of progressive neurological deterioration with seizures, spasticity, and lack of psychomotor development. Brain imaging shows severe leukodystrophy and abnormalities of neuronal migration. Lactic acidosis is common. The disease is usually fatal in early childhood.", "ORPHA ID": 569274, "Summary": ""}
{"Disease Name": "Multiple mitochondrial dysfunctions syndrome type 6", "Disease Definition": "A rare mitochondrial disease characterized by onset of episodic developmental regression in the first year of life, often in the setting of febrile illnesses, as well as hypotonia and seizures or refractory epileptic encephalopathy. Other observed features include ataxia, dystonia, or optic atrophy, among others. Patients do not achieve independent ambulation or meaningful speech. Brain imaging may show progressive cerebellar or diffuse atrophy and signal abnormalities of the basal ganglia. Serum lactate is often elevated.", "ORPHA ID": 569290, "Summary": ""}
{"Disease Name": "Multiple mitochondrial dysfunctions syndrome", "Disease Definition": "Multiple mitochondrial dysfunctions syndrome describes a group of rare inborn errors of energy metabolism due to defects in mitochondrial [4Fe-4S] protein assembly. Patients present with a neonatal/infancy onset of metabolic lactic acidosis (that may be associated with hyperglycinemia and other abnormal metabolic testing results), muscular hypotonia, absence of psychomotor development or developmental regression, as well as abnormal neuroimaging findings (including leukodystrophy, brain developmental defects, white matter abnormalities, cerebral atrophy), and other variable clinical features (e.g., optic atrophy, cardiomyopathy, pulmonary hypertension, seizures, and dysmorphic features). Early fatal outcome is usual.", "ORPHA ID": 289573, "Summary": ""}
{"Disease Name": "Multiple myeloma", "Disease Definition": "Multiple myeloma (MM) is a malignant tumor of plasma cell characterized by overproduction of abnormal plasma cells in the bone marrow and skeletal destruction. The clinical features are bone pain, renal impairment, immunodeficiency, anemia and presence of abnormal immunoglobulins (Ig).", "ORPHA ID": 29073, "Summary": ""}
{"Disease Name": "Multiple osteochondromas", "Disease Definition": "A primary bone disorder characterized by development of two or more cartilage capped bony outgrowths (osteochondromas) at the surface of the bones.", "ORPHA ID": 321, "Summary": "Epidemiology\nMultiple osteochondromas (MO) prevalence is estimated at 1:50,000, and seems to be higher in males (male-to-female ratio 1.5:1).\nClinical description\nOsteochondromas develop and increase in size in the first decade of life, and usually cease to grow when the growth plates close at puberty. They are pedunculated or sessile (broad base) and can vary widely in size. The number of osteochondromas may vary significantly within and between families, the mean number of locations is 15-18. The majority are asymptomatic and located in bones that develop from cartilage, especially the long bones of the extremities, predominantly around the knee. The facial bones are not affected. Bone lesions on flat bones, vertebrae, and the ribs are less common and the skull is usually not involved. Osteochondromas may cause pain, functional problems and deformities (especially of the forearm), which may provide reason for surgical removal. The most important complication is malignant transformation of osteochondroma towards secondary peripheral atypical cartilaginous tumor or chondrosarcoma, which is estimated to occur in 0.5-5% of cases.\nEtiology\nGermline mutations in the tumor suppressor genes, EXT1 (8q24.11) or EXT2 (11p11.2), are found in almost 90% of MO patients. The EXT genes encode glycosyltransferases, catalyzing heparan sulphate polymerization.\nDiagnostic methods\nThe diagnosis is based on radiological and clinical documentation, supplemented with, if available, histological evaluation of the osteochondromas. Diagnostic criteria (WHO 2020) include radiological findings of at least two osteochondromas of the juxta-epiphyseal region of long bones, and a positive family history and/or a proven germline mutation in one of the EXT genes.\nDifferential diagnosis\nMO should be distinguished from metachondromatosis, dysplasia epiphysealis hemimelica and Ollier disease.\nAntenatal diagnosis\nIf the exact mutation is known antenatal diagnosis is technically possible.\nGenetic counseling\nMO is an autosomal dominant disorder and is genetically heterogeneous. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nManagement includes removal of osteochondromas when they are the cause of complaints. Removed osteochondromas should be examined for malignant transformation towards secondary peripheral atypical cartilaginous tumor or chondrosarcoma. Patients should be well instructed and regular follow-up for early detection of malignancy seems justified. For secondary peripheral chondrosarcoma, en-bloc resection of the lesion and its pseudocapsule with tumor-free margins should be performed, preferably in a bone tumor referral centre.\nPrognosis\nOsteochondromas are benign lesions and do not affect life expectancy.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Pr J.V.M.G. [Judith] BOVÉE"}
{"Disease Name": "Multiple paragangliomas associated with polycythemia", "Disease Definition": "A rare, endocrine disease characterized by early onset of polycythemia, and later occuring multiple parangliomas. Clinical presentation includes hypertension, headaches, fatigue, nausea, anxiety, and high concentration of red blood cells, leading to increased risk of stroke and pulmonary thromboembolism.", "ORPHA ID": 324299, "Summary": ""}
{"Disease Name": "Multiple pterygium syndrome", "Disease Definition": "A group of rare genetic disorders characterized by the presence of joint contractures and multiple soft tissue webs (pterygia) across the neck and various joints, as well as typical facial appearance and a variety of other congenital anomalies. Both lethal (lethal and X-linked lethal multiple pterygium syndrome) and non-lethal (autosomal recessive and autosomal dominant multiple pterygium syndrome) forms occur.", "ORPHA ID": 294060, "Summary": ""}
{"Disease Name": "Multiple pterygium-malignant hyperthermia syndrome", "Disease Definition": "An extremely rare arthrogryposis syndrome, described in only two pairs of siblings from two unrelated families to date, and characterized by the association of arthrogryposis, congenital torticollis, dysmorphic facial features (i.e. asymmetry of the face, myopathic facial movements, ptosis, posteriorly rotated ears, cleft palate), progressive scoliosis and episodes of malignant hyperthermia. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 2215, "Summary": ""}
{"Disease Name": "Multiple sclerosis-ichthyosis-factor VIII deficiency syndrome", "Disease Definition": "Multiple sclerosis-ichthyosis-factor VIII deficiency syndrome is characterized by the association of multiple sclerosis with lamellar ichthyosis (see this term) and hematological anomalies (beta thalassemia minor and a quantitative deficit of factor VIII-von Willebrand complex). Other clinical manifestations may include eye involvement (optic atrophy, diplopia), neuromuscular involvement (ataxia, pyramidal syndrome, gait disturbance) and sensory disorder. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 3151, "Summary": ""}
{"Disease Name": "Multiple self-healing squamous epithelioma", "Disease Definition": "Multiple self-healing squamous epithelioma (also known as Ferguson-Smith disease (FSD)) is a rare inherited skin cancer syndrome characterized by the development of multiple locally invasive skin tumors resembling keratoacanthomas of the face and limbs which usually heal spontaneously after several months leaving pitted scars.", "ORPHA ID": 65748, "Summary": "Epidemiology\nThe prevalence is unknown but to date over 100 cases have been reported with several large affected families originating in western Scotland.\nClinical description\nTumors typically start as a reddish macule which becomes papular, enlarged and ulcerated. As the tumor involutes, a horny plug forms that falls out leaving a deep pit with irregular, over-hanging edges. Tumors have a predilection for sun-exposed areas, especially nose, ears and circumoral regions. Lesions on the limbs are often larger and leave flat scars. The trunk is seldom affected. Lifetime tumor numbers range from a few to over a hundred. The age of onset of a first tumor is very variable ranging from 8 to over 70 years (median 28 years). Histological assessment of these tumors reveals well differentiated squamous carcinomas. Treatment with radiotherapy must be avoided because more numerous, more invasive tumors arise in previously irradiated skin.\nEtiology\nFSD may be due to loss of function mutations in the gene TGFBR1 (9q22) which encodes a transmembrane serine/threonine kinase receptor involved in TGF-β signaling. Mutations in the gene TGFBR1 are also found in Loeys-Dietz syndrome (LDS; see this term) but the spectrum of TGFBR1 mutations differs and the mutations found in most FSD families have not been associated with a predisposition to aortic aneurysm or other developmental defects that occur in LDS. It has been suggested that FSD is an oligogenic trait. Inherited permissive variants at TGFBR1 and a second, as yet unidentified, linked locus on the long arm of chromosome 9 appear to be required for tumor development. 90% of TGFBR1 mutation carriers in affected families developed the condition by age 60. Palmar and plantar skin are not affected suggesting that the tumors arise from hair follicles.\nGenetic counseling\nAlthough FSD is likely to be an oligogenic trait, the condition is inherited in an autosomal dominant manner because the TGFBR1 mutations and predisposing variants at the second linked locus are usually inherited together in affected families.\n\n                            Last update: \n                            February 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Malcolm FERGUSON-SMITH  - Dr David GOUDIE"}
{"Disease Name": "Multiple sulfatase deficiency", "Disease Definition": "A rare lysosomal disease characterized by a clinical phenotype that combines the features of different sulfatase deficiencies (whether lysosomal or not). Clinical manifestations can include developmental delay, progressive neurologic deterioration, hydrocephalus, hypotonia, coarse facial features, retinopathy, skeletal anomalies, hepatomegaly and ichthyosis to a variable degree. Multiple sulfatase deficiency (MSD) comprises severe to attenuated forms historically classified as neonatal (most severe form), infantile (most common form) or juvenile (rarest form).", "ORPHA ID": 585, "Summary": "Epidemiology\nThe estimated prevalence is 1/500,000. So far, there are approximately 150 reported cases without apparent ethnological and sexual distribution.\nClinical description\nThis disease begins between birth and the juvenile period. Patients with an early neonatal form can present with intrauterine growth retardation and respiratory distress at birth. They may also have facial dysmorphism, skeletal abnormalities, splenomegaly, congenital heart defects, ichthyosis and muscle hypotonia. Failure to thrive is a common clinical sign inherent to the different clinical MSD presentations. The infantile form often presents with developmental delay preventing the child from reaching developmental milestones, mildly coarse facial features, ichthyosis, organomegaly, dysostosis multiplex, and ichthyosis of variable degree. Attenuated forms differ from severe forms in that the disease progresses more slowly and not all clinical signs need to be present. Patients often achieve independent ambulation and speech before neurocognitive decline begins. Retinopathy, gallbladder sludge, hydrocephalus, hypertrichosis, dysostosis multiplex, and neuropathy can occur at all stages and in every form of MSD.\nEtiology\nAn autosomal recessive mutation in the SUMF1 gene on chromosome 3p26 causes MSD. The mutation alters the function of the sulfatase-activating enzyme FGE (Formylglycine-generating enzyme). There exist over 50 pathogenic mutations of SUMF1 most of which are missense mutations allowing residual FGE function towards sulfatase activation that result in reduced (to a variable degree) or completely absent activity sulfatases (lysosomal or not).\nDiagnostic methods\nClinical manifestations associated with a detection of glycosaminoglycans and sulfatides in the urine is indicative of MSD. The diagnosis is confirmed if there is loss of activity of at least two sulfatases in leukocytes or if a genetic test reveals a pathogenic mutation in the SUMF1 gene.\nDifferential diagnosis\nDifferential diagnosis includes all single sulfatase deficiencies like metachromatic leukodystrophy (arylsulfatase A deficiency), Hunter syndrome, Maroteaux-Lamy syndrome, or Sanfilippo syndrome type A and D among others. X-linked ichthyosis, saposin B deficiency, mucolipidosis and other lysosomal diseases are additional differential diagnosis.\nAntenatal diagnosis\nPreimplantation and prenatal genetic testing can be performed if pathogenic SUMF1 variants have been identified in an affected family member.\nGenetic counseling\nThe transmission is autosomal recessive. With each pregnancy, there is a 25% chance that the child will be affected and a 50% chance that the child will be a carrier.\nManagement and treatment\nCurrently, no specific treatment exists. A multidisciplinary approach is essential to increase quality of life and includes physiotherapy, skin treatment, neurological examinations, and monitoring of bone fragility, hearing, vision, gastrointestinal and respiratory disorders.\nPrognosis\nMSD has multiple clinical expressions and a prognosis can be hard to establish. However there exist different categories of MSD which may help evaluate its severity. The 50% survival rate has been estimated to be approximately 13 years. High motor function, achievement of speech, low number of clinical signs at a given age and high residual functionality of the FGE variant correlate with an attenuated course of MSD, and vice versa.\n\n                            Last update: \n                            December 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Laura ADANG  - Dr Rebecca AHRENS-NICKLAS  - Dr Lars SCHLOTAWA"}
{"Disease Name": "Multiple symmetric lipomatosis", "Disease Definition": "A rare subcutaneous tissue disease characterized by growth of symmetric non-encapsulated masses of adipose tissue mostly around the face and neck, with variable clinical repercussions (e.g. reduced neck mobility, compression of respiratory structures).", "ORPHA ID": 2398, "Summary": "Epidemiology\nMultiple symmetric lipomatosis (MSL) primarily affects men and has a sex ratio of 15:1 to 30:1, depending on the region. The disorder may occur in all ethnic groups. Prevalence and incidence are not known but estimates are available for certain countries (e.g. prevalence for males in Italy 1/25,000). More than 300 cases have been reported.\nClinical description\nMSL generally occurs in mid- to late-adulthood (30-60 years of age), but cases in childhood, adolescence and in elderly have also been reported. The course of the disease is characterized by rapid early development, followed by slow progressive growth of adipose deposits in and around the face, neck, occipital region, supraclavicular fossa, and shoulder areas. The thighs may be affected. Patients often initially present to medical attention for esthetic reasons and/or difficulties when dressing. Over time, neck muscles may become compressed, reducing the size of the trachea and esophagus with associated respiratory obstruction and obstructive sleep apnea. Patients also often have polyneuropathy, liver disease, and metabolic syndrome with abnormal glucose tolerance, and hyperlipidemia. Most affected patients are obese but some rare cases (10%) show a normal body weight. Malignant transformation into liposarcoma has been reported in very rare cases. MSL can also be associated with partial lipodystrophy and myopathy.\nEtiology\nThe pathogenesis of MSL is not fully understood, but it may be related to defective noradrenergic regulation of mitochondria in brown fat. The disease is strongly associated with alcohol abuse (up to 90% of patients). Rare genetic forms have also been described, generally occurring earlier in a familial form. Disease-causing mutations have been reported in MFN2 (1p36.22) and LIPE (19q13.2) genes, encoding the mitofusin 2 and the hormone sensitive lipase, respectively.\nDiagnostic methods\nDiagnosis of MSL may be complicated because of confusion with obesity. Clinical findings showing a specific distribution of adipose tissue are diagnostic (specifically, sparing of the distal arms and legs), as is alcohol abuse. Nevertheless, a family history of MSL should be searched. Ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) can confirm the presence of symmetrical, non-encapsulated fat deposits. Biopsy of fatty masses can also be used to rule out liposarcoma. Dyslipidemia, insulin resistance and diabetes should also be investigated.\nDifferential diagnosis\nObesity and liposarcoma are the main differential diagnoses. Other disorders to consider include Cushing syndrome, familial partial lipodystrophy, especially Dunnigan syndrome related to LMNA gene mutations, familial angiolipomatosis, Prune belly syndrome and lymphoma.\nGenetic counseling\nA mitochondrial and autosomal recessive inheritance have been reported. MSL can also be transmitted following an autosomal dominant mode of inheritance.\nManagement and treatment\nIn some patients, treatment may not be required. When treatment is needed for esthetic reasons, or due to sleep apnea, aerodigestive tract compression, or severe pain, it generally involves surgery such as lipectomy, liposuction (or ultrasound-assisted liposuction). Cessation of alcohol intake is recommended but generally not associated with a decrease of lipomatosis. Weight loss may help in halting progression in some cases. The treatment of associated morbidities (diabetes, cirrhosis) is required. Screening for alcohol- (and often tobacco-) associated cancers is useful.\nPrognosis\nMSL is basically a benign condition but in some cases, there may be serious physical, cosmetic and psychological repercussions. Associated disorders may affect the prognosis. Alcoholism plays a greater role in morbidity and mortality than MSL itself.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Marie-Christine VANTYGHEM"}
{"Disease Name": "Multiple synostoses syndrome", "Disease Definition": "Multiple synostoses syndrome (MSS) is a rare developmental bone disorder characterized by proximal symphalangism of the fingers and/or toes often associated with fusion of carpal and tarsal, humeroradial, and cervical spine joints.", "ORPHA ID": 3237, "Summary": ""}
{"Disease Name": "Multiple system atrophy, cerebellar type", "Disease Definition": "Multiple system atrophy, cerebellar type (MSA-c) is a form of multiple system atrophy (MSA; see this term) with predominant cerebellar features (gait and limb ataxia, oculomotor dysfunction, and dysarthria).", "ORPHA ID": 227510, "Summary": "Epidemiology\nMSA-c is observed predominantly in patients from Asia. A Japanese study reported a high percentage of patients (83.8%) exhibiting MSA-c features with only 16.2% of patients being categorized as MSA-parkinsonian type (MSA-p; see this term). In the Western Hemisphere, one third of all MSA patients have MSA-c. Genders are equally distributed.\nClinical description\nThe mean age of disease onset is 55 to 60 years. Gait ataxia is the most typical early symptom of MSA-c. Autonomic dysfunction (bladder dysfunction including early urinary incontinence, orthostatic hypotension, constipation, Raynaud syndrome) occurs early and is mandatory for the diagnosis of MSA-c. Additional features of MSA-c include dysphonia, dysphagia and other cerebellar features including limb ataxia and occulomotor dysfunction (sustained gaze-evoked nystagmus, positional down-beat nystagmus). All patients develop at least some parkinsonian signs (bradykinesia, rigidity, irregular jerky postural tremor) in the course of the disease. Pyramidal signs (generalized hyper-reflexia and, in some cases, positive Babinski sign) may be observed. Respiratory disturbances (sleep apnea, stridor and inspiratory sighs) and night time sleep disturbances, including rapid eye movement (REM) sleep behavior disorder (RBD) and periodic limb movements in sleep (PLMS), are frequently observed.\nEtiology\nThe exact etiology of MSC-c is unknown while the presence of cytoplasmic aggregates of α-synuclein, primarily in the oligodendroglia, in combination with predominant neurodegeneration of the olivopontocerebellar structures are pathological hallmark features of MSA-c. Mutations in the COQ2 gene (4q21.23 ) (encoding an enzyme involved in the biosynthesis of coenzyme Q10) have been shown in multiplex families with MSA, while some variants were associated with an increased for sporadic MSA.\nGenetic counseling\nMSA-c occurs sporadically. However, some familial cases of MSA have been described.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Wassilios MEISSNER"}
{"Disease Name": "Multiple system atrophy, parkinsonian type", "Disease Definition": "Multiple system atrophy, parkinsonian type (MSA-p) is a form of multiple system atrophy (MSA; see this term) with predominant parkinsonian features (bradykinesia, rigidity, irregular jerky postural tremor, and postural instability).", "ORPHA ID": 98933, "Summary": "Epidemiology\nMSA-p is observed predominantly in patients from the Western Hemisphere. 68% of MSA cases are MSA-p. Genders are equally distributed.\nClinical description\nThe mean age of disease onset is 55 to 60 years. MSA-p is characterized by parkinsonism (bradykinesia, rigidity, irregular jerky tremor and postural instability) and autonomic failure in the form of bladder dysfunction (including early urinary incontinence) and/or orthostatic hypotension. The presence of autonomic failure is mandatory for the diagnosis of MSA-p. Additional features include dysphonia, dysphagia and other autonomic features (respiratory disturbances such as sleep apnea, stridor and inspiratory sighs, as well as constipation and sexual dysfunction). In the course of the disease, all patients with MSA-p display at least some cerebellar signs (gait and limb ataxia, oculomotor dysfunction, dysarthria). Abnormal postures (camptocormia (see this term), Pisa syndrome and disproportionate antecollis) are frequently observed. Neuropsychiatric features and sleep disturbances may be observed and include: rapid eye movement (REM) sleep behavior disorder (RBD), periodic limb movements in sleep (PLMS), depression, apathy and anxiety. In some cases, pyramidal signs (generalized hyper-reflexia with a positive Babinski sign) may also be observed. Patients with MSA-p may develop early-onset levodopa-induced orofacial and craniocervical dystonia.\nEtiology\nThe exact etiology of MSA-p is still unknown but the presence of cytoplasmic aggregates of α-synuclein, primarily in oligodendroglia, in combination with predominant neurodegeneration of the striatonigral pathway are the pathological hallmark features of MSA-p. Mutations in the COQ2 gene (4q21.23) (encoding an enzyme involved in the biosynthesis of coenzyme Q10) have been shown in multiplex families with MSA, while some variants were associated with an increased risk for sporadic MSA.\nGenetic counseling\nMSA-p occurs sporadically. However, some familial cases of MSA have been described.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Wassilios MEISSNER"}
{"Disease Name": "Multiple system atrophy", "Disease Definition": "Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure (cardiovascular and/or urinary), parkinsonism, cerebellar impairment and corticospinal signs with a median survival of 6-9 years.", "ORPHA ID": 102, "Summary": "Epidemiology\nPrevalence ranges from 1/50,000-1/20,000. MSA-parkinsonian type (MSA-p) predominates in the Western Hemisphere and MSA-cerebellar type (MSA-c) predominates in the Eastern Hemisphere. Genders are equally distributed.\nClinical description\nMSA is an adult-onset disorder (>30 years, mean age 55-60 years). Clinical manifestations include autonomic failure (orthostatic hypotension, syncope, respiratory disturbances (sleep apnea, stridor and inspiratory sighs), constipation, bladder dysfunction (early urinary incontinence), erectile dysfunction in males and Raynaud syndrome). In some cases, pyramidal signs (generalized hyperreflexia and positive Babinski sign) are observed. MSA-p, a form of MSA with predominant parkinsonian features, comprises bradykinesia, rigidity, irregular jerky postural tremor and abnormal postures (camptocormia, Pisa syndrome and disproportionate antecollis). Patients with MSA-p may develop levodopa-induced orofacial and craniocervical dystonia. Classic pill-rolling rest tremor is uncommon. MSA-c is a form of MSA with predominant cerebellar features such as gait and limb ataxia, oculomotor dysfunction and dysarthria. The predominant motor feature can change with time and patients with cerebellar ataxia can develop increasingly severe parkinsonian features which dominate the clinical presentation. Neuropsychiatric features, oculomotor dysfunction and sleep disturbances are also observed in MSA and include apathy, anxiety, depression, rapid eye movement sleep behavior disorder and periodic limb movements in sleep.\nEtiology\nEtiology of MSA is unknown but presence of cytoplasmic aggregates of α-synuclein, primarily in oligodendroglia, in combination with neurodegeneration in striatonigral and olivopontocerebellar structures are the pathological hallmark features. Mutations in COQ2 (4q21.23) (encoding an enzyme involved in biosynthesis of coenzyme Q10) have been shown in multiplex families with MSA, while some variants were associated with an increased risk for sporadic MSA.\nDiagnostic methods\nDiagnosis of ''probable'' MSA requires presence of parkinsonism with poor levodopa response or cerebellar signs together with severe autonomic failure (otherwise unexplained urinary incontinence or an orthostatic decrease of blood pressure within 3 min of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic). MRI findings include atrophy of putamen and middle cerebellar peduncles, as well as putaminal and cerebellar hypometabolism on [18F]-fluorodeoxyglucose positron emission tomography. ''Definite'' MSA requires post-mortem demonstration of α-synuclein positive glial cytoplasmic inclusions with neurodegeneration of striatonigral and olivopontocerebellar structures.\nDifferential diagnosis\nDifferential diagnosis of MSA-p includes Parkinson's disease and other atypical parkinsonian disorders (progressive supranuclear palsy, corticobasal syndrome). Differential diagnosis of MSA-c includes dominantly inherited spinocerebellar ataxias (SCAs 1, 2, 3, 6, and 7), fragile X-associated tremor/ataxia syndrome (FXTAS) and mitochondriopathies (POLG1 gene mutations).\nGenetic counseling\nMSA occurs sporadically. However, some familial cases have been described.\nManagement and treatment\nTherapy mainly targets parkinsonism and autonomic failure. Levodopa may transiently improve parkinsonism (20-30% of patients). No effective neuroprotective therapy is available.\nPrognosis\nMSA is rapidly progressive and is associated with wheelchair dependence, unintelligible speech, intermittent urinary catheterization, disabling orthostatic hypotension, and cognitive impairment (executive dysfunction). Disease progression is assessed using the unified MSA rating scale (UMSARS), which rates activities of daily life, autonomic and motor impairment, as well as overall disability. Prognosis is poor with a median survival of 6-9 years.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Wassilios MEISSNER"}
{"Disease Name": "Multisystem inflammatory syndrome in children and adults", "Disease Definition": "A rare systemic disease characterized by a life-threatening hyperinflammatory state several weeks after infection with SARS-CoV-2, predominantly occurring in children. The primary infection is typically mild or asymptomatic, and patients are generally previously healthy individuals. Typical presenting signs and symptoms are persistent fever, gastrointestinal symptoms, mucocutaneous inflammation, lymphopenia, and high levels of circulating inflammatory markers. Some patients develop severe disease with cardiac involvement, hypotension, and shock. Presentation is similar in adults, although the severity of cardiac dysfunction, incidence of thrombosis, and mortality may be higher.", "ORPHA ID": 598363, "Summary": ""}
{"Disease Name": "Multisystemic smooth muscle dysfunction syndrome", "Disease Definition": "A rare, genetic, vascular disease characterized by congenital dysfunction of smooth muscle throughout the body, manifesting with cerebrovascular disease, aortic anomalies, intestinal hypoperistalsis, hypotonic bladder, and pulmonary hypertension. Congenital mid-dilated pupils non-reactive to light associated with a large, persistent patent ductus arteriosus are characteristic hallmarks of the disease.", "ORPHA ID": 404463, "Summary": ""}
{"Disease Name": "Murine typhus", "Disease Definition": "A Rickettsial disease characterized by headache, fever and macular or maculopapular rash, with only one-third of patients manifesting all three symptoms. Other common symptoms are chills, malaise, stomach pain, myalgia, loss of appetite, and in some cases confusion and altered level of consciousness. Classical laboratory abnormalities include elevated liver enzymes, lactate dehydrogenase, erythrocyte sedimentation rate and hypoalbuminemia. In children, typical symptoms occur in only half of patients, and abdominal pain, diarrhea, sore throat and anemia are more common.", "ORPHA ID": 83315, "Summary": ""}
{"Disease Name": "Muscle filaminopathy", "Disease Definition": "Muscle filaminopathy is a rare myofibrillar myopathy characterized by slowly progressive, proximal skeletal muscle weakness, which is initially more prominent in lower extremities and involves upper extremities with disease progression. Patients present with difficulty climbing stairs, a waddling gait, marked winging of scapula, lower back pain, paresis of limb girdle musculature, hypo-/areflexia and/or mild facial muscle weakness in rare cases. Respiratory muscle weakness is common and cardiac anomalies (conduction blocks, tachycardia, diastolic dysfunction, left ventricular hypertrophy) have been reported in some cases.", "ORPHA ID": 171445, "Summary": ""}
{"Disease Name": "Muscle-eye-brain disease with bilateral multicystic leucodystrophy", "Disease Definition": "A rare congenital muscular alpha-dystroglycanopathy with brain and eye anomalies disease characterized by a severe muscle-eye-brain disease-like phenotype associated with intellectual disability, muscular dystrophy, macrocephaly and extended bilateral multicystic white matter disease.", "ORPHA ID": 370997, "Summary": ""}
{"Disease Name": "Muscle-eye-brain disease", "Disease Definition": "A rare, congenital muscular dystrophy due to dystroglycanopathy characterized by early onset muscular dystrophy, severe muscular hypotonia, severe intellectual disability and typical brain and eye malformations including pachygyria, polymicrogyria, agyria, brainstem and cerebellar structural anomalies, severe myopia, glaucoma, optic nerve and retinal hypoplasia. A broad clinical spectrum is observed with variable involvement of each organ system.", "ORPHA ID": 588, "Summary": "Epidemiology\nPrevalence is unknown but it is very rare among other congenital muscular dystrophies. It is more frequently observed in Northern European countries (Scandinavian region) due to a founder mutation.\nClinical description\nPatients carrying the Finish founder mutation present with marked hypotonia and global developmental delay from birth. They have generalized muscle weakness, including facial and neck muscles. Severe eye disease is often present and includes congenital myopia, pachygyria, polymicrogyria, agyria, cerebellar and brainstem hypoplasia, cerebellar cysts, congenital glaucoma, pallor of the optic discs, and /or retinal hypoplasia. Adults have severe intellectual and motor disability, extremely limited communication skills, visual impairment, epilepsy, and spine and joint deformities. Many patients have associated behavioral difficulties (bruxism, autism, temper tantrums, self-mutilation). Creatine kinase (CK) levels are increased, and the biopsy shows abnormal alpha-dystroglycan expression. Brain MRI may reveal cortical neuronal migration disorder, with type II lissencephaly in the most severe cases, white matter abnormalities, flat brainstem, cerebellar hypoplasia, and hydrocephalus. Electroencephalograms are abnormal and often show paroxysmal tracing. Patients with other mutations present with a broad clinical spectrum ranging from severe (prenatal death, and brain and posterior fossa malformations) to mild muscular dystrophies (with or without eye or brain structural abnormalities, constant speech and cognitive delay, but possible acquired walking). Almost all develop seizures, such as myoclonic jerks or refractory partial/generalized epilepsy.\nEtiology\nMuscle-eye-brain disease (MEB) is caused by mutations in the POMGnT1 gene (Chr 1p32-34), encoding protein O-linked mannose b1,2-N-acetylglucosaminyltransferase 1 (POMGnT1). Other gene variants have been identified in a small number of patients.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation, characteristic neuroimaging and electromyography findings, muscle biopsy results, and molecular genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes other dystroglycanopathies and muscular dystrophies with brain and/or cognitive impairment. Patients presenting with MEB symptoms would be diagnosed with Fukuyama congenital muscular dystrophy (FCMD) in Japan. Therefore, there is an increasing tendency to use the global term MEB/FCMD syndrome. Other dystroglycanopathies include CMD due to FKRP, ISPD with brain involvement or cognitive delay, Walker-Warbourg Syndrome, laminin subunit alpha 2-related congenital muscular dystrophy, Duchenne muscular dystrophy with cognitive involvement, CDG-syndromes, and chromosomal disorders.\nAntenatal diagnosis\nGenetic prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement includes physiotherapy, treatment of orthopedic, respiratory and cardiac complications, respiratory aid, and medical or surgical treatment for spinal or joint contractures, nutritional and gastrointestinal problems. Control of seizures requires antiepileptic drugs. Surveillance includes monitoring for respiratory and cardiac function. Severe intellectual disability and behavior disturbances may require specific care and management in specialized centers.\nPrognosis\nPrognosis depends mainly on the severity of neurologic, cardiac or respiratory complications. Patients may remain ambulant into adulthood.\n\n                            Last update: \n                            January 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI | EURO-NMD* - Pr Susana QUIJANO-ROY | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "Muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome", "Disease Definition": "A rare hereditary ataxia characterized by neurogenic muscular atrophy associated with signs of cerebellar ataxia, hypesthesia, degeneration of the retina, and diabetes mellitus. Onset of the disease is in adolescence and the course is slowly progressive. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 2579, "Summary": ""}
{"Disease Name": "Muscular dystrophy, Selcen type", "Disease Definition": "Selcen type muscular dystrophy is characterized by progressive limb and axial muscle weakness associated with cardiomyopathy and severe respiratory insufficiency during adolescence. The disease manifests during childhood and progresses rapidly.", "ORPHA ID": 199340, "Summary": "Epidemiology\nTo date, three cases have been described.\nClinical description\nTwo patients presented with a rigid spine and one a peripheral neuropathy. Disintegration of Z disks, extensive accumulation of granular debris and larger inclusions, and apoptosis of a small fraction of the nuclei characterize the disease.\nEtiology\nThe disease is due to a mutation in the BAG3 gene, encoding a protein localized to the Z disk.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            October 2009"}
{"Disease Name": "Muscular hypertrophy-hepatomegaly-polyhydramnios syndrome", "Disease Definition": "Muscular hypertrophy-hepatomegaly-polyhydramnios syndrome is a rare genetic disease characterized by symmetrical muscular hypertrophy, hepatomegaly, polyhydramnios, macrocephaly and mild delay in motor, speech and language development.", "ORPHA ID": 324416, "Summary": ""}
{"Disease Name": "Muscular pseudohypertrophy-hypothyroidism syndrome", "Disease Definition": "Muscular pseudohypertropy - hypothyroidism, also known as Kocher-Debre-Semelaigne syndrome is a rare disorder characterized by pseudohypertrophy of muscles due to longstanding hypothyroidism (see this term).", "ORPHA ID": 2349, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe syndrome usually presents between 18 months and 10 years but has been reported at earlier ages including during the neonatal period. Patients present with clinical features of hypothyroidism, including decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia, along with muscle pseudohypertrophy. Pseudohypertrophy involves the muscles of the extremities, limb girdle, trunk, hands and feet but is more prominent in the limbs, resulting in an athletic appearance.\nEtiology\nThe etiology of the muscle pseudohypertrophy is not known but it is thought to be a result of long standing hypothyroidism. Hypothyroidism, or thyroid hormone deficiency, may be congenital and may be permanent or transient (see these terms).\nDiagnostic methods\nDiagnosis is based on the presence of clinical features and myopathic changes. In countries with newborn screening programs (with either a primary thyroxine (T4)-follow-up thyroid-stimulating hormone (TSH) or primary TSH test), infants with congenital hypothyroidism are diagnosed after detection by screening tests.\nManagement and treatment\nTreatment is based on thyroid supplements. With treatment, reversal of the pseudohypertrophy and clinical symptoms is possible.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Musculocontractural Ehlers-Danlos syndrome", "Disease Definition": "A rare systemic disease characterized by congenital multiple contractures, characteristic craniofacial features (like large fontanel, hypertelorism, downslanting palpebral fissures, blue sclerae, ear deformities, high palate) evident at birth or in early infancy, and characteristic cutaneous features like skin hyperextensibility, skin fragility with atrophic scars, easy bruising, and increased palmar wrinkling. Additional features include recurrent/chronic dislocations, chest and spinal deformities, peculiarly shaped fingers, colonic diverticula, pneumothorax, and urogenital and ophthalmological abnormalities, among others. Molecular testing is obligatory to confirm the diagnosis.", "ORPHA ID": 2953, "Summary": ""}
{"Disease Name": "Mutilating hereditary sensory neuropathy with spastic paraplegia", "Disease Definition": "A rare genetic neurological disorder characterized by infantile to childhood onset of progressive sensory neuropathy in association with spastic paraplegia and mutilating acropathy. Patients present lower limb spasticity and progressive severe sensory loss leading to chronic ulcerations in both upper and lower limbs. Electrophysiological studies are consistent with axonal sensory neuropathy, and nerve biopsy shows axonopathy with loss of myelinated nerve fibers of all diameters as well as of unmyelinated axons.", "ORPHA ID": 139578, "Summary": ""}
{"Disease Name": "Mutilating palmoplantar keratoderma with periorificial keratotic plaques", "Disease Definition": "A hereditary palmoplantar keratoderma characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma and periorificial keratotic plaques.", "ORPHA ID": 659, "Summary": ""}
{"Disease Name": "Myalgia-eosinophilia syndrome associated with tryptophan", "Disease Definition": "Myalgia-eosinophilia syndrome associated with tryptophan is a rare systemic disease characterized by severe myalgia and peripheral eosinophilia associated with tryptophan dietary supplementation. The symptoms do not subside after tryptophan discontinuation. Clinical presentation includes muscle tenderness and cramps, fatigue, weakness, paresthesia, peripheral edema, arthralgia, dyspnea, skin rash, dry mouth, and development of scleroderma-like skin abnormalities.", "ORPHA ID": 2582, "Summary": ""}
{"Disease Name": "Myasthenia gravis", "Disease Definition": "Myasthenia gravis (MG) is a rare, clinically heterogeneous, autoimmune disorder of the neuromuscular junction characterized by fatigable weakness of voluntary muscles.", "ORPHA ID": 589, "Summary": "Epidemiology\nThe prevalence is estimated to be 1/5,000 and the incidence to be 1/250,000 to 1/33,000 in Europe. MG affects both males and females: mainly females before the age of 40 years and males and females equally after the age of 50 years.\nClinical description\nMyasthenia gravis can develop at any age but there is a bimodal peak in the age of onset in the adult-onset form, with primarily female patients before 40 years of age, and primarily males after 50 years of age (adult-onset myasthenia gravis; see this term). Patients have fluctuating weakness, worsening with repetitive activities, heat and stress while improving with rest and with involvement of skeletal muscle groups of ocular, bulbar, extremities and neck. Ocular manifestations include fluctuating diplopia and ptosis. Bulbar involvement may manifest with fatigable chewing, dysphagia and dysarthria. Some patients develop generalized muscle weakness, which may become serious with respiratory muscle weakness. In the juvenile form, onset is before 18 years of age (juvenile myasthenia gravis; see this term) and patients also present with ocular and possibly generalized muscle weakness. A transient neonatal form causing hypotonia and feeding difficulties occurs in some newborns born to mothers with MG (transient neonatal myasthenia gravis; see this term). Congenital genetic forms of MG with a different pathogenesis also occur (congenital myasthenic syndrome, see this term).\nEtiology\nThe exact pathogenesis is not known but MG is related to circulating antibodies to various muscle receptors, including acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK). Another target, the low density lipoprotein receptor-related protein 4 (LRP4), has been also described. The thymus is thought to trigger antibody production in the form with anti-AChR antibodies. These antibodies have been found to play a pathogenic role in all the forms of the disease. MG can also be drug induced (by D-penicillamine, interferon alpha, and bone marrow transplantation). An initial infection (EBV) may be responsible for some cases of MG. The role of infections has been strongly suggested by evidence of the involvement of interferon type I in the disease, but direct evidence is lacking.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Sonia BERRIH-AKNIN  - Pr Bruno EYMARD"}
{"Disease Name": "MYBPC1-related autosomal recessive non-lethal arthrogryposis multiplex congenita syndrome", "Disease Definition": "A rare arthrogryposis syndrome characterized by arthrogryposis multiplex congenita with contractures involving multiple joints of the upper and lower limbs, camptodactyly of fingers and toes, skeletal abnormalities such as scoliosis and pectus excavatum, as well as variable speech and motor delay and hypotonia. Facial dysmorphism includes long eyelashes, periorbital fullness, ptosis, epicanthal folds, high arched/cleft palate, and micrognathia.", "ORPHA ID": 498693, "Summary": ""}
{"Disease Name": "Mycetoma", "Disease Definition": "Subcutaneous inflammatory pseudotumors containing fungal or actinomycetic (bacteria with branched filaments) granules or grains.", "ORPHA ID": 2583, "Summary": "Epidemiology\nAnnual incidence is unknown. The condition is endemic in the northern tropical zone and was first described by McGill in the area of Madura (hence the term 'Madura foot') during the last century.\nClinical description\nThe typical characteristic of fungal mycetomas is a painless tumefaction slowly forming on the foot with fistulae that release grains. Actinomycetic mycetomas are more frequent in Latin America and are more likely to cause inflammatory and painful tumefactions with many fistulae and grains. In both cases, the underlying bone is often affected.\nEtiology\nThe agents causing mycetoma are very common saprophytes that are found in the soil and on thorny shrubs in semi-desert climates. Humans are infected as the result of localized skin trauma (implantation of a needle or wood splinter) or through a pre-existing wound.\nDiagnostic methods\nDiagnosis is made by microscopic examination of the grains and by analysis of cultures.\nDifferential diagnosis\nDifferential diagnoses include tumefactions of other origins.\nManagement and treatment\nMedical treatment with sulfones can cure actinomycetic mycetomas, whereas surgery is the main treatment for fungal mycetomas. Prophylaxis consists of disinfecting wounds and wearing shoes.\nPrognosis\nThe prognosis is poor for fungal mycetomas.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Annick DATRY"}
{"Disease Name": "Mycophenolate mofetil embryopathy", "Disease Definition": "Mycophenolate mofetil (MMF) embryopathy is a malformative syndrome due to the teratogenic effect of MMF, an effective immunosuppressive agent widely used for the prevention of organ rejection after organ transplantation.", "ORPHA ID": 268249, "Summary": "Epidemiology\nTo date, 25 cases have been reported, the majority being offspring of women who received a solid organ transplant.\nClinical description\nNewborns or fetuses generally show external ear anomalies ranging from hypoplastic auricle (microtia) to complete absence of external ear (anotia) almost always associated with hypoplasia or atresia of the auditory canal (aural atresia) which can ultimately lead to deafness. Cleft lip-palate (see this term) with micrognathia is frequently observed. Aberrant orofacial cleft has been observed in one case. Ocular anomalies, such as microphthalmia and iris or chorioretinal coloboma, (see this term) are also frequent and can induce visual defects including severe visual impairment. Distal limbs anomalies (hypoplastic toe nails) as well as congenital malformations of the heart, kidneys and/or central nervous system may also be observed. Esophageal atresia, congenital diaphragmatic hernia (see these terms) and vertebral anomalies have been described in some cases. Intellectual deficit is usually absent, or only mild.\nEtiology\nMMF embryopathy is due to exposure to MMF during the intrauterine developmental period. MMF is an immunosuppressive agent that has been increasingly used in recent years in the prevention of organ transplant rejection and treatment of many autoimmune diseases because of its high efficacy and good tolerability. No dose-related effect has been demonstrated; however, exposure to low doses of MMF seems potentially teratogenic.\nDiagnostic methods\nDiagnosis is based on clinical examination (presence of the characteristic features in the fetus/newborn) and on maternal history of exposure to MMF during pregnancy.\nDifferential diagnosis\nThe differential diagnosis includes 18q deletion (distal), CHARGE syndrome and isotretinoin embryopathy (see these terms). 18q deletion is excluded by cytogenetic studies, CHARGE syndrome by CHD7 gene mutation scanning, and isotretinoin embryopathy by maternal interview.\nAntenatal diagnosis\nWhen relevant malformations are present (oro-facial clefts, heart defects, central nervous system malformations, diaphragmatic hernia), prenatal diagnosis by fetal ultrasonography is possible before 18 week gestation.\nManagement and treatment\nIn more than 90% of cases, internal ear anomalies require hearing-aids, and speech therapy is recommended during childhood. Oro-facial clefts and heart defects are treated surgically. To prevent the disease, it is recommended for women on MMF planning a pregnancy to replace MMF by an alternative immunosuppressive agent at least 6 weeks before stopping contraception.\nPrognosis\nCases with severe cardiac malformations and/or diaphragmatic hernia may have a poor prognosis with early neonatal death. If no life-threatening malformations are present, patients may have a normal life expectancy.\n\n                            Last update: \n                            September 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Antonio PÉREZ AYTÉS"}
{"Disease Name": "Mycoplasma encephalitis", "Disease Definition": "Mycoplasma encephalitis is a rare infectious encephalitis characterized by an acute onset of neurological signs and symptoms (e.g. altered consciousness, seizures, headaches, meningeal signs, behavioral changes) due to bacterial infection by Mycoplasma pneumoniae. Patients typically present unspecific signs and symptoms, such as fever, nausea, vomiting, fatigue, prior to onset of neurological manifestations and frequently have a history of a respiratory tract infection (e.g. pneumonia, bronchiolitis, pharyngitis).", "ORPHA ID": 83482, "Summary": ""}
{"Disease Name": "Mycosis fungoides and variants", "Disease Definition": "A group of disorders including the most common forms of cutaneous T-cell lymphomas. The term Mycosis fungoides (MF) is restricted to the classical form characterized by the slow progression of patches, plaques and tumors, and to variants with a similar indolent course.", "ORPHA ID": 178566, "Summary": "Epidemiology\nThe annual incidence is estimated at between 1/350,000 and 1/110,000. The male to female ratio is 2:1. MF and its variants typically occur in adults and the elderly.\nClinical description\nBesides \"classical\" MF (Alibert-Bazin type), three distinct variants have been considered as sufficiently distinct to be included in the WHO-EORTC (European organisation for research and treatment of cancer) classification of cutaneous lymphomas: follicular mycosis fungoides, characterized by pilotropic lesions with or without deposition of mucin within the hair follicles; pagetoid reticulosis, characterized by localized lesions with intraepidermal proliferation of neoplastic T-cells usually involving the extremities; and granulomatous slack skin, characterized by areas of pendulous lax skin predominantly in the major skin folds (see these terms). Patches are often hypo- or hyperpigmented in dark-skinned individuals. Pruritus may be present, particularly in cases of folliculotropic MF. Extracutaneous involvement may occur in classical MF.\nEtiology\nThe etiology remains unknown.\nDiagnostic methods\nThe diagnosis is based on clinical presentation and should be confirmed by a skin biopsy.\nDifferential diagnosis\nDifferential diagnoses include inflammatory dermatoses (i.e. atopic dermatitis) in the early stages of MF, and other large cell non-Hodgkin lymphomas (see this term) in later stages.\nManagement and treatment\nManagement in the early stages includes mainly PUVA (photochemotherapy), interferon alpha-2a, retinoids, topical chemotherapy, and topical steroids. Total body electron beam irradiation may be used in case of severe forms of the disease. A variety of more aggressive treatments have been used for advanced stages of MF.\nPrognosis\nMF and its variants are slowly progressive. The prognosis depends on the type of MF but is usually favorable.\n\n                            Last update: \n                            June 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Lorenzo CERRONI"}
{"Disease Name": "Myelocystocele", "Disease Definition": "A rare closed neural tube defect characterized by cystic dilatation of the central canal of the spinal cord, herniating through a posterior vertebral arch defect (spina bifida) into an expanded cerebrospinal fluid (CSF) filled dural sac (meningocele). It can be located at the caudal part of the spinal cord (terminal myelocystocele) or above conus (non terminal myelocystocele).", "ORPHA ID": 268813, "Summary": ""}
{"Disease Name": "Myelodysplastic neoplasm with increased blasts type 1", "Disease Definition": "A severe type of RAEB characterized by cytopenias and the following hematological parameters: uni- or multilineage dysplasia, 5% to 9% blasts in bone marrow or 2% to 4% in peripheral blood, and no Auer rods (abnormal, needle-shaped or round inclusions in the cytoplasm of myeloblasts and promyelocytes). Median survival has been reported to be 18 months.", "ORPHA ID": 100019, "Summary": ""}
{"Disease Name": "Myelodysplastic neoplasm with increased blasts type 2", "Disease Definition": "A very severe type of RAEB characterized by cytopenias and the following hematological parameters: uni- or multilineage dysplasia, 10% to 19% blasts in bone marrow or 5% to 19% in peripheral blood, variable presence of Auer rods (abnormal, needle-shaped or round inclusions in the cytoplasm of myeloblasts and promyelocytes). Median survival has been reported to be 18 months.", "ORPHA ID": 100020, "Summary": ""}
{"Disease Name": "Myelodysplastic neoplasm with increased blasts", "Disease Definition": "Refractory anemia with excess blasts (RAEB) is a frequent severe subtype of myelodysplastic syndrome (MDS; see this term) characterized by cytopenias with unilineage or multilineage dysplasia and 5% to 19% blasts in bone marrow or blood.", "ORPHA ID": 86839, "Summary": "Epidemiology\nExact prevalence is unknown but RAEB accounts for about 40% of patients with MDS which has a prevalence estimated to be 1/25,000 to 1/33,000. The disease tends to occur in older adults with a male predominance.\nClinical description\nTwo types of RAEB are recognized: type 1 and type 2 (RAEB-1 and RAEB-2; see these terms) which are differentiated based on the percentage of blasts in bone marrow or blood. Patients usually present with symptoms related to one or more cytopenias. Survival is lower in patients with RAEB-2 and there is a higher rate of transformation into acute myeloid leukemia in these patients. Most RAEB patients die from neutropenia-, thrombocytopenia- and anemia-related complications.\nEtiology\nThe etiology is not known but is thought to involve inherited susceptibility or hematopoietic stem cell damage.\n\n                            Last update: \n                            February 2015"}
{"Disease Name": "Myelodysplastic neoplasm with low blasts", "Disease Definition": "Refractory cytopenias with unilineage dysplasia (RCUD) is a frequent low-risk subtype of myelodysplastic syndrome (MDS; see this term) characterized by refractory cytopenias associated with dysplasia limited to one cell lineage.", "ORPHA ID": 98826, "Summary": "Epidemiology\nExact prevalence is unknown but RCUD accounts for about 10% to 20% of patients with MDS which has a prevalence estimated to be 1/25,000 to 1/33,000. The disease tends to occur in older adults with a male predominance.\nClinical description\nClinical features are often nonspecific and are related to the underlying cytopenia. Patients are often asymptomatic and cytopenia is detected on routine blood tests. RCUD often has a prolonged and sometimes indolent course. Most patients with RCUD have refractory anemia (unilineage erythroid dysplasia), and very rarely refractory neutropenia (unilineage granulocytic dysplasia) or thrombocytopenia (unilineage megakaryocytic dysplasia). Anemia may be normocytic/normochromic but is often macrocytic. Blasts are absent or account for less than 1% in peripheral blood or less than 5% in bone marrow, and no Auer rods are present.\nEtiology\nThe etiology is not known but is thought to involve inherited susceptibility or hematopoietic stem cell damage.\nPrognosis\nMedian survival is reported to be 6 to 7 years and 5% to 10% of patients progress to acute leukemia.\n\n                            Last update: \n                            February 2015"}
{"Disease Name": "Myelodysplastic syndrome associated with isolated del(5q) chromosome abnormality", "Disease Definition": "A rare myelodysplastic syndrome characterized by macrocytic anemia (with or without other cytopenias and/or thrombocytosis), and with del(5q) occurring either in isolation, or with one other cytogenetic abnormality, other than monosomy 7 or del(7q). The bone marrow is typically hypercellular with erythroid hypoplasia and increased numbers of megakaryocytes, which show non-lobated and hypolobated nuclei. Myeloblasts constitute less than 5% of the nucleated bone marrow cells and less than 1% of the peripheral blood leukocytes. Auer rods are absent. Ring sideroblasts may be observed. Patients present with anemia and often thrombocytosis, while thrombocytopenia or pancytopenia are uncommon. Transformation to acute myeloid leukemia may occur in a small number of patients.", "ORPHA ID": 86841, "Summary": ""}
{"Disease Name": "Myelodysplastic syndrome", "Disease Definition": "A group of myeloid hemopathies characterized by blood cytopenias, marrow dysplasia and a high risk of progression to acute myeloid leukemia (AML).", "ORPHA ID": 52688, "Summary": "Epidemiology\nThe annual incidence is 1/17,000-25,000 people, with a median age at diagnosis of 70 years. Only 5-10% of patients are diagnosed below the age of 50.\nClinical description\nClinical symptoms are consequences of blood cytopenias, mainly anemia (e.g. fatigue, dyspnea, possible angina, etc.), and less often of thrombocytopenia (spontaneous bleeding) or neutropenia (bacterial or less often fungal infections).\nEtiology\nThe etiology is unknown in 80% of the cases. In the remaining 20% it has either acquired causes (previous treatment with chemo or radiotherapy, occupational exposure to benzene derivatives or ionizing radiation) or inherited causes, such as inherited gene point mutations mainly in DDX41, GATA2, RUNX, and telomerase genes, or DNA instability (Fanconi anemia patients are prone to develop MDS).\nDiagnostic methods\nBlood count reveals aregenerative anemia, which is often macrocytic, with or without neutropenia and thrombocytopenia. Cytological/ Histological analysis of bone marrow aspirate or biopsy generally reveals hypercellularity, with dysplasia in one to three myeloid lineages, without (<5%) or with (5-20%) excess of blasts. Cytogenetics of bone marrow show acquired clonal abnormality in 50 % of the cases, especially chromosome loss (-7, del 5q, del 20q) or gain (+8). Marrow cell mutations analysis by NGS method reveals at least one acquired mutation in myeloid genes panel in 90% of the cases especially in spliceosome genes (SF3B1,SRSF2), epigenetic genes (TET2, DNMT3a, ASXL1), RUNX1, or TP53.\nDifferential diagnosis\nThe differential diagnosis includes other bone marrow failures such as aplastic anemia, AML, or peripheral and clonal hematopoiesis in the elderly.\nManagement and treatment\nManagement and treatment depends on the prognostic score of patients in the revised International Prognostic Scoring System for Myelodysplastic Syndromes (IPSS-R), recently improved by the addition of acquired mutations (IPSS-M). Higher risk MDS are treated with allogeneic bone marrow transplantation when possible, otherwise with hypomethylating agents (azacytidine, decitabine), and less often chemotherapy. Lower risk MDS patients receive treatment for anemia with erythropoietin or derivatives, or other drugs in specific cases (lenalidomide in case of 5q deletion; Luspatercept in MDS with ringed sideroblasts).\nPrognosis\nMDS may progress into AML in ~30% of patients. The prognosis differs depending on a set of criteria scored by the IPSS-R and IPSS-M, including the number and importance of cytopenias, marrow blast percentage, and marrow cytogenetic abnormalities. This score separates schematically patients into lower risk (mainly characterized by anemia and less often thrombocytopenia) and higher risk (with generally severe cytopenias, including also neutropenia) of progression to AML, into five (IPSS-R) or six (IPSS-M) categories going from very low risk (2.8% risk of transformation into AML by 4 years) to very high risk (42.8% risk of transformation into AML by 4 years).\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Pierre FENAUX | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Myeloid sarcoma", "Disease Definition": "Myeloid sarcoma is a rare solid tumor of the myelogenous cells occurring in an extramedullary site.", "ORPHA ID": 86850, "Summary": "Epidemiology\nThe exact prevalence is unknown.\nClinical description\nThe clinical presentation depends on the site of involvement. Commonly involved sites of occurrence include the subperiosteal bone structures of the skull, paranasal sinuses, sternum, ribs, vertebrae, pelvis, as well as the lymph nodes and skin. Rare sites include the pancreas, heart, brain, mouth, breast, gastrointestinal and biliary tract, prostate, urinary bladder and gynecologic tract.\n\n                            Last update: \n                            January 2007"}
{"Disease Name": "Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement", "Disease Definition": "A rare, malignant, neoplastic disease characterized by clonal proliferation of myeloid and/or lymphoid precursors harboring translocations or insertions involving the chromosome band 8p11 and the FGFR1 gene, in the blood, bone marrow and often other tissues as well (spleen, liver, lymph nodes, breast, etc.). It usually presents as myeloproliferative neoplasm with eosinophilia, T lymphoblastic lymphoma with eosinophilia or, less frequently, acute myeloid leukemia. The presenting signs and symptoms include eosinophilia, leukocytosis with leukemoid reaction, monocytosis, fatigue, sweating, weight loss, lymphadenopathy, splenomegaly and/or hepatomegaly. Extranodal involvement may include the tonsils, lungs and breasts.", "ORPHA ID": 168953, "Summary": ""}
{"Disease Name": "Myeloid/lymphoid neoplasm associated with PDGFRA rearrangement", "Disease Definition": "A rare, malignant, neoplastic disease characterized by clonal proliferation of myeloid and/or lymphoid precursors harboring rearrangements in the PDGFRA gene, in the blood, bone marrow and often other tissues as well (spleen, lymph nodes, skin, etc.). It usually presents as chronic eosinophilic leukemia or, less commonly, as acute myeloid leukemia or T-lymphoblastic leukemia with eosinophilia. Patients usually present with eosinophilia, anemia, thrombocytopenia, neutrophilia, splenomegaly, lymphadenopathy, fever, sweating and/or weight loss. Tissue infiltration by eosinophils can manifest with skin rash, erythema, cough, neurological alterations, gastrointestinal symptoms or, rarely, endomyocardial fibrosis and restrictive cardiomyopathy.", "ORPHA ID": 168947, "Summary": ""}
{"Disease Name": "Myeloid/lymphoid neoplasm associated with PDGFRB rearrangement", "Disease Definition": "A rare, malignant, neoplastic disease characterized by clonal proliferation of myeloid and/or lymphoid precursors harboring rearrangements in the PDGFRB gene, in the blood, bone marrow and often other tissues as well (spleen, lymph nodes, skin, etc.). It usually presents as chronic myelomonocytic leukemia with eosinophilia, chronic eosinophilic leukemia, atypical chronic myelogenous leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, acute myeloid leukemia or acute lymphoblastic leukemia. Patients usually present with anemia, leukocytosis, monocytosis, eosinophilia and/or splenomegaly, or systemic symptoms, such as fever, sweating and/or weight loss.", "ORPHA ID": 168950, "Summary": ""}
{"Disease Name": "Myeloperoxidase deficiency", "Disease Definition": "A rare primary immunodeficiency due to a defect in innate immunity characterized by a marked decrease or absence of myeloperoxidase activity in neutrophils and monocytes. Clinically, most patients are asymptomatic. Occasionally, severe infectious complications may occur, particularly recurrent candida infections, being especially severe in the setting of comorbid diabetes mellitus.", "ORPHA ID": 2587, "Summary": ""}
{"Disease Name": "MYH9-related disease", "Disease Definition": "MYH9-related disease (MYH9-RD) is an inherited giant platelet disorder with a complex phenotype characterized by congenital thrombocytopenia and possible subsequent manifestations of sensorineural hearing loss, presenile cataracts, elevation of liver enzymes, and/or progressive nephropathy often leading to end-stage renal disease (ESRD). Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly and Sebastian syndrome, previously described as distinct disorders, represent some of the different clinical presentations of MYH9-RD.", "ORPHA ID": 182050, "Summary": "Epidemiology\nPrevalence in Italy is estimated at 1/400,000-1/300,000. More than 300 MYH9-RD pedigrees have been reported worldwide.\nClinical description\nThrombocytopenia is present at birth and can be associated with spontaneous bleeding (usually mild or moderate). Bleeding symptoms include easy bruising, epistaxis, gum bleeding, and/or menorrhagia. Life-threatening hemorrhage is rare. Patients have an increased risk of hemorrhages after surgery, biopsy, or deliveries. Hearing loss is seen in almost all cases with the age of onset ranging from the 1st to 6th decade and the severity of hearing loss varying greatly (from mild defects to profound deafness). Proteinuric nephropathy occurs in about 30% of patients and in 75% is diagnosed before the age of 35. The majority of patients with kidney damage progress to ESRD within a few years. Patients that develop kidney involvement later in life often have a slower progression towards ESRD. Cataracts occur in about 20% of patients, are often bilateral and usually appear in early adulthood, but congenital cases have been reported.\nEtiology\nMYH9-RD is due to mutations in the MYH9 gene (22q13.1), encoding the heavy chain of the isoform A of the non-muscle myosin of class II (myosin-9). Myosin-9 is expressed in most cell types and tissues, including blood cells, cochlea, kidney, and hepatocytes. Neutrophil inclusions originate from co-precipitation of mutant myosin-9 with wild-type proteins within the cytoplasm.\nDiagnostic methods\nDiagnosis is suspected on hematological findings and possible association with extra-hematological manifestations. Diagnosis is confirmed by immunofluorescence assay on peripheral blood slides revealing typical myosin-9 neutrophil inclusions. Kidney damage is revealed by proteinuria with or without renal failure. Audiometric and ophthalmologic examinations identify a hearing defect and/or cataract, respectively. About 50% of patients have chronic or intermittent elevation of liver enzymes. Molecular genetic testing can identify the causative MYH9 mutation, which can predict the clinical evolution.\nDifferential diagnosis\nDifferential diagnoses include Bernard-Soulier syndrome, Alport syndrome and immune thrombocytopenia purpura (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible in families where a disease causing mutation has been identified.\nGenetic counseling\nMYH9-RD is inherited in an autosomal dominant manner with sporadic de novo mutations also being observed. Genetic counseling is possible.\nManagement and treatment\nIn cases of severe hemorrhages or before major hemostatic stresses (pregnancy, surgery), platelet transfusions (when possible from HLA-matched donors) are recommended. Eltrombopag has been successful in increasing platelet counts and abolishing the tendency to bleed. Desmopressin can shorten bleeding time in some patients; a test dose should be given to observe responsiveness. Surgery treats cataracts. A cochlear implant was beneficial in one patient with severe deafness. Angiotensin receptor blockers and/or angiotensin-converting enzyme inhibitors may reduce proteinuria in those with renal involvement. ESRD requires treatment with dialysis or kidney transplantation. Regular blood counts, annual urine analysis as well as audiometric and ophthalmologic evaluations are recommended. Medications that interfere with platelet function should be avoided.\nPrognosis\nOverall life-expectancy is not affected. Quality of life can be seriously affected in patients who develop kidney involvement and deafness, as well as in rare cases with severe spontaneous bleeding.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Alessandro PECCI"}
{"Disease Name": "Myhre syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by short stature, distinctive facial dysmorphism, brachydactyly, stiff and thick skin, muscular pseudohypertrophy, restricted joint mobility, hearing loss, and variable intellectual disability. Cardiovascular and respiratory involvement are common.", "ORPHA ID": 2588, "Summary": "Epidemiology\nTo date, less than 100 cases have been reported, with no apparent ethnic or sex predilection.\nClinical description\nThe first manifestation is typically intrauterine growth retardation; however, diagnosis is typically later in childhood due to the absence of cardiac features early on. During the first years of life the main features are short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails. The more common clinical features become recognizable in late childhood and include the distinctive facial features (short palpebral fissures, mid-face hypoplasia, short philtrum, prognathism, narrow mouth, small ears), short stature, limited joint mobility (with particular difficulty in fist-clenching and in arm-raising), thickened skin, and muscular pseudohypertrophy. Mild-to-moderate intellectual disability and developmental delay are common, but not constant. Autistic-like behavior has been reported. Morphological cardiovascular anomalies affect about 70% of patients (septal defects, patent ductus arteriosus, obstructive defects of the left heart, aortic coarctation and arterial obstructions), and pericarditis, restrictive cardiomyopathy and systemic and pulmonary hypertension are frequently observed. Respiratory involvement consists of choanal stenosis, laryngotracheal narrowing, obstructive airway disease, or restrictive pulmonary disease (increasing with age). Gastrointestinal (GI) involvement includes pyloric stenosis, duodenal atresia and severe constipation. Proliferative fibrosis/scarring (on the serosal surfaces of heart, airway, lungs, GI tract, skin) may occur spontaneously or following trauma, endotracheal intubation or surgery. Ocular anomalies may include refractive errors and strabismus. Recurrent infections (particularly otitis media and pneumonia) are frequently reported. Hearing loss is observed in most (83%) individuals. Additional anomalies include cleft lip and/or palate, velopharyngeal insufficiency, and facial nerve weakness/paralysis (rare).\nEtiology\nMyhre Syndrome is due to heterozygous pathogenic variant in the SMAD4 gene (18q21.2).\nDiagnostic methods\nThe diagnosis may be challenging and relies on the characteristic clinical features and the radiological findings (thickened skull, brachydactyly, broad ribs, vertebral fusions, large vertebral pedicles and hypoplastic iliac wings) and is confirmed by genetic analysis.\nDifferential diagnosis\nDifferential diagnosis include other genetic syndromes characterized by short stature, brachydactyly, stiff and thick skin, restricted joint mobility and cardiovascular involvement.\nAntenatal diagnosis\nPrenatal genetic testing is possible for at-risk pregnancies, where a pathogenic variant has previously been identified in an affected family member.\nGenetic counseling\nThe inheritance pattern is autosomal dominant, but most cases occur de novo. Penetrance seems to be complete, but data about familial cases are limited.\nManagement and treatment\nTreatment is mainly symptomatic, requiring a multidisciplinary medical team. Annual ophthalmologic, audiology, respiratory, cardiovascular, physical skill development and joint mobility evaluations are recommended. Hearing aids may be necessary for hearing loss. Oxygen supplementation may be necessary, as well as long-term tracheostomy. Limiting tissue trauma is important due to the increased risk of scarring/stenosis and proliferative fibrosis after surgical procedures and endotracheal intubation; alternative non-invasive approaches should be considered where possible. Restrictive lung disease, systemic/pulmonary hypertension and heart failure should be managed accordingly. Treatment may be necessary for constipation. Physical therapy may be helpful for joint mobility, as well as supportive management of intellectual disability and developmental delay.\nPrognosis\nMyhre syndrome is a progressive disorder with life-threatening complications. Restrictive and obstructive respiratory disease, pericarditis and laryngotracheal involvement are major causes of morbidity.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Livia GARAVELLI | ITHACA* - Dr Simonetta ROSATO \n\n\n                                * European Reference Network"}
{"Disease Name": "Myoclonic epilepsy in non-progressive encephalopathies", "Disease Definition": "A rare epilepsy syndrome characterized by recurrent, long-lasting myoclonic status in infants and young children with a non-progressive encephalopathy, associated with transient and recurring motor, cognitive and/or behavioral disturbances.", "ORPHA ID": 86913, "Summary": ""}
{"Disease Name": "Myoclonic epilepsy of infancy", "Disease Definition": "A rare infantile epilepsy syndrome characterized by infancy-onset of myoclonic seizures in otherwise neurologically and developmentally normal patients. Jerks may vary in severity, can be singular or occur in a series, and occur spontaneously or (less commonly) after sensory stimuli. Seizures are self-limiting and remit within several months to years from onset, although generalized tonic-clonic seizures or other forms of epilepsy may be seen later in life. Developmental delay and cognitive and behavioral difficulties have been reported in a considerable percentage of patients.", "ORPHA ID": 86909, "Summary": ""}
{"Disease Name": "Myoclonic-astatic epilepsy", "Disease Definition": "A rare, childhood onset epilepsy syndrome characterized by multiple seizure types including myoclonic-atonic (MA) seizures that occur usually in previously healthy children.", "ORPHA ID": 1942, "Summary": "Epidemiology\nThe prevalence is estimated at 1-2% of all childhood epilepsies with a sex ratio of 2.7-3.1:1 males to females.\nClinical description\nOnset is between 2-5 years (peak 3-4 years), occurring typically in normally developing children. In 20 % of patients, simple febrile seizures have occurred before onset. Generalized tonic-clonic seizure (GTCS) is usually the first seizure type. After days to months, additional myoclonic, atonic and/or myoclonic-atonic seizures and atypical absences occur with increasing frequency until a ''stormy phase''. MA seizure consists of proximal muscle myoclonic jerks followed by an atonic phase. Brief tonic seizures may be seen in some patients. Children often display a non-convulsive status epilepticus (NCSE) with episodes of drowsiness, gait impairment and erratic myoclonus, which may last hours to days.\nEtiology\nEtiology is unknown in the majority of cases and a polygenic inheritance is suspected. The most common monogenic causes include SLC6A1 (3p25.3), CHD2 (15q26.1), AP2M1 (10q23.2). Other causal variants reported include SLC2A1 (1p34.2), SCN1A (2q24.3), SYNGAP1 (6p21.32), KCNA2, and NEXMIF (Xq13.3).\nDiagnostic methods\nDiagnosis is based on history, seizure semiology, neurologic examination and electroencephalogram (EEG) findings. EEG may be normal at onset or display a slowing of the background activity and generalized 2-3 Hz spike-wave discharges. Myoclonic, atonic and MA seizures can cause drops, and video-EEG with electromyogram (EMG) of deltoids and neck is essential to differentiate them from other seizures types (tonic, epileptic spasms). Neuroimaging is normal. Genetic and metabolic testing should be performed if differential diagnosis is suspected, and when clinical features are suspicious for a specific genetic mutation. Intermittent photic stimulation at low frequencies should be systematically performed during EEG to exclude neuronal ceroid lipofuscinosis type 2 (CLN2 disease).\nDifferential diagnosis\nDravet disease differs by earlier onset and prolonged febrile seizures. Myoclonic epilepsy of infancy also occurs earlier and displays brief myoclonic seizures as the single seizure type; Lennox-Gastaut syndrome is frequently associated with structural/metabolic etiology and tonic seizures in sleep and atypical absences as the main seizure types. CLN2 disease, with onset in the same age range, is the other important differential diagnosis.\nGenetic counseling\nPatients with an identified de novo variant and families with a known genetic mutation can benefit from genetic counseling.\nManagement and treatment\nEven in children with a favorable clinical course, seizures can be initially resistant to anti-seizure medicines (ASMs). Broad spectrum ASMs are recommended, often a bi or tri-therapy is needed: sodium valproate, combination of sodium valproate with lamotrigine (synergistic effect), levetiracetam, ethosuximide (especially if myoclonic seizures are prominent). Other alternatives are zonisamide, topiramate, clobazam or clonazepam. Ketogenic diet is the most effective therapy in myoclonic-astastic epilepsy (> 50% seizure reduction in 50-90% of cases) and is recommended as soon as the first line ASMs fail. Vigabatrin and sodium channel blockers like carbamazepine or phenytoin are contraindicated as they worsen seizures. Benzodiazepines or steroids are suggested for treating NCSE. Few cases have undergone epilepsy surgery (corpus callosotomy, vagal nerve stimulator).\nPrognosis\nOutcome is variable. 60% of patients evolve with normal cognition or a mild cognitive delay. Cognition and behavior are impaired in unfavorable cases where seizures persist after 3 years of evolution. NCSE, tonic seizures, atypical absence seizures and epileptic encephalopathy are risk factors of unfavorable outcome.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Nicolas JANNONE-PEDRO | EpiCARE* - Dr Anna KAMINSKA | EpiCARE* - Dr Vicente VILLANUEVA | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Myoclonus-cerebellar ataxia-deafness syndrome", "Disease Definition": "This syndrome is characterised by the association of myoclonus, cerebellar ataxia and sensorineural hearing loss.", "ORPHA ID": 2589, "Summary": "Epidemiology\nSo far, less than 10 cases have been reported in the literature.\nClinical description\nThe hearing loss was generally diagnosed during childhood or early adulthood and the myoclonic jerks began during adolescence.\nGenetic counseling\nTransmission appears to be autosomal dominant.\n\n                            Last update: \n                            July 2008"}
{"Disease Name": "Myoclonus-dystonia syndrome", "Disease Definition": "Myoclonus-dystonia syndrome (MDS) is a rare movement disorder characterized by mild to moderate dystonia along with 'lightning-like' myoclonic jerks.", "ORPHA ID": 36899, "Summary": "Epidemiology\nThe estimated prevalence of MDS in Europe is 1/500,000.\nClinical description\nDisease onset usually occurs in the first or second decade of life. Myoclonus is usually the presenting manifestation and is described as swift ''lightning-like'' jerks that can rarely appear at rest but that are usually triggered by complex motor tasks such as drawing and writing. These movements mainly affect the neck, arms and trunk but can also rarely be seen in the legs or the larynx. In two thirds of cases, dystonia is also experienced in the form of focal or cervical dystonia (see these terms), which may be only mild and does not exacerbate with time. Postural and other forms of tremor have sometimes been reported. MDS is often associated with depression, anxiety, panic attacks, obsessive-compulsive behavior and personality disorders and alcohol abuse. Isolated torticollis is seen in extremely rare cases.\nEtiology\nThe only known causative gene of MDS is the epsilon-sarcoglycan (SGCE) gene (7q21.3), encoding a transmembrane protein that is part of the dystrophin-associated glycoprotein complex found in skeletal and cardiac muscle. The epsilon-sarcoglycan protein is also abundant in monoaminergic neurons, cerebellar Purkinje cells, the cortex and the hippocampus of the brain. In one family with MDS, linkage to chromosome 18p has been reported (named DYT15), but the gene has not yet been identified.\nDiagnostic methods\nDiagnosis is based on the presence of characteristic clinical symptoms. Neuroimaging studies are normal. Genetic molecular testing of SGCE can confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes cervical dystonia, Dopa-responsive dystonia, Tourette syndrome, familial cortical myoclonus, Wilson disease, spinocerebellar ataxia type 3 (SCA3) and type 14 (SCA14), ataxia with vitamin E deficiency, genetic disorders with myoclonus as a major component (e.g. Unverricht-Lundborg disease, Lafora disease) (see these terms) and other secondary forms of dystonia.\nAntenatal diagnosis\nPrenatal testing is possible in families where a disease-causing mutation is identified.\nGenetic counseling\nMDS is inherited in an autosomal dominant manner. However, the SGCE gene is maternally imprinted, therefore in most cases (95%) a patient who inherits the mutation from their mother will remain healthy and only those that inherit the mutation from their father will develop MDS. De novo mutations also occur. Genetic counseling is recommended in those with a known mutation.\nManagement and treatment\nTreatment plans are individualized to a patient's presenting symptoms. Benzodiazepines (clonazepam) and antiepileptic drugs (valproate, levetiracetam) are effective in relieving myoclonus and tremor, but patients should be carefully monitored. Similarly, alcohol frequently improves symptoms temporarily, but its long term use is not recommended. Injections of botulinum toxin can relieve focal and cervical dystonia. If these treatments fail or are insufficient, bilateral deep brain stimulation (DBS) of the internal globus pallidum (Gpi) and the central intermediate nucleus (VIM) of the thalamus have shown positive results in providing lasting relief from both myoclonus and dystonia. Gpi stimulation is often sufficient in treating MDS, and may be favored over VIM stimulation, which generally has very little effect on dystonia. In a staged surgical procedure, quadruple stimulation (VIM and Gpi) may also be considered in selected cases.\nPrognosis\nPatients with MDS have normal life-expectancy, but quality of life can be severely affected.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "Myofibrillar myopathy", "Disease Definition": "Myofibrillar myopathy (MFM) describes a group of skeletal and cardiac muscle disorders, defined by the disintegration of myofibrils and aggregation of degradation products into intracellular inclusions, and is typically clinically characterized by slowly-progressive muscle weakness, which initially involves the distal muscles, but is highly variable and that can affect the proximal muscles as well as the cardiac and respiratory muscles in some patients.", "ORPHA ID": 593, "Summary": ""}
{"Disease Name": "Myopathic Ehlers-Danlos syndrome", "Disease Definition": "A rare systemic disease characterized by congenital muscle hypotonia and/or muscle atrophy that improves with age, proximal joint contractures (knee, hip, elbow), and hypermobility of distal joints. Additional features include soft, doughy skin, atrophic scarring, delayed motor development, and myopathic findings in muscle biopsy. Abnormal craniofacial features have been reported in some patients. Molecular testing is obligatory to confirm the diagnosis.", "ORPHA ID": 536516, "Summary": ""}
{"Disease Name": "Myopathy and diabetes mellitus", "Disease Definition": "A rare, genetic, mitochondrial DNA-related mitochondrial myopathy disorder characterized by slowly progressive muscular weakness (proximal greater than distal), predominantly involving the facial muscles and scapular girdle, associated with insulin-dependent diabetes mellitus. Neurological involvement and congenital myopathy may be variably observed.", "ORPHA ID": 2596, "Summary": ""}
{"Disease Name": "Myopathy with hexagonally cross-linked tubular arrays", "Disease Definition": "Myopathy with hexagonally cross-linked tubular arrays is a rare, congenital, non-dystrophic, mild, slowly progressive, proximal myopathy characterized by exercise intolerance and post-exercise myalgia without rhabdomyolysis, associated with highly organized hexagonally cross-linked tubular arrays in skeletal muscle biopsy. Additional features may include muscle atrophy (or diffuse hypotrophy), myalgia with or without musclar weakness, paresis of truncal and limb-girdle musculature, minimal ptosis, lumbar hyperlordosis, decreased deep tendon reflexes, contractures and pes equinovarus.", "ORPHA ID": 171889, "Summary": ""}
{"Disease Name": "Myopericytoma", "Disease Definition": "A rare soft tissue tumor characterized by a benign subcutaneous lesion composed of oval-to-spindle shaped myoid appearing cells with a tendency for concentric perivascular growth. The tumor usually presents as a painless, slowly growing nodule, which may be solitary or appear as multiple lesions, which then arise metachronously and usually involve a particular anatomic region. Recurrence after surgical excision may occur in poorly circumscribed tumors. Malignancy is very rare.", "ORPHA ID": 289685, "Summary": ""}
{"Disease Name": "Myosclerosis", "Disease Definition": "Myosclerosis is a rare, genetic, non-dystrophic myopathy characterized by early, diffuse, progressive muscle and joint contractures that result in severe limitation of movement of axial, proximal, and distal joints, walking difficulties in early childhood and toe walking. Patients typically present thin, sclerotic muscles with a woody consistency, mild girdle and proximal limb weakness with moderate distal weakness and scoliosis. Muscle biopsy shows partial collagen VI deficiency at the myofiber basement membrane and absent collagen VI around most endomysial/perimysial capillaries.", "ORPHA ID": 289380, "Summary": ""}
{"Disease Name": "Myosin storage myopathy", "Disease Definition": "A rare congenital myopathy characterized by generalized proximal and distal muscle weakness and/or atrophy with slow progression. A subset of patients present with scapuloperoneal weakness and scapular winging. Disease onset usually occurs during infancy/childhood, but adult-onset cases have also been reported. Patients may have respiratory problems and/or cardiomyopathy. Muscle biopsies show hyaline body inclusions in type I fibers.", "ORPHA ID": 53698, "Summary": ""}
{"Disease Name": "Myospherulosis", "Disease Definition": "A rare maxillo-facial surgical disease characterized by an inflammatory, granulomatous lesion, most commonly of iatrogenic origin due to interaction of extravasated erythrocytes with exogenous lipids, in particular petrolatum-based antibiotic ointment used after surgical procedures. Most frequent locations are the paranasal sinuses and jaws, although the lesion can occur in any part of the body. It is typically found incidentally as an asymptomatic soft tissue swelling.", "ORPHA ID": 306553, "Summary": ""}
{"Disease Name": "Myotonia fluctuans", "Disease Definition": "A form of potassium-aggravated myotonia (PAM) which is cold insensitive, dramatically fluctuating and profoundly worsened by potassium ingestion.", "ORPHA ID": 99734, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nFluctuating myotonia develops during childhood or adolescence and involves the extraocular, bulbar and limb muscles. Eyelid myotonia is often the first sign of the disease. Episodes of stiffness vary in severity and frequency and may be separated by prolonged periods of normality. Myotonia is aggravated by potassium ingestion and appears with a delayed onset (10-30 min) after exercise (exercise-induced delayed-onset myotonia). Cold has no effect on myotonia. Paralysis is never observed. Episodic weakness is rare.\nEtiology\nMyotonia fluctuans is a sodium muscle channelopathy due to missense mutations of the SCN4A gene encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            October 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Savine VICART"}
{"Disease Name": "Myotonia permanens", "Disease Definition": "A very rare, persistent and more severe form of potassium-aggravated myotonia (PAM).", "ORPHA ID": 99735, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nContinuous and severe myotonia begins during childhood (usually before 10 years of age) and involves mainly the face, neck, limbs, and thoracic muscles. It can be aggravated by exercise or potassium ingestion and less often by cold. Occasionally, patients have muscle hypertrophy, especially of the neck and shoulders. Paralysis is never observed. Severe stiffness of the pharyngeal and respiratory muscles may provoke episodes of hypoxia and acidosis that can compromise the respiratory function. Close monitoring is necessary during surgery as rigidity and rhabdomyolysis may occur. Depolarizing agents can cause severe ventilation problems due to a paradoxical increase of stiffness in respiratory muscles and must be avoided.\nEtiology\nMyotonia permanens is a muscle sodium channelopathy due to missense mutations of the SCN4A gene encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            October 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Savine VICART"}
{"Disease Name": "Myxofibrosarcoma", "Disease Definition": "A rare soft tissue sarcoma characterized by a malignant, fibroblastic lesion with variably myxoid stroma, pleomorphism, and a distinctively curvilinear vascular pattern. The majority of tumors arise in the limbs including the limb girdles, more often in dermal/subcutaneous tissues than in the underlying fascia and skeletal muscle, and usually present as a slowly growing, painless mass. Depth of the lesion and tumor grade do not influence the high rate of local recurrence, while the percentage of metastasis and tumor-associated mortality are much higher in deep-seated and high-grade neoplasms.", "ORPHA ID": 79105, "Summary": ""}
{"Disease Name": "Myxoid/round cell liposarcoma", "Disease Definition": "Myxoid/round cell liposarcoma (MRCLS) is a type of liposarcoma (LS; see this term) mostly located in the limbs, with a variable behavior depending on the histological subtype. Both myxoid and round cell are distinct histological subtypes of LS.", "ORPHA ID": 99967, "Summary": "Epidemiology\nThe incidence is approximately 1/769, 000 per year and it accounts for 30% or less of all LS cases.\nClinical description\nMRCLS presents at a younger age than other LS subtypes with typical age of diagnosis ranging from 35-55 years. It predominantly occurs in the limbs (most frequently in the thighs) and rarely arises in the retroperitoneum or subcutaneous tissue. One third of MRCLS cases will become metastatic with tumors spreading to unusual bone and soft tissue locations with multifocal synchronous or metachronous spread to fat pad areas in the retroperitoneum, trunk, pericardium and axilla.\nEtiology\nNinety percent of MRCLS lesions have a characteristic chromosomal translocation leading to the fusion of the DDIT3 and FUS genes on chromosome regions 12q13 and 16p11. The consequence is the creation of a FUS-DDIT3 hybrid protein that promotes malignant transformation by dysregulating RNA transcription and thereby dysregulating adipocyte differentiation and cell-cycle control.\nDiagnostic methods\nWhen a mass is detected, computed tomography (CT) or magnetic resonance imaging (MRI) is performed. Chest and abdominal lesions do not require pretreatment biopsy unless resection is likely to be incomplete or highly morbid. Extremity lesions are generally sampled by multiple core biopsies to identify the histological subtype (myxoid versus round cell component) and to stage the disease. MRCLS tumors are composed of uniform, round to oval, primitive nonlipogenic mesenchymal cells and small signet-ring lipoblasts in a prominent myxoid stroma with plexiform vasculature. The diagnosis can be confirmed by evidence of the DDIT3-FUS translocation from fluorescence in situ hybridization (FISH) or RT-PCR. High levels of the round cell component predict a poorer outcome, so it must be determined whether the tumor is more myxoid (<5% round cell component) or round cell (>5% round cell component).\nDifferential diagnosis\nMRCLS can be mistaken for Ewing sarcoma, lymphoma and pleomorphic undifferentiated sarcomas (see these terms). Other myxoid neoplasms must also be excluded.\nManagement and treatment\nTreatment involves the surgical excision of the tumor and surrounding tissue for low grade myxoid liposarcoma. In rare cases amputation of the limb is necessary. High grade round cell LS that is large (>5 cm), or marginally resectable tumors, may be treated with pre-operative chemotherapy and/or pre-operative or post-operative radiotherapy. MRCLS, compared to other subtypes, responds well to radiotherapy and chemotherapy. Chemotherapeutic agents doxorubicin and ifosfamide are usually first line treatment options whereas ecteinascidin is used as a second line treatment. Lifelong follow-up is recommended in order to monitor for recurrence at the initial site as well as distant metastasis.\nPrognosis\nThe prognosis of MRCLS is good for patients with low grade myxoid liposarcoma (defined as pure myxoid or less than a 5% round cell component), the 5-year survival rate is 92%. A significant (5% or greater) round cell component is associated with a much poorer prognosis, with a 5-year survival rate of 74%.\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Samuel SINGER"}
{"Disease Name": "Myxopapillary ependymoma", "Disease Definition": "Myxopapillary ependymoma (MEPN) describes a slow growing ependymoma located almost exclusively in the conus medullaris-cauda equina-filum terminale region of the spinal cord, presenting in all age groups, and manifesting with variable symptoms such as neck pain, vomiting and unsteady gait and metastasis. It has a more aggressive disease course and is seen in the pediatric population.", "ORPHA ID": 251643, "Summary": ""}
{"Disease Name": "Ménétrier disease", "Disease Definition": "Ménétrier disease (MD) is a rare premalignant hyperproliferative gastropathy characterized by massive overgrowth of foveolar cells in the gastric lining, resulting in large gastric folds, and manifesting with epigastric pain, nausea, vomiting, peripheral edema and, less commonly, anorexia and weight loss.", "ORPHA ID": 2494, "Summary": "Epidemiology\nExact prevalence and incidence data are not available. MD appears to affect males slightly more than females.\nClinical description\nThe usual age of onset is between 30 and 60 years (average 55 years), although cases in childhood have been reported. The childhood variant often involves sudden onset and spontaneous regression. In adults, onset is often insidious with a wide spectrum of clinical manifestations. Affected patients typically present with abdominal pain, vomiting and nausea. Edema of peripheral tissues is often found. Other symptoms include asthenia, anorexia, and weight loss. Some individuals with MD are only mildly affected or are asymptomatic. Loss of protein from the gastrointestinal tract leads to hypoalbuminemia and peripheral edema. Mucosal ulceration is also described and can result in gastrointestinal bleeding. Disease course tends to be progressive, leading to gastric adenocarcinoma in 2-15% of cases. Complications include severe or recurrent infections and vascular thromboembolism.\nEtiology\nThe etiology is currently unknown but is thought to be acquired and to involve enhanced epidermal growth factor receptor (EGFR) signaling in the gastric mucosa with local overproduction of transforming growth factor-alpha (TGF-alpha). In children, some MD cases have been linked to cytomegalovirus (CMV) and in adults some have been linked to Helicobacter pylori; however, the possible role of these infections remains to be elucidated. Rare familial cases point to a possible genetic component. The mechanism(s) underlying carcinogenesis in MD remain unknown.\nDiagnostic methods\nMD is suspected on the basis of the constellation of clinical signs and symptoms but there are no formal diagnostic criteria. Diagnosis requires gastroscopic examination (showing enlarged gastric folds primarily involving the gastric corpus) with biopsy, preferably of full thickness gastric mucosa, which reveals characteristic histological features (extensive foveolar hyperplasia with corkscrew morphology in the absence of distortion of overall linear architecture, decreased or absent parietal cells, variable amounts of chronic inflammation with scattered clusters of eosinophils, and scattered strands of smooth muscle between mucous glands). Gastric acid secretion is generally markedly decreased or absent, while gastric mucous secretion is elevated. Serum gastrin levels remain relatively normal.\nDifferential diagnosis\nDifferential diagnoses include Zollinger-Ellison syndrome (see this term), hypertrophic hypersecretory gastropathy, hypertrophic lymphocytic gastritis, infiltrating neoplasm, polyps, and polyposis syndromes (e.g. juvenile polyposis syndrome, Peutz-Jeghers syndrome, and gastric adenocarcinoma and proximal polyposis of the stomach; see these terms).\nGenetic counseling\nMD is an acquired gastropathy but a genetic predisposition with autosomal dominant inheritance has been suggested in a few families.\nManagement and treatment\nThere is no recommended standard treatment. In some patients, treatment may be limited to supportive care with a high-protein diet. Inconsistent results have been achieved with anticholinergic drugs, acid suppression therapy, treatment against CMV infection in children, and H. pylori eradication in adults. Treatment with cetuximab, an EGFR neutralizing monoclonal antibody, has been successfully carried out. If there is concern about malignant transformation or in severe cases, partial or total gastrectomy may be required. Although there is no official recommendation, endoscopic surveillance may be offered every 1-3 years.\nPrognosis\nMD tends to be a progressive disorder. Most of the patients ultimately require gastrectomy, either due to worsening symptoms or the risk of developing gastric cancer. The risk of malignant transformation is not well characterized.\n\n                            Last update: \n                            October 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Won Jae HUH  - Pr ROBERT J. COFFEY"}
{"Disease Name": "Müllerian aplasia and hyperandrogenism", "Disease Definition": "A rare syndrome with 46,XX difference of sex development characterized by Müllerian duct hypoplasia or agenesis associated with clinical and biological evidence of hyperandrogenism in 46,XX females. Patients present with hypoplastic or absent uterus, variable abnormalities of other reproductive organs, primary amenorrhea, acne, hirsutism, and sometimes renal anomalies. External genitalia and secondary sexual characteristics are normal. Hormonal analysis shows variably elevated serum levels of androstenedione, dehydroepiandrosterone, and/or total and free testosterone.", "ORPHA ID": 247768, "Summary": ""}
{"Disease Name": "Müllerian derivatives-lymphangiectasia-polydactyly syndrome", "Disease Definition": "A rare genetic disease characterized by the presence of Müllerian duct derivatives (rudimentary uterus, fallopian tubes, and atretic vagina) and other genital anomalies (cryptorchidism, micropenis) in male newborns, intestinal and pulmonary lymphangiectasia, protein-losing enteropathy, hepatomegaly, and renal anomalies. Postaxial polydactyly, facial dysmorphism (including broad nasal bridge, bulbous nasal tip, long and prominent upper lip with smooth philtrum, hypertrophic alveolar ridges, and mild retrognathia, among other features), and short limbs have also been described. The syndrome is fatal in infancy.", "ORPHA ID": 1655, "Summary": ""}
{"Disease Name": "Müllerian duct anomalies-limb anomalies syndrome", "Disease Definition": "A rare disorder characterized by the association of mullerian duct and distal limb anomalies. Females present with anomalies ranging from a vaginal septum to complete duplication of uterus and vagina, and males present with micropenis. The limb anomalies varied from postaxial polydactyly to severe upper limb hypoplasia with split hand.", "ORPHA ID": 2491, "Summary": ""}
{"Disease Name": "N syndrome", "Disease Definition": "A rare, fatal multiple congenital anomalies/dysmorphic syndrome characterized by facial dysmorphism (incl. dolichocephaly/scaphocephaly, high frontal hairline, laterally overlapping upper eyelids, hypertelorism, prominent eyelashes, deep-set eyes, macrocornea, nystagmus, dysplastic ears, abnormal auricles, prominent nasal bridge, dental dysplasia), visual impairment, deafness, seizures, generalized skeletal dysplasia, high fingerprint ridge count, cryptorchidism, hypospadias, spasticity and severe intellectual disability. An increased chromosome breakage and a fatal lymphoid malignancy have been reported. There has been no further description in the literature since 1974.", "ORPHA ID": 2608, "Summary": ""}
{"Disease Name": "NAD(P)HX dehydratase deficiency", "Disease Definition": "A rare neurometabolic disease characterized by infantile onset of repeated episodes of developmental regression and neurodegeneration, often triggered by febrile illnesses. Patients present with lethargy, hypotonia, irritability, gait ataxia, loss of speech, movement disorder, seizures, ophthalmoplegia, and hearing loss. Brain imaging shows generalized cerebral atrophy and bilateral basal ganglia abnormalities. Extensive skin lesions, cardiomyopathy, and pancytopenia have been reported in association. The condition is fatal in the first years of life.", "ORPHA ID": 555402, "Summary": ""}
{"Disease Name": "NAD(P)HX epimerase deficiency", "Disease Definition": "A rare neurometabolic disease characterized by infantile onset of rapidly progressive neurological deterioration, typically precipitated by a febrile illness. Patients present with hypotonia, loss of previously acquired motor milestones and cognitive skills, ataxia, nystagmus, tremor, seizures, tetraparesis, and respiratory failure, eventually resulting in a vegetative state. Imaging of the brain and spinal cord may show white matter abnormalities, cerebral atrophy, cerebellar edema, and spinal myelopathy. Subacute development of extensive bullous skin lesions within weeks of onset of neurological symptoms has also been reported.", "ORPHA ID": 555407, "Summary": ""}
{"Disease Name": "Naegeli-Franceschetti-Jadassohn syndrome", "Disease Definition": "A rare ectodermal dysplasia that affects the skin, sweat glands, nails, and teeth.", "ORPHA ID": 69087, "Summary": "Epidemiology\nSeveral families with multiple affected members (males and females) from several generations have been reported so far. Prevalence is estimated at 1 in 3 million.\nClinical description\nThe cardinal features are absence of dermatoglyphics (fingerprints), reticular cutaneous hyperpigmentation (starting at about the age of 2 years without a preceding inflammatory stage), hypohidrosis with diminished sweat gland function and discomfort provoked by heat, nail dystrophy, tooth enamel defects, and moderate hyperkeratosis of the palms and soles. Diffuse palmoplantar keratoderma may coexist with punctate keratoses that are sometimes accentuated in the creases or exhibit a linear pattern. Congenital misalignment of the great toenails was reported in some patients.\nEtiology\nNFJ is inherited as an autosomal dominant condition and is caused by mutations in the KRT14 gene (17q11.2-17q21) encoding keratin 14. The disease is allelic to dermatopathia pigmentosa reticularis (see this term).\nDiagnostic methods\nDiagnosis is based on the typical clinical features and can be confirmed by molecular analysis.\nDifferential diagnosis\nDifferential diagnoses include incontinentia pigmenti, dermatopathia pigmentosa reticularis, dyskeratosis congenita, pachyonychia congenita and Dowling-Degos disease (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis has not been reported so far.\nManagement and treatment\nTreatment is symptomatic. The dry skin has to be moisturized with emollients, and hyperthermia should be prevented by use of appropriate clothing and physical cooling with wet dressings or cool water during warm periods. Dental care is imperative to prevent caries and tooth loss.\nPrognosis\nThe reticulate pigmentation fades after puberty and sometimes disappears completely in old age. Hypohidrosis, the most problematic symptom for patients, remains constant. Teeth are always severely affected, leading to early total loss.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Peter ITIN"}
{"Disease Name": "Nager syndrome", "Disease Definition": "A congenital malformation syndrome characterized by mandibulofacial dystosis (malar hypoplasia, micrognathia, external ear malformations) and variable preaxial limb defects.", "ORPHA ID": 245, "Summary": "Epidemiology\nThe prevalence is unknown; more than 100 cases of NAFD have been published.\nClinical description\nNAFD is characterized by mandibulofacial anomalies that include downward slant of palpebral fissures, ptosis of upper lids, coloboma of lower lids, deficiency of eyelashes of the medial one-third to two-thirds of the lower eyelids, hypoplasia of the malar eminences, hypoplasia of the maxilla, cleft palate, absence or hypopoplasia of the palatal velum, choanal atresia, extension of a ''tongue'' of temporal hair down the sides of the cheeks. Cleft lip is rare. Limb defects are predominantly preaxial with hypoplasia or absence of thumbs being the most characteristic feature, frequently associated with radio-ulnar synostosis and/or aplasia/hypoplasia of the radius. Triphalangeal thumbs and other abnormalities of the digits have also been reported and a small percentage of patients also have lower limb malformations. Otologic and oral anomalies frequently lead to bilateral conductive hearing loss, speech difficulties and upper respiratory airways obstruction. Most Nager syndrome individuals have normal vision and intelligence.\nEtiology\nIn approximately 50% of patients, NAFD has been associated with heterozygous mutations in the SF3B4 gene (1q21.2), coding for a component of the splicing machinery.\nDiagnostic methods\nDiagnosis is based on physical and radiological examination or the identification of a mutation in SF3B4.\nDifferential diagnosis\nDifferential diagnosis may include mandibulofacial dysostosis syndromes such as Treacher-Collins syndrome, and other acrofacial dysostoses (AFD) such as the AFD Catania type, the AFD Palagonia type, the AFD Genee-Wiedemann type, the AFD Rodriquez type as well as mandibulofacial dysostosis with microcephaly (see these terms). Patients with the oculoauriculovertebral (OAV) spectrum (see this term) may also have overlapping features.\nAntenatal diagnosis\nAntenatal diagnosis can be performed by ultrasonography or molecular testing of SF3B4.\nGenetic counseling\nNager syndrome is likely genetically heterogenous with confirmed autosomal dominant inheritance, but autosomal recessive inheritance is suspected based on sibling recurrence in consanguineous families. Genetic counseling requires careful evaluation of parents and sibs of an affected child, in order to determine if the disease has a familial origin or if it occurred sporadically. If one parent is mildly affected, recurrence risk is 50% and a 25% risk cannot be excluded when parents are apparently normal.\nManagement and treatment\nManagement must focus on neonatal respiratory distress (tracheostomy) and feeding difficulties (gastrostomy). Surgery can be considered for repair of clefts, management of severe micrognathia as well as temporomandibular joint dysfunction. Hearing aids can be proposed. Language and phonological impairment must be managed by a specific speech therapy.\nPrognosis\nAfter infancy, most patients are healthy and are presumed to have a normal lifespan. Ongoing medical issues are usually only related to airway obstruction or temporomandibular joint dysfunction in patients with more severe manbibular malformations.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr François BERNIER"}
{"Disease Name": "Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome", "Disease Definition": "Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome is a rare genetic ectodermal dysplasia syndrome characterized by short stature, nail dystrophy and/or nail loss, oral mucosa and/or tongue hyperpigmentation, dentition abnormalities (delayed teeth eruption, hypodontia, enamel hypoplasia), keratoderma on the margins of the palms and soles and focal hyperkeratosis on the dorsum of the hands and feet. Additionally, dysphagia with esophageal strictures, sensorineural deafness, bronchial asthma and severe iron-deficiency anemia have been observed.", "ORPHA ID": 423454, "Summary": ""}
{"Disease Name": "Nail-patella syndrome", "Disease Definition": "A rare hereditary patellar dysostosis characterized by nail hypoplasia or aplasia, aplastic or hypoplastic patellae, elbow dysplasia, and the presence of iliac horns as well as renal and ocular anomalies.", "ORPHA ID": 2614, "Summary": "Epidemiology\nThe reported prevalence is 1/50,000; however, epidemiological studies are lacking.\nClinical description\nNail-patella syndrome (NPS) is a multisystemic disorder characterized by significant inter- and intrafamilial variability in clinical manifestations and severity of the disease. Cases can range from mild with no functional impact to severe leading to disability. The classical tetrad involves nails dysplasia, absent or hypoplastic patellae, presence of iliac horns, and elbow deformities. Adults can have a slight lower bone mineral density of the hip and spine (8 -20%) leading to a higher risk of fractures and scoliosis. Glaucoma and ocular hypertension have been described in NPS patients and may require early ophthalmological screening. Renal complications are reported in 30-60% of the cases. Other extraskeletal abnormalities described are loss of the normal skin creases over the distal interphalangeal joints and, neurological symptoms such as numbness, tingling and neuropathic pain.\nEtiology\nNPS is an autosomal-dominant disorder and the majority of the cases are caused by LMX1B mutations (9q33.3) leading to loss of function of the LMX1B protein. About 10% are caused by a de novo pathogenic variant.\nDiagnostic methods\nThe diagnosis is based on clinical findings. Molecular test can identified the LMX1B gene mutations in around 95% of the cases, thus helping to confirm the clinical diagnosis or cases where clinical signs and symptoms are not clear.\nDifferential diagnosis\nAs patients with NPS may present a broad phenotypic spectrum, differential diagnosis may be necessary, as the association of systemic and musculoskeletal findings may also occur in other genetic syndromes including Coffin-Siris, Meier-Gorlin, Genitopatellar, RAPADILINO, DOORS, and coxopodopatellar syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is possibile when there is a positive familiar history for the disorder. Some skeletal signs (ie, talipes equinovarus or large iliac horns) may be identified on fetal ultrasound examination in the third trimester of pregnancy. When the disease-causative variant is found in the affected individual of the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.\nGenetic counseling\nNPS is inherited in an autosomal dominant manner. Each child of an NPS affected individual has a 50% chance of inheriting the LMX1B pathogenic variant of the disease. The penetrance of the disease is complete, but the clinical expression is variable even in individuals of the same family. About 90% of NPS patients have an affected parent. In NPS, somatic and germline mosaicism has been reported in unaffected parents.\nManagement and treatment\nThe management and treatment is focused on the clinical manifestations, which may require a multidisciplinary team. Joint limitations or anatomical abnormalities may need surgical treatment. Early ocular and renal screening may be helpful and a medical follow up can be required if any alteration is identified. Pain management is important and physical and pharmacological options are available.\nPrognosis\nPatients with NPS live a normal lifespan. The renal pathology is a major determinant of the prognosis, as proteinuria, hypertension, and hematuria occur in 30 - 60% of the patients; 5 % progress to chronic renal failure.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Luca SANGIORGI | ERN BOND*\n\n\n                                * European Reference Network"}
{"Disease Name": "Nail-patella-like renal disease", "Disease Definition": "A rare genetic glomerular disease characterized by variably severe nephropathy with microscopic hematuria and proteinuria, in the absence of nail and bone abnormalities. Characteristic ultrastructural findings are irregular thickening and moth-eaten appearance of the glomerular basement membrane with focal deposition of type III collagen fibrils.", "ORPHA ID": 2613, "Summary": ""}
{"Disease Name": "Nance-Horan syndrome", "Disease Definition": "Nance-Horan syndrome (NHS) is characterized by the association in male patients of congenital cataracts with microcornea, dental anomalies and facial dysmorphism.", "ORPHA ID": 627, "Summary": "Epidemiology\nPrevalence is unknown. NHS is a rare but probably underdiagnosed disorder; 36 families have been reported in the literature.\nClinical description\nThe ocular problem consists of congenital cataract (100% of cases), bilateral, usually severe, dense and most often total, associated with microcornea (96%), or even microphthalmia. In 93% of the cases, it is responsible for severe visual impairment evidenced by nystagmus (93%), sometimes associated with strabismus (43%). Dental abnormalities, although easily overlooked, are nearly constant, involve permanent and deciduous teeth and are of high diagnostic value. The most frequent are diastema, supernumerary incisors or posterior teeth, which are often impacted, and shape abnormalities (the most typical being screwdriver-shaped teeth). Facial dysmorphism is frequent and characterized by a long face, prognathism, a large nose, with a high nasal bridge, and large often protruding ears. Intellectual impairment is observed in about 30% of cases with inter- and intrafamilial variability. It is usually mild or moderate (80%), without motor delay, but in 20% of cases it is severe/profound and associated with autistic features. In heterozygote females, clinical manifestations are identical to those of affected males but they are attenuated and often limited to infraclinical findings.\nEtiology\nCausative mutations have been identified in the NHS gene (localized to Xp22.2) and typically result in a truncated protein. The differential expression of two NHS isoforms, NHS-A and NHS-1A, and differences in the subcellular localization of these isoforms may partly explain the various clinical manifestations.\nDiagnostic methods\nDiagnosis is based on clinical findings as there is no biological marker. The recognition of dental abnormalities requires careful physical and radiological dental examination.\nDifferential diagnosis\nDifferential diagnosis includes: X-linked microphthalmia, Lenz syndrome, Oculo-facio-cardio-dental (OFCD) syndrome, and Oculo-cerebro-renal (Lowe) syndrome (see these terms).\nAntenatal diagnosis\nMolecular study may be performed for the purpose of genetic counseling and antenatal diagnosis.\nGenetic counseling\nNHS is a genetic condition with X-linked semi-dominant transmission and high penetrance in heterozygote females.\nManagement and treatment\nOcular abnormalities usually require surgery for cataract extraction although the results are poor. Complications (glaucoma, retinal detachment, etc) are treated medically or surgically depending on the type and severity. The ocular problem requires education appropriate for the degree of visual handicap and often necessitates education in a special school for the visually impaired. Dental anomalies may require orthodontic treatment. Intellectual impairment requires special education.\n\n                            Last update: \n                            September 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Annick TOUTAIN"}
{"Disease Name": "Nanophthalmos", "Disease Definition": "A rare ophthalmic disease and a severe form of microphthalmia (small eye phenotype) characterized by a small eye with a short axial length, severe hyperopia, an elevated lens/eye ratio, and a high incidence of angle-closure glaucoma.", "ORPHA ID": 35612, "Summary": "Epidemiology\nThe exact prevalence of nanophthalmos is unknown but is likely to be below 1/2,000. However, the prevalence is higher among consanguineous populations.\nClinical description\nThe disease occurs neonatally or during infancy. Typical clinical signs include an axial length inferior to 20 mm, a lens/eye ratio 4 to 8 times greater than normal, thickened and abnormally dense sclera, a thickened lens and choroids, and severe hyperopia (+7.00 D to +13.00 D). Despite its small size, the functionality and organization of the eye are preserved. Nanophthalmos is generally bilateral. Strabismus is present in most patients. The association of nanophthalmos and pigmentary retinopathy or Best disease has been reported. The condition can be simple (occurring in isolation), complex (associated with other malformations such as colobomas, anterior segment dysgenesis, and lens and posterior segment abnormalities) or syndromic (as part of a rare syndrome).\nEtiology\nTo date, five genes have been associated with the disease : MFRP (11q23.3, coding for a frizzled protein playing a role in the regulation of cell growth, differentiation and polarity during development), TMEM98 (17q11.2, coding for an ubiquitous protein which could be involved in the scleral pathologic thickening and secondary glaucoma development in the disease), PRSS56 (2q37.1, the exact physiopathological mechanism is unknown), BEST1 (11q12.3, involved for example in the development of angle-closure glaucoma) and CRB1 (1q31.3, coding for a protein essential for the neuronal development of the retina). Other loci are also associated with nanophthalmos.\nDiagnostic methods\nDiagnosis is based on clinical findings and ophthalmologic examinations involving ocular biometry, ultrasonography, as well as corneal diameter and intraocular pressure measurements.\nDifferential diagnosis\nNanophthalmos should be differentiated from posterior microphthalmos.\nGenetic counseling\nThe disease may be inherited as an autosomal dominant or recessive trait. It can also occur sporadically.\nManagement and treatment\nTreatment may include surgery (iridotomy, iridoplasty, glaucoma filtering surgery, and lens extraction), but side effects (malignant glaucoma, uveal effusion, nonrhegmatogenous retinal detachment and expulsive hemorrhage) may occur. Complications can be prevented by performing a sclerectomy before any intraocular intervention.\nPrognosis\nAngle-closure glaucoma is a constant finding in patients with nanophthalmia but the prognosis is favorable if this manifestation is correctly managed.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Alain BRON  - Pr Paul FOSTER"}
{"Disease Name": "Narcolepsy type 1", "Disease Definition": "A rare neurologic disease characterized by excessive daytime sleepiness associated with uncontrollable sleep urges and cataplexy (sudden loss of muscle tone while awake, often triggered by pleasant emotions).", "ORPHA ID": 2073, "Summary": "Epidemiology\nNarcolepsy type 1 prevalence is estimated between 1/2,000 and 1/5,000.\nClinical description\nThe age of onset varies between 10 and 30 years old and symptoms are lifelong. The average time between the age of appearance of the symptoms and the diagnosis is still very long, 10 years. Other, non specific, clinical signs include hypnagogic hallucinations, sleep paralysis, disturbed nocturnal sleep, and weight gain, especially in children.\nEtiology\nThe disease is due to loss or impairment of the orexin/hypocretin neurons of the lateral hypothalamus that results in decreased hypocretin-1 levels in the cerebrospinal fluid. An autoimmune origin for the disease is highly suspected, particularly environmental factors interacting with susceptibility genes (more than 98% of the patients carry the HLA-DQB1*0602 allele); however, this is unproven.\nDiagnostic methods\nDefinitive diagnosis requires the presence of clinical symptoms, characteristic polysomnography findings and/or low hypocretin-1 levels in cerebral spinal fluid. Nocturnal and daytime polysomnography demonstrate an average sleep latency of under eight minutes with at least two sleep onset rapid eye movement periods (SOREMP) on multiple sleep latency tests. The presence of low hypocretin-1 levels (<110 pg/ml) in the cerebrospinal fluid can confirm the diagnosis with an excellent sensibility and specificity.\nDifferential diagnosis\nCataplexy must be typical to be confident with the diagnosis. In absence of typical cataplexy, other causes of sleepiness must be considered, such as chronic insufficient sleep, idiopathic hypersomnia or narcolepsy without cataplexy, now called narcolepsy type 2.\nGenetic counseling\nRare familial cases have been reported (<2%); however the mode of inheritance is unclear.\nManagement and treatment\nTreatment is nowadays only symptomatic, as the loss of orexin neurons is irreversible. It comprises stimulants (modafinil, methylphenidate, amphetamine, pitolisant, solriamfetol), anticataplectic drugs (antidepressants) or sodium oxybate. First-line treatment of diurnal sleepiness is often with modafinil but it can be also with pitolisant or sodium oxybate. Second-line treatments are methylphenidate, solriamfetol or amphetamines. Sodium oxybate is efficient for sleepiness, cataplexy and disturbed nocturnal sleep. A good sleep hygiene is always recommended, with scheduled short naps, and regular sleep habits.\nPrognosis\nNarcolepsy can severely disable scholarly and professional performances. The evolution of the disease is often stable with a frequent improvement of sleepiness and cataplexy, but with age there is an aggravation of the poor quality of night sleep.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Lucie BARATEAU  - Pr Yves DAUVILLIERS"}
{"Disease Name": "Narcolepsy type 2", "Disease Definition": "A rare neurologic disease characterized by excessive daytime sleepiness associated with uncontrollable sleep urges and sometimes sleep paralysis, and hypnagogic/hypnopompic hallucinations.", "ORPHA ID": 83465, "Summary": "Epidemiology\nNo clear epidemiological data are available. Narcolepsy type 2 prevalence numbers are controversial, sometimes higher and sometimes lower than those of narcolepsy type 1, depending on reports.\nClinical description\nNarcolepsy type 2 manifests generally between the age of 10 and 30 years old, although onset in childhood is rare. Narcolepsy type 2 has a variable phenotype and evolution, with sometimes improvement or even disappearance of the symptoms, rarely the development of cataplexy (conversion to narcolepsy type 1), or a change in the phenotype to idiopathic hypersomnia. It can also be a lifelong disease, with stable symptomatology.\nEtiology\nThe etiology is still unknown, probably because this disorder is heterogeneous. Reduction of hypocretin-1 levels is found in the cerebrospinal fluid in 10-20% of cases, and in which case the disorder is reclassified narcolepsy type 1. The presence of the HLA DQB1*0602 allele is reported in 40% of cases (more than in the general population but less than in cases of narcolepsy type 1, 98%).\nDiagnostic methods\nDefinitive diagnosis requires the presence of clinical symptoms and characteristics polysomnography findings. Nocturnal and daytime polysomnography demonstrates an average sleep latency of under eight minutes with at least two sleep onset rapid eye movement periods (SOREMP) on multiple sleep latency tests. A pure clinical diagnosis is not possible due to the absence of pathognomonic symptom such as cataplexy, and daytime sleepiness being a non-specific symptom.\nDifferential diagnosis\nOther causes of sleepiness, including narcolepsy type 1, chronic insufficient sleep and idiopathic hypersomnia (especially the form without long sleep time), must be systematically taken into account.\nGenetic counseling\nRare familial cases have been reported; however, the mode of inheritance is unclear.\nManagement and treatment\nTreatment is only symptomatic, based on stimulant drugs and a good sleep hygiene (sufficient sleep duration at night is required, with scheduled short naps during the day). Modafinil or pitolisant are the first line treatments with the best benefit/risk ratio. Second-line treatments include methylphenidate, sodium oxybate, solriamfetol or amphetamines.\nPrognosis\nThe disease has a negative impact on scholarly and professional performances. Spontaneous evolution of the disease has not been much studied, but the phenotype and evolution seems variable : stability, disappearance of the symptoms, development of cataplexy (conversion to narcolepsy type 1) , or change to idiopathic hypersomnia.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Lucie BARATEAU  - Pr Yves DAUVILLIERS"}
{"Disease Name": "NARP syndrome", "Disease Definition": "A clinically heterogeneous progressive condition characterized by a combination of proximal neurogenic muscle weakness, sensory-motor neuropathy, ataxia, and pigmentary retinopathy.", "ORPHA ID": 644, "Summary": "Epidemiology\nWordwide prevalence is unknown but may be estimated at 0.8-1/100,000.\nClinical description\nNARP (Neuropathy, Ataxia, and Retinitis Pigmentosa) syndrome is characterized by a great phenotypic variability and habitually clearly manifests in young adulthood. Early childhood manifestations often describe learning difficulties, developmental delay and ataxia, whereas ocular signs, proximal neurogenic muscle weakness with sensory neuropathy usually develop in the second decade of life. Ocular manifestations are variable and range from early salt and pepper retinopathy to retinitis pigmentosa, sluggish pupils, nystagmus, ophthalmoplegia, night blindness and loss of visual field. Other features may include short stature, seizures, corticospinal tract atrophy, depression, dementia, sleep apnea, hearing loss or cardiac arrhythmias.\nEtiology\nNARP syndrome is caused in the large majority of patients by a m.8993T>C/G in the subunit 6 of mitochondrial H(+)-ATPase gene (MTATP6). Most NARP patients have 70-90% mutated mitochondrial DNA. The m.8993T>G mutation is also present in 8-10% of patients with Leigh syndrome when mutated mitochondrial DNA is > 90%. Less common ATP6 heteroplasmic mutations include m.8839G>C, m.8989G>C, m.8618-8619insT, m.9032T>C, and m.9127-9128 delAT microdeletion, all identified in single families.\nDiagnostic methods\nDiagnosis is based on clinical manifestations, electroretinogram, and genetic testing. Peripheral neuropathy may be demonstrated by electromyography, whereas an MRI may pick up cerebral and cerebellar atrophy in later stages. Serum lactate may be normal or elevated. At muscle biopsy, histochemical or biochemical signs of oxidative phosphorylation may be absent.\nDifferential diagnosis\nDifferential diagnosis includes maternally inherited Leigh syndrome (MILS, like NARP syndrome part of the same group of disorders of mitochondrial oxidative phosphorylation), Refsum disease, Cockayne syndrome, abetalipoproteinemia, Usher syndrome (see these terms), neurological complication of lipidosis or rare cases of spinocerebellar disorder/ataxia.\nAntenatal diagnosis\nPrenatal diagnosis by amniocentesis or chorionic villus sampling and cytogenetic analysis if the mutation has been identified in an affected family member. Preimplantation genetic diagnosis is available for affected couples in few centers.\nGenetic counseling\nNARP syndrome is a maternally inherited syndrome and women can transmit to all their offspring. Clinical severity usually depends on the mutation load. There must be extreme caution in predictive counseling because of the genetic shift between mother and offspring.\nManagement and treatment\nManagement and treatment is only supportive and may include sodium bicarbonate or sodium citrate for acute aggravation of acidosis; antioxidant treatment, treatment of epileptic seizures by appropriate anticonvulsants; treatment of dystonia (e.g., benzhexol, baclofen, tetrabenazine, and gabapentin); and anticongestive therapy in case of cardiomyopathy. Patients require psychological support and should be followed up periodically by neurologists, ophthalmologists and cardiologists to monitor disease progression. Agents to avoid include Sodium Valproate, barbiturates and anesthesia (in general) as well as dichloroacetate.\nPrognosis\nAs NARP syndrome is progressive, patients may become increasingly dependent of others. The quality of life is severely reduced. Patients may go blind and deaf and may experience depression and dementia. Due to the progressive neurogenic muscle weakness patients may become wheelchair bound.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Claudia NESTI  - Pr Filippo SANTORELLI"}
{"Disease Name": "Nasal dermoid cyst", "Disease Definition": "A rare otorhinolaryngological malformation characterized by a dermoid cyst along the nasal dorsum or glabella, lined by keratinized squamous epithelium and containing intraluminal keratin and mature adnexal structures, such as hair follicles, sebaceous and sweat glands. The majority of nasal dermoid cysts are superficial, rarely they extend intracranially. The cysts are typically benign but are susceptible to recurrent infections that may progress to osteomyelitis, meningitis or an intracranial abscess.", "ORPHA ID": 141103, "Summary": ""}
{"Disease Name": "Nasal dorsum fistula", "Disease Definition": "A rare otorhinolaryngological malformation characterized by the presence of a dermoid cyst, located on the dorsum of the nose, which presents a fistula, often extending to the intracranial region. Patients present a firm, slow-growing mass, which contains skin and dermal elements (including hair follicles and sebaceous glands), that do not transilluminate or compress, and may be associated with intermittent or chronic discharge of sebaceous material, soft tissue and skeletal deformity, and local infection. Meningitis, convulsions and cerebral abscess may be observed if intracranial extension exists.", "ORPHA ID": 141219, "Summary": ""}
{"Disease Name": "Nasal encephalocele", "Disease Definition": "Nasal encephalocele is an extracranial herniation of intracranial contents (that maintain a connection to the subarachnoid space) into the fonticulus frontalis, presenting with nasal broadening and/or as a compressible, blue, pulsatile mass near the nasal bridge (that enlarges on crying or with jugular vein compression) or as an intranasal mass originating in the cribiform plate and that can cause nasal obstruction or respiratory distress. Hydrocephalus and increased intracranial pressure are also reported in some cases.", "ORPHA ID": 141118, "Summary": ""}
{"Disease Name": "Nasal ganglioglioma", "Disease Definition": "Nasal ganglioglioma is a rare tumor, presenting in newborns, containing both neuronal and astrocytic components and that can be endonasal, extranasal or both. It is usually identified as a nasal mass that may cause feeding difficulties and nasal obstruction.", "ORPHA ID": 141115, "Summary": ""}
{"Disease Name": "Nasal glial heterotopia", "Disease Definition": "Nasal glial heterotopia is a rare developmental abnormality presenting usually at birth or in early childhood (rarely in adulthood) as a benign, non-pulsatile mass that can lead to nasal obstruction, deformation of the septum and nasal bone, and respiratory distress if untreated. Nasal glial heterotopias have no communication with the central nervous system; however an associated defect in the cribriform plate is sometimes reported.", "ORPHA ID": 141112, "Summary": ""}
{"Disease Name": "Nasolacrimal duct cyst", "Disease Definition": "Nasolacrimal duct cyst describes a unilateral or bilateral congenital cyst of the nasolacrimal duct, which is almost always associated with dacryocystocele, presenting most commonly at birth or a few weeks of age (but rarely presenting in adulthood) as a benign, grayish blue mass in the inferomedial canthus or in the nasal cavity, that can cause epiphora, dacryocystitis (inflammation of the lacrimal sac) and nasal obstruction. It is more commonly reported in females.", "ORPHA ID": 141083, "Summary": ""}
{"Disease Name": "Nasopalpebral lipoma-coloboma syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by nasopalpebral lipomas, bilateral lid coloboma, and telecanthus.", "ORPHA ID": 2399, "Summary": "Epidemiology\nNasopalpebral lipoma-coloboma-telecanthus syndrome (NPLCS) is a very rare syndrome. About 20 patients from 5 families were reported in the literature.\nClinical description\nNPLCS is characterized by a congenital facial malformation associating bilateral upper eyelid and nasopalpebral lipomas, colobomas of upper and lower eyelids, telecanthus, and maxillary hypoplasia. Additional features may include displaced or aplastic lacrimal punctae, epiphora, aberrant eyelashes, conjunctival hyperemia, corneal and lens opacities, strabismus, nanophtalmos, limbal dermoid, dysplastic ears and nasopalpebral hamartomas. No extra-facial abnormalities are described.\nEtiology\nA heterozygous frameshift variant in the zinc finger transcription factor, encoded by ZDBF2 (2q33.3) has been identified in one sporadic patient. However, no functional studies were published to support the pathogenicity of this variant and no further patients have been reported since.\nDiagnostic methods\nThe diagnostic is based on clinical examination.\nDifferential diagnosis\nThe main differential diagnoses include congenital infiltrating lipomatosis of the face, oculocerebrocutaneous syndrome, and conditions with eyelid coloboma and hypertelorism such as frontonasal dysplasia, craniofrontonasal syndrome, and oculoauriculofrontonasal syndrome.\nAntenatal diagnosis\nGenetic prenatal diagnosis is not available since the molecular basis is unknown.\nGenetic counseling\nVertical, male-to-male transmission in 3 and 4 generations suggests autosomal dominant mode of inheritance with complete penetrance. Genetic counseling should be offered to affected families.\nManagement and treatment\nPlastic and reconstructive surgery can be performed, notably excision of the lipomas and eyelid coloboma repair.\nPrognosis\nThere are limited data in the literature regarding the prognosis of the affected individuals. Cognitive development seems to be normal.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence OLIVIER-FAIVRE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Nasopharyngeal carcinoma", "Disease Definition": "Nasopharyngeal carcinoma (NPC) is a tumor arising from the epithelial cells that cover the surface and line the nasopharynx.", "ORPHA ID": 150, "Summary": "Epidemiology\nThe annual incidence is around 1/100 000 in Western countries. Incidence is higher in the Chinese and Tunisian populations. Although rare, NPC accounts for about one third of childhood nasopharyngeal neoplasms.\nClinical description\nThree subtypes of NPC are recognized in the World Health Organization (WHO) classification: 1) squamous cell carcinoma, typically found in the older adult population; 2) non-keratinizing carcinoma; 3) undifferentiated carcinoma. The tumor can extend within or out of the nasopharynx to the other lateral wall and/or posterosuperiorly to the base of the skull or the palate, nasal cavity or oropharynx. It then typically metastases to cervical lymph nodes. Cervical lymphadenopathy is the initial presentation in many patients, and the diagnosis of NPC is often made by lymph node biopsy. Symptoms related to the primary tumor include trismus, pain, otitis media, nasal regurgitation due to paresis of the soft palate, hearing loss and cranial nerve palsies. Larger growths may produce nasal obstruction or bleeding and a 'nasal twang'.\nEtiology\nEtiological factors include Epstein-Barr virus (EBV), genetic susceptibility and consumption of food with possible carcinogens - volatile nitrosamines.\nDiagnostic methods\nDiagnostic methods include indirect nasopharyngoscopy to assess the primary tumor, clinical evaluation of the size of cervical lymph nodes and biopsy of either the lymph nodes or primary tumor for histological examination. Other potential sites of metastasis are further investigated by neurological examination of cranial nerves, computed tomography (CT)/magnetic resonance imaging (MRI) scan of the head and neck, chest radiotherapy and bone scintigraphy. EBV viral capsid antigen and EBV DNA can be detected by serum analysis.\nManagement and treatment\nThe recommended treatment schedule consists of three courses of neoadjuvant chemotherapy, irradiation, and adjuvant interferon (IFN)-beta therapy.\nPrognosis\nPresentation with lymphadenopathy implies that the disease has spread beyond the primary site. However, in childhood, the presence of metastatic disease in cervical lymph nodes at diagnosis does not adversely affect prognosis. Factors associated with a poor prognosis are skull base involvement, extent of the primary tumor and cranial nerve involvement.\n\n                            Last update: \n                            July 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Bernadette BRENNAN"}
{"Disease Name": "Nasu-Hakola disease", "Disease Definition": "Nasu-Hakola disease (NHD), also referred to as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare inherited leukodystrophy characterized by progressive presenile dementia associated with recurrent bone fractures due to polycystic osseous lesions of the lower and upper extremities.", "ORPHA ID": 2770, "Summary": "Epidemiology\nOver 200 cases have been reported worldwide in the literature, the majority of them being in the Japanese and Finnish population. The prevalence in Finland is estimated between 1/500,000 and 1/1,000,000.\nClinical description\nThe disease course is generally divided into four stages: latent, osseous, early neurologic, and late neurologic. After a normal development during childhood (latent stage), the disease starts manifesting during adolescence or young adulthood (typical age of onset 20-30 years) with pain in the hands, wrists, ankles, and feet. Patients then start suffering from recurrent bone fractures due to polycystic osseous and osteoporotic lesions in the limb bones (osseous stage). During the third or fourth decade of life (early neurologic stage), patients present with pronounced personality changes (e.g. euphoria, lack of concentration, loss of judgment and social inhibitions) characteristic of a frontal lobe syndrome. Patients also typically suffer from initially mild, but progressive, memory disturbances. Epileptic seizures are frequently observed. Finally (late neurologic stage), patients progress to a profound dementia, are unable to speak and move, and usually die by the age of 50 years. Occasionally, the disease presents a different course with the neurologic symptoms preceding the osseous ones.\nEtiology\nNHD is due to mutations in either the TYROBP or TREM2 genes encoding the tyrosine kinase binding adaptor protein and the triggering receptor expressed on myeloid cells 2 respectively. These genes encode components of a signaling complex involved in the regulation of immune responses, the differentiation of dendritic cells and osteoclasts, and in the phagocytic activity of microglia. The exact pathogenic mechanism is unknown.\nDiagnostic methods\nDiagnosis is based on clinical and radiologic examination. X-ray imaging shows multifocal cystic lesions on the bones of hands, wrists, feet and ankles. Brain computed tomography (CT) or magnetic resonance imaging (MRI) shows frontally accentuated atrophy of the cerebral white matter. Bilateral calcifications of the basal ganglia are typical. EEG is normal in the early stages but shows diffuse slowing and irritative activity in late stages. Histopathologically, loss of axons and myelin as well as fibrillary gliosis are observed. Molecular genetic testing confirms the diagnosis in ambiguous cases.\nDifferential diagnosis\nThe combination of frontal-type dementia starting in the fourth decade and radiologically demonstrable polycystic osseous lesions is unique and facilitates the differentiation of NHD from other forms of familial and non-familial frontotemporal dementia such as frontotemporal dementia and parkinsonism linked to chromosome 17 (see this term).\nAntenatal diagnosis\nDue to the low carrier frequency of the mutation in the general population, prenatal diagnostic procedures are usually not reasonable, except in genetic isolates.\nGenetic counseling\nTransmission is autosomal recessive. Children of an NHD patient are healthy carriers of the mutation unless they have also inherited a disease-causing mutation in the TYROBP or TREM2 genes from the other parent. Presymptomatic testing is commercially available.\nManagement and treatment\nThere is no curative treatment for the disease. Management is supportive. Antiepileptic drugs are prescribed to prevent seizures. A regular orthopedic and neurologic surveillance is recommended.\nPrognosis\nNHD is a progressive disease that is fatal usually during the fifth decade of life.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Juha PALONEVA"}
{"Disease Name": "Nathalie syndrome", "Disease Definition": "A rare, genetic developmental defect during embryogenesis disorder characterized by sensorineural hearing impairment, childhood-onset cataract, underdeveloped secondary sexual characteristics, spinal muscular atrophy, growth retardation, and cardiac and skeletal anomalies. Sudden death, as well as fatal cardiomyopathy and heart failure, have been described in some cases.", "ORPHA ID": 2663, "Summary": ""}
{"Disease Name": "Native American myopathy", "Disease Definition": "Native American myopathy (NAM) is a neuromuscular disorder characterized by weakness, arthrogryposis, kyphoscoliosis, short stature, cleft palate, ptosis and susceptibility to malignant hyperthermia during anesthesia.", "ORPHA ID": 168572, "Summary": "Epidemiology\nNAM is reported exclusively in Native American Indians (Lumbee Indian population of North Carolina). Within this population, the prevalence of NAM is estimated at approximately 1:5,000.\nEtiology\nThe NAM locus has been localized to 12q13.13-14.1.\nGenetic counseling\nThe disease is transmitted in an autosomal recessive manner.\n\n                            Last update: \n                            February 2009"}
{"Disease Name": "Navajo neurohepatopathy", "Disease Definition": "A rare, life-threatening, mitochondrial DNA depletion syndrome disease characterized by severe, progressive sensorimotor neuropathy associated with corneal ulceration, scarring or anesthesia, acral mutilation, metabolic and immunologic derangement, and hepatopathy (which can manifest with fulminant hepatic failure, a Reye-like syndrome or indolent progression to liver cirrhosis, depending on clinical form involved), present in the Navajo Native American population. Clinical presentation includes failure to thrive, distal limb weakness with reduced sensation, limb contractures with loss of function, areflexia, recurrent metabolic acidosis with intercurrent illness, immunologic anomalies manifesting with severe systemic infections, and sexual infantilism.", "ORPHA ID": 255229, "Summary": ""}
{"Disease Name": "Naxos disease", "Disease Definition": "A rare arrhythmogenic right ventricular cardiomyopathy (ARVC) and a cutaneous phenotype, characterized by peculiar woolly hair and palmoplantar keratoderma.", "ORPHA ID": 34217, "Summary": "Epidemiology\nNaxos disease was first described in families originating from the Greek island of Naxos. Moreover, affected families have been identified in other Aegean islands, Turkey, Israel, Saudi Arabia, India, Argentina and French-Canadian families. A syndrome with the same cutaneous phenotype and predominantly left ventricular involvement has been described in families from India and Ecuador (carvajal syndrome).\nClinical description\nWoolly hair appears from birth, palmoplantar keratoderma develop during the first year of life and cardiomyopathy is clinically manifested by adolescence with 100% penetrance. Patients present with syncope, sustained ventricular tachycardia or sudden death. Symptoms of right heart failure appear during the end stages of the disease.\nEtiology\nMutations in the JUP gene encoding the desmosomal proteins plakoglobin and desmoplakin have been identified as the cause of Naxos disease. Defects in the linking sites of these proteins can interrupt the contiguous chain of cell adhesion, particularly under conditions of increased mechanical stress or stretch, leading to cell death, progressive loss of myocardium and fibro-fatty replacement.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation based on palmoplantar keratoderma with hair shaft abnormalities, mostly of woolly hair type present from infancy, fulfilling the diagnostic criteria of ARVC later in adolescence or early adulthood. It is confirmed by the presence of a JUP variant in homozygosity on genetic testing.\nDifferential diagnosis\nNaxos disease should be differentiated from carvajal syndrome that is caused by homozygous variants in desmoplakin (DSP), clinically manifested during childhood and leading more frequently to heart failure. It presents with similar cutaneous features as those of Naxos disease, in infancy, but the cardiac phenotype is compatible with arrhythmogenic cardiomyopathy with left ventricular predominance.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nNaxos disease transmission is autosomal recessive. If both individuals are carriers of the disease-causing variant, there is a 25% risk of having an affected child at each pregnancy. Therefore it is recommended that genetic counseling be offered to at-risk couples.\nManagement and treatment\nImplantation of an automatic cardioverter defibrillator is indicated for prevention of sudden cardiac death. Antiarrhythmic drugs are used for preventing recurrences of episodes of sustained ventricular tachycardia and classical pharmacological treatment for congestive heart failure, while heart transplantation is considered at the end stages.\nPrognosis\nPrognosis in Naxos disease tracks that of other genetic cases of ARVC (Arrhythmogenic Right Ventricular Cardiomyopathy). Patients are at risk of developing life-threatening arrhythmias and heart failure.\n\n                            Last update: \n                            August 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Alexandros PROTONOTARIOS  - Dr Adalena TSATSOPOULOU"}
{"Disease Name": "NDE1-related microhydranencephaly", "Disease Definition": "NDE1-related microhydranencephaly is a rare, hereditary syndrome with a central nervous system malformation as major feature characterized by extreme microcephaly and growth restriction, severe motor delay and mental retardation, and typical radiological findings of gross dilation of the ventricles resulting from the absence (or severe delay in the development) of cerebral hemispheres, hypoplasia of the corpus callosum, cerebellum, and brainstem. Associated features are thin bones and scalp rugae.", "ORPHA ID": 443162, "Summary": ""}
{"Disease Name": "Necrobiosis lipoidica", "Disease Definition": "A rare skin disease characterized by enlarging, annular plaques with red-brown edges and atrophic, yellow-brown, telangiectatic centers. The lesions are commonly asymptomatic, but affected skin areas may be fragile, and painful ulcerations develop in many cases. In rare cases, development of squamous cell carcinoma within longstanding lesions has been reported. The lower legs, especially the shins, are the most frequently involved site. The condition is often associated with diabetes mellitus.", "ORPHA ID": 542592, "Summary": ""}
{"Disease Name": "Necrobiotic xanthogranuloma", "Disease Definition": "Necrobiotic xanthogranuloma is a rare, chronic and progressive, non-Langerhans cell histiocytosis disease typically characterized by multiple, indurated, asymptomatic to pruritic, yellow-orange plaques or nodules that tend to ulcerate and are usually located in the periorbital area, trunk and/or extremities. Strong association with paraproteinemia and/or malignant lymphoproliferative disease has been reported.", "ORPHA ID": 158011, "Summary": ""}
{"Disease Name": "Necrotizing enterocolitis", "Disease Definition": "A rare intestinal disease characterized by potentially life-threatening inflammatory bowel necrosis predominantly affecting preterm neonates. Patients may present with feeding intolerance, lethargy, temperature instability, abdominal distention, blood-stained stools, diarrhea, bilious vomiting, apnea, and signs of sepsis. Radiographic features include pneumatosis intestinalis, portal venous gas, presence of fixed, dilated intestinal loops, bowel wall edema, and (in case of bowel perforation) pneumoperitoneum.", "ORPHA ID": 391673, "Summary": ""}
{"Disease Name": "Necrotizing soft tissue infection", "Disease Definition": "A rare infectious disease characterized by painful, rapidly progressive infection of deep soft tissue structures. Infections can be mono- or polymicrobial and involve gram-positive cocci, enteric gram-negative bacilli, anaerobes, among others. Fungal infections have also been described in rare cases. Physical examination findings are often subtle and may include erythema, bullae, induration of subcutaneous tissues, and tenderness to palpation.", "ORPHA ID": 440368, "Summary": ""}
{"Disease Name": "NEK9-related lethal skeletal dysplasia", "Disease Definition": "NEK9-related lethal skeletal dysplasia is a rare, lethal, primary bone dysplasia characterized by fetal akinesia, multiple contractures, shortening of all long bones, short, broad ribs, narrow chest and thorax, pulmonary hypoplasia and a protruding abdomen. Short bowed femurs may also be associated.", "ORPHA ID": 464366, "Summary": ""}
{"Disease Name": "Nelson syndrome", "Disease Definition": "A rare, acquired, endocrine disease characterized by the triad of diffuse skin and mucosa hyperpigmentation, markedly elevated serum adrenocorticotropin (ACTH) levels and an enlarging corticotroph adenoma, which manifest following total bilateral adrenalectomy performed for the treatment of Cushing's disease. Additionally, patients may present with headaches, visual field defects, cranial nerve palsy, pituitary apoplexy, diabetes insipidus, panhypopituitarism, and, occasionally, paraovarian or paratesticular tumors.", "ORPHA ID": 199244, "Summary": ""}
{"Disease Name": "Nemaline myopathy", "Disease Definition": "Nemaline myopathy (NM) encompasses a large spectrum of myopathies characterized by hypotonia, weakness and depressed or absent deep tendon reflexes, with pathologic evidence of nemaline bodies (rods) on muscle biopsy.", "ORPHA ID": 607, "Summary": "Epidemiology\nAnnual incidence has been estimated at 1/50,000 live births in a Finnish study but the disease is more common in the Amish community.\nClinical description\nThe age of onset varies from birth to adulthood. The main clinical manifestations include weakness (usually most severe in the face, the neck flexors and the proximal limb muscles), hypotonia and depressed or absent deep tendon reflexes. Facial weakness may lead to sucking, swallowing and speech difficulties. Respiratory muscles are frequently involved. NM is divided into 6 clinically overlapping subtypes depending on the age at onset and the severity of motor and respiratory involvement. Typical NM (approximately 50% of patients, see this term) is a moderate form of the disease with onset in the neonatal period. Most patients are able to live an independent, active life. Severe congenital NM (10-20% of patients; see this term) is characterized by severe hypotonia and little spontaneous movement. Survival after infancy is rare. Intermediate NM (20% of patients; see this term) is characterized by slow achievement of gross motor milestones, and loss of ambulation and/or independent respiration by age 11 years. Adult-onset NM is usually sporadic (<5% of patients; see this term). Onset is between 20 and 50 years of age. This form is characterized by rapid progression. Mild NM or childhood onset NM (10-15% of patients; see these terms) is characterized by the development of symmetric weakness of ankle dorsiflexion and foot drop around 10 years of age. Weakness is slowly progressive. An Amish NM (see this term) has been observed in several families. It has a neonatal onset and life expectancy rarely exceeds 2 years.\nEtiology\nSeven genes involved in muscle thin filament structure and function, have been linked to NM: NEB (2q22), TPM2 (9p13), TPM3 (1q21.2), ACTA1 (1q42.13), TNNT1 (19q13.4), CFL2 (14q12) and KBTBD13 (15q22.31). Clear genotype/phenotype correlations have not been established.\nDiagnostic methods\nDiagnosis is based on clinical examination and histopathological findings on muscle biopsy, which may reveal a change in fiber type proportion and size and, if combined with the Gomori trichrome staining method, show rod-shaped structures (nemaline bodies) in the sarcolemma and more rarely in the nucleus. Muscle imaging studies such as ultrasonography, computed tomography or magnetic resonance imaging (MRI), may help selecting muscles to biopsy and can guide genetic testing. Muscle enzymes are generally normal or mildly increased. Molecular genetic testing may confirm the diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes other neuromuscular diseases displaying nemaline bodies: dermatomyositis, myotonic dystrophy type 1 and mitochondrial myopathy.\nAntenatal diagnosis\nAntenatal diagnosis is feasible since genetic tests are available to detect mutations in ACTA1, NEB, TPM3, TPM2,TNNT1, CFL2 and KBTBD13. It requires prior identification of the familial causative mutation(s).\nManagement and treatment\nA multidisciplinary approach is needed to handle respiratory insufficiency (permanent or intermittent use of mechanical ventilation and treatment of lower respiratory tract infections) and feeding difficulties (feeding techniques and calorie-enriched diets). Scoliosis, joint contractures or speech anomalies must be managed as usual. Cardiac function must be monitored.\nPrognosis\nPrognosis depends on the NM type, and life expectancy ranges from few months to a near-normal lifespan.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Monique RYAN"}
{"Disease Name": "Neonatal acute respiratory distress due to SP-B deficiency", "Disease Definition": "A rare genetic interstitial lung disease characterized by progressive, life-threatening, refractory respiratory distress in full-term neonates associated with surfactant protein B deficiency. In most cases, the disease is fatal within the first months of life. Lung biopsy reveals changes characteristic of pulmonary alveolar proteinosis with interstitial fibrosis and inflammation, as well as accumulation of lipid-rich, eosinophilic, proteinaceous, granular material consisting of desquamated type II pneumocytes and foamy macrophages within the alveolar air spaces.", "ORPHA ID": 217563, "Summary": ""}
{"Disease Name": "Neonatal adrenoleukodystrophy", "Disease Definition": "A variant of intermediate severity of the PBD-Zellweger syndrome spectrum (PBD-ZSS) charcterized by hypotonia, leukodystrophy, and vision and sensorineural hearing deficiencies. Phenotypic overlap is seen between NALD and infantile Refsum disease (IRD).", "ORPHA ID": 44, "Summary": "Epidemiology\nThe estimated birth prevalence for PBD-ZSS is 1/50,000 in North America and 1/500,000 in Japan. More than half of patients with PBD-ZSS have the NALD-IRD forms.\nClinical description\nNALD has an onset at birth or early infancy, but manifestations may be subtle enough that it is not diagnosed until late infancy or early childhood (or when a leukodystrophy develops). It is characterized by hypotonia, seizures, diffuse encephalopathy, sensorineural hearing loss, peripheral neuropathy, mild facial dysmorphism (hypertelorism and a flat midface), failure to thrive and severely delayed psychomotor development. Eye findings include chorioretinopathy, optic nerve dysplasia and cataracts. Hepatic dysfunction is first displayed in infants with jaundice and later in some with episodes of intracranial bleeding due to vitamin K-responsive coagulopathy. Adrenal insufficiency and renal calcium oxalate stones can present in older children. Vision and hearing dysfunction are progressive and result in blindness and deafness. Osteoporosis and fractures can occur in patients who are less mobile. Neurological regression reflects a leukodystrophy, leading to the loss of previously acquired skills, dementia and ultimately death.\nEtiology\nPBD-ZSS is caused by mutations in one of 13 PEX genes encoding peroxins. Mutations in these genes lead to abnormal peroxisome biogenesis.\nDiagnostic methods\nNALD is suspected on physical examination and confirmed with biochemical evaluation. Plasma very-long-chain fatty acid (VLCFA) levels indicate defects in peroxisomal fatty acid metabolism with elevated plasma concentrations of C26:0 and C26:1 and elevated ratios of C24/C22 and C26/C22. Erythrocyte membrane concentrations of plasmalogens C16 and C18 are reduced. Plasma pipecolic acid levels and bile acid intermediates (THCH and DHCA) are increased. Sequence analysis of the 13 PEX genes can be performed. MRI can be used to identify leukodystrophy, neuronal migration defects or other brain malformations.\nDifferential diagnosis\nThe main differential diagnoses include Usher syndrome I and II, other PBD-ZSS disorders (see these terms), single enzyme defects in peroxisome fatty acid beta-oxidation, and disorders that feature severe hypotonia, neonatal seizures, liver dysfunction or leukodystrophy. X-linked adrenoleukodystrophy (see this term) should not be confused with NALD.\nAntenatal diagnosis\nPrenatal screening of cultured amniocytes and chorionic villus sampling for VLCFA and plasmalogen synthesis is possible. If both disease causing alleles in parents have been identified, prenatal diagnosis can be performed as well as preimplantation genetic diagnosis.\nGenetic counseling\nNALD is inherited in an autosomal recessive manner so genetic counseling is possible.\nManagement and treatment\nThere is no cure for NALD and treatment is symptomatic. Cataracts should be removed in early infancy and glasses used to improve vision. Hearing aids are provided to those with hearing impairment, and cochlear implants considered when hearing loss is profound. Hepatic coagulopathy can be treated with vitamin K supplementation and liver function may improve with primary bile acid therapy. A gastrostomy tube may be necessary to allow for adequate calorie intake. Foods rich in phytanic acid (such as cow's milk) should be restricted. Docosahexanoic acid can be provided. Standard epileptic drugs are used for seizures. Lifelong follow up is needed to monitor changes in hearing, vision and liver function.\nPrognosis\nPrognosis is poor with most patients dying in infancy and early childhood. Some have lived until their teenage years.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nancy BRAVERMAN"}
{"Disease Name": "Neonatal alloimmune neutropenia", "Disease Definition": "A rare acquired neutropenia characterized by isolated neutropenia in a newborn due to maternal alloimmunization against human neutrophil antigens (HNA) inherited from the father and present on fetal neutrophils, and subsequent increased breakdown of the latter. The condition is self-limiting and resolves after several weeks. It usually presents with only mild bacterial infections or may even be asymptomatic, although severe forms with sepsis and fatal outcome have also been reported.", "ORPHA ID": 464370, "Summary": ""}
{"Disease Name": "Neonatal antiphospholipid syndrome", "Disease Definition": "Neonatal antiphospholipid syndrome is a rare, secondary, neonatal autoimmune disease characterized by single or recurrent episodes of venous, arterial or mixed thrombosis in a neonate whose mother does not have antiphospholipid syndrome manifestations. Patients present positive antiphospholipid antibodies and may have additional abnormalities associated (e.g. cardiac valve disease, livedo reticularis, thrombocytopenia, nephropathy, neurological manifestations).", "ORPHA ID": 398097, "Summary": ""}
{"Disease Name": "Neonatal autoimmune hemolytic anemia", "Disease Definition": "A rare, secondary, neonatal autoimmune disease characterized by onset of hemolytic anemia in the neonatal period associated with a positive direct antiglobulin test. Hepatosplenomegaly may be associated.", "ORPHA ID": 398109, "Summary": ""}
{"Disease Name": "Neonatal brainstem dysfunction", "Disease Definition": "Neonatal brainstem dysfunction is a rare neurologic disease characterized by the association of suction-swallowing dysfunction, abnormal laryngeal sensitivity and motility (manifesting with dyspnea or obstructive apnea-hypopnea), gastroesophageal reflux (generally resistant to medication) and cardiac vagal overactivity (e.g. brachycardia, vasovagal episodes) of varying degrees of severity. Impaired social interaction has also been reported.", "ORPHA ID": 137929, "Summary": ""}
{"Disease Name": "Neonatal dermatomyositis", "Disease Definition": "A rare secondary neonatal autoimmune disease characterized by generalized weakness, severe hypotonia, absent or reduced deep tendon reflexes, and highly elevated serum creatine kinase levels presenting in the neonatal period. Perifascicular atrophy in the presence of a diffuse perivascular inflammatory cell exudate is observed on muscle biopsy.", "ORPHA ID": 398117, "Summary": ""}
{"Disease Name": "Neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome", "Disease Definition": "A rare genetic disease characterized by intrauterine growth retardation, permanent neonatal diabetes mellitus, and congenital hypothyroidism. Additional manifestations include congenital glaucoma, hepatic disease (hepatitis, fibrosis, and cirrhosis), polycystic kidneys, exocrine pancreatic dysfunction, sensorineural hearing impairment, developmental delay, and mild facial dysmorphism (such as flat nasal bridge, epicanthal folds, long philtrum, and low-set ears), among others.", "ORPHA ID": 79118, "Summary": ""}
{"Disease Name": "Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome", "Disease Definition": "A rare mitochondrial disease characterized by neonatal onset of severe cardiac and/or neurologic signs and symptoms mostly associated with a fatal outcome in the neonatal period or in infancy, although a milder phenotype with later onset and slowly progressive neurologic deterioration has also been reported. Clinical manifestations are variable and include respiratory insufficiency, hypotonia, cardiomyopathy, and seizures. Serum lactate is elevated in most cases. Brain imaging may show cerebellar atrophy or hypoplasia.", "ORPHA ID": 457185, "Summary": ""}
{"Disease Name": "Neonatal epileptic encephalopathy due to glutaminase deficiency", "Disease Definition": "A rare genetic neurometabolic disease characterized by early neonatal refractory seizures, hypotonia, and respiratory failure. Brain imaging reveals simplified gyral pattern of the frontal lobes, white matter abnormalities, gliosis and volume loss in various brain regions, and vasogenic edema. Serum glutamine levels are significantly elevated. Death occurs within weeks after birth.", "ORPHA ID": 557064, "Summary": ""}
{"Disease Name": "Neonatal glycine encephalopathy", "Disease Definition": "Neonatal glycine encephalopathy is a frequent, usually severe form of glycine encephalopathy (GE; see this term) characterized by coma, apnea, hypotonia, seizure and myoclonic jerks in the neonatal period, and subsequent developmental delay.", "ORPHA ID": 289857, "Summary": "Epidemiology\nThe prevalence of neonatal glycine encephalopathy is not known.\nClinical description\nPatients develop disease manifestations within the first hours or days of life. Symptoms include progressive lethargy, hypotonia, myoclonic jerks leading to apnea. In the absence of intubation and ventilation, apnea may be fatal. With supportive measures, most patients regain spontaneous respiration and some show improvement in alertness over time. Subsequently, they have profound intellectual deficit and increasingly intractable seizures over the first year of life, which often require multiple anticonvulsants. In the vast majority of cases (85%), the course is severe, but some patients have a milder course and less severe clinical outcome. In severe cases, patients make little developmental progress and have limited interaction with their environment. Early spasticity, scoliosis and club feet have also been reported. In milder cases, developmental progress is considerably greater with patients learning to walk and interact, and seizures are generally easier to treat.\nEtiology\nMutations in two genes are known to cause glycine encephalopathy: GLDC (9p22), AMT (3p21.2-p21.1).\nGenetic counseling\nNeonatal GE is inherited in an autosomal recessive manner.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                             Shigeo KURE"}
{"Disease Name": "Neonatal hemochromatosis", "Disease Definition": "A rare iron storage disorder present at birth characterized by the association of severe hepatocellular failure with hyperbilirubinemia, signs of hemorrhage, edema, ascites, hypoglycemia, and lactic acidosis with little to no elevation of transaminases. It is a distinct entity that differs from other forms of hemochromatosis with respect to its pathogenesis and molecular origin.", "ORPHA ID": 446, "Summary": ""}
{"Disease Name": "Neonatal hypoxic and ischemic brain injury", "Disease Definition": "A rare neonatal encephalopathy characterized by alterations in mental status ranging from irritability and decreased responsiveness to coma, as well as abnormal primitive reflexes, hypotonia, seizures, and abnormalities in feeding and respiration, with an onset within the first hours of life. The condition is associated with high mortality. Long-term sequelae include a spectrum of signs and symptoms including behavioral deficits, developmental delay, learning disabilities, cognitive impairment, seizures, visual and auditory dysfunction, and cerebral palsy.", "ORPHA ID": 137577, "Summary": ""}
{"Disease Name": "Neonatal ichthyosis-sclerosing cholangitis syndrome", "Disease Definition": "Neonatal ichthyosis-sclerosing cholangitis (NISCH syndrome) is a very rare complex ichthyosis syndrome characterized by scalp hypotrichosis, scarring alopecia, ichthyosis and sclerosing cholangitis.", "ORPHA ID": 59303, "Summary": "Epidemiology\nLess than ten patients (from unrelated consanguineous Moroccan families and from Sweden) have been reported so far.\nClinical description\nThe ichthyosis presents with diffuse white scales sparing the skin folds, and is accompanied by scalp hypotrichosis, cicatricial alopecia, and sparse eyelashes/eyebrows. Additional manifestations may include oligodontia, hypodontia and enamel dysplasia. All patients present with neonatal sclerosing cholangitis with jaundice and pruritus, hepatomegaly, and biochemical cholestasis. Overall, the clinical picture mimics biliary atresia (see this term). Portal hypertension, patent extrahepatic bile duct obstruction and splenomegaly may also be present. Histology shows extensive fibrosis and bile duct proliferation. Leukocyte vacuolization is a common finding. The hepatic disease may have variable expressivity, ranging from a progressive disease resulting in liver failure to regression of cholestasis.\nEtiology\nNISCH syndrome is caused by a mutation in the CLDN1 gene coding for the tight junction protein claudin-1.\nDiagnostic methods\nDiagnosis is based on clinical, biochemical and histological features.\nDifferential diagnosis\nThe differential diagnosis should include Dorfman-Chanarin syndrome and other syndromic forms of ichthyosis (see these terms).\nGenetic counseling\nNISCH syndrome shows an autosomal recessive pattern of inheritance.\nManagement and treatment\nTreatments aim at improving symptoms and survival. Liver transplant remains the only effective treatment in case of liver failure. Ichthyosis is managed by hydration of the skin (topical application of creams and emollient oils), retinoids and sunlight exposure.\n\n                            Last update: \n                            April 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Dominique VALLA"}
{"Disease Name": "Neonatal inflammatory skin and bowel disease", "Disease Definition": "Neonatal inflammatory skin and bowel disease is a rare, life-threatening, autoinflammatory syndrome with immune deficiency disorder characterized by early-onset, life-long inflammation, affecting the skin and bowel, associated with recurrent infections. Patients present perioral and perianal psoriasiform erythema and papular eruption with pustules, failure to thrive associated with chronic malabsorptive diarrhea, intercurrent gastrointestinal infections and feeding troubles, as well as absent, short or broken hair and trichomegaly. Recurrent cutaneous and pulmonary infections lead to recurrent blepharitis, otitis externa and bronchiolitis.", "ORPHA ID": 294023, "Summary": ""}
{"Disease Name": "Neonatal intrahepatic cholestasis due to citrin deficiency", "Disease Definition": "A mild subtype of citrin deficiency characterized clinically by low birth weight, failure to thrive, transient intrahepatic cholestasis, multiple aminoacidemia, galactosemia, hypoproteinemia, hepatomegaly, decreased coagulation factors, hemolytic anemia, variable but mostly mild liver dysfunction, and hypoglycemia.", "ORPHA ID": 247598, "Summary": ""}
{"Disease Name": "Neonatal iodine exposure", "Disease Definition": "Neonatal iodine exposure is a rare endocrine disease characterized by the appearance of transient hypothyroidism, usually in preterm newborns, following long or short-term topical iodine exposure. Parenteral exposure from iodinated contrast agents may similarly alter thyroid function in term neonates.", "ORPHA ID": 238688, "Summary": ""}
{"Disease Name": "Neonatal lupus erythematosus", "Disease Definition": "A rare systemic autoimmune disease characterized by cutaneous lesions, hepatic dysfunction, hematological abnormalities, and/or cardiac arrhythmia, and caused by transplacental passage of maternal SS-A and SS-B autoantibodies. The most typical cutaneous manifestation is a macular annular erythema affecting the head, but also trunk and extremities. Other reversible features include anemia, neutropenia, thrombocytopenia, and elevation of liver parameters with hepatomegaly. The most severe presentation of the disease is irreversible congenital total atrioventricular block.", "ORPHA ID": 398124, "Summary": ""}
{"Disease Name": "Neonatal Marfan syndrome", "Disease Definition": "Neonatal Marfan syndrome is a rare, severe and life-threatening genetic disease, occuring during the neonatal period, characterized by classical Marfan syndrome manifestations in addition to facial dysmorphism (megalocornea, iridodonesis, ectopia lentis, crumpled ears, loose redundant skin giving a 'senile' facial appearance), flexion joint contractures, pulmonary emphysema, and a severe, rapidly progressive cardiovascular disease (including ascending aortic dilatation and severe mitral and/or tricuspid valve insufficiency). Additionally, skeletal manifestations (arachnodactyly, dolichostenomelia, pectus deformities) are also associated.", "ORPHA ID": 284979, "Summary": ""}
{"Disease Name": "Neonatal scleroderma", "Disease Definition": "A rare secondary neonatal autoimmune disease characterized by neonatal-onset of erythematous skin lesions with a linear appearance that gradually become indurated and hyperpigmented and progressively present skin atrophy. Positive serum antibodies (in particular antinuclear antibodies and/or rheumatoid factor) may be associated.", "ORPHA ID": 398127, "Summary": ""}
{"Disease Name": "Neonatal severe cardiopulmonary failure due to mitochondrial methylation defect", "Disease Definition": "A rare mitochondrial disease characterized by a variable clinical phenotype ranging from fetal hydrops and postnatal hypotonia, bradycardia, and respiratory failure, resulting in death in the neonatal period, to infantile onset of episodes of acute cardiopulmonary failure associated with severe lactic acidosis, and slowly progressive muscle weakness. Muscle biopsy shows reduced activity of mitochondrial complexes I, III, and IV.", "ORPHA ID": 466784, "Summary": ""}
{"Disease Name": "Neonatal severe primary hyperparathyroidism", "Disease Definition": "Neonatal severe primary hyperparathyroidism (NSHPT) is characterized by severe hypercalcemia (> 3.5 mM) from birth and associated with major hyperparathyroidism.", "ORPHA ID": 417, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nThe clinical manifestations are early (with onset occurring during the first days of life) and severe, including respiratory distress due to hypotonia and rib cage deformities, bone under mineralization, and multiple fractures, all of which influence the immediate vital prognosis.\nEtiology\nNSHPT is associated in most cases with homozygous inactivating mutations in the CASR gene, localized to 3q21.1. This gene encodes the calcium-sensing receptor (CaSR), a member of the subfamily of G protein-coupled transmembrane receptors. CaSR plays a key role in the regulation of phosphocalcic metabolism by controlling parathyroid hormone (PTH) secretion and calcium urinary excretion in response to variations in serum calcium levels.\nDiagnostic methods\nBiologically, children present with extremely high serum calcium and serum PTH levels and a relative hypocalciuria, but in some cases they present with a markedly elevated calciuria.\nDifferential diagnosis\n'Familial hypocalciuric hypercalcemia (FHH; see this term) is a differential diagnosis. Hypercalcemia is usually milder and PTH levels are lower in FHH than in NSHPT and FHH is asymptomatic in most cases.'\nAntenatal diagnosis\nPrenatal diagnosis might be proposed to parents if they are both suffering from FHH.\nGenetic counseling\nNSHPT represents the homozygous form of FHH and is transmitted as an autosomal recessive trait. However, sporadic forms of NSHPT occur and are associated with a heterozygous de novo mutation in the CASR gene. To date, there have been no reports of severe neonatal hyperparathyroidism with homozygous mutations in those with FHH type 2 or 3 (see these terms) but their molecular identification is still too recent to make any definite conclusions.\nManagement and treatment\nThe control of hypercalcemia is often obtained through progressive therapeutic intervention involving the use of bisphosphonates, dialysis or even calcimimetics. If this is unsuccessful, a total parathyroidectomy is required. After parathyroidectomy, life-long treatment with 1-alpha hydoxylated vitamin D is required.\nPrognosis\nPatients can die from complications of hypercalcemia during the neonatal period from respiratory distress and dramatic hypercalcemia.\n\n                            Last update: \n                            May 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Anne LIENHARDT-ROUSSIE"}
{"Disease Name": "Neovascular glaucoma", "Disease Definition": "Neovascular glaucoma is the most common type of secondary glaucoma, usually caused by diabetic retinopathy, central retinal vein occlusion and carotid artery obstruction but sometimes by trauma, uvietis or ocular tumors, and characterized by severe eye pain, synechial angle glaucoma, high intraocular pressure and leading to loss of vision.", "ORPHA ID": 94058, "Summary": ""}
{"Disease Name": "Nephroblastoma", "Disease Definition": "A rare malignant renal tumor, typically affecting the pediatric population, characterized by an abnormal proliferation of cells that resemble the kidney cells of an embryo (metanephroma), leading to the term embryonal tumor.", "ORPHA ID": 654, "Summary": "Epidemiology\nThe annual incidence is estimated at about 1/10,000 births and it affects boys as well as girls.\nClinical description\nNephroblastoma mainly affects young children, between the ages 1 and 5 years, but 15% of nephroblastomas occur before the age of 1 year and 2% after the age of 8 years. Adult forms are very rare. An abdominal mass (unilateral in most cases) is frequently present. Patients sometimes experience abdominal pain (around 10% of cases), hypertension, fever (20% of cases), hematuria and anemia. The evolution of the disease is very rapid, with regional dissemination in the retroperitoneal space, lymph nodes, vessels (renal vein and inferior vena cava) and in the peritoneal cavity in cases of tumor effraction, and a strong likelihood of metastases in the lungs and liver.\nEtiology\nNephroblastoma is sporadic in 99% of cases and, among these cases, 10% are associated with congenital anomalies (aniridia, hemihypertrophy, genitourinary defects) or form part of specific syndromes (Beckwith-Wiedemann, Denys-Drash, WAGR or Perlman syndromes; see these terms). Genetic anomalies found in different chromosomal regions, including 11p13 (containing the WT1 gene), 11p15.5 (containing the H19 gene), 16q, 1p, 1q and 17p, have been found within the tumors. Familial forms are very rare (1% of cases) and are transmitted in an autosomal dominant fashion.\nDiagnostic methods\nDiagnosis is based on imagery, particularly CT or MRI scans. The concentration of urinary metabolites of catecholamines is normal. Analysis of the extent of the disease is also conducted using imagery (ultrasound and abdominal CT analyzing particularly the liver and contralateral kidney, and thoracic radiography and CT).\nDifferential diagnosis\nDifferential diagnoses include other renal tumors in children such as mesoblastic nephroma (especially in infants), clear cell sarcoma, neuroblastoma (extremely rare in the kidney but may invade the kidney by contiguity), rhabdoid tumors (see these terms) and metanephric stromal tumors.\nManagement and treatment\nDisease management is multidisciplinary and may involve chemotherapy and surgery with or without radiotherapy. Chemotherapy enables preoperative reduction in tumor size and eradicates metastases. Surgery should be accomplished without tumor effraction, which usually means that total nephrectomy is required. Nephroblastoma can be confirmed on microscopic examination, which also allows the stage of the tumor in the kidney to be evaluated. This in turn determines the choice of post-operative chemotherapy. Radiotherapy is reserved for the most extensive cases or cases with the least favorable histology.\nPrognosis\nIn the majority of cases, the prognosis is favorable with a survival rate of over 90%. Adult forms have the same prognosis and should be treated following the same methods, even when adult patients tolerate chemotherapy less well than children (which may lead to a reduction in treatment and as a result a worse prognosis).\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Catherine PATTE"}
{"Disease Name": "Nephrogenic syndrome of inappropriate antidiuresis", "Disease Definition": "Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare genetic disorder of water balance, closely resembling the far more frequent syndrome of inappropriate antidiuretic secretion (SIAD), and characterized by euvolemic hypotonic hyponatremia due to impaired free water excretion and undetectable or low plasma arginine vasopressin (AVP) levels.", "ORPHA ID": 93606, "Summary": "Epidemiology\nNSIAD is a very rare disease with 21 cases of hyponatremia due to NSIAD having been reported to date, the majority of them coming from 5 families. NSIAD affects mainly males.\nClinical description\nAge at diagnosis can range from the first day of life to more than 70 years. When disease onset occurs in childhood, it generally presents with hyponatremic seizures. Asymptomatic female carriers have also been described. Symptoms of NSIAD are the classical symptoms of hyponatremic encephalopathy (cerebral edema) such as nausea, vomiting, dizziness and gait disturbances. The life-threatening symptoms of acute and severe hyponatremia (altered consciousness, respiratory arrest and death) have never been reported in NSIAD but can theoretically occur.\nEtiology\nNSIAD is due to a gain of function mutation in the type 2 AVP receptor (AVPR2) gene (location Xq28), thus representing the mirror image of nephrogenic diabetes insipidus (see this term). This mutation leads to constant activation of the AVPR2 receptor on renal collecting duct cells, which causes an increase in free water reabsorption and an increase in urine concentration. Three mutations in this gene have been identified, 2 of them have been described in only one patient.\nDiagnostic methods\nThe first step in diagnosing NSIAD is to diagnose SIAD. The diagnostic criteria are as follows: euvolemic hypotonic hyponatremia, increased urinary osmolality (> 100 mosm/kg), increased urinary sodium (> 30 mmol/l), normal thyroid, adrenal, cardiac and renal function and no use of diuretics. The circumstances in which the AVPR2 mutation should be screened are 'idiopathic' SIAD with low or undetectable plasma AVP levels, familial history of NSIAD or unexplained SIAD in childhood. A mutation in the AVPR2 gene confirms diagnosis.\nDifferential diagnosis\nThe main differential diagnosis is idiopathic SIAD.\nGenetic counseling\nNSIAD is an X-linked disorder, affecting mainly males, with females often being asymptomatic carriers (only 3 cases of symptomatic hyponatremic females have been reported). Genetic counseling is possible.\nManagement and treatment\nTreatment of NSIAD is lifelong. Fluid restriction is the cornerstone of treatment. It is generally sufficient to avoid episodes of hyponatremia and is well tolerated (good compliance). There is a concern of restricting fluids in young infants due to the risk of malnutrition. Oral urea is the second step of treatment and acts by increasing free water clearance (osmotic diuresis). It is safe and well tolerated in children and adults, even over long-term use. Intermittent urea intake (non-daily) can be an option in some patients. Urea can also be used to correct an acute episode of hyponatremia. Non-peptide vasopressin receptor antagonists (vaptans), which have received market authorization for the management of SIAD, have shown inefficacy in a patient with mutant R137C - V2R but could be of interest in patients with the recently described mutant F229V-V2R on the basis of in vitro data. Patients must be monitored when increased water intake is anticipated (sports, heat wave) or in case of postoperative perfusion.\nPrognosis\nThe prognosis of NSAID is good, if episodes of severe hyponatremia are avoided.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Frederic VANDERGHEYNST"}
{"Disease Name": "Nephrogenic systemic fibrosis", "Disease Definition": "Nephrogenic systemic fibrosis (NSF) is a rare systemic fibrosing condition observed in renally impaired patients and characterized by a hardening and thickening of the skin with fibrotic plaques or papules, pruritus, joint pain and stiffness, muscle weakness, limitation of range of motion, and yellowed eyes. It is generally associated with administration of gadolinium-based magnetic resonance imaging contrast agents (GBCA) in patients with kidney disease.", "ORPHA ID": 137617, "Summary": ""}
{"Disease Name": "Nephronophthisis", "Disease Definition": "A rare, genetic, renal ciliopathy characterized by reduced ability of the kidneys to concentrate solutes, chronic tubulointerstitial nephritis, occasional presence of cysts, and progression to end stage renal disease (ESRD). The three clinical subtypes are characterized by the age of onset of ESRD which includes infantile, juvenile and late onset.", "ORPHA ID": 655, "Summary": "Epidemiology\nThe prevalence is unknown; however, at birth it is estimated at 1: 80,000 in Finland. Nephronophthisis (NPHP) is responsible for 2.4 to 15% of ESRD in children.\nClinical description\nThree main forms have been described. Juvenile NPHP, the most frequent form, progresses to end-stage renal failure at median age of 13 and is responsible for 15% of cases of childhood ESRD. Infantile NPHP can present in utero with oligohydramnios sequence or postnatally with reduced kidney function and progresses to ESRD before age 3. Late-onset NPHP is a rare form of the disease and presents clinical and histological signs similar to the juvenile form but with ESRD occurring later (median age of 19 years). The typical clinical symptoms include polyuria, polydipsia with regular fluid intake, impaired sodium reabsorption that cause hypovolemia and hyponatremia, anemia and growth delay. Renal ultrasonography in early stages is normal or shows unspecific changes with increased renal echogenicity, with advancing kidney disease poor cortico-medullary differentiation is described; corticomedullary cysts are present in the 70% of patients. Renal histopathology in NPHP is characterized by the triad of tubular cysts, tubular basement membrane disruption, and interstitial fibrosis with interstitial cell infiltration. Retinal degeneration is the most frequent extrarenal findings (10%), cerebellar vermis aplasia, liver fibrosis and skeletal defects could be also present. Extrarenal phenotypes are distinct but they overlap in some syndromic forms of NPHP (such as Joubert syndrome, Senior-Loken syndrome, Meckel-Gruber syndrome).\nEtiology\nTo date, mutations in 14 genes have been identified in affected individuals. The majority of these genes encode for ciliary proteins that cluster to distinct subcellular localizations. The NPHP1 gene, that encodes for nephrocystin-1, is deleted or mutated in 25% of juvenile NPHP. Mutations in the gene INVS  (9q31.1), coding for inversin, is frequently responsible for infantile NPHP. Mutations in NPHP3 (3q22.1), NPHP4 (1p36.31), NEK8 (17q11.2) genes give rise to late-onset nephronophthisis, however these genes are associated also with the Senior-Loken syndrome and Meckel-Gruber syndrome and predispose to multiorgan polycystic disease.\nDiagnostic methods\nThe diagnosis is suggested by clinical features and confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes early onset autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease and congenital anomalies of kidney and urinary tract (CAKUT). Furthermore, juvenile NPHP forms part of a spectrum of NPHP-related ciliopathies which includes Joubert syndrome, Senior-Loken syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome and Skeletal Ciliopathies (Oral-facial-digital syndrome, Cranioectodermal dysplasia, Short-rib thoracic dysplasia). The infantile form should also be distinguished from renal hypodysplasia.\nAntenatal diagnosis\nOnce the pathogenic variants have been identified in an affected family member, prenatal testing or preimplantation genetic diagnosis can be considered.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive, with homozygous or compound heterozygous mutations possible. The parents are obligate heterozygotes (carriers) and are asymptomatic with no risk of developing the disorder. Each sib of an affected individual has a 50% risk of being an asymptomatic carrier, 25% to be affected, and 25% to be unaffected and not a carrier. Offspring of an affected individual will be obligate carriers.\nManagement and treatment\nThe management is supportive to maintain fluid and metabolic balance including: correction of water and electrolyte imbalances; anemia treatment, and proteinuria treatment if necessary. For the ESRD management, dialysis or renal transplantation are necessary.\nPrognosis\nThe prognosis is dependent on the age of ESRD onset. Despite the risk of complications, transplant outcomes are excellent with no recurrence of the disease.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Luisa MURER | ERKNet* - Dr Susanna NEGRISOLO | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Nephropathy-deafness-hyperparathyroidism syndrome", "Disease Definition": "A rare syndromic deafness characterized by renal failure without hematuria, parathyroid hyperplasia and sensorineural deafness. There have been no further reports since 1989.", "ORPHA ID": 2668, "Summary": ""}
{"Disease Name": "Nephrosis-deafness-urinary tract-digital malformations syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies syndrome characterized by urinary tract anomalies, nephrosis, conductive deafness, and digital malformations, including short and bifid distal phalanges of thumbs and big toes. There have been no further descriptions in the literature since 1962.", "ORPHA ID": 2669, "Summary": ""}
{"Disease Name": "Nephrotic syndrome-epidermolysis bullosa-sensorineural deafness syndrome", "Disease Definition": "A rare, genetic, renal disease characterized by hereditary nephritis leading to nephrotic syndrome and end-stage renal failure associated with sensorineural hearing loss and pretibial skin blistering followed by atrophy. Other reported manifestations include bilateral lacrimal duct stenosis, dystrophic teeth and nails, bilateral cervical ribs, unilateral kidney, distal vaginal agenesis and anemia due to beta-thalassemia minor.", "ORPHA ID": 300333, "Summary": ""}
{"Disease Name": "Nestor-Guillermo progeria syndrome", "Disease Definition": "Nestor-Guillermo progeria syndrome is a rare, genetic, progeroid syndrome characterized by a prematurely aged appearance associated with severe osteolysis (notably on mandible, clavicles, ribs, distal phalanges, and long bones), osteoporosis, generalized lipoatrophy and absence of cardiovascular, atherosclerotic and metabolic complications, presenting a relatively long survival. Additional characteristics include growth retardation, joint stiffness (mainly of fingers, hands, knees, and elbows), wide cranial sutures, dysmorphic facial features (prominent eyes, convex nasal ridge, malocclusion, dental crowding, thin lip vermillion, microretrognathia) and persistent eyebrows, eyelashes and scalp hair.", "ORPHA ID": 280576, "Summary": ""}
{"Disease Name": "Netherton syndrome", "Disease Definition": "Netherton syndrome (NS) is a skin disorder characterized by congenital ichthyosiform erythroderma (CIE), a distinctive hair shaft defect (trichorrhexis invaginata; TI) and atopic manifestations.", "ORPHA ID": 634, "Summary": "Epidemiology\nIncidence is estimated at 1/200,000 births.\nClinical description\nPatients generally present at birth with generalized erythroderma and scaling, and failure to thrive. Frequent complications include hypernatremic dehydration, recurrent infections, and diarrhea and intestinal malabsorption. The disease course is heterogeneous: the generalized erythroderma may persist in some patients, but more frequently it evolves during childhood into ichthyosis linearis circumflexa (ILC). ILC is a milder and highly characteristic skin disorder marked by migratory erythematous plaques with a double-edged scale. Hair anomalies usually become apparent after infancy, with sparse and brittle hair caused by TI (bamboo hair viewed by light microscopy) and other hair shaft anomalies (pili torti and/or trichorrhexis nodosa). Eyebrows and eyelashes are also affected. The large majority of NS patients develop atopic manifestations including asthma, atopic dermatitis, food allergies, urticaria, angioedema, and elevated IgE levels. Other clinical findings are delayed growth and development, short stature, and, rarely, intermittent aminoaciduria. Intellectual deficit has been associated in some cases.\nEtiology\nNS is caused by mutations in the SPINK5 gene (5q31-q32) encoding the serine protease inhibitor LEKTI. LEKTI deficiency results in an increase in trypsin-like hydrolytic activity in the stratum corneum (SC) leading to SC premature desquamation and a severe skin barrier defect.\nDiagnostic methods\nEarly diagnosis may be problematic as the most distinctive findings (TI and ILC) do not generally become apparent until childhood. Immunohistochemistry of skin biopsies revealing LEKTI deficiency has been proposed as a useful diagnostic test for NS, but identification of the disease-causing mutation allows molecular confirmation of the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other infantile erythrodermas, particularly nonbullous congenital ichthyosiform erythroderma (see this term) and erythrodermic psoriasis. Atopic dermatitis, lamellar ichthyosis (see this term), primary immunodeficiency syndromes, seborrheic dermatitis, and acrodermatitis enteropathica (see this term) should also be excluded.\nAntenatal diagnosis\nMolecular prenatal diagnosis is feasible.\nGenetic counseling\nNS is an autosomal recessive disorder and genetic counseling should be proposed for affected families.\nManagement and treatment\nTreatment is symptomatic and requires prompt management of the neonatal complications and long-term use of emollients for treatment of the skin disorder. Use of topical steroids and topical immunomodulators (tacrolimus and pimecrolimus) has been described as beneficial in some cases, but these agents are not indicated for long-term use or treatment of large surface areas as the skin barrier defect allows increased systemic drug absorption.\nPrognosis\nThe prognosis may be severe in neonates with life-threatening complications and postnatal lethality is high. The skin manifestations and hair anomalies persist throughout life, but the disease usually improves with age and most patients begin to thrive during the second year of life.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "Neu-Laxova syndrome", "Disease Definition": "Neu-Laxova syndrome (NLS) is a rare, multiple malformation syndrome characterised by severe intrauterine growth retardation (IUGR), severe microcephaly with a sloping forehead, severe ichthyosis (collodion baby type), and facial dysmorphism.", "ORPHA ID": 2671, "Summary": "Epidemiology\nAbout 60 cases of this syndrome have been reported from diverse ethnic backgrounds.\nClinical description\nSevere central nervous system (CNS) defects are present: lissencephaly type III, hypoplastic cerebellum and brainstem, enlarged ventricles, and sometimes intracerebral calcifications, Dandy-Walker anomaly or agenesis of the corpus callosum. Facial features include severe proptosis with ectropion (giving the impression of missing eyelids), hypertelorism, micrognathia, flattened nose, and malformed ears. The lips are thick with a round, gaping mouth. Other inconstant malformations include abnormal limbs (contractures and, sometimes, radial ray defects), abnormal external genitalia, and arthrogryposis multiplex. Clinical features show significant intra and interfamilial variation.\nDiagnostic methods\nThe diagnosis is easily made at birth on the basis of the clinical malformations. The histopathological findings include a triad of dermatological features (ichthyosis, massive fat with hypertrophy of fat cells, oedema), poor formation of the cortical bone, and central nervous system (CNS) anomalies.\nAntenatal diagnosis\nRoutine ultrasonography (at 19 to 20 weeks of gestation) may show polyhydramnios, IUGR, hypoechogenic skeletal structures, microcephaly, prominent eyes, retrognathism, hypomobility with flexion deformities. It also shows massive swelling of the scalp, knee, elbow joints, hands and feet, giving the impression of absent digits. At risk pregnancies should be carefully monitored by ultrasonography: at 6-8 weeks for accurate dating, at 12-16 weeks for analysis of activefoetal limb movements, and at 16-24 weeks for the detection of facial and skeletal anomalies, IUGR and polyhydramnios.\nGenetic counseling\nThe syndrome is transmitted in an autosomal recessive manner. Parents should be informed of a 25% recurrence rate in future offspring.\nPrognosis\nThe prognosis is poor: affected newborns either are stillborn or die immediately after birth.\n\n                            Last update: \n                            October 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES"}
{"Disease Name": "Neuhauser anomaly", "Disease Definition": "Neuhauser anomaly is a rare cardiovascular morphological anomaly due to maldevelopment of embryonal aorta resulting in right aortic arch and left ligamentum arteriosum characterized by tracheoesophageal compression symptoms (stridor, dyspnea, dysphagia, apnoeic episodes, recurrent respiratory infections).", "ORPHA ID": 99078, "Summary": ""}
{"Disease Name": "Neuhauser-Eichner-Opitz syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by infantile or childhood onset of recurrent acute encephalopathic episodes with cerebellar and extrapyramidal involvement following febrile illnesses. During the episodes, patients typically show sudden onset of truncal ataxia, occasionally accompanied by lethargy and impairment of speech, as well as choreic and athetoid movements, seizures, loss of deep tendon reflexes, and presence of pathological reflexes. Episodes last from day to weeks and may leave residual symptoms such as speech impairment and poor coordination. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 2672, "Summary": ""}
{"Disease Name": "Neuralgic amyotrophy", "Disease Definition": "A rare disorder of the peripheral nervous system characterized by the sudden onset of extreme pain in the upper extremity followed by rapid multifocal motor weakness and atrophy and a slow recovery in months to years. NA includes both an idiopathic (INA, also known as Parsonage-Turner syndrome) and hereditary (HNA) form.", "ORPHA ID": 2901, "Summary": "Epidemiology\nThe minimum incidence of NA is estimated at 1/50,000-1/30,000 but under recognition and initial misdiagnosis is common. HNA is thought to be 10 times less common than INA.\nClinical description\nNA can occur at any age but is most frequently seen in those between the 3rd-7th decades of life and is more frequent in men. Those with HNA usually present earlier than those with INA but clinically they are virtually indistinguishable. The classic presentation (71% of cases) manifests with sudden onset of aching, burning, or stabbing pains, most often in the shoulders, neck, and/or arm region, showing an upper brachial plexus distribution. Weakness in the periscapular and periglenohumeral muscles follows hours to weeks after the initial onset of pain. These pains are usually relentless, worse at night and last for about 3 weeks. Other manifestations may occur due to the involvement of nerves outside the brachial plexus such as the lumbosacral plexus or phrenic nerves. Certain patients with HNA (with a R88W point mutation) display characteristic physical features (ex. hypotelorism, slanted eyes, epicanthal folds, oval face, cleft palate). Some patients experience a relapsing/remitting course with symptom-free intervals while others have an incomplete recovery with persisting neurologic deficit. Recurrences can occur (75% in HNA and 25% in INA) and persistent musculoskeletal pain develops in 2/3 of patients.\nEtiology\nThe exact etiology is unknown but genetic, autoimmune and external factors are thought to play a role. The brachial plexus has an underlying predisposition to mechanical injury and attacks caused by an immune-mediated response in this nerve. A viral infection or immunization can precede NA. Bacterial and parasitic infections, surgery, anesthesia, rheumatic disease, trauma, pregnancy and childbirth have all been implicated as possible contributing factors of NA attacks. HNA is associated with a point mutation or duplication of the susceptibility gene SEPT9 on chromosome 17q25.3 in 50% of cases.\nDiagnostic methods\nDiagnosis is based on the typical clinical features and the exclusion of other disorders (ex. neuroborreliosis, cervical radiculopathy or Pancoast syndrome) using laboratory tests, electromyography and imaging of the cervical spine and brachial plexus. In those where HNA is suspected, a molecular genetic test can be used to identify a SEPT9 mutation, but since HNA is genetically heterogeneous, a negative test does not exclude the diagnosis.\nAntenatal diagnosis\nAntenatal diagnosis is not routinely offered.\nGenetic counseling\nGenetic counseling is possible in families with the HNA susceptibility gene.\nManagement and treatment\nTreatment in the acute stage involves pain management, relying mostly on a combination of long-acting opioids and nonsteroidal anti-inflammatory drugs. Those with chronic pain can be given co-analgesics. Oral prednisone decreases the duration of pain and accelerates recovery in some patients if given in the first weeks of an attack. A daily dose of 1mg/kg for 1 week which is tapered during the 2nd week is recommended. Follow-up is recommended every 6 months. Rehabilitation therapy is now considered important and excessive strain to the affected area should be avoided.\nPrognosis\nThe prognosis is variable but thought to be good with patients recovering 70-90% of their previous health after 1-2 years. However, many are left with exercise intolerance and poor muscular coordination in the affected and compensating muscles. Quality of life can be affected in those with an incomplete recovery but early diagnosis and proper treatment increase the chances of a full functional recovery.\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                            Dr N. [Nens] VAN ALFEN"}
{"Disease Name": "Neurenteric cyst", "Disease Definition": "A rare, congenital, non-syndromic malformation of neurenteric canal, spinal cord and column, characterized by intraspinal, predominantly intradural-extramedullary cystic mass located typically ventral to the spinal cord. Histopathology reveals columnar or cuboidal epithelium with or without cilia and mucus globules. Patients may be asymptomatic or present with signs and symptoms of compression of the spinal cord and associated nerve roots, such as focal weakness, progressive paresis, paresthesias, gait disturbance, or radicular pain. Concomitant congenital vertebral anomalies are frequently observed.", "ORPHA ID": 268865, "Summary": ""}
{"Disease Name": "Neuroacanthocytosis", "Disease Definition": "Neuroacanthocytosis (NA) syndromes are a group of genetic diseases characterized by the association of red blood cell acanthocytosis (deformed erythrocytes with spike-like protrusions) and progressive degeneration of the basal ganglia.", "ORPHA ID": 263440, "Summary": "Epidemiology\nNA syndromes are exceptionally rare with an estimated prevalence of less than 1 to 5/1,000,000 for each disorder.\nClinical description\nNA syndromes include choreacanthocytosis, McLeod neuroacanthocytosis syndrome, pantothenate-kinase-associated neurodegeneration, and Huntington disease-like 2 (see these terms) which have a Huntington disease-like phenotype consisting of a choreatic movement disorder, psychiatric manifestations and cognitive decline, and additional multi-system features including myopathy and axonal neuropathy. Cardiomyopathy including arrhythmias may occur in McLeod syndrome.\nEtiology\nNA syndromes are caused by disease-specific genetic mutations. The mechanisms by which these mutations cause neurodegeneration are not known. The association of the acanthocytic membrane abnormality with selective degeneration of the basal ganglia, however, suggests a common pathogenetic pathway.\nGenetic counseling\nChoreacanthocytosis follows an autosomal recessive pattern of inheritance, McLeod neuroacanthocytosis syndrome an X-linked pattern, and Huntington disease-like 2 an autosomal dominant pattern.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Hans JUNG"}
{"Disease Name": "Neuroblastoma", "Disease Definition": "Neuroblastoma is a malignant tumor of neural crest cells, the cells that give rise to the sympathetic nervous system, which is observed in children.", "ORPHA ID": 635, "Summary": "Epidemiology\nIt represents about 10% of solid tumors in infants and children under the age of 15, with an annual incidence of about 1/70,000 in children in this class of age.\nClinical description\nIn 90% of cases the neuroblastoma is diagnosed before the age of five. The clinical presentation of neuroblastoma is very variable and depends on the stage and location of the tumor, which can develop at any site in the sympathetic nervous system (around 80% of cases develop in the abdomen). Localized forms are discovered fortuitously or are revealed by the presence of an abdominal or thoracic mass that can be associated with pain. At the time of diagnosis, metastatic forms represent about 50% of cases. The most frequent metastatic sites are bone marrow, bone, liver and skin. Symptoms of metastasis including bone pain, limp, paralysis, hepatomegaly (Pepper's syndrome), and exophthalmia (Hutchinson's syndrome), indicate metastatic neuroblastoma. The disease can also be associated with arterial hypertension, fever, and an altered general state (weight loss, pain, irritability, and anemia).\nEtiology\nNeuroblastoma has been linked to numerous genetic anomalies which affect prognosis: amplification of the oncogene MYCN (2p24.3) is a factor for poor prognosis; triploidy, numerical anomalies of chromosomes are associated with a good prognosis, while di- or tetraploidy and segmental chromosomal anomalies (including loss from 1p, from 11q, or gains of 17q) are associated with poor prognosis. Recently, a mutation of the ALK gene has been described in about 12% of cases.\nDiagnostic methods\nDiagnosis is based on evidence of an elevated level of metabolites of urinary catecholamines (VMA, HVA, and dopamine) and on an image of the initial tumor by ultrasound and brain scan or by MRI. MIBG (iodine-131-meta-iodobenzylguanidine) scintigraphy and medullary analysis are useful for finding metastases. Tumor biopsy confirms the diagnosis, allows histological classification and helps find amplification of MYCN.\nDifferential diagnosis\nDifferential diagnoses include nephroblastoma, which makes it necessary to systematically check urinary catecholamines in case of an abdominal tumor. Bone pain and limp can be interpreted as synovitis of the hip. Possible bilateral peri-orbital hematomas, caused by orbital metastases, should not lead to a diagnosis of maltreatment.\nAntenatal diagnosis\nNeuroblastoma can be identified using antenatal ultrasound and therefore adequate management after the birth can be provided.\nManagement and treatment\nLocalized forms of neuroblastoma are treated by surgical resection, sometimes preceded by chemotherapy. Treatment of metastatic forms in children of more than one year and forms with amplification of MYCN is by: conventional chemotherapy, surgery of the initial tumor, high dose chemotherapy with hematopoietic stem cell transplantation, local radiotherapy and maintenance therapy with retinoic acid.\nPrognosis\nThe majority of localized tumors have an excellent prognosis after surgery. Children under one year have a better prognosis than older children. Some tumors may even show spontaneous regression. In contrast, approximately 60% of children older than one year with neuroblastoma present metastatic disease at diagnosis with poor outcome, even with intensive treatment. In children older than one year, the five-year survival rate varies between 95% for some localized tumors to 30% in cases of metastatic neuroblastoma.\n\n                            Last update: \n                            March 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Dominique VALTEAU-COUANET"}
{"Disease Name": "Neurocutaneous melanocytosis", "Disease Definition": "Neurocutaneous melanocytosis (NCM) is a rare congenital neurological disorder characterized by abnormal aggregations of nevomelanocytes within the central nervous system (leptomeningeal melanocytosis) associated with large or giant congenital melanocytic nevi (CMN; see this term). NCM can be asymptomatic or present as variably severe and progressive neurological impairment, sometimes resulting in death.", "ORPHA ID": 2481, "Summary": "Epidemiology\nPrevalence is estimated at 1/50,000-1/200,000. The incidence of symptomatic NCM appears to be approximately a third to a half of these.\nClinical description\nA large, or giant, CMN is a pigmented skin lesion of more than 20 cm projected adult diameter (40 for \"giant\"), composed of aggregated melanocytes in a delimited area of the body, and presenting with an elevated risk of malignant transformation. Leptomeningeal melanocytosis nearly always presents with CMN, though not conversely; a case with no pigmented lesions and another with only café-au-lait spots have been reported. Symptoms of NCM, when they do occur, generally appear before the age of five and can include headaches, seizures, vomiting, visual disorders, movement and learning disorders, paralysis, intellectual deficit, papilledema, and/or hydrocephalus associated with other brain malformations, such as Dandy-Walker complex. NCM has also been reported with Chiari malformation of the brainstem, congenital heart anomalies (transposition of the great arteries, ventricular septal defect), renal agenesis, skeletal malformations, lipomatosis, or hemihypertrophy.\nEtiology\nNCM is believed to result from the prenatal, abnormal proliferation of neural crest-derived melanocytes in the central nervous system, but the pathogenic mechanism is still unclear. Their common origin with forebrain-specific pericytes may favor the differentiation and dissemination of nevomelanocytes in situ during meningeal development.\nDiagnostic methods\nDiagnosis is based on physical examination and neuroimaging. CMN patients with more than twenty CMN or with a large/giant CMN covering the posterior midline axis are more likely to have NCM, though these signs are not in themselves pathognomic. Neuroimaging is based on MRI examination of either symptomatic or asymptomatic NCM, that may reveal areas of increased signal on T1 corresponding to melanocyte aggregation, generally involving the anterior temporal lobes, amygdala, or cerebellum. Biopsy shows variable degrees of differentiation of proliferating nevomelanocytes, ranging from benign-looking cells to atypical melanoma-like cells within the leptomeninges and focally invading the brain.\nDifferential diagnosis\nDifferential diagnosis includes primary central nervous system melanoma, meningeal melanocytoma (see these terms), idiopathic hydrocephalus, idiopathic epilepsy, and meningeal melanoma.\nGenetic counseling\nOnly sporadic cases of NCM have been reported to date.\nManagement and treatment\nClose dermatologic and neurologic follow-up for asymptomatic patients is recommended at least annually. In cases with hydrocephalus, ventriculo-peritoneal shunt is generally performed to reduce intracranial pressure with a reported risk of clogging the shunting catheter with the proliferating nevomelanocytes. Seizures have been successfully treated with standard temporal lobotomy.\nPrognosis\nAsymptomatic NCM shows a normal life expectancy. Symptomatic NCM has a poor prognosis in retrospective studies, though this can be extremely variable (from weeks to months). Death can result from complications of hydrocephalus or from the development of melanocytoma or CNS melanoma.\n\n                            Last update: \n                            February 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Heather ETCHEVERS"}
{"Disease Name": "Neurodegeneration due to 3-hydroxyisobutyryl-CoA hydrolase deficiency", "Disease Definition": "Neurodegeneration due to 3-hydroxyisobutyryl-CoA hydrolase deficiency is characterised by delayed motor development, hypotonia and progressive neurodegeneration. To date, it has been described in four boys. The syndrome is caused by mutations affecting the two alleles of the  HIBCH gene, encoding 3-hydroxyisobutyryl-CoA hydrolase. The mode of transmission has not yet been established.", "ORPHA ID": 88639, "Summary": ""}
{"Disease Name": "Neurodegeneration with brain iron accumulation", "Disease Definition": "Neurodegeneration with brain iron accumulation (NBIA, formerly Hallervorden-Spatz syndrome) encompasses a group of rare neurodegenerative disorders characterized by progressive extrapyramidal dysfunction (dystonia, rigidity, choreoathetosis), iron accumulation in the brain and the presence of axonal spheroids, usually limited to the central nervous system.", "ORPHA ID": 385, "Summary": "Epidemiology\nAn estimated prevalence of 1-3/1,000,000 has been suggested based on observed cases in a population. The most common form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN; see this term), which accounts for approximately 50% of cases.\nClinical description\nNBIA can present as early onset with rapid progression: classic pantothenate kinase-associated neurodegeneration (PKAN), infantile neuroaxonal dystrophy (INAD) and atypical neuroaxonal dystrophy (atypical NAD) (see these terms); or later onset with slower progression: atypical PKAN, neuroferritinopathy and aceruloplasminemia (see these terms). Idiopathic NBIA can have either type of onset and progression.\nEtiology\nClassic and atypical PKAN are caused by mutations in the PANK2 gene (20p13-p12.3), infantile and atypical neuroaxonal dystrophy are caused by mutation in the PLA2G6 gene (22q13.1), aceruloplasminemia is caused by mutation of the ceruloplasmin (CP) gene (3q23-q24) and neuroferritinopathy is caused by mutations in the ferritin light chain (FTL1) gene (19q13.3-q13.4). Idiopathic NBIA is likely caused by several additional, as yet undiscovered genes.\nDiagnostic methods\nThis heterogeneous group of disorders can be differentiated by clinical, radiographic, and molecular features. Brain MRI is standard in the diagnostic evaluation of all forms of NBIA. Individuals with PKAN and HARP syndrome, which is considered part of the PKAN disease spectrum, show a characteristic \"eye of the tiger''sign on MRI, a central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus. Infantile and atypical NAD have characteristic axonal swellings throughout the central and peripheral nervous system. Diagnosis of aceruloplasminemia is based on the absence of serum ceruloplasmin in combination with MRI findings of iron accumulation.\nGenetic counseling\nThe majority of NBIA types are transmitted in an autosomal recessive manner, except neuroferritinopathy which is transmitted in an autosomal dominant manner with high penetrance.\nManagement and treatment\nAt this time most treatments for NBIA are palliative. Research is currently underway to identify additional NBIA genes and improve treatment possibilities by characterizing the underlying causes of these disorders.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Allison GREGORY  - Pr Susan HAYFLICK"}
{"Disease Name": "Neurodevelopmental delay-seizures-ophthalmic anomalies-osteopenia-cerebellar atrophy syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability characterized by global developmental delay, early-onset seizures, cerebellar atrophy, osteopenia, nystagmus and dysmorphic facial features, including bitemporal narrowing, prominent forehead, anteverted nares. Dysarthria, dysmetria, ataxic gait, spasticity and dysmorphic features have also been associated.", "ORPHA ID": 529665, "Summary": ""}
{"Disease Name": "Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, hypotonia, craniofacial dysmorphism (such as ridged metopic sutures, long palpebral fissures, broad nasal bridge, hypoplastic alae nasi, low-set, prominent ears, prominent midline tongue groove, and downturned mouth), congenital heart defects, and variable skeletal abnormalities including hip dysplasia, vertebral anomalies, and scoliosis. Additional reported manifestations include high pain tolerance and genitourinary anomalies. Brain imaging may show a thin corpus callosum or white matter abnormalities.", "ORPHA ID": 453499, "Summary": ""}
{"Disease Name": "Neuroectodermal melanolysosomal disease", "Disease Definition": "A rare genetic neurological disease characterized by silvery hair, profound dysfunction of central nervous system, abnormal melanocytes and melanosomes and abnormal inclusion bodies in fibroblast and other cells.", "ORPHA ID": 33445, "Summary": "Epidemiology\nFewer than 20 cases have been reported worldwide; the prevalence is less than 1/1 000 000 worldwide.\nClinical description\nPresentation is in neonates with silver-leaden hair of the scalp, eyebrows and eyelashes, and a silvery sheen present over the body hair. Over time, sun-exposed skin becomes hyperpigmented with a bronze color with generalized hypopigmentation of covered skin. Neurological dysfunction presents either in early infancy or in childhood, manifesting with seizures, severe hypotonia and intellectual disability, and typically progressing to either flaccid or spastic hemiplegia, quadriplegia and ataxia. Individuals with childhood onset initially have normal psychomotor development but subsequently suffer sudden severe neurological regression, including loss of speech, mobility, the ability to feed ones-self, and typically remain bed-ridden. Affected individuals have a wide spectrum of ocular abnormalities including mild vascular sheathing with features of papilledema, nystagmus, diplopia, amaurosis, and absence of pupillary reflex. Brain imaging may show abnormalities including cerebellar and cortical atrophy.\nEtiology\nThe disease is associated with MYO5A mutations. The hyperpigmentation results from defective transfer of melanin from melanocytes to keratinocytes. Neurological abnormalities are linked to impaired function of a molecule playing a common role in melanocytic and neuronal organelle function.\nDiagnostic methods\nDiagnosis requires light microscopic examination of skin and hair shafts, immunological and peripheral blood smear evaluation. Skin biopsy shows irregular distribution and size of melanin granules in the basal layer, and inclusion bodies in fibroblasts. Hair shafts demonstrate large melanin clumps irregularly distributed along the shaft. Additional laboratory analysis should exclude immunological impairment, abnormal giant intracytoplasmic granules in neutrophils and connective tissue disease.\nDifferential diagnosis\nThe disease appears to be related or allelic to Griscelli syndrome type 1. Two other silvery hair syndromes, Griscelli syndrome type 2 and Chédiak-Higashi syndrome, are excluded due to lack of accelerated phase and presence of immunological impairment.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nFamilial cases indicate that the pattern of inheritance is autosomal recessive, with a sibling recurrence risk of 25%.\nManagement and treatment\nManagement and treatment are symptomatic. Steroids, anticonvulsants and antipyretics have been used without success. Seizures have been reported to show improvement in one patient with ACTH therapy.\nPrognosis\nThe disease typically results with death in childhood due neurological complications; the oldest patient reported was 12 years old and had achieved some developmental milestones.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Lokesh LINGAPPA  - Dr Prithuja PODYAL"}
{"Disease Name": "Neuroendocrine carcinoma of pancreas", "Disease Definition": "A rare neuroendocrine neoplasm of pancreas characterized by a high-grade malignant epithelial tumor with neuroendocrine differentiation. Based on histopathologic appearance, a small cell (composed of diffuse sheets of cells) and a large cell type (showing a nesting/trabecular pattern) are distinguished. Synaptophysin and chromogranin are positive on immunohistochemistry. The Ki-67 proliferation index is typically very high (>60 - 80%). Patients present with back pain, jaundice, and/or non-specific abdominal symptoms. Serum hormone activity is unusual. The tumor is highly aggressive with poor prognosis.", "ORPHA ID": 506098, "Summary": ""}
{"Disease Name": "Neuroendocrine cell hyperplasia of infancy", "Disease Definition": "Neuroendocrine cell hyperplasia of infancy (NCHI) is a non-lethal pediatric form of interstitial lung disease (ILD, see this term) characterized by tachypnea without respiratory failure.", "ORPHA ID": 217560, "Summary": "Epidemiology\nPrevalence of this disease is not known. It appears to affect young infants (mean age 3.8 months found in a large series) but cases have been reported in older children.\nClinical description\nClinical presentation is typically persistent tachypnea.\nEtiology\nHigh-resolution computed tomography (HRCT) shows patchy central ground-glass opacifications and air trapping. Lung biopsy shows hyperplasia of neuroendocrine cells within bronchioles documented by bombesin immunohistochemistry.\nManagement and treatment\nFollow-up reveals in some cases the persistence of tachypnea and oxygen requirement for several months.\nPrognosis\nThe prognosis is usually good.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Annick CLEMENT"}
{"Disease Name": "Neuroendocrine neoplasm of appendix", "Disease Definition": "A rare sporadic neoplasm of the appendix and the second most common type of digestive endocrine tumor, often with no specific clinical presentation. They are divided into either classic endocrine tumor of the appendix or the more aggressive goblet cell carcinoma (GCC).", "ORPHA ID": 100079, "Summary": ""}
{"Disease Name": "Neuroendocrine neoplasm of esophagus", "Disease Definition": "A group of esophageal epithelial neoplasms characterized by neuroendocrine differentiation, comprising well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms, an umbrella category including mixed adenoneuroendocrine carcinoma. The tumors typically occur in the lower esophagus, often in association with Barrett mucosa. NECs may also arise in other parts of the esophagus. On endoscopy, NETs usually appear as small polypoid or nodular submucosal masses, while NECs are large, infiltrative, and ulcerated. Patients most commonly present with dysphagia, pain, weight loss, and sometimes melena. Metastatic NETs may be associated with carcinoid syndrome.", "ORPHA ID": 506136, "Summary": ""}
{"Disease Name": "Neuroendocrine neoplasm", "Disease Definition": "A group of rare tumors characterized by predominantly neuroendocrine differentiation, potentially arising in most organs of the body, including the central nervous system, respiratory tract, larynx, gastrointestinal tract, thyroid, skin, breast, and urogenital system. The gastrointestinal tract and lungs are the most common primary tumor sites. Based on clinical behavior, histology, and proliferation rate, the tumors may be categorized as well differentiated (low grade to intermediate grade) neuroendocrine tumors and poorly differentiated (high grade) neuroendocrine carcinomas. They may or may not be associated with clinical hormone hypersecretion syndromes.", "ORPHA ID": 877, "Summary": ""}
{"Disease Name": "Neuroendocrine tumor of anal canal", "Disease Definition": "A are epithelial tumor of the anal canal arising from enterochromaffin cells in the colorectal-type epithelium above the dentate line and in the anal transition zone. The tumors are slow growing and the majority of cases are diagnosed in later advanced stages. It may present with symptoms related to the anatomical location of the tumor (rectal mass, rectal bleeding and pain, tenesmus or changes in bowel habits), symptoms of carcinoid syndrome (flushing and increased gut motility) or nonspecific symptoms of advanced disease (hepatomegaly, fever, weight loss, anorexia, malaise).", "ORPHA ID": 100082, "Summary": ""}
{"Disease Name": "Neuroendocrine tumor of pancreas", "Disease Definition": "Pancreatic endocrine tumor, also known as pancreatic neuroendocrine tumor (PNET), describes a group of endocrine tumors originating in the pancreas that are usually indolent and benign, but may have the potential to be malignant. They can be functional, exhibiting a hormonal hypersecretion syndrome, but can be non-functional presenting with non-specific symptoms and include insulinoma, glucagonoma, VIPoma, somatostatinoma (SSoma), PPoma and Zollinger-Ellison syndrome (ZES, or gastrinoma) and other ectopic hormone producing tumors (such as GRFoma) (see these terms).", "ORPHA ID": 97253, "Summary": "Epidemiology\nPrevalence in the U.S. is estimated at 1/4,000-1/3,300 and 1/37,000 in Japan, but this is likely an underestimate due to a low detection rate.\nClinical description\nPNETs, when functional, usually present in the 5th decade of life as various hypersecretion syndromes. These include insulinoma presenting with hyperinsulinemic hypoglycemia; glucagonoma with necrolytic migratory erythema, diabetes mellitus, and thomboembolisms; VIPoma with watery diarrhea, hypokalemia and or hypo/achlorhydia; SSoma with diabetes mellitus, cholelithiasis, steatorrhea and hypochlorhydria; and ZES with severe peptic ulcer disease. Rarely PNETs secrete ectopic hormones (i.e. growth regulatory hormone). Non-functioning PNETs are not associated with distinct hormonal features but may still secrete hormones (i.e. PPoma). They are usually discovered incidentally in the 4-5th decade of life, due to non-specific symptoms, and in many cases have already metastasized to the liver. Malignant behavior is seen in >50% of PNETs (except insulinoma, ~10%). PNETs can also be associated with familial endocrine tumor syndromes (10% of cases) such as multiple endocrine neoplasia type 1, neurofibromatosis type 1, and Von Hippel-Lindau disease (see these terms).\nEtiology\nEtiology is unknown. They are thought to be derived from pluripotential epithelial cells in pancreatic ductules or Langerhans islet cells and are most commonly located in the pancreas. SSoma and gastrinoma can also be found in the upper small intestine. Inactivation of tumor suppressor genes or activation of oncogenes may be causative as seen in familial endocrine tumor syndromes.\nDiagnostic methods\nDiagnosis requires clinical examination, endocrine testing, imaging studies and histopathology examination (HPE) of the tumor. Computed tomography, MRI, endoscopic ultrasound and somatostatin receptor scintigraphy allows for the visualization of a PNET (>0.5) as well as liver, lymph node and peritoneal metastases. HPE and immunohistochemistry help to identify and grade the tumor. Chromogranin A, neuron-specific enolase and pancreastatin are often elevated. Elevated hormone levels may help to identify functional PNETs.\nDifferential diagnosis\nDifferential diagnosis is tumor specific and includes endocrine tumor and carcinoid syndrome (see this term).\nGenetic counseling\nMost PNETs are sporadic but about 10% are associated with autosomal dominantly inherited endocrine tumor syndromes.\nManagement and treatment\nManagement involves resolving the hormone-excess state and treating the tumor itself. Removal of as much of the primary and (if present) metastatic tumors is the current approach. Systemic therapy, with somatostatin analogues (octreotide and lanreotide), effectively treats most functional tumors. If ineffective, systemic interferon-alpha can be given. Complications caused by specific functional tumors should equally be addressed. Surgical procedures involve enucleation and pancreatectomies (with regional lymphadenectomy in most cases). In those with liver metastases, locoregional therapy (i.e. chemoembolization as well as radiofrequency, alcohol and microwave ablation) is recommended to treat liver metastases. Chemotherapy is considered only in those with an intermediate-high grade PNET.\nPrognosis\nPrognosis is variable. A less favorable prognosis is associated with higher tumor grade and liver and lymph node metastasis. The 5-year survival rate is 30% for nonfunctional PNETs and up to 97% for functional resectable PNETs. Hormonal complications can be life threatening.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Run YU"}
{"Disease Name": "Neuroendocrine tumor of stomach", "Disease Definition": "A rare subtype of neuroendocrine neoplasm, arising from enterochromaffin-like cells in the stomach, with a variable clinical presentation, disease course and prognosis, depending on the disease type and histological grade. Most patients are asymptomatic, with diagnosis usually occurring incidentally during gastroscopy, however, symptoms of dyspepsia, anemia, pain, weight loss and gastrointestinal bleeding can be observed. Association with Zollinger-Ellison syndrome and multiple endocrine neoplasia type I has been reported.", "ORPHA ID": 100075, "Summary": ""}
{"Disease Name": "Neuroendocrine tumor of the colon", "Disease Definition": "A rare epithelial tumor of the large intestine, arising from enterochromaffin cells, most commonly in the cecum or ascending colon. The tumor is usually slow-growing and can be diagnosed as an incidental finding in an asymptomatic patient, while in the later stages patients can present with abdominal pain, palpable abdominal mass, changes in bowel habits, signs of bowel obstruction, gastrointestinal bleeding, anorexia, weight loss or, rarely, carcinoid syndrome (facial flushing, diarrhea, tachycardia, hypo- and hypertension, cardiac abnormalities).", "ORPHA ID": 100080, "Summary": ""}
{"Disease Name": "Neuroendocrine tumor of the rectum", "Disease Definition": "Neuroendocrine tumor of the rectum is a rare epithelial tumor of rectum arising from enterochromaffin cells, most often in the mid-rectum. The tumors are slow growing, in early stages majority are asymptomatic and are diagnosed incidentally. Later in the course, the tumor may present with rectal bleeding, abdominal or rectal pain, tenesmus, changes in bowel habits, or weight loss. In some cases it may present with carcinoid symptoms of flushing and increased gut motility.", "ORPHA ID": 100081, "Summary": ""}
{"Disease Name": "Neurofaciodigitorenal syndrome", "Disease Definition": "Neurofaciodigitorenal syndrome is a rare multiple developmental anomalies syndrome characterized by neurological abnormalities (including megalencephaly, hypotonia, intellectual disability, abnormal EEG), dysmorphic facial features (high prominent forehead, grooved nasal tip, ptosis, ear anomalies) and acrorenal defects (such as triphalangism, broad halluces, unilateral renal agenesis). Additionally, intrauterine growth restriction, short stature and congenital heart defects may be associated. There have been no further descriptions in the literature since 1997.", "ORPHA ID": 2673, "Summary": ""}
{"Disease Name": "Neuroferritinopathy", "Disease Definition": "Neuroferritinopathy is a late-onset type of neurodegeneration with brain iron accumulation (NBIA; see this term) characterized by progressive chorea or dystonia and subtle cognitive deficits.", "ORPHA ID": 157846, "Summary": "Epidemiology\nPrevalence of neuroferritinopathy is unknown. To date fewer than 50 cases have been reported.\nClinical description\nThe disease presents typically in the fourth to sixth decades, although cases with symptoms in their late teens have been observed. Symptoms are restricted to the nervous system and include chorea, dystonia, bradykinesia, dystonic dysarthria, and Parkinsonian features. Choreiform movements tend to occur in the face, orolingual musculature and upper limbs and onset is usually asymmetrical. Dystonia can affect the face, tongue, arms and legs and onset is also usually asymmetrical. The majority of individuals develop a characteristic orofacial action-specific dystonia related to speech that leads to dysarthrophonia. Frontalis overactivity is common, as is orolingual dyskinesia. Cognitive deficits, behavioral issues and dysphagia can be a late feature.\nEtiology\nNeuroferritinopathy is caused by mutations in the ferritin light chain (FTL) gene (19q13.3-q13.4) and is inherited in an autosomal dominant manner with high penetrance.\nDiagnostic methods\nDiagnosis is based on clinical findings including adult-onset chorea or dystonia, low serum ferritin (typically 20 micrograms/L or less) and iron deposition in the basal ganglia shown on brain MRI. Molecular genetic testing is available on a limited basis.\nDifferential diagnosis\nDifferential diagnoses include Huntington disease and spinocerebellar ataxia type 17 (see these terms), although neither has the characteristic findings on neuroimaging; choreoacanthocytosis and McLeod neuroacanthocytosis syndrome (see these terms), although, unlike in these two diseases, the reflexes are preserved in neuroferritinopathy, and juvenile-onset Parkinson disease, aceruloplasminemia and Neimann-Pick type C (see these terms), although these disorders do not show the characteristic neuroimaging of neuroferritinopathy. The MRI findings are similar to those found in pantothenate kinase-associated neurodegeneration (PKAN; see this term). Individuals with neuroferritinopathy also show the 'eye of the tiger'' sign.\nAntenatal diagnosis\nPrenatal testing for pregnancies at increased risk may be available through laboratories offering prenatal testing if the disease-causing mutation in the family is known.\nManagement and treatment\nTreatment is of the manifestations of the disease and includes levodopa, tetrabenazine, benzhexol, sulpiride, diazepam, clonezepam and deanol for the movement disorder and botulinum toxin for painful focal dystonia. Treatment also includes ensuring adequate caloric intake and physiotheraphy to maintain mobility. Iron supplements are not recommended.\nPrognosis\nThe movement disorder is progressive, involving additional limbs in five to ten years and becoming more generalized within 20 years.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Patrick CHINNERY"}
{"Disease Name": "Neurofibroma", "Disease Definition": "A rare benign peripheral nerve sheath tumor characterized by a well-demarcated intraneural or diffusely infiltrative extraneural space-occupying lesion consisting of Schwann cells, perineurial-like cells, and fibroblasts. It presents as a cutaneous nodule, a circumscribed mass in a peripheral nerve, a plexiform enlargement of a major nerve trunk, or with diffuse but localized involvement of skin and subcutaneous tissue. Multiple neurofibromas are typically associated with neurofibromatosis 1. Malignant transformation occurs almost exclusively in plexiform neurofibromas and neurofibromas of major nerves.", "ORPHA ID": 252183, "Summary": ""}
{"Disease Name": "Neurofibromatosis type 1", "Disease Definition": "Neurofibromatosis type 1 (NF1) is a clinically heterogeneous, neurocutaneous genetic disorder characterized by café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, and multiple neurofibromas.", "ORPHA ID": 636, "Summary": "Epidemiology\nPrevalence is reported to be 1/3,000 live births. NF1 is reported in many ethnic groups and affects males and females equally.\nClinical description\nThe clinical features are highly variable, even within the same family. Multiple café-au-lait macules are found in almost all patients (some at birth and most before the first year). Intertriginous freckling develops starting at 5 years of age. Multiple cutaneous and subcutaneous neurofibromas develop in adults. In older patients, they continue to increase in number and size. Cutaneous neurofibromas do not become malignant. Plexiform neurofibromas (growing along the nerve and its branches) may cause disfigurement, pain, and functional problems and are usually present at birth and may become malignant later in life. Ocular manifestations include optic pathway gliomas and iris hamartomas (Lisch nodules). Optic pathway gliomas usually develop before age 6 years, and rarely progress thereafter. Osteopenia, osteoporosis, bone overgrowth, short stature, macrocephaly, scoliosis, skeletal dysplasia (sphenoid wing, vertebral), and pseudoarthrosis may be present. Other features include hypertension, vasculopathy, intracranial tumors, malignant peripheral nerve sheath tumor (MPNST; see this term), and occasionally seizures or hydrocephalus. Intellectual development is usually not severely affected but cognitive deficits and learning difficulties are frequent (50%-75%). The overall cancer risk is higher than the general population (lifetime risk of 10-12% for MPNST, mostly between 20-40 years; increased risk of breast cancer before age 50). Familial spinal and segmental forms of NF1 have been described. Watson syndrome forms part of the NF1 spectrum. Neurofibromatosis-Noonan syndrome is a variant of NF1 in 99% of cases (see these terms).\nEtiology\nNF1 is caused by mutations in the tumor suppressor neurofibromin 1 NF1 gene (17q11.2) and rarely by 17q11 microdeletion (only 5%).\nDiagnostic methods\nFormal diagnostic criteria have been established. 2 or more of the following are diagnostic: more than 5 café-au-lait macules, 2 or more neurofibromas or one plexiform neurofibroma, optic glioma, freckling, 2 or more Lisch nodules, specific bone dysplasias, first-degree relative. Magnetic resonance imaging can determine the extent of plexiform neurofibromas. Molecular genetic testing can be requested but is mostly not needed.\nDifferential diagnosis\nLegius syndrome (see this term) is often clinically indistinguishable from NF1 and is seen in about 2% of people fulfilling NF1 diagnostic criteria. There are however a small number of individuals with NF1 who like Legius syndrome patients do not develop non-pigmentary manifestations. Constitutional mismatch repair deficiency syndrome should be considered. Other differential diagnoses include McCune-Albright syndrome, Noonan syndrome with lentigines and Proteus syndrome. Most cases of multiple non-ossifying fibromatosis are cases of NF1 (see these terms).\nAntenatal diagnosis\nPrenatal and preimplantation genetic testing for at-risk pregnancies is possible\nGenetic counseling\nThe mode of inheritance is autosomal dominant. 1 in 2 cases is caused by de novo NF1 mutations. Penetrance is 100% but disease manifestations vary widely, complicating genetic counseling.\nManagement and treatment\nSpecific cardiovascular, ocular, neurological and orthopedic manifestations should be treated by corresponding specialists. Cutaneous or subcutaneous neurofibromas can be removed surgically. Plexiform neurofibromas are far more difficult to treat.\nPrognosis\nOverall prognosis is good but significant morbidity is common. MPNST generally has a poor prognosis. Malignancy and vascular disease are the most common causes of early demise.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Eric LEGIUS"}
{"Disease Name": "Neurofibromatosis-Noonan syndrome", "Disease Definition": "Neurofibromatosis-Noonan syndrome (NFNS) is a RASopathy and a variant of neurofibromatosis type 1 (NF1) characterized by the combination of features of NF1, such as café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, optic nerve glioma and multiple neurofibromas, and Noonan syndrome (NS), such as short stature, typical facial features (hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly rotated ears with a thickened helix, and a broad forehead), congenital heart defects and unusual pectus deformity. As these three entities have significant phenotypic overlap, molecular genetic testing is often necessary for a correct diagnosis (such as when café-au-lait spots are present in patients diagnosed with NS).", "ORPHA ID": 638, "Summary": ""}
{"Disease Name": "Neurogenic arthrogryposis multiplex congenita", "Disease Definition": "A form of arthrogryposis multiplex congenita characterized by congenital immobility of the limbs with fixation of multiple joints and muscle wasting. This condition is secondary to neurogenic muscular atrophy.", "ORPHA ID": 1143, "Summary": ""}
{"Disease Name": "Neurogenic scapuloperoneal syndrome, Kaeser type", "Disease Definition": "A rare, genetic, neuromuscular disease characterized by adult-onset muscle weakness and atrophy in a scapuloperoneal distribution, mild involvement of the facial muscles, dysphagia, and gynecomastia. Elevated serum CK levels and mixed myopathic and neurogenic abnormalities are associated clinical findings.", "ORPHA ID": 85146, "Summary": ""}
{"Disease Name": "Neurogenic thoracic outlet syndrome", "Disease Definition": "Neurogenic thoracic outlet syndrome (NTOS) is a form of thoracic outlet syndrome (TOS; see this term) that presents with pain, paresthesias and weakness in an upper extremity and is divided into true NTOS and disputed NTOS.", "ORPHA ID": 100073, "Summary": "Epidemiology\nThe incidence of NTOS is unknown. It affects women more than men. Disputed NTOS is the most controversial form and accounts for approximately 95% of all cases of TOS and 99% of cases with neurologic symptoms\nClinical description\nNTOS presents with upper extremity paresthesias, pain and weakness. True NTOS manifests slowly with the progressive unilateral atrophic weakness of the intrinsic hand muscles and sensory abnormalities in a T1 distribution due to a lower trunk brachial plexopathy. Disputed NTOS does not cause muscle atrophy, but there is scalene muscle tenderness and symptoms worsen with arm use and provocative maneuvers.\nEtiology\nTrue NTOS is caused by lower trunk brachial plexus compression in the thoracic outlet at the interscalene triangle, costoclavicular space, or subcoracoid space deep to the pectoralis minor tendon. Disputed NTOS may be due to scarring of scalene muscles, poor posture or a congenital anomaly.\nDiagnostic methods\nRadiographs may identify compressive sources including an elongated C7 transverse process or anomalous first rib. Electrodiagnostic (EDX) findings demonstrate a lower trunk brachial plexopathy. MRI identifies compressive sources and rules out other causes such as a Pancoast tumor. Disputed NTOS is a clinical diagnosis that depends on scalene muscle tenderness and provocative maneuvers eliciting pain and paresthesias in the affected extremity as it lacks objective EDX evidence. It is most often a diagnosis of exclusion.\nDifferential diagnosis\nDifferential diagnoses include arterial and venous TOS (see these terms), cervical radiculopathy, carpal tunnel syndrome or any disorder involving nerve fibers derived from C8 or T1 nerve roots such as cubital tunnel syndrome. EDX testing differentiates the lower trunk brachial plexopathy of NTOS from other neurologic diagnoses. Arterial TOS presents with ischemia and venous TOS presents with venous congestion.\nManagement and treatment\nDisputed NTOS is treated with physical therapy, medication and use of orthoses and neck collars. Refractory cases may undergo surgical decompression. For true NTOS surgical decompression is considered based on the degree of nerve injury and is indicated if there is acute or sub-acute progressive weakness or disabling pain and paresthesias.\nPrognosis\nIn cases of true NTOS, decompression relieves pain, but full neurologic recovery requires time for remyelination or axonal regeneration. If there is axonal loss, recovery may be incomplete. Success rates for surgical decompression of disputed NTOS are 91%-93% immediately after treatment, but drop to 64% to 71% after 10 years due to a high rate of recurrence.\n\n                            Last update: \n                            May 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Joseph FEINBERG  - Dr Paul SCHOLTEN"}
{"Disease Name": "Neuroleptic malignant syndrome", "Disease Definition": "A rare neuropsychiatric syndrome associated with administration of antipsychotic or other central dopamine (D2) receptor antagonists, and characterized by hyperthermia, muscular rigidity, autonomic dysfunction and altered consciousness.", "ORPHA ID": 94093, "Summary": "Epidemiology\nNeuroleptic malignant syndrome (NMS) occurs in 1/5,000 to 10,000 patients treated with antipsychotics or other central dopamine (D2) receptor antagonists (all age groups; male:female ratio 2:1 in some studies; higher incidence rates have been reported in the past). The incidence may be lower with newer less potent antipsychotics and with reduced severity of symptoms, particularly for clozapine.\nClinical description\nIn about 16% of patients, the syndrome occurs within 24 hours after the initiation of the antipsychotic treatment, 66% within the first week, and less commonly within or after 30 days on stable medication regimens. Manifestations include hyperthermia, muscular rigidity and tremor, mental status alteration and autonomic dysfunction. Other signs may include profuse diaphoresis, tachycardia, tachypnea, labile blood pressure, acidosis, incontinence, and elevated serum creatine kinase (CK) and transaminases from rhabdomyolysis with risk of subsequent renal failure. Once symptoms develop, they last on average 7-10 days after discontinuation of oral triggering drugs, with peak intensity within the first 72 hours. Risk factors include prior NMS episodes, physical exhaustion, agitation, dehydration, pre-existing catatonia, use of restraints, use of high doses, high potency drugs, acute parenteral forms of antipsychotics, and rapid antipsychotic dosage increase.\nEtiology\nThe syndrome is thought to result from acute central dopamine receptor blockade. All antipsychotic agents, typical or atypical, may trigger the syndrome, although potent antipsychotics (haloperidol, fluphenazine) are more frequently associated. Dopamine blocking agents used in non-psychiatric settings (metoclopramide, prochlorperazine, droperidol) and dopamine depleting agents (tetrabenazine) have also been implicated.\nDiagnostic methods\nDiagnosis is based on clinical signs of the syndrome in the context of treatment with dopamine blocking agents, and the exclusion of alternative etiologies via thorough investigation with laboratory and imaging tests. Although elevated CK is a frequent correlate of muscle dysfunction in NMS, it is nonspecific. The likelihood of an NMS diagnosis can be assessed using the International Expert Consensus (IEC) criteria which are based on priority scores assigned to major clinical features (antipsychotic exposure, hyperthermia, rigidity, mental status changes, CK elevation, etc.). A total cut-off threshold score of ≥74 on the IEC criteria offers 69.6% sensitivity and 90.7% specificity in diagnosing NMS.\nDifferential diagnosis\nThe differential diagnosis is of prime importance. It includes malignant hyperthermia of anesthesia, serotonin syndrome, parkinsonism hyperpyrexia syndrome, heat stroke, idiopathic malignant catatonia, infections (sepsis, meningitis, encephalitis), autoimmune disorders (limbic encephalitis with NMDA receptor antibodies, lupus cerebritis) delirium tremens, status epilepticus, salicylate poisoning, endocrinopathies, stroke, and brain trauma.\nManagement and treatment\nImmediate cessation of the antipsychotic medication and supportive measures (volume resuscitation, physical cooling) are essential in management. Specific treatments are unproven. Benefits in cases treated empirically based on phenomenology, severity and duration of symptoms with benzodiazepines, dopaminergic agents (bromocriptine, amantadine), dantrolene (in cases with extreme hyperthermia, rigidity and rhabdomyolysis) and electroconvulsive therapy have been reported. Careful monitoring for cardiorespiratory failure, renal failure, aspiration pneumonia and coagulopathies is required. Ventilatory assistance and dialysis may be required.\nPrognosis\nAfter discontinuation of oral psychotropic agents, resolution usually occurs within 1-2 weeks in most uncomplicated cases. However, the syndrome is still potentially lethal. Death may result from sudden cardiorespiratory arrest, aspiration pneumonia, pulmonary emboli, myoglobinuric renal failure, or disseminated intravascular coagulation. Mortality rate is estimated at 5-10% with adverse outcomes more likely with potent antipsychotics, older age and pre-existing cardiorespiratory disease. Most patients recover completely but amnestic syndromes, extrapyramidal and cerebellar disorders, peripheral neuropathy, myopathy and contractures have been reported in rare cases.\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Pr STANLEY CAROFF  - Dr Henry ROSENBERG"}
{"Disease Name": "Neurolymphomatosis", "Disease Definition": "Neurolymphomatosis is a rare syndrome of peripheral and cranial nerve dysfunction in patients with hematologic malignancies, mostly non-Hodgkin's lymphoma or acute leukemia, characterized by painful or painless involvement of peripheral or cranial nerves or nerve roots. The clinical presentation is diverse depending on the site involved and includes plexopathy, mononeuritis multiplex, peripheral neuropathy, radiculopathy and cranial nerve palsies.", "ORPHA ID": 206586, "Summary": ""}
{"Disease Name": "Neurometabolic disorder due to serine deficiency", "Disease Definition": "Serine-deficiency syndrome is a very rare infantile-onset potentially treatable neurometabolic disorder characterized clinically by microcephaly, neurodevelopmental disorders and seizures. Three serine-deficiency syndromes have been described: 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, 3-phosphoserine phosphatase (3-PSP) deficiency, and phosphoserine aminotransferase deficiency (see these terms).", "ORPHA ID": 35705, "Summary": ""}
{"Disease Name": "Neuromyelitis optica spectrum disorder", "Disease Definition": "A rare inflammatory disease of the central nervous system characterized mainly by attacks of uni- or bilateral optic neuritis (ON) and acute myelitis.", "ORPHA ID": 71211, "Summary": "Epidemiology\nNeuromyelitis optica spectrum disorder (NMOSD) has a worldwide distribution and estimated prevalence of 1-5/100,000. The average annual incidence is 1/770,000 worldwide. Nearly 90% of affected individuals are female.\nClinical description\nPatients are predominantly female with onset typically in late middle-age. Presentation is with acute, often severe, attacks of blindness and paraparesis or quadriparesis, accompanied by sensory and sphincter impairments. Most patients have relapsing attacks (more frequent in women), separated by months or years with partial recovery, typically with sequential episodes of ON and myelitis. More rarely, the disease course is monophasic, with nearly simultaneous episodes of ON and myelitis. This form may occur in younger individuals with no sex predilection. Rarely, patients experience other neurological manifestations, including intractable vomiting and nausea due to inflammation in the medulla, endocrine and sleep disorders due to involvement of the hypothalamus, and attacks of cerebral edema that may cause confusion or coma. Patients frequently have other systemic autoimmune disorders, such as systemic lupus erythematosus (SLE), Sjögren's syndrome or myasthenia gravis.\nEtiology\nEtiology is unknown but NMO is believed to be an autoimmune disease associated with autoantibodies to aquaporin-4 (AQP4) in 70% and autoantibodies to myelin oligodendrocyte glycoprotein (MOG) in 15% of patients. 15% of patients are double seronegative for these antibodies. Patients with autoantibodies to MOG have overlapping clinical features, but have demographic and clinical differences from patients with autoantibodies to AQP4 and patients with these antibodies are diagnosed with MOG associated disorders (MOGAD).\nDiagnostic methods\nDiagnosis is primarily clinical, but MRI evidence of long spinal cord lesions extending over three or more vertebral segments during an acute attack of myelitis is helpful in differentiating this disorder from multiple sclerosis (MS), as are normal brain MRI findings in the early stages of NMOSD. When aquaporin-4 antibodies are detected, their specificity permits diagnosis in circumstances when the clinical diagnosis is less straightforward, such as in patients with a first event of transverse myelitis or in patients with atypical brain lesions. Detection of MOG antibodies is generally reliable in diagnosis of MOG associated disorders, as distinct from MS and NMOSD, but the serology is less specific when antibodies are detected in low titer and a combination of clinical, radiologic and serologic data is necessary to achieve a specific diagnosis in patients with low titer MOG antibodies.\nDifferential diagnosis\nDifferential diagnoses include MS; idiopathic, viral, paraneoplastic and connective tissue disease (e.g. SLE)-associated myelitis; ischemic and connective tissue associated optic neuropathies.\nGenetic counseling\nFewer than 5% of individuals report relatives with NMOSD; polygenic inheritance is thought to be responsible for the small excess of familial cases relative to expected.\nManagement and treatment\nAcute attacks are treated with high dose intravenous corticosteroids and if this fails, with plasma exchange. For patients with AQP4 antibodies, three agents are approved (in the USA and Europe) eculizumab, inebilizumab and satralizumab, and which reduce clinical attacks by 75-95%. Alternative maintenance treatments for patients with AQP4 antibodies or MOG antibodies are immunosuppressive drugs (e.g. azathioprine or mycophenolate mofetil), often combined with corticosteroids, or rituximab.\nPrognosis\nThe prognosis is variable: patients may recover completely from individual attacks, but residual neurological deficits are common and sometimes severe. Unrecognized or untreated, up to 30% of patients may die in the first 5 years of their illness due to an attack of severe myelitis leading to respiratory failure. A high proportion of patients will become legally blind in one or both eyes and/or have substantial residual paraparesis. The prognosis for good recovery from attacks is much better for those with MOG antibodies compared to those with AQP4 antibodies.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Brian WEINSHENKER"}
{"Disease Name": "Neuronal ceroid lipofuscinosis", "Disease Definition": "Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited progressive degenerative brain diseases characterized clinically by a decline of mental and other capacities, epilepsy, and vision loss through retinal degeneration, and histopathologically by intracellular accumulation of an autofluorescent material, ceroid lipofuscin, in the neuronal cells in the brain and in the retina.", "ORPHA ID": 216, "Summary": "Epidemiology\nThe exact prevalence and incidence of this group of disorders are unknown.\nClinical description\nThe clinical presentation varies widely between forms but the clinical hallmark is a combination of dementia, visual loss, and epilepsy. Manifestations may begin between the neonatal period and young adult age depending on the form, leading to the original classification of NCLs by age at onset into congenital, infantile, late infantile, juvenile and adult NCL subgroups (see these terms). A Northern epilepsy variant (progressive epilepsy-intellectual deficit, Finnish type; see this term), in which the visual problems may be absent or be mild and go unrecognized, has also been described.\nEtiology\nTo date, at least 10 genetic NCL disorders have been reported and are designated as CLN1 to CLN10. The majority of NCLs are inherited in an autosomal recessive manner, however, autosomal dominant inheritance has been reported in one adult-onset form designated as a CLN4 disease.\nDiagnostic methods\nDiagnosis is based on clinical findings, electron microscopy studies revealing storage material with autofluorescent ceroid lipopigments, and enzymatic testing for deficiencies in palmitoyl-protein thioesterase 1, tripeptidyl-peptidase 1 and cathepsin D, present in patients with the CLN1, CLN2 and CLN10 diseases, respectively. With the exception of the CLN4 and CLN9 diseases (for which the causative genes have not yet been identified), the diagnosis can be confirmed by molecular testing.\nDifferential diagnosis\nThe differential diagnoses should include other causes of vision loss, dementia and seizures with an appropriate age of onset (typically mitochondrial disorders, inborn errors of metabolism and other lysosomal storage disorders).\nAntenatal diagnosis\nPrenatal diagnosis is feasible through molecular testing if the disease-causing mutation in the family has already been identified or through enzymatic analysis in some cases.\nManagement and treatment\nThere is no curative treatment for NCLs and management is supportive only.\nPrognosis\nAlthough all NCLs lead to severe disability, the prognosis is variable with life expectancy ranging from a few hours or days after birth for the congenital form to survival into the fifth decade for patients with the adult-onset form.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Alfried KOHLSCHÜTTER"}
{"Disease Name": "Neuronal intestinal pseudoobstruction", "Disease Definition": "Neuronal intestinal pseudoobstruction is a form of chronic intestinal pseudoobstruction caused by a developmental failure of the enteric neurons to differentiate or migrate properly and manifests as a bowel obstruction.", "ORPHA ID": 99811, "Summary": ""}
{"Disease Name": "Neuronal intranuclear inclusion disease", "Disease Definition": "Neuronal intranuclear inclusion disease (NIID) is a very rare multisystem neurodegenerative disorder characterized by the presence of eosinophilic intranuclear inclusions in neuronal and glial cells, and neuronal loss.", "ORPHA ID": 2289, "Summary": "Epidemiology\nInfantile, juvenile, and adult-onset cases have been described in approximately 30 patients word-wide.\nClinical description\nAs any part of the nervous system can be affected (central, peripheral, and autonomic nervous systems), the clinical manifestations depend on the sites involved, and widely vary. The most common neurological signs include ataxia, extra-pyramidal signs (tremor and oculogyral crises), lower motor neuron findings (absent deep tendon reflexes, weakness, muscle wasting, foot deformities), and less apparent behavioural or cognitive difficulties. Dementia is reported as a predominant neurological symptom in adult patients, while infantile/juvenile cases show disproportionate ataxia and other movement symptoms. Occasionally, gastrointestinal dysmotility with severe weight loss may be present, if the enteric nervous system is involved.\nDiagnostic methods\nNIID may be diagnosed by a full thickness rectal biopsy.\nDifferential diagnosis\nThe differential diagnosis should consider spinocerebellar ataxias, progressive juvenile parkinsonism and dystonia.\nGenetic counseling\nMost cases are sporadic. Despite reports of several familial cases (including a pair of identical twins), no causative gene has been identified. Autosomal dominant transmission has been suggested in these families.\nManagement and treatment\nThere is no cure or treatment that slows the progression of the disease. Symptomatic treatments may improve the quality of life.\nPrognosis\nNIID is slowly progressive (within 10 to 20 years) and fatal.\n\n                            Last update: \n                            April 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Bertrand FONTAINE"}
{"Disease Name": "Neuropathy with hearing impairment", "Disease Definition": "This syndrome is characterized by the association of sensorineural hearing impairment and peripheral neuropathy.", "ORPHA ID": 139512, "Summary": "Epidemiology\nIt has been described in members from four generations of a Spanish family.\nClinical description\nThe hearing impairment was mild and often asymmetrical. The neuropathy was demyelinating with predominantly sensory involvement but severity was variable ranging from asymptomatic individuals to patients with skin ulcers and osteomyelitis requiring amputation.\nEtiology\nNeuropathy with hearing impairment is caused by mutations in the GJB3 gene (1p34).\nGenetic counseling\nThe syndrome is transmitted in an autosomal dominant manner.\n\n                            Last update: \n                            January 2009"}
{"Disease Name": "Neurotrophic keratopathy", "Disease Definition": "Neurotrophic keratopathy is a rare degenerative disease of the cornea characterized by reduction or loss of corneal sensitivity that can be asymptomatic or present with red-eye and, during the early stages of the disease, a minor decrease in visual acuity. It eventually leads to loss of vision.", "ORPHA ID": 137596, "Summary": "Epidemiology\nNo epidemiological data are available. However, prevalence can be estimated at around 1/2,380 in Europe.\nClinical description\nNeurotrophic keratopathy (NK) most commonly occurs in adults, and rarely presents in children. It is often asymptomatic, but early signs can include red-eye, blurred vision, and decreased visual acuity. As the disease progresses, epithelial defects and corneal ulcers may develop; corneal scarring and astigmatism can lead to further reduction of visual function. Eventually, progression towards corneal melting and perforation can result in vision loss.\nEtiology\nNK results from an impairment of trigeminal innervation that provides trophic support to the cornea. The most common causes are viral infection (e.g. herpes simplex) and surgery that damages the trigeminal nerve. Other causes of corneal nerve impairment include: chronic use of topical medications (e.g. timolol, betaxolol), iatrogenic injury (e.g. long-term use of contact lenses), systemic diseases (e.g. diabetes mellitus, multiple sclerosis), chemical burns, and intracranial masses (e.g. schwannoma, aneurysms). Congenital causes (e.g. HSAN4) are extremely rare and most often reported in children.\nDiagnostic methods\nDiagnosis is based on clinical findings of impaired corneal sensitivity, associated with corneal epithelial changes and medical history. Corneal sensitivity is commonly evaluated using the wisp of a cotton-tipped applicator (although the quantitative method is Cochet-Bonnet aesthesiometry). Slit-lamp and dilated fundus oculi examinations should be carried out and Schirmer and tear film break-up time tests prove useful. Corneal and conjunctival vital staining (with fluorescein, rose Bengal or lissamine green) highlight epithelial defects. Corneal nerve morphology is evaluated by in vivo corneal confocal microscopy. Microbiological examination excludes infections. NK staging uses the Mackie classification system: stage 1) punctate keratopathy, epithelial irregularities, stromal scarring, and superficial neovascularization; stage 2) persistent corneal epithelial defect (PED), possible stromal swelling; stage 3) involvement of the corneal stroma, with corneal ulcer progressing to perforation and/or stromal lysis.\nDifferential diagnosis\nDifferential diagnoses include all ocular surface and corneal diseases involving the epithelium or causing stromal ulceration: dry-eye, exposure keratitis, corneal limbal stem-cell deficiency, topical drug toxicity, contact-lens abuse, infectious keratitis, corneal dystrophies, and endothelial decompensation.\nManagement and treatment\nManagement depends on stage of the disease. In stage 1, artificial tears every 2-4 hours and lubricant ointment at night is prescribed to prevent epithelial breakdown. In addition to artificial tears and lubricant ointment, patients with stage-2 NK, are managed with corneal/scleral contact lenses and topical antibiotic eye drops. Surgery is generally reserved for refractory cases, with partial or total tarsorrhaphy being the most common procedure. For refractory neurotrophic corneal ulcers and severe cases with impending perforation, amniotic membrane transplantation and conjunctival flap surgery is performed, respectively. Small perforations are repaired with cyanoacrylate glue, and a soft-bandage contact lens. Frequent monitoring, ranging from every 1-2 weeks for stage 1 NK to daily for stage 3 disease, is necessary. New treatment methods (e.g. neuropeptides and nerve growth factors), aiming to restore corneal nerves and sensitivity, are currently under investigation.\nPrognosis\nThe prognosis of NK is variable and depends on many factors. A longer duration of the disease, together with severe comorbidities, results in a poorer prognosis.\n\n                            Last update: \n                            March 2017\n\n\n                            - Expert reviewer(s): \n                            Dr Paolo RAMA  - Dr Marta SACCHETTI"}
{"Disease Name": "Neutral lipid storage disease with ichthyosis", "Disease Definition": "A form of autosomal recessive neutral lipid storage disease characterized by the accumulation of lipid vacuoles in granulocytes (so-called Jordan's anomaly) and a variety of other cell types. Clinically, the skin symptoms with ichthyosiform erythroderma and scaling are initially in the foreground. Later, steatosis hepatis, hepatomegaly and muscle weakness develop. Other manifestations include growth delay, cataracts, sensorineural hearing loss, intellectual disability and bowel disease.", "ORPHA ID": 98907, "Summary": "Epidemiology\nThe disease is very rare and the prevalence is unknown. Approximately 150 cases have been described in the literature.\nClinical description\nThe infants are often born with a collodion membrane and develop a pronounced generalized ichthyosiform erythroderma with mostly fine white scaling. In more than half of the cases, moderate myopathy and moderate hepatomegaly (or functional impairment of the liver) occur in adulthood. Other symptoms include intellectual deficits, eye abnormalities (cataracts, retinopathy) and hearing impairment, as well as neuropathy and short stature.\nEtiology\nNeutral lipid storage disease with ichthyiosis (NLSD-I) is caused by biallelic mutations in the gene ABHD5 which is located on chromosome 3p21. ABHD5 codes for an enzyme involved in the breakdown of triglycerides in the cell. The disruption of this process leads to an accumulation of lipid vacuoles in many cell types.\nDiagnostic methods\nA simple diagnostic method is a blood smear which reveals lipid droplets in peripheral leucocytes (Jordan's anomaly). The accumulation of lipid vacuoles can also be detected histologically, in biopsies from skin or muscle. Elevated liver and muscle enzyme levels can be detected in a blood test. The current standard procedure is next generation sequencing test of the ABDH5 gene to detect biallelic variants.\nDifferential diagnosis\nDifferential diagnoses include : congenital ichthyosiform erythroderma, other syndromic ichthyoses, neutral lipid storage disease with myopathy (mutations in ATGL/PNPLA2) and different mitochondrial diseases with accumulation of cytoplasmic triglycerides (e.g. deficiencies in carnitine, cartinine palmitoyl transferase or fatty acid oxidation enzymes).\nAntenatal diagnosis\nPrenatal diagnosis based on molecular genetic testing (after amniocentesis or chorionic villus sampling) is possible if the pathogenic variants in ABDH5 has previously been identified in a family member.\nGenetic counseling\nNLSD-I belongs to the syndromic ichthyoses spectrum and is inherited in an autosomal recessive manner. Couples at risk (both persons are carriers of a disease-causing mutation) should receive genetic counseling in which they are informed that there is a 25% risk of having an affected child with each pregnancy.\nManagement and treatment\nA diet with high medium chain triglycerides/long chain triglycerides ratio can be beneficial. Retinoids (standard treatment for ichthyosis) should be used with caution due to the risk of liver toxicity.\nPrognosis\nIn NLSD-I, the severity of the disease depends primarily on the severity of liver involvement and myopathy. Cases in which a liver transplant was necessary have been described. The development of the disease varies from patient to patient but is relatively slow; most patients do not have a significantly reduced life expectancy.\n\n                            Last update: \n                            December 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Judith FISCHER | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Neutral lipid storage disease with myopathy", "Disease Definition": "A form of neutral lipid storage disease characterized by adult onset of slowly progressive muscular weakness of the limbs and axial muscles, and accumulation of lipid droplets in the muscles and leukocytes.", "ORPHA ID": 98908, "Summary": "Epidemiology\nPrevalence and incidence of Neutral Lipid Storage Disease with Myopathy (NLSD-M) are unknown. About 100 cases have been described in the literature, with about 30 different gene mutations. The disease is diffuse worldwide, with more reported cases in Italy, China and Japan. It is thought that the disease, due to lack of knowledge, may be underdiagnosed.\nClinical description\nThe expression of phenotype is highly variable, from very mild to severe disease. Generally, the disease starts in young-adult age with an asymmetrical weakness and atrophy of proximal muscle of a limb which frequently involves cervical and lumbar muscles, and finally, the distal muscles of limbs. Generally, bulbar and respiratory muscles are spared. Some patients are wheelchair confined. Cardiomyopathy is developed by a little less than 50% of patients in the later disease course. Additional, less frequent, variable manifestations include triglycerides infiltration of liver, thyroid, pancreas and kidney. Serum creatine kinase is always elevated.\nEtiology\nThe pathophysiology of the disease is largely unclear and phenotype-genotype correlations remain incomplete. The disease is associated with mutations of the PNPLA2 gene. PNPLA2 gene encode for ATGL, a lipase that is a lipid droplet-associated protein and catalyzes the first step in the hydrolysis of triacylglycerols. The mutations in both alleles of the PNPLA2 gene cause the production of a defective protein. The detachment of fatty acids from triglycerides is compromised, therefore triglycerides accumulate in lipid droplets within the cytoplasm of cells. There is evidence of altered mitochondrial metabolism, likely a consequence of the low availability of fatty acids. However, many unresolved issues remain, such as muscle fiber damage resulting in muscle atrophy.\nDiagnostic methods\nThe diagnosis is suspected when a patient presents hyperckemia and limb weakness. Peripheral blood smear reveals triacylglycerol-containing lipid droplets in leukocytes (Jordan's anomaly), a very sensitive diagnostic marker present in 100% of patients. Muscle biopsy reveals a massive accumulation of lipid droplets. The diagnosis is then confirmed by genetic testing.\nDifferential diagnosis\nBased on the clinical phenotype, many hereditary and acquired myopathies can be differentially diagnosed with NLSD-M. Furthermore, from a histological point of view, all myopathies with lipid accumulation, such as multiple acyl-CoA dehydrogenase deficiency or primary carnitine deficiency, can constitute a diagnostic alternative.\nAntenatal diagnosis\nThe disease is very rare and the mode of transmission is recessive, so prenatal screening is not required except in the cases of consanguinity of parents with a family history of NLSD-M.\nGenetic counseling\nGenetic counseling could be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. There is no genotype-phenotype correlation; therefore, it is impossible to predict the expression of the genetic mutation in a child of a carrier couple.\nManagement and treatment\nThere is no specific therapy. Supportive therapies can improve cardiomyopathy and generally the consequences of damage to internal organs. Some cases required implantation of cardiac devices. Strength training or aerobic exercise programs, or both, might optimize muscle and cardiorespiratory function and prevent additional disuse atrophy and deconditioning.\nPrognosis\nQuality of life is mainly influenced by motor disability. There are no studies on the life expectancy of people affected by this disease.\n\n                            Last update: \n                            January 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI | EURO-NMD* - Dr Elena PENNISI \n\n\n                                * European Reference Network"}
{"Disease Name": "Neutral lipid storage disease", "Disease Definition": "Neutral lipid storage disease (NLSD) refers to a group of diseases characterized by a deficit in the degradation of cytoplasmic triglycerides and their accumulation in cytoplasmic lipid vacuoles in most tissues of the body. The group is heterogeneous: currently cases of NLSD with icthyosis (NLSDI/Dorfman-Chanarin disease; see this term) and NLSD with myopathy (NLSDM/neutral lipid storage myopathy; see this term) can be distinguished.", "ORPHA ID": 165, "Summary": "Epidemiology\nThe group of diseases is very rare and the prevalence is unknown (around 50 cases have been reported in medical literature, of which 3 had NLSDM) because of the vagueness of the descriptions.\nClinical description\nIn NLSDI, generalized ichthyosis occurs in 95% of cases, moderate myopathic syndrome (or abnormal serum muscle enzyme levels), intellectual deficit and moderate hepatomegaly (or functional impairment of the liver) occur in 60% of cases, ocular (cataract, retinopathy) and hearing abnormalities (deafness) occur in 40% of cases, and neuropathy and short stature occur in 20% of cases.\nEtiology\nNLSDI/Dorfman-Chanarin disease is caused by mutations in the ABHD5 gene (3p21), NLSDM by mutations in the PNPLA2/ATGL gene (localized to 11p15.5).\nDiagnostic methods\nBiological diagnosis is based on evidence of leukocytes in the vacuoles of neutral lipids and a deficiency in the degradation of cytoplasmic triglycerides in cultured cells (lymphoblasts or fibroblasts), while mitochondrial function (in particular the transport and b-oxidation of fatty acids) is normal. Genetic diagnosis is also possible.\nDifferential diagnosis\nDifferential diagnoses include mitochondrial diseases with accumulation of cytoplasmic triglycerides (deficiencies in carnitine, cartinine palmitoly transferase or fatty acid oxidation enzymes; see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible by genetic testing (for mutations in chorionic or amniotic cells) when parental mutations have been identified.\nGenetic counseling\nTransmission of the disorder is autosomal recessive.\nManagement and treatment\nThere is no treatment to correct the metabolic deficiency.\nPrognosis\nFor NLSDI/Dorfman-Chanarin disease, the severity of the disease is linked to the myopathy and any associated disorders (which may include ocular and cerebral involvement). The evolution of the disease varies between patients, but is relatively slow because some patients reach late adulthood.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Judith FISCHER  - Dr Anne NEGRE-SALVAYRE  - Pr Robert SALVAYRE"}
{"Disease Name": "Neutropenia-monocytopenia-deafness syndrome", "Disease Definition": "Neutropenia-monocytopenia-deafness syndrome is characterised by neutropenia with myeloid marrow hypoplasia, monocytopenia, and congenital deafness. It has been described in three siblings who suffered recurrent bacterial infections.", "ORPHA ID": 2690, "Summary": ""}
{"Disease Name": "NEVADA syndrome", "Disease Definition": "A rare, life-threatening, cutaneous disease characterized by a keratinocytic epidermal nevus presenting thick, hystrix-like, white or brownish hyperkeratosis associated with multiple extracutaneous vascular malformations, including angiodysplasia that involves large-vessel arteriovenous shunts that may be fatal during the neonatal period.", "ORPHA ID": 370059, "Summary": ""}
{"Disease Name": "Nevus comedonicus syndrome", "Disease Definition": "A rare, syndromic nevus characterized by the association of typically unilateral, closely arranged, linear, slightly elevated, multiple, nevus comedonicus lesions located usually on the face, neck, trunk or limbs (with or without a central, dark, firm, hyperkeratotic plug and secondary acneiform lesions) with extracutaneous ocular, skeletal, and/or central nervous system abnormalities, such as ipsilateral cataract, corneal erosion, poly-/syndactyly, absent fifth finger, scoliosis, vertebral defects, corpus callosum agenesis, seizures, interhemispheric cyst, intellectual deficiency, and/or developmental delay.", "ORPHA ID": 64754, "Summary": ""}
{"Disease Name": "Nevus of Ito", "Disease Definition": "Nevus of Ito is a benign dermal melanocytosis occurring most frequently in the Asian populations and characterized by unilateral, asymptomatic, blue, gray or brown skin pigmentation within the acromioclavicular and upper chest area (involving the side of the neck, the supraclavicular and scapular areas, and the shoulder region). It is usually diagnosed in early infancy and in early adolescence. Nevus of Ito may progressively enlarge and darken in color (particularly with puberty) and its appearance usually remains stable once adulthood is reached. Spontaneous regression does not occur. Malignant melanoma has rarely been reported within a nevus of Ito. It shares the clinical features of nevus of Ota, except its anatomic location and in rare occasions, mayoccur together with the latter.", "ORPHA ID": 263432, "Summary": ""}
{"Disease Name": "Nevus of Ota", "Disease Definition": "Nevus of Ota is an oculodermal melanocytosis more commonly found in Asian and African populations, usually present at birth and characterized by a usually unilateral, bluish gray, patchy, speckled pigmentation (that may progressively enlarge and darken) affecting the skin of the face along the distribution of the ophthalmic and maxillary divisions of the trigeminal nerve (periorbital region, temple, forehead, malar area, nose). In 2/3 cases the ipsilateral sclera is affected. Nevus of Ota usually remains stable once adulthood is reached but an increased risk of glaucoma and uveal melanoma may be observed. Extracutaneous lesions may also occur in cornea, retina, tympanum, nasal mucosa, pharynx, palate. Nevus of Ota occurs as solitary conditions but seldom may occur together with the nevus of Ito or nevus spilus.", "ORPHA ID": 263425, "Summary": ""}
{"Disease Name": "New-onset refractory status epilepticus", "Disease Definition": "New-onset refractory status epilepticus is an acute encephalopathy with inflammation-mediated status epilepticus characterized by an acute refractory status epilepticus, typically of the tonic-clonic type, following prodromal symptoms of confusion, fever, fatigue, headache, symptoms of gastrointestinal or upper respiratory tract infection, behavioral changes or hallucinations. Brain MRI abnormalities and abnormal findings in CSF, including pleocytosis and/or elevated protein levels, are frequently found during acute episode. Treatment-resistant epilepsy, cognitive and psychiatric impairments are usual consequences.", "ORPHA ID": 363558, "Summary": ""}
{"Disease Name": "Nicolaides-Baraitser syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability characterized by short stature, sparse hair, characteristic coarse face, brachydactyly with prominent interphalangeal joints, seizures and intellectual disability. Facial characteristics include triangular shaped face, dense and prominent eyelashes, rounded premaxilla, broad nasal base, thick alae nasi, upturned nasal tip, broad philtrum, thin upper vermilion, thick and everted lower vermilion and wide mouth.", "ORPHA ID": 3051, "Summary": "Epidemiology\nAlthough the prevalence of the disorder is unknown, it is thought to be less than 1/1,000,000. To date, there are fewer than 100 molecularly confirmed, affected individuals reported in the literature. No significant difference in male-to-female ratio or geographical distribution has been reported.\nClinical description\nAt birth, patients may be small for gestational age (one-third of cases), have facial hypertrichosis, a low anterior-lateral hairline, and microcephaly (one-quarter). Postnatally, microcephaly and proportional short stature is present in over half of the patients. Sparse scalp hair is present in almost all patients and may be evident in the first months of life. Prominent inter-phalangeal joints due to decreased subcutaneous fat, are the most characteristic sign, and may be accompanied by fetal pads (half of patients). Radiological findings of the hands include short metacarpals, short phalanges, cone-shaped epiphyses, and ivory epiphyses in a few cases. Patients can show mild shortening of the toes, sandal gap and some thickening of the distal phalanx of the hallux. Most of these characteristics, particularly limbs and facial features, tend to be more evident with time. Hypotonia is reported in one third of patients, but major motor milestones such as sitting and walking independently are usually not very delayed. Intellectual disability (ID) is severe in nearly half, moderate in a third, and mild in the remainder of cases. Nearly a third never develop speech or language skills. Epilepsy occurs in two-thirds of patients, with onset between 18 to 24 months, and may correlate with regression. Seizure type is variable, even within the same individual and can be difficult to manage. Disposition is generally happy and very friendly, but temper outbursts and bouts of aggression are possible. Other congenital anomalies are variably observed.\nEtiology\nThe disorder is due to missense variants (80% of case) or intragenic deletions in SMARCA2 (9p24.3). This gene encodes a protein belonging to the ATP-dependent chromatin remodeling enzymes, implicated in the regulation of gene expression and cell cycle control. In almost 17% of patients, no variant has been identified.\nDiagnostic methods\nDiagnosis is suspected on peculiar combination of facial features with sparse hair, intellectual disability, brachydactyly with prominent interphalangeal joints and seizures. Molecular diagnosis is based on identification of variants in SMARCA2.\nDifferential diagnosis\nDifferential diagnosis includes Coffin-Siris syndrome, Williams syndrome and Cornelia de Lange syndrome.\nAntenatal diagnosis\nIf the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at theoretic increased risk is possible.\nGenetic counseling\nTransmission is autosomal dominant. To date, all affected individuals have had a de novo SMARCA2 pathogenic variant, suggesting a low risk to siblings. However, because of the theoretic possibility of parental germline mosaicism, the empiric recurrence risk to siblings is approximately 1%.\nManagement and treatment\nClinical management requires periodical evaluation by a child neurologist/neuropsychiatrist in order to monitor the evolution of the intellectual development or onset of seizures. Enabling and supporting therapies (including non-verbal communication) and special school program are required. Anti-epileptic drugs appear necessary for controlling seizures, sometimes unsuccessfully and with consequent need for hospitalization. Regular follow up of ophthalmologic and/or audiologic abnormalities is recommended.\nPrognosis\nPrognosis is variable and is predominantly influenced by the age of onset of seizures and the difficulty in managing it. Independent living depends on the degree of intellectual disability, and is likely never totally achieved.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Gianluca CONTRO | ITHACA* - Dr Livia GARAVELLI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Niemann-Pick disease type C", "Disease Definition": "A rare lysosomal lipid storage disease characterized by variable clinical signs, depending on the age of onset, such as prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly, and progressive, often severe neurological symptoms such as cognitive decline, cerebellar ataxia, vertical supranuclear gaze palsy (VSPG), dysarthria, dysphagia, dystonia, seizures, gelastic cataplexy, and psychiatric disorders.", "ORPHA ID": 646, "Summary": "Epidemiology\nPrevalence at birth of Niemann-Pick disease type C (NPDC) ranges between 1/45,000-286,000 worldwide.\nClinical description\nThe clinical onset and presentation is heterogeneous. NPDC is classically a neurovisceral condition with hepatosplenomegaly usually preceding the neurological symptoms, occurring in infancy or childhood but possibly occurring much later. Some patients exhibit lung disease early on and a small subset of patients can develop rapidly deteriorating hepatic or respiratory failure in early infancy. Neurological onset varies between early infancy to adulthood. Typically, neurologic involvement is progressive and consists mainly of dystonia, cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. VSGP and cataplexy (with or without narcolepsy) are characteristic. Psychiatric disturbances are frequent in late-onset patients.\nEtiology\nMost patients (95%) have mutations in the NPC1 gene (localized to 18q11.2), which encodes a membrane glycoprotein. The remainder have mutations in the NPC2 gene (localized to 14q24.3 ), which encodes a soluble lysosomal protein that binds cholesterol. The loss of function of those proteins blocks cholesterol egress from lysosomes leading to accumulation of lipid membrane components (unesterified cholesterol, glucosylceramide, and gangliosides) in the late endosomal/lysosomal compartment of the cell.\nDiagnostic methods\nThe diagnosis of NPDC must be confirmed by mutation analysis and, if necessary, filipin test (based on the reaction of unesterified cholesterol with fluorescent antibiotic filipin). Several biomarkers are used alone or in combination as a first-line test to screen for NPDC: oxysterols (cholestane-3β, 5α, 6β-triol); lyso-SM-509 and lyso-sphingomyelin. Foam cells and sea-blue histiocytes are usually present in the bone marrow.\nDifferential diagnosis\nIn the first 2 years of life, NPDC must be differentiated from Niemann-Pick types A and B, Wolman disease, Gaucher disease type II/III, idiopathic neonatal hepatitis, and other causes of cholestatic jaundice. In older children and adults, neurodegenerative disorders such as mitochondrial diseases, Wilson disease, late-onset lysosomal storage diseases, Friedreich Ataxia, progressive supranuclear palsy, Huntington disease, Alzheimer disease, Pick disease, frontotemporal dementias, amyotrophic lateral sclerosis, primary psychiatric illnesses must be ruled out. Acquired conditions such as pineal region or midbrain tumors, attention-deficit disorder, learning disabilities, absence seizures, other dementia illnesses, HIV encephalopathy, sleep disorders, and syncope also should also be included in the differential diagnosis.\nAntenatal diagnosis\nPrenatal diagnosis of NPDC should be offered to couples at risk. Molecular genetic analysis is the preferred strategy.\nGenetic counseling\nNPDC is an autosomal recessive disease. Genetic counseling should be offered to at-risk couples informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement of NPDC remains largely symptomatic. Treatment with an iminosugar inhibitor of glucosylceramide synthase (miglustat) was approved for the management of neurologic manifestations of NPDC in several countries. There are presently some therapies under investigation, including 2-hydroxypropyl-beta-cyclodextrin and arimoclomol.\nPrognosis\nLifespan varies from a few days (in case of fetal hydrops) to a few decades. Death in early infancy can be due to either liver failure or severe pulmonary insufficiency (usually before 3-6 months). Early infantile, severe, neurological onset is often fatal between 3-5 years of age, late-infantile neurologic onset typically between 7-12, and juvenile neurologic onset between adolescence and 30 years of age.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Ekaterina ZAKHAROVA"}
{"Disease Name": "Night blindness-skeletal anomalies-dysmorphism syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphyc syndrome characterized by slowly progressive night blindness, skeletal abnormalities (sloping shoulders, joint hyperextensibility, minor radiological anomalies) and characteristic facial features (periorbital anomalies, malar flatness, retrognathia). Additional manifestations include myopia and extinguished electroretinograms. There have been no further descriptions in the literature since 1979.", "ORPHA ID": 1390, "Summary": ""}
{"Disease Name": "Nijmegen breakage syndrome-like disorder", "Disease Definition": "Nijmegen breakage syndrome-like disorder is a rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by growth retardation, short stature, developmental delay, intellectual disability, craniofacial dysmorphism (i.e. severe microcephaly, sloping forehead, prominent eyes, broad nasal ridge, hypoplastic nasal septum, epicanthal folds), spontaneous chromosomal instability, cellular hypersensitivity to ionizing radiation and radioresistant DNA synthesis, without severe infections, immunodeficiency or cancer predisposition. Additional reported features include mild spasticity, slight and nonprogressive ataxia, hyperopia, multiple pigmented nevi, widely spaced nipples, and clinodactyly.", "ORPHA ID": 240760, "Summary": ""}
{"Disease Name": "Nijmegen breakage syndrome", "Disease Definition": "A rare, genetic chromosomal instability syndrome presenting at birth with microcephaly, dysmorphic facial features which become more noticeable with age, growth delay, recurring sinopulmonary infections and extremely high frequency of malignancies.", "ORPHA ID": 647, "Summary": "Epidemiology\nWhilst global prevalence is unknown, the disease seems to occur worldwide, but has a much higher prevalence among Central and Eastern European Slavic populations due to a founder mutation. Average prevalence of NBS in patients with Eastern Slavic origin (Belarus, Ukraine, Russia, and Latvia) was recently estimated as 1/1,000,000 and, based on carrier frequency, the prevalence in the Western Slavic region (Poland, Slovakia and Czech Republic) is estimated at 1/330,000.\nClinical description\nClinical manifestations are not pathognomonic and may vary in severity. The main signs are microcephaly, present at birth and progressing with age, dysmorphic facial features (prominent midface emphasized by a sloping forehead and receding mandible), mild growth retardation and, in females, premature ovarian insufficiency are common. Various congenital anomalies have been reported, including central nervous system (hydrocephaly, schizencephaly, arachnoid cysts), respiratory tract (cleft lip/palate, choanal atresia), urogenital system (horseshoe kidney, ectopic/dystopic kidneys, hypospadias, cryptorchidism, ovary hypoplasia), mild skeletal anomalies (pre- and postaxial polydactyly, hypoplastic or duplicated thumb, clinodactyly of 5th fingers). Café au lait and/or vitiligo spots are frequently observed and, in some patients, multiple pigmented nevi occur. Other principal manifestations include immune deficiency with recurrent respiratory tract infections, a strong predisposition to malignancies (predominantly lymphoid, but solid tumors also occur), and radiosensitivity. By age 20, over 40% of patients develop a malignant disease and are prone to develop secondary malignancies. Cognitive development is close to the average (normal/borderline) in infancy and preschool age, but intellectual skills gradually decline with age (from mild to moderate).\nEtiology\nNijmegen breakage syndrome (NBS) is caused by mutations in the NBN gene (8q21-q24), specifically within exons 6-10, which lead to partially functional truncated fragments of nibrin, the gene product involved in repairing DNA double strand breaks. Over 90% of patients are homozygous for the founder mutation of Slavic origin (c.657_661del5).\nDiagnostic methods\nDiagnosis is based on the clinical manifestations and confirmed by either single gene sequencing (typically for Slavic populations) or multigene next generation sequencing panels. Where genetic testing is unavailable, diagnosis can be supported by evidence of chromosomal instability (spontaneous and induced), increased cellular sensitivity to ionizing radiation in vitro, combined immunodeficiency, and complete absence of full-length nibrin. A family history (malignancies, microcephaly or hydrocephaly, early death of a sibling) can also support diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes Fanconi anemia, LIG4 syndrome, Cernunnos-XLF deficiency, NBS-like disorder, ataxia-telangiectasia-like disorder, Bloom syndrome.\nAntenatal diagnosis\nAffected families may be offered prenatal diagnosis by molecular analysis if both disease-causing gene mutations are known.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Parents of an affected child are obligate carriers of NBN mutations and thus, for each pregnancy, there is a 25% risk that offspring inherit the disease. Carriers of a Slavic founder mutation should be offered monitoring for cancer, in particular breast in women and prostate in men.\nManagement and treatment\nThere is no specific therapy. Early diagnosis is important to avoid severe recurrent infections, unnecessary radiation exposure for diagnostic purposes and adverse effects of radiotherapy of tumors. Patients require multidisciplinary management and long-term follow-up (malignancy, immunodeficiency, growth, hypergonadotropic hypogonadism in females). Monitoring of the immune system is extremely important throughout life; specific modes and types of immunization are necessary (acellular vaccines are recommended). In case of lymphoid malignancy, hematopoietic stem cell transplantation (HSCT) is recommended after the first complete remission. Females should be monitored for puberty progress from the age of 12 (endocrinologist/ gynecologist) and hormonal replacement therapy should be offered at appropriate age.\nPrognosis\nPrognosis is poor, with malignancy as the major cause of death. Patients who developed lymphoma or leukemia died from disease progression, relapses and secondary malignancies. A beneficial effect of HSCT on the long-term survival has been confirmed in recent studies.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Krystyna CHRZANOWSKA | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "NIK deficiency", "Disease Definition": "A rare, genetic, primary combined T and B cell immunodeficiency characterized by recurrent, severe viral and bacterial infections. Immunologic findings include decreased immunoglobulin levels, decreased numbers of B and NK cells, reduced relative CD19+ B cells in peripheral blood, impaired memory responses to viral infections and defective antigen-specific T-cell proliferation.", "ORPHA ID": 447731, "Summary": ""}
{"Disease Name": "Nipah virus disease", "Disease Definition": "Nipah virus disease, caused by the Nipah virus, is a recently discovered zoonotic disease characterized by fever, constitutional symptoms and encephalitis, sometimes accompanied by respiratory illness.", "ORPHA ID": 99825, "Summary": "Epidemiology\nNipah virus disease is endemic to south Asia, where sporadic outbreaks have been noted in Malaysia, Singapore, India, and Bangladesh since the virus was first isolated in 1999. Less than 20 cases are typically reported per year worldwide, although systematic surveillance is lacking.\nClinical description\nThe incubation period is typically 4-20 days. Patients usually present with fever, malaise, headache, myalgia, sore throat, nausea and vomiting, sometimes accompanied by vertigo and disorientation. Severe cases progress to encephalitis, which may be complicated by seizures and coma. Atypical pneumonia, sometimes leading to the acute respiratory distress syndrome, may be seen. Asymptomatic infections have been documented. Cases of relapse occurring weeks or even months after recovery have also been described. Neurologic sequelae occur in up to 20% of survivors of Nipah encephalitis and include persistent seizures and personality or mood changes.\nEtiology\nNipah virus is a member of the Paramyxoviridae family, genus Henipavirus. The virus appears to be maintained in fruit bats (Pteropus genus), which may infect humans through direct exposure to their saliva or excreta, including through contaminated food, especially palm tree sap. Bats may also transmit the virus to intermediate hosts, especially pigs, which develop respiratory disease and may pass the virus on to humans. Serologic evidence of infection has also been noted in cats, dogs and horses. Swine farmers and abattoir workers are at increased risk. Human-to-human transmission has been occasionally noted through exposure to bodily fluids.\nDiagnostic methods\nCommon diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories.\nDifferential diagnosis\nNipah virus disease is difficult to distinguish from a host of other febrile illnesses, at least during its onset. More common causes of viral pneumonia, including adenovirus and influenza, and viral encephalitis, in particular Japanese encephalitis (see this term), which is also transmitted by swine, need to be excluded.\nManagement and treatment\nPatients should be isolated and precautions (face shields, surgical masks, double gloves, surgical gowns and aprons) should be used to prevent nosocomial transmission. As there is presently no antiviral drug available for Nipah virus disease, treatment is supportive. Ribavirin has been used on a few patients but its efficacy for Nipah virus disease has not yet been determined.\nPrognosis\nThe case-fatality varies from 40-70% depending on whether encephalitic or severe manifestations are noted and whether adequate healthcare facilities are available. Advanced age, underlying diabetes, and neurological symptoms confer a poor prognosis.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Daniel BAUSCH  -  Andrew BENNETT"}
{"Disease Name": "NK-cell enteropathy", "Disease Definition": "Natural killer (NK)-cell enteropathy is a benign NK-cell lymphoproliferative disease characterized by minor abdominal symptoms (abdominal pain, diverticulosis, constipation and reflux) due to NK cell-derived lesions in the mucosal layer of the gastrointestinal tract and often mistaken for NK or T-cell lymphoma (see these terms).", "ORPHA ID": 263665, "Summary": ""}
{"Disease Name": "NKX6-2-related autosomal recessive hypomyelinating leukodystrophy", "Disease Definition": "A rare leukodystrophy characterized by a spectrum of progressive neurologic manifestations comprising rapidly progressive early-onset nystagmus, spastic tetraplegia, and visual and hearing impairment, resulting in death in early childhood, as well as later onset of slowly progressive complex spastic ataxia with pyramidal and cerebellar symptoms and loss of developmental milestones. Brain imaging shows diffuse hypomyelination of the subcortical and deep white matter, cerebellar atrophy, and diffuse spinal cord volume loss.", "ORPHA ID": 527497, "Summary": ""}
{"Disease Name": "NLRC4-related familial cold autoinflammatory syndrome", "Disease Definition": "A rare hereditary periodic fever syndrome characterized by infantile or childhood onset of episodes of fever and cold-induced urticaria-like rash and arthralgias. Ocular features such as conjunctivitis and uveitis may also be present. Presentation is typically mild, and symptoms resolve without treatment in most cases.", "ORPHA ID": 576349, "Summary": ""}
{"Disease Name": "NLRP12-associated hereditary periodic fever syndrome", "Disease Definition": "A rare autoinflammatory syndrome characterized by episodic and recurrent periods of fever combined with various systemic manifestations such as myalgia, arthralgia, joint swelling, urticaria, headache and skin rash. Common trigger of these episodes is cold.", "ORPHA ID": 247868, "Summary": ""}
{"Disease Name": "NLRP3-associated autoinflammatory disease", "Disease Definition": "Cryopyrin associated periodic syndrome (CAPS) defines a group of autoinflammatory diseases, characterized by recurrent episodes of systemic inflammatory attacks in the absence of infection or autoimmune disease. CAPS comprises 3 disorders on a continuum of severity: severe CINCA syndrome, intermediate Muckle-Wells syndrome (MWS) and milder familial cold urticaria (FCAS) (see these terms).", "ORPHA ID": 208650, "Summary": "Epidemiology\nThe prevalence in France is estimated to be 1/360,000. Males and females are equally affected.\nClinical description\nCAPS comprises 3 disorders on a continuum of severity: FCAS which usually has an early-onset after birth (< 20 years), and is characterized by recurrent episodes of urticarial rash triggered by exposure to cold, low-grade fever (malaise), conjunctivitis, abdominal discomfort, and arthromyalgia; MWS which usually presents at birth or later in childhood, with recurrent urticarial rash, fever, abdominal pain, arthralgia/arthritis, myalgias, secondary amyloidosis (see this term) and/or premature deafness; and CINCA syndrome characterized by the triad of arthropathy, chronic urticarial rash (neonatal onset), and central nervous system (CNS) involvement (ranging from hearing loss to chronic aseptic meningitis and intellectual disability). Non-pruriginous urticarial rash (diffuse, erythematous, edematous plaques on a background of generalized, faintly erythematous patches) is a key feature of CAPS and is generally present with marked intensification during acute episodes. These disorders were previously thought to be distinct conditions but represent now three grades of severity in which FCAS and CINCA syndrome are the extremes in a single spectrum of clinical manifestations.\nEtiology\nCAPS is due to mutations in the  NLRP3 (1q44; gene encoding cryopyrin), which result in a gain of function of cryopyrin, leading to increased secretion of interleukin (IL)-1 beta and and dysregulated inflammation. Patients with identical amino acid substitution may present distinct clinical subtypes, suggesting the role of additional genetic and/or environmental factors in disease expression. Somatic NLRP3 mosaicism could explain 30-60% of these patients. Some patients with MWS, FCAS or CINCA syndrome may not have mutations in NLRP3.\nDiagnostic methods\nDiagnosis is based on clinical manifestations and on laboratory findings revealing generalized leukocytosis and neurophilia along with others elevated acute phase reactants (C reactive protein and serum amyloid A). Progressive secondary amyloidosis manifests as proteinuria and is observed in the most severe cases (25% of cases). In CINCA syndrome, an increase in cytokine or neopterin levels in the cerebrospinal fluid may be detected. Histologic examination of affected skin shows a characteristic neutrophilic dermal infiltration in the reticular dermis. Diagnosis is confirmed by genetic screening of the NLRP3 gene.\nDifferential diagnosis\nDifferential diagnosis includes systemic-onset juvenile idiopathic arthritis, rheumatoid arthritis, systemic lupus erythematosus, familial mediterranean fever, Schnitzler syndrome, PLCG2-associated antibody deficiency and immune dysregulation, mevalonate kinase deficiency, TRAPS syndrome (see these terms), acquired cold and common allergic urticaria and serum sickness-like reaction.\nGenetic counseling\nCAPS can occur sporadically or be inherited as an autosomal dominant trait. In the latter case, genetic counseling may be proposed.\nManagement and treatment\nThe only effective treatment for CAPS is IL-1 blockade using anakinra, riloncept, or canakinumab. Supportive treatment is essential to manage the global burden of the disease including learning and cognitive impairment, growth and pubertal retardation, psychological /psychiatric distress, consequences of visual and hearing impairments.\nPrognosis\nCAPS is a life-long disease, and early diagnosis and early treatment may improve prognosis. With optimal treatment adjustments, progression of hearing loss and vision loss can be halted in most patients.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Isabelle KONE-PAUT"}
{"Disease Name": "NMDA receptor encephalitis", "Disease Definition": "A rare limbic encephalitis characterized by the presence of autoantibodies against NMDA receptors in serum and cerebrospinal fluid. It may be of paraneoplastic (most commonly associated with ovarian teratoma) or non-paraneoplastic origin and is life-threatening but potentially treatable. Patients present with acute behavioral change, psychosis, and catatonia, rapidly progressing to seizures, memory deficit, dyskinesias, speech problems, and autonomic and breathing dysregulation.", "ORPHA ID": 217253, "Summary": ""}
{"Disease Name": "Nocardiosis", "Disease Definition": "Nocardiosis is a local (skin, lung, brain) or disseminated (whole body) acute, subacute, or chronic bacterial infection.", "ORPHA ID": 31204, "Summary": "Epidemiology\nAnnual incidence in the United States is estimated at around 1/250,000 inhabitants, but may be underestimated. The exact incidence in Europe is unknown. Men are more frequently affected than women (sex ratio: 3:1).\nClinical description\nNocardiosis may occur in any age group, but it is more common in middle-aged adults. Clinical manifestations depend on the site of infection. Most patients present with pulmonary disease. Frequent signs are fatigue, fever, chills, coughing (similar to the cough in pneumonia or tuberculosis), dyspnea, pleural chest pain, and weight loss. Primary cutaneous nocardiosis may present as cutaneous, lymphocutaneous or subcutaneous infection. Cutaneous infection manifests as cellulitis, pustules, pyoderma, paronychia, ulcerations or localized abscesses. Similar lesions are present with lymphocutaneous infection but are associated with ascending regional lymphadenopathy. Subcutaneous infection manifests as the apparition of mycetoma (see this term), predominantly affecting the extremities. Disseminated nocardiosis typically affects immunocompromised hosts. Lesions in the brain or meninges are frequent.\nEtiology\nThe disease is caused by Nocardia infections. Nocardia is an aerobic, Gram-positive branching filamentous bacteria found in soil, decaying vegetable matter, and aquatic environments. Infection may occur through direct inhalation or inoculation. At least 13 species of Nocardia are reported to cause human disease, with the most frequently identified causes being N. asteroids complex and N. brasiliensis. Nocardiosis is often associated with a patient history of trauma (puncture wounds or cat scratches), immunodeficiency, resistance to previous antibiotic therapy, or fever.\nDiagnostic methods\nThe diagnosis is based on analysis of cultures of the causative organism from the infection site and on identification of Nocardia throughmolecular techniques (RFLP or PCR assays). Chest radiography may also be required.\nDifferential diagnosis\nThe differential diagnosis should include tuberculosis, aspergillosis, histoplasmosis, Kaposi sarcoma, sporotrichosis, non-Hodgkin lymphoma (see these terms), lung abscess and pneumonia.\nManagement and treatment\nManagement includes antibiotic therapy, in particular with trimethoprim-sulfamethoxazole (TMP-SMX). The duration of therapy (1 to 12 months) depends on the type of Nocardia infection. Surgical resection may be feasible for localized abscesses.\nPrognosis\nPrognosis is generally favorable, except in cases of disseminated nocardiosis in immunocompromised patients.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr François TREMOLIERES"}
{"Disease Name": "Nodal marginal zone B-cell lymphoma", "Disease Definition": "Nodal marginal zone B-cell lymphoma is a rare, indolent B-cell non-Hodgkin lymphoma, characterized by abnormal clonal proliferation of mature B-lymphocytes with involvement of the lymph nodes, sometimes the bone marrow, and rarely the blood. Clinically it presents with disseminated peripheral, abdominal and/or thoracic lymphadenopathy. Cytopenia and bulky tumors (greater than 5 cm) are rare. Association with Hepatitis C virus and chronic inflammation has been reported.", "ORPHA ID": 86867, "Summary": ""}
{"Disease Name": "Nodular cutaneous amyloidosis", "Disease Definition": "Primary localized cutaneous nodular amyloidosis (PLCNA) is the most rare form of primary cutaneous amyloidosis (see this term), a skin disease characterized by the accumulation of amyloid deposits in the dermis, characterized clinically by yellowish waxy crusted nodules and papules on the face, lower extremities, trunk, scalp, and genitalia and histologically by the localized deposition of immunoglobulin-derived amyloid in the papillary dermis and subcutis. PLCNA can be associated with connective tissue disorders such as Sjögren’s syndrome and CREST syndrome (see these terms).", "ORPHA ID": 137810, "Summary": ""}
{"Disease Name": "Nodular fasciitis", "Disease Definition": "A rare soft tissue tumor characterized by a solitary mass-forming fibrous proliferation that usually occurs in the subcutaneous tissue, composed of uniform fibroblastic/myofibroblastic cells displaying a loose growth pattern. Upper extremities, trunk, and head and neck are most frequently affected. The lesion typically grows rapidly and almost always measures less than five centimeters in diameter. Macroscopically, it may appear circumscribed or infiltrative but is not encapsulated. Recurrence after excision is very rare, and metastasis does not occur.", "ORPHA ID": 477742, "Summary": ""}
{"Disease Name": "Nodular lichen myxedematosus", "Disease Definition": "Nodular lichen myxedematosus is a rare form of localized lichen myxedematosus (see this term) characterized by the development of skin-coloured mucinous nodules on the limbs and trunk, with mild or absent papular eruption.", "ORPHA ID": 90393, "Summary": ""}
{"Disease Name": "Nodular lymphocyte predominant Hodgkin lymphoma", "Disease Definition": "Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma (HL; see this term) characterized histologically by malignant lymphocyte predominant (LP) cells and the absence of typical Hodgkin and Reed-Sternberg (HRS) cells.", "ORPHA ID": 86893, "Summary": "Epidemiology\nNLPHL accounts for only 5-10% of HL cases and has an annual incidence of approximately 1/ 830,000.\nClinical description\nDisease onset usually occurs before the age of 40 and there is a 3:1 male predominance for the disease. Unlike classical Hodgkin lymphoma (CHL; see this term) NLPHL has a greater tendency to be restricted to peripheral lymph nodes (neck, axilla or inguino-femoral). Mediastinal involvement is rare and nodal spread is discontiguous. More than 80% of cases present with stage 1 or 2 disease. B-symptoms (fever, drenching night sweats and unexplained weight loss) are also less commonly observed and there is usually no impaired immunity in NLPHL patients. Extranodal disease is extremely uncommon in NLPHL but it can occur in the spleen (10-15% of cases), the liver (<5% of cases) and bone marrow or lungs (<5% of cases). Long-term complications include secondary malignancies (diffuse large B-cell lymphoma (25% risk by 20 years; see this term) or epithelial cancers (lung, breast, GI), which often arise from within a prior irradiated area).\nEtiology\nThe exact cause is unknown. Unlike the Hodgkin cells and multinucleated Reed-Sternberg (HRS) cells seen in CHL, LP cells are usually negative for all EBV markers. Genetics may play a role as LP cells frequently contain rearranged immunoglobulin genes and chromosomal abnormalities are observed in two thirds of cases.\nDiagnostic methods\nA biopsy (usually of a lymph node) is first performed in order to diagnose NLPHL. Diagnosis is based on the presence of CD20 positive, CD15 negative and CD30 negative LP cells. LP cells are monoclonal B cells of germinal center origin. Staging (based on the Cotswold staging system) is then performed in order to determine the severity and spread of NLPHL and decide on the best course of therapy.\nDifferential diagnosis\nDifferential diagnosis includes lymphocyte-rich classical HL (see this term), progressive transformation of germinal centers and T-cell rich large B-cell lymphoma.\nManagement and treatment\nPreviously the usual treatment for limited stage 1 or 2 disease was involved-field radiation therapy (IFRT) at 30-36Gy; however; many authorities now recommend that NLPHL be treated the same as CHL. Chemotherapy or combined modality therapy is necessary in advanced disease stages. Relapses are common (seen in 10-15%) and can occur multiple times. In cases where salvage therapies used in CHL are unsuccessful, rituximab shows promise for the treatment of recurrent NLPHL as it attacks LP cells via surface CD20. Patients need to be monitored for secondary malignancies and cardiopulmonary disease as these long-term complications can arise due to therapy-related toxicity.\nPrognosis\nPrognosis is good with usually a 90-100% remission rate with primary therapy. Relapse is common (seen in 10-15% of patients) and occurs on average 3-6 years after diagnosis. Overall 10 year survival rates are >90% in limited stage disease.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Joseph CONNORS"}
{"Disease Name": "Nodular neuronal heterotopia", "Disease Definition": "A rare non-syndromic cerebral malformation due to abnormal neuronal migration characterized by clusters of disorganized neurons in abnormal locations such as periventricular and subcortical. The extent of the lesions ranges from isolated single to bilateral confluent nodules. Pediatric patients typically show variable degrees of developmental delay, intellectual disability, and intractable epilepsy, and concomitant cerebral and/or systemic malformations are frequent. Milder forms may present with onset of seizures in adulthood.", "ORPHA ID": 2149, "Summary": ""}
{"Disease Name": "Nodular non-suppurative panniculitis", "Disease Definition": "A rare skin disorder characterized by recurring inflammation in the subcutaneous layer of fat.", "ORPHA ID": 33577, "Summary": "Epidemiology\nNodular non-suppurative panniculitis, known as Weber-Christian disease (WCD) prevalence is unknown. It occurs more often in adult women (approximately 75% of reported cases).\nClinical description\nWCD is characterized by single or multiple, tender or painful edematous and often erythematous subcutaneous nodules (1-2 cm large, most often affecting the lower extremities) healing with a depressed scar. The upper extremities, buttocks, abdominal wall, breasts, and face can also be involved. In most cases WCD is associated with fever, malaise, myalgia, arthralgia, and abdominal pain. Nausea, vomiting, weight loss, and hepatomegaly may occur. The disease tends to recur at intervals of weeks or months. WCD can present as a severe systemic illness. Unusual nodule locations include the abdomen (as an abscess), mesentery of the small or large bowel (with bowel obstruction), lungs, heart, liver, spleen, adrenal glands, kidneys, scrotum, and cranium. In patients with systemic disease, morbidity and mortality are significant.\nEtiology\nEtiology remains unknown.\nDiagnostic methods\nHistological examination of a subcutaneous nodule is necessary to confirm the diagnosis (the fat lobules are replaced by neutrophils, lymphocytes, and histiocytes in the early stages, and by macrophages and fibrotic tissue later).\nDifferential diagnosis\nDifferential diagnosis includes erythema nodosum and erythema induratum of Bazin, which represent the commonest forms of predominantly septal panniculitis and predominantly lobular panniculitis with vasculitis, respectively, as well as a variety of distinctive disease entities associated with panniculitis. The latter comprise bacterial, viral and fungal infections, connective tissue disorders, disturbances of lipid metabolism, pancreatic and renal diseases, gout, lymphoproliferative neoplasia, trauma, alpha1-antitrypsin deficiency (see this term).\nManagement and treatment\nTreatment is symptomatic and supportive and may include systemic steroids and nonsteroidal anti-inflammatory drugs. Responses to fibrinolytic agents, hydroxychloroquine, azathioprine, thalidomide, cyclophosphamide, tetracycline, and cyclosporin A have been reported in some patients.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna ZAMBRUNO"}
{"Disease Name": "Nodular regenerative hyperplasia of the liver", "Disease Definition": "A form of portosinusoidal vascular disease characterized histologically by the absence of cirrhosis and diffuse benign transformation of the hepatic parenchyma into multiple small nodules (typically 1-3 mm).", "ORPHA ID": 48372, "Summary": ""}
{"Disease Name": "Noma", "Disease Definition": "Noma is a gangrenous disease that causes severe destruction of the soft and osseous tissues of the face.", "ORPHA ID": 2700, "Summary": "Epidemiology\nIts exact prevalence is unknown. The disease was present in the Western world up until the start of the 20th century, but it now mainly affects children between 2 and 6 years of age living in the poorest regions of the world. Rare cases of noma have been described in adults with severe immunodeficiency (individuals with AIDS or myelopathy, or those being treated with immunosuppressants) in Africa and in the Western world.\nClinical description\nIn addition to the severe facial destruction, children with noma often present with rhinolalia aperta, uncontrollable drooling, and socially handicapping halitosis. The most debilitating sequela is permanent jaw constriction. Spontaneous resolution of the disease is associated with the formation of extremely dense and fibrous scars that may lead to osseous ankylosis between the mandible and maxilla or the mandible and the malar bone. The buccal opening in these children is limited to between 0 and 10 mm making intake of solid foods problematic or impossible. The risk factors associated with noma are malnutrition, intercurrent disease such as rubella or malaria, poor oral hygiene, and the presence of a lesion of the gingival mucosa (an early sign of necrotising gingivitis).\nEtiology\nThe aetiology remains unknown. A bacterial aetiology has long since been suggested but carrying out extensive studies in the regions most affected by the disease is problematic. The few studies reported have indicated that bacteria from the Prevotella and Fusobacteria groups may play a role in the disease.\nManagement and treatment\nThe management of acute noma is aimed at improving the health status (introduction of a balanced diet and vitamin supplements, and sufficient hydration) of affected individuals and providing topical care. Antibiotics are recommended to prevent the often lethal complications associated with infection and to help limit extension of the lesion. If the lesion is still intrabuccal and limited, antibiotics may also prevent progression of the disease in some cases. Once the cicatrisation stage is complete, stepwise reconstructive surgery (aimed at relieving the stricture of the mouth and then reconstruction of the mandible and maxilla, cheek, lips and nose) can be considered. In addition to reconstruction of the face of affected children, reconstructive surgery can be used to allow improvement of impaired function (elocution, salivary continence, buccal opening).\nPrognosis\nNoma is associated with significant morbidity and mortality, often due to complications such as generalised sepsis, intracerebral septic emboli, bronchial aspiration or inanition. The disease develops very rapidly and in isolated regions medical care is often only sought after the lesions are well established. Delayed treatment will not allow a return to status quo ante. The disease leads to social exclusion of affected children: they are rarely admitted into schools for fear of contamination (which in reality does not occur) and are often rejected by their families and village, who continue to view noma as a malediction.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Denise BARATTI-MAYER"}
{"Disease Name": "Non-24-hour sleep-wake syndrome", "Disease Definition": "A rare neurological disease which is a circadian rhythm sleep disorder characterized by non-synchronization to a 24-hour day leading to insomnia and daytime sleepiness with sometimes severe associated manifestations.", "ORPHA ID": 73267, "Summary": "Epidemiology\nApproximately half of all people with complete blindness are thought to be affected by non-24 hour disorder. Rare cases are found in partially blind subjects. The disorder may be largely underdiagnosed in blind individuals. Sighted individuals with the disorder are far less numerous and about 100 cases have been reported in the medical literature to date.\nClinical description\nNon-24 hour sleep-wake syndrome can occur at any age in sighted individuals but often develops in childhood. In blind people, it can occur at any age. In affected patients, the circadian system does not synchronize with the 24-hour day. Patients have gradual delays in sleep onset time from one day to the next. Sleep onset therefore occurs later and later during the night and then eventually during the daytime. In rare cases, sleep onset time moves backward from one day to the next. Constant and changing misalignment between the patient's circadian rhythm and standard times can result in fragmented sleep and signs of sleepiness when the patient attempts to maintain a regular 24h sleep-wake cycle. These manifestations include diurnal sleepiness, nocturnal insomnia, and fatigue. Other repercussions may include headaches, depression, difficulty concentrating, confusion, memory disorders, decreased appetite, ataxia, and psychological difficulties (loneliness, isolation). At certain times, the sleep pattern coincides with standard times providing temporary remission of symptoms.\nEtiology\nDefective functioning of the suprachiasmatic nucleus (SCN) located in the hypothalamus, which controls circadian rhythms, is thought to underlie the disorder, especially in sighted patients. The circadian clock has a slight deviation from 24h (generally 24.2h) which is corrected in healthy people by environmental time cues (including the solar light-dark cycle). Core body temperature cycle and production of melatonin are also affected. Absence of perception of light in completely blind subjects is thought to lead to failed sleep training. Abnormal development of the brain, trauma, and iatrogenic factors may play a role in sighted patients with non-24 disorder.\nDiagnostic methods\nThe diagnosis is based on recurrent or relapsing insomnia and daytime drowsiness. The disorder should be suspected in blind individuals with recurrent insomnia and daytime sleepiness. At certain times, the sleep pattern coincides with standard times due to misalignment between the 24-hour light-dark cycle and the undeveloped endogeneous circadian rhythm. Symptoms persist for at least 3 months. Daily sleep logs and actigraphy, for at least 14 days, demonstrates a pattern of sleep and wake times that delay each day with a circadian period that is usually longer than 24 hours. A non-24-hour pattern of cortisol or melatonin secretion may assist diagnosis.\nDifferential diagnosis\nDifferential diagnoses include delayed sleep phase disorder, irregular sleep-wake disorder, sleep apnea syndrome, Kleine Levin syndrome, and idiopathic hypersomnia.\nManagement and treatment\nSome patients may find relief by following their own changing sleep-wake cycle. This is however generally not compatible with regular occupational and social constraints. Phototherapy in the morning and scototherapy late in the day has been found to successfully improve sleep cycles in some sighted patients. Melatonin can also be used to this end in both sighted and blind patients. Hypnotics and/or stimulants may also play a role in the management. Tasimelteon, a melatonin-receptor agonist, is used for treatment of non-24 hour disorder in blind patients without light perception.\nPrognosis\nWithout treatment, this disorder disrupts social, emotional and occupational functioning and may be severely debilitating.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Yves DAUVILLIERS"}
{"Disease Name": "Non-acquired combined pituitary hormone deficiency-sensorineural hearing loss-spine abnormalities syndrome", "Disease Definition": "Non-acquired combined pituitary hormone deficiency-sensorineural hearing loss-spine abnormalities syndrome is a rare, genetic, non-acquired, combined pituitary hormone deficiency disorder characterized by panhypopituitarism (with or without ACTH deficiency) associated with spine abnormalities, including frequent rigid cervical spine and short neck with limited rotation, and variable degrees of sensorineural hearing loss. The anterior pituitary gland is usually abnormal (typically hypoplastic) and rarely a mild developmental delay or intellectual disability may be associated.", "ORPHA ID": 231720, "Summary": ""}
{"Disease Name": "Non-acquired combined pituitary hormone deficiency", "Disease Definition": "Congenital hypopituitarism is characterized by multiple pituitary hormone deficiency, including somatotroph, thyrotroph, lactotroph, corticotroph or gonadotroph deficiencies, due to mutations of pituitary transcription factors involved in pituitary ontogenesis.", "ORPHA ID": 467, "Summary": "Epidemiology\nCongenital hypopituitarism is rare compared with the high incidence of hypopituitarism induced by pituitary adenomas, transsphenoidal surgery or radiotherapy. The incidence of congenital hypopituitarism is estimated to be between 1:3000 and 1:4000 births.\nClinical description\nClinical presentation is variable, depending on the type and severity of deficiencies and on the age at diagnosis. If untreated, main symptoms include short stature, cognitive alterations or delayed puberty.\nEtiology\nCongenital hypopituitarism is due to mutations of several genes encoding pituitary transcription factors. Phenotype varies with the factor involved: PROP1 (somatolactotroph, thyrotroph, gonadotroph and sometimes corticotroph deficiencies; pituitary hyper and hypoplasia), POU1F1 (somatolactotroph and thyrotroph deficiencies, pituitary hypoplasia), HESX1 (variable pituitary deficiencies, septo-optic dysplasia), and less frequently LHX3 (somatolactotroph, thyrotroph and gonadotroph deficiencies, limited head and neck rotation) and LHX4 (variable pituitary deficiencies, ectopic neurohypophysis, cerebral abnormalities).\nDiagnostic methods\nA diagnosis of combined pituitary hormone deficiency (CPHD) must be suspected when evident causes of hypopituitarism (sellar tumor, postsurgical or radioinduced hypopituitarism. . .) have been ruled out. Clinical, biological and radiological work-up is very important to better determine which transcription factor should be screened. Confirmation is provided by direct sequencing of the transcription factor genes.\nGenetic counseling\nType of transmission varies with the factor and the mutation involved (recessive transmission for PROP1 and LHX3, dominant for LHX4, autosomal or recessive for POU1F1 and HESX1).\nManagement and treatment\nAn appropriate replacement of hormone deficiencies is required. Strict follow-up is necessary because patients develop new deficiencies (for example late onset corticotroph deficiency in patients with PROP1 mutations).\nPrognosis\nPrognosis is equivalent to patients without pituitary deficiencies if treatment is started immediately when diagnosis is confirmed, and if a specialized follow-up is performed.\n\n                            Last update: \n                            March 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Thierry BRUE  - Dr Frédéric CASTINETTI"}
{"Disease Name": "Non-acquired isolated growth hormone deficiency", "Disease Definition": "A rare non-acquired pituitary hormone deficiency characterized by growth deficiency, delayed bone age, and short stature of variable severity and age of onset, and with variable response to treatment with recombinant human growth hormone, depending on the respective subtype of the disease. Hormone deficiency may be quantitative or qualitative in nature.", "ORPHA ID": 631, "Summary": ""}
{"Disease Name": "Non-acquired panhypopituitarism", "Disease Definition": "A rare genetic pituitary disease characterized by variable deficiency of all hormones produced in the anterior lobe of the pituitary gland. Clinical manifestations include hypothyroidism, hypogonadism, growth retardation and short stature, and secondary adrenal insufficiency. Age of onset is variable. Signs and symptoms usually develop gradually, and loss of the different hormones is often sequential.", "ORPHA ID": 90695, "Summary": ""}
{"Disease Name": 2, "Disease Definition": "Non-amyloid fibrillary glomerulopathy (non-amyloid FGP) is a rare cause of glomerulonephritis (GN) characterized by glomerular accumulation of non-amyloid fibrils in the mesangium and the glomerular (and rarely tubular) basement membrane, that mainly presents with renal insufficiency, micro-hematuria and nephrotic range proteinuria. Non-amyloid FGP and immunotactoid glomerulopathy (ITG, see this term) are often grouped together as pathogenetically related diseases.", "ORPHA ID": 97566, "Summary": "Epidemiology\nNon-amyloid FGP is encountered in approximately 0.5 to 1.0% of native kidney biopsies. A peak of occurrence between the fifth and sixth decades of life is observed. Females are slightly more affected than men, and the disease mainly affects the Caucasian population.\nClinical description\nThe disease is characterized by subnephrotic or nephrotic range proteinuria, frequently associated with macro- or microscopic hematuria, hypertension and renal insufficiency. Patients present with edema, ascites, pleural effusion and an elevated risk of blood clots and infection.\nEtiology\nNon-amyloid FGP etiology is unknown. The disease is generally considered idiopathic but it may be associated with secondary causes such as a monoclonal (mainly immunoglobulin G4; IgG4) or oligoclonal (containing both IgG1 and IgG4) gammopathy, hepatitis B and C infections, autoimmune diseases and malignancies.\nDiagnostic methods\nThe diagnosis of non-amyloid FGP is based on the biopsy specimen's absence of reactivity with Congo red and other agents typically used for the histochemical demonstration of amyloid tissues (i.e. Thioflavin T), as well as observation on light, fluorescence and electron microscopy. Crescents may be present, sometimes associated with crescentic fibrillary GN (FGN). Common histological patterns include those of a membranoproliferative GN, mesangial proliferative GN, diffuse proliferative GN with endocapillary exudation, sclerosing GN or membranous thickening of the capillary tufts. At the ultrastructural level, glomerular structures are infiltrated by amorphous acellular material composed of randomly arranged, non-branching fibrils, around twice the size of amyloid fibrils, and with no apparent lumen. Fibrillary deposits usually consist of polyclonal IgG and complement component 3. Granular electron-dense deposits may also be present and admixed among the accumulations of fibrils. Other laboratory features may include low serum albumin and an increase in creatinine and blood cholesterol.\nDifferential diagnosis\nDifferential diagnosis includes amyloidosis, ITG (see these terms) and the immune deposits seen in lupus nephritis (lupus membranous GN).\nManagement and treatment\nDifferent therapeutic strategies have been reported for the disease, but treatment options are still not defined. The treatment of nephrotic syndrome is based on prednisone, alone in patients with preserved renal function, or associated with cyclophosphamide in cases with crescentic FGN. Clinical trial data demonstrated the association of rituximab with a decrease of proteinuria and a possible role of rituximab in preventing or slowing the progression of renal disease in patients with preserved renal function has been hypothesized.\nPrognosis\nDespite treatment, non-amyloid FGP prognosis remains poor, with progression to end-stage renal failure occurring within a few months to a few years in about half of patients. Fibril deposition may recur in transplanted allografts but the recurrent disease has a relatively benign course.\n\n                            Last update: \n                            March 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Laure Hélène NOEL"}
{"Disease Name": "Non-amyloid monoclonal immunoglobulin deposition disease", "Disease Definition": "A rare, secondary glomerular disease characterized by proteinuria, dysproteinemias, nephrotic syndrome, and nodular glomerulopathy leading to renal failure, with or without extra-renal manifestations. The renal biopsy shows typical deposits of monoclonal immunoglobulins that do not show a fibrillar organization and are negative for Congo red staining. Associated signs and symptoms depend on the involvement of other organs, liver, heart, nerve fibers, gastrointestinal tract, or skin.", "ORPHA ID": 86861, "Summary": ""}
{"Disease Name": "Non-distal deletion 10q", "Disease Definition": "Non-distal monosomy 10q is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the long arm of chromosome 10, with a highly variable phenotype principally characterized by developmental delays (usually of language and speech), variable cognitive impairment and neurobehavioral abnormalities such as autism spectrum disorders and attention deficit disorder. Macrocephaly and mild dysmorphic features may by associated. Overlap with other syndromes, such as Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and juvenile polyposis syndrome has been reported.", "ORPHA ID": 1581, "Summary": ""}
{"Disease Name": "Non-distal deletion 12q", "Disease Definition": "A partial autosomal monosomy characterized by variable combination of developmental delay, intellectual disability, ectodermal, genitourinary and minor cardiac anomalies, and specific dysmorphic features (prominent forehead and low-set ears). Specific combination depends on the size and breakpoints of deleted regions.", "ORPHA ID": 96160, "Summary": ""}
{"Disease Name": "Non-distal duplication 10q", "Disease Definition": "Non-distal trisomy 10q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 10, characterized by mild to moderate developmental delay, postnatal growth retardation, central hypotonia, craniofacial dysmorphism (incl. microcephaly, prominent forehead, flat, thick ear helices, deep-set, small eyes, epicanthus, upturned nose, bow-shaped mouth, highly arched palate, micrognathia), ocular anomalies (e.g. iris coloboma, retinal dysplasia, strabismus), long, slender limbs and skeletal and digital anomalies (scoliosis, poly/syndactyly). Additional features reported include cardiac defects (e.g. septal ventricular defect), anal atresia, and cryptorchidism.", "ORPHA ID": 1695, "Summary": ""}
{"Disease Name": "Non-distal duplication 13q", "Disease Definition": "Non-distal trisomy 13q is a rare chromosomal anomaly disorder, resulting from the partial duplication of the proximal long arm of chromosome 13, with a highly variable phenotype principally characterized by increased polymorphonuclear leucocyte projections and persistence of fetal hemoglobin, as well as growth and developmental delay and craniofacial dysmorphism (incl. microcephaly, depressed nasal bridge, stubby nose, low-set, malformed ears, cleft lip/palate, micrognathia). Strabismus, clinodactyly and undescended testes in males may also be associated.", "ORPHA ID": 1702, "Summary": ""}
{"Disease Name": "Non-distal duplication 9q", "Disease Definition": "Non-distal trisomy 9q is a rare chromosomal anomaly syndrome, resulting from the partial trisomy of the long arm of chromosome 9, with a highly variable phenotype principally characterized by developmental delay, short stature, intellectual disability, and craniofacial dysmorphism (e.g. microcephaly, broad forehead, low set ears, epicanthus, prominent nose, and retrognathia). Cardiac, ocular, thyroid and esophagus defects, as well as central nervous system and behavioral/psychiatric abnormalities, have also been reported.", "ORPHA ID": 96112, "Summary": ""}
{"Disease Name": "Non-eruption of teeth-maxillary hypoplasia-genu valgum syndrome", "Disease Definition": "Noneruption of teeth - maxillary hypoplasia - genu valgum is an extremely rare syndrome that is characterized by multiple unerupted permanent teeth, hypoplasia of the alveolar process and of the maxillo-zygomatic region, severe genu valgum and deformed ears.", "ORPHA ID": 2972, "Summary": ""}
{"Disease Name": "Non-functioning paraganglioma", "Disease Definition": "A rare neuroendocrine tumor arising from neural crest-derived paraganglion cells (most often in the para-aortic region at the level of renal hilia, organ of Zuckerkandl, thoracic paraspinal region, bladder, and carotid body) not associated with catecholamine secretion. These tumors are usually clinically silent and symptoms, if present, are nonspecific and depend on the location of the tumor. Association with certain hereditary cancer-predisposing syndromes, such as multiple endocrine neoplasia, neurofibromatosis type 1 or von Hippel lindau syndrome, may be observed.", "ORPHA ID": 94080, "Summary": ""}
{"Disease Name": "Non-functioning pituitary adenoma", "Disease Definition": "A rare pituitary tumor originating from normally hormone-producing cells of the adenohypophysis, characterized by a sellar or extrasellar mass manifesting with clinical signs secondary to mass effect, but without evidence for hormonal hypersecretion. Typical manifestations are visual disturbances, headaches, cranial nerve dysfunction, and hypopituitarism but the mass may also be discovered incidentally.", "ORPHA ID": 91349, "Summary": "Epidemiology\nPrevalence of pituitary adenoma in the general population ranges between 1/1000 - 1,300; non-functioning pituitary adenoma (NFPA) accounts for 15-30% of these. Annual incidence is estimated at 1/100,000 worldwide.\nClinical description\nNFPA is most often diagnosed in middle-aged adults (average age 50-60 years). The vast majority of NFPAs are revealed by mass effects on anatomic structures in the vicinity of the pituitary (headache, optic chiasm compression) and/or on pituitary hormonal function, leading to hypopituitarism. Pituitary stalk compression can also produce hyperprolactinemia causing amenorrhea and galactorrhea. Pituitary apoplexy may be the presenting feature of NFPA, with severe headaches of sudden onset, meningismus, a variably depressed sensorium, and visual disturbances. However, an increasing proportion of pituitary tumors are detected incidentally on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain performed for unrelated reasons. Very rarely, gonadotropin hypersecretion can stimulate the gonads: macro-orchidism has been reported in males and an ovarian hyperstimulation syndrome in premenopausal women with FSH (Follicle Stimulating Hormone)-secreting tumors.\nEtiology\nNFPAs are sporadic in the vast majority. The gene aryl hydrocarbon receptor interacting protein, AIP (11q13.3), has been identified as a susceptibility factor, particularly in cases of familial isolated pituitary adenomas (FIPA) or when NFPA begins in childhood or adolescence. NFPA may also be part of multiple endocrine neoplasia syndrome such as MEN1 (gene MEN1, 11q13).\nDiagnostic methods\nAssessment of tumor volume and extension is based on imaging studies (MRI). Potential visual problems related to compression of optic pathways are diagnosed by evaluation of visual acuity, visual fields and occasionally optic coherence tomography (OCT). Hypopituitarism is diagnosed by measurement of the various pituitary hormones and hormones from the target glands (cortisol, thyroid hormones, etc.). Dynamic tests may be necessary, particularly for assessment of corticotropic axis. Hyperprolactinemia may be found related to pituitary stalk compression and disinhibition of the dopaminergic tone that normally acts at the level of pituitary lactotrophs. Gonadotropins serum levels, particularly FSH may be increased arguing for the gonadotroph nature of the NFPA.\nDifferential diagnosis\nIn case of hyperprolactinemia, prolactin (PRL) serum levels are always below 150-200 ng/ml in patients with NFPAs. This distinguishes them from macroprolactinomas, which are associated with much higher PRL levels proportional to tumor size. Other differential diagnoses include other tumors of the sellar region (meningiomas, craniopharyngiomas, metastasis, etc.) and inflammatory process (hypophysitis, sarcoidosis, histiocytosis).\nManagement and treatment\nTreatment is aimed at correcting (or preventing) tumor compression by excising the disease-causing lesion. Transsphenoidal surgery is often the first-line treatment. If a tumor remnant persists (a frequent situation in patients with large and often invasive adenomas), watchful waiting is preferred to routine radiotherapy, as long as the tumor residue does not grow. NFPA can sometimes recur even after complete resection. Postoperative irradiation is only considered in case of residual tumor growth or relapse. NFPA discovered incidentally may require a different approach, especially when they are small and/or remote from the optic pathways. If hypopituitarism persists, adequate hormone replacement is indicated.\nPrognosis\nA small excess mortality rate in women and in patients with a young age at diagnosis has been reported.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Philippe CHANSON"}
{"Disease Name": "Non-histaminic angioedema", "Disease Definition": "A disorder that is characterized by the occurrence of transitory and recurrent subcutaneous and/or submucosal edemas resulting in swelling and/or abdominal pain.", "ORPHA ID": 658, "Summary": "Epidemiology\nPrevalence is estimated at 1/100,000.\nClinical description\nTwo forms have been described: hereditary angioedema (HAE; 90% of cases) usually occurring in childhood or adolescence, and acquired angioedema (AAE) usually occurring after 50 years of age (see these terms). Patients present with white, circumscribed nonpruritic edemas that remain for a period of 48 to 72 hours and recur with variable frequency. The edemas may involve the digestive tract resulting in a clinical picture similar to that seen in intestinal occlusion syndrome, sometimes associated with ascites and hypovolemic shock. Laryngeal edema can be life-threatening with a risk of death of 25% in the absence of appropriate treatment. Dental procedures are a triggering factor for laryngeal edema. Edemas of the face are a risk factor for laryngeal involvement.\nEtiology\nAngioedema can be caused by quantitative or functional defects of the plasma protease C1 inhibitor (C1-INH encoded by the SERPING1 gene; 11q12-q13-1) or by gain-of-function mutations of coagulation factor 12 (Hageman factor; F12; 5q33-qter). Angioedema is triggered by bradykinin excess. Transmission of HAE is autosomal dominant and AAE may be associated with a lymphoproliferative syndrome or the presence of anti-C1-INH autoantibodies. It may also be a rare side effect of renin-angiotensin-aldosterone system blockers (RAAS-blocker-induced angioedema; see this term).\nDiagnostic methods\nDiagnosis is based on clinical findings, measurement of C4 concentrations and on quantitative and functional analysis of C1-INH. C1q levels are low in patients with AAE but are normal in patients with HAE.\nDifferential diagnosis\nDifferential diagnoses include intestinal occlusion syndrome and histamine-induced angioedema (of allergenic or nonallergenic origin) generally associated with urticaria.\nManagement and treatment\nManagement of acute attack includes administration of subcutaneous icatibant or intravenous administration of C1-INH concentrate. Tranexamic acid and danazol can be administered for long term prophylaxis. For the acquired form, management aims to treat the associated disease.\nPrognosis\nWith proper diagnosis and treatment, prognosis for patients with HAE is good. The prognosis of AAE depends on the underlying disorder.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence BOUILLET"}
{"Disease Name": "Non-Hodgkin lymphoma", "Disease Definition": "A heterogeneous group of malignant tumors of the lymphoid system.", "ORPHA ID": 547, "Summary": ""}
{"Disease Name": "Non-hypoproteinemic hypertrophic gastropathy", "Disease Definition": "A rare gastroesophageal disease characterized by diffusely enlarged gastric folds, excessive mucus secretion, normal serum protein and gastric TGF-alpha levels. Patients typically present anemia, abdominal pain not related to eating or bowel habits and absence of peripheral edema.", "ORPHA ID": 329883, "Summary": ""}
{"Disease Name": "Non-immune hydrops fetalis", "Disease Definition": "Non-immune hydrops fetalis (NIHF), a form of HF, is a severe fetal condition defined as the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities, and is the end-stage of a wide variety of disorders.", "ORPHA ID": 363999, "Summary": "Epidemiology\nThe prevalence of NIHF is unknown as it is difficult to obtain when many cases are not diagnosed before intrauterine death or may spontaneously resolve antenatally. Currently, NIHF constitutes up to 90% of all HF cases.\nClinical description\nNIHF presents during the gestational period and manifests as pleural and pericardial effusion, ascites and subcutaneous edema in the fetus. Decreased fetal movements may be noted prior to diagnosis. Often associated are polyhydramnios, fetal tachycardia, and antenatal hemorrhage. Mothers may develop massive anasarca, hypertension, and proteinuria (mirror syndrome). Death of fetus is usually due to heart failure and hypoxia. Surviving newborns may present with respiratory distress, pale skin, severe edema (mainly of abdomen) and enlarged liver and spleen. There is sometimes a risk of death of the mother.\nEtiology\nNIHF is the result of an increase in interstitial fluid production or, in turn, of an obstruction of lymphatic return. Causes can be: cardiovascular (21.7%; Ebstein malformation, tetralogy of Fallot), hematologic (10.4%; Hb Bart's HF), chromosomal (13.4%; Turner syndrome) and more rarely: infectious (TORCHES-CLAP (Toxoplasma gondii; Rubella virus; Cytomegalovirus; Herpes simplex virus; Enterovirus; Syphilis; Chickenpox virus; Lyme disease; Aids; Parvovirus B19)), syndromic (Costello syndrome, Meckel syndrome, thanatophoric dysplasia) or idiopathic. Other causes can include lymphatic dysplasia, inborn errors of metabolism (transaldolase deficiency, mucopolysaccharidosis, Niemann-Pick disease type C, GM1 gangliosidosis type 1), thoracic and urinary tract malformations, cardiac /extra thoracic tumors, and congenital diaphragmatic hernia.\nDiagnostic methods\nDecreased fetal movements, polyhydramnios, and maternal pre-eclampsia may lead one to suspect NIHF. Diagnosis is usually by ultrasound (showing fluid accumulations) during the 2nd to 3rd trimester of gestation. Having a placenta thickness of 5 mm or more, especially with a ''ground glass'' appearance on ultrasound may also be indicative of NIHF. Maternal laboratory tests such as blood typing, antibody screens for TORCHES-CLAP, hemoglobin electrophoresis, maternal anti-SSA/SSB antibodies as well as Kleihauer-Betke and alpha-fetoprotein tests, can also aid in the diagnosis of NIHF.\nDifferential diagnosis\nThe many disorders associated with HF are differential diagnoses such as neonatal hemochromatosis, twin-to-twin transfusion syndrome, congestive heart failure, hepatitis B, hypercalcemia, hypernatremia, hypothrombinemia, hypothyroidism and diabetes (in mother). Conditions that mimic full-blown HF include obstructed or mature bowel, fetal abdominal cysts and an obstructed urinary system.\nAntenatal diagnosis\nPrenatal diagnosis is by ultrasound.\nGenetic counseling\nIf NIHF is due to a genetic disorder, counseling can be offered in regards to that disease.\nManagement and treatment\nTreatment depends on the cause. Intrauterine treatment can involve thoraco-amniotic drainage, antiarrhythmic drugs (digoxin, sotalol, propranolol) and blood transfusion when anemia is present. In many cases, especially those caused by chromosomal abnormalities, the mother may choose to terminate the pregnancy. If the fetus comes to term it should be delivered at a tertiary care center where the neonate can receive intensive resuscitation procedures in the delivery room, intensive neonatal care, high frequency ventilation, parenteral nutrition, medications for the kidneys and removal of excessive fluid from around the lungs and abdomen as necessary.\nPrognosis\nIn most cases, prognosis is poor with a perinatal mortality rate ranging from 55-98%, but it is dependent on etiology.\n\n                            Last update: \n                            December 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Carlo BELLINI"}
{"Disease Name": "Non-insulinoma pancreatogenous hypoglycemia syndrome", "Disease Definition": "A rare familial hyperinsulinism characterized by postprandial hyperinsulinemic hypoglycemia, negative 72-hour fasts, negative preoperative localization studies for insulinoma, and positive selective arterial calcium infusion tests. Histopathological analysis reveals diffuse islet hyperplasia with increased number and size of islet cells.", "ORPHA ID": 276608, "Summary": ""}
{"Disease Name": "Non-involuting congenital hemangioma", "Disease Definition": "Non-involuting congenital hemangiomas (NICH) are a distinctive type of large congenital hemangioma that are fully formed in utero and differ from rapidly involuting congenital hemangiomas (RICH; see this term) mainly because they do not undergo a postnatal involuting phase.", "ORPHA ID": 141179, "Summary": "Epidemiology\nPrevalence is unknown but the lesions appear to be rare.\nClinical description\nNICH have long been confused with infantile immature hemangiomas in their involuting stage, however, NICH are now clearly distinguished on the basis of their clinical features, course, pathology and immunophenotype. NICH are generally less expansive at birth than RICH. They are flat or slightly bossed, round or oval, and are usually solitary. The outer area appears white. The centre varies from pinkish with minor telangiectasia, to deep purple with closely packed thin telangiectasia. NICH are mainly located on the head or neck (43% of cases), and limbs (38% of cases). NICH will not regress: they persist indefinitely with proportionate growth as the child becomes older.\nEtiology\nThe etiology is unknown.\nDiagnostic methods\nAt birth, color Doppler ultrasound reveals a fast-flow lesion and minor arteriovenous fistulas are occasionally detected. However, in some patients, NICH may increase equatorial venous drainage and arteriovenous fistulas may become obvious on examination by color Doppler ultrasound. On MRI, NICH show isointensity on T1-weighted images, hyperintensity on T2-weighted images, and intensive enhancement after intravenous gadolinium administration. However, all of these findings are similar to those seen in infantile hemangiomas (IH). Immunohistochemical studies can be used to differentiate NICH and IH, as in contrast to IH, the endothelial cells of NICH lack immunoreactivity for GLUT-1. Histopathologic studies reveal that NICH consist of rather large lobules made of small capillaries lined by endothelial cells with hobnailed nuclei. Lobules are separated by dense fibrous tissue. Elongated thin-walled vessels and a large distorted channel are present in their center. Extralobular vessels are large. Calcifications may be seen. Numerous alpha-actin-positive cells are observed in the lobules.\nDifferential diagnosis\nFor lesions of intermediate size it may be difficult to distinguish between NICH and RICH at birth. NICH must also be differentiated from the congenital, single plaque-type of tufted angioma and from a kaposiform hemangioendothelioma (see these terms), and a biopsy may be indicated.\nAntenatal diagnosis\nIn contrast to RICH, prenatal color Doppler ultrasound follow-up during pregnancy rarely leads to detection of NICH. NICH are not associated with any specific risks during delivery.\nGenetic counseling\nGenetic counseling should not be recommended as this rare tumor is sporadic. NICH never involute.\nManagement and treatment\nThe only therapeutic option is surgical excision and plastic reconstruction when there is cosmetic impairment. Neither arterial embolization alone, nor pulsed dye laser photocoagulation are of benefit. Performed 24 hours before excision, arterial embolization prevents excess intra-operative bleeding in some large NICH with arteriovenous fistulas detected by Doppler ultrasound.\nPrognosis\nPrognosis is good: NICH is a benign lesion, only impairing the cosmetic aspect of the skin. No severe complications have been reported.\n\n                            Last update: \n                            September 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Odile ENJOLRAS  - Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Non-progressive cerebellar ataxia with intellectual disability", "Disease Definition": "A rare subtype of autosomal dominant cerebellar ataxia type 1 (ADCA type 1) characterized by the onset in infancy of cerebellar ataxia, neonatal hypotonia (in some), mild developmental delay and, in later life, intellectual disability. Less common features include dysarthria, dysmetria and dysmorphic facial features (long face, bulbous nose long philtrum, thick lower lip and pointed chin).", "ORPHA ID": 314647, "Summary": ""}
{"Disease Name": "Non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy", "Disease Definition": "A rare mitochondrial disease characterized by a distinctive MRI pattern of cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. The clinical picture varies widely between acute neurometabolic decompensation in infancy with loss of developmental milestones, seizures, and pyramidal signs rapidly evolving into spastic tetraparesis, to subtle neurological symptoms presenting in adolescence. The disease course tends to stabilize over time in most patients, and marked recovery of milestones may be observed.", "ORPHA ID": 436271, "Summary": ""}
{"Disease Name": "Non-recovering obstetric brachial plexus lesion", "Disease Definition": "A rare acquired peripheral neuropathy characterized by paresis of the supraspinatus, infraspinatus, deltoid, and biceps muscles (in C5-C6 injury), wrist and finger extensor muscles (C7 injury), or impaired hand function (C8-Th1 injury) on the affected side due to a traction lesion of the brachial plexus during delivery. The upper trunk of the brachial plexus is most commonly affected, while isolated injury to the lower trunk is very rare. Potential sequelae of brachial plexus injury are muscle atrophy, pain, sensory deficits, and secondary deformities.", "ORPHA ID": 439202, "Summary": ""}
{"Disease Name": "Non-rhizomelic chondrodysplasia punctata", "Disease Definition": "Non-rhizomelic chondrodysplasia punctata is a form of chondrodysplasia punctata (see this term), a group of diseases in which the common characteristic is bone calcifications near joints from birth. Non-rhizomelic chondrodysplasia punctata is not an entity in itself but covers several diseases with variable clinical findings and modes of transmission.", "ORPHA ID": 176, "Summary": "Epidemiology\nThe overall prevalence of these diseases as a group is unknown.\nClinical description\nX-linked dominant chondrodysplasia punctata (or Conradi-Hünermann-Happle syndrome; see this term) is characterized by the association of asymmetrical limbs, lamellar ichthyosiform erythroderma and cataract that may be unilateral. Intelligence is normal. The disease predominantly affects females and is severe or even lethal in males. Brachytelephalangic chondrodysplasia (see this term) associates severe facial dysmorphism (Binder's maxillonasal dysostosis; see this term), calcifications predominantly found in the tarsus and lower limbs, and hypoplastic distal phalanges. Stature and intelligence are normal to near-normal. Other forms of non-rhizomelic chondrodysplasia punctata include chondrodysplasia punctata tibial-metacarpal type, Toriello-Higgins-Miller syndrome and chondrodysplasia punctata, Sheffield type (see these terms).\nEtiology\nX-linked dominant chondrodysplasia punctata is transmitted in an X-linked dominant manner and is caused by mutations in the EBP gene encoding an enzyme involved in cholesterol metabolism. Brachytelephalangic chondrodysplasia is inherited in an X-linked recessive manner and is caused by a mutation in the ARSE gene.\nDiagnostic methods\nChondrodysplasia punctata may be detected by ultrasound follow up, most often in the later stages of pregnancy, but identification of the exact form requires biochemical investigations (screening for abnormal sterols and long chain fatty acid analysis) of amniotic fluid samples.\nDifferential diagnosis\nMaternal intake of anticoagulants during pregnancy, deficiency of vitamin K-dependent coagulation factors and maternal vitamin K deficiency (see these terms) can cause symptoms that are very similar to those of brachytelephalangic chondrodysplasia punctata. Calcifications around the epiphyses may also be caused by fetal alcohol syndrome (see this term) and may be seen in fetuses born to mothers with disseminated lupus erythematosus (see this term).\nManagement and treatment\nTreatment should be adapted depending on the form of chondrodysplasia punctata present.\nPrognosis\nPrognosis is very variable.\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Non-seminomatous germ cell tumor of testis", "Disease Definition": "A form of testicular germ cell tumor occurring in the third decade of life with a usually painless unilateral mass in the scrotum or, in some cases, with gynaecomastia and/or back and flack pain. The clinical course is more aggressive than testicular seminomatous germ cell tumors with rapid involvement of blood vessels and a poorer prognosis. Histologically, the tumour can be either undifferentiated (embryonal carcinoma), differentiated (teratoma, yolk sac tumor, choriocarcinoma), or can consist of a mixture of seminomatous and nonseminomatous components.", "ORPHA ID": 363494, "Summary": ""}
{"Disease Name": "Non-specific early-onset epileptic encephalopathy", "Disease Definition": "A rare infantile epilepsy syndrome characterized by early onset of seizures of variable type and severity, potentially associated with a spectrum of clinical signs and symptoms including delay or lack of psychomotor development, intellectual disability, poor or absent speech development, behavioral abnormalities, hypotonia, movement disorders, spasticity, microcephaly, and dysmorphic facial features, among others. Brain imaging findings are also variable and may include cerebral atrophy or white matter abnormalities.", "ORPHA ID": 442835, "Summary": ""}
{"Disease Name": "Non-specific interstitial pneumonia", "Disease Definition": "A rare idiopathic interstitial pneumonia characterized by temporally uniform alveolar and interstitial mononuclear cell inflammation (cellular type) and/or fibrosis of the alveolar walls (fibrotic type) with preserved alveolar architecture. Other types of interstitial lung disease must be excluded. Symptoms are non-specific and include dyspnea, cough, and often constitutional symptoms such as fever and fatigue. Pulmonary function test reveals a restrictive pattern. Computed tomography shows predominantly lower lobe subpleural reticular changes, traction bronchiectasis, and ground-glass opacities. The cellular type of the disease is less common but carries a better prognosis.", "ORPHA ID": 91364, "Summary": ""}
{"Disease Name": "Non-specific syndromic intellectual disability", "Disease Definition": "A rare genetic intellectual disability characterized by the association of intellectual disability with variable other anomalies in the absence of a well-characterized syndrome. Associated abnormalities may include facial dysmorphism, neurological signs and symptoms, behavioral problems, and abnormalities of various other organ systems.", "ORPHA ID": 528084, "Summary": ""}
{"Disease Name": "Non-spherocytic hemolytic anemia due to hexokinase deficiency", "Disease Definition": "Nonspherocytic haemolytic anaemia due to hexokinase deficiency is characterised by severe hemolysis, appearing in infancy. Seventeen affected families have been reported so far. Transmission is autosomal recessive. Mutations have been described in HK1, the gene that encodes red blood cell-specific hexokinase-R.", "ORPHA ID": 90031, "Summary": ""}
{"Disease Name": "Non-syndromic anorectal malformation", "Disease Definition": "A wide spectrum of malformations involving the distal anus and rectum as well as the urinary and genital tracts, which can affect boys and girls.", "ORPHA ID": 557, "Summary": "Epidemiology\nThey occur in approximately 1 in 5000 live births.\nClinical description\nDefects range from mild anal anomalies to complex cloacal malformations. They can therefore be classified into the following groups: imperforated anus without fistula, ARM with rectourinary or rectogenital fistula and complex ARM (cloaca). Associated anomalies include genitourinary defects (in approximately 50% of patients) and spinal anomalies. A cloaca is associated with a urological problem (such as obstructive uropathy) in 90% of babies and with hydrocolpos in 50%. Sacral anomalies (hemisacrum and sacral hemivertebrae) have been described; hemivertebrae may also affect the lumbar and thoracic spine, leading to scoliosis. A tethered spinal cord (in 25% of patients) may result in motor and sensory disturbances of the lower extremities. Syringomyelia and myelomeningocele can occur.\nEtiology\nThe etiology remains unclear and is likely multifactorial. Familial cases have been described.\nDiagnostic methods\nThe radiological evaluation of a newborn with imperforate anus should include an abdominal and pelvic ultrasound to evaluate for genitourinary defects as they need to be dealt with in the newborn period to avoid serious complications. Spinal ultrasound in the first three months of life and magnetic resonance imaging thereafter are useful radiological modalities for detecting spinal anomalies.\nDifferential diagnosis\nARM can occur in association with multisystem syndromes, such as Townes-Brocks syndrome, Currarino syndrome, Pallister-Hall syndrome, and Down syndrome (see these terms).\nGenetic counseling\nThe risk of ARM for a sibling of a patient with ARM can reach 1%.\nManagement and treatment\nPatients can either undergo a primary repair procedure (anoplasty) or a protective colostomy and definitive repair at a later date, depending on the malformation. The surgical approach to repairing these defects changed dramatically in 1980 with the introduction of the posterior sagittal approach, which allowed surgeons to view the anatomy of these defects clearly, to repair them under direct vision, and to learn about the complex anatomic arrangement between the rectum and genitourinary tract.\nPrognosis\nEarly diagnosis, management of associated anomalies and efficient meticulous surgical repair can ensure a good functional outcome in terms of bowel and urinary control, and sexual function. However, fecal and urinary incontinence can occur due mainly to associated problems such as a poorly developed sacrum, deficient nerve supply, and spinal cord anomalies. For these patients, an effective bowel management program, including enema and dietary restrictions improves the quality of life.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Marc LEVITT  - Pr Alberto PENA"}
{"Disease Name": "Non-syndromic bicoronal craniosynostosis", "Disease Definition": "Isolated brachycephaly is a relatively frequent nonsyndromic craniosynostosis consisting of premature fusion of both coronal sutures leading to skull deformity with a broad flat forehead and palpable coronal ridges.", "ORPHA ID": 35099, "Summary": "Epidemiology\nIncidence at birth is in the range of 1/20,000.\nClinical description\nThe skull deformity is characterized by a short anteroposterior diameter with a compensatory increase in bitemporal width. Supraorbital recession and exorbitism may also be present. Brachycephaly may be associated with facial anomalies (midface hypoplasia, slight hypertelorism and bulging temporal fossae). Increased intracranial pressure (ICP) is frequent and may lead to intellectual deficit if left untreated. In adults, elevated ICP is associated with bony defects in the absence of treatment.\nEtiology\nThe extent to which nonsyndromic brachycephaly is genetically determined is still uncertain. Although the majority of cases are sporadic, familial forms (accounting for 14% of all cases) have been reported, with dominant inheritance in around 10% of cases. In addition, recurrent (paternally inherited) P250R mutations in fibroblast growth factor receptor 3 (FGFR3; 4p16.3) were identified in 74% of familial cases, as well as in 17% of sporadic cases. Among patients carrying the P250R mutation, females are more severely and more frequently affected than males (female to male ratio of 2:1) and mild hearing impairment is common. Minor radiologic anomalies including brachydactyly or fusion of metacarpal bones may occur in some FGFR3 mutation carriers. A mutation in the TWIST 1 gene (7p21) has been reported recently in a single case of isolated bicoronal synostosis, but a genetic origin has not been confirmed for most remaining cases. Several other determinants might be involved including mechanical constraints during pregnancy and after birth.\nDiagnostic methods\nDiagnosis is based on clinical examination, radiologic studies, and 3D CT scans and/or MRI of the skull. Since postoperative morphological and functional outcomes appear to be better in non-carriers of the FGFR3 mutation, molecular screening is recommended for all families with nonsyndromic forms of brachycephaly.\nDifferential diagnosis\nClinical distinction between syndromic and nonsyndromic forms brachycephaly is often difficult owing to phenotypic variability in patients carrying the P250R mutation. Although the cranial appearance of some patients might be reminiscent of the Saethre-Chotzen or Pfeiffer syndromes (see these terms), the absence of obvious hand and/or feet anomalies is a hallmark of nonsyndromic brachycephalic patients. Marked bulging of temporal fossae, seen mainly in female carriers of the FGFR3 mutation, might be instructive for differential diagnosis.\nManagement and treatment\nCranial vault reconstructive surgery is the main treatment to improve skull shape and increase intracranial volume. This usually results in reduced ICP. Early identification of hearing loss allows timely intervention when required.\nPrognosis\nThe intellectual outcome of patients after cranial expansion surgery is usually good. However, patients carrying the FGFR3 mutation are five times more likely to require a second operation and show a poorer post surgical outcome than non-carriers.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Jacky BONAVENTURE  - Pr Dominique RENIER"}
{"Disease Name": "Non-syndromic bilambdoid and sagittal craniosynostosis", "Disease Definition": "A rare cranial malformation syndrome characterized by the premature closure of both lambdoid sutures and the posterior sagittal suture, resulting in abnormal skull contour (frontal bossing, anterior turricephaly with mild brachycephaly, biparietal narrowing, occipital concavity) and dysmorphic facial features (low-set ears, midfacial hypoplasia). Short stature, developmental delay, epilepsy, and oculomotor dyspraxia have also been reported. Associated anomalies include enlargement of the cerebral ventricles, agenesis of the corpus callosum, Arnold-Chiari malformation type I, venous anomalies of skull, and hydrocephalus.", "ORPHA ID": 1516, "Summary": ""}
{"Disease Name": "Non-syndromic genetic deafness", "Disease Definition": "Deafness is the most frequent form of sensorial deficit. In the vast majority of cases, the deafness is termed nonsyndromic or isolated and the hearing loss is the only clinical anomaly reported. In developed counties, 60-80% of cases of early-onset hearing loss are of genetic origin.", "ORPHA ID": 87884, "Summary": "Epidemiology\nBetween 1 in 1,000 and 1 in 700 children were born with profound or severe hearing loss.\nClinical description\nThe majority of cases presenting at birth concern perceptive deafness (with a neurosensory origin associated with the inner ear) rather than conductive deafness (anomalies in the amplification of sound waves between the middle ear - tympanum and auditory ossicles - and the outer ear). Autosomal dominant forms are characterised by very early onset and bilateral hearing loss with varying degrees of severity (ranging from mild to profound). No malformations of the inner ear can be detected by CT scan. Mutations in the PDS gene are responsible for 7% of cases of childhood deafness. In these cases, the deafness is marked by early-onset, usually bilateral (but sometimes asymmetric) hearing loss with autosomal recessive transmission. This form of deafness is always associated with malformations of the inner ear that can be detected by CT scan. In rare cases, thyroid gland disease may also be present. For the autosomal dominant forms of deafness, mutations in the COCH gene result in progressive postlingual deafness associated with severe attacks of vertigo and subjective tinnitus. This form of deafness should be distinguished from Meniere's disease (see this term). Autosomal dominant mutations in the  WFS1 gene cause either a form of hearing loss affecting mainly low frequency sounds or deafness associated with optic atrophy.\nEtiology\nTo date, 86 causative genes for sensorineural deafness have been identified and localised and 37 of these genes have been cloned. Eleven of these genes have been implicated in both isolated and syndromic forms of deafness. Mutations in the gene encoding connexin 26 appear to be responsible for the majority of cases of childhood perceptive deafness.\nDiagnostic methods\nHearing loss can be evaluated by audiogram and grouped as either mild (loss between 20 and 40 dB), moderate (loss between 41 and 70 dB), severe (loss between 71 and 90 dB), profound (loss between 91 and 120 dB) or as cophosis (loss beyond 120 dB).\nGenetic counseling\nIn 85% of cases, the deafness is transmitted as an autosomal recessive trait (DFNB type). Autosomal dominant inheritance accounts for between 10 and 15% of cases (DFNA type), whereas only 1% of cases are inherited as an X-linked trait (DFN type).\nManagement and treatment\nManagement should be multidisciplinary (involving a paediatrician, general practitioner, ORL specialist, speech therapist and hearing aid specialist). Hearing aids (either implanted or external) generally provide the only management option for improving hearing loss, although surgical treatment may sometimes be proposed for some forms of conductive hearing loss.\n\n                            Last update: \n                            July 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Sandrine MARLIN"}
{"Disease Name": "Non-syndromic hemimelia", "Disease Definition": "Hemimelia is a limb malformation characterized by the absence or gross shortening of the lower portion of one or more of the limbs. The condition is designated according to which bone of the distal arm or leg is absent or defective and includes fibular, radial, tibial, or ulnar hemimelia (see these terms). Hemimelia ranges in severity.", "ORPHA ID": 2130, "Summary": ""}
{"Disease Name": "Non-syndromic male infertility due to sperm motility disorder", "Disease Definition": "Non-syndromic male infertility due to sperm motility disorder is a rare, genetic, non-syndromic male infertility disorder characterized by infertility due to sperm with defects in their cilia/flagella structure, leading to absent motility or reduced forward motility in fresh ejaculate. Reduced semen volume, oligospermia and an increased number of abnormally structured spermatozoa is often present.", "ORPHA ID": 276234, "Summary": ""}
{"Disease Name": "Non-syndromic metopic craniosynostosis", "Disease Definition": "Isolated trigonocephaly is a nonsyndromic form of craniosynostosis characterized by the premature fusion of the metopic suture.", "ORPHA ID": 3366, "Summary": "Epidemiology\nIncidence is estimated at 1/15,000 births. Males are more frequently affected than females (sex ratio of 2:1) and the frequency of trigonocephalic twins is unexpectedly high.\nClinical description\nThe premature closure of the metopic suture results in deformation of the anterior portion of the calvarium and a triangular-shaped forehead. In mild forms, only prominent ridging of the metopic suture is visible; while in more severe forms marked narrowing of the frontal and temporal regions affects the supraorbital rims leading to hypotelorism. The psychomotor development of patients is usually normal and the majority of cases are mild.\nEtiology\nThe underlying genetic cause of isolated trigonocephaly remains to be delineated. However, the concordance rate of isolated trigonocephaly in monozygotic twins is 43%, suggesting that both genetic and environmental factors are involved in the etiology of this disorder.\nDiagnostic methods\nDiagnosis is based on clinical and ultrasound examination, radiological evaluation by X-rays, and 3D CT scans and/or MRI of the skull. Since fusion of the metopic suture normally occurs during early childhood, CT scans for metopic synostosis should be performed before 6 months of age to avoid misdiagnosis. Premature fusion of the metopic suture may occur both in syndromic and in nonsyndromic forms of synostosis.\nDifferential diagnosis\nThe differential diagnosis should include trisomy 13 and other chromosomal disorders (distal monosomy 9p and 11q), as well as C syndrome (see these terms), and is based on the presence of multiple anomalies (including facial dysmorphism, organ anomalies and intellectual deficit) in the syndromic forms. Fetal exposure to valproic acid during pregnancy usually leads to trigonocephaly, which in this case is often associated with intellectual deficit and dysmorphic features, and therefore fetal valproate syndrome (see this term) should also be included in the differential diagnosis.\nGenetic counseling\nMost cases are sporadic but familial forms with apparently autosomal dominant transmission have been reported (representing 7-8% of all cases).\nManagement and treatment\nSurgery is the only treatment for correction of the skull deformation. Primary orbitocranioplasty is performed according to different techniques including reshaping with metallic fixation or use of primary bone grafting and resorbable fixation to expand the frontal region. Anterolateral expansion of the supraorbital bar and stabilization of the construct via bone grafting and resorbable fixation give the best esthetic outcome with a low incidence of reoperation.\nPrognosis\nThe clinical outcome for patients having undergone surgery is usually satisfactory with a low requirement for additional interventions, especially in the mild forms. Recurrence of a prominent metopic ridge may occur in some rare cases.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Jacky BONAVENTURE  - Pr Dominique RENIER"}
{"Disease Name": "Non-syndromic pontocerebellar hypoplasia", "Disease Definition": "A rare group of neurodegenerative disorders with a prenatal onset characterized by hypoplasia and/or atrophy of the cerebellum and pons. Involvement of supratentorial structures is variable. Multiple forms have been described based on severity, age of onset and clinical presentation.", "ORPHA ID": 98523, "Summary": "Epidemiology\nPrevalence of pontocerebellar hypoplasias (PCH) is unknown. Most subtypes appear to be very rare.\nClinical description\nPCH is a clinically heterogeneous group of disorders, characterized by hypoplasia and/or atrophy of cerebellum and pons. Atrophy of supratentorial structures is variably present. There is great clinical variation both between and within the different forms. Delayed or absence of cognitive and voluntary motor development, intellectual deficit, spasticity, chorea/dyskinesia, swallowing difficulties and epilepsy are common clinical findings.\nEtiology\nThe majority of PCH cases encompass mutations in tRNA splicing endonuclease. Mutations responsible for PCH2, PCH4, PCH5 include mutations in TSEN2 (PCH2), TSEN34 (PCH2; 19q13.42), TSEN15 (1q25.3), and TSEN54 (PCH2 4, 5; 17q25.1). PCH6 is due to mutations in mitochondrial arginyl-tRNA synthetase (RARS2; 6q15) gene. Approximately half the cases of PCH1 are due to mutations in the gene EXOSC3 (9p13.2). In addition, mutations in VRK1 (14q32.2), EXOSC8 (13q13.3) and EXOSC9 (4q27) are associated with PCH1. PCH3 is caused by mutations in the PCLO gene (7q21.11). Mutations in TOE1 (1p34.1) underlie PCH7, PCH8 is caused by a loss-of-function mutation in the CHMP1A gene (16q24.3). PCH9 is caused by mutation in the AMPD2 gene (1p13.3), and PCH10 by mutations in the CLP1 gene (11q12.1). The two most recently described genes associated with PCH are TBC1D23 (3q12.1-q12.2), associated with PCH11, and COASY (17q21.2), linked to PCH12.\nDiagnostic methods\nDiagnosis is made on clinical symptoms and neuroradiological findings (magnetic resonance imaging; MRI). It can be confirmed by molecular genetic analyses. MRI demonstrates a pontocerebellar hypoplasia, with often more severely affected cerebellar hemispheres than vermis, atrophy of ventral pons and to a lesser extent the cerebral cortex. Other neuroanatomical features include a severe progressive microcephaly and ventriculomegaly.\nDifferential diagnosis\nDifferential diagnosis includes progressive cerebello-cerebral atrophy (PCCA), infantile cerebral and cerebellar atrophy (ICCA), congenital disorders of glycosylation type 1A and D, phosphoserine aminotransferase deficiency, certain congenital mitochondrial disorders, progressive encephalopathy with edema hypsarrhythmia and optic atrophy (PEHO) syndrome, dystroglycanopathies like Walker-Warburg syndrome, MEB-disease, Fukuyama congenital muscular dystrophy, lissencephaly, X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum, congenital fibrosis of the extraocular muscles type 3 (CFEOM3) with extraocular involvement, acquired cerebellar hypoplasia in extreme premature births (<32 weeks) which may disrupt normal brain development, and mutations in the CASK¬ gene, that cause Microcephaly and Pontocerebellar Hypoplasia (MICPCH).\nAntenatal diagnosis\nIf the disease causing mutation is known in carrier parents, routine methods for prenatal testing or preimplantation genetic diagnosis are available.\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling for the affected family is recommended. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.\nManagement and treatment\nTreatment is symptomatic, as there is no cure for PCH, and involves medication for treatment of dystonia, dyskinesia and seizures, percutaneous endoscopic gastrostomy tube feeding and sometimes respiratory support may be necessary. Cot death, sleep apnea, rhabdomyolysis and malignant hyperthermia may be life threatening complications for PCH2 patients.\nPrognosis\nPrognosis is poor. Many children live only into infancy or childhood, although some affected individuals have lived into adulthood.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK"}
{"Disease Name": "Non-syndromic posterior hypospadias", "Disease Definition": "A rare, non-syndromic, congenital, urogenital tract malformation affecting males and characterized by penoscrotal, scrotal or perineal displacement of the urethral meatus, and commonly associated with curvation of the penis. The scrotum might appear bifid in severe cases, and the boy can also have a micropenis.", "ORPHA ID": 95706, "Summary": "Epidemiology\nPosterior hypospadias occurs in about 5% to 9% of hypospadias, for which the mean birth prevalence is estimated to be 1/500 in Europe.\nClinical description\nThe consequences of hypospadias, apart from the appearance, include spraying of the urinary stream, inability to urinate in standing position, and later in life curvature, unless corrected, leads to difficulties during intercourse. Fertility problems and decreased satisfaction with genital appearance are more common. Severe hypospadias and concomitant undescended testis, is regarded as a disorder of sex development (DSD) and should be referred to special multidisciplinary teams for molecular and hormonal evaluation.\nEtiology\nPosterior hypospadias arises early during urethra development in fetal weeks 8-16. The malformation is generally considered ''complex'' with both a genetic and environmental background. To date, the two genes MAMLD1 (Xq28) and AR (Xq12) have been associated with the isolated form of posterior hypospadias. However, there are an increasing number of genes involved in sex development that may lead to hypospadias, either as a part of syndrome or a result of gonadal dysgenesis.\nDiagnostic methods\nThe diagnosis is set by an external inspection of the penis, usually just after birth. Hormonal, genetic and anatomic evaluations are required when the hypospadias is part of a DSD.\nDifferential diagnosis\nDifferential diagnoses include congenital adrenal hyperplasia in girls and, in patients with an XY karyotype, androgen insensitivity syndrome, steroid 5-alpha-reductase deficiency and 17-beta-hydroxysteroid dehydrogenase 3 deficiency. In addition, infants are screened for WT1 mutations to exclude Denys-Drash syndrome.\nAntenatal diagnosis\nUltrasound diagnosis is sometimes possible since the tip of the penis can be smaller and quadrangular.\nGenetic counseling\nThe familial recurrence risk is difficult to determine due to the complex genetic and environmental factors involved; however, genetic counseling is recommended. For hypospadias in general, the risk that a brother of an affected boy will also have hypospadias is 9-17%. The risk for the next boy in a family with an affected father and son is 25%. Where MAMLD1 is responsible, mutations may occur sporadically or through X-linked inheritance.\nManagement and treatment\nCurrent guidelines consider optimal age for hypospadias repair between 9 and 18 months, depending on the severity and the need for multiple procedures. Surgery for posterior hypospadias remains challenging and no single technique is applicable to all patients. Patients frequently require extra tissue to restore the missing urethra after correction of the curvature, usually the inner prepuce or, in redo surgery, buccal mucosal is used. Affected males should be followed up into adulthood by a urologist or andrologist.\nPrognosis\nThere is a greater dissatisfaction with the genital appearance in patients treated for posterior and complex hypospadias. Lower urinary tract symptoms are common postoperatively. Sexual problems like anejaculation are more common in posterior hypospadias; although fertility is diminished, sexual life is generally regarded as satisfactory.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Agneta NORDENSKJÖLD"}
{"Disease Name": "Non-syndromic sagittal craniosynostosis", "Disease Definition": "Isolated scaphocephaly is a form of nonsyndromic craniosynostosis characterized by premature fusion of the sagittal suture.", "ORPHA ID": 35093, "Summary": "Epidemiology\nIt is a relatively common malformation accounting for around 50% of all cases of nonsyndromic craniosynostosis and with an incidence of 1/5,000 live births. Males are more frequently affected than females (male/female ratio of 3.5:1) and the frequency of affected twins is unexpectedly high.\nClinical description\nThe premature fusion of the sagittal suture results in compensatory anteroposterior elongation of the skull. The mean cranial length is significantly increased and the sagittal suture is larger than normal. Frontal bossing and occipital bulging may occur depending on the extent of the premature fusion. Elevated intracranial pressure is rare and intelligence is usually normal.\nEtiology\nThe underlying cause of isolated scaphocephaly remains to be determined: a mutation in the TWIST1 gene (7p21) has been reported in a single case. However, the concordance rate in monozygotic twins was found to be 30%, suggesting some cases might be genetically determined, whereas environmental determinants are involved in others.\nDiagnostic methods\nDiagnosis is based on clinical examination and radiological evaluation by X-rays, 3D CT scans and/or MRI of the skull.\nDifferential diagnosis\nSagittal synostosis can be isolated or occur as part of a syndrome (such as familial scaphocephaly with radioulnar synostosis or sagittal craniosynostosis with Dandy-Walker malformation and hydrocephalus; see these terms). The syndromic and nonsyndromic forms can be clearly distinguished due to the absence in isolated scaphocephaly of additional clinical features.\nGenetic counseling\nThe majority of cases are sporadic but familial cases with autosomal dominant inheritance have been described (6% of all cases).\nManagement and treatment\nManagement may involve cranial vault reconstructive surgery to correct skull shape.\nPrognosis\nThe clinical outcome of patients having undergone surgery is usually good with normal intelligence and psychomotor development.\n\n                            Last update: \n                            December 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Jacky BONAVENTURE  - Pr Dominique RENIER"}
{"Disease Name": "Non-syndromic syndactyly", "Disease Definition": "A group of rare, congenital, non-syndromic distal limb malformation disorders characterized by webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. The morphological anomaly can be unilateral or bilateral, symmetrical or asymmetrical, depending on the specific type.", "ORPHA ID": 90025, "Summary": ""}
{"Disease Name": "Noonan syndrome with multiple lentigines", "Disease Definition": "A rare multisystem genetic disorder characterized by cutaneous lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features.", "ORPHA ID": 500, "Summary": "Epidemiology\nExact prevalence and incidence rates for Noonan syndrome with multiple lentigines (NSML) are not known. About 300 cases have been described to date. A slight male predominance has been reported.\nClinical description\nPatients with NSML have a characteristic facial appearance including a broad forehead, hypertelorism, ptosis, down-slanting palpebral fissures, a high-arched palate, and low-set posteriorly rotated ears. Pectus deformity is common. Multiple lentigines, presenting as flat, black-brown macules, are located mainly on the face, neck, and upper trunk, sparing the mucosa, and constitute a hallmark feature of the syndrome. Lentigines appear at 4 to 5 years of age and increase in number until puberty. Café-au-lait spots may also be observed alone or along with lentigines. About one quarter of patients show growth delay with short stature in adulthood. Cardiac defects include ECG (electrocardiogram) anomalies, pulmonary valve stenosis, progressive conduction defects and hypertrophic cardiomyopathy, and are found in about 50% of patients. Some affected individuals have abnormal genitalia: unilateral or bilateral cryptorchidism and hypospadias in about one third of affected males; urinary tract defects and, less commonly, ovarian abnormalities. Sensorineural hearing loss is a less common feature (20%). Intellectual disability is generally mild and affects about 30% of cases. NSML can be associated with the development of neuroblastoma, acute myeloid leukemia, and acute lymphoblastic leukemia.\nEtiology\nNSML is mainly caused by mutations in the PTPN11 gene (12q24.1). Mutations are different from those known to cause Noonan syndrome, explaining the distinct clinical phenotype. Some cases are reported to involve mutations in RAF1 (3p25) , BRAF (7q34), or MAP2K1 (15q22.1-q22.33; one patient). There may be other currently unidentified causative genes.\nDiagnostic methods\nClinical diagnosis may be difficult because of the absence of characteristic lentigines. Patients may have an initial diagnosis of Noonan syndrome. Molecular genetic testing may be useful to confirm diagnosis or to distinguish between overlapping syndromes.\nDifferential diagnosis\nThe clinical presentation overlaps significantly with Noonan syndrome and the main distinguishing manifestation is multiple lentigines. Other differential diagnoses include cardio-facio-cutaneous, Costello, and Turner syndromes.\nAntenatal diagnosis\nPrenatal diagnosis is possible if a causative gene mutation has been identified in an affected family member.\nGenetic counseling\nNSML follows an autosomal dominant pattern of inheritance. The proportion of de novo mutations is unknown. Genetic counseling should be provided to affected families informing them that there is a 50% risk of transmission from an affected individual to their offspring.\nManagement and treatment\nIsolated lentigines may be treated with cryosurgery or laser treatment. Treatment of lentigines may also include tretinoin and hydroquinone creams. Treatment of cardiovascular manifestations follows standard methods and periodic cardiac monitoring is recommended. Cryptorchidism in affected males is also treated with conventional techniques. Hearing loss may require hearing aids, educational support, or cochlear implantation.\nPrognosis\nLife expectancy is normal in most affected patients, with the exception of patients with severe hypertrophic cardiomyopathy. The prognosis is mainly related to the severity of cardiac manifestations.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Maria Cristina DIGILIO | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Noonan syndrome-like disorder with juvenile myelomonocytic leukemia", "Disease Definition": "A rare, genetic, polymalformative syndrome characterized by a Noonan-like phenotype associated with increased risk of developing juvenile myelomonocytic leukemia (JMML). The Noonan-like (NS) phenotype includes dysmorphic facial features (i.e. high forehead, hypertelorism, downslanting palpebral fissures, ptosis, low-set ears, prominent philtrum and short neck with or without pterygium colli), developmental delay, hypotonia and small head circumference. It can be associated with congenital heart defects or cardiomyopathy, ectodermal anomalies, and short stature. The NS phenotype is subtle or even inapparent in a large proportion of subjects, but may occasionally be severe. Leukemia can be the only clinical manifestation of the syndrome.", "ORPHA ID": 363972, "Summary": ""}
{"Disease Name": "Noonan syndrome-like disorder with loose anagen hair", "Disease Definition": "A Noonan-related syndrome, characterized by facial anomalies suggestive of Noonan syndrome, loose anagen hair, frequent congenital heart defects, distinctive skin features (darkly pigmented skin, keratosis pilaris, eczema or ichtyosis), and short stature that is often associated with a growth hormone deficiency. Psychomotor delay with attention deficit/hyperactivity disorder (ADHD) is frequently observed.", "ORPHA ID": 2701, "Summary": "Epidemiology\nTo date, more than 70 cases have been reported in the literature.\nClinical description\nAt birth and during childhood, the clinical features generally observed in Noonan syndrome appear more severe, but the phenotype generally improves with age. In particular, macrocephaly, high and prominent forehead, loose anagen hair and diffuse dark skin pigmentation are the features that may be observed early at birth or in infancy. The facial features, reminiscent of Noonan syndrome, include high broad forehead, hypertelorism, palpebral ptosis and downward slanting palpebral fissures, low-set, thick, posteriorly rotated ears, deep philtrum, micrognathia, and short neck. Hair is sparse, thin, easily plucked and slow growing despite being in the anagen phase. The roots lack inner and outer sheaths. Other ectodermal anomalies, include darkly pigmented and hairless skin, eczema and occasionally neonatal ichthyosis. The voice is hypernasal. Congenital heart abnormalities are common and predominated by mitral valve dysplasia and septal defects; hypertrophic cardiomyopathy (HCM) is observed in approximately 25% of cases. Short stature is often associated with proven growth hormone (GH) deficiency. Patients benefit from long-term GH-therapy, although they do not show the characteristic catch-up growth of isolated GH deficiency. Pubertal development is variable, showing a prolonged and delayed puberty or rapid pubertal progression that could impair the final height. A mild psychomotor delay with attention deficit/hyperactivity disorder (ADHD) is frequent. Sporadic neurological abnormalities such as ventriculomegaly, focal epilepsy, chronic complex tics, moyayamoya syndrome and neuroblastoma have been reported.\nEtiology\nSHOC2 gene encodes a protein that is a positive modulator of the RAS-MAPK signaling pathway. The p.Ser2Gly change in SHOC2 creates an N-myristoylation site, resulting in constitutive targeting of the mutated protein to the plasma membrane and enhanced signaling through the MAPK cascade. PPP1CB gene is a component of RAS/MAPK pathway and missense mutations in PPP1CB have also been identified in patients with this phenotype.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and confirmed by molecular testing.\nDifferential diagnosis\nThe principal differential diagnosis includes Noonan syndrome and the other related disorders.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. It may also be suspected prenatally due to ultrasound abnormalities.\nGenetic counseling\nTransmission is autosomal dominant; however, most cases arise de novo and thus the risk of sibling recurrence is low.\nManagement and treatment\nA multidisciplinary approach is mandatory. Regular evaluations by a pediatrician, endocrinologist, cardiologist, dermatologist, neurologist, psychologist should be recommended. GH therapy is a possible approach for short stature.\nPrognosis\nNo longitudinal data are available for the estimation of life expectancy. The phenotype often improves with age. Quality of life depends on the degree of multiorgan and cognitive impairment and on the rehabilitation program adopted.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Laura MAZZANTI | ITHACA* - Dr Annamaria PERRI  - Dr Emanuela SCARANO  - Dr Federica TAMBURRINO \n\n\n                                * European Reference Network"}
{"Disease Name": "Noonan syndrome", "Disease Definition": "A rare, highly variable, multisystemic disorder mainly characterized by short stature, distinctive facial features, congenital heart defects, cardiomyopathy and an increased risk to develop tumors in childhood.", "ORPHA ID": 648, "Summary": "Epidemiology\nThe birth prevalence of Noonan syndrome (NS) is estimated between 1:1000 to 1:2500.\nClinical description\nNS typically presents in the neonatal period with feeding difficulties and failure to thrive. Characteristic facial features are often more obvious in infancy : high broad forehead, hypertelorism, palpebral ptosis and downward slanting palpebral fissures, low-set, thick, posteriorly rotated ears, deep philtrum, micrognathia, curly hair and a short neck with sometimes a pterygium colli. With age, the face becomes triangular, with marked skinfolds. The most common congenital heart defect is pulmonary valve stenosis (50-60%) with pulmonic valve dysplasia and various types of cardiac malformations (atrial septal defects, ventricular septal defects ect.). Hypertrophic cardiomyopathy of antenatal onset is common (20%) and may be stable or rapidly progressive. Dilation of coronary arteries and moya-moya disease may develop with aging. Growth delay affects 50%, uncommonly associated with growth hormone deficiency. Weight gain is difficult and many patients remain lean throughout life. Major orthopedic manifestations include sternal deformity, talipes equinovarus, and progressive scoliosis (onset at adolescence). Skin is often dry and sometimes hyperkeratotic on hands and feet. Hair is curly and may be thick or sparse. Peripheral lymphedema may be present and may be progressive and extensive in some. Ocular anomalies (strabismus, refractive errors), and dental crowding are common. Hearing loss is present in 10%. Delayed speech and learning difficulties affect 30-40%. Intellectual disability (often mild) is present in 10-20%. Dyspraxia (clumsiness), attention deficit disorder, agitation, mood disorders and emotional disturbances are not rare, as well as difficulties in identifying and expressing emotions, which can lead to more difficult social interactions. Motor development and puberty are delayed and short stature is present in 50%. Unilateral or bilateral cryptorchidism is present in two-thirds of boys, and hypofertility may affect males, but not females. Thyroid dysfunction may occur. Coagulation defects are frequent but rarely clinically significant. In childhood, there is an increased risk of tumors and leukemias (noteworthy juvenile myelomonocytic leukemia), with a cumulative cancer risk of about 4% by age 20. The risk of common adult cancer does not appear increased.\nEtiology\nNS is caused by mutations in PTPN11 (12q24.13) seen in 50% of cases, SOS1 (2p22.1) in 15%, RAF1 (3p25.2), RIT1 (1q22) and LZTR1(22q11.21), and less commonly in other genes associated with the RAS/MAPK signaling pathway. The clinical spectrum of NS may differ slightly between causative genes, and some forms have been described as ''Noonan like'' (NS-like disorder with juvenile myelomonocytic leukemia and NS-like disorder with loose anagen hair).\nDiagnostic methods\nThe diagnosis relies on clinical manifestations but may be difficult because of the highly variable presentation. Molecular genetic testing of the causative genes helps diagnosis and genetic counseling. Mild cases may remain undiagnosed and only brought to clinical attention in adulthood after the birth of a more severely affected child.\nDifferential diagnosis\nDifferential diagnoses include Cardio-Facio-Cutaneous syndrome, Costello syndrome, Neurofibromatosis type 1, Noonan syndrome with multiple lentigines (all RASopathies), Baraitser-Winter, Aarskog and Escobar syndromes.\nAntenatal diagnosis\nPrenatal diagnosis is possible on chorionic villi or amniotic fluid. Prenatal signs of NS are nonspecific: increased nuchal translucency, cystic hygroma and/or ascites (that may lead to fetal demise), polyhydramnios, cardiomyopathy and congenital heart defect.\nGenetic counseling\nInheritance of NS is autosomal dominant, except LZTR1 which can be either dominant or recessive. Genetic counseling should be offered to affected families.\nManagement and treatment\nTreatment requires a multidisciplinary approach. Cardiovascular anomalies are treated with standard approaches. Treatment of growth retardation with growth hormone is still controversial. Developmental disabilities should be addressed early.\nPrognosis\nThe prognosis is variable since the presentation ranges from mild/unrecognized manifestations in adulthood to severe disorder with life-threatening heart disease or malignancy in infancy. Severe cardiomyopathy may lead to early demise.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Norrie disease", "Disease Definition": "A rare developmental defect during embryogenesis characterized by abnormal retinal development with congenital blindness. Common associated manifestations include sensorineural hearing loss and developmental delay, intellectual disability and/or behavioral disorders.", "ORPHA ID": 649, "Summary": "Epidemiology\nTo date, more than 400 cases have been described. Affected patients are almost always male.\nClinical description\nThe ocular findings in affected males are usually bilateral and symmetrical. The iris, anterior chamber and cornea may be normal at birth but greyish-yellow elevated masses (pseudogliomas) are often observed behind the lens along with retinal vascular dysgenesis and leukocoria. Partial or complete retinal detachment develops within the first few weeks or months of life. In infancy and childhood, patients may develop cataracts, nystagmus, anterior/posterior synechiae, band keratopathy and a shallow anterior chamber with increased intraocular pressure. Phthisis bulbi is found later on, along with opacified corneas and sunken orbits. Vision varies from light perception to congenital complete blindness. Most affected males develop progressive asymmetrical sensorineural hearing loss starting in childhood (median age of onset is 12 years). Hearing loss may be severe and bilateral by mid-adulthood. Developmental delay and intellectual disability are found in about 20-30% of patients. Some have cognitive and psychosocial behavioral disorders, including psychosis. Other associated manifestations are highly variable and may include growth failure, microphthalmia, varied chronic seizure disorders, peripheral vascular disease (peripheral ulcers) and erectile dysfunction. Very rare cases of carrier females with retinal findings, such as retinal detachment, abnormal retinal vasculature with associated vision loss or mild sensorineural hearing loss, have been reported.\nEtiology\nNorrie disease is caused by mutations in the NDP gene (Xp11.4-p11.3), encoding the norrin cystine knot growth factor NDP which is involved in the vascular development of the eye and ear. A large number of disease-causing mutations have been identified.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical ocular findings and can be confirmed by molecular genetic testing of NDP. No biochemical or functional assays are available. A causative mutation in the NDP gene is recovered in around 85% of male probands. If negative, search for a rearrangement should be conducted.\nDifferential diagnosis\nDifferential diagnosis includes retinoblastoma in cases with unilateral pseudoglioma, and other disorders related to NDP mutations such as retinopathy of prematurity, persistent hyperplastic primary vitreous, and familial exudative vitreoretinopathy.\nAntenatal diagnosis\nPrenatal testing for at-risk pregnancies is possible if the disease-causing mutation has been identified in the family. In rare cases, particularly where there is a family history, ocular abnormalities have been detected on ultrasonography in the third trimester.\nGenetic counseling\nNorrie disease is inherited in an X-linked manner. Rare de novo mutations have been reported. Genetic counseling should be offered to affected families. Where a female carries the mutation, there will be a 50% risk that male offspring will inherit the disease, and a 50% risk that female offspring will be carriers. Where a male is affected, male offspring are unaffected whereas female offspring are obligate carriers\nManagement and treatment\nMany patients have complete retinal detachment at birth making treatment for preservation of sight difficult. Those that do not have complete retinal detachment may benefit from surgery or laser therapy. Enucleation of the eye may be required in rare cases. Hearing aids should be provided to correct hearing loss and cochlear implantation can be considered. Supportive therapy should be provided for behavioral disorders.\nPrognosis\nOverall health is generally good in patients with ND. Life expectancy may however be reduced due to general risks associated with the disabling manifestations of the disease.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Patrick CALVAS"}
{"Disease Name": "North Carolina macular dystrophy", "Disease Definition": "A non-progressive autosomal dominant macular disorder of congenital or infantile onset characterized by loss of central vision, the accumulation of drusen in the macula and atrophy of photoreceptor cells with a variable phenotype at macular examination.", "ORPHA ID": 75327, "Summary": ""}
{"Disease Name": "NPHP3-related Meckel-like syndrome", "Disease Definition": "NPHP3-related Meckel-like syndrome is a rare, genetic, syndromic renal malformation characterized by cystic renal dysplasia with or without prenatal oligohydramnios, central nervous system abnormalities (commonly Dandy-Walker malformation), congenital hepatic fibrosis, and absence of polydactyly.", "ORPHA ID": 3032, "Summary": ""}
{"Disease Name": "NRXN1-related severe neurodevelopmental disorder-motor stereotypies-chronic constipation-sleep-wake cycle disturbance", "Disease Definition": "A rare, genetic, neurodevelopmental disorder characterized by global developmental delay, severe intellectual disability and absence of expressive language. Muscular hypotonia, seizures, autistic behavior and stereotypic movements are common.", "ORPHA ID": 600663, "Summary": "Epidemiology\nTo date, 11 affected individuals have been described in the literature worldwide. The exact prevalence is not known.\nClinical description\nThe main clinical characteristics are global developmental delay and severe intellectual disability. Speech is usually absent or very limited. Motor development is moderately to severely delayed, with walking after 2 years or even inability to walk in some individuals. Muscular hypotonia, severe deficits in social interaction, and motor stereotypies are very common. Moreover, abnormal sleep-wake cycle, abnormality in breathing and chronic constipation may occur. Electroencephalogram abnormalities and seizures were observed in several individuals with variable onset between the first months of life and adolescence. Brain imaging is normal in the majority of cases, but may also show moderate cortical atrophy, cysts or asymmetry of the ventricular system. Additional features such as failure to thrive, pulmonary stenosis, valve or septal defects, hearing impairment, microcephaly, gastroesophageal reflux, early onset puberty and scoliosis are present in single or few cases. Mild but non-specific facial dysmorphisms, such as a broad mouth, strabismus or protruding tongue with drooling, have occasionally been described.\nEtiology\nThe disorder is caused by homozygous or compound heterozygous intragenic deletions or truncating variants in the NRXN1 gene (2p16.3). NRXN1 belongs to the evolutionarily conserved family of neurexins, presynaptic transmembrane proteins and has an important role in synaptic function.\nDiagnostic methods\nDiagnosis is usually made by untargeted approaches such as chromosomal microarray analysis and/or multigene panel or exome sequencing. Detection of a heterozygous, deleterious variant in NRNX1 in an individual with a fitting phenotype should prompt careful investigation of the second allele.\nDifferential diagnosis\nDifferential diagnosis includes other non-specific severe neurodevelopmental disorders with or without seizures.\nAntenatal diagnosis\nPrenatal diagnosis and preimplantation-diagnostic are possible where the pathogenic variant(s) has/have been identified in an affected family member and/or carrier status in the parents has been confirmed.\nGenetic counseling\nInheritance is autosomal recessive; genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. Heterozygous deletions or variants in NRXN1 are associated with an increased risk for variable neuropsychiatric abnormalities.\nManagement and treatment\nOngoing developmental assessments are required to tailor educational services to individual needs, e.g. physical, occupational, speech therapies and behavioral management strategies. For patients with seizures, the appropriate seizure management is required.\nPrognosis\nThere are patients living in their fourth decade. Usually severe cognitive impairment is present with dependence on others help for daily living.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Katalin HETZELT | ITHACA* - Pr Christiane ZWEIER \n\n\n                                * European Reference Network"}
{"Disease Name": "Null syndrome", "Disease Definition": "The null syndrome is part of the Pelizaeus-Merzbacher disease (PMD; see this term) spectrum and is characterized by mild PMD features associated with demyelinating peripheral neuropathy.", "ORPHA ID": 280234, "Summary": "Epidemiology\nIts prevalence is unknown. It predominantly affects males.\nClinical description\nThe disease manifests during childhood. Patients may have mild developmental delay, delayed sitting and walking beginning usually in the first 2 to 3 years of life, later associated with mild peripheral neuropathy, mild spastic quadriparesis, hyperreflexia, Babinski signs, ataxia, and/or mild intellectual deficit.  Patients do not have nystagmus. Although they usually are ambulatory during childhood and have good speech, patients with the null syndrome tend to decline more rapidly beginning in adolescence or early adulthood compared to patients with other PMD forms.\nEtiology\nThe syndrome is due to null mutations of the PLP1 gene (on Xq22) that cause hypomyelination of the central nervous system. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20).\nGenetic counseling\nThe disease has an X-linked inheritance pattern.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr James GARBERN"}
{"Disease Name": "NUT midline carcinoma", "Disease Definition": "A rare tumor characterized by a rapidly growing mass usually arising along the midline, defined by the presence of NUTM1 rearrangements. Histopathological examination shows a poorly differentiated carcinoma, often with evidence of squamous differentiation. Patients present with unspecific signs and symptoms due to mass effect, depending on the location. Extensive local invasion of adjacent structures, lymph node involvement, and distant metastatic disease are often present at the time of diagnosis. Prognosis is generally poor.", "ORPHA ID": 443167, "Summary": ""}
{"Disease Name": "O'Sullivan-McLeod syndrome", "Disease Definition": "A rare acquired motor neuron disease characterized by an initial unilateral weakness in the intrinsic hand muscles that eventually spreads to the opposite limb (with an asymmetrical distribution) and that has a very slow progression of muscular atrophy over a 20 year period.", "ORPHA ID": 99965, "Summary": ""}
{"Disease Name": "Obesity due to CEP19 deficiency", "Disease Definition": "A rare, genetic form of obesity characterized by morbid obesity, hypertension, type 2 diabetes mellitus and dyslipidemia leading to early coronary disease, myocardial infarction and congestive heart failure. Intellectual disability and decreased sperm counts or azoospermia have also been reported.", "ORPHA ID": 397615, "Summary": ""}
{"Disease Name": "Obesity due to congenital leptin deficiency", "Disease Definition": "Congenital leptin deficiency is a form of monogenic obesity characterised by severe early-onset obesity and marked hyperphagia.", "ORPHA ID": 66628, "Summary": "Epidemiology\nIt has been described in less than 30 patients.\nClinical description\nPatients with congenital leptin deficiency are severely hyperphagic from early infancy and, although birthweight is normal, they rapidly become obese during early childhood. An increased susceptibility to infections has also been reported in these infants and appears to be associated with reduced numbers of circulating CD4+ T cells, and impaired T cell proliferation and cytokine release. Other features of the disorder include hyperinsulinaemia, advanced bone age, hypothalamic hypothyroidism and hypogonadotropic hypogonadism leading to a failure to undergo puberty.\nEtiology\nLeptin is an adipocyte-derived hormone that plays an important role in energy balance and appetite suppression. Whilst the majority of obese patients display hyperleptinaemia, patients with congenital leptin deficiency have undetectable levels of leptin in the serum. This absence of serum leptin is caused by homozygous frameshift or missense mutations in the ob gene (7q31.3) and is inherited as an autosomal recessive trait. However, a similar phenotype has been observed in three individuals from one consanguineous family who carried homozygous mutations in the gene encoding the leptin receptor (LEPR, 1p31).\nDiagnostic methods\nFamily history, severe hyperphagia and early-onset obesity may lead to suspicion of a monogenic obesity syndrome. The diagnosis of congenital leptin deficiency can be confirmed by analysis of serum leptin levels or identification of mutations in the ob gene.\nManagement and treatment\nCongenital leptin deficiency can be successfully treated with daily subcutaneous injections of recombinant human leptin, resulting in sustained positive effects on weight loss, reducing appetite, appropriate pubertal development and hyperinsulinaemia.\nPrognosis\nAs a result, the prognosis for patients undergoing treatment appears to be excellent. However, misdiagnosed patients are at risk of developing the complications normally associated with severe obesity (in particular type 2 diabetes), with the prognosis being hampered further by an increased rate of mortality due to childhood infection.\n\n                            Last update: \n                            May 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Sebastiano FILETTI"}
{"Disease Name": "Obesity due to leptin receptor gene deficiency", "Disease Definition": "A rare, genetic, non-syndromic, obesity disease characterized by severe, early-onset obesity, associated with major hyperphagia and endocrine abnormalities, resulting from leptin receptor deficiency.", "ORPHA ID": 179494, "Summary": ""}
{"Disease Name": "Obesity due to melanocortin 4 receptor deficiency", "Disease Definition": "Melanocortin 4 receptor (MC4R) deficiency is the commonest form of monogenic obesity identified so far. MC4R deficiency is characterised by severe obesity, an increase in lean body mass and bone mineral density, increased linear growth in early childhood, hyperphagia beginning in the first year of life and severe hyperinsulinaemia, in the presence of preserved reproductive function.", "ORPHA ID": 71529, "Summary": "Epidemiology\nThe prevalence in the general population is probably around 1 in 2000. The prevalence of MC4R mutations has been estimated at between 0.5 and 1% in obese adults (body mass index >30) with higher values among populations with severe childhood-onset obesity and variability between ethnic groups.\nEtiology\nMC4R is a G protein-coupled receptor involved in the hypothalamic leptin-melanocortin signalling pathway. Activation of the MC4R plays a key role in the maintenance of energy homeostasis and is associated with suppression of food intake. The majority of patients described so far are carriers of heterozygous mutations in the MC4R gene (18q22). Rare homozygous carriers have been described and display a more severe phenotype. However, one homozygous patient with complete absence of MC4R function has been reported and did not display hyperinsulinaemia.\nDiagnostic methods\nThe majority of MC4R deficient cases reported so far have been identified through genetic screening of large cohorts of obese patients, however, diagnosis may be suspected on the basis of the clinical features of the disorder and confirmed by detection of a MC4R mutation.\nGenetic counseling\nMC4R deficiency is transmitted in a codominant manner, with expressivity and penetrance varying between ethnic groups.\nManagement and treatment\nAt present, there is no specific treatment for MC4R deficiency. However, future development of small molecule MC4R agonists might lead to the generation of highly effective treatments for this disorder.\nPrognosis\nAs with other forms of obesity, the prognosis is dependent on the complications present, with obese patients being at increased risk of cardiovascular disease, cancer and type 2 diabetes.\n\n                            Last update: \n                            May 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Sebastiano FILETTI"}
{"Disease Name": "Obesity due to pro-opiomelanocortin deficiency", "Disease Definition": "Pro-opiomelanocortin (POMC) deficiency is a form of monogenic obesity resulting in severe early-onset obesity, adrenal insufficiency, red hair and pale skin.", "ORPHA ID": 71526, "Summary": "Epidemiology\nIt is has been described in less than 10 patients.\nClinical description\nPatients with POMC deficiency usually present in the neonatal period with hypoglycaemic seizures, hyperbilirubinaemia and cholestasis to due to secondary congenital hypocortisolism. Hyperphagia is noted from the first weeks of life leading to severe obesity before one year of age. Subclinical hypothyroidism was also reported.\nEtiology\nComplete POMC deficiency is caused by homozygous or compound heterozygous loss-of-function mutations in the POMC gene (chromosome 2p23.3). POMC is regulated by leptin and is cleaved by prohormone convertases to produce the melanocortin receptor (MC-R) ligands adrenocorticotrophin (ACTH) and melanocyte-stimulating hormones (MSH) alpha, beta and gamma. The red hair pigmentation, adrenal insufficiency and obesity are caused by deficiencies in the ligands and subsequent lack of activation of the MC1, MC2, and MC4 receptors, respectively. In addition to complete POMC deficiency, a few individuals with isolated deficiency of the MC4-R POMC-derived ligand, beta-MSH, have also been described. These individuals carry a distinct POMC mutation in the region encoding beta-MSH. This isolated deficiency of beta-MSH leads to a clinical phenotype similar to that observed in MC4-R deficiency (childhood obesity, hyperphagia and increased linear growth) but is not associated with red hair or adrenal insufficiency.\nDiagnostic methods\nDiagnosis of complete POMC deficiency may be suspected on the basis of the clinical manifestations of the disease and can be confirmed by identification of mutations in the POMC gene. Analysis of the serum reveals an absence of pituitary-derived POMC peptides, even after stimulation.\nDifferential diagnosis\nDifferential diagnosis includes combined pituitary hormone deficiencies, which can be excludedby multiple pituitary hormone stimulation tests.\nGenetic counseling\nComplete POMC deficiency is transmitted as an autosomal recessive trait.\nManagement and treatment\nAt present, there is no specific treatment. The neonatal complications of POMC deficiency may lead to lethal hepatic failure if left untreated, with patients requiring prompt and long-term hydrocortisone substitution therapy. Advances in melanocortin peptide therapy may lead to the development of MC4R agonists capable of improving melanocortin function in these patients. However, an initial 3-month trail with intranasal administration the ACTH 4-10 melancortin fragment did not lead to a reduction in body weight. Administration of thyroid hormone was also found to have no effect on the obesity.\nPrognosis\nAlthough the specific prognosis for this disease has not yet been defined, it is likely these patients are at increased risk of complications (cardiovascular disease, cancer and type 2 diabetes) present in other obese patients.\n\n                            Last update: \n                            May 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Sebastiano FILETTI"}
{"Disease Name": "Obesity due to prohormone convertase I deficiency", "Disease Definition": "A rare genetic endocrine disease characterized by early onset of severe intractable diarrhea and intestinal malabsorption, followed by obesity and hormonal deficiencies due to insufficient activation of several prohormones, resulting in hypocortisolism, hypothyroidism, diabetes insipidus, hypogonadism, growth deficiency, and diabetes mellitus. Extent and age of onset of hormone deficiencies are variable between patients.", "ORPHA ID": 71528, "Summary": ""}
{"Disease Name": "Obesity due to SIM1 deficiency", "Disease Definition": "A rare, genetic form of obesity characterized by severe early-onset obesity, hyperphagia, and variable presence of cognitive impairment and behavioral disorder, including autistic spectrum behavior, impaired concentration and memory deficit. Some patients present with Prader-Willi-like features such as hypotonia, developmental delay, intellectual disability, short stature, hypopituitarism and dysmorphic facial features.", "ORPHA ID": 369873, "Summary": ""}
{"Disease Name": "Obesity-colitis-hypothyroidism-cardiac hypertrophy-developmental delay syndrome", "Disease Definition": "Obesity-colitis-hypothyroidism-cardiac hypertrophy-developmental delay syndrome is characterised by precocious obesity, congenital hypothyroidism, neonatal colitis, cardiac hypertrophy, craniosynostosis and developmental delay. It has been described in two brothers, one of whom died within the first month of life. The parents of the two children were nonconsanguineous and in good health, however, the pregnancies were complicated by a maternal HELLP syndrome (Haemolysis, Elevated Liver enzymes and Low Platelets). The mode of inheritance has not yet been clearly established.", "ORPHA ID": 88643, "Summary": ""}
{"Disease Name": "Occipital horn syndrome", "Disease Definition": "A rare congenital disorder of copper metabolism that is principally characterized by bony exostoses (including the pathognomonic occipital horns), and connective tissue manifestations with cutis laxa and bladder diverticula. Central nervous system involvement is variable.", "ORPHA ID": 198, "Summary": "Epidemiology\nOccipital horn syndrome (OHS) is a very rare X-linked disease and the exact prevalence is unknown. To date approximately 35 cases have been reported and all but one were male.\nClinical description\nAge of onset ranges from infancy to childhood. Observations at birth may include cephalhematoma (12% of cases), loose and wrinkled skin, and umbilical or inguinal hernias. About one third of all patients primarily present with central nervous system involvement (hypotonia, developmental delay and/or seizures). Initial clinical presentation may occur later with bladder diverticula or skeletal manifestations. Bladder diverticula affects the majority of patients (>80%) and may manifest through recurrent urinary tract infections or pollakisuria. The most typical skeletal manifestation (present in 96% of all patients) is an exostosis on the occiput at the insertion of the trapezoid muscle (occipital horn), but exostoses may also occur on the tibia and radius. Other, more variable, skeletal features are hammer-shaped claviculae, scoliosis, pectus deformity, coxa valga, genua valga as well as dislocations of the radial head. Less frequently reported skeletal manifestations include bowing of the long bones, mid-diaphyseal broadening, metaphyseal spurring, rounding of the iliac wings and, rarely, osteopenia. Facial features become distinctive with age and includes a long face (46%), large ears (38%), sagging cheeks (45%) and coarse hair (74%). Trichoscopy may show pili torti. The skin is often hyperextensible and soft with fine wrinkling on the hands and feet. Skin redundancy is remarkable on the belly. Vascular tortuosity is common in the intracranial arteries (65%), but may also affect the cervical, splenic and splanchnic circulation and imposes a risk for aneurysm formation. Aortic root dilatation and dissection may rarely occur. Dysautonomia with postural orthostatic hypotension, temperature instability and chronic diarrhea is present in most patients (>90%). About half of all patients show a delayed motor development due to muscle hypotonia and joint hypermobility, and may report unusual clumsiness. Distal motor neuropathy has been recorded in at least one patient. About half of all patients have intellectual disability (ID) which is usually mild, but moderate to severe impairment may occur.\nEtiology\nOHS is due to pathogenic variants (missense, frameshift and splice variants) in the ATP7A gene (Xq21.1) encoding the copper-transport ATPase 1. OHS is allelic with Menkes disease; there are no clear genotype-phenotype correlations, nor a correlation between the type or location of the variant and serum copper levels. However, certain variants may lead to a partially functional protein or reduced amounts of an otherwise normal protein.\nDiagnostic methods\nDiagnosis is based on clinical features. Radiography shows the characteristic occipital horns. Diagnosis is confirmed by identification of a pathogenic variant.\nDifferential diagnosis\nMenkes disease is the main differential diagnosis and allelic to OHS. Other conditions to be considered include other forms of cutis laxa, including autosomal dominant cutis laxa, and autosomal recessive cutis laxa type 1a and 1c, Ehlers-Danlos syndrome, dermatosparaxis type, and hereditary multiple exostoses.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is X-linked recessive. Genetic counseling should be offered to couples where the mother is a carrier of a pathogenic variant, informing them that the risk for a male fetus to be affected is 50% at each pregnancy. The possibility of germ-line mosaicism should be discussed when counselling non-carrier mothers of singleton cases; although not yet described for OHS it has been described for Menkes disease.\nManagement and treatment\nTreatment is symptomatic. No data exist on early parenteral copper-histidine supplementation. Notably, individuals with OHS are at increased risk for post-surgery apnea, and should benefit from prolonged post-surgery monitoring.\nPrognosis\nPrognosis is variable in OHS. Most patients reach adulthood. Risks for early demise include seizures, bladder rupture, vascular ruptures and postsurgical apnea. Inguinal hernia often recur after surgery.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Bert CALLEWAERT | ERN-Skin* - Pr Zeynep TÜMER | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Occipital pachygyria and polymicrogyria", "Disease Definition": "A rare, genetic, cerebral malformation characterized by the presence of cortical smoothening with loss of secondary and tertiary gyri, associated with an excessive number of small, irregular gyri with increased cortical thickness, located in the occipital lobes. Patients usually present with seizures (including myoclonic-astatic, absence, atypical absence, vision loss, myoclonic-atonic, generalized tonic-clonic) and variable (absent to moderate) developmental and/or intellectual delay.", "ORPHA ID": 280640, "Summary": ""}
{"Disease Name": "Occult macular dystrophy", "Disease Definition": "Occult macular dystrophy is a rare, genetic retinal dystrophy disease characterized by bilateral progressive decline of visual acuity, due to retinal dysfunction confined only to the macula, associated with normal fundus and fluorescein angiograms and severly attenuated focal macular and multifocal electroretinograms.", "ORPHA ID": 247834, "Summary": ""}
{"Disease Name": "Occupational allergic alveolitis", "Disease Definition": "Occupational allergic alveolitis designates a hypersensitivity pneumonitis (see this term) resulting from the inhalation of an antigen to which an individual has been previously sensitized in his/her occupational environment. Symptoms vary depending on the antigen and the form (acute, subacute, chronic) of the disease. They may be cough, dyspnea, chills, fever, weight loss, loss of appetite and general malaise", "ORPHA ID": 99909, "Summary": ""}
{"Disease Name": "Ocular albinism with late-onset sensorineural deafness", "Disease Definition": "Ocular albinism with late-onset sensorineural deafness is a rare, X-linked inherited subtype of ocular albinism characterized by severe visual impairment, translucent pale-blue irises, a reduction in the retinal pigment and moderately severe deafness with onset ranging from adolescence to fourth or fifth decade of life.", "ORPHA ID": 1000, "Summary": ""}
{"Disease Name": "Ocular anomalies-axonal neuropathy-developmental delay syndrome", "Disease Definition": "A rare mitochondrial disease characterized by signs and symptoms within a phenotypic and metabolic spectrum that includes global developmental delay, hypotonia, intellectual disability, optic atrophy, axonal neuropathy, hypertrophic cardiomyopathy, lactic acidosis, and increased excretion of Krebs cycle intermediates. Other variable features are spasticity, seizures, ataxia, congenital cataract, and dysmorphic facial features. Age of onset is in the neonatal period or infancy.", "ORPHA ID": 496790, "Summary": ""}
{"Disease Name": "Ocular cicatricial pemphigoid", "Disease Definition": "A rare inflammatory eye disease characterized by sub-epithelial blistering manifesting with bilateral, asymmetrical, chronic or recurrent conjunctivitis and aberrant tissue regeneration leading to progressive conjunctival fibrosis, secondary corneal vascularization and, in some cases, blindness. Patients typically present with conjunctival redness, increased lacrimation, burning and/or foreign body sensation, edema, limbitis and/or varying degrees of ocular pain. Ankyloblepharon may be observed in end stages of the disease.", "ORPHA ID": 99922, "Summary": ""}
{"Disease Name": "Ocular cystinosis", "Disease Definition": "Ocular cystinosis is the benign, adult form of cystinosis (see this term), a metabolic disease characterized by an accumulation of cystine crystals in the cornea and conjunctiva responsible for tearing and photophobia and associated with no other additional manifestations.", "ORPHA ID": 411641, "Summary": ""}
{"Disease Name": "Ocular motor apraxia, Cogan type", "Disease Definition": "Ocular motor apraxia, Cogan type is characterised by impairment of voluntary horizontal eye movements and compensatory head thrust. Around 50 cases have been described so far. The oculomotor manifestations tend to improve with age but the syndrome may also be associated with learning and speech difficulties, or, in some cases, cerebral malformations. Both sporadic and familial forms have been described, with sporadic forms being more frequent. The mode of transmission of the familial form has not yet been clearly established. A gene located on the long arm of chromosome 2, near to the NPHP1 gene involved in nephronophthisis, may be associated with ocular motor apraxia, Cogan type.", "ORPHA ID": 1125, "Summary": ""}
{"Disease Name": "Oculo-auriculo-vertebral spectrum", "Disease Definition": "A rare congenital malformation syndrome, most commonly presenting with hemifacial microsomia associated with ear and/or eye malformations and vertebral anomalies of variable severity. Additional malformations involving the heart, kidneys, central nervous, digestive and skeletal systems may also be associated.", "ORPHA ID": 141132, "Summary": "Epidemiology\nThe prevalence at birth is less than 1/26,000 in Europe, with a slight male predominance.\nClinical description\nThe phenotypic spectrum ranges from isolated mild facial asymmetry to severe bilateral craniofacial microsomia and additional multiple extracranial abnormalities. Craniofacial involvement is typically unilateral; the most common manifestations are auricular abnormalities, preauricular appendages and/or fistulas, hypoplasia of the mandible, maxilla, malar bone, and/or zygomatic arch, and epibulbar dermoids. Although exceptional, airway obstruction due to mandibular and maxillary hypoplasia can be life threatening. Auricular abnormalities are usually unilateral and include microtia, ear malpositioning and external auditory canal atresia or stenosis, with or without hearing loss. Ocular involvement may range from an upper eyelid coloboma to micro/anophthalmia in severe cases. Facial palsy, asymmetric palatal elevation, impairment of extraocular movements and trigeminal anesthesia have been reported. Congenital heart defects, such as tetralogy of Fallot, septal defects, transposition of the great vessels, aortic arch anomalies, situs inversus, and dextrocardia are not uncommon. Additional features may include renal (unilateral kidney agenesis, double ureter, renal ectopia, hydronephrosis, hydroureter) and central nervous system (developmental delay, microcephaly, encephalocele, hydrocephaly, corpus callosum hypoplasia, Arnold-Chiari malformation, holoprosencephaly) anomalies. Intelligence is typically normal.\nEtiology\nThe etiology is poorly understood but is suspected to be heterogeneous and multifactorial. The gene MYT1 (20q13.33) has been Implicated in a few rare cases, and chromosomal abnormalities have been associated with some of the congenital malformations associated with this condition.\nDiagnostic methods\nDiagnosis is based on clinical findings. Microtia and/or mandibular hypoplasia with a preauricular tag have been suggested as diagnostic; however, there are no established guidelines for the minimum diagnostic criteria.\nDifferential diagnosis\nDifferential diagnosis includes syndromes associated with microtia and mandibular hypoplasia, including Treacher Collins syndrome, Townes-Brocks syndrome, CHARGE syndrome, branchio-oto-renal spectrum disorders, mandibulofacial dysostosis with microcephaly, and Wildervanck syndrome.\nAntenatal diagnosis\nPrenatal diagnosis of craniofacial microsomia is uncommon. Where there is a family history, non-invasive prenatal diagnosis is advised. Fetal ultrasound allows detection of severe extracranial anomalies and some cases with severe mandibular hypoplasia, whereas 3D ultrasound scans may enable identification of cases with milder defects.\nGenetic counseling\nThe condition usually occurs sporadically, but autosomal dominant inheritance has been reported. To assess recurrence risk, parents and siblings should be evaluated for the clinical manifestations. Due to the phenotypic heterogeneity of the disease, predicting the severity in offspring is difficult. In cases where no family history or chromosomal abnormality exists, sibling recurrence risk is estimated at 2-3%.\nManagement and treatment\nTreatment is multidisciplinary and should be divided into stages, according to the patient's age, and tailored according to the extent and severity of observed abnormalities. A full evaluation is necessary to assess skeletal, renal, cardiac, dental and auricular involvement. Prompt treatment may be required for airway obstruction and extracranial abnormalities. Correction of malformations usually requires a longitudinal, multistage and coordinated treatment plan. Surgeries for facial asymmetry may be complicated by temporomandibular joint aplasia/hypoplasia. The timing and most effective interventions for mandibular correction is still controversial. Many professionals currently advocate for intervention after completion of facial growth where possible, thereby avoiding relapses and numerous surgeries.\nPrognosis\nOutcome depends on the complexity of the abnormalities, as well as the timing of diagnosis and interventions. Long-term outcomes may be hard to predict.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Carrie HEIKE  - Dr Daniela LUQUETTI"}
{"Disease Name": "Oculo-palato-cerebral syndrome", "Disease Definition": "Oculopalatocerebral syndrome is characterised by the association of four anomalies: intellectual deficit, microcephaly, palate anomalies and ocular abnormalities.", "ORPHA ID": 2714, "Summary": "Epidemiology\nIt has been described in five patients (three boys and two girls).\nClinical description\nMaternal hypertension, oligoamnios and intrauterine growth retardation (IUGR) are often noted during pregnancy. The clinical manifestations are evident from birth. The palate anomaly is usually cleft palate. In the majority of cases, postnatal growth is marked by statural (between -2.5 and -4 SD) and ponderal retardation. Microcephaly is present in all patients (between -2 and -5.6 SD). Persistent hyperplastic primary vitreous (uni- or bilateral) was present in all cases reported so far and may be associated with microphthalmia, cataract or optic atrophy. Facial dysmorphology is characterised by full cheeks, a bulbous nasal tip, and long ears with thickened helices. Hands and feet are small. Anomalies of the external genitalia were reported in some of the male patients, with two of the boys displaying cryptorchidism. Skeletal anomalies include pectus excavatum, joint hyperlaxity and kyphoscoliosis. Intellectual deficit (moderate to severe) is a constant feature and is associated with cerebral atrpohy or quadriplegia in some cases. Hearing difficulties may also be present and a tendency for atopy is often noted.\nEtiology\nSo far, neither a causative gene nor locus has been identified.\nDiagnostic methods\nDiagnosis is based in the clinical manifestations, in particular on the presence of a persistent hyperplastic primary vitreous in association with other malformations.\nDifferential diagnosis\nDifferential diagnosis should include cerebro-oculo-nasal syndrome (see this term) and other syndromes associated with a persistent hyperplastic primary vitreous.\nAntenatal diagnosis\nPrenatal diagnosis is possible but relies on detection of the malformations and growth retardation by foetal ultrasound.\nGenetic counseling\nFamilial reoccurrence and evidence of consanguinity in two of the three reported families are suggestive of autosomal recessive inheritance. Genetic counselling of families with an affected child should take into account a risk of reoccurrence of 25%.\nManagement and treatment\nTreatment should include surgical correction of the palate anomalies and management of the visual problems. Physical and speech therapy should also be recommended.\nPrognosis\nAlthough no data are available on the long-term prognosis, the nature of the anomalies suggests that life expectancy for these patients is normal.\n\n                            Last update: \n                            January 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Pierre SARDA"}
{"Disease Name": "Oculoauricular syndrome, Schorderet type", "Disease Definition": "Oculoauricular syndrome, Schorderet type is a rare, genetic developmental defect during embryogenesis syndrome characterized by various ophthalmic anomalies (including congenital microphthalmia, microcornea, cataract, anterior segment dysgenesis, ocular coloboma and early onset rod-cone dystrophy) and abnormal external ears (low-set pinna with crumpled helix, narrow intertragic incisures, abnormal bridge connecting the crus of the helix and the antihelix, narrow external acoustic meatus, and lobule aplasia).", "ORPHA ID": 157962, "Summary": ""}
{"Disease Name": "Oculoauriculofrontonasal syndrome", "Disease Definition": "A rare dysostosis syndrome characterized by vertical, median craniofacial clefting of fronto-naso-maxillary structures associated with auriculo-mandibular malformations, manifesting with highly variable craniofacial features which include hypertelorism, eyelid colobomas, orbital dystopia, epibulbar dermoids, nasal anomalies (e.g. wide nasal bridge, bifid nose, widely separated, slit-like nares, nasal bone dysplasia), auricular and middle ear dysplasia (microtia, aural stenosis, pre-auricular skin tags/pits), cleft lip/palate, mandibular/maxillary hypoplasia and facial asymmetry. Intracranial abnormalities and extra-craniofacial features are frequently associated.", "ORPHA ID": 398156, "Summary": ""}
{"Disease Name": "Oculoauriculovertebral spectrum with radial defects", "Disease Definition": "A rare branchial arches and limb primordia development disorder characterized by variable degrees of uni- or bilateral craniofacial malformation and radial defects that result in extremely variable phenotypic manifestations. Characteristic features include low postnatal weight, short stature, vertebral defects, hearing loss, and facial dysmorphism (incl. facial asymmetry, external, middle, and inner ear malformations, orofacial clefts, and mandibular hypoplasia). These features are invariably associated with radial defects, such as preaxial polydactyly, thumb and/or radius hypoplasia/agenesis, or triphalangeal thumb. Cardiac, pulmonary, renal, and central nervous system involvement has also been reported.", "ORPHA ID": 2549, "Summary": ""}
{"Disease Name": "Oculocerebral hypopigmentation syndrome, Cross type", "Disease Definition": "Oculocerebral hypopigmentation syndrome, Cross type is a rare congenital syndrome characterized by cutaneous and ocular hypopigmentation, various ocular anomalies (e.g. corneal and lens opacity, spastic ectropium, and/or nystagmus), growth deficiency, intellectual deficit and other progressive neurologic anomalies such as spastic tetraplegia, hyperreflexia, and/or athetoid movements. The clinical picture varies among patients and may also include other anomalies such as urinary tract abnormalities, Dandy-Walker malformations, and/or bilateral inguinal hernia.", "ORPHA ID": 2719, "Summary": ""}
{"Disease Name": "Oculocerebral hypopigmentation syndrome, Preus type", "Disease Definition": "Oculocerebral hypopigmentation syndrome, Preus type is a rare congenital syndrome characterized by skin and hair hypopigmentation, growth retardation, and intellectual deficit that are associated with a combination of various additional clinical anomalies such as ocular albinism, cataract, delayed neuropsychomotor development, sensorineural hearing loss, dolicocephaly, high arched palate, widely spaced teeth, anemia, and/or nystagmus.", "ORPHA ID": 2720, "Summary": ""}
{"Disease Name": "Oculocerebrocutaneous syndrome", "Disease Definition": "A rare neurologic disease typically characterized by the triad of eye, central nervous system and skin malformations, and often associated with an intellectual disability.", "ORPHA ID": 1647, "Summary": "Epidemiology\nPrevalence is unknown, but around 40 cases have been reported to date. Oculocerebrocutaneous syndrome (OCCS) is predominantly found in males.\nClinical description\nNeonates, predominantly boys, typically present with an orbital cyst or cystic microphthalmia, often in combination with eyelid colobomata. Cutaneous features often include striated muscle hamartoma, multiple cutaneous tags in the periorbital region (pedunculated/finger-like), and focal aplasia/hypoplasia (mainly on the neck, face and scalp). Developmental delay and intellectual disability may vary from very mild to profound. About half of the patients have a history of epileptic seizures, however they are well controlled in most cases. OCCS has a wide spectrum of clinical symptoms beyond the typical clinical triad, with skull, rib and vertebral anomalies, craniofacial clefts including a defect of the nasal ala in some cases, and abnormal ear pinnae. Cryptorchidism is occasionally reported.\nEtiology\nEtiology remains elusive. OCCS is hypothesized to be a postzygotic mosaic condition.\nDiagnostic methods\nDiagnosis is based on the presence of the triad of eye, central nervous system (CNS) and cutaneous clinical features. It is confirmed on magnetic resonance imaging (MRI) by the demonstration of : 1) mainly asymmetrical forebrain malformations with polymicrogyria (PMG), periventricular nodular heterotopias located beneath the PMG, interhemispheric or intraventricular cysts, enlarged ventricles or hydrocephalus, and partial or complete agenesis of the corpus callosum; and 2) provisionally unique mid-hindbrain malformations, characterized by giant tectum, absent or severely malformed vermis and posterior fossa malformation with cerebellar hypoplasia and widening of the fourth ventricular outflow tract. Electroencephalogram (EEG) is abnormal in 50% of cases.\nDifferential diagnosis\nDifferential diagnosis includes encephalocraniocutaneous lipomatosis, but the multitude of mesenchymal tumors (in particular lipomas, and choristomas) and CNS anomalies exclude it from OCCS. The brain malformations overlap substantially with those seen in Aicardi syndrome although the mid-hindbrain malformation is unkown in Aicardi syndrome and the typical chorioretinal lacunae associated with Aicardi syndrome are unknown in OCCS. Goldenhar syndrome, focal dermal hypoplasia and microphthalmia with linear skin defects should also be considered. The mid-hindbrain malformations may be confused with Dandy-Walker malformation, but are often complex and severe in OCCS.\nGenetic counseling\nOCCS occurs sporadically. The preponderance of males suggests that OCCS may be an X-linked disorder.\nManagement and treatment\nManagement should involve a multidisciplinary team composed of an ophthalmologist, neurologist and pediatrician. Removal of the orbital cyst may be done by aspiration and dissection from the adjacent periocular region. Sclerosing therapy with ethanolamine oleate may be used. Because of the cerebral or cerebellar malformations and consequent manifestations, a neurological evaluation is necessary before deciding on a surgical intervention.\nPrognosis\nOCCS has been fatal in 15% of the reported cases. Most surviving patients have significant psychomotor deficiencies but a normal development has been reported in at least 15% of the cases.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Ute MOOG"}
{"Disease Name": "Oculocerebrofacial syndrome, Kaufman type", "Disease Definition": "A rare, genetic, syndromic intellectual disability characterized by severe intellectual disability, distinctive craniofacial features and variable multiple congenital anomalies including ocular, brain, urogenital and skeletal abnormalities.", "ORPHA ID": 2707, "Summary": "Epidemiology\nTo date, 19 molecularly diagnosed cases have been described in the scientific and medical literature.\nClinical description\nThe most prominent clinical findings are severe intellectual disability, pre-and postnatal growth retardation, microcephaly, and typical craniofacial features which include non-progressive microcephaly of prenatal onset, prominence of the zygomatic region of the face, full cheeks, prominent frontal tubers, sparse and arched eyebrows, blepharophimosis with epicanthal folds, upslanted palpebral fissures, preauricular skin tags, underdeveloped and abnormally folded ears, wide nasal base, low nasal bridge, anteverted nares, long and flat philtrum and retrognathia. Hypotonia, feeding difficulties, failure to thrive and poor speech development are universal findings. Many patients require tube-feeding. Perceptive language is better than expressive, some patients acquire a few words and basic ambulation skills such as eating and dressing independently. Brain abnormalities may include absent or hypoplastic corpus callosum and changes in white matter signal intensity on MRI, but major structural brain malformations are absent. Epilepsy may occur. Ocular abnormalities include short and narrow palpebral fissures, microcornea/microphtalmos, refractive errors and strabismus. Other less frequently observed congenital anomalies include hearing loss, urogenital abnormalities (hypoplastic external genitals, hypospadias, vesicoureteral reflux, duplicated renal pelvis), skeletal abnormalities (including clinodactyly, hypoplastic or absent distal phalanges of some digits, pectus carinatum, coxa valga, pes talus varus and scoliosis). Ectodermal anomalies include thin, sparse hair, and light colored, fine skin. Gastroesophageal reflux is a frequent problem. Congenital heart malformations and breathing problems (tracheo/laryngomalacia, subglottic stenosis) are frequent. About half of patients have abnormal cholesterol levels (low total HDL/LDL levels). Patients have an overall friendly disposition.\nEtiology\nThe syndrome is caused by biallelic inactivating mutations in the UBE3B gene (12q24.11), which encodes ubiquitin protein ligase E3B, a putative calmodulin-regulated mitochondria-associated enzyme involved in the protein ubiquitination pathway.\nDiagnostic methods\nDiagnosis is established in a proband with developmental delay/intellectual disability, characteristic craniofacial anomalies and biallelic UBE3B pathogenic variants.\nDifferential diagnosis\nDifferential diagnosis principally includes other syndromes featuring association of blepharophimosis and intellectual disability (e.g. blepharophimosis-intellectual disability syndrome, Maat-Kievit Brunner type), as well as Toriello-Carey syndrome, Smith-Lemli-Opitz syndrome, and DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation and Seizures) if digital anomalies are present.\nAntenatal diagnosis\nPrenatal testing for at risk pregnancies is possible where the UBE3B pathogenic variants have been identified previously in a family member.\nGenetic counseling\nGenetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nFull multisystem evaluation should be performed following the diagnosis, and growth, developmental progress, vision, hearing and contractures/scoliosis should be regularly followed up. Educational intervention and speech therapy should start as early as possible. Intervention for feeding problems may be needed. Treatment of the encountered congenital and functional anomalies is standard.\nPrognosis\nPrognosis depends on the severity of symptoms; however, data is limited.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Katalin SZAKSZON | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Oculocerebrorenal syndrome of Lowe", "Disease Definition": "A rare multisystem disorder characterized by congenital cataracts, glaucoma, intellectual disabilities, seizures, postnatal growth retardation and renal tubular dysfunction with chronic renal failure.", "ORPHA ID": 534, "Summary": "Epidemiology\nThe estimated prevalence is 1/500,000 and males are almost exclusively affected.\nClinical description\nOculocerebrorenal syndrome of Lowe (OCRL) is a congenital disorder characterized by ocular abnormalities (bilateral congenital discoid cataracts, glaucoma with or without buphthalmos, strabismus, hypermetropia and corneal and conjunctival cheloids), neurological involvement (developmental delay, seizures, hypotonia present at birth typically with absence of deep tendon reflexes), stereotypic behavior (temper tantrums, aggressiveness and obsessive compulsive behavior), postnatal growth retardation, mild to severe intellectual disability (mean IQ 40-50), stereotypic hand movements, renal dysfunction of the Fanconi type (proximal tubular acidosis; phosphate wasting leading to renal rickets, osteomalacia and pathological fractures) and progressive decline in kidney function leading to end-stage renal failure in adulthood. Subtle cataracts are obligate findings in female carriers after puberty. Other clinical manifestations include facial dysmorphism (frontal bossing, deep-set eyes, chubby cheeks, fair complexion), destructive teno-synovitis in older patients, short stature, mucocutaneous anomalies (eruptive vellus hair cysts, tricoepithiloma, excess skin folds and eruption cysts in oral cavity), dental malformations, cryptorchidism and bleeding tendency due to platelet dysfunction.\nEtiology\nOCRL results from mutations in OCRL (Xq25), leading to phosphatidylinositol (4,5) bisphosphate accumulation, defective membrane trafficking and disturbed actin cytoskeleton remodeling. In the kidney, disturbed endosomal trafficking impairs protein reabsorption and digestion in the proximal tubules. In the eye, abnormal actin remodeling leads to disorganization of embryonic lens epithelium and abnormal development of the trabecular meshwork that regulates aqueous humor outflow from the eye.\nDiagnostic methods\nDiagnosis of OCRL is based on specific ophthalmologic, neurologic and renal abnormalities. Laboratory findings reveal features of renal Fanconi syndrome and elevations in plasma creatine kinase, lactate dehydrogenase and transaminases levels. The presence of low-molecular weight proteinuria is the first renal abnormality and is invariably present after birth. Brain imaging reveals brain atrophy, delayed myelination, pachygyrias, hydrocephalus as well as white matter lesions suggestive of periventricular leukomalacia. Diagnosis is confirmed by genetic screening of OCRL.\nDifferential diagnosis\nDifferential diagnosis includes Dent disease type 2 (an allelic disease with a milder phenotype), congenital infections (such as congenital rubella syndrome), Nance-Horan syndrome, Smith-Lemli-Opitz syndrome, muscle-eye-brain disease, cystinosis and peroxisomal disorders.\nAntenatal diagnosis\nPrenatal testing is possible and unless the mutation in the family has been defined previously, assay of enzyme activity is preferred. Elevated maternal serum and amniotic fluid alpha-fetoprotein or presence of cataract on ultrasound may be used for prenatal screening.\nGenetic counseling\nThe pattern of inheritance is X-linked and genetic counseling is recommended for affected families. If the mother is a carrier, 50% of her sons will inherit the disease whereas 50% of her daughters will be carriers. De novo mutations are reported in 30% of affected males.\nManagement and treatment\nTreatment of OCRL includes early cataract extraction to avoid amblyopia, glaucoma control by either medications or surgery and postoperatively, eye glasses. Contact lenses are contraindicated. Nasogastric tube feedings or feeding gastrostomy may be required. Treatment also includes physical and speech therapy, use of drugs (clomipramine, paroxetine and risperidone) for behavioral problems, correction of tubular dysfunction by alkali supplements, phosphate, potassium and water. Potassium citrate may be useful to prevent nephrocalcinosis.\nPrognosis\nQuality of life depends on extent of neurological and renal manifestations. Life span rarely exceeds 40 years and death occurs between 20-40 years, as a consequence of renal disease, hypotonia, increased susceptibility to infectious disease, seizures and sudden death. Glaucoma is often difficult to control.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Arend BÖKENKAMP"}
{"Disease Name": "Oculocutaneous albinism type 1", "Disease Definition": "A form of oculocutaneous albinism (OCA) characterized by a spectrum of hypopigmentation of skin hair and eyes, ranging from little or no pigmentation to localized pigementation. Nystagmus, photophobia and reduced visual acuity are frequently present. The subtypes include OCA1A, OCA1B, type 1 minimal pigment oculocutaneous albinism (OCA1-MP) and type 1 temperature sensitive oculocutaneous albinism (OCA1-TS).", "ORPHA ID": 352731, "Summary": ""}
{"Disease Name": "Oculocutaneous albinism type 1A", "Disease Definition": "A severe form of oculocutaneous albinism type 1 (OCA1) characterized by complete absence of melanin and manifesting as white hair and skin, blue, fully translucent irises, nystagmus and misrouting of the optic nerves.", "ORPHA ID": 79431, "Summary": "Epidemiology\nThe worldwide prevalence of OCA1 is estimated at 1/40,000. OCA type 1A (OCA1A) is considered to account for about half of the overall OCA1 cases among non-Hispanic, Caucasian patients.\nClinical description\nPatients have white skin and hair at birth. Irises are blue to pink and fully translucent. These features do not change throughout a patient's life. Nystagmus may be present at birth or it may develop in the first 3 to 4 months of life. It continues throughout life but usually slows down after childhood and is less noticeable when a person is relaxed and well rested. Visual acuity ranges from 20/100 and 20/400 and an alternating strabismus is often present. The reduction in visual acuity is associated with foveal hypoplasia. Severe photophobia is common. Nevi and ephelides are common but are unpigmented and pink. Patients do not tan, and if proper sun protection methods are not followed, skin becomes rough, coarse, thickened and can have solar keratoses. Patients have an increased risk of developing basal and squamous cell carcinomas but melanomas are rare.\nEtiology\nOCA1A is caused by a mutation in the TYR gene (11q14.2) encoding tyrosinase. The mutation leads to a completely inactive or incomplete tyrosinase enzyme polypeptide. Melanocytes contain no melanin, as without this enzyme the melanin biosynthetic pathway is blocked.\nDiagnostic methods\nThe characteristic clinical findings along with confirmatory genetic testing are used to diagnose OCA1A. Ophthalmologic examination reveals visualization of the choroidal blood vessels, reduced retinal pigment and foveal hypoplasia. Alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP) are associated with the characteristic misrouting of the optic nerves at the chiasm. Molecular genetic testing is usually necessary to make the correct diagnosis of this subtype.\nDifferential diagnosis\nDifferential diagnoses include the other forms of OCA and X-linked ocular albinism (XLOA) as well as syndromes with albinism as a feature such as Hermansky-Pudlak syndromes 1-11, Chediak-Higashi syndrome, Griscelli syndromes 1-3, and Waardenburg syndrome type II.\nAntenatal diagnosis\nPrenatal testing is possible for at risk pregnancies by molecular genetic testing.\nGenetic counseling\nThis disorder is inherited autosomal recessively. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nAnnual ophthalmologic examination is necessary and corrective lenses or glasses are given to improve visual acuity. Dark glasses may be needed to relieve photophobia. Strabismus surgery can be performed for functional or cosmetic reasons. Protection from sunlight is imperative and patients should wear clothing and sunscreen on exposed skin to prevent burning and reduce the risk of skin cancer. Annual skin examinations should also be performed to identify any pre-cancerous or cancerous lesions.\nPrognosis\nOCA1A is not life threatening, unless malignancies develop, and remains stable after childhood. The medical and social consequences can however have major impacts on a patient's daily life.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Masahiro HAYASHI  - Dr Tamio SUZUKI"}
{"Disease Name": "Oculocutaneous albinism type 1B", "Disease Definition": "A form of oculocutaneous albinism type 1 (OCA1) characterized by skin and hair hypopigmentation, nystagmus, reduced iris and retinal pigment and misrouting of the optic nerves.", "ORPHA ID": 79434, "Summary": "Epidemiology\nThe worldwide prevalence of OCA1 is estimated at 1/40,000. OCA1B is considered to account for about half of all overall OCA1 cases among non-Hispanic, Caucasian patients\nClinical description\nNewborns have white or very light yellow hair but with age the hair can darken to blond or light brown. Eyelash hair can be darker than scalp and eyebrow hair. Skin remains creamy white but a minimal amount of tanning is possible along with freckles and pigmented nevi. Nystagmus is sometimes visible at birth but in others not until 3 to 4 months of age. It continues throughout life but becomes less rapid with age and is usually more noticeable in times of stress, anger or tiredness. Iris color is blue at birth and can change to brownish tan or greenish hazel or remain unchanged. Visual acuity ranges from 20/100 to 20/200. With time, skin can become rough, coarse and thickened if sun protection procedures are not followed. Patients have an increased risk of developing basal and squamous cell carcinomas but melanomas are rare.\nEtiology\nOCA1B is caused by a mutation in the TYR gene located on chromosome 11q14.2 encoding tyrosinase. The mutation causes the production of a partially active or hypomorphic tyrosinase enzyme that leads to minimal melanin formation in melanocytes.\nDiagnostic methods\nThe characteristic clinical findings along with confirmatory genetic testing are used to diagnose OCA1B. Ophthalmologic examination reveals visualization of the choroidal blood vessels, reduced retinal pigment and foveal hypoplasia. Alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP) are associated with the characteristic misrouting of the optic nerves at the chiasm. Molecular genetic testing is necessary to obtain a definitive diagnosis, as some OCA1B patients have a certain degree of phenotypical variation which may lead to confusion in distinguishing it from other OCAs. This overlap of clinical symptoms emphasizes the importance of genetic analysis in the diagnosis of albinism.\nDifferential diagnosis\nDifferential diagnoses include the other forms of OCA and X-linked recessive ocular albinism (XLOA) as well as syndromes with albinism as a feature, such as Hermansky-Pudlak syndromes 1-11, Chediak-Higashi syndrome, Griscelli syndromes 1-3, and Waardenburg syndrome type II.\nAntenatal diagnosis\nPrenatal testing is possible for at risk pregnancies by molecular genetic testing.\nGenetic counseling\nThis disorder is inherited autosomal recessively and genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nAnnual ophthalmologic examination is necessary and corrective lenses or glasses are given to improve visual acuity. Dark glasses may be needed to relieve photophobia. Strabismus surgery can be performed for functional or cosmetic reasons. Protection from sunlight is imperative and patients should wear clothing and sunscreen on exposed skin to prevent burning and reduce the risk of skin cancer. Annual skin examinations should also be performed to identify any pre-cancerous or cancerous lesions.\nPrognosis\nOCA1B is not life threatening and remains stable after childhood. The medical and social consequences can however have major impacts on a patient's daily life.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Masahiro HAYASHI  - Dr Tamio SUZUKI"}
{"Disease Name": "Oculocutaneous albinism type 2", "Disease Definition": "A form of oculocutaneous albinism characterized by variable hypopigmentation of the skin and hair, numerous characteristic ocular changes and misrouting of the optic nerves at the chiasm.", "ORPHA ID": 79432, "Summary": "Epidemiology\nThe prevalence of Oculocutaneous albinism type 2 (OCA2) is estimated at 1/38,000-1/40,000 in most populations throughout the world except in the African population that has a higher prevalence of 1/3,900-1/1,500.\nClinical description\nSkin and hair pigmentation ranges from minimal to near normal. Most infants develop nystagmus before the age of 3-4 months, which may start off as rapid but usually slows down over time. Strabismus and visual inattention is also present in the first six months of life. Adult visual acuity usually ranges from 20/60-20/100 and does not worsen over time. Iris color ranges from blue to brown. Newborns all have pigmented hair ranging from light yellow to light brown and skin color is creamy white. Hair color may darken over time but does not change after adolescence. In Africans, a phenotype of light brown hair and skin and gray irises occurs, known as brown OCA (BOCA), which is part of the spectrum of OCA2. Patients of other ethnicities with BOCA have almost normal pigmentation. Exposure to sun can overtime lead to rough, coarse and thickened skin along with solar keratoses. Patients have an increased risk of developing basal and squamous cell carcinomas but melanomas are rare.\nEtiology\nOCA2 is caused by a mutation in the OCA2 gene (15q12-q13), encoding the OCA2 protein. The precise function of this protein is unknown, however, several studies have reported possible roles in the maintenance of proper intramelanosomal pH or the melanosomal structural matrix. Patients with OCA2 have melanocytes that still produce small amounts of melanin, but it is mostly yellow pheomelanin.\nDiagnostic methods\nThe characteristic clinical findings along with genetic testing are used to diagnose OCA2. Ophthalmologic examination reveals visualization of the choroidal blood vessels, reduced retinal pigment and foveal hypoplasia. Alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP) are associated with the characteristic misrouting of the optic nerves at the chiasm. Molecular genetic testing for a mutation in the OCA2  gene can confirm diagnosis of OCA2 and distinguish it from other forms of OCA.\nDifferential diagnosis\nDifferential diagnoses include the other forms of OCA and X-linked recessive ocular albinism (XLOA) as well as syndromes with albinism as a feature such as Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome, and Waardenburg syndrome type II. The BOCA phenotype can also be seen in OCA3.\nAntenatal diagnosis\nPrenatal testing is possible when the disease causing mutation in the parent is known.\nGenetic counseling\nOCA2 is inherited autosomal recessively and genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation), informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nNo curative treatment has been found for OCA to date. Protection from sunlight is imperative and patients should wear clothing and sunscreen on exposed skin to prevent burning and reduce the risk of skin cancer. Annual skin examinations should also be performed to identify any pre-cancerous or cancerous lesions. Periodical ophthalmologic examination is necessary and corrective lenses or glasses are given to improve visual acuity. Dark glasses may be needed to relieve photophobia. Strabismus surgery can be performed for functional or cosmetic reasons.\nPrognosis\nThe disease is not life threatening and stabilizes after childhood. However, the medical and social consequences can have an impact on patient's daily life.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Masahiro HAYASHI  - Dr Tamio SUZUKI"}
{"Disease Name": "Oculocutaneous albinism type 3", "Disease Definition": "A form of oculocutaneous albinism (OCA) characterized by rufous or brown albinism and occurring mainly in the African population.", "ORPHA ID": 79433, "Summary": "Epidemiology\nOculocutaneous albinism type 3 (OCA3) has an estimated prevalence of 1/8,500 individuals in Africa. It is rarely seen in other populations.\nClinical description\nVisual anomalies, such as nystagmus, are frequently undetectable and patients usually present with one of two phenotypes: rufous OCA (ROCA), characterized by red-bronze skin color, blue or brown irises and ginger-red hair, or brown OCA (BOCA), characterized by light to brown hair and a light to brown or tan skin color. The clinical features of OCA3 have been considered as rather mild, and in the rare cases of non-African patients, reddish hair color has been reported. A Japanese girl was reported with having OCA3 who presented with blond hair and light skin (with a small Mongolian spot), was able to tan and was negative for nystagmus.\nEtiology\nOCA3 is caused by a mutation in the tyrosinase-related protein 1, TYRP1, gene located on chromosome 9p23. The majority of BOCA cases are seen in OCA2, but a few BOCA phenotypes have been reported with mutations in the TYRP1 gene, indicating OCA3.\nDiagnostic methods\nThe clinical findings along with genetic testing are used to diagnose OCA3. Hypopigmentation of hair and skin are milder than other forms of OCA and some degree of tanning may be possible. Red reflex on transillumination of the iris and nystagmus are important clues to the diagnosis, however, some patients lack nystagmus or strabismus. Molecular genetic testing for a mutation in the TYRP1  gene can confirm diagnosis of OCA3 and distinguish it from other forms of OCA.\nDifferential diagnosis\nDifferential diagnoses include the milder forms of OCA (except for OCA1A), as well as syndromes with albinism as a feature such as Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome, and Waardenburg syndrome type II.\nAntenatal diagnosis\nPrenatal testing is theoretically possible when the disease causing mutation in the parent is known, however, there are no reports of it having been performed.\nGenetic counseling\nOCA3 is inherited autosomal recessively and genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation), informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nAnnual ophthalmologic examination is necessary and corrective lenses or glasses may be given when the patients have impaired visual acuity. Dark glasses may be needed to relieve photophobia. Strabismus surgery can be performed for functional or cosmetic reasons. Protection from sunlight is imperative and patients should wear clothing and sunscreen on exposed skin to prevent burning and reduce the risk of skin cancer. Annual skin examinations should also be performed to identify any pre-cancerous or cancerous lesions.\nPrognosis\nOCA3 is not life threatening and stabilizes after childhood. However, the medical and social consequences can have an impact on patient's daily life.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Masahiro HAYASHI  - Dr Tamio SUZUKI"}
{"Disease Name": "Oculocutaneous albinism type 4", "Disease Definition": "A form of oculocutaneous albinism characterized by varying degrees of skin and hair hypopigmentation, numerous ocular changes and misrouting of the optic nerves at the chiasm.", "ORPHA ID": 79435, "Summary": "Epidemiology\nThe estimated world prevalence of oculocutaneous albinism type 4 (OCA4) is 1/100,000 but it is more common in Japan.\nClinical description\nCutaneous hypopigmentation is often visible at birth and signs of nystagmus and strabismus present in the first year of life. Nystagmus is not always present at birth and can develop at 3 to 4 months of age. It can start off as rapid and slow down in later life and it is usually more noticeable when patients are tired, stressed, anxious or angry. Foveal hypoplasia is associated with a reduction in visual acuity. Alternating strabismus and reduced stereoscopic vision are also noted. Visual changes are not progressive and usually stabilize after childhood. A wide range of clinical phenotypes can be found with OCA4. Iris color can range from blue to brown. Photophobia is common. Hair color in newborns ranges from silvery white to light yellow. It may darken slightly with time (to light brown) but usually remains relatively unchanged. Skin color is usually creamy white. Over time, skin can become coarse, thickened and rough and solar keratoses are common in those who have not limited their exposure to the sun. Patients have an increased risk of developing basal and squamous cell carcinomas but melanomas are rare.\nEtiology\nOCA4 is caused by mutations in the membrane-associated transporter protein (MATP) gene, SLC45A2 (5p13.2), encoding a transporter protein which is thought to mediate melanin synthesis. Melanocyte cultures established from a mouse model of OCA4 have demonstrated that tyrosinase processing and trafficking is disrupted before delivery to melanosomes. Patients with OCA4 have melanocytes that still produce small amounts of melanin, but it is mostly yellow pheomelanin.\nDiagnostic methods\nThe characteristic clinical findings along with genetic testing are used to diagnose OCA4. Ophthalmologic examination reveals visualization of the choroidal blood vessels, reduced retinal pigment and foveal hypoplasia. Alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP) are associated with the characteristic misrouting of the optic nerves at the chiasm. Molecular genetic testing for a mutation in the SLC45A2 gene can confirm diagnosis of OCA4 and distinguish it from other forms of OCA.\nDifferential diagnosis\nDifferential diagnoses include the other forms of OCA and X-linked recessive ocular albinism (XLOA) as well as syndromes with albinism as a feature such as Hermansky-Pudlak syndromes 1-7, Chediak-Higashi syndrome , Griscelli syndrome, and Waardenburg syndrome type II.\nAntenatal diagnosis\nPrenatal diagnosis is possible when a parent has been identified to have the disease causing mutation, but it is rarely performed.\nGenetic counseling\nOCA4 is inherited autosomal recessively and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nOphthalmic care is ongoing and glasses or contact lenses can usually improve visual acuity. In some cases strabismus surgery may be performed. Patients must avoid exposure to sun as this can lead to pachydermia, premalignant lesions and an increased risk of developing skin cancer. A hat with a brim can protect the skin and eyes from the sun's harmful rays and patients should always wear sunscreen and cover exposed skin when outside. Dark glasses can be used to alleviate photophobia. Annual skin examinations should also be performed to identify any pre-cancerous or cancerous lesions.\nPrognosis\nThe disease is not life threatening and usually remains stable after childhood. The medical and social consequences can however have an impact on a patient's daily life.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Masahiro HAYASHI  - Dr Tamio SUZUKI"}
{"Disease Name": "Oculocutaneous albinism type 5", "Disease Definition": "A form of oculocutaneous albinism characterized by white skin, golden hair, photophobia, nystagmus, foveal hypoplasia and impaired visual acuity, that affects males and females equally. Patients have been reported only in a consanguineous Pakistani family. The responsible gene has not yet been detected.", "ORPHA ID": 370091, "Summary": ""}
{"Disease Name": "Oculocutaneous albinism type 6", "Disease Definition": "A form of oculocutaneous albinism characterized by light hair at birth that darkens with age, white skin, transparent irides, photophobia, nystagmus, foveal hypoplasia and reduced visual acuity.", "ORPHA ID": 370097, "Summary": ""}
{"Disease Name": "Oculocutaneous albinism type 7", "Disease Definition": "A form of oculocutaneous albinism (OCA) characterized by skin and hair hypopigmentation (light blond to dark brown), nystagmus, iris transillumination, visual acuity ranging from 6/9 to 3/60 and hypopigmentation of the peripheral ocular fundus. Photophobia is not a major feature.", "ORPHA ID": 352745, "Summary": ""}
{"Disease Name": "Oculocutaneous albinism type 8", "Disease Definition": "A type of oculocutaneous albinism characterized by mild hypopigmentation of the skin, hair, and eyes with moderate reduction of visual acuity and nystagmus. The ocular phenotype includes moderate foveal hypoplasia, iris transillumination, and hypopigmentation of the retina.", "ORPHA ID": 597733, "Summary": ""}
{"Disease Name": "Oculocutaneous albinism", "Disease Definition": "A group of rare genetic hypopigmentation disorders characterized by a generalized reduction in pigmentation of hair, skin and eyes and variable ocular findings including nystagmus, reduced visual acuity and photophobia. Variants include OCA1A (the most severe form), OCA1B, OCA1-minimal pigment (OCA1-MP), OCA1-temperature sensitive (OCA1-TS), OCA2, OCA3, OCA4, OCA5, OCA6, OCA7 and OCA8.", "ORPHA ID": 55, "Summary": ""}
{"Disease Name": "Oculodental syndrome, Rutherfurd type", "Disease Definition": "Oculodental syndrome, Rutherfurd type is a rare genetic disorder that is primarily characterized by the classical triad of gingival fibromatosis, non-eruption of tooth and corneal dystrophy (bilateral corneal vascularization and opacity). Abnormally shaped teeth have also been reported. The syndrome is transmitted as an autosomal dominant trait.", "ORPHA ID": 2709, "Summary": ""}
{"Disease Name": "Oculodentodigital dysplasia", "Disease Definition": "A rare congenital malformation syndrome characterized by craniofacial, ocular, dental, digital anomalies and neurologic symptoms.", "ORPHA ID": 2710, "Summary": "Epidemiology\nLess than 300 cases have been described worldwide, predominantly in Caucasian families. There are some reports in the Asian population.\nClinical description\nOculodentodigital dysplasia (ODDD) is characterized by great phenotypic variability. Typical craniofacial anomalies include thin nose with hypoplastic alae nasi, small anteverted nares and a prominent columella, mandibular overgrowth, cleft palate, and microcephaly. Limb malformations include syndactyly type 3 (involving the fourth and fifth fingers) and/or syndactyly of second to fourth toes, camptodactyly, and clinodactyly due to hypoplasia or aplasia of the middle phalanges. Cranial hyperostosis and broad tubular bones can occur. Ophthalmological anomalies include decreased visual acuity, microphthalmia, microcornea, cataracts, glaucoma, iris abnormalities and optic atrophy. Less often, nystagmus, palpebral fissure hypoplasia, epicanthal folds and convergent strabismus are found. Most patients have abnormal primary and permanent dentition with microdontia, partial anodontia, enamel hypoplasia, multiple caries and early tooth loss. Frequent neurological manifestations vary and include dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures. Some patients have dysplastic ears and conductive hearing loss. Mild global development delay has been described. Brain magnetic resonance imaging may show white matter abnormalities. Brittle nails and hair abnormalities (hypotrichosis and slow growth) may be present. Cardiac anomalies, including arrhythmias or congenital malformations (ventricular septal defect) have been described.\nEtiology\nODDD is caused by mutations in the GJA1 gene (6q22-q23), encoding Cx43 protein. Around 70 causative mutations have been identified, resulting in variable ODDD phenotypes. Most missense variants are located in the connexin domain.\nDiagnostic methods\nDiagnosis is based on clinical findings. Careful phenotype evaluation of facial dysmorphism and digital anomalies, ophthalmological and dental examination, and hand X-ray are required. Neurological symptoms might also be present. The clinical diagnosis can be confirmed by molecular analysis of GJA1 gene.\nDifferential diagnosis\nDifferential diagnosis includes syndromes presenting with skeletal, ocular, dental and neurological features. Syndactyly type 3 is also linked with GJA1 mutations.\nAntenatal diagnosis\nGenetic prenatal diagnosis is theoretically possible if GJA1 mutation has been identified in the family.\nGenetic counseling\nInheritance is mostly autosomal dominant (AD) with high penetrance and variable expression. Genetic counselling should be offered to affected individuals and their families. For AD variants, the risk for each pregnancy is 50 %. GJA1 variants may occur de novo. Advanced paternal age has been noted in sporadic cases. A few families with autosomal recessive inheritance have been reported in the recent years.\nManagement and treatment\nManagement is multidisciplinary. Early recognition is crucial to prevent and treat the variety of clinical manifestations. Follow-up should include a complete eye, neurological, hearing and dental evaluation. As blindness due to glaucoma can occur, patients at risk should receive anti-glaucoma treatment. Neurological symptoms may be subtle or appear only late in life. Instrumental tests can detect structural anomalies if no symptoms are present. Cardiac arrhythmias have been associated with ODDD and may require cardiologist monitoring. Plastic or orthopedic surgery is indicated for severe limb malformations.\nPrognosis\nPrognosis varies based on the severity. Functional, social and psychological care help to lessen the impact on the everyday life. Life expectancy depends on other system (neurological and cardiac) involvement. In cases of cardiac involvement, there is a risk of progressive heart failure. However, further understanding of cardiac anomalies in ODDD is needed.\n\n                            Last update: \n                            August 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Ausra MATULEVICIENE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Oculoectodermal syndrome", "Disease Definition": "A rare ectodermal dysplasia characterized by the association of epibulbar dermoids and aplasia cutis congenital.", "ORPHA ID": 3339, "Summary": ""}
{"Disease Name": "Oculofaciocardiodental syndrome", "Disease Definition": "Oculo-facio-cardio-dental syndrome (OFCD) is a very rare multiple congenital anomaly syndrome characterized by dental radiculomegaly, congenital cataract, facial dismorphism and congenital heart disease.", "ORPHA ID": 2712, "Summary": "Epidemiology\nTo date, 20 cases have been reported worldwide.\nClinical description\nThe most consistent and pathognomic dental finding of OFCD is radiculomegaly (extremely long roots), particularly of the canines and occasionally of other teeth including premolars and incisors. The dental eruption in both the deciduous and the permanent dentition is consistently slow and delayed. Oligodontia, fused teeth, supernumerary teeth, malformed permanent teeth, enamel defects, root dilacerations, malposition and malocclusion, have also been reported. Ocular abnormalities include bilateral congenital cataracts, microphthalmia, regressive vision impairment, secondary glaucoma, and ptosis. Exotropia is very common. The facial features described include a long narrow face, high nasal bridge, broad nasal tip with separated nasal cartilages, laterally curved and thick eyebrows, long philtrum, clefts of the hard/soft palate. Cardiac defects reported include ventricular septal defect, atrial septal defect, mild cardiomegaly, ventricular and atrial hypertrophy, benign peripheral pulmonic stenosis, mitral valve prolapse. Occasional reports have noted skeletal findings (syndactly of the second and third toes, hammer-type flexion of the second and fourth toes, radio-ulnar synostosis, and vertebral and rib anomalies), intestinal malrotation, hearing impairment, intellectual and psychomotor deficit.\nEtiology\nThe BCOR gene on chromosome Xp11.4 is causative, however its exact function remains unknown.\nDiagnostic methods\nDiagnosis of OFCD is hard for medical specialists and the syndrome is often unrecognized. The specific dental findings (visible on a panoramic radiograph of the jaws) can be easily diagnosed by an orthodontist or a dentist.\nGenetic counseling\nOFCD is an X-linked dominant syndrome that is lethal in males.\nManagement and treatment\nManagement requires appropriate cardiac, ophthalmic and dental care.\n\n                            Last update: \n                            November 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN"}
{"Disease Name": "Oculogastrointestinal muscular dystrophy", "Disease Definition": "Oculogastrointestinal muscular dystrophy is an extremely rare autosomal recessively inherited neuromuscular disease characterized by ocular manifestations such as ptosis and diplopia followed by chronic diarrhea, malnutrion and intestinal peudo-obstruction.", "ORPHA ID": 1876, "Summary": ""}
{"Disease Name": "Oculomaxillofacial dysostosis", "Disease Definition": "Oculomaxillofacial dysostosis is a rare, genetic bone developmental disorder characterized by short stature, orbital region and ocular abnormalities (e.g. asymmetric orbits, anophthalmia, down-slanted and S-shaped palpebral fissures, sparse eyebrows/eyelashes, abnormal eyelids, ectropion, symblepharon, corneal leukoma), abnormal nose (e.g. broad and abnormally modeled nasal root, bridge and tip, lateral deviation), malar hypoplasia, cleft lip/palate, and oblique facial clefts. Intellectual disability, microcephaly, micrognathia and limb anomalies (e.g. hemimelia, abnormal scapular girdle, brachydactyly, syndactyly, broad halluces) have also been reported.", "ORPHA ID": 1794, "Summary": ""}
{"Disease Name": "Oculoosteocutaneous syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by short stature and particularly pronounced shortening of the third to fifth metacarpals and metatarsals, congenital anodontia, sparse hair, dyspigmentation of the skin, hypoplastic nipples and underdeveloped external genitals in females, and multiple ocular abnormalities (such as distichiasis, strabismus, nystagmus, lenticular opacities, and severe myopia, among others). Dysmorphic craniofacial features include brachycephaly, downslanting palpebral fissures, broad nasal root, low-set ears, and small maxilla and prominent mandible. There have been no further descriptions in the literature since 1968.", "ORPHA ID": 2713, "Summary": ""}
{"Disease Name": "Oculootodental syndrome", "Disease Definition": "A contiguous gene syndrome comprising otodental syndrome (characterized by globodontia and sensorineural high-frequency hearing deficit) associated with eye abnormalities including, typically, iris and chorioretinal coloboma, as well as, on occasion, microcornea, microphtalmos, lenticular opacity, lens coloboma and iris pigment epithelial atrophy.", "ORPHA ID": 99806, "Summary": ""}
{"Disease Name": "Oculopharyngeal muscular dystrophy", "Disease Definition": "A rare, adult-onset, progressive myopathy characterized by progressive eyelid ptosis, ophthalmoplegia, dysphagia, dysarthria and proximal limb weakness.", "ORPHA ID": 270, "Summary": "Epidemiology\nOculopharyngeal muscular dystrophy (OPMD) occurs worldwide with varying prevalence rates. The estimated prevalence rate in Europe is 1/100,000-200,000. The highest prevalence rate of 1/1,000 is found in French Canadians in Quebec and 1/600 in Israel's Bukharan Jews.\nClinical description\nDisease onset occurs in the fifth to sixth decade of life. Early signs include ptosis, ophthalmoplegia without diplopia, limb weakness, dysarthria and dysphagia. Symptoms usually begin after the age of 45 years, and ptosis is the most common presenting feature. Other signs that occur as the disease progresses include tongue weakness and atrophy, proximal upper and lower extremity weakness, dysphonia, dysarthria, facial muscle weakness, and limitation of upward gaze. In several cases, limb weakness has preceded dysphagia. In 5-10% of patients, the disease is more severe, with ptosis and dysphagia presenting before the age of 45 and incapacitating distal leg weakness occurring before the age of 60. The manifestations of autosomal recessive OPMD usually present later (after the age of 60) than those of the autosomal dominant form.\nEtiology\nOPMD is caused by an expansion in the polyalanine tract in the PABPN1 gene (14q11.2), which leads to overexpression of a mutant protein, polyadenylate-binding protein 2, and consequently to the accumulation of nuclear aggregates in the muscles.\nDiagnostic methods\nOPMD is diagnosed by genetic confirmation of a mutation in the PABPN1 gene. Supportive evidence comes from the family history, late-onset clinical characteristics, and muscle biopsy findings (tubulofilamentous inclusions in the nuclei of myocytes using electron microscopy, as well as muscle fibers containing rimmed vacuoles). However, a muscle biopsy is not needed for diagnosis and is nowadays rarely performed. Creatine kinase (CK) levels can be slightly elevated and electromyogram (EMG) studies may suggest a mild myopathic process.\nDifferential diagnosis\nDifferential diagnoses include first and foremost myasthenia gravis, mitochondrial myopathies, and myotonic dystrophy type 1. Other less likely but possible differential diagnoses are oculopharyngodistal myopathy, proximal myotonic myopathy, congenital fibrosis of extraocular muscles, blepharophimosis-epicanthus inversus-ptosis syndrome, and autosomal dominant distal myopathy.\nAntenatal diagnosis\nPrenatal diagnosis is possible, but as this condition presents in adulthood, it is very rarely performed.\nGenetic counseling\nOPMD is inherited autosomal dominantly in the vast majority of cases, but can be found recessively in certain regions. Genetic counseling is possible when a PABPN1 mutation has been identified in a family.\nManagement and treatment\nNo pharmacological treatment is presently available, but surgical treatments are offered that can help with ptosis and dysphagia. A blepharoplasty can treat ptosis when the eyelids cover more than 50% of the pupils or when neck pain is present. A cricopharyngeal myotomy or botulinum toxin injection of the cricopharyngeal muscle can be performed to achieve normal swallowing, but dysphagia usually recurs years after surgery. The intake of dietary supplements and a diet of foods that are soft and easy to swallow are often necessary. Some patients may need a wheelchair if muscle atrophy is severe.\nPrognosis\nPtosis and dysphagia typically recur within five to fifteen years after surgery. There is usually no decrease in life expectancy, but quality of life can be reduced in those where the disease is debilitating. Premature death, if it happens, is usually due to aspiration pneumonia or malnutrition (with severe weight loss) in elderly patients.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Pr John VISSING"}
{"Disease Name": "Oculopharyngodistal myopathy", "Disease Definition": "A rare, genetic neuromuscular disease characterized by progressive external ocular, facial and pharyngeal muscle weakness, leading to variable degrees of ptosis, ophthalmoparesis, facial muscle atrophy, dysarthria and dysphagia, as well as distal muscle weakness and atrophy of lower and upper extremities. Respiratory muscle involvement is common, but sensorineural hearing loss, asymmetrical extremity weakness and severe proximal weakness are rare.", "ORPHA ID": 98897, "Summary": ""}
{"Disease Name": "Oculoskeletodental syndrome", "Disease Definition": "A rare ciliopathy characterized by congenital cataract with secondary glaucoma, developmental delay, short stature, multiple skeletal abnormalities (spinal deformities, limb anomalies, delayed bone age), dental anomalies (oligodontia, enamel defects), dysmorphic facial features (including coarse facies, low hairline, epicanthal folds, flat and broad nasal bridges, and retrognathia), and stroke. Other recurrent manifestations are hearing loss and nephrocalcinosis.", "ORPHA ID": 557003, "Summary": ""}
{"Disease Name": "Oculotrichoanal syndrome", "Disease Definition": "Oculotrichoanal syndrome is a form of rare, multiple congenital anomalies/dysmorphic syndrome characterized by a combination of various nose, eye, gastrointestinal and genitourinary abnormalities. Clinical presentation is variable and often includes bifid and broad nasal tip, aberrant anterior hairline, coloboma, cryptophthalmos or unilateral anophthalmia, anal anomalies, and omphalocele. Intelligence and global development is normal.", "ORPHA ID": 2717, "Summary": ""}
{"Disease Name": "Oculotrichodysplasia", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by bilateral retinitis pigmentosa, trichodysplasia (generalized hypotrichosis, structural changes), dental anomalies, onychodysplasia, and dry and scaly skin. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 2718, "Summary": ""}
{"Disease Name": "Odonto-onycho dysplasia-alopecia syndrome", "Disease Definition": "Odonto-onycho dysplasia-alopecia syndrome is a rare, genetic ectodermal dysplasia syndrome characterized by almost total alopecia with only sparse, thin, brittle, slow-growing scalp hair, fair and sparse eyebrows and eyelashes, absent axillary and pubic hair, fragile and brittle fingernails, thick and brittle toenails (both with a subungual corneal layer), hypodontia, microdontia, widely spaced teeth with hypoplastic enamel, mild palmoplantar keratosis, café-au-lait spots and areolae anomalies. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 2722, "Summary": ""}
{"Disease Name": "Odonto-onycho-dermal dysplasia", "Disease Definition": "A rare, genetic, ectodermal dysplasia syndrome characterized by dental abnormalities (primarily agenesis of the permanent and deciduous teeth with cone-shaped incisors and canines), onychodysplasia, palmoplantar hyperkeratosis, dry skin and, more variably, hypotrichosis, and sweat gland dysfunction (hyper- or hypohidrosis).", "ORPHA ID": 2721, "Summary": ""}
{"Disease Name": "Odonto-tricho-ungual-digito-palmar syndrome", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by neonatal teeth, trichodystrophy (with straw-like, discolored and fragile hair), onychodystrophy, and malformation of the hands and feet consisting of simian-like hands with transverse palmar creases and prominent interdigital folds, brachydactyly, and marked shortness of the first metacarpal and metatarsal bones with hypoplasia of the distal phalanges. There have been no further descriptions in the literature since 1997.", "ORPHA ID": 69082, "Summary": ""}
{"Disease Name": "Odontochondrodysplasia", "Disease Definition": "A rare primary bone dysplasia characterized by the association of spondylometaphyseal dysplasia, generalized joint laxity, and dentinogenesis imperfecta. Main skeletal abnormalities comprise short stature, narrow chest, scoliosis, mesomelic limb shortening, and brachydactyly. Radiographic features include severe metaphyseal irregularities of the tubular bones, platyspondyly with coronal clefts, cone-shaped epiphyses of the hands, square iliac wings, and coxa valga. Additional extraskeletal manifestations like pulmonary hypoplasia, cystic renal disease, and non-obstructive hydrocephalus have also been reported.", "ORPHA ID": 166272, "Summary": ""}
{"Disease Name": "Odontohypophosphatasia", "Disease Definition": "A particular form of hypophosphatasia (HPP) characterized by reduced activity of unfractionated serum alkaline phosphatase, premature exfoliation of primary and/or permanent teeth and/or severe dental caries, in the absence of skeletal system abnormalities.", "ORPHA ID": 247685, "Summary": "Epidemiology\nThe prevalence of odonto-HPP is not known. It is thought that odonto-HPP is the most frequent form of HPP because 74% of the cases are heterozygotes.\nClinical description\nThe main feature of odontohypophosphatasia is premature exfoliation of fully rooted primary teeth and/or severe dental caries. The anterior deciduous teeth are most commonly affected along with the incisors. X-rays reveal reduced alveolar bone, reduced thickness of dentin, and enlarged pulp chambers and root canals. Patients with other forms of HPP often have dental manifestations but these are always associated with skeletal abnormalities and other manifestations.\nEtiology\nMutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. Specific mutations are thought to underlie this phenotype and its variable severity.\nDiagnostic methods\nDiagnosis is based on clinical presentation, dental panorex and laboratory findings, and can be confirmed by genetic testing.\nDifferential diagnosis\nOther causes for premature exfoliation should be excluded. The presence of bone symptoms (osteomalacia, fractures) distinguish adult HPP from odontohypophosphatasia.\nGenetic counseling\nAutosomal recessive and autosomal dominant patterns of inheritance are reported in odonto-HPP.\nManagement and treatment\nManagement is with observation and supportive measures such as implementation of an oral health program, protection of the existing teeth, and aesthetic and functional restoration of the mouth (with braces or other dental devices).\nPrognosis\nLoss of teeth may have functional and aesthetic consequences. Overall prognosis is generally good.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Severine BACROT  - Dr Etienne MORNET"}
{"Disease Name": "Odontomatosis-aortae esophagus stenosis syndrome", "Disease Definition": "Odontoma-dysphagia syndrome is a malformation syndrome, characterized by odontomas (undifferentiated mass of the esophagus) and severe dysphagia.", "ORPHA ID": 2724, "Summary": "Epidemiology\nLess than ten cases have been reported so far.\nClinical description\nThree of the reported patients manifested multiple odontomas. Occasionally, cardiac (stenosis of the intrathoracic descendent aorta, interstitial myocarditis), renal (pyelonephritis) and hepatic (hepatic sclerosis) involvement has been described.\nEtiology\nHypertrophy and dysmotility of the esophageal smooth muscles is suggested to have causative role for dysphagia.\nGenetic counseling\nIn several cases, autosomal dominant inheritance has been suspected. Currently, there are no genes associated with this condition.\n\n                            Last update: \n                            July 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN"}
{"Disease Name": "Odontomicronychial dysplasia", "Disease Definition": "A rare, hereditary ectodermal dysplasia syndrome characterized by involvement of teeth and nails - precocious eruption and shedding of deciduous dentition, precocious eruption of secondary dentition with short, rhomboid roots, and short, thin, slow growing nails.", "ORPHA ID": 1811, "Summary": ""}
{"Disease Name": "Odontotrichomelic syndrome", "Disease Definition": "A rare genetic disease characterized by intellectual disability, growth delay, absence deformities of upper and lower limbs, hypotrichosis, hypoplastic nails, abnormal dentition, abnormal auricles, hypoplastic nipples, thyroid enlargement, and abnormalities of tyrosine and/or tryptophane metabolism. Hypogonadism and cleft lip have also been reported. No new cases have been confirmed since 1970.", "ORPHA ID": 2723, "Summary": ""}
{"Disease Name": "Off-periods in Parkinson disease not responding to oral treatment", "Disease Definition": "A rare clinical situation occurring in the context of Parkinson disease characterized by return or worsening of symptoms (including motor and/or non-motor symptoms) under antiparkinsonian therapy. Types of off-periods are Morning Off (experienced before the first dose of the day), Delayed On (occurring more frequently after the first dose of the day or after meals), Wearing Off (end-of-dose deterioration), Sudden Off (sudden transition from on to off), and Dose Failure.", "ORPHA ID": 391655, "Summary": ""}
{"Disease Name": "Ogden syndrome", "Disease Definition": "Ogden syndrome is a rare, genetic progeroid syndrome characterized by a variable phenotype including postnatal growth delay, severe global developmental delay, hypotonia, non-specific dysmorphic facies with aged appearance and cryptorchidism, as well as cardiac arrthymias and skeletal anomalies. Patients typically present with widely opened fontanels, mainly truncal hypotonia, a waddling gait with hypertonia of the extremities, small hands and feet, broad great toes, scoliosis and redundant skin with lack of subcutaneous fat.", "ORPHA ID": 276432, "Summary": ""}
{"Disease Name": "Oguchi disease", "Disease Definition": "Oguchi disease is an autosomal recessive retinal disorder characterized by congenital stationary night blindness (see this term) and the Mizuo-Nakamura phenomenon.", "ORPHA ID": 75382, "Summary": "Epidemiology\nOguchi disease is a very rare condition with approximately 50 cases described in the literature to date. It was originally discovered in Japan where the prevalence is the highest but has been found occasionally in European, American, Pakistani and Indian patients.\nClinical description\nThe disease is characterized by congenital stationary night blindness and the Mizuo-Nakamura phenomenon which is a unique morphological and functional abnormality of the retina that presents with a typical golden-yellow or silver-gray discoloration of the fundus in the presence of light that disappears after dark-adaptation and appears again after the onset of light. Patients have non progressive night blindness since young childhood with normal day vision, but they often claim improvement of light sensitivities when they remain a long time in a dark environment. Eye fundus shows the Mizuo-Nakamura phenomenon as the only fundus feature. A prolonged dark adaptation of 3 hours or more leads to disappearance of the Mizuo-Nakamura phenomenon fundus changes. No evidence of spicules, macular changes or chorioretinal atrophy is observed. Normal visual acuity, normal caliber of retinal blood vessels and usually normal cone response on electroretinogram (ERG) recording suggest retinal dysfunction rather than degeneration.\nEtiology\nOguchi disease is caused by mutations in the SAG gene coding for arrestin located on chromosome 2q37(Oguchi type 1) or by mutations in the GRK1 gene that codes for the rhodopsin kinase located on the chromosome 13q34 (Oguchi type 2). Remarkably, some mutations in the SAG gene are associated with Oguchi disease and retinitis pigmentosa (RP) in the same family. Some mutations in SAG lead to RP.\nDiagnostic methods\nThe diagnosis is clinical and is based on the presence of night blindness and the observation of the Mizuo-Nakamura phenomenon by funduscopy and electroretinography (ERG). The clinical diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nThe differential diagnosis includes Stargardt disease, RP in female carriers, juvenile retinoschisis, and progressive cone dystrophy (see these terms). All these conditions may have fundus changes but without the classical Mizuo-Nakamura phenomenon.\nGenetic counseling\nOguchi disease is an autosomal recessive condition. Brothers and sisters of an affected case have a 25% risk to be also affected.\nManagement and treatment\nTo date, there is not a specific treatment for Oguchi disease.\nPrognosis\nIn Oguchi disease the visual prognosis is good in absence of progression of symptoms. Although Oguchi disease is categorized as a stationary condition it can lead to reduced visual acuity or constricted visual fields, especially in older patients.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Elena ALLER  - Dr Carmen AYUSO  - Dr José María MILLÁN SALVADOR"}
{"Disease Name": "Okihiro syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by the association of uni- or bilateral radial defects, uni- or bilateral Duane anomaly (congenital limited horizontal eye movement accompanied by globe retraction which results in narrowing of the palpebral fissure), renal abnormalities, sensorineural and/or conductive hearing loss, and, less frequently, imperforate anus and scoliosis.", "ORPHA ID": 93293, "Summary": "Epidemiology\nTo date, 125 patients from 38 families have been reported.\nClinical description\nOkihiro syndrome has been originally characterized by the association of radial defects, Duane anomaly and deafness. Uni- or bilateral radial defects are observed in more than 90% of the patients and range from isolated thenar hypoplasia and/or hypoplasia or aplasia of the thumbs (40%) to hypoplasia or aplasia of the radii (30%), with sometimes ulnar or humeral hypoplasia (10%). Triphalangeal thumbs and pre-axial polydactyly have also been reported (20%). Duane anomaly is observed in 50% of the patients (bilateral in 20%). Renal abnormalities may include kidney ectopia, and rarely renal hypoplasia or horseshoe kidney. Sensorineural or conductive deafness is observed in 30% of the patients, sometimes associated with ear dysplasia. Heart defects (10%), such as ventricular or atrial septal defects, tetralogy of Fallot, or conduction disturbances (5%) have also been reported. Scoliosis is observed in 10% of patients. Gastrointestinal manifestations (anal stenosis, imperforate anus, choanal atresia) could be associated.\nEtiology\nOkihiro syndrome is caused by heterozygous variants in SALL4 gene (20q13.2). The phenotypes caused by SALL4 deletions are not different from those caused by point mutations.\nDiagnostic methods\nOkihiro syndrome is suspected on clinical findings and sometimes on family history. Careful clinical examination (sometimes upper limb defects can be mild, such as thenar hypoplasia), a complete eye examination by an ophthalmologist with special attention to extraocular movements, and hearing tests are required. Abdominal and cardiac ultrasound, spinal X-rays and complete blood cell count should be performed to look for associated features, sometimes suggesting a differential diagnosis. The clinical suspicion can be confirmed by SALL4 molecular analysis.\nDifferential diagnosis\nThe phenotype overlaps with Holt-Oram syndrome, Townes-Brocks syndrome Fanconi anemia, VACTERL/VATER association, isolated Duane retraction and fetal valproate syndrome.\nAntenatal diagnosis\nSome features can be diagnosed during pregnancy, such as severe limb involvement, heart defects or renal abnormalities. Genetic prenatal diagnosis is possible if the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nOkihiro syndrome is an autosomal dominant genetic condition. Genetic counseling should be provided to affected individuals and their families informing them that, for each pregnancy, there is a 50% risk of disease transmission from an individual with a pathogenic variant to their offspring. The phenotype is highly variable and mostly fully penetrant. SALL4 variants may occur de novo. Parental segregation analysis should be performed, even in absence of symptoms, to determine genetic counselling.\nManagement and treatment\nManagement is multidisciplinary and includes, at diagnosis, ophthalmological, cardiac, renal, hearing and genetic evaluations. Treatment depends on manifestations: limb, eye and/or heart surgery, occupational therapy, limb prothesis, orthoptic reeducation, physiotherapy, hearing aids, pacemaker. Surveillance depends on manifestations. Electrocardiogram is recommended regularly for adults. The social and psychological impact of the condition should be assessed and assisted. Women with Okihiro syndrome and cardiac defects should be evaluated by a cardiologist to determine what monitoring and care may be needed during pregnancy.\nPrognosis\nPrognosis is highly variable, according to the severity of the clinical manifestations, and their functional, social and psychological impacts in everyday life. Life expectancy depends on the severity of heart defects and renal function.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Clémence VANLERBERGHE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Oligoarticular juvenile idiopathic arthritis", "Disease Definition": "A rare inflammatory rheumatic disease characterized by juvenile onset arthritis that affects fewer than 5 joints during the first 6 months after disease onset.", "ORPHA ID": 85410, "Summary": "Epidemiology\nThe incidence of juvenile idiopathic arthritis in Caucasians is 8.3/100,000. Oligoarticular juvenile idiopathic arthritis is the most common form in North America and Europe, comprising 30% to 60% of children with juvenile idiopathic arthritis. It affects girls more than boys and is rare in individuals of African, Native American or Sourthern Asian descent.\nClinical description\nThe disease is typically asymmetrical, affecting between one to four joints, predominantly those of the lower limbs (knee or foot) although the wrist and elbows could be rarely affected. Onset occurs between the ages of 2 and 4. The disease is divided into persistent oligoarthritis, in which there is no more than 4 joints involved after the first six months of illness, and extended oligoarthritis, in which there is involvement of more than 4 joints involved after the first six months. Pain is not a constant feature in young children and the most common reasons for seeking medical advice are an increase in the volume of the joint and/or limping. The association of this form of arthritis with nonsymptomatic iridocyclitis (no pain or visible redness) is a specific feature that is present in a third of cases. Systemic manifestations other than uveitis are characteristically absent. Therefore, fever, rash, or other constitutional symptoms suggest a different diagnosis.\nEtiology\nThe etiology is not currently known. All juvenile idiopathic arthritis subtypes are most likely complex genetic traits as they lack single-gene, Mendelian patterns of inheritance. Inherited risk factors for both disease susceptibility and disease severity have been reported; the highly polymorphic HLA genes confer the strongest genetic effects.\nDiagnostic methods\nDiagnosis is based on the clinical manifestations, and exclusion of other potential causes. The presence of iridocyclitis and/or antinuclear antibodies without fever or psoriasis are strong diagnostic indicators. Exclusion criteria includes presence of systemic arthritis, psoriasis, ankylosing spondylarthritis, enthesitis and arthritis, sacroiliitis with an inflammatory enteropathy or acute anterior uveitis in the patient or a first-degree relative. In addition, HLA B27-positivity in males with onset of arthritis after 6 years of age and presence of rheumatoid factor IgM must be excluded.\nDifferential diagnosis\nDifferential diagnosis principally includes the other subtypes of juvenile idiopathic arthritis as well as Lyme disease, inflammatory bowel disease, pigmented villonodular synovitis, malignancy, plant thorn synovitis, septic arthritis, osteomyelitis, or tuberculosis.\nManagement and treatment\nFirst step of treatment is non-steroidal anti-inflammatory agent (NSAID) , but their efficacy is quite rare. Intra-articular glucocorticoids injections are often necessary and effective. Methotrexate and, if ineffective, biologics are recommended for children with disease that extends to involve five or more joints or require repeat injections.\nPrognosis\nSeveral long-term complications may occur, the most frequent and significant ones being temporomandibular joint arthritis with retrognatism, uveitis complications (glaucoma or synechia), leg-length discrepancy in case of delayed diagnosis. Arthritis may extend to involve five or more joints within several years of diagnosis.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Chantal DESLANDRE"}
{"Disease Name": "Oligoastrocytoma", "Disease Definition": "Oligoastrocytoma is a type of low-grade glioma with a mixed astrocytoma and oligodendroglioma histology, manifesting with headaches, speech and motor problems, seizures and, in some, subarachnoid haemorrhage.", "ORPHA ID": 251656, "Summary": ""}
{"Disease Name": "Oligocone trichromacy", "Disease Definition": "A rare non-progressive form of cone photoreceptor dysfunction syndrome characterized by reduced visual acuity, normal fundus appearance and absent or reduced cone responses on electroretinography. In contrast to all other forms of cone dysfunction color vision is normal.", "ORPHA ID": 75378, "Summary": "Epidemiology\nThe syndrome is very rare with less than 15 cases reported in the literature so far.\nClinical description\nIndividuals with this disorder have reduced visual acuity from a young age and usually have a mild degree of photophobia. Best corrected visual acuity is usually in the range of 6/12 to 6/36. Fundus examination is normal. Electroretinography demonstrates absent or markedly abnormal cone responses; rod responses are normal. Color vision testing is usually normal but some patients show a very mild reduction in color discrimination. This is in contrast to other forms of inherited cone dystrophy where color vision is severely impaired.\nEtiology\nThe causative gene has not been identified. There have been a few reports of patients with a similar phenotype who have mutations in genes normally associated with achromatopsia but the phenotype is atypical and more suggestive of an incomplete form of achromatopsia. One suggestion is that oligocone trichromacy (OT) is a very mild form of incomplete achromatopsia but this is not supported by current molecular genetic data. The reason for the presence of normal color vision despite the reduced visual acuity and electrophysiological evidence of severe cone dysfunction is uncertain. It has been proposed that patients with OT may have reduced numbers of normal functioning cones with preservation of the three cone types in normal proportions thereby enabling normal color vision (trichromacy). This hypothesis is supported by the findings of adaptive optics scanning laser ophthalmoscopic imaging (AOSLO) of the cone mosaic in patients with OT where there are reduced numbers of functioning cones in the fovea.\nDiagnostic methods\nDiagnostic methods include color vision testing, retinal imaging and electroretinography (ERG). Molecular genetic testing is also helpful in excluding other forms of cone dystrophy.\nDifferential diagnosis\nDifferential diagnosis should include other cone dysfunction syndromes, namely achromatopsia, Blue cone monochromatism and X-linked cone dysfunction syndrome with myopia, where there is reduced or absent color vision. The disorder also needs to be distinguished from bradyopsia where extended ERG testing beyond the ISCEV (International Society for Clinical Electrophysiology of Vision) standard needs to be performed to distinguish this rare disorder from OT. Molecular genetic testing using next generation sequencing of retinal disease gene panels will also help distinguish these disorders (where the molecular genetic basis is known) from OT.\nGenetic counseling\nAlthough most reported cases are sporadic, the disorder is likely to be inherited as an autosomal recessive trait as a number of affected sibling pairs have been reported. One family has been reported in which there may be dominant inheritance with incomplete penetrance. Affected individuals and their families should be counselled on the basis that the inheritance is likely to be autosomal recessive (unless the family history suggests otherwise).\nManagement and treatment\nThere is no effective treatment for the underlying retinal disorder. Patients should be provided with accurate visual aids: eyeglasses that can be tinted if photophobia is a prominent feature. The minority of patients with more severe visual loss may benefit from low vision aids.\nPrognosis\nAlthough few patients with this disorder have been followed up long term, it appears that the prognosis is good as the disorder is usually non-progressive.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Tony MOORE"}
{"Disease Name": "Oligodendroglial tumor", "Disease Definition": "Oligodendrogliomas are cerebral tumors that are differentiated from other gliomas on the basis of their unique genetic characteristics and better response to chemotherapy. These tumors are classified according to their grade (low grade oligodendrogliomas: grade II of the WHO classification and anaplastic oligodendrogliomas: grade III of the WHO classification) and according to their pure or mixed histology (oligoastrocytomas).", "ORPHA ID": 46484, "Summary": "Epidemiology\nUntil now, the incidence of these tumors has been largely underestimated. Oligodendrogliomas may represent up to 30% of all adult gliomas. Annual incidence can therefore be estimated at around one new case per 100,000 individuals per year. Prevalence is estimated at 1/300,000.\nClinical description\nLow grade tumors are usually diagnosed after a prolonged history of seizures and headaches. Clinical presentation of malignant forms is usually more acute with rapidly progressive neurological deficits and signs of intracranial hypertension (headaches and vomiting). Malignant forms can arise from transformation of a benign tumor several years after its diagnosis. These tumors may develop anywhere in the central nervous system but arise most frequently in the cerebral hemispheres.\nEtiology\nThe etiology is not known but no hereditary forms of oligodendroglioma have been reported. However, specific genetic characteristics, such as loss of chromosomes 1p and 19q, are observed.\nDiagnostic methods\nMRI may reveal infiltration of the brain parenchyma. Enhancement after contrast injection is indicative of an aggressive and malignant oligodendroglioma.\nDifferential diagnosis\nThe differential diagnosis should include low grade astrocytomas (see this term).\nManagement and treatment\nTreatment starts with surgery. Radiotherapy is mandatory for malignant tumors, regardless of the extent of the surgical resection. Chemotherapy is beneficial and is often used during treatment of the initial tumor and for treatment of a recurring malignant oligodendroglioma. In the case of low grade partially resected tumors, chemotherapy now tends to replace radiotherapy as thefirst-line treatment. Management requires a multidisciplinary team with experience in neuro-oncology. The treatment protocol should follow the recommendations resulting from prospective studies.\nPrognosis\nThe prognosis is usually better than that for other gliomas, such as astrocytomas. As a result of combined treatment with surgery, chemotherapy and radiotherapy, survival rates in patients without recurrence are also good, even for patients with malignant (anaplastic) tumors.\n\n                            Last update: \n                            November 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Jacques GRILL"}
{"Disease Name": "Oligodendroglioma", "Disease Definition": "A rare glial tumor characterized by a highly cellular lesion that is diffusly infiltrating at the periphery and consists of evenly-spaced monomorphic cells with the oligodendroglial phenotype. It typically occurs in the supratentorial white matter. Histologically, the cells are uniformly round to oval with round nuclei, delicate chromatin and small nucleoli. Most patients present with seizures.", "ORPHA ID": 251627, "Summary": ""}
{"Disease Name": "Oligodontia-cancer predisposition syndrome", "Disease Definition": "A rare, genetic, odontologic disease characterized by congenital absence of six or more permanent teeth (excluding the third molars) in association with an increased risk for malignancies, ranging from gastrointestinal polyposis to early-onset colorectal cancer and/or breast cancer. Ectodermal dysplasia (manifesting with sparse hair and/or eyebrows) may also be associated.", "ORPHA ID": 300576, "Summary": ""}
{"Disease Name": "Oligodontia", "Disease Definition": "Oligodontia is a rare developmental dental anomaly in humans characterized by the absence of six or more teeth.", "ORPHA ID": 99798, "Summary": "Epidemiology\nThe prevalence of isolated oligodontia is unknown. In European populations the estimated prevalence of both syndromic and non-syndromic oligodontia varies from 1/625 to 1/1,250 depending on the studies.\nClinical description\nClinical features of oligodontia include six or more missing teeth, lack of development of maxillary and mandibular alveolar bone height and reduced lower facial height. Variation in tooth morphology is also observed along with problems in tooth development, eruption and exfoliation.\nEtiology\nPossible causes of oligodontia include viral disease during pregnancy, genetic predisposition, metabolic imbalances, developmental abnormalities and environmental factors. Autosomal dominant mutations in PAX9 and MSX1 have been found in patients with molar non-syndromic oligodontia. The most recent gene identified as causing oligodontia is an autosomal recessive mutation in LTBP3 which was found in one case. WNT10A gene mutations, responsible for autosomal recessive forms of HED, odonto-onycho-dermal dysplasia and Schöpf-Schulz-Passarge syndrome (see these terms) are also seen in a substantial proportion (30 to 50% cases according to studies) of non-syndromic oligodontia cases. EDA and EDARADD, genes involved in different forms of X-linked and hypohidrotic ectodermal dysplasia (HED, see this term), are also mutated in non-syndromic oligodontia. The dental phenotype associated with autosomal dominant HED is usually less severe than that seen in autosomal recessive HED. Oligodontia-cancer predisposition syndrome (see this term) is due to AXIN2 gene mutations. IKBKG gene mutations are also associated to syndromic oligodontia, observed in incontinentia pigmenti and HED with immunodeficiency (see these terms).\nDiagnostic methods\nClinical examination along with a panoramic radiograph (and intra-oral X-rays if needed) is performed when teeth are thought to be missing. Delayed eruption of teeth, persistence of primary teeth, alveolar bone hypotrophy, and the presence of diastemas all suggest a diagnosis of oligodontia. In normal conditions all primary teeth and crypts of permanent first molars are visible on radiography at birth and crowns of permanent teeth (except third molars) at 6 years of age. When more than six teeth are absent then a diagnosis of oligodontia is given.\nDifferential diagnosis\nIsolated oligodontia should be distinguished from syndromic forms. Oligodontia is seen in X-linked hypohidrotic ectodermal dysplasia with immunodeficiency (HED), ECC syndrome, orofaciodigital syndrome type I and oral facial clefting syndromes such as Van Der Woude syndrome, Ellis-Van Creveld syndrome or Rapp-Hodgkin syndrome, hidrotic ectodermal dysplasia, focal facial dermal dysplasia (see these terms), oligodontia-taurodontism-hypotrichosis syndrome or trichothiodystrophies.\nAntenatal diagnosis\nGenetic antenatal diagnosis is possible but is never performed.\nGenetic counseling\nGenetic counseling is necessary to exclude syndromic oligodontia and discuss issues related to inheritance.\nManagement and treatment\nTreatment of oligodontia requires a multidisciplinary approach. Prosthetic treatment includes removable partial dentures, fixed partial dentures and over dentures. Osseointegrated dental implants are also possible when there is adequate bone height as they offer a more stable, long-term solution. Early implant therapy consists of the placement of 2 symphyseal implants from the age of 6 years old, allowing for the stabilization of a mandibular prosthesis that will be modified regularly to follow mandibular bone growth. Maxillary implants are placed upon the completion of skeletal growth.\nPrognosis\nWith proper dental treatment, patients can have normal dentition and orofacial functions\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN  - Dr François CLAUSS"}
{"Disease Name": "Oligomeganephronia", "Disease Definition": "A rare kidney malformation characterized by a reduction of 80% in nephron number and a marked hypertrophy of the glomeruli and tubules.", "ORPHA ID": 2260, "Summary": "Epidemiology\nPrevalence is unknown. The male to female ratio is of 3:1.\nClinical description\nOligomeganephronia is usually detected on routine ultrasound screening with small but normal shaped kidneys. Birth weight is often below the average value. Patients may present at birth with polyuria/polydipsia or signs of kidney dysfunction. During the first year of life, the usual symptom is persistent anorexia with vomiting, fever, and growth delay. Chronic kidney disease typically occurs during childhood or adolescence. Adult-onset oligomeganephronia has been reported in some rare cases.\nEtiology\nThe etiology of oligomeganephronia is not fully understood, but is hypothesized to be caused by premature termination of nephrogenesis. This may be linked to the same factors as renal hypoplasia, but with a more severe reduction in nephron numbers. Such factors include intrauterine growth restriction, maternal diseases (diabetes, hypertension), maternal drug intake (inhibitors of the renin-angiotensin system or non-steroidal anti-inflammatory drugs (NSAIDs)) or intoxication (smoking and alcohol). Premature birth (before the 36th week) is also a risk factor due to incomplete nephrogenesis. Oligomeganephronia can occur as part of a multi-organ syndrome such as renal coloboma syndrome, which is caused by mutations in the PAX2 gene (10q24.31), or can be caused by chromosomal disorders including 22q11 deletion syndrome or Wolf-Hirschhorn syndrome.\nDiagnostic methods\nDiagnosis can be suspected by bilateral, small and echogenic kidneys on ultrasound. CT-scan may, in addition to small, normal-shaped kidneys, show a thickened cortex and medulla with striated nephrograms. The diagnosis is confirmed histologically by a reduced number of nephrons, hypertrophic glomeruli with diameters being two to three times the normal size, hypertrophic tubules and thickening of Bowman's capsule. Both kidneys are symmetrically affected.\nDifferential diagnosis\nDifferential diagnosis includes renal dysplasia, nephronophthisis, autosomal dominant tubulointerstitial kidney disease, kidney infarction or ischemic kidney disease, and diffuse kidney parenchymal disease.\nAntenatal diagnosis\nAntenatal ultrasonographic screening allows detection of oligomeganephronia from midway through gestation.\nGenetic counseling\nMost cases are sporadic, but familial occurrence has been described.\nManagement and treatment\nAngiotensin-converting-enzyme inhibitors may slow the progression of the disease. Once having reached the stage of kidney failure, management includes a dialysis-transplantation program.\nPrognosis\nWith the increasing metabolic demands on the kidney during growth, a decline in kidney function is seen resulting in chronic kidney disease at a mean age of 10 years (range 6 months to 20 years).\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Pr M.F. [Michiel] SCHREUDER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Oliver syndrome", "Disease Definition": "Oliver syndrome is a very rare syndrome characterized by intellectual deficit, postaxial polydactyly, and epilepsy.", "ORPHA ID": 2920, "Summary": "Epidemiology\nTo date, seven individuals in three families have been reported.\nClinical description\nFacial features are not characteristic except for a prominent jaw. Concordant features in all subjects are postaxial polydactyly, which in four individuals affect also the feet, and intellectual deficit, which is usually severe, with absent or indistinct speech. Seizures are common with onset in the first months of life or in early childhood. Cutaneous syndactyly, camptodactyly and clinodactyly of fingers and brachydactyly and syndactyly of the toes have been recorded.\nGenetic counseling\nThe condition is probably hereditary, and transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            March 2010"}
{"Disease Name": "Olivopontocerebellar atrophy-deafness syndrome", "Disease Definition": "Olivopontocerebellar atrophy-deafness syndrome is characterised by infancy-onset olivopontocerebellar atrophy, sensorineural deafness and speech impairment. It has been described in less than 15 children. Most cases were sporadic, but autosomal recessive inheritance was suggested in three cases.", "ORPHA ID": 2732, "Summary": ""}
{"Disease Name": "Ollier disease", "Disease Definition": "A rare primary bone dysplasia characterized by multiple enchondromas (benign cartilage-forming tumors). The lesions are generally unilateral or asymmetrically distributed. The most common affected site is the appendicular skeleton.", "ORPHA ID": 296, "Summary": "Epidemiology\nPrevalence of Ollier disease (OD) is estimated at 1/100,000, but mild presentations without skeletal deformities may be underdiagnosed. OD is approximately evenly represented in both sexes.\nClinical description\nClinical expression of the disease is variable, it can involve a single bone segment or multiple limbs. The lesions develop during childhood and adolescence (median age of 13), but presentation in adulthood is also possible. It usually manifests with painless bony masses, which mostly occur in an asymmetric bilateral fashion, albeit symmetrical distribution has been described. The most frequently affected sites are the bones of the appendicular skeleton, in particular the hands (phalanges and metacarpals) and the metaphyses and diaphyses of the long tubular bones (i.e. femur, tibia, humerus). Rarely, spine, ribs, sternum, and skull can be involved. Pelvis involvement can lead to scoliosis. Patients present with multiple swelling, leading to apparent morphological abnormalities. Rarely, bone shortening can be the only presenting feature. Deformity around the joints, angular deformity, genu valgus, cubitus varus, joint mobility limitation, leg-length discrepancy, pathological fractures, facial asymmetry, and cranial nerve palsy can also be associated. OD is associated with an increased risk of malignancies compared to the general population such as chondrosarcoma (variably estimated but as high as 50% in some studies), central nervous system tumors, and occasionally gliomas, acute myeloid leukemia, and juvenile granulosa cell tumors.\nEtiology\nThe disease is due to somatic variants in IDH1 (2q34), IDH2 (15q26.1) and, more rarely, PTH1R (3p21.31), coding for isocitrate dehydrogenase 1, 2 and parathyroid hormone 1 receptor, respectively. Mutations are limited to the involved tissues. No familial case has been reported.\nDiagnostic methods\nThe diagnosis relies on clinical features and imaging findings, in particular conventional radiological evaluation. Enchondromas appear as slow growing, radiolucent defects that originate in the metaphyses. Both CT and MRI are useful for monitoring the disease, with MRI allowing evaluation of intraosseous and soft tissue involvement.\nDifferential diagnosis\nThe differential diagnoses include multiple hereditary exostosis (also known as multiple osteochondromas), osteitis fibrosa cystica, chondroma and chondrosarcoma.\nManagement and treatment\nNo specific therapy exists for OD. The management is usually conservative, but surgical approach can be proposed and is at present the only option when complications (e.g. pathological fractures) occur. Because of the risk of malignant transformation, annual monitoring of patients is recommended. Scintigraphy, ultrasound or biopsy for histological examination can be indicated for surveillance of lesions that become symptomatic (pain, increase in size) or suspected of malignant transformation. No specific guideline is available for the surveillance of other cancers risk due to the small number of patients reported and the limited data about the real incidence of other neoplasms in OD.\nPrognosis\nPrognosis is difficult to assess due to the wide clinical expression and variability of the disease. Depending on the extent of skeletal involvement, OD may result in severe deformities with functional and quality of life repercussions. Negative predictors are early onset, gross asymmetrical distribution, with severe shortening or deformity of the skeletal segment involved (e.g. limb asymmetry or phalangeal deformity) and malignant transformation (which is the most serious complication, potentially affecting the life span).\n\n                            Last update: \n                            May 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Luca SANGIORGI | ERN BOND*\n\n\n                                * European Reference Network"}
{"Disease Name": "Omenn syndrome", "Disease Definition": "Omenn syndrome (OS) is an inflammatory condition characterized by erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly, associated with severe combined immunodeficiency (SCID; see this term).", "ORPHA ID": 39041, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nOS presents during the first year of life with features of SCID including chronic diarrhea, pneumonitis and failure to thrive. In addition, patients present with inflammatory symptoms including lymphadenopathy, hepatosplenomegaly and generalized erythroderma, which may often cause alopecia and loss of eyebrows and eyelashes; protein loss may lead to generalized edema and metabolic disturbances. The signs and symptoms of OS can evolve over time and may not appear simultaneously. Some patients present with some but not all of these symptoms and may be described as having atypical Omenn syndrome. OS may also be associated with syndromic disorders including cartilage-hair hypoplasia (CHH), adenosine deaminase (ADA) deficiency, monosomy 22q11, coloboma of the eye, CHARGE syndrome and ligase 4 deficiency (see these terms).\nEtiology\nOS is not caused by a defined genetic defect. Rather than a distinct form of SCID, it is a distinct inflammatory phenotype that can be associated with genetically diverse SCIDs. The majority of cases reported to date have hypomorphic mutations in RAG1 and RAG2 genes (11p13). The other cases have mutations in the RMRP, ADA, IL2RG, IL7RA, DCLRE1C, CHD7 and LIG4 genes (9p21-p12, 20q13.11, Xq13, 5p13, 10p, 8q12.2 and 13q22-q34).\nDiagnostic methods\nOS may pose a diagnostic challenge because lymphocyte counts may be normal or high, unlike in typical SCID. Diagnosis is based on inflammation with evidence of abnormal expansion of one or more T-cell clones in peripheral blood and tissue, skin biopsies showing acanthosis and parakeratosis on staining with hematoxylin and eosin, evidence of dysplastic thymus with few remnant lymphoid cells and lymphadenopathy. Typically B cells are absent, as are immunoglobulins apart from IgE which is often raised. Eosinophilia is also observed.\nDifferential diagnosis\nDifferential diagnoses include graft-versus-host disease, histiocytosis, Job syndrome, Netherton syndrome, and severe combined immunodeficiencies (see these terms), particularly those associated with maternal T-cell engraftment.\nAntenatal diagnosis\nOS is not a single genetic disorder, but if the causative gene is identified in the index patient, prenatal diagnosis may be offered, although subsequent individuals are likely to have SCID.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nInitial treatment is based on immunosuppressive drugs including prednisone and cyclosporin followed by hematopoietic stem cell transplantation, in a centre recognized as treating such disorders ideally using HLA-identical family donors or, if this is not available, other appropriate donors after use of appropriate conditioning regimens.\nPrognosis\nIf untreated, prognosis is poor and the disease is fatal. Skin inflammation worsens with time leading to severe barrier problems that facilitate life-threatening and overwhelming bacterial and fungal infections in already severely immunocompromised patients. Viral infections are most severe and life-threatening. Survival rates with treatment have been reported as greater than 80%.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Omodysplasia", "Disease Definition": "Omodysplasia is a rare skeletal dysplasia characterized by severe limb shortening and facial dysmorphism. Two types of omodysplasia have been described: an autosomal recessive or generalized form (also referred to as micromelic dysplasia with dislocation of radius) marked by severe micromelic dwarfism with predominantly rhizomelic shortening of both the upper and lower limbs, and an autosomal dominant form in which stature is normal and shortening is limited to the upper limbs.", "ORPHA ID": 2733, "Summary": "Epidemiology\nIn total, less than 40 cases of omodysplasia have been described in the literature so far, with the majority of reported cases concerning the autosomal recessive form of the disease.\nClinical description\nThe facial dysmorphism is characterized by frontal bossing, a depressed nasal bridge with a short nose and a long and prominent philtrum. Decreased mobility of the elbows and knees is also a common feature. Other less frequent manifestations include midline hemangiomas, congenital heart defects, craniosynostosis and cryptorchidism in males.\nEtiology\nThe etiology remains unknown but a paternally-inherited paracentric inversion of 15q13 to q21.3 has been detected in one family.\nDiagnostic methods\nDiagnosis is based on the clinical and radiological phenotype with major radiological findings including shortening and club-like tapering of the humeri and femora, proximal radioulnar diastasis and proximal radial head dislocation. Although the hands are generally considered to be normal in omodysplasia, short first metacarpals have been reported in the majority of patients with the autosomal dominant form.\nDifferential diagnosis\nThe differential diagnosis for the autosomal recessive form should include diastrophic dysplasia, atelosteogenesis and Larsen syndrome (see these terms), whereas the major differential diagnosis for the autosomal dominant form is Robinow syndrome (see this term).\nAntenatal diagnosis\nFor affected families, detection of long bone anomalies by ultrasonography may allow prenatal diagnosis as early as at 13 weeks of gestation.\nGenetic counseling\nGenetic counseling should be recommended.\nManagement and treatment\nTreatment is symptomatic only, involving mainly orthopedic management for recurrent joint dislocation.\nPrognosis\nThe prognosis is variable.\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Omphalocele syndrome, Shprintzen-Goldberg type", "Disease Definition": "Shprintzen–Goldberg omphalocele syndrome is a very rare inherited malformation syndrome characterized by omphalocele, scoliosis, mild dysmorphic features (downslanted palpebral fissures, s-shaped eyelids and thin upper lip), laryngeal and pharyngeal hypoplasia and learning disabilities.", "ORPHA ID": 3164, "Summary": ""}
{"Disease Name": "Omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by a large omphalocele containing liver and small intestine, diaphragmatic hernia, cardiovascular anomalies (e. g. aortic coarctation), variable limb malformations (including radioulnar synostosis, agenesis of the radius and/or thumb, generalized syndactyly, and numerical reduction of toes), and dysmorphic facial features. Additional reported manifestations are unilateral absence of umbilical artery, intestinal malrotation, hypoplastic ovaries, and unilateral renal agenesis, among others. The condition is mostly fatal in the neonatal period.", "ORPHA ID": 496693, "Summary": ""}
{"Disease Name": "Omphalocele", "Disease Definition": "A rare, non-syndromic, abdominal wall malformation characterized by a hernia of the abdominal wall, centered on the umbilical cord, in which the protruding viscera are protected by a sac.", "ORPHA ID": 660, "Summary": "Epidemiology\nIn Europe, the prevalence at birth of omphalocele (isolated and syndromic forms combined) is estimated at about 1/8,000 births. At least half of patients have other abnormalities associated.\nClinical description\nOmphalocele occurs very early in development and is typically detected prenatally. The hernia occurs at the umbilical ring allowing protrusion of the abdominal organs (midgut, liver, spleen and gonads) through the umbilical cord. The protruding viscera is encased in a sac consisting of three layers: the outer amniotic layer, a middle layer of Wharton's jelly and the inner peritoneal layer. The defect is classified based in the predominant location (epigastric, umbilical or hypogastric) and further classified into small, giant and ruptured. A small omphalocele is less than 5 cm with a sac that may contain a few intestinal loops. A giant omphalocele is greater than 5 cm with a whole or large part of the liver and bowel protruding. Membrane rupture, resulting in evisceration, can occur in utero, during delivery or postnatally, although it is a rare complication. Almost half of patients with omphalocele have other malformations associated, including cardiac, gastrointestinal, genitourinary, musculoskeletal and central nervous system malformations.\nEtiology\nWhile the exact pathogenic mechanism of omphalocele is unknown, there is a wide consensus that it is due to the defective closure of the abdominal wall in the embryo before 9 weeks of gestation.\nDiagnostic methods\nDiagnosis is usually made before birth by ultrasound, and can be detect as early as 11 to 14 weeks gestation in tertiary level referral centers. Associated malformations can then be sought for and management of the infant can be timely prepared in specialized units.\nDifferential diagnosis\nDifferential diagnosis includes gastroschisis, especially when the covering sac is damaged, and other celosomias that can be associated. Omphalocele can be part of polymalformative syndromes including Beckwith-Wiedemann syndrome, and trisomy 13, 18 or 21.\nAntenatal diagnosis\nPrenatal diagnosis is usually made in the first trimester. Fetal karyotype must then be assessed, and accurate screening for associated malformations has to be repeated along pregnancy.\nManagement and treatment\nManagement is surgical and aims to close the abdominal opening and return the protruding viscera to the abdomen. Various techniques can be applied when primary closure is not possible.\nPrognosis\nThe prognosis for isolated omphalocele depends on the size of the defect; prognosis for small omphalocele is very good; however, giant omphalocele have a risk of pulmonary hypoplasia. Recent improvements to resuscitation and surgical techniques (through abdominal prostheses) have notably improved the prognosis of giant isolated omphaloceles, who present with some degree of pulmonary hypoplasia, over the last three decades. In syndromic cases, the main prognostic factor is the associated anomalies, especially cardiac defects.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Sylvie BEAUDOIN"}
{"Disease Name": "Omphalomesenteric cyst", "Disease Definition": "A rare non-syndromic diaphragmatic or abdominal wall malformation, a remnant of omphalomesenteric duct, characterized by cuboidal or columnar epithelium with gastrointestinal differentiation. Patients may be asymptomatic or present with infraumbilical mass, umbilical lesion with secretions, abdominal pain, hernia, abscess, gastrointestinal tract bleeding, intestinal obstruction, and acute abdomen.", "ORPHA ID": 490, "Summary": ""}
{"Disease Name": "Omsk hemorrhagic fever", "Disease Definition": "Omsk hemorrhagic fever (OHF), caused by Omsk hemorrhagic fever virus (OHFV), is a zoonotic disease characterized by fever, nausea, myalgia and moderately severe hemorrhagic manifestations as well as in some cases meningitis, pneumonia and nephrosis.", "ORPHA ID": 319266, "Summary": ""}
{"Disease Name": "Onchocerciasis", "Disease Definition": "A form of filariasis, caused by the parasitic worm  Onchocerca volvulus, transmitted by the black fly. The infection can either be asymptomatic or manifest as an ocular disease (river blindness) with itchy eyes, erythema, photophobia, onchodermatitis or onchocercal skin disease (classified into acute papular, chronic papular, lichenified, atrophic, and depigmentated) and onchocercomas (over bony prominences). Other classic clinical manifestations are ichthyosis-like lesions (''lizard skin'') and ''hanging groin'', which may be associated with lymphadenopathy.", "ORPHA ID": 2737, "Summary": ""}
{"Disease Name": "Oncogenic osteomalacia", "Disease Definition": "A rare paraneoplastic syndrome characterized by renal phosphate wasting and bone demineralization due to a phosphaturic mesenchymal tumor of the mixed connective tissue variant. It causes osteomalacia in adults with bone pain and pathological fractures, and rickets in children.", "ORPHA ID": 352540, "Summary": "Epidemiology\nThe prevalence of the disease is not known. Since the association between phosphate reabsorption and tumor was first made, approximately 400 cases of oncogenic osteomalacia have been reported in the literature.\nClinical description\nDisease onset typically is in adulthood, with mean age of 45 years of age, although a few pediatric cases have been reported. Typical features are chiefly related to chronic hypophosphatemia caused by hyperphosphaturia. The causative tumors are typically small and benign, occur in either bone or soft tissue, and cause no local symptoms. Patients usually present with symptoms of isolated hypophosphatemia. This means that the diagnosis is usually made late, and even when it is, the tumors are often not found. Typically, both calcium and parathyroid hormone levels are normal, as is the serum 25 hydroxyvitamin D (25OH vitamin D) concentration. Osteomalacia causes bone pain and can lead to pathological fractures or rickets in young patients where the epiphyses have not matured. Severe hypophosphatemia can cause muscle weakness.\nEtiology\nThis syndrome is caused by phosphatonin secretion by the causative tumor. Classically the phosphatonin is FGF-23 (Fibroblast Growth Factor 23), other phosphatonins (Matrix Extracellular Phosphoglycoprotein - MEPE and secreted frizzled-related protein 4 - sFRP4) appear to have the same biochemical effect, and were, in fact discovered by examination of patients with these tumors. FGF-23 causes urinary phosphate wasting by downregulating the main renal phosphate reabsorption transporter, the type 2 sodium-phosphate cotransporter (NaPi2a), localized in the proximal tubule. FGF-23 overexpression may also affect bone mineralization by suppressing osteoblast differentiation.\nDiagnostic methods\nThe finding of isolated hypophosphatemia, urinary phosphate wasting in the absence of the renal Fanconi syndrome and without hereditary hypophosphatemic rickets, should prompt the search for a causative tumor. As these mesenchymal tumors generally express somatostatin receptors, they can be demonstrated by somatostatin/octreotide scanning. All imaging should be whole body (vertex to toes).\nDifferential diagnosis\nDifferential diagnosis may include other forms of hypophosphatemic osteomalacia (X-linked, autosomal dominant or recessive hypophosphatemic rickets) as well as primary or acquired renal Fanconi syndrome.\nManagement and treatment\nDefinitive treatment is with surgical resection of the tumor. If the tumor cannot be found or removed, medical treatment involves the supplementation of phosphate and active vitamin D (e.g. alfacalcidol). Radiotherapy may be helpful if the tumor is located but is non-resectable for anatomical reasons. A new anti-FGF23 monoclonal antibody has been promising in the treatment of X-linked hypophosphatemic rickets, and may therefore be effective in FGF-23 mediated oncogenic osteomalacia; however, this remains to be proven.\nPrognosis\nExcellent recovery after complete tumor excision with complete resolution of symptoms and biochemical abnormalities. Long term monitoring is required as local recurrence and metastases have been reported, even if rarely.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Laura CESCA  - Pr T. [Tom] NIJENHUIS | ERKNet* - Dr Stephen WALSH | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Onychocytic matricoma", "Disease Definition": "A rare, benign, nail tumor originating in the nail matrix characterized by localized pachyonychia and variable degrees of pigmentation: pigmented, melanocytic (common, longitudinal melanonychia that may simulate a foreign body) or hypopigmented. Histopathology demonstrates a purely epithelial tumor with endokeratinization in the deep portion and concentrically arranged nests of prekeratogenous and keratogenous cells.", "ORPHA ID": 300504, "Summary": ""}
{"Disease Name": "Onychomatricoma", "Disease Definition": "Onychomatricoma is a rare, benign nail tumor originating in the nail matrix characterized by localized or diffuse thickening of the nail plate, increased transverse or longitudinal overcurvature, a yellow longitudinal band of variable width, swelling of the proximal nail fold, multiple splinter hemorrhages and the presence of honeycomb-like cavities in the distal margin of the nail plate. Nail dystrophy and dorsal pterygium may be associated. Occasionally, a pigmented lesion has been reported.", "ORPHA ID": 300512, "Summary": ""}
{"Disease Name": "Open spinal dysraphism with a myelomeningocele", "Disease Definition": "A rare form of spina bifida cystica (saccular, open neural tube defect (NTD)) characterized by a non-neurulated spinal cord (neural placode) on the surface of the cystic extension of dysplastic meninges (non-epidermised posterior meningocele). The spinal cord extends through a spina bifida (posterior vertebral defect) with typically everted or parallel laminae. Nerve roots are connected to the borders of the neural placode and are visible inside the sac. Myelomeningocele is characteristically associated with a Chiari II malformation. It can be either isolated or associated with split cord malformation.", "ORPHA ID": 93969, "Summary": ""}
{"Disease Name": "Open spinal dysraphism", "Disease Definition": "A rare neural tube closure defect characterized by a skin defect with exposed neural tissue in the area of the spinal column, with or without a protruding sac at the location of the defect. Signs and symptoms are variable depending on the content (only meninges or also spinal cord tissue), location, and severity of the lesion, but may include motor, sensory, and/or sphincter dysfunction, hydrocephalus, and/or skeletal anomalies (e. g. scoliosis, hemivertebrae), among others.", "ORPHA ID": 268369, "Summary": ""}
{"Disease Name": "Ophthalmomandibulomelic dysplasia", "Disease Definition": "Ophthalmomandibulomelic dysplasia is characterized by complete blindness due to corneal opacities, difficult mastication due to temporomandibular fusion and anomalies of the arms.", "ORPHA ID": 2741, "Summary": "Epidemiology\nThree cases in one family have been described so far (two males, one female).\nClinical description\nMicrognathia, shortening and bowing of the forearm, ulnar deviation and bowed radius, short fibula, genu valgum and coxa vara have been reported. Intelligence is normal.\nEtiology\nThe causative gene has not yet been identified.\nGenetic counseling\nAutosomal dominant inheritance has been suggested.\n\n                            Last update: \n                            November 2009"}
{"Disease Name": "Ophthalmoplegia-intellectual disability-lingua scrotalis syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder characterized by congenital, external, nuclear ophthalmoplegia, lingua scrotalis, progressive chorioretinal sclerosis and intellectual disability. Bilateral ptosis, bilateral facial weakness, Parinaud's syndrome, convergence paresis and myopia may be associated. There have been no further descriptions in the literature since 1975.", "ORPHA ID": 2743, "Summary": ""}
{"Disease Name": "Opitz GBBB syndrome", "Disease Definition": "A rare X-linked congenital midline malformation syndrome characterized by hypertelorism, laryngo-tracheo-esophageal defects and hypospadias.", "ORPHA ID": 2745, "Summary": "Epidemiology\nWhilst epidemiological data is limited, the prevalence of X-linked Optiz GBBB syndrome (GBBB) has been suggested to range from 1/50,000 to 1/100,000. Males are more severely affected. More than 150 patients are reported with MID1 mutation. The clinical diagnostic is unreliable in older literature due to phenotypic confusion.\nClinical description\nGBBB syndrome usually presents with characteristic facial dysmorphism: prominent forehead, hypertelorism (>95% of cases) and telecanthus, cleft lip/palate (50%), broad nasal bridge, broad nasal tip and anteverted nares. Malformations include hypospadias (80%), imperforate or ectopic anus (20%), laryngeal cleft (50%), dysphagia, reflux and other esophageal problems (30%) and, less commonly, congenital heart malformations (20%) and agenesis of the corpus callosum or hypoplasia of the vermis. Developmental delay or intellectual deficiency (ID) affect one-third of males. Female carriers mostly show only hypertelorism (>90%) and rarely other manifestations. A mild form of GBBB has been reported in a single family with a MID2 variant.\nEtiology\nOpitz GBBB is caused by mutations in the MID1 gene (Xp22) encoding the midline-1 protein which is an ubiquitin E3 ligase associated with microtubules. The original report described two distinct X-linked midline defects either with (G syndrome) or without (BBB syndrome) laryngeal malformations. Both phenotypes were later assigned to the same gene, without genotype/phenotype correlation; a wide variability in clinical manifestations is noted even among patients harboring the same mutation.\nDiagnostic methods\nOpitz GBBB syndrome is suspected on clinical findings: boy with ocular hypertelorism and at least one other of the major findings (hypospadias or laryngo-tracheoesophageal abnormalities). Diagnosis is confirmed by identification of a MID1 mutation.\nDifferential diagnosis\nSPECC1L syndrome (Teebi hypertelorism syndrome) is the main differential diagnosis of GBBB syndrome. SPECC1L syndrome has strikingly overlapping craniofacial phenotype, leading to confusion in the past literature between MID1-confirmed GBBB and various overlapping conditions. Earpits, uterine malformations, omphalocoele, diaphragmatic herniae and, rarely, craniosynostosis and aortic root dilation are specific to SPECC1L, whereas laryngeal and anorectal defects are specific to GBBB. ID is more common in the latter. Further nosologic confusion came from exceptional observation of ''BBBG-like'' phenotype in patients with 22q11.2 deletion syndrome. Baraitser-Winter cerebrofrontofacial syndrome (ACTB and ACTG1), craniofrontonasal dysplasia (EFNB1), frontonasal dysplasia and Aarskog syndrome (FGD1) share marked hypertelorism.\nAntenatal diagnosis\nPrenatal testing is possible for at-risk pregnancies if a MID1 mutation has been identified in a family member.\nGenetic counseling\nThe pattern of inheritance is X-linked. Genetic counseling is recommended for young adults who are affected, are carriers, or are at risk of being carriers. Where the female is the carrier, there is a 50% risk of future male offspring being affected and a 50% risk for future female offspring to be a carrier. For affected males, future male offspring are always unaffected, whereas future female offspring are always a carrier.\nManagement and treatment\nMultidisciplinary medical support with a pediatrician, craniofacial, ENT (ear, nose and throat) and urologic surgeons, cardiologist, and medical geneticist is required. Neurodevelopmental support and speech therapy may be necessary.\nPrognosis\nPrognosis is variable but usually favorable, depending on the severity of malformations and associated ID.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Opsismodysplasia", "Disease Definition": "Opsismodysplasia is a skeletal dysplasia characterized by congenital dwarfism and facial dysmorphism.", "ORPHA ID": 2746, "Summary": "Epidemiology\nTwenty five cases (16 males and 9 females) have been reported in the literature so far.\nClinical description\nThe disorder is evident at birth. The facial dysmorphism includes macrocephaly, prominent brow, large fontanels, depressed nasal bridge, a small nose, anteverted nares and a long philtrum, hypertelorism, and exophthalmos. Additional features include a short neck, narrow thorax, predominantly rhizomelic micromelia with very short long bones, short feet and hands, muscular hypotonia, severe platyspondyly, marked delay of bone maturation, and increased susceptibility to respiratory infections.\nEtiology\nEtiology remains unknown.\nGenetic counseling\nAutosomal recessive transmission has been suggested.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Opsoclonus-myoclonus syndrome", "Disease Definition": "Opsoclonus myoclonus syndrome (OMS) is a rare neuroinflammatory disease of paraneoplastic, parainfectious or idiopathic origin, characterized by opsoclonus, myoclonus, ataxia, and behavioral and sleep disorders.", "ORPHA ID": 1183, "Summary": "Epidemiology\nThe annual incidence is estimated at around 1/5,000,000.\nClinical description\nOMS typically presents between 1 and 3 years of age, although it can occur earlier or later in childhood. It is characterized by opsoclonus (rapid, multi-directional, conjugate eye movements), myoclonic jerks, ataxia, irritability and sleep disturbances. The clinical course may be monophasic or chronic relapsing. OMS is associated in approximately 50% of pediatric cases with a neuroblastoma (see this term); this tumour is usually (but not always) of low grade with a good oncological outcome. A similar adult-onset condition also occurs but is associated with different types of cancer, most commonly small-cell lung cancer (see this term) and adenocarcinoma of the breast.\nEtiology\nOMS may have a paraneoplastic, parainfectious or idiopathic origin. In the majority of pediatric paraneoplastic cases, a neuroblastoma is found. Infections triggering OMS include a variety of viral and bacterial agents including streptococci, mycoplasma and varicella zoster. The exact pathomechanism is unknown but an autoimmune-mediated brainstem and/or cerebellar dysfunction has been suggested; the opsoclonus may reflect disinhibition of the fastigial nucleus of the cerebellum or disordered interaction between the omnipause and burst neurons, but the cognitive and behavioral elements of the condition, as well as recent imaging studies, suggest a wider neurological process.\nDiagnostic methods\nThe diagnosis is clinical, based on the presence of 3 out of the 4 following criteria: 1) neuroblastoma, 2) opsoclonus, 3) a movement disorder with myoclonus and/or ataxia, and 4) behavioural and/or sleep disturbance. Brain MRI in the acute presentation is normal. Neuroblastoma is detected by detailed MRI with particular focus on the whole length para-spinal regions, the carotids, the mediastinum, the adrenals, the abdomen and pelvis. Functional tests, including urinary vanillylmandelic and homovanillic acid tests and a metaiodobenzylguanidine scan, should be performed but may produce a false negative result as neuroblastomas in OMS are usually low grade and therefore not metabolically active. Serological tests may allow for the identification of a parainfectious etiology. No consistent neural antibody has yet been identified in pediatric OMS, in contrast to adult OMS in which Hu anti-neuronal nuclear antibodies (anti-Hu) have been found.\nDifferential diagnosis\nDifferential diagnosis includes acute inflammatory cerebellar ataxia that is differentiated from OMS by the type of eye movement (nystagmus), the absence of irritability, and the usually rapid recovery without treatment.\nManagement and treatment\nTreatment usually includes resection of the neuroblastoma if present; occasionally, higher grade neuroblastoma may require chemotherapy. Treatment also includes immunomodulation. Treatment regimens have not been standardized but may include corticosteroids, adrenocorticotropin hormone, cyclophosphamide, intravenous immunoglobulin, and/or rituximab.\nPrognosis\nOutcome is variable. Some children have a monophasic illness, respond well to steroids and have little or no sequelae. Others may be treatment-resistant, have a chronic relapsing course and motor, cognitive and/or behavioral sequelae. Opsoclonus usually remits. The presence or absence of neuroblastoma does not seem to affect outcome.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Mark GORMAN  - Dr Michael PIKE  - Pr Marc TARDIEU"}
{"Disease Name": "Optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome", "Disease Definition": "A rare mitochondrial disease characterized by a variable clinical phenotype with the core features of optic atrophy, ataxia, and hypotonia. Additional common manifestations include global developmental delay with or without regression, neuropathy, spasticity, and microcephaly, less frequently seizures, movement disorder, hearing loss, and respiratory failure. Brain imaging may show abnormalities of the corpus callosum, basal ganglia, and midbrain, cerebral or cerebellar atrophy, or white matter abnormalities. The condition is frequently fatal at an early age.", "ORPHA ID": 543470, "Summary": ""}
{"Disease Name": "Optic atrophy-intellectual disability syndrome", "Disease Definition": "Optic atrophy-intellectual disability syndrome is a rare, hereditary, syndromic intellectual disability characterized by developmental delay, intellectual disability, and significant visual impairment due to optic nerve atrophy, optic nerve hypoplasia or cerebral visual impairment. Other common clinical signs and symptoms are hypotonia, oromotor dysfunction, seizures, autism spectrum disorder, and repetitive behaviors. Dysmorphic facial features are variable and nonspecific.", "ORPHA ID": 401777, "Summary": ""}
{"Disease Name": "Optic disc pit", "Disease Definition": "A rare ophthalmic disorder characterized by a usually congenital and unilateral round or oval, gray, white, or yellowish depression in the optic disc. There may be more than one pit present in one eye, and the anomaly is most commonly found in the inferotemporal region of the optic disc, although any sector may be involved. Patients are often asymptomatic, or may present with visual field defects, in particular paracentral arcuate scotoma connected to an enlarged blind spot. A number of patients develop serous macular detachment, with loss of vision typically becoming apparent in the third or fourth decade of life.", "ORPHA ID": 519404, "Summary": ""}
{"Disease Name": "Optic pathway glioma", "Disease Definition": "Optic pathway glioma (OPG) is a benign tumor that develop along the optic nerve (chiasm, tracts, and radiations) characterized by impairment or loss of vision and may be accompanied by diencephalic symptoms such as reduced growth and alteration in sleeping patterns. OPG are often linked to neurofibromatosis type 1 (NF1, see this term).", "ORPHA ID": 2086, "Summary": ""}
{"Disease Name": "Oral submucous fibrosis", "Disease Definition": "Oral submucous fibrosis (OSMF) is a chronic, progressive disease that alters the fibroelasticity of the oral submucosa, prevalent in India and Southeast Asia but rare elsewhere, and characterized by burning and pain in the oral cavity, loss of gustatory sensation, the presence of blanched fibrous bands and stiffening of the oral mucosa and oro-pharynx (leading to trismus and a progressive reduction in mouth opening) and an increased risk of developing oral squamous cell cancer (3-19%). It is usually associated with the chewing of the areca nut (an ingredient in betel quid) but the exact etiology is unknown and there is currently no effective treatment.", "ORPHA ID": 357154, "Summary": ""}
{"Disease Name": "Oral-facial-digital syndrome with short stature and brachymesophalangy", "Disease Definition": "A rare ciliopathy characterized by oral anomalies (multiple oral frenula, missing incisors), facial dysmorphism (such as square face with small forehead, upslanting palpebral fissures, and cleft lip, among other features), digital anomalies (brachydactyly, brachymesophalangy, polydactyly), and short stature. Additional reported manifestations include short femoral neck, bilateral cervical ribs, abnormal vertebral bodies, and gracile long bones.", "ORPHA ID": 508501, "Summary": ""}
{"Disease Name": "Orbital leiomyoma", "Disease Definition": "Orbital leiomyoma is a rare benign smooth muscle tumor arising from the walls of orbital vessels characterized by its slow growth and well encapsulated nature. It is usually located in an extraconal position, commonly manifesting with painless proptosis. The tumor is composed of spindle cells arranged in a fibrous stroma rich in dilated sinusoidal capillaries. The nuclei of tumor cells are oval with blunted ends and there are no mitotic figures. Orbital leiomyoma when excised has excellent prognosis for vision and life. One case of orbital leiomyosarcoma that possibly represents sarcomatous change in an orbital leiomyoma following radiation treatment has been reported.", "ORPHA ID": 52994, "Summary": ""}
{"Disease Name": "Orgasm-induced seizures", "Disease Definition": "Orgasm-induced seizures is a rare neurologic disease characterized by complex partial seizures with or without secondary generalization, or idiopathic primarily generalized epilepsy, triggered by sexual orgasm. Seizures usually start immediately, shortly after or a few hours after the achievement of orgasm, last a few seconds or minutes, and are followed, in very rare cases, by intense migraine.", "ORPHA ID": 166421, "Summary": ""}
{"Disease Name": "Ornithine transcarbamylase deficiency", "Disease Definition": "A rare, genetic disorder of urea cycle metabolism and ammonia detoxification characterized by either a severe, neonatal-onset disease found mainly in males, or later-onset (partial) forms of the disease. Both present with episodes of hyperammonemia that can be fatal and which can lead to neurological sequelae.", "ORPHA ID": 664, "Summary": "Epidemiology\nOrnithine transcarbamylase deficiency (OTCD) is the most common type of urea cycle disorder. Worldwide prevalence estimates range between 1/56,500 to 1/113,000 live births.\nClinical description\nMales with the severe, neonatal-onset type are normal at birth but develop poor sucking, hypotonia and lethargy after a few days, rapidly progressing into somnolence and coma. Seizures and hyperventilation may also be present. If untreated, severe encephalopathy will develop with a high risk for death. Patients with a milder form can present at any age. In infants, symptoms can be induced when switching from breast milk to whole milk. In children and adults, environmental stressors (i.e. fasting, high protein diet, pregnancy and the postpartum period, intercurrent illness, surgery) can trigger episodes of hyperammonemic encephalopathy along with nausea, vomiting, headaches, erratic behavior, delirium and combativeness. These episodes can also result in hyperammonemic coma. Neurological complications of hyperammonemic coma include developmental delay and, sometimes, severe cognitive impairment. Many female carriers are asymptomatic; however, they can be affected to the same extent as males if the degree of X-inactivation of the disease allele is unfavorable. Coagulopathy is a frequent finding during metabolic decompensation and sometimes evolves into acute liver failure.\nEtiology\nOTCD is due to mutations in the OTC gene (Xp21.1) which encodes OTC, responsible for catalyzing the synthesis of citrulline (in liver and small intestine) from carbamoyl phosphate and ornithine. Mutations that abolish OTC activity completely result in the severe, neonatal-onset form while mutations leading to decreased OTC activity result in the late-onset phenotypes.\nDiagnostic methods\nDiagnosis is based on clinical manifestations and plasma ammonia levels are typically high (>200 µmol/L) when encephalopathy is present. Plasma amino acid analysis reveals low citrulline and arginine levels and high glutamine. Urine organic acid analysis usually reveals elevated orotic acid levels. Molecular genetic testing confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses include carbamoyl-phosphate synthetase deficiency, argininosuccinic aciduria, hyperammonemia due to N-acetylglutamate synthase deficiency, citrullinemia type 1 and argininemia.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease causing mutation.\nGenetic counseling\nOTCD is inherited in an X-linked manner. Where the female parent is a carrier, male offspring have a 50% risk of inheriting the disease. Where the male is affected, male offspring are unaffected and females are obligate carriers. Female heterozygotes may be symptomatic due to skewed X-chromosome inactivation.\nManagement and treatment\nPatients presenting with a hyperammonemic coma must be treated immediately in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration methods), ammonia scavenger therapy implemented, catabolism reversed (through glucose and lipid infusions) and special care taken to reduce the risk of neurological damage (electroencephalogram surveillance and treatment of seizures if necessary). Long-term therapy involves life-long restriction of protein intake and nitrogen scavenger therapy (with sodium benzoate and/or sodium or glycerol phenylbutyrate). A liver transplantation may also be considered in patients with severe, neonatal-onset OTCD (usually performed by 3-6 months of age) or those with frequent hyperammonemic episodes. Valproate, haloperidol, fasting and known stressors should be avoided. Pregnant women with OTCD should be carefully monitored, especially also in the postpartum period.\nPrognosis\nPrognosis depends on disease severity but is considered bleak in patients with early neonatal disease. Without early diagnosis and treatment of hyperammonemic episodes, the neurological outcome is poor.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Johannes HÄBERLE"}
{"Disease Name": "Orofaciodigital syndrome type 1", "Disease Definition": "Oral-facial-digital syndrome type 1 (OFD1) is a rare neurodevelopmental disorder in the ciliopathy group that is lethal in males and characterized by variable anomalies including external malformations (craniofacial and digital), and possible involvement of the central nervous system (CNS) and of viscera (kidneys, pancreas and ovaries) in females.", "ORPHA ID": 2750, "Summary": "Epidemiology\nEstimated annual incidence of 1/250,000 to 1/50,000 live births has been reported. Almost all patients are female. Exceptional cases of affected males have been described.\nClinical description\nOFD1 is associated with prenatal male lethality in almost all cases. In female patients, there is a very high degree of phenotypic variability ranging from multiple severe malformations and visceral involvement to only renal cysts or dysmorphic features. Manifestations include oral malformations in >95% (lobed tongue, tongue hamartomas or lipomas, ankyloglossia, cleft or highly arched palate, accessory gingival frenulae, missing (hypodontia, see this term) or extra teeth, enamel dysplasia, and malocclusion), craniofacial abnormalities in about 87% including facial dysmorphism (ocular hypertelorism or telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft upper lip, micrognathia, downslanting palpebral fissures), abnormal hair/alopecia, evanescent facial milia, digital malformations in about 88% (brachydactyly, syndactyly, 5th finger clinodactyly, duplicated hallux/broad thumb, preaxial or postaxial polydactyly), involvement of the CNS in about 50% including brain abnormalities (intracerebral cysts, corpus callosum agenesis, cerebellar agenesis with or without Dandy-Walker malformation) and mild to moderate intellectual deficit. Visceral involvement includes polycystic kidney disease (at least 50%), and hepatic and pancreatic cystic disease. Hearing problems have also been described in about 6%.\nEtiology\nOFD1 is caused by mutations in the OFD1 gene (Xp22) encoding a protein localized in the centrosome and basal body of primary cilia, which play an important role in development. A fraction of cases displays genomic deletions. High penetrance has been reported but expression is highly variable.\nDiagnostic methods\nDiagnosis is often made at birth on the basis of characteristic oral, facial, and digital anomalies. In other affected individuals, diagnosis is suspected only in later childhood or adulthood after polycystic kidney disease is found. Diagnostic methods include direct sequencing of OFD1 and dosage analysis in negative cases to detect genomic rearrangements not identifiable by direct sequencing due to the presence of the wild-type allele.\nDifferential diagnosis\nDifferential diagnoses include other OFD syndromes and disorders (OFD2, 3, 4, 5, 6, 8 and 9), and familial cystic renal disease (see these terms). Meckel and Joubert syndromes (see these terms) should also be considered.\nAntenatal diagnosis\nPrenatal diagnosis and preimplantation genetic diagnosis are recommended for at-risk pregnancies and require identification of the disease-causing mutation in the family.\nGenetic counseling\nOFD1 follows an X-linked dominant pattern of inheritance. The gene mutations commonly occur de novo. About 75% of affected female cases involve a single family member. Carrier testing for at-risk relatives is recommended.\nManagement and treatment\nTreatment involves cosmetic or reconstructive surgery for cleft lip and/or palate, tongue nodules, and accessory frenulae, removal of accessory teeth, orthodontia for malocclusion, surgery to repair syndactyly, as well as routine management of kidney disease and seizures. Management requires special educational evaluation for learning disabilities.\nPrognosis\nMale mortality usually occurs in the first or second trimester of pregnancy. The prognosis in affected females is variable and depends on the associated malformations and/or visceral involvement, severity, treatment, and the course of the disease.\n\n                            Last update: \n                            September 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Brunella FRANCO"}
{"Disease Name": "Orofaciodigital syndrome type 11", "Disease Definition": "Orofaciodigital syndrome type 11 is an extremely rare, sporadic form of Orofaciodigital syndrome (OFDS; see this term) with only a few reported cases, and characterized by facial (blepharophimosis, bulbous nasal tip, broad nasal bridge, downslanting palpebral fissures and low set ears) and skeletal (post-axial polydactyly and fusion of vertebrae) malformations along with severe intellectual disability, deafness and congenital heart defects.", "ORPHA ID": 141000, "Summary": ""}
{"Disease Name": "Orofaciodigital syndrome type 14", "Disease Definition": "Orofaciodigital syndrome type 14 is a rare subtype of orofaciodigital syndrome, with autosomal recessive inheritance and C2CD3 mutations, characterized by severe microcephaly, trigonocephaly, severe intellectual disability and micropenis, in addition to oral, facial and digital malformations (gingival frenulae, lingual hamartomas, cleft/lobulated tongue, cleft palate, telecanthus, up-slanting palpebral fissures, microretrognathia, postaxial polydactyly of hands and duplication of hallux). Corpus callosum agenesis and vermis hypoplasia with molar tooth sign, on brain imaging, are also associated.", "ORPHA ID": 434179, "Summary": ""}
{"Disease Name": "Orofaciodigital syndrome type 2", "Disease Definition": "Oral-facial-digital (OFD) type 2 is characterized by hand and feet deformities, facial deformities, midline cleft of the upper lip and tongue hamartomas.", "ORPHA ID": 2751, "Summary": "Epidemiology\nLess than 20 cases have been reported so far.\nClinical description\nMain clinical features include bilateral preaxial polydactyly of hands and feet, partial duplication of hallux, brachydactyly, syndactyly, scoliosis, pectus excavatums, short stature, muscular hypotonia, conductive hearing loss. Facial dysmorphism may include midface hypoplasia, hypertelorism, antimongoloid slant, broad nasal root, bifid nasal tip, cleft palate, microglossia, lobulated tongue, thick frenulum and low set ears. Microcephaly, porencephaly and internal hydrocephalus are also observed. Intelligence is normal in the majority of cases. Intellectual deficit and increased susceptibility to respiratory infections have been described in some patients. Involvement of the central nervous system (cerebellar atrophy) seems to be a clinical feature of OFD2.\nEtiology\nThe causative gene has not yet been identified.\nGenetic counseling\nAutosomal recessive inheritance has been suggested.\n\n                            Last update: \n                            November 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Orofaciodigital syndrome type 4", "Disease Definition": "Oral-facial-digital syndrome, type 4 is characterized by lingual hamartoma, postaxial polysyndactyly of hands and feet, and mesomelic shortening of the legs with supinate equinovarus feet.", "ORPHA ID": 2753, "Summary": "Epidemiology\nApproximately 15 cases have been reported so far.\nClinical description\nAdditional features include hypoplastic mandible, micrognathia, cleft palate, prominent eyes, low-set ears and normal intelligence.\nEtiology\nThe causative gene has not yet been identified.\nGenetic counseling\nAutosomal recessive inheritance has been suggested.\n\n                            Last update: \n                            November 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Orofaciodigital syndrome type 5", "Disease Definition": "A rare orofaciodigital syndrome characterized by median cleft of the upper lip, postaxial polydactyly of hands and feet, and oral manifestations (duplicated frenulum).", "ORPHA ID": 2919, "Summary": ""}
{"Disease Name": "Orofaciodigital syndrome type 6", "Disease Definition": "Joubert syndrome with orofaciodigital defect (or oral-facial-digital syndrome type 6, OFD6) is a very rare subtype of Joubert syndrome and related disorders (JSRD, see this term) characterized by the neurological features of JS associated with orofacial anomalies and often polydactyly.", "ORPHA ID": 2754, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nTypical oral findings include bifid or lobulated tongue, lingual hamartomas and multiple oral frenulae, but cleft lip and/or palate can also be present. Polydactyly is typically mesaxial with Y-shaped metacarpals, but can also be preaxial or postaxial. A subset of patients present with hypothalamic hamartoma that has never been reported in other JSRD subgroups.\nEtiology\nTwo OFD6 patients, including one fetus, were found to carry a homozygous mutation in the TMEM216 gene (11q13.1), but mutations in this gene were excluded in several other patients, and the genetic basis of this condition still remains elusive.\nGenetic counseling\nMales and females are equally affected and an autosomal recessive pattern of inheritance was observed in familial cases.\n\n                            Last update: \n                            July 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE"}
{"Disease Name": "Orofaciodigital syndrome type 8", "Disease Definition": "Oral-facial-digital syndrome, type 8 is characterized by tongue lobulation, hypoplasia of the epiglottis, median cleft upper lip, broad or bifid nasal tip, hypertelorism or telecanthus, bilateral preaxial and postaxial polydactyly, abnormal tibiae and/or radii, duplication of the halluces, short stature, and mild intellectual deficit.", "ORPHA ID": 2755, "Summary": "Epidemiology\nThe syndrome has been described in one family with four affected males in three generations.\nClinical description\nIncreased susceptibility to respiratory infections has been noted.\nEtiology\nX-linked recessive transmission has been suggested, but the causative gene has not yet been identified.\n\n                            Last update: \n                            November 2009"}
{"Disease Name": "Orofaciodigital syndrome type 9", "Disease Definition": "Oral-facial-digital syndrome, type 9 is characterized by highly arched palate with bifid tongue and bilateral supernumerary lower canines, hamartomatous tongue, multiple frenula, hypertelorism, telecanthus, strabismus, broad and/or bifid nasal tip, short stature, bifid halluces, forked metatarsal, poly- and syndactyly, mild intellectual deficit and specific retinal abnormalities (bilateral optic disc coloboma and retinal dysplasia with partial detachment).", "ORPHA ID": 141007, "Summary": "Epidemiology\nLess than ten cases have been described in the literature.\nClinical description\nRecurrent aspiration pneumonia and severe microcephaly have been reported occasionally.\nEtiology\nThe causative gene has not yet been identified.\nGenetic counseling\nAutosomal and X-linked recessive inheritance were initially suggested. Taking into consideration all reported cases so far, autosomal recessive inheritance seems most likely.\n\n                            Last update: \n                            November 2009"}
{"Disease Name": "Oromandibular dystonia", "Disease Definition": "A form of focal dystonia, affecting the lower part of the face and jaws. It is characterized by sustained or repetitive involuntary jaw and tongue movements and facial grimacing caused by involuntary spasms of the masticatory, facial, pharyngeal, lingual, and lip muscles.", "ORPHA ID": 93958, "Summary": ""}
{"Disease Name": "Oromandibular-limb hypogenesis syndrome", "Disease Definition": "Oromandibular-limb hypogenesis syndromes (OLHS) are a group of dysmorphic complexes (including Charlie M syndrome, Hanhart syndrome and glossopalatine ankylosis; see these terms) characterized by the association of severe asymmetric limb defects (primarily involving distal segments) and abnormalities of the oral cavity and mandible (hypoglossia, aglossia, micrognathia, glossopalatine ankylosis, cleft palate, and gingival anomalies).", "ORPHA ID": 2749, "Summary": "Epidemiology\nPrevalence is estimated at 1:500,000.\nClinical description\nThe clinical features are evident at birth. Intelligence is normal.\nEtiology\nEtiology remains unknown.\n\n                            Last update: \n                            September 2009"}
{"Disease Name": "Osgood-Schlatter disease", "Disease Definition": "Osgood-Schlatter disease is a traction apophysitis of the anterior tibial tubercle described in active adolescents and characterized by gradual onset of pain and swelling of the anterior knee causing limping that usually disappears at the end of growth.", "ORPHA ID": 97335, "Summary": ""}
{"Disease Name": "OSLAM syndrome", "Disease Definition": "A rare genetic disease characterized by the association of osteosarcoma with limb anomalies (such as bilateral radioulnar synostosis and clinodactyly, as well as other abnormalities of the hands and feet) and erythroid macrocytosis without anemia. There have been no further descriptions in the literature since 1977.", "ORPHA ID": 2760, "Summary": ""}
{"Disease Name": "Ossification anomalies-psychomotor developmental delay syndrome", "Disease Definition": "A rare primary bone dysplasia characterized by global developmental delay, hypotonia, ossification anomalies of the cranial vault, abnormalities of the long bones due to defective remodeling, thoracic deformity, and progressive osteopenia. Dysmorphic craniofacial features include microcephaly, hypertelorism, narrow mouth, cleft palate, and micrognathia.", "ORPHA ID": 73230, "Summary": ""}
{"Disease Name": "Osteoblastoma", "Disease Definition": "A rare, neoplastic disease characterized by a typically benign, locally aggressive, non self-limiting, osteoblastic bone tumor, usually located on the spine, proximal humerus and hip (although any bone may be involved), generally manifesting with slowly progressive, dull aching pain which is difficult to localize and is not relieved by nonsteroidal anti-inflammatory drugs or aspirin. Neurologic symptoms, such as cranial nerve palsies, myelopathy, neuralgia, radiculopathy, paraparesis or paraplegia, may be associated if the spine is involved. Imaging reveals a lytic (or mixed lytic and blastic) lesion with a radiolucent nidus (> 2 cm) associated with reactive sclerotic bone.", "ORPHA ID": 58040, "Summary": ""}
{"Disease Name": "Osteochondritis dissecans", "Disease Definition": "Osteochondritis dissecans (OCD) is a rare bone disease characterized by an acquired idiopathic necrotic lesion of subchondral bone with the formation of a sequestrum, which may detach to form loose bodies in joints. OCD mainly affects the knee, ankle and elbow joints and can lead to pain, functional limitations and secondary osteoarthritis.", "ORPHA ID": 2764, "Summary": ""}
{"Disease Name": "Osteochondrosis of the metatarsal bone", "Disease Definition": "A rare bone disease characterized by avascular necrosis of a metatarsal head, most commonly involving the second, but also the third or fourth, metatarsal. Patients may present with pain on weight-bearing, swelling, and tenderness. Radiological features include widening of the metatarsophalangeal joint space and flattening of the affected metatarsal head, at later stages metatarsal head sclerosis, cortical thickening, and intra-articular loose bodies. The condition can be bilateral in some cases and shows a significant predilection for females in the second or third decade of life.", "ORPHA ID": 564003, "Summary": ""}
{"Disease Name": "Osteochondrosis of the tarsal bone", "Disease Definition": "A rare bone disease characterized by avascular necrosis of the navicular bone in children. Patients present with sudden unexplained foot pain, inability to bear weight, and limping. Radiographic features include flattening, fragmentation, and patchy sclerosis of the navicular bone. Soft tissue swelling may be associated. The condition is most commonly unilateral and self-limiting. Boys are more often affected than girls.", "ORPHA ID": 563991, "Summary": ""}
{"Disease Name": "Osteocraniostenosis", "Disease Definition": "Osteocraniostenosis is a lethal skeletal dysplasia characterized by a cloverleaf skull anomaly, facial dysmorphism, limb shortness, splenic hypo/aplasia and radiological anomalies including thin tubular bones with flared metaphyses and deficient calvarial mineralization.", "ORPHA ID": 2763, "Summary": "Epidemiology\nFirst described in 1989, less than 30 cases have been reported so far.\nClinical description\n'This multiple congenital anomalies syndrome is characterized by dysmorphic features of the fetus and the newborn: the skull is misshapen, combining acrocephaly and cloverleaf deformity, fontanelles are very large; facial dysmorphism includes midface hypoplasia with telecanthus, short upturned nose, short philtrum, small inverted V-shaped mouth and low-set ears; limbs are also affected with bowed forearms, micromelia and acromicria with brachydactyly.'\nEtiology\nEtiology of osteocraniostenosis is not well known, but some histological findings report growth plate disorganization and adjacent diaphyseal ossification. Recently, heterozygous mutations of the FAM111A gene, encoding a protein of unknown function and responsible of some autosomal dominant forms of Kenny-Caffey syndrome (see this term) with hypothyroidism and slender and dense bone, have been identified in patients with osteocraniostenosis. A clinical and genetic heterogeneity remains likely.\nDiagnostic methods\nDiagnosis is based mainly on radiological and pathological examination. Radiological examination reveals hypomineralisation of the skull, flat and dense vertebral bodies, thin tubular bones with flared and dense metaphyses, brachymetacarpia and brachyphalangy with ''diabolo appearance'' (very thin tubular bones with abrupt metaphyseal flare) and lack of ossification of the distal phalanges. The spleen is hypoplasic or even absent. Diaphyseal fractures are frequent at birth.\nDifferential diagnosis\nDifferential diagnosis includes the hypo/akinesia sequence, Hallermann-Streiff-FranÁois syndrome, Kenny-Caffey syndrome and other slender bone dysplasias, and some cases of osteogenesis imperfecta with slender bones (see these terms).\nAntenatal diagnosis\nPrenatal ultrasound observation reveals micromelic dwarfism, cranial deformity, mild intra-uterine growth retardation and sometimes fractures.\nGenetic counseling\nCases with FAM111A gene mutations show an autosomal dominant mode of inheritance with a majority of de novo mutations.\nManagement and treatment\nThere is no treatment for osteocraniostenosis.\nPrognosis\nPrognosis is very poor as most cases are stillborn or die in their first days of life.\n\n                            Last update: \n                            May 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Osteofibrous dysplasia", "Disease Definition": "Osteofibrous dysplasia is a rare, genetic primary bone dysplasia characterized by the presence of a benign, fibro-osseous, osteolytic tumor typically located in the tibia (occasionally the fibula, or both) and usually involving the anterior diaphyseal cortex with adjacent cortical expansion. It may on occasion be asymptomatic or may present with a palpable mass, pain, tenderness and/or anterior bowing of the tibia.", "ORPHA ID": 488265, "Summary": ""}
{"Disease Name": "Osteogenesis imperfecta type 1", "Disease Definition": "A mild form of osteogenesis imperfecta (OI) characterized by increased bone fragility and low bone mass that clinically manifests with increased susceptibility to bone fractures (including vertebral crush fractures), normal height or short stature (typically between 0 and -2.0 SD scores), mild (Cobb angle <30 degrees) or no scoliosis, blue sclera, and in dentinogenesis imperfecta, and mild long bone bowing bone deformities.", "ORPHA ID": 216796, "Summary": ""}
{"Disease Name": "Osteogenesis imperfecta type 2", "Disease Definition": "A lethal type of osteogenesis imperfecta (OI) characterized by increased bone fragility, low bone mass and susceptibility to bone fractures and presenting with multiple rib and long bone fractures at birth, marked deformities, broad long bones, low density skull on X-ray, and dark sclera.", "ORPHA ID": 216804, "Summary": "Epidemiology\nThe overall prevalence of OI is estimated at between 1/10,000 and 1/20,000 but the prevalence of type II is unknown.\nClinical description\nThere are three subtypes of OI type II (A, B and C) that are characterized by different radiological features. Patients with OI type IIA present with broad ribs with multiple fractures, continuous beaded ribs and severe under-modeling of the femur. OI type IIB presents with normal or thin ribs with some fractures, discontinuous beaded ribs and some under-modeling of the femur. OI type IIC presents with varying thickness of the ribs, discontinuous beading of the ribs, malformed scapulae and ischiae, and long bones with thin shafts and expanded metaphyses. Type IIC is extremely rare and its existence is even doubted.\nEtiology\nVariants in the COL1A1 and COL1A2 genes (17q21.31-q22 and 7q22.1 respectively) cause OI type IIA and IIB, and transmission is autosomal dominant. Type IIB can also be autosomal recessive, caused by mutations in the CRTAP gene (3p22; sometimes described as OI type VII) or the P3H1 gene (1p34; sometimes described as OI type VIII) or the PPIB gene (15q21-q22; sometimes described as OI type IX). OI type IIC appearances have been reported in fetuses with mutations in the MESD gene (15q25).\nDiagnostic methods\nDiagnosis is typically prenatal due to suspicious ultrasound findings.\nDifferential diagnosis\nDifferential diagnosis includes thanatophoric dwarfism, severe hypophosphatasia, and mucolipidosis type II.\nAntenatal diagnosis\nPrenatal diagnosis of type II OI may be suggested by fetal ultrasound appearances, and confirmed by genetic testing of amniocytes.\nGenetic counseling\nThe disease is either autosomal dominant or autosomal recessive depending on the gene involved. Autosomal dominant cases occur either sporadically or due to germline mosaicism. The appropriate genetic counseling should be offered to affected families.\nManagement and treatment\nManagement is initially expectant; some infants with apparently very severe changes on ultrasound may nevertheless survive with intensive support and early institution of bone-directed therapy such as bisphosphonates.\nPrognosis\nThe majority of those identified of having type II changes antenatally will die either before birth or in the perinatal period. A few may survive with continued intensive treatment.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Nick BISHOP"}
{"Disease Name": "Osteogenesis imperfecta type 3", "Disease Definition": "A severe type form osteogenesis imperfecta characterized by increased bone fragility and low bone mass clinically manifesting as susceptibility to bone fractures, severe short stature, a triangular face, moderate to severe scoliosis, blue or blue-grey sclera, and dentinogenesis imperfecta.", "ORPHA ID": 216812, "Summary": ""}
{"Disease Name": "Osteogenesis imperfecta type 4", "Disease Definition": "A moderately severe form of osteogenesis imperfecta characterized by increased bone fragility and low bone mass that clinically manifests from infancy as susceptibility to bone fractures, short stature, mild to moderate scoliosis in most, gray-blue or white sclera, and dentinogenesis imperfecta.", "ORPHA ID": 216820, "Summary": ""}
{"Disease Name": "Osteogenesis imperfecta type 5", "Disease Definition": "A moderate form of osteogenesis imperfecta characterized by increased bone fragility and low bone mass that clinically manifests with susceptibility to bone fractures of variable severity, metaphyseal changes at birth, short stature, dislocation of the radial head, mineralized interosseous membranes, hyperplasic callus (occurring more often during periods of more rapid growth), white sclera and absence of dentinogenesis imperfecta.", "ORPHA ID": 216828, "Summary": ""}
{"Disease Name": "Osteogenesis imperfecta-retinopathy-seizures-intellectual disability syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by severe global developmental delay, osteogenesis imperfecta, presence of wormian bones, seizures, ocular abnormalities (blue sclerae, optic atrophy, retinal detachment), and dysmorphic facial features (including frontal bossing, low anterior hairline, medial flare of the eyebrows, long eyelashes, hypertelorism, depressed nasal bridge, and low-set, large ears). There have been no further descriptions in the literature since 1994.", "ORPHA ID": 2773, "Summary": ""}
{"Disease Name": "Osteogenesis imperfecta", "Disease Definition": "A rare, genetic, primary bone dysplasias characterized by increased bone fragility, low bone mass, and susceptibility to bone fractures. The clinical severity is heterogeneous.", "ORPHA ID": 666, "Summary": "Epidemiology\nPrevalence is estimated at between 1/10,000 and 1/20,000.\nClinical description\nAge at diagnosis depends on the severity of the disease. Five clinically distinct types of osteogenesis imperfecta (OI) have been identified. The most clinically relevant characteristic of all types of OI is bone fragility, which manifests as multiple spontaneous fractures. Type I is mild and nondeforming with normal height or short stature, blue sclera, and no dentinogenesis imperfecta (DI). Patients with type II present multiple rib and long bone fractures at birth, marked deformities, broad long bones, low density on skull X-rays, and dark sclera. These patients die at birth, or shortly after. Type III is severe and the main signs include severe short stature, a triangular face, severe scoliosis, grayish sclera, and DI. Type IV and 5 are moderate or severe forms. Patients with type IV have moderate short stature, variable severity of scoliosis, grayish or white sclera, and some have DI. Type V is characterized by mild to moderate short stature, metaphyseal dysplasia at birth, dislocation of the radial head, mineralized interosseous membranes of the forearm and lower leg, hyperplastic callus (particularly when growth is more rapid e.g. during infancy or puberty), white sclera, and no DI. They have variable severity of scoliosis.\nEtiology\nIn approximately 90% of cases, OI is caused by monoallelic variants in the COL1A1 and COL1A2 genes (17q21.33 and 7q21.3) encoding the alpha1 and alpha2 chains of type 1 collagen. These variants can cause types I-IV of OI. In Type V, the variant is in the promoter region of the IFITM5 gene (11p15.5). Over 15 causal genes have been identified and some geno-phenotypes are emerging: in children with BMP1 variants, high bone mass can be observed. Children with homozygous WNT1 variants have ptosis and neurodevelopmental delay; and craniosynostosis defects are associated with P4HB or SEC24D variants.\nDiagnostic methods\nDiagnosis is based on skeletal and extra-skeletal clinical findings. Radiological studies reveal osteoporosis and the presence of Wormian bones. Bone densitometry confirms the low bone mass.\nDifferential diagnosis\nDifferential diagnoses include in utero diagnosis of chondrodysplasia, idiopathic juvenile osteoporosis, osteoporosis-pseudoglioma syndrome, Cole-Carpenter and Bruck syndromes, hyper or hypophosphatasia, panostotic form of polyostotic fibrous dysplasia, non-accidental injury (multiple fractures without osteoporosis), and osteoporosis due to medication, nutritional deficiency, metabolic disease, or leukemia.\nAntenatal diagnosis\nAntenatal diagnosis may be suspected through ultrasonography and/or confirmed through molecular analysis of amniocytes or chorionic villus cells if the causative mutation in the family has been identified.\nGenetic counseling\nTransmission is autosomal dominant for both Type I Collagen and IFITM5 variants. Autosomal recessive forms are also observed and are caused by variants in at least 15 other genes, and are typically severe; however, variability in severity has been noted especially for Type VI due to SERPINF1 variants; and for OI due to BMP1 or PPIB variants. Transmission is X-linked for MBTPS2 variants. Genetic counselling is recommended for affected families.\nManagement and treatment\nManagement should be multidisciplinary involving experienced medical, orthopedic, physiotherapy and rehabilitation specialists. Bisphosphonates with potent antiresorptive properties are now considered as the standard of care for severe forms but do not constitute a cure. Prevention of vitamin D and calcium deficiency is essential throughout life. Surgical management is essential for the correction of bone and spinal deformities and the prevention of long bone fractures (insertion of intramedullary rods in long bones; spinal rods when growth is complete, or nearly complete). Early physiotherapy may improve autonomy by helping to evaluate any motor deficits, reducing the risk of falls and encouraging patients to take up a sporting activity. Occupational therapy and attendance to fine motor activities has strong relevance for school performance. Many families need psychological and social care support.\nPrognosis\nFunctional prognosis depends on the severity of the disease and on the quality of management. Vital prognosis depends on the severity of any respiratory complications associated with spinal deformities.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Nick BISHOP"}
{"Disease Name": "Osteoglosphonic dysplasia", "Disease Definition": "A rare disorder characterized by dwarfism, severe craniofacial abnormalities and multiple unerupted teeth.", "ORPHA ID": 2645, "Summary": "Epidemiology\nLess than ten cases have been reported so far.\nClinical description\nMain clinical features include craniosynostosis, acrocephaly, a prominent forehead, depressed nasal bridge, hypertelorism, midface hypoplasia, macroglossia, unerupted teeth, short neck, short and bowed limbs, short and broad hands and fingers, and flat feet. The main radiographic features are craniostenosis, fibrous dysplasia, metaphyseal lucencies and platyspondyly. Intelligence is usually normal.\nEtiology\nOsteoglosphonic dysplasia (OGD) is caused by mutations in the FGFR1 gene (8p11.2-p11.1).\nGenetic counseling\nOGD is transmitted in an autosomal dominant manner.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Osteomesopyknosis", "Disease Definition": "Osteomesopyknosis is a very rare benign bone disorder characterized by bone dysplasia manifested by patchy sclerosis of the axial skeleton and increased bone mineral content.", "ORPHA ID": 2777, "Summary": "Epidemiology\nThe prevalence and incidence of this disorder are not known. It has been reported in fewer than 5 families, primarily in France.\nClinical description\nOsteomesopyknosis may be underdiagnosed due to confusion with autosomal dominant osteopetrosis (Albers-Schönberg osteopetrosis, see this term). The condition is usually found incidentally on radiological examination and is very mild, sometimes accompanied by pain. Increased density of the vertebral plates, pelvis and occasionally of the upper femur have been reported, as well as kyphoscoliosis and femoral cysts.\nEtiology\nThe genetic basis underlying the disorder is not known.\nGenetic counseling\nThe disorder appears to follow an autosomal dominant pattern of inheritance.\n\n                            Last update: \n                            June 2012"}
{"Disease Name": "Osteonecrosis of the jaw", "Disease Definition": "A rare osteonecrosis characterized by an exposed necrotic lesion in the mandible or maxilla present for more than eight weeks, arising as a complication of antiresorptive medication, dental interventions, or trauma and infections. Patients may present with pain, altered neurosensory functions, secondary infections, and (in advanced stages) pathological fractures, or fistulae.", "ORPHA ID": 399293, "Summary": ""}
{"Disease Name": "Osteopathia striata-cranial sclerosis syndrome", "Disease Definition": "Osteopathia striata with cranial sclerosis (OS-CS) is a bone dysplasia characterized by longitudinal striations of the metaphyses of the long bones, sclerosis of the craniofacial bones, macrocephaly, cleft palate and hearing loss.", "ORPHA ID": 2780, "Summary": "Epidemiology\nFewer than 100 cases have been reported in the literature.\nClinical description\nThe clinical presentation is highly variable even within the same family, ranging from mild skeletal manifestations to multisystem organ involvement. Cardiac malformations (ventricular septal defect, aortic stenosis), developmental delay, cranial nerve palsies, anal malformations, cataracts and nervous system malformations are frequent. Vertebral anomalies (scoliosis, spondylolisthesis), anomalies of extremities (clubfoot, unusually long and thin fingers with clinodactyly of distal phalanges), hypertelorism, frontal bossing, broad nasal bridge, prominent occipital bony protrusion and mild intellectual impairment have also been documented. In rare cases, OS-CS has been reported in association with Hirschsprung disease, Pierre Robin sequence, coronal craniostenosis, hydrocephalus and laryngotracheomalacia (see these terms).\nEtiology\nOS-CS is associated with mutations in the Wilms tumour gene on the X chromosome (WTX), a repressor of WNT signaling (beta-catenin pathway implicated in control of target genes in the nucleus).\nDiagnostic methods\nDiagnosis is based on clinical and radiological examination, which reveals cranial sclerosis, longitudinal striations in the widened metaphyses of the long bones, and sclerosis of the ribs. Genetic testing is available to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes a large number of conditions with primary or secondary bone sclerosis. As the macrocephaly seems to be an early and constant clinical feature, OS-CS should be considered in the differential diagnosis of fetuses/infants with unexplained macrocephaly.\nAntenatal diagnosis\nIn the most severe cases, the disorder can be diagnosed prenatally by detection of increased biparietal diameter of the fetal head on ultrasound examination. Prenatal genetic diagnosis is available if the disease-causing mutation in the family is known.\nGenetic counseling\nOS-CS follows an X-linked dominant pattern of inheritance, with frequent lethality in males.\nManagement and treatment\nManagement is supportive and aims at providing multidisciplinary surveillance and symptomatic management of complications.\nPrognosis\nCases with severe multiple manifestations and those associated with Hirschsprung disease, Pierre Robin sequence and coronal craniostenosis have poor prognosis.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Ravi SAVARIRAYAN  - Dr Zornitza STARK"}
{"Disease Name": "Osteopathia striata-pigmentary dermopathy-white forelock syndrome", "Disease Definition": "A rare primary bone dysplasia characterized by the association of osteopathia striata (longitudinal striations through most of the long bones) with a macular, hyperpigmented dermopathy and a white forelock.", "ORPHA ID": 2779, "Summary": ""}
{"Disease Name": "Osteopenia-intellectual disability-sparse hair syndrome", "Disease Definition": "A rare syndrome characterized by sparse hair, osteopenia, intellectual disability, minor facial abnormalities, joint laxity and hypotonia. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 2324, "Summary": ""}
{"Disease Name": "Osteopetrosis and related disorders", "Disease Definition": "Osteopetrosis, also known as marble bone disease, is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs.", "ORPHA ID": 2781, "Summary": "Epidemiology\nThe overall prevalence and incidence of these conditions is difficult to estimate but autosomal recessive malignant osteopetrosis (ARO; see this term) has an incidence of 1/ 250,000 births, and autosomal dominant osteopetrosis (ADO or Albers-Schönberg osteopetrosis; see this term) has an incidence of 1 in 20,000 births.\nClinical description\nOsteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or ''malignant'' ARO; see this term), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis; see this term). Classic ARO is characterized by fractures, short stature, compressive neuropathies, hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. The presence of primary neurodegeneration, intellectual deficit, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO.\nEtiology\nOsteopetrosis is caused by failure of osteoclast development or function, and mutations in at least ten genes have been identified as causative in humans, accounting for 70% of all cases.\nDiagnostic methods\nDiagnosis is largely based on clinical and radiographic evaluation and should be confirmed by gene testing where applicable. Once the diagnosis of a primary osteopetrotic condition is made, it is important to distinguish between different subtypes. Correct diagnosis is essential for predicting and understanding the natural history of the disease, providing specific treatments where available, and offering adapted counseling regarding recurrence risks and prenatal diagnosis for severe forms.\nDifferential diagnosis\nAlternative diagnoses include fluorosis; beryllium, lead and bismuth poisoning; myelofibrosis; Paget's disease (sclerosing form); and malignancies (lymphoma, osteoblastic cancer metastases) (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible if the mutations causing the condition in the family are known.\nGenetic counseling\nThese conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive.\nManagement and treatment\nTreatment of osteopetrotic conditions is largely symptomatic, although hematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure, and currently offers the best chance of longer-term survival for patients in this group.\nPrognosis\nThe severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a consequence of bone marrow suppression. Life expectancy in the adult-onset forms is normal.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Ravi SAVARIRAYAN  - Dr Zornitza STARK"}
{"Disease Name": "Osteopetrosis with renal tubular acidosis", "Disease Definition": "Osteopetrosis with renal tubular acidosis is a rare disorder characterized by osteopetrosis (see this term), renal tubular acidosis (RTA), and neurological disorders related to cerebral calcifications.", "ORPHA ID": 2785, "Summary": "Epidemiology\nPrevalence of this disorder is not known. Fewer than 100 cases have been reported to date. Many reports involved families of North African and Middle Eastern descent, but cases have been documented worldwide.\nClinical description\nPatients present a triad of mild osteopetrosis, mixed proximal and distal RTA, and intracerebral calcifications. Other clinical manifestations include fractures, growth failure and short stature, developmental delay, intellectual deficit, dental malocclusions/malalignment, cranial nerve compression and hearing impairment.\nEtiology\nOsteopetrosis with renal tubular acidosis is caused by mutations in the CA2 gene (8q22) encoding carbonic anhydrase II.\nDiagnostic methods\nDiagnosis is based on radiological findings in the presence of acidosis and intracerebral calcifications, and can be confirmed by molecular genetic testing.\nAntenatal diagnosis\nAntenatal diagnosis is possible if the mutation(s) causing the condition in the family are known.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment is symptomatic. Referral to a renal physician to manage the acidosis is recommended.\nPrognosis\nSeverity is variable but the disorder has a milder course than in patients with classic osteopetrosis.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Ravi SAVARIRAYAN  - Dr Zornitza STARK"}
{"Disease Name": "Osteopetrosis-hypogammaglobulinemia syndrome", "Disease Definition": "Osteopetrosis-hypogammaglobulinemia syndrome is an extremely rare primary bone dysplasia with increased bone density disorder characterized by severe osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Patients typically present infantile malignant osteopetrosis (manifesting with increased bone density, bone fractures, abnormal eye movements/visual loss, nystagmus), hematologic abnormalities with bone marrow failure (e.g. anemia, hepatosplenomegaly) and immunological deficiency (manifesting as recurrent respiratory infections) associated with reduced immunoglobulin levels due to impaired peripheral B cell differentiation.", "ORPHA ID": 178389, "Summary": ""}
{"Disease Name": "Osteoporosis-oculocutaneous hypopigmentation syndrome", "Disease Definition": "A rare genetic disease characterized by congenital oculocutaneous hypopigmentation, visual impairment, generalized osteoporosis with skeletal anomalies such as short stature, short neck and trunk, kyphosis, scoliosis, and platyspondyly, and dysmorphic facial features (including long philtrum, small mouth, micrognathia, and prominent ears). Moderate joint hyperelasticity and muscular hypotrophy have also been reported.", "ORPHA ID": 2786, "Summary": ""}
{"Disease Name": "Osteoporosis-pseudoglioma syndrome", "Disease Definition": "A rare bone disease characterized by congenital or infancy-onset blindness and juvenile-onset osteoporosis with spontaneous and low trauma fractures.", "ORPHA ID": 2788, "Summary": "Epidemiology\nThe estimated prevalence is 1/2,000,000 but is higher in some founder populations (eg. Old Order Mennonites in Pennsylvania; 1.4/1000). Less than 100 cases have been reported.\nClinical description\nOsteoporosis-pseudoglioma (OPPG) syndrome patients have reduced bone formation and poor bone quality. Fractures typically occur in both long bones and vertebrae, after age 2 until puberty. Some patients have eye pain severe enough to require enucleation. Additional clinical manifestations may include microphthalmos, cataracts, persistence of fetal fibrovascular system and absent retinal development, vitreoretinal dysplasia, pseudogliomatous retinal detachments and phthisis bulbi, short stature, microcephaly, ligamental laxity, and hypotonia. Cognitive difficulty and behavioral issues have been reported but most patients have neither.\nEtiology\nThe disease is caused by biallelic mutations in the low-density lipoprotein receptor related protein 5 gene (LRP5). The severity of the osteoporosis varies by mutation but most patients have complete blindness by early infancy. With less severe mutations, some vision may persist into childhood. Heterozygotes may have reduced bone density or osteoporosis but have normal vision.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation (typically congenital blindness and white pupils) and confirmed by genetic testing. Fragility fractures are generally not diagnosed < age 2 and normative bone density data are not available for children < age 3, so fragility fractures and osteoporosis by bone density are not required for diagnosis.\nDifferential diagnosis\nOsteogenesis imperfecta is the primary differential diagnosis for osteoporosis. Familial exudative vitreoretinopathy and Norrie disease are the differential diagnoses for congenital blindness and pseudoglioma.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic LRP5 variant has been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation). Heterozygote carriers have normal vision but may have low bone mass or osteoporosis.\nManagement and treatment\nExamination by an ophthalmologist is recommended as soon as possible. In rare patients who have retained light perception at birth, laser therapy (for retinal detachment) may be successful in maintaining some vision, at least temporarily. For osteoporosis, intravenous (pamidronate) and oral (alendronate) bisphosphonates have been used successfully to increase bone density and appear to reduce fracture risk. However, due to the rarity of OPPG, no placebo-controlled trial has been reported. Maintenance of vitamin D sufficiency is important. Age of initiation and duration of treatment need to be individualized. Treatment can be delayed until after age 3 since fractures typically do not occur prior to age 2. Treatment can generally be stopped at puberty when fracture risk decreases. In patients treated from childhood until puberty, it is possible that treatment may need to be restarted when bone aging starts (after menopause in women and after 50 in men). Anabolic bone agents are contraindicated in children, but teriparatide has been reported to be successful in an adult and an adolescent with OPPG. As in other forms of juvenile osteoporosis, leg bowing may occur in childhood and may require surgical management.\nPrognosis\nBesides blindness and osteoporosis there are no other chronic medical problems that have definitively been associated with OPPG. There is no known impact on life expectancy. With appropriate osteoporosis treatment, ambulation is maintained in most patients. Chronic pain due to compression fractures of the spine can occur. Morbidity in most patients is due to blindness, which is complete (no light perception) in most. There have been no quality of life studies reported in OPPG.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Elizabeth STREETEN"}
{"Disease Name": "Osteoradionecrosis of the mandible", "Disease Definition": "A rare radiation-induced disorder characterized by exposed irradiated bone that fails to heal over a period of three months without evidence of persisting or recurrent tumor. Patients present with pain, dysesthesia, dysgeusia, fetor oris, trismus, ulceration or necrosis of the mucosa with exposure of necrotic bone, and local suppuration. Complications include pathological fractures, formation of intra- or extra-oral fistulae, and infection. MRI shows cortical destruction, abnormal bone marrow signal, and irregular contrast enhancement.", "ORPHA ID": 521127, "Summary": ""}
{"Disease Name": "Osteosarcoma", "Disease Definition": "Osteosarcoma is a primary malignant tumour of the skeleton characterised by the direct formation of immature bone or osteoid tissue by the tumour cells.", "ORPHA ID": 668, "Summary": "Epidemiology\nClassic osteosarcoma is a rare (0.2% of all malignant tumours) highly malignant tumour, with an estimated incidence of 3 cases/million population/year.\nClinical description\nOsteosarcoma arises predominantly in the long bones and rarely in the soft tissues. The age at presentation ranges from 10 to 25 years of age.\nDiagnostic methods\nPlain radiographs, computed tomography, magnetic resonance imaging, angiography and dynamic bone scintigraphy are used for diagnosis, evaluation the extent of tumour involvement and for making decisions about the type of operation and, if necessary, the type of reconstruction required.\nManagement and treatment\nIn the past, all patients with osteosarcoma were treated by amputation but the cure rate was under 10% and almost all patients died within a year from diagnosis. At present, the percentage of patients cured varies between 60% and 70% for localised osteosarcoma at onset (80% of cases) treated in specialised bone tumour centres with pre- and postoperative chemotherapy associated with surgery. Surgery is conservative (limb salvage) in more than 90% of patients.\nPrognosis\nPrognosis is more severe (cure rate about 30%) for tumours located in the axial skeleton and in patients with metastasis at onset.\n\n                            Last update: \n                            January 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Piero PICCI"}
{"Disease Name": "Osteosclerosis-developmental delay-craniosynostosis syndrome", "Disease Definition": "This newly described syndrome is characterized by osteosclerosis, developmental delay and craniosynostosis (see this term).", "ORPHA ID": 178377, "Summary": "Epidemiology\nIt has been reported in 13 patients from a four-generation family.\nClinical description\nOsteosclerosis was constant and most pronounced in the cranial base and calvarium. Craniosynostosis was reported in four patients and a mild developmental delay in three patients. Dysmorphic features were constant and included macrocephaly, brachycephaly, wide and high forehead, hypertelorism, prominent cheekbones and prominent jaw.\nEtiology\nA missense mutation A214T in the low-density lipoprotein receptor related protein 5 gene, LRP5, was found in all analyzed affected individuals. In this family, findings are consistent with autosomal dominant inheritance.\n\n                            Last update: \n                            November 2010"}
{"Disease Name": "Osteosclerosis-ichthyosis-premature ovarian failure syndrome", "Disease Definition": "A rare genetic disease characterized by sclerosing dysplasia affecting the diaphyseal and metaphyseal regions of the long bones, as well as the skull and metacarpals, in association with skin changes like those seen in ichthyosis vulgaris and premature ovarian failure with bilateral hypoplasia of the ovaries. Patients present in adulthood, primarily with swelling of the extremities and occasional mild pain in the legs.", "ORPHA ID": 75325, "Summary": ""}
{"Disease Name": "Osteosclerotic bone dysplasia", "Disease Definition": "A rare disorder defined by generalized osteosclerosis with periosteal bone formation, characteristic facial dysmorphism, brain abnormalities including intracerebral calcifications, and neonatal lethal course.", "ORPHA ID": 1832, "Summary": "Epidemiology\nTen cases in eight families have been reported, the majority of a Middle East origin. Parental consanguinity was frequently present.\nClinical description\nThe cranial features are a wide anterior fontanelle, expressed proptosis with everted lower eyelids, severely depressed nasal bridge, small nose, low-set ears, and severe midface hypoplasia leading to choanal atresia. The mouth is usually triangular, gum hypertrophy is expressed, and there may be natal teeth and cleft palate/uvula. The radiological findings include generalized osteosclerosis of all bones and the base of the skull, with cortical hyperostosis and periosteal new bone formation. An obtuse mandibular angle is characteristic, as are irregularly formed ribs. Radiologically, widespread bilateral calcification in the periventricular white matter, basal ganglia, and thalamus is found and in some cases calcifications are also seen in the corpus callosum, falx, tentorium, and meninges. Extra-skeletal features can be hydronephrosis and ureteral stenosis.\nEtiology\nMutations in the FAM20C gene have a causative role in lethal osteosclerotic bone dysplasia.\nDiagnostic methods\nDiagnosis is based on clinical presentation and calcification demonstrable by ultrasound, plain X-rays and computing tomography (CT).\nAntenatal diagnosis\nPrenatal diagnosis by ultrasound or molecular testing is feasible.\nGenetic counseling\nThe condition is transmitted in an autosomal recessive manner.\n\n                            Last update: \n                            February 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM"}
{"Disease Name": "Otodental syndrome", "Disease Definition": "Otodental syndrome is a very rare inherited condition characterized by grossly enlarged canine and molar teeth (globodontia) associated with sensorineural hearing loss.", "ORPHA ID": 2791, "Summary": "Epidemiology\nPrevalence of this disorder is not known. It has been described in about 10 families of European, Chinese and Brazilian descent.\nClinical description\nPatients have striking pathognomonic dental features characterized by globodontia of the primary and secondary dentition, sparing the incisors. Missing teeth, especially premolars, are also reported. Due to abnormal crown morphology, there is a great propensity to formation of caries. There is a high rate of endodontic-periodontic lesions due to the aberrant coronal and pulpal morphology. The dental conditions are associated with bilateral sensorineural high-frequency hearing deficit with an age of onset that varies from early childhood to middle age. Variable facial dysmorphism has also been reported. One family was found to have an associated bilateral iris and retinal ocular coloboma.\nEtiology\nHaploinsufficiency in the fibroblast growth factor 3 (FGF3) gene (11q13) has been reported in patients with otodental syndrome and is thought to cause the phenotype. In the family with the associated ocular coloboma, a microdeletion in the Fas-associated death domain (FADD) gene (11q13.3) was found to be responsible for ocular features.\nDiagnostic methods\nThe dental findings are diagnostic. Molecular genetic testing confirms the diagnosis.\nDifferential diagnosis\nAlthough the association of sensorineural hearing loss and dental anomalies can be found in other syndromes, none display the striking dental manifestations of otodental syndrome.\nGenetic counseling\nThe condition appears to be inherited in an autosomal dominant manner with complete to variable penetrance and variable expressivity. Genetic counseling should be offered to affected families.\nManagement and treatment\nDental management is complex, interdisciplinary and requires regular follow up, scheduled tooth extraction and eventually orthodontic treatment. Monitoring of hearing and, if necessary, hearing aids are mandatory. A preventive program is mandatory in order to maintain proper oral hygiene and health. Endodontic therapy can be difficult due to duplicated pulp canals in the affected posterior teeth. Multiple extractions may be needed and fixed or removable prostheses should be constructed. Implants are also a potential consideration.\nPrognosis\nThe functional prognosis is mostly good with appropriate dental treatment and hearing aids. Quality of life may be affected by psychological and functional aspects.\n\n                            Last update: \n                            November 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN"}
{"Disease Name": "Otofaciocervical syndrome", "Disease Definition": "Otofaciocervical syndrome is a rare, genetic developmental defect during embryogenesis syndrome characterized by distinct facial features (long triangular face, broad forehead, narrow nose and mandible, high arched palate), prominent, dysmorphic ears (low-set and cup-shaped with large conchae and hypoplastic tragus, antitragus and lobe), long neck, preauricular and/or branchial fistulas and/or cysts, hypoplastic cervical muscles with sloping shoulders and clavicles, winged, low, and laterally-set scapulae, hearing impairment and mild intellectual deficit. Vertebral defects and short stature may also be associated.", "ORPHA ID": 2792, "Summary": ""}
{"Disease Name": "Otoonychoperoneal syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by the association of dysplastic external ears, nail hypoplasia, and variable skeletal malformations, such as hypoplastic or absent fibulae, abnormalities of the scapula, clavicle, and acromioclavicular joint, and talipes equinovarus, among others. Joint contractures and mild facial dysmorphism have also been reported.", "ORPHA ID": 2793, "Summary": ""}
{"Disease Name": "Otopalatodigital syndrome spectrum disorder", "Disease Definition": "Otopalatodigital syndrome spectrum disorder is a primary bone dysplasia and encompasses a group of congenital anomalies that are characterized by skeletal dysplasia of varying clinical severity and an X linked dominant pattern of inheritance. This group includes otopalatodigital syndrome type 1 and 2 (OPD1, OPD2) which are characterized in affected males by cleft palate, conductive hearing loss, craniofacial abnormalities and skeletal dysplasia; Melnick-Needles syndrome (MNS) which displays skeletal deformities in females and embryonic or perinatal lethality in most males; frontometaphyseal dysplasia (FMD); and terminal osseous dysplasia - pigmentary defects.", "ORPHA ID": 364541, "Summary": ""}
{"Disease Name": "Otopalatodigital syndrome type 1", "Disease Definition": "A disorder that is the mildest form of otopalatodigital syndrome spectrum disorder, and is characterized by a generalized skeletal dysplasia, mild intellectual disability, conductive hearing loss, and typical facial anomalies.", "ORPHA ID": 90650, "Summary": "Epidemiology\nTo date, more than 100 cases have been described in the world literature.\nClinical description\nOPD1 is a congenital disorder characterized by generalized skeletal dysplasia which include camptodactyly, long spatulate fingers, short first digits (''tree frog'' hands and feet), pectus carinatum, mild campomelia, mild femoral bowing, limitation of joint movement (elbow extension, wrist abduction) and malformed auditory ossicles leading to conductive hearing loss in some individuals. Additional features include typical craniofacial anomalies (occipital prominence, frontal bossing with prominent supraorbital ridges, flat nasal bridge, hypertelorism, microstomia, dental abnormalities, and cleft palate (pugilistic face)). In affected females, a similar but usually milder spectrum of expressivity is observed.\nEtiology\nOPD1 is caused by gain of function mutations in the gene FLNA (Xq28) that encodes filamin A. However the pathogenesis of OPD1 is still elusive. OPD1 is allelic with 4 other skeletal dysplasias (OPD2, Melnick-Needles syndrome (MNS), terminal osseous dysplasia - pigmentary defects (TOD) and frontometaphyseal dysplasia (FMD)).\nGenetic counseling\nOPD1 is inherited in an X-linked dominant manner. Male-to-male transmission has not been reported. The risk of transmitting the mutation in each pregnancy is 50%; males inheriting the mutation will be affected while females who inherit the mutation have a broad range of phenotypic expression.\n\n                            Last update: \n                            May 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Stephen ROBERTSON"}
{"Disease Name": "Otopalatodigital syndrome type 2", "Disease Definition": "A severe form of otopalatodigital syndrome spectrum disorder, and is characterized by dysmorphic facies, severe skeletal dysplasia affecting the axial and appendicular skeleton, extraskeletal anomalies (including malformations of the brain, heart, genitourinary system, and intestine) and poor survival.", "ORPHA ID": 90652, "Summary": "Epidemiology\nTo date, more than 40 cases of Otopalatodigital syndrome type 2 (OPD2) have been described in the literature.\nClinical description\nOPD2 is a congenital disorder. Intrauterine growth is usually normal and affected infants have large anterior fontanels, and facial dysmorphism including broad forehead and lateral fullness of the supraorbital ridge, hypertelorism, downslanting palpebral fissures, stubby nose with a flat root, midfacial hypoplasia, microstomia (with typical down turned bow of the upper lip), micrognathia, Pierre Robin sequence, posterior cleft palate (submucosal cleft palate or cleft velum), glossoptosis, malformed and/or apparently low-set ears. Additional features include skeletal anomalies: pectus deformity, short limbs, campomelia, fibular agenesis, flexion contractures of elbows, knees, rocker bottom or equinovarus feet, syndactyly (usually involving fingers III and IV in the hands and toes II to V in the feet), camptodactyly of fingers, and absent halluces. Extraskeletal malformations include malformations of the central nervous system (myelomeningocele /encephalocele, cerebellar hypoplasia, hydrocephalus), heart (congenital valvular heart defects), intestine, genitourinary system (hydronephrosis ± urethral valve/reflux, hypospadias, epispadias). Congenital corneal opacities, bilobed tongue, deafness, and Dandy-Walker malformation have been reported in a minority of OPD2 cases. Congenital glaucoma and cataracts have been described in one patient. Psychomotor development varies from normal to mild intellectual disability. Carrier females with OPD2 can be asymptomatic or exhibit a phenotype that can extend from a mild subclinical osteodysplasia to a presentation indistinguishable from that of affected males. Prognosis of OPD2 is poor and perinatal death is common, secondary to cardio respiratory failure.\nEtiology\nOPD2 is caused by gain of function mutations in the gene FLNA (Xq28) that encodes filamin A. However the pathogenesis is still elusive. OPD2 is allelic with 4 other skeletal dysplasias (OPD1, Melnick-Needles syndrome (MNS), terminal osseous dysplasia - pigmentary defects (TOD) and frontometaphyseal dysplasia (FMD)).\nGenetic counseling\nOPD2 is inherited in an X-linked dominant manner. Male-to-male transmission has not been reported. The risk of transmitting the mutation in each pregnancy is 50%; males inheriting the mutation will be affected while females who inherit the mutation are less severely affected.\n\n                            Last update: \n                            May 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Stephen ROBERTSON"}
{"Disease Name": "Otospondylomegaepiphyseal dysplasia", "Disease Definition": "Otospondylomegaepiphyseal dysplasia (OSMED) is an inborn error of cartilage collagen formation characterized by sensorineural hearing loss, enlarged epiphyses, skeletal dysplasia with disproportionately short limbs, vertebral body anomalies and a characteristic facies.", "ORPHA ID": 1427, "Summary": "Epidemiology\nThe prevalence is unknown but less than 30 cases have been described in the literature so far.\nClinical description\nTypical facial features include midface hypoplasia, a short nose with anteverted nares and a flat nasal bridge, a long philtrum, cleft palate/bifid uvula, micrognathia, and hypertelorism. Joint pain and restricted mobility of the metacarpophalangeal joints appear during the second decade of life. The sensorineural hearing loss is generally described as moderate and nonprogressive. Early onset of osteoarthritis has also been reported.\nEtiology\nOSMED is classed among the type XI collagenopathies as the majority of reported cases have been associated with homozygous mutations in the COL11A2 gene (6p21.3), encoding the alpha2 chain of type XI collagen.\nDiagnostic methods\nDiagnosis is made on the basis of the clinical phenotype and typical radiographic findings: shortening of the long bones (humerus, radius, ulna, tibia, and fibula) with large epiphyses and metaphyseal flaring, coronal clefting and mild to moderate platyspondyly.\nDifferential diagnosis\nOSMED shows significant clinical overlap with Weissenbacher-Zweymuller syndrome (WZS) and Stickler syndrome (see these terms). Whilst OSMED and Stickler syndrome can be distinguished early in life due to the absence of ocular anomalies in OSMED, differentiation of OSMED and WZS (also associated with heterozygous mutations in the COL11A2 gene) may be more problematic.\nGenetic counseling\nOSMED is inherited as an autosomal recessive trait.\nManagement and treatment\nTreatment is symptomatic only, involving closure of the cleft palate, audiometry and adapted management of the hearing loss, and treatment of the joint pain.\nPrognosis\nThe prognosis depends on the severity of the osteoarthritis (which may require early joint replacement), hearing loss and joint pain.\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Ovarian dysgerminoma", "Disease Definition": "A rare malignant germ cell tumor of ovary characterized by a solid, lobulated mass, usually with a diameter of more than 10 cm, generally occurring in children or young women who present with abdominal pain or an abdominal mass and elevated serum LDH. It is bilateral in about 20% of cases, although the contralateral tumor may not be evident on macroscopic examination. Histopathologically, tumor cells are uniform rounded primitive germ cells with clear cytoplasm and macronucleoli, arranged in nests or cords separated by thin fibrous septa containing lymphocytes. Immunohistochemistry should be positive for OCT4 or SALL4, KIT (CD117), and/or D2-40.", "ORPHA ID": 99912, "Summary": ""}
{"Disease Name": "Ovarian fibroma", "Disease Definition": "A rare benign ovarian tumor of sex cord / stromal origin characterized by an abdominal mass which may present with abdominal pain, distension, or menorrhagia, among others, or may also be asymptomatic. Association with ascites and hydrothorax is known as Meigs syndrome. The tumor can be solid and/or cystic in nature. Histologically it features bundles of spindle cells forming variable amounts of collagen, without cellular atypia or atypical mitoses.", "ORPHA ID": 314473, "Summary": ""}
{"Disease Name": "Ovarian fibrothecoma", "Disease Definition": "Ovarian fibrothecoma is a rare, benign, sex cord-stromal neoplasm, with a typically unilateral location in the ovary, characterized by mixed features of both fibroma and thecoma. Patients may be asymptomatic or may present with pelvic/abdominal pain and/or distension and, occasionally, with post-menopausal bleeding. Large tumors (>10cm) are often associated with pleural effusion and ascites (the Meigs syndrome triad).", "ORPHA ID": 314478, "Summary": ""}
{"Disease Name": "Ovarian hyperstimulation syndrome", "Disease Definition": "A rare non-malformative gynecological disease affecting pre-menopausal women usually following treatment with ovarian stimulating hormones, characterized by ovarian enlargement and, to varying degrees, shift of serum from the intravascular space to the third space, mainly into the peritoneal, pleural, and to a lesser extent to the pericardial cavities. Presenting symptoms include abdomen distention, pain, nausea, and vomiting. Severity ranges from mild to life-threatening and is complicated by increased risk of thrombosis, acute hepato-renal failure, acute respiratory distress syndrome, and ovarian torsion and rupture.", "ORPHA ID": 64739, "Summary": ""}
{"Disease Name": "Overgrowth syndrome with 2q37 translocation", "Disease Definition": "A rare overgrowth syndrome with skeletal involvement characterized by long and slim body habitus and multiple skeletal manifestations, such as scoliosis, macrodactyly of the big toes, arachnodactyly of fingers and toes, camptodactyly and clinodactyly, and progressive valgus deformities of the feet. Epimetaphyseal dysplasia, bowing of the tibiae, and dysmorphic facial features (hypertelorism, high palate, or micrognathia), as well as aortic root dilatation and umbilical hernia have also been reported.", "ORPHA ID": 498488, "Summary": ""}
{"Disease Name": "Overgrowth-macrocephaly-facial dysmorphism syndrome", "Disease Definition": "A rare overgrowth syndrome characterized by tall stature, learning difficulties and facial dysmorphism.", "ORPHA ID": 137634, "Summary": ""}
{"Disease Name": "Overgrowth-metaphyseal undermodeling-spondylar dysplasia syndrome", "Disease Definition": "A rare overgrowth syndrome with skeletal involvement characterized by pre- or postnatal onset of overgrowth, accelerated bone age in infancy and early childhood, tall stature, bony overgrowth of the skull base, spondylar dysplasia, and undermodeling of the tubular bones. Facial dysmorphism includes mild hypertelorism, depressed nasal bridge, short and broad nose, and full lower lip. Additional reported features are scoliosis, as well as delayed puberty, cryptorchidism, and hypospadias.", "ORPHA ID": 498485, "Summary": ""}
{"Disease Name": "Overhydrated hereditary stomatocytosis", "Disease Definition": "Overhydrated hereditary stomatocytosis (OHSt) is a disorder of red cell membrane permeability to monovalent cations and is characterized clinically by hemolytic anemia.", "ORPHA ID": 3203, "Summary": "Epidemiology\nOHSt is very rare with only seven cases described in the literature so far.\nClinical description\nOnset occurs during the neonatal period or infancy with hemolytic anemia that may require occasional blood transfusions. Splenomegaly or hepatosplenomegaly are present. The disease course is marked by the usual complications of hemolytic anemia (biliary lithiasis) and, remarkably, by a strong tendency for iron overload.\nEtiology\nIn the majority of cases, OHSt is caused by mutations in the RHAG gene (6p21-qter) encoding the Rh-associated glycoprotein component of the Rh complex.\nDiagnostic methods\nDiagnosis is based on a massive right shift of the osmotic gradient ektacytometry curve indicating overhydrated red cells and decreased osmotic resistance, together with a substantial increase in the monovalent cation leak compared to controls, and a sharp decrease of the leak as a function of decreasing temperature. Blood smears show an elevated percentage of well formed stomatocytes. There is macrocytosis, a low mean cell hemoglobin concentration (MCHC) and a high reticulocyte count. Electrophoresis reveals that the membrane protein stomatin is absent or present at only low levels.\nDifferential diagnosis\nThe differential diagnosis should include the most common form of hereditary stomatocytosis, dehydrated hereditary stomatocytosis, as well as hereditary cryohydrocytosis with reduced stomatin (see these terms).\nGenetic counseling\nOHSt is transmitted as an autosomal dominant trait but de novo mutations are quite common.\nManagement and treatment\nTreatment involves blood transfusions, when necessary, together with management of biliary lithiasis and iron overload. Splenectomy is contraindicated in OHSt patients as it may induce venous thromboembolic complications.\nPrognosis\nWith correct management of the complications, the prognosis is good.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Jean DELAUNAY"}
{"Disease Name": "Overlap myositis", "Disease Definition": "A rare idiopathic inflammatory myopathy (IIM) with a heterogeneous phenotype characterized by myositis with at least one clinical and/or autoantibody overlap feature. Possible clinical overlap features include polyarthritis, Raynaud's phenomenon, sclerodactyly, scleroderma (proximal to metacarpophalangeal joints), lung interstitial pneumonia, and/or clinical signs of systemic lupus erythematosus (SLE).", "ORPHA ID": 206572, "Summary": "Epidemiology\nPrevalence and annual incidence are not known. Estimates are difficult to determine because of low recognition levels of this form of IIM. The disorder is more common in adult women and is frequently associated with other connective tissue disorders such as systemic sclerosis, SLE, rheumatoid arthritis, and Sjögren syndrome.\nClinical description\nOverlap myositis (OM) is a clinically heterogeneous, poorly recognized subtype of idiopathic inflammatory myopathy. Patients with myositis and one clinical and/or autoantibody overlap feature are considered to have OM. Possible clinical overlap features include polyarthritis, Raynaud's phenomenon, sclerodactyly, scleroderma (proximal to metacarpalphalangeal joints), lung interstitial pneumonia, and/or clinical signs of systemic lupus erythematosus (SLE). Overlap autoantibodies include those observed with scleroderma (such as anti-Ku or anti-PMScl), mixed connective tissue disease (MCTD; with anti-RNP), SLE (frequent ANA positivity), and/or some inflammatory myopathies such as anti-synthetase syndrome (anti-JO1).\nEtiology\nOM covers a range of inflammatory myopathies and other connective tissue diseases for which the etiology is generally poorly understood.\nDiagnostic methods\nThe precise diagnostic criteria are still debated. Sometimes OM is defined as the combination of myositis and another connective tissue disorder (systemic sclerosis, SLE, RA, Sjögren syndrome, etc.). Sometimes, OM is defined as a myositis with overlap features without fulfilling criteria of another connective tissue disorder. The diagnosis of this disorder improves with the increased screening for myositis-specific and myositis-associated autoantibodies. Some antibodies may delineate homogeneous subgroup of myositis patients, such as anti-RNP with specific extramuscular manifestations (puffy hands / Raynaud's phenomenon, arthralgia / ILD).\nDifferential diagnosis\nThe differential diagnoses include other IIM disorders (dermatomyositis, anti-synthetase syndrome, immune-mediated necrotizing myopathy and inclusion body myositis). There is still debate about OM as a distinct entity as opposed to a specific CTD with muscle involvement.\nManagement and treatment\nThere is no specific recommendation for therapeutic management. The treatment is usually based on the use of corticosteroids and/or other immunosuppressants.\nPrognosis\nDue to the heterogeneity of the diagnostic criteria and the small number of patients in the published studies, the specific prognosis of OM is not well known.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE"}
{"Disease Name": "Oxoglutaric aciduria", "Disease Definition": "A rare, genetic, inborn error of metabolism disorder characterized by neonatal-onset of developmental delay, hypotonia, hepatomegaly, lactic acidemia, increased creatine kinase levels, elevated alpha-ketoglutaric acid in urine, and a decreased plasma beta-hydroxybutyrate-to-acetoacetate ratio. Pyruvate dehydrogenase deficiency can be associated, leading to hypoglycemia and neurologic anomalies, including seizures.", "ORPHA ID": 31, "Summary": ""}
{"Disease Name": "Pachydermoperiostosis", "Disease Definition": "Pachydermoperiostosis (PDP) is a form of primary hypertrophic osteoarthropathy (see this term), a rare hereditary disorder, and is characterized by digital clubbing, pachydermia and subperiosteal new bone formation associated with pain, polyarthritis, cutis verticis gyrata, seborrhea and hyperhidrosis. Three forms have been described: a complete form with pachydermia and periostitis, an incomplete form with evidence of bone abnormalities but lacking pachydermia, and a forme frusta with prominent pachydermia and minimal-to-absent skeletal changes.", "ORPHA ID": 2796, "Summary": "Epidemiology\nThe prevalence is unknown. PDP occurs predominantly in men (male to female ratio: 7:1) and the disease is more severe in men than in women.\nClinical description\nPDP typically begins during childhood or adolescence and may stabilize after 5-20 years of progression, or progress constantly. However, in the neonatal period, late closure of the fontanels and a patent arterial duct (see this term) may be observed. PDP presents with digital clubbing and dermatological (pachydermia, thickening and furrowing of the facial features, cutis verticis gyrata, seborrhea, edema, hyperhidrosis) and rheumatological symptoms (joint effusion, arthritis, acro-osteolysis, periosteal ossification). Patients may develop severe kyphosis, restricted motion and neurological manifestations. PDP may also be associated with congenital heart disease, particularly patent arterial duct.\nEtiology\nMutations in the HPGD gene (4q33-q34) have been identified. The gene encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the main enzyme of prostaglandin degradation. Patients with homozygous mutations have chronically elevated prostaglandin E2 levels.\nDiagnostic methods\nDiagnosis is based on clinical signs, X-ray exam, magnetic resonance imaging (MRI) and/or radionucleotide bone imaging showing typical bone abnormalities, such as diaphyseal periostosis and acro-osteolysis.\nDifferential diagnosis\nDifferential diagnoses include cranio-osteoarthropathy (see this term), secondary hypertrophic osteoarthropathy, chronic recurrent multifocal osteomyelitis, SAPHO and Camurati-Engelman disease (see these terms), thyroid acropachy and syphilitic periostosis.\nGenetic counseling\nPDP is inherited as an autosomal recessive trait; however, heterozygous carriers can have a mild phenotype. Genetic counseling should be offered to patients and their families.\nManagement and treatment\nRheumatologic symptoms can be improved by nonsteroidal anti-inflammatory drugs, corticosteroids or colchicine. Clinical improvement of the dermatological symptoms is achieved by retinoids. Plastic surgery may be helpful for facial involvement. Surgical reduction of finger clubbing has been performed with success.\nPrognosis\nPDP may progress constantly, leaving patients with chronic debilitating complications, such as clubbing and arthritis.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Hermann GIRSCHICK"}
{"Disease Name": "Pachygyria-intellectual disability-epilepsy syndrome", "Disease Definition": "A rare, genetic neurological disorder characterized by the presence of diffuse pachygyria and arachnoid cysts, psychomotor developmental delay and intellectual disability. Seizures (absence, atonic and generalized tonic-clonic) and, on occasion, headache are also associated.", "ORPHA ID": 2798, "Summary": ""}
{"Disease Name": "Pachyonychia congenita", "Disease Definition": "A rare genetic skin disease predominantly featuring painful palmoplantar keratoderma, thickened nails, cysts and white plaques affecting tongue and oral mucosa.", "ORPHA ID": 2309, "Summary": "Epidemiology\nThe prevalence is not known but over a thousand patients have been registered to date worldwide in the International Pachyonychia Congenita Research Registry (IPCRR). It is estimated that there are five to ten thousand cases worldwide.\nClinical description\nPachyonychia congenita (PC) presents clinically as a spectrum of conditions. PC onset is variable with most cases manifesting soon after birth, others becoming clinically apparent only in late childhood and rarely in adulthood. The first signs of the disease usually are thickened nails or neonatal teeth. At least 3 phenotypes of hypertrophic nail dystrophy of feet and hands can be observed: nail grows to full length but a distal prominent hyperkeratosis causes an upward slant with an accentuated curvature of the nail; nail plate terminates prematurely leaving a distal region of hyperkeratosis and an exposed fingertip; or nail plate is thin with little or no hyperkeratosis. When children start walking, typically in the first years of life, a focal palmoplantar keratoderma develops, with underlying blistering causing severe pain. In some cases, the onset of keratoderma is not seen until later childhood. By about 12 years of age the majority of patients have painful plantar keratoderma. Oral leukokeratosis occurs early, may possibly cause feeding difficulties and should be distinguished from oral candidiasis in infants. Laryngeal leukokeratosis may cause hoarseness, and rarely, causes airway obstruction. Follicular keratoses on the trunk and extremities may be seen at friction points such as waist, elbows and knees. Excessive sweating of palms and soles due to palmoplantar hyperhidrosis, widespread steatocystomas appearing during or after puberty, axillary and groin cysts are other findings observed in some PC patients.\nEtiology\nAlthough historically two subtypes have been described, PC-1 and PC2, it is today recommended to classify PC patients into five subgroups based on the underlying molecular etiology: PC-K6a, PC-K6b, PC-K6c, PC-K16 and PC-K17, as PC is caused by dominant negative mutations in at least 5 genes (KRT6A, KRT6B, KRT6C, KRT16 and KRT17) encoding keratins preferentially expressed in basal and suprabasal layers of palmoplantar skin, epidermal appendages and oral mucosa.\nDiagnostic methods\nDiagnosis is based on clinical examination and is confirmed by molecular genetic testing.\nDifferential diagnosis\nThe differential diagnosis includes variants of PC (steatocystoma multiplex, which develops at puberty with little or no nail dystrophy) and disorders manifesting with dystrophic nails such as epidermolysis bullosa, Clouston syndrome (distinguished by the presence of alopecia or hypotrichosis), autosomal recessive nail dysplasia (only nail involvement), other disorders presenting with palmoplantar keratoderma such as palmoplantar keratoderma-esophageal carcinoma syndrome, striate palmoplantar keratoderma and acquired disorders such as psoriasis and lichen planus.\nAntenatal diagnosis\nAntenatal molecular diagnosis is feasible provided the causative mutation is known.\nGenetic counseling\nRecent data suggesting the possibility that the disease may rarely be inherited in a semi-dominant fashion emphasizes the importance of accurate molecular diagnosis for proper genetic counseling.\nManagement and treatment\nThere is no curative treatment for PC yet. Treatment of manifestations will focus primarily on grooming of nails and management of pain due to palmoplantar keratoderma: it includes the use of emollients and oral retinoids to reduce hyperkeratosis and strategies to limit frictions and trauma of the feet. Novel treatment modalities under investigation include small interfering RNA (siRNA) strategies, the use of topical rapamycin, oral and topical erlotinib and injection of botulinum toxin.\nPrognosis\nComplications may include secondary infection that is usually well controlled by antibiotic therapy.\n\n                            Last update: \n                            December 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Edel O'TOOLE | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Paget disease of the nipple", "Disease Definition": "Paget disease of the nipple describes a rare presentation of breast cancer, seen most frequently in women aged 50-60, manifesting with nipple drainage and itching, erythema, crusty and excoriated nipple, thickened plaques, and hyperpigmentation (less frequently). It is due to tumor cells invading the nipple-areola complex and represents 1-3% of all new breast cancer diagnoses.", "ORPHA ID": 180275, "Summary": ""}
{"Disease Name": "PAGOD syndrome", "Disease Definition": "PAGOD syndrome is a severe developmental syndrome characterized by multiple congenital anomalies including cardiovascular defects, pulmonary hypoplasia, diaphragmatic defects and genital anomalies.", "ORPHA ID": 991, "Summary": "Epidemiology\nSince the first publication in 1991, only 11 patients have been described.\nClinical description\nNeonates with PAGOD syndrome present with several visceral anomalies: hypoplasia of right or left lung, diaphragmatic hernia, omphalocele, various cardiac anomalies including, amongst others, atrial septal defect, left ventricular hypoplasia or ventricular septal defect, and great vessels anomalies such as aortic hypoplasia and pulmonary artery hypoplasia or atresia. Cardiac and mediastinal structures may be in dextroposition. Ambiguous external genitalia can be observed in some cases and all patients present gonadal agenesis or hypoplasia and developmental anomalies of Wolffian and Mullerian duct structures.\nEtiology\nEtiology is unknown but vitamin A deficiency has been suggested to play a role in the development of the syndrome.\nGenetic counseling\nAlmost all cases are sporadic, except for 2 siblings, suggesting autosomal recessive inheritance.\nPrognosis\nLife expectancy is reduced due to cardiac and respiratory complications.\n\n                            Last update: \n                            December 2011"}
{"Disease Name": "Pai syndrome", "Disease Definition": "A rare frontonasal dysplasia characterized by median cleft of the upper lip (MCL), midline polyps of the facial skin, nasal mucosa, and pericallosal lipomas. Hypertelorism with ocular anomalies are also observed, generally with normal neuropsychological development.", "ORPHA ID": 1993, "Summary": "Epidemiology\nPai syndrome (PS) has been reported in 67 patients to date, however, the incidence seems to be underestimated.\nClinical description\nPS presents at birth with a variable phenotype ranging from mild facial dysmorphism to more severe anomalies resembling frontonasal dysplasia. Most patients present with a marked hypertelorism with downward slanting palpebral fissures and may include a bifid nose in the most extreme cases. Midline cleft lip with midline nasal and facial polyps manifest generally as a bifid uvula with high palate, polyps are located over the nasal septum or extend from the nostril from an attachment to the nasal septum. These anomalies may lead to respiratory impairment, increased respiratory infections, speech impediments or early childhood difficulties in eating solids. Skin lipomas containing cartilage may be seen on the forehead. Ocular anomalies may include anterior segment dysgenesis, persistent papillary membrane, corneal leukoma, microcornea, posterior lenticonus, heterochromia iris and conjunctival lipoma. Coloboma of the iris has been reported. Neuropsychological development is usually normal, but some patients may present with epilepsy and impaired neuropsychological development. Sacral dimples may be observed at birth, and hypospadias has been reported in some male patients.\nEtiology\nThe etiology of PS is unknown.\nDiagnostic methods\nPS is diagnosed strictly by clinical signs, the presence of a congenital nasal polyp plus one or more of the three following traits: MCL (with or without cleft alveolus), mid-anterior alveolar process congenital polyp and pericallosal lipoma. MRI may reveal pericallosal lipomas and an abnormal configuration of the third ventricle. An ophthalmological exam is recommended.\nDifferential diagnosis\nDifferential diagnoses include Loeys-Dietz syndrome, oculocerebrocutaneous syndrome, frontonasal dysplasia, Goldenhar syndrome, as well as a variety of chromosomal anomalies.\nGenetic counseling\nOne case of father to son transmission has been reported to date, but no recurrence in sibs has ever been reported. Recurrence risk in families with no history of PS is therefore thought to be low.\nManagement and treatment\nDetection of potential oral or respiratory difficulties in newborns must be treated immediately. Multistage craniofacial surgery may be necessary in many cases. Surgical restoration of orbicular muscle continuity and excision of skin lipomas may be performed early in childhood, correction of the nasal pyramid should be performed after the pubertal growth spurt. In patients presenting with ocular anomalies, corneal or cataract surgery may improve vision in some cases, and optical iridectomy may be necessary in cases presenting with corneal leukoma. All patients should be regularly monitored for increases in intraocular pressure.\nPrognosis\nBoth cosmetic and functional restoration of buccal and nasal anomalies is feasible and the prognosis is good for most patients.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Damien LEDERER"}
{"Disease Name": "Painful orbital and systemic neurofibromas-marfanoid habitus syndrome", "Disease Definition": "Painful orbital and systemic neurofibromas-marfanoid habitus syndrome is a rare, benign, peripheral nerve sheath tumor disorder characterized by multiple, painful, mucin-rich plexiform neurofibromas located in the orbits, cranium, large spinal nerves and mucosa, associated with a marfanoid habitus, enlarged corneal nerves, congenital neuronal migration anomalies and facial dysmorphism which includes ptosis, proptosis, prominent nose, full lips, gingival hyperplasia, and multiple subcutaneous and submucosal nodules in the lips and sublingual zone.", "ORPHA ID": 300501, "Summary": ""}
{"Disease Name": "Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome", "Disease Definition": "Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome is a rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, axial hypotonia, palate abnormalities (including cleft palate and/or high and narrow palate), dysmorphic facial features (including prominent forehead, hypertelorism, downslanting palpebral fissures, wide nasal bridge, thin lips and widely spaced teeth), and short stature. Additional manifestations may include digital anomalies (such as brachydactyly, clinodactyly, and hypoplastic toenails), a single palmar crease, lower limb hypertonia, joint hypermobility, as well as ocular and urogenital anomalies.", "ORPHA ID": 477993, "Summary": ""}
{"Disease Name": "Pallister-Hall syndrome", "Disease Definition": "Pallister-Hall syndrome (PHS), a pleiotropic autosomal dominant malformative disorder, is characterized by hypothalamic hamartoma, pituitary dysfunction, bifid epiglottis, polydactyly, and, more rarely, renal abnormalities and genitourinary malformations.", "ORPHA ID": 672, "Summary": "Epidemiology\nApproximately 100 patients have been reported to date.\nClinical description\nMost patients with PHS present at birth with skeletal polydactyly of the third or fourth digit or postaxial polydactyly; either may be accompanied by cutaneous syndactyly and nail dysplasia. Facial features may include a short nose, flat nasal bridge, and low-set, posteriorly angled ears. Cleft palate, cleft uvula and multiple buccal frenula have been reported in some patients. An asymptomatic bifid epiglottis is nearly pathognomonic, however, some patients present with more severe posterior laryngeal clefts leading to potentially fatal respiratory insufficiency. Hypothalamic hamartoma is often asymptomatic, however, it may be associated with panhypopituitarism. Acute primary adrenal insufficiency (see this term) may also occur in severe cases, as well as milder forms of adrenal insufficiency. Precocious puberty manifests in some cases. Neurological involvement can include gelastic epilepsy (seizures that manifest as facial grimacing, smiling or laughter) or other seizure types. Renal agenesis or dysplasia as well as other genitourinary anomalies have been reported, including vaginal atresia or hydrometrocolpos, microphallus, or cryptorchidism. Other findings may include intrauterine growth retardation, abnormal lung lobation, generalized skeletal dysplasia with mesomelic shortening and radial bowing of limbs, imperforate anus and congenital heart defects (see this term).\nEtiology\nPHS is due to mutations of the GLI3 gene (7p13) that encodes a transcription factor activated by the sonic hedgehog pathway. Mutations lead to alterations in gene expression during development.\nDiagnostic methods\nClinical diagnostic criteria of patients with at least one family member with PHS require two findings: hypothalamic hamartoma, visualized on magnetic resonance imaging (MRI) as a non-enhancing, midline hypothalamic mass that is isointense to gray matter on all pulse sequences, and mesoaxial polydactyly. This may be confirmed by full sequence analysis of GLI3.\nDifferential diagnosis\nDifferential diagnoses include oral-facial-digital syndrome type 6, Holzgreve-Wagner-Rehder syndrome, McKusick-Kaufman syndrome, Holt-Oram syndrome, Bardet-Biedl syndrome, Smith-Lemli-Opitz syndrome, as well as craniopharyngioma, Greig cephalopolysyndactyly syndrome Ellis Van Creveld syndrome (see these terms) and congenital hypothalamic hamartoma syndrome.\nAntenatal diagnosis\nAntenatal genetic testing may be considered in families harboring a known PHS causative mutation of GLI3 and fetal MRI can exclude hypothalamic hamartoma. However, familial occurrences of PHS are generally milder than sporadic ones.\nGenetic counseling\nPHS is autosomal dominant, passed on to 50% of offspring, but expression is highly variable and many cases are sporadic, due to de novo mutations.\nManagement and treatment\nTreatment is symptomatic. Medical imaging should include MRI to assess the hypothalamic hamartoma, X-rays of hands and feet and a full-skeletal survey as well as renal ultrasound. Laboratory assessment including a full endocrinological function and cholesterol synthesis analysis should be performed. At birth, breathing of patients with polydactyly should be monitored and indirect laryngoscopy should be performed. Tracheotomy may be necessary. If present, surgical intervention for imperforate anus must be undertaken. Multiple lifelong hormone replacement therapies may be required.\nPrognosis\nPrognosis should be assumed to be excellent until proven otherwise. However, in its most severe forms, panhypopituitarism and severe airway malformations can be lethal; imperforate anus may also be lethal if not recognized. Intellectual deficits and behavioral alterations have not been directly correlated with the syndrome.\n\n                            Last update: \n                            May 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Leslie BIESECKER"}
{"Disease Name": "Palmoplantar keratoderma, Nagashima type", "Disease Definition": "A rare autosomal recessive, isolated diffuse palmoplantar keratoderma charactized by transgressive and nonprogressive palmoplantar keratoderma resembling a mild form of mal de Meleda.", "ORPHA ID": 140966, "Summary": ""}
{"Disease Name": "Palmoplantar keratoderma-deafness syndrome", "Disease Definition": "Palmoplantar keratoderma-deafness syndrome is a keratinization disorder characterized by focal or diffuse palmoplantar keratoderma. A patchy distribution is observed with accentuation on the thenars, hypothenars and the arches of the feet. The disease becomes apparent in infancy and is associated with sensorineural hearing loss that shows a variable age of onset. Due to genetic and clinical similarities, it has been proposed that palmoplantar keratoderma-deafness syndrome, knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome and keratoderma hereditarium mutilans may represent variants of one broad disorder of syndromic deafness with heterogeneous phenotype. The disease is transmitted in an autosomal dominant manner with incomplete penetrance.", "ORPHA ID": 2202, "Summary": ""}
{"Disease Name": "Palmoplantar keratoderma-esophageal carcinoma syndrome", "Disease Definition": "A rare genetic disease characterized by thickening of the skin on palms and soles restricted to areas of weight bearing and/or friction (focal, non-epidermolytic palmoplantar keratoderma) and oral and esophageal leukokeratosis, associated with a very high lifetime risk of developing squamous cell carcinoma of the esophagus. The skin lesions appear in childhood and can be complicated by fissuring and infection.", "ORPHA ID": 2198, "Summary": ""}
{"Disease Name": "Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome", "Disease Definition": "A rare, genetic, autosomal dominant hereditary axonal motor and sensory neuropathy disorder characterized by childhood-onset palmoplantar keratoderma associated with motor and sensory polyneuropathy manifestating with late-onset, predominantly distal, lower limb muscle weakness and atrophy (later associating mild proximal weakness and upper limb involvement), moderate sensory impairment (hypoesthesia with stocking-glove distribution), and normal or near‐normal nerve conduction velocities. Additional variable manifestations include impaired vibratory sensation, reduced tendon reflexes, paresthesia, pain, talipes equinovarus, pes cavus, and nail dystrophy.", "ORPHA ID": 538574, "Summary": ""}
{"Disease Name": "Palmoplantar keratoderma-spastic paralysis syndrome", "Disease Definition": "A rare, genetic punctate palmoplantar keratoderma disease characterized by discrete, focal, punctate keratoderma on the palms and soles and/or slowly progressive spastic paralysis, predominantly affecting the lower limbs. Lesional histology reveals pronounced orthokeratosis, acanthosis, papillomatosis, and regular undulation to the surface keratin. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 2201, "Summary": ""}
{"Disease Name": "Palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome", "Disease Definition": "Palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome is characterised by sex reversal in males with a 46, XX (SRY-negative) karyotype, palmoplantar hyperkeratosis and a predisposition to squamous cell carcinoma. To date, five cases (four of whom were brothers) have been described. The aetiology is unknown.", "ORPHA ID": 85112, "Summary": ""}
{"Disease Name": "Pancreatic agenesis-holoprosencephaly syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of pancreatic agenesis and lobar/semilobar holoprosencephaly. Insulin-dependent diabetes mellitus and pancreatic exocrine deficiency manifest early after birth. Additional reported manifestations include intrauterine growth retardation, muscle weakness, seizures, mild intellectual disability and dysmorphic craniofacial features, and agenesis of the gallbladder.", "ORPHA ID": 556955, "Summary": ""}
{"Disease Name": "Pancreatic colipase deficiency", "Disease Definition": "A rare disorder of lipid metabolism characterized by childhood onset of steatorrhea due to isolated pancreatic colipase deficiency, while other exocrine pancreatic enzymes are normal. Early formation of gallstones, as well as vitamin B12 deficiency with megaloblastic anemia have also been reported. There have been no further descriptions in the literature since 1982.", "ORPHA ID": 309108, "Summary": ""}
{"Disease Name": "Pancreatic hypoplasia-diabetes-congenital heart disease syndrome", "Disease Definition": "A rare, syndromic diabetes mellitus characterized by partial pancreatic agenesis, diabetes mellitus, and heart anomalies (including transposition of the great vessels, ventricular or atrial septal defects, pulmonary stenosis, or patent ductus arteriosis).", "ORPHA ID": 2255, "Summary": ""}
{"Disease Name": "Pancreatic insufficiency-anemia-hyperostosis syndrome", "Disease Definition": "A rare syndromic mitochondrial disease characterized by exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis.", "ORPHA ID": 199337, "Summary": "Epidemiology\nIt has been described in four children, three boys and one girl, from two consanguineous families.\nEtiology\nThe disease is due to a mutation in the COX4I2 gene, encoding a mitochondrial cytochrome C oxidase sub-unit.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            October 2009"}
{"Disease Name": "Pancreatic triacylglycerol lipase deficiency", "Disease Definition": "A rare genetic disorder of lipid metabolism characterized by neonatal to childhood onset of impaired absorption of dietary fat with greasy/oily and voluminous stools, but normal growth and development. Decreased levels of fecal elastase, as well as low serum levels of the fat-soluble vitamins A, D, and E, have been reported.", "ORPHA ID": 309031, "Summary": ""}
{"Disease Name": "Pancreatoblastoma", "Disease Definition": "A rare neoplastic gastroenterologic disease most often found in children, which usually presents with the non-specific symptoms of a palpable mass, vomiting, abdominal pain, jaundice, and weight loss/failure to thrive. Histologically, this malignant epithelial pancreatic neoplasm of the exocrine cells is characterized by multiple lines of differentiation (acinar, ductal, mesenchymal, neuroendocrine) and the presence of squamoid nests.", "ORPHA ID": 677, "Summary": "Epidemiology\nThe incidence is less than 1/1,000,000 in Europe. Pancreatoblastoma accounts for 0.5% of all pancreatic exocrine tumors and occurs equally in females and males. It is the most common malignant pancreatic tumor in young children and has a mean age of diagnosis of 5 years.\nClinical description\nPancreatoblastoma most often presents in children under the age of 10 (mean of 5 years). Onset in adulthood (third/fourth decade) is extremely rare, and patients are more likely to develop metastases. Symptoms are often non-specific and include a large abdominal mass, abdominal distension/pain, failure to thrive, diarrhea, vomiting and jaundice. Tumors in the head of the pancreas can lead to mechanical obstruction of the upper duodenum and gastric outlet, as well as gastrointestinal bleeding. Local invasion and metastasis to the liver (most commonly), lungs and/or regional lymph nodes can often be discovered at diagnosis. Pancreatoblastoma can sometimes be associated with Beckwith-Wiedemann syndrome and familial adenomatous polyposis (FAP).\nEtiology\nThe etiology is unknown but pancreatoblastoma can occur in any part of the pancreas. It is a malignant embryonal tumor that seems to recapitulate the embryogenesis of the pancreas, presumably because it originates from the pluripotent pancreatic stem cells during foregut development. Sporadic and FAP-associated pancreatoblastomas have frequent alterations in the adenomatous polyposis coli (APC)/beta-catenin pathway, and allelic loss in chromosome 11p.\nDiagnostic methods\nDiagnosis is based on histological characteristics. Pancreatoblastoma is usually a large (2 to 20 cm), encapsulated mass with a histological picture of multiple squamoid nests composed of whorls of spindle-shaped cells that are diagnostic of this tumor. It shows significant acinar cell differentiation but also ductal, mesenchymal and neuroendocrine differentiation. The tumor marker alpha-fetoprotein (AFP) is raised in 68% of cases, regardless of age. Full staging needs to be performed, including ultrasound and computed tomography (CT) or magnetic resonance imaging (MRI) scans of the primary tumor, as well as CT scans of the chest to detect any metastasis.\nDifferential diagnosis\nDifferential diagnoses include poorly differentiated adenocarcinomas, solid pseudopapillary tumors, pancreatic carcinoma, pancreatic neuroendocrine tumors and autoimmune pancreatitis.\nManagement and treatment\nTreatment involves complete surgical resection of the tumor. Procedures include a distal pancreatectomy with or without splenectomy (for tumors in the body and tail of pancreas) and pancreaticoduodenectomy (for those in the head of the pancreas). Chemotherapy (usually cisplatin and doxorubicin) and radiotherapy are used in cases of unresectable, recurrent or metastatic tumors with variable results. In adults, 5-fluorouracil/doxorubicin/mitomycin and doxorubicin/carboplatin have been given as adjuvant therapy.\nPrognosis\nThe prognosis for pediatric cases is usually good if the tumor is resectable, but recurrences still occur. If unresectable and in the presence of metastasis, pancreatoblastoma has an aggressive course and prognosis is poor. Adult cases usually have a poorer prognosis, with a median survival time of 15 months.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Ewa BIEN  - Pr Bernadette BRENNAN"}
{"Disease Name": "Pancytopenia due to IKZF1 mutations", "Disease Definition": "A rare syndrome with combined immunodeficiency characterized by a variable clinical presentation ranging from asymptomatic individuals to potentially life-threatening, recurrent bacterial infections associated with progressive loss of serum immunoglobulins and B cells.", "ORPHA ID": 317473, "Summary": ""}
{"Disease Name": "Pancytopenia-developmental delay syndrome", "Disease Definition": "A rare constitutional aplastic anemia characterized by progressive trilineage bone marrow failure (with hypocellularity), developmental delay with learning disabilities, and microcephaly. Mild facial dysmorphism and hypotonia have also been reported.", "ORPHA ID": 401764, "Summary": ""}
{"Disease Name": "PANDAS", "Disease Definition": "PANDAS is an acronym for Pediatric Autoimmune Neuropsychiatric Disorders Associated with a group A beta-hemolytic Streptococcal infection and applied to a subgroup of children with obsessive-compulsive disorder (OCD) and/or tic disorders.", "ORPHA ID": 66624, "Summary": "Epidemiology\nThe prevalence is unknown but the boy-to-girl ratio is 2.6:1.\nClinical description\nThe current diagnostic criteria for the PANDAS are: presence of OCD and/or a tic disorder, very young age at onset (prepubertal), sudden and dramatic onset of symptoms, association between streptococcal infections and episodic relapsing-remitting exacerbations manifesting as neuropsychiatric symptoms (motor hyperactivity or adventitious movements including choreiform movements or tics). The increased severity of symptoms usually persists for at least several weeks, but may last for several months or longer, followed by a slow, gradual improvement. The major distinctive feature of PANDAS is the temporal association between neuropsychiatric symptom exacerbations and streptococcal infections. Additional neuropsychiatric symptoms occur frequently: emotional lability, separation anxiety, anorexia, impulsivity, distractibility and motor hyperactivity characteristic of attention deficit hyperactivity disorder (ADHD). Comorbid disorders include major depression (36%), major dysthymia (6%) and separation anxiety disorder (20%).\nEtiology\nThe etiology is uncertain. One theory is that streptococcal infections trigger an antibody response in some children that causes changes in the basal ganglia. No specific genetic factors have been identified.\nDiagnostic methods\nDiagnosis of PANDAS is clinical. Neuroimaging studies may reveal increased basal ganglia volumes.\nManagement and treatment\nManagement includes standard interventions for obsessive-compulsive and tic disorders: cognitive-behavioural therapy, reversal therapy in the case of tic disorders and pharmacologic therapy (neuropsychiatric drugs, antibiotics to prevent infections and intravenous immunoglobulin therapy).\n\n                            Last update: \n                            November 2006"}
{"Disease Name": "Panhypophysitis", "Disease Definition": "A type of primary hypophysitis characterized by an inflammation of the entire pituitary gland. Common clinical presentation is diabetes insipidus with polyuria and polydipsia and partial or panhypopituitarism. Other symptoms may include headaches, nausea/vomiting, visual disturbances and fatigue.", "ORPHA ID": 95513, "Summary": ""}
{"Disease Name": "Panner disease", "Disease Definition": "A rare osteochondrosis of the capitellum of the humerus, characterized by involvement of the dominant upper limb and onset before the age of 10 years. It results from lateral compression injuries of the elbow typically occurring in children practising sports such as baseball and throw. It should be distinguished from osteochondritis dissecans of the capitellum, occurring later, in adolescents.", "ORPHA ID": 97336, "Summary": ""}
{"Disease Name": "Panniculitis-induced localized lipodystrophy", "Disease Definition": "Panniculitis-induced localized lipodystrophy is a rare, acquired, localized lipodystrophy disorder characterized by eruption of tender, occasionally painful, erythematous nodules and plaques which enlarge radially and resolve into lipoatrophic lesions, often located in the upper and lower limbs. Histologically, lesions are characterized by lipophagic, lobular panniculitis and absence of vasculitis.", "ORPHA ID": 90159, "Summary": ""}
{"Disease Name": "Pantothenate kinase-associated neurodegeneration", "Disease Definition": "Pantothenate kinase-associated neurodegeneration (PKAN) is the most common type of neurodegeneration with brain iron accumulation (NBIA; see this term), a rare neurodegenerative disorder characterized by progressive extrapyramidal dysfunction (dystonia, rigidity, choreoathetosis), iron accumulation on the brain and axonal spheroids in the central nervous system.", "ORPHA ID": 157850, "Summary": "Epidemiology\nPrevalence is estimated at 1-2/1,000,000.\nClinical description\nClassic PKAN (75% of cases) is characterized by early onset, usually before six years of age, and rapid progression. Atypical PKAN (25% of cases) has later onset, between 13 and 14 years of age, and slower progression. Patients present with symptoms anywhere along a continuum between the two. In classic PKAN, patients present with impaired gait and falling, often related to dystonia, rigidity, impaired balance, or spasticity, and usually lose the ability to ambulate by 10-15 years after onset. Episodes of rapid decline, which may include status dystonicus, occur interspersed with longer periods of relative stability. Developmental delay (primarily motor, sometimes global) may occur. Patients frequently develop pigmentary retinal degeneration and dysarthria. Later in disease course common complications include dysphagia, gastro-oesophageal reflux, chronic constipation, aspiration pneumonia and malnutrition. In atypical PKAN, patients present with speech difficulty, mild gait abnormalities, prominent psychiatric symptoms that may include depression, emotional lability, impulsivity, or violent outbursts, pigmentary retinal degeneration (less frequently than in classic PKAN) and both verbal and motor tourettism. Motor involvement is generally less severe and loss of ambulation occurs within 15-40 years of onset. The association of hyperprebetalipoproteinemia, acanthocytes and retinitis pigmentosa (HARP syndrome) is within the PKAN spectrum.\nEtiology\nPKAN is caused by mutations in the PANK2 gene (20p13-p12.3).\nDiagnostic methods\nPKAN is usually suspected following MRI evidence of the classic `eye-of-the-tiger' sign, a central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus. Genetic analysis is required to confirm diagnosis.\nDifferential diagnosis\nDifferential diagnoses include Wilson disease (see this term), which is excluded by normal plasma ceruloplasmin concentration or copper metabolism, and other types of NBIA, which can be differentiated using MRI findings and genetic testing.\nAntenatal diagnosis\nPrenatal testing is available if both disease-causing mutations have been identified in an affected family member.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment aims to alleviate symptoms, including baclofen (oral or intrathecal pump) and trihexyphenidyl for dystonia and spaciticy, and botulinum toxin for patients whose quality of life is improved by treating a limited body region. Patients with PKAN do not typically benefit from L-dopa. Deep brain stimulation (DBS) may relieve some symptoms. Frequent contact with patients and treatment adjustments are required to maintain as high a quality of life as possible. Dietary assessment, gastrostomy tube feeding and dental extraction (in cases with severe orobuccolingual dystonia) may be required.\nPrognosis\nPKAN is a progressive disorder and lost skills are usually not regained. Rate of progression correlates with age at onset; those with early symptoms decline more rapidly. Life span is variable but premature death does occur.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Allison GREGORY  - Pr Susan HAYFLICK"}
{"Disease Name": "PAPA syndrome", "Disease Definition": "Pyogenic arthritis-pyoderma gangrenosum-acne syndrome is a rare pleiotropic autoinflammatory disorder of childhood, primarily affecting the joints and skin.", "ORPHA ID": 69126, "Summary": "Epidemiology\nTo date, only 34 patients with PAPA syndrome have been reported worldwide, from five families (two in the USA, one in Italy, one in the Netherlands, and one in New Zealand).\nClinical description\nThe first affected family contained ten affected members from three generations and manifested variable expression of a pauciarticular, nonaxial, arthritis that began in childhood; pyoderma gangrenosum; and severe cystic acne in adolescence and beyond. PAPA syndrome is a self-limiting disease, but it can lead to severe joint destruction. Synovial fluid is purulent with neutrophil accumulation, but cultures are invariably negative. Recurrent sterile arthritis usually occurs after minor trauma, but can also occur spontaneously. Other less commonly associated features include adult-onset insulin-dependent diabetes mellitus, proteinuria, and abscess formation at the site of parenteral injections (pathergy).\nEtiology\nThe gene responsible for the syndrome, the proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) gene (previously known as the CD2 binding protein 1 (CD2BP1) gene), was cloned in 2002. Only two mutations account for the known cases. Recently, the PSTPIP1 protein has been demonstrated to bind pyrin/marenostrin (P/M), the protein encoded by the MEFV gene, mutations in which cause Familial Mediterranean Fever. PAPA-associated PSTPIP1 mutants exhibit increased binding to P/M.\nDifferential diagnosis\nDifferential diagnosis for PAPA syndrome should include juvenile idiopathic arthritis and periodic fever.\nGenetic counseling\nPAPA syndrome is inherited in an autosomal dominant manner.\nManagement and treatment\nArthritis and skin lesions have sometimes been reported to be responsive to glucocorticoids. However, two alternative therapeutics have been suggested so far. In one report, the disease underwent rapid and sustained clinical remission after treatment withthe tumor necrosis factor inhibitor, etanercept. Another recent paper described the effect of recombinant human interleukin (IL)-1 receptor antagonist (anakinra), which appeared to be an effective therapy to treat disease flares in PAPA syndrome.\n\n                            Last update: \n                            October 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Isabelle TOUITOU"}
{"Disease Name": "Papillary glioneuronal tumor", "Disease Definition": "A rare mixed neuronal-glial tumor characterized by a supratentorial space-occupying lesion in periventricular location, often with prominent cystic change. The histological hallmark of this low-grade neoplasm is its pseudopapillary appearance with a single layer of cuboidal cells around hyalinized blood vessels, associated with sheets or focal collections of neuronal cells. Clinical presentation is variable and non-specific, most frequently with headache and seizures. Prognosis is favorable after complete resection.", "ORPHA ID": 251962, "Summary": ""}
{"Disease Name": "Papillary intralymphatic angioendothelioma", "Disease Definition": "A rare vascular tumor characterized by an ill-defined, slowly growing, asymptomatic cutaneous plaque or nodule mostly involving the limbs, in fewer cases the trunk. The tumor is composed of lymphatic-like channels with prominent intraluminal papillary tufts with hyaline cores lined by hobnail endothelial cells. It is locally aggressive, while metastasis is rare. Infants and children are much more often affected than adults.", "ORPHA ID": 458768, "Summary": ""}
{"Disease Name": "Papillary renal cell carcinoma", "Disease Definition": "Papillary renal cell carcinoma is a rare subtype of renal cell carcinoma, arising from the renal tubular epithelium and showing a papillary growth pattern, which typically manifests with hematuria, flank pain, palpable abdominal mass or nonspecific symptoms, such as fatigue, weight loss or fever. Symptoms related to metastatic spread, such as bone pain or persistent cough, are frequently associated since early diagnosis is not common. It is typically multifocal, bilateral, and in most cases sporadic, although different hereditary syndromes, such as Hereditary leiomyoma renal cell carcinoma, Birt-Hogg-Dubé syndrome and Tuberous sclerosis, may predispose to the development of papillary renal cell carcinoma.", "ORPHA ID": 319298, "Summary": ""}
{"Disease Name": "Papillary tumor of the pineal region", "Disease Definition": "Papillary tumor of the pineal region (PTPR) is a very rare neoplasm of the pineal region that is thought to arise from the specialized ependymocytes of the subcommissural organ and that manifests with visual disturbances, headaches, loss of coordination and balance, nausea and vomiting due to obstructive hydrocephalus.", "ORPHA ID": 251915, "Summary": ""}
{"Disease Name": "Papilloma of choroid plexus", "Disease Definition": "A rare benign type of choroid plexus tumor often occurring in the fourth ventricle (in adults) and the lateral ventricle (in children) but sometimes arising ectopically in the brain parenchyma, and presenting with nausea, vomiting, papilledema, abnormal eye movements, as well as enlarged head circumference, seizures and gait impairment due to an increase in intracranial pressure.", "ORPHA ID": 2807, "Summary": ""}
{"Disease Name": "Papillon-Lefèvre syndrome", "Disease Definition": "Papillon-Lefèvre syndrome (PLS) is a rare ectodermal dysplasia characterized by palmoplantar keratoderma associated with early-onset periodontitis.", "ORPHA ID": 678, "Summary": "Epidemiology\nThe prevalence is estimated between 1/250,000 and 1/1,000,000 individuals. The male to female ratio is 1:1. PLS is found in all ethnic groups.\nClinical description\nDiffuse palmoplantar keratoderma (see this term) with erythematous plaques develops between the first and fourth years of life, with the soles being usually more severely affected than the palms. Psoriasiform hyperkeratosis can overflow onto the dorsal surfaces of the hands and feet (transgredient spread) and, less frequently, lesions can be seen on the limbs (knees, elbows). Skin lesions are followed by intense gingivitis that rapidly progresses into periodontitis with alveolar bone lysis and early loss of primary dentition. The skin lesions are aggravated by cold and during episodes of severe periodontitis. During childhood, the phenomenon of periodontal disease recurs with rapid loss of permanent dentition. Cases of PLS with mild and/or late-onset periodontal disease have been reported occasionally. PLS is accompanied, in half of the patients, by enhanced susceptibility to cutaneous and systemic infections (furunculosis, skin abscesses, pyoderma, hidradenitis suppurativa (see this term), respiratory tract infection...). Patients may also present with malodorous hyperhidrosis, follicular hyperkeratosis, nail dystrophy or dural calcifications. The association of PLS with malignant melanoma or squamous cell carcinoma has been reported in very rare occasions.\nEtiology\nPLS is due to mutations in the CTSC gene (11q14.2) that codes for cathepsin C (also known as dipeptidyl peptidase I), a lysosomal protease playing a role in epidermal differentiation and desquamation and in activation of serine proteases expressed in cells of the immune system. CTSC mutations lead to an almost total loss of cathepsin C activity which seems to result in susceptibility to specific virulent pathogens. It is also suggested that other immune-mediated deficiencies in the host defense mechanism could be involved in the pathogenesis of PLS.\nDiagnostic methods\nDiagnosis is based on clinical signs. Dental radiography shows atrophy of the alveolar bone. Neutrophil function tests reveal anomalies of chemotaxis and phagocytosis by polymorphonuclear leukocytes. Skin biopsy shows hyperkeratosis with focal parakeratosis, moderate perivascular infiltration, hypergranulosis, and acanthosis. Biochemical analysis reveals a loss of CTSC activity. Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes two rare disorders that are allelic variants of PLS, Haim-Munk syndrome (see this term) and prepubertal/aggressive periodontitis. Other diseases with similar dermatologic features include localized epidermolytic palmoplantar keratoderma (Vörner), mal de Meleda, Howel-Evans syndrome, transgrediens et progrediens palmoplantar keratoderma (Greither's disease) (see these terms), and keratosis punctata.\nAntenatal diagnosis\nAntenatal diagnosis is theoretically possible but has never been reported.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to the parents of an affected individual informing them of the 25% risk their offspring has of inheriting the disease causing mutation.\nManagement and treatment\nTreatment is based on oral retinoids which attenuate the palmoplantar keratoderma and slow the alveolar bone lysis. Antibiotics, along with oral hygiene and use of mouth rinses, are also recommended for slowing the progression of periodontitis. Ultimately, primary or remaining teeth are extracted and are replaced by dental implants. Antibiotherapy is also used in the treatment of recurrent infections. Etretinate (a synthetic retinoid) shows promising results in the treatment of PLS.\nPrognosis\nDespite meticulous dental care, all patients eventually become edentulous at the beginning of adulthood. Life expectancy is normal.\n\n                            Last update: \n                            November 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Fanny MORICE-PICARD  - Pr Alain TAIEB"}
{"Disease Name": "Papular elastorrhexis", "Disease Definition": "A rare, acquired, dermis elastic tissue disorder characterized by multiple, asymptomatic, firm, well-demarcated, nonfollicular, hypopigmented or skin-colored papules, with a diameter of less than 1 cm, distributed symmetrically over trunk and/or proximal limbs (rarely, head, neck, shoulders, armpits, thighs), with no extracutaneous manifestations. Histopathology typically reveals decreased and fragmented elastic fibers, thickened and/or homogenized collagen bundles and, in some, a mild, perivascular, lymphocytic infiltrate in the dermis.", "ORPHA ID": 228264, "Summary": ""}
{"Disease Name": "Papular mucinosis of infancy", "Disease Definition": "Papular mucinosis of infancy is a rare pediatric non progressive form of localized lichen myxedematosus (see this term) characterized by the development of firm opalescent mucinous papules on the upper arms and the trunk.", "ORPHA ID": 90395, "Summary": ""}
{"Disease Name": "Papular xanthoma", "Disease Definition": "Papular xanthoma is a form of non-Langerhans cell histiocytosis characterized by cutaneous presentation of solitary or disseminated yellow to orange-brown papular or papulonodular, noncoalescent, asymptomatic skin lesions located predominantly on the head, neck, trunk and extremities (rarely on oral mucosa), in the presence of normolipidemia. Microscopically, the lesions consist of monomorphous infiltrate of xanthomatized macrophages and numerous Touton giant cells, with scant or absent inflammatory infiltrate. It is usually not associated with systemic disease.", "ORPHA ID": 158008, "Summary": ""}
{"Disease Name": "Paracetamol poisoning", "Disease Definition": "A rare intoxication due to a medical product occurring as a result of accidental or intentional overdosing of paracetamol (acetaminophen). Patients may develop gastroenteritis within hours and hepatotoxicity within 24 to 72 hours after ingestion, potentially leading to acute liver injury and liver failure. Possible non-hepatic sequelae include renal failure, thrombocytopenia, pancreatitis, and subendocardial myocyte necrosis. Chronic paracetamol poisoning may be asymptomatic or include all signs and symptoms potentially occurring in acute poisoning.", "ORPHA ID": 464458, "Summary": ""}
{"Disease Name": "Parachute tricuspid valve", "Disease Definition": "Parachute tricuspid valve is a rare congenital heart malformation defined as an insertion of the chordal apparatus into a single papillary muscle or a muscle group, making a pathognomonic 'pear' shape sign in the four-chamber echocardiographic view with the atrium forming the larger base of the pear and the leaflets the apex. Isolated parachute tricuspid valve may be asymptomatic or present with symptoms of tricuspid stenosis (diastolic inspiratory murmur, pulsation of jugular veins, hepatomegaly, edema, epigastric discomfort, right atrial enlargement, right ventricular hypertrophy, electrocardiography abnormalities). It may also be associated with other heart malformations and present with symptoms of the complex of malformations.", "ORPHA ID": 99056, "Summary": ""}
{"Disease Name": "Paracoccidioidomycosis", "Disease Definition": "A rare mycosis characterized by an acute form mostly occurring in children and young adults presenting with fever, weight loss, lymph node enlargement, hepatosplenomegaly, and bone marrow dysfunction, versus a chronic form which usually involves the lungs and mucosae of the upper respiratory tract, skin, lymph nodes, and adrenal glands, but may affect any part of the body. The most common sequelae are chronic respiratory insufficiency and Addison's disease. The infectious agent, Paracoccidioides brasiliensis, is a fungus limited to Latin America.", "ORPHA ID": 73260, "Summary": ""}
{"Disease Name": "Paramedian nasal cleft", "Disease Definition": "Paramedian nasal cleft is a rare developmental defect during embryogenesis characterized by a unilateral or bilateral coloboma of the nose, ranging in severity from a small notch, resulting in minor deviation of the nasal septum, to variable-sized clefts of the nasal ala which may be associated with small cysts or sinuses in the nasal midline. Defect may be isolated or may occur in association with cleft lip and/or other craniofacial anomalies (e.g. hypertelorism, broadening of nasal root, midline cleft). Dorsum and apex of nose are usually well preserved.", "ORPHA ID": 141242, "Summary": ""}
{"Disease Name": "Paramyotonia congenita of Von Eulenburg", "Disease Definition": "A rare genetic skeletal muscle ion channel disorder, part of the non-dystrophic myotonias, characterized by exercise and/or cold-exacerbated myotonia.", "ORPHA ID": 684, "Summary": "Epidemiology\nThe exact prevalence is unknown but is estimated to be < 1/100,000 people in Europe (0.17/100,000 in UK).\nClinical description\nSymptoms usually manifest in the first decade of life with an usual onset in early childhood. The major clinical manifestation is episodic muscle stiffness as a consequence of myotonia which, in paramyotonia congenita (PC), is called « paradoxical » because of its worsening with repeated exercice. Muscle stiffness commonly follows severe attacks of stiffness in case of prolonged exercise and/or prolonged cold exposure, it presents an extreme cold sensitivity and can be also exacerbated by other factors, like fasting and some hormonal conditions (menstruation, pregnancy). Myotonia can last seconds to minutes whereas weakness may persist for hours, even if the muscles are rewarmed. Facial, tongue, and hand muscles are predominantly affected whereas the lower limbs are generally only mildly affected.\nEtiology\nPC is a muscle sodium channelopathy due to missense mutations of the SCN4A gene (17q23.3) encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4. Pathological variants of SCN4A lead to an increased membrane excitability. The rapid inactivation phase of the sodium channels, which normally follows muscle contraction, is altered. The sodium channels are prematurely reactivated, and new action potentials are generated, resulting in myotonic bursts.\nDiagnostic methods\nDiagnosis is based on clinical history, physical exam, electromyographic and genetic tests. EMG records myotonic discharges and reveals specific muscle excitability anomalies after provocative test, showing gradual decrease of compound motor muscle action potential (CMAP) after repeated short exercise tests at room temperature and after cooling. CPK levels vary depending on the myotonia severity. Long exercise test may show progressive and prolonged decrease in the amplitude of CMAPs. Muscle biopsy is not useful for diagnosis. It can reveal a vacuolar myopathy in case of associated attacks of weakness.\nDifferential diagnosis\nThe differential diagnosis includes the other non-dystrophic myotonic syndromes such as Thomsen and Becker disease, other sodium channel myotonias, and hyperkalemic periodic paralysis with paradoxical myotonia.\nAntenatal diagnosis\nPrenatal and preimplantation genetic testing are possible when the pathogenic variant has been identified in an affected family member, but are rarely performed because of the non life-threatening prognosis.\nGenetic counseling\nPC is transmitted as an autosomal dominant disease with a complete penetrance. Sporadic cases and de novo mutations have been reported. Genetic counseling should be offered to patients informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement of patients consists in medical therapy and avoidance of triggering factors (cold exposure, fasting and strenuous/prolonged exercice). Muscle stiffness (myotonia) responds well to sodium channel blockers. Mexiletine or carbamazepine are treatments of choice. Acetazolamide can be useful to prevent attacks of weakness and may also improve myotonia in some cases. Physiotherapy with massages and stretching may be useful against pain and retractions. Close monitoring is necessary during surgery and anesthesia. Depolarizing agents can induce masseter spasms and stiffness of respiratory and other muscles and can therefore impair intubation and mechanical ventilation. Depolarizing muscle relaxants are therefore contraindicated. Myotonic patients are considered to be susceptible to malignant hyperthermia; volatile anesthetics and suxamethonium should be prohibited.\nPrognosis\nPrognosis is good and symptoms are stable during life. There is no impact on life expectancy. Even if the disease is nonprogressive and not life-threatening, the disability resulting from the symptoms can have a significant functionnal impact on daily life activities, affecting quality of life, personal, social, and professional spheres.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Savine VICART | EURO-NMD* - Dr Nur VILLAR | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "Parana hard skin syndrome", "Disease Definition": "A rare genetic skin disorder characterized by very early-onset of progressive skin thickening over the entire body (except for eyelids, neck and ears), progressively limited joint mobility with gradual freezing of joints, and eventual severe chest and abdomen movement restriction, manifesting with restrictive pulmonary disease, which may lead to death. Additional features include severe growth restriction and osteoporosis. There have been no further descriptions in the literature since 1974.", "ORPHA ID": 2812, "Summary": ""}
{"Disease Name": "Paraneoplastic neurologic syndrome", "Disease Definition": "Paraneoplastic neurological syndromes (PNS) can be defined as remote effects of cancer that are not caused by the tumor and its metastasis, or by infection, ischemia or metabolic disruptions.", "ORPHA ID": 36388, "Summary": "Epidemiology\nPNS are rare, affecting less than 1/10,000 patients with cancer.\nClinical description\nOnly the Lambert-Eaton myasthenic syndrome is relatively frequent, occurring in about 1% of patients with small cell lung cancer. The other most common PNS are subacute cerebellar ataxia, limbic encephalitis (LE), opsoclonus-myoclonus (OM), retinopathies (cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), Stiff-Person syndrome (SPS), chronic gastrointestinal pseudoobstruction (CGP), sensory neuronopathy (SSN), encephalomyelitis (EM) and dermatomyositis (see these terms). PNS can affect any part of the central or peripheral nervous system, the neuromuscular junction, and muscle. They can be isolated or occur in association. PNS are usually severely disabling.\nEtiology\nThey are caused by autoimmune processes triggered by the cancer and directed against antigens common to both the cancer and the nervous system (onconeural antigens).\nDiagnostic methods\nIn most patients, the neurological disorder develops before the cancer becomes clinically overt and the patient is referred to the neurologist for identification of the neurological disorder as paraneoplastic. Due to their high specificity, the best way to diagnose a neurological disorder as paraneoplastic is to identify one of the well-characterized anti-onconeural protein antibodies in the patient's serum. In addition, as these antibodies are associated with a restricted range of cancers, they can guide the search for the underlying tumor at a stage when it is frequently not clinically overt.\nManagement and treatment\nThis is a critical point as, to date, the best way to stabilize PNS is to treat the cancer as soon as possible. Unfortunately, about one-third of patients do not have detectable antibodies and 5% to 10% have an atypical antibody that is not well-characterized. As PNS are believed to be immune-mediated, suppression of the immune response represents another treatment approach.\n\n                            Last update: \n                            May 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Christophe ANTOINE  - Pr Jérôme HONNORAT"}
{"Disease Name": "Paraneoplastic pemphigus", "Disease Definition": "A rare form of autoimmune bullous skin disease characterized by polyformative skin lesions, typically beginning on the oral mucus membranes, and generally associated with lymphoma or chronic lymphoid leukemia.", "ORPHA ID": 63455, "Summary": "Epidemiology\nThe prevalence of this form of pemphigus is unknown. About 500 cases of paraneoplastic pemphigus have been reported worldwide in the literature. This form accounts for 3-5% of all pemphigus cases.\nClinical description\nParaneoplastic pemphigus occurs in a background of suspected or proven neoplasia. The associated cancers are mostly lymphomas, chronic lymphoid leukaemia and in some cases, Kaposi sarcoma, Castelman's disease, thymomas, carcinomas, and poorly differentiated sarcomas. The disease almost always begins with severe diffuse blisters in the mouth, on the lips and on the oesophagus. Eyes are frequently involved. Skin lesions vary and can be misleading, presenting as bullous lichenoid lesions, evocative of urticaria or polymorphous erythema. Lungs can also be involved (in 30% to 40% of cases), as well as the gastrointestinal tract.\nEtiology\nThe etiology and pathogenesis of paraneoplastic pemphigus are poorly understood.\nDiagnostic methods\nHistopathological analysis shows intra-epidermal acantholysis with the presence of necrotic keratinocyte cells, vacuolisation of the basal layer and dermic lichenoid inflammatory infiltrate. Direct immunofluorescence test usually shows granular-linear IgG and/or C3 deposits in the epidermal intercellular spaces, and/or at the dermo-epidermal junction (basement membrane zone). IgA and IgM can also be detected. Anti-plakine antibodies can be present (desmoplakin, periplakin, envoplakin), as well as anti-plectin, anti-desmoglein 1 and 3 antibodies, anti-BP180, and anti-BP230 antibodies.\nDifferential diagnosis\nDifferential diagnosis includes some forms of bullous pemphigoid, pemphigus vulgaris, drug-induced rash (toxic epidermal necrolysis, Stevens-Johnson syndrom), erythema multiforme, Graft Versus Host Disease (GVHD), lichen planus, or major aphthous stomatitis.\nManagement and treatment\nThe progression of paraneoplastic pemphigus rarely parallels neoplastic progression. The most commonly used treatment is systemic corticosteroids, but immunosuppressant drugs are often required. Some patients have been treated with intravenous immunoglobulin, plasmapheresis, and monoclonal antibodies. However, the efficacy of treatment varies depending on the underlying malignancy.\nPrognosis\nParaneoplastic pemphigus is often fatal (in 90% of cases), however, the prognosis depends on the nature of the underlying malignancy and is improved when the associated tumor is benign. The high mortality rate is explained by the occurrence of severe infections (sometimes due to immunosuppressive drugs), the evolution of the underlying malignancy, or bronchiolitis obliterans which is related to the autoimmune response in paraneoplastic pemphigus.\n\n                            Last update: \n                            May 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Marion CASTEL | ERN-Skin* - Pr Pascal JOLY | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Paraneoplastic uveitis", "Disease Definition": "A rare ophthalmic disorder characterized by a non-infectious uveitis potentially involving all parts of the uveal tract and due to a paraneoplastic autoimmune reaction. The signs and symptoms usually precede the tumor diagnosis and may include ocular redness and pain, light sensitivity, blurred vision, floaters, and decreased vision. The most classic form is the intermediate uveitis associated with anti-CV2 antibodies in small-cell lung cancer or other neoplasms. Other ocular and/or extra-ocular manifestations are commonly present in addition.", "ORPHA ID": 279928, "Summary": ""}
{"Disease Name": "Paraparetic variant of Guillain-Barré syndrome", "Disease Definition": "Paraparetic variant of Guillain-Barré syndrome is a rare variant of Guillain-Barré syndrome characterized by isolated leg weakness, areflexia and radicular leg pain that may simulate a cauda equina or spinal cord syndrome. The arms, ocular, facial, and oropharyngeal muscles are spared, and sphincteric function is normal.", "ORPHA ID": 231445, "Summary": ""}
{"Disease Name": "Paraplegia-intellectual disability-hyperkeratosis syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by intellectual impairment of variable severity, progressive lower limb spasticity, and diffuse palmoplantar hyperkeratosis. Additional manifestations include pes cavus, extensor plantar responses, hand tremor, and mild dysmorphic facial features.", "ORPHA ID": 2824, "Summary": ""}
{"Disease Name": "Paraquat poisoning", "Disease Definition": "A rare intoxication with paraquat (a non-selective bipyridilium herbicide that has been banned in Europe), usually occurring through ingestion of the poison, and that presents with caustic injury of the oral cavity and pharynx, as well as nausea, vomiting, epigastric pain, lethargy, loss of consciousness and fever. Patients may develop potentially life-threatening complications such as hepatic dysfunction, acute tubular necrosis and renal insufficiency, and respiratory failure (due to pulmonary fibrosis) due to its inherent toxicity and lack of effective treatment. Intoxication via inhalation, injection and dermal or mucus contact have also been reported.", "ORPHA ID": 31827, "Summary": ""}
{"Disease Name": "Paratesticular adenocarcinoma", "Disease Definition": "A rare, locally invasive or malignant, urogenital tumor characterized by a gland-forming epithelial neoplasm arising from paratesticular structures, typically manifesting with a palpable scrotal mass, with or without hydrocele, and/or testicular pain.", "ORPHA ID": 363478, "Summary": ""}
{"Disease Name": "Parathyroid carcinoma", "Disease Definition": "A rare endocrine tumor characterized by a malignant neoplasm derived from parathyroid parenchymal cells, localized in one of the normally located parathyroid glands or other sites where parathyroid tissue may be present. Signs and symptoms are predominantly due to excess secretion of parathyroid hormone, with marked hypercalcemia and renal and bone involvement. In rare cases, the tumor may be non-functioning and only present as a palpable mass in the neck region. Recurrent laryngeal nerve paralysis is also observed. The tumor can occur sporadically or on a genetic background. The extent of invasion of adjacent structures positively correlates with the development of recurrent or metastatic disease.", "ORPHA ID": 143, "Summary": ""}
{"Disease Name": "Paratyphoid fever", "Disease Definition": "A rare form of salmonellosis caused by Salmonella enterica serovar Paratyphi A, B and C, characterized by typical symptoms of enteric fever including high fever, headache, abdominal pain and intestinal symptoms, dry cough, chills, and rashes, followed by a long period of recovery. The infection can be complicated by intestinal hemorrhage and perforation, as well as cardiac involvement, and may even be fatal. Transmission of the pathogen is via the fecal-oral route, with humans as the sole reservoir of infection.", "ORPHA ID": 443227, "Summary": ""}
{"Disease Name": "PARC syndrome", "Disease Definition": "PARC syndrome is a rare genetic developmental defect during embryogenesis syndrome characterized by the association of congenital poikiloderma (P), generalized alopecia (A), retrognathism (R) and cleft palate (C). There have been no further descriptions in the literature since 1990.", "ORPHA ID": 2825, "Summary": ""}
{"Disease Name": "Parenteral nutrition-associated cholestasis", "Disease Definition": "A rare hepatic disease characterized by intrahepatic cholestasis and deterioration of liver function in patients receiving parenteral nutrition for extended periods of time (signs may appear as early as within the first two weeks of initiation of parenteral nutrition). The condition commonly occurs in neonates and usually resolves with transition to enteral feeding, although severe cases may progress to liver fibrosis, cirrhosis, and portal hypertension.", "ORPHA ID": 567983, "Summary": ""}
{"Disease Name": "Parietal foramina with clavicular hypoplasia", "Disease Definition": "A rare genetic bone development disorder characterized by parietal foramina in association with hypoplasia of the clavicles (short abnormal clavicles with tapering lateral ends, with or without loss of the acromion). Additional features may include mild craniofacial dysmorphism (macrocephaly, broad forehead and frontal bossing). No dental abnormalities were reported.", "ORPHA ID": 251290, "Summary": ""}
{"Disease Name": "Paris-Trousseau thrombocytopenia", "Disease Definition": "Paris-Trousseau thrombocytopenia (TCPT) is a contiguous gene syndrome characterized by mild bleeding tendency, variable thrombocytopenia (THC), dysmorphic facies, abnormal giant alpha-granules in platelets and dysmegakaryopoiesis.", "ORPHA ID": 851, "Summary": ""}
{"Disease Name": "Parkes Weber syndrome", "Disease Definition": "A rare congenital complex vascular malformation syndrome characterized by overgrowth of a limb (most commonly a leg) involving bones and soft tissue, in association with capillary malformations usually in the form of port-wine stains and multiple arteriovenous fistulas with high-flow arteriovenous shunting. The latter can also lead to other severe complications including abnormal bleeding and heart failure. Lymphatic malformations may also be present.", "ORPHA ID": 90307, "Summary": ""}
{"Disease Name": "Parkinson-dementia complex of Guam", "Disease Definition": "A rare neurodegenerative disease characterized by extrapyramidal symptoms (rigidity, tremor, bradykinesia) and dementia, typically beginning in the fifth or sixth decade of life and progressing to a vegetative state with pelvicrural flexion contractures within few years. Oculomotor signs, olfactory dysfunction, and autonomic disturbances may also be observed. Neuropathological hallmarks are frontotemporally accentuated cerebral atrophy, as well as neurofibrillary tangles and neuronal loss in a characteristic distribution in cortical and subcortical regions. The disease is endemic to the Pacific island of Guam.", "ORPHA ID": 90020, "Summary": ""}
{"Disease Name": "Parkinsonian-pyramidal syndrome", "Disease Definition": "Parkinsonian-pyramidal syndrome is a rare, genetic, neurological disorder characterized by the association of both parkinsonian (i.e. bradykinesia, rigidity and/or rest tremor) and pyramidal (i.e. increased reflexes, extensor plantar reflexes, pyramidal weakness or spasticity) manifestations, which vary according to the underlying associated disease (e.g. neurodegenerative disease, inborn errors of metabolism).", "ORPHA ID": 171695, "Summary": ""}
{"Disease Name": "Paroxysmal cold hemoglobinuria", "Disease Definition": "Paroxysmal cold hemoglobinuria (PCH) is a very rare subtype of autoimmune hemolytic anemia (AIHA, see this term), caused by the presence of cold-reacting autoantibodies in the blood and characterized by the sudden presence of hemoglobinuria, typically after exposure to cold temperatures.", "ORPHA ID": 90035, "Summary": "Epidemiology\nPCH is thought to account for at most 2-10% of cases of AIHA, whose annual incidence is estimated to be between 1/35,000-1/80,000 in North America and Western Europe.\nClinical description\nAcute cases almost exclusively affect children and are often preceded by symptoms of infection. Chronic idiopathic cases also occur but are extremely rare. Acute cases of the disease are characterized by an abrupt onset with features of severe intravascular hemolysis including high fever, chills, back and/or leg pain. Other symptoms may include nausea, headache, vomiting and diarrhea. Typically hemoglobinuria occurs, producing dark red to black urine. Hemolysis can be severe and even life-threatening and results from exposure to cold, which may even be localized (eg from drinking cold water, from washing hands in cold water). Chronic forms of PCH are characterized by recurrent episodes of hemolysis precipitated by cold exposure.\nEtiology\nPCH is most often acute and occurs secondary to an infection, mainly upper respiratory, and the causative agent is often not identified. Late-stage or congenital syphilis was historically linked to cases of PCH in adulthood but this is becoming less and less common.\nDiagnostic methods\nDiagnosis is based on evidence of anemia linked to hemolysis, the presence of hemoglobin in urine, a positive result from the Donath-Landsteiner (DL) test and evidence of anti-P specificity of the IgG autoantibodies.\nDifferential diagnosis\nThe main differential diagnosis is acute cold AIHA (see this term) induced by an infection (for example Mycoplasma pneumoniae or the Epstein Barr virus) due to the presence of IgM autoantibodies which are cold agglutinins.\nManagement and treatment\nMost cases of PCH are self-limited so treatment is usually symptomatic, including keeping the patient warm and red blood cell transfusion if necessary. Patients with few clinical symptoms and slight anemia may not require drug therapy. Corticosteroids and splenectomy are usually ineffective and should not be considered. In cases of life-threatening PCH, plasmapheresis can temporarily dampen the hemolysis. Some patients may respond to rituximab, although responses are usually short-lived. If syphilis is present, treatment with antibiotics generally eliminates the concurrent hemolysis.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Marc MICHEL"}
{"Disease Name": "Paroxysmal dyskinesia", "Disease Definition": "Paroxysmal dyskinesia (PD) is a rare heterogenous group of movement disorders manifesting as abnormal involuntary movements that recur episodically and last only a brief time. PD includes paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD), paroxysmal exertion-induced dyskinesia (PED) and a variant form of PKD, infantile convulsion and choreoathetosis (ICCA syndrome) (see these terms).", "ORPHA ID": 1431, "Summary": "Epidemiology\nThe prevalence of PD is still unknown. The worldwide prevalence of PKD and PNKD is estimated to be 1/150,000 and 1/1,000,000 respectively.\nClinical description\nThe age of onset is typically in childhood. The paroxysmal movements are mainly dystonic and choreic but can be ballistic or a mixture of these. There is no alteration in consciousness. PD can be classified according to duration and precipitating factors and is thus divided into: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD) and paroxysmal exertion-induced dyskinesia (PED). Between attacks, patients are generally completely normal and neurological examination is typically normal. Infantile convulsion and choreoathetosis (ICCA syndrome) is considered a variant form of PKD.\nEtiology\nThe exact etiology of PD is still elusive and the causes multifactorial. A number of genes have been associated with different forms of PD, namely: PNKD (2q35) mutations have been found to cause PNKD in families whose attacks can be triggered by caffeine and alcohol, PRRT2 (16p11.2) mutations account for some families with PKD or ICCA syndrome, and SLC2A1 (solute carrier family 2 (facilitated glucose transporter), member 1) (1p34.2 ) mutations have been identified to cause PED.\nDiagnostic methods\nDiagnosis of PD is essentially based on medical history and clinical examination which includes recordings of dystonia, abnormal postures and tremor, electroencephalogram, brain imaging (computed tomography or magnetic resonance imaging) and blood chemistry. Diagnosis is confirmed by the detection of known pathogenic mutations.\nDifferential diagnosis\nPD can occur secondary to other disorders such as multiple sclerosis, Aicardi-Goutières syndrome (see these terms), myelopathy, cerebral palsy, cerebral infarcts and hemorrhages, focal seizures, encephalitis, radiculopathy, hypoparathyroidism, hypoglycemia and reflex sympathetic dystrophy.\nAntenatal diagnosis\nPrenatal diagnosis for pregnancies at increased risk for PRRT2, PNKD, and SLC2A1 mutations associated with familial PKD or ICCA syndrome, PNKD, and PED respectively is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at 15-18 weeks' gestation) or chorionic villus sampling (usually performed at 10-12 weeks' gestation). The disease-causing mutation of an affected family member must be identified in the family before prenatal testing can be performed.\nGenetic counseling\nPD can be sporadic or familial with autosomal dominant inheritance. Genetic counseling should be offered to all patients and families.\nManagement and treatment\nTreatment is different for each of the 4 subtypes. Attacks may be controlled with anticonvulsant drugs such as carbamazepine and phenytoin. Deep brain stimulation may act as a potential therapeutic option in medically refractory PD.\nPrognosis\nThe frequency of attacks typically diminishes with age in the familial cases and the disease often completely remits. There are no long term implications for life expectancy.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Sian SPACEY"}
{"Disease Name": "Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity", "Disease Definition": "A rare, genetic, paroxysmal dystonia disorder characterized by childhood to adolescent-onset of episodic paroxysmal choreoathetosis, triggered mainly by sudden movements, prolonged exercise, anxiety and emotional stress, in association with progressive spastic paraparesis (onest in adulthood), gait ataxia, mild to moderate cognitive impairment, and/or epileptic seizures. Episodes typically last from a few minutes to hours, have a variable frequency (daily to yearly), and are relieved by rest. Frequency of episodes tends to decrease with age.", "ORPHA ID": 53583, "Summary": ""}
{"Disease Name": "Paroxysmal exertion-induced dyskinesia", "Disease Definition": "Paroxysmal exertion-induced dyskinesia (PED) is a form of paroxysmal dyskinesia (see this term), characterized by painless attacks of dystonia of the extremities triggered by prolonged physical activities.", "ORPHA ID": 98811, "Summary": "Epidemiology\nThe prevalence is unknown but 20 sporadic cases and 9 families have been described to date.\nClinical description\nThe age of onset is usually in childhood, but may range from 1 to 30 years. PED is characterized by dyskinesias induced by prolonged exercise of 15-60 minutes of duration. The attacks last between 5 minutes and 2 hours and are typically restricted to the exercised limbs. The dystonic movements are usually bilateral and are aggravated by cold, psychological stress, fatigue and lack of sleep. The frequency of attacks varies between one per day to one per month. Brisk, deep tendon reflexes, developmental delay and intellectual disability (most frequently mild) may also be observed. In some familial forms, epilepsy or migraine can co-occur. PED can be associated with paroxysmal dystonic choreathetosis with episodic ataxia and spasticity, benign familial infantile seizures (BFIE), infantile convulsions and choreoathetosis (ICCA syndrome) or rolandic epilepsy - paroxysmal exercise-induced dystonia - writer's cramp (see these terms).\nEtiology\nThe pathophysiology of PED is still unknown but some familial cases were found to be associated with mutations in the SLC2A1 (solute carrier family 2 (facilitated glucose transporter), member 1) gene (1p34.2). SLC2A1 encodes the glucose transporter GLUT1. All mutations in this gene responsible for PED have been found to affect the ability of GLUT1 to transport glucose. It has thus been proposed that an energy deficiency upon exertion caused by a reduced glucose transport rate is a cause of this paroxysmal movement disorder in SLC2A1 related cases.\nDiagnostic methods\nThe diagnosis of PED relies on clinical examination and laboratory investigations showing hypoglycorrhachia and hypoglycemia. Electroencephalography (EEG) and brain imaging are normal. The diagnosis is confirmed by molecular genetic screening of SLC2A1 gene.\nDifferential diagnosis\nThe differential diagnosis includes paroxysmal kinesigenic dyskinesia (PKD), young adult-onset Parkinsonism and encephalopathy due to GLUT1 deficiency (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis for pregnancies at increased risk of PED is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at 15-18 weeks' gestation) or chorionic villus sampling (usually performed at 10-12 weeks' gestation). The disease-causing mutation of an affected family member must be identified in the family before prenatal testing can be performed.\nGenetic counseling\nSporadic and familial cases with autosomal dominant mode of inheritance have been reported for PED. Genetic counseling should be offered to patients and families.\nManagement and treatment\nThere is no specific cure or treatment but avoiding precipitating events such as prolonged physical exercise may largely improve the symptoms. Moreover, a ketogenic diet for patients may prevent attacks and may lead to improvement of developmental delay in affected children.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Sian SPACEY"}
{"Disease Name": "Paroxysmal extreme pain disorder", "Disease Definition": "A rare, genetic, neurological disorder characterized by severe episodic perirectal pain accompanied by skin flushing that is typically precipitated by defecation. Ocular and submaxillary pain, associated with triggers including cold or other irritants, may become more prominent with age.", "ORPHA ID": 46348, "Summary": "Epidemiology\nThis disorder is rare but about a dozen families have been described.\nClinical description\nThis condition presents at childbirth or in the first year of life with episodes of severe rectal and peri-rectal pain following bowel movements. This is often accompanied by reflex anoxic seizures (RAS). Finally, there can be a color change down one half of the body; either horizontally from the waist down or involving one half of the body as in the harlequin phenomenon. Adults experience similar attacks although they are rare. Triggers include defecation, tactile stimulation in the peri-rectal area, unexpected falls, sexual activity and vivid dreams. Older children and adult patients are affected by painful eye and jaw crises. Other symptoms that may accompany the pain include tonic nonepileptic seizures, tachycardia and bradycardia, bronchospasm, lacrimation, hypersalivation, and rhinorrhea. Patients may have any or all of these in different episodes. The pain is typically felt in the deep tissues and can start with an itch-like sensation, which becomes burning and escalates to sharp, lancinating or a stabbing sensation. Pain appears suddenly and can last from seconds to several minutes.\nEtiology\nThis disorder is caused by mutations in the sodium channel gene SCN9A (2q24.3). The mutations confer a gain-of-function by impairing fast-activation of sodium channel NaV1.7, which is preferentially expressed in dorsal root ganglion and sympathetic ganglion neurons.\nDiagnostic methods\nDiagnosis is based on a careful history, a normal examination and normal electroencephalography (EEG), electrocardiogram (ECG) and nerve conduction studies. Screening for SCN9A mutations can provide confirmatory information.\nDifferential diagnosis\nDifferential diagnoses include primary erythermalgia and hyperekplexia.\nGenetic counseling\nParoxysmal extreme pain disorder follows an autosomal dominant pattern of inheritance.\nManagement and treatment\nIn children it is important to manage the inevitable constipation that ensues from stool withholding secondary to fear of defecation. The frequency of painful episodes may be reduced by medications used in the management of chronic neuropathic pain disorders, namely anticonvulsants. Carbamazepine, an activity-dependent sodium channel blocker, is the most effective of these treatments.\nPrognosis\nWith maturation, rectal pain may be accompanied by or replaced by periocular or perimandibular pain.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Stephen G WAXMAN  - Dr Betsy R SCHULMAN"}
{"Disease Name": "Paroxysmal hemicrania", "Disease Definition": "A rare primary headache disorder characterized by multiple attacks of unilateral pain that occur in association with ipsilateral cranial autonomic symptoms. The hallmarks of this syndrome are the relative shortness of the attacks and the complete response to indomethacin therapy.", "ORPHA ID": 157835, "Summary": "Epidemiology\nParoxysmal hemicrania (PH) prevalence is unknown. There is a male-to-female ratio of 1:1.\nClinical description\nThe mean age of onset is 40 years (range 3-81 years). PH patients experience purely unilateral, severe to very severe attacks of head pain. The pain is often in the temporal, orbital or supraorbital region. The pain has an abrupt start and cessation and is accompanied by ipsilateral autonomic features, including lacrimation, conjunctival injection, rhinorrhoea, nasal congestion, periorbital oedema, facial flushing, miosis and/or ptosis. PH attacks last 2-30 minutes and occur more than 5 times a day up to 40 times a day with a mean of 11 a day. Patients can have unilateral photophobia and phonophobia ipsilateral to the side of the attack. Osmophobia, nausea or vomiting during the attacks has been reported. Although attacks are most usually spontaneous, attacks can be triggered by neck movements, or pressure over the neck or greater occipital nerves. PH can be classified as episodic or chronic, depending on the duration of pain-free period when untreated. Episodic paroxysmal hemicrania patients have bouts lasting from 7 days to 1 year and separated by pain-free periods more than 3 months, whereas in chronic patients the pain-free period is less than 3 months. As this is a primary headache disorder, patients have normal neurological tests.\nEtiology\nEtiology remains unclear.\nDiagnostic methods\nDiagnosis is based on clinical history and response to indomethacin. Patients with suspected paroxysmal hemicrania should undergo an oral indomethacin trial or placebo-controlled intramuscular indomethacin test. In adults, one could start with 25mg three times a day, titrating up to 75mg three times a day over the course of 3 weeks. With intramuscular indomethacin 100-200 mg could be used.\nDifferential diagnosis\nCluster headache is the main differential diagnosis, given the overlap in duration of the attacks. It is very important to differentiate PH from cluster headache, as treatment differs greatly.\nGenetic counseling\nRare cases of familial PH have been reported.\nManagement and treatment\nA complete response to indomethacin confirms the diagnosis of PH. Treatment with indomethacin with a median dose of 150 mg/day (ranging from 30-300mg/day) results in dramatic relief of the disabling symptoms caused by PH.\nPrognosis\nThis is a debilitating headache condition if not accurately diagnosed and managed.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Peter GOADSBY  - Dr Diana WEI"}
{"Disease Name": "Paroxysmal kinesigenic dyskinesia", "Disease Definition": "Paroxysmal kinesigenic dyskinesia (PKD) is a form of paroxysmal dyskinesia (see this term), characterized by recurrent brief involuntary hyperkinesias, such as choreoathetosis, ballism, athetosis or dystonia, triggered by sudden movements.", "ORPHA ID": 98809, "Summary": "Epidemiology\nThe prevalence is estimated to be 1/150,000 worldwide. PKD is the most common form of paroxysmal dyskinesia. Males are more commonly affected than females (sex ratio of 3 or 4 to 1) in the sporadic form.\nClinical description\nThe age of disease onset is typically in childhood or adolescence with a peak in puberty. PKD is triggered by a sudden movement from rest (such as rising from a chair or starting to walk, or by exercise) and is characterized by brief attacks of dystonia, chorea or athetosis movements preceded by aura (that usually last less than 1 min), without alteration of consciousness. Attacks are often unilateral, but can alternate or be bilateral, and their frequency is variable. Some patients have additional neurologic disorders such as benign familial infantile epilepsy (BFIE) (see this term). Infantile convulsion and choreoathetosis (ICCA; see this term) is considered to be a variable form of PKD.\nEtiology\nThe exact etiology of PKD is still unknown but the PRRT2 (proline-rich transmembrane protein 2) gene (16p11.2) is believed to be the major causative gene. The PRRT2 gene encodes a protein that is hypothesized to interact with the SNAP25 protein which plays a role in presynaptic neurotransmitter release. It has been postulated that mutations in PRRT2 lead to a reduction of SNAP25 resulting in the dysregulation of neurotransmitter release, thus causing the symptoms seen in PKD.\nDiagnostic methods\nThe clinical diagnosis of PKD relies on the following proposed criteria: (1) identification of kinesigenic trigger of the attacks; (2) short duration of attacks (<1min); (3) no loss of consciousness or pain during attacks; (4) exclusion of other organic diseases and normal neurologic examination in the case of primary PKD; (5) control of attacks with phenytoin or carbamazepine, if attempted; and (6) age of onset between 1 year and 20 years, if no family history of PKD. Moreover, molecular genetic screening of the PRRT2 gene may help to confirm the diagnosis.\nDifferential diagnosis\nThe differential diagnosis of PKD includes paroxysmal non-kinesigenic dyskinesia, juvenile myoclonic epilepsy, hyperekplexia, episodic ataxia, autosomal dominant nocturnal frontal lobe epilepsy, encephalopathy due to GLUT1 deficiency (see these terms) and shuddering attacks.\nGenetic counseling\nMore than 60% of the patients with PKD have a family history of a similar disorder. PKD is mainly a familial disorder with autosomal dominant inheritance and incomplete penetrance, but sporadic cases occur. Individuals with onset before 20 years of age, and having a positive family history, should be screened for PRRT2 mutations.\nManagement and treatment\nAttacks are suppressed or dramatically reduced by low-dose anticonvulsant medication such as carbamazepine or phenytoin. Moreover, treatment based on caffeine citrate, that may help to reduce the severity and frequency of attacks, has been described in a single case report.\nPrognosis\nThe prognosis of PKD is usually favorable, with improvement of the attacks and even remission in adulthood. A gender difference in prognosis is also observed, with woman having a better prognosis and a higher chance of complete remission. An improvement of attacks can also be observed during pregnancy.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Sian SPACEY"}
{"Disease Name": "Paroxysmal nocturnal hemoglobinuria", "Disease Definition": "Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder characterized by corpuscular hemolytic anemia, bone marrow failure and frequent thrombotic events.", "ORPHA ID": 447, "Summary": "Epidemiology\nAlthough PNH has been described worldwide, exact prevalence data are not available. It is estimated at 1/80,000 in France. An incidence estimate of about 1/770,000/year has been reported with a predicted prevalence of approximately 1/62,500 in Great Britain. Higher frequency is suggested in Southeast Asia and in the Far East. Men and women are equally affected.\nClinical description\nThe disease may occur at any age but it preferentially affects young adults. The variable clinical manifestations include hemolytic anemia, medium and large vessel thrombosis (mainly involving the hepatic, abdominal, cerebral, and dermal veins), and moderate to severe hematopoietic deficiency that may lead to pancytopenia. Pallor, fatigue and stress dyspnea with activity are the usual manifestations. Hemoglobinuria results in the production of classically dark urine during the night and in the morning (about 25 % of patients), and patients may present with renal insufficiency. Jaundice may be present. Depending on their localization, thromboses (which affect 30-40 % of untreated patients) may manifest as abdominal pain, hepatomegaly, ascites and headaches. PNH is a chronic disease with hemolytic crises that may be triggered by several factors such as common infection, vaccination, surgery or certain antibiotics. Bone marrow failure may occur prior, along, or as a late complication of the disease (40-50 % of cases).\nEtiology\nPNH is caused by somatic mutations in the PIGA gene (Xp22.1), encoding a protein involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. The mutation occurs in one or several hematopoietic stem cell(s) and leads to a lack (total or partial) of all GPI-anchored cell membrane proteins (the most important being CD55 and CD59, involved in the regulation of hemolysis due to complement).\nDiagnostic methods\nDiagnosis is based on the clinical features and presence of hemolytic anemia, especially since it is associated with thrombosis and/or peripheral blood cytopenia. Diagnosis is confirmed by flow cytometry to detect GPI-linked antigen deficiency in red cells, monocytes and granulocytes. Molecular analysis is unreliable for diagnosis as the causative mutations are non-homogenous and non-repetitive.\nDifferential diagnosis\nDifferential diagnoses include all the other forms of anemia (in particular autoimmune hemolytic anemia) and other causes of deep vein thromboses, according to their clinical presentation.\nManagement and treatment\nUntil 2007, treatment was primarily symptomatic: transfusions, use of anticoagulants and treatment of an associated aplasia. In June 2007, the monoclonal antibody Eculizumab received an orphan drug designation in Europe for the treatment of PNH. It reduces significantly the hemolysis, the need of transfusions, fatigue, the occurrence of thrombosis, the risk of renal failure, and improves the patients' survival. Bone marrow transplantation can cure PNH but is only indicated in case of severe associated medullar aplasia, due to the severe complications of this technique in this context.\nPrognosis\nThe 6-year survival of patients treated since 2005 is 92 %, and median survival has increased significantly due to the use of Eculizumab and improvements in both supportive measures and management of disease complications.\n\n                            Last update: \n                            October 2017\n\n\n                            - Expert reviewer(s): \n                            Pr Régis PEFFAULT DE LA TOUR  - Dr Flore SICRE DE FONTBRUNE  - Pr Gérard SOCIE"}
{"Disease Name": "Paroxysmal non-kinesigenic dyskinesia", "Disease Definition": "Paroxysmal non-kinesigenic dyskinesia (PNKD) is a form of paroxysmal dyskinesia (see this term), characterized by attacks of dystonic or choreathetotic movements precipitated by stress, fatigue, coffee or alcohol intake or menstruation.", "ORPHA ID": 98810, "Summary": "Epidemiology\nThe prevalence of PNKD is estimated to be 1/1,000,000 worldwide. A male preponderance is observed (1.4:1).\nClinical description\nThe age of onset is variable ranging from 1 to 77 years. PNKD is characterized by attacks of spontaneous or induced (by alcohol, caffeine, stress, menstruation, sleep deprivation or exercise) dystonia, chorea, athetosis and ballism in the limbs, face, and trunk lasting from minutes to hours without a change in the level of alertness. The movements can be partial and unilateral, but are mostly bilateral and generalized. The frequency of the attacks varies from 1-3 per day to months of attack-free intervals. Dysarthria and oculogyric crisis can also be observed during episodes of severe attacks. An aura-like sensation (paresthesia, tension in the limbs or dizziness) prior to the onset of the motor manifestations and migraine headaches may be observed. Symptomatic PNKD is most commonly reported in association with multiple sclerosis (see this term) or vascular thalamic lesions.\nEtiology\nThe pathophysiology of PNKD still remains to be elucidated but approximately 60% of patients exhibit mutations in the PNKD gene (2q35), encoding the PNKD protein (formerly named myofibrillogenesis regulator 1 protein, MR-1). Furthermore, subsequent linkage analysis in a Canadian kindred identified a novel gene locus at chromosome 2q31 (named PNKD2).\nDiagnostic methods\nThe diagnosis is purely clinical and molecular screening of the PNKD gene can help to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis of PNKD includes: Wilson disease, paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions and choreoathetosis (ICCA syndrome), paroxysmal exertion-induced dyskinesia (PED), autosomal dominant nocturnal frontal lobe epilepsy, paroxysmal dystonic choreathetosis with episodic ataxia and spasticity, and Huntington disease (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis for pregnancies at increased risk of having PNKD mutations associated with familial PNKD is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at 15-18 weeks' gestation) or chorionic villus sampling (usually performed at 10-12 weeks' gestation). The disease-causing mutation of an affected family member must be identified in the family before prenatal testing can be performed.\nGenetic counseling\nAlthough sporadic cases have been reported, PNKD is usually inherited as an autosomal dominant trait with high penetrance. Haplotype analysis in the PNKD2 family demonstrated a disease penetrance of 89%.\nManagement and treatment\nPNKD patients do not respond to antiepileptic drugs such as carbamazepine, but clonazepam or other benzodiazepines can be helpful in some PNKD mutation carrier patients. Because PNKD may be triggered by emotional stress, fatigue, alcohol or caffeine, the avoidance of these possible precipitating factors is recommended. Deep brain stimulation may act as a potential therapeutic option in medically refractory PNKD.\nPrognosis\nNo long-term sequelae are associated with PNKD. Moreover, 61% of patients with PNKD show a tendency to decrease the frequency of their attacks with age. However, in some patients, episodes may remain unchanged or worsen with age. Disappearance of attacks during pregnancy has also been described.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Sian SPACEY"}
{"Disease Name": "Partial androgen insensitivity syndrome", "Disease Definition": "A difference of sex development (DSD) distinct from complete AIS (CAIS) characterized by the presence of abnormal genital development in a 46,XY individual with normal testis development and partial responsiveness to age-appropriate levels of androgens.", "ORPHA ID": 90797, "Summary": "Epidemiology\nThere are no available data on the prevalence of PAIS in the general population. Nevertheless, resistance to androgens is the most frequent cause of XY DSD.\nClinical description\nPatients have a highly variable genital appearance. The prototypic form of presentation is severe hypospadias, micropenis, and bifid scrotum in which the testes may or may not be descended. In the more severe form of PAIS, patients have female external genitalia with clitoromegaly, partial labial fusion and labial swellings comprising testes. A mild end of the spectrum, labeled MAIS (mild or minimal AIS), is a male with gynecomastia at puberty or an adult presenting with male factor infertility.\nEtiology\nThe condition is due to missense mutations in the androgen receptor (AR) gene (Xq11-12) coding for the AR nuclear transcription factor, and results in variable degrees of AR function. An AR mutation is found in only approximately 20% of patients with PAIS.\nDiagnostic methods\nThe diagnosis is based on clinical and biochemical findings in XY patients with varying degrees of under-masculinization. The typical hormone profile is increased luteinizing hormone (LH) and testosterone levels, which is used as a screening test for MAIS with male factor infertility. Serum anti-Mullerian hormone (AMH) levels may be normal or increased. A pelvic ultrasound, MRI or cysto-urethroscopy confirm the presence of Wolffian duct structures and the absence of Müllerian structures. A utriculus or vaginal remnant is often visualized on urethroscopy. Positive mutation analysis of the AR gene and the mutant AR confirmed to be pathogenic in a reporter gene assay confirms the diagnosis.\nDifferential diagnosis\nHuman chorionic gonadotropin (hCG) stimulation should be performed to exclude an androgen biosynthetic defect. A urinary steroid profile is reliable to exclude 5-alpha-reductase deficiency (see this term) after six months of age. Other differential diagnoses include 46,XY partial gonadal dysgenesis, congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency, Denys-Drash syndrome, Smith-Lemli-Opitz syndrome (see these terms), and PAIS with a normal AR. The latter condition is strongly associated with low birth weight due to fetal growth restriction.\nAntenatal diagnosis\nAntenatal diagnosis is seldom indicated.\nGenetic counseling\nThe condition is X-linked recessive. Affected families should be offered genetic counseling only when an AR gene mutation has been identified and shown to be pathogenic. Counseling should be based on the variable expression of the same AR mutation between, and even within, affected families.\nManagement and treatment\nManagement depends on the sex of rearing that the parents and healthcare professionals should assign as early as possible in infancy. Those raised as male require hypospadias repair (two procedures or more) and orchiopexy for undescended testes. Those raised as female need gonadectomy before puberty and puberty induction with estrogen. The onset of puberty in PAIS patients raised male is unpredictable and large doses of androgens may be required to induce adequate virilization. Gynecomastia is treated by reduction mammoplasty. High dose androgens can rarely restore fertility in MAIS patients. Psychological support from birth to adulthood is necessary.\nPrognosis\nPrognosis is variable in terms of sexual function and quality of life in those raised male. Infertility is invariable. There is an increased risk of gonadal tumor, particularly if the testis remains undescended.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Ieuan HUGHES"}
{"Disease Name": "Partial atrioventricular septal defect", "Disease Definition": "A rare congenital cardiac malformation that is a variant of an atrioventricular septal defect (AVSD) with an interatrial communication (ostium primum defect) just above the common atrioventricular (AV) valve, no interventricular communication just below the atrioventricular valve, a common atrioventricular junction but separate right and left atrioventricular valvar orifices, and a three-leaflet, left-sided component of the common atrioventricular valve (''cleft''). Shunting is restricted to the atrial level because of fusion of the leaflets of the common AV valve with the crest of the ventricular septum.", "ORPHA ID": 1330, "Summary": "Epidemiology\nPartial atrioventricular septum defect (PAVSD) accounts for 1-2% of all congenital heart malformations and its prevalence is estimated to be 1/5,000-1/2,500.\nClinical description\nMost patients with PAVSD are asymptomatic until late in life. The clinical presentation depends on the degree of mitral regurgitation and on the associated cardiac defects. The two most common clinical manifestations are impaired exercise capacity and exertional dyspnea. Rarely, cardiac failure may occur in infancy. Additional features in adults include palpitations, presyncope or syncope, and sustained atrial arrhythmias. The ventricles may be equal or nearly equal in size (balanced) or one of the ventricles may be significantly larger than the other (unbalanced). Unbalanced ventricles are associated with hypoplasia of the arterial valve above and aortic coarctation if the left ventricle is hypoplastic.\nEtiology\nCRELD1 (3p25.3), GATA4 (8p23.1-p22), GATA6 (18q11-q12) and NR2F2 (15q26) have been associated with a small fraction of PAVC cases. These genes encode developmental transcription factors that are critical for normal cardiac morphogenesis.\nDiagnostic methods\nDiagnosis of PAVC is established by means of 2D-echocardiography. Transesophageal echocardiography or cardiac catheterization can be useful in adults (to assess pulmonary vascular resistance and status of the left AV valve and, in patients > 40 years, to exclude coexisting coronary arterial disease). An elevated pulmonary arterial pressure and moderate to severe left atrioventricular valve regurgitation may be observed. First-degree AV block, right bundle branch block, and a superior QRS axis may be noted on electrocardiogram.\nDifferential diagnosis\nDifferential diagnosis includes the complete and intermediate forms of atrioventricular septal defects. Intermediate (transitional) atrioventricular septal defect is a variant of complete atrioventricular septal defect with a restrictive ventricular component due to multiple attachments of the bridging leaflets on the crest of the ventricular septum. PAVSD may be associated with syndromes including the RASopathies (particularly Noonan syndrome caused by mutations in PTPN11 and RAF1), Ellis Van Creveld and Down, and CHARGE syndrome.\nAntenatal diagnosis\nPAVSD may be detectable prenatally by 4-chamber view screening during obstetric ultrasonography.\nManagement and treatment\nThe early diagnosis of PAVSD requires cardiology follow-up and elective complete repair between 3 and 5 years of age, which involves closure of a primum atrial septal defect with an appropriately shaped patch through right atriotomy, and partial suture of the ''cleft'' of the left component of the common atrioventricular valve. A pacemaker insertion may be required for complete AV block, which may spontaneously develop after repair. A continuous lifelong follow-up is recommended to avoid late complications. Symptom free patients may be referred for PAVSD repair because of a substantial left-to right atrial shunt (pulmonary to systemic flow ratio 1.8:1) and echocardiographic evidence of right heart volume overload.\nPrognosis\nLong-term survival after repair of partial AVSD is the rule. The elective age for repair is 3-5 years, but some patients will not present until later in life. The later the repair is made, the greater the loss of ventricular function that occurs. High morbidity and need for reoperation, often related to residual problems of the systemic AV valve such as LAVV regurgitation, may be observed. Furthermore, the prognosis can be severely impaired if the left ventricle and left component of the common atrioventricular valve are hypoplastic or severely malformed. Norwood-type intervention in infancy can be required, as well as prosthetic replacement of the left AV valve.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Lucile HOUYEL"}
{"Disease Name": "Partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome", "Disease Definition": "Partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome is a rare, hereditary, cerebral malformation with epilepsy syndrome characterized by severe global developmental delay with no ability to walk and no verbal language, intractable epilepsy, partial agenesis of the corpus callosum and cerebellar vermis hypoplasia with posterior fossa cysts.", "ORPHA ID": 401959, "Summary": ""}
{"Disease Name": "Partial hydatidiform mole", "Disease Definition": "A form of hydatiform mole characterized by abnormal hyperplastic trophoblasts and hydropic villi due to fertilization of a normal ovocyte by two spermatozoa or one abnormal spermatozoon (allowing for some fetal development), and that manifests with vaginal bleeding accompanied by nausea and frequent vomiting, hyperemesis gravidarum, hyperthyroidism and risk of spontaneous miscarriage.", "ORPHA ID": 254693, "Summary": ""}
{"Disease Name": "Partial pancreatic agenesis", "Disease Definition": "Partial agenesis of the pancreas is characterized by the congenital absence of a critical mass of pancreatic tissue.", "ORPHA ID": 2805, "Summary": "Epidemiology\nIt is a rare disorder with only around 50 cases being reported in the literature so far.\nClinical description\nThe severity of the disease depends on the amount of functional pancreatic tissue present. Pancreatic agenesis is commonly associated with other malformations, in particular pancreaticobiliary duct anomalies, leading to acute or chronic pancreatitis, hyperglycemia (50% of cases), or, more rarely, polysplenia. In the majority of cases, patients are diagnosed after reporting abdominal pain. Agenesis of the dorsal pancreas usually manifests as diabetes.\nEtiology\nPancreatic agenesis has been associated with mutations in the PDX1 gene (13q12.2), which encodes the insulin promoter factor-1 (IPF-1) transcription factor. In addition, missense mutations in the PTF1A gene (10p12.3) have been found to be responsible for the autosomal recessive syndrome of neonatal diabetes mellitus associated with cerebellar and/or pancreatic agenesis (see this term).\nDiagnostic methods\nDiagnosis is made by imaging studies revealing the partial absence of the pancreas.\nDifferential diagnosis\nThe principle differential diagnosis is pancreas divisum.\nManagement and treatment\nManagement involves treatment of the diabetes and exocrine deficiency, when present.\nPrognosis\nThe prognosis for patients is variable, depending on the quality of treatment received.\n\n                            Last update: \n                            May 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Frédéric BARGY  - Pr Pierre BOUGNERES"}
{"Disease Name": "Partial septate uterus", "Disease Definition": "Partial septate uterus is a rare, non-syndromic uterovaginal malformation characterized by a uterus that has a longitudinal septum which extends from the uterine fundus and does not reach the internal cervical os (variable lengths and widths may be observed). Although frequently asymptomatic, an increased risk of poor reproductive outcome has been observed. Urinary tract abnormalities are very rarely associated.", "ORPHA ID": 180129, "Summary": ""}
{"Disease Name": "Partially involuting congenital hemangioma", "Disease Definition": "A rare congenital hemangioma characterized by a superficial, red to violaceous lesion with overlying telangiectasia and a surrounding pale halo, which initially behaves like a rapidly involuting congenital hemangioma, beginning to involute shortly after birth. Involution is then aborted, and a residual tumor virtually indistinguishable from non-involuting congenital hemangioma remains. This lesion grows proportionally with the child and does not regress.", "ORPHA ID": 458785, "Summary": ""}
{"Disease Name": "Partington syndrome", "Disease Definition": "Partington syndrome is a form of syndromic X-linked mental retardation (S-XLMR) characterised by the association of mild to moderate intellectual deficit, dysarthria and dystonic hand movements. So far, less than 20 cases have been described in the literature. The syndrome is caused by mutations in the Aristaless-related homeobox (ARX) gene (Xp22.13). Transmission is X-linked recessive.", "ORPHA ID": 94083, "Summary": ""}
{"Disease Name": "PASH syndrome", "Disease Definition": "A rare skin disease belonging to the spectrum of autoinflammatory syndromes characterized by the triad of pyoderma gangrenosum (PG), suppurative hidradenitis (SH) and acne.", "ORPHA ID": 289478, "Summary": ""}
{"Disease Name": "Patent ductus arteriosus-bicuspid aortic valve-hand anomalies syndrome", "Disease Definition": "A rare heart-hand syndrome that is characterized by a variety of cardiovascular anomalies including patent arterial duct, bicuspid aortic valve and pseudocoarctation of the aorta in conjunction with hand anomalies such as brachydactyly and ulnar ray derivative i.e. fifth metacarpal hypoplasia.", "ORPHA ID": 228190, "Summary": ""}
{"Disease Name": "Patent urachus", "Disease Definition": "Patent urachus is a type of congenital urachal anomaly (see this term) characterized by a persistent communication between the bladder and the umbilicus, secondary to non occlusion of the urachal lumen, manifesting as clear drainage from the umbilicus.", "ORPHA ID": 431341, "Summary": ""}
{"Disease Name": "Paternal 20q13.2q13.3 microdeletion syndrome", "Disease Definition": "Paternal 20q13.2q13.3 microdeletion syndrome is a recently described syndrome characterized by severe pre- and post-natal growth retardation, microcephaly, intractable feeding difficulties, mild psychomotor retardation, hypotonia and facial dysmorphism.", "ORPHA ID": 261304, "Summary": "Epidemiology\nIt has been reported in 2 unrelated patients.\nClinical description\nFacial dysmorphism includes high forehead, broad nasal bridge, thin upper lip, small chin and malformed ears. In addition, the patients presented with skin, iris and hair hypopigmentation and abnormal adipose tissue distribution.\nEtiology\nThe syndrome is caused by an interstitial deletion of paternal origin at 20q13.2q13.3. In the 2 cases, the deletion was approximately 4.5Mb in size and encompassed the GNAS imprinted locus; the loss of the paternally expressed GNAS gene might account for the severe pre- and post-natal retardation and intractable feeding difficulties observed in the patients.\n\n                            Last update: \n                            June 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "Paternal uniparental disomy of chromosome 1", "Disease Definition": "Paternal uniparental disomy of chromosome 1 is an uniparental disomy of paternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only father is a carrier.", "ORPHA ID": 251004, "Summary": ""}
{"Disease Name": "Paternal uniparental disomy of chromosome 13", "Disease Definition": "Paternal uniparental disomy of chromosome 13 is an uniparental disomy of paternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only father is a carrier.", "ORPHA ID": 99324, "Summary": ""}
{"Disease Name": "Paternal uniparental disomy of chromosome 20", "Disease Definition": "Paternal uniparental disomy of chromosome 20 is a very rare chromosomal anomaly in which both copies of chromosome 20 are inherited from the father. The main features described are high birth weight and/or early-onset obesity, relative macrocephaly, and tall stature. Most patients were ascertained during sporadic pseudohypoparathyroidism type 1b (see this term) testing and have UPD involving variable segments of the long arm of chromosome 20.", "ORPHA ID": 96194, "Summary": ""}
{"Disease Name": "Paternal uniparental disomy of chromosome 21", "Disease Definition": "Paternal uniparental disomy of chromosome 21 is an uniparental disomy of paternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only father is a carrier.", "ORPHA ID": 96195, "Summary": ""}
{"Disease Name": "Paternal uniparental disomy of chromosome 5", "Disease Definition": "Paternal uniparental disomy of chromosome 5 is an uniparental disomy of paternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only father is a carrier.", "ORPHA ID": 96190, "Summary": ""}
{"Disease Name": "Paternal uniparental disomy of chromosome 6", "Disease Definition": "Paternal uniparental disomy of chromosome 6 is an uniparental disomy of paternal origin characterized by intrauterine growth retardation, transient neonatal diabetes mellitus, and macroglossia.", "ORPHA ID": 96191, "Summary": ""}
{"Disease Name": "Paternal uniparental disomy of chromosome 7", "Disease Definition": "Paternal uniparental disomy of chromosome 7 is an uniparental disomy of paternal origin that most likely do not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only father is a carrier (e.g., cystic fibrosis, congenital chloride diarrhea, sensorineural hearing loss).", "ORPHA ID": 96192, "Summary": ""}
{"Disease Name": "Paternal uniparental disomy of chromosome X", "Disease Definition": "A uniparental disomy of paternal origin that does not seem to have an adverse impact on the phenotype of an individual. There is a possibility of homozygosity for a recessive disease mutation for which the father is a carrier and specific phenotype depends on the inherited disorder.", "ORPHA ID": 261524, "Summary": ""}
{"Disease Name": "Patterson-Stevenson-Fontaine syndrome", "Disease Definition": "Patterson-Stevenson-Fontaine syndrome is a very rare variant of acrofacial dysostosis characterized by mandibulofacial dysostosis and limb anomalies.", "ORPHA ID": 2439, "Summary": "Epidemiology\nIt has been described in less of ten patients.\nClinical description\nThe mandibulofacial dysostosis consists of retrognathism, complete or occult posterior cleft palate, and anomalies of the external ears. Limb anomalies consist of split-foot deformity with syndactyly of some toes.\nGenetic counseling\nThe condition is transmitted as an autosomal dominant trait with variable penetrance and expressivity.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Pauci-immune glomerulonephritis with ANCA", "Disease Definition": "A form of pauci-immune glomerulonephritis characterized by a rapidly progressive glomerulonephritis in association with the presence of circulating antineutrophilic cytoplasmic antibodies (ANCA), mostly directed against proteinase-3 (PR3) and myeloperoxidase (MPO). Patients usually present with urinary abnormalities and rapidly declining renal function, often leading to dialysis within weeks without treatment. Cutaneous, pulmonary, musculoskeletal and nervous involvement may be observed in case of systemic disease, and the correlation between ANCA titer and disease activity has been demonstrated.", "ORPHA ID": 97563, "Summary": ""}
{"Disease Name": "Pauci-immune glomerulonephritis without ANCA", "Disease Definition": "A form of pauci-immune glomerulonephritis characterized by rapidly progressive glomerulonephritis and the absence of antineutrophilic cytoplasmic antibodies (ANCA). In comparison with pauci-immune GN with ANCA, patients lacking ANCA may be younger at onset of the disease, have fewer extra renal manifestations (e.g. involvement of lung, eye, ear, nose and throat), fewer constitutional symptoms (e.g. fever, weight loss, muscle pain and arthralgia) and a high prevalence of nephrotic syndrome and chronic renal lesions. The prognosis is generally poorer.", "ORPHA ID": 97564, "Summary": ""}
{"Disease Name": "Pauci-immune glomerulonephritis", "Disease Definition": "A rare small vessel vasculitis associated with rapidly progressive glomerulonephritis (GN) and clinically characterized by renal manifestations such as urinary abnormalities (hematuria and/or proteinuria) and hypertension leading to renal failure within days or weeks, and distinguished by the absence of immune deposits on immunofluorescent microscopy. The disease can occur as a renal-limited disease or as a component of systemic necrotizing small-vessel vasculitis.", "ORPHA ID": 93126, "Summary": "Epidemiology\nPauci-immune GN is the most common cause of rapidly progressive glomerulonephritis. The incidence of pauci-immune GN in the United States is estimated at 3.1/1,000,000, with significantly higher rates for Caucasians, males and individuals over 65. In the European population, the incidence is estimated between 1-2/100,000, with an increasing trend in recent years.\nClinical description\nPatients with pauci-immune GN may present with different clinical pictures, and predominantly occurs in patients over 55 years of age, although rarely it may occur earlier. Most patients report a prodromal 'flu-like' illness preceding the overt vasculitic syndrome. Pauci-immune GN can occur as a renal-limited disease or as a component of systemic vasculitis. Systemic symptoms including fever, asthenia, arthralgias, weight loss, and myalgias can precede the renal presentation of the disease. Clinically, it is characterized by renal manifestations such as urinary abonormalities (hematuria and/or proteinuria) and hypertension leading to renal failure within days or weeks. It can also be associated with extrarenal manifestations depending on the disease process and may involve the upper and lower respiratory tract, nerves, skin, and musculoskeletal system. Risk factors for progression to end stage renal disease (ESRD) include increased initial serum creatinine or decreased estimated glomerular filtration rate (eGFR) at baseline, older age, presence of pulmonary hemorrhage, and dialysis-dependent acute kidney injury.\nDiagnostic methods\nThe disease is associated with the presence of serum anti-neutrophil cytoplasmic antibodies (ANCAs) in a high percentage of subjects. Renal biopsy is essential for the diagnosis and subsequent management of pauci-immune GN, and is used to to determine the activity and chronicity of the renal lesions as well as the risk associated with immunotherapy of ANCA pauci-immune necrotizing glomerulonephritis. The histological hallmarks of the disease are the presence of extracapillary proliferation and segmental necrosis on light microscopy, and the absence of immune deposits on immunofluorescence microscopy. Immunologic classification is based on the presence or absence of circulating ANCAs, namely pauci-immune-GN with ANCAs and pauci-immune GN without ANCAs. Other laboratory data such as erythrocyte sedimentation rate, C-reactive protein (CRP) and urine test are not specific but can help with the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other forms of crescentic GN.\nManagement and treatment\nConventional induction therapies for pauci-immune GN have been defined and include Cyclophosphamide (CYC) for at least 3 months, with a corticosteroid taper followed by maintenance immunosuppression for up to 2 years with azathioprine or mycophenolate mofetil. Clinical trials have shown that rituximab (RTX) is an effective induction therapy for pauci-immune ANCA-associated GN. Since preventing relapses and maintaining remission are critical to slowing chronic kidney disease (CKD) progression to ESRD in this group of patients, a number of trials have focused on repeat doses of RTX at 4/6 month intervals. As with other forms of CKD, patients with stable but decreased eGFR usually benefit from blood pressure control with long-term inhibition of RAAS axis to reduce glomerular hyperfiltration, a low-sodium diet, and moderate protein intake.\nPrognosis\nDespite the substantial progress in treatment, pauci-immune glomerulonephritis remain a group of diseases with significant morbidity and mortality related to the disease itself. Renal involvement is one of the most threatening aspects\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Roberta FENOGLIO | ERKNet* - Pr Dario ROCCATELLO | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "PCNA-related progressive neurodegenerative photosensitivity syndrome", "Disease Definition": "A rare developmental defect during embyogenesis caused by homozygous mutations in the PCNA gene and characterized by neurodegeneration, postnatal growth retardation, prelingual sensorineural hearing loss, premature aging, ocular and cutaneous telangiectasia, learning difficulties, photophobia, and photosensitivity with evidence of predisposition to sun-induced malignancy. Progressive neurologic deterioration leads to gait disturbances, muscle weakness, speech and swallowing difficulties and progressive cognitive decline.", "ORPHA ID": 438134, "Summary": ""}
{"Disease Name": "PDE4D haploinsufficiency syndrome", "Disease Definition": "PDE4D haploinsufficiency syndrome is a rare syndromic intellectual disability characterized by developmental delay, intellectual disability, low body mass index, long arms, fingers and toes, prominent nose and small chin.", "ORPHA ID": 439822, "Summary": ""}
{"Disease Name": "Pearson syndrome", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder due to large-scale single deletion of mitochondrial DNA characterized by hyporegenerative anemia in early infancy with vacuolization of bone marrow precursors, lactic acidosis and multi-organ dysfunctions such as exocrine pancreatic dysfunction, and renal tubulopathy.", "ORPHA ID": 699, "Summary": "Epidemiology\nApproximately 200 cases have been reported in the literature. Both males and females are affected. The prevalence of Pearson syndrome is approximately 1/1,000,000.\nClinical description\nMost patients present with sideroblastic anemia in infancy. Additional symptoms comprise failure to thrive, neurological (hypotonia, speech delay, muscular hypertrophy) and gastrointestinal (vomiting, chronic diarrhea and feeding difficulties) symptoms. All organs can be affected and various complications develop during the course, which are generally irreversible. Hepatic dysfunction (hepatomegaly, splenomegaly), exocrine pancreatic insufficiency and renal tubulopathy are common early complications, while ophthalmological complications (such as retinitis pigmentosa and cataract) and cardiac conduction defects usually occur at a later stage of the disease. Patients often develop multiple endocrine disorders. Interestingly, hematological recovery spontaneously occurs in a majority of patients at 1-3 years of age, while some patients develop myeloid neoplasms in early childhood. Patients who survive early infancy can demonstrate a Kearns-Sayre syndrome-like phenotype.\nEtiology\nPearson syndrome is caused by large-scale mitochondrial DNA (mtDNA) deletions which lead to a deficiency in mitochondrial respiratory chain function. Heteroplasmy (mixture of both wild-type and deleted mtDNA in the same cell) can be observed in patients and explains the high variability in clinical expression, both between patients and between the various organs of an affected subject. Cellular dysfunction appears only if the level of heteroplasmy exceeds a certain critical threshold.\nDiagnostic methods\nThe diagnosis of Pearson syndrome is usually suspected based on the typical bone marrow cytology with vacuolization in erythroid and myeloid precursors. Iron staining reveals ring-sideroblasts in 70-85% of patients. The diagnosis should be confirmed by genetic testing (detection of large-scale mtDNA deletion).\nDifferential diagnosis\nPatients with Pearson syndrome can be misdiagnosed as Diamond-Blackfan anemia, a congenital hypogenerative anemia that presents in infancy.\nGenetic counseling\nMost cases are sporadic. Although deleted mtDNA can be maternally inherited, the unpredictable heteroplasmy status in a child makes genetic counseling challenging.\nManagement and treatment\nSimilar to the majority of patients with primary mitochondrial diseases, there is no curative therapy for children with Pearson syndrome. Therapy is largely supportive and includes blood transfusions, treatment of infections, prevention of metabolic decompensations, and therapy for various organ complications such as pancreatic insufficiency and endocrine disorders. Most patients receive supplements such as coenzyme Q10, L-carnitine and/or various vitamins, despite limited evidence for efficacy.\nPrognosis\nPatients with Pearson syndrome have a dismal prognosis. About half of patients die by 4 years of age. Patients who reach 15 years of age are rare. The most common cause of death is metabolic decompensation with lactic acidosis. Patients who survive early infancy typically undergo phenotypic change: hematological manifestations spontaneously resolve, whereas neurological and myopathic signs either appear or worsen. Some patients develop Kearns-Sayre syndrome (KSS) with ophthalmoplegia, ataxia, pigmentary retinitis, conduction defects and myopathy.\n\n                            Last update: \n                            May 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Sarah GRÜNERT | MetabERN* - Dr Ayami YOSHIMI | PaedCan-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Pectus excavatum-macrocephaly-dysplastic nails syndrome", "Disease Definition": "Pectus excavatum-macrocephaly-dysplastic nails syndrome is a rare multiple congenital anomalies syndrome characterized by relative macrocephaly, pectus excavatum, short stature, nail dysplasia, and motor developmental delay (that resolves during childhood). There have been no further descriptions in the literature since 1992.", "ORPHA ID": 2835, "Summary": ""}
{"Disease Name": "Pediatric arterial ischemic stroke", "Disease Definition": "A rare neurologic condition characterized by focal cerebral ischemia and infarction due to blockage of a brain artery with subsequent impairment of blood supply and oxygenation of brain tissue. Most children present with hemiparesis with or without facial palsy at stroke onset. In addition, compared to adults, children more often suffer strokes in the posterior circulation, leading to ataxia or oculomotor disturbance. Likewise, aphasia is more frequent in pediatric patients. Other signs and symptoms include seizures, headache, vomiting, and alterations in the level of consciousness. Children under one year of age are more likely to present with seizures and altered level of consciousness, while older children more often show focal neurological deficits.", "ORPHA ID": 439175, "Summary": ""}
{"Disease Name": "Pediatric collagenous gastritis", "Disease Definition": "A rare gastroenterologic disease characterized by the histopathological finding of a thickened (> 10 µm) gastric subepithelial collagen layer in association with an inflammatory infiltrate in the lamina propria. Patients typically present with upper abdominal pain and severe iron deficiency anemia. The condition is not commonly associated with autoimmune diseases, and involvement of the colon is less frequent than in the adult form. The disease takes a generally benign course with limited long-term morbidity and no increased mortality.", "ORPHA ID": 487809, "Summary": ""}
{"Disease Name": "Pediatric hepatocellular carcinoma", "Disease Definition": "A rare, aggressive and malignant hepatic tumor arising from the hepatocytes. It develops mainly in children over 10 years of age, either in a cirrhotic background, or more commonly in a non-cirrhotic background (70% of cases).", "ORPHA ID": 33402, "Summary": "Epidemiology\nPrimary liver malignancies are rare in children and adolescents. Hepatocellular carcinoma (HCC) constitutes less than 25% of them. Annual incidence is about 1/2,000,000, with higher incidence rates found in sub-Saharan Africa and Southeast Asia as a result of endemic hepatitis B (HBV) and aflatoxin exposure. HCC is found more frequently in males (2-3:1). Incidence is higher among adolescents (1/1,250,000).\nClinical description\nHCC mostly develops in pediatric patients with no underlying liver disease, unlike in adults, when it is usually associated with hepatic cirrhosis due to alcohol intake. Pediatric HCC is mostly found in children and adolescents and rarely in children under 5 years of age. The main presenting manifestations are abdominal mass with pain, swelling and discomfort, weight loss, and anorexia. Splenomegaly, nausea, vomiting and jaundice are less commonly observed. Metastases to the mediastinal lymph nodes, lungs, brain and bone marrow are common in advanced disease (25% at presentation). HCC may be associated with congenital diseases, such as biliary atresia, tyrosinemia type 1 (in 50% of cases), alpha-1-antitrypsin deficiency, progressive familial intrahepatic cholestasis, Alagille or Gardner syndrome, Wilson or glycogen storage diseases I-IV, Fanconi anemia, familial adenomatous polyposis (FAP), focal nodular hyperplasia and hemochromatosis. A specific HCC variant, fibrolamellar carcinoma (FLC), occurs in older children and young adults, and has an equally dismal prognosis despite a slower growth and less tendency to metastasize.\nEtiology\nThe pathophysiology of HCC is not well understood. Underlying liver dysfunction is the main predisposing condition (HBV, HCV). Children with neonatal hepatitis, intrahepatic cholestasis, biliary atresia, glycogen-storage diseases and other types of cirrhotic diseases are predisposed to the tumor. The Wnt/beta-catenin pathway is frequently activated via stabilizing mutations in beta-catenin: some patients have been found to harbor mutations in the CTNNB1 (3p21) and MET (7q31) genes. TP53 (17p13.1) gene and the TERT promoter are mutated in 25-30% and 60% of HCC cases, respectively. However, so far, the key genomic alteration in HCC has not yet been identified, and no mutation is used in clinical practice to predict a therapeutic response.\nDiagnostic methods\nDiagnosis is based on the clinical manifestations, elevated alpha-fetoprotein (AFP) in 50% of cases, histological findings, and on liver imaging. A slowly enlarging mass may be found on physical examination. Abnormal levels of beta human chorionic gonadotropin (b-hCG) may also be detected (rare). Ultrasound typically shows a heterogeneous hyperechoic mass with increased vascularity. Chest CT and abdominal CT/MRI scans with intravenous contrast should be performed for initial staging. Other imaging techniques may also be required to determine possible metastatic spread.\nDifferential diagnosis\nThe main differential diagnosis is hepatoblastoma, the most common hepatic tumor in the pediatric population in Western countries. Others include focal nodular hyperplasia (FNH), hepatic adenoma and undifferentiated embryonal sarcoma, as well as other less common liver malignancies.\nManagement and treatment\nAt-risk patients should be monitored closely. Screening for HBV and HCV should be performed. Monitoring with ultrasound and AFP every 6 months for all cirrhotic children, those with chronic HBV infection, inherited metabolic diseases or congenital porto-systemic shunts is suggested. The mainstay of curative therapy in non-metastatic patients is primary complete surgical resection (possible in about 25% of presenting children), delayed surgical resection (after neo-adjuvant chemotherapy) or liver transplantation (often across the Milan criteria). Transarterial chemo-embolization (TACE), radio-embolization (TARE) and radiofrequency ablation (RFA) are possible palliative options. Immunotherapies (CAR T cells, PD-1/PD-L1 and CTLA-4 checkpoint inhibitors) are newly emerging field for HCC.\nPrognosis\nThe prognosis currently depends on success rates of resection in resectable tumors. 5-year survival rates are moderate in low stage tumors but these rates drop below 20-30% in advanced disease.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Piotr CZAUDERNA  - Dr Maciej MURAWSKI"}
{"Disease Name": "Pediatric multiple sclerosis", "Disease Definition": "Pediatric multiple sclerosis (MS) is a rare multiple sclerosis variant characterized by the onset of multiple sclerosis (i.e. one or multiple episodes of clinical CNS symptoms consistent with acquired CNS demyelination, with radiologically proven dissemination of inflammatory lesions in space and time, following exclusion of other disorders) before the age of 18 years old. Pediatric MS patients present a predominantly relapsing-remitting course with first attack usually consisting of optic neuritis, transverse myelitis, acute disseminated encephalomyelitis and monofocal or polyfocal neurological deficits. A high burden of T2-hyperintense lesions on initial MRI, primarily of the supratentorial region and/or of the cervical spinal cord, has been reported.", "ORPHA ID": 477738, "Summary": ""}
{"Disease Name": "Pediatric systemic lupus erythematosus", "Disease Definition": "A rare, systemic, autoimmune disease characterized by inflammation in any organ system, with onset prior to adulthood, presenting highly variable clinical manifestations, which usually have a more aggressive course and higher rate of major organ involvement than adult-onset systemic lupus erythematosus, resulting in potential damage to a variety of organs (e.g. the skin, kidneys, lungs, nervous system).", "ORPHA ID": 93552, "Summary": ""}
{"Disease Name": "Pediatric-onset glaucoma of genetic origin", "Disease Definition": "A clinically diverse group of rare eye disorders with genetic predisposition characterized by elevated intraocular pressure (IOP) and glaucomatous changes of the optic nerve head, leading to field defects, visual loss and blindness. It can be sub-classified as primary (congenital glaucoma, juvenile glaucoma) or secondary according to the presence or absence of systemic or other ocular anomalies (iridogoniodysgenesis, Stickler syndrome, Coats syndrome). The clinical presentation is variable and is based on age, severity of glaucoma, presence of ocular abnormalities and development of secondary IOP related abnormalities.", "ORPHA ID": 359, "Summary": ""}
{"Disease Name": "Pediatric-onset Graves disease", "Disease Definition": "A rare endocrine disease characterized by the presence of serum autoantibodies against thyroid-stimulating hormone receptors, leading to increased thyroid hormone production and secretion, causing diffuse toxic goiter. Patients present in childhood with signs of thyrotoxicosis (such as tachycardia, weight loss, hand tremor, and sweating), diffuse enlargement of the thyroid gland, and orbitopathy. Additional signs and symptoms include decreased academic and athletic performance, accelerated growth, restlessness, fatigue, sensitivity to heat, and amenorrhea, among others.", "ORPHA ID": 525731, "Summary": ""}
{"Disease Name": "Peeling skin syndrome type A", "Disease Definition": "A noninflammatory form of generalized PSS characterized by white scaling and superficial painless peeling of the skin.", "ORPHA ID": 263548, "Summary": "Epidemiology\nThe prevalence is unknown. To date, few cases have been reported in the literature.\nClinical description\nOnset of symptoms can be at birth or later in life. Individuals may present with erythroderma accompanied by dry skin and superficial peeling of the skin upon minor trauma leaving red, denuded areas. The lesions heal with hyperpigmentation without scarring. Warm and humid environments aggravate the peeling tendency. Hyperkeratosis and scaling may also be present over the knees and elbows. Pruritus is variably observed. Hair is normal. There is no history of erythema or atopy and patients are in good general health.\nEtiology\nThere are three different causal genes reported to date: CHST8, SERPINB8 and FLG2. These genes are involved in skin homeostasis and barrier function but their specific role in the epidermis remains elusive, except for FLG2 which is known to be involved in skin moisturization.\nDiagnostic methods\nDiagnosis is based on clinical features. Histological examination of skin lesion biopsies reveals a slight hyperkeratosis, thinning of the granular layer and a separation of the stratum corneum from the underlying stratum granulosum or an intracorneal split. Molecular analysis, if performed, may reveal mutations in one of the three causal genes.\nDifferential diagnosis\nDifferential diagnosis includes other forms of PSS, PLACK syndrome and staphylococcal scalded skin syndrome.\nAntenatal diagnosis\nThe disease does not seem to be severe enough to justify prenatal screening.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to affected families informing them of the risk of 25% for a healthy carrier parent to have an affected child.\nManagement and treatment\nNo effective treatment has been reported. Emollients are often used to reduce skin peeling.\nPrognosis\nNoninflammatory skin peeling has a good prognosis and is mainly a cosmetic problem. In young patients, the condition may improve during childhood.\n\n                            Last update: \n                            January 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Peeling skin syndrome type B", "Disease Definition": "A form of generalized peeling skin syndrome (PSS) characterized by superficial patchy peeling of the entire skin with underlying erythroderma, pruritus, and atopy.", "ORPHA ID": 263553, "Summary": "Epidemiology\nThe prevalence is unknown; the disease is rare.\nClinical description\nSkin anomalies manifest at birth or shortly thereafter. Patients show painless widespread, superficial asymptomatic and spontaneous peeling. Peeling of the skin consists of exfoliative white flakes of variable shape and size that evolves into mildly erythematous denuded areas with a peeling border. Palms and soles are spared or may show redness and mild skin thickening or hyperlinearity. Underlying erythroderma is present. Seasonal variations are generally observed. Pruritus is frequent and often severe, and is exacerbated with warm temperatures. In most cases, hair can be easily plucked (hair-anchoring deficiency). Mild to moderate nail changes are sometimes reported (koilonychia, onycholysis, thickness, yellowish appearance). Atopic manifestations are frequent (e.g. food allergies, episodes of angioedema, urticaria and asthma) and Staphylococcus aureus skin infections are reported. Patients are usually in good general health but may present with mild failure to thrive.\nEtiology\nPSS type B is an autosomal recessive monogenic disease caused by mutations in the CDSN gene (6p21.3). CDSN encodes corneodesmosin, an adhesive protein specific to corneodesmosomes, the cell-junction structures responsible for the cohesion of the stratum corneum. Most of these mutations (single nucleotide substitutions or deletions) result in total absence of the mutated protein in the epidermis which leads to impaired cell-cell adhesion, detachment of the epidermal corneal layers and disruption of the epidermal barrier that leads to increased penetration of allergens into the epidermis and an abnormal inflammatory response.\nDiagnostic methods\nClinical presentation is highly suggestive of the disease. Total IgE levels can be markedly elevated. Histological examination of skin lesion biopsies reveals acanthosis, hyperkeratosis, parakeratosis and extensive detachment of the stratum corneum from the subjacent stratum granulosum. A moderate mononuclear infiltrate can be seen in the superficial dermis. Immunohistochemistry is a rapid and easy diagnostic test that shows an absence of corneodesmosin. Molecular analysis, confirms the diagnosis and reveals CDSN mutations.\nDifferential diagnosis\nDifferential diagnosis includes other forms of PSS (acral peeling skin syndrome, peeling skin syndrome type A), epidermolytic ichthyosis, autosomal recessive congenital ichthyosis, staphylococcal scalded skin syndrome, Netherton syndrome, severe dermatitis-multiple allergies-metabolic wasting (SAM) syndrome, atopic dermatitis and peeling skin induced by retinoid therapy.\nAntenatal diagnosis\nGenetic prenatal diagnosis is available for inherited ichthyoses and can be proposed for PSS type B because of the potential severity of the disease.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to affected families informing them of the risk of 25% for a healthy carrier parent to have an affected child.\nManagement and treatment\nNo effective treatment has been reported, especially for pruritus. Emollients are often used to reduce skin peeling. Topical and oral steroids, retinoids, methotrexate, dupilumab and UVB phototherapy have been tested but without any success. Antibiotic therapy is required to treat secondary infection.\nPrognosis\nThe severity of PSS type B is variable. Life expectancy is normal but the disease may severely impair the quality of life because of pruritus, lack of effective treatment and complications due to associated manifestations.\n\n                            Last update: \n                            January 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Peeling skin syndrome", "Disease Definition": "A group of rare autosomal recessive forms of ichthyosis clinically characterized by superficial, asymptomatic, spontaneous peeling of the skin and histologically by a shedding of the outer layers of the epidermis. PSS presents with either an acral (acral PSS) or a generalized distribution for generalized PSS type A (noninflammatory) or B (inflammatory).", "ORPHA ID": 817, "Summary": ""}
{"Disease Name": "Peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome", "Disease Definition": "A rare genetic skin disease characterized by generalized skin peeling or superficial blisters without scarring, leukonychia, acral punctate keratoses coalescing into focal keratoderma on the weight-bearing areas, painful angular cheilitis, and knuckle pads with multiple hyperkeratotic micropapules. The skin appears dry and scaly with superficial exfoliation and underlying erythema. Histopathologic examination of affected skin areas is not specific and shows hyperkeratosis, acanthosis, and occasional intraepidermal clefting with irregular acantholysis.", "ORPHA ID": 444138, "Summary": ""}
{"Disease Name": "PEHO syndrome", "Disease Definition": "A rare early childhood onset progressive encephalopathy characterized by extreme cerebellar atrophy, infantile-onset hypotonia, infantile spasms with hypsarrhythmia, profound intellectual disability, and optic atrophy. PEHO stands for the main features of the syndrome: Progressive encephalopathy with Edema, Hypsarrhythmia and Optic atrophy.", "ORPHA ID": 2836, "Summary": "Epidemiology\nPEHO syndrome is enriched in the Finnish population, where the minimum incidence is estimated at 1 in 74,000. A few patients have been described from other countries including Estonia, The Netherlands, and Spain, but mainly before the molecular genetic analysis or neuroimaging techniques were available.\nClinical description\nOnset occurs during the first few weeks or months of life with hypotonia, poor feeding, drowsiness and abnormal movements. Infantile spasms, hypsarrhythmia and seizures appear during the first year of life. Visual loss, abnormal eye movements and optic atrophy also occur during infancy. Other features include early arrest of psychomotor development, severe intellectual deficit, microcephaly, edema (particularly of the extremities), tapered fingers and facial dysmorphism (including a 'Pear-shaped' face with a narrow forehead and full cheeks, receding chin, epicanthic folds, an open mouth with a curved upper lip, protruding ear lobes and a short nose with anteverted nostrils).\nEtiology\nPEHO syndrome is an autosomal recessive disorder caused by mutations in the ZNHIT3 gene. ZNHIT3 encodes an evolutionarily conserved nuclear protein implicated in transcription regulation and chromatin remodeling.\nDiagnostic methods\nDiagnosis is based on molecular genetic testing. The clinical diagnostic criteria include: early-onset severe hypotonia; the occurrence of seizures, infantile spasms and hypsarrhythmia after the first two weeks of life; onset of optic atrophy before two years of age; and failure to obtain any of the milestones for motor, visual and language development. An additional criterion is demonstration of cerebellar and brainstem atrophy by MRI.\nDifferential diagnosis\nA significant number of patients have been described as displaying most of the diagnostic criteria and features of PEHO syndrome, but without the typical changes in neuroimaging studies, or without ophthalmologic signs. This group of patients was diagnosed with PEHO-like syndrome. NESCAV syndrome also presents with PEHO-like features. The differential diagnosis should also include Aicardi syndrome, mevalonic aciduria, the carbohydrate-deficient glycoprotein (CDG) syndromes, autosomal recessive cerebellar hypoplasia, Joubert syndrome and olivo-pontine cerebellar atrophies.\nAntenatal diagnosis\nPrenatal diagnosis is available for the families with identified pathogenic variants.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment is symptomatic only. The infantile spasms are refractory to antiepileptic drugs or adrenocorticotropic hormone (ACTH) therapy.\nPrognosis\nThe prognosis is poor and most patients die before 15 years of age, mainly as a result of pneumonia or aspiration.\n\n                            Last update: \n                            April 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Anna-Kaisa ANTTONEN | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "PEHO-like syndrome", "Disease Definition": "PEHO-like syndrome is a rare, genetic neurological disease characterized by progressive encephalopathy, early-onset seizures with a hypsarrhythmic pattern, facial and limb edema, severe hypotonia, early arrest of psychomotor development and craniofacial dysmorphism (evolving microcephaly, narrow forehead, short nose, prominent auricles, open mouth, micrognathia), in the absence of neuro-ophthalmic or neuroradiologic findings. Poor visual responsiveness, growth failure and tapering fingers are also associated.", "ORPHA ID": 99807, "Summary": ""}
{"Disease Name": "Pelizaeus-Merzbacher disease in female carriers", "Disease Definition": "Pelizaeus-Merzbacher disease (PMD) in female carriers is the presentation of PMD (see this term) in some women carrying mutations in the PLP1 gene (Xq22).", "ORPHA ID": 280229, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nHeterozygous females are not usually affected in families with the more severe PMD forms, including classical, transitional and connatal forms (see these terms), but are more likely to develop symptoms, possibly during adulthood, in families with more mildly affected males, such as in the null syndrome and SPG2 kindreds (see these terms). In some of the families with more severe male phenotypes, heterozygous females may manifest transient neurologic signs similar to those of boys with PMD, but from which they recover as they reach late childhood or adolescence.\nEtiology\nPMD is due to mutations or dosage alterations of the PLP1 gene (on Xq22) that cause hypomyelination of the central nervous system. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20). PMD is inherited as an X-linked disorder, usually with only males being affected. With the severe forms of the disease, oligodendrocytes undergo apoptosis. In heterozygous females, the degenerating oligodendrocytes are replaced by oligodendrocytes that have inactivated the mutated PLP1 allele. Therefore, unless there is severely unfavourably skewed X-inactivation, such females will be unaffected, and the disorder will have an X-linked recessive inheritance pattern. In contrast, in families where the PLP1 mutation causes little or no oligodendrocyte apoptosis, such as in the null syndrome, the defective oligodendrocytes survive in heterozygous females, who are more likely to have neurologic signs, typically later in adult life. In such cases, the disorder can be argued to have an X-linked dominant transmission pattern with variable penetrance.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr James GARBERN"}
{"Disease Name": "Pelizaeus-Merzbacher disease, classic form", "Disease Definition": "The classic form of Pelizaeus-Merzbacher disease (PMD) is the infantile form of PMD.", "ORPHA ID": 280219, "Summary": "Epidemiology\nPMD has an estimated prevalence of 1/400,000. The classic form accounts for approximately 70% of all cases of PMD. It predominantly affects males.\nClinical description\nThe classic form of PMD manifests during the first months of life with nystagmus and hypotonia, which is progressively replaced by spasticity. Later signs include ataxia, sometimes associated with dystonia of the axis and limbs, weakness, dysarthria, impaired motor development and intellectual deficit. Patients may learn to walk with assistance and their speech is understandable but slow.\nEtiology\nThe classic form of PMD is due most often to duplications but can also result from missense mutations of the PLP1 gene (on Xq22) that cause hypomyelination of the central nervous system. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20).\nGenetic counseling\nThe disease has an X-linked inheritance pattern.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr James GARBERN"}
{"Disease Name": "Pelizaeus-Merzbacher disease, connatal form", "Disease Definition": "The connatal form of Pelizaeus-Merzbacher disease (PMD) is the most severe form of PMD (see this term).", "ORPHA ID": 280210, "Summary": "Epidemiology\nPMD has an estimated prevalence of 1/400,000. The connatal form accounts for approximately 10 to 15 % of all cases of PMD. It predominantly affects males.\nClinical description\nConnatal PMD presents, from birth, with hypotonia, nystagmus, respiratory distress, stridor, feeding difficulties and sometimes seizures. Subsequently, there is profound motor and cognitive delay and spastic quadriparesis. Patients never learn to walk, have limited language skills and usually die from respiratory complications by the second decade.\nEtiology\nThe connatal form of PMD is due to missense mutations of the PLP1 gene (on Xq22) that cause hypomyelination of the central nervous system with profound myelin loss. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20).\nGenetic counseling\nThe disease has an X-linked inheritance pattern.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr James GARBERN"}
{"Disease Name": "Pelizaeus-Merzbacher disease, transitional form", "Disease Definition": "The transitional form of Pelizaeus-Merzbacher disease (PMD) is the intermediate form of PMD (see this term).", "ORPHA ID": 280224, "Summary": "Epidemiology\nPMD has an estimated prevalence of 1/400,000. The transitional form accounts for about 15% of all cases of PMD. It predominantly affects males.\nClinical description\nThe predominant clinical findings are early-onset nystagmus, initial hypotonia that is replaced by spasticity later in life, moderate cognitive impairment and inability to ambulate.\nEtiology\nThe transitional form of PMD is most often due to missense mutations of the PLP1 gene (on Xq22) that cause hypomyelination of the central nervous system. Some duplications or triplications of the gene can also cause the transitional form. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20).\nGenetic counseling\nThe disease has an X-linked inheritance pattern.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr James GARBERN"}
{"Disease Name": "Pelizaeus-Merzbacher disease", "Disease Definition": "Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy characterized by developmental delay, nystagmus, hypotonia, spasticity, and variable intellectual deficit. It is classified into three sub-forms based on the age of onset and severity: connatal, transitional, and classic PMD (see these terms).", "ORPHA ID": 702, "Summary": "Epidemiology\nThe estimated prevalence is 1/400,000. PMD affects males but some female heterozygotes presenting with a milder phenotype have also been reported (PMD in female carriers; see this term).\nClinical description\nThe disease has a broad clinical spectrum. The connatal form is the most severe form presenting, since birth, with hypotonia, nystagmus, respiratory distress, and stridor, with subsequent motor and cognitive delay and spastic quadriparesis. The classic form manifests during the first 2 months of life with nystagmus and hypotonia which is progressively replaced by spasticity. Later signs include ataxia, impaired motor development and intellectual deficit. The transitional form is of intermediate severity between the connatal and classic forms. The mildest presentation of PMD (mild developmental and motor delay beginning at 2-3 years old, later associated with spastic paraplegia, ataxia, and/or mild intellectual deficit) is not clearly distinguishable from PLP1 null syndrome (see this term), which consists on mild PMD features associated with peripheral neuropathy, and complicated spastic paraplegia 2 (SPG2; see this term), a disorder primarily characterized by spastic gait in its pure form.\nEtiology\nPMD is an X-linked disorder due to mutations or dosage alterations of the PLP1 gene (Xq22) that cause hypomyelination of the central nervous system (CNS). PMD is allelic to SPG2 which is also due to PLP1 mutations. PLP1 encodes the proteolipid protein PLP1, the most abundant protein of the myelin sheath in the CNS, and its alternatively spliced isoform DM20. PLP1 duplications lead to the classic form, missense substitutions from connatal to pure SPG2 forms, and PLP1 null mutations to the null syndrome. Patients without PLP1 mutations but with similar clinical and nearly identical neuroradiologic features as PMD are referred to as having PMD-like disease (PMLD; see this term).\nDiagnostic methods\nDiagnosis is based on clinical, electrophysiologic, and neuroradiological findings. Magnetic resonance imaging (MRI) reveals complete (connatal, some transitional forms), partial (mild PMD) or diffuse (null syndrome) hypomyelination. Brainstem auditory evoked potentials (BAEP) may be helpful to differentiate PMD (lack of waves II-V) from PMLD (recordable II-V waves). Genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes Krabbe disease, Canavan disease, metachromatic leukodystrophy, Alexander disease, familial SPG, PMLD (see these terms), and cerebral palsy.\nAntenatal diagnosis\nPrenatal and preimplantation genetic testing are possible when a family's underlying PLP1 mutation has been identified.\nManagement and treatment\nManagement is multidisciplinary and involves neurologists, physical therapists, orthopedic doctors, pneumologists, and gastroenterologists. Treatment may include gastrostomy for dysphagia, antiepileptic drugs for seizures, physical therapy with antispasticity drugs (baclofen, diazepam, tizanidine) for spasticity, or corrective surgery for pulmonary compromise in case of severe scoliosis. Regular surveillance is necessary.\nPrognosis\nPMD has a progressive course that varies depending on the phenotype. In the most moderate forms, life expectancy is quite long and the disease progresses slowly after adolescence. In the most severe forms, death usually occurs by the second decade.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr James GARBERN"}
{"Disease Name": "Pelizaeus-Merzbacher-like disease", "Disease Definition": "Pelizaeus-Merzbacher like disease (PMLD) is an autosomal recessive leukodystrophy sharing identical clinical and radiological features as X-linked Pelizaeus-Merzbacher disease (PMD; see this term).", "ORPHA ID": 280270, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nIt is characterized by early-onset nystagmus, delayed motor milestones, progressive spasticity, ataxia, and diffuse leukodystrophy on MRI.\nEtiology\nOne PMLD form is due to mutations in the GJC2 gene encoding the gap junction protein C2. There are very likely other PMLD forms that have not been defined but that are caused by mutations affecting other genes involved in myelination. Other syndromes have also been referred to as PMLD but their inclusion as PMLD has been debated because of their severity and of the evidence of neuronal, besides white matter, involvement on MRI. These syndromes include an autosomal recessive syndrome due to mutations in the HSPD1 gene, encoding the heat shock protein 1, that resembles severe PMD (nystagmus, developmental delay, spasticity, feeding and breathing problems, early-onset lethality) and that is associated with acquired microcephaly, as well as a syndrome due to mutations in the AIMP1 gene, encoding the aminoacyl tRNA synthetase complex-interacting multifunctional protein 1, and characterized by nystagmus, axial hypotonia, spastic paraparesis, severe developmental delay, kyphoscoliosis, microcephaly, intellectual deficit, and absence of speech. An X-linked syndrome, allelic to Allan-Herndon-Dudley syndrome (see this term), has also been referred to as a PMLD. This syndrome is characterized by neonatal hypotonia, nystagmus, progressive spastic paraplegia, ataxia and developmental delay, and is due to mutations in the SLC16A2 gene encoding the monocarboxylate transporter 8 involved in thyroid hormone transport. However, MRI findings are not as severe as those of PMD (diffuse hypomyelination), and tend to improve over time, making this more of a delayed myelination disorder that is probably secondary to a neuronal dysfunction related to impaired thyroid hormone transport.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr James GARBERN"}
{"Disease Name": "Pellagra", "Disease Definition": "Pellagra is a nutritional disorder caused by a deficiency in niacin (vitamin B3) or its precursor (tryptophan) that is mainly observed in Asia and Africa where it is generally due to poor nutrition. It is characterized by dermatitis (symmetrical photodistributed erythema that may be accompanied by vesicles and bullae, and that develops into hyperkeratotic and hyperpigmented skin), gastrointestinal symptoms (diarrhea), and neuropsychiatric disorders (dementia). It can be life-threatening without a correct management.", "ORPHA ID": 97352, "Summary": ""}
{"Disease Name": "Pellucid marginal degeneration", "Disease Definition": "A rare disorder of the anterior segment of the eye characterized by slowly progressive, bilateral, non-ulcerative, non-inflammatory, clear thinning of the inferior portion of the peripheral cornea (extending from the 4 o'clock to the 8 o'clock position), with an area of corneal protrusion above the point of maximal thinning, resulting in against-the-rule astigmatism with decreased visual acuity. The central cornea is of normal thickness.", "ORPHA ID": 137672, "Summary": ""}
{"Disease Name": "Pelvic dysplasia-arthrogryposis of lower limbs syndrome", "Disease Definition": "Pelvic dysplasia-arthrogryposis of lower limbs syndrome is a rare, genetic, dysostosis syndrome characterized by intrauterine growth restriction, short stature (with short lower segment), lower limb joint contractures and muscular hypotrophy, narrow, small pelvis, lumbar hyperlordosis with scoliosis, and foot deformity (short, overlapping toes). Imaging reveals ovoid/wedge-shaped vertebral bodies, pelvic and skeletal hypoplasia with metatarsal fusion in the lower limbs, and normal skull and upper limbs.", "ORPHA ID": 2840, "Summary": ""}
{"Disease Name": "Pelvis-shoulder dysplasia", "Disease Definition": "Pelvis-shoulder dysplasia is a rare focal skeletal dysostosis characterized by symmetrical hypoplasia of the scapulae and the iliac wings of the pelvis.", "ORPHA ID": 2839, "Summary": "Epidemiology\nApproximately 10 patients have been reported so far.\nClinical description\nAdditional skeletal abnormalities may include hypoplasia of the clavicles, ribs, femora and fibula, together with spina bifida and prominent lumbar lordosis. Eye anomalies (coloboma of iris and retina) have occasionally been reported. Intelligence is described as normal.\nEtiology\nPelvis-shoulder dysplasia seems to be a genetically heterogeneous disorder but no causative genes have been identified so far.\nDifferential diagnosis\nPelvis-shoulder dysplasia is phenotypically similar to pelvis-scapular dysplasia (Cousin syndrome, which also presents with craniocervical abnormalities; see this term), and, according to some authors, the two entities represent different manifestations of the same disease.\nGenetic counseling\nAutosomal dominant inheritance has been described in some cases.\n\n                            Last update: \n                            December 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM"}
{"Disease Name": "Pelviscapular dysplasia", "Disease Definition": "Pelviscapular dysplasia (Cousin syndrome) is characterized by the association of pelviscapular dysplasia with epiphyseal abnormalities, congenital dwarfism and facial dysmorphism.", "ORPHA ID": 93333, "Summary": "Epidemiology\nPelviscapular dysplasia was initially described in a North African brother and sister. Two other unrelated patients (a German and a Turkish girl) from consanguineous families have recently been reported.\nClinical description\nThe facial dysmorphism is characterized by frontal bossing, hypertelorism, narrow palpebral fissures, deep-set eyes, strabismus, low-set posteriorly rotated and malformed ears, dysplasia of conchae, a small chin, a short neck with redundant skin folds, and a low hairline. Intelligence may vary from normal to moderately impaired. Pelviscapular dysplasia is phenotypically similar to pelvis-shoulder dysplasia (Kosenow syndrome, scapuloiliac dysostosis; see this term), and the two entities may represent different manifestations of the same disease. However, Kosenow syndrome is not associated with craniocervical abnormalities and seems to be inherited as an autosomal dominant trait.\nEtiology\nMutations in the TBX15 gene have been identified as potentially causative.\nDiagnostic methods\nRadiographic features comprise aplasia of the body of the scapula, hypoplasia of the iliac bone, humeroradial synostosis, dislocation of the femoral heads, and moderate brachydactyly.\nGenetic counseling\nAn autosomal recessive mode of transmission has been suggested.\n\n                            Last update: \n                            December 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM"}
{"Disease Name": "Pemphigoid gestationis", "Disease Definition": "A rare autoimmune bullous skin disease characterized by pruritus with or without polymorphic skin eruption, affecting pregnant women typically during the second and third trimester.", "ORPHA ID": 63275, "Summary": "Epidemiology\nThe estimated incidence ranges between 1/3,000-60,000 pregnancies.\nClinical description\nPemphigoid gestationis (PG) typically presents during the second or third trimesters, although onset during the first trimester and postpartum is possible. Pruritus may remain the only symptom. Clinical presentation typically include urticarial papules and annular plaques, erythema multiform-like changes, eczematous lesions, or papulovesicles that in some cases may develop into large tense blisters. Lesions first erupt around the umbilicus and subsequently spread to the abdomen and the extremities. The mucous membranes and the face are typically spared. The clinical course is fairly benign and PG typically resolves with an average duration of 4-6 months. A flare may occur immediately after delivery but typically resolves within 4 weeks. There is an increased risk of small-for-gestational-age baby, premature birth, and development of mild, self-limiting skin lesions in the neonate (10-11% of cases). PG can be associated with the autoimmune Graves disease in the mother.\nEtiology\nPG is caused by production of anti-BP180 IgG antibodies that result from antigen presentation by MHC class II molecules aberrantly expressed on amniochorionic stromal cells and on the trophoblast. PG is strongly associated with maternal MHC class II antigens haplotypes HLA-DR3 and HLA-DR4.\nDiagnostic methods\nClinical and histological features are not specific to PG; therefore, additional tests are required for diagnosis. Direct immunofluorescence demonstrates a linear deposition of C3 and IgG autoantibodies at the dermal-epidermal junction as in bullous pemphigoid. Indirect immunofluroescence detects serum IgG autoantibodies targeting the basement membrane of the skin in 30%-100% of cases. ELISA (enzyme-linked immunosorbent assay) can reveal circulating IgG antibodies against BP180.\nDifferential diagnosis\nDifferential diagnosis includes atopic eruption of pregnancy, polymorphic eruption of pregnancy, and intrahepatic cholestasis of pregnancy, herpes virus infection, urticaria, drug hypersensitivity reactions, contact dermatitis and other eczemas, pityriasis rosea, pityriasis versicolor, yeast folliculitis as well as other types of folliculitis, miliaria, and scabies.\nManagement and treatment\nMost patients are controlled with potent or super-potent topical corticosteroids in combination with H1-receptor antagonists such as cetirizine. In more severe cases, oral corticosteroids are necessary. Preferred corticosteroids are prednisone and prednisolone. Minimum effective doses should be used to reduce the risk of side effects, and gradually tapered to a lower maintenance dose. If exacerbation in the peripartum period occurs, the maintenance dose can be increased. Ultraviolet light therapy is relatively contraindicated. In unresponsive cases, patients may benefit from systemic immunoadsorption, or intravenous immunoglobulin. In cases of persisting (postnatal) symptoms, systemic immunosuppressants might be beneficial.\nPrognosis\nThe disease is typically self-limiting; however, onset in the first or second trimester and presence of blisters is associated with adverse pregnancy outcomes. Recurrence in subsequent pregnancies is common (35-50%), and is typically more severe with earlier onset. The disease can persist and converts to bullous pemphigoid (in less than 5% of patients).\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Marion CASTEL | ERN-Skin* - Pr Pascal JOLY | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Pemphigus erythematosus", "Disease Definition": "A rare superficial pemphigus disease characterized clinically by well-demarcated, localized, erythematous, scaly, hyperkeratotic, crusted plaques, with frequent butterfly distribution over the malar area of the face (but also commonly involving trunk and scalp, and less frequently the extremities, with a photoexposed distribution). Histologically, granular deposits along the dermal-epidermal junction, in addition to intercellular deposition in the upper epidermis, are observed.", "ORPHA ID": 79480, "Summary": ""}
{"Disease Name": "Pemphigus foliaceus", "Disease Definition": "A rare superficial pemphigus disease characterized by multiple, pruritic, scaly, crusted cutaneous erosions, with flaky circumscribed patches, localized mostly on the face, scalp, trunk and extremities, often presenting an erythematous base. Mucosal involvement is rarely observed.", "ORPHA ID": 79481, "Summary": ""}
{"Disease Name": "Pemphigus vegetans", "Disease Definition": "A rare autoimmune bullous skin disease characterized by mucocutaneous bullae with subsequent erosion and formation of vegetative plaques, predominantly affecting intertriginous areas and the oral mucosa. Two clinical forms of the disease are recognized: the Hallopeau type, which presents an indolent course with pustules healing as vegetative plaques and frequent lack of involvement of the oral mucosa, and the Neumann type, which takes a more severe, refractory course with vegetations developing during an eruption of vesiculobullous lesions and involvement of the oral mucosa. Serum analysis reveals antibodies against desmoglein 1 and 3.", "ORPHA ID": 79479, "Summary": ""}
{"Disease Name": "Pemphigus vulgaris", "Disease Definition": "A rare autoimmune bullous skin diseases characterized by painful, flaccid blisters and erosions of the oral mucosa, predominantly involving the buccal area, and with or without extension to the epidermis. Mucosa of the larynx, oesophagus, conjunctiva, nose, genitalia and anus, are less frequently affected.", "ORPHA ID": 704, "Summary": "Epidemiology\nAnnual incidence worldwide ranges from 1/143,000 to 1,430,000.\nClinical description\nOnset occurs on average at 50-60 years, although childhood onset forms have been described. The disease begins with blisters (bullae) in the mouth, which are often mistaken for aphthae. The blisters are flaccid and are easily broken, often leading to painful lesions or erosions. The disease is classified into three subtypes: mucosal dominant type with blisters in the deep layers of the oral mucosa and limited cutaneous involvement, the mucocutaneous type involving both the mucosa and epidermis, and the cutaneous type with blisters in the deep layers of the epidermis only. Blistering can also affect the oesophagus, rectum, nose or the lining of the eyelids. Skin lesions appear several weeks or several months after the onset of mucosal erosions. Nikolsky's sign can appear on perilesional skin or, in some cases, even on healthy skin. Pemphigus vegetans is a clinical variant characterized by intertriginous lesions developing into vegetating plaques.\nEtiology\nThe exact etiology of the disease is unknown. Autoantibodies directed against desmosome components cause acantholysis and intraepidermal cleft. In pemphigus vulgaris, autoantibodies bind to desmogleine 1 and 3 (keratinocyte membrane molecules).\nDiagnostic methods\nDiagnosis should be considered in the presence of bullae on chest or scalp. It can be confirmed by standard histopathological analysis and direct immunofluorescence (DIF) test. Intraepidermal blisters due to suprabasal acantholysis and IgG (mostly IgG1 and IgG4) and/or C3 complement deposits can be detected at the cell surface of keratinocytes. The disease grade is correlated with the level of circulating antibodies.\nDifferential diagnosis\nDifferential diagnosis includes the full range of subepidermal diseases, mainly mucous membrane pemphigoid and epidermolysis bullosa acquisita. Oral erosive lichen planus and recurrent buccal aphtosis are characterized by a negative DIF pattern.\nManagement and treatment\nSystemic steroid therapy, given as a 12-month course in absence of relapse, is the treatment of choice. Rituximab can be proposed at first line therapy in association with systemic steroids. Immunosuppressant drugs can be administered in case of relapse or non-responsive disease\nPrognosis\nThe prognosis of pemphigus has markedly improved over the last decades with steroid therapy. Nevertheless, mortality remains an issue (5% of cases). In these cases, death occurs during the first years of disease progression, mostly as a consequence of treatment-related systemic infections and in a smaller proportion, as a consequence of superinfected lesions. Prognosis can be improved by early use of rituximab allowing a rapid tapering of steroids.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Christophe BEDANE"}
{"Disease Name": "Pendred syndrome", "Disease Definition": "A syndromic genetic deafness clinically variable characterized by bilateral sensorineural hearing loss and euthyroid goiter.", "ORPHA ID": 705, "Summary": "Epidemiology\nPendred syndrome (PDS) is one of the most frequent forms of syndromic genetic deafness. Although precise prevalence is unknown, PDS may account for up to 7.5% of cases of congenital hearing loss.\nClinical description\nConsiderable phenotypic variability is found even within families. The main presenting clinical sign is prelingual sensorineural deafness, although occasionally the hearing loss develops later in childhood. The degree of hearing loss is variable: it can be mild-to-moderate and progressive in some patients, and severe-to-profound in others. Fluctuations in hearing are also common and may be associated with or preceded by vertigo. The onset and presentation of euthyroid goiter (75%) is highly variable within and between families, with thyroid enlargement usually developing in late childhood or early adulthood. The thyromegaly reflects a defect in iodide transport from the thyrocyte to the colloid, although organification itself is not impaired. Hypothyroidism may develop if nutritional iodide intake is low. Genetic deafness at the DFNB4 locus is part of the phenotypic spectrum that includes PDS at one extreme and autosomal recessive non-syndromic sensorineural deafness type DFNB4 at the other. In patients with the latter disease, thyroid function is normal.\nEtiology\nBiallelic or double heterozygous genetic mutations are identified in about half of patients: biallelic mutations in SLC26A4 (7q31), or double heterozygous mutations in SLC26A4 and FOXI1 (5q34), or in SLC26A4and KCNJ10 (1q23.2). Nearly all mutations identified in SLC26A4 are biallelic and affect the encoded protein, pendrin, a 780-amino acid multifunctional anion exchanger. Less than 1% of affected persons present with double heterozygous mutations.\nDiagnostic methods\nThe diagnosis of PDS is based on the presence of hearing impairment, temporal bone anomalies of the inner ear, and an abnormal perchlorate discharge test (if available) or goiter. The anomalies can be diagnosed by computed tomography (CT) and/or magnetic resonance imaging (MRI), although the former provides better resolution of bony changes. Diagnosis is confirmed by molecular genetic testing which is available clinically.\nDifferential diagnosis\nThe differential diagnosis includes congenital cytomegaloviral infection (cCMV), BOR syndrome, and deafness at the DFNX2 locus (POU3F4).\nAntenatal diagnosis\nPrenatal testing for at-risk pregnancies is possible when mutations in a family are known.\nGenetic counseling\nPDS follows an autosomal recessive pattern of inheritance. Genetic counseling should be provided to affected families.\nManagement and treatment\nManagement includes annual audiograms with suitable amplification (hearing aids) as soon as hearing impairment is diagnosed. Patients with severe-to-profound hearing loss should be evaluated for cochlear implantation, and when appropriate, specific educational programs for the hearing impaired should be considered. Abnormal thyroid function should be treated with standard therapy.\nPrognosis\nPatients with PDS may have progressive hearing loss, although it is not yet possible to identify these patients in advance. As a general rule, however, progression of hearing loss is more common in patients with more severe inner ear anomalies.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Richard SMITH"}
{"Disease Name": "Penile agenesis", "Disease Definition": "Penile agenesis is a rare urogenital tract malformation characterized by complete congenital absence of the phallus. It is usually accompanied by a well-developed scrotum and presence of a skin tag at the anal verge (with or without a urethral meatal opening within it). Often, other genitourinary (e.g. cryptorchidism, renal agenesis and dysplasia, urinary reflux, prostate agenesis) as well as non-genitourinary abnormalities (including skeletal and neural disorders, anal stenosis, imperforate anus, cardiac defects) are associated.", "ORPHA ID": 49, "Summary": ""}
{"Disease Name": "Penoscrotal transposition", "Disease Definition": "A rare congenital genital anomaly in which the scrotum is positioned superior and anterior to the penis. PST may present with a broad spectrum of anomalies ranging from simple shawl scrotum (doughnut scrotum) to very complex extreme transposition with craniofacial, central nervous system, cardiac, gastrointestinal, urological, and other genital (undescended testicles, hypospadias, chordee) malformations. Growth deficiency and intellectual disability may also be noticed (60% of cases).", "ORPHA ID": 2842, "Summary": ""}
{"Disease Name": "PENS syndrome", "Disease Definition": "PENS syndrome is a rare, genetic, neurocutaneous syndrome characterized by the presence of randomly distributed, small, white to yellowish, multiple, rounded or irregular polycyclically-shaped, epidermal keratotic papules and plaques of ''gem-like'' appearance with a rough surface, typically located on the trunk and proximal limbs, associated with variable neurological abnormalities, including psychomotor delay, epilepsy, speech and language impairment and attention deficit-hyperactivity disorder. Clumsiness, dyslexia and oftalmological abnormalities have also been reported.", "ORPHA ID": 313936, "Summary": ""}
{"Disease Name": "Pentalogy of Cantrell", "Disease Definition": "Pentalogy of Cantrell (POC) is a lethal multiple congenital anomalies syndrome, characterized by the presence of 5 major malformations: midline supraumbilical abdominal wall defect, lower sternal defect, diaphragmatic pericardial defect, anterior diaphragmatic defect and various intracardiac malformations. Ectopia cordis (EC) is often found in fetuses with POC.", "ORPHA ID": 1335, "Summary": "Epidemiology\nThe prevalence of POC is estimated to be 1/65,000-1/200,000 live births.\nClinical description\nPOC is a congenital disorder characterized by the presence of 5 major malformations: midline supraumbilical abdominal wall defect (diastasis recti, epigastric and umbilical hernia), lower sternal defect (sternal cleft (see this term), absent xiphoid process, short sternum and defective formation of lower two third), diaphragmatic pericardial defect, anterior diaphragmatic defect and heart malformations (ventricular septal defect (72%), interauricular communication (35%), cardiac diverticulum (32%), congenital pulmonary valve stenosis (PS; 31%) (isolated PS or in combination with double outlet right ventricle in fetuses with EC and univentricular heart in fetuses without EC), tetralogy of Fallot (17%), dextrocardia (15%), and transposition of the great arteries (TGA; 6%) (see these terms)). Thoraco-abdominal wall defects may lead to omphalocele (see this term) and EC, with the heart located outside the thoracic wall and sometimes covered by pigmented loose skin. The heart can be partially or completely repositioned into the thoracic cavity when the patient is in a supine position. Neonates usually present with severe respiratory distress and cyanosis. Additional features that may be observed include craniofacial and central nervous system (CNS) anomalies (cleft lip and/or palate, encephalocele, craniorachischisis (see these terms) and hydrocephalus), limb defects (club foot, absence of tibia/radius, hand and foot oligodactyly, phocomelia (see this term), and abdominal organ defects (gallbladder agenesis and polysplenia, as part of heterotaxia (see this term)). POC may occur in association with Trisomy 13, 18, Down syndrome and Turner syndrome (see these terms).\nEtiology\nThe etiology of POC is still unknown. It has been postulated that at around 14 to 18 days post conception, a failure of the lateral mesodermal folds to migrate to the midline may cause the sternal and abdominal wall defects and abnormal development of the septum transversum result in defects in the anterior diaphragm and pericardium.\nDiagnostic methods\nDiagnosis of complete POC relies on the following classification: class 1, a definite diagnosis, when all 5 defects are present; class 2, a probable diagnosis with 4 defects being present, including intracardiac and ventral wall abnormalities; and class 3, an incomplete expression with various combinations of defects being present, including a sternal abnormality.\nDifferential diagnosis\nDifferential diagnosis includes limb body wall complex, omphalocele (see these terms), thoracic EC and amniotic bands (see this term).\nAntenatal diagnosis\nPrenatal diagnosis can be made in first-trimester ultrasonography by detection of multiple thoraco-abdominal defects, including EC and CNS anomalies.\nGenetic counseling\nPOC usually occurs sporadically but rare cases of chromosomal anomalies, autosomal or X-linked transmission have also been reported.\nManagement and treatment\nManagement is surgical, consisting of palliative repair of the ventral hernia and diaphragmatic defect and palliative or corrective repair of the cardiovascular anomalies. Surgical repair to relocate the heart into the chest cavity is usually performed in the neonatal period or in infancy. For patients unable to tolerate a single-staged approach, an intraoperative ''heart restoring'' trial may be proposed. If heart position can be successfully restored without obvious hemodynamic changes, one-staged operation is advised; if hemodynamic changes are minor, a combined operation may be possible.\nPrognosis\nThe prognosis of POC is poor and only few patients survive through early childhood. The main causes of death are tachyarrhythmias, bradycardia, low blood pressure, rupture of the diverticulum, and heart failure.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Suresh CHANDRAN"}
{"Disease Name": "Pentasomy X", "Disease Definition": "Pentasomy X is a sex chromosome anomaly caused by the presence of three extra X chromosomes in females (49,XXXXX instead of 46,XX).", "ORPHA ID": 11, "Summary": "Epidemiology\nThe prevalence is unknown but less than 40 cases have been described in the literature so far.\nClinical description\nPentasomy X is associated with developmental delays, short stature, craniofacial anomalies and musculoskeletal abnormalities. The craniofacial anomalies may include microcephaly, micrognathia, plagiocephaly, hypertelorism, upslanting palpebral fissures, a flat nasal bridge and ear malformations. The hands and feet are generally small and camptodactyly, clinodactyly, and radioulnar synostosis are common findings. Immunoglobulin anomalies and an increased susceptibility to infection have also been reported. Cardiovascular malformations may also be present. External genitalia are generally normal but gonadal dysfunction has been reported. Developmental profiles usually show global developmental delay and intellectual disability; however, receptive language skills are usually less severely affected than expressive language abilities.\nEtiology\nPentasomy X is generally thought to arise as a result of successive maternal nondisjunction during meiosis.\n\n                            Last update: \n                            January 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Natalie AYARI  - Dr A BERGE  - Dr Susan HOWELL  - Dr Nicole TARTAGLIA"}
{"Disease Name": "Pentosuria", "Disease Definition": "Pentosuria is an inborn error of metabolism which is characterized by the excretion of 1 to 4 g of the pentose L-xylulose in the urine per day.", "ORPHA ID": 2843, "Summary": "Epidemiology\nThe condition occurs essentially in Ashkenazi Jews with an estimated incidence of the heterozygote mutation of 1/79.\nClinical description\nPentosuria is benign and shows no symptoms. The sole biological feature is the constant excretion of L-xylulose in the urine that may be mistaken with glycosuria.\nEtiology\nIt is due to mutations in the DCXR gene on chromosome 17 that codes for L-xylulose reductase (or L-xylitol dehydrogenase), an enzyme that catalyzes the conversion of 1-xylulose into xylitol.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            August 2011"}
{"Disease Name": "Pericardial and diaphragmatic defect", "Disease Definition": "Pericardial and diaphragmatic defect is a rare combination of absent pericardium with congenital diaphragmatic defect.", "ORPHA ID": 2847, "Summary": "Epidemiology\nIt has been reported in less than 20 patients.\nClinical description\nThe absence of pericardic tissue is complete or partial. The diaphragmatic hernia is most often left-sided. Some patients have additional digestive tract malformations.\nGenetic counseling\nThe few reported cases were all sporadic except in a family in which the recurrence of these anomalies in two sibs and the parental consanguinity suggested an autosomal recessive inheritance.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Perinatal lethal hypophosphatasia", "Disease Definition": "A rare, genetic form of hypophosphatasia (HPP) characterized by markedly impaired bone mineralization in utero due to reduced activity of serum alkaline phosphatase (ALP) and causing stillbirth or respiratory failure within days of birth.", "ORPHA ID": 247623, "Summary": "Epidemiology\nIncidence of Perinatal lethal hypophosphatasia (PL-HPP) is not known. However, the birth prevalence for severe HPP (both perinatal-lethal and infantile forms) is estimated at 1/300,000 in North and West Europe.\nClinical description\nAffected infants may have characteristic skin-covered osteochondral spurs protruding from the forearms or legs and often a small thoracic cavity. They may have hypercalcemia associated with apnea or seizures, and marked shortening of the long bones. Patients rarely survive for more than a few days due to inadequate chest size, hypoplastic lungs and rachitic deformities, leading to respiratory failure.\nEtiology\nLoss of function mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The specific mechanisms underlying PL-HPP have not been elucidated.\nDiagnostic methods\nDiagnosis is suspected either on prenatal ultrasound findings or clinical presentation at birth, and confirmed by genetic testing (Sanger or next generation sequencing of ALPL).\nDifferential diagnosis\nA benign form of HPP (prenatal benign HPP) has been described in which skeletal abnormalities resolve spontaneously and patients subsequently develop nonlethal HPP, often adult or childhood HPP. Osteogenesis Imperfecta is the most frequent differential diagnosis of this severe form of HPP. Other differential diagnoses include campomelic dysplasia, chondrodysplasia and Stuve Wiedemann syndrome.\nAntenatal diagnosis\nSuspicious ultrasound findings include short and/or bowed limbs, skeletal hypomineralization, osteochondral spurs and, sometimes, the absence of certain bones (skull, ribs, vertebrae, pubis). Confirmation by genetic testing is indispensable, although correlation between the genotype and the prognosis remains a challenge. Genetic prenatal testing is also possible in at risk families with a previous index case and where at least one mutation has been identified.\nGenetic counseling\nThe reported pattern of inheritance in this form of HPP is autosomal recessive but is not necessarily predictive of the lethal form of HPP.\nManagement and treatment\nVentilation support is initiated shortly after birth. Prompt diagnosis is essential in order to start targeted therapy. Asfotase alfa is approved (Europe and USA) for enzyme replacement therapy (ERT) in patients with pediatric-onset hypophosphatasia and is associated with improvement of the skeletal manifestations as well as respiratory and motor function.\nPrognosis\nPerinatal HPP is of poor prognosis when not treated with ERT; however, long term prognosis with ERT is currently unknown.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Severine BACROT  - Dr Etienne MORNET"}
{"Disease Name": "Periodic fever-infantile enterocolitis-autoinflammatory syndrome", "Disease Definition": "A rare genetic systemic or rheumatologic disease characterized by neonatal or infantile onset of enterocolitis (which resolves with age), periodic fever, and episodes of severe systemic inflammation, which may be precipitated by infections, stress, or fatigue. Signs and symptoms include splenomegaly, urticaria-like rashes, arthralgia, and myalgia. Associated laboratory findings are elevated inflammatory markers (such as ferritin, C-reactive protein), pancytopenia, and elevated transaminases. If left untreated, flares can progress to coagulopathy, organ failure, and death.", "ORPHA ID": 436166, "Summary": ""}
{"Disease Name": "Periodic paralysis with later-onset distal motor neuropathy", "Disease Definition": "Periodic paralysis with later-onset distal motor neuropathy is a rare, genetic, neuromuscular disease characterized by acute episodic muscle weakness in upper and lower extremities (which responds to acetazolamide treatment) associated with later-onset, chronic, slowly progressive, distal, axonal neuropathy.", "ORPHA ID": 397750, "Summary": ""}
{"Disease Name": "Periodic paralysis with transient compartment-like syndrome", "Disease Definition": "A rare genetic neuromuscular channelopathy characterized by normokalemic episodes of painful muscle cramping followed by progressive, permanent, flaccid weakness, triggered by stress, cold and exercise, associated with myopathic myopathy and painful acute edema with neuronal compression, foot drop and muscle degeneration when located in the tibialis anterior muscle group.", "ORPHA ID": 397755, "Summary": ""}
{"Disease Name": "Periodontal Ehlers-Danlos syndrome", "Disease Definition": "A rare type of Ehlers-Danlos syndrome characterized by childhood or adolescence onset of severe, intractable periodontitis, lack of attached gingiva, and presence of pretibial plaques. Additional manifestations are easy bruising, hypermobility mainly of the distal joints, skin hyperextensibility and fragility, abnormal scarring, recurrent infections, hernias, marfanoid facial features, acrogeria, and prominent vasculature.", "ORPHA ID": 75392, "Summary": ""}
{"Disease Name": "Perioral myoclonia with absences", "Disease Definition": "A rare epilepsy syndrome characterized by absence seizures with perioral myoclonia as the main seizure type, accompanied by generalized tonic-clonic seizures, appearing before or together with absences. Consciousness is usually impaired, although to variable degree. Commonly observed absence status epilepticus, poor response to antiepileptic drugs and persistence of seizures into adulthood, in the presence of normal neurological status and intelligence, are additional clinical features of this syndrome.", "ORPHA ID": 139426, "Summary": ""}
{"Disease Name": "Peripapillary staphyloma", "Disease Definition": "A rare congenital optic disc excavation characterized by deep fundus excavation of chorioretinal atrophy surrounding a relatively normal appearing optic disc. Retinal vasculature is normal, and retinochoroidal coloboma and glial anomalies are absent. Patients present with mostly unilateral markedly reduced visual acuity. Association with other congenital defects or systemic diseases is uncommon.", "ORPHA ID": 519400, "Summary": ""}
{"Disease Name": "Peripartum cardiomyopathy", "Disease Definition": "Peripartum cardiomyopathy (PPCM) is an idiopathic, potentially fatal form of dilated cardiomyopathy that develops during the final month of pregnancy or within five months after delivery.", "ORPHA ID": 563, "Summary": ""}
{"Disease Name": "Peripheral demyelinating neuropathy-central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease", "Disease Definition": "Peripheral demyelinating neuropathy-central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease (PCWH) is a systemic disease characterized by the association of the features of Waardenburg-Shah syndrome (WSS) with neurological features of variable severity.", "ORPHA ID": 163746, "Summary": "Epidemiology\nPrevalence is unknown. Less than 50 cases have been reported in the literature so far.\nClinical description\nPCWH occurs in the neonatal and infancy period, and includes features of WSS (sensorineural hearing loss, iris heterochromia, skin hypopigmentation associated with Hirschsprung disease) and neurological features (neonatal hypotonia, intellectual disability of variable severity, nystagmus, progressive spasticity, ataxia and epilepsy). These signs are not fully penetrant (PCWH without Hirschsprung disease is sometimes referred as PCW), the depigmentation may not be obvious, and there is a broad range of severity for the neurologic features. Autonomic dysfunction (asialia, alacrima and hypohidrosis, bradycardia and arrhythmia) may also be present. Delayed white matter myelination is observed on brain magnetic resonance imaging (MRI), and may also be responsible for neuropathy at the peripheral level. MRI often shows defects of the semi-circular canals and agenesis of the olfactory bulbs. Kallmann syndrome can be associated.\nEtiology\nMost of the cases are caused by mutations involving the SOX10 gene (22q13.1, coding for the SOX10 transcription factor). Most frequently truncating mutations of the last coding exon induce escape from NMD (non-sense mediated mRNA decay), although a few gene deletions and missense mutations have also been described.\nDiagnostic methods\nDiagnosis is suspected on recognition of the clinical picture and should be confirmed by genetic molecular analysis.\nDifferential diagnosis\nThe disease overlaps with central or peripheral neuropathies/dysmyelination, and the diagnosis may be difficult in absence of the typical Waardenburg syndrome depigmentation.\nAntenatal diagnosis\nPrenatal diagnosis is possible by fetal DNA mutation analysis if a causal mutation is identified in a member of the family (either in case of an affected parent (a rare situation) or due to the risk of germline mosaicism).\nGenetic counseling\nThe inheritance pattern of PCWH is autosomal dominant (parents of an affected individual have a probability of 50% to transmit the causal mutation to the offspring). Most cases are sporadic but a few patients with an affected sibling have been reported and are associated with germinal mosaicism in one of the parents. Genetic counseling should be offered to affected families in order to provide more information about this genetic condition, its risk of recurrence and the availability of prenatal diagnosis.\nManagement and treatment\nManagement is only symptomatic, consisting in the management of WS (protection from exposure to ultraviolet light, avoidance of sunburn, management of hearing loss), Hirschprung disease (surgical treatment) and the neurologic manifestations.\nPrognosis\nThe prognosis and disease course may be severe with onset of deafness, intellectual disability and sometimes motor impairment. In rare cases, the disease is fatal shortly after birth. Long-term evolution in adulthood is not well established.\n\n                            Last update: \n                            March 2018\n\n\n                            - Expert reviewer(s): \n                            Dr Véronique PINGAULT"}
{"Disease Name": "Peripheral motor neuropathy-dysautonomia syndrome", "Disease Definition": "Peripheral motor neuropathy-dysautonomia syndrome is characterised by distal, slowly progressive muscular weakness, childhood-onset amyotrophy, autonomic dysfunction characterized by profuse sweating, distal cyanosis related to cold weather, orthostatic hypotension, and esophageal achalasia. It has been described in two sisters. Inheritance appears to be autosomal recessive.", "ORPHA ID": 2400, "Summary": ""}
{"Disease Name": "Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome", "Disease Definition": "Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome is a rare, syndromic genetic deafness characterized by a combination of muscle weakness, chronic neuropathic and myopathic features, hoarseness and sensorineural hearing loss. A wide range of disease onset and severity has been reported even within the same family.", "ORPHA ID": 397744, "Summary": ""}
{"Disease Name": "Peripheral primitive neuroectodermal tumor", "Disease Definition": "A rare, aggressive, malignant, neoplastic disease characterized by a usually ill-defined, solid, multilobulated mass, frequently having necrosis, located on any site of the body (except the central nervous system), composed of small, round, poorly differentiated cells, with or without Homer-Wright rosettes, showing varying degrees of neuroectodermal differentiation. Manifestations are variable depending on location, with osteolytic destruction being common when arising from bone.", "ORPHA ID": 370348, "Summary": ""}
{"Disease Name": "Peripheral pulmonary stenosis", "Disease Definition": "Peripheral pulmonary stenosis is a rare congenital anomaly of the great arteries that may occur at single or multiple sites, in isolation or in association with other congenital heart defects (valvular pulmonary stenosis, atrial, or ventricular septal defects or tetralogy of Fallot) and genetic syndromes (Williams, Alagile syndrome). Clinical presentation is variable and includes heart murmurs, dyspnea, syncope, chest pain and pulmonary hypertension-associated symptoms.", "ORPHA ID": 99084, "Summary": ""}
{"Disease Name": "Peritoneal inclusion cyst", "Disease Definition": "Peritoneal cystic mesothelioma is a rare benign tumor characterized by the formation of intra-abdominal multilocular cystic masses.", "ORPHA ID": 168816, "Summary": "Epidemiology\nFewer than 150 cases have been reported to date. It occurs more frequently in women of child-bearing age.\nClinical description\nClinical features include lower abdominal or pelvic pain, presence of a palpable mass, amenorrhea, dysuria, dyspareunia, and more rarely weight loss. In women, the masses are generally located on the peritoneal surface of the uterus and rectum, while in men they are generally located on the peritoneal surface of the bladder and rectum. The tumor can also spread into the upper portions of the peritoneal cavity.\nEtiology\nPeritoneal cystic mesothelioma seems to originate from the peritoneal mesothelium. However, etiology is unknown. There is no relation with asbestos exposure. Peritoneal cystic mesothelioma occurs frequently in women with previous history of surgery, pelvic inflammation or endometriosis. Chronic peritoneal irritation may be an aggravating factor.\nDiagnostic methods\nDiagnosis is based on abdominal and pelvic ultrasound, abdominal computerized tomography (CT) and laparoscopic examination that reveal abdominal multicystic separated grapelike structures. Biopsy shows vascularized, translucent fluid-filled, thin-walled cysts composed of loose connective tissue. Immunohistochemistry confirms the diagnosis by showing the mesothelial origin of the parietal cells (this examination must be reviewed by an expert pathologist).\nDifferential diagnosis\nThe main differential diagnoses include cystic peritoneal lymphangioma, pseudomyxoma peritonei (see this term), and other cystic neoplastic lesions.\nManagement and treatment\nThe treatment approach is multidisciplinary and must be discussed by a panel of physicians in a specialized center. There are currently no validated recommendations on clinical management and no cytotoxic agents have been granted a European Marketing Authorization (MA) in this indication. Treatment is surgical and is based on ablation of cysts. In case of recurrence or even in first-line treatment, certain teams have proposed combination of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) (off-label use) in specific patients (young patients with good general status).\nPrognosis\nPrognosis is usually good. 5-year survival is 100% when the combined treatment is given. With surgery alone, disease inevitably recurs or persists. Invasive or malignant progression has been described.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Olivier GLEHEN"}
{"Disease Name": "Perivascular epithelioid cell neoplasm", "Disease Definition": "A rare soft tissue tumor characterized by distinctive perivascular epitheloid cells, often arranged radially around a vascular lumen, as well as spindled cells in variable proportion. Melanocytic and muscle markers are typically positive. The tumors have been reported in the uterus, falciform ligament, and large and small intestine, among others. Depending on their location, they may present as a painful or painless mass, or with vaginal bleeding. Tumors displaying infiltrative growth, marked hypercellularity, nuclear enlargement and hyperchromasia, high mitotic activity, atypical mitotic figures, and/or coagulative necrosis should be regarded as malignant.", "ORPHA ID": 595133, "Summary": ""}
{"Disease Name": "Periventricular nodular heterotopia", "Disease Definition": "Periventricular nodular heterotopia (PNH) is a brain malformation, due to abnormal neuronal migration, in which a subset of neurons fails to migrate into the developing cerebral cortex and remains as nodules that line the ventricular surface. Classical PNH is a rare X-linked dominant disorder far more frequent in females who present normal intelligence to borderline intellectual deficit, epilepsy of variable severity and extra-central nervous system signs, especially cardiovascular defects or coagulopathy. The disorder is generally associated with prenatal lethality in males.", "ORPHA ID": 98892, "Summary": ""}
{"Disease Name": "Perlman syndrome", "Disease Definition": "Perlman syndrome is characterized principally by polyhydramnios, neonatal macrosomia, bilateral renal tumours (hamartomas with or without nephroblastomatosis), hypertrophy of the islets of Langerhans and facial dysmorphism.", "ORPHA ID": 2849, "Summary": "Epidemiology\nSo far, about 30 patients have been reported in the literature.\nClinical description\nThe facial dysmorphism is considered as characteristic with upsweeping anterior scalp hair, a depressed nasal bridge, hypotonic appearance with an open mouth, a prominent everted upper lip, and mild micrognathia. Agenesis of the corpus callosum, choroid plexus haemangiomas, cleft palate, dextroposition of the heart, interrupted aortic arch, diaphragmatic hernia, visceromegaly including nephromegaly, hepatomegaly, cardiomegaly, thymus hyperplasia, hepatic fibrosis with porto-portal bridging, abdominal muscular hypoplasia, distal ileal atresia, and cryptorchidism were also described in some patients and maybe components of this syndrome. Hyperinsulinism appears to be an important feature of this disease and may be a preventable cause of death.\nDifferential diagnosis\nThe principle differential diagnoses are the Beckwith-Wiedemann (BWS) and Simpson-Golabi-Behmel syndromes (see these terms): mutations the GPC3 gene were excluded as being causative anomalies in several publications and genetic or epigenetic alterations of the 11p15 region (involved in BWS) have never been reported in patients with Perlman syndrome, despite the strong phenotypic similarities between the two syndromes.\nAntenatal diagnosis\nPrenatal diagnosis may be oriented by ultrasonography searching for macroglossia and renal anomalies (cysts or hypertrophy).\nGenetic counseling\nThe syndrome appears to be inherited in an autosomal recessive manner.\nManagement and treatment\nManagement is supportive and should be multidisciplinary.\nPrognosis\nThe prognosis for Perlman syndrome is poor with a high mortality rate, especially in the neonatal period, due to sepsis or progressive respiratory insufficiency. Among the infants who survived beyond the neonatal period, two thirds developed a Wilms' tumor and most had some degree of developmental delay. However, one girl was reported to be alive at the age of 9 and displayed normal psychomotor development.\n\n                            Last update: \n                            May 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES"}
{"Disease Name": "Permanent congenital hypothyroidism", "Disease Definition": "Permanent congenital hypothyroidism is a type of congenital hypothyroidism (CH; see this term), a thyroid hormone deficiency present from birth.", "ORPHA ID": 226292, "Summary": "Epidemiology\nIncidence of permanent CH varies widely with geographic location with reported incidences between 1/800 and 1/10,000 live births and an average incidence of 1/3,000 live births.\nClinical description\nThe clinical manifestations are often subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own.More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment CH results in severe intellectual deficit and short stature.\nEtiology\nPermanent CH has a variety of primary, secondary and peripheral causes and may occur as part of a syndrome (primary, secondary, peripheral or syndromic hypothyroidism; see these terms). Primary causes include defects in thyroid gland development (thyroid dysgenesis; see this term), deficiencies in thyroid hormone production (thyroid dyshormonogenesis; see this term), or defects of thyroid-stimulating hormone (TSH) binding or signal transduction (due to TSH receptor mutations; see this term). Secondary or central CH is most commonly due to a pituitary defect. Other causes include isolated TSH deficiency (see this term), which is transmitted in an autosomal recessive manner and is caused by mutations in the TSH beta subunit gene (1p13), by thyrotropin releasing hormone (TRH) resistance (see this term), which results from mutations in the TRH receptor gene (TRHR; 8q23), or by mutations in genes regulating pituitary gland development (see this term) including HESX1, LHX3, LHX4, POU1F1 and PROP1 (3p21.2-p21.1, 9q34.3, 1q25, 3p11 and 5q). Peripheral CH (see this term) may be caused by peripheral resistance to the action of thyroid hormone (see this term), of which 90% of cases are due to dominantly inherited mutations in genes encoding for thyroid hormone receptor beta. The majority of these individuals have normal thyroid function but some hypothyroid individuals have been described. Peripheral hypothyroidism may also be caused by defects in thyroid hormone transport, such as in Allan-Herndon-Dudley syndrome (see this term) where X-linked peripheral hypothyroidism is associated with intellectual deficiency and neurologic abnormalities including quadriplegia. Permanent CH may also be associated with a syndrome such as Pendred or Bamforth syndromes among others (see these terms).\nManagement and treatment\nRecombinant human TSH (rhTSH) may be of use in the future confirmation of permanent CH. If at any time after the first 6 months of age, the serum TSH rises above 20mU/L due to undertreatment, permanent CH is assumed. If permanent CH has not been established by 2-3 years of age a 30 day trial off l-thyroxine therapy is recommended. If serum or free T4 is low and TSH elevated, permanent CH is confirmed and the patient is restarted on therapy.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome", "Disease Definition": "A rare neurologic disease characterized by neonatal diabetes mellitus associated with cerebellar and/or pancreatic agenesis. Absence or hypoplasia of the cerebellum and severe intra-uterine growth retardation can be detected prenatally. Patients also present with facial dysmorphism (a triangular face, small chin, low set ears), flexion contractures of the arms and legs, very little subcutaneous fat, and optic nerve hypoplasia. The disease is lethal in the neonatal period.", "ORPHA ID": 65288, "Summary": ""}
{"Disease Name": "Peroxisomal acyl-CoA oxidase deficiency", "Disease Definition": "Peroxisomal acyl-CoA oxidase deficiency is a rare neurodegenerative disorder that belongs to the group of inherited peroxisomal disorders and is characterized by hypotonia and seizures in the neonatal period and neurological regression in early infancy.", "ORPHA ID": 2971, "Summary": "Epidemiology\nAcyl-CoA oxidase deficiency is a rare disease with only 30-40 patients identified world-wide so far.\nClinical description\nThe disease manifests in the neonatal period with hypotonia (92%) and seizures (91%) as dominant features. Facial dysmorphism (50%) with hypertelorism, epicanthus, low nasal bridge, and low-set ears may be present. Some children have polydactyly and hepatomegaly. Psychomotor development is delayed, but children are usually able to walk and say a few words. However, neurological regression occurs usually at the age of 1-3 years (mean age: 28 months). Hypotonia is replaced by hypertonia with hyperreflexia. Epilepsy may become more severe and sensorineural hearing loss may appear. Strabismus, nystagmus, and optic atrophy can also occur.\nEtiology\nPeroxisomal acyl-CoA oxidase deficiency is caused by mutations in the ACOX1 gene (17q25.1) encoding peroxisomal straight-chain acyl-CoA oxidase.\nDiagnostic methods\nDiagnosis is based on laboratory studies revealing increased serum very-long chain fatty acids (VLCFA) and markedly reduced acyl-CoA oxidase activity in fibroblasts. MRI examination of the brain shows abnormal white matter signals. Diagnosis can be confirmed by the presence of mutations in the ACOX1 gene.\nDifferential diagnosis\nDifferential diagnoses include Usher syndrome (see this term) and all causes of neonatal hypotonia. The other peroxisomal disorders should also be discarded, especially neonatal adrenoleukodystrophy (see this term), which presents similar clinical manifestations.\nAntenatal diagnosis\nAntenatal diagnosis is possible through biochemical and/or molecular analysis of amniocytes or chorionic villus cells.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to the families of patients.\nManagement and treatment\nNo specific treatment is available. Multidisciplinary supportive care should be offered.\nPrognosis\nPrognosis is unfavorable; death usually occurs at around 5 years from respiratory issues.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Pr R.J.A. [Ronald] WANDERS"}
{"Disease Name": "Peroxisome biogenesis disorder", "Disease Definition": "Peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD-ZSS) is a group of autosomal recessive disorders affecting the formation of functional peroxisomes, characterized by sensorineural hearing loss, pigmentary retinal degeneration, multiple organ dysfunction and psychomotor impairment, and is comprised of the phenotypic variants Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) (see these terms).", "ORPHA ID": 79189, "Summary": "Epidemiology\nThe estimated incidence for PBD-ZSS is 1/50,000 births in the United States and 1/500,000 births in Japan.\nClinical description\nThe term PBD-ZSS reflects the disease spectrum seen in the severe, mild and intermediate variants that were described before their peroxisome etiology was known. The three subtypes have overlapping clinical phenotypes of varying degrees of severity, with ZS being the most, and IRD the least severe. Their distinction is not always clear in individual cases as patients with NALD and IRD display phenotypes that often overlap while ZS patients tend to have a more uniform presentation. Onset of manifestations is usually soon after birth or in childhood and includes neonatal seizures, hypotonia, distinctive craniofacial features (flattened facies, broad nasal bridge, widely split sutures, large anterior fontanelle), liver dysfunction, and in older children progressive sensorineural hearing loss, retinal dystrophy and developmental delays. Additional complications that can develop include adrenal insufficiency, calcium oxalate renal stones and episodes of hemorrhage and intracranial bleeding, the latter secondary to liver dysfunction and coagulopathy. The craniofacial features are most prominent in ZS, although they can still be recognizable in NALD and IRD. Atypical presentations of PBD-ZSS have recently been recognized.\nEtiology\nThe mutations found in 90% of PBD-ZSS patients are in the PEX1, PEX6, PEX10, PEX12 or PEX26 genes. Genetic defects in the PEX1 gene (seen in approximately 70% of cases), and subsequent alteration of the metabolic function of the peroxisome organelle is the most common cause of PBD-ZSS. The other less common disease causing mutations are found in the PEX13, PEX14, PEX16, PEX19, PEX2, PEX3, PEX5, and PEX11B genes. Two PEX genes, PEX11G and PEX11A remain thus far unassociated with disease. Impaired metabolism results in the accumulation of very-long-chain fatty acids (VLCFAs), which damage developing neural cells. Accumulation of toxic bile acid intermediates damages the liver. The decreased synthesis of docosahexanoic acid (DHA) and ether phospholipids (plasmalogens) impairs cell membranes. In the 13 PEX genes associated with PBD-ZSS, there are no correlations between disease severity and the causative PEX gene. Rather, there is a general correlation between the predicted effects of the PEX gene mutation on the function of the encoded PEX protein (peroxin). Thus, mutations that encode nonfunctional peroxins are associated with ZS, and mutations that encode peroxins with residual functions are associated with less severe phenotypes.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nancy BRAVERMAN"}
{"Disease Name": "Perrault syndrome", "Disease Definition": "A rare genetic disease characterized by a clinical picture of variable severity associating sensorineural hearing impairment with ovarian dysgenesis in females, sometimes progressive neurologic disorder, and exceptionally renal disease. The disease affects both sexes, but hypogonadism is not a feature in males.", "ORPHA ID": 2855, "Summary": "Epidemiology\nPrevalence of Perrault syndrome (PS) is unknown but over 100 patients whose diagnosis has been confirmed by molecular analysis have been reported so far, with an approximately 2:1 female to male ratio. The disease is most likely underdiagnosed, especially in the male population where it remains undetected in the absence of an affected sister.\nClinical description\nPerrault syndrome is subdivided in two types. Type 1, static, presents with deafness and ovarian dysgenesis in females. Type 2 presents with additional neurological, and rarely, muscular or renal manifestations. Mean age at diagnosis is 26 years old, and based on presentation with delayed puberty in females with sensorineural deafness. Hearing defects (mean age at diagnosis of 7 years) were noted in all but one of the reported cases. The hearing loss is sensorineural and generally bilateral, prelingual, and asymmetric, with a variable severity (mild to profound) even in affected patients from the same family. It is classically an auditory neuropathy (with presence of otoacoustic emissions initially). Ovarian dysgenesis has been reported in all female cases, but no gonadal dysgenesis has been reported in males. Amenorrhea is generally primary, but can also be secondary. Neurological features are inconstant, progressive, and of variable severity; they include cerebellar dysfunction with ataxia, sensitive or sensitive-motor neuropathy, and less frequently, developmental delay.\nEtiology\nPS is a heterogeneous disease. Biallelic, homozygotous, or compound heterozygous mutations in 8 genes have been identified, but molecular analysis remains inconclusive in half of the patients. PS is due to alterations of mitochondrial (CLPP, ERAL1, HARS2, LARS2, RMND1, TWNK genes) or metabolic functions (HSD17B4, GGSP1 genes). Outside of disease forms presenting with constant neurologic disorders (which sometimes precede hearing loss) associated with mutations in TWNK, or exceptional renal symptoms associated with RMND1 mutations, there is no correlation between genotype and phenotype.\nDiagnostic methods\nHearing loss is evaluated by otoacoustic emissions (OAE) and auditory evoked potentials (AEP). CT scans reveal that the hearing loss is not associated with temporal bone malformations. Hormonal tests (LH, FSH, AMH levels), which are required in deaf females with no signs of puberty at 11 years old, reveal hypergonadotropic hypogonadism. Pelvic examinations reveal absent ovaries or streak gonads, and a very hypoplasic uterus. Neurologic investigations reveal reduced nerve conduction velocities, and cerebral MRI may show a nonspecific white matter hypersignal or cerebellar atrophy. Genetic analysis can reveal causal mutations in half of patients.\nDifferential diagnosis\nTurner syndrome is the main differential diagnosis.\nAntenatal diagnosis\nPrenatal diagnosis is possible when the pathogenic variants have previously been identified in a family member.\nManagement and treatment\nTreatment and follow-up should be multidisciplinary, including audiologists, endocrinologists, neurologists and psychologists. Hearing aids or cochlear implants may help for the hearing defect. Puberty induction and ovarian preservation should be discussed with the family.\nPrognosis\nLife expectancy is normal for patients with Perrault syndrome type 1. Outcome is variable in patients with Perrault syndrome type 2 who present with progressive neurological disease.\n\n                            Last update: \n                            March 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Catherine VINCENT-DELORME | ERN CRANIO*\n\n\n                                * European Reference Network"}
{"Disease Name": "Perry syndrome", "Disease Definition": "A rare inherited neurodegenerative disorder characterized by rapidly progressive early-onset parkinsonism, central hypoventilation, weight loss, insomnia and depression.", "ORPHA ID": 178509, "Summary": "Epidemiology\nThe prevalence is unknown. It has been described in 53 cases from 11 families to date in Canada, U.S., U.K., France, Turkey and Japan.\nClinical description\nPerry syndrome has a mean age of onset of 48 years (range 35-61) and presents with parkinsonism (akinetic-rigid and rather symmetric), psychiatric changes manifesting as depression, lethargy, withdrawal, apathy, and changes in character, as well as sleep difficulties. The usual duration of Perry syndrome is about 5 years, with severe weight loss and central hypoventilation being seen late in the disease course. Marked autonomic dysfunction was reported in one family from Japan. Patients are often bedridden or wheelchair bound as motor impairment may be severe at a later stage of the disease.\nEtiology\nPerry syndrome is caused by mutations (five identified to date) in exon 2 of the dynactin DCTN1 gene coding for p150glued, the major subunit of the dynactin protein complex. Mutations in this gene alter the binding affinity of dynactin for microtubules and consequently this leads to the impairment of this important transport protein. Nigral neurons seem to be more affected by the dysfunction of this protein, explaining their increased cell death and the distinct pathology seen in Perry syndrome.\nDiagnostic methods\nDiagnosis is based on clinical findings of early-onset parkinsonism combined with depression, weight loss and hypoventilation and is confirmed by a molecular genetic test finding a mutation in the DCTN1 gene. Major histological findings consist of neuronal loss and TAR DNA-binding protein (TDP-43)-positive pathology in the substantia nigra and locus coeruleus, without Lewy bodies. Sleep studies should be performed to detect hypoventilation.\nDifferential diagnosis\nThe main differential diagnoses are other forms of familial early-onset parkinsonism (in particular those associated with mutations in the PARK2, PINK1, PARK7 and LRRK2 genes) as well as frontotemporal dementia (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible in laboratories that offer custom prenatal testing for families with a known DCTN1 mutation.\nGenetic counseling\nPerry syndrome is inherited in an autosomal dominant manner with full penetrance and children of a parent with the disease have a 50% risk of also having the mutation and developing the disease. Pre-symptomatic diagnosis can be offered to at-risk individuals.\nManagement and treatment\nThere is no cure for Perry syndrome. Symptomatic treatment requires a multidisciplinary team. Dopaminergic therapy is given to patients to help with parkinsonism, usually using levodopa / carbidopa. Response to levodopa can be erratic or absent but large doses (>2g) have been successful in reducing symptoms in several patients. Patients with hypoventilation require ventilator support (invasive or non-invasive), particularly at night. Respiratory function should be monitored continuously. Psychiatric follow-up along with antidepressant drugs are needed to manage depression and prevent suicide. Weight should be monitored and a high caloric diet should be implemented when weight loss is present. With worsening symptoms hospitalization and major medical assistance is often required.\nPrognosis\nPerry syndrome progresses rapidly and the prognosis is poor. Death is due to respiratory insufficiency or suicide or, in some cases, can be sudden and unexplained. Ventilation assistance may prolong survival with an acceptable quality of life.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Christian WIDER"}
{"Disease Name": "Persistent eustachian valve", "Disease Definition": "A rare congenital anomaly of the inferior vena cava characterized by the postnatal presence of an eustachian valve remnant, which may be asymptomatic and considered a normal variant or prominent and clinically significant. Clinical presentation is variable and includes obstruction of the inferior vena cava, cyanosis, thrombosis, pulmonary embolism, infective endocarditis, and when combined with persistent foramen ovale, it may generate permanent right-to-left shunt.", "ORPHA ID": 99120, "Summary": ""}
{"Disease Name": "Persistent fifth aortic arch", "Disease Definition": "A rare, congenital anomaly of the great arteries characterized by an extrapericardial vessel arising from the ascending aorta proximal to the brachiocephalic artery and terminating either in the dorsal aorta or in pulmonary arteries via a persistently patent arterial duct. The resulting connection is a systemic-to-systemic or systemic-to-pulmonary. Clinical manifestation include exercise intolerance, reduced femoral pulses, cyanosis with or without pulmonary hypertension and heart failure. Other congenital cardiovascular anomalies are often present and influence the clinical presentation.", "ORPHA ID": 99076, "Summary": ""}
{"Disease Name": "Persistent hyperplastic primary vitreous", "Disease Definition": "A rare ophthalmic disorder characterized by mostly unilateral failure of the regression of a fetal ocular vessel component, the tunica vasculosa lentis and/or the hyaloid system, resulting in an anterior (presenting with microphthalmia, leukocoria, cataract, glaucoma, elongated ciliary processes, shallow anterior chamber, and retrolental fibrovascular membranes, among others) or posterior disease subtype (with microphthalmia, leukocoria, presence of a retinal fold or detachment, hypo- or dysplastic optic nerve, and vitreous membranes and stalk), respectively. Most patients present with a combination of the two subtypes.", "ORPHA ID": 91495, "Summary": ""}
{"Disease Name": "Persistent idiopathic facial pain", "Disease Definition": "A rare neurological disease characterized by a generally deep, poorly localized, persistent facial pain that does not present characteristics of a cranial neuralgia and which cannot be attributed to another disorder.", "ORPHA ID": 398147, "Summary": ""}
{"Disease Name": "Persistent left superior vena cava connecting through coronary sinus to left-sided atrium", "Disease Definition": "A rare, congenital vascular malformation of the major vessels characterized by a persitent left superior vena cava which drains through the left coronary sinus to the left atrium. Patients are usually asymptomatic and discovered incidentally, however hypoxia, cyanosis, murmurs, palpitations, cardiac structural anomalies (e.g. atrial septal defect, bicuspid aortic valve, cor triatriatum) and risk of paradoxical embolism may be associated.", "ORPHA ID": 99109, "Summary": ""}
{"Disease Name": "Persistent left superior vena cava connecting to the roof of left-sided atrium", "Disease Definition": "A rare congenital anomaly of superior vena cava characterized by a persistent left superior vena cava that drains into the left atrium through a direct connection to its roof, creating a right-to-left shunt. Patients are at risk of developing chronic hypoxia, decreased exercise tolerance, cyanosis, embolic cerebrovascular events, and heart failure.", "ORPHA ID": 99111, "Summary": ""}
{"Disease Name": "Persistent Müllerian duct syndrome", "Disease Definition": "Persistent Müllerian duct syndrome (PMDS) is a rare disorder of sex development (DSD) characterized by the persistence of Müllerian derivatives, the uterus and/or fallopian tubes, in otherwise normally virilized boys.", "ORPHA ID": 2856, "Summary": "Epidemiology\nThe exact prevalence in the general population is unknown.\nClinical description\nAll affected subjects are, by definition, genotypically (46, XY) and phenotypically (normally virilized external genitalia) male. Index symptoms are cryptorchidism or inguinal hernia. Testes are normally differentiated and, in the absence of long-standing cryptorchidism, usually contain germ cells. However, affected males may be infertile as the testes are frequently not properly connected to male excretory ducts due to aplasia of the epididymis and the upper part of the vas deferens. Testosterone levels are usually normal, unless testicular degeneration has occurred.\nEtiology\nGenetic analysis of more than 100 families has shown that around 45% of cases are caused by mutations in the anti-Müllerian hormone gene (AMH; 19p13.3). Mutations in the gene encoding the AMH receptor (anti-Müllerian hormone receptor, type II, AMHR2; 12q13) are responsible for a further 40% of cases, with around half of these patients carrying the same mutation (a 27-base pair deletion in exon 10). Ovarian function appears to be normal in female relatives of affected males, however, further studies are required to determine whether female homozygous carriers of AMH or AMHR2 mutations are subject to early menopause.\nDiagnostic methods\nPMDS is usually discovered incidentally during surgery for undescended testes or inguinal hernia in boys with normal external genitalia. A specific ELISA test can be used to determine AMH levels in the serum and is a useful screening method to guide the molecular diagnosis.\nGenetic counseling\nPMDS is transmitted in an autosomal recessive manner.\nManagement and treatment\nTreatment is surgical and consists of replacement of the gonads within the scrotum, requiring careful dissection of the Müllerian derivatives. Total hysterectomy is not recommended because of the risk to the vas deferens.\nPrognosis\nEarly diagnosis and treatment may decrease the risks of degeneration and malignancy of the testes associated with longstanding cryptorchidism. Sexual function is normal, but fertility is compromised, even in treated patients. Hemospermia has been observed in older patients, but otherwise the presence of Müllerian derivatives is not harmful.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Jean-Yves PICARD"}
{"Disease Name": "Persistent placoid maculopathy", "Disease Definition": "Persistent placoid maculopathy is characterised by white plaque-like lesions involving the macula but sparing the peripapillary areas of both eyes. It has been described in five patients. In contrast to patients with macular serpiginous choroiditis presenting with similar lesions, the five patients reported so far with persistent placoid maculopathy had good visual acuity until the onset of choroidal neovascularization (CNV) or pigmentary mottling. The macular lesions fade after several months or years, but the vascular anomalies persist leading to a loss of central vision.", "ORPHA ID": 97341, "Summary": ""}
{"Disease Name": "Persistent polyclonal B-cell lymphocytosis", "Disease Definition": "Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare, generally benign, lymphoproliferative hematological disease characterized by: chronic, stable, persistent, polyclonal lymphocytosis of memory B-cell origin, the presence of binucleated lymphocytes in the peripheral blood, and a polyclonal increase in serum immunoglobulin M (IgM). Patients are most frequently asymptomatic or may present with mild splenomegaly.", "ORPHA ID": 300324, "Summary": ""}
{"Disease Name": "Peters anomaly", "Disease Definition": "Peters anomaly (PA) is a congenital corneal opacity disorder characterized by a central corneal leukoma that obstructs the pupil leading to visual loss as well as absence of the posterior corneal stroma and Descemet membrane.", "ORPHA ID": 708, "Summary": ""}
{"Disease Name": "Peters plus syndrome", "Disease Definition": "Peters plus syndrome is an autosomal recessively inherited syndromic developmental defect of the eye (see this term) characterized by a variable phenotype including Peters anomaly (see this term) and other anterior chamber eye anomalies, short limbs, limb abnormalities (i.e. rhizomelia and brachydactyly), characteristic facial features (upper lip with cupid bow, short palpebral fissures), cleft lip/palate, and mild to severe developmental delay/intellectual disability. Other associated abnormalities reported in some patients include congenital heart defects (i.e. hypoplastic left heart, absence of right pulmonary vein, bicuspid pulmonary valve), genitourinary anomalies (hydronephrosis, renal hypoplasia, renal and ureteral duplication, multicystic dysplastic kidneys, glomerulocystic kidneys) and congenital hypothyroidism.", "ORPHA ID": 709, "Summary": ""}
{"Disease Name": "Peutz-Jeghers syndrome", "Disease Definition": "A genetic intestinal polyposis syndrome characterized by development of characteristic hamartomatous polyps throughout the gastrointestinal (GI) tract, and by mucocutaneous pigmentation. This disorder carries a considerably increased risk of GI and extra-GI malignancies.", "ORPHA ID": 2869, "Summary": "Epidemiology\nPeutz-Jeghers syndrome (PJS) prevalence estimates range from 1/25,000 to 1/300,000 births.\nClinical description\nDespite high variability between families, characteristic PJS polyps generally occur in childhood and early adulthood, with onset often during the first 10 years of life. Hamartomatous polyps can occur at any site in the GI (gastrointestinal tract) tract, but are most frequent in the small intestine. Other sites include the stomach, large intestine, nares, and rarely the renal pelvis, urinary bladder, and lungs. Although benign, polyps can lead to complications including bowel obstruction, rectal prolapse, and severe GI bleeding with secondary anemia, and intussusception. Adenomas and hyperplastic polyps may also occur. During infancy or childhood, patients may develop dark blue to dark brown macules around the mouth, eyes, nares, and in the perianal area and buccal mucosa. Hyperpigmentation may also be found on the fingers and toes. The lesions may fade in adolescence and adulthood but tend to persist in the buccal mucosa. They can cause psychological stress. GI and extra-GI malignancies mainly concern adult patients and include colorectal and gastric cancer (estimated lifetime risk (LTR) of 15% by 50 years of age, and 57% by 70 years), pancreatic cancer (LTR 5% by 50 years of age, and 17% by 70 years), and breast and ovarian cancer in females (LTR 8% by 40 years of age, and 32% by 60 years of age). Female patients may also develop adenoma malignum of the cervix, and typically benign bilateral multifocal sex cord tumors with annular tubules (SCTAT).\nEtiology\nThe disorder is usually caused by germline mutations in the STK11 gene (19p13.3). Mutations in this tumor suppressor gene are found in more than 80% of affected families. There are no clear genotype-phenotype correlations. One study showed that individuals with missense mutations had a significantly later time to onset of first polypectomy and of other symptoms compared with those either with truncating mutations or no detectable mutation.\nDiagnostic methods\nDiagnosis is based on clinical findings and can be made in a patient presenting one of the following signs: two or more histologically confirmed PJ polyps, any number of PJ polyps and a family history of PJS, characteristic mucocutaneous pigmentation and a family history, or any number of PJ polyps associated with characteristic mucocutaneous pigmentation. Molecular genetic testing of the STK11 gene confirms the diagnosis and is available clinically. Aside from mutations affecting the STK11 protein, large deletions of STK11 have also been reported to cause PJS and should be considered when sequencing fails to identify a protein coding or splice variant.\nDifferential diagnosis\nDifferential diagnoses include juvenile polyposis syndrome, hereditary mixed polyposis syndrome, the PTEN hamartoma tumor syndromes, and Carney complex.\nAntenatal diagnosis\nPrenatal diagnosis for increased risk pregnancies is available provided that the disease-causing mutation has been identified in the family.\nGenetic counseling\nThe syndrome is inherited in an autosomal dominant manner. The number of cases related to de novo gene mutations is not known. A recent report found that 9 of 14 sporadic cases presenting in children were caused by de novo mutations and the cause of the other 5 cases could not be determined. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nRoutine treatment methods should be used for polyp resection, intussusception and malignancies. Some evidence indicates routine endoscopy and intraoperative eneteroscopy with polypectomy decreases the requirement for laparotomy and bowel loss. Newer technologies such as video capsule endoscopy, magenetic resonance enterography and balloon-assisted enteroscopy are being suggested to reduce the management burden. Although generally recommended, there is no control data on the value of surveillance strategies for cancer management in PJS patients. The aim of surveillance is to reduce polyp related complications in younger patients and for early detection of malignancies in older patients.\nPrognosis\nThe prognosis depends on the severity of polyp complications and on the development of malignancies. Routine surveillance of polyp growth will lead to better management.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Christopher AMOS"}
{"Disease Name": "PFAPA syndrome", "Disease Definition": "PFAPA (Periodic fever - aphthous stomatitis- pharyngitis - adenopathy) syndrome is an auto inflammatory syndrome characterized by recurrent febrile episodes associated with aphthous stomatitis, pharyngitis and cervical adenitis.", "ORPHA ID": 42642, "Summary": "Epidemiology\nPrevalence of PFAPA is unknown, over 500 cases have been reported and patients are predominantly male (>60%).\nClinical description\nPFAPA usually presents during early childhood (<5 years old) with recurrent episodes of fever (>39°C) lasting 3-7 days, during which children appear very ill. Aphthous stomatitis is characterized by relatively painless small, round and shallow lesions on the tongue and oral mucosa (70% of cases) that recover completely in 10-14 days. Most patients present with tonsillitis, occasionally with white exudates (mimicking streptococci infection), and a general pharyngitis (75% of cases) with diffuse hyperemia of the entire palate. Swelling of upper cervical lymph nodes appears in >75% of cases. Abdominal pain has also been reported in many cases (65%) and generally correlates with mesenteric adenopathy. Other reported features include chills, headache, vomiting, diarrhea, hepatosplenomegaly and joint pain. Episodes recur every 3-5 weeks, often in a predictable fashion with patients describing a mild malaise the day before recurrence. Patients are in good health between episodes and generally develop normally, but leg pain and chronic fatigue are often reported.\nEtiology\nPFAPA is an idiopathic inflammatory condition. Elevated levels of IL-2, TNF-alpha, decreased levels of IL-10 and a significant over expression of IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes are noted during the episodes.\nDiagnostic methods\nPFAPA is a diagnosis of exclusion based on clinical manifestations. The regularity of acute episodes during the active phase of the disease is an important clue. Marked leukocytosis and elevated CRP levels are observed in blood samples collected during acute episodes. Oral culture swabs are negative for infection, and patients fail to respond to antipyretic or antibiotic treatment.\nDifferential diagnosis\nDifferential diagnosis includes other diseases characterized by periodic fever such as recurrent tonsillitis, streptococcal infection, juvenile idiopathic arthritis, Behçet's disease, cyclic neutropenia, familial Mediterranean fever, TRAPS syndrome, and mevalonate kinase deficiency (see these terms).\nManagement and treatment\nPFAPA has no specific treatment. Fever does not respond to non-steroidal anti-inflammatory medications. A dose of corticosteroid (prednisone, 1-2 mg/kg, or betametasone, 0.1-0.2 mg/kg) given upon the first signs of an episode can shorten or even end the episode within hours. This treatment has, however, been reported to reduce the interval between episodes. Cimetidine and colchicine have had some success in preventing relapse through regular administration. Tonsillectomy may be considered in more severe cases with very frequent flare ups.\nPrognosis\nEpisodes usually decrease in frequency and resolve during the patient's second decade. Tonsillectomy may cure the disease in most cases.\n\n                            Last update: \n                            July 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Isabelle KONE-PAUT"}
{"Disease Name": "Pfeiffer syndrome", "Disease Definition": "An acrocephalosyndactyly associated with craniosynostosis, midfacial hypoplasia, hand and foot malformation with a wide range of clinical expression and severity. Most of the affected patients show various other associated manifestations.", "ORPHA ID": 710, "Summary": "Epidemiology\nPfeiffer syndrome (PS) birth prevalence is 1/100,000. The disorder affects males and females equally.\nClinical description\nAbnormal skull shape is usually detected in the neonatal period (possibly on prenatal ultrasound). Characteristic cranial features include a wide cranial vault, a flat occiput, broad forehead, a small nose with depressed nasal bridge, orbital hypertelorism and proptosis. The clinical picture depends on the extent of craniosynostosis (mostly bicoronal) and the associated functional disorders (respiratory, otological, ocular, neurological). Three forms of PS have been described (PS type 1, type 2, and type 3). Type 1 described as the \"classic PS\", is the less severe form of PS and is characterized by mild-to-moderate midface hypoplasia, minimal hand and foot abnormalities, little to no ocular proptosis and usually normal intellectual development. In contrast, types 2 and 3 are associated with more severe manifestations such as extreme proptosis and choanal stenosis or atresia, finger and toes abnormalities, elbow ankylosis or synostosis, and complications (hydrocephalus and seizures) resulting in a poorer prognosis. Other complications include brain development disorders, exposure keratopathy, exorbitism, bilateral and symmetrical hearing loss, airway obstruction, and obstructive sleep apnea. Type 2, the most severe form, is distinguished from type 3 by the presence of a cloverleaf skull. Types 2 and 3 have occurred only in sporadic cases and have increased risk of early death due to severe neurological compromise and respiratory problems.\nEtiology\nThe majority of cases are caused by  de novo mutations in the FGFR2 gene (10q25.3-q26), and very rarely in type 1 cases, by mutations in the FGFR1 (8p11.23-p11.22) gene. Patients meeting criteria for a clinical diagnosis of Pfeiffer syndrome without a mutation in FGFR1 or FGFR2 are estimated to be as high as 21%. Spontaneous mutations have been associated with advanced paternal age.\nDiagnostic methods\nThe diagnosis is based on the presence of the characteristic clinical findings including craniosynostosis or cloverleaf skull, facial features, and variable hand and foot malformations. Diagnosis can be confirmed by molecular genetic testing.\nDifferential diagnosis\nDifferential diagnoses include other acrocephalosyndactyly syndromes (Apert, Crouzon, Carpenter, Saethre-Chotzen, Waardenburg) and other syndromic forms of craniosynostosis such as Jackson-Weiss, Muenke and Antley-Bixler syndromes and Cutis gyrata-acanthosis nigricans-craniosynostosis.\nAntenatal diagnosis\nPrenatal molecular genetic testing is possible. Results of genetic testing for low-risk pregnancies are of little prognostic value. Prenatal imaging may also be used for diagnosis if physical findings are apparent. Some ultrasound findings could pose the suspicion of the disease.\nGenetic counseling\nGenetic counseling should be provided to affected families. Inheritance from an affected parent in an autosomal dominant manner is reported in less severe cases of Pfeiffer syndrome. PS shows complete penetrance, although the expressivity is variable. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring. When prenatal features are evocative for PS, gene molecular testing for mutation, after standard and molecular karyotyping should be suggested.\nManagement and treatment\nTreatment is symptomatic and corrective, depending on the extent of disease manifestations. A multidisciplinary approach should be adopted to plan multiple-stage surgical interventions and other treatments with the aim of improving cosmetics, function and quality of life. The psychosocial aspects of the disease should also be addressed.\nPrognosis\nThe success of timely treatment is the main prognostic factor. Favorable outcomes can be achieved but the prognosis remains poor in severe cases with a high risk of early demise due to respiratory and neurological complications.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Chiara BOCCHERINI  - Dr Valentina D'AMBROSIO  -  Antonella GIANCOTTI  - Dr Antonio PIZZUTI"}
{"Disease Name": "Pfeiffer-Palm-Teller syndrome", "Disease Definition": "Pfeiffer-Palm-Teller syndrome is a very rare dysmorphic syndrome described in two sibs and characterized by a short stature, unique facies, enamel hypoplasia, progressive joint stiffness, high-pitched voice, cup-shaped ears, and narrow palpebral fissures with epicanthal folds, and intellectual deficit.", "ORPHA ID": 2871, "Summary": ""}
{"Disease Name": "PGM1-CDG", "Disease Definition": "A rare, genetic, congenital disorder of glycosylation and glycogen storage disease characterized by a wide range of clinical manifestations, most commonly presenting with bifid uvula with or without cleft palate at birth, associated with growth delay, hepatopathy with elevated aminotransferase serum levels, myopathy (including exercise-related fatigue, exercise intolerance, muscle weakness), intermittent hypoglycemia, and dilated cardiomyopathy and/or cardiac arrest, due to decreased phosphoglucomutase 1 enzyme activity. Less common manifestations include malignant hyperthermia, rhabdomyolysis, and hypogonadotropic hypogonadism with delayed puberty.", "ORPHA ID": 319646, "Summary": ""}
{"Disease Name": "PGM3-CDG", "Disease Definition": "A rare congenital disorder of glycosylation caused by mutations in the PGM3 gene and characterized by neonatal to childhood onset of recurrent bacterial and viral infections, inflammatory skin diseases, atopic dermatitis and atopic diatheses, and marked serum IgE elevation. Early neurologic impairment is evident including developmental delay, intellectual disability, ataxia, dysarthria, sensorineural hearing loss, myoclonus and seizures.", "ORPHA ID": 443811, "Summary": ""}
{"Disease Name": "PHACE syndrome", "Disease Definition": "PHACE is an acronym used to describe a syndrome characterised by the association of Posterior fossa brain malformations, large facial Haemangiomas, anatomical anomalies of the cerebral Arteries, aortic coarctation and other Cardiac anomalies, and Eye abnormalities. Sternal anomalies are also sometimes present, and in these cases the syndrome is referred to as PHACES. Two additional manifestations have recently been added to the clinical spectrum of PHACE syndrome: stenosis of the vessels at the base of the skull and segmental longitudinal dilations of the internal carotid artery.", "ORPHA ID": 42775, "Summary": "Epidemiology\nThis association of manifestations is rare and less than 100 cases have been reported in the literature so far. The syndrome is much more common in females than in males (8:1).\nClinical description\nNewborns and infants are affected. Expression of the complete clinical picture of PHACE syndrome is extremely rare and most patients display only a partial phenotype (or incomplete clinical spectrum). The posterior fossa malformations include cerebellar hypoplasia, arachnoid cysts, cortical dysgenesis and Dandy-Walker malformation. The capillary haemangiomas have the same morphological, clinical and evolutive characteristics as those of sporadic benign haemangiomas. Intracranial and subarachnoid lesions may occur concurrently, with the intracranial lesions evolving in the same manner as the maxillofacial or cervical haemangiomas. Two types of arterial anomalies have been described: persistence of embryological arteries and agenesis of the carotid or vertebral artery. These anatomical arrangements allow normal cerebral function but limit the capacity for collateral circulation in case of an associated occlusive or stenotic lesion. The ophthalmological anomalies include glaucoma, coloboma, microphthalmia, cryptophthalmia and optic nerve hypoplasia. In most cases, the vascular lesions are uni- and homolateral, indicating that PHACE syndrome is a member of the group of cerebrofacial syndromes with involvement of several adjacent segments of the neural crest. Sternal anomalies resulting from ventral developmental defects are rare and include sternal clefts and/or malformations of the supraumbilical raphe. Progressive stenotic lesions of the intracerebral arteries (which are usually unilateral) are localised to the anterior or posterior divisions of the internal carotid artery. They result from concentric proliferation of the vascular wall causing a progressive reduction in the size of the lumen. Thickening of the vascular wall is also responsible for elongation of the internal carotid artery segments. The resulting neurological symptoms are variable, depending on the size and associated territory of the occluded vessels. Other manifestations such as headaches or delayed psychomotor development may also be caused by the same ischemic aetiology.\nEtiology\nThe aetiology of the syndrome is unknown.\nDiagnostic methods\nDiagnosis can be confirmed by CT scan, MRI and cardiopulmonary investigations. Angiography is not performed systematically. Early diagnosis and treatment decreases the number and lessens the severity of complications.\nGenetic counseling\nThe female predominance indicates male-lethal X-linked dominant transmission.\nManagement and treatment\nManagement should be multidisciplinary with the aim of stabilising the cardiac and neurological manifestations and preventing angioma growth. Depending on the volume and location of the lesions, drug treatment or surgical management may be proposed for the capillary haemangiomas. Treatment with aspirin is often recommended to prevent ischemic accidents and cerebral revascularisation, a surgical intervention often indicated for a patients with Moya-moya, may be also be proposed for PHACE.\nPrognosis\nThe prognosis depends on the severity of the clinical signs associated with the cerebral and arterial anomalies. Neurological sequelae are frequent.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Hortensia ALVAREZ  - Pr Pierre LASJAUNIAS"}
{"Disease Name": "Phacoanaphylactic uveitis", "Disease Definition": "A rare ophthalmic disorder characterized by a zonal granulomatous inflammatory reaction centered around the lens secondary to its traumatic rupture. Signs and symptoms include photophobia, ocular irritation or pain, blurred vision, redness, mutton-fat keratic precipitates, posterior synechiae, and sometimes hypopyon. Intraocular pressure may be elevated due to blockage of the trabecular meshwork by inflammatory cells or lens material.", "ORPHA ID": 209959, "Summary": ""}
{"Disease Name": "Phakomatosis pigmentokeratotica", "Disease Definition": "A rare epidermal nevus disorder characterized by the association of speckled lentiginous nevi with epidermal sebaceous nevi, and extracutaneous anomalies.", "ORPHA ID": 2874, "Summary": ""}
{"Disease Name": "Phakomatosis pigmentovascularis", "Disease Definition": "A rare skin disease characterized by the co-occurrence of a widespread vascular nevus (typically nevus flammeus) and a pigmentary nevus, potentially associated with a variety of other cutaneous nevi, and with or without extracutaneous (most commonly central nervous system, ocular, or musculoskeletal) involvement. Several subtypes are distinguished based on phenotypic characteristics.", "ORPHA ID": 2875, "Summary": ""}
{"Disease Name": "Phalangeal microgeodic syndrome", "Disease Definition": "A rare primary osteolysis disorder characterized by multiple small osteolytic areas and sclerosis in the phalanges of one or both hands associated with swelling and redness of the phalanges. Condition is benign, self-limited and may be associated with cold exposure.", "ORPHA ID": 352636, "Summary": ""}
{"Disease Name": "Pharyngeal-cervical-brachial variant of Guillain-Barré syndrome", "Disease Definition": "Pharyngeal-cervical-brachial variant of Guillain-Barré syndrome is a rare, acquired peripheral neuropathy disease characterized by rapidly progressive oropharyngeal (facial palsy, dysarthria) and cervicobrachial weakness, associated with upper limb weakness and hypo/areflexia, in the absence of ophthalmoplegia, ataxia, altered consciousness, and prominent lower limb weakness. The presence of monospecific IgG anti-GT1a antibodies is associated.", "ORPHA ID": 231426, "Summary": ""}
{"Disease Name": "PHAVER syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by the association of limb pterygia, heart anomalies, autosomal recessive inheritance, vertebral defects, ear anomalies and radial defects.", "ORPHA ID": 2876, "Summary": ""}
{"Disease Name": "Phelan-McDermid syndrome", "Disease Definition": "A rare genetic neurodevelopmental disorder characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features.", "ORPHA ID": 48652, "Summary": "Epidemiology\nA rare genetic neurodevelopmental disorder characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features.\nClinical description\nThe severity of the developmental delay tends to vary with deletion size, with most individual functioning in the severe to profound range. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. Major milestones are delayed, receptive language skills typically exceed expressive skills, and many individuals are nonverbal. Other neurological features include seizures, ataxic gait, sleep disturbance, abnormal brain imaging, and regression or loss of skills. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Between 10 to 25% of individuals have gastrointestinal reflux, cardiac abnormalities renal anomalies, lymphedema, or visual defects.\nEtiology\nThe majority of cases result from the loss of 22q13.3 due to a simple deletion, translocation, ring chromosome or other structural chromosome changes involving the SHANK3 gene (PMS-SHANK3 related). About 15% of people have a heterozygous pathogenic variant in the SHANK3 gene. Less frequently, an individual may have an interstitial deletion of 22q13 that does not involve the SHANK3 gene (PMS-SHANK3 unrelated).\nDiagnostic methods\nThe diagnosis of monosomy 22q13.3 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Chromosomal microarray is recommended as the first tier of testing. Detection of pathogenic variants of SHANK3 requires gene testing (genome sequencing, exome sequencing).\nDifferential diagnosis\nDifferential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like behavior (Prader-Willi, Angelman, Williams, Smith-Magenis, fragile X, Sotos, FG, and velocardiofacial syndromes, autism spectrum disorders and cerebral palsy).\nAntenatal diagnosis\nAntenatal diagnosis is possible where a parental chromosome rearrangement or pathogenic variant has previously been identified. Because of the difficulty detected parental mosaicism, antenatal diagnosis may also be offered to parents of children with apparently de novo deletions or pathogenic variants.\nGenetic counseling\nTransmission is autosomal dominant; while most cases occur sporadically, genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. The risk of affected offspring is also increased for parents who carry balanced structural abnormalities of chromosome 22. The risk to a translocation carrier depends on the type of chromosome abnormality, the size of the chromosome segments involved, the mode of ascertainment, the sex of the transmitting parent, and other factors. Most risk estimates will fall below 30%.\nManagement and treatment\nIndividuals with monosomy 22q13.3 should have routine examinations by the primary care physician, as well as genetic evaluations with referral to specialists if neurological, gastrointestinal, renal, or other systemic problems are suspected. Affected individuals benefit from early intervention programs, intense occupational and communication therapies, adaptive exercise and sport programs, and other therapies to strengthen their muscles and increase their communication skills. Because ring chromosome 22 is associated with a specific risk of neurofibromatosis type 2 (NF2), individuals ring 22 must undergo increased surveillance for symptoms of NF2.\nPrognosis\nNo apparent life-threatening organic abnormalities accompany the diagnosis of monosomy 22q13.3.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Katy PHELAN"}
{"Disease Name": "Phenobarbital embryopathy", "Disease Definition": "A teratologic disorder associated with intrauterine exposure of phenobarbital during the first trimester of pregnancy. Infants are usually asymptomatic but an increased risk of intellectual disability, tetralogy of Fallot, unilateral cleft lip, hypoplasia of the mitral valve and some other mild abnormalities such as hypertelorism, epicanthus, hypoplasia and low insertion of the nose, low insertion of the ears, prognathism, finger hypoplasia, brachydactyly and hypospadias have been reported in rare cases.", "ORPHA ID": 1919, "Summary": ""}
{"Disease Name": "Phenylketonuria", "Disease Definition": "A rare inborn error of amino acid metabolism characterized by elevated blood phenylalanine and low levels or absence of phenylalanine hydroxylase enzyme. If not detected early or left untreated, the disorder manifests with mild to severe mental disability.", "ORPHA ID": 716, "Summary": "Epidemiology\nThe prevalence of phenylketonuria (PKU) shows considerable geographic variation. It is estimated to be 1/10,000 live births in Europe with a higher rate in some countries (Ireland, Italy). Prevalence is particularly high in Turkey: 1/4,000 live births. PKU is far rarer in the Finnish, African and Japanese populations.\nClinical description\nIn the absence of neonatal diagnosis, symptoms develop within a few months of birth, may be very mild to severe and include gradual developmental delay, stunted growth, microcephaly, seizures, tremors, eczema, vomiting, and musty odor. Untreated patients subsequently develop intellectual disability, behavioral disorders (hyperactivity) and motor disorders. Patients often have fair coloring as a result of tyrosine deficiency. The most common form of the condition is known as classical phenylketonuria and is characterized by severe symptoms. A mild form has also been described (mild PKU), and an even milder form known as mild hyperphenylalaninemia (mild HPA or non-PKU HPA). A subset of patients with milder phenotypes has been found to be responsive to tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydroxylase (BH4-responsive HPA).\nEtiology\nPKU is caused by a wide range of variants in the PAH gene (12q22-q24.2) coding for phenylalanine hydroxylase. Non-PAH variants have been reported to cause a disorder known as hyperphenylalaninemia due to BH4 deficiency. Variant frequency varies among different ethnic groups. Lower levels or absence of the phenylalanine hydroxylase enzyme underlie the clinical manifestations, as a result of toxic accumulation of phenylalanine in the blood and brain.\nDiagnostic methods\nThe disorder is usually diagnosed through neonatal screening programs.\nDifferential diagnosis\nPKU should be distinguished from BH4 deficiency.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThe mainstay of treatment is a low-phenylalanine diet and amino acids mixture for the forms that require treatment. According to the European guidelines for the management of PKU, the recommended maintenance level is usually between 120 and 360 micromol/L in newborns, with treatment considered essential in older patients with levels above 600 micromol/L.\nPrognosis\nPrognosis is variable, but favorable if diagnosed early and treated properly.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Nenad BLAU"}
{"Disease Name": "Pheochromocytoma-paraganglioma", "Disease Definition": "A rare neuroendocrine tumor arising from chromaffin cells of the adrenal medulla (pheochromocytoma) or from sympathetic and parasympathetic ganglia (paraganglioma). These tumors are most often benign and may produce catecholamines in excess causing hypertension and sometimes severe acute cardiovascular complications.", "ORPHA ID": 573163, "Summary": "Epidemiology\nPheochromocytomas and paragangliomas (PPGL) are rare, occurring in 0.1 to 0.6% of patients with hypertension and 5% with adrenal incidentaloma. The incidence is approximately 0.57 per 100,000 person-years (0.46 for pheochromocytomas and 0.11 for paragangliomas).\nClinical description\nThe symptomatology may be related to hypersecretion of catecholamines. It is variable, fluctuating, non-specific and even sometimes completely non-existent. Hypertension is the most common sign and can be permanent (50-60%) or paroxysmal (35%) and associated with orthostatic hypotension. Blood pressure can also be normal, especially in patients with low or no hypersecretion. A sudden discharge of catecholamines can cause paroxysmal symptoms that may or not occur concomitantly: headache (60-90%), sweating (55-75%), and palpitations (50-70%). The specificity and sensitivity of this triad for the diagnosis of pheochromoctyoma and/or catecholamines-producing paraganglioma are 94% and 91% respectively. Ten to 15% of PPGL are diagnosed after an acute cardiomyopathy, the most frequent being the Takotsubo cardiomyopathy. The others symptoms, less frequent, are general impairment, weight loss, constipation, anxiety, hyperglycemia and nausea. Head and neck paraganglioma are classically non-secreting tumors: the discovery could be made because of the palpation of a cervical mass or a swelling sometimes pulsatile, tinnitus, hypoacousia or even paralysis of the cranial nerves (dysphonia, dysphagia...). In genetically determined forms, others tumors or signs may be associated. For instance, gastrointestinal stromal tumors in patients with Carney-Stratakis syndrome.\nEtiology\nAbout 40% of PPGL occur in the context of an autosomal inherited syndrome. More than 15 predisposing genes have been identified (SDHA, SDHB, SDHC, SDHD, RET, VHL, NF1, TMEM127, MAX, FH...). About 60% are sporadic but up to 30% of sporadic tumors actually carry somatic mutations in these known susceptibility genes.\nDiagnostic methods\nThe diagnosis of secreting PPGL is based on plasma free metanephrines or 24-hour urinary fractionated metanephrines measurements. A radiological evaluation is necessary to locate the tumor with conventional and nuclear medicine imaging. Biopsy should not be performed due to the high risk of acute catecholamines-induced hypertensive crisis and of hematoma. An early onset and/or the presence of multiple, extra-adrenal PPGL, bilateral pheochromocytoma or of metastases suggest a genetic form.\nDifferential diagnosis\nIn patients with paroxysmal symptoms, main differential diagnoses are panic disorder, hot flashes, carcinoid syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is not performed except for patients with VHL disease. Genetic testing may be offered to children at risk over 6 years old.\nGenetic counseling\nGenetic testing is recommended for all patients diagnosed with PPGL because 40% of cases occur in the context of an autosomal inherited syndrome. Moreover, patient follow-up is adapted according to the mutated gene (for example, intensive follow-up for SDHB mutation because the risk of malignancy is increased). It is also important to offer screening to first-degree relatives of mutation-carriers.\nManagement and treatment\nFor catecholamines-producing PPGL, referral treatment is surgical excision. Patients need to undergo preoperative alpha-adrenergic blockade and rehydration for preventing hypertensive crisis during surgery. In case of tachycardia, a cardioselective beta-blocker can be added in a second step. Radiotherapy can be proposed for non-functioning paragangliomas of the skull base and neck. Indeed, the risk of neurovascular damage is important with surgery. For metastatic PPGL, there is no consensus. The therapeutic decision requires a multidisciplinary discussion by an expert team (surgery, metabolic or conventional radiotherapy, embolization, chemotherapy, targeted therapy...). Patients management should be organized in a referral center.\nPrognosis\nThe acute cardiovascular complications (sudden death, acute stress cardiomyopathy, myocardial infarction, heart failure...) represent the most frequent causes of morbi-mortality. Moreover, a metastatic evolution or a recurrence can be observed in about 15% of the cases, especially in cases of genetic predisposition.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence AMAR  - Dr Alexandre BUFFET  - Dr Nelly BURNICHON  - Dr Erika CORNU  - Pr Anne-Paule GIMENEZ-ROQUEPLO"}
{"Disease Name": "PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by variable developmental delay and intellectual disability, overweight or obesity, behavioral abnormalities (including hyperactivity, aggressive behavior, anxiety, mood disorder, or autistic features), and facial dysmorphism (such as high forehead, full eyebrows and/or synophrys, upturned nose, and fleshy ears, among others). Additional reported manifestations are hypotonia, ocular anomalies, anomalies of the fingers and toes, joint hypermobility, or abnormal pigmentation. Brain imaging may show mild nonspecific abnormalities.", "ORPHA ID": 589905, "Summary": ""}
{"Disease Name": "Phocomelia, Schinzel type", "Disease Definition": "A rare genetic syndrome with limb reduction defects characterized by skeletal malformations comprising absent or hypoplastic pelvic bones (including sacral agenesis or hypoplasia), intercalary limb deficiencies (phocomelia potentially combined with polydactyly, oligodactyly or ectrodactyly), and skull defects (frequently a defect of the occipital bone with or without meningocele). Additional features may include thoracic dystrophy, dysmorphic facial features (dysplastic and large ears, and a high and narrow palate), and genital malformations (Mullerian aplasia, agenesis of the uterus and vagina, micropenis with cryptorchidism). Growth and mental development are not affected.", "ORPHA ID": 2879, "Summary": ""}
{"Disease Name": "Phosphoenolpyruvate carboxykinase deficiency", "Disease Definition": "A rare gluconeogenesis disorder that results from impairment in the enzyme phosphoenolpyruvate carboxykinase, and comprised of cytosolic and mitochondrial forms of enzyme deficiency. Onset of symptoms is neonatal or a few months after birth and includes hypoglycemia associated with acute episodes of severe lactic acidosis, progressive neurological deterioration, severe liver failure, renal tubular acidosis and Fanconi syndrome. Patients also present progressive multisystem damage with failure to thrive, muscular weakness and hypotonia, developmental delay with seizures, spasticity, lethargy, microcephaly and cardiomyopathy. To date, there is no conclusive evidence of the existence of an isolated form of this disorder.", "ORPHA ID": 2880, "Summary": ""}
{"Disease Name": "Phosphoribosylpyrophosphate synthetase superactivity", "Disease Definition": "A rare X-linked disorder of purine metabolism associated with hyperuricemia and hyperuricosuria, and comprised of two forms: an early-onset severe form characterized by gout, urolithiasis, and neurodevelopmental anomalies and a mild late-onset form with no neurologic involvement.", "ORPHA ID": 3222, "Summary": "Epidemiology\nPhosphoribosylpyrophosphate (PRPP) synthetase superactivity is is a rare disorder with 30 families described in the literature to date. Males are predominantly affected.\nClinical description\nMost individuals (approximately 75%) are affected by the milder form (mild PRPP synthetase superactivity), which manifests in late adolescence or early adulthood, usually with uric acid crystalluria and (kidney and/or bladder) urinary stones, followed by the development of gouty arthritis and eventually renal failure as a result of obstructive uropathy from uric acid crystal deposition. The severe form (severe PRPP synthetase superactivity) usually starts from infancy or early childhood and shares the same clinical features with the mild form but also shows neurologic impairment, mainly sensorineural hearing loss, hypotonia, ataxia, developmental delay, and /or intellectual disability. Heterozygous carrier women are either asymptomatic or display mild metabolic and neurologic symptoms.\nEtiology\nThe disease is due to overactivity of ribose-phosphate pyrophosphokinase 1 (PRS-I), an enzyme that catalyzes the synthesis of PRPP, a cofactor involved in the synthesis of purine and pyrimidine nucleotides. PRS-I overactivity results in the overproduction of purine nucleotides and uric acid (a waste product of purine breakdown). In the severe form, PRS-I overactivity is due to gain-of-function point mutations in the open reading frame of the PRPS1 gene (Xq22.3) encoding PRS-I, that lead to defective allosteric control of PRS-I isoform activity. The exact molecular mechanism leading to the mild form is not yet well understood as no mutations have been found in PRPS1, but it seems to be linked to increased rates of PRPS1 transcription. Loss of function mutations in PRPS1 are linked to Charcot-Marie-Tooth X type 5, X-linked non-syndromic sensorineural deafness and Arts syndrome, together these diseases form part of a spectrum of PRPS1-related disorders.\nDiagnostic methods\nIn both forms, diagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by a PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes. Molecular genetic testing also confirms the diagnosis in the severe form.\nDifferential diagnosis\nDifferential diagnosis includes hypoxanthine-guanine phosphoribosyltransferase deficiency and psychomotor delay due to S-adenosylhomocysteine hydrolase deficiency.\nAntenatal diagnosis\nPrenatal genetic testing in male fetuses are possible if the mutation has been previously identified in the family.\nGenetic counseling\nPRPP synthetase superactivity is an X-linked recessive disorder with complete penetrance. An affected mother has a 50% risk of transmitting the mutation to any of her offspring; an affected father transmits the mutation only to his daughters. De novo PRSP1 mutations have also been reported. Heterozygous carrier women are either asymptomatic or display mild metabolic and neurologic symptoms.\nManagement and treatment\nTreatment of uric acid overproduction with xanthine oxidase inhibitors like allopurinol or febuxostat successfully reverses or prevents the consequences of hyperuricemia and hyperuricosuria. A high daily fluid intake is warranted; and, as needed, potassium citrate to alkalinize the urine in order to avoid the formation of kidney stones. A low-purine and low-fructose diet along with regular surveillance of serum urate concentration is essential. For patients with the severe form, regular audiometric and neurologic evaluations are also recommended.\nPrognosis\nThe prognosis is uncertain in the severe form of the disease. Severe gout can lead to renal impairment, if not properly treated. Of note, the interventions have no known beneficial effect on hearing loss or neurologic impairment.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Arjan DE BROUWER"}
{"Disease Name": "Phosphoserine aminotransferase deficiency, infantile/juvenile form", "Disease Definition": "A rare form of serine deficiency syndrome characterized clinically by acquired microcephaly, psychomotor retardation, intractable seizures and hypertonia.", "ORPHA ID": 284417, "Summary": ""}
{"Disease Name": "Photosensitive epilepsy", "Disease Definition": "A rare reflex epilepsy characterized by seizures and photoparoxysmal responses triggered by flashing or flickering lights, or patterns. Exact nature of the stimulus and seizure type are variable. The disorder mainly presents in childhood and adolescence and can either occur as an isolated condition, or be associated to other epilepsy syndromes.", "ORPHA ID": 166409, "Summary": ""}
{"Disease Name": "Phyllodes tumor of the breast", "Disease Definition": "A rare fibroepithelial tumor of the breast characterized by a painless, circumscribed, firm mass potentially arising in any part of the breast, histologically showing a prominent intracanalicular growth pattern with leaf-like stromal fronds, capped by luminal epithelial and myoepithelial cell layers, accompanied by stromal hypercellularity. The tumor may be benign, borderline, or malignant.", "ORPHA ID": 180261, "Summary": ""}
{"Disease Name": "Phyllodes tumor of the prostate", "Disease Definition": "A rare urogenital tumor characterized by stromal and epithelial components forming cysts lined by hyperplastic epithelium in a cellular or sarcomatoid stroma. The tumors may be clinically benign or malignant and tend to recur after transurethral resection. Metastatic spread is to lungs, bone, and liver. Patients may present with obstructive voiding symptoms, dysuria, hematuria, urinary retention, or a palpable abdominal mass. The prostate is palpably enlarged but feels soft and spongy.", "ORPHA ID": 498228, "Summary": ""}
{"Disease Name": "Piebald trait-neurologic defects syndrome", "Disease Definition": "Piebald trait-neurologic defects syndrome is a rare, genetic, pigmentation anomaly of the skin syndrome characterized by ventral as well as dorsal leukoderma of the trunk and a congenital white forelock, in association with cerebellar ataxia, impaired motor coordination, intellectual disability of variable severity and progressive, mild to profound, uni- or bilateral sensorineural hearing loss. There have been no further descriptions in the literature since 1971.", "ORPHA ID": 2885, "Summary": ""}
{"Disease Name": "Piebaldism", "Disease Definition": "Piebaldism is a rare congenital pigmentation skin disorder characterized by the presence of hypopigmented and depigmented skin areas (leukoderma) on various parts of the body, preferentially on the forehead, chest, abdomen, upper arms, and lower extremities, that are associated with a white forelock (poliosis), and in some cases with hypopigmented and depigmented eyebrows and eyelashes.", "ORPHA ID": 2884, "Summary": ""}
{"Disease Name": "Pierpont syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by axial hypotonia after birth, prolonged feeding difficulties, moderate to severe global developmental delay, seizures (in particular absence seizures), fetal digital pads, distinctive plantar fat pads anteromedial to the heels, and deep palmar and plantar grooves. Over time, fat pads may become less prominent and disappear. Distinct craniofacial dysmorphic features include a broad face with high forehead, high anterior hairline, narrow palpebral fissures that take on a crescent moon shape when smiling, broad nasal bridge and tip with anteverted nostrils, mild midfacial hypoplasia, long, smooth philtrum, thin upper lip vermillion, small, widely spaced teeth, and flat occiput/microcephaly/brachycephaly.", "ORPHA ID": 487825, "Summary": ""}
{"Disease Name": "Pierre Robin syndrome-faciodigital anomaly syndrome", "Disease Definition": "A rare orofacial clefting syndrome characterized by the association of Pierre Robin sequence (retrognathia, cleft palate and glossoptosis) with facial dysmorphism (high forehead with frontal bossing) and digital anomalies (tapering fingers, hyperconvex nails, clinodactyly of the fifth fingers and short distal phalanges, finger-like thumbs and easily subluxated first metacarpophalangeal joints). Growth and mental development were normal.", "ORPHA ID": 2888, "Summary": ""}
{"Disease Name": "Pierson syndrome", "Disease Definition": "A rare primary glomerular disease characterized by the association of congenital nephrotic syndrome, early onset renal failure and ocular anomalies with microcoria and severe neurodevelopment deficits.", "ORPHA ID": 2670, "Summary": "Epidemiology\nLess than 70 cases have been described in the literature to date.\nClinical description\nPresentation is typically with congenital microcoria and heavy proteinuria. Proteinuria is usually nephrotic range, at or shortly after birth and progresses rapidly to early onset renal failure. The histological finding is usually diffuse mesangial sclerosis characterized by small and condensed appearance of glomerulus in which mesangial region shows some collagenous tissue. Ocular anomalies are usually bilateral but may vary in severity which include microcoria, iris hypoplasia, posterior embryotoxon, megalo- or microcornea, cataract, lenticonus, persistent fetal vasculature, retinal detachment, glaucoma, and phthisis bulbi. Neurological manifestations include severe global development delay, marked muscle hypotonia, movement disorders, and blindness. It should be noted that some cases with this disease show mild phenotypes of late onset proteinuria without ocular or neurological abnormalities.\nEtiology\nMutations in the LAMB2 gene (3p21) encoding laminin beta 2 have been identified. Laminin beta 2 is expressed in the glomerular basement membrane, at the neuromuscular junctions, as well as in the intraocular muscles, lens and retina.\nDifferential diagnosis\nEarly onset severe proteinuria accompanied by ocular anomalies are rare. Therefore, in typical cases, it is relatively easy to suspect this disease. Lowe syndrome (proteinuria, mostly low molecular weight protein, and congenital cataract) or renal-coloboma syndrome (due to PAX2 gene pathogenic variants) can be candidates for differential diagnosis.\nAntenatal diagnosis\nPrenatal diagnosis is difficult, but sometimes may be suspected on hyperechogenic kidneys and oligohydramnios. Only genetic testing allows early and reliable prenatal diagnosis. Prenatal diagnosis may be offered to families in which the disease-causing mutation has already been identified in affected siblings.\nGenetic counseling\nThe disease is transmitted as an autosomal recessive trait. Where both parents are unaffected carriers of the disease, there is a 25% risk of transmission to offspring. Carrier testing of healthy family members is possible where the mutation has been identified in a family with at least one affected member.\nManagement and treatment\nThere is no specific treatment available. Since protein loss is limited, nephrectomy to prevent protein loss to urine is rarely needed. Angiotensin converting enzyme (ACE) inhibitors could help reduce urine protein loss and can delay the progression to end-stage kidney disease (ESKD) due to their renal protective effects. Renal replacement therapies including kidney transplantation are successfully employed. To date, there is no-evidence of disease-recurrence reported in the grafts after kidney transplantation. Careful ophthalmological follow up is required for the care of retinal detachment.\nPrognosis\nThe kidney prognosis is severe with most patients progressing towards renal failure within the first year of life. Visual prognosis is generally poor: visual acuity ranges from no light perception to 20/200. Mild to severe intellectual disability is always observed. Survival into adult is reported with renal replacement therapies.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Iijima KAZUMOTO  - Pr Kandai NOZU  - Dr Kusuhara SENTARO"}
{"Disease Name": "PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis", "Disease Definition": "A rare genetic primary lymphedema characterized by uniform, widespread lymphedema, often with systemic involvement such as intestinal and pulmonary lymphangiectasia, pleural and pericardial effusions, and chylothorax. There is a high incidence of non-immune hydrops fetalis, which may result in fetal demise or fully resolve after birth. Severe, recurrent facial cellulitis is observed in some patients. Presence of epicanthic folds or micrognathia has occasionally been reported, while intelligence is normal, and seizures are absent.", "ORPHA ID": 568062, "Summary": ""}
{"Disease Name": "Pigeon-breeder lung disease", "Disease Definition": "Pigeon-breeder's lung disease, also called bird fancier’s lung, is a hypersensitivity pneumonitis (see this term) induced by inhalation of bird derived-proteins. Presentation can be acute with chills, cough, fever, shortness of breath, chest tightness usually resolving within 24 h after cessation of antigen exposure, sub-acute with cough and dyspnea over several days to weeks, whereas chronic form results in breathlessness, coughing, lack of appetite and weight loss.", "ORPHA ID": 99908, "Summary": ""}
{"Disease Name": "Pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome", "Disease Definition": "A rare genetic skin disease characterized by infantile onset of diffuse alopecia, abnormal skin pigmentation (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), palmoplantar keratoderma, and nail dystrophy. Patients develop recurrent spinocellular carcinomas later in life. Brittle teeth resulting in early loss of dentition have also been described.", "ORPHA ID": 447961, "Summary": ""}
{"Disease Name": "Pigmented paravenous retinochoroidal atrophy", "Disease Definition": "Pigmented paravenous retinochoroidal atrophy (PPRCA) is a rare, commonly bilateral and symmetric retinal disease characterized by non-progressive or slowly progressive chorioretinal atrophy, peripapillary pigmentary changes and accumulation of ''bone-corpuscle'' pigmentation along the retinal veins and which is usually asymptomatic or can present with mild blurred vision.", "ORPHA ID": 251295, "Summary": ""}
{"Disease Name": "Pili bifurcati", "Disease Definition": "An uncommon transitory hair shaft dysplasia characterized by segmental duplication of the hair shaft: a ramification generates two parallel branches which fuse to form a single shaft again. Each branch is covered by its own cuticle.", "ORPHA ID": 720, "Summary": "Epidemiology\nPrevalence is unknown, only a few cases have been reported.\nClinical description\nPatients generally present with diffuse alopecia which can be more apparent in some areas. Hypopigmentation can be observed. This anomaly of the hair shaft occurs in normal hair, pili canaliculi, or monilethrix (see this term) and has been associated with the mosaic trisomy 8 syndrome (see this term), pseudomonilethrix type II or protein deficiency states. It can also be secondary to ulcerative colitis (see this term) and extensive bowel resection.\nEtiology\nPili bifurcati is caused by a transient duplication of the papilla's tip during the anagen phase, leading to the transitory production a two complete shafts, in the same follicular matrix, that emerge through a single pilary canal. When the two papilla tips fuse, both parallel branches form a single shaft again. When the transient duplication of the papilla tip occurs repetitively during the anagen phase, a serie of bifurcation-fusion can be observed along the shaft. This situation is called pili multi-bifurcati. As a duplicated papilla tip can split again, a doubly bifurcated shaft may be observed: pili bi-bifurcati.\nDiagnostic methods\nDiagnosis is based on the trichogram analysis, which could show a high prevalence of dystrophic anagen hairs presenting the characteristic bifurcation(s), reduction in the shaft caliber and pigmentation and telogen effluvium.\nManagement and treatment\nManagement could include a protein complementation diet; mechanical procedures for care of the hair must be avoided.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Francisco CAMACHO-MARTÍNEZ"}
{"Disease Name": "Pili gemini", "Disease Definition": "Pili gemini defines a situation where the papilla's tip of a hair follicle splits during the anagen phase and consequently grows two hair shafts emerging through a single pilary canal. A papilla tip that divides in several tips will produce several hair shafts, a situation named pili multigemini. Pili gemini or multigemini can occur in each type of hair.", "ORPHA ID": 79492, "Summary": "Epidemiology\nThe prevalence of this anomaly is unknown but might be very high, so much so that it could be supposed to be an evolutional trait.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Francisco CAMACHO-MARTÍNEZ"}
{"Disease Name": "Pili torti-developmental delay-neurological abnormalities syndrome", "Disease Definition": "Pili torti-developmental delay-neurological abnormalities syndrome is characterized by growth and developmental delay, mild to moderate neurologic abnormalities, and pili torti. It has been described in a brother and his sister born to consanguineous Puerto Rican parents.", "ORPHA ID": 2891, "Summary": ""}
{"Disease Name": "Pili torti-onychodysplasia syndrome", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by congenital onychodystrophy (particularly of the distal nail) and severe hypotrichosis with alopecia involving the eyebrows, eyelashes and body hair. Scalp, beard, pubic and axillary hair is brittle and shows a twisting pattern on electron microscopy. There have been no further descriptions in the literature since 1991.", "ORPHA ID": 2890, "Summary": ""}
{"Disease Name": "Pili torti", "Disease Definition": "Pili torti is a hair shaft abnormality characterized by flat hair that is twisted at irregular intervals. Hair is normal at birth but progressively stops growing long and becomes fragile. Pili torti can be isolated or occur in association with syndromes such as Menkes disease or Bazex syndrome (see these terms).", "ORPHA ID": 2889, "Summary": ""}
{"Disease Name": "Pilocytic astrocytoma", "Disease Definition": "Pilocytic astrocytoma is a rare subtype of low-grade glioma of the central nervous system characterized by a well circumscribed, often cystic, brain tumor with a discrete mural nodule and long, hair-like projections that extend from the neoplastic astrocytes. Depending on the primary localization and the size of the tumor, patients can present with signs of raised intracranial pressure (headache, vomiting, papilledema), blurred vision, decreased visual acuity, ataxia and/or nystagmus, among others. It is most commonly located in the cerebellum, but ocurrence in the hypothalamus, brain stem, optic chiasma, and hemispheres has also been reported.", "ORPHA ID": 251612, "Summary": ""}
{"Disease Name": "Pilodental dysplasia-refractive errors syndrome", "Disease Definition": "Pilodental dysplasia-refractive errors syndrome is a rare ectodermal dysplasia syndrome characterized by dysplastic abnormalities of the hair and teeth (including hypodontia, abnormally shaped teeth, scalp hypotrichosis and pili annulati), follicular hyperkeratosis on the trunk and limbs, and hyperopia. Intensified delineation, reticular hyperpigmentation of the nape and astigmatism have also been reported. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 2892, "Summary": ""}
{"Disease Name": "Pilomatrix carcinoma", "Disease Definition": "A rare skin tumor characterized by an asymptomatic, solitary, often ulcerated nodule most commonly located in the face, involving the deep dermis, subcutaneous tissue, and skeletal muscle and fascia. Histopathologically, the lesion is composed of aggregates of atypical basaloid cells with numerous mitoses. Typical features include shadow cells, keratin cysts, and trichohyalin and keratohyalin granules. The tumor is locally aggressive and shows a tendency to recur after incomplete excision. Regional lymph node or visceral metastasis has been reported.", "ORPHA ID": 499182, "Summary": ""}
{"Disease Name": "Pilomatrixoma", "Disease Definition": "Pilomatrixoma is a rare and benign hair cell-derived tumor occurring mostly in young adults (usually under the age of 20) and characterized as a 3-30 mm solitary, painless, firm, mobile, deep dermal or subcutaneous tumor, most commonly found in the head, neck or upper extremities. When superficial, the tumors tint the skin blue-red. Multiple pilomatrixomas are seen in myotonic dystrophy, Gardner syndrome, Rubinstein-Taybi syndrome, and Turner syndrome (see these terms).", "ORPHA ID": 91414, "Summary": ""}
{"Disease Name": "Pineal parenchymal tumor of intermediate differentiation", "Disease Definition": "A rare type of pineal parenchymal tumor (PPT) of intermediate-grade malignancy manifesting with visual disturbances, headaches, loss of coordination and balance, nausea and vomiting due to obstructive hydrocephalus, and that is classified as either grade II PPTID (pineal parenchymal tumor of intermediate differentiation) or grade III PPTID according to the degree of neuronal differentiation and mitotic activity.", "ORPHA ID": 251919, "Summary": ""}
{"Disease Name": "Pineoblastoma", "Disease Definition": "Pineoblastoma is a rare, malignant type of supratentorial primitive neuroectodermal tumor (sPNET), found mainly in children (less than 10% of cases are reported in adults), and located in the pineal region of the brain but that can metastasize along the neuroaxis. As it is the most aggressive of the pineal parenchymal tumors, it is usually associated with a poor prognosis.", "ORPHA ID": 251909, "Summary": ""}
{"Disease Name": "Pineocytoma", "Disease Definition": "Pineocytoma is the least aggressive form of pineal parenchymal tumors, manifesting with symptoms such as Parinaud's syndrome (a group of eye movement abnormalities and pupil dysfunction, including deficiency in upward-gaze and convergence-retraction nystagmus), headaches, balance impairment, urinary incontinence, and changes in mood and that are not known to disseminate in a diffuse manner. They are usually associated with a good prognosis.", "ORPHA ID": 251912, "Summary": ""}
{"Disease Name": "Pinnae fistula or cyst", "Disease Definition": "Pinnae fistula or cyst is a rare otorhinolaryngological malformation characterized by the presence of a, usually unilateral, sinus tract or cyst located in the vicinity of the auricle (most frequently identified by a small pit near the anterior margin of the first ascending portion of the helix). Typically, patients are asymptomatic and usually only present symptoms (pain, erythema, discharge from pit) in relation to infection. Renal and inner ear anomalies may be associated.", "ORPHA ID": 155838, "Summary": ""}
{"Disease Name": "Pitt-Hopkins syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by the association of intellectual deficit, characteristic facial morphology and problems of abnormal and irregular breathing.", "ORPHA ID": 2896, "Summary": "Epidemiology\nReliable prevalence figures have not been published but based on the number of known affected individuals in the United Kingdom and the Netherlands prevalence is estimated between 1/225 000-300 000.\nClinical description\nThe facial features are recognizable by a narrow forehead, thin lateral eyebrows, wide nasal bridge and ridge, broad nasal tip, prominent midface, full cheeks, wide mouth and thickened or overfolded helices of the ears. Half of the affected individuals have marked and early onset myopia and also squint is relatively common. Psychomotor development is disturbed from early on and severe with hypotonia, late-acquired unstable walking and complete or almost complete absence of language. Malformations of internal organs are uncommon. Severe constipation and gastro-esophageal reflux are common, and in 50% fingers are slender and demonstrate a single transverse palmar crease. Microcephaly is uncommon, and various types of seizures occur in 40% of affected individuals. Breathing disorders can appear during (early) childhood or adolescence and occur only when the patient is awake. Typically, the bouts of hyperventilation come without eliciting factor, have a duration of 2-5 minutes, and are often followed by apnea. Hyperventilation and apnea may also occur independently. Frequency is extremely variable. Underdevelopment of external and internal reproductive organs (small penis, cryptorchidism, labial fusions) occurs regularly in males and females.\nEtiology\nThe syndrome is caused by heterozygous, usually de novo mutations in the TCF4 gene (18q21), coding for a ubiquitous b-HLH transcription factor. Germline or low-grade parental mosaicism has been reported in 2-3% of published cases.\nDiagnostic methods\nDiagnosis is based on clinical examination, and cytogenetic and molecular studies.\nDifferential diagnosis\nThe principal differential diagnosis includes Angelman syndrome, Rett syndrome and Mowat-Wilson syndrome.\nAntenatal diagnosis\nDetection of the mutation by amniocentesis should be discussed with the parents of an index case during subsequent pregnancies.\nGenetic counseling\nTransmission is autosomal dominant; however, most cases arise de novo and thus the risk of sibling recurrence is low. The empirical recurrence risk is 2%.\nManagement and treatment\nManagement requires a lifelong multidisciplinary approach. Regular follow‐up by a pediatrician, neurologist, psychologist/psychiatrist, and speech therapist will have a major impact. Developmental assessments are needed to tailor medical services to each individual's needs. The use of syndrome‐specific information booklets is recommended for affected families and caregivers; adequate information regarding the breathing disturbances is especially important to avoid mismanagement.\nPrognosis\nThe course of the disease is non-progressive. Longitudinal data are insufficient to determine life expectancy, although survival into adulthood is typical and, at the present, there is no reason that life expectancy is limited. Autonomy is likely to be limited and affected individuals will probably require life-long support from caregivers.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Pituicytoma", "Disease Definition": "A rare glial tumor originating from pituicytes, the specialized glial cells of the neurohypophysis, characterized by a sellar or suprasellar mass manifesting with clinical signs secondary to mass effect. Typical manifestations are visual disturbances, headaches, and hypopituitarism. Pituicytomas are low-grade tumors, and prognosis is good after total resection.", "ORPHA ID": 251623, "Summary": ""}
{"Disease Name": "Pituitary apoplexy", "Disease Definition": "A rare pituitary disease characterized by hemorrhagic or non-hemorrhagic necrosis of the pituitary gland. Clinical manifestations typically comprise sudden and severe headache (often with nausea and vomiting), visual disturbances (visual-field defects, loss of visual acuity), oculomotor palsies, and variable degrees of altered consciousness, ranging from lethargy to coma. Acute endocrine dysfunction may also be present, most commonly corticotropic deficiency with severe hypotension and hyponatremia as well as secondary adrenal failure, but also thyrotropic and gonadotropic deficiency.", "ORPHA ID": 95613, "Summary": ""}
{"Disease Name": "Pituitary carcinoma", "Disease Definition": "A rare pituitary tumor characterized by the presence of a pituitary adenoma that has metastasized either within the central nervous system, or to distant sites. The vast majority of pituitary carcinomas are hormonally active, most frequently with ACTH or prolactin production. The most common clinical symptoms are diabetes insipidus, optic nerve dysfunction, anterior pituitary dysfunction, palsy of cranial nerves III, IV, or VI, and headaches, although patients may also be asymptomatic. The tumors behave aggressively, and prognosis is poor.", "ORPHA ID": 300385, "Summary": ""}
{"Disease Name": "Pituitary deficiency due to empty sella turcica syndrome", "Disease Definition": "A rare pituitary deficiency characterized by herniation of the subarachnoid space into the sella turcica, resulting in flattening of the pituitary gland and endocrine dysfunction. Most common endocrine abnormalities are hyperprolactinemia and growth hormone deficit. Clinical symptoms are highly variable and include headaches, irregular menstruation, galactorrhea, obesity, and visual disturbances, among others.", "ORPHA ID": 91354, "Summary": ""}
{"Disease Name": "Pituitary deficiency due to Rathke cleft cysts", "Disease Definition": "A rare, acquired pituitary hormone deficiency characterized by combination of headache, visual field defects that correlate with cyst size, and pituitary dysfunction. Most frequent hormonal manifestations are hypogonadism with amenorrhea/impotence or low libido and galactorrhea.", "ORPHA ID": 91350, "Summary": ""}
{"Disease Name": "Pituitary dermoid and epidermoid cysts", "Disease Definition": "Pituitary dermoid and epidermoid cysts is a rare, acquired pituitary hormone deficiency characterized by the presence of rare, benign tumor in the sellar region. Clinical presentation is either acute or insidious, and is variable according to the cyst location, size and potential rupture. Most commonly patients present with headache, visual disturbances, and pituitary dysfunction.", "ORPHA ID": 91351, "Summary": ""}
{"Disease Name": "Pituitary gigantism", "Disease Definition": "A rare endocrine disease characterized by excessively tall stature and rapid growth velocity due to growth hormone excess from a pituitary adenoma/hyperplasia occurring before closure of the epiphyseal growth plates. Additional features may include pubertal delay, visual defects, headache, excessive appetite, hyperhidrosis, menstrual irregularity, prognathism, coarse facial features and large hands/feet.", "ORPHA ID": 99725, "Summary": "Epidemiology\nThe epidemiology of pituitary gigantism is unknown. Among acromegaly populations, pediatric and adolescent onset cases are rare (<5%).\nClinical description\nDisease onset is from early infancy to late adolescence as long as the epiphyseal growth plates remain open. Pituitary gigantism is associated with excessive height (>2 standard deviations over the population mean) and growth velocity. Pituitary gigantism predominantly affects males (78%), probably due to amplification by excess GH of greater pubertal height gain in males. Median age at first symptoms is approximately 14 years, but long delays in establishing a diagnosis give a median age at diagnosis of 21 years. The GH-secreting pituitary adenoma is usually a macroadenoma in pituitary gigantism. Patients develop symptoms related to tumor mass effects, deficiencies of other pituitary hormones and chronic excess of GH and insulin-like growth factor 1. Pituitary gigantism patients can have classical signs/symptoms of acromegaly (growth of hands/feet, facial changes, metabolic disease, cardiovascular effects and musculoskeletal disease).\nEtiology\nIn nearly 50% of cases of pituitary gigantism the pituitary adenoma is caused by a known genetic abnormality such as: germline AIP mutations (29%), GPR101 duplications in X-linked acrogigantism syndrome (X-LAG; 10%), somatic mosaic activating mutations in GNAS in McCune-Albright syndrome (5%), germline mutations in MEN1 and PRKAR1A.\nDiagnostic methods\nClinical assessment of overgrowth by physicians should lead to establishment of a diagnosis of elevated GH and insulin-like growth factor 1 (IGF1) by hormonal testing. MRI is also used.\nDifferential diagnosis\nGigantism and overgrowth can be due to an extensive range of normal and pathological conditions. Excess GH and IGF-1 from a pituitary adenoma/hyperplasia distinguishes pituitary gigantism from other forms of constitutional, familial or pathological tall stature/overgrowth.\nAntenatal diagnosis\nGermline mutations in AIP, MEN1, PRKAR1A can be inherited but are not usually screened for in prenatal testing strategies. In X-LAG related pituitary gigantism, chromosome Xq26.3 duplications can be passed from affected mother to affected son.\nGenetic counseling\nIn AIP mutation carriers, 20% develop a pituitary macroadenoma in their life-time, as the disease is autosomal dominant with incomplete penetrance. Familial cases of gigantism have been described in familial isolated pituitary adenoma (FIPA) kindreds with AIP mutations, in X-LAG and in those with no known genetic cause. Pituitary gigantism is exceptionally rare in MEN1 and PRKAR1A mutation carriers. McCune Albright syndrome due to post-zygotic mosaicism for GNAS activating mutations is not inherited.\nManagement and treatment\nThe management of pituitary gigantism focuses on early and effective control of elevated GH and IGF-1 levels to limit final adult height. Patients with pituitary gigantism are usually have large and aggressive pituitary adenomas and these tumors can be relatively treatment-resistant. Multimodal therapy employs neurosurgery to resect the adenoma, usually in combination with medical therapy (somatostatin analogs, pegvisomant and dopamine agonists). Radiotherapy is reserved for individual cases. Replacement of deficient hormonal axes should be pursued. In cases where the patient has entered the pubertal growth spurt, some reduction in final height can be gained by orthopedic epiphysiodesis to destroy the growth plates at the knee joint.\nPrognosis\nEarly diagnosis and rapid achievement of GH and IGF-1 control leads to lower final height in pituitary gigantism, which is a desirable outcome. Multimodal treatment can also lead to a high level of pituitary axis deficiencies, which require lifelong replacement. There are no formal outcome studies on life expectancy in patients with pituitary gigantism.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Albert BECKERS  - Dr Adrian DALY"}
{"Disease Name": "Pituitary stalk interruption syndrome", "Disease Definition": "Pituitary stalk interruption syndrome (PSIS) is a congenital abnormality of the pituitary that is responsible for pituitary deficiency and is usually characterized by the triad of a very thin or interrupted pituitary stalk, an ectopic (or absent) posterior pituitary (EPP) and hypoplasia or aplasia of the anterior pituitary visible on MRI. In some patients the abnormality may be limited to EPP (also called ectopic neurohypophysis) or to an interrupted pituitary stalk.", "ORPHA ID": 95496, "Summary": "Epidemiology\nThe prevalence of PSIS is unknown but to date around 1,000 cases with and without the full triad have been reported.\nClinical description\nIn the neonatal period, PSIS presents with hypoglycemia, prolonged jaundice, congenital abnormalities and microphallus and/or cryptorchidism, which are all suggestive of hypothalamic-pituitary deficiency. PSIS is also associated with higher than normal frequency of breech presentation, Cesarean section and/or low Apgar score. The birth conditions are probably a consequence rather than the cause of PSIS. Later in childhood, signs suggestive of PSIS include short stature, decreased growth rate and/or a difference between the target and actual heights of greater than 1.5 SD. Patients may also present with seizures, hypotension and/or intellectual delay. PSIS can be associated with septooptic dysplasia and Fanconi anemia (see these terms).\nEtiology\nThe exact etiology of PSIS is unknown. Mutations in the transcription factor HESX1 (3p21.2-p21.1) have been found both in patients with isolated PSIS and in those with PSIS associated with septooptic dysplasia. Mutations in the LHX4 gene (1q25) have also been associated with PSIS. In the majority of cases no genetic cause is found, however, the presence of familial forms and the association of PSIS with microphallus and congenital abnormalities, particularly of the eyes, suggest an antenatal origin.\nDiagnostic methods\nDiagnosis is suspected on clinical findings and on the basis of a low growth hormone (GH) peak after stimulation test and low insulin-like growthfactor 1. MRI, showing EPP as a hypterintense nodule in the region of the infundibular recess of the third ventricle, confirms the diagnosis. The diagnosis of PSIS indicates a permanent GH deficiency. It is necessary to determine if GH deficiency is isolated or associated with other anterior pituitary deficiencies (as occurs in 70% of PSIS). If PSIS is diagnosed from MRI there is no other possible diagnosis.\nGenetic counseling\nThe risk of the familial form is less than or equal to 5%.\nManagement and treatment\nTreatment is based on replacement of deficient hormones, particularly GH, thyroxine, hydrocortisone and, at puberty, sex steroids. It is important to diagnose PSIS at birth to avoid hypoglycemia and secondary adrenal deficiency and their associated cerebral and vital risks.\nPrognosis\nThe prognosis is good if there is timely diagnosis and treatment. Delay in diagnosis and treatment may result in seizures due to hypoglycemia and/or hypotension due to cortisol deficiency and/or intellectual delay due to thyroid deficiency. As a result of these risks, mortality and morbidity in patients with PSIS are higher than in the general population, mainly occurring before 2 years of age.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Raja BRAUNER"}
{"Disease Name": "Pityriasis rubra pilaris", "Disease Definition": "Pityriasis rubra pilaris is a rare chronic papulosquamous disorder of unknown etiology characterized by small follicular papules, scaly red-orange patches, and palmoplantar hyperkeratosis, which may progress to plaques or erythroderma. Although most of the cases are sporadic and acquired, a familial form of the disease exists.", "ORPHA ID": 2897, "Summary": ""}
{"Disease Name": "PLAA-associated neurodevelopmental disorder", "Disease Definition": "A rare genetic neurological disorder characterized by infantile onset of progressive leukoencephalopathy, microcephaly, severe global developmental delay, and spasticity resulting in quadriparesis and posture deformation. Additional features include an abnormally exaggerated startle reflex, seizures, dystonia, and hypomimia or amimia, as well as progressive chest deformities and contractures of large and hyperextensibility of small joints, among others. Thin corpus callosum is a prominent feature in brain imaging, in addition to white matter abnormalities consistent with leukoencephalopathy.", "ORPHA ID": 521426, "Summary": ""}
{"Disease Name": "Placental insufficiency", "Disease Definition": "A rare obstetric disease characterized by inadequate blood flow to the placenta during pregnancy, resulting in a decrease in trans-placental transfer of oxygen and nutrients to the fetus, potentially leading to fetal growth retardation, distress, or death. Maternal risk factors include preeclampsia, gestational diabetes, and smoking, among others.", "ORPHA ID": 439167, "Summary": ""}
{"Disease Name": "Placental site trophoblastic tumor", "Disease Definition": "A rare gestational trophoblastic neoplasm characterized histologically by invasion of myometrium by intermediate trophoblastic cells without chorionic villi and containing human placental lactogen hormone (hPL). Tissue necrosis is usually absent and hemorrhage is mild. The tumor develops from the placental implantation site and always occurs following pregnancy, voluntary termination of pregnancy (VTP) or miscarriage. Indicative signs are irregular metrorrhagia some time after spontaneous miscarriage or VTP, presence of metastasis or unexplained metrorrhagia in the weeks and months following normal childbirth or ectopic pregnancy.", "ORPHA ID": 99928, "Summary": ""}
{"Disease Name": "Plague", "Disease Definition": "Plague is a severe bacterial infection caused by the Gram-negative bacterium Yersinia pestis.", "ORPHA ID": 707, "Summary": "Epidemiology\nIt is extremely rare in Europe but still spreads in Africa and, to a lesser degree, in Asia and Latin America.\nClinical description\nThere are two clinical forms of the disease: bubonic plague, characterized by painfully inflamed lymph nodes called \"buboes'', an elevated temperature and an altered clinical state; and pulmonary plague which manifests itself as thoracic pain, a cough with bloody expectoration, an elevated temperature, an altered clinical state and consciousness disorders.\nEtiology\nPlague is transmitted from animals to humans by fleas. Rodents are the reservoir for the disease. Plague is also transmitted between humans via the respiratory route.\nDiagnostic methods\nDiagnosis is based on isolation of the bacterium in the bubo, blood or expectoration, or from serology.\nManagement and treatment\nMany classes of antibiotics are effective against Yersinia pestis (aminoglycosides, tetracyclines, cotrimoxazole, rifampicin, fluoroquinolones etc.).\nPrognosis\nWithout treatment, the course of the disease is rapidly fatal.\n\n                            Last update: \n                            November 2009\n\n\n                            - Expert reviewer(s): \n                            Dr F RACHILLAS"}
{"Disease Name": "Plasma cell leukemia", "Disease Definition": "A rare plasma cell neoplasm characterized by peripheral plasmacytosis, usually with extensive and diffuse infiltration of the bone marrow, and monoclonal paraproteinemia. Neoplastic plasma cells may also be found in extramedullary sites, such as the liver or spleen, among others. Most cases present as primary plasma cell leukemia without previous diagnosis of myeloma. The condition can also represent leukemic transformation of plasma cell myeloma (secondary plasma cell leukemia). Clinical manifestations include lymphadenopathy, organomegaly, renal failure, bone marrow failure, and peripheral neuropathies. High serum levels of lactate dehydrogenase and beta2-microglobulin, as well as hypercalcemia (potentially leading to hypercalcemic crisis) are typically observed.", "ORPHA ID": 454714, "Summary": ""}
{"Disease Name": "Plasmablastic lymphoma", "Disease Definition": "A rare aggressive B-cell non-Hodgkin lymphoma characterized by neoplastic cells resembling B immunoblasts or plasmablasts with a CD20-negative plasmacytic phenotype. The tumor may occur in the oral cavity, the gastrointestinal tract, or other, predominantly extranodal, sites and is typically associated with immunodeficiency or -suppression. The tumor cells are EBV-positive in most cases. Patients often present with disseminated bone involvement. Paraproteinemia may also be detected. Prognosis is generally poor.", "ORPHA ID": 289666, "Summary": ""}
{"Disease Name": "Plasmacytoma", "Disease Definition": "Plasmacytoma is a localized mass of neoplastic monoclonal plasma cells that represents approximately 5% of all plasma cell neoplasms. There are two separate entities: primary plasmacytoma of the bone and extramedullary plasmacytoma of the soft tissues. Of the extramedullary plasmacytomas, 80% occur in the head and neck, usually in the upper respiratory tract. The median age at diagnosis is 50 years and the male to female ratio is 3:1. Long-term survival is possible following local radiotherapy, particularly for soft tissue presentations.", "ORPHA ID": 86855, "Summary": ""}
{"Disease Name": "Platyspondylic dysplasia, Torrance type", "Disease Definition": "Platyspondylic lethal skeletal dysplasia (PLSD), Torrance type (PLSD-T) is a skeletal dysplasia characterised by severe limb shortening (short and broad long bones), platyspondyly with wafer-like vertebral bodies, short ribs with anterior cupping, severe hypoplasia of the lower ilia and radial bowing. Histological findings include slightly enlarged chondrocytes and hypercellularity. The prevalence is unknown. The disorder is transmitted as an autosomal dominant trait and is caused by mutations in the C-propeptide domain of the COL2A1 gene. Although PLSD-T is generally lethal, survival to adulthood has been reported in two families.", "ORPHA ID": 85166, "Summary": ""}
{"Disease Name": "PLCG2-associated antibody deficiency and immune dysregulation", "Disease Definition": "A rare, hereditary, immune deficiency with skin involvement characterized by early-onset cold urticaria after generalized exposure to cold air or evaporative cooling and not after contact with cold objects. Additional immunologic abnormalities are often present - antibody deficiency, recurrent infections, autoimmune disease and symptomatic allergic disease.", "ORPHA ID": 300359, "Summary": ""}
{"Disease Name": "PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement", "Disease Definition": "A rare, inherited, epidermolysis bullosa simplex characterized by primarily acral blistering with onset typically at birth. Patients have easy bruisability, hemorrhagic blistering, and onychogryphosis.", "ORPHA ID": 79401, "Summary": ""}
{"Disease Name": "Plectin-related limb-girdle muscular dystrophy R17", "Disease Definition": "A form of limb-girdle muscular dystrophy characterized by proximal muscle weakness presenting in early childhood (with occasional falls and difficulties in climbing stairs) and a progressive course resulting in loss of ambulation in early adulthood. Muscle atrophy and multiple contractures have also been reported in rare cases.", "ORPHA ID": 254361, "Summary": ""}
{"Disease Name": "Pleomorphic liposarcoma", "Disease Definition": "Pleomorphic liposarcoma (PLS), the rarest subtype of liposarcoma (LS; see this term), is an aggressive, fast growing tumor located usually in the deep soft tissues of the lower and upper extremities. It is characterized by a variable number of pleomorphic lipoblasts and, in contrast to dedifferentiated liposarcoma, it lacks any association with well-differentiated liposarcoma (see these terms).", "ORPHA ID": 99969, "Summary": "Epidemiology\nThe incidence is approximately 1/2,000,000 per year and it accounts for 5-10% of all LS cases.\nClinical description\nPLS usually presents in older individuals with a typical age at diagnosis of 50-70 years. PLS is most commonly a firm, rapidly growing mass in the deep compartments of the lower and upper extremities but can also be located in the abdomen or chest wall in rare cases. PLS has a high (>50%) risk of metastasis, primarily to the lungs. Metastasis is rapid, often leading to death.\nEtiology\nThe etiology is unknown. PLS is characterized by highly complex chromosome alterations, including polyploidy and various chromosomal duplications, deletions and complex rearrangements.\nDiagnostic methods\nWhen a mass is detected, computed tomography (CT) or magnetic resonance imaging (MRI) is performed. Chest and abdominal lesions do not require pretreatment biopsy unless resection is likely to be incomplete or highly morbid. Extremity lesions are generally sampled by multiple core biopsies to make the histological diagnosis of PLS. Histologically PLS contains a variable number of pleomorphic lipoblasts, with hemorrhage and necrosis commonly observed.\nDifferential diagnosis\nPLS can often be mistaken for myxofibrosarcoma or pleomorphic undifferentiated sarcoma (see these terms).\nManagement and treatment\nTreatment involves the surgical excision of the tumor and surrounding normal tissue. In rare cases amputation of the limb is necessary. Tumors that are large (>5-8 cm) or marginally resectable may be treated with preoperative chemotherapy. Adjuvant radiation is recommended if the surgical margin is narrow or positive for sarcoma. Lifelong follow-up is recommended in order to monitor for recurrence at the initial site as well as distant metastasis.\nPrognosis\nPLS has the poorest prognosis of all the LS subtypes. Five-year survival is 59%.\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Samuel SINGER"}
{"Disease Name": "Pleomorphic rhabdomyosarcoma", "Disease Definition": "A rare soft tissue sarcoma characterized by a high-grade lesion occurring almost exclusively in adults, composed of bizarre polygonal, round, and spindle cells with evidence of skeletal muscle differentiation. Patients usually present with a rapidly growing, painful mass located in the deep soft tissues of the extremities, but also other anatomic regions. Prognosis is generally poor.", "ORPHA ID": 293199, "Summary": ""}
{"Disease Name": "Pleomorphic salivary gland adenoma", "Disease Definition": "A rare tumor of salivary glands characterized by a benign, well-circumscribed, slow-growing, painless mass most commonly occurring in the parotid gland (but also the palate, submandibular gland, or nasal septal mucosa), histopathologically composed of epithelial and myoepithelial / stromal components. Possible signs and symptoms depend on the location of the tumor and include facial nerve weakness, mild dysphagia, or unilateral nasal obstruction. Recurrence rates are low, although tumor rupture and spillage have been reported. Malignant transformation may occur in a small percentage of cases.", "ORPHA ID": 454821, "Summary": ""}
{"Disease Name": "Pleomorphic xanthoastrocytoma", "Disease Definition": "A rare low-grade astrocytoma characterized by superficial location in the cerebral hemispheres with involvement of the meninges, composed of GFAP-expressing cells showing nuclear and cytoplasmic pleomorphism and xanthomatous change, surrounded by a reticulin network. The tumor corresponds to WHO grade II and typically affects children and young adults, who often present with a long history of seizures. Extent of resection and mitotic index are important prognostic factors.", "ORPHA ID": 251607, "Summary": ""}
{"Disease Name": "Pleural empyema", "Disease Definition": "A rare pulmonary condition characterized by accumulation of pus in the pleural cavity, most commonly as a consequence of pneumonia, but also trauma and surgical procedures. Clinical signs and symptoms depend on host factors, as well as the nature of the causative microorganism, among others, and include cough, chest pain, dyspnea, and fever.", "ORPHA ID": 449266, "Summary": ""}
{"Disease Name": "Pleural mesothelioma", "Disease Definition": "Malignant mesothelioma is a fatal asbestos-associated malignancy arising in the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as in the pericardium and the tunica vaginalis.", "ORPHA ID": 50251, "Summary": "Epidemiology\nThe exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10-20 years.\nClinical description\nPleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are chest pain and dyspnea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations.\nEtiology\nMesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational 'environmental' exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million.\nDiagnostic methods\nA combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. The most suggestive CT findings indicating malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of >1cm and 4) mediastinal pleural involvement.\nDifferential diagnosis\nDistinguishing malignant from benign pleural disease can be challenging.\nManagement and treatment\nInvolvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with terminal care. Compensation issues must also be considered.\nPrognosis\nLife expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis.\n\n                            Last update: \n                            December 2008\n\n\n                            - Expert reviewer(s): \n                            Pr John MOORE  - Dr Robert PARKER  - Pr John WIGGINS"}
{"Disease Name": "Pleuro-pericardial cyst", "Disease Definition": "Pleuro-pericardial cyst is a rare, mostly congenital, pericardium anomaly characterized by the presence of, usually asymptomatic, cysts which are typically located in the right costophrenic angle and are usually incidentally diagnosed. On occasion, it manifests with chest pain, dyspnea, tachycardia, persistent cough or cardiac arrhythmias. The condition is usually benign, but rare complications, such as cardiac tamponade, cardiogenic shock, mitral valve prolapse, hoarseness atrial fibrillation, right ventricular outflow, tract obstruction, spontaneous internal hemorrhage, pulmonary stenosis and sudden death, may occur.", "ORPHA ID": 99131, "Summary": ""}
{"Disease Name": "Pleuropulmonary blastoma", "Disease Definition": "A rare respiratory tumor characterized by an aggressive, malignant, dysontogenetic neoplasm of intrathoracic (pulmonary, pleural, or combined) mesenchyme occurring in young children. Three subtypes can be distinguished, type 1 being purely cystic, type 2 cystic and solid, and type 3 purely solid. Type 1 lesions may progress to the more malignant types 2 and 3, which are associated with central nervous system and bone metastasis. The tumor is often part of pleuropulmonary blastoma family tumor and dysplasia syndrome. It can also be associated with multilocular cystic nephroma or other neoplasms. Patients usually present with dyspnea or other respiratory problems, and sometimes pneumothorax.", "ORPHA ID": 64742, "Summary": ""}
{"Disease Name": "PLIN1-related familial partial lipodystrophy", "Disease Definition": "A rare genetic lipodystrophy characterized by loss of subcutaneous adipose tissue primarily affecting the lower limbs and gluteal region due to a defect in the PLIN1 gene. Associated features of insulin resistance, hepatic steatosis, dyslipidemia, hypertension, axillary acanthosis nigricans and muscular hypertrophy of the lower limbs are typical.", "ORPHA ID": 280356, "Summary": ""}
{"Disease Name": "Plummer-Vinson syndrome", "Disease Definition": "Plummer-Vinson or Paterson-Kelly syndrome presents as a classical triad of dysphagia, iron-deficiency anemia and esophageal webs.", "ORPHA ID": 54028, "Summary": "Epidemiology\nExact data about the epidemiology of the syndrome are not available; the syndrome is extremely rare.\nClinical description\nMost of the patients are white middle-aged women, in the fourth to seventh decade of life, but the syndrome has also been described in children and adolescents. The dysphagia is usually painless and intermittent or progressive over years, limited to solids and sometimes associated with weight loss. Symptoms resulting from anemia (weakness, pallor, fatigue, tachycardia) may dominate the clinical picture. Additional features are glossitis, angular cheilitis and koilonychia. Enlargement of the spleen and thyroid may also be observed. One of the most important clinical aspects of Plummer-Vinson syndrome is the association with upper alimentary tract cancers.\nEtiology\nThe etiopathogenesis of Plummer-Vinson syndrome is unknown. The most important possible etiological factor is iron deficiency. Other possible factors include malnutrition, genetic predisposition or autoimmune processes.\nManagement and treatment\nPlummer-Vinson syndrome can be treated effectively with iron supplementation and mechanical dilation. In case of significant obstruction of the esophageal lumen by esophageal web and persistent dysphagia despite iron supplementation, rupture and dilation of the web are necessary. Since Plummer-Vinson syndrome is associated with an increased risk of squamous cell carcinoma of the pharynx and the esophagus, the patients should be followed closely.\n\n                            Last update: \n                            September 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Gottfried NOVACEK"}
{"Disease Name": "PMM2-CDG", "Disease Definition": "A rare congenital disorder of N-glycosylation and is characterized by cerebellar dysfunction, abnormal fat distribution, inverted nipples, strabismus and hypotonia. 3 forms of PMM2-CDG can be distinguished: the infantile multisystem type, late-infantile and childhood ataxia-intellectual disability type (3-10 yrs old), and the adult stable disability type. Infants usually develop ataxia, psychomotor delay and extraneurological manifestations including failure to thrive, enteropathy, hepatic dysfunction, coagulation abnormalities and cardiac and renal involvement. The phenotype is however highly variable and ranges from infants who die in the first year of life to mildly involved adults.", "ORPHA ID": 79318, "Summary": ""}
{"Disease Name": "PMP2-related Charcot-Marie-Tooth disease type 1", "Disease Definition": "A rare autosomal dominant hereditary demyelinating motor and sensory neuropathy characterized by progressive distal muscle weakness and atrophy, distal sensory impairment, and decreased or absent reflexes in the affected limbs, with an onset in the first or second decade of life. Median motor nerve conduction velocities are typically less than 38 m/s. Patients often have foot deformities. Sural nerve biopsy shows decrease in myelinated fibers, myelin abnormalities, and onion bulb formation. Fatty replacement of muscle tissue predominantly affects the anterior and lateral compartment of the lower legs.", "ORPHA ID": 476394, "Summary": ""}
{"Disease Name": "PMP22-RAI1 contiguous gene duplication syndrome", "Disease Definition": "A rare partial duplication of the long arm of chromosome 17 characterized by a combination of features of 17p11.2 microduplication syndrome and Charcot-Marie-Tooth disease type 1A. Patients present with infantile onset of global developmental delay, hypotonia, feeding difficulties, and failure to thrive, as well as childhood onset of peripheral neuropathy with distal extremity weakness or atrophy, gait impairment, sensory loss, reduced or absent deep tendon reflexes of the ankles, and foot deformities. Facial dysmorphism, cardiac and renal anomalies, and syringomyelia may also be observed.", "ORPHA ID": 477817, "Summary": ""}
{"Disease Name": "Pneumococcal meningitis", "Disease Definition": "A rare infectious disease of the nervous system caused by the bacterium Streptococcus pneumoniae, which is commonly part of the bacterial flora colonizing the nasopharyngeal mucosa. The disease is clinically characterized by typical symptoms of acute leptomeningitis, like fever, headache, neck stiffness, vomiting, and clouding of consciousness. It is frequently fatal and, in surviving patients, often accompanied by long-term sequelae, especially focal neurological deficits, hearing loss, cognitive impairment, and epilepsy.", "ORPHA ID": 55655, "Summary": ""}
{"Disease Name": "Pneumocystosis", "Disease Definition": "Human pneumocystosis is caused by an infectious agent, which (after recent nomenclature and taxonomy revisions) is now classed as the fungus Pneumocystis jiroveci. The prevalence is unknown. Pneumocystis jiroveci is an opportunistic infectious agent, developing in immunosuppressed patients. It is an air-borne infection, localised to the lungs. However, extrapulmonary involvement is seen in AIDS patients. The disease manifests progressively with coughing, respiratory problems (dyspnea) and fever, followed by acute respiratory insufficiency and death within a few weeks in untreated cases. The most reliable diagnostic method is bronchoalveolar lavage. The treatment of choice is cotrimoxazole.", "ORPHA ID": 723, "Summary": ""}
{"Disease Name": "Pneumonia caused by Pseudomonas aeruginosa infection", "Disease Definition": "A rare pulmonary disease characterized by primary or nonbacteremic pneumonia most frequently arising in an intensive care setting, or bacteremic pneumonia, which is typically associated with neutropenia. Chronic lower respiratory tract infection with development of episodes of pneumonia is common in patients with cystic fibrosis. Acute infections are potentially life-threatening. Patients present with fever, chills, dyspnea, cyanosis, productive cough, as well as signs of severe systemic toxicity. Alveolar hemorrhage, necrosis, and, eventually, cavity formation, are commonly seen.", "ORPHA ID": 90066, "Summary": ""}
{"Disease Name": "POEMS syndrome", "Disease Definition": "POEMS syndrome is a paraneoplastic syndrome characterized by polyradiculoneuropathy (P), organomegaly (O), endocrinopathy (E), clonal plasma cell disorder (M), and skin changes (S). Other features include papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis/erythrocytosis, and elevated VEGF levels.", "ORPHA ID": 2905, "Summary": "Epidemiology\nExact prevalence and incidence rates are not known. The only estimates are from Japan. In this country, prevalence has been reported to be about 1/330,000. Male predilection has been reported (2.5:1).\nClinical description\nThe average age of onset is in the 5th or 6th decade. The disease covers a wide clinical spectrum depending on the systems involved. Neuropathy is the primary manifestation and is usually peripheral, ascending, and symmetrical with distal weakness and paresthesia. It is both sensory and motor and may cause pain, hyperesthesia, and areflexia. A clonal plasma cell disorder (PCD) is the second major feature. Organomegaly mainly includes hepatomegaly, splenomegaly, and/or lymphadenopathy (Castleman disease; see this term). Various and extensive endocrine disorders may be found causing hypogonadism, thyroid abnormalities, adrenal insufficiency, and/or erectile dysfunction and gynecomastia in men. The skin is commonly affected with development of hyperpigmentation, hemangiomas, hypertrichosis, leukonychia or nail clubbing, sclerodermoid changes, lipodystrophy, and flushing. The main ocular manifestation is papilledema. Extravascular overload mainly manifests as peripheral edema, and sometimes as pleural effusion, ascites, and pericardial effusions. An increased risk of arterial and/or venous thrombosis is reported (up to 20% of patients). Disease severity depends on the systems involved and the course is chronic. Some patients have a mild presentation while others have debilitating disease. 25% have respiratory manifestations including restrictive lung disease, pulmonary hypertension, and respiratory muscle weakness.\nEtiology\nThe pathogenesis has not been clearly elucidated. Vascular endothelial growth factor (VEGF) appears to play a significant role in this plasma cell disorder.\nDiagnostic methods\nAll of the clinical features are not required for diagnosis. Patients with three of the major criteria necessarily including polyradiculoneuropathy and clonal PCD (plus possibly Castleman, sclerotic bone lesions, VEGF elevation), plus at least one minor criterion can be diagnosed with POEMS. Minor criteria are organomegaly, endocrinopathy, papilledema, extravascular overload, and skin changes. Patient with POEMS features who do not have both peripheral neuropathy and PCD are considered as having the Castleman disease variant of POEMS. Radiographic assessment of bones, elevated VEGF, and bone marrow biopsy aid in confirming the diagnosis. VEGF levels correlate with disease activity.\nDifferential diagnosis\nThe main differential diagnoses are chronic inflammatory demyelinating polyneuropathy, AL amyloidosis and Guillain-Barré syndrome (see these terms). Monoclonal gammopathy of undetermined significance (MGUS) and should also be considered.\nManagement and treatment\nPatients with dominant sclerotic plasmacytoma are treated with radiotherapy. Radiation is also used in patients with diffuse sclerotic lesions or disseminated bone marrow involvement. Some patients progress after radiation therapy and require systemic treatment. Alkylators are the main treatment, along with lenalidomide and to a lesser extent thalidomide and bortezomib. High-dose chemotherapy with peripheral blood stem cell transplant may be successful. Supportive care should also be provided (orthotics, physical therapy, and continuous positive airway pressure (CPAP)).\nPrognosis\nThe prognosis is generally good if diagnosis is early and appropriate treatment is provided. Causes of death include progressive anasarca, thrombosis, and inanition.\n\n                            Last update: \n                            March 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Angela DISPENZIERI"}
{"Disease Name": "POGLUT1-related limb-girdle muscular dystrophy R21", "Disease Definition": "A rare autosomal recessive limb-girdle muscular dystrophy characterized by adult onset of progressive muscle weakness and atrophy in the proximal upper and lower limbs, leading to scapular winging and loss of independent ambulation. Respiratory function may become impaired in the course of the disease. Fatty degeneration of internal regions of thigh muscles sparing external areas has been reported, as well as a reduction of alpha-dystroglycan in muscle biopsies.", "ORPHA ID": 480682, "Summary": ""}
{"Disease Name": "Poikiloderma with neutropenia", "Disease Definition": "Poikiloderma with neutropenia is a rare, genetic hereditary poikiloderma disorder characterized by early-onset poikiloderma (which typically begins in the extremities, progresses centripetally and eventually involves the trunk, face and ears) associated with chronic neutropenia, recurrent infections, pachyonychia and palmoplantar keratoderma. Growth and/or develomental delay and hepato- and/or splenomegaly are additional reported features.", "ORPHA ID": 221046, "Summary": ""}
{"Disease Name": "Poland syndrome", "Disease Definition": "A rare congenital malformation characterized by a unilateral, complete or partial, absence of the pectoralis major (and often minor) muscle, ipsilateral breast and nipple anomalies, hypoplasia of the pectoral subcutaneous tissue, absence of pectoral and axillary hair, and possibly accompanied by chest wall and/or upper limb defects.", "ORPHA ID": 2911, "Summary": "Epidemiology\nThe incidence is estimated at 1/30,000, but this is likely an underestimate. It affects more frequently men (male/female ratio of 2:1).\nClinical description\nThe major feature of Poland syndrome (PS) is complete or partial (sternocostal head) agenesis of the pectoralis major muscle, manifesting as an asymmetric appearance. Generally, the pectoralis minor muscle is also absent. The malformation is typically unilateral with the right side predominantly affected; bilateral involvement is possible but rare (1% of cases). The associated upper limb and rib anomalies determine the severity of PS. According to the combination of these additional features, three forms of PS can be described: type-1 (minimal form) is defined as an isolated pectoral muscle defect, type-2 (partial form) is defined by pectoral muscle defect associated with either upper limb (2a, upper limb variant) or rib (2b, thoracic variant) anomaly, and type-3 (complete form) by pectoral muscle defect associated with both upper limb and rib anomalies. Additional muscle involvement may include the serratus anterior, latissimus dorsi and trapezius. Chest defects can include absence of the anterior part of the rib with lung herniation, rib hypoplasia, contralateral pectus carinatum and/or pectus excavatum. Dextrocardia occurs in 10% of cases, associated with left rib agenesis. Upper limb anomalies are present in 56% of the patients, including brachydactyly, syndactyly or a combination of the two; aplasia/hypoplasia of the middle phalanges of the hand is frequently observed. Hypoplastic/absent hand(s) and short forearm are rarely observed. In all females, the breast and nipple areola complex is aplasitic or hypoplasitic with superolateral localization of the nipple.\nEtiology\nThe etiology is unknown.\nDiagnostic methods\nDiagnosis is by clinical evaluation. The pectoral muscle anomaly is generally observed by asking the patient to push the palms of the hands against each other with the arms positioned in front of the body. Cough or other maneuvers increasing thoracic pressure will demonstrate lung herniation in case of rib agenesis. Echography can confirm the diagnosis and delineate the extent of the muscular anomaly and detect cartilage rib anomaly and, in postpubertal females, breast anomaly. Chest X-ray can confirm rib agenesis and dextrocardia.\nDifferential diagnosis\nDifferential diagnosis includes other chest wall anomalies, breast/nipple anomalies, isolated thoracic lipoatrophy, and isolated hand/upper limb anomalies without pectoralis major muscle involvement. Syndromes rarely associated with PS include Moebius, Klippe Feil, Pierre-Robin, Sprengel deformity and Carey-Fineman-Ziter.\nAntenatal diagnosis\nAntenatal diagnosis is rare; however, suspicion may arise if hand anomaly is detected.\nGenetic counseling\nPS is typically a sporadic condition but around 4% of cases are familial. Most cases are probably multifactorial with a low recurrence risk. Autosomal dominant and recessive patterns are described in literature.\nManagement and treatment\nUsually, the aim of surgical treatment is cosmetic. However, in a minority of cases thoracic surgery is required to improve respiratory dynamics due to rib cage defect or heart compression by sternal compression. TNB (thorax, breast and nipple) classification guides surgical choice. Patients should be evaluated for surgery at the beginning of puberty (and before complete growth). A combined approach (pediatric/thoracic and plastic surgery) is beneficial. In case of multiple rib agenesis, non-absorbable mesh or metallic or custom prostheses can be used. Breast/pectoral, custom-made, implants can be used to correct the soft tissue and breast defect. Breast/pectoral expander can be used as first step. Fat grafting is beneficial either as first step or to improve final result. For symmetry reasons, surgery to the contralateral breast can be considered. Muscle transpositions require careful evaluation of the benefits and risks, and should only be considered in selected cases and never in children. Correction of syndactyly should generally begin between 12 and 24 months of life. In case of phalangeal absence, non-microvascular free phalangeal transfer from the foot, or microvascular digital transfer from the foot can be proposed.\nPrognosis\nAesthetic achievement after surgery is typically satisfactory. Usually, there is not a significant muscle weakness.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Maria Teresa DIVIZIA  - Dr Margherita LERONE  - Dr Aldamaria PULITI  - Dr Maria Victoria ROMANINI  - Dr Michele TORRE"}
{"Disease Name": "Poliomyelitis", "Disease Definition": "Poliomyelitis is a viral infection caused by any of three serotypes of human poliovirus, which is part of the family of enteroviruses.", "ORPHA ID": 2912, "Summary": "Epidemiology\nProgress in global poliomyelitis eradication, since its beginning in 1988, has been remarkable. In 1988, 125 countries were endemic for poliomyelitis and an estimated 1000 children were being paralyzed every day by wild poliovirus. By the end of 2003, six polio-endemic countries remained (Afghanistan, Egypt, India, Niger, Nigeria, Pakistan), and less than 3 children per day were being paralyzed by the poliovirus. The Global Poliomyelitis Eradication Initiative is ongoing. There remain only 4 endemic countries (Pakistan, Afghanistan, India, and Nigeria) and just 2000 reported cases globally in 2006.\nClinical description\nIt primarily affects children under the age of 5. Generally the infection is limited to the grastrointestinal tract and nasopharynx and is often asymptomatic. The central nervous system, primarily the spinal cord, may be affected, leading to rapidly progressive paralysis. Motor neurons are mainly affected. Encephalitis may also occur.\nEtiology\nTransmission is mainly person-to-person, principally through the fecal-oral route. The virus replicates in the nervous system and particularly affects motor neurons in the anterior horn of the spinal cord (`polio' means `gray').\nDifferential diagnosis\nPoliomyelitis must be distinguished from other paralytic conditions by isolation of virus from stool.\nManagement and treatment\nPrevention is the only cure for paralytic poliomyelitis. Two vaccines against poliomyelitis are available: an inactive injectable vaccine and a live attenuated vaccine that is taken orally. Europe was certified as polio-free in June 2002 and immunization and disease surveillance continue to ensure the region remains polio-free\n\n                            Last update: \n                            January 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Bruce AYLWARD  - Dr David HEYMANN"}
{"Disease Name": "Polyarteritis nodosa", "Disease Definition": "A rare, clinically heterogeneous, systemic disease characterized by necrotizing inflammatory lesions affecting medium-sized blood vessels. It most commonly affects skin, joints, peripheral nerves and the gastrointestinal tract.", "ORPHA ID": 767, "Summary": "Epidemiology\nPrevalence of polyarteritis nodosa (PAN) has been estimated at 1/33,000 in France, Norway and Sweden. Changes in classification of systemic vasculitis and more precise delineation of these disorders make it difficult to determine exact epidemiological data.\nClinical description\nPAN is defined as vasculitis affecting medium-sized vessels and has no pathognomonic clinical or laboratory features. There is a very broad range of clinical presentations depending on the underlying cause and age of onset, with different presenting features, courses, therapeutic implications, and prognoses. The most frequent form of the disease is a potentially life-threatening, idiopathic condition affecting mainly adults, and has a presentation with fever, fatigue, weight loss, myalgia and arthralgia, often with multisystem involvement (systemic PAN). In this form, cutaneous manifestations are common at onset. A limited form with subcutaneous nodules, indurated erythema, and livedo reticularis, and mild extracutaneous features has also been described, with no significant internal organ involvement (cutaneous PAN). Rare limited forms affecting the peripheral nerves, testicles, ureter, breasts, or ovaries have also been described and are known as single-organ PAN.\nEtiology\nThe disease can be primary (primary PAN) or secondary, e.g. related to viral infection such as hepatitis B virus (secondary PAN).\nDiagnostic methods\nDiagnosis is based on the clinical features but often requires tissue biopsy showing necrotizing medium-sized vessel vasculitis, and/or angiography showing microaneurysms. Laboratory findings are non-specific and PAN is never associated with anti-neutrophil cytoplasm antibodies (ANCA).\nDifferential diagnosis\nThe main differential diagnoses are other medium-sized vessel vasculitides such as Kawasaki disease and also small-sized vessel necrotizing vasculitides, mainly microscopic polyangiitis.\nManagement and treatment\nThe main factors guiding treatment are the extent of organ involvement and disease progression. Glucocorticoids combined with 6 to 9 intravenous cyclophosphamide injections are prescribed to treat systemic PAN with factors of poor prognosis, as defined by the Five Factor Score (FFS). Milder cases (FFS=0) can be treated with glucocorticoids alone. Once remission is obtained, maintenance treatment with azathioprine is given for one year. When PAN is caused by HBV infection, treatment involves a combination of anti-viral drugs and plasma exchanges. Corticosteroids and immunosuppressants are not recommended because they stimulate viral replication and favor the development of liver cirrhosis.\nPrognosis\nLimited forms tend to have a favorable prognosis. Factors of poor prognosis are GI involvement, renal insufficiency, cardiac manifestations and central nervous system involvement. Causes of death include uncontrolled vasculitis and infections, as well as renal, gastrointestinal and cardiovascular manifestations.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Xavier PUECHAL  - Pr Benjamin TERRIER"}
{"Disease Name": "Polyarticular juvenile idiopathic arthritis", "Disease Definition": "A rare type of juvenile idiopathic arthritis characterized by arthritis with an onset prior to the age of 16 years persisting for longer than six weeks and affecting at least five joints during the first six months of the disease. Other possible causes of joint inflammation must be excluded. Two subgroups of the disease can be distinguished, based on the presence of absence of rheumatoid factor. Both subgroups are more common in girls and may be associated with mild fever, weight loss, anemia, moderate hepatosplenomegaly, and mild growth retardation.", "ORPHA ID": 404580, "Summary": ""}
{"Disease Name": "Polyclonal hyperviscosity syndrome", "Disease Definition": "A rare hematologic disease characterized by high serum viscosity due to polyclonal expansion of immunoglobulins, most commonly in the context of Waldenström's macroglobulinemia, as well as a variety of disorders of immune dysregulation. Patients present with signs and symptoms involving multiple organs, such as bleeding diathesis, mucosal bleeding, retinal hemorrhage, headache, stroke, pulmonary hypertension, and congestive heart failure.", "ORPHA ID": 450322, "Summary": ""}
{"Disease Name": "Polycythemia vera", "Disease Definition": "Polycythemia vera (PV) is an acquired myeloproliferative disorder characterized by an elevated absolute red blood cell mass caused by uncontrolled red blood cell production, frequently associated with uncontrolled white blood cell and platelet production.", "ORPHA ID": 729, "Summary": "Epidemiology\nAnnual incidence is estimated at approximately 1/36,000-1/100,000 and prevalence at 1/3,300. PV occurs at all ages but is most common in those aged 50-70 years.\nClinical description\nSymptoms are often insidious at onset and may include headache, dizziness, vertigo, tinnitus, visual disturbances, and pruritus after bathing, a ruddy complexion that manifests in the face, palms, nailbeds, mucosa and conjunctiva. Complications may be associated including arterial thrombosis (in cerebrovascular, myocardial or peripheral territories), angina pectoris or intermittent claudications, or venous thromboses including deep vein thrombosis, pulmonary embolism, splanchnic thrombosis (portal vein thrombosis and Budd-Chiari syndrome; see these terms) and bleeding including gum bleeding, ecchymoses and gastrointestinal bleeding. PV may also be characterized by splenomegaly. Myelofibrosis and acute leukemia or a myelodysplastic syndrome occur in a minority of patients, usually late in the disease.\nEtiology\nSymptoms are related to blood hyperviscosity, which impairs microcirculation and is caused by a marked increase in the cellular elements of blood. This is due to the presence of abnormal clonal stem cell expansion that interferes with or suppresses normal stem cell growth and maturation. The exact origin of this stem cell transformation is still a matter of debate, however, a somatic mutation (JAK2-V617F) in exon 14 of the JAK2 gene (9p24) is present in the vast majority of patients and, less frequently, a somatic mutation in exon 12 of JAK2.\nDiagnostic methods\nDiagnosis is based on evidence of a combination of some of the following criteria: hematocrit (Hct) greater than 52% or hemoglobin (Hb) greater than 185 g/L in male patients, Hct greater than 48% or Hb greater than 165 g/L in female patients, an increased (greater than 125% of normal value) red blood cell mass, the presence of a V617F or an exon 12 mutation of JAK2, low circulating erythropoietin (EPO) levels, spontaneous colony formation by erythroid progenitor cells, and, in rare cases where a JAK2 mutation is lacking, evidence of a myeloproliferative disorder on bone marrow biopsy.\nDifferential diagnosis\nDifferential diagnosis includes elimination of Ph1 negative myeloproliferative disease (MPD) including essential thrombocytosis and agnogenic myeloid metaplasia (see these terms). In patients with polyglobuly without JAK2 mutation, causes of congenital primary erythrocytosis and secondary erythrocytosis (see these terms) should be considered. In patients with PV associated with MPD in the same family, the diagnosis of familial predisposition to MPD must be considered.\nManagement and treatment\nPatients with PV should be individually assessed. Treatment is based on phlebotomy to improve blood circulation. The targeted Hct is 45%. In patients with an increased risk of thrombosis due to age over 60 years, previous thrombosis, peripheral vascular disease or hypertension, cytoreduction should be considered. Hydroxyurea remains the reference drug for elderly patients. In those with no specific contraindication, low-dose aspirin has been proved to reduce the risk of thrombosis. Treatment with interferon alpha may be proposed for pregnant patients. Anagrelide may also be used to decrease platelet counts.\nPrognosis\nPV is a chronic disease. Survival of treated patients in the literature is either identical to the general population or decreased (with mortality 1.6 times higher than that of the general population).\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Jean BRIERE"}
{"Disease Name": "Polydactyly of a biphalangeal thumb and/or hallux", "Disease Definition": "A rare non-syndromic limb malformation characterized by the duplication of one or more skeletal components of a biphalangeal thumb and/or hallux. Hands are preferentially affected (in bilateral), and the right hand is more commonly involved than the left. Hallux duplication may present concomitantly to, or independently of thumb polydactyly and is predominantly unilateral right.", "ORPHA ID": 93339, "Summary": ""}
{"Disease Name": "Polydactyly of a triphalangeal thumb", "Disease Definition": "Polydactyly of a triphalangeal thumb or PPD2 is a form of preaxial polydactyly of fingers (see this term), a limb malformation syndrome, that is characterized by the presence of a usually opposable triphalangeal thumb with or without additional duplication of one or more skeletal components of the thumb. The thumb appearance can differ widely in shape (wedge to rectangular) or it can be deviated in the radio-ulnar plane (clinodactyly). PPD2 is also associated with systemic syndromes, including Holt-Oram syndrome and Fanconi anemia (see these terms).", "ORPHA ID": 93336, "Summary": ""}
{"Disease Name": "Polydactyly of an index finger", "Disease Definition": "Polydactyly of an index finger or PPD3 is a form of preaxial polydactyly of fingers (see this term), a limb malformation syndrome, where the thumb is replaced by one or two triphalangeal digits with dermatoglyphic pattern specific of the index finger. Two forms of PPD3 have been characterized: unilateral and bilateral (see these terms). There have been no further descriptions in the literature since 1962.", "ORPHA ID": 93337, "Summary": ""}
{"Disease Name": "Polydactyly-myopia syndrome", "Disease Definition": "Polydactyly-myopia syndrome is an exceedingly rare autosomal dominant developmental anomaly reported in 1986 in nine individuals among four generations of the same family. The syndrome is characterized clinically by four-limb postaxial polydactyly and progressive myopia. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 2917, "Summary": ""}
{"Disease Name": "Polyembryoma", "Disease Definition": "A rare malignant germ cell tumor characterized by predominant composition of embryoid bodies consisting of a central core of embryonal carcinoma cells, an amnion-like cavity, and a yolk sac tumor component. The tumor usually occurs as the dominant component of a mixed germ cell tumor, with teratoma being the most common associated element. It may manifest as an abdominal mass or with abdominal pain, menstrual irregularities, or precocious puberty in women, while men typically present with testicular enlargement. Serum alpha-fetoprotein and/or beta-human chorionic gonadotropin can be elevated.", "ORPHA ID": 180229, "Summary": ""}
{"Disease Name": "Polyendocrine-polyneuropathy syndrome", "Disease Definition": "A rare genetic disease characterized by childhood onset of multiple endocrine manifestations in combination with central and peripheral nervous system abnormalities. Reported signs and symptoms include postnatal growth retardation, moderate intellectual disability, hypogonadotropic hypogonadism, insulin-dependent diabetes mellitus, central hypothyroidism, demyelinating sensorimotor polyneuropathy, and cerebellar and pyramidal signs. Progressive hearing loss and a hypoplastic pituitary gland have also been described. Brain imaging shows moderate white matter abnormalities.", "ORPHA ID": 453533, "Summary": ""}
{"Disease Name": "Polyglucosan body myopathy type 1", "Disease Definition": "Polyglucosan body myopathy type 1 is a rare, genetic, glycogen storage disorder characterized by polyglucosan accumulation in various tissues, manifesting with progressive proximal muscle weakness in the lower limbs and rapidly progressive, usually dilated, cardiomyopathy. Hepatic involvement and growth retardation may be associated. Early-onset immunodeficiency and autoinflammation, presenting with recurrent bacterial infections, have also been reported.", "ORPHA ID": 397937, "Summary": ""}
{"Disease Name": "Polyglucosan body myopathy type 2", "Disease Definition": "A rare glycogen storage disease characterized by slowly progressive myopathy with storage of polyglucosan in muscle fibers. Age of onset ranges from childhood to late adulthood. Patients present proximal or proximodistal weakness predominantly of limb-girdle muscles. Variable features include exercise intolerance or myalgia. Serum creatine kinase is normal or mildly elevated. There is usually no overt cardiac involvement.", "ORPHA ID": 456369, "Summary": ""}
{"Disease Name": "Polymalformative genetic syndrome with increased risk of developing cancer", "Disease Definition": "Polymalformative genetic syndrome with increased risk of developing cancer (PGSIRC) comprises a wide range of syndromes characterized by congenital malformations with a high risk of developing tumors including up to 50 different rare diseases.", "ORPHA ID": 183422, "Summary": "Epidemiology\nThere are no published data on the prevalence of the set of all syndromes included in this category but, as each syndrome has its specific prevalence, it can be roughly estimated at 1/10,000.\nClinical description\nPGSIRC encompasses different syndromes: the Overgrowth Syndromes, among which the Beckwith-Wiedemann syndrome with a 10% cumulative risk of cancer at 4 years of age mainly hepatoblastoma and Wilms' tumor, Costello syndrome with up to 10% risk of rhabdomyosarcoma, and other syndromes such as Simpson-Golabi-Behmel or Perlman (see these terms). Some other genetic rare diseases associated with an increased risk of cancer include tuberous sclerosis, Xeroderma pigmentosum or WAGR syndrome (see these terms). Because of this predisposition, it is essential to establish an early multidisciplinary follow-up protocol for each patient after the diagnosis. The clinical characteristics are specific to each syndrome.\nEtiology\nThe etiology is specific to each syndrome. The genetic alterations associated with tumorigenesis can occur in the germ-line, resulting in hereditary predisposition to cancer, or have their monoclonal origin in somatic cells, resulting in sporadic tumors. The exact mechanism by which alterations in cancer-related genes (i.e. RAS genes) produce both congenital polymalformative abnormalities as well as sporadic tumors is still under investigation.\nGenetic counseling\nThe inheritance pattern is specific to each syndrome. In most cases of familial cancer, those not associated with congenital abnormalities, tumor susceptibility is inherited in an autosomal dominant pattern. In cancer associated to genetic rare diseases characterized by congenital malformations, the overall tumor susceptibility is inherited mainly in an autosomal recessive pattern, regardless of the inheritance pattern associated with the specific rare disease.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Víctor MARTÍNEZ-GLEZ"}
{"Disease Name": "Polymicrogyria due to TUBB2B mutation", "Disease Definition": "A rare, genetic, complex cerebral cortical malformation characterized by generalized or focal dysgyria (also named polymicrogyria-like cortical dysplasia) or alternatively by microlissencephaly with dysmorphic basal ganglia and dysgenesis of the corpus callosum. Clinical manifestations are variable and include microcephaly, seizures, hypotonia, developmental delay, severe psychomotor delay, ataxia, spastic diplegia or tetraplegia, and ocular abnormalities (strabismus, ptosis or optic atrophy).", "ORPHA ID": 300573, "Summary": ""}
{"Disease Name": "Polymicrogyria with optic nerve hypoplasia", "Disease Definition": "Polymicrogyria with optic nerve hypoplasia is a rare genetic syndrome with central nervous system malformations characterized by severe developmental delay, neonatal hypotonia, seizures, optic nerve hypoplasia and distinct central nervous system malformations including extensive bilateral polymicrogyria, dysplastic or absent corpus callosum and malformed brainstem with loss of demarcation of the pontomedullary junction.", "ORPHA ID": 250972, "Summary": ""}
{"Disease Name": "Polymicrogyria", "Disease Definition": "A heterogenous group of cerebral cortical malformations characterized by excessive cortical folding and abnormal cortical layering that, depending on its topographic distribution, presents with variable combinations of neurological symptoms of varying severity such as epilepsy, developmental delay, intellectual disability, motor dysfunction (e.g. spasticity), and pseudobulbar palsy.", "ORPHA ID": 35981, "Summary": ""}
{"Disease Name": "Polymyositis", "Disease Definition": "A rare idiopathic inflammatory myopathy (IIM) historically characterized by symmetric proximal muscle weakness, elevated muscle enzymes (creatine kinase), myopathic findings on electromyography, and muscle biopsy showing endomyial infiltration composed mainly of macrophages and lymphocytes. The features are non-specific, thus the disease should be distinguished from similar entities with specific clinical, immunological, histological features, notably dermatomyositis, immune-mediated necrotizing myopathy, anti-synthetase syndrome, inclusion body myositis, and myositis associated with other connective tissue disorder.", "ORPHA ID": 732, "Summary": ""}
{"Disease Name": "Polyneuropathy associated with IgM monoclonal gammopathy with anti-MAG", "Disease Definition": "A demyelinating polyneuropathy characterized clinically by sensory ataxia, tremor, paresthesia, and impaired gait.", "ORPHA ID": 639, "Summary": ""}
{"Disease Name": "Polyneuropathy-hearing loss-ataxia-retinitis pigmentosa-cataract syndrome", "Disease Definition": "This rare neurologic disease is a slowly-progressive Refsum-like disorder associating signs of peripheral neuropathy with late-onset hearing loss, cataract and pigmentary retinopathy that become evident during the third decade of life.", "ORPHA ID": 171848, "Summary": "Epidemiology\nThe syndrome has been described in three patients from a consanguineous family (one brother, one sister and a male cousin).\nClinical description\nThe disease manifests during childhood with pes cavus and tendoachilles contractures. A disorder of gait, due to ataxia and spasticity, develops during adulthood. Contrarily to Refsum disease, plasmatic phytanic and pristanic acid levels as well as alpha-oxidation enzymatic activity are normal.\nEtiology\nThe disease was mapped on chromosome 20 (20p11.21-q12).\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            October 2009"}
{"Disease Name": "Polyneuropathy-intellectual disability-acromicria-premature menopause syndrome", "Disease Definition": "Polyneuropathy-intellectual disability-acromicria-premature menopause syndrome is a rare genetic syndromic intellectual disability characterized by intellectual disability, polyneuropathy, short stature and short limbs, brachydactyly, and premature ovarian insufficiency. Only one familial case with three affected females was described and there have been no further descriptions in the literature since 1971.", "ORPHA ID": 2928, "Summary": ""}
{"Disease Name": "Polyrrhinia", "Disease Definition": "A rare, major congenital malformation characterized by complete duplication of the nose resulting in twofully developed noses often associated with choanal atresia, causing respiratory distress and necessitating surgical repair.", "ORPHA ID": 141091, "Summary": ""}
{"Disease Name": "Polysyndactyly-cardiac malformation syndrome", "Disease Definition": "A rare, life-threatening developmental defect during embryogenesis characterized by polysyndactyly of fingers and toes as well as complex congenital heart defects (e.g. atrioventricular septal defects, aortic dextroposition, single ventricle, hypo- or hypertrophy of one side of the heart). Additional features may include dysmorphic traits (large fontanel, high forehead, ptosis, hypertelorism, epicanthus, low-set malformed ears, prominent root of the nose, bulbous nose, anteverted nares, long and smooth philtrum, thin upper lip, micrognathism, hirsutism, single transverse crease) nail hypoplasia, phalange agenesis/hypoplasia, flexion contractures, polysplenia, multiple hepatic/renal cysts, atrophic biliary vesicle, ductal plate malformation and genital anomalies (e.g. micropenis, undescended testes, hypoplastic scrotum). The syndrome is usually fatal in utero or in infancy, but survival cases have been reported.", "ORPHA ID": 2934, "Summary": ""}
{"Disease Name": "Polysyndactyly", "Disease Definition": "Polysyndactyly or PPD4 is a form of preaxial polydactyly of fingers (see this term), a limb malformation syndrome, characterized by the presence of a thumb showing the mildest degree of duplication, being broad, bifid or with radially deviated distal phalanx. Syndactyly of various degrees of third-and-fourth fingers is occasionally present.", "ORPHA ID": 93338, "Summary": ""}
{"Disease Name": "POMGNT1-related limb-girdle muscular dystrophy R15", "Disease Definition": "A form of limb-girdle muscular dystrophy characterized by an onset in childhood or adolescence of rapidly progressive proximal limb muscle weakness (particularly affecting the neck, hip girdle, and shoulder abductors), hypertrophy in the calves and quadriceps, ankle contractures, and myopia.", "ORPHA ID": 206564, "Summary": ""}
{"Disease Name": "POMGNT2-related limb-girdle muscular dystrophy R24", "Disease Definition": "A rare autosomal recessive limb-girdle muscular dystrophy characterized by infantile to adolescent onset of a milder form of limb-girdle muscular dystrophy with or without intellectual disability. Patients present variable proximal limb muscular weakness with calf hypertrophy and elevated serum creatine kinase.", "ORPHA ID": 565899, "Summary": ""}
{"Disease Name": "POMT1-related limb-girdle muscular dystrophy R11", "Disease Definition": "A form of limb-girdle muscular dystrophy characterized by the onset of slowly progressive proximal muscle weakness during childhood (with fatigue and difficulty running and climbing stairs) and developmental delay. Mild intellectual deficit and microcephaly, without any obvious structural brain abnormality, are found in all patients. Mild pseudohypertrophy and joint contractures of the ankles have also been reported.", "ORPHA ID": 86812, "Summary": ""}
{"Disease Name": "POMT2-related limb-girdle muscular dystrophy R14", "Disease Definition": "A form of limb-girdle muscular dystrophy characterized by proximal weakness (manifesting as slowness in running) presenting in infancy, along with calf hypertrophy, mild lordosis, scapular winging and normal intelligence (or mild intellectual disability).", "ORPHA ID": 206559, "Summary": ""}
{"Disease Name": "Pontiac fever", "Disease Definition": "Pontiac fever (PF) is a mild form of legionellosis (see this term) manifesting with flu-like symptoms such as nausea, myalgia, fever, cough and headache but without pneumonia.", "ORPHA ID": 99748, "Summary": "Epidemiology\nThe incidence is unknown. Due to the disease's mild and non-specific manifestations it is thought to be underreported. PF is characterised by a high attack rate (number of patients affected / number of people exposed) of up to 95%.\nClinical description\nPontiac fever has a short incubation period ranging from 30-90 hours after infection and affects mainly adults but also children. The disease manifests as an influenza-like syndrome with fever, headache, myalgia and fatigue. In some cases, patients may also experience thoracic pain, dyspnea, diarrhea and vomiting, ocular redness with photophobia and arthralgia. These symptoms usually last 2-7 days and patients recover without treatment.\nEtiology\nPF is caused by an infection with Legionella pneumophila and Legionella non-pneumophila by inhalation of aerosols from contaminated water, most frequently from showers, whirlpools, spas and hot tubs. The bacteria are found in wet soil and water. It is currently unknown why infection with Legionella evolves into LD or PF in any given case, but as PF is usually observed in immunocompetent patients, immune system status could play a role.\nDiagnostic methods\nLaboratory diagnosis is rarely performed and is usually done retrospectively by detecting seroconversion or high titers of antibody to Legionella in serum samples. The diagnosis can also be made by detection of the L. pneumophila antigen in urine samples.\nDifferential diagnosis\nInfluenza closely resembles PF and must therefore be excluded.\nManagement and treatment\nNo treatment is needed for PF and recovery without treatment is the rule.\nPrognosis\nThere is no fatality associated with PF.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Sophie JARRAUD"}
{"Disease Name": "Pontine autosomal dominant microangiopathy with leukoencephalopathy", "Disease Definition": "A rare genetic cerebral small vessel disease characterized by recurrent ischemic strokes, often with a predilection for the pons, with typical onset in the fourth or fifth decade of life. Patients present progressive cognitive and motor impairment with pyramidal, bulbar, and cerebellar symptoms, among others. Brain imaging shows multiple lacunar infarcts, typically with involvement of the pons, as well as variable leukoencephalopathy of the cerebral hemispheres.", "ORPHA ID": 477749, "Summary": ""}
{"Disease Name": "Pontine tegmental cap dysplasia", "Disease Definition": "A rare, central nervous system malformation characterized by specific pattern of congenital anomalies affecting the pons, medulla, and cerebellum. Clinical manifestations of multiple cranial nerves deficits, pyramidal and cerebellar signs include neonatal hypotonia, ataxia, sensorineural deafness, reduced vision, language and speech disorders, feeding and swallowing difficulties, facial paralysis and intellectual disability. Various cardiac, gastrointestinal, genitourinary and skeletal defects have been sometimes reported.", "ORPHA ID": 269229, "Summary": ""}
{"Disease Name": "Pontocerebellar hypoplasia type 1", "Disease Definition": "A severe, genetic form of pontocerebellar hypoplasia (PCH) characterized by spinal cord anterior horn cell degeneration in addition to pontocerebellar hypoplasia. Clinically, patients manifest with a severe global development deficit that is evident early on from difficulties in feeding and swallowing", "ORPHA ID": 2254, "Summary": "Epidemiology\nAbout 115 patients with pontocerebellar hypoplasia type 1 (PCH1) have been reported.\nClinical description\nThe clinical course is severe. Neonates with PCH1 present with hypotonia, impaired swallowing with subsequent feeding difficulties, and progressive, postnatal microcephaly. A severe psychomotor deficit subsequently becomes apparent. If patients survive past infancy, patients have oculomotor manifestations including strabismus, nystagmus and oculomotor apraxia. The most severe cases of PCH1 manifest prenatally with polyhydramnios and arthrogryposis multiplex congenital.\nEtiology\nPCH1 is genetically heterogeneous. Recessive mutations in the EXOSC3 gene (9p13.2) are found in 40-50% of patients and are the most prevalent cause of PCH1. Mutations in EXOSC8 (13q13.3) and EXOSC9 (4q27) are recently described as a rare cause of PCH1. Mutations in 3 families have been identified in SLC25A46 (5q22.1) and VRK1 (14q32.2) in 2 families. In single cases, recessive mutations have been found in TSEN54 (17q25.1) and RARS2 (6q15). From the small groups reported, severity is suggested to depend on genotype.\nDiagnostic methods\nMRI shows pontocerebellar hypoplasia with cerebellar hemispheres variably affected. Variable findings include spinal anterior horn degeneration and absence of pontine hypoplasia. Lack of awareness often results in a delay in diagnosis or a diagnosis is never made.\nDifferential diagnosis\nPCH type 2 and 4 (TSEN54-related PCH) can be considered. PCH2 is the most common type of PCH, characterized by dyskinesia and seizures. Brain MRI typically shows pontocerebellar hypoplasia with relative sparing of the vermis compared to the hemispheres, similar to PCH1. In PCH1 however, the pons may be unaffected while in PCH2 the ventral pons is flattened. PCH4 is a more severe than PCH2 and often associated with congenital contractures and polyhydramnios. Spinal Muscular Atrophy (SMA) type 1, caused by biallelic pathogenic variants in SMN1, is characterized by anterior horn cell degeneration, similar to that observed in PCH1. Cognitive function is normal in SMA.\nAntenatal diagnosis\nPrenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal testing or pre-implantation genetic diagnosis (PGD) should be offered.\nGenetic counseling\nPCH1 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH1. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.\nManagement and treatment\nTreatment is symptomatic in PCH.\nPrognosis\nPrognosis is poor; the majority of patients will only live into infancy. Patients with EXOSC3 mutation have a less severe prognosis.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK"}
{"Disease Name": "Pontocerebellar hypoplasia type 10", "Disease Definition": "A rare, genetic, pontocerebellar hypoplasia subtype characterized by severe psychomotor developmental delay, progressive microcephaly, progressive spasticity, seizures, and brain abnormalities consisting of mild atrophy of the cerebellum, pons and corpus callosum and cortical atrophy with delayed myelination. Patients may present dysmorphic facial features (high arched eyebrows, prominent eyes, long palpebral fissures and eyelashes, broad nasal root, and hypoplastic alae nasi) and an axonal sensorimotor neuropathy.", "ORPHA ID": 411493, "Summary": ""}
{"Disease Name": "Pontocerebellar hypoplasia type 2", "Disease Definition": "A rare, genetic form of pontocerebellar hypoplasia characterized by pontocerebellar hypoplasia and progressive neocortical atrophy that manifests clinically with uncoordinated sucking and swallowing, and generalized clonus in the neonate. In early childhood, spasticity, chorea/dyskinesia, seizures and progressive microcephaly develop. Voluntary motor development is lacking.", "ORPHA ID": 2524, "Summary": "Epidemiology\nPontocerebellar hypoplasia type 2 (PCH2) is reported in at least 81 families to date. It is the most common form of pontocerebellar hypoplasia.\nClinical description\nAfter an uneventful pregnancy and birth without dysmorphic features, affected neonates present usually, but not always, with dysphagia due to bucco-pharyngeal incoordination, respiratory and feeding difficulties and generalized clonus. Extrapyramidal dyskinesia with mixed spasticity such as chorea, athetosis and dystonia develop later. From infancy onward, affected children develop progressive microcephaly, central visual impairment, seizures and a severe impairment of cognitive and motor development, marked by an impaired motor development with failing head control, lack of voluntary hand control and the absence of speech and communication. PCH2 is often fatal in early childhood.\nEtiology\nPCH2 is generally caused by homozygous mutations in the TSEN54 gene (17q25.1), most frequently a founder mutation, prevalent in families of European extraction: p.A307S/A307S or missense mutations. Rarely mutations in the TSEN2 (3p25.2), TSEN34 (19q13.42), TSEN15 (1q25.3), SEPSECS (4p15.2) or VPS53 (17p13.3) genes are reported.\nDiagnostic methods\nDiagnosis is made is based on a combination of neuroradiologic and clinical findings : MRI demonstrates variable neocortical atrophy, progressive in time, flattening of the caudate nuclear heads, and pontocerebellar hypoplasia with a typical dragonfly-like cerebellar pattern on coronal sections caused by the flat hemispheres heavily reduced in size together with a comparatively spared vermis. Genetic testing is recommended to confirm the diagnosis.\nDifferential diagnosis\nDue to phenotypic overlap, other subtypes of PCH should be considered, as well as mutations in the CASK gene. Congenital Disorder of Glycosylation type 1A (CDG1A) caused by mutations in the PMM2 gene can resemble PCH. Extreme prematurity (gestational age <32 weeks) can cause cerebellar hypoplasia of variable degrees.\nAntenatal diagnosis\nIn case of risk for recurrence of PCH2, genetic prenatal diagnosis, by amniocentesis or chorionic villus sampling and cytogenetic analysis, may be offered. Prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal testing or pre-implantation genetic diagnosis (PGD) should be offered.\nGenetic counseling\nPCH2 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH2. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.\nManagement and treatment\nTreatment is symptomatic in PCH and involves medication for treatment of dystonia, dyskinesia and seizures and percutaneous endoscopic gastrostomy tube feeding.\nPrognosis\nPrognosis is variable; the majority of patients will not reach puberty. Life threatening complications include sleep apnea, rhabdomyolysis and malignant hyperthermia. Cot death is possible.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK"}
{"Disease Name": "Pontocerebellar hypoplasia type 3", "Disease Definition": "A rare, genetic form of pontocerebellar hypoplasia (PCH) characterized by neocortical and pontocerebellar hypoplasia with pons and cerebellum equally affected and that clinically manifests with neonatal hypotonia and impaired swallowing followed by seizures, optic atrophy and short stature from infancy onward. Movement disorders, as seen in other forms of PCH, are absent.", "ORPHA ID": 97249, "Summary": "Epidemiology\nPontocerebellar hypoplasia type 3 (PCH3) is reported in only 3 families.\nClinical description\nNeonatally, PCH3 is characterized by hypotonia and impaired swallowing. From infancy onwards, the main features of PCH3 include progressive microcephaly with brachycephaly, optic atrophy, seizures during the first year of life, severe developmental delay, truncal hypotonia, with increased limb deep tendon reflexes and signs of spasticity of the limbs. Other characteristics such as facial dysmorphism (low set ears and prominent eyes), short stature and low weight are also reported. None of the clinical findings are specific. Characteristic movement disorders, as seen in PCH type 2, appear to be absent.\nEtiology\nMutations in the PCLO gene (7q21.11) has been identified in a family from the Sultanate of Oman. It is however unclear if PCLO mutations are causative in the other reported PCH3 families reported in literature. PCH3 is inherited in an autosomal recessive manner.\nDiagnostic methods\nMRI demonstrates neocortical and pontocerebellar hypoplasia with pons and cerebellum equally affected, a small brainstem, prominent sulci and lateral ventricles and decreased cerebral white matter volume. Genetic testing is recommended to confirm the diagnosis.\nDifferential diagnosis\nDue to phenotypic overlap, other subtypes of PCH should be considered, as well as mutations in the CASK gene. Congenital disorder of glycosylation type 1A (CDG1A) caused by mutations in the PMM2 gene can resemble PCH.\nAntenatal diagnosis\nPrenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal testing or pre-implantation genetic diagnosis (PGD) should be offered.\nGenetic counseling\nPCH3 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH3. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.\nManagement and treatment\nTreatment is symptomatic in PCH.\nPrognosis\nThere is no information on life expectancy, but reported PCH3 patients do not appear to regress.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK"}
{"Disease Name": "Pontocerebellar hypoplasia type 4", "Disease Definition": "A severe, genetic form of pontocerebellar hypoplasia (PCH) characterized by delayed neocortical maturation with underdeveloped cerebral hemispheres and pontocerebellar hypoplasia and a severely affected vermis. Clinically, the disorder manifests with prenatal onset of polyhydramnios and contractures followed by hypertonia, severe clonus, primary hypoventilation leading to an early postnatal death.", "ORPHA ID": 166063, "Summary": "Epidemiology\nPontocerebellar hypoplasia type 4 (PCH4) has been reported in 10 families to date.\nClinical description\nPCH4 is characterized prenatally by polyhydramnios. Neonates present with microcephaly, central apnea requiring respiratory support, dysmorphism (sloping forehead, midface hypoplasia, micrognathia), congenital arthrogryposis (50%), severe clonus, and hypertonia. Weaning from mechanical ventilation is difficult and usually fails. Survival beyond the neonatal period is rare.\nEtiology\nPCH4 is caused by a compound heterozygosity for p.A307S plus non-sense or splice site mutations in the TSEN54 gene (17q25.1).\nDiagnostic methods\nMRI (usually performed at autopsy) demonstrates microcephaly due to delayed neocortical maturation with underdeveloped cerebral hemispheres, increased volume of extracerebral cerebrospinal fluid, wide midline cava, pontocerebellar hypoplasia with large denuded areas without folia of the cerebellar hemispheric cortex and a severely affected vermis. Genetic testing is recommended to confirm the diagnosis.\nDifferential diagnosis\nOther types of PCH at the severe end of the spectrum should be considered, such as severe forms of PCH1 or SLC25A46-related PCH.\nAntenatal diagnosis\nIn families in which the causal mutation is detected, prenatal genetic testing or pre-implantation genetic diagnosis should be offered. In general, prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation.\nGenetic counseling\nPCH4 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH4. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.\nManagement and treatment\nTreatment is symptomatic in PCH.\nPrognosis\nSurvival beyond the neonatal period is rare in PCH4.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK"}
{"Disease Name": "Pontocerebellar hypoplasia type 6", "Disease Definition": "A rare, genetic form of pontocerebellar hypoplasia (PCH) characterized by neocortical and severe cerebral cortical atrophy associated with pontocerebellar hypoplasia with the pons and cerebellum equally affected. Clinically the disorder manifests at birth with hypotonia, clonus, epilepsy, impaired swallowing and from infancy by progressive microcephaly, spasticity and lactic acidosis.", "ORPHA ID": 166073, "Summary": "Epidemiology\nPontocerebellar hypoplasia type 6 (PCH6) is reported in at least 31 cases to date.\nClinical description\nPCH6 manifests at birth by generalized hypotonia, lethargy and dysphagia. The clinical profile is characterized from infancy by a profound developmental delay, progressive microcephaly, hypotonia or spasticity and treatment-resistant epilepsy.\nEtiology\nPCH6 is caused by nonsense, missense and splice site mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene located to 6q16.1.\nDiagnostic methods\nMRI demonstrates neocortical and severe cerebral cortical atrophy (more severe than in other types of PCH) as well as pontocerebellar hypoplasia with the pons and cerebellum equally affected. In some patients, early MRI is normal or only shows mild vermal hypoplasia, followed by rapidly progressive brain atrophy. Lactic acid is elevated in cerebrospinal fluid in the majority of patients, which can be accompanied by respiratory chain enzyme deficiency in muscle or fibroblasts. Genetic testing is recommended to confirm the diagnosis\nDifferential diagnosis\nDue to phenotypic overlap, other subtypes of PCH should be considered, as well as mutations in the genes encoding mitochondrial aminoacyl-tRNA synthetases, which can also cause early onset mitochondrial epileptic encephalopathies.\nAntenatal diagnosis\nPrenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal genetic testing or pre-implantation genetic diagnosis should be offered.\nGenetic counseling\nPCH6 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH6. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.\nManagement and treatment\nTreatment is symptomatic in PCH.\nPrognosis\nPrognosis is poor, exact life expectancy is unknown but in most cases does not exceed infancy.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr F. [Frank] BAAS  - Dr Tessa VAN DIJK"}
{"Disease Name": "Pontocerebellar hypoplasia type 7", "Disease Definition": "Pontocerebellar hypoplasia type 7 (PCH7) is a novel very rare form of pontocerebellar hypoplasia (see this term) with unknown etiology and poor prognosis reported in four patients and is characterized clinically during the neonatal period by hypotonia, no palpable gonads, micropenis and from infancy by progressive microcephaly, apneic episodes, poor feeding, seizures and regression of penis. MRI demonstrates a pontocerebellar hypoplasia. PCH7 is expressed as PCH with 46,XY disorder of sex development (see this term) in individuals with XY karyotype, and may be expressed as PCH only in individuals with XX karyotype.", "ORPHA ID": 284339, "Summary": ""}
{"Disease Name": "Pontocerebellar hypoplasia type 8", "Disease Definition": "Pontocerebellar hypoplasia type 8 (PCH8) is a novel very rare form of pontocerebellar hypoplasia (see this term) characterized clinically by progressive microencephaly, feeding difficulties, severe developmental delay, although walking may be achieved, hypotonia often associated with increased muscle tone of lower extremities and deep tendon reflexes, joint deformities in the lower extremities, and occasionally complex seizures. PCH8 is caused by a loss-of-function mutation in the CHMP1A gene. MRI demonstrates a pontocerebellar hypoplasia with vermis and hemispheres equally affected and mild to severely reduced cerebral white matter volume with a fully formed very thin corpus callosum.", "ORPHA ID": 324569, "Summary": ""}
{"Disease Name": "Pontocerebellar hypoplasia type 9", "Disease Definition": "A rare, genetic, non-syndromic pontocerebellar hypoplasia characterized by progressive cerebellum and brainstem atrophy, corpus callosum hypo-/aplasia and progressive post-natal microcephaly. Patients typically present profound global developmental delay, spastic tetraparesis, seizures, cortical visual impairment and, on neuroimaging, abnormal brain morphology that includes pontocerebellar hypoplasia, ''figure of 8'' midbrain appearance, and, more variably, interhemispheric cysts, ventriculomegaly and cerebral dysmyelination.", "ORPHA ID": 369920, "Summary": ""}
{"Disease Name": "Porencephaly-cerebellar hypoplasia-internal malformations syndrome", "Disease Definition": "Porencephaly-cerebellar hypoplasia-internal malformations syndrome is rare central nervous system malformation syndrome characterized by bilateral porencephaly, absence of the septum pellucidum and cerebellar hypoplasia with absent vermis. Additionally, dysmorphic facial features (hypertelorism, epicanthic folds, high arched palate, prominent metopic suture), macrocephaly, corneal clouding, situs inversus, tetralogy of Fallot, atrial septal defects and/or seizures have been observed.", "ORPHA ID": 2941, "Summary": ""}
{"Disease Name": "Porencephaly-microcephaly-bilateral congenital cataract syndrome", "Disease Definition": "A rare, genetic, central nervous system malformation syndrome characterized by bilateral congenital cataracts and severe hemorrhagic destruction of the brain parenchyma with associated massive cystic degeneration, enlarged ventricles and subependymal calcification. Patients typically present generalized spasticity, increased deep tendon reflexes and seizures. Hepatomegaly and renal anomalies have also been reported.", "ORPHA ID": 306547, "Summary": ""}
{"Disease Name": "Porencephaly", "Disease Definition": "A rare, genetic or acquired, cerebral malformation characterized by an intracerebral fluid-filled cyst or cavity with or without communication between the ventricle and subarachnoid space. Clinical manifestations depend on location and severity and may include hemiparesis, seizures, intellectual disability, and dystonia.", "ORPHA ID": 2940, "Summary": "Epidemiology\nPoint prevalence of acquired and genetic forms is unknown. However, birth prevalence of porencephaly is estimated at 1/19,000 in Japan and 1/28,500 in the USA.\nClinical description\nPorencephaly may manifest before or after birth. The cysts or cavities can be located anywhere within the cerebral parenchyma and are typically lined by smooth walls and surrounded by an atrophic cortex. The clinical picture is highly variable, even within affected families, with severe cases presenting major disability to mild cases with only slight, or even undetected, neurological involvement. The main clinical manifestations include hypotonia, microcephaly, spastic hemiparesis or quadriparesis, seizures, and global developmental delay. Intellectual disability is also a common finding and ranges from very mild to severe.\nEtiology\nPrenatal- and postnatally-acquired cysts (acquired porencephaly) may be due to a number of causes including hemorrhage, local damage from ischemia or traumatic brain injury. Mutations in the COL4A1 (13q34) and COL4A2 (13q34) genes have been identified in familial (Familial porencephaly) and de novo  cases. In these genetic cases, porencephaly results from antenatal or perinatal hemorrhage and is often associated with other brain abnormalities (bilateral white matter changes, calcifications, microbleeds) and ocular involvement (congenital cataract, retinal arterial tortuosity).\nDiagnostic methods\nThe diagnosis is suspected based on the clinical manifestations and is confirmed radiologically by computed tomography (CT), magnetic resonance imaging (MRI), or ultrasonography showing characteristic intracerebral lesions. Cysts or cavities are well demarcated, contain cerebrospinal fluid and do not show contrast enhancement.\nDifferential diagnosis\nDifferential diagnoses include arachnoid cyst, schizencephaly, ependymal cyst, encephalomalacia, hydranencephaly, and other COL4A1 or COL4A2 related diseases, including childhood stroke, CADASIL and retinal vasculopathy with cerebral leukodystrophy.\nAntenatal diagnosis\nUltrasonography may detect porencephaly prenatally after the 30th week of gestation.\nGenetic counseling\nThe pattern of inheritance for familial porencephaly is autosomal dominant. Genetic counseling should inform parents of the 50% risk of transmission for future offspring. Occasionally, genetic cases arise de novo.\nManagement and treatment\nNo specific treatment is available for porencephaly. Treatment is therefore symptomatic and supportive and may include physical therapy, speech therapy, and anticonvulsant medication to treat seizures.\nPrognosis\nPrognosis is variable and depends on the site and extent of the lesion.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Patrick VAN BOGAERT"}
{"Disease Name": "Porokeratosis of Mibelli", "Disease Definition": "A rare skin disease that is characterized by the presence of brownish single or multiple annular plaques of varying size, that are sometimes confluent, with a distinctive sharply-defined keratotic border.", "ORPHA ID": 735, "Summary": "Epidemiology\nPorokeratosis of Mibelli (PM) prevalence is unknown. It is more prevalent in males than females with a ratio of 2-3:1.\nClinical description\nDisease onset usually occurs in children, adolescents or young adults (sometimes immunosuppressed). It presents with brownish dry hyperkeratotic plaques of varying size that may coalesce. The lesions have a sharply-defined keratotic border and are usually asymptomatic, but rarely pruritic. They most commonly occur on the limbs (hands and feet) but other areas such as the trunk, palms and soles and genitalia can also be affected. Facial and mucosal lesions are rare. In around 7% of cases, PM lesions undergo malignant transformation, mostly toward squamous cell carcinoma, or less commonly, basal cell carcinoma.\nEtiology\nThe exact etiology is unknown but the lesions are thought to originate from the localized expansion of a clone of abnormal keratinocytes. Contributing factors include immunosuppression, exposure to ultraviolet radiation and drugs, as well as genetic factors (mutations in mevalonate kinase gene).\nDiagnostic methods\nDiagnosis is based on physical examination and a cutaneous biopsy showing the distinctive cornoid lamella, i.e. a narrow, vertical stack of parakeratotic corneocytes within the horny layer seated on a depression of the underlying epidermis.\nDifferential diagnosis\nThe main differential diagnoses are actinic keratosis, elastosis perforans serpiginosa, annular lichen planus, circumscribed palmoplantar hypokeratosis, psoriasis, focal palmoplantar keratoderma and Bowen's disease.\nGenetic counseling\nAutosomal dominant inheritance has been reported, although PM is often sporadic.\nManagement and treatment\nPM lesions can be treated with surgical excision. Alternative, albeit less efficient, options include topical 5-fluorouracil (5-FU), imiquimod, cryotherapy, dermabrasion, carbon dioxide laser ablation and photodynamic therapy. However the lesions often recur after treatment. Regular follow-up is recommended to monitor the development of any possible malignancies, and sun exposure should be limited in order to decrease their risk.\nPrognosis\nPM is a chronically progressive disease and can have a negative impact on a patient's quality of life due to the presence of lesions. Rarely (in around 7% of cases), long-standing lesions may transform into squamous cell carcinoma, which has exceptionally proven fatal.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jean KANITAKIS"}
{"Disease Name": "Porokeratosis plantaris palmaris et disseminata", "Disease Definition": "A rare genetic disease which is a rare form of porokeratosis occurring mainly in adolescence and characterized by small pruritic or painful keratotic papules that first appear on the palms and soles, and may gradually spread to other body zones.", "ORPHA ID": 737, "Summary": "Epidemiology\nPorokeratosis plantaris palmaris et disseminata (PPPD) prevalence is unknown but it is one of the rarest forms of porokeratosis. The disease is more frequently seen in males.\nClinical description\nThe disease often begins in adolescence but some cases have presented in adulthood. Keratotic papules are first noticed on the palms and soles but later spread over the entire body, although lesions on the trunk might be less keratotic. The lesions are usually punctate on the palms and soles and annular on the rest of the body with the characteristic hyperkeratotic border. Foot pain is common due to plantar keratoses. Men are more often affected than women.\nEtiology\nThe exact etiology is unknown. A possible locus for PPPD has been found on chromosome 12q24.1-q24.2.\nDiagnostic methods\nDiagnosis is based on physical examination and a cutaneous biopsy showing the distinctive pathologic finding known as cornoid lamella. The characteristic clinical findings of papular-keratotic, rather than annular, lesions and an initial onset on the palms and soles also aids in the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other (genetic) punctate palmoplantar keratodermas such as acrokeratoelastoidosis of Costa, hyperkeratosis-hyperpigmentation syndrome, punctate palmoplantar keratoderma type 1 and hereditary papulotranslucent acrokeratoderma.\nGenetic counseling\nPPPD usually follows a dominant (autosomal or X-linked) pattern of inheritance. Sporadic cases have been reported and may be due to spontaneous mutations resulting in abnormal proliferating clones of epidermal cells.\nManagement and treatment\nThere is no standard treatment for PPPD. Oral retinoids combined with topical 5-fluorouracil (5-FU) have been successful in reducing the number of lesions in some patients, but relapses are common. Physical methods (shave excision, cryotherapy, curettage, dermabrasion and linear excision) have had varying degrees of success in removing lesions but are not a feasible option in cases where the lesions are generalized.\nPrognosis\nPPPD has a negative impact on a patient's quality of life as the lesions are tender or painful, limiting the patient's ability to walk, and their treatment is often unsuccessful.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jean KANITAKIS"}
{"Disease Name": "Porphyria cutanea tarda", "Disease Definition": "A rare hepatic porphyria with cutaneous expression (PCT) characterized by bullous photodermatosis.", "ORPHA ID": 101330, "Summary": "Epidemiology\nThis is the most common form of cutaneous porphyria. Its prevalence in Western Europe is around 1/25,000. Men are more affected than women.\nClinical description\nOccurring in adults, PCT is acquired (75% of cases) or familial (25% of cases). Manifestations generally appear earlier in familial cases. Some risk factors can trigger symptoms: excessive alcohol consumption, hepatitis C, estrogen intake, iron metabolism gene mutations with overload (hemochromatosis). The main clinical symptoms include extreme skin fragility, followed by bullous skin lesions on sun-exposed surfaces (hands, face). Healing is slow and often followed by hyper- and hypopigmentation. Skin lesions of varying ages are highly characteristic of the disease. These symptoms may be accompanied by hypertrichosis (especially facial) and, more rarely, by sclerodermiform lesions. Hepatopathy should be investigated (siderosis, steatosis, chronic inflammatory disorders, etc.).\nEtiology\nPCT is caused by a deficiency in uroporphyrinogen decarboxylase (UROD, the fifth enzyme in the heme biosynthesis chain). In the familial form of the disease, this deficiency is due to heterozygous mutations in the UROD gene (NM_000374.5), which codes for UROD and leads to an accumulation of porphyrins (uro- and hepta-carboxylic porphyrins) in the liver.\nDiagnostic methods\nDiagnosis is based on high concentrations of porphyrins in plasma, with a fluorimetric peak at 620 nm, and high concentrations of isocoproporphyrins in stools, which is specific to PCT. UROD deficiency in red blood cells confirms the diagnosis of familial PCT. In contrast, normal UROD activity in red blood cells is in favor of sporadic PCT. Skin biopsy is not very informative and is not recommended.\nDifferential diagnosis\nDifferential diagnosis mainly includes variegate porphyria (diagnosed on the basis of a characteristic fluorometric peak in plasma), hereditary coproporphyria, the photodermatosis of acute intermittent porphyria (in renal failure condition), and pseudo-porphyrias.\nAntenatal diagnosis\nAntenatal diagnosis is theoretically possible in familial forms, but is not offered.\nGenetic counseling\nThe pattern of transmission for familial PCT is autosomal dominant, with low penetrance. Therefore, genetic counseling should be offered to those families to identify individuals likely to develop or transmit the disease.\nManagement and treatment\nManagement includes removal of triggers, management of underlying liver disease, phlebotomy and/or low-dose chloroquine (100 mg twice weekly) to achieve complete remission whether or not there is iron overload. A relapse is possible, and the treatment will be the same. Discontinuation of alcohol and estrogen-progestin therapy, and treatment of concomitant hepatitis C, are essential for remission.\nPrognosis\nPCT is not life-threatening and its prognosis is good. It is, however, a risk factor for the development of hepatocellular carcinoma.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Neila TALBI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Porphyria due to ALA dehydratase deficiency", "Disease Definition": "A rare acute hepatic porphyria characterized by neurovisceral attacks without skin symptoms.", "ORPHA ID": 100924, "Summary": "Epidemiology\nFewer than a dozen cases have been reported in the literature to date.\nClinical description\nThe disease is reported among children. Patients suffer acute neuro-visceral episodes that can last several weeks, manifesting as intense abdominal pain, neurological disorders and psychological disturbances.\nEtiology\nDoss porphyria is due to a deficiency in delta aminolevulinic acid dehydratase (ALAD, the second enzyme in the heme biosynthesis pathway), which leads to an accumulation of porphyrin precursors (delta aminolevulinic acid, ALA) in the liver. The enzyme deficiency is due to mutations in the ALAD gene (NM_000031) coding for ALAD (to date, 9 mutations known and expressed). Patients most often have a compound heterozygosity. The transmission pattern is autosomal recessive.\nDiagnostic methods\nThe diagnosis is made on the basis of massive accumulation of ALA in the urine, with no increase in PBG. Diagnosis is based on the identification of a causal mutation in the ALAD gene.\nDifferential diagnosis\nDifferential diagnosis should consider acute hepatic porphyria (in acute attack situations), type I tyrosinemia, and lead poisoning.\nAntenatal diagnosis\nPrenatal diagnosis is theoretically possible in families at risk, but is not offered.\nGenetic counseling\nGenetic counseling is recommended to patients and families to identify individuals at risk of developing or transmitting the disease, and to advise them on measures to take to reduce the risk of an episode It should also be offered to at-risk couples (both individuals are carriers of a heterozygous pathogenic variant) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nAdministration of human hemin is of limited effectiveness in acute episode as is liver transplantation. In 2020, treatment with weekly blood transfusions and hydroxyurea was successfully attempted.\nPrognosis\nIn some patients, acute attacks are recurrent and disabling, sometimes fatal. In some cases, they can lead to severe paralysis. The disease is often progressive.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Neila TALBI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Porphyria", "Disease Definition": "A group of rare hereditary metabolic diseases characterized by intermittent neurovisceral manifestations and/or skin lesions.", "ORPHA ID": 738, "Summary": "Epidemiology\nPrevalence depends on the type of porphyria.\nClinical description\nThe group includes eight diseases with different manifestations. Symptoms mainly appear in adulthood, but some also affect children. Porphyrias can be classified into two groups, hepatic and erythropoietic, depending on the tissue predominantly affected by the metabolic abnormality. Clinical signs of hepatic porphyrias with cutaneous expression and erythropoietic porphyrias are bullous cutaneous lesions and/or acute pain in areas exposed to the sun (painful lesions). They are not associated with acute neurovisceral attacks. On the contrary, acute hepatic porphyrias can be associated with neurovisceral attacks manifested by intense abdominal pain (very often accompanied with nausea, vomiting and severe constipation), neurological disorders and mental disturbances. Two acute hepatic porphyrias (variegate porphyria and hereditary coproporphyria) can present with cutaneous photosensitivity as well.\nEtiology\nAll porphyrias are caused by a deficiency or a gain-of-function in one of the enzymes involved in heme biosynthesis. These deficiencies or gains of function lead to an accumulation of porphyrins and/or their precursors (delta aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver or bone marrow. Precursors, and especially ALA, are responsible for neurological manifestations (direct or indirect neurotoxicity). The deficits or gains in enzyme function are the result of mutations of the coded corresponding genes.\nDiagnostic methods\nDiagnosis is essentially based on the measurement of porphyrins and their precursors in biological samples (urine, stools, blood).\nDifferential diagnosis\nThe differential diagnosis includes Guillain-Barré syndrome, and all causes of abdominal pain when the patient presents with acute pain, and photodermatoses when the patient presents with cutaneous symptoms.\nAntenatal diagnosis\nAntenatal diagnosis may be proposed for the families at risk of congenital erythropoietic porphyria and homozygous acute hepatic porphyrias.\nGenetic counseling\nTransmission of hereditary porphyrias is autosomal and either dominant with low penetrance or recessive with complete penetrance. One type of porphyria is X-linked dominant. The risk of transmitting the disease varies from 25% to 50%, depending on the type of porphyria. Penetrance varies from less than 2% to 100%, depending on the type of porphyria and the affected family members. Genetic counselling should be offered to affected families to identify individuals likely to develop or transmit the disease.\nManagement and treatment\nAcute attacks must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Cutaneous manifestations are mainly treated by phlebotomy and/or low-dose regimen of chloroquine.\nPrognosis\nPrognosis depends on the type of porphyria.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Neila TALBI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Port-wine nevi-mega cisterna magna-hydrocephalus syndrome", "Disease Definition": "A rare developmental defect during embryogenesis syndrome characterized by a glabellar capillary malformation, congenital communicating hydrocephalus, and posterior fossa brain abnormalities, including Dandy-Walker malformation, cerebellar vermis agenesis, and mega cisterna magna. Seizures are occasionally associated. There have been no further descriptions in the literature since 1979.", "ORPHA ID": 2703, "Summary": ""}
{"Disease Name": "Post-transplant lymphoproliferative disease", "Disease Definition": "A group of rare immunodeficiency-associated lymphoproliferative disorders characterized by lymphoid or plasmacytic proliferations developing in the context of immunosuppression in a recipient of a solid organ or stem cell allograft. The group includes non-destructive post-transplant lymphoproliferative disorders (PTLDs), polymorphic PTLD, monomorphic PTLDs, and classic Hodgkin lymphoma PTLD. Patients may have more than one type of PTLD in a single or in different locations. The most commonly involved sites are lymph nodes, gastrointestinal tract, lungs, and liver, although the disease may occur almost anywhere in the body. In solid organ transplant recipients, PTLD may also involve the allograft.", "ORPHA ID": 70568, "Summary": ""}
{"Disease Name": "Post-traumatic pituitary deficiency", "Disease Definition": "A rare, acquired, endocrine disorder characterized by deficiency of one or more of the pituitary hormones resulting as a consequence of traumatic or medically-induced injury of the pituitary gland. Clinical presentation is variable depending on the nature and acuity of the injury and the resulting order and amount of hormone deficiency.", "ORPHA ID": 95619, "Summary": ""}
{"Disease Name": "Postaxial acrofacial dysostosis", "Disease Definition": "A rare acrofacial dysostosis that is characterized by mandibular and malar hypoplasia, small and cup-shaped ears, lower lid ectropion, and symmetrical postaxial limb deficiencies with absence of the fifth digital rays and ulnar hypoplasia.", "ORPHA ID": 246, "Summary": "Epidemiology\nLess than 30 cases of Postaxial acrofacial dysostosis (POADS) have been described in the literature.\nClinical description\nClinical features further include cholestasis, bilateral inguinal hernia and cleft palate. The patients can develop myopic astigmatism and speech delay can be present. Facial features include sparse eyebrows, almond shaped eyes with up-slanting palpebral fissures, malar hypoplasia, long philtrum, small mouth, and low-set, malformed ears.\nEtiology\nThe disease arises from biallelic gene mutations for the enzyme dihydroorotate dehydrogenase (DHODH, 16q22.2), involved in pyrimidine biosynthesis. Nonetheless, despite demonstrated loss of enzyme activity, dihydroorotate (DHO) has not been shown to accumulate.\nDiagnostic methods\nDHODH mutations can be determined by PCR and Sanger sequencing. Analysis of DHO and orotic acid (OA) in urine, plasma and blood-spot test can be performed using liquid chromatography-tandem mass spectrometry.\nDifferential diagnosis\nThe clinical phenotype of Miller syndrome overlaps with mandibulofacial and other acrofacial dysostosis syndromes including Treacher Collins, Guion-Almeida (mandibulofacial dysostosis with microcephaly) and Nager syndromes.\nAntenatal diagnosis\nDue to postaxial oligodactyly of fingers and toes, the diagnosis can be established prenatally on clinical grounds and confirmed by molecular testing.\nGenetic counseling\nInheritance appears to be autosomal recessive. For parents of an affected individual, there is a 25% risk of having and affected child at each pregnancy. Recurrence risk for children of an affected individual is low if there is no consanguinity.\nManagement and treatment\nThe patients do not usually need surgical treatment, but sometimes need hearing aids. Logopedic treatment might be helpful.\nPrognosis\nThere is usually no reduced life expectancy, but intrauterine death has been described.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Dagmar WIECZOREK | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Postaxial polydactyly type A", "Disease Definition": "A rare congenital limb malformation characterized by duplication of the fifth digit in a hand or foot, with an extra, well-formed, functional digit at the metacarpophalangeal/metatarsophalangeal or carpometacarpal/tarsometatarsal joint. The malformation can be an isolated finding or be associated with a large number of other anomalies.", "ORPHA ID": 93334, "Summary": ""}
{"Disease Name": "Postaxial polydactyly type B", "Disease Definition": "A rare congenital limb malformation characterized by duplication of the fifth digit in a hand or foot, the sixth digit being rudimentary, poorly developed, and non-functional, frequently consisting of additional soft tissue on a pedicle. The anomaly can be unilateral or bilateral.", "ORPHA ID": 93335, "Summary": ""}
{"Disease Name": "Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome", "Disease Definition": "Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome is a rare, genetic developmental defect during embryogenesis disorder characterized primarily by congenital hypopituitarism and/or postaxial polydactyly. It can be associated with short stature, delayed bone age, hypogonadotropic hypogonadism, and/or midline facial defects (e.g. hypotelorism, mild midface hypoplasia, flat nasal bridge, and cleft lip and/or palate). Hypoplastic anterior pituitary and ectopic posterior pituitary lobe are frequent findings on MRI examination.", "ORPHA ID": 420584, "Summary": ""}
{"Disease Name": "Postaxial polydactyly-dental and vertebral anomalies syndrome", "Disease Definition": "Postaxial polydactyly-dental and vertebral anomalies syndrome is a rare, genetic, developmental defect during embryogenesis syndrome characterized by postaxial polydactyly and other abnormalities of the hands and feet (e.g. brachydactyly, broad toes), hypoplasia and fusion of the vertebral bodies, as well as dental abnormalities (fused teeth, macrodontia, hypodontia, short roots). There have been no further descriptions in the literature since 1977.", "ORPHA ID": 2916, "Summary": ""}
{"Disease Name": "Postaxial tetramelic oligodactyly", "Disease Definition": "Postaxial tetramelic oligodactyly is a rare, genetic, congenital limb malformation disorder characterized by isolated, postaxial oligodactyly in all four extremities. Patients present a consistent pattern of malformation ranging from complete absence of the 5th metacarpals, metatarsals and phalanges to complete absence of the 5th metacarpals and metatarsals, with some residual distal 5th phalanges. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 2730, "Summary": ""}
{"Disease Name": "Postcardiotomy right ventricular failure", "Disease Definition": "A rare cardiac condition characterized by acute severe right ventricular failure with subsequent hemodynamic instability following a cardiac surgical procedure. Predisposing factors include suboptimal myocardial protection during surgery, long cardiopulmonary bypass time, right ventricular myocardial ischemia or infarction, atrial arrhythmias, reperfusion lung injury with secondary pulmonary hypertension, post-operative pulmonary micro- or macro-embolism, and pre-existing pulmonary vascular disease, among others.", "ORPHA ID": 263352, "Summary": ""}
{"Disease Name": "Posterior amorphous corneal dystrophy", "Disease Definition": "Posterior amorphous corneal dystrophy (PACD) is a very rare form of stromal corneal dystrophy (see this term) characterized by irregular amorphous sheet-like opacities in the posterior corneal stroma and in Descemet membrane and mildly impaired vision.", "ORPHA ID": 98971, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is not known. To date cases have been reported primarily in the USA.\nClinical description\nPatients usually develop corneal abnormalities in infancy or childhood. The condition is non-progressive or slowly progressive. Visual acuity is usually only minimally affected but in some more severe cases, penetrating keratoplasty (PK) may be warranted. Unlike other corneal dystrophies, non-corneal manifestations have been observed and include abnormalities of the iris (iridocorneal adhesions, corectopia, and pseudopolycoria).\nEtiology\nThe etiology of the condition is not known but it is thought to be genetic. The chromosomal locus of the gene responsible for PACD has not been determined.\nDiagnostic methods\nOpacities are diffuse gray-white and sheet-like and can involve any layer of the stroma but are most prominent posteriorly. The lesions can be centroperipheral, extending to the limbus, or peripheral, the latter with less pronounced findings and symptoms. There are often transparent stromal breaks in the opacification.\nGenetic counseling\nAn autosomal dominant pattern of inheritance has been reported.\nManagement and treatment\nSince the entire stroma is involved, a penetrating kertopasty is indicated if visual impairment is clinically significant.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Posterior column ataxia-retinitis pigmentosa syndrome", "Disease Definition": "Posterior column ataxia - retinitis pigmentosa is characterized by the association of progressive sensory ataxia and retinitis pigmentosa.", "ORPHA ID": 88628, "Summary": "Epidemiology\nAround 20 cases have been described in the last 50 years.\nClinical description\nOnset of symptoms usually occurs in childhood. The clinical picture is progressive, homogenous and includes severe sensory ataxia, proprioceptive loss (affecting the iliac crest, upper limbs and thorax), generalized areflexia and diffuse pigmentary retinopathy leading to blindness. Scoliosis, camptodactyly, achalasia and/or gastrointestinal motility dysfunction may also be present.\nEtiology\nThe disease is associated with degeneration of the posterior column of the spinal cord. The causative gene, FLVCR1 (1q32.3), has been identified and localized to the AXPC1 locus (1q32-q31).\nGenetic counseling\nTransmission is autosomal recessive or pseudodominant.\nPrognosis\nThe disease evolves progressively, in some cases leading to a total loss of walking ability and vision after 10 to 30 years of progression.\n\n                            Last update: \n                            May 2011"}
{"Disease Name": "Posterior corneal dystrophy", "Disease Definition": "Posterior corneal dystrophies refers to a group of rare genetically determined corneal dystrophies (CDs) characterized by lesions affecting the corneal endothelium and Descemet membrane, and variable effects on vision depending on the type of dystrophy.", "ORPHA ID": 98627, "Summary": "Epidemiology\nPrevalence of this group of corneal dystrophies is unknown.\nClinical description\nAge of onset is variable. Five subtypes of posterior CD have been identified and include: Fuchs endothelial CD, Posterior polymorphous CD, Congenital hereditary endothelial dystrophy I and II, and X-linked endothelial CD (see these terms).\nEtiology\nPosterior corneal dystrophies, like other corneal dystrophies, appear to be genetic disorders. Although the various subtypes have mostly been described in detail, a relationship between some of them has been suggested on the basis of molecular genetic data. There is both phenotypic and allelic heterogeneity. Mutations in the following genes have been found in association with posterior CD: COL8A2 (1p34.2-p32.3), SLC4A11 (20p12), VSX1 (20p11.21), and ZEB1 (10p11.22).\nGenetic counseling\nTransmission is autosomal dominant or recessive, or X-linked recessive depending on the type.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Posterior cortical atrophy", "Disease Definition": "A rare neurologic disease characterized by impairment of higher visual processing skills and other posterior cortical functions without any evidence of ocular abnormalities, relatively intact memory and language in the early stages, and atrophy of posterior brain regions.", "ORPHA ID": 54247, "Summary": "Epidemiology\nPosterior Cortical Atrophy (PCA) prevalence is unknown, largely due to the lack of awareness of the syndrome, delayed diagnosis and the variable terminology referring to it (now partially addressed through international consensus criteria).\nClinical description\nEarly PCA symptoms include visuoperceptual and visuospatial dysfunction, apraxia and alexia. Features of Bálint syndrome (simultanagnosia, optic ataxia and oculomotor apraxia) and Gerstmann syndrome (acalculia, agraphia, finger agnosia and left-right disorientation) are commonly described. The disorder typical onset is between 50-65 years of age. Earliest reported symptoms include difficulties with complex visual behaviors (e.g. driving, reading, and telling the time from an analogue watch). Reading problems include getting lost on the page (visual disorientation), overlapping or miscombined letters (visual crowding) or better reading of small than large print. Odd visual manifestations like abnormally prolonged color after-images and perception of movement of static stimuli are also reported. People with PCA tend to have relatively well preserved memory, insight, and judgment early in the disease course, athough language problems (word finding problems, phonological errors) often emerge early. It should also be noted that PCA is a relatively heterogenous syndrome with some experiencing a very focal visual syndrome, whilst others show a more mixed cognitive picture with prominent visual but also evident episodic memory deficits from early in the disease course. Individuals with PCA often experience anxiety and depression from early on. Extrapyramidal signs, myoclonus, and grasp reflex have also been reported in PCA patients. An international consensus classification framework distinguishes two syndromic description levels. Classification 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present.\nEtiology\nA third level of the international classification framework provides disease-level descriptions of the underlying causes of the PCA syndrome, based on available pathophysiological biomarker evidence. This distinguishes between Alzheimer's disease as the most common underlying pathology (PCA-AD), and other causes including Lewy Body disease (PCA-LBD), corticobasal degeneration (PCA-CBD) and prion disease (PCA-prion).\nDiagnostic methods\nPCA is an under-recognized disorder resulting often in a significant delay in diagnosis. Diagnosis of this clinico-radiological syndrome is based on neurological assessment, specific visual and cognitive testing, and (optional supportive) brain imaging and routine blood tests. MRI characteristically shows bilateral atrophy in the occipital, parietal and posterior temporal lobes, often asymmetric being more pronounced in the right hemisphere. Single photon emission computed tomography (SPECT) or PET show hypometabolism of the posterior cerebral areas as well as in the frontal eye fields in more advanced stages. Conclusive diagnosis of the underlying disease is confirmed on brain autopsy, though CSF and amyloid imaging may help to refine the clinical diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes the most commonly associated neuropathology Alzheimer disease, but may also include Lewy body disease, cortico-basal degeneration, and prion diseases such as Creutzfeldt-Jakob disease.\nManagement and treatment\nThere is currently no cure for any of the neurodegenerative conditions that most commonly underly the PCA syndrome. Medications like acetylcholinesterase inhibitors, used in the treatment of Alzheimer's disease, are available and might bring relief for some symptoms. Management of PCA is based on visual aids, rehabilitation programs that include psychoeducation, compensatory strategies, and cognitive exercises to cope with visual disabilities. Antidepressant treatments may benefit individuals with PCA who have relatively preserve insight into their decline and often deal with depression, irritability, frustration and a loss of self-confidence. People with PCA and their caregivers are likely to have different needs to people with more typical presentations of Alzheimer's disease, and may benefit from specialized support groups.\nPrognosis\nPrognosis is poor as PCA is progressive disorder. Life expectancy after PCA diagnosis is thought to be similar (8-12 years) to individuals affected with Alzheimer's disease.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Sebastian CRUTCH"}
{"Disease Name": "Posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome", "Disease Definition": "A rare syndrome characterized by congenital ptosis and posterior fusion of the lumbosacral vertebrae. It has been described in a mother and her two daughters.", "ORPHA ID": 2064, "Summary": ""}
{"Disease Name": "Posterior polymorphous corneal dystrophy", "Disease Definition": "A rare mild subtype of posterior corneal dystrophy characterized by small aggregates of apparent vesicles bordered by a gray haze at the level of Descemet membrane, generally with no effect on vision.", "ORPHA ID": 98973, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is unknown.\nClinical description\nLesions generally develop in early childhood and are mostly bilateral but may be asymmetrical or unilateral in some cases. Most patients are asymptomatic with no corneal edema, but progressive visual impairment due to stromal clouding may rarely occur.\nEtiology\nPPCD is a genetically heterogenous condition with extremely variable expression. Three genes have been implicated: VSX1 (20p11.21), COL8A2 (1p34.2-p32.3), and ZEB1 (10p11.22), but the evidence implicating VSX1 and COL8A2 is questionable.\nDiagnostic methods\nMultiple layers of collagen manifesting as focal fusiform or nodular excrescences are found on the posterior surface of Descemet membrane.\nDifferential diagnosis\nPPCD should be distinguished from congenital endothelial dystrophy type 1 (CHED1, see this term), since the two conditions share certain morphological and clinical features.\nGenetic counseling\nAn autosomal dominant pattern of inheritance has been reported.\nManagement and treatment\nMost patients with PPCD do not require therapy, but some may eventually require a penetrating keratoplasty or a procedure for repairing the posterior surface of the cornea, such as a deep lamellar endothelial keratoplasty (DLEK), Descemet stripping endothelial keratoplasty (DSEK), or Descemet stripping automated endothelial keratoplasty (DSAEK).\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Posterior urethral valve", "Disease Definition": "A rare, congenital, fetal lower urinary tract obstruction (LUTO) anomaly characterized by an abnormal congenital obstructing membrane or leaflets that are located within the posterior urethra associated with significant obstruction of the male bladder restricting normal bladder emptying.", "ORPHA ID": 93110, "Summary": "Epidemiology\nIt is the most common anomaly of LUTO with a prevalence estimated at 1/4,750-6,250 male births. Posterior urethral valves (PUV) occur exclusively in males.\nClinical description\nPUV represents a spectrum of severity ranging from a disease fatal in infancy to a disease that is minimal and may not manifest until later in life. In the most severe cases, characterized by antenatal oligohydramnios or anhydramnios, the newborn may presents with severe pulmonary distress and features of Potter sequence including wide-set eyes, flattened nose, receding chin and large, low-set ears deficient in cartilage. In toddlers and older children PUV may present with urinary incontinence, poor growth, urinary tract infections, hypertension, lethargy and ultimately renal failure.\nEtiology\nThe embryology of the urethra is not completely understood, particularly as it pertains to pathologic anomalies. Several different theories have been proposed in the development of PUV. It represents a spectrum of severity based on the timing and severity of obstruction. Congenital obstruction of the urinary tract at a critical time in organogenesis has a profound and lifelong effect on kidney, ureteral and bladder function. The inability of urine to pass out of the body of the fetus results in oligohydramnios which in turn may lead to pulmonary hypoplasia and the features of Potter sequence.\nDiagnostic methods\nPostnatal diagnosis is suggested on renal ultrasound with findings of dilated, thick-walled bladder and a dilated posterior urethra. Postnatal diagnosis is confirmed with voiding cystotourethrography and cystoscopy.\nDifferential diagnosis\nDifferential diagnoses include anterior urethral valves, congenital urethral stricture, urethral atresia and Prune Belly syndrome. The diagnosis is then confirmed by postnatal physical examination and postnatal renal ultrasonography along with voiding cystourethrography.\nAntenatal diagnosis\nAntenatal diagnosis is based on ultrasound, possibly aided by magnetic resonance imaging studies. PUV is characterized by variably enlarged thick-walled, non-emptying urinary bladder and a dilated posterior urethra. Counseling is dependent upon the ultrasound findings that also suggest possible associated renal dysplasia at the time of prenatal diagnosis.\nGenetic counseling\nThe majority of cases occur sporadically; however, some rare cases observed in siblings indicate autosomal recessive or x-linked recessive inheritance.\nManagement and treatment\nAntenatal treatment involves urinary decompression with a vesico-amniotic shunt. Postnatally, PUV is treated using primary valve ablation or creation of a vesicostomy. Further surgical intervention is dependent on the status of the bladder function as well as renal function. Immediately after birth, infants are placed on antibiotic prophylaxis and a means of draining their bladder is accomplished using suprapubic or transurethral catheter diversion. Pulmonary function is assessed and fluid and electrolyte management performed.\nPrognosis\nThe prognosis of PUV is variable depending on the degree of severity of the LUTO. Patients may be susceptible to urinary incontinence, urinary tract infections and progressive renal damage. Approximately one third of patients born with PUV progress to end stage renal disease and all patients need periodic long-term urologic follow-up care. Without intervention, patients are at risk of renal failure and bladder dysfunction. Fertility may be compromised in patients who are uremic.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Yazan RAWASHDEH | EUROGEN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Posterior-predominant lissencephaly-broad flat pons and medulla-midline crossing defects syndrome", "Disease Definition": "A rare genetic syndrome with a central nervous system malformation as a major feature, characterized by cortical malformations including posterior predominant lissencephaly and diffuse pachygyria, as well as midline crossing defects, thin corpus callosum, dysplastic hippocampi, narrowing of the brainstem with small pons and midbrain, widening of the medulla, and small cerebellum. Clinically, patients present global developmental delay, severe intellectual disability with poor or absent speech, axial hypotonia, and early-onset seizures, among others.", "ORPHA ID": 572013, "Summary": ""}
{"Disease Name": "Postinfectious vasculitis", "Disease Definition": "Vasculitis, characterized by inflammatory lesions in the wall of vessels, may be due to different viruses.", "ORPHA ID": 48435, "Summary": "Clinical description\nCMV induces vasculitis mainly in immunocompromised patients. Lesions may be cerebral, retinal, colonic, radicular... In less common cases, vasculitis affects immunocompetent patients, thus resembling polyarteritis nodosa (PAN) or cutaneous angiitis. Varicella-Zoster virus (VZV) is responsible for two types of vasculitides which are sometimes associated: · a vasculitis affecting large arteries which usually affects the anterior cerebral circulation and is characterized by an acute focal deficit. Most often it occurs in immunocompetent adults after zoster of trigeminal distribution. · a vasculitis affecting small cerebral vessels occurring in immunocompromised individuals and is responsible for multifocal deficit. VZV vasculitis can appear a few months after rash or even without any rash. HIV is responsible for a protean group of vasculitides. Vessels of all sizes may be affected and histological findings are variable. Nevertheless a particular form consists in a necrotizing vasculitis of the aorta and large arteries (resembling Takayasu's arteritis) with aneurysm formation and risk of rupture. Parvovirus B19 has been incriminated in some cases of PAN, cutaneous and placenta angiitis or pseudo Henoch-Schönlein purpura. Other case reports mention vasculitis related to hepatitis A virus, HTLV1 (Human T-cell Leukemia Virus 1), EBV (Epstein-Barr virus) persistent infection, Hantaan virus.\nEtiology\nPathophysiology is partially misunderstood. However, mechanisms including direct injury by the virus or vascular damage resulting from immune reaction are incriminated. For instance, endothelial infection by CMV (cytomegalovirus) seems to play a major role in the occurrence of a vasculitis. Immune complexes, associating an immunoglobulin and a viral antigen, can lead to vasculitis because of the activation of complement and inflammatory cells. Few virus are thought to be responsible for vasculitis even though their triggering role is not always easily confirmed.\nManagement and treatment\nTreatment is based on antiviral agents. Corticotherapy and immunosuppressants are very controversial because of the risk of virus replication. A least, for some authors, adjuvant treatment with immunoglobulins or plasma exchange may be helpful.\n\n                            Last update: \n                            September 2003"}
{"Disease Name": "Postnatal microcephaly-infantile hypotonia-spastic diplegia-dysarthria-intellectual disability syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by postnatal microcephaly, hypotonia during infancy followed in most cases by progressive spasticity mainly affecting the lower limbs, and spastic diplegia or paraplegia, intellectual disability, delayed or absent speech, and dysarthria. Seizures and mildly dysmorphic features have been described in some patients.", "ORPHA ID": 477673, "Summary": ""}
{"Disease Name": "Postorgasmic illness syndrome", "Disease Definition": "Postorgasmic illness syndrome is a rare urogenital disease characterized by the appearance of flu-like symptoms (fever, extreme fatigue, myalgia, itchy burning eyes, nasal congestion/rhinorrhea), as well as mood changes, irritability and concentration, memory and attention difficulties, within a few minutes to a few hours after ejaculation. Symptoms disappear spontaneously 3-7 days after onset.", "ORPHA ID": 279947, "Summary": ""}
{"Disease Name": "Postpartum psychosis", "Disease Definition": "A rare gynecologic or obstetric disease characterized by an abrupt onset of psychiatric symptoms during the first weeks after childbirth. Clinical features include mood changes, depression, anxiety, delusions, and hallucinations, among others. The disease is associated with a risk of suicide or infanticide, as well as an increased risk for recurrence after the next pregnancy and future non-pregnancy related psychotic episodes.", "ORPHA ID": 443173, "Summary": ""}
{"Disease Name": "Postpoliomyelitis syndrome", "Disease Definition": "Postpoliomyelitis syndrome (PPS) is a neurologic disorder characterized by the development of new neuromuscular symptoms such as progressive muscular weakness or abnormal muscle fatigability occurring in survivors of the acute paralytic form of poliomyelitis (see this term), 15-40 years after recovery from the disease, and that is unexplained by other medical causes. Other manifestations that can occur gradually include generalized fatigue, muscle atrophy, muscle and joint pain, intolerance to cold, and difficulties sleeping, swallowing or breathing.", "ORPHA ID": 2942, "Summary": ""}
{"Disease Name": "Posttransplant acute limbic encephalitis", "Disease Definition": "Posttransplant acute limbic encephalitis is a rare, acquired, non-paraneoplastic limbic encephalitis disorder, that develops in the setting of treatment-related immunosuppression, typically after allogeneic hemapoietic stem cell transplantation, characterized by onset of confusion, headache, anterograde amnesia, seizures and/or loss of consciousness 2-6 weeks following transplantation. Bilateral, non-enhancing T2 hyperintensities in limbic structures are observed on magnetic resonance imaging. Mild cerebrospinal fluid pleocytosis and syndrome of inappropriate antidiuretic hormone secretion may also be associated.", "ORPHA ID": 163921, "Summary": ""}
{"Disease Name": "Postural orthostatic tachycardia syndrome due to NET deficiency", "Disease Definition": "A rare, genetic, primary orthostatic disorder characterized by dizziness, palpitations, fatigue, blurred vision and tachycardia following postural change from a supine to an upright position, in the absence of hypotension. A syncope with transient cognitive impairment and dyspnea may also occur. The norepinephrine transporter deficiency leads to abnormal uptake and high plasma concentrations of norepinephrine.", "ORPHA ID": 443236, "Summary": ""}
{"Disease Name": "Potassium-aggravated myotonia", "Disease Definition": "A muscular channelopathy presenting with a pure myotonia dramatically aggravated by potassium ingestion, with variable cold sensitivity and no episodic weakness. This group includes three forms: myotonia fluctuans, myotonia permanens, and acetazolamide-responsive myotonia.", "ORPHA ID": 612, "Summary": "Epidemiology\nThese diseases are very rare and their prevalence is unknown.\nClinical description\nMyotonia develops during childhood or adolescence and is, by definition, aggravated by potassium ingestion. Cold sensitivity is not systematic but when present, it can be of varying severity. Myotonia is rarely associated with attacks of weakness. Some patients describe a warm-up phenomenon while others report an exacerbation with exercise. Myalgias and cramps are frequent. Intensity and topography of myotonic symptoms may vary. In myotonia fluctuans, episodes of stiffness vary in severity and frequency, and occur during the resting period following exercise. In myotonia permanens, myotonia is continuous and severe and can significantly impair respiration. In acetazolamide-responsive myotonia, stiffness is often painful and myotonia is triggered by fasting and mildly by exercise and cold exposure.\nEtiology\nPAM is a sodium muscle channelopathy due to missense mutations of the SCN4A gene encoding the alpha subunit of the skeletal muscle voltage-gated sodium channel Nav1.4.\nDiagnostic methods\nDiagnosis is based on clinical history, physical exam, electromyographic (EMG) and genetic tests. EMG features comprise myotonic discharges and normal responses to the provocative tests (repeated short exercise tests with and without cooling). CPK levels vary depending on myotonia severity.\nDifferential diagnosis\nDifferential diagnoses include myotonia congenita (see this term), and cold sensitive myotonias such as paramyotonia congenita and hyperkalemic periodic paralysis with paramyotonia.\nGenetic counseling\nTransmission is autosomal dominant. Genetic counseling should be offered to affected families informing them of the 50% risk that the child of an affected parent has of inheriting the disease-causing mutation.\nManagement and treatment\nManagement of patients consists in medical therapy and avoidance of triggering factors (such as potassium-rich food). Mexiletine or carbamazepine is the treatment of choice except in acetazolamide-responsive myotonia where symptoms dramatically improve with acetazolamide. Physical therapy management with massages and stretching may be useful for pain and retractions. In each condition, close monitoring is necessary during surgery. Depolarizing agents can cause severe ventilation problems due to a paradoxical increase of stiffness in respiratory muscles and must be avoided.\nPrognosis\nPrognosis is good with stability of symptoms during life but respiratory function may be compromised in severe myotonia permanens.\n\n                            Last update: \n                            October 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Savine VICART"}
{"Disease Name": "Potocki-Shaffer syndrome", "Disease Definition": "A rare partial autosomal monosomy characterized by global developmental delay, intellectual disability, multiple cartilaginous exostoses, and craniofacial anomalies (such as brachycephaly, biparietal foramina, large fontanels, craniosynostosis, ptosis, epicanthic folds, prominent nasal bridge with broad, depressed nasal tip, hypoplastic nares, short philtrum, downturned upper lip, and micrognathia). Additional reported features include behavioral abnormalities, myopia, strabismus, and sensorineural hearing loss, among others.", "ORPHA ID": 52022, "Summary": ""}
{"Disease Name": "Pouchitis", "Disease Definition": "A rare intestinal disease characterized by non-specific inflammation of the ileal reservoir following ileal pouch anal anastomosis surgery. It generally occurs after the restoration of the fecal stream through the pouch and may be classified as acute or chronic, depending on the symptom duration (less or more than 4 weeks). Clinical presentation is variable and unspecific and commonly includes increased stool frequency and fluidity, rectal bleeding, abdominal cramps, bowel urgency, tenesmus, and nocturnal bowel incontinence.", "ORPHA ID": 217067, "Summary": ""}
{"Disease Name": "PPARG-related familial partial lipodystrophy", "Disease Definition": "A rare familial partial lipodystrophy characterized by adult onset of distal lipoatrophy with gluteofemoral fat loss, as well as increased fat accumulation in the face and trunk and visceral adiposity. Additional manifestations include diabetes mellitus, atherogenic dyslipidemia, eyelid xanthelasmas, arterial hypertension, cardiovascular disease, hepatic steatosis, acanthosis nigricans on axillae and neck, hirsutism, and muscular hypertrophy of the lower limbs.", "ORPHA ID": 79083, "Summary": ""}
{"Disease Name": "PPoma", "Disease Definition": "PPoma is a type of pancreatic endocrine tumor (see this term) that hypersecretes pancreatic polypeptide (PP) but that does not cause a hypersecretion syndrome (is non-functioning) and instead presents with only non-specific symptoms such as weight loss, abdominal pain, jaundice, diarrhea and/or an abdominal mass, hence leading to a late diagnosis. PPoma can be associated with multiple endocrine neoplasia 1 (MEN-1; see this term).", "ORPHA ID": 97278, "Summary": ""}
{"Disease Name": "Prader-Willi syndrome", "Disease Definition": "A rare genetic, neurodevelopmental syndrome characterized by hypothalamic-pituitary dysfunction with severe hypotonia and feeding deficits during the neonatal period followed by an excessive weight gain period with hyperphagia with a risk of severe obesity during childhood and adulthood, learning difficulties, deficits of social skills and behavioral problems or severe psychiatric problems.", "ORPHA ID": 739, "Summary": "Epidemiology\nPrevalence at birth is estimated at 1/15,000-30,000 worldwide\nClinical description\nThe severe hypotonia at birth is associated with poor oral and social skills which remain, albeit less clinically evident, throughout life. Characteristic facial features (a narrow forehead, almond-shaped eyes, a thin upper lip and down-turned mouth), as well as very small hands and feet, are frequently observed. After this initial phase, followed by an excessive weight gain without changes in eating, the most striking signs appear: hyperphagia and absence of satiety often leading to severe obesity in affected children as young as three years of age. The situation may deteriorate quickly without strict control of food access. Other associated endocrine abnormalities include short stature due to a growth hormone (GH) deficiency, incomplete pubertal development due to hypogonadism of mixed (central and peripheral) origin, hypothyroidism, premature pubarche and, rarely, corticotropin deficiency. The degree of cognitive dysfunction varies widely but is mild/moderate in most of the individuals. It is associated with learning disabilities, and impaired speech and language development that are aggravated further by psychological and behavioral troubles, impaired social abilities, and control of emotions. Associated comorbidities may include diabetes, sleep-related breathing disorders, gastrointestinal problems, and infections. The Prader-Willi syndrome (PWS) phenotype also occurs in 10% of Fragile X syndrome.\nEtiology\nThe disease is clinically and genetically heterogeneous. Frequently it is caused by either a paternally derived 15q11-q13 deletion, maternal disomy or, very rarely, imprinting defects in the same region.\nDiagnostic methods\nPWS should be suspected on the presentation of severe neonatal hypotonia, and confirmed by genetic testing which should include methylation analysis, fluorescent in situ hybridization and uniparental disomy testing.\nDifferential diagnosis\nAt birth, genetic testing should be used to exclude other causes of hypotonia. If the neonatal phenotype evokes PWS and the genetics are negative, genes for the Prader-Willi-like syndrome (PWS-like) should be searched. In older individuals, the differential diagnosis is of other syndromic obesities such as Bardet-Biedl syndrome, Alström syndrome and, particularly, PWS-like.\nAntenatal diagnosis\nDiagnosis may be suspected in the last trimester on detection of polyhydramnios, decreased fetal movements and abnormal positions of hand and feet with or without fetal growth restriction. Genetic testing can confirm diagnosis but note that comparative genomic hybridization is not sufficient to exclude PWS.\nGenetic counseling\nMost cases are sporadic; however, in rare cases dominant transmission may occur with 50% risk where the father carries the imprinting defect.\nManagement and treatment\nMultidisciplinary management should be implemented very early, with particular attention paid to families with psychosocial difficulties. Principally, management is with a strict control of food access and exercise program and, growth hormone (GH) treatment. Associated comorbidities require systematic screening and evaluation. Currently, there are no approved medications to specifically improve the behavioral problems or degree of autonomy obtained. Clinical trials are ongoing for various drugs targeting hyperphagia and behavior.\nPrognosis\nObesity is a major factor influencing morbidity and mortality. Early diagnosis, early multidisciplinary care and GH treatment have greatly improved the quality of life of affected children. GH treatment in particular has shown to stabilize body mass index, improve linear growth and adult height and, in children treated before 1 year of age, improve cognitive development. Adolescents benefit from continuing GH treatment. Adults who have received GH as children have lower BMI and less comorbidities. Autonomies can be reached but not complete autonomy.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Gwenaëlle DIENE  - Pr Maithé TAUBER"}
{"Disease Name": "Prader-Willi-like syndrome", "Disease Definition": "A rare group of multiple congenital anomalies/dysmorphic syndrome characterized by autism spectrum disorder, developmental delay, intellectual disability, hyperphagia/obesity, and short stature (clinical features overlapping with Prader-Willi syndrome). However, it is a clinically and genetically heterogenous group where patients may completely lack or manifests in minority some classical clinical features of Prader-Willi syndrome such as short stature, hypotonia, hypogonadism, hyperphagia and morbid obesity.", "ORPHA ID": 398073, "Summary": ""}
{"Disease Name": "Pre-Descemet corneal dystrophy", "Disease Definition": "Pre-Descemet corneal dystrophy (PDCD) is a rare form of stromal corneal dystrophy characterized by focal, fine, gray opacities in the deep stroma immediately anterior to the Descemet membrane, with no effect on vision.", "ORPHA ID": 293462, "Summary": "Epidemiology\nThe prevalence of this rare entity is unknown.\nClinical description\nOnset is usually after 30 years of age but cases have been reported in children as young as 3 years of age. Opacities have a variety of shapes. Large lesions can occur. The rest of the cornea is normal. Various subforms appear to exist but are not clearly defined. Most show progression, while the punctiform and polychromatic pre-Descemet subform is non-progressive.\nEtiology\nThe etiology is unknown; it is unclear whether PDCD is a hereditary or a degenerative disorder.\nGenetic counseling\nNo defnite pattern of inheritance has been identified.\nManagement and treatment\nThe deep corneal stroma and Descemet membrane can be stripped. The epithelium and superficial corneal stroma should not be excised.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Preaxial polydactyly-colobomata-intellectual disability syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, growth retardation, unilateral preaxial polydactyly, and colobomatous anomalies (including coloboma of the iris, optic nerve head, choroid, and retina). There have been no further descriptions in the literature since 1987.", "ORPHA ID": 2921, "Summary": ""}
{"Disease Name": "Precursor B-cell acute lymphoblastic leukemia", "Disease Definition": "A rare acute lymphoblastic leukemia characterized by infiltration of bone marrow and peripheral blood by small to medium-sized blast cells typically positive for the B-cell markers CD19, cCD79a, and cCD22. Predilection sites for extramedullary involvement are the central nervous system, lymph nodes, spleen, liver, and testes. Patients present with evidence of bone marrow failure (i. e. thrombocytopenia, anemia, and/or neutropenia) and variable leukocyte count, as well as lymphadenopathy, hepatomegaly, splenomegaly, bone pain, and arthralgias.", "ORPHA ID": 99860, "Summary": ""}
{"Disease Name": "Precursor T-cell acute lymphoblastic leukemia", "Disease Definition": "A rare acute lymphoblastic leukemia characterized by a neoplasm of lymphoblasts committed to the T-cell lineage, involving bone marrow and blood. A value of >25% bone marrow blasts may be used to define leukemia (as opposed to lymphoma) in cases with the presence of a mass lesion in addition to bone marrow involvement. Patients typically present with leukocytosis, and frequently with a large mediastinal or other tissue mass. Lymphadenopathy and hepatosplenomegaly are common.", "ORPHA ID": 99861, "Summary": ""}
{"Disease Name": "Predisposition to invasive fungal disease due to CARD9 deficiency", "Disease Definition": "A rare, genetic primary immunodeficiency characterized by increased susceptibility to fungal infections, typically manifesting as recurrent, chronic mucocutaneous candidiasis, systemic candidiasis with meningoencephalitis, and deep dermatophystosis with dermatophytes invading skin, hair, nails, lymph nodes, and brain, resulting in erythematosquamous lesions, nodular subcutaneous or ulcerative infiltrations, severe onychomycosis, and lymphadenopathy.", "ORPHA ID": 457088, "Summary": ""}
{"Disease Name": "Predisposition to severe viral infection due to IRF7 deficiency", "Disease Definition": "A rare primary immunodeficiency characterized by a severe, potentially life-threatening course of influenza A infection with acute respiratory distress. Production of type I and III interferons in response to influenza virus is very low, while other immunological abnormalities are absent and no further unusual viral infections occur.", "ORPHA ID": 574918, "Summary": ""}
{"Disease Name": "Preeclampsia", "Disease Definition": "A hypertensive disorder of pregnancy that is characterized by new-onset hypertension with proteinuria presenting after 20 weeks of gestation, and depending on mild or severe forms may initially present with severe headache, visual disturbances, and hyperreflexia.", "ORPHA ID": 275555, "Summary": ""}
{"Disease Name": "Premature closure of the arterial duct", "Disease Definition": "Premature closure of the arterial duct is a rare arterial duct anomaly, defined as a significant constriction or closure of the fetal arterial duct in the absence of structural heart defects with pathognomonic features of increased right ventricular afterload, tricuspid regurgitation and, consequently, right atrial dilation and right ventricular hypertrophy. The severity of symptoms is related to the degree and rate of ductal constriction and ranges from mild postnatal respiratory distress to development of ventricular failure with fetal hydrops and intrauterine death or severe cardiopulmonary compromise in the postnatal period. It may be associated with a prenatal exposure to cyclooxygenase inhibitors or corticosteroids.", "ORPHA ID": 95486, "Summary": ""}
{"Disease Name": "Prenatal benign hypophosphatasia", "Disease Definition": "A very rare form of hypophosphatasia characterized by prenatal skeletal manifestations (limb shortening and bowing) that slowly resolve spontaneously and later may develop into the moderate childhood or adult forms of the disease.", "ORPHA ID": 247638, "Summary": "Epidemiology\nThe prevalence of prenatal benign hypophosphatasia (PB-HPP) is not known. About 50 cases have been reported to date.\nClinical description\nPB-HPP may be identified on prenatal ultrasound examination. Patients manifest variable limb shortening and bowing and often have dimples overlaying long bones deformities. Postnatally, skeletal manifestations slowly resolve and patients eventually develop manifestations corresponding to other, non-lethal forms of HPP (either childhood-onset, adult hypophosphatasia or odontohypophosphatasia). Patients display progressive improvement of the skeletal anomalies and mineralization during the third trimester of pregnancy and after birth. Mothers of affected infants generally have biochemical evidence of hypophosphatasia but no clinical manifestations.\nEtiology\nMutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The specific mechanisms underlying PB-HPP have not been elucidated.\nDiagnostic methods\nDiagnosis may be suspected pre- or postnatally on radiological and clinical presentation, respectively. However, it is likely that many patients go undiagnosed until later on when they present with another form of HPP (childhood, adult or odonto HPP). Genetic testing confirms the enzyme deficiency.\nDifferential diagnosis\nAntenatally, the main differential diagnoses include osteogenesis imperfect and perinatal lethal HPP. PB-HPP is differentiated from the perinatal lethal form by normal chest and abdominal circumference in utero and a benign post-clinical course.\nAntenatal diagnosis\nThe disorder may be suspected on prenatal ultrasound findings of limb bowing, limb shortening and/or skeletal hypomineralization. Chest and abdominal circumference are typically normal. A family history of hypophosphatasia and/or genetic testing support diagnosis.\nGenetic counseling\nAutosomal recessive and autosomal dominant patterns of inheritance have been reported, explaining the wide clinical spectrum. AD inheritance appears to be predictive of a benign course. A significant part of PB-HPP cases are dominantly inherited and seem to display a maternal bias of transmission, the fetus being affected only when the mutation is of maternal origin.\nManagement and treatment\nCesarean section may be indicated where diagnosis is not confirmed. Management is with observation. Enzyme replacement therapy with recombinant alkaline phosphatase may be indicated where skeletal manifestations persist.\nPrognosis\nThe prognosis is generally good.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Severine BACROT  - Dr Etienne MORNET"}
{"Disease Name": "Prenatal-onset spinal muscular atrophy with congenital bone fractures", "Disease Definition": "A rare genetic motor neuron disease characterized by decreased or absent fetal movements, congenital proximal and distal joint contractures (consistent with arthrogryposis multiplex congenita), and multiple congenital fractures of the long bones. Further manifestations are neonatal respiratory distress, severe muscular hypotonia, areflexia, dysphagia, congenital heart defects, and dysmorphic facial features. Muscle biopsy shows increased fiber-size variation and grouping of larger type I fibers. The disease is usually fatal in infancy due to respiratory failure.", "ORPHA ID": 486811, "Summary": ""}
{"Disease Name": "Prepubertal anorexia nervosa", "Disease Definition": "A rare neurologic disease with psychiatric involvement characterized by significantly lower-than-expected body weight due to voluntary reduction of food intake, intense fear of becoming overweight, and a distorted body image, in prepubescent children. Secondary manifestations include growth, developmental, and pubertal delay, decreased bone density, severe metabolic and endocrine dysfunction, cognitive impairment, depression, deterioration of academic or athletic performance, as well as difficulties in familial and peer relations, among others.", "ORPHA ID": 525738, "Summary": ""}
{"Disease Name": "Pressure-induced localized lipoatrophy", "Disease Definition": "Pressure-induced localized lipoatrophy is a rare, acquired, localized lipodystrophy characterized by band-like, horizontal, asymptomatic, lipoatrophic depressions with clinically normal overlying skin usually involving the anterolateral aspect of the thighs. An identifiable history of the repeated mechanical microtrauma due to occupational or postural habits is present.", "ORPHA ID": 90160, "Summary": ""}
{"Disease Name": "Primary acquired pure red cell aplasia", "Disease Definition": "A rare acquired aplastic anemia characterized by a severe normocytic anemia with normal peripheral leukocyte and platelet counts, reticulocytopenia, high serum ferritin and transferrin saturation levels and isolated, almost complete absence of erythroblasts in the bone marrow with normal granulopoesis and megakaryopoesis. It presents with signs of severe anemia (fatigue, lethargy, pallor, intolerance of physical exercise and exertional dyspnea) in the absence of hemorrhagic symptoms.", "ORPHA ID": 98872, "Summary": ""}
{"Disease Name": "Primary adult heart tumor", "Disease Definition": "A rare disorder that manifest in adults and generally present with a variety of non-specific manifestations (depending on tumor site and infiltration) such as weight loss, exhaustion, hemorrhagic pericardial effusion, heart failure, arrhythmias, and embolisms, or that can also be asymptomatic. In adults 75% of heart tumors are benign, with myxoma being the most common benign tumor (accounting for 50-70% of all primary heart tumors) and rhabdomyosarcoma comprising 75% of malignant heart tumors. Other malignant tumors of the heart include fibrosarcoma and leiomyosarcoma.", "ORPHA ID": 874, "Summary": ""}
{"Disease Name": "Primary anetoderma", "Disease Definition": "Primary anetoderma is a rare skin disease characterized by loss of elastin tissue resulting in localized areas of flaccid skin in the absence of a secondary cause.", "ORPHA ID": 228272, "Summary": ""}
{"Disease Name": "Primary angiitis of the central nervous system", "Disease Definition": "A rare, medium or small vessel vasculitis characterized by focal and/or diffuse neurologic symptoms due to a documented arteritic process in the central nervous system, in the absence of other identified underlying cause (infectious, systemic, other neurologic diseases, etc.). It presents with non-specific symptoms of headache, stroke or transient ischemic attacks with cognitive impairment, hemiplegia, weakness, and rarely, with cranial nerve involvement, seizures and ataxia.", "ORPHA ID": 140989, "Summary": "Epidemiology\nThe prevalence is unknown, but it is estimated to account for 1% of the systemic vasculitides.\nClinical description\nPrimary angiitis of the central nervous system (PACNS) usually affects middle-aged adults (mean age 51 years). Clinical presentation is variable, ranging from hyper acute to chronic and insidious, but typically has a progressive clinical evolution. The most common symptom is headache, variable in description but very rarely a thunderclap headache. Other symptoms include cognitive impairment (usually insidious), stroke (typically multiple, occurring over a (long) period and affecting different areas of the vascular bed) and transient ischemic attacks. Rarely, cranial nerve involvement, myelopathy, seizures or ataxia are observed. Associated angiographic abnormalities are common, cerebral MRI is almost invariably abnormal with nonspecific findings (including, rarely, solitary mass lesion), and cerebrospinal fluid (CSF) examination shows aseptic inflammatory abnormalities. Constitutional symptoms such as fever, weight loss and visceral organ involvement are rare and if present, should raise the suspicion of more systemic illnesses.\nEtiology\nThe primary defect is unknown. Pathological inflammation process affecting the small and medium-sized cerebral vessels causes them to become narrowed, occluded and thrombosed, leading to tissue ischemia and necrosis of the territories of the involved vessels.\nDiagnostic methods\nDiagnosis of PACNS is established in a patient who: (i) has a history of unexplained neurologic deficit after thorough clinical and laboratory evaluation, (ii) has a documented (by cerebral angiography and/or tissue examination) of an arteritic process within the central nervous system, and (iii) no evidence of systemic vasculitis or any other condition to which the angiographic or pathological features could be secondary. Angiography abnormalities encountered in PACNS are characterized by irregular eccentric notched appearance with distal cutoffs and neovascularization, and typically asymmetric involvement. CSF findings resemble those of an aseptic meningitis with modest lymphocytic pleocytosis, normal glucose levels, elevated protein levels and, occasionally, the presence of oligoclonal bands and elevated IgG synthesis.\nDifferential diagnosis\nDifferential diagnosis of PACNS is extensive and challenging, and comprises a range of systemic inflammatory conditions, infections, conditions with cerebral angiographic abnormalities (in particular, reversible vasoconstriction syndrome (RCVS) has highly similar clinical presentation; however, the associated headache is predominantly thunderclap by quality), and other neoplastic, genetic or neurological conditions.\nManagement and treatment\nGlucocorticoids combined with immunosuppressive agents, i.e. cyclophosphamide, has been successful in most cases. Accompanying prophylaxis for P. jirovecii and osteoporosis is necessary.\nPrognosis\nThe disease is chronic and relapses are not uncommon.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Xavier PUECHAL  - Pr Benjamin TERRIER"}
{"Disease Name": "Primary autoimmune enteropathy", "Disease Definition": "A rare intestinal disease characterized by immune-mediated injury of the intestinal mucosa, leading to severe, chronic, intractable diarrhea, malabsorption, and severe weight loss or failure to thrive. Characteristic histologic findings in the small intestine include partial or complete blunting of the villi, deep crypt lymphocytosis, increased crypt apoptosis, and minimal surface intraepithelial lymphocytosis. In addition, the stomach, colon, and esophagus may also be involved. Circulating autoantibodies against enterocytes and/or goblet cells are found in many, but not all, patients. The diagnosis requires exclusion of other causes of villous atrophy.", "ORPHA ID": 522037, "Summary": ""}
{"Disease Name": "Primary basilar invagination", "Disease Definition": "A rare skeletal developmental defect characterized by congenital upward translocation of the upper cervical spine and clivus into the foramen magnum. It can be asymptomatic or associated with severe neurological dysfunction.", "ORPHA ID": 2285, "Summary": ""}
{"Disease Name": "Primary biliary cholangitis", "Disease Definition": "A rare autoimmune cholestatic liver disease characterized by autoimmune mediated damage of small intrahepatic bile ducts leading to cholestasis, fibrosis, and potential cirrhosis.", "ORPHA ID": 186, "Summary": "Epidemiology\nPrimary biliary cholangitis (PBC) incidence rates range from 0.33 to 5.8 per 100,000 inhabitants/year and prevalence rates range from 1.91 to 40.2 per 100,000 inhabitants Women are predominantly affected with a sex ratio of 9:1.\nClinical description\nOnset is generally in the 4th to 6th decades of life. Many patients are asymptomatic at diagnosis and are identified incidentally. The initial presenting manifestations include fatigue (80%) and pruritus (20-70%), both of which fluctuate throughout the disease course. Pruritus is prominently on the palms and soles with worsening at night and can have significant impact on quality of life (occupational ability, depression, obsessive-compulsive disorder). Right upper quadrant discomfort is found less commonly. In late stages, xanthomas and xanthelasmas may develop. Osteopenia and osteoporosis with a risk of fractures are also found, along with hyperlipidemia, hypercholesterolemia, and vitamin deficiencies (vitamin A, D and rarely E). Complications related to cirrhosis include portal hypertension (with spider nevi, hyperpigmentation, palmar erythema, ascites, intra-abdominal varices), splenomegaly, muscle wasting, peripheral edema, and hepatocellular carcinoma. Neurological complications include impaired concentration and memory and disturbed sleep. Concomitant autoimmune disorders are common and include Sjögren's syndrome, CREST syndrome, autoimmune thyroid disease, rheumatoid arthritis and Raynaud syndrome, and often correlate with the autonomic dysfunction observed.\nEtiology\nThe liver damage is due to T-cell-mediated destruction of small bile duct epithelial cells causing ductopenia and persistent cholestasis. The exact etiology is currently unknown; however, it is currently believed to involve a combination of environmental factors (e.g. toxins, chemical substances, smoking and infectious agents), genetic predisposition and loss of immune tolerance.\nDiagnostic methods\nIn adult patients with cholestasis (elevated alkaline phosphatase (ALP) and/or gammaglutamyltransferase (GGT)), PBC can be suspected after excluding obstructive jaundice by abdominal ultrasound and systemic diseases. Diagnosis can be made when disease-specific autoantibodies are detected (i.e. antimitochondrial autoantibodies (AMA titer>1:40) and anti-nuclear autoantibodies (ANA) anti-sp100 and anti-gp210). A liver biopsy is recommended when PBC-specific antibodies are absent, autoimmune hepatitis (AIH) or non-alcoholic steatohepatitis (NASH) are suspected, or when other systemic co-morbidities are present and may have a role in the differential diagnosis of cholestasis.\nDifferential diagnosis\nDifferential diagnoses include autoimmune hepatitis, primary sclerosing cholangitis, alcoholic and non-alcoholic steatohepatitis and drug-induced hepatotoxicity.\nGenetic counseling\nWhilst a causal gene has not been identified, first-degree relatives have a higher risk of developing the disease.\nManagement and treatment\nThe aim of treatment is to reduce symptoms and slow disease progression. Ursodeoxycholic acid (UDCA) at dosage of 13-15 mg/kg/day is highly effective in improving transplant-free survival, although has limited effect in treating fatigue and pruritus. In patients with inadequate response (25%‐40%), obeticholic acid should be added. Response to UDCA is evaluated, after a period of 6 to 24 months of treatment, based on changes in bilirubin, transaminases and ALP. Patients with advanced disease should be screened for hepatocellular carcinoma, esophageal varices and considered for liver transplant (LT). Cholestyramine is the first line treatment for pruritus; for intolerant or refractory patients rifampin is indicated.\nPrognosis\nLT-free survival of patients with normal or near-normal liver biochemistry on UDCA is similar to that of the general population, whereas it is significantly reduced in those with abnormal liver biochemistry on treatment. After liver transplant, the recurrence of disease rate may be as high as 18 percent at five years, and up to 30 percent at 10 years. There is no consensus on risk factors for recurrence of the disease. HCC is infrequent in PBC; however, lack of UDCA-response after 12 months of therapy and male sex are associated with increased risk of developing HCC.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Marco CARBONE  - Dr Laura CRISTOFERI  - Dr Alessio GERUSSI  - Pr Pietro INVERNIZZI | RARE-LIVER*\n\n\n                                * European Reference Network"}
{"Disease Name": "Primary biliary cholangitis/primary sclerosing cholangitis and autoimmune hepatitis overlap syndrome", "Disease Definition": "A rare hepatic disease characterized by the overlap of primary biliary cholangitis and/or primary sclerosing cholangitis with autoimmune hepatitis, defined by the presence of at least two of the three recognized biochemical, serological, and histological criteria of each disease. The onset of the overlapping diseases can be simultaneous or sequential, with a variable interval of up to several years. Age of onset, gender predisposition, and clinical phenotype vary between each of the diseases, and the clinical presentation ranges from asymptomatic disease or unspecific symptoms such as fatigue, arthralgia, and pruritus, to established cirrhosis and decompensation, or also acute, fulminant hepatitis and liver failure. Association with extrahepatic autoimmune diseases is common.", "ORPHA ID": 562639, "Summary": ""}
{"Disease Name": "Primary bone lymphoma", "Disease Definition": "Primary bone lymphoma is a rare lymphoid hemopathy defined as single or multiple tumors in the bone, not associated with infringement or violation of other extranodal malignant lymph nodes outside the area. It usually presents with bone pain, nerve compression, a palpable mass or fracture, while systemic features (fever, night sweats, fatigue, loss of appetite, weight loss) are not common.", "ORPHA ID": 314684, "Summary": ""}
{"Disease Name": "Primary CD59 deficiency", "Disease Definition": "A rare, genetic, hematologic and neurologic disease characterized by chronic, Coombs-negative hemolysis associated with early-onset, relapsing, immune-mediated, inflammatory, axonal or demyelinating, sensory-motor, peripheral polyneuropathy and isolated or recurrent cerebrovascular events (in anterior or posterior circulation).", "ORPHA ID": 169464, "Summary": ""}
{"Disease Name": "Primary central nervous system lymphoma", "Disease Definition": "Primary central nervous system lymphoma (PCNSL) is a rare nervous system tumor, predominantly due to diffuse large B-cell lymphoma, that involves brain, leptomeninges, eyes, or rarely spinal cord, in the absence of systemic diffusion at the time of diagnosis. It is characterized by a solitary tumor that, depending on its location, can lead to a variety of symptoms such as headache, nausea, vomiting (and other signs of raised intracranial pressure), focal neurologic deficits, neuropsychiatric and ocular symptoms, seizures and personality changes.", "ORPHA ID": 46135, "Summary": ""}
{"Disease Name": "Primary ciliary dyskinesia-retinitis pigmentosa syndrome", "Disease Definition": "Primary ciliary dyskinesia - retinitis pigmentosa is an X-linked ciliary dysfunction of both respiratory epithelium and photoreceptors of the retina leading to ocular disorders (mild night blindness, constriction of the visual field, and scotopic and photopic ERG responses reduced to 30-60%) associated with primary ciliary dyskinesia (see this term) manifestations (chronic bronchorrhea with bronchoectasis and chronic sinusitis) and sensorineural hearing loss.", "ORPHA ID": 247522, "Summary": ""}
{"Disease Name": "Primary ciliary dyskinesia", "Disease Definition": "A rare, genetically heterogeneous, primarily respiratory disorder characterized by chronic upper and lower respiratory tract disease. Approximately half of the patients have an organ laterality defect (situs inversus totalis or situs ambiguus/heterotaxy).", "ORPHA ID": 244, "Summary": "Epidemiology\nPrimary ciliary dyskinesia (PCD) has an estimated incidence of 1/15,000-1/30,000 live births, but this is probably underestimation. Prevalence is difficult to determine.\nClinical description\nAffected patients develop signs of PCD at birth or within the first few months of life. However, owing to the diagnostic challenges, some cases of PCD are not diagnosed until the adulthood. Most full-term neonates have respiratory distress with tachypnea (infant acute respiratory distress syndrome) and usually require supplemental oxygen for days, some for weeks. The usual findings in infants and children are daily rhinitis, and daily year-round wet cough occurring soon after birth, with associated recurrent or chronic bacterial infections of the lower airways. Chronic otitis media is common, sometimes with temporary or permanent hearing loss and impaired speech development. Most patients have recurrent sinus infections. Bronchiectasis develops in an age-dependent manner, and is nearly universal in adults. Pectus excavatum and scoliosis have been reported rarely (5-10%), as well as digital clubbing. Almost all males with PCD are infertile, due to dysmotility of spermatozoa, although a few have normal sperm motility. Reduced fertility or a history of ectopic pregnancies has been reported in affected women. Situs inversus totalis, a mirror-image reversal of all visceral organs, is found in 40-50% of individuals and is known as the Kartagener type. Heterotaxy (discordance of right and left patterns of normally asymmetric structures) is present in at least 12%, and a subset of those have structural congenital heart disease. A very rare association of X-linked PCD with either retinitis pigmentosa or intellectual deficiency has been reported.\nEtiology\nPulmonary disease in PCD is related to defects in lung defense mechanisms due to abnormal ciliary structure and function with impaired mucociliary clearance. Mutations in around 46 different genes throughout the genome have been found to be causative. Some of these include DNAH5, CCDC39, DNAI1, CCDC40, DNAH11, ZMYND10, CCDC103, CCDC151 and ARMC4. A third of currently recognized patients do not have mutations in these genes.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical signs. Methods include molecular genetic testing identifying biallelic pathogenic variants (or hemizygous in males for X-linked genes, or mono-allelic for autosomal dominant trait) in one of the causative genes, as well as transmission electron microscopy identifying specific ciliary ultrastructural defects in biopsy samples. Other supportive tests include measurement of nasal nitric oxide in upper airways (in patients aged of 5 years or more) that tends to be low in PCD, after cystic fibrosis link has been ruled out, high-speed videomicroscopy to assess cilia waveform and beat frequency, immunofluorescent staining to study ciliary structure, and mucociliary clearance analysis to assess impairment.\nDifferential diagnosis\nThe main differential diagnoses are cystic fibrosis, immunodeficiency syndromes and gastroesophageal reflux. Additionally, PCD has been noted in patients with Cri du chat syndrome due to the common locus on chromosome 5p. Segmental deletion of chromosome 5p in Cri du chat syndrome usually includes PCD-associated gene DNAH5 and the pathogenic variant in the remaining allele of DNAH5 renders it to PCD.\nAntenatal diagnosis\nIf disease-causing mutations are known in a family, prenatal diagnosis can be performed using molecular analysis.\nGenetic counseling\nPCD is usually inherited in an autosomal recessive manner. Some cases with autosomal dominant and X-linked trait have been observed. Genetic counseling should be provided to affected families.\nManagement and treatment\nRegular clinical visits to monitor disease status are key. Aggressive treatment is recommended to improve mucus clearance. Antibiotic therapy is required and routine immunization is advised. Sinus disease can be treated with nasal steroids and nasal lavage. Polyps may require surgical treatment. Audiological assessment, hearing aids, and communication assistance should be offered where necessary. Patients with end-stage lung disease are candidates for lung transplantation.\nPrognosis\nThe prognosis depends on timely diagnosis and appropriate treatment. Life expectancy is likely somewhat shortened, although quantitative estimates are not currently available.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Michael KNOWLES  - Pr Maimoona ZARIWALA"}
{"Disease Name": "Primary condylar hyperplasia", "Disease Definition": "A rare temporomandibular joint anomaly characterized by progressive, asymmetrical, non-neoplastic overgrowth of a mandibular condyle. It is unilateral in most cases and leads to progressive facial asymmetry, mandibular deviation, articular dysfunction, and dental malocclusion.", "ORPHA ID": 477781, "Summary": ""}
{"Disease Name": "Primary congenital hypothyroidism without thyroid developmental anomaly", "Disease Definition": "Primary congenital hypothyroidism without thyroid developmental anomaly is a type of primary congenital hypothyroidism (see this term) in which the thyroid gland is anatomically normal.", "ORPHA ID": 95714, "Summary": "Epidemiology\nThyroid dyshormonogenesis accounts for 10-15% of permanent congenital hypothyroidism (see this term) while TSH receptor mutations cause less than 5%.\nEtiology\nIt may be caused by either resistance to thyroid stimulating hormone (TSH) as a result of TSH receptor mutations or by inborn errors of thyroid hormone synthesis, also known as thyroid dyshormonogenesis (see these terms), and it results in permanent thyroid hormone deficiency that is present from birth.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Primary congenital hypothyroidism", "Disease Definition": "Primary congenital hypothyroidism is a type of permanent congenital hypothyroidism (see this term), a permanent thyroid hormone deficiency that is present from birth.", "ORPHA ID": 226295, "Summary": "Epidemiology\nPrevalence is estimated at 1/2,000-1/4,000.\nEtiology\nPrimary congenital hypothyroidism may be due to a developmental anomaly, also known as thyroid dysgenesis where the thyroid gland fails to develop normally, or may occur without a developmental anomaly as a result of an inborn error of thyroid hormone biosynthesis, also known as dyshormonogenesis, or as a result of thyroid-stimulating hormone (TSH) receptor mutations (see these terms). In iodine sufficient countries, 85% of permanent congenital hypothyroidism is due to thyroid dysgenesis. The remaining 10-15% of cases can be attributed to dyshormonogenesis or to defects in peripheral thyroid hormone transport, metabolism or action. Primary congenital hypothyroidism may also be idiopathic (see this term).\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma", "Disease Definition": "Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma is a rare form of primary cutaneous T-cell lymphoma characterized by rapidly progressing, localized or disseminated nodules, tumors or eczematous skin lesions. It has a particularly aggressive clinical course with a high tendency to spread, in advanced stages, to extracutaneous locations (the central nervous system, lung, testes). Lymph nodes are often spared.", "ORPHA ID": 178528, "Summary": ""}
{"Disease Name": "Primary cutaneous amyloidosis", "Disease Definition": "A rare group of skin diseases characterized histologically by the extracellular accumulation of amyloid deposits in the dermis. Rare forms include lichen amyloidosus, X-linked reticulate pigmentary disorder, primary localized cutaneous nodular amyloidosis, and macular amyloidosis.", "ORPHA ID": 137807, "Summary": ""}
{"Disease Name": "Primary cutaneous anaplastic large cell lymphoma", "Disease Definition": "Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is a rare T-cell non-Hodgkin lymphoma that affects the skin and generally shows no extracutaneous involvement at presentation. It belongs to the spectrum of primary cutaneous CD30+ lymphoproliferative disorders along with lymphomatoid papulosis (see this term) with which it shares overlapping clinical and histopathologic features.", "ORPHA ID": 300865, "Summary": "Epidemiology\nThe prevalence of primary C-ALCL is unknown but it accounts for approximately 9% of cutaneous lymphomas. The male/female ratio is of 3:2.\nClinical description\nPrimary C-ALCL generally occurs in adults and rarely in children and adolescents. Large solitary or multiple slow-growing erythematous skin plaques, nodules or tumors develop, in either a localized or multifocal distribution. These lesions may ulcerate and/or itch. In 10% of cases, primary C-ALCL extends beyond the skin to lymph nodes and manifests as a painless swelling, especially in the neck, armpit or groin. It can also extend to extranodal sites. General symptoms, usually present in cases with extracutaneous involvement, include loss of appetite, weight loss, fatigue, and night sweats (B symptoms).\nEtiology\nEtiology is unknown.\nDiagnostic methods\nDiagnosis is based on physical examination and medical history, and is confirmed by histopathological and immunohistochemical evaluation of skin biopsies showing cell infiltrates of anaplastic cytology (atypical large cells with abundant cytoplasm, prominent nucleoli, and horseshoe-like or reniform nuclei), within the dermis or subcutis, with constant membrane expression of the CD30 T-cell antigen in the majority (>75%) of neoplastic cells, a variable loss of pan-T antigens (CD2, CD3, CD5), and a lack of expression of epithelial membrane antigen (EMA) and CD15. Additional tests include blood analysis and imagery (PET-scan, CT-scan, MRI) that are used to differentiate the cutaneous from the systemic form.\nDifferential diagnosis\nDifferential diagnosis includes lymphomatoid papulosis, metastatic melanoma, squamous cell carcinoma, diffuse large B cell lymphoma and Hodgkin lymphoma (see these terms).\nManagement and treatment\nIf lesions are solitary or localized to a single area, excision and/or radiation therapy is performed. If lesions are disseminated in multiple sites on the body, chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like regimens constitutes the first-line treatment. Chemotherapy can be combined with autologous stem cell transplantation. Recently, anti-CD30 monoclonal antibody therapy (e.g. brentuximab vedotin) has emerged as a promising alternative therapeutic option.\nPrognosis\nThe prognosis is generally good, with a five-year survival rate of 90%. In 25% of cases, spontaneous regression is observed. Relapses, generally without any extracutaneous dissemination, may sometimes occur (approximately in 30% of cases).\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Martine BAGOT"}
{"Disease Name": "Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma", "Disease Definition": "A rare, primary cutaneous T-cell lymphoma characterized by solitary cutaneous nodule or only regional disease, typically occurring on the head and neck, and involving entire dermis. Sometimes, subcutis and adnexal structures are involved, as well. The infiltrate is nodular or diffuse, composed of small to medium sized pleomorphic lymphocytes and showing mild to moderate cytologic atypia. Neoplastic T-cells are mixed with B-cells, histiocytes, plasma cells and eosinophils.", "ORPHA ID": 178522, "Summary": ""}
{"Disease Name": "Primary cutaneous diffuse large B-cell lymphoma, leg type", "Disease Definition": "A rare, aggressive, primary cutaneous B-cell lymphoma characterized by rapidly progressive, red to bluish, often ulcerating, nodular tumors predominantly involving the lower legs. Histology shows sheets of centroblasts and immunoblasts that spare the epidermis, but infiltrate the dermis and subcutaneous tissues, and often disseminate extracutaneously. The neoplastic cells typically express CD20, CD79a, Bcl-2, MUM-1, and FOXP1, but are negative for CD10.", "ORPHA ID": 178544, "Summary": ""}
{"Disease Name": "Primary cutaneous follicle center lymphoma", "Disease Definition": "A rare, indolent primary cutaneous B-cell lymphoma characterized by a solitary or grouped erythematous plaques or tumors, preferentially located on the head, neck or trunk region, and composed of centroblasts and centrocytes arranged in a follicular, diffuse, or mixed growth pattern. The lesions are smooth and typically do not ulcerate. The neoplastic cells express pan B cell markers and Bcl-6, and typically lack Bcl-2.", "ORPHA ID": 178540, "Summary": ""}
{"Disease Name": "Primary cutaneous gamma/delta-positive T-cell lymphoma", "Disease Definition": "Primary cutaneous gamma/delta-positive T-cell lymphoma is a rare, usually aggressive, subtype of cutaneous T-cell lymphoma characterized by infiltration of the epidermis, dermis or subcutaneous tissue by a clonal population of mature, gamma/delta positive cytotoxic T-cells. Typically it presents with ulcerating plaques, tumors, or subcutaneous nodules on the skin of the extremities, however, frequent involvement of mucosal and extranodal sites (such as the nasal cavity, gastrointestinal tract or lungs) is also observed. Cases associated with panniculitis may present with hemophagocytic syndrome (abrupt onset of fever, rash, cytopenia, hepatosplenomegaly and neurological compromise). Infiltration of lymph nodes, spleen and bone marrow is uncommon and resistance to multilineage chemotherapy is reported.", "ORPHA ID": 178533, "Summary": ""}
{"Disease Name": "Primary cutaneous lymphoma", "Disease Definition": "Cutaneous lymphoma is a heterogeneous entity with respect to its clinical and pathological features, evolutive profile, prognosis, molecular aetiology and response to therapy. These specifications have been taken into account in recent classifications, which have placed particular importance on the prognostic implications of these different entities.", "ORPHA ID": 542, "Summary": "Clinical description\nCutaneous T-cell lymphomas can be subdivided into forms with a good prognosis (Mycosis fungoides and CD30+ cutaneous T-cell lymphoma), forms with a poor prognosis (Sezary syndrome and peripheral T-cell lymphoma) and forms with a variable prognosis (pleomorphic small/medium-sized T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous T/NK cell lymphomas (referred to as nasal-type lesions), epidermotropic CD8+ T-cell lymphomas and the TCRgamma-delta phenotype). The group of cutaneous B-cell lymphomas includes marginal zone B-cell lymphomas and primary cutaneous follicular lymphomas (both of which have a good prognosis), cutaneous large B-cell lymphomas of the leg (with a variable prognosis), and blastic NK lymphomas (associated with a poor prognosis).\nManagement and treatment\nWhile treatment is effective and the prognosis is favourable for low grade forms, recent therapeutic innovations relying on the use of biological tools are likely to improve the prognosis for the most severe forms, such as those already existing in the form of anti-CD20 monoclonal antibodies (rituximab) for disseminated cutaneous B-cell lymphomas, and anti-CD52 monoclonal antibody (alemtuzumab) for refractory forms of cutaneous T-cell lymphoma. Deciphering the key molecular mechanisms underlying these malignancies should create new therapeutic perspectives in the close future.\n\n                            Last update: \n                            April 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Hervé BACHELEZ"}
{"Disease Name": "Primary cutaneous marginal zone B-cell lymphoma", "Disease Definition": "A rare, indolent primary cutaneous B-cell lymphoma characterized by multifocal, red to violaceous papules, plaques or nodules localized predominantly on the trunk and extremities. Histologically, these are dermis infiltrates consisting of small, marginal zone B cells, lymphoplasmacytic cells, and plasma cells. Marginal zone B cells express CD20, CD79a and Bcl-2, and are negative for CD5, CD10 and Bcl-6. Plasma cells are typically located at the periphery, and express CD138, CD79a, and monotypic light chains.", "ORPHA ID": 178536, "Summary": ""}
{"Disease Name": "Primary cutaneous peripheral T-cell lymphoma not otherwise specified", "Disease Definition": "An extremely rare, primary cutaneous T-cell lymphoma disorder characterized by solitary, or multifocal and diffuse, cutaneous lesions, ranging from tumor-like patches, plaques, papules, nodules, and/or erythroderma, located on any area of the body, which rapidly progress and may become ulcerated and/or infected. Systemic involvement may be associated.", "ORPHA ID": 86885, "Summary": ""}
{"Disease Name": "Primary cutaneous plasmacytosis", "Disease Definition": "A rare acquired skin disease characterized by benign proliferation of mature plasma cells with a typical triad of cutaneous lesions, polyclonal hypergammaglobulinemia, and superficial lymphadenopathy, without an apparent underlying cause. The skin lesions consist of multiple round-to-oval, red-to-dark-brown macules, papules, and plaques most commonly found on the trunk, but also the face, neck, and axillae.", "ORPHA ID": 451602, "Summary": ""}
{"Disease Name": "Primary cutis verticis gyrata", "Disease Definition": "A progressive cutaneous disorder predominantly affecting males, characterized by hypertrophy and thickening of the skin of the scalp, forming convoluted furrows with deep, tender, and cerebriform cutaneous folds. Hair is usually normal in the furrows and sparse on the folds. It can be isolated or associated with other abnormalities, such as intellectual deficit, epilepsy, cataract, blindness, and deafness.", "ORPHA ID": 671, "Summary": ""}
{"Disease Name": "Primary desmosis coli", "Disease Definition": "A rare intestinal disease characterized by congenital partial or complete lack of the collagen mesh network in the intestinal wall, resulting in hypoperistalsis or aperistalsis. The enteric nervous system is normal or near-normal in the affected areas, although hypo- and dysganglionosis may be found in some proximal segments of the colon and/or small bowel. Patients present with chronic intractable slow transit constipation.", "ORPHA ID": 565641, "Summary": ""}
{"Disease Name": "Primary dystonia, DYT13 type", "Disease Definition": "A rare primary torsion dystonia characterized by focal or segmental dystonia with onset either in the cranial-cervical region or in the upper limbs. Age of onset varies between 5 years and adulthood, with a mean age of onset of 16 years. Clinical manifestations are generally mild and slowly progressive.", "ORPHA ID": 98807, "Summary": ""}
{"Disease Name": "Primary dystonia, DYT17 type", "Disease Definition": "Primary dystonia, DYT17 type is a rare, genetic, isolated dystonia initially presenting as torticollis, and later progressing to segmental or generalized dystonia. Dysphonia and dysarthria also occur later in the disease course.", "ORPHA ID": 370103, "Summary": ""}
{"Disease Name": "Primary dystonia, DYT2 type", "Disease Definition": "A rare isolated dystonia characterized by segmental dystonia that predominantly affects the distal limbs and leads to abnormal posture. This disease has a progressive clinical course and may develop into generalized dystonia but remains mild overall.", "ORPHA ID": 99657, "Summary": ""}
{"Disease Name": "Primary dystonia, DYT21 type", "Disease Definition": "Primary dystonia, DYT21 type is a subtype of mixed dystonia with a late-onset form of pure torsion dystonia.", "ORPHA ID": 306734, "Summary": ""}
{"Disease Name": "Primary dystonia, DYT27 type", "Disease Definition": "A rare genetic dystonia characterized by focal or segmental isolated dystonia involving the face, neck, upper limbs (commonly writing dystonia), larynx, or trunk, with an onset from childhood to early adulthood. Dystonia may be tremulous, giving rise to head or hand tremor. Mode of inheritance is autosomal recessive.", "ORPHA ID": 464440, "Summary": ""}
{"Disease Name": "Primary dystonia, DYT4 type", "Disease Definition": "DYT4 type primary dystonia is characterized by predominantly laryngeal dystonia (manifesting as whispering dysphonia) and cervical dystonia (manifesting as torticollis).", "ORPHA ID": 98805, "Summary": "Epidemiology\nSo far, the disease has been reported in one large Australian family.\nClinical description\nThe age of onset varies from 13 to 37 years. Some patients develop generalized dystonia and psychiatric symptoms.\nEtiology\nThe locus for DYT4 remains unknown.\nGenetic counseling\nThe disease is transmitted in an autosomal dominant manner.\n\n                            Last update: \n                            April 2009"}
{"Disease Name": "Primary dystonia, DYT6 type", "Disease Definition": "A rare genetic movement disorder characterized by dystonia affecting at first an upper limb, less frequently beginning in the head and neck region, before slowly spreading to other locations. The clinical spectrum, like age of onset, is variable with focal, segmental, or generalized distribution, but cranial involvement with speech difficulties and cervical involvement are typical, whereas lower limbs are often spared. With progression of the disease, many patients suffer from generalized dystonia while mostly remaining ambulatory.", "ORPHA ID": 98806, "Summary": ""}
{"Disease Name": "Primary effusion lymphoma", "Disease Definition": "Primary effusion lymphoma (PEL) is a large B-cell lymphoma located in the body cavities, characterized by pleural, peritoneal, and pericardial fluid lymphomatous effusions and that is always associated with human herpes virus-8 (HHV-8).", "ORPHA ID": 48686, "Summary": "Epidemiology\nThe prevalence is unknown but it accounts for less than 1% of non-AIDS related lymphomas and approximately 3% of AIDS-related lymphomas.\nClinical description\nPEL is most frequently found in young men that are positive for HIV or have pre-existing AIDS. Very rare non-HIV related cases have been reported but these patients are almost all elderly or immunodeficient due to another cause. Peritoneal, pleural, and pericardial fluid lymphomatous effusions are observed with, in the majority of cases, no mass-like extranodal extension of lymphoma. Symptoms of PEL depend on the body cavity affected and are caused by the accumulation of the malignant effusion. Pleural or pericardial disease has dyspnea as a symptom while abdominal distension is experienced in peritoneal disease. PEL is usually extremely aggressive and dissemination of lymphoma to distant sites, opportunistic infections and HIV-related complications are often fatal. In the rare HIV-negative cases the outcome may be better.\nEtiology\nThe precise etiology is unknown. PEL is always associated with HHV-8, also known as Kaposi sarcoma-associated herpes (KSHV) and is most frequently found in immunodeficient patients, especially those with advanced AIDS. An infection with Epstein-Barr virus (EBV) is also present in the majority of PEL cases. The gene products of these viral genomes are thought to inhibit cell apoptosis and promote uncontrolled cell division and subsequent neoplastic transformation.\nDiagnostic methods\nBody cavity fluid is analyzed cytologically and by flow cytometry for the presence of clonal large neoplastic cells (with immunoblastic, anaplastic or plasmablastic appearances) with prominent nucleoli, round to irregular nuclei and occasionally vacuolated cytoplasm. To be given a diagnosis with PEL an infection with HHV-8 must be present. A latency-associated nuclear antigen-1 (LANA-1) assay detects any evidence of HHV-8 in tissue samples. Complete blood counts and positron emission tomography/computed tomography (PET/CT) scans should also be performed to determine the extent of the disease.\nDifferential diagnosis\nDifferential diagnoses include diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, which can present with lymphomatous effusion, anaplastic large cell lymphoma (ALCL; see these terms) and pyothorax-associated lymphoma (PAL).\nManagement and treatment\nPEL is usually refractory to conventional chemotherapy and treatment guidelines are not well defined. Highly active antiretroviral therapy (HAART) should be administered concurrently with chemotherapy in all HIV positive PEL patients. The chemotherapy regimen cyclophosamide, doxorubicin, vincristine and prednisone (CHOP) is most commonly used. Research into molecular targeting therapy for the treatment of PEL is ongoing. There is a single case report of a durable remission for more than 18 months with the use of sobuzoxane.\nPrognosis\nPEL has a very poor prognosis with an average life expectancy of 3-4 months after diagnosis. Rare patients with HIV-negative PEL have durable progression free survival after chemotherapy.\n\n                            Last update: \n                            October 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Ephraim HOCHBERG"}
{"Disease Name": "Primary erythromelalgia", "Disease Definition": "Primary erythermalgia is characterized by intermittent attacks of red, warm, painful burning extremities. It spontaneously arises during early childhood and adolescence in the absence of any detectable underlying disorder.", "ORPHA ID": 90026, "Summary": "Epidemiology\nIt may occur sporadically or as an inherited disease, but less than 30 kindreds with familial primary erythermalgia have been reported in the literature so far.\nClinical description\nClinically, it is characterized by episodes of symmetrical red congestion, vasodilatation, and burning pain in both the feet and lower legs provoked by exercise, long standing and exposure to warmth that usually compels patients not to wear socks or closed shoes even in winter and to search for relief by immersion of feet in ice-cold water.\nEtiology\nThe gene for autosomal dominant erythermalgia, SCN9a, is located on chromosome 2q. SCN9a is a 26 exon gene encoding the voltage-gated sodium channel alpha subunit Nav1.7. This channel is found mainly in dorsal root ganglia and sympathetic ganglia neurons. All mutations detected so far are missense and lead to a gain of function by lowering the activation threshold of Nav1.7, resulting in hyperexcitability of pain signaling neurons.\nDiagnostic methods\nThe molecular diagnosis relies on sequencing of all coding exons of SCN9a. All mutations so far detected are private mutations (i.e. all families have their own unique mutations). Clinical diagnostic criteria are: attacks of local red congestion and vasodilation with increased local skin temperature and burning pain; a bilateral and symmetric distribution of symptoms; onset and aggravation of symptoms in response to distress, exercise and heat; relief provided by cold, rest and elevation of the affected extremities; the absence of a primary or associated disease; the condition being refractory to treatment.\nDifferential diagnosis\nDifferential diagnosis includes erythromelalgia and secondary erythermalgia. In erythromelalgia, the burning pain and red congestion are usually unilateral or asymmetrically distributed with preferential involvement of one or more toes, the forefoot soles or fingertips. The platelet count is always elevated > 400 x 10 9/L, and aspirin relieves symptoms. Secondary erythermalgia is acquired, mostly develops at a later age and is invariably linked with the use of drugs or underlying disease (vasculitis, neuropathy). In contrast to erythromelalgia, the platelet count in both secondary and inherited primary erythermalgia is normal.\nGenetic counseling\nIn familial cases, the disorder is inherited as an autosomal dominant trait. Genetic counselling should be adapted according to the family history of the patient and affected parents should be informed of the 50% risk of reoccurrence.\nManagement and treatment\nAnalgesic therapy for the neuropathic pain is problematic. However, voltage-gated sodium channels are potential targets for local anesthetics (lidocaine), systemic antiarrhythmics (mexiletine) and antiepileptic drugs such as phenytoin. In several patients, oral mexiletine (600 mg daily) rapidly improved symptoms suggesting that blocking the voltage-gated sodium channels is a valid therapeutic option.\nPrognosis\nPrognosis depends on the severity of the disease. In severe cases the burning pain leads to an urgent need to cool the affected extremities. As a consequence, the affected skin from the limb (mostly the feet) can macerate resulting in skin fissures, skin infections and, possibly life-threatening sepsis. Amputation may be required in case of repeated infections. The very severe burning pain can lead to profound psychological consequences and depression.\n\n                            Last update: \n                            January 2007\n\n\n                            - Expert reviewer(s): \n                            Pr J.P.H. [Joost] DRENTH"}
{"Disease Name": "Primary essential cutis verticis gyrata", "Disease Definition": "Primary essential cutis verticis gyrata is a rare, progressive dermis disorder characterized by thickening of the scalp resulting in redundancy of the skin which gives rise to folds and grooves that give the scalp a cerebriform appearance. Folds cannot be corrected by pressure or traction and typically are symmetric and extend anteroposteriorly from vertex to occiput and/or transversely in occipital region. Additional features may include mild subungual hyperkeratosis and distal onycholysis of the nail plates of the great toes. It is not associated with neurological and ophthalmological changes, nor with secondary causes.", "ORPHA ID": 357220, "Summary": ""}
{"Disease Name": "Primary failure of tooth eruption", "Disease Definition": "A rare genetic odontologic disease characterized by failure of eruption of non-ankylosed permanent teeth without evidence of obvious mechanical obstruction. Posterior teeth are preferentially affected (typically with involvement of all teeth distal to the most mesial non-erupted tooth), resulting in a posterior open bite. Non-ankylosed teeth tend to become ankylosed, and orthodontic treatment of affected teeth is generally unsuccessful.", "ORPHA ID": 412206, "Summary": ""}
{"Disease Name": "Primary familial polycythemia", "Disease Definition": "Primary familial polycythemia is an inherited hematological disorder resulting from mutations in the erythropoietin (EPO) receptor and is characterized by an elevated absolute red blood cell mass caused by uncontrolled red blood cell production in the presence of low EPO levels.", "ORPHA ID": 90042, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe hematological disorder is present at birth but the clinical symptoms, if they develop, can be discovered at any time during childhood or adulthood. Clinical features can include headache, dizziness, epistaxis and exertional dyspnea. Thrombotic events have been observed. The hematological features include the presence of isolated erythrocytosis without evolution into leukemia or other myeloproliferative disorders, absence of splenomegaly, normal white blood cell and platelet counts, and low plasma EPO levels.\nEtiology\nPrimary familial polycythemia is caused by mutations in the EPO receptor (EPOR) gene (19p13.3-p13.2) resulting in hypersensitivity to EPO. The mutations result in a receptor that is ''switched on'' to stimulate red blood cell production by erythroid progenitor cells but that has no ''switch off'' mechanism.\nDiagnostic methods\nDiagnosis is based on evidence in kindreds of isolated erythrocytosis without splenomegaly, low serum EPO levels, normal hemoglobin oxygen affinity and bone marrow erythroid progenitors that exhibit EPO hypersensitivity.\nDifferential diagnosis\nDifferential diagnoses include polycythemia vera (see this term), although there is no propensity to leukemic transformation or development of other myeloproliferative neoplasms in primary familial polycythemia, and secondary polycythemia (see these term). Polycythemia vera can be excluded on the basis of the absence of mutations in the JAK2 gene (9p24), and secondary polycythemia should be suspected if EPO levels are normal to high.\nGenetic counseling\nTransmission is usually autosomal dominant although sporadic cases have been reported. At least 14 different mutations have been described in single families.\nManagement and treatment\nPatients with polycythemia should be individually assessed. Reducing the hematocrit (Hct) by phlebotomy reduces the blood viscosity and may be of benefit. Clinical symptoms are effectively relieved by phlebotomy. However, the increased risk of cardiovascular morbidity is not ameliorated by maintaining a normal Hct. If venesection is judged appropriate, the sparse evidence suggests it can reduce the Hct when it is over 54%. In patients with an increased risk of thrombosis, previous thrombosis, peripheral vascular disease, diabetes or hypertension, venesection should be considered at Hct less than 54%. In those with no specific contraindication, low-dose aspirin is relatively safe and may be of benefit to patients with erythrocytosis.\nPrognosis\nPrimary familial polycythemia does not necessarily carry an adverse prognosis in early life and most patients have a benign clinical course, but it is associated with an increased risk of thrombosis and vascular mortality in later life.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Jean BRIERE"}
{"Disease Name": "Primary Fanconi renotubular syndrome", "Disease Definition": "A rare generalized, genetic disorder of proximal tubular transport characterized by excessive urine output with loss of low molecular weight solutes (amino acids, glucose, low-molecular weight proteins, organic acids, carnitine, calcium, phosphate, potassium, bicarbonate) and water, and which can be life threatening.", "ORPHA ID": 3337, "Summary": "Epidemiology\nThe prevalence of the condition is not known.\nClinical description\nOnset is typically between infancy and childhood with symptoms related to tubular loss of nutrients, water and electrolytes. Typical clinical features include failure to thrive and rickets, normoglycemic glycosuria and polyuria with bicarbonaturia leading to hyperchloremic metabolic acidosis. Nephrocalcinosis and kidney stones are less common.\nEtiology\nThe genetic etiology has been identified in a handful of families, and includes mutations in either GATM (15q21.1), involved in mitochondrial function, EHHADH (3q27.2), due to a specific mutation (c.7G>A) that introduces a mitochondrial targeting motif, or SLC34A1 (5q35.3) which encodes the proximal tubular sodium-phosphate transporter, NaPi-IIa. However, the disease may be due to unidentified mutations. Of note, the gene SLC34A1 is also associated with two other diseases: autosomal recessive infantile hypercalcemia and dominant hypophosphatemia with nephrolithiasis or osteoporosis.\nDiagnostic methods\nDiagnosis is based on clinical presentation as well as plasma electrolytes levels and evaluation of urinary solute excretion (aminoaciduria, proteinuria, phosphaturia, calciuria, uricosuria, glycosuria).\nDifferential diagnosis\nBefore the diagnosis of primary Fanconi renotubular syndrome is made all causes of secondary Fanconi syndrome must be ruled out, including both inherited (cystinosis, tyrosinemia type I, fructosemia, Wilson's disease, galactosemia, glycogen storage disease, Dent disease, Oculocerebrorenal syndrome of Lowe, arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, mitochondrial cytopathies) and acquired disorders (drug or heavy metal poisoning, malignancies).\nGenetic counseling\nThe majority of reported cases are sporadic and may be associated with de novo mutations. However, hereditary forms have been reported. The pattern of inheritance is autosomal dominant for EHHADH and GATM, and autosomal recessive for SLC34A1. The risk of transmission to offspring is 50% for autosomal dominant disease and, where both parents are heterozygous for the pathogenic mutation, 25% in autosomal recessive disease.\nManagement and treatment\nTreatment is symptomatic. Kidney transplantation is curative.\nPrognosis\nWith adequate fluid, electrolyte and nutrient supplementation, adequate physical and neurocognitive development is usually possible. Mutations in GATM are associated with progressive chronic kidney disease, whereas this has not been observed with EHHADH-associated disease.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Detlef BÖCKENHAUER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Primary hepatic neuroendocrine carcinoma", "Disease Definition": "Primary hepatic neuroendocrine carcinoma (PHNEC) is a rare hepatic tumor that may manifest with abdominal pain or fullness, as well as diarrhea or weight loss. More than 10% of cases are asymptomatic and in rare cases a carcinoid syndrome may be observed.", "ORPHA ID": 100085, "Summary": "Epidemiology\nPHNEC has been estimated to have an incidence of approximately 1/500,000, accounting for <1% of all malignancies. PHNEC is slightly more frequent in females.\nClinical description\nThe age of onset is variable. In the early stages of PHNEC, patients may exhibit nonspecific symptoms, including upper abdominal pain and distension or fullness, while some may suffer from carcinoid syndrome (paroxysmal flushing, episodes of asthma-like wheezing, right-side heart failure and diarrhea). Progression of PHNEC is accompanied by the symptoms caused by tumor compression to adjacent organs, dyspepsia, weight loss and fatigue. More than 10% of cases are asymptomatic. PHNEC is not associated with cirrhosis or other forms of preexisting liver disease.\nEtiology\nThe etiology of PHNEC is still unknown but it is thought to arise from Kulchitsky cells originating in the neural crest. It is also hypothesized that chronic inflammation in the biliary system may initiate intestinal metaplasia, which predisposes to the development of neuroendocrine tumors. Another possibility is that they originate from ectopic pancreatic or adrenal tissues within the liver.\nDiagnostic methods\nDiagnosis relies on laboratory findings showing negative serum alpha-fetoprotein levels and negative results for other conventional tumor markers (carcinoembryonic antigen, CA125 and CA19‑9) in addition to non-contrasted computed tomography (CT) scans showing low-density masses, with some having a cystic component. Dynamic contrast CT reveals enhanced masses in the early phase and low density masses in the late phase. On magnetic resonance imaging (MRI), PHNEC usually presents with low intensity on T1-weighted images and high intensity on T2-weighted images, and appears as a large dominant hypervascular mass accompanied by satellite nodules, with rapid washout and capsular enhancement on dynamic MRI and restricted diffusion on diffusion-weighted imaging. An octreoscan is recommended as it may detect small metastatic masses. Histologically, PHNEC appears as a hemorrhagic, non-capsulated mass, with central, irregular fibrosis and hyaline degeneration. The diagnosis may be confirmed by immunohistochemistry where the cells present a strong positivity for neurosecretory markers such as chromogranin, synaptophysin, neuron specific enolase, and S-100 protein.\nDifferential diagnosis\nDifferential diagnosis includes hepatic adenoma, hepatocellular carcinoma, cholangiocarcinoma, congenital liver hemangioma (see these terms), focal nodular hyperplasia, primary hepatic angiosarcoma, secondary hepatic neuroendocrine carcinoma, or hepatic metastases from any other primary cancer site.\nManagement and treatment\nSurgery is often the only curative option and provides the most favorable outcome. For ill-defined lesions, a palliative cytoreductive surgery in combination with transcatheter arterial embolization (TACE) and subsequent administration of lanreotide (a long acting somatostatin analogue) may be effective. Targeted radiation therapy, given as either SIRT (selective internal radiation therapy) or PRRT (peptide receptor radiation therapy) is of theoretical benefit.\nPrognosis\nEarly detection and treatment are key in achieving a good prognosis. The prognosis depends on the pathological type, degree of differentiation, and size and boundary of the tumor as well as the presence of metastasis and the physical status of the patient.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Graeme POSTON"}
{"Disease Name": "Primary hyperaldosteronism-seizures-neurological abnormalities syndrome", "Disease Definition": "A rare, genetic, neurologic disease characterized by primary hyperaldosteronism presenting with early-onset, severe hypertension, hypokalemia and neurological manifestations (including seizures, severe hypotonia, spasticity, cerebral palsy and profound developmental delay/intellectual disability).", "ORPHA ID": 369929, "Summary": ""}
{"Disease Name": "Primary hypereosinophilic syndrome", "Disease Definition": "A rare hypereosinophilic syndrome characterized by hypereosinophilia produced by clonal eosinophils derived from neoplastic stem cells in the absence of any secondary cause of eosinophilia and persisting for at least six months. The condition is associated with signs of organ infiltration, dysfunction, and damage. Clinical manifestations are highly variable, depending on the organ systems involved, and include dermatologic, pulmonary, cardiac, gastrointestinal, and cerebral manifestations, among others.", "ORPHA ID": 314950, "Summary": ""}
{"Disease Name": "Primary hypergonadotropic hypogonadism-partial alopecia syndrome", "Disease Definition": "A rare endocrine disorder characterized by primary hypogonadism and partial alopecia. Females present with Mûllerian hypoplasia, absent or streak ovaries, hypoplastic internal genitalia, primary amenorrhea, and sparse or absent axillary and pubic hair. Some patients also presented sparse eyebrows, microcephaly, flat occiput, dorsal kyphosis or mild intellectual disability. The only described male presents with germinal cell aplasia. Affected individual all present partical scalp alopecia.", "ORPHA ID": 2232, "Summary": ""}
{"Disease Name": "Primary hyperoxaluria", "Disease Definition": "A disorder of glyoxylate metabolism characterized by an excess of oxalate resulting in kidney stones, nephrocalcinosis and ultimately renal failure and systemic oxalosis. There are 3 types of PH, types 1-3, all caused by liver-specific enzyme defects.", "ORPHA ID": 416, "Summary": "Epidemiology\nPrimary Hyperoxalurias (PH) prevalence ranges from 1-3/1 000 000 and the estimated incidence is between 1-2/10 000 000 per year with no differences between sexes. There are higher rates reported in isolated populations, especially in the Middle East and North Africa. A significant proportion of patients are diagnosed at adulthood which implies an important underdetection of patients. PH1 accounts for 85% of patients, PH2 8-10% and PH3 5-7%.\nClinical description\nHyperoxaluria may lead to kidney stones, nephrocalcinosis and ultimately renal failure and systemic oxalosis. Symptoms can appear at any age and may vary from infantile failure to thrive and cortical nephrocalcinosis with renal failure to hematuria, medullary nephrocalcinosis or sporadic stone disease, even within one family. PH1 is the most severe form; overall, more than 70% of PH1 patients develop end-stage kidney disease over time; this may even occur in patients with sporadic stone disease. Storage of oxalate occurs in severe renal failure and may affect bone, eyes, heart, arteries and peripheral nerves (systemic oxalosis). PH2 has a more benign course; no infantile oxalosis has been described and end-stage kidney disease occurs at relatively late age in about 20% of patients. PH3 is most benign with so far only a few reports of renal impairment and no end-stage kidney disease.\nEtiology\nPH type 1 is caused by mutations of the AGXT gene causing dysfunction of the liver-specific peroxisomal enzyme alanine glyoxylate aminotransferase (AGT). Over 50 different mutations have been found, leading to either absence or dysfunction of AGT. Two common Western mutations (G170A, Phe152Ile) lead to a mitochondrial mistargeting of AGT. Type 2 is caused by mutations of GHRPR gene causing dysfunction of the cytosolic enzyme glyoxylate/hydroxypyruvate reductase, type 3 by mutations in HOGA1 causing dysfunction of the mitochondrial enzyme 4-hydroxy-2- oxoglutarate aldolase.\nDiagnostic methods\nDiagnosis methods consist of an analysis of urine collection for 24h (at least 2 consecutive assessments) on oxalate, creatinine, glycolate (PH1), citrate (decreased in PH1), L-glycerate (PH2) and HOGA (PH3). Mutation analysis on AGTX gene can be done in case of hyperoxaluria. If negative or in case of high l-glycerate or HOGA mutation analysis on GRHPR or HOGA1 genes are realized. Assessment for systemic oxalosis in case of high plasma-oxalate and /or eGFR<40: fundoscopy, US heart, bone assessment.\nDifferential diagnosis\nDifferential diagnosis includes hypercalciuria, hypocitraturia, cystinuria.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nIf eGFR>30 ml/min/1.73m2: the patient needs first high fluid intake (>3 liter/day/m2 body surface). Then pyridoxine challenge in PH1 starting dose 5 mg/kg/day, increase to max 20; reduction urine oxalate >30% = positive response (about 30% of patients in Europe). In third potassium-citrate 0,5 mmol/kg/day. If eGFR<30 ml/min/1.73m2 it is consider to direct combined liver-kidney transplantation, sequential liver-kidney transplantation in case of severe systemic oxalosis or kidney transplantation in B6 responsive PH1 patients. Dietary oxalate restriction is probably of limited use.\nPrognosis\nSevere infantile oxalosis has a poor prognosis quoad vitam. The prognosis for other PH1 B6 unresponsive patients is poor with respect to renal function (> 80% renal failure over time), better for B6 responsive patients, if timely diagnosed and treated. End-stage kidney disease has been found in 20% of PH2 patients, so far not in PH3.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Pr J.W. [Jaap] GROOTHOFF | ERKNet* - Pr Bernd HOPPE \n\n\n                                * European Reference Network"}
{"Disease Name": "Primary hypertrophic osteoarthropathy", "Disease Definition": "Primary hypertrophic osteoarthropathy (PHO) is a genetically and clinically heterogeneous inherited disorder characterized by digital clubbing and osteoarthropathy, with variable features of pachydermia, delayed closure of the fontanels, and congenital heart disease. There are two types of PHO: pachydermoperiostosis and cranio-osteoarthropathy (see these terms).", "ORPHA ID": 248095, "Summary": "Epidemiology\nPrevalence is unknown. Cranio-osteoarthropathy is the rarest form, with about 30 cases reported to date.\nClinical description\nPatients typically present in infancy with clubbing, hyperhidrosis, bone and joint pain and skin thickening. The clinical constellation of PHO includes skin thickening and excessive sweating (pachydermoperiostosis), delayed closure of the cranial sutures (cranio-osteoarthropathy) and congenital heart disease, especially patent arterial duct (see this term).\nEtiology\nMutations in the HPGD gene (4q33-q34) encoding 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the main enzyme of prostaglandin degradation, have been identified.\nDiagnostic methods\nDiagnosis is based on clinical signs and X-ray exam, magnetic resonance imaging (MRI) or radionucleotide bone imaging showing typical bone abnormalities, such as diaphyseal periostosis and acro-osteolysis.\nDifferential diagnosis\nDifferential diagnoses include secondary hypertrophic osteoarthropathy, chronic recurrent non-bacterial osteomyelitis, SAPHO and Camurati-Engelman syndromes (see these terms) and chronic bacterial osteomyelitis.\nGenetic counseling\nPHO is inherited as an autosomal recessive trait; however, heterozygous carriers can have a mild phenotype. Since mutations in the HPGD gene have recently been reported, genetic counseling and prenatal diagnosis might be considered.\nManagement and treatment\nRheumatological symptoms can be improved by nonsteroidal anti-inflammatory drugs, which have been shown to directly influence the pathogenesis. In addition, corticosteroids or colchicine have been tried. Clinical improvement of the dermatological symptoms is achieved by retinoids. Plastic surgery may be helpful for facial involvement. Finger clubbing surgical reduction has been tried with success.\nPrognosis\nPHO progresses constantly, leaving patients with chronic debilitating complications, such as clubbing and arthritis.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Hermann GIRSCHICK"}
{"Disease Name": "Primary hypomagnesemia with hypercalciuria and nephrocalcinosis with severe ocular involvement", "Disease Definition": "Familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis with severe ocular involvement (FHHNCOI) is a form of familial primary hypomagnesemia (FPH, see this term), characterized by excessive magnesium and calcium renal wasting, bilateral nephrocalcinosis, progressive renal failure and severe ocular abnormalities.", "ORPHA ID": 2196, "Summary": "Epidemiology\nTo date, approximately 72 cases have been described in the literature.\nClinical description\nFHHNCOI has a childhood onset. The initial symptoms may include recurrent urinary tract infections, polyuria and polydipsia. Additional features include nephrocalcinosis, nephrolithiasis, enuresis, abdominal pain, muscular twitches and failure to thrive. The clinical hallmark of this disorder is an ocular abnormality involving severe bilateral myopia with divergent squint, nystagmus, keratoconus, corneal calcifications, cataract, chorioretinitis, pigmentary retinitis, pigmentary maculopathy, macular coloboma, strabismus or visual loss. Renal function generally declines progressively in most patients and patients may reach end stage renal disease in their adolescence or young adulthood. 50% of patients require renal replacement therapy in the second decade of life.\nEtiology\nFHHNCOI is caused by mutations in CLDN19 (1p34.2) which encodes claudin-19, a protein member of the claudin family which is highly expressed in the tight junctions of the thick ascending limb of Henle's loop, as well as in the retinal epithelium.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Rosa VARGAS-POUSSOU"}
{"Disease Name": "Primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement", "Disease Definition": "Familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement (FHHN) is a form of familial primary hypomagnesemia (FPH; see this term), characterized by recurrent urinary tract infections, nephrolithiasis, bilateral nephrocalcinosis, renal magnesium (Mg) wasting, hypercalciuria and kidney failure.", "ORPHA ID": 31043, "Summary": "Epidemiology\nTo date, more than 110 individuals have been reported in the literature.\nClinical description\nFHHN has an onset in childhood and the clinical manifestations are recurrent urinary tract infections, polyuria, polydipsia, enuresis, hematuria, nephrolithiasis and bilateral nephrocalcinosis. Some patients fail to thrive during early childhood and experience seizures, vomiting, abdominal pain, tetany and rarely rickets. Ocular involvement is rare and when observed it is relatively mild (myopia, hypermetropia, astigmatism and strabism). Approximately one third of patients progress to renal failure or end-stage renal disease (ESRD) during adolescence.\nEtiology\nFHHN is characterized by impaired tubular reabsorption of Mg and calcium (Ca) in the thick ascending limb of Henle's loop due to mutations in CLDN16 (3q27), which encodes claudin-16 (previously known as paracellin 1). A significant residual function is observed in several missense mutations, whereas a complete loss of claudin-16 function appears to be more severe (disease presenting earlier and often progressing to kidney failure at a significantly younger age).\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Rosa VARGAS-POUSSOU"}
{"Disease Name": "Primary hypomagnesemia with hypercalciuria and nephrocalcinosis", "Disease Definition": "Familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a form of familial primary hypomagnesemia (FPH, see this term), characterized by renal magnesium (Mg) and calcium (Ca) wasting, nephrocalcinosis, kidney failure and, in some cases, severe ocular impairment. Two subtypes of FHHNC are described: FHHNC with severe ocular involvement (FHHNCOI) and without severe ocular involvement (FHHN) (see these terms).", "ORPHA ID": 306516, "Summary": "Epidemiology\nTo date, approximately 200 cases have been reported in the literature.\nClinical description\nThe median age of onset ranges from 1 to 8 years. The most common presenting features are recurrent urinary tract infections, nephrolithiasis, nephrocalcinosis, polyuria, polydipsia, enuresis, hematuria and pyuria. Additional manifestations include failure to thrive, seizures, abdominal pain, muscular tetany and, rarely, rickets. Patients develop chronic kidney disease (CKD) that progresses to end-stage renal disease (ESRD). Two subtypes of FHHNC have been described: FHHNCOI and FHHN. Both forms share identical renal manifestations. By contrast, severe ocular involvement (macular coloboma, pigmentary retinitis, nystagmus, or visual loss) has been described in FHHNCOI, while mild nonspecific ocular involvement (myopia, astigmatism, hypermetropia, or strabismus) has been reported in some cases of FHHN.\nEtiology\nThe disease is caused by mutations in the genes CLDN16 (3q28) and CLDN19 (1p34.2), encoding claudin-16 and claudin-19 respectively. Both proteins are expressed in the thick ascending limb of Henle's loop where they interact to form heteromultimers and play a role in the paracellular reabsorption of Mg and Ca. Inactivating mutations in either gene results in urinary loss of Mg and Ca. Ocular involvement occurs in patients with the CLDN19 mutation as claudin-19 is expressed in retinal pigment epithelium.\nDiagnostic methods\nDiagnosis is based on the triad of hypomagnesemia, hypercalciuria and nephrocalcinosis. Hypocalcemia, hyperuricemia, incomplete distal renal tubular acidosis and hypocitraturia are supportive findings. Parathyroid hormone levels are high before onset of CKD. High fractional urinary excretion of Mg is found while serum level is inappropriately low. Ocular abnormalities are detected by fundoscopy and optical coherence tomography (OCT). Diagnosis is confirmed by genetic screening of CLDN16 and CLDN19.\nDifferential diagnosis\nDifferential diagnosis includes Bartter syndrome, autosomal dominant hypocalcemia, Dent disease, hereditary hypophosphatemic rickets with hypercalciuria, distal renal tubular acidosis and other tubular disorders causing early nephrocalcinosis (like primary hyperoxaluria) (see these terms).\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\nManagement and treatment\nManagement is mainly supportive and includes administration of Mg supplements in high doses and thiazide diuretics to reduce urinary Ca excretion and the progression of nephrocalcinosis. Indomethacin may be used to increase Ca reabsorption. Therapies aimed at delaying progression of CKD should be provided as well as conventional management strategies for kidney stones. Renal transplantation is the optimal treatment for ESRD. Lens implantation can be proposed to patients suffering from severe ocular abnormalities.\nPrognosis\nProgression to ESRD is frequent (50% of patients at 20 years). Follow-up data in one of the described cohorts suggested that patients harboring CLDN19 mutations have a higher risk of progression to CKD than patients with CLDN16 mutations.\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Rosa VARGAS-POUSSOU"}
{"Disease Name": "Primary hypomagnesemia with secondary hypocalcemia", "Disease Definition": "Primary hypomagnesemia with secondary hypocalcemia (PHSH) is a form of familial primary hypomagnesemia (FPH, see this term), characterized by severe hypomagnesemia and secondary hypocalcemia associated with neurological symptoms, including generalized seizures, tetany and muscle spasms. PHSH may be fatal or may result in chronic irreversible neurological complications.", "ORPHA ID": 30924, "Summary": "Epidemiology\nTo date, approximately 100 cases have been described in the literature. Both sexes are equally affected.\nClinical description\nDisease onset is often in the neonatal period and always before the end of the first year of life. The predominant symptom at initial presentation is generalized and recurrent seizures which are refractory to the conventional convulsive therapy. Additional features that are observed in the newborn period include tetany (that fails to respond to calcium therapy), failure to thrive, restlessness, tremors, muscle spasms, and perioral cyanosis. Cardiac arrhythmia may be observed.\nEtiology\nMutations in the gene TRPM6 (9q21.13), encoding the transient receptor potential cation channel subfamily M, member 6, have been found to be responsible for this disease The pathophysiological hallmark of PHSH is the impaired intestinal absorption of magnesium (Mg) accompanied by renal Mg wasting as a result of a reabsorption defect in the distal convoluted tubule. The renal defect is only detected after an intravenous Mg load test. Hypocalcemia seems to be caused by diminished parathyroid hormone (PTH) release as a result of profound hypomagnesemia.\nDiagnostic methods\nDiagnosis relies on laboratory findings which reveal severely reduced serum Mg levels accompanied by hypocalcemia and barely detectable PTH levels. Urinary calcium (Ca) values are normal. Renal defects may be detected after an intravenous Mg load test. The diagnosis is confirmed by genetic screening of TRPM6. One case of bilateral basal ganglia calcification has been detected by computed tomography brain scan.\nDifferential diagnosis\nDifferential diagnosis includes Gitelman and Bartter syndromes, familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement (see these terms), and nutritional rickets.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.\nManagement and treatment\nManagement is mainly symptomatic and the standard treatment consists of the exclusive and lifelong administration of Mg. During manifestations, intravenous or intramuscular administrations are preferred, whereas maintenance therapy usually consists of an oral administration of high doses of Mg. However, because of gastrointestinal side effects, some patients require additional parenteral Mg.\nPrognosis\nPrognosis of PHSH depends on the rapidity of diagnosis. Indeed, delayed diagnosis, or delayed administration of the appropriate treatment may result in convulsions that can be fatal or that may result in chronic, irreversible neurological complications.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Rosa VARGAS-POUSSOU"}
{"Disease Name": "Primary hypomagnesemia-refractory seizures-intellectual disability syndrome", "Disease Definition": "A rare genetic disorder of magnesium transport characterized by infantile onset of generalized seizures and severe hypomagnesemia due to massive renal magnesium wasting. Seizures persist despite magnesium supplementation and are associated with significant global developmental delay and intellectual disability. Brain MRI may show reduced cerebral volume.", "ORPHA ID": 564178, "Summary": ""}
{"Disease Name": "Primary immunodeficiency syndrome due to P14/LAMTOR2 deficiency", "Disease Definition": "Primary immunodeficiency syndrome due to p14 deficiency is characterised by short stature, hypopigmentation, coarse facies and frequent bronchopulmonary Streptococcus pneumoniae infections.", "ORPHA ID": 90023, "Summary": "Epidemiology\nTo date, it has been described in four members of one family.\nEtiology\nLinkage analysis led to the identification of a homozygous deletion in the coding region of the ROBLD3 gene, resulting in reduced expression of the endosomal adaptor protein p14.\n\n                            Last update: \n                            March 2007"}
{"Disease Name": "Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency", "Disease Definition": "A rare DNA repair defect other than combined T-cell and B-cell immunodeficiencies characterized by intrauterine and postnatal growth retardation resulting in short stature, microcephaly, glucocorticoid deficiency, natural killer cell deficiency, and recurrent viral infections. Patients may also have increased susceptibility to cancer.", "ORPHA ID": 75391, "Summary": ""}
{"Disease Name": "Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection", "Disease Definition": "Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection is a rare primary immunodeficiency due to a defect in innate immunity disorder characterized by selective susceptibility to viral infections, particularly after systemic challenge with live viral vaccines, such as the measles, mumps and rubella (MMR) vaccine. Patients present severe, potentially fatal, manifestations to viral illness, including encephalitis, hepatitis and pneumonitis.", "ORPHA ID": 431166, "Summary": ""}
{"Disease Name": "Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies", "Disease Definition": "A group of interstitial lung diseases (ILD) induced by genetic mutations disrupting surfactant function and gas exchange in the lung. The disorders caused by these mutations affect full-term infants and older children and exhibit considerable overlap in their clinical and histologic presentation.", "ORPHA ID": 100049, "Summary": ""}
{"Disease Name": "Primary intestinal lymphangiectasia", "Disease Definition": "A rare intestinal disease characterized by dilated intestinal lacteals which cause lymph leakage into the small bowel lumen. Clinical manifestations include edema related to hypoalbuminemia (protein-losing gastro-enteropathy), asthenia, moderate diarrhea, lymphedema, serous effusion and failure to thrive in children.", "ORPHA ID": 90362, "Summary": "Epidemiology\nPrevalence is unknown. Less than 500 cases have been reported worldwide.\nClinical description\nPrimary intestinal lymphangiectasia (PIL) is generally diagnosed before 3 years of age but may be diagnosed in older patients with very few symptoms. The main symptom is predominantly bilateral lower limb edema related to protein-losing enteropathy associated with hypoalbuminemia. Edema may be moderate (in foot, ankle, calf) to severe with anasarca and can be associated with pericarditis, ascites (chylous or not) or pleural effusion. Fatigue, abdominal pain, weight loss, inability to gain weight, failure to thrive in children, moderate diarrhea, fat-soluble vitamin deficiencies due to malabsorption or iron deficiency with moderate anemia may also be present. In some patients, limb lymphedema is associated with PIL and it is difficult to distinguish from edema. Stemmer's sign is an important element to confirm the diagnosis and also differentiate lymphedema from edema: it is impossible to lift and pinch the skin on the second toe basis because of skin-thickening as the result of fibrosis.\nEtiology\nThe etiology remains unknown. Very rare familial cases of PIL have been reported.\nDiagnostic methods\nExsudative enteropathy is confirmed by elevated 24-hour stool alpha-1 antitrypsin clearance. Diagnosis of PIL is confirmed by endoscopic observation of dilated intestinal lacteals with the corresponding histology of intestinal biopsy specimens. Videocapsule endoscopy may be useful to visualize intestinal lymphangiectasia (localization, extent) when endoscopic findings are not conclusive. Characteristic biochemical findings related to lymph leakage into bowel lumen include lymphopenia, hypoalbuminemia, hypogammaglobulinemia, hypocalcemia, and hypocholesterolemia.\nDifferential diagnosis\nThe main differential diagnosis includes enteropathy-associated T-cell lymphoma, Whipple disease, Crohn disease, sarcoidosis, tuberculosis (with extrapulmonary involvement), systemic sclerosis, and constrictive pericarditis.\nManagement and treatment\nA strictly low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL medical management. The absence of fat in the diet prevents chyle engorgement of the intestinal lymphatic vessels thereby preventing their rupture with ensuing lymph loss. Medium-chain triglycerides are absorbed directly into the portal venous circulation and prevent lacteal overloading. Octreotide has been effective in treating some PIL patients. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet withdrawal. Albumin infusion is a symptomatic treatment proposed in patients with important serous effusion or uncomfortable lower limb edema. Repeated albumin infusions may be useful in reducing edema but their efficacy is transient. Repeated fat-soluble vitamin supplementation, particularly vitamin D, is required. A prolonged clinical and biological follow-up is recommended.\nPrognosis\nThe prognosis varies. PIL may be asymptomatic or mildly symptomatic in moderate forms of the disease or in patients who follow a low-fat diet. PIL outcome may be poor or even life-threatening when voluminous serous effusion(s) (pleural, pericardial) spontaneously occur, after low-fat diet withdrawal, or in cases with malignant complications. So, several B-cell lymphomas confined to the gastrointestinal tract (stomach, jejunum, mid gut or ileum) or with extra-intestinal localizations have also been reported in PIL patients.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Stéphane VIGNES"}
{"Disease Name": "Primary intrahepatic lithiasis", "Disease Definition": "A rare biliary tract disease characterized by stone formation within the intrahepatic bile ducts without any known cause, leading to bile stasis and repeated cholangitic episodes. The condition is rare in the Western world but frequent in eastern Asia. Patients usually present before the age of forty with right upper quadrant pain, jaundice, and/or fever. Stones are typically calcium bilirubinate (pigment) stones, and bacteria are present in the bile in almost all cases. Complications are biliary strictures, liver abscess, liver fibrosis, and secondary biliary cirrhosis. Association with cholangiocarcinoma has also been reported.", "ORPHA ID": 480506, "Summary": ""}
{"Disease Name": "Primary intraosseous venous malformation", "Disease Definition": "Primary intraosseous venous malformation is a rare, genetic vascular anomaly characterized by severe blood vessel expansion (most frequently within the craniofacial bones) with painless bone enlargement (usually of mandibule, maxilla and/or orbital, nasal, and frontal bones), typically resulting in facial asymmetry and contour deformation. Midline abnormalities, such as diastasis recti, supraumbilical raphe, and hiatus hernia, are commonly associated. Additional features reported include gingival bleeding, ectopic tooth eruption, exophthalmos, loss of vision, nausea, and vomiting.", "ORPHA ID": 140436, "Summary": ""}
{"Disease Name": "Primary laryngeal lymphangioma", "Disease Definition": "Primary laryngeal lymphangioma is a rare, benign, congenital malformation of the lymphatic system characterized by a polypoidal, variable-sized, soft tissue mass located in the larynx. Most lesions manifest by the 2nd year of life and, depending on the size, patients may present with changes in voice, dysphagia, stridor, airway obstruction and/or respiratory distress. Cystic hygroma of the neck is frequently associated.", "ORPHA ID": 137926, "Summary": ""}
{"Disease Name": "Primary lateral sclerosis", "Disease Definition": "Primary lateral sclerosis (PLS) is an idiopathic non-familial motor neuron disease characterized by slowly progressive upper motor neuron dysfunction leading to spasticity, mild weakness in voluntary muscle movement, hyperreflexia, and loss of motor speech production.", "ORPHA ID": 35689, "Summary": ""}
{"Disease Name": "Primary lipodystrophy", "Disease Definition": "A heterogeneous group of very rare diseases characterized by a generalized or localized loss of body fat (lipoatrophy).", "ORPHA ID": 90970, "Summary": "Epidemiology\nPrevalence has been estimated at less than 1 case in 100 000.\nClinical description\nIn some forms, lipoatrophy is associated with selective hypertrophy of other fat deposits. Clinical signs of insulin resistance are often present: acanthosis nigricans, signs of hyperandrogenism. All lipodystrophies are associated with dysmetabolic alterations with insulin resistance, altered glucose tolerance or diabetes, and hypertriglyceridemia leading to a risk of acute pancreatitis. The diabetes leads to chronic complications involving the retina, kidney, nerves and cardiovascular system, and to liver steatosis that could result in cirrhosis.\nEtiology\nGenetic forms of generalized lipodystrophy (or Berardinelli-Seip syndrome, see this term) result, in most cases, from recessive mutations in one of two genes: either BSCL2 coding seipin or BSCL1 coding AGPAT2, an acyltransferase involved in triglyceride synthesis. The origin of acquired generalized lipodystrophy (Lawrence syndrome, see this term) is unknown but the syndrome is sometimes associated with signs of autoimmunity. Partial lipodystrophies can be familial with dominant transmission. Heterozygous mutations have been identified in the LMNA gene encoding nuclear lamin A/C, or in the PPARG gene encoding the adipogenic transcription factor PPARgamma. Some less typical forms of lipodystrophy, associated with signs of premature aging, have been linked to mutations in the LMNA gene or in the ZMPSTE24 gene encoding the protease responsible for the maturation of prelamin A into lamin A. Acquired partial lipodystrophy (Barraquer-Simons syndrome, see this term) is characterized by cephalothoracic fat loss. Its etiology is unknown but mutations in the LMNB2 gene, encoding the lamina protein lamin B2, may represent susceptibility factors. Highly active antiretroviral treatments for HIV infection are currently the most frequent cause of acquired secondary lipodystrophic syndromes.\nDiagnostic methods\nThe genetic diagnosis is performed in specialized laboratories and, in the most severe forms, antenatal diagnosis may be proposed.\nManagement and treatment\nTreatment of diabetes, dyslipidemia and the resulting complications involves the classical intervention strategies. Insulin-sensitizing drugs are useful. Therapeutic trials with recombinant human leptin in patients with very low leptin levels have reported good results with respect to the metabolic and liver alterations.\nPrognosis\nThe prognosis is linked to the precocity and severity of the diabetic, cardiovascular and liver complications.\n\n                            Last update: \n                            April 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Jacqueline CAPEAU"}
{"Disease Name": "Primary lymphedema", "Disease Definition": "Primary lymphedema is a lymphatic system malformation characterized by swelling of an extremity that can be associated with other lymphatic effusions, due to an underlying developmental anomaly of the lymphatic system (abnormal lymphoangiogenesis). It can be hereditary or not and be congenital or late onset.", "ORPHA ID": 77240, "Summary": ""}
{"Disease Name": "Primary lymphoma of the conjunctiva", "Disease Definition": "Primary lymphoma of the conjunctiva is an extremely rare clonal lymphoid proliferation of the ocular surface, with an indolent course. Clinically it presents with treatment-resistant conjunctivitis, ptosis, excessive tear production or as a painless, salmon-pink, ''fleshy'' patch, with a smooth or multinodular surface, on the bulbar conjunctiva. Histologically it is usually B-cell Non-Hodgkin lymphoma (most often extranodal marginal zone B-cell lymphoma, followed by follicular and diffuse large B-cell lymphoma), with conjunctival T-cell Non-Hodgkin lymphoma being very rare.", "ORPHA ID": 319667, "Summary": ""}
{"Disease Name": "Primary mediastinal large B-cell lymphoma", "Disease Definition": "A rare subtype of diffuse large B-cell lymphoma (DLBCL), arising from B cells of thymic origin, predominantly affecting women between the ages of 20-30, and that usually presents with a bulky and rapidly expanding anterior mediastinal mass, often with pleural and pericardial effusions, and that can invade the lungs, superior vena cava, pleura, pericardium, and chest wall, leading to manifestations of cough, dyspnea, and superior vena cava syndrome.", "ORPHA ID": 98838, "Summary": ""}
{"Disease Name": "Primary melanoma of the central nervous system", "Disease Definition": "Primary melanoma of the central nervous system is a rare tumor of meninges arising from leptomeningeal melanocytes, typically in the perimedullary or high cervical region, in the absence of melanoma outside the CNS. The tumor is typically a darkly pigmented, solid mass, often containing hemorrhagic or necrotic areas, composed of sheets of pleomorphic cells with prominent nucleoli, with frequent mitotic figures and parenchymal invasion. Intracranial tumor may present with signs of raised intracranial pressure, focal neurological symptoms related to tumor location, seizures or subarachnoid hemorrhage, spinal tumor may present with back pain, muscle weakness, numbness, plegia or urinary incontinence.", "ORPHA ID": 252050, "Summary": ""}
{"Disease Name": "Primary membranoproliferative glomerulonephritis", "Disease Definition": "A rare glomerular disease characterized by a pattern of glomerular injury on kidney biopsy with characteristic light microscopic changes: mesangial hypercellularity, endocapillary proliferation, and thickening of the glomerular basement membrane (GBM). On the basis of immunofluorescence (IF) the disorder is divided into C3 glomerulopathy (C3G) or immunoglobulin-mediated membranoproliferative glomerulonephritis. Through electron microscopy C3G is further divided into Dense deposit disease, with highly electrondense deposits in the glomerular basement membrane, and C3 glomerulonephritis, with mesangial, intramembranous, subendothelial and subepithelial deposits. Secondary causes (autoimmune, infectious, malignancies) are excluded.", "ORPHA ID": 54370, "Summary": ""}
{"Disease Name": "Primary membranous glomerulonephritis", "Disease Definition": "A rare glomerular disease, histologically characterized by thickening of the capillary wall, with immune deposits predominantly containing IgG4 and C3 on the sub-epithelial side, and typically manifesting with nephrotic syndrome.", "ORPHA ID": 97560, "Summary": "Epidemiology\nGlobally, the overall incidence of membranous nephropathy (MN) is approximately 1/100,000, of which approximately 80% are Primary membranous nephropathy (PMN). The male to female ratio is 2:1. PMN is rare in children.\nClinical description\nDisease onset is typically between 50-60 years of age, presenting with either nephrotic syndrome (edema with confirmed proteinuria, hypoalbuminemia and hyperlipidemia), or nephrotic-range or subnephrotic proteinuria. Renal function is typically normal at presentation. Disease progression is gradual, and occasionally complicated by thrombo-embolic events. Hematuria, hypertension, and reduced glomerular filtration rate can present initially or develop during the disease course. End stage renal disease (ESRD) develops in up to a third of patients 10 years after disease onset.\nEtiology\nPMN is an auto-immune disease limited to the kidney. Antibodies to the podocytic antigen m-type phospholipase receptor (PLA2R) are detectable in approximately 70% of patients, and antibodies against thrombospondin type-1 domain-containing 7A (THSD7A) in approximately 3% of patients. The pathophysiology of antibody formation is unclear. A genetic predisposition and associations with HLA genes and with polymorphisms in the PLA2R gene have been found.\nDiagnostic methods\nTypically, diagnosis of PMN is made on kidney biopsy. Diagnostic features include capillary wall thickening, normal cellularity, IgG and C3 along capillary walls on immunofluorescence, and subepithelial deposits on electron microscopy. However, a diagnosis of PMN is strongly suspected on detection of circulating PLA2R antibodies.\nDifferential diagnosis\nSecondary causes of MN should be excluded. These include malignances, infections (Hepatitis B, hepatitis C, syphilis), systemic diseases (SLE, sarcoidosis, IgG4-related kidney disease), drugs (NSAID'S, penicillamine, gold), and paraproteinemia.\nManagement and treatment\nAll patients should be managed with optimized conservative therapy, targeting blood pressure, proteinuria, and cholesterol. Use of angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker along with statins is preferred. Patients should also adhere to life-style changes (stop smoking, body weight, dietary sodium and protein restrictions). In patients with severe hypoalbuminemia, prophylactic anticoagulant therapy should be considered. In adults without high risk features, a period of 6 months of conservative therapy is advised before considering additional immunosuppressive therapy. Laboratory parameters (serum creatinine, serum albumin, urine protein to creatinine ratio, anti PLA2R ab levels, urinary LMW proteins) and blood pressure are important parameters to estimate (risk of) progression. In patients with progressive renal insufficiency, or patients with severe nephrotic syndrome and high risk of progression, treatment with immunosuppressive drugs should be started. Current guidelines discuss the use of alkylating agents, calcineurin inhibitors, and rituximab. Prednisone monotherapy is not effective in adults.\nPrognosis\nPatients with non-nephrotic proteinuria typically have non-progressive disease. In patients with nephrotic syndrome, the natural course of disease is variable ranging from spontaneous remission to ESRD. With current treatment strategies the risk of ESRD has decreased, and only 5-10 % of patients will be non-responsive.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Laura CESCA  - Pr Pierre RONCO | ERKNet* - Dr Marina VIVARELLI | ERKNet* - Pr J.F.M. [Jack] WETZELS | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome", "Disease Definition": "Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome is a rare, genetic, neurologic disease characterized by congenital microcephaly, severe, early-onset epileptic encephalopathy (manifesting as intractable, myoclonic and/or tonic-clonic seizures), permanent, neonatal, insulin-dependent diabetes mellitus, and severe global developmental delay. Muscular hypotonia, skeletal abnormalities, feeding difficulties, and dysmorphic facial features (including narrow forehead, anteverted nares, small mouth with deep philtrum, tented upper lip vermilion) are frequently associated. Brain MRI reveals cerebral atrophy with cortical gyral simplification and aplasia/hypoplasia of the corpus callosum.", "ORPHA ID": 306558, "Summary": ""}
{"Disease Name": "Primary microcephaly-mild intellectual disability-young-onset diabetes syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder characterized by congenital, persistent microcephaly, low birth weight, short stature, childhood-onset seizures, global development delay, mild intellectual disability, and adolescent or young adult-onset diabetes mellitus. Gait ataxia, skeletal abnormalities, dorsocervical fat pad, and infantile cirrhosis may also be associated. Brain morphology is typically normal, although delayed myelination and hypoplastic brainstem have been reported.", "ORPHA ID": 391408, "Summary": ""}
{"Disease Name": "Primary myelofibrosis", "Disease Definition": "A rare myeloproliferative neoplasm characterized by stem-cell derived clonal over proliferation of mature myeloid lineages, such as erythrocytes, leukocytes, and megakaryocytes, with variable degrees of megakaryocyte atypia, associated with reticulin and/or collagen bone marrow fibrosis, osteosclerosis, ineffective erythropoiesis, angiogenesis, extramedullary hematopoiesis, and abnormal cytokine expression.", "ORPHA ID": 824, "Summary": "Epidemiology\nThe annual incidence of primary myelofibrosis (PMF) is approximately 1 case per 100,000 individuals, although an increased prevalence is noted in Ashkenazi Jews.\nClinical description\nAge at diagnosis is usually in adulthood, around the sixth decade of life. Clinical manifestations depend on the type of blood cell(s) affected and may include severe anemia, pallor, petechiae, ecchymosis, bleeding, thrombosis, pancytopenia, pruritus, hypermetabolic state, marked hepato/splenomegaly, and/or constitutional symptoms, such as fatigue, fever, and night sweats. Symtomatic portal hypertension and non hepatosplenic extramedullary hematopoiesis may lead to variceal bleeding, ascites, pleural effusion and/or pulmonary hypertension. Leukemic transformation is observed in approximately 20% of patients.\nEtiology\nEvidence strongly suggests that PMF is attributed to the dysregulation of the JAK2-STAT5 signaling pathway. The mutation JAK2V617F on the JAK2 gene is the most prevalent mutation reported. Additionally, mutations in the MPL gene, which encodes the thrombopoietin receptor, and CALR. Furthermore, the megakaryocyte lineage contributes to the pathogenesis as these cells produce various profibrotic, angiogenic and pro-inflammatory cytokines, which are believed to play a role in bone marrow fibrosis, osteosclerosis and angiogenesis.\nDiagnostic methods\nThe diagnosis is based on the presence of major and minor criteria. It requires meeting all three major criteria, and at least one minor criterion. Major criteria include megakaryocytic proliferation and presence of reticulin and/or collagen fibrosis grades 2 or 3; the absence of other sign of blood and bone marrow cells proliferation and tumour (WHO classification); the mutations test for JAK2, CALR or MPL. Minor criteria include results of blood test for anemia with leukocytosis, increased LDH level and leukoerythroblastosis.\nDifferential diagnosis\nDifferential diagnosis of PMF includes other closely related myeloid neoplasms, such as chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, myelodysplastic syndromes, chronic myelomonocytic leukemia, acute panmyelosis with myelofibrosis and acute megakaryoblastic leukemia.\nGenetic counseling\nThe pathology is not inherited although it is linked with important gene mutations which occur at any time in life. Although most cases appear to be sporadic, familial predisposition has been recognized for many years in a subset of cases and epidemiological studies have indicated the presence of common susceptibility alleles.\nManagement and treatment\nHistorically, splenectomy and hematopoietic stem cell transplantation (HSCT) have been the treatment for PMF, with the latter being the only treatment modality which prolongs survival or potentially cures PMF. HSCT, however, is associated with important morbidity and high transplant-related death therefore, individual patient risk-benefit assessment is necessary. Drug therapy with JAK inhibitors improves symptoms and splenomegaly but has not been shown to favorably modify disease natural history or prolong survival and therefore risk-benefit should also be carefully evaluated.\nPrognosis\nSeverity and prognosis are variable depending on the affected genes and symptoms. Risk assessment using the International Prognostic Scoring System (IPSS) and the Dynamic IPSS (DIPSS) has proven useful in classifying patients into risk categories at diagnosis and later time points. A more recent score (MIPSS70) is particularly useful for risk stratification for transplantation-age patients.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Elisa RUMI"}
{"Disease Name": "Primary non-essential cutis verticis gyrata", "Disease Definition": "A rare genetic dermis disorder characterized by slowly progressive thickening of the scalp, which becomes raised and forms ridges and furrows with symmetrical distribution resembling the cerebral gyri and cannot be flattened by traction or pressure, associated with ophthalmologic (e.g. congenital cataract) and/or neurological abnormalities (e.g. intellectual disability, epilepsy, microcephaly, encephalopathy).", "ORPHA ID": 357225, "Summary": ""}
{"Disease Name": "Primary non-gestational choriocarcinoma of ovary", "Disease Definition": "Primary non-gestational choriocarcinoma of ovary is a rare ovarian germ cell malignant tumor (see this term), arising from primordial germ cells, usually presenting with nausea, vomiting, abdominal pain, menstrual irregularities, and characterized by fast growth pattern, metastasis to lung, liver and brain and production of human chorionic gonadotrophin (hCG). It is apparently chemoresistant and has a worse prognosis than gestational choriocarcinoma (see this term) and hence should be distinguished from the latter by DNA polymorphism.", "ORPHA ID": 289356, "Summary": ""}
{"Disease Name": "Primary oculocerebral lymphoma", "Disease Definition": "Primary oculocerebral lymphoma is a rare, primary, organ-specific, extranodal non-Hodgkin's lymphoma (typically diffuse large B-cell lymphoma), simultaneously affecting the intraocular compartments (retina, vitreous, optic nerve, uvea and others) and the central nervous system (commonly the cerebellum, spinal cord or pia mater). The presenting symptoms vary depending on the localization of the tumor and may include vitreous floaters or blurred vision, raised intracranial pressure (headache, vomiting, papilledema) and/or focal neurological deficits.", "ORPHA ID": 279897, "Summary": ""}
{"Disease Name": "Primary orthostatic tremor", "Disease Definition": "A rare tremor disorder characterized by an isolated high frequency (>12 Hz) tremor that occurs when standing, typically in weight-bearing muscles, causing a feeling of unsteadiness or discomfort, which disappears when not standing.", "ORPHA ID": 238606, "Summary": "Epidemiology\nPrevalence is unknown, however, hundreds of cases have been reported all over the world, with female preponderance (sex ratio: 2:1), and a mean onset around 55-60 years old (range 13-85).\nClinical description\nPrimary orthostatic tremor (POT) appears on standing and is associated with an intense and disabling sense of unsteadiness, a fear of falling, discomfort, dizziness, shaking, trembling sensations and/or trembling of limbs and trunk. An action tremor (5-10 Hz) may be present in the arms. Symptoms during stance are reduced/abolished by walking, support, sitting, and lying down. Patients often shuffle, wobble, or seek support when standing. Prevalent signs during stance and walking are bent knees, hem sign (trembling of hem of skirt/shirt), and a broad base of support. Tandem gait may be abnormal (with normal heel-to-shin test). The fast tremor may be visible, palpable, and muscle auscultation may reveal a thudding sound (helicopter sign). The 'Orthostatic Tremor Severity and Disability Scale (OT-10)' is an online-available self-report scale which captures OT-related severity and disability based on the presentation of symptoms, such as unsteadiness, discomfort, or shaking when standing, and how they affected the patient's activities of daily living over the course of their past week. The term orthostatic tremor plus is used when OT is accompanied by other neurological symptoms.\nEtiology\nThe pathophysiology of POT is unknown. Strong intermuscular coherence at tremor frequency, also between bilateral head muscles, is thought to be driven by a supraspinal (possibly cerebellar or brainstem) oscillator. The oscillator may also be active in healthy subjects who are made unsteady; POT may represent an exaggerated activity in otherwise physiological pathways involved in postural responses. An alternative hypothesis is that POT is triggered by the weight of the body when standing still, and that the slight imbalance which ensues aggravates the tremor.\nDiagnostic methods\nDiagnosis is based on clinical examination of symptoms. The diagnostic procedure consists in confirmation of >12 Hz tremor in weight-bearing muscles during stance and absence after sitting (by electromyography) and not placing weight on the feet. There should be no extrapyramidal, cerebellar and/or other signs (except arm tremor), nor abnormal findings at adaptive optics (AO) imaging, electroneurography, or blood tests, which might point to OT-plus, secondary OT, or a comorbidity.\nDifferential diagnosis\nDifferential diagnoses include AO slow OT (4-12 Hz), orthostatic myoclonus (irregular bursts), essential tremor, Parkinson's disease, functional neurological disorder, restless legs syndrome, polyneuropathy, neurogenic claudication, and vertigo.\nGenetic counseling\nA positive family history is rare.\nManagement and treatment\nThere is no cure or standard treatment for POT. Effective medication includes benzodiazepines (clonazepam), anti-seizure medication (gabapentin and perampanel), and possibly beta-blockers (propranolol). Treatment response can be poor or wear off, and side-effects can limit daily dosages. Surgical treatment, described in limited numbers of medication refractory patients, includes deep brain stimulation, which showed (variable) improved ability to stand still, possibly diminishing over time, and side-effects. Bilateral spinal cord stimulation improved ability to stand for a majority of patient but had no effect in some. Physical aids (portable/high stool), training muscle strength, conditioning, medical statement and patient brochure/leaflet might be helpful.\nPrognosis\nPOT is often slowly progressive. Severity of symptoms, effect of treatment, and experienced quality of life vary largely between patients.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Anne-Fleur VAN ROOTSELAAR"}
{"Disease Name": "Primary pediatric heart tumor", "Disease Definition": "Cardiac tumours are benign or malignant neoplasms arising primarily in the inner lining, muscle layer, or the surrounding pericardium of the heart. They can be primary or metastatic.", "ORPHA ID": 875, "Summary": "Epidemiology\nPrimary cardiac tumours are rare in paediatric practice with a prevalence of 1.7/1000 to 28/1000 in autopsy series. In contrast, the incidence of cardiac tumours during foetal life has been reported to be approximately 1.4/1000. The incidence of cardiac metastases associated with all types of malignant tumours is estimated to be approximatively 1% (and is 10-20 times higher than primary malignancies of the heart).\nClinical description\nThe vast majority of primary cardiac tumours in children are benign, whilst approximately 10% are malignant. In contrast, the majority of secondary tumours are malignant. In adults, however, the frequency and type of cardiac tumours in adults differ from those in children with 75% being benign and 25% being malignant. Myxomas are the most common primary tumours in adults constituting 40% of benign tumours. Sarcomas make up 75% of malignant cardiac masses. Rhabdomyoma is the most common cardiac tumour during foetal life and childhood. It accounts for more than 60% of all primary cardiac tumours. The manifestations of a cardiac tumour in foetal life include arrhythmia, congestive heart failure, hydrops, and not infrequently stillbirth. In postnatal life cardiac tumours may lead to cyanosis, murmur, respiratory distress, myocardial dysfunction, valvular insufficiency, arrhythmias, and sudden death.\nDiagnostic methods\nEchocardiography, Computing Tomography (CT) and Magnetic Resonance Imaging (MRI) of the heart are the main non-invasive diagnostic tools. Cardiac catheterisation is seldom necessary. Tumour biopsy with histological assessment remains the gold standard for confirmation of the diagnosis.\nManagement and treatment\nSurgical resection of primary cardiac tumours should be considered to relieve symptoms and mechanical obstruction to blood flow. Patients with primary cardiac malignancies may benefit from palliative surgery but this approach should not be recommended for patients with metastatic cardiac tumours. Surgery, chemotherapy and radiotherapy may prolong survival.\nPrognosis\nThe outcome of surgical resection in symptomatic, non-myxomatous benign cardiac tumours is favourable. The prognosis for malignant primary cardiac tumours is generally extremely poor.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Joseph DE GIOVANNI  - Dr Jonathan PARSONS  - Dr Orhan UZUN  - Dr Gordon VUJANIC  - Dr Dirk WILSON"}
{"Disease Name": "Primary peritoneal carcinoma", "Disease Definition": "Primary peritoneal carcinoma (PPC) is a rare malignant tumor of the peritoneal cavity of extra-ovarian origin, clinically and histologically similar to advanced-stage serous ovarian carcinoma (see this term).", "ORPHA ID": 168829, "Summary": "Epidemiology\nPPC accounts for about 10% of pelvic serous carcinomas.\nClinical description\nIt is almost exclusively found in women. PPC can occur many years after oophorectomy performed for benign diseases or prophylactic oophorectomy. The tumor appears during adulthood with a mean age at diagnosis of 60 years. Clinical features include abdominal swelling, constipation, gastrointestinal disorders, nausea, vomiting, anorexia and weight loss. The tumor develops in the peritoneum and spreads to the abdomen, pelvis and ovaries.\nEtiology\nPrimary peritoneal carcinoma has an epithelial origin and probably derives from coelomatic embryonal epithelium. The fallopian tubes are suspected as the primary site. Women with breast cancer type 1 (BRCA1) gene mutations present an increased risk of developing a PPC.\nDiagnostic methods\nDiagnosis is based on elevated cancer markers, with elevated cancer antigen 125 (CA125), and on imaging examinations such as ultrasound and chest-abdominal computed tomography (CAP-CT). Diagnosis is confirmed by biopsies performed during laparotomy or laparoscopy, especially when ovaries are normal or absent.\nDifferential diagnosis\nThe main differential diagnosis is epithelial ovarian cancer. PPC and serous ovarian carcinoma are histologically similar, and it is often impossible to determine the organ of origin at late stages when the ovaries, abdominal cavity and fallopian tubes are all involved.\nManagement and treatment\nManagement should be multidisciplinary and must be discussed by a panel of physicians in a specialized center. There are currently no validated recommendations on clinical management and no cytotoxic agents have been granted a European Marketing Authorization (MA) in this indication. Combination of cytoreductive surgery (visceral resections and peritonectomy procedures) with hyperthermic intraperitoneal chemotherapy (HIPEC) (off-label use) has been considered in specific patients (i.e. young patients with good general status and low tumor volume) before or after systemic chemotherapy (off-label use) if the disease does not respond to optimal cytoreductive surgery.\nPrognosis\nPrognosis is poor, similar to or worse than that of ovarian carcinoma.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Olivier GLEHEN"}
{"Disease Name": "Primary progressive aphasia", "Disease Definition": "Primary progressive aphasia (PPA) is a neurodegenerative disorder, characterized by a primary dissolution of language, with relative sparing of other mental faculties for at least the first 2 years of illness. PPA is recognized as the language variant in the frontotemporal dementia (FTD; see this term) spectrum of disorders. PPA can be classified into 3 subtypes based on specific speech and language features: semantic dementia (SD), progressive non-fluent aphasia (PNFA) and logopenic progressive aphasia (lv-PPA) (see these terms).", "ORPHA ID": 95432, "Summary": ""}
{"Disease Name": "Primary progressive apraxia of speech", "Disease Definition": "Primary progressive apraxia of speech is a rare neurodegenerative disease characterized by impaired planning or programming of the movements for speech, leading to phonetically and prosodically abnormal speech, in absence, at onset, of any other neurological features (such as aphasia, memory loss, pyramidal signs). Patients usually present articulatory distortions/groping, slow rate, distorted sound substitutions and/or trial and error articulatory movements which begin insiduously and worsen over time.", "ORPHA ID": 314566, "Summary": ""}
{"Disease Name": "Primary progressive freezing gait", "Disease Definition": "Primary progressive freezing gait is a rare, heterogeneous, progressively incapacitating neurodegenerative disease characterized by freezing of gait (usually during the first 3 years), later associating postural instability, eventually resulting in a wheelchair-bound state. Other features may include mild bradykinesia, rigidity, postural tremor, hyperreflexia, speech disorder and dementia. The disease is unresponsive to dopaminergic treatments.", "ORPHA ID": 75567, "Summary": ""}
{"Disease Name": "Primary pulmonary hypoplasia", "Disease Definition": "Primary pulmonary hypoplasia is a rare, isolated, genetic developmental defect during embryogenesis characterized by congenital malformation of pulmonary parenchyma with absence of other anomalies. Neonatally patients present with decreased breath sounds, small lung volume and severe respiratory distress that is not responsive to aggressive treatment (including surfactant instillation/ mechanical respiratory support). It is usually not compatible with life.", "ORPHA ID": 2257, "Summary": ""}
{"Disease Name": "Primary pulmonary lymphoma", "Disease Definition": "A rare neoplastic disease defined as a clonal lymphoid proliferation affecting one or both lungs (parenchyma and/or bronchi) in a patient with no detectable extrapulmonary involvement at diagnosis or during the subsequent 3 months. PPL comprises low grade/indolent B cell PPL forms, the most frequent form represented by the marginal B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma) and other non-MALT low grade lymphomas; and more rarely high-grade B-cell PPL (including diffuse large B cell lymphoma) and lymphomatoid granulomatosis (LYG).", "ORPHA ID": 2420, "Summary": "Epidemiology\nPrimary pulmonary lymphoma (PPL) is very rare and represents only 3-4% of extranodal non-Hodgkin lymphoma (NHL, less than 1% of NHL, and only 0.5-1% of primary pulmonary malignancies. MALT lymphoma represents 85-90% of PPL cases and is the most common type of pulmonary lymphoma. The ratio of male to female patients is close to 1:1.\nClinical description\nPPL onset generally occurs in the 5th and 6th decades of life, and very occasionally affects those under 30 years of age. The clinical presentations of PPL are variable and depend on the distinct B-cell histological subtype: Low grade B cell PPL including MALT lymphomas have an indolent presentation while high-grade B-cell PPL and LYG may have an aggressive clinical picture. 50% of patients with MALT lymphoma are asymptomatic at presentation. When present, symptoms are not specific and include coughing, mild dyspnea, chest pain, wheezing, and occasionally hemoptysis. Fever and weight loss are present in less than 25% of cases. Patients with high-grade B-cell PPL usually present respiratory manifestations, fever and weight loss while patients with LYG frequently have brain, kidney and otorhinolaryngeal manifestations.\nEtiology\nPPL are lymphoproliferative disorders that originate frequently from clonal proliferation of the B cell-lineage, most commonly marginal zone B-cells of MALT of the bronchus. MALT lymphomas are thought to be acquired as a result of chronic antigenic stimulation such as smoking, autoimmune disease, or infection while LYG is associated with Epstein-Barr virus (EBV) infection.\nDiagnostic methods\nDiagnosis of PPL relies on clinical and radiographic findings which are nonspecific and include solitary nodule, multiple ill-defined nodules, consolidated mass with air bronchograms, pleural effusions, atelectasis, and cavities. Histological examination helps diagnose the type of tumor. Immunohistochemical analysis reveals CD19-CD20+ cells.\nDifferential diagnosis\nRadiological appearance may mimic cryptogenic organizing pneumonia, lymphoid interstitial pneumonia (LIP), diffuse lymphoid hyperplasia, follicular bronchitis and bronchioloalveolar carcinoma. LIP may be associated with PPL in case of autoimmune disease.\nManagement and treatment\nThe treatment options include watchful observation for indolent types of PPL, surgery in localized tumors, chemotherapy with or without rituximab if the lesions are diffuse or involve both lungs and radiotherapy for patients with a unique, small lesion.\nPrognosis\nThe prognosis for low grade PPL is good with survival equal to that of the general population. However, survival rate for high grade PPL and LYG can be poorer.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Jacques CADRANEL"}
{"Disease Name": "Primary renal tubular acidosis", "Disease Definition": "A group of rare renal tubular diseases characterized by primary defects in bicarbonate reabsorption from urine (proximal renal tubular acidosis) and/or hydrogen excretion into the lumen (distal renal tubular acidosis), resulting in metabolic acidosis with hyperchloremia and a normal plasma anion gap. The glomerular filtration rate is relatively normal.", "ORPHA ID": 314822, "Summary": ""}
{"Disease Name": "Primary sclerosing cholangitis", "Disease Definition": "Primary sclerosing cholangitis (PSC) is a rare, slowly progressive liver disease characterized by inflammation and destruction of the intra- and/or extra-hepatic bile ducts that lead to cholestasis, liver fibrosis, liver cirrhosis and ultimately liver failure.", "ORPHA ID": 171, "Summary": "Epidemiology\nThe prevalence of PSC in Europe ranges from 1/446,000-1/6,170. A male preponderance is observed with a male to female ratio of approximately 2:1.\nClinical description\nPSC can occur at any age with a peak incidence around 40 years of age. Symptoms and clinical findings are variable, depending on the stage of the disease. In early stages, unspecific manifestations such as fever, fatigue, pruritus, malaise, abdominal pain, and weight loss are reported, however about 40-50% of patients may be asymptomatic at time of diagnosis. Hepatomegaly, splenomegaly, jaundice, portal hypertension and, in more advanced cases, spider angiomata, ascites and muscle atrophy are observed. The disease course is also highly variable, but in the majority of cases, PSC is slowly progressive, leading to liver cirrhosis, liver failure and the need for liver transplantation over a period of 13-21 years following diagnosis. Several immune-mediated comorbidities are observed in PSC. The most common co-existing condition is inflammatory bowel disease, reported in up to 60-80% of patients of Northern European decent. Other immune-mediated conditions, such as autoimmune hepatitis, thyroid disease, type 1 diabetes mellitus, and celiac disease, are also observed with slightly increased frequencies in PSC patients. A proportion of PSC patients develop malignancies; mainly cholangiocarcinoma, but also increased risk of carcinoma of the large intestine in patients with concomitant IBD. Small-duct PSC is a PSC-variant manifesting with chronic cholestasis, biochemical and histological findings similar to those found in PSC, and a normal cholangiography.\nEtiology\nThe precise etiology of PSC has not yet been established, but it is believed to be multifactorial. Genetic susceptibility factors are known to be involved, and a strong association to genetic variants within the HLA-region on chromosome 6 is observed. The disease is thought to be related to an abnormal immune response to a still unidentified environmental stimulus.\nDiagnostic methods\nPSC is suspected based on clinical manifestations and altered liver function tests and diagnosis is confirmed through magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) showing bile duct changes with strictures and dilatations characteristic of the disease.\nDifferential diagnosis\nDifferential diagnoses include other hepatic diseases, such as autoimmune hepatitis and primary biliary cholangitis. Exclusion of multiple secondary causes leading to PSC-like bile duct changes, such as IgG4-associated sclerosing cholangitis, mast cell cholangiopathy, infections, biliary calculi or trauma, and other identifiable causes of insults to the biliary tree (leading to the ERCP or MRCP features seen in PSC) is mandatory to establish the diagnosis of PSC.\nManagement and treatment\nImmunosuppressants and chelators are used to treat the symptoms and manage the complications, however, to date there are no medical therapies that cure or alter the disease course of PSC. Replacement therapy of fat-soluble vitamins A, D, E, and K is frequently necessary since patients frequently present deficiency of these vitamins. Liver transplantation is currently the only definitive treatment for patients with advanced disease and the majority of patients require a liver transplantation 13-21 years after diagnosis; either due to disease progression or disease complications, such as treatment-resistant bacterial cholangitis. Endoscopic dilatation, with or without stenting, of biliary strictures may be performed to relieve symptoms of biliary obstruction.\nPrognosis\nPrognosis after liver transplantation is generally good, however, in a proportion of patients PSC may recur in the transplanted liver, with recurrence rates varying from 10-37%.\n\n                            Last update: \n                            March 2017\n\n\n                            - Expert reviewer(s): \n                            Dr Trine FOLSERAAS  - Dr Tom Hemming KARLSEN"}
{"Disease Name": "Primary Sjögren syndrome", "Disease Definition": "A rare systemic autoimmune disease characterized by exocrine gland dysfunction, resulting predominately in keratoconjunctivitis sicca and xerostomia, but also affecting exocrine glands of the skin, as well as respiratory, urogenital, and digestive tract. Extraglandular manifestations include arthritis, interstitial lung disease, renal disease, and peripheral neuropathy. The disease is accompanied by a substantially increased risk to develop B-cell non-Hodgkin lymphoma, especially MALT (mucosa-associated lymphoid tissue) lymphoma.", "ORPHA ID": 289390, "Summary": ""}
{"Disease Name": "Primary syringomyelia", "Disease Definition": "A rare central nervous system malformation characterized by a fluid-filled longitudinally oriented cavity (syrinx) within the spinal cord, which may or may not communicate with the central canal, does not have an ependymal lining, and is either idiopathic or seen as a familial malformation. Clinical manifestations in symptomatic patients include neuropathic pain, as well as sensory and motor disturbances. Typical presentations may be cape-like loss of pain and temperature sensation along the torso and arms, or disproportionately greater motor impairment in upper compared to lower extremities.", "ORPHA ID": 99856, "Summary": ""}
{"Disease Name": "Primary tethered cord syndrome", "Disease Definition": "Primary tethered cord syndrome is a genetic, non-syndromic congenital malformation of the neurenteric canal, spinal cord and column characterized by progressive neurologic deterioration (pain, sensorimotor deficits, abnormal gait, decreased tone or abnormal reflexes), musculoskeletal changes (foot deformities and asymmetry, muscle atrophy, limb weakness and numbness, gait disturbances, scoliosis) and/or genitourinary manifestations (bladder and bowel dysfunction). Midline cutaneous stigmata in the lumbosacral region, such as turfs of hair, skin appendages, dimples, subcutaneous lipomas, skin discoloration or hemangiomas, are frequently associated.", "ORPHA ID": 268861, "Summary": ""}
{"Disease Name": "Primary triglyceride deposit cardiomyovasculopathy", "Disease Definition": "A rare inborn error of metabolism characterized by massive accumulation of triglycerides in the myocardium and coronary arteries, while plasma triglyceride levels are normal. Patients present in adulthood with signs and symptoms of coronary artery disease and severe heart failure. Concomitant skeletal myopathy is common. Vacuole formation in polymorphonuclear leukocytes is typically observed.", "ORPHA ID": 565612, "Summary": ""}
{"Disease Name": "Primary unilateral adrenal hyperplasia", "Disease Definition": "Primary unilateral adrenal hyperplasia (PUAH) is a surgically-correctable form of primary (hyper) aldosteronism (PA; see this term) characterized by renin suppression, unilateral aldosterone hypersecretion, and moderate to severe hypertension secondary to hyperplasia of the adrenal gland.", "ORPHA ID": 231580, "Summary": "Epidemiology\nThe prevalence of primary unilateral adrenal hyperplasia is unknown.\nClinical description\nPUAH may be associated with hypokalemia, which, when present, may be symptomatic with muscular weakness, cramps, paresthesia or palpitations with or without atrial fibrillation.\nEtiology\nThe etiology of PUAH is not known.\nDiagnostic methods\nDiagnostic methods include peripheral aldosterone and renin determinations, adrenal venous sampling which makes it possible to differentiate unilateral from bilateral aldosterone hypersecretion, and CT scan showing normal adrenals or unilateral adrenal hyperplasia.\nManagement and treatment\nUnilateral adrenalectomy abolishes aldosterone hypersecretion and hypokalemia in most patients with PUAH.\nPrognosis\nBlood pressure is significantly improved in the majority of the patients, but hypertension is cured in only 50% of cases.\n\n                            Last update: \n                            July 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence AMAR  - Pr Pierre-François PLOUIN  - Dr Olivier STEICHEN"}
{"Disease Name": "Primitive neuroectodermal tumor of the cervix uteri", "Disease Definition": "Primitive neuroectodermal tumor of the cervix uteri is a rare cancer of cervix uteri derived from neural crest cells, histologically composed of small, round neoplatic cells with variable degree of neural, glial and ependymal differentiation. Macroscopically, the tumor is often a large, soft, poorly circumscribed mass with infiltrative borders and necrotic areas. It presents with dysfuntional vaginal bleeding or discharge, lower abdominal pain and uterine enlargement.", "ORPHA ID": 213812, "Summary": ""}
{"Disease Name": "Primitive neuroectodermal tumor of the corpus uteri", "Disease Definition": "Primitive neuroectodermal tumor of the corpus uteri is a rare cancer of corpus uteri derived from neural crest cells, characterized by small, round neoplastic cells with variable degree of neural, glial and ependymal differentiation. Macroscopically, the tumor is often a large, poorly circumscribed polypoid mass with necrotic areas and hemorrhage. It usually presents with lower abdominal or pelvic pain, irregular vaginal bleeding or discharge, pelvic mass and uterine enlargement.", "ORPHA ID": 213630, "Summary": ""}
{"Disease Name": "Primitive portal vein thrombosis", "Disease Definition": "Portal vein thrombosis (PVT) is associated with acute (recent) or chronic (long-standing) thrombosis of the portal system.", "ORPHA ID": 854, "Summary": "Epidemiology\nPrevalence of the primary form (PVT not associated with cirrhosis or a tumour) is estimated at between 1 and 9/100,000. PVT may occur at any age.\nClinical description\nAcute thrombosis may be asymptomatic or may manifest as abdominal pain, fever and intestinal ischemia (ileus, rectal bleeding, and ascites). In some cases, intestinal necrosis (manifesting as peritonitis and multivisceral failure) may occur if treatment is delayed. Chronic PVT is associated with cavernous transformation resulting in portal hypertension. PVT may be discovered fortuitously as a result of investigations for hypersplenism or intestinal varices. Haemorrhage due to rupture of these varices is a major complication. Portal cholangiopathy (due to biliary compression resulting from cavernous transformation) leads to calculus or cholestasis in rare cases.\nEtiology\nThe most frequent causes of PVT are advanced cirrhosis and malignant tumours in adults, and neonatal omphalitis or cannulation of the umbilical vein in children. In the absence of a tumour or advanced cirrhosis, PVT may be caused by localised intra-abdominal inflammation or be associated with a general prothrombotic state caused by a myeloproliferative syndrome (25% of cases), G20210A mutations in the factor II (prothrombin) gene (10% of cases), antiphospholipid syndrome, or by deficiencies of antithrombin, protein C, protein S or factor V Leiden. PVT is generally caused by an association of these causes.\nDiagnostic methods\nDiagnosis of acute PVT or cavernous transformation can be easily established through non-invasive imaging techniques: Doppler ultrasound and tomodensitometry. MRI is a useful tool for diagnosing portal cholangiopathy. It is essential to search for the local or generalised cause of PVT.\nDifferential diagnosis\nDifferential diagnosis should include all other causes of abdominal pain (with or without fever) for acute PVT and all other causes of portal hypertension without hepatic insufficiency for chronic PVT.\nGenetic counseling\nAlthough some causes of PVT are hereditary, PVT is not an inherited disease. Genetic counselling should be proposed for patients with a hereditary predisposition for thrombosis.\nManagement and treatment\nTreatment of acute PVT includes administration of anticoagulants (for 3 to 6 months) and treatment of the underlying causative factor(s). Permeability is restored after treatment in 10-40% of cases. Exploratory laparotomy and intestinal resection may be necessary if intestinal necrosis is present. In chronic PVT, the portal hypertension is treated according to the same protocols as those established for cirrhosis. If management of the portal hypertension is satisfactory, long-term anticoagulant therapy is recommended for patients in a permanent prothrombotic state or in case of extension to the superior mesenteric vein.\nPrognosis\nFor patients receiving early diagnosis and appropriate treatment, the prognosis is good but varies depending on the associated conditions and age at onset.\n\n                            Last update: \n                            April 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Dominique VALLA"}
{"Disease Name": "PRKAR1B-related neurodegenerative dementia with intermediate filaments", "Disease Definition": "A rare, genetic neurodegenerative disease characterized by dementia and mild parkinsonism with poor levodopa response. Presenting clinical manifestations are memory problems, short attention span, disorientation, language impairment, rigidity, bradykinesia, postural instability and behavioral changes, including apathy, anxiety and delusions.", "ORPHA ID": 412066, "Summary": ""}
{"Disease Name": "Proboscis lateralis", "Disease Definition": "Proboscis lateralis (PL) is a rare congenital facial abnormality characterized by failed development of the external nose on one side that is replaced by a tubular structure composed of skin and soft tissue usually attached at the inner canthus of the eye and therefore often associated with maldevelopment of the nasal cavity or paranasal sinuses of the affected side. PL is also associated with other craniofacial abnormalities such as orbital anomalies, cleft lip/palate, frontal encephalocele and holoprosencephaly (see these terms).", "ORPHA ID": 141099, "Summary": ""}
{"Disease Name": "Progeria-short stature-pigmented nevi syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by intrauterine growth retardation and short stature, microcephaly, premature aging, bird-like facies with lack of facial subcutaneous fat, multiple pigmented nevi, sensorineural hearing loss, and variable intellectual disability. Immunodeficiency and development of tumors have also been described.", "ORPHA ID": 2959, "Summary": ""}
{"Disease Name": "Progeroid and marfanoid aspect-lipodystrophy syndrome", "Disease Definition": "A rare systemic disease characterized by a neonatal progeroid appearance (not associated with other manifestations of premature aging) associated with facial dysmorphism (e.g. macrocephaly or arrested hydrocephaly, proptosis, downslanting palpebral fissures, retrognathia), generalized, extreme, congenital lack of subcutaneous fat tissue (except in the breast and iliac region) and incomplete signs of Marfan syndrome (mainly severe myopia, joint hyperextensibility and arachnodactyly). Metabolic disturbances are not associated.", "ORPHA ID": 300382, "Summary": ""}
{"Disease Name": "Progeroid features-hepatocellular carcinoma predisposition syndrome", "Disease Definition": "A rare inherited cancer-predisposing syndrome characterized by early-onset hepatocellular carcinoma, genomic instability, and progeroid features, such as short stature, low body weight, muscular atrophy, lipodystrophy, bilateral cataracts, and premature hair graying. Dysmorphic craniofacial features include triangular face, small, deep-set eyes, and micrognathia. Kyphoscoliosis, sloping shoulders, mild pectus excavatum, bilateral contractures of the elbows and fingers, bilateral clinodactyly, and pes planus have also been reported.", "ORPHA ID": 435953, "Summary": ""}
{"Disease Name": "Progeroid syndrome, Petty type", "Disease Definition": "Progeroid syndrome, Petty type is a rare premature aging syndrome characterized by pre-and postnatal growth retardation, a congenital premature-aged appearance with distinctive craniofacial dysmorphism (wide calvaria with large open anterior fontanel and wide metopic suture, broad forehead, small face, micrognathia), markedly diminished subcutaneous fat, cutis laxa and wrinkled skin, without delay in psychomotor development. Scant, brittle hair, hypoplastic nails and delayed, abnormal dentition, as well as hypoplastic distal phalanges, umbilical hernia and eye abnormalities (myopia/hyperopia, strabismus), are also commonly associated.", "ORPHA ID": 2963, "Summary": ""}
{"Disease Name": "Progressive autosomal recessive ataxia-deafness syndrome", "Disease Definition": "A rare genetic disease characterized by severe progressive sensorineural hearing loss and progressive cerebellar signs including gait ataxia, action tremor, dysmetria, dysdiadochokinesis, dysarthria, and nystagmus. Absence of deep tendon reflexes has also been reported. Age of onset is between infancy and adolescence. Brain imaging may show variable cerebellar atrophy in some patients.", "ORPHA ID": 448251, "Summary": ""}
{"Disease Name": "Progressive bifocal chorioretinal atrophy", "Disease Definition": "Progressive bifocal chorioretinal atrophy (PBCRA) is an early-onset chorioretinal dystrophy characterized by large atrophic macular and nasal retinal lesions, nystagmus, myopia, poor vision, and slow disease progression.", "ORPHA ID": 75373, "Summary": "Epidemiology\nIt has been described in two large families.\nEtiology\nTransmission is autosomal dominant and the causative gene has been mapped to a region on chromosome 6q, close to the macular dystrophy retinal 1 (MCDR1) locus.\n\n                            Last update: \n                            September 2006"}
{"Disease Name": "Progressive cavitating leukoencephalopathy", "Disease Definition": "A rare leukoencephalopathy characterized by acute episodes of neurological deficit (ataxia, dysarthria, seizures) with irritability and opisthotonus followed by either steady deterioration or alternating periods of rapid progression and prolonged periods of stability.", "ORPHA ID": 139447, "Summary": "Epidemiology\nSo far around 20 patients have been reported in the literature.\nClinical description\nOnset occurs in infancy or early childhood.\nEtiology\nThe etiology remains unknown.\nDiagnostic methods\nMRI imaging reveals irregular asymmetric patches of leukoencephalopathy with cavities, vascular permeability and cystic degeneration affecting principally the corpus callosum, cerebral and cerebellar white matter, and spinal cord.\nGenetic counseling\nThe mode of transmission is autosomal recessive.\n\n                            Last update: \n                            September 2008"}
{"Disease Name": "Progressive cerebello-cerebral atrophy", "Disease Definition": "A rare genetic neurological disorder characterized by postnatal onset of severe global developmental delay, profound mental retardation, progressive microcephaly, progressive spasticity evolving into spastic quadriplegia with joint contractures, generalized seizures, and irritability. Severe choreoathetosis and dysmorphic features are absent. Brain imaging shows progressive cerebellar atrophy followed by cerebral atrophy affecting both white and grey matter, but no pontine involvement.", "ORPHA ID": 247198, "Summary": ""}
{"Disease Name": "Progressive cone dystrophy", "Disease Definition": "A rare retinal dystrophy characterized by photophobia, progressive loss of visual acuity, nystagmus, visual field abnormalities, abnormal color vision, and psychophysical and electrophysiological evidence of abnormal cone function. Progressive cone dystrophy usually presents in childhood or early adult life, and patients tend to develop rod photoreceptor dysfunction in later life.", "ORPHA ID": 1871, "Summary": ""}
{"Disease Name": "Progressive deafness with stapes fixation", "Disease Definition": "Stapes fixation (stapedovestibular ankylosis) is a hearing loss condition that appears as a consequence of annular ligament destruction followed by excessive connective tissue production during the healing process. This condition is mainly observed in otosclerosis, but is also found in chronic otitis media with tympanosclerosis, and other rare bone diseases such as Paget's disease and osteogenesis imperfecta (Lobstein disease).", "ORPHA ID": 3235, "Summary": "Epidemiology\nThe prevalence of symptomatic otosclerosis is estimated as 0.1 to 0.5% of the population in the United-States and Western Europe, thus this is not a rare disease. The prevalence of otosclerosis appears to be lower in the Chinese, Japanese, and Latin American populations, and is much lower in the Black population. Tympanosclerosis occurs in 9 to 38% of chronic otitis media cases. The prevalence of Paget's disease associated with temporal bone involvement is estimated as 0.2 to 1% of Caucasian adults. The prevalence of osteogenesis imperfecta is 1/20 000 births. Hearing loss is observed in 26 to 60% of these patients.\nEtiology\nThe etiology of otosclerosis is still unknown. Otosclerosis appears to be a multifactorial disease. Autosomal dominant and a low penetrance (40%) transmission is observed in familial cases. The role of infection with the measles virus as a triggering factor is currently being investigated. Osteogenesis imperfecta is principally related to the mutation of the collagen 1A1 (COL1A1) and 1A2 (COL1A2) genes. The etiology of Paget's disease is still unclear. Tympanosclerosis is a sequela of middle ear chronic inflammation.\nDiagnostic methods\nOtoscopy is normal in otosclerosis, Paget's disease, and osteogenesis imperfecta. It reveals middle ear lesions in tympanosclerosis. Audiometry shows a conductive or mixed hearing loss with abolished stapedial reflexes. Computerised tomography (CT) scanning is crucial for the diagnosis of stapes fixation. It detects the bone lesions of otosclerosis as a hypodense regions mainly localized to the anteriorpart of the oval window. In osteogenesis imperfecta and Paget's disease, lesions involve the whole temporal bone and the skull, and result in thickening of the ossicles. In tympanosclerosis, calcified plaques are typically diffuse in the middle ear cleft and involve the oval window.\nDifferential diagnosis\nDifferential diagnosis should include minor ossicular malformations presenting with a normal otoscopy, a conductive hearing loss, and abolished stapedial reflexes. In case of otosclerosis, an audiometry with stapedial reflex assessment should be recommended for the parents, siblings, and children (above 20 years of age) of the patient. In all the above etiologies, the progression of the hearing loss is generally slow.\nManagement and treatment\nThe hearing loss due to stapes fixation is rarely profound and should always resolve early during follow-up. The conductive component of the hearing loss can be restored by surgery or hearing aids. The associated sensorineural component is managed by hearing aids or cochlear implants, depending on its severity. Sodium fluoride has been reported to slow the progression of otosclerosis lesions, and the consequent sensorineural hearing loss.\n\n                            Last update: \n                            September 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Alexis BOZORG GRAYELI"}
{"Disease Name": "Progressive encephalomyelitis with rigidity and myoclonus", "Disease Definition": "A rare stiff person syndrome spectrum disorder characterized by limb and truncal rigidity, stimulus-sensitive spasms, myoclonus, hyperekplexia, autonomic disturbance, and brainstem involvement or other neurological defects. The condition is progressive and potentially life-threatening, especially due to respiratory failure. It may be associated with the presence of glycine receptor or glutamic acid decarboxylase antibodies, as well as thymomas or lymphomas.", "ORPHA ID": 438266, "Summary": ""}
{"Disease Name": "Progressive encephalopathy with leukodystrophy due to DECR deficiency", "Disease Definition": "Progressive encephalopathy with leukodystrophy due to DECR deficiency is a rare mitochondrial disease, which presents with neonatal hypotonia, central nervous system abnormalities (ventriculomegaly, corpus callosum hypoplasia, cerebellar atrophy), acquired microcephaly, failure to thrive, developmental delay and intermittent lactic acidosis provoked by catabolic stress (e.g. infection). Hyperlysinemia and elevated C10:2 carnitine can be detected in plasma. Later on, epilepsy, cerebellar ataxia, renal tubular acidosis, severe encephalopathy, dystonia, spastic quadriplegia and other complications may develop.", "ORPHA ID": 431361, "Summary": ""}
{"Disease Name": "Progressive epilepsy-intellectual disability syndrome, Finnish type", "Disease Definition": "Progressive epilepsy-intellectual deficit, Finnish type (also known as Northern epilepsy) is a subtype of neuronal ceroid lipofuscinosis (NCL; see this term) characterized by seizures, progressive decline of intellectual capacities and variable loss of vision.", "ORPHA ID": 1947, "Summary": "Epidemiology\nPrevalence is unknown but the disorder is principally reported in Northern Finland.\nClinical description\nThe disorder is characterized by generalized tonic-clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The seizures increase in frequency until puberty after which the epileptic activity starts to decline. The intellectual deficit is severe, develops 2-5 years after the onset of seizures and progresses continuously through adulthood. Visual problems are not a prominent feature of this disorder; if present they may be mild and go unrecognized.\nEtiology\nProgressive epilepsy-intellectual deficit, Finnish type is caused by mutations in the CLN8 gene (8p23.3) encoding a putative transmembrane protein of unknown function.\nDiagnostic methods\nDiagnosis is based on the clinical picture, family history and electron microscopy studies of tissue specimens showing intracellular accumulation of storage material. The diagnosis can be confirmed by molecular analysis.\nDifferential diagnosis\nThe differential diagnosis should include other causes of dementia and seizures starting at school age, including atypical forms of other NCL disorders (typically juvenile NCL (see this term) caused by mutations in PPT1 (CLN1 disease), TPP1 (CLN2 disease), or CTSD (CLN10 disease)), as well as mitochondrial disorders and chronic types of encephalitis (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is feasible for families in which the disease-causing mutation has already been identified and genetic counseling should be provided.\nGenetic counseling\nProgressive epilepsy-intellectual deficit, Finnish type is transmitted in an autosomal recessive manner\nManagement and treatment\nTreatment is supportive only with palliative care including administration of anticonvulsants, as well as educational, psychological, and psychiatric management.\nPrognosis\nAlthough patients suffer from slow cognitive decline, life expectancy is less severely reduced than in other forms of NCL with juvenile onset and patients may reach 50 or 60 years of age.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Alfried KOHLSCHÜTTER"}
{"Disease Name": "Progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome", "Disease Definition": "A rare genetic syndromic intellectual disability characterized by global developmental delay, moderate to severe intellectual disability, motor and language impairment, behavioral abnormalities (with mood instability, aggression, and self-mutilation), and progressive hand tremor. Facial dysmorphism includes narrow palpebral fissures, large ears, long philtrum, and prominent chin.", "ORPHA ID": 457212, "Summary": ""}
{"Disease Name": "Progressive external ophthalmoplegia-myopathy-emaciation syndrome", "Disease Definition": "Progressive external ophthalmoplegia-myopathy-emaciation syndrome is a rare mitochondrial oxidative phosphorylation disorder due to nuclear DNA anomalies characterized by progressive external ophthalmoplegia without diplopia, cerebellar atrophy, proximal skeletal muscle weakness with generalized muscle wasting, profound emaciation, respiratory failure, spinal deformity and facial muscle weakness (manifesting with ptosis, dysphonia, dysphagia and nasal speech). Intellectual disability, gastrointestinal symptoms (e.g. nausea, abdominal fullness, and loss of appetite), dilated cardiomyopathy and renal colic have also been reported.", "ORPHA ID": 352447, "Summary": ""}
{"Disease Name": "Progressive familial intrahepatic cholestasis type 1", "Disease Definition": "PFIC1, a type of progressive familial intrahepathic cholestasis (PFIC, see this term), is an infantile hereditary disorder in bile formation that is hepatocellular in origin and associated with extrahepatic features.", "ORPHA ID": 79306, "Summary": "Epidemiology\nEstimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000 births. PFIC1 is the less frequent type of PFIC.\nClinical description\nIts onset occurs mostly during infancy. Clinical signs of cholestasis (discolored stools, dark urine) usually appear in the first months of life with recurrent or permanent jaundice associated with hepatomegaly and severe pruritus. Patients usually develop fibrosis and end-stage liver disease before adulthood. Extrahepatic features have been reported including persistent short stature, watery diarrhea, pancreatitis and sensorineural deafness.\nEtiology\nPFIC1 is due to mutations in the ATP8B1 gene (18q21-22) encoding the FIC1 protein expressed at the canalicular membrane of hepatocytes as well as in other epithelia. In hepatocytes, abnormal protein might indirectly disrupt biliary bile acid secretion, explaining the low biliary bile acid concentration found in PFIC1 patients. Extrahepatic features of the disease are probably related to the extrahepatic expression of FIC1.\nDiagnostic methods\nPFIC1 should be suspected in children with a clinical history of cholestasis of unknown origin after exclusion of the other main causes of cholestasis presenting with normal serum gamma-GT activity and high serum bile acid concentration. Usually, serum alpha-fetoprotein level is normal and alanine aminotransferase values are below five times the upper limit of normal. Liver ultrasonography is usually normal but may reveal a huge gallbladder. Liver histology reveals canalicular cholestasis and the absence of true ductular proliferation with only periportal biliary metaplasia of hepatocytes. When performed, cholangiography shows a normal biliary tree and allows bile collection. Biliary lipid analysis reveals mildly decreased biliary bile salt concentration. Genotyping confirms the diagnosis.\nDifferential diagnosis\nIn the scope of cholestasis with normal gamma-GT, differential diagnosis includes mainly primary bile acid synthesis defects and PFIC2 (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis can be proposed if a mutation has been identified in each parent.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nUrsodeoxycholic acid therapy (UDCA) should be initiated in all patients to prevent liver damage but is not fully effective. Rifampicin is helpful to control pruritus. Nasobiliary drainage may help to select potential responders to biliary diversion. However, because of severe cholestasis, half of patients are ultimately candidates for liver transplantation (LT). Diarrhea often worsens after LT and might be favorably managed by bile adsorptive resin treatment. LT does not prevent extrahepatic progression of the disease, and does not lead to catch-up growth. Furthermore, severe steatohepatitis of the liver graft has been reported. Specialized follow-up is mandatory lifelong. FIC1 defect predisposes to development of intrahepatic cholestasis of pregnancy (see this term).\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Christiane BAUSSAN  - Pr Emmanuel GONZALES  - Pr Emmanuel JACQUEMIN  - Dr Anne SPRAUL"}
{"Disease Name": "Progressive familial intrahepatic cholestasis type 2", "Disease Definition": "Progressive familial intrahepatic cholestasis type 2 (PFIC2), a type of progressive familial intrahepatic cholestasis (PFIC, see this term), is a severe, neonatal, hereditary disorder in bile formation that is hepatocellular in origin and not associated with extrahepatic features. Initially, PFIC2 was reported under the name Byler syndrome.", "ORPHA ID": 79304, "Summary": "Epidemiology\nEstimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000. PFIC2 represents half of PFIC cases.\nClinical description\nOnset occurs in the neonatal period. Clinical signs of cholestasis (discolored stools, dark urine) usually appear in the first months of life with recurrent or permanent jaundice associated with hepatomegaly and severe pruritus. Early appearance of liver failure and/or progression to hepatocellular carcinoma within the first years of life may complicate the course of PFIC2. Patients usually develop fibrosis and end-stage liver disease before adulthood.\nEtiology\nPFIC2 is due to mutations in the ABCB11 gene (2q24) encoding the bile salt export pump (BSEP) protein resulting in impaired biliary bile acid secretion which leads to decreased bile flow and bile salt accumulation in hepatocytes with ongoing severe hepatocellular damage. BSEP is only expressed in hepatocytes, and extrahepatic features are not present in PFIC2.\nDiagnostic methods\nPFIC2 should be suspected in children with a clinical history of cholestasis of unknown origin after exclusion of the other main causes of cholestasis presenting with normal serum gamma-GT activity and high serum bile acid concentration. Usually, serum alpha-fetoprotein level is elevated and alanine aminotransferase values are over five times the upper limit of normal. Liver ultrasonography is usually normal but may reveal a huge gallbladder and sometimes biliary stones. Liver histology reveals canalicular cholestasis, the absence of true ductular proliferation with only periportal biliary metaplasia of hepatocytes, pronounced lobular and portal fibrosis and inflammation, hepatocellular necrosis and giant cell transformation. BSEP immunostaining is helpful for diagnosis. When performed, cholangiography shows a normal biliary tree and allows bile collection. Biliary lipid analysis reveals dramatically decreased biliary bile salt concentration. Genotyping confirms the diagnosis.\nDifferential diagnosis\nIn the scope of cholestasis with normal gamma-GT, differential diagnosis includes mainly primary bile acid synthesis defects and PFIC1 (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis can be proposed if a mutation has been identified in each parent.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nUrsodeoxycholic acid therapy (UDCA) should be initiated in all patients to prevent liver damage but is not fully effective. Rifampicin is helpful to control pruritus. Nasobiliary drainage may help to select potential responders to biliary diversion. However, because of severe cholestasis, liver failure or hepatocellular carcinoma, half of patients are ultimately candidates for liver transplantation (LT). Close monitoring of hepatocellular carcinoma should be offered from the first year of life. Due to hepatocellular carcinoma and rapid liver failure, the course in patients with PFIC2 appears to be more severe than in patients with PFIC1.\nPrognosis\nEarly treatment with UDCA or biliary diversion may prevent significant morbidity and mortality from end-stage liver disease. Furthermore, patients may develop biliary stones, drug-induced cholestasis, and/or intrahepatic cholestasis of pregnancy (see this term) further in the disease course. Specialized follow-up is mandatory and lifelong.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Christiane BAUSSAN  - Pr Emmanuel GONZALES  - Pr Emmanuel JACQUEMIN  - Dr Anne SPRAUL"}
{"Disease Name": "Progressive familial intrahepatic cholestasis type 3", "Disease Definition": "Progressive familial intrahepatic cholestasis type 3 (PFIC3), a type of progressive familial intrahepatic cholestasis (PFIC, see this term), is a late-onset hereditary disorder in bile formation that is hepatocellular in origin. Onset may occur from infancy to young adulthood.", "ORPHA ID": 79305, "Summary": "Epidemiology\nEstimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000. PFIC3 represents one third of PFIC cases.\nClinical description\nClinical signs of cholestasis (discolored stools, dark urine) appear within the first year of life in about one third of patients, or later with recurrent episodes of jaundice and mild pruritus. PFIC3 evolves into secondary biliary cirrhosis. Gastrointestinal bleeding due to portal hypertension might be the presenting symptom in adolescents or young adults.\nEtiology\nPFIC3 is due to mutations in the ABCB4 gene (7q21), encoding the multi-drug resistant 3 protein (MDR3), resulting in impaired biliary phospholipid (PL) secretion. Detergent effects of hydrophobic bile salts are not countered by biliary PLs and lead to cholangitis. Low biliary PL levels are insufficient to maintain solubility of cholesterol and promote bile lithogenicity.\nDiagnostic methods\nPFIC3 should be suspected in children, adolescents, or young adults with a clinical history of cholestasis of unknown origin after exclusion of the other main causes of cholestasis. Patients present with high serum gamma-GT activity, normal cholesterol levels and moderately elevated bile acid concentrations. Liver ultrasonography is usually normal but may reveal a huge gallbladder and sometimes biliary stones. Liver histology reveals portal fibrosis and true ductular proliferation with mixed inflammatory infiltrate and, at a later stage, signs of biliary cirrhosis. MDR3 immunostaining is helpful for diagnosis. Cholangiography shows a normal biliary tree making it possible to rule out sclerosing cholangitis. Bile collection allows biliary lipid analysis showing decreased biliary phospholipid levels. Genotyping confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes biliary tract diseases and causes of intrahepatic cholestasis and of cirrhosis with elevated gamma-GT.\nAntenatal diagnosis\nPrenatal diagnosis can be proposed if a mutation has been identified in each parent.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nUrsodeoxycholic acid therapy (UDCA) should be initiated in all patients to prevent liver damage. Beneficial effects of UDCA are usually observed in patients who harbored at least one missense mutation. In half of the patients, UDCA therapy fails and liver transplantation is required due to liver failure. In patients responding to UDCA, PFIC3 may be complicated by cirrhosis, portal hypertension and hepatocellular carcinoma. Furthermore, patients are at high risk of biliary stones, drug-induced cholestasis, and/or intrahepatic cholestasis of pregnancy (see this term) further in the disease course, especially if UDCA therapy is stopped. Specialized follow-up is mandatory and lifelong.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Christiane BAUSSAN  - Pr Emmanuel GONZALES  - Pr Emmanuel JACQUEMIN  - Dr Anne SPRAUL"}
{"Disease Name": "Progressive familial intrahepatic cholestasis", "Disease Definition": "Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin.", "ORPHA ID": 172, "Summary": "Epidemiology\nThe exact prevalence remains unknown, but the estimated prevalence at birth varies between 1/50,000 and 1/100,000.\nClinical description\nThree types of PFIC have been identified and are related to mutations in hepatocellular transport system genes involved in bile formation. PFIC1 and PFIC2 (see these terms) usually appear in the first months of life, whereas onset of PFIC3 (see this term) may also occur later in infancy, in childhood or even during young adulthood. Main clinical manifestations include cholestasis, pruritus and jaundice. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Additional manifestations may include short stature, sensorineural deafness, watery diarrhea, pancreatitis, elevated sweat electrolyte concentration and liver steatosis.\nEtiology\nBoth PFIC1 and PFIC2 are caused by impaired bile salt secretion due respectively to defects in ATP8B1 encoding the FIC1 protein, and in ABCB11 encoding the bile salt export pump protein (BSEP). Defects in ABCB4, encoding the multi-drug resistant 3 protein (MDR3), impair biliary phospholipid secretion resulting in PFIC3.\nDiagnostic methods\nDiagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests for excluding other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates in whom genotyping could be proposed to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include diseases that present with progressive cholestatic liver disease of childhood.\nAntenatal diagnosis\nAntenatal diagnosis can be proposed for affected families in which a mutation has been identified.\nManagement and treatment\nUrsodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 or PFIC2 patients, biliary diversion can also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of hepatocellular carcinoma, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy or specific targeted pharmacotherapy may represent alternative treatments in the future.\nPrognosis\nPFIC patients usually develop fibrosis and end-stage liver disease before adulthood.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Christiane BAUSSAN  - Pr Emmanuel GONZALES  - Pr Emmanuel JACQUEMIN  - Dr Anne SPRAUL"}
{"Disease Name": "Progressive hemifacial atrophy", "Disease Definition": "Progressive hemifacial atrophy (PHA) is a rare acquired disorder, characterized by unilateral slowly progressive atrophy of the skin and soft tissues of half of the face leading to a sunken appearance. Muscles, cartilage and the underlying bony structures may also be involved.", "ORPHA ID": 1214, "Summary": "Epidemiology\nThe prevalence is estimated to be at least 1/700,000 individuals, women being slightly more affected than men.\nClinical description\nPHA usually presents during the first 20 years of life, characterized by slowly progressive unilateral atrophy of various tissues (skin, connective tissue, fat, muscle and rarely, underlying bony structures) in the territory of the 5th cranial nerve. PHA may start with alopecia, hair hypopigmentation, and atrophy may be preceded by cutaneous induration and hypo- or hyperpigmentation. PHA may extend to the upper lip and/or one side of the tongue and the masticatory muscles, resulting in deviation of the nose/mouth toward the affected side, unusual twisted or raised appearance of the upper lip, micrognathia, difficulty opening/closing the jaws and chewing/smiling/speaking, trismus, abnormal exposition of certain teeth, late eruption and/or atrophic roots and malocclusion. Rarely both sides of the face and the skin on the arms/trunk/leg or the entire body may be involved. Seizures and headaches are the most common neurologic symptoms. Ophthalmologic anomalies (enophthalmos, globe retraction, ptosis, iris heterochromia, uveitis, retinal vasculitis, glaucoma and eyelid atrophy) may result in visual impairment or blindness. Ear involvement (ipsilateral misshaping of the ear, abnormal small appearance and protrusion from the head) may also be observed. Anxiety and depression are common. A significant overlap between clinical and histological features of PHA and localized scleroderma ''en coup de sabre'' is reported.\nEtiology\nThe exact etiology of PHA is unknown. Due to the presence of autoimmune diseases in several cases (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and ankylosing spondylitis), autoimmunity may be a cause of PHA, along with facial or head trauma, meningoencephalitis, abnormal development or hyperactivity of the sympathetic nervous system, neuro-vasculitis, angiogenesis anomalies, and slow viral infections.\nDiagnostic methods\nPHA diagnosis is based on clinical and histopathology features. The skin biopsy reveals homogenized dermal sclerosis, fat atrophy, decrease in adnexal structures, and perivascular plasma cells and lymphocytes. Computerized tomography (CT) and magnetic resonance imaging (MRI) may display infarction, hemorrhage and white matter hyper-density. Ultrasounds, ocular/dental imaging and photographs allow the monitoring of disease activity and progression.\nDifferential diagnosis\nDifferential diagnosis includes localized scleroderma, Rasmussen syndrome, hemifacial microsomia, Goldenhar syndrome, idiopathic facial palsy, Berardinelli-Seip congenital lipodystrophy and partial acquired lipodystrophy. Patients with face injuries (e.g. burns), fat necrosis and congenital deformities (e.g. wry neck) should also be considered.\nGenetic counseling\nPHA is sporadic in most cases, but rare familial cases have been reported. The effective transmission of the disease has not yet been reported. Genetic counseling is not recommended at this time.\nManagement and treatment\nPHA management is symptomatic, requiring a multidisciplinary approach (pediatricians or internists, plastic surgeons, dentists, ophthalmologists, dermatologists, neurologists). Surgical management (fat/silicone injections, flap/pedicle grafts or bone implants) is usually not advised until the progression of PHA is stabilized. Patients with cerebral involvement may be considered for immunosuppressive therapy.\nPrognosis\nIn some cases, the atrophy stops before the entire face is affected, with rare recurrence and no disability other than the cosmetic effects in the mild cases. Occasionally, PHA course may be accelerated, secondary to stress, surgery and pregnancy or shortly after childbirth.\n\n                            Last update: \n                            July 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Nirav PATEL  - Dr Stanislav TOLKACHJOV  - Dr Megha TOLLEFSON"}
{"Disease Name": "Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome", "Disease Definition": "Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome is a rare, genetic, neuro-ophthalmological syndrome characterized by post-natal, progressive microcephaly and early-onset seizures, associated with delayed global development, bilateral cortical visual impairment and moderate to severe intellectual disability. Additional manifestations include short stature, generalized hypotonia and pulmonary complications, such as recurrent respiratory infections and bronchiectasis. Auditory and metabolic screenings are normal.", "ORPHA ID": 477814, "Summary": ""}
{"Disease Name": "Progressive muscular atrophy", "Disease Definition": "A rare motor neuron disease characterized by isolated lower motor neuron features, including progressive flaccid weakness, muscle atrophy, fasciculations, and reduced or absent tendon reflexes. Onset is in late adulthood, with men being affected more often than women. Upper motor neuron signs may develop later in some cases. Occurrence of respiratory insufficiency determines the prognosis. Neuropathological analysis shows intraneuronal Bunina bodies and ubiquitin-positive inclusions.", "ORPHA ID": 454706, "Summary": ""}
{"Disease Name": "Progressive myoclonic epilepsy type 1", "Disease Definition": "A rare progressive myoclonic epilepsy (PME) disorder characterized by action- and stimulus-sensitive myoclonus, and tonic-clonic seizures with ataxia, but with only a mild cognitive decline over time.", "ORPHA ID": 308, "Summary": "Epidemiology\nProgressive myoclonic epilepsy type 1 (EPM1) has the highest incidence among the progressive myoclonus epilepsies (PMEs), with prevalence reportedly higher in certain geographic areas (Finland, Italy, Tunisia, Algeria, Morocco, and Reunion Island). The prevalence in Finland is estimated at 1/50,000. Whilst the disorder is recognized worldwide, it appears to be underdiagnosed. Both genders are equally affected.\nClinical description\nThe first symptoms are stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures appearing between 6-15 years of age. Prompt treatment of myoclonic seizures may prevent generalized tonic-clonic seizures (GTCS). Gradually, patients develop additional neurological symptoms including ataxia, dysarthria, intentional tremor, and decreased coordination. Depression is common. Cognitive performance is mostly within the normal range. However, patients may exhibit poor performance in tests dependent on motor functions. The tonic-clonic seizures are well controlled by anti-seizure medications, but the myoclonic jerks are progressive, action activated, treatment resistant and can be severely disabling.\nEtiology\nThe majority of cases are due to a homozygous expansion of an unstable dodecamer repeat (typically 30 to 125 repeats) in the promoter region of CSTB (21q22.3), resulting in the classic phenotype. In a minority of patients, the dodecamer repeat expansion occurs as a compound heterozygous form with a mutation in the coding region of CSTB. The clinical phenotype is the result of a partial loss of function in CSTB.\nDiagnostic methods\nDiagnosis is suspected on electroencephalogram demonstrating photosensitivity at onset and action myoclonus detected through polygraphy. Diagnosis is confirmed on targeted molecular genetic testing for the dodecamer expansion of CSTB. When heterozygosity for the dodecamer expansion is found in an affected individual, it is appropriate to pursue molecular genetic testing for other CSTB pathogenic variants either by targeted analysis for a broader panel of pathogenic variants or by sequence analysis.\nDifferential diagnosis\nThe initial symptoms may be so mild that a diagnosis of juvenile myoclonic epilepsy is made, and the signs of EPM1 may become evident only with the progression of the disease. Differential diagnosis includes other PMEs with preserved cognition, for example PRICKLE1 and SCARB2-related PME, that have been identified in a few families with a similar clinical phenotype.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy. Pre-symptomatic testing is not recommended.\nManagement and treatment\nAnti-seizure and anti-myoclonic interventions include valproate, clonazepam, piracetam (the latter only for myoclonus), levetiracetam, brivaracetam, perampanel, topiramate and zonisamide. Phenytoin and fosphenytoin should be avoided as these trigger detrimental neurological side effects. In addition, other sodium channel blockers such as carbamazepine should be excluded as they may negatively contribute to myoclonic seizures.\nPrognosis\nThe disease course is progressive, showing remarkable individual variation, with myoclonus usually presenting as the most disabling symptom. One third of patients become severely incapacitated, wheelchair-bound or even unable to eat on their own. On the other hand, some patients are able to live fully autonomous lives. With modern medical care, the survival rates are comparable to controls up to 40 years of age, but are poorer in the long-term. Death occurs mainly due to respiratory infections. Compound heterozygous mutations are associated with a more severe phenotype than homozygous dodecamer repeat expansions.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Tiziana GRANATA | EpiCARE* - Pr Reetta KÄLVIÄINEN | EpiCARE* - Pr Rima NABBOUT | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Progressive myoclonic epilepsy type 3", "Disease Definition": "A rare, genetic, neuronal ceroid lipofuscinosis disorder characterized by infantile- to early childhood-onset of progressive myoclonic seizures (occasionally accompanied by generalized tonic-clonic seizures) and severe, progressive neurological regression, leading to psychomotor and cognitive decline, cerebellar ataxia, dementia and, frequently, early death. Vision loss may be associated. EEG typically reveals epileptiform activity with predominance in the posterior region and photosensitivity.", "ORPHA ID": 263516, "Summary": ""}
{"Disease Name": "Progressive myoclonic epilepsy type 5", "Disease Definition": "A rare, genetic neurological disorder characterized by early-onset progressive ataxia associated with myoclonic seizures, generalized tonic-clonic seizures (which are often sleep-related), and normal to mild intellectual disability. Dysarthria, upward gaze palsy, sensory neuropathy, developmental delay and autistic disorder have also been associated.", "ORPHA ID": 402082, "Summary": ""}
{"Disease Name": "Progressive myoclonic epilepsy type 6", "Disease Definition": "A rare, genetic, neurological disorder characterized by early-onset, progressive ataxia associated with myoclonic seizures (frequently associated with other seizure types such as generalized tonic-clonic, absence and drop attacks), scoliosis of variable severity, areflexia, elevated creatine kinase serum levels, and relative preservation of cognitive function until late in the disease course.", "ORPHA ID": 280620, "Summary": ""}
{"Disease Name": "Progressive myoclonic epilepsy type 7", "Disease Definition": "A rare, genetic, neurological disorder characterized by childhood to adolescent onset of progressive myoclonus (which becomes very severe and results in major motor impediment) associated with infrequent tonic-clonic seizures, and, occasionally, ataxia. Learning disability prior to seizure onset and mild cognitive decline may be associated.", "ORPHA ID": 435438, "Summary": ""}
{"Disease Name": "Progressive myoclonic epilepsy type 8", "Disease Definition": "A rare, genetic, neurological disorder characterized by childhood to adolescent-onset of action myoclonus, generalized tonic-clonic seizures, and slowly progressive, moderate to severe cognitive impairment that may lead to dementia. EEG reveals progressive slowing of background activity and epileptic abnormalities and brain MRI shows cerebellar and brainstem atrophy.", "ORPHA ID": 424027, "Summary": ""}
{"Disease Name": "Progressive myoclonic epilepsy type 9", "Disease Definition": "A rare, genetic, neurological disorder characterized by childhood-onset severe myoclonic and tonic-clonic seizures and early-onset ataxia leading to severe gait disturbances associated with normal to slightly diminished cognition. Scoliosis, diffuse muscle atrophy and subcutaneous fat loss, as well as developmental delay, may be associated. Brain MRI may reveal complete agenesis of the corpus callosum, ventriculomegaly, interhemispheric cysts, and simplified gyration (frontally).", "ORPHA ID": 457265, "Summary": ""}
{"Disease Name": "Progressive myoclonic epilepsy with dystonia", "Disease Definition": "Progressive myoclonic epilepsy with dystonia is a rare, genetic epilepsy syndrome characterized by neonatal or early infantile onset of severe, progressive, typically frequent and prolonged myoclonic seizures that are refractory to treatment, associated with localized and/or generalized paroxysmal dystonia (which later becomes persistent). Other features include severe hypotonia, hemiplegia, psychomotor regression (or lack of psychomotor development) and progressive cerebral and cerebellar atrophy, with affected individuals becoming progressively non-reactive to environmental stimuli.", "ORPHA ID": 352596, "Summary": ""}
{"Disease Name": "Progressive nodular histiocytosis", "Disease Definition": "Progressive nodular histiocytosis is a rare, normolipemic, non-Langerhans cell histiocytosis characterized by progressive growth of multiple to disseminated, asymptomatic skin lesions that range in appearance from yellow plaques to coalescence-prone red-brown papules, nodules and pedunculated tumors up to 5 cm in size, located typically on the face, trunk and extremities (and rarely on conjuctiva and mucous membranes). Characteristic microscopic findings include a storiform spindle cell infiltrate in the deep dermis with xanthomatized macrophages and some Touton cells in the upper dermis. It is usually not associated with systemic disease.", "ORPHA ID": 158022, "Summary": ""}
{"Disease Name": "Progressive non-fluent aphasia", "Disease Definition": "Progressive non-fluent aphasia (PNFA) is a form of frontotemporal dementia (FTD; see this term), characterized by agrammatism, laborious speech, alexia, and agraphia, frequently accompanied by apraxia of speech (AOS). Language comprehension is relatively preserved.", "ORPHA ID": 100070, "Summary": ""}
{"Disease Name": "Progressive non-infectious anterior vertebral fusion", "Disease Definition": "Progressive non-infectious anterior vertebral fusion (PAVF) is an early childhood spinal disorder characterized by the gradual onset of thoracic and/or lumbar spine ankylosis often in conjunction with kyphosis with distinctive radiological features.", "ORPHA ID": 2062, "Summary": "Epidemiology\nPrevalence is unknown, but PAVF (mostly isolated cases) has been reported in approximately 80-100 cases. Girls (60%) seem slightly more affected than boys.\nClinical description\nOnset is in early childhood and often discovered in young children while exploring a spinal deformity. This is the start of the progressive anterior vertebral ankylosis in the thoracic and/or lumbar areas observed during the disease course (months or years after onset) often clinically manifested by thoracolumbar kyphosis. The anterior vertebral ankylosis extends with time to the posterior part. PAVF usually presents with mild pain, stiffness of neck and/or back with developing thoracolumbar kyphosis. Often however PAVF is asymptomatic. Neurological abnormalities are exceptional. PAVF can occur isolated or less frequently, as part of a syndrome. Syndrome associated manifestations include facial dysmorphism, absence of one cervical vertebrae, radio-ulnar synostosis, exostosis, generalized overgrowth, split cord malformation and/or situs inversus totalis (see this term).\nEtiology\nEtiology is unknown.\nDiagnostic methods\nPAVF may be discovered fortuitously. MRI and X-ray confirm PAVF when distinctive radiological features of PAVF are present. MRI examination is favored, since the precise degree of the intervertebral ankylosis of the disc condition can be evaluated. The typical anterior vertebral endplate narrowing associated with irregularities and osteosclerosis of the vertebral corners may be visible early on.\nDifferential diagnosis\nSynspondylism, spondylothoracic dysplasia and familial Scheuermann disease should be considered in the differential diagnosis. Other differential diagnoses in case of infection include infectious spondylodiscitis and congenital vertebral block.\nManagement and treatment\nConservative treatment includes a routine annual or semestrial (during pubertal growth spurt) clinical and medical imaging check-up and a multi-disciplinary approach. It seems very important to prevent sagittal imbalance at a very young age by a regular clinical monitoring and early bracing as soon as hypolordosis appears. At adult age, bracing has a very limited effect. Surgical treatment has to be discussed on an individual basis. In some patients presenting with lumbar hypolordosis, a lordotic restoration using Boston-type braces with progressive correction, assists in addressing chronic pain in addition to class 1 WHO painkillers. PVO (posterior vertebral osteotomies) can be considered in patients when restoring a satisfying sagittal balance is impossible or very challenging. In patients with moderate deformities but with severe chronical pain, posterior intervertebral fusion is useful. Long term follow-up is recommended.\nPrognosis\nPrognosis is fairly good as it does not involve vital issues. However, almost all patients complain with low back pain and junctional thoraco-lumbar pain.\n\n                            Last update: \n                            September 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Nathalie BOUTRY  - Dr Eric NECTOUX"}
{"Disease Name": "Progressive osseous heteroplasia", "Disease Definition": "Progressive osseous heteroplasia (POH) is a rare genetic bone disorder characterized clinically by progressive extraskeletal bone formation presenting in early life with cutaneous ossification, that progressively involves subcutaneous and then subsequently deep connective tissues, including muscle and fascia. POH overlaps with a number of related genetic disorders including Albright hereditary osteodystrophy, pseudohypoparathyroidism (see these terms), and primary osteoma cutis, that share the common features of superficial heterotopic ossification in association with inactivating mutations of GNAS gene (20q13.2-q13.3), coding for guanine nucleotide-binding proteins. POH can, however, be distinguished clinically by the deep and progressive nature of the heterotopic bone formation.", "ORPHA ID": 2762, "Summary": ""}
{"Disease Name": "Progressive polyneuropathy with bilateral striatal necrosis", "Disease Definition": "Progressive polyneuropathy with bilateral striatal necrosis is a rare, genetic disorder of thiamine metabolism and transport characterized by the childhood-onset of recurrent episodes of flaccid paralysis and encephalopathy, associated with bilateral striatal necrosis and chronic progressive axonal polyneuropathy with proximal and distal muscle weakness, areflexia, contractures and foot deformities.", "ORPHA ID": 217396, "Summary": ""}
{"Disease Name": "Progressive pseudorheumatoid arthropathy of childhood", "Disease Definition": "A rare spondyloepiphyseal dysplasia (SED) characterized by an association with progressive arthropathy.", "ORPHA ID": 1159, "Summary": "Epidemiology\nThe prevalence of progressive pseudorheumatoid arthropathy (dysplasia) of childhood (PPAC; PPD) has been estimated at 1/1,000,000.\nClinical description\nMost patients present the disease before the age of 8 years (the onset varies between 2 and 11 years). Typically, there are no symptoms in the newborn period. The most common signs at diagnosis are progressive stiffness and swelling of small joints of hands (interphalangeal) without obvious signs of inflammation. Other joints are progressively affected: toes, elbows, writs, knees, ankles and spine. Bowing of the legs, motion range limitation, deformities and pain develop gradually, and spread to other joints. Many patients have spinal involvement manifesting as exaggerated lumbar lordosis, thoracic kyphosis, and/or scoliosis. Radiologically, the condition presents as SED (reduced joint space, abnormal and often large epiphyses and platyspondyly) with osteoporosis. Extraskeletal manifestations (besides those secondary to the bony changes) have not been reported. Patients have normal facial appearance and intelligence.\nEtiology\nThe responsible gene CCN6 (mapping to human chromosome 6q22) encodes a secreted growth regulator.\nDiagnostic methods\nDiagnosis is based on clinical and radiographic findings. Molecular testing is available on research basis.\nDifferential diagnosis\nPPAC can be initially misdiagnosed as juvenile idiopathic (rheumatoid) arthritis but is distinguished on radiographic analysis (especially the platyspondyly and generalised epiphyseal dysplasia) and the absence of inflammatory joint disease. PPAC must be differentiated from juvenile idiopathic arthritis to ensure optimal treatment and to avoid unnecessary exposure to immunosuppressants.\nAntenatal diagnosis\nAntenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThere is no specific treatment for PPAC. No clear prevention, improvement or slowing the disease course with anti-inflammatory drugs has been demonstrated.\nPrognosis\nPPAC does not affect life expectancy, but the progressive nature of the disease frequently requires joint replacement by early adulthood.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Katta GIRISHA"}
{"Disease Name": "Progressive retinal dystrophy due to retinol transport defect", "Disease Definition": "Progressive retinal dystrophy due to retinol transport defect is a rare, genetic, metabolite absorption and transport disorder characterized by progressive rod-cone dystrophy, usually presenting with impaired night vision in childhood, progressive loss of visual acuity and severe retinol deficiency without keratomalacia. Association with ocular colobomas, severe acne and hypercholesterolemia has been reported.", "ORPHA ID": 352718, "Summary": ""}
{"Disease Name": "Progressive scapulohumeroperoneal distal myopathy", "Disease Definition": "A rare genetic muscular dystrophy characterized by progressive muscle weakness in a scapulo-humero-peroneal and distal distribution, featuring wrist extensor weakness, finger and foot drop, scapular winging, mild facial weakness, contractures of the Achilles tendon, elbow, and shoulder, and diminished or absent deep tendon reflexes. A predilection for the upper extremities has been reported in some patients. Respiratory muscles are spared until late in the disease course. Age of onset, progression, and severity of the disease vary significantly between individuals. Muscle biopsy shows groups of atrophic type I fibers and increased internal nuclei.", "ORPHA ID": 447977, "Summary": ""}
{"Disease Name": "Progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome", "Disease Definition": "A rare disorder characterized by progressive, late onset, autosomal dominant sensorineural hearing loss, QT interval prolongation, and mild cardiac hypertrophy.", "ORPHA ID": 228012, "Summary": ""}
{"Disease Name": "Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and intellectual disability, progressive spondyloepimetaphyseal dysplasia, short stature, short fourth metatarsals, and dysmorphic craniofacial features (including microcephaly, hypertelorism, epicanthal folds, mild ptosis, strabismus, malar hypoplasia, short nose, depressed nasal bridge, full lips, small, low-set ears, and short neck). Craniosynostosis, generalized hypotonia, as well as asymmetry of the cerebral hemispheres and mild thinning of the corpus callosum on brain imaging have also been described.", "ORPHA ID": 457395, "Summary": ""}
{"Disease Name": "Progressive supranuclear palsy-corticobasal syndrome", "Disease Definition": "An atypical variant of progressive supranuclear palsy (PSP), a rare late-onset neurodegenerative disease, characterized by a variable mixture of progressive asymmetric limb rigidity, apraxia, cortical sensory loss, alien limb, dystonia and bradykinesia that is unresponsive to levodopa. Postural instability and axial rigidity develop as the disease progresses. Neuropathological characteristics includes tau pathology and neuronal loss in specific brain areas, especially in the midfrontal and inferior parietal cortices.", "ORPHA ID": 240103, "Summary": ""}
{"Disease Name": "Progressive supranuclear palsy-predominant parkinsonism syndrome", "Disease Definition": "An atypical variant of progressive supranuclear palsy (PSP), a rare late-onset neurodegenerative disease, characterized by prominent early parkinsonism (tremor, limb bradykinesia, axial and limb rigidity) rather than falls and cognitive change. Over the years, patients ultimately develop clinical features characteristic of classical PSP. Neuropathological characteristics includes tau pathology and neuronal loss in specific brain areas, especially in the subthalamic nucleus and substantia nigra. The tau pathology is less severe than in classical PSP.", "ORPHA ID": 240085, "Summary": ""}
{"Disease Name": "Progressive supranuclear palsy-progressive non-fluent aphasia syndrome", "Disease Definition": "An atypical variant of progressive supranuclear palsy (PSP), a rare late-onset neurodegenerative disease, characterized by an initial presentation of an isolated speech and language disorder (apraxia of speech, agrammatism, and phonemic errors) years before developing other motor features of PSP. Neuropathological characteristics includes tau pathology and neuronal loss in specific brain areas, especially in the temporal cortex and superior frontal gyrus.", "ORPHA ID": 240112, "Summary": ""}
{"Disease Name": "Progressive supranuclear palsy-pure akinesia with gait freezing syndrome", "Disease Definition": "An atypical variant of progressive supranuclear palsy (PSP), a rare late-onset neurodegenerative disease, characterized by progressive freezing of gait, speech and writing early in the disease course. Later, axial rigidity, and facial immobility can occur, and supranuclear downgaze paresis may emerge after a decade. Neuropathological characteristics include tau pathology and neuronal loss in specific brain areas, especially in the globus pallidus, subthalamic nucleus, and substantia nigra. The tau pathology is less widespread compared to the other PSP sub-types.", "ORPHA ID": 240094, "Summary": ""}
{"Disease Name": "Progressive supranuclear palsy", "Disease Definition": "A rare late-onset neurodegenerative disease characterized by ocular motor dysfunction, postural instability, akinesia-rigidity, and cognitive dysfunction.", "ORPHA ID": 683, "Summary": "Epidemiology\nEstimates of prevalence of progressive supranuclear palsy (PSP) range between 1/13,000-34,000. It mainly affects adults older than 50 years of age.\nClinical description\nPSP usually manifests during the sixth or seventh decade of life. Five clinical variants have been described with clinicopathological correlations. Classical PSP (Richardson's syndrome) is the most common clinical variant and manifests with slowing of vertical saccadic eye movements, falls due to postural instability, axial akinetic-rigid syndrome, and cognitive impairment. Progressively patients develop other problems such as problems in speech and eventually a supranuclear gaze palsy and difficulties in swallowing. PSP with predominant Parkinsonism (PSP-P) is characterized by prominent early parkinsonism (tremor, limb bradykinesia, axial and limb rigidity) rather than falls and cognitive change. Over the years, patients ultimately develop clinical features characteristic of classical PSP. PSP with progressive gait freezing (PSP-PGF) is characterized by progressive freezing of gait, speech and writing early in the disease course. Later, axial rigidity, and facial immobility can occur, and supranuclear downgaze paresis may emerge after a decade. PSP with predominant corticobasal syndrome (PSP-CBS) is characterized by progressive apraxia/cortical sensory loss and limb rigidity/bradykinesia dystonia/myoclonus. PSP with predominant speech/language disorder (PSP-SL) is characterized by speech anomalies (apraxia of speech, agrammatism, nonfluent/agrammatic variant of primary progressive aphasia). Motor symptoms appear later in the course of the disease. PSP with predominant frontal presentation (PSP-F) presents with frontal cognitive/behavioral symptoms. Other variant manifestations of PSP include PSP with predominant ocular motor dysfunction (PSP-OM), PSP with predominant postural instability (PSP-PI), and PSP with predominant frontal presentation (PSP-F).\nEtiology\nPSP is a 4R tauopathy composed of a preponderance of four-repeat (exon 10 positive) tau isoforms and a characteristic biochemical profile (doublet tau 64 and tau 69). The MAPT H1-clade specific sub-haplotype, H1c, is a risk factor for this disease. PSP is also characterized by deficits in several neurotransmitter systems (e.g., dopaminergic, cholinergic, GABAergic). The factors that initiate tau-neurodegeneration are unknown.\nDiagnostic methods\nDiagnosis is based on the clinical picture and neuropsychological evaluation. On autopsy, PSP is characterized neuropathologically by neuronal loss and gliosis with tau-immunoreactive astrocytic plaques and neurofibrillary tangles in the brainstem and basal ganglia more than in cerebral cortex and cerebellum. Differences in the anatomical distribution of accumulation of phosphorylated tau protein correlate with the clinical variants.\nDifferential diagnosis\nDifferential diagnosis includes Parkinson disease and other atypical parkinsonian disorders (APD) such as multiple system atrophy and corticobasal degeneration. Similar eye movement abnormalities can occur in Niemann-Pick disease type C and Whipple disease.\nGenetic counseling\nPSP is a sporadic, non-hereditary disease.\nManagement and treatment\nThere is no treatment curing the disease. Some drugs, depending on the clinical variant, reduce morbidity and improve quality of life (e.g., levodopa responsiveness of patients with PSP-Parkinsonism). Amantadine may improve gait freezing, coenzyme Q10 may positively affect motor and cognitive dysfunction, and other anticholinergic medications occasionally improve voice and speech disturbance.\nPrognosis\nProgressively, patients become wheel-chair dependent due to the frequent falls. Difficulties in breathing and swallowing, and infections are the main causes of death, generally 6-12 years after onset of the disease.\n\n                            Last update: \n                            November 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Günter HÖGLINGER | ERN-RND*\n\n\n                                * European Reference Network"}
{"Disease Name": "Prolactinoma", "Disease Definition": "A rare, usually benign, neoplasm of the anterior pituitary gland that results in hyperprolactinemia. The most common clinical manifestations are amenorrhea and infertility in women; and impotence, decreased libido and infertility in men.", "ORPHA ID": 2965, "Summary": "Epidemiology\nIn Europe, the prevalence of prolactinoma is reported at between 1/1,600-2,200 (Belgium, UK and Switzerland). A notable female preponderance is observed, particularly among premenopausal women. Prolactinoma accounts for 66% of clinically relevant pituitary adenomas.\nClinical description\nDisease onset is usually in the second to fourth decades of life with galactorrhea, amenorrhea and infertility presenting in women and impotence, decreased libido and infertility in men. In male patients prolactinoma may exhibit more aggressive clinical course. Prolactinoma can also cause mass effects (visual field defects, headaches) or psychiatric manifestations (anxiety, depression).\nEtiology\nProlactinoma is a prolactin-secreting pituitary adenoma. The mechanism that leads to this benign growth of prolactin secreting cells is still unknown in most cases, however; very rarely, inactivating mutations of the AIP gene (11q13.3) in young patients can rarely lead to sporadic, isolated prolactinoma. Almost all AIP mutation-related prolactinomas are macroadenomas with male predominance and a young age at diagnosis. Hyperprolactinemia inhibits secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus, which results in decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and finally in decreased estrogen (females) and testosterone (males) levels. Prolactin itself stimulates lactation from breast tissue.\nDiagnostic methods\nDiagnosis includes laboratory hormonal testing showing hyperprolactinemia and decreased sex hormone levels (estrogen in females, testosterone in males). Pituitary adenomas may be visualized by pituitary magnetic resonance imaging (MRI). Tumors are classified according to their size: microadenomas (less than or equal to 10 mm), macroadenomas (greater than 10 mm), or giant adenomas (greater than 40 mm). Pre-menopausal females with prolactinomas usually have microadenomas, while male patients more frequently have macroadenomas.\nDifferential diagnosis\nProlactinoma can rarely occur as part of multiple endocrine neoplasia type 1 (MEN1) and familial isolated pituitary adenoma (FIPA). Causes of hyperprolactinemia without pituitary adenoma include: pregnancy, lactation, exercise, stress and polycystic ovary syndrome. Pituitary lesions that do not produce prolactin can also cause hyperprolactinemia by pituitary stalk impingement (stalk effect).\nGenetic counseling\nProlactinomas usually occur sporadically and with the exception of prolactinoma due to MEN1 or FIPA, the occurrence of prolactinomas as part of inherited syndromes is exceptionally rare. In patients with a pathogenic variant of AIP, the inheritance is autosomal dominant and thus offspring of an affected individual have a 50% risk of inheriting the mutation; however, penetrance is variable.\nManagement and treatment\nInitial therapy is a dopamine agonist (cabergoline or bromocriptine) for normalizing hyperprolactinemia and decreasing tumor size. Dopamine agonist treatment should start at low doses and be titrated upwards gradually according to hormonal response and tolerability. For dopamine analog-resistant patients, changing to another dopamine agonist, increasing the dose of the drug, or neurosurgery may be proposed. Patients receiving high doses of dopamine agonists should be screened and monitored with echocardiography to identify cardiac valve dysfunction. Other medical therapies (e.g. temozolamide) may be needed for aggressive, invasive prolactinomas or rare carcinomas that are refractory to other therapies. Radiotherapy can also be considered in cases where both dopamine agonists and surgery have failed.\nPrognosis\nProlactinomas are usually readily controlled with dopamine agonists that improve symptoms/signs and shrink and/or control the pituitary tumor mass. Patients with MEN1 and those harboring mutations in AIP can have a poorer response to therapy.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Albert BECKERS  - Dr Adrian DALY"}
{"Disease Name": "Prolidase deficiency", "Disease Definition": "Prolidase deficiency is an inherited disorder of peptide metabolism characterized by severe skin lesions, recurrent infections (involving mainly the skin and respiratory system), dysmorphic facial features, variable cognitive impairment, and splenomegaly.", "ORPHA ID": 742, "Summary": "Epidemiology\nThe exact prevalence is unknown but a prevalence estimate of 1/1,235,000 live births has been suggested. A higher carrier frequency of 1/21 has been reported in the Druze community. Approximately 90 patients from different ethnic groups have been reported in the literature to date, but due to underdiagnosis the exact number is probably higher.\nClinical description\nClinical manifestations and age of onset are quite variable. Prolidase deficiency can present in infancy with splenomegaly. Diarrhea, vomiting, and dehydration may also occur. Dysmorphic facial features include low anterior and posterior hairline, hypertelorism, proptosis, flat nasal bridge, thin vermilion of the upper lip and prognathism. Skin involvement usually appears during childhood (but can appear as early as 6 months and as late as 30 years of age) with severe, chronic, recalcitrant, and painful skin ulcers of the feet, lower legs and, less commonly, the hands. Telangiectasia of the face and hands may precede ulcers as well as erythematous, maculopapular lesions or purpuric lesions. Most patients have some degree of intellectual disability, ranging from mild to severe. Pulmonary (e.g. asthma-like chronic reactive airway disease), immunologic (susceptibility to infections with recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis) and hematologic (e.g. anemia, thrombocytopenia) manifestations have also been reported. Additional, less commonly reported manifestations include short stature, lymphedema, joint laxity, protuberant abdomen, hirsutism, dental dysplasia and keratitis. Some patients, however, remain asymptomatic. An association between prolidase deficiency and systemic lupus erythematosus (SLE; see this term) has been reported.\nEtiology\nProlidase deficiency is due to a mutation in the PEPD gene (19q13.11), encoding Xaa-Pro dipeptidase, which plays an important role in the biosynthesis and degradation of collagen. Mutations in this gene lead to impaired collagen synthesis and wound healing.\nDiagnostic methods\nDiagnosis is based on clinical and laboratory findings. Urine amino acid analysis reveals massive imidodipeptiduria (10-30 mmol/day) in all cases. Patients also usually have elevated liver enzymes, mild anemia, mild thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia. Molecular genetic testing, identifying a mutation in the PEPD gene, confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses include Werner syndrome, beta-thalassemia, vasculitis (see these terms), autosomal dominant and recessive forms of hyper-IgE syndrome, sickle cell disease, pressure ulcers, and arterial and venous insufficiency.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease-causing mutation.\nGenetic counseling\nProlidase deficiency is inherited in an autosomal recessive manner. Parents of an affected child should be informed of the 25% risk of transmission to future offspring.\nManagement and treatment\nTreatment is symptomatic. Care should be provided by a multidisciplinary team in order to monitor and treat skin, lung, and immunologic manifestations. Topical proline plus glycine ointment, steroids, methylprednisolone, blood transfusions, plasmapheresis, and topical growth hormone ointment have all been used to treat ulcers, with varying degrees of improvement reported. Antibiotic prophylaxis may be necessary in some cases. In patients with splenomegaly, contact sports should be avoided.\nPrognosis\nPrognosis varies but patients often have a decreased life-expectancy due to severe and sometimes fatal infections. Quality of life is also reduced due to infections and chronic pulmonary complications. When severe, ulcers can lead to amputation.\n\n                            Last update: \n                            April 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Heng WANG"}
{"Disease Name": "Proliferating trichilemmal cyst", "Disease Definition": "A rare large, multinodular, usually benign, tumor that is generally located in the posterior part of the scalp in aged women (over 50 years). It first appears as a painless nodule that later grows into a solid or partially cystic tumor that is mobile over the underlying subcutaneous tissues. It can present ulceration, inflammation or even bleeding and can cause necrosis of the adjacent tissues.", "ORPHA ID": 492, "Summary": ""}
{"Disease Name": "Prominent glabella-microcephaly-hypogenitalism syndrome", "Disease Definition": "A rare syndrome described and characterized by prenatal onset of growth deficiency, microcephaly, hypoplastic genitalia, and birth onset of convulsions.", "ORPHA ID": 2083, "Summary": ""}
{"Disease Name": "Properdin deficiency", "Disease Definition": "Properdin deficiency is a rare, hereditary, primary immunodeficiency due to a complement cascade protein anomaly characterized by significantly increased susceptibility to Neisseria species infections. It only affects males, typically presenting with severe or fulminant meningococcal disease.", "ORPHA ID": 2966, "Summary": ""}
{"Disease Name": "Propionic acidemia", "Disease Definition": "Propionic acidemia (PA) is an organic aciduria caused by the deficient activity of the propionyl Coenzyme A carboxylase and is characterized by life threatening episodes of metabolic decompensation, neurological dysfunction and that may be complicated by cardiomyopathy.", "ORPHA ID": 35, "Summary": "Epidemiology\nThe prevalence rate is probably about 1 in 100,000 live births worldwide. A high prevalence rate is noted in certain countries like Saudi Arabia.\nClinical description\nPropionic acidemia can present in one of the following forms: severe neonatal onset, intermittent late onset or a chronic progressive form. In the severe neonatal onset form, the affected infants present with symptoms of metabolic intoxication (poor feeding, vomiting, altered sensorium) and pancytopenia within several hours to weeks after birth. In the intermittent late onset form, the disease presents after a year or even later in life with episodes of metabolic decompensation provoked by periods of catabolic stress like fever, vomiting and trauma. Patients may also present with acute neurological crisis characterized by dystonia, rigidity, choreoathetosis and dementia (due to infarction of basal ganglia). In the chronic progressive form, the disease presents as failure to thrive, chronic vomiting, psychomotor delay, hypotonia, seizures and movement disorders. Intellectual disability, optic neuropathy, cardiomyopathy, long QT syndrome, pancreatitis, dermatitis, and immune dysfunction are known complications.\nEtiology\nPA is caused by mutations in either the PCCA (13q32) or PCCB (3q21-q22) genes encoding the α- and β-subunits of the propionyl CoA carboxylase.\nDiagnostic methods\nExtended newborn screening test identifies PA by detecting an elevated level of propionyl carnitine. Symptomatic cases present during metabolic decompensation with acidosis, ketosis, increased anion gap, hyperlactatemia, hyperglycinemia, hyperammonemia, hypoglycemia and cytopenias. Urine analysis by gas chromatography-mass spectrometry reveals a characteristic pattern with 3 hydroxy propionate, methyl citrate, propionyl glycine and propionyl carnitine that persists in between crisis. Confirmation of the diagnosis relies on detection of either deficient enzymatic activity or mutations in PCCA or PCCB genes.\nDifferential diagnosis\nDifferential diagnosis includes neonatal sepsis, other branched chain organic acidurias, pyloric stenosis or other common causes of increased anion gap acidosis. In the infantile chronic form, failure to thrive, chronic vomiting and neutropenia may mimic cow milk intolerance, celiac disease (see this term) or immune deficiencies.\nAntenatal diagnosis\nPrenatal diagnosis can be made by measuring propionyl carnitine, methyl citrate and 3 hydroxy propionate in the amniotic fluid or by DNA assay or direct enzyme assay in families with a known mutation.\nGenetic counseling\nInheritance is autosomal recessive.\nManagement and treatment\nConfirmation of the diagnosis is not indispensable to start the treatment. Reversal of catabolism by stopping protein intake and administering non-protein calories in the form of intravenous fluids is the mainstay of treatment of a crisis. Hyperammonemia is treated by administering sodium benzoate, carbamyl glutamate or by hemodialysis. Nutrition management, in particular protein restriction, is a cornerstone to the long term treatment of patients with PA. Growth is regularly monitored. Carnitine supplementation helps in detoxification. Avoiding metabolic decompensation and promptly treating the episodes with standard treatment may improve intellectual outcome.\nPrognosis\nEarly detection and treatment has led to a reduction in the mortality rate in the first year of life and improved survival rates in early and mid-childhood but morbidity in terms of impaired cognitive development remains high. The question whether a liver transplantation can be performed early in infancy to improve the prognosis is still under investigation.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Marie SAUDUBRAY"}
{"Disease Name": "Propylthiouracil embryofetopathy", "Disease Definition": "Propylthiouracil embryofetopathy is a rare teratologic disease characterized by variable congenital anomalies resulting from maternal treatment and prenatal exposure to propylthiouracil. Anomalies frequently encountered include ear malformations (e.g. accessory auricle, preauricular sinus/fistula/cyst), urinary system malformations (e.g. isolated unilateral kidney, congenital hydronephrosis), gastrointestinal anomalies (e.g. congenital bands with intestinal malrotation) and cardiac defects (e.g. situs inversus dextrocardia, cardiac outflow tract defects).", "ORPHA ID": 485358, "Summary": ""}
{"Disease Name": "Proteasome-associated autoinflammatory syndrome", "Disease Definition": "A rare, autosomal recessive autoinflammatory disorder characterized by early-onset erythematous popular/nodular skin eruptions, recurrent fever, possible joint contractures, lipodystrophy, erythematous inflammatory skin changes, joint and muscle involvement (joint contractures, arthralgia, muscle weakness), and hepatosplenomegaly.", "ORPHA ID": 324977, "Summary": "Epidemiology\nTo date less than 50 cases have been reported in the scientific and medical literature; the distribution is worldwide.\nClinical description\nThe disease presents as spectrum with onset ranging from the neonatal period to childhood, with the majority of reported cases occurring in infancy. The principal manifestations are of pernio-like and/or erythematous lesions and periodic fever. Lesions can be annular, nodular or maculopapular involving the hands and feet or periorbital regions, and may be associated with seasonal variation. Variable skin manifestations include heliotrope-like rash on eyelids, nodular episcleritis, ear and nose chondritis, plantar hyperkeratosis, hyperhidrosis of hands and feet. Lipodystrophy is first noted in the face and upper limbs, giving a characteristic thin and angular facial appearance, and may become generalized to include the abdomen and lower limbs. Lipodystrophy is progressive and irreversible. Joint contractures affect mainly the hands and feet at first but can later spread to other joints and can cause pain and joint deformities. Fingers may appear long and clubbed. Arthralgia without arthritis may be noted. Hepatosplenomegaly is frequently reported and delayed physical development (low height and weight) is possible. Other less common manifestations include conjunctivitis, short stature, and attacks of aseptic meningitis, seizures, microcytic anemia.\nEtiology\nThe disease is due to loss of function variants in the gene PSMB8 (6p21.3) encoding the beta5i subunit of immunoproteasome. In all reported Japanese patients, the disease is due to the homozygous c.602G>T (p.Gly201Val) variant. The immunoproteasome is involved in proteolysis and maintenance of cell homeostasis. If proteolysis is disrupted, this can lead to an increase in interferon (IFN) signaling and cell stress. This dysregulation of the IFN pathway is thought to be responsible for the manifestations seen in this disease. Some cases remain to be genetically determined, indicating the possibility of other disease-causing genes.\nDiagnostic methods\nDiagnosis is based on clinical presentation and family history and confirmed by genetic testing. In Japan, clinical diagnosis is established on presentation of five or more major clinical characteristics (autosomal recessive heritability, skin rash, periodic fever, nodular erythema, lipodystrophy ranging from localized to near generalized, muscular atrophy, elongated clubbed fingers or joint contractures, hepato-splenomegaly, or calcification in the basal ganglia). Histopathologic examination of skin biopsy reveals focal mononuclear cell infiltration with vasculopathy. Laboratory findings include constantly elevated serum C-reactive protein (CRP) levels and hyper-gamma-globulinemia. Autoantibody titers increase as the disease progresses in some but remain negative in others. Molecular genetic testing can identify disease causing variants, confirming diagnosis.\nDifferential diagnosis\nDifferential diagnoses include cryopyrin-associated periodic syndrome, mucopolysaccharidosis, familial partial lipodystrophy, systemic lupus erythematosus, lupus erythematosus panniculitis, dermatomyositis, Sjögren syndrome, inclusion body myositis, Aicardi-Goutières syndrome, and Weber-Christian disease.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive and genetic counseling should be offered to affected families. Where both parents are unaffected carriers, there is a 25% risk of transmission to offspring at each pregnancy.\nManagement and treatment\nThere is no effective therapeutic regimen. Fever and skin lesions respond well to systemic steroid administration but usually reoccur after tapering. Biologics (notably tocilizumab and baricitinib) have been used to varying effect; however, randomized controlled trials are lacking. These treatments are all ineffective in halting lipodystrophy progression.\nPrognosis\nLife expectancy can be compromised, with death often the result of multi-organ inflammation. Quality of life is largely affected as patients suffer from reduced activity, fever, pain and repeated episodes of severe inflammation.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Abhimanyu GARG"}
{"Disease Name": "Proteus syndrome", "Disease Definition": "A rare complex overgrowth syndrome characterized by progressive overgrowth of the skeleton, skin, adipose, and central nervous systems.", "ORPHA ID": 744, "Summary": "Epidemiology\nApproximately 200 cases of Proteus syndrome (PS) have been reported to date. The prevalence is estimated to be less than 1/1,000,000 live births.\nClinical description\nProteus syndrome presents in a wide range of severity and anatomic distribution. Individuals usually have no signs or symptoms at birth but onset of overgrowth typically occurs in the first 2 years of life. This often manifests as overgrowth of the hands or legs. Skeletal overgrowth is progressive and may involve the limbs, the skull, and spine. Cerebriform connective tissue nevi (CCTN) typically occur on the feet or hands during childhood beginning as small nodules that coalesce to the cerebriform lesion. Vascular malformations, most commonly venous or capillary, and epidermal nevi may occur in the first months of life and generally stabilize with time. Neurological features include hemimegalencephaly, developmental delay and intellectual disability. Additional features include cystic lung disease, and an increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). Tumors may arise in individuals and are mainly benign, particularly gonadal cystadenoma, parotid adenoma, and meningioma, but rare malignant tumors have been reported.\nEtiology\nSomatic activating variants in AKT1 are associated with Proteus syndrome. The most common is the c.49G>A (p.Glu17Lys) variant but others have been reported.\nDiagnostic methods\nDiagnosis should be based on phenotype and genotype. This dyadic approach has been proposed with use of a scoring system. The score includes the following features of Proteus syndrome: CCTN (5 points), asymmetric bony overgrowth (5 points), organ/visceral overgrowth (5 points), cystic lung disease (2 points), dysregulated adipose tissue (2 points), vascular malformations (2 points), tumors associated with Proteus syndrome (1 point), history of DVT or PE (2 points), and a facial phenotype (2 points). Presence of prenatal overgrowth or ballooning overgrowth (-5 points each) may favor a diagnosis of other than Proteus syndrome, such as PIK3CA-related overgrowth spectrum. In the absence of a somatic AKT1 variant, a score of 15 or greater indicates a clinical diagnosis of Proteus syndrome. If a somatic AKT1 variant is present, a score of 10 or greater indicates a diagnosis of AKT1- related Proteus syndrome. Genetic testing requires sampling of an affected tissue, such as a skin biopsy. Blood is not an appropriate source for genetic testing.\nDifferential diagnosis\nDifferential diagnoses include PIK3CA-related overgrowth spectrum disorders such as Klippel-Trenaunay syndrome and CLOVES syndrome, as well as other disorders of overgrowth such as PTEN hamartoma tumor syndrome (PHTS), neurofibromatosis type 1, Ollier disease, and Maffucci syndrome.\nAntenatal diagnosis\nPrenatal testing is not performed as PS is a mosaic disorder and not inherited.\nGenetic counseling\nProteus syndrome is not thought to be inherited because the activating AKT1 variant is hypothesized to be lethal in the heterozygous state. There are reports of individuals with Proteus syndrome who have unaffected children.\nManagement and treatment\nTreatment requires a multidisciplinary approach and must be tailored to an individual's unique presentation. Surgical interventions used to control overgrowth include physeal arrest, epiphysiodesis, and spinal fusion. Physical and occupational therapy is critical as custom designed orthotics or footwear may be necessary. Dermatological care along with management of malodor (if present) is needed for those with CCTN. Perioperative anticoagulation prophylaxis should be strongly considered as PE is the leading cause of death. Individuals should be counseled about the risk of tumor predisposition. Psychosocial counseling can be beneficial for individuals and their families. Targeted therapy using AKT inhibitors to mitigate disease progression is ongoing in clinical trials.\nPrognosis\nPrognosis varies depending on the severity of complications.\n\n                            Last update: \n                            May 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Christopher OURS"}
{"Disease Name": "Proteus-like syndrome", "Disease Definition": "A rare genetic disease characterized by patients presenting with a multitude of clinical features of Proteus syndrome without meeting the diagnostic criteria for the disease.", "ORPHA ID": 2969, "Summary": "Epidemiology\nThe prevalence is unknown. There have been only 7 case reports of patients with proteus-like syndrome; 5 out of 7 were confirmed to have a germline pathogenic PTEN variant.\nClinical description\nProteus-like syndrome has the clinical features of Proteus syndrome but lacks some of the required criteria necessary for diagnosis. The main clinical features include skeletal overgrowth, hamartomous overgrowth of multiple tissues, cerebriform connective tissue nevi, vascular malformations and linear epidermal nevi.\nEtiology\nMutations in the PTEN gene are found in more than half of Proteus-like syndrome cases, making them a part of the PTEN harmatoma tumor syndrome (PHTS) group. To date, mutations in AKT1 have not been reported in Proteus-like patients. It is possible that Proteus-like patients will have somatic mosaic or germline mutations in genes encoding other components of the phosphatidylinositol 3-kinase signaling pathway.\nDiagnostic methods\nClinical diagnosis can be made using the Proteus syndrome clinical criteria. Individuals who present with clinical features but do not meet the clinical criteria for Proteus syndrome are diagnosed clinically as having Proteus-like syndrome. Germline genetic testing for a pathogenic PTEN variant can confirm a genetic diagnosis of Proteus-like syndrome.\nDifferential diagnosis\nThe differential diagnosis includes Proteus syndrome and PTEN hamartoma tumor syndromes (PHTS) such as Cowden syndrome.\nAntenatal diagnosis\nAntenatal diagnosis is in theory possible if the pathogenic variant has previously been identified in the family. It has not been described in the literature.\nGenetic counseling\nInheritance is autosomal dominant in those with a PTEN mutation, with a high de novo rate. Genetic counseling should be offered to at-risk family members to inform them of their health risks and the 50% transmission risk for each pregnancy.\nManagement and treatment\nGermline PTEN pathogenic variants predispose to a wide spectrum of benign and malignant tumors and surveillance recommendations for PTEN carriers including Proteus-like syndrome, have been described under the term of PTEN hamartoma tumor syndrome (PHTS) and Cowden syndrome. Management and surveillance for Proteus-like syndrome with a germline PTEN pathogenic variant would be as described for PHTS, which includes the following: 1) annual comprehensive physical examination starting at age 18 or 5 years before youngest age of diagnosis of cancer in the family, with attention to thyroid exam; 2) yearly dermatological exam for children and adults; 3) yearly thyroid ultrasound from the time of diagnosis; 4) monthly breast self-examination from age 18, clinical breast examination annually from age 25, and annual MMG staring from age 30-35; 5) endometrial cancer screening by biopsy can be considered starting age 35; 6) colonoscopies starting from age 35 and repeating every 5 years; 7) management tailored to clinical presentation and personalized follow-up with annual clinical review has been suggested in literature. More data is required to optimize screening and management for Proteus-like syndrome patients.\nPrognosis\nPrognosis could be dependent on the risk associated with the development of cancer.\n\n                            Last update: \n                            December 2023\n\n\n                            - Expert reviewer(s): \n                             Manasadevi KARTHIKEYAN  - Dr Joanne NGEOW"}
{"Disease Name": "Proton-pump inhibitor-responsive esophageal eosinophilia", "Disease Definition": "Proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is a rare, gastroenterologic disease characterized by typical clinical, endoscopic and histological features of eosinophilic oesophagitis (i.e. symptomatic oesophageal dysfunction associated with eosinophil-predominant mucose infiltrate) which completely remits upon proton pump inhibitor therapy.", "ORPHA ID": 411696, "Summary": ""}
{"Disease Name": "Proximal 16p11.2 microdeletion syndrome", "Disease Definition": "The proximal 16p11.2 microdeletion syndrome is a chromosomal anomaly characterized by developmental and language delays, mild intellectual disability, social impairments (autism spectrum disorders), mild variable dysmorphism and predisposition to obesity.", "ORPHA ID": 261197, "Summary": "Epidemiology\nThe prevalence of proximal 16p11.2 microdeletion syndrome is estimated at 1/5,000 in the general population. Proximal 16p11.2 microdeletion syndrome is a common etiology in autism spectrum disorder (ASD) estimated at approximately 1:150 individuals diagnosed with ASD.\nClinical description\nThe clinical presentation of proximal 16p11.2 microdeletion syndrome can be extremely variable, ranging from intellectual deficiency with multiple congenital anomalies, autism, cognitive and language problems, to a normal phenotype. Nearly all individuals do present with some degree of developmental delay including a cognitive delay and a language delay specifically in the onset and development of expressive language (childhood apraxia of speech) as well as to a lesser extent feeding difficulties, linked to hypotonia and a delay in gross and fine motor and coordination skills. Furthermore, they often present with autistic features. Intellectual disability is usually mild but can be absent. About half of affected individuals have a tendency to be overweight. Dysmorphic features may be present but are often mild and inconsistent. Additional less frequent features reported include hypotonia, EEG abnormalities, psychiatric disease other than ASD and minor cardiac anomalies.\nEtiology\nThe proximal 16p11.2 microdeletion syndrome most commonly refers to a distinct deletion of approximately 593 kb at chromosomal coordinates 29.5-30.1 Mb comprising 24 genes. The relationship between genotype and clinical phenotype remains elusive. Patients with larger deletions including this region or patients with a more distally located (coordinates 28.73-28.95 Mb), smaller (200 kb) 16p11.2 deletion are not described here.\nDiagnostic methods\nDiagnosis is based on clinical manifestations leading to chromosomal analysis. Molecular techniques that may be used for the genetic characterization of the proximal 16p11.2 microdeletion include fluorescence in situ hybridization (FISH), Multiplex Ligation-dependent Probe Amplification (MLPA), Microarray-based Comparative Genomic Hybridization (aCGH) and quantitative polymerase chain reaction (qPCR). Electroencephalographic (EEG) testing is performed in cases with seizures.\nDifferential diagnosis\nDifferential diagnosis includes many entities presenting with a developmental delay with or without autistic features and minor dysmorphisms.\nAntenatal diagnosis\nIn cases with a family history, preimplantation genetic diagnosis or prenatal testing is technically feasible by amniocentesis or chorionic villus sampling and cytogenetic analyses, but genetic counseling for affected individuals should be provided before starting a family. The outcome of the genetic diagnosis cannot accurately predict the clinical phenotype.\nGenetic counseling\nProximal 16p11.2 microdeletion syndrome is a contiguous deletion syndrome. Proximal 16p11.2 microdeletions almost always appear de novo, but may, in a small number of cases, be inherited from affected parents in an autosomal dominant manner.\nManagement and treatment\nManagement involves a regular assessment by appropriate specialists and tailored neurodevelopmental therapies. Early diagnosis and access to therapies with attention to speech and language are recommended together with nutritional education and weight management.\nPrognosis\nPrognosis depends on the severity of clinical manifestations. Long-term clinical follow-up studies are not available to date. One may expect that the long-term health consequences of obesity occurring in the general population will also occur in individuals with proximal 16p11.2 microdeletion syndrome.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM"}
{"Disease Name": "Proximal 16p11.2 microduplication syndrome", "Disease Definition": "Proximal 16p11.2 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from a partial duplication of the short arm of chromosome 16 characterized by developmental delay and intellectual disability of a highly variable degree, autism spectrum, obsessive-compulsive, attention deficit hyperactivity disorder, speech articulation abnormalities, muscular hypotonia, tremor, hyper- or hyporeflexia, seizures, microcephaly, neuroimaging abnormalities, decreased body mass index and schizophrenia or bipolar disorder later on in life.", "ORPHA ID": 370079, "Summary": ""}
{"Disease Name": "Proximal myopathy with extrapyramidal signs", "Disease Definition": "Proximal myopathy with extrapyramidal signs is a rare, hereditary non-dystrophic myopathy characterized by proximal muscle weakness, delayed motor development, learning difficulties, and progressive extrapyramidal motor signs including chorea, dystonia and tremor. Variable additional features have been reported - ataxia, microcephaly, ophthalmoplegia, ptosis, and optic atrophy.", "ORPHA ID": 401768, "Summary": ""}
{"Disease Name": "Proximal myopathy with focal depletion of mitochondria", "Disease Definition": "A rare genetic neuromuscular disease characterized by late onset of mild, progressive, proximal muscle weakness, severe myalgias during and after exercise, and susceptibility to rhabdomyolysis. Intellectual disability is mild or absent. There are no abnormalities of the skin. Muscle biopsy shows focal depletion of mitochondria especially at the center of muscle fibers, surrounded by enlarged mitochondria at the periphery.", "ORPHA ID": 521305, "Summary": ""}
{"Disease Name": "Proximal myotonic myopathy", "Disease Definition": "A rare myotonic dystrophy of juvenile or adult-onset characterized by mild and fluctuating myotonia, muscle weakness, and rarely cardiac conduction disorders.", "ORPHA ID": 606, "Summary": "Epidemiology\nPrevalence estimates of around 1/100,000 in Germany and 1/600,000 in the United Kingdom have been suggested. Most cases have been reported in individuals of European origin (mainly in Eastern Europe with a founder effect).\nClinical description\nThe clinical presentation is marked by significant variability as is the age of onset (juvenile to late adulthood). The primary manifestations include muscle weakness (with early involvement of neck flexors or finger flexors, later involving hip girdle muscles), myotonia, and possibly severe fluctuating or episodic muscle pain, and stiffness. Cataracts, hypogonadism or testicular failure in males, insulin insensitivity, excessive sweating, cognitive abnormalities are rare features. Cardiac disorders are rare and may include conduction abnormalities (atrioventricular and bundle branch block) and cardiac arrhythmias. Gastrointestinal complications are common and can include constipation, dysphagia, and abdominal pain. Increased risk of cancer involving colon, brain and pancreas has been reported. The phenotype may be particularly mild in a large number of affected individuals.\nEtiology\nThe disease is caused by a CCTG expansion in the first intron of the cellular nucleic acid binding protein gene (CNBP; 3q21). Mutant alleles have 75 to 11,000 uninterrupted CCTG repeats. The pathogenesis is poorly understood.\nDiagnostic methods\nThere may be considerable difficulty and delay in the diagnosis due to the wide clinical spectrum and non-specific manifestations. The diagnosis is based on molecular genetic testing.\nDifferential diagnosis\nThere are several overlapping features with Steinert myotonic dystrophy; whilst the diseases are similar, they are genetically distinct and have different courses and management requirements. The main difference is the absence of congenital form, which is seen in Steinert myotonic dystrophy.\nAntenatal diagnosis\nPrenatal diagnosis is possible in affected families with an index patient.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. Genetic counselling should be provided to affected families. There is a 50% risk of disease transmission to offspring from an affected parent. A parent with intermediate CCTG repeat expansion is considered to have a premutation and thus there is a risk of transmitting the disorder to their offspring.\nManagement and treatment\nManagement primarily involves monitoring of cataracts, insulin metabolism, and cardiac conduction.\nPrognosis\nThe prognosis is generally good with no impact on life expectancy.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanni MEOLA"}
{"Disease Name": "Proximal renal tubular acidosis", "Disease Definition": "A rare renal tubular disease characterized by impaired ability of the proximal tubule to reabsorb bicarbonate from the glomerular filtrate leading to hyperchloremic metabolic acidosis.", "ORPHA ID": 47159, "Summary": "Epidemiology\nPrevalence is unknown but isolated hereditary pRTA is very rare. Drug-induced pRTA occurs relatively frequently.\nClinical description\nOnset of hereditary pRTA occurs in childhood, manifesting initially with very alkaline urine due to bicarbonate wastage. Autosomal recessive pRTA (AR pRTA) is associated with severe growth retardation leading to short stature, intellectual disability and ocular abnormalities such as band keratopathy, cataracts, and glaucoma. Growth retardation and reduced bone density, due to metabolic acidosis, are seen in autosomal dominant pRTA (AD pRTA). Hypokalemia may be present in some cases of pRTA and can occasionally cause symptoms of hypokalemic periodic paralysis. Rickets and osteomalacia are common due to vitamin D deficiency and phosphate wasting. In cases where pRTA is associated with primary Fanconi syndrome, glycosuria, aminoaciduria, phosphaturia, uric acid wastage and tubular proteinuria can occur.\nEtiology\nIsolated pRTA can be acquired or is inherited either recessively (in most cases) or dominantly. AR pRTA is due to a mutation in the SLC4A4 gene (4q13.3) that encodes the electrogenic sodium bicarbonate cotransporter 1 (kNBC1). AD pRTA is due to mutations in a gene that has not yet been identified. As the proximal tubule reabsorbs around 80% of the filtered load of bicarbonate, a defect in it leads to the loss of bicarbonate. Certain drugs can be responsible for the development of acquired pRTA. Carbonic anhydrase inhibitors cause isolated pRTA while others (including oxaplatin, ifosfamide, adefovir, tenofovir, cidofovir, valproic acid, aminoglycosides, topiramate and didanosine) can all cause pRTA associated with Fanconi syndrome. In glomerular diseases, pRTA has been rarely reported and attributed to associated tubular damage and, in some cases, has been associated with multiple myeloma..\nDiagnostic methods\nUnlike patients with distal RTA (dRTA), patients with pRTA retain the ability to lower urine pH < 5.5 when the plasma HCO3- is low enough and below the renal threshold for tubular HCO3- reabsorption. Diagnosis involves the demonstration of urinary HCO3- wastage (increased fractional HCO3- excretion). An HCO3- titration test confirms a diagnosis of pRTA by demonstrating an exaggerated increase in urinary HCO3- excretion and urine pH as plasma HCO3- rises above the renal threshold. Molecular genetic analysis can identify a mutation in the SLC4A4 gene.\nDifferential diagnosis\nThe main differential diagnosis is dRTA. Other inherited proximal tubulopathies such as oculocerebrorenal syndrome, Dent disease and glycogen storage disease due to GLUT2 deficiency should be excluded.\nAntenatal diagnosis\nPrenatal diagnosis is possible in AR pRTA where the pathogenic variants have previously been identified in a family member but is not applicable in AD forms.\nGenetic counseling\nIn families with AR pRTA genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. In families with AD pRTA genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment depends on the etiology of the disease. Inherited pRTA requires life-long bicarbonate replacement therapy. Large amounts of bicarbonate (10-15 mEq/kg/day) are needed to normalize serum bicarbonate in children. Thiazide diuretics (e.g. hydrochlorothiazide 25-50 mg daily) are also sometimes prescribed in order to enhance bicarbonate reabsorption and thereby reduce the amount of bicarbonate needed. Plasma potassium should be monitored, and a mixture of sodium and potassium bicarbonate (or citrate) salts can be necessary in some cases. Drug induced pRTA is usually reversible by cessation of the drug.\nPrognosis\nWith proper treatment the prognosis of acidosis is good, but associated extrarenal features impact on patient outcome.\n\n                            Last update: \n                            March 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Gema ARICETA  - Dr Daniel BATLLE"}
{"Disease Name": "Proximal spinal muscular atrophy type 1", "Disease Definition": "A rare, genetic proximal spinal muscular atrophy characterized by degeneration of alpha motor neurons in the anterior horns of the spinal cord and lower brain stem manifesting with onset of severe and progressive muscle weakness in the first 6 months of life and presenting with severe, generalized hypotonia and weakness,. Dysphagia and respiratory impairment may also be present at presentation or appear at a later stage. Classically, before the advent of recent therapies, type 1 patients never achieved sitting without support.", "ORPHA ID": 83330, "Summary": "Epidemiology\nThe average prevalence of proximal spinal muscular atrophy (SMA) is estimated at 1/12,000, of which approximately 60% account for type 1.\nClinical description\nDisease onset occurs before 6 months of age. The severe, symmetrical muscle weakness affects predominantly proximal limbs but often also involves the extremities. Cries are weak. Poor sucking ability and reduced swallowing are frequent, leading to feeding difficulties. Deep tendon reflexes are absent. Patients have paradoxical breathing, a bell shaped chest and develop respiratory failure. Mild contractures (of the knees and, more rarely, of the elbows), and scoliosis may be present. Classically, patients were not able to achieve sitting without support but this has changed following the availability of new treatments.\nEtiology\nThe disease is a result of degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei. Causal homozygous mutations/deletions in the SMN1 gene (5q12.2-q13.3) are responsible. SMN1 encodes the survival motor neuron protein (SMN) which is known to participate in critical pathways related to RNA processing and transport, and it is believed that motor neurons are particularly vulnerable to impairments in these processes. Modifier genes include SMN2 (5q13.2), a homologous centromeric copy of SMN1, and NAIP (5q13.1), encoding neuronal apoptosis inhibitory protein. The number of copies of the SMN2 is inversely correlated to disease severity.\nDiagnostic methods\nThe diagnosis is clinically suggested by muscle weakness and hypotonia with sparing of the facial muscles, loss of reflexes, typical respiratory pattern with predominance of diaphragmatic movements compared to poor intercostal movements, and tremor. Diagnosis is confirmed by genetic testing of SMN1 deletion/mutation and, if possible, SMN2 copy number testing. Muscle biopsy and electromyography should not be performed in patients with typical presentation.\nDifferential diagnosis\nDifferential diagnoses include, other spinal muscular atrophies with infantile onset (infantile-onset X-linked spinal muscular atrophy and spinal muscular atrophy with respiratory distress type 1), congenital muscular dystrophies, congenital myopathies, congenital myasthenic syndromes, some early-onset mitochondrial disorders, and carbohydrate metabolism disorders (glycogen storage disease due to acid maltase deficiency).\nAntenatal diagnosis\nAntenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus samples.\nGenetic counseling\nTransmission is autosomal recessive and thus the risk of transmission to offspring is 25% where both parents are unaffected carriers. However, around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to affected families.\nManagement and treatment\nSymptomatic management is multidisciplinary and aims to improve quality of life. This includes respiratory support (noninvasive ventilation and airway clearance), physiotherapy, gastrostomy, and antibiotic treatment in case of pulmonary infection. In the last few years, nusinersen, an antisense oligonucleotide, has been approved and made available for treatment of all SMA types in Europe and the USA. Clinical trials and real world data have shown that it reduces the risk of death and improves motor milestones in type 1 patients, with a number of patients achieving sitting without support. The best results are seen following early intervention and in presymptomatic patients. Risdiplam (a small molecule) has a also recently successfully completed clinical trials and has become commercially available in US and, for compassionate use, also in Europe. A different approach, using gene therapy, onasemnogene abeparvovec, has also been approved in US and Europe. The results of the clinical trials in young patients also indicate a very high rate of survival beyond 2 years and an improvement of motor function. Real world data are being collected in older patients but are not yet publicly available.\nPrognosis\nThe prognosis is generally poor with most patients dying within the first two years of life due to respiratory failure. Data on long term outcomes with nusinersen treatment and with other drugs are now becoming increasingly available, suggesting long term survival.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Eugenio MERCURI | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "Proximal spinal muscular atrophy type 2", "Disease Definition": "A rare, genetic proximal spinal muscular atrophy characterized by degeneration of alpha motor neurons in the anterior horns of the spinal cord and lower brain stem manifesting with onset between 6 to 18 months of age with progressive, proximal muscle weakness, mild to moderate hypotonia and finger polymyoclonour tremor, with areflexia. Motor milestones are classically limited to independent sitting or standing.", "ORPHA ID": 83418, "Summary": "Epidemiology\nIn Europe the average prevalence at birth of proximal spinal muscular atrophy (SMA) type 2 is estimated at 1/50,000. Worldwide the prevalence ranges from 1/11,00-175,000.\nClinical description\nDisease onset occurs between the ages of 6 and 18 months. Classically, before the advent of the new therapies, affected children achieve sitting independently and may acquire standing but do not acquire independent walking. Progressive proximal muscle weakness is symmetrical and greater in the legs than the arms. Finger trembling is frequent. Scoliosis, joint contractures and ankyloses of the mandible are very common . Progressive respiratory muscle weakness can lead to restrictive lung disease. Cognition is normal.\nEtiology\nThe disease is a result of degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei. Causal homozygous mutations/deletions in the SMN1 gene (5q12.2-q13.3) are responsible. SMN1 encodes the survival motor neuron protein (SMN) which is known to participate in critical pathways related to RNA processing and transport, and it is believed that motor neurons are particularly vulnerable to impairments in these processes. Modifier genes include SMN2 (5q13.2), a homologous centromeric copy of SMN1, and NAIP (5q13.1), encoding neuronal apoptosis inhibitory protein. The number of copies of the SMN2 is inversely correlated to disease severity.\nDiagnostic methods\nThe disease is suspected based on clinical history and examination. The gold standard in diagnosis is genetic testing of SMN1 deletion/mutation and, if possible, SMN copy number testing. Muscle biopsy and electromyography should not be performed in patients with typical presentation.\nDifferential diagnosis\nDifferential diagnoses include, congenital muscular dystrophies, congenital myopathies, congenital myasthenic syndromes, neuromuscular junction disease (botulism), and carbohydrate metabolism disorders (glycogen storage disease due to acid maltase deficiency).\nAntenatal diagnosis\nAntenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus cells.\nGenetic counseling\nTransmission is autosomal recessive but around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to affected families.\nManagement and treatment\nSymptomatic management is multidisciplinary and aims to improve quality of life. Assisted airway clearance and non-invasive ventilations are helpful. Physiotherapy and occupational therapy are recommended to prevent scoliosis, maintain joint mobility and promote function and mobility. Antibiotic therapy is required in case of pulmonary infection. The scoliosis may require a corset/back brace for support, and almost invariably needs surgical correction. In the last few years, nusinersen, an antisense oligonucleotide, has been approved and made available for treatment of all SMA types in Europe and the USA. Clinical trials and real world data have shown that it improves motor function in type 2 patients, with a number of patients achieving walking. The best results are seen following early intervention and in presymptomatic patients. Risdiplam (a small molecule) has a also recently, successfully completed a clinical trials and has become commercially available in US and for compassionate use in Europe. Clinical trials are ongoing to identify other potential drug treatments.\nPrognosis\nLife expectancy for affected individuals is variable but, with the new standards of care, particularly for respiratory insufficiency, the majority of patients survive up to adulthood.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Eugenio MERCURI | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "Proximal spinal muscular atrophy type 3", "Disease Definition": "A rare, genetic proximal spinal muscular atrophy characterized by degeneration of alpha motor neurons in the anterior horns of the spinal cord and lower brain stem manifesting with onset of progressive proximal muscle weakness (legs greater than arms) between 18 months and adulthood. Motor development is heterogeneous but walking is typically acquired.", "ORPHA ID": 83419, "Summary": "Epidemiology\nThe average prevalence at birth of proximal spinal muscular atrophy (SMA) is estimated at 1/12,000, of which more than 10% account for type 3. Prevalence worldwide ranges between 1/70,00-285,000, although studies are limited.\nClinical description\nThe disease manifests between 18 months of age and adulthood, typically presenting with frequent falls, difficulty climbing steps and proximal weakness. Patients are subdivided based on age of onset: early onset is between 18 months and 3 years of age (type 3a) and is associated with a plateau in motor development, reduced or absent reflexes, finger polymyoclonus tremor and, frequently, loss of ambulation before or around puberty. Later onset (type 3b), between 3 and 21 years of age, is associated with comparatively milder decline in gross motor function. The muscle weakness predominantly affects the legs and hip muscles and then progresses to the shoulders and arms. Abnormal gait characteristics are common in order to compensate for weakness. Typically, patients are spared scoliosis and respiratory muscle weakness but these may be a feature after loss of ambulation. Cognition is normal.\nEtiology\nThe disease is a result of degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei. Causal homozygous mutations/deletions in the SMN1 gene (5q12.2-q13.3) are responsible. SMN1 encodes the survival motor neuron protein (SMN) which is known to participate in critical pathways related to RNA processing and transport. Modifier genes include SMN2 (5q13.2), a homologous centromeric copy of SMN1, and NAIP (5q13.1), encoding neuronal apoptosis inhibitory protein. Type 3 is associated with 3-4 copy numbers of SMN2.\nDiagnostic methods\nThe disease is suspected based on clinical history and examination. The gold standard in diagnosis is genetic testing of SMN1 deletion/mutation. Muscle biopsy and electromyography should not be performed in a typical presentation.\nDifferential diagnosis\nDifferential diagnoses include other disorders of the peripheral nervous system including myopathies or muscular dystrophies (dystrophinopathies, limb girdle muscular dystrophy, metabolic myopathies, or inflammatory myopathies), inflammatory neuropathies (Guillain-Barré syndrome), neuromuscular junction disorders (myasthenia gravis or congenital myasthenic syndromes), and other motor neuron disorders (non-5q form of SMA or late onset hexosaminidase A deficiency).\nAntenatal diagnosis\nAntenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus samples.\nGenetic counseling\nTransmission is autosomal recessive but around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to patients and their families.\nManagement and treatment\nSymptomatic management is multidisciplinary and aims to improve quality of life. Physiotherapy and occupational therapies are recommended and include exercise programs. Clinical evaluations should include timed function tests including the six-minute walk test. Nusinersen, an antisense oligonucleotide, is approved for treatment of SMA in Europe and the USA. Real world data following commercial availability of the drug suggest efficacy in type 3 children and adult patients.\nPrognosis\nA wheelchair may be required during childhood for some patients (more commonly those with type 3a), whilst others retain the ability to walk into adulthood. Progression is slow and life expectancy is typically normal. Data on long-term outcomes with nusinersen treatment are not currently available.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Eugenio MERCURI | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "Proximal spinal muscular atrophy type 4", "Disease Definition": "A rare, genetic proximal spinal muscular atrophy characterized by degeneration of alpha motor neurons in the anterior horns of the spinal cord and lower brain stem manifesting with adult onset, slowly progressive, mild proximal muscle weakness.", "ORPHA ID": 83420, "Summary": "Epidemiology\nThe average prevalence at birth of proximal spinal muscular atrophy (SMA) is estimated at 1/12,000 of which approximately 1% are type 4.\nClinical description\nDisease onset is typically in the second or third decade of life. The muscle weakness predominantly affects the legs and hip muscles and then progresses to the shoulders and arms. Waddling gait is common. Finger trembling, fasciculation and calf hypertrophy may occur. The clinical picture is similar to that seen in SMA type 3 but the motor weakness is less severe. Cognition is unaffected.\nEtiology\nThe disease is a result of degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei. Causal homozygous mutations/deletions in the SMN1 gene (5q12.2-q13.3) are responsible. SMN1 encodes the survival motor neuron protein (SMN) which is known to participate in critical pathways related to RNA processing and transport, and it is believed that motor neurons are particularly vulnerable to impairments in these processes. The disease is modified by the gene SMN2 (5q13.2), a homologous centromeric copy of SMN1 (5q13.1), the copy number of which is inversely correlated to disease severity.\nDiagnostic methods\nThe diagnosis is based on clinical history and examination. In patients with SMN1 anomalies, the diagnosis may be confirmed by genetic testing. Electromyography and muscle biopsy may be necessary.\nDifferential diagnosis\nDifferential diagnoses include the amyotrophic lateral sclerosis, primary lateral sclerosis, Kennedy disease, myasthenia gravis, and carbohydrate metabolism disorders.\nAntenatal diagnosis\nPrenatal diagnosis is possible for families in which the mutations in the SMN1 gene have been identified.\nGenetic counseling\nThe SMN1 gene deletions are transmitted in an autosomal recessive manner. Genetic counseling should be provided.\nManagement and treatment\nManagement is symptomatic, involves a multidisciplinary approach, and aims to improve quality of life. Physiotherapy and occupational therapies are recommended. Walking aids may be required as the disease progresses. Documenting functional status in SMA is important, since all patients show limitations in daily functioning. Nusinersen, an antisense oligonucleotide, is now approved for treatment of SMA in Europe and the USA. There is no data currently available concerning treatment in SMA type 4; however, it is believed that nusinersen may be most effective when started as soon as possible after diagnosis. Other clinical trials are ongoing to identify other potential treatments.\nPrognosis\nAffected individuals have a normal life expectancy. The greatest morbidity is on quality of life, with impairment of daily activities. Some patients may lose the ability to walk.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Eugenio MERCURI | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "Proximal spinal muscular atrophy", "Disease Definition": "A group of neuromuscular disorders characterized by progressive muscle weakness resulting from the degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei.", "ORPHA ID": 70, "Summary": "Epidemiology\nPrevalence is estimated at around 1/30,000.\nClinical description\nFour subtypes have been defined according to the age of onset and severity of the disease: type 1 (SMA1), the most severe form, with onset before six months of age; type 2 (SMA2), with onset between 6 and 18 months of age, type 3 (SMA3), with onset between childhood and adolescence, and type 4 (SMA4), the least severe form, with adult onset (see these terms). All types are characterized by muscle weakness and atrophy of varying severity, particularly affecting the lower limbs and respiratory muscles. The weakness is almost always symmetric and progressive. Scoliosis, muscle retractions, and joint contractures may occur. Constipation and gastroesophageal reflux are frequent.\nEtiology\nAround 95% of cases of SMA are caused by homozygous deletions (either of exon 7, or of exons 7 and 8) in the SMN1 gene (5q12.2-q13.3) encoding the SMN (survival motor neuron) protein. A second SMN gene (SMN2; 5q13.2) has also been identified and contributes to the production of only 10% of the full-length SMN protein. However, although there is some variation, disease severity in SMA is inversely correlated with the number of copies of the SMN2 gene, with patients with three or four copies more frequently manifesting SMA3/4, rather than SMA1. Deletions of the NAIP (5q13.1) gene have also been identified and may play a role in modifying disease severity.\nDiagnostic methods\nDiagnosis is based on clinical history and examination and can be confirmed by genetic testing. Electromyography and muscle biopsy may also be performed.\nDifferential diagnosis\nDifferential diagnoses include amyotrophic lateral sclerosis, congenital muscular dystrophies, congenital myopathies, primary lateral sclerosis, myasthenia gravis, and carbohydrate metabolism disorders (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is feasible through molecular analysis of amniocytes or chorionic villus samples.\nGenetic counseling\nTransmission of SMN1 and NAIP deletions is autosomal recessive. Around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to patients and their families.\nManagement and treatment\nClinical trials are ongoing to identify potential drug treatments for SMA, mainly targeted towards increasing the levels of the full length SMN protein. However, at present, management remains symptomatic, involving a multidisciplinary approach that aims to improve quality of life. Physiotherapy and occupational and respiratory therapies are necessary. Noninvasive ventilation and gastrostomy may be required. Antibiotic therapy is used in case of pulmonary infection. The scoliosis and joint manifestations may require surgical correction. Patients may require a wheelchair, or use a corset/back brace for support.\nPrognosis\nThe prognosis depends on the severity of the disease, which generally correlates with the age of onset: earlier-onset forms are generally associated with a poor prognosis, whereas life expectancy may be close to normal in later-onset forms. Death may occur due to respiratory insufficiency and infections.\n\n                            Last update: \n                            July 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Haluk TOPALOGLU"}
{"Disease Name": "Proximal symphalangism", "Disease Definition": "A rare genetic bone disorder characterized by ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and conductive hearing loss in some patients.", "ORPHA ID": 3250, "Summary": ""}
{"Disease Name": "Proximal Xq28 duplication syndrome", "Disease Definition": "A rare X-linked genomic disorder associated with interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. It is characterized in males by infantile onset hypotonia, severe global developmental delay, intellectual disability, progressive spasticity, seizures, gastrointestinal symptoms and recurrent respiratory infections. In females, the phenotype is more variable.", "ORPHA ID": 1762, "Summary": "Epidemiology\nAbout 250 patients with cryptic duplications encompassing the MECP2 gene have been reported. The global prevalence of the disorder remains unknown but is estimated to be approximately 1% in males with unexplained X-linked mental retardation.\nClinical description\nClinical presentation is typically in the neonatal period with severe feeding difficulties, hypotonia and global development delay. Whilst affected children may acquire certain development milestones (independent sitting, walking, early speech skills and purposeful hand use) regression is commonly observed. Intellectual disability is moderate to severe in most affected males and speech is most often absent. Behavioral features often include hand stereotypies, bruxism, decreased sensitivity to pain, screaming spells and night laughing. Respiratory infections occur in over three-quarters of males and over one third of females. Seizures develop in over 50% of affected individuals by 9 years of age, and may be daily, weekly or monthly. Non-epileptic seizures have also been described. Progressive spasticity during childhood, predominantly of the lower limbs appears, affects more than 60% of males. Gastrointestinal symptoms may include, constipation, abdominal bloating and infantile gastro-esophageal reflux; gastrointestinal feeding may be required. Scoliosis, divergent strabismus, hypermetropia and facial dysmorphism (large ears, midface hypoplasia, teeth anomalies, open mouth appearance) are frequent. The phenotype and severity in females is highly variable and depends on the level of skewed X-inactivation.\nEtiology\nThe syndrome is due to Xq28 duplications (< 4 Mb) involving the dosage-sensitive gene MECP2.\nDiagnostic methods\nDiagnosis is based on clinical features and is confirmed by array-comparative genomic hybridization techniques or gene-targeted duplication analysis.\nDifferential diagnosis\nDifferential diagnoses include Xq28 functional disomy due to cytogenetically visible rearrangements, int22h1/int22h2-mediated Xq28 duplication syndrome, Prader-Willi syndrome, Alpha thalassemia X-linked intellectual disability syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is possible for families with a proband and is performed by cytogenetic testing including fluorescence in situ hybridization and/or DNA quantification methods.\nGenetic counseling\nThe pattern of inheritance is X-linked. The recurrence risk is significant if the duplication encompassing the MECP2 gene is inherited from the mother, but very low if the duplication is de novo. There is full disease penetrance in males and variable penetrance in females due the level and type of X-inactivation.\nManagement and treatment\nManagement is multidisciplinary and symptomatic only, with special attention to prevent malnutrition and recurrent infections. Educational and rehabilitation support should be offered to all patients.\nPrognosis\nMalformations do not contribute significantly to the morbidity associated with this syndrome, but early death (before 25 years of age), mostly from respiratory infections, has been reported in 27-39% of patients and may be underestimated. The use of a wheelchair might be necessary in adulthood due to progressive spasticity. Neurological deterioration seems associated with seizures severity.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Mathilde PUJALTE  - Pr Damien SANLAVILLE | ITHACA* - Pr Caroline SCHLUTH BOLARD \n\n\n                                * European Reference Network"}
{"Disease Name": "PrP systemic amyloidosis", "Disease Definition": "A rare, autosomal dominant neurological disorder due to truncation mutations of the prion protein gene PRNP (20p13) leading to deposition of prion protein amyloid. Onset is usually in the fourth decade of life and reported clinical manifestations include diarrhea, nausea, autonomic failure (areflexia, weakness), neurogenic bladder and urinary infections.", "ORPHA ID": 397606, "Summary": ""}
{"Disease Name": "Prune belly syndrome", "Disease Definition": "A rare lower urinary tract obstruction (LUTO) characterized by varying degrees of an enlarged urinary bladder, dilated ureters, hydronephrosis, and poorly contractile and disorganized detrusor and ureteral smooth muscle, in association with hypoplastic or absent midline abdominal skeletal musculature, and bilaterally undescended testes in males.", "ORPHA ID": 2970, "Summary": "Epidemiology\nData on prevalence is limited. Birth prevalence is estimated in Canada and the United states at 1/29,000 and 1/26,500, respectively; 95% of cases occur in males.\nClinical description\nThe spectrum ranges from mildly affected individuals to lethality. Prune belly syndrome (PBS) often presents antenatally on routine ultrasound with oligohydramnios and a very large, distended bladder, mild to severe bilateral hydroureteronephrosis, fetal ascites and, occasionally, renal dysplasia and a patent urachus. Other anomalies include cryptorchidism, pulmonary hypoplasia, club foot and features of Potter sequence. The syndrome is associated with pulmonary, skeletal, cardiac, and gastrointestinal defects and may be associated with atresia of the urethra. Newborns present with a wrinkled abdomen that later develops a 'pot belly' appearance. There is a predisposition to urinary tract infections due to incomplete bladder emptying in children.\nEtiology\nWhilst the exact mechanism is still unknown, pathogenesis is mainly related to urethral obstruction or mesodermal developmental defect. Urethral obstruction early in development causes massive bladder distention and urinary ascites that leads to underdevelopment of the abdominal wall musculature and failure of testicular descent. The impaired elimination of urine from the bladder leads to oligohydramnios and, depending on severity, lung hypoplasia and Potter sequence, as well as a profound and lifelong effect on kidney, ureteral and bladder function. Whilst most cases are sporadic, a few cases of siblings have been linked to mutations in CHRM3 (1q43). Several candidate genes have been suggested, but there is limited evidence to support them as a monogenic cause. Copy number variations may cause unexplained genetic cases of PBS.\nDiagnostic methods\nDiagnosis is usually antenatal. Postnatal diagnosis is based on characteristic clinical findings, assessment of pulmonary function, renal function, ultrasound and voiding cystourethrogram.\nDifferential diagnosis\nDifferential diagnoses in utero include megacystis/megaureter, megacystis microcolon intestinal hypoperistalsis syndrome or posterior urethral valves. PBS has also been reported in trisomy 13, 18, 21 and large chromosome 6 deletions.\nAntenatal diagnosis\nAntenatal diagnosis is based on ultrasound findings. As with all forms of LUTO, counseling should include the spectrum of postatal manifestations.\nGenetic counseling\nThe majority of the cases are sporadic. Autosomal recessive inheritance is reported for CHRM3. Autosomal dominant and X linked inheritance havs been suggested in other familial cases.\nManagement and treatment\nSonographic monitoring of the urinary tract and amniotic fluid volume is required throughout pregnancy. Early decompression of severe bladder outlet obstruction that contributes to oligohydramnios is advised. Antibiotic prophylaxis is started at birth. Where possible patients are managed conservatively. Indication for early surgery is only mandatory when urethral atresia is present, and when there is a decline in renal function or failure to prevent or eradicate infection using conservative measures . Further treatment may include bilateral orchidopexies, abdominoplasty in addition to potential urologic reconstructive surgery. Transplantation is indicated for renal failure.\nPrognosis\nThe postnatal course of PBS infants is dictated by renal function and by their co-morbidities, and the risk is stratified accordingly. 20% of patients are at a high risk of severe renal dysfunction and pulmonary hypoplasia; another 40% patients have the classic features of PBS with prognosis related to the degree of renal dysplasia, and for who there is a 4% risk of acute renal failure. 40% of patients are low risk with normal renal function and mild phenotypic features of PBS. Prematurity is common and engenders cardiovascular and pulmonary problems. Perinatal mortality rates for PBS are quoted between 10 and 25%.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Giovanni MOSIELLO | EUROGEN*\n\n\n                                * European Reference Network"}
{"Disease Name": "PRUNE1-related neurological syndrome", "Disease Definition": "A rare genetic syndromic intellectual disability characterized by infantile onset of global developmental delay and profound intellectual disability in association with a heterogeneous spectrum of manifestations, such as features of lower motor neuron disease, hypotonia, spasticity, contractures, seizures, respiratory insufficiency, and optic atrophy, among others. Dysmorphic craniofacial features include microcephaly, tall forehead, bitemporal narrowing, flat nasal bridge, low-set ears, and high-arched palate. Brain imaging may show cerebral and cerebellar atrophy, delayed myelination, and thin corpus callosum.", "ORPHA ID": 544469, "Summary": ""}
{"Disease Name": "Pruritic urticarial papules and plaques of pregnancy", "Disease Definition": "A rare skin disease characterized by urticarial papules and plaques with severe pruritus mainly on the abdomen, buttocks, and proximal thighs. The condition usually develops during the third trimester of the first pregnancy, although presentation in the postpartum period, which may also feature other types of skin lesions, has been described in some cases. The symptoms generally resolve within few weeks.", "ORPHA ID": 64745, "Summary": ""}
{"Disease Name": "Pseudo-Meigs syndrome", "Disease Definition": "A rare neoplastic disease characterized by the presence of a benign or malignant, pelvic or abdominal tumor (other than ovarian fibroma or fibroma-like and localized outside of the ovaries, fallopian tubes, and broad ligaments) associated with hydrothorax and ascites that resolve after tumor resection. Patients usually present with dyspnea, pelvic mass with or without a tender, distended abdomen and/or weight loss.", "ORPHA ID": 314459, "Summary": ""}
{"Disease Name": "Pseudo-von Willebrand disease", "Disease Definition": "A bleeding disorder characterized by mild to moderate mucocutaneous bleeding, which becomes more pronounced during pregnancy or following ingestion of drugs that have anti-platelet activity. This disease is due to hyperresponsive platelets, resulting in thrombocytopenia.", "ORPHA ID": 52530, "Summary": ""}
{"Disease Name": "Pseudoachondroplasia", "Disease Definition": "Pseudoachondroplasia is characterized by severe growth deficiency and deformations such as bow legs and hyperlordosis.", "ORPHA ID": 750, "Summary": "Epidemiology\nPrevalence is estimated at around 1/60,000.\nClinical description\nThe disorder is usually discovered during the second year of life with the onset of slow growth and walking difficulties. The short stature becomes more prominent with age and the hands and feet appear short and wide. Joint laxity is a general feature, but predominantly affects the hands. Defective epiphyseal growth causes early arthrosis. The limb deformation is caused by metaphyseal lesions.\nEtiology\nThe disorder is caused by small mutations or deletions in the COMP gene (19p13.1) coding for the cartilage oligomeric matrix protein.\nDiagnostic methods\nDiagnosis is made on the basis of epiphyseal and metaphyseal anomalies detected on radiographs during the second year of life.\nDifferential diagnosis\nThe principle differential diagnosis is achondroplasia (see this term), but the craniofacial anomalies present in this disorder are absent in patients with pseudoachondroplasia and radiographic findings differ significantly. Forms of multiple epiphyseal dysplasia (see these terms) may also be included in the differential diagnosis.\nAntenatal diagnosis\nPrenatal diagnosis is feasible if the mutation has been detected in an affected parent.\nGenetic counseling\nTransmission is autosomal dominant, but most isolated cases are due to de novo mutations. Genetic counseling may be proposed and the recurrence risk is 50%.\nManagement and treatment\nTreatment is based on physiotherapy, management of the spinal deformation and corrective orthopedic surgery. Intensive physical activity should be avoided. The limb deformation should be corrected surgically at the end of the growth period.\nPrognosis\nThe final height prognosis is variable but the short stature may be moderately severe.\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Pseudoaminopterin syndrome", "Disease Definition": "Pseudoaminopterin syndrome is a developmental anomalies syndrome that resembles the aminopterin embryopathy (see this term) without history of fetal exposure to aminopterin. It is characterized by skull (craniosynostosis and poorly mineralized cranial vault), dysmorphic (ocular hypertelorism, palpebral fissure anomalies, micrognathia cleft lip and/or high arched palate and small and low set/rotated ears) and limb (brachydactyly, syndactyly and clinodactyly) anomalies, associated with mild-to-moderate intellectual deficit and short stature.", "ORPHA ID": 221120, "Summary": ""}
{"Disease Name": "Pseudodiastrophic dysplasia", "Disease Definition": "Pseudodiastrophic dysplasia is characterized by rhizomelic shortening of the limbs and severe clubfoot deformity, in association with elbow and proximal interphalangeal joint dislocations, platyspondyly, and scoliosis. It has been described in about 10 patients. An autosomal recessive inheritance has been suggested. Pseudodiastrophic dysplasia differs from diastrophic dysplasia (see this term) on the basis of clinical, radiographic, and histopathologic findings. Clubfoot can be treated by surgical therapy, and neonatal contractures and scoliosis can be relieved by physical therapy. Several of the reported patients died in the neonatal period or during infancy.", "ORPHA ID": 85174, "Summary": ""}
{"Disease Name": "Pseudohypoaldosteronism type 1", "Disease Definition": "A rare, primary form of mineralocorticoid resistance characterized by mild to profound salt wasting either restricted to the kidney (renal pseudohypoaldosteronism type 1), or generalized affecting many organs (generalized pseudohypoaldosteronism type 1). Clinical presentation is in the neonatal period with failure to thrive, vomiting and dehydration with biochemical findings of hyperkalaemia, metabolic acidosis and, elevated plasma aldosterone and renin concentration.", "ORPHA ID": 756, "Summary": "Epidemiology\nThe overall prevalence at birth in the United Kingdom is estimated at 1/47,000, with prevalence at birth for renal pseudohypoaldosteronism type 1 (renal PHA1) and generalized pseudohypoaldosteronism type 1 (generalized PHA1), estimated at of 1/66,000 and 1/166,000, respectively. Epidemiological data is limited elsewhere.\nClinical description\nThe two different forms can be distinguished at the clinical and genetic level: i) renal PHA1 is the most frequent form and presents with mild mineralocorticoid resistance that is restricted to the kidneys and that usually improves in early childhood; ii) generalized PHA1 is a more severe form with salt wasting from multiple organs (including lung, kidney, colon, sweat and salivary glands) and persistence into adulthood. In both forms, presentation is in the neonatal period with a salt-losing syndrome, failure to thrive, vomiting and dehydration. Biological findings include hyponatremia, hyperkaliemia, metabolic acidosis and inappropriately high urinary sodium excretion. The generalized form may present with respiratory involvement (including persistent rhinorrhea, infections, tachypnea, recurrent coughing and wheezing, and, less frequently, respiratory distress syndrome), and cutaneous lesions (caused by inflammation of eccrine structures). The clinical course may be complicated by cardiac dysrhythmias and cardiac arrest in generalized PHA1.\nEtiology\nRenal PHA1 is caused by mutations or exon deletions in the gene encoding the mineralocorticoid receptor, NR3C2 (4q31.23). Generalized PHA1 is caused by mutations in the genes coding for one of the subunits of the amiloride-sensitive sodium channel including SCNN1A (12p13.31), SCNN1B (16p12.2) and SCNN1G (16p12.2).\nDiagnostic methods\nDiagnosis is confirmed by the presence of high plasma and urinary aldosterone and high plasma renin levels. Neonatal genetic diagnosis on cord blood may allow rapid diagnosis and management of the condition in affected offspring from families with identified mutations of PHA1.\nDifferential diagnosis\nThe main differential diagnoses include congenital adrenal hyperplasia (21-hydroxylase deficiency, 3b-hydroxysteroid dehydrogenase deficiency), aldosterone synthase deficiency (familial hyperreninemic hypoaldosteronism type I and II) and transient pseudohypoaldosteronism (in infants with urinary tract malformations). Occasionally, antenatal or early postnatal hyperkalemia may complicate antenatal Bartter syndrome and erroneously suggest the diagnosis of PHA1.\nAntenatal diagnosis\nIn families with a history of generalized PHA1 (autosomal recessive), prenatal genetic testing may be requested.\nGenetic counseling\nRenal PHA1 is transmitted in an autosomal dominant manner or occurs sporadically. Generalized PHA1 is transmitted in an autosomal recessive manner. Genetic counselling should be offered to affected families, corresponding to the form of PHA1.\nManagement and treatment\nTreatment consists in salt supplementation and rehydration and, where indicated, correction of hyperkalemia and acidosis. Salt supplementation is administered in accordance with disease severity. Mineralocorticoid replacement therapy with fludrocortisone and hydrocortisone may be undertaken while proceeding through differential diagnosis. Symptomatic treatment is necessary for the respiratory tract illness and to correct the skin phenotype.\nPrognosis\nRenal PHA1 improves with age and treatment can be discontinued after a variable period of time in most patients, generally around age 18-24 months. With age, patients compensate for the distal salt loss by up-regulating the mineralocorticoid receptor axis. Early diagnosis within the first week of life is critical to survival in patients with generalized PHA1. In this form, no remission has been reported and patients are prone to life-threatening episodes of salt loss into adulthood.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Maria-Christina ZENNARO"}
{"Disease Name": "Pseudohypoaldosteronism type 2", "Disease Definition": "A rare genetic form of hypertension characterized by hyperkalemia, mild hyperchloremic metabolic acidosis, normal or elevated aldosterone, low renin, with normal renal glomerular filtration rate (GFR).", "ORPHA ID": 757, "Summary": "Epidemiology\nThe prevalence of the disorder is unknown. To date, more than 180 affected individuals and families have been reported.\nClinical description\nPatients generally develop hypertension in adulthood. Hyperkalemia, mild hyperchloremic acidosis and low renin are present from a young age and are constant findings. Aldosterone levels may be normal to high. Hypervolemia is frequently observed. Growth failure has been described in some cases. Patients do not present renal failure. Spitzer-Weinstein syndrome is believed to be the early presentation of Pseudohypoaldosteronism type 2 (PHA2) with hypertension associated with other clinical findings such as short stature, muscle weakness, periodic paralysis and dental abnormalities.\nEtiology\nThere are five etiological subtypes: PHA type 2A has been mapped to chromosome 1q31-q42, but no specific gene has so far been identified. PHA type 2B is due to mutations in WNK4 (17q21.2), PHA type 2C due to mutations in WNK1 (12p13.33), PHA type 2D due to mutations in KLHL3 (5q31.2), and PHA type 2E due to mutations in CUL3 (2q36.2). WNK1 and WNK4 encode serine/threonine-protein kinase WNK1 and WNK4, respectively, which regulate sodium and potassium reabsorption in the distal renal tubule. Disease-causing mutations in these genes lead to increased sodium reabsorption and decreased potassium secretion. The protein products of CUL3 and KLHL3 function together as part of the cullin-RING-based E3 ubiquitin ligase complex, which has a role in ubiquitin-mediated degradation of the proteins produced by WNK1 and WNK4.\nDiagnostic methods\nDiagnosis is established by the typical constellation of clinical and biochemical findings including hypertension, hyperkalemia (in the setting of normal GFR) with inappropriately low urinary potassium excretion, hyperchloremia, metabolic acidosis, low or suppressed plasma renin activity, hypercalciuria and family history. The diagnosis can be confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes other causes of hyperkalemia, notably chronic kidney disease. If GFR is normal, differential diagnoses include hyperkalemic renal tubular acidosis, as seen with PHA1, hypoaldosteronism, primary adrenal insufficiency, and hyperkalemia secondary to medication (e.g. potassium-sparing diuretics, nonsteroidal anti-inflammatory drugs, angiotensin inhibitors, trimethoprim, these forms of hyperkalemic RTA are typically associated with hypovolemia and low blood pressure. An acquired form of PHA2 can be seen with calcineurin inhibitors, especially tacrolimus.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the genetic mutation has previously been identified in an affected family member.\nGenetic counseling\nThe pattern of inheritance for PHA2 is typically autosomal dominant; however, PHA2 due to KLHL3 mutations can be inherited in an autosomal recessive or dominant manner. The risk to offspring of inheriting the mutation from an affected parent is 50% for the autosomal dominant forms. Offspring of an individual with autosomal recessive PHA2 are obligate carriers, and typically asymptomatic. Pathogenic variants arising de novo are possible. PHA2 due to CUL3 gene is typically the most severe form. The phenotype of PHA type II due to the WNK1 is typically less severe than PHA2 due to WNK4 or dominant or recessive mutation in the KLHL3 gene.\nManagement and treatment\nTreatment is based on low-dose thiazide diuretics that are very effective in the correction of hypertension (important to prevent secondary complications), hyperkalemia, and hypercalciuria. Exogenous mineralocorticoids do not improve the biochemical abnormalities and likely worsen the hypertension.\nPrognosis\nPrognosis is good with lifelong therapy. Nephrolithiasis can be a complication of the disease if untreated and hypercalciuria persists.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Detlef BÖCKENHAUER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Pseudohypoparathyroidism type 1A", "Disease Definition": "Pseudohypoparathyroidism type 1A (PHP1a) is a type of pseudohypoparathyroidism (PHP; see this term) characterized by renal resistance to parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, and elevated PTH; resistance to other hormones including thydroid stimulating hormone (TSH), gonadotropins and growth-hormone-releasing hormone (GHRH); and a constellation of clinical features known as Albright hereditary osteodystrophy (AHO; see this term).", "ORPHA ID": 79443, "Summary": "Epidemiology\nPrevalence of PHP (1a and 1b) has been estimated at 1/295,000 in a Japanese study. The prevalence of PHP (1a, 1b and pseudopseudohypoparathyroidism (PPHP); see these terms) has been estimated at 1/150,000in Italy.\nClinical description\nOnset of endocrine symptoms occurs during childhood, although cases with severe hypothyroidism at neonatal screening have been reported. Patients present with varying degrees of AHO features (including obesity). Ectopic ossifications may range from absent to extensive and generate severe pain. Developmental delay is highly variable, even in families with the same mutation. PTH resistance is not typically present at birth but develops over time, in some patients from a few months of age. Other symptoms related to hypocalcemia include: numbness, seizures, tetany, cataract or dental problems. Mild TSH resistance is often present at birth and may be diagnosed through neonatal screening of congenital hypothyroidism (see this term). It is usually asymptomatic. Gonadal dysfunction with delayed or incomplete sexual maturation, amenorrhea or oligomenorrhea and/or infertility is very frequent. Growth hormone (GH) deficiency is present in around 60% of patients, while resistance to calcitonin and to epinephrine is rare. Hormone resistance may develop over time, up until late adulthood. Rheumatologic complications have also been reported. The evolution of bone mineralization remains unclear.\nEtiology\nIn about 70-80% of cases, PHP-Ia is caused by haploinsufficiency due to maternally-inherited heterozygous inactivating mutations in the GNAS gene (20q13). In a subset of patients negative for these mutations, methylation defects at the same locus have been reported.\nDiagnostic methods\nDiagnosis of PTH resistance is based on measurement of serum calcium, phosphate and PTH. After infusion of biosynthetic PTH (which may be useful in difficult cases), nephrogenic cAMP and urinary excretion of phosphate do not increase. AHO is diagnosed both clinically and on X-ray, showing typical shortening of the 4th metacarpal. Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnoses include primary hypothyroidism, secondary hyperparathyroidism due to vitamin D deficiency, and other types of PHP.\nAntenatal diagnosis\nAntenatal diagnosis is possible when a disease causing mutation in the family is known.\nGenetic counseling\nTransmission is autosomal dominant with parental imprinting. Resistance to hormones develops only after maternal inheritance. In de novo mutations (25% of cases), hormone resistance is associated with a mutation on the maternal allele of the gene. In cases where methylation defects are found, genetic counseling may be difficult or impossible.\nManagement and treatment\nTreatment is based on maintaining normocalcemia and, when possible, normalizing serum levels of PTH, with an active form of vitamin D (alfacalcidol or calcitriol) and calcium supplementation. Associated endocrinopathies should be treated when present (particularly hypothyroidism, growth hormone deficiency and hypogonadism) with levothyroxine and sex hormones. GH replacement therapy should be started as soon as possible. There is no treatment for AHO. Subcutaneous ossifications may be surgically removed when particularly large or causing pain/discomfort.\nPrognosis\nWith proper treatment, prognosis is good, but quality of life may be affected by subcutaneous ossifications and the presence of severe short stature and obesity. Life expectancy is normal provided that endocrine disorders are correctly treated.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna MANTOVANI"}
{"Disease Name": "Pseudohypoparathyroidism type 1B", "Disease Definition": "Pseudohypoparathyroidism type 1B (PHP-1b) is a type of pseudohypoparathyroidism (PHP; see this term) characterized by localized resistance to parathyroid hormone (PTH) mainly in the renal tissues which manifests with hypocalcemia, hyperphosphatemia and elevated PTH levels. About 60-70% of patients also present with elevated TSH levels due to TSH resistance.", "ORPHA ID": 94089, "Summary": "Epidemiology\nThe prevalence is unknown. The estimated prevalence of PHP (1a, 1b and PPHP) in Italy is 1/150,000.\nClinical description\nPHP1b usually presents in childhood with symptoms of hypocalcemia, including numbness, seizures, tetany, cataracts, and dental problems. Patients may present with skeletal abnormalities, similar to those that occur in patients with hyperparathyroidism, such as reduced bone mineral density and osteitis fibrosa. TSH resistance is usually asymptomatic in PHP1b. Severity of symptoms can vary greatly between patients and even among kindreds.\nEtiology\nThe majority of cases of PHP1b are sporadic, but an autosomal dominant transmission has also been described. About 70% of PHP-Ib patients display methylation defects, sporadic or genetic-based, at GNAS (20q13.2-q13.3) differentially methylated regions (DMRs). PHP-Ib familial form is typically characterized by an isolated loss of methylation at the A/B DMR, secondary to genetic deletions disrupting the upstream imprinting control region in the STX16 gene (20q13.32). Hormonal resistance seen in PHP-1b develops after maternal inheritance of the disease, while paternal inheritance is not associated with any endocrine abnormalities. In sporadic cases, broad methylation alterations at all GNAS DMRs are usually detected and in a subset of such patients, paternal uniparental disomy of chromosome 20 (see this term) may explain this pattern of alteration.\nDiagnostic methods\nDiagnosis of PTH resistance is based on measurement of serum calcium, phosphate and PTH. After infusion of biosynthetic PTH (which may be useful in difficult cases), nephrogenic cAMP and urinary excretion of phosphate do not increase. Gs-alpha activity in erythrocytes and fibroblasts is usually normal. Mild TSH resistance is often present at birth and may be diagnosed through neonatal screening of congenital hypothyroidism (see this term). Genetic testing can confirm diagnosis.\nDifferential diagnosis\nDifferential diagnoses include primary hypoparathyroidism (which can be ruled out by the absence of hypercalciuria), secondary hyperparathyroidism, autoimmune polyendocrinopathy (see this term), and vitamin D deficiency. It should also be excluded from other forms of PHP (see this term) based on the absence of Albright hereditary osteodystrophy (AHO; see this term) and normal expression of Gs protein.\nAntenatal diagnosis\nAntenatal diagnosis is possible only in those families with known deletions within GNAS or upstream of this locus.\nGenetic counseling\nThe majority of cases of PHP1b are sporadic but familial transmission, following an autosomal dominant pattern of inheritance, has also been described and genetic counseling is possible in these cases.\nManagement and treatment\nTreatment is based on maintaining normocalcemia and normalizing serum levels of PTH with active vitamin D metabolites (alfacalcidol or calcitriol) and calcium supplementation. Patients should be treated for other associated endocrinopathies when present, particularly hypothyroidism, with levothyroxine. Blood biochemistries and urinary calcium excretion should be monitored annually. Treatment is lifelong but calcium and calcitriol dosages can usually be progressively lowered over time.\nPrognosis\nWith treatment the prognosis is good and life expectancy is predicted to be comparable with the normal population, provided that endocrine disorders are correctly treated.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna MANTOVANI"}
{"Disease Name": "Pseudohypoparathyroidism type 1C", "Disease Definition": "Pseudohypoparathyroidism type 1c (PHP1c) is a rare type of pseudohypoparathyroidism (PHP; see this term) characterized by resistance to parathyroid hormone (PTH) and other hormones, which manifests with hypocalcemia, hyperphosphatemia and elevated PTH levels, a constellation of clinical features collectively termed Albright's hereditary osteodystrophy (AHO; see this term), but normal activity of the stimulatory protein G (Gs alpha).", "ORPHA ID": 79444, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nClinical manifestations of PHP1c are similar to those seen in pseudohypoparathyroidism type 1a (PHP1a; see this term). They display the symptoms and signs of AHO (brachydactyly (most often the shortening of the 3, 4 and 5th metacarpals), rounded face, short stature, central obesity, subcutaneous ossifications and variable development delay) as well as PTH-resistance leading to hypocalcemia and hyperphosphatemia, and resistance towards TSH and, sometimes, other hormones.\nEtiology\nThe exact etiology is unknown as mutations in the GNAS gene (20q13) are only rarely found. Other components of the cAMP-dependent signaling pathway, such as adenylyl cyclase, inhibitory G proteins, or phosphodiesterases might be impaired.\nGenetic counseling\nIn familial cases the disease is inherited autosomal dominantly and genetic counseling is possible.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna MANTOVANI"}
{"Disease Name": "Pseudohypoparathyroidism type 2", "Disease Definition": "Pseudohypoparathyroidism type 2 (PHP2) is a type of pseudohypoparathyroidism (PHP; see this term) characterized by resistance to parathyroid hormone (PTH), which manifests with hypocalcemia, hyperphosphatemia and elevated PTH levels, absence of Albright's hereditary osteodystrophy (AHO; see this term), and normal expression of the Gs protein with a normal urinary cAMP response.", "ORPHA ID": 94090, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nThe clinical manifestations of PHP-2 have been poorly characterized but are similar to those seen in pseudohypoparathyroidism type1b (PHP-1b; see this term). Patients present with symptoms related to low levels of calcium including: seizures, tetany (including muscle twitches and hand and foot spasms), numbness cataracts, and dental problems. Unlike PHP-1b, those with PHP-2 demonstrate a normal urinary cAMP response.\nEtiology\nTo date, no specific genetic alteration responsible for this disorder has been detected. It has been hypothesized that in most cases it may be an acquired defect secondary to vitamin D deficiency such as in misdiagnosed secondary renal hyperparathyroidism.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna MANTOVANI"}
{"Disease Name": "Pseudohypoparathyroidism", "Disease Definition": "Pseudohypoparathyroidism (PHP) is a heterogeneous group of endocrine disorders characterized by normal renal function and resistance to the action of parathyroid hormone (PTH), manifesting with hypocalcemia, hyperphosphatemia and elevated PTH levels and that includes the subtypes PHP type 1a (PHP-1a) , PHP type 1b (PHP-1b), PHP type 1c (PHP-1c), PHP type 2 (PHP-2) and pseudopseudohypoparathyroidism (PPHP) (see these terms).", "ORPHA ID": 97593, "Summary": "Epidemiology\nThe exact prevalence is unknown. PHP occurs twice as frequently in females as in males. The estimated prevalence (of PHP-1a, 1b and PPHP) in Italy is 1/150,000. The estimated prevalence in Japan (of PHP-1a and 1b) is 1/295,000.\nClinical description\nAll forms of PHP can present in infancy, especially if significant hypocalcemia occurs. Symptoms related to low levels of calcium can include: paresthesias, numbness, seizures and tetany (including muscle twitches and hand and foot spasms).Some forms of PHP may remain unnoticed if patients do not have hypocalcemia (or if hypocalcemia is misdiagnosed and treated as ''seizures'') and/or characteristic physical features, which include short stature, rounded face, short neck, centripetal obesity, brachydactyly and soft-tissue and calcifications/ossifications, and are collectively termed Albright hereditary osteodystrophy (AHO; see this term). AHO is observed in patients with PHP-1a, PHP-1c and PPHP but is absent in patients with PHP-1b and PHP-2. Intellectual disability is sometimes observed in patients with AHO features while it is almost always present in PHP-1A and PHP -1C. There have also been reports that olfaction is impaired in PHP-1a but not in PPHP or PHP-1b. Patients with PHP can also present with symptoms of resistance to hormones other than PTH including thyroid-stimulating hormone (TSH) (in PHP1a, PHP1c and sometimes PHP1b), gonadotropins (in PHP1a, PHP1c) and growth-hormone-releasing hormone (GHRH) (in PHP1a). Cataracts, dental problems and intracranial calcifications (bilateral striopallidodentate calcinosis; see this term) represent the long-term complications.\nEtiology\nPHP-1a, PPHP, and PHP-1b are all due to molecular defects in the same locus of the GNAS (20q13.2-q13.3) gene coding the alpha sub-unit of the stimulatory G protein. Patients inheriting PHP from the mother display all the signs of AHO with multi-hormone resistance, while patients inheriting the disease from the father have AHO without any resistance to hormone action (PPHP). This pattern of inheritance is consistent with a tissue-specific paternal imprinting of the gene causing the disease. Those with the autosomal dominant form of PHP-Ib display an isolated loss of methylationat exon A/B associated with a recurrent 3-kb deletion in the STX16 gene (20q13.32). To date, the genetic anomaly responsible for PHP2 and PHP1c has not yet been identified, although in a few PHP1c patients, GNAS heterozygous mutations have been detected. It has been hypothesized that in most cases, PHP2 may be an acquired defect secondary to vitamin D deficiency.\nGenetic counseling\nPHP can be sporadic or inherited autosomal dominantly with parental imprinting. In inherited cases, genetic counseling is possible.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna MANTOVANI"}
{"Disease Name": "Pseudoleprechaunism syndrome, Patterson type", "Disease Definition": "Pseudoleprechaunism syndrome, Patterson type is a rare, genetic, adrenal disorder characterized by congenital bronzed hyperpigmentation, cutis laxa of the hands and feet, body disproportion (comprising large hands, feet, nose and ears), hirsutism and severe intellectual disability. Patients additionally present hyperadrenocorticism, cushingoid features, premature adrenarche and diabetes mellitus, as well as skeletal deformities (not present at birth and which progress with age). There have been no further descriptions in the literature since 1981.", "ORPHA ID": 2976, "Summary": ""}
{"Disease Name": "Pseudomyxoma peritonei", "Disease Definition": "Pseudomyxoma peritonei is characterized by disseminated intra-peritoneal mucinous tumors and mucinous ascites in the abdomen and pelvis.", "ORPHA ID": 26790, "Summary": "Epidemiology\nAnnual incidence is estimated at 1/1,000,000 with female predominance.\nClinical description\nThe disease is usually diagnosed after the age of 40. In 30 to 50% of cases, patients present with progressive abdominal distension (so-called ``jelly belly''). Diagnosis may follow discovery of an ovarian mass in women or recent development of inguinal hernia, appendicitis or intestinal occlusion. Other less common signs include abdominal pain, weight loss, urinary symptoms, constipation, vomiting, and dyspnea.\nEtiology\nIn 90% of cases, the primary lesion is an appendiceal mucinous tumor, but ovarian mucinous tumors have been reported (7%) and, more rarely, mucinous tumors of the colon, stomach, pancreas, and urachus.\nDiagnostic methods\nThe diagnosis is based on chest-abdominal-pelvic computed tomography (CAP-CT) findings (revealing the characteristic compartmentalized distribution pattern of mucinous ascites) and on pathology (performed by two experts), while tumor markers (carcinoembryonic antigen and CA19-9) are relatively non-specific.\nDifferential diagnosis\nThe differential diagnosis includes secondary peritoneal carcinomatoses and other rare peritoneal tumors.\nManagement and treatment\nTreatment strategies require a multidisciplinary approach and must be discussed by a panel of physicians in a specialized center. There are currently no validated recommendations on clinical management and no cytotoxic agents have been granted a European Marketing Authorization (MA) in this indication. Nonetheless, the best curative option appears to be complete cytoreductive surgery (visceral resections and peritonectomy procedures) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) (off-label use), sometimes followed by intravenous chemotherapy (off-label use) which can only be considered in young patients with good general status.\nPrognosis\nPseudomyxoma peritonei is slowly progressive but recurrence after complete tumor removal may occur. Following combined treatment (complete cytoreductive surgery and HIPEC), the 5-year survival rate reaches 70% for non-aggressive peritoneal pseudomyxoma in patients treated in a specialized center.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Pr François-Noël GILLY  - Pr Olivier GLEHEN"}
{"Disease Name": "Pseudopelade of Brocq", "Disease Definition": "Pseudo-pelade of Brocq is a rare hair abnormality characterized by onset in adulthood of soft, irregular, flesh-toned patches of alopecia primarily in the parietal and vertex portions of the scalp, without follicular hyperkeratosis or perifollicular inflammation.", "ORPHA ID": 129, "Summary": ""}
{"Disease Name": "Pseudoprogeria syndrome", "Disease Definition": "A rare syndromic intellectual deficiency characterized by psychomotor delay, severe progressive spastic quadriplegia, microcephaly, and a Hallerman-Streiff-like phenotype including absence of eyebrows and eyelashes, glaucoma, and small, beaked nose. Structural central nervous system abnormalities (cervical spinal cyst, occipital cranium bifidum occulatum) were additional findings. There have been no further descriptions in the literature since 1974.", "ORPHA ID": 2985, "Summary": ""}
{"Disease Name": "Pseudopseudohypoparathyroidism", "Disease Definition": "Pseudopseudohypoparathyroidism (pseudo-PHP) is a disease characterized by a constellation of clinical features collectively termed Albright hereditary osteodystrophy (AHO; see this term) but no evidence of resistance to parathyroid hormone (PTH), which is seen in other forms of pseudohypoparathyroidism (PHP; see this term).", "ORPHA ID": 79445, "Summary": "Epidemiology\nPrevalence is unknown but series of patients usually include one patient with pseudo-PHP for every two patients with PHP 1a (see this term).\nClinical description\nDue to the absence of hormone resistance, the age at diagnosis varies from birth to late adulthood. Patients display various features of AHO including short stature which develops over time, absence of pubertal growth spurt (mean final height is between -2 and -3 SD), rounded face, brachydactyly, absence of widening of the lumbar spine, and ectopic ossifications of soft-tissues, which may develop spontaneously or after trauma. The spectrum of the ectopic ossifications ranges from absent to extensive and may generate severe pain. Patients with extensive ectopic ossifications may also be considered as having progressive osseous heteroplasia (POH; see this term). Cognitive impairment is present in only 10% of the patients. Unlike in PHP 1a, obesity is not constant and, when present, is only moderate.\nEtiology\nThe disease is caused by paternally inherited heterozygous molecular defects in the GNAS gene (20q13) encoding the alpha sub-unit of the stimulatory G protein (Gs alpha), which results in a reduction in the expressioctivity of Gs alpha. In families in which PHP 1a and pseudo-PHP co-exist, mutations in the gene can be detected in all affected members.\nDiagnostic methods\nDiagnosis is based on the presence of features of AHO and the exclusion of other forms of PHP (by measuring serum calcium, phosphate and PTH). X-rays show typical shortening of the fourth metacarpal and advanced bone age. All metacarpals and metatarsals may be affected. Molecular genetic testing identifying a mutation in the GNAS gene confirms diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes PHP 1a, PHP 1c and 2q37 microdeletion syndrome (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible when a disease causing mutation in the family is known.\nGenetic counseling\nTransmission is autosomal dominant with parental imprinting. Pseudo-PHP most frequently occurs in relatives of patients with PHP 1a, but may present in families without PHP as an isolated defect. Paternal inheritance of the mutation is responsible for pseudo-PHP. Genetic counseling is possible.\nManagement and treatment\nThere are no specific treatments for the various manifestations of AHO, although subcutaneous ossifications may be surgically removed when particularly large or causing pain/discomfort.\nPrognosis\nPseudo-PHP is not life threatening but quality of life can be affected in those with severe ectopic ossification.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanna MANTOVANI"}
{"Disease Name": "Pseudotyphus of California", "Disease Definition": "Pseudotyphus of California is a rare, flea-borne Rickettsial disease caused by a Rickettsia felis  infection. Patients can be asymptomatic or can present with unspecific symptoms (such as fever, headache, generalized maculopapular rash, myalgia, arthralgia and, ocasionally, eschar, lymphadenopathy, nausea, vomiting, loss of appetite and abdominal pain). Rarely, serious manifestations may occur and include neurological dysfunction (photophobia, hearing loss, and signs of meningitis) and pulmonary compromise.", "ORPHA ID": 83316, "Summary": ""}
{"Disease Name": "Pseudounicornuate uterus", "Disease Definition": "A rare, non-syndromic uterovaginal malformation characterized by a crescent-shaped, small-sized uterus containing a single horn and fallopian tube associated with a rudimentary second horn (which can be solid or contain a cavity with functioning endometrium and be communicating or non-communicating). Urinary tract anomalies are frequently associated.", "ORPHA ID": 180079, "Summary": ""}
{"Disease Name": "Pseudoxanthoma elasticum-like papillary dermal elastolysis", "Disease Definition": "Pseudoxanthoma elasticum-like papillary dermal elastolysis (PXE-PDE) is a rare, acquired, idiopathic dermal tissue disorder characterized by numerous, asymptomatic, 2-3 mm, yellowish, non-follicular papules that tend to converge into cobblestone-like plaques which are distributed symmetrically over the posterior neck, supraclavicular region, axillae, and sometimes abdomen. Unlike PXE, these skin lesions show select elimination (absence or marked loss) of elastic fibers in the papillary dermis and there is no systemic involvement.", "ORPHA ID": 228293, "Summary": ""}
{"Disease Name": "Pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa", "Disease Definition": "A rare, genetic, dermis elastic tissue disorder characterized by yellowish skin papules (resembling pseudoxanthoma elasticum) located on the neck, chest and/or flexural areas associated with loose, redundant, sagging skin on trunk and upper limbs, and retinitis pigmentosa, in the absence of clotting abnormalities. Patients present reduced night and peripheral vision, as well as optic nerve pallor, retinal pigment epithelium loss, attenuated retinal vessels and/or black pigment intra-retinal clumps.", "ORPHA ID": 436274, "Summary": ""}
{"Disease Name": "Pseudoxanthoma elasticum", "Disease Definition": "A rare, genetic, metabolic disease with connective tissue and eye involvement, characterized by progressive ectopic mineralization and fragmented elastic fibers in the skin, retina and vascular walls.", "ORPHA ID": 758, "Summary": "Epidemiology\nPrevalence is estimated at between 1/40,000 and 1/100,000 in the general population, with, for unknown reason, female predominance (female to male ratio 4:1).\nClinical description\nDisease onset is typically in adolescence or young adulthood but may appear at any age. The first clinical sign is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules subsequently coalesce, and the skin becomes loose and wrinkled. Dystrophic calcification of Bruch's membrane of the retina, revealed by angioid streaks at fundus examination, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. The disease may be limited to one organ (skin, eye, or blood vessels) in some patients or affect two or all three organs. Cardiac complications (angina pectoris, myocardial infarction) are relatively rare but, when present, deserve thorough investigation. Transient ischemic attacks and, more rarely, ischemic strokes have been reported. Gastrointestinal hemorrhage occurs in about 5% of cases. Calcification of other organs, such as the kidneys, breasts, pancreas, testicles, liver and spleen may be observed.\nEtiology\nThe vast majority of cases are caused by biallelic pathogenic variants in the ABCC6 gene (16p13.11). Rarely, patients with pseudoxanthoma elasticum (PXE)-like clinical features harbor pathogenic variants in the ENPP1 gene (6q23.2), which is usually associated with generalized arterial calcification of infancy (GACI). Both genes are presumably part of one metabolic way, and the pathogenic variants are thought to lead to decreased circulating pyrophosphate (PPi), a major anti-mineralization factor.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation of characteristic yellow cobblestone skin lesions at the predilection sites. Biopsy of the affected skin using elastin and calcium-specific staining reveals abundant morphological alterations with fragmented, clustered and calcified elastin fibers in the middle and lower dermis. Fundus examination reveals characteristic retinopathy with angioid streaks, drusen or maculopathy. Genetic testing for ABCC6 can confirm diagnosis or rule it out in clinically ambiguous cases.\nDifferential diagnosis\nDifferential diagnosis of angioid streaks includes hemoglobinopathies (sickle cell disease, Beta-thalassemia, spherocytosis), dermal elastic tissue disorders (solar elastosis, perforating calcific elastosis, PXE-like late-onset focal dermal elastosis, PXE-like papillary dermal elastolysis) and other multisystem disorders (cutis laxa) as well as combined vitamin K-dependent clotting factors deficiency.\nGenetic counseling\nThe pattern of transmission is autosomal recessive, with a 25% risk of recurrence in siblings. Pseudo-dominant pattern of inheritance due to high frequency of ABCC6 heterozygotes (around 1/200), has been occasionally observed. Genetic counseling for affected families is recommended.\nManagement and treatment\nThere is no specific therapy; the main symptomatic treatments include direct injection of vascular endothelial growth factor inhibitor in the eyes (for choroidal neovascularization), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), vascular surgery (for severe arteriosclerosis), and plastic surgery (for excess skin folds).\nPrognosis\nIt is a life-long progressive disease with high debilitating potential, but the life-span is normal in most patients.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Dominique GERMAIN"}
{"Disease Name": "Pseudoxanthomatous diffuse cutaneous mastocytosis", "Disease Definition": "Pseudoxanthomatous diffuse cutaneous mastocytosis (PDCM) is a rare form of diffuse cutaneous mastocytosis (DCM; see this term) characterized by yellow-orange infiltrated and xanthogranuloma-like lesions with only limited blistering.", "ORPHA ID": 280794, "Summary": "Epidemiology\nOnly a small number of cases (around 10) of PDCM have been reported in the literature to date.\nClinical description\nOnset most commonly occurs in early infancy with small vesicles and pseudoxanthomatous lesions developing after puberty.\nEtiology\nMutations in the KIT gene (4q11-q12) have been detected in patients with DCM.\n\n                            Last update: \n                            June 2013\n\n\n                            - Expert reviewer(s): \n                            Pr A.P. [Arnold] ORANJE"}
{"Disease Name": "Psoriasis-related juvenile idiopathic arthritis", "Disease Definition": "A rare pediatric inflammatory rheumatic disease characterized by the presence of arthritis accompanied by either psoriasis or at least two of the following supporting features; presence of nail pitting, onycholysis, dactylitis, or a family history of psoriasis in a first degree relative. Patients are younger than 16 years of age and the disease lasts longer than 6 weeks.", "ORPHA ID": 85436, "Summary": "Epidemiology\nThe incidence of juvenile idiopathic arthritis (JIA) in Caucasian is 8.3/100,000. Psoriatic juvenile idiopathic arthritis represents up to 10% of all JIA subtypes. Incidence and prevalence vary among populations, depending on race, immunogenetic susceptibility, and environmental influences.\nClinical description\nJuvenile idiopathic arthritis is considered an autoimmune disease, which may arise from an abnormal immunologic response triggered by environmental factors such as infection or trauma in a genetically predisposed subject. The onset of arthritis precedes the psoriatic cutaneous manifestations in more than 60% of cases, sometimes several years earlier, and it usually presents in an asymmetric oligoarthritis pattern. Monoarthritis (inflammation at one joint at a time) is relatively common at the onset, with isolated involvement of knee and small joints of hands and feet.\nEtiology\nThe etiology of psoriasis-related juvenile idiopathic arthritis is not currently known, although all juvenile idiopathic arthritis subtypes are most likely complex genetic traits as they lack single-gene, Mendelian patterns of inheritance. Inherited risk factors for both disease susceptibility and disease severity have been reported; the highly polymorphic HLA genes confer the strongest genetic effects.\nDiagnostic methods\nDiagnosis relies on observation of the clinical manifestations and ruling out other potential causes or illnesses. The disease is characterized either by the presence of a form of arthritis and psoriasis, or by the presence of arthritis associated with two or more of the following signs: dactylitis, nail pitting or onycholysis, or a family history of psoriasis in a first-degree relative. Exclusion criteria include the presence of systemic arthritis, HLA B27-positivity in males with onset of arthritis after 6 years of age, detection of rheumatoid Factor IgM in two test samples taken three months apart, the presence, or family history in a first degree relative, of ankylosing spondylarthritis, enthesitis and arthritis, sacroiliitis with an inflammatory bowel disease, or acute anterior uveitis.\nDifferential diagnosis\nThe differential diagnosis of arthritis associated with psoriasis is extensive. It includes other diseases associated with arthritis, including infectious, inflammatory and hemato-oncologic diseases. Specific examples include ankylosing spondylitis, reactive arthritis, inflamatory bowel disease, Behçet disease, Kawasaki disease, sarcoidosis, Blau syndrome, systemic lupus erythematosus, Sweet syndrome, and some infections such as Lyme or Whipple disease.\nManagement and treatment\nTreatment of psoriasis-related JIA usually involves treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and, when insufficient, disease modifying anti-rheumatic drugs (DMARDs; methotrexate) and then biological DMARDs (TNF inhibitor agents: etanercept or adalimumab).\nPrognosis\nJuvenile idiopathic arthritis has been considered (before the use of biological DMARDs) an important cause of short- and long-term acquired disability in children, impaired physical health, reduced quality of life and higher unemployment later on in life. Effective therapy helps avoid progression to the polyarticular form from the monarticular form. Furthermore, chronic uveitis may occur in 10 to 15% of children with psoriatic juvenile idiopathic arthritis. Therefore, early detection and intervention is extremely important.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Chantal DESLANDRE"}
{"Disease Name": "Psychogenic movement disorders", "Disease Definition": "A rare neurologic disease characterized by the manifestation of an underlying psychiatric illness or malingering, and that cannot be attributed to any known structural or neurochemical diseases. Most cases fall in the psychiatric diagnostic category of conversion disorder, also referred to as functional neurological symptom disorder.", "ORPHA ID": 71519, "Summary": "Epidemiology\nThe exact prevalence of psychogenic movement disorders (PMD) is unknown. At tertiary care centers, 2-4% of movement disorders patients are diagnosed with PMD.\nClinical description\nPMD present typically during adolescence or adulthood. Childhood cases and new onset in the elderly are rare, but do occur. Symptoms may include one or several types of abnormal movements seen in organic movement disorders (tremor, dystonia, chorea, bradykinesia, myoclonus, tics, athetosis, ballism, cerebellar incoordination), and also affect speech and gait. Typically, PMD present with complex movements of multiple different phenomenologies, usually incongruent with an organic movement disorder and affecting several body regions. Tremor appears to be the most commonly observed phenomenon, followed by dystonia, bradykinesia, myoclonus, and other unclassifiable abnormal movements. Symptoms often occur abruptly, and maximal symptom severity and disability are reached quickly. Other typical features are: deliberate slowness of movement, distractibility, variability, suggestibility, paroxysmal symptoms, and resolution with placebo administration or when the patient is unaware of being observed. Frequently, PMD are accompanied by other psychogenic symptoms such as false weakness, sensory findings, or excessive pain. Depression and anxiety are common comorbidities.\nEtiology\nUnderlying causes for PMD fall into three categories: Conversion disorder (also referred to as functional neurological symptom disorder), somatic symptom disorders, or, in rare cases, factitious disorder, and malingering. Risk factors include female gender, history of childhood trauma or sexual abuse, previous injury, surgery, and major stressful life events.\nDiagnostic methods\nThe diagnosis is usually made on clinical grounds, but certain ancillary tests may be helpful. Electromyography-based tremor and myoclonus analysis can be used to distinguish psychogenic tremor and myoclonus from their organic counterparts. Neuroimaging in the form of [123 I]-beta-CIT SPECT and [18F]-DOPA-PET is sometimes used in difficult to diagnose cases of psychogenic parkinsonism to exclude an organic etiology.\nDifferential diagnosis\nThe differential diagnosis of PMD lies in the organic counterparts of each individual presenting abnormal movement. In cases of tremor as the presenting symptom for example, Parkinson's disease and essential tremor will be considered. Some patients with PMD have movements that resemble seizures, and epilepsy should be ruled out.\nAntenatal diagnosis\nPrenatal diagnosis does not exist for this disorder.\nManagement and treatment\nAvoidance of iatrogenic damage by unnecessary invasive tests or inappropriate medications, early and precise diagnosis, and the facilitation of the appropriate psychiatric and physical rehabilitation treatment are important. Clinical trials are sparse, but the available literature suggests that a combination of psychotherapy with individualized psychiatric medication (aimed at treating coexisting conditions such as depression or anxiety) may be beneficial. Some centers also offer interdisciplinary inpatient programs, combing intense physiotherapy with psychotherapy.\nPrognosis\nThe prognosis of PMD is variable, but is better than that for patients with other somatoform complaints such as sensory symptoms, weakness or pain. The presence of psychiatric comorbidity (depression or an anxiety disorder) is a positive prognostic factor. Long-standing symptoms, insidious onset of movements and primary psychiatric diagnosis of hypochondriasis, a factitious disorder, or malingering are negative prognostic factors. If left untreated, PMD tend to be chronic, and follow-up data in several series show persistent symptoms in 65-95% of patients.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Vanessa HINSON"}
{"Disease Name": "Psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome", "Disease Definition": "A rare genetic disease characterized by onset of neurological deterioration in the first two years of life, progressing to severe intellectual disability, profound ataxia, mild dyskinesia, axial hypotonia, camptocormia, and oculomotor apraxia. Some patients also develop nephropathy with features of tubulointerstitial nephritis, hypertension, and a tendency for hyperkalemia.", "ORPHA ID": 505242, "Summary": ""}
{"Disease Name": "PTEN hamartoma tumor syndrome", "Disease Definition": "A group rare skin tumor or hamartoma diseases characterized by a germline PTEN mutation and clinical manifestations of hamartomas, overgrowth, and increased risk of neoplasia, notably breast carcinomas, epithelial thyroid carcinomas, endometrial carcinomas, renal cell carcinomas, and colorectal carcinoma. Non-malignant manifestations include macrocephaly, benign thyroid pathology (especially Hashimoto thyroiditis), mucocutaneous hamartomas, colonic polyps, and vascular malformations. Diseases in this group include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, and Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome.", "ORPHA ID": 306498, "Summary": ""}
{"Disease Name": "Pterin-4 alpha-carbinolamine dehydratase deficiency", "Disease Definition": "A rare genetic, transient and benign form of hyperphenylalaninemia due to tetrahydrobiopterin deficiency and characterized by muscular hypotonia, irritability (detected by EEG), slow acquisition of psychomotor skills, age-dependent movement disorders, including dystonia and an accompanying excretion of 7-substituted pterins. Neurological developement is normal with dietary control of blood phenyalanine.", "ORPHA ID": 1578, "Summary": ""}
{"Disease Name": "Pterygium colli-intellectual disability-digital anomalies syndrome", "Disease Definition": "A rare disorder characterized by pterygium colli, digital anomalies (abnormal small thumbs, widened interphalangeal joints, and broad terminal phalanges), and craniofacial abnormalities (brachycephaly, epicanthic folds, angulated eyebrows, upward slanting of the palpebral fissures, ptosis, hypertelorism, and prominent low-set, posteriorly rotated ears). It has been described in a woman and her son, but the manifestations were much less severe in the mother. The son also had intellectual deficit. The inheritance is either X-linked dominant or autosomal dominant.", "ORPHA ID": 2988, "Summary": ""}
{"Disease Name": "Ptosis-strabismus-ectopic pupils syndrome", "Disease Definition": "A rare disorder characterized by the association of ptosis, strabismus and ectopic pupils. It has been described in one family (in a mother and three of her children). Transmission is autosomal dominant.", "ORPHA ID": 2999, "Summary": ""}
{"Disease Name": "Ptosis-upper ocular movement limitation-absence of lacrimal punctum syndrome", "Disease Definition": "A rare opthalmic disorder characterized by bilateral ptosis, upper ocular movement limitation, absence of the lacrimal punctum and facial dysmorphism including, narrow and squared forehead, bilateral thick and arched eyebrows, absence of bilateral lower medial eyelashes, telechantus, mild anteverted nostrils, a relatively long philtrum and maxillary hypoplasia. Some patients may have low set and dysplastic ears.", "ORPHA ID": 228396, "Summary": ""}
{"Disease Name": "Ptosis-vocal cord paralysis syndrome", "Disease Definition": "Ptosis-vocal cord paralysis syndrome is a rare, hereditary disorder with ptosis characterized by the combination of congenital bilateral recurrent laryngeal nerve paralysis and congenital bilateral ptosis. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 2997, "Summary": ""}
{"Disease Name": "Pudendal nerve entrapment syndrome", "Disease Definition": "A rare, acquired peripheral neuropathy characterized by chronic neuropathic pain involving the sensory territory of the pudendal nerve (from clitoris to anus or from penis to anus) aggravated by sitting. It is often associated with pelvic dysfunction.", "ORPHA ID": 60039, "Summary": "Epidemiology\nThe prevalence of Pudendal neuralgia (PN) is unknown. A female predominance is reported, with a female/male ratio of 6:4.\nClinical description\nPN usually presents between the ages of 50-70 years. and manifests with neuropathic pain of varying intensity in the perineal region. The pain is described as an intense, sharp, burning sensation, and sometimes as numbness. Rectal or vaginal foreign body sensations (sympathalgia) are commonly reported. Pain is unilateral or often medial, and is more intense during the day, when sitting or when wearing tight clothing. The pain is often associated with pelvic sensitization, which explains the urinary (pollakiuria, dysuria), anorectal (dyschezia, increased pain after bowl movement) and sexual (dyspareunia, intolerance of vulval contact, post-coital exacerbation of pain, persistent genital arousal, erectile dysfunction) problems as well as myofascial pain in the buttocks. The co-occurrence of truncal sciatica is common. Several forms of PN exist: benign, regressive, evolutive with flares, stable, and very debilitating forms with progressive symptom aggravation.\nEtiology\nThe pudendal nerve can be compressed or entrapped by posterior pelvis ligaments (comprised of the sacrotuberous and sacrospinalis ligaments), or in the Alcock's canal (due to splitting of the obturator muscle aponeurosis). There is also the possibility of proximal entrapment at the level of the sub-piriformis canal and distal entrapment of the dorsal nerve of the clitoris/penis at the level of the sub-pubic canal. Other causes of pudendal neuralgia may include birth-related difficulties (due to excessive stretching), trauma, surgical, radiation sequalae, intense bicycling, spinal deviation, pelvic skeletal fractures or a tumor. In these cases, the pain is likely to be permanent and sitting position has little or no effect on it.\nDiagnostic methods\nThe diagnostic criteria (Nantes criteria) for PN includes the presence of pain in the distribution of the pudendal nerve that is worsened by sitting, with no objective sensory impairment, which does not provoke awakening in the night, and that is relieved with anesthesia by pudendal nerve block. The diagnosis is strictly clinical and no additional examination can validate the diagnosis with certainty. Imaging tests may be necessary to rule out other diagnoses (pelvic and lumbosacral MRI, endoscopy, infection check-up, etc.). Normal imaging findings do not exclude a diagnosis of PN.\nDifferential diagnosis\nDifferential diagnoses include neuropathies of the neighboring nerves (ilio-inguinal, genitofemoral, lower cluneal), coccygodynia (given the location of pain projecting into the anus and rectum, aggravated by sitting position) and myofascial syndromes of the deep gluteus muscles (piriformes, obturator internus muscle, levator ani). Dermatological inflammatory pathologies (psoriasis, vulvar sclerotrophic lichen) should be systematically eliminated. When the pain is not triggered by sitting position, but rather by sexual intercourse, vestibulodynia should be considered. Isolated chronic urethralgia or bladder pain syndrome may be considered when perineal pain varies with urination.\nManagement and treatment\nManagement includes the treatment of neuropathic pain with antidepressant therapy (amitriptyline at low dose or duloxetine) or antiepileptic (pregabalin, gabapentin) and percutaneous posterior tibial nerve stimulation. Physiotherapy, osteopathy and short-term psychotherapy are also proposed as first-line solutions. The effect of anesthetic infiltration of the pudendal nerve is limited and its therapeutic effects in the medium and long term have not been demonstrated. In refractory forms, surgical decompression of the pudendal nerve has been effective (the trans-gluteal pathway being the only surgery whose efficacy has been proved). In those where surgery has been ineffective, an implanted neurostimulator can be proposed at the conus medullaris level or on sacral roots and pudendal nerve level.\nPrognosis\nPN greatly affects quality of life, but has no effect on life expectancy.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Amélie LEVESQUE"}
{"Disease Name": "Pulmonary agenesis", "Disease Definition": "A rare, non-syndromic respiratory or mediastinal malformation characterized by unilateral complete absence of lung tissue, bronchi, and pulmonary vessels. It may be isolated or associated with congenital malformations, most commonly with heart anomalies. Presentation is highly variable including airway narrowing, stridor, respiratory distress, recurrent respiratory tract infections, and pulmonary hypertension.", "ORPHA ID": 984, "Summary": ""}
{"Disease Name": "Pulmonary alveolar microlithiasis", "Disease Definition": "A rare genetic respiratory disease characterized by widespread intra-alveolar accumulation of minute calcium phosphate microliths, leading to pulmonary fibrosis, pulmonary hypertension, and chronic respiratory failure. Age of onset is highly variable, and most patients are asymptomatic for years or decades, before signs and symptoms like dyspnea on exertion, dry cough, chest pain, hemoptysis, or finger clubbing develop. The disease takes a long-term progressive course. Routine chest radiographs typically show a fine, ''sandstorm-like'' micronodular pattern that is more pronounced in the bases than in the apices.", "ORPHA ID": 60025, "Summary": ""}
{"Disease Name": "Pulmonary arterial hypertension associated with another disease", "Disease Definition": "Pulmonary arterial hypertension associated with another disease is a group of conditions that lead to PAH (see this term); connective tissue diseases (lupus erythematosus, systemic sclerosis and mixed connective tissues disease), congenital heart disease (Eisenmenger syndrome), HIV infection, portal hypertension, schistosomiasis and chronic hemolytic anemia (see these terms),which is characterized by elevated pulmonary arterial resistance leading to right heart failure that is progressive and potentially fatal.", "ORPHA ID": 275791, "Summary": ""}
{"Disease Name": "Pulmonary arterial hypertension associated with chronic hemolytic anemia", "Disease Definition": "Pulmonary arterial hypertension associated with chronic hemolytic anemia (PAH-CHA) is a form of PAH (see this term) characterized by an elevated pulmonary arterial resistance leading to right heart failure observed as a complication of chronic hemolytic anemia.", "ORPHA ID": 275828, "Summary": ""}
{"Disease Name": "Pulmonary arterial hypertension associated with congenital heart disease", "Disease Definition": "Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a form of pulmonary arterial hypertension (PAH, see this term), characterized by elevated pulmonary arterial resistance leading to right heart failure occurring as a common complication of congenital heart malformations (see this term) with left to right cardiac shunts. Eisenmenger syndrome (see this term) is the most advanced form of PAH-CHD and is defined as the complete or partial reversal of an initial left-to-right shunt to a right-to-left shunt, causing cyanosis and limited exercise capacity. PAH-CHD also includes mild to moderate systemic-to-pulmonary shunts with no cyanosis at rest, patients with small defects, and those with residual PAH following corrective cardiac surgery.", "ORPHA ID": 275803, "Summary": ""}
{"Disease Name": "Pulmonary arterial hypertension associated with connective tissue disease", "Disease Definition": "A form of pulmonary arterial hypertension (PAH) characterized by an elevated pulmonary arterial resistance leading to right heart failure observed as a complication of a connective tissue disease.", "ORPHA ID": 275798, "Summary": ""}
{"Disease Name": "Pulmonary arterial hypertension associated with HIV infection", "Disease Definition": "A form of pulmonary arterial hypertension characterized by elevated pulmonary arterial resistance leading to right heart failure observed as a complication of HIV infection.", "ORPHA ID": 275808, "Summary": ""}
{"Disease Name": "Pulmonary arterial hypertension associated with portal hypertension", "Disease Definition": "Pulmonary arterial hypertension associated with portal hypertension (PAH-PH) is a form of pulmonary arterial hypertension (PAH), characterized by an elevated pulmonary arterial resistance leading to right heart failure observed as a complication of portal hypertension.", "ORPHA ID": 275813, "Summary": ""}
{"Disease Name": "Pulmonary arterial hypertension associated with schistosomiasis", "Disease Definition": "Pulmonary arterial hypertension associated with schistosomiasis (PAHS) is a form of pulmonary arterial hypertension (see this term) characterized by an elevated pulmonary arterial resistance leading to right heart failure, observed as a complication of a chronic schistosomiasis (see this term).", "ORPHA ID": 275823, "Summary": ""}
{"Disease Name": "Pulmonary arterial hypertension", "Disease Definition": "Pulmonary arterial hypertension (PAH) is a group of diseases characterized by elevated pulmonary arterial resistance leading to right heart failure. PAH is progressive and potentially fatal. PAH may be idiopathic and/ or familial, or induced by drug or toxin (drug-or toxin-induced PAH, see these terms) or associated with other diseases like congenital heart disease, connective tissue disease, HIV, schistosomiasis, portal hypertension (PAH associated with other disease, see this term).", "ORPHA ID": 182090, "Summary": "Epidemiology\nPrevalence of PAH, in all of its forms, is estimated around 5/1,000,000.\nClinical description\nMost forms of PAH develop in adults, and in rare cases in children; women are twice as likely as men to be affected. Initial symptoms include dyspnea, syncope, chest pain, palpitations and pedal edema. Precordial signs include loud and palpable second heart sound, pulmonary ejection click and murmurs of pulmonary and tricuspid regurgitation. 70% of patients present with severe heart failure. More rarely, abdominal distension, clubbing of digits and Raynaud phenomenon (predominantly in females) are observed. Hemoptysis has also been reported.\nEtiology\nPAH is caused by vascular remodeling of pulmonary arteries leading to widespread obliteration of the smallest arteries; sufficient occlusion of these vessels increases the resistance to pulmonary blood flow and a compensating increased pressure in the right ventricle. Mutations in BMPR2 gene (2q33) and also in ACVRL1(12q13), Endoglin(9q34), CAV1 (7q31), KCNK3(2p23),Smad9 (13q12) and TBX4 (17q21)have been described in heritable PAH. Mutations in PAH predisposing genes were identified in patients with idiopathic and/or familial form of PAH and in PAH associated with intake of drugs or toxins. Patients carrying a mutation in PAH predisposing gene, and those displaying a familial form of the disease (with or without mutations identified), are grouped under the term heritable PAH (see this term).\nDiagnostic methods\nChest X-ray reveals an enlarged pulmonary artery and lung hyper perfusion and ECG shows right ventricular strain and hypertrophy. Echocardiography allows an estimate of pulmonary artery systolic pressure and detects cardiac disease. Right-heart catheterization is essential to establish the diagnosis:. PAH is diagnosed when resting mean pulmonary artery pressure is >25mmHg and a normal Pulmonary capillary wedge pressure.\nDifferential diagnosis\nRarer forms of pulmonary hypertension include pulmonary veno-occlusive disease /pulmonary capillary hemangiotosis (PVOD /PCH, see these terms).Differential diagnoses include asthma, chronic obstructive pulmonary disease, hypoplastic left heart syndrome, chronic thromboembolic pulmonary hypertension and complete atrio-ventricular canal - left heart obstruction (see these terms).\nAntenatal diagnosis\nPregnancy is considered to be associated with a high rate of mortality (30-50%) in PAH patients. Prenatal genetic testing could be considered in cases of heritable PAH (see this term).\nGenetic counseling\nGenetic counseling and testing have to be proposed to patients with idiopathic or heritable form of PAH (transmitted as an autosomal dominant disease with an incomplete penetrance) and to patients displaying drug-or toxin-induced PAH.\nManagement and treatment\nManagement includes general measures (aggressive management of respiratory tract infections, annual influenza vaccination, family planning) and medical therapy (oxygen, anticoagulants, diuretics, digoxin. Calcium channel blockers are indicated only in patients with acute vasodilator response to Nitric oxide during right heart catheterization. Endothelin receptor agonists (ambrisentan,), prostanoids (epoprostenol) and phosphodiestrease inhibitors (sildenafill) have been used. Lung transplantation is the last option for resistant patients.\nPrognosis\nPrognosis varies between different forms, but is generally poor; the mean survival rate after diagnosis is <3 years. However, early therapeutic intervention may lead to better survival.\n\n                            Last update: \n                            January 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Barbara GIRERD  - Pr David MONTANI"}
{"Disease Name": "Pulmonary arteriovenous malformation", "Disease Definition": "An aberrant communication between one or more pulmonary arteries and one or more pulmonary veins leading to an anatomic intrapulmonary right-to-left shunt.", "ORPHA ID": 2038, "Summary": "Epidemiology\nIn Japan, prevalence estimated by screening thoracic CT scans is 1/2,600 for all causes of pulmonary arteriovenous malformations (PAVMs).\nClinical description\nPAVMs differ from other thoracic vascular anomalies in that the right-to-left shunt places individuals at high risk of paradoxical embolic complications, particularly neurological, and these risks are present whether or not the individual has symptoms from the PAVM(s). In most cases, PAVMs are asymptomatic because of successful physiological compensations such as polycythemia, and higher cardiac outputs. The mean age for presentation is over 50 years of age, though lower if screening programs are utilized. If present, exercise intolerance and dyspnea usually reflect concurrent conditions such as low hemoglobinemia, mild airflow limitation, and/or other cardiorespiratory impairments. Hemoptysis is rare, but is the most frequent cause of maternal death in pregnancy. Major neurological complications such as early onset ischemic strokes, transient ischemic attacks, and cerebral abscesses affect more than 15% of adult patients in recent European studies, but are extremely rare in children. Tachyarrhythmias and angina may be present at diagnosis, although they usually reflect a more complex underlying pathology; particularly iron deficiency and/or visceral arteriovenous malformations (AVMs) due to underlying hereditary hemorrhagic telangiectasia (HHT). HHT is present in more than 70% of people with PAVMs.\nEtiology\nThe exact pathogenesis is still unknown. As many as 20% of PAVMs are idiopathic (sporadic), although PAVMs generally occur in the context of HHT, or, less frequently, other vascular malformation syndromes. PAVMs can also result from surgical corrections of cyanotic congenital heart disease; gestational trophoblastic disease; the hepatopulmonary syndrome; telomeric disorders, or trauma.\nDiagnostic methods\nDiagnosis is based on imaging demonstrating one or more AVMs usually located in the lower lobes of the lungs. Although PAVMs may be clearly visible on chest X-rays, many are not, even when clinically significant. Computed tomography is generally considered the gold-standard investigation for diagnosing PAVMs. AVMs can be isolated or multiple, unilateral or bilateral. 'Simple' lesions consist of an aneurysmal venous sac communicating with a dilated feeding artery and draining vein. Complex PAVMs are supplied by more than one pulmonary artery and/or drained by more than one vein; diffuse PAVMs are multiple small PAVMs affecting one or more segments of one or more lobes. Arterial partial pressure of oxygen and oxygen saturation, are often low, and are inversely related to the size of the right-to-left shunt. Approximately one-third of patients demonstrate orthodeoxia, but platypnea is seldom observed.\nDifferential diagnosis\nDifferential diagnoses include pulmonary artery aneurysms, pulmonary varices, bronchoceles, systemic artery-pulmonary artery communications and vascular tumors.\nAntenatal diagnosis\nPrenatal genetic testing is possible for inherited forms of PAVM but is not necessary for proper pregnancy and delivery management.\nGenetic counseling\nWhere PAVMs are multiple and no other precipitants can be identified, the condition is likely inherited, and genetic testing should be suggested. If negative, screening of children for PAVMs is suggested after puberty. Single PAVMs may be due to inherited conditions even in the absence of other symptoms and signs, with mosaic cases described and potentially heritable.\nManagement and treatment\nTreatment of adult patients is recommended irrespective of respiratory symptoms. Percutaneous transcatheter embolization of the pulmonary artery/ies feeding the PAVMs is the treatment of choice, irrespective of respiratory symptoms. Additional recommendations include judicious dental hygiene; antibiotic prophylaxis prior to dental and surgical procedures; optimization of iron status; and pregnancy-specific recommendations. In highly selected cases, parenchymal sparing surgery may be considered.\nPrognosis\nWith appropriate management and interventions, prognosis is generally very good with many patients reaching their 9th and 10th decades of life. During pregnancy, however, there is a 1% maternal death rate. Difficult management issues arise in patients who continue to experience neurological complications, or when PAVMs acquire a systemic arterial supply, increasing the risk of hemoptysis.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Ali ALSAFI  - Pr Claire SHOVLIN"}
{"Disease Name": "Pulmonary artery coming from patent ductus arteriosus", "Disease Definition": "Pulmonary artery coming from patent ductus arteriosus is a rare, congenital, non-syndromic heart malformation characterized by the presence of a single (or a double) patent ductus arteriosus which associates one or both pulmonary arteries originating from it. Manifestations are variable, frequently presenting with neonatal cyanosis, severe progressive hypoxia, persistent pulmonary hypertension, increased susceptibility to pulmonary infections, and thoracic asymmetry resulting from asymmetric lung volumes.", "ORPHA ID": 99049, "Summary": ""}
{"Disease Name": "Pulmonary artery hypoplasia", "Disease Definition": "A rare, congenital anomaly of the great arteries characterized by various clinical signs and symptoms, including shortness of breath, recurrent lower respiratory tract infections, lung hypoplasia, pulmonary hypertension, and haemoptysis. The anomaly can be isolated or associated with congenital heart disease, such as tetralogy of Fallot, atrial septal defect, coarctation of the aorta, right aortic arch, truncus arteriosus, patent ductus arteriosus and pulmonary atresia.", "ORPHA ID": 99083, "Summary": ""}
{"Disease Name": "Pulmonary atresia with ventricular septal defect", "Disease Definition": "Pulmonary atresia with ventricular septal defect (PA-VSD) is a rare cyanotic congenital heart malformation characterized by underdevelopment of the right ventricular outflow tract and atresia of the pulmonary valve, ventricular septal defect (VSD) and pulmonary collateral vessels. Clinical features depend on the anatomic variability of the lesion and patients may be minimally symptomatic, severely cyanotic or may develop congestive heart failure. PA-VSD may represent a severe form of Tetralogy of Fallot (see this term).", "ORPHA ID": 1207, "Summary": ""}
{"Disease Name": "Pulmonary atresia-intact ventricular septum syndrome", "Disease Definition": "A rare cardiac malformation characterized by congenital either membranous or long segment muscular atresia of the right ventricular outflow tract in the absence of communication at the level of ventricles. The spectrum ranges from simple membranous pulmonary atresia with normal-appearing right ventricle (RV) to hypoplastic RV with abnormal connections between the RV and coronary arteries. Major presenting symptoms are cyanosis and desaturation.", "ORPHA ID": 1208, "Summary": ""}
{"Disease Name": "Pulmonary blastoma", "Disease Definition": "A biphasic primary lung neoplasm, belonging to the group of sarcomatoid lung carcinomas (SLCs). The tumor contains both an epithelial well-differentiated component, showing tubular architecture resembling the normal fetal lung, and a mesenchymal undifferentiated stroma with a so-called ''blastema-like'' configuration that resembles an embryonic lung.", "ORPHA ID": 64741, "Summary": "Epidemiology\nPB is a rare tumor, accounting for less than 0.25% of all primary malignant lung tumors, with only around 350 cases having been reported in the literature so far. PB occurs almost exclusively in adults and has a peak incidence in the fourth decade of life (earlier than other forms of SLC), with a marked female predominance (70% of cases) and frequent association with tobacco smoking.\nClinical description\nSymptomatic patients present with nonspecific respiratory manifestations (cough, hemoptysis and chest pain). Other features may include dyspnea, fever, weight loss, and recurrent pneumonia. However, up to 40% of patients may be identified presymptomatically after a chest radiograph for another indication. PBs are usually well-demarcated solitary tumors (average size 10 cm) with cystic and necrotic features and are often located in the peripheral lung. Common sites of metastases include the brain, lymph nodes and liver.\nEtiology\nLittle is known about the pathogenesis and histogenesis of PB. Molecular studies indicate that mesenchymal and epithelial components are derived from a single precursor cell. Mutations in several genes (including TP53, CTNNB1 and EGFR) may be identified in some PB tumors.\nDiagnostic methods\nClinical laboratory and imaging studies are nonspecific and definitive diagnosis of PB requires identification of both the epithelial and mesenchymal components of the tumor, through histological studies on a resected specimen. Bronchoscopy and fine needle biopsy have been useful for diagnosis in some cases.\nDifferential diagnosis\nThe differential diagnosis should include other forms of SLC (pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and adenocarcinoma (particularly fetal adenocarcinoma); see these terms). PB also has to be distinguished from the childhood tumor pleuropulmonary blastoma (see this term).\nManagement and treatment\nIn many cases, the tumor is initially thought to be a bronchogenic carcinoma. Complete surgical resection with mediastinal lymph node dissection ensures both diagnosis and therapy. Adjuvant treatment, mostly consisting of radiotherapy, has been reported in a few cases, following incomplete resection, or in patients with N2 mediastinal involvement. For unresectable tumors, chemotherapy may be based on protocols used for sarcomas, including doxorubicin and ifosfamide.\nPrognosis\nPB is an aggressive tumor and the prognosis has historically been reported as being poor: 5-year survival rates for patients with stage I disease were around 30%. In most recent reports, survival -adjusted by stage- is better than that for non-small cell lung cancer, especially in completely resected cases. Recurrences (occurring in 30-40% of patients) and metastases are common.\n\n                            Last update: \n                            November 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Nicolas GIRARD"}
{"Disease Name": "Pulmonary fibrosis-hepatic hyperplasia-bone marrow hypoplasia syndrome", "Disease Definition": "A rare disease, manifesting with idiopathic pulmonary fibrosis, hepatic nodular regenerative hyperplasia leading to portal hypertension and thrombocytopenia due to bone marrow hypoplasia. The condition was associated with 100% mortality.", "ORPHA ID": 210136, "Summary": ""}
{"Disease Name": "Pulmonary interstitial glycogenosis", "Disease Definition": "Pulmonary interstitial glycogenosis (PIG) is a rare non-lethal pediatric form of interstitial lung disease (ILD, see this term).", "ORPHA ID": 217557, "Summary": "Epidemiology\nVery few cases have been described to date but there appears to be male predominance.\nClinical description\nNeonates present with respiratory distress syndrome shortly after birth. The characteristic histological feature of PIG is the accumulation of monoparticulate glycogen in interstitial cells on lung biopsy.\nEtiology\nThe disease is thought to be the result of a maturation defect of interstitial cells leading to glycogen accumulation within the cytoplasm.\nPrognosis\nPrognosis is dependent on the type of lung growth abnormalities associated with the infiltrative disease.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Annick CLEMENT"}
{"Disease Name": "Pulmonary nodular lymphoid hyperplasia", "Disease Definition": "Pulmonary nodular lymphoid hyperplasia (PNHL) is a reactive lymphoid proliferation manifesting as solitary or multiple nodules in the lung.", "ORPHA ID": 60026, "Summary": ""}
{"Disease Name": "Pulmonary non-tuberculous mycobacterial infection", "Disease Definition": "A rare bacterial infectious disease caused by non-tuberculous mycobacteria (including Mycobacterium avium complex, Mycobacterium kansasii, or Mycobacterium xenopi, among others), characterized by chronic pulmonary disease with symptoms like chronic cough (with or without sputum production), chest pain, and weight loss. Predisposing factors are preexisting lung conditions, neoplasms, immunosuppression, or thoracic skeletal abnormalities.", "ORPHA ID": 411703, "Summary": ""}
{"Disease Name": "Pulmonary valve agenesis-intact ventricular septum-persistent ductus arteriosus syndrome", "Disease Definition": "A rare, life-threatening, congenital, non-syndromic, conotruncal heart malformation disease characterized by absent or severely undeveloped pulmonary valve leaflets (with a restrictive ring of thickened tissue at the place of the pulmonary valve annulus), associated with an intact ventricular septum and a patent ductus arteriosus, manifesting with marked respiratory insufficiency. Additional features include dilated main pulmonary artery (with or without dilatation of pulmonary artery branches), to-and-fro flow at site of the dysplastic pulmonary valve, and systolic pressure gradient across narrowed pulmonary valve. Tricuspid atresia and variable extra-cardiac anomalies (e.g. diaphragmatic hernia or cleft lip/palate), may be present.", "ORPHA ID": 99048, "Summary": ""}
{"Disease Name": "Pulmonary valve agenesis-tetralogy of Fallot-absence of ductus arteriosus syndrome", "Disease Definition": "Pulmonary valve agenesis-tetralogy of Fallot-absence of ductus arteriosus syndrome is a rare congenital heart malformation characterized by a tetralogy of Fallot (pulmonary stenosis, overriding aorta, ventricular septal defect and right ventricular hypertrophy), complete absence or rudimentary pulmonary valve that is both stenotic and regurgitant and an absence of the ductus arteriosus. It presents prenatally with cardiomegaly, polyhydramnios, fetal heart failure, hydrops fetalis and fetal demise or postnatally with cyanosis and respiratory failure due to bronchomalacia secondary to bronchial compression from dilated pulmonary arteries. It is frequently associated with 22q11 deletion.", "ORPHA ID": 101206, "Summary": ""}
{"Disease Name": "Pulmonary valve agenesis", "Disease Definition": "Pulmonary valve agenesis is a rare congenital heart malformation characterized by a total or partial absence of the pulmonary valve leaflets associated with stenosis of the pulmonary artery orifice and aneurysmal dilatation of the pulmonary arteries. It usually occurs in association with additional cardiovascular malformations such as teralogy of fallot or ventricular septal defect, or can occur as part of a syndrome (e.g. 22q11.2 deletion syndrome). Clinical features depend on the presence of associated cardiac malformations and include pulmonary insufficiency, bronchial obstruction (secondary to compression by aneurysmally dilated pulmonary arteries), pulmonary stenosis, cyanosis, and cardiac failure.", "ORPHA ID": 982, "Summary": ""}
{"Disease Name": "Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis", "Disease Definition": "A disorder that constitutes a rare subgroup of rare pulmonary hypertension characterized by obliterative fibrosis of the small pulmonary veins and venules and/or capillary infiltration of the pulmonary interstitium leading to increased pulmonary vascular resistance and right ventricular dysfunction.", "ORPHA ID": 431353, "Summary": "Epidemiology\nPulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD and/or PCH) annual incidence has been estimated at between 1 in 5-10 millions but this likely to be an underestimate. PVOD and/or PCH is believed to account for up to 5 to 10% of patients initially diagnosed with idiopathic pulmonary arterial hypertension (PAH).\nClinical description\nOnset may occur at any age and there is no overall sex predilection in the genetic form of the disease but a male predominance in sporadic PVOD cases. Patients present with non-specific respiratory symptoms, most commonly progressive exertional dyspnea and fatigue. PVOD and/or PCH and idiopathic PAH share the same clinical presentation and clinical examination is unhelpful to distinguish them. As the disease progresses, patients may show signs of right ventricular failure and the use of PAH drugs is associated with a potential risk of life-threatening pulmonary edema.\nEtiology\nSeveral factors have been suspected to influence disease development including various chemotherapy regimens as well as bone marrow and hematopoietic blood stem cell transplantation. Occupational exposure is a frequently encountered risk factor for PVOD (mainly organic solvents, as trichloroethylene (a chlorinated solvent)). Pulmonary venous involvement may also occur in patients with connective tissue diseases (systemic sclerosis), sarcoidosis, and adult pulmonary Langerhans cell histiocytosis. Familial cases of PVOD and/or PCH have also been reported and around 10 to 20% of PVOD and/or PCH patients have a heritable form of the disease due to bi-allelic mutations in the EIF2AK4 gene (15q13.3).\nDiagnostic methods\nRight heart catheterisation confirms pulmonary hypertension and shows pattern of precapillary PH with normal pulmonary artery wedge pressure. Although histology is considered the gold standard for definite diagnosis, lung biopsy carries a high risk of morbidity and mortality. Hence the diagnosis is usually based on the combination of clinical findings, pulmonary function tests and blood gas measurements (resting hypoxemia and low carbon monoxide diffusion capacity), bronchoalveolar lavage (occult alveolar hemorrhage) and high resolution CT scans (septal thickening, ground-glass opacities and lymphadenopathy). Mutations in EIF2AK4 gene confirm the diagnosis.\nDifferential diagnosis\nThe main differential diagnoses are PAH (idiopathic or secondary to chronic lung diseases), and chronic thromboembolic pulmonary hypertension.\nAntenatal diagnosis\nPrenatal diagnosis can be considered in families with identified bi-allelic mutations in EIF2AK4 gene.\nGenetic counseling\nGenetic counseling and screening for the EIF2AK4 gene are offered to PVOD/PCH patients. Heritable PVOD and/or PCH is an autosomal recessive disease.\nManagement and treatment\nThe usual recommended regimens involve oxygen therapy, anticoagulants and antithrombotic agents, immunosuppressants, pneumococcal and influenza vaccinations, and limiting physical activity. The use of PAH-specific therapies (endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, prostacyclins) remains controversial due to the high risk of pulmonary edema. Importantly, PVOD patients who respond acutely to inhaled NO may develop severe pulmonary oedema rapidly after initiation of calcium channel blocker therapy. Given the above considerations, acute vasoreactivity testing is contraindicated in PVOD. At present, it is recommended that PVOD and/or PCH patients be treated in highly specialized centers for PAH and that they be fully informed of the risks if PAH-specific therapies are initiated. Because of poor prognosis, lung transplantation should be discussed early in the course of the disease.\nPrognosis\nThe prognosis for PVOD and/or PCH patients remains poor in the absence of lung transplantation.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Barbara GIRERD  - Pr David MONTANI"}
{"Disease Name": "PUM1-associated developmental disability-ataxia-seizure syndrome", "Disease Definition": "A rare genetic syndromic intellectual disability characterized by developmental delay, intellectual disability, ataxia, and, more variably, seizures and short stature. Behavioral abnormalities may also be observed, as well as variable facial and other dysmorphic features (such as broad nasal bridge, hypertelorism, almond-shaped eyes, high-arched palate, and anomalies of the fingers and toes). Brain imaging may reveal dilated ventricles, small corpus callosum, or posterior fossa abnormalities.", "ORPHA ID": 589515, "Summary": ""}
{"Disease Name": "Punctate acrokeratoderma freckle-like pigmentation", "Disease Definition": "A rare epidermal disease characterized by the association of punctate acrokeratoderma with a pigmentary disorder. Patients present skin-colored keratotic papules on the hands and feet and pronounced hyperkeratosis of the palms and soles. Freckle-like pigmentation on the dorsal surfaces of the hands and feet is also reported. Histological examination reveals no fragmentation of dermal elastic tissue. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 99710, "Summary": ""}
{"Disease Name": "Punctate inner choroidopathy", "Disease Definition": "A rare ophthalmic disorder characterized by typically bilateral, asymmetric, yellowish, punctate chorioretinal lesions of the posterior pole forming a linear branching pattern and progressing to atrophic scars. Subretinal neovascular membranes occur in many cases. Vitritis is always absent. Patients may present with blurred vision, scotoma, floaters, photopsia, and metamorphopsia. Choroidal neovascular membrane formation and subretinal fibrosis are the major causes of visual loss. The condition predominantly occurs in young myopic females.", "ORPHA ID": 580951, "Summary": ""}
{"Disease Name": "Punctate palmoplantar keratoderma type 1", "Disease Definition": "A rare hereditary skin disease characterized by irregularly distributed epidermal papular/punctate hyperkeratosis of the palms and soles with wide variation among patients.", "ORPHA ID": 79501, "Summary": "Epidemiology\nThe prevalence of PPKP1 has been estimated at 1.17/100,000 in Croatia and 3.3/100,000 in Slovenia. PPKP1 has been reported in over 400 patients worldwide to date.\nClinical description\nTypical clinical characteristics are multiple hyperkeratotic papules and central indentations that are irregularly distributed on the palms and soles. The lesions usually start to develop in early adolescence but can also present earlier or later in life. Sometimes additional confluent thickening of the soles can be observed. Depending on the clinical presentation, PPKP1 can be associated with pain at pressure points, especially on the soles. The lesions may coalesce over pressure points. There can be considerable variation between affected family members.\nEtiology\nMutations in the AAGAB gene (15q22.33-q23) have been identified as one of the causes of PPKP1. This gene encodes for the alpha and gamma-adaptin-binding protein p34 which is involved in the clathrin-mediated pathway and when disrupted causes an increase in the half-life of several receptor tyrosine kinases in basal keratinocytes, leading to hyperproliferation and hyperkeratosis. COL14A1 (8q24.12) is another gene that has been suggested to be implicated in the pathogenesis of PPKP1, but this association needs further confirmation, as it has only been reported once in a few cases from the same Chinese family.\nDiagnostic methods\nMutational analysis of the AAGAB gene and the COL14A1 gene confirms the clinical diagnosis. Although not specific for PPKP1, histological examination of papules reveals hypergranulosis and hyperkeratosis with a well-defined central epidermal depression.\nDifferential diagnosis\nDifferential diagnosis includes verrucae vulgaris and any other form of palmoplantar keratoderma, primarily the focal types, such as porokeratosis punctata palmaris et plantaris (PPKP2) and focal acral hyperkeratosis (or PPKP3 without elastoidosis).\nGenetic counseling\nPPKP1 is inherited in an autosomal-dominant manner. Genetic counseling is possible.\nManagement and treatment\nMechanical removal of the hyperkeratosis is the most effective symptomatic treatment. Keratolytic creams can support the treatment. In some patients with a severe phenotype, oral retinoids have been shown to reduce symptoms.\nPrognosis\nAlthough the clinical appearance of lesions can worsen over time, the general prognosis is good. Depending on the clinical severity and pain sensitivity of patients, quality of life can be affected.\n\n                            Last update: \n                            December 2022\n\n\n                            - Expert reviewer(s): \n                            Dr M.C. [Marieke] BOLLING | ERN-Skin* - Dr P.C. [Peter] VAN DEN AKKER | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Punctate palmoplantar keratoderma type 2", "Disease Definition": "Punctate palmoplantar keratoderma type 2 is a type of isolated, punctate, hereditary palmoplantar keratoderma characterized by multiple, asymptomatic, 1 to 2 mm-long, firm, hyperkeratotic projections ('spiny keratosis') on the palms, soles and digits (typically confined to their volar and/or lateral aspects). Histopathologically, compact columnar parakeratosis over hypo- or agranular epidermis is observed.", "ORPHA ID": 79502, "Summary": ""}
{"Disease Name": "PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome", "Disease Definition": "A rare neurologic disease characterized by neonatal hypotonia, global developmental delay, feeding difficulties, and often seizures or seizure-like episodes. Other frequently observed signs and symptoms include variable dysmorphic features, myopathic facies, respiratory problems, and visual abnormalities, such as strabismus or esotropia. Brain imaging may show delayed myelination and other white matter abnormalities.", "ORPHA ID": 438213, "Summary": ""}
{"Disease Name": "Pure autonomic failure", "Disease Definition": "Pure autonomic failure (PAF) is a neurodegenerative disease that affects the sympathetic branch of the autonomous nervous system and that manifests with orthostatic hypotension.", "ORPHA ID": 441, "Summary": "Epidemiology\nThe exact prevalence is unknown.\nClinical description\nThe disease affects adults. PAF manifests initially with orthostatic hypotension, erectile dysfunction and urinary disorders. Other symptoms, including sweat disorders and Horner syndrome (see this term), indicate a deficit of the sympathetic nervous system. There are no associated neurological signs.\nEtiology\nPAF is sporadic and its etiology is unknown. It is a synucleinopathy with Lewy bodies and neuronal rarefaction in the intermediate-lateral tract of the medulla and in the sympathetic ganglia.\nDiagnostic methods\nDiagnosis of PAF is indicated in cases with clinical signs compatible with chronic sympathetic deficiency, without associated neurological signs. The diagnosis is confirmed with evidence of neurogenic orthostatic hypotension (falling >= 20/10 mm Hg of arterial pressure when standing without reactive tachycardia). Ambulatory blood pressure monitoring can reveal a disappearance or reversal of the day/night rhythm. Specific tests for PAF (Ewing test, pupillary or sudoral function, analysis of heart rate and blood pressure variability, sympathetic microneurography and MIBG scintigraphy) are carried out by some laboratories. Plasma levels of noradrenaline are low at rest and do not increase on standing. The EMG and cerebral MRI/CT are normal. Examinations to identify an immunologic, deficiency, metabolic or toxic cause are negative.\nDifferential diagnosis\nDifferential diagnoses include iatrogenic (including cardiovascular, urologic and psychotropic drugs) or curable (dehydration, venous insufficiency, anemia) causes of orthostatic hypotension, dopamine beta-hydroxylase deficiency (see this term), which is ruled out by the presence of plasma noradrenaline in patients affected by orthostatic hypotension that is considered idiopathic, primary or secondary peripheral polyneuropathy (including diabetes, amyloidosis, renal dysfunction, Guillain-Barré syndrome (see these terms), those due to deficiency or paraneoplasic syndrome) or neurodegenerative disease dysautonomias (multiple system atrophy, Parkinson's disease; see these terms), which are ruled out by normal neurological and paraclinical examinations in patients affected by PAF. The progression of PAF is slow, which distinguishes it from acute or sub-acute pandysautonomias.\nManagement and treatment\nManagement includes non medicinal measures (tight support stockings, abdominal binders, frequent meals, standing up slowly, increased liquid and salt intake, and avoiding prolonged orthostatism, alcohol, and warm environments). Standard medical treatment is with midodrine (an alpha-adrenergic agonist) and fludrocortisone (a hypokalemic mineralocorticoid). The efficacy of indirect sympathomimetics (heptaminol) and ergot derivatives (dihydroergotamine) have not been proven. Other drugs are subject to ongoing trials (pyridostigmine, droxidopa) or are designed for particular situations such as anemia (erythropoietin) or postprandial hypotension (octreotide). Decubitus arterial hypertension can be prevented by following simple rules (avoiding taking a vasoconstrictor before sleeping, resting in a semi-sitting position over night, taking an antihypertensive drug in extreme cases).\nPrognosis\nProgression of PAF lasts over 20 years. The appearance of neurological signs during the course of autonomic deficiency progression allows orthostatic hypotension to be a posteriori linked to multiple system atrophy or Parkinson's disease.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Luc ELGHOZI  - Pr Jean-Michel SENARD"}
{"Disease Name": "Pure hair and nail ectodermal dysplasia", "Disease Definition": "Pure hair and nail ectodermal dysplasia is characterised by the association of onychodystrophy and severe hypotrichosis, which is mainly limited to the scalp but may also affect the eyelashes and eyebrows. Less than 20 cases have been reported so far. The mode of transmission is autosomal dominant.", "ORPHA ID": 69084, "Summary": ""}
{"Disease Name": "Pure mitochondrial myopathy", "Disease Definition": "Pure mitochondrial myopathy is a rare mitochondrial disease characterized by exclusive skeletal muscle involvement, without clinical evidence of other organ involvement, manifesting with progressive limb weakness, proximal limb muscle atrophy, and eye muscle anomalies (e.g. ocular motility restriction, ptosis). Patients may present with lactic acidosis, diffuse myalgia and overall fatigability (particularly during/after physical activities), dysphagia, and diminished deep tendon reflexes.", "ORPHA ID": 254854, "Summary": ""}
{"Disease Name": "Purine nucleoside phosphorylase deficiency", "Disease Definition": "A rare immune disease characterized by progressive immunodeficiency leading to recurrent and opportunistic infections, autoimmunity and malignancy as well as neurologic manifestations.", "ORPHA ID": 760, "Summary": "Epidemiology\nTo date, more than 70 patients have been reported with Purine nucleoside phosphorylase (PNP) deficiency in the world literature. PNP deficiency accounts for less than 4% of patients with severe combined immunodeficiency (SCID).\nClinical description\nPNP deficiency typically manifests in the 1st years of life, with recurrent, opportunistic infections caused by bacterial, viral (such as varicella zoster virus), and fungal (such as Pneumocystis carinii) pathogens. The susceptibility to infections is variable ranging from classical SCID in infancy to infrequent infections during childhood and even the 2nd decade of life. Failure to thrive has also been reported. Up to 2/3 of patients have neurologic involvement including motor system dysfunction, hyper/hypotonia, spastic paresis, ataxia, hyperactivity, and behavioral problems. Cerebrovascular accidents and sensorineural deafness are less commonly observed. The neurologic involvement often precedes immune abnormalities. Autoimmune manifestations are reported in 1/3 of cases and include autoimmune hemolytic anemia, immune thrombocytopenic purpura and systemic lupus erythematosus.\nEtiology\nPNP deficiency is caused by loss-of-function mutations in the PNP gene (14q11.2) which encodes a key enzyme (PNP) in the purine salvage pathway. PNP is vital for removal of metabolites of DNA breakdown and promotes recycling of purine bases. Lack of PNP allows intracellular accumulation of such metabolites which are particularly toxic to immature lymphoid cells, leading to lymphopenia and impaired cell-mediated immunity. Intracellular accumulation of purine bases has also been suggested to cause neuronal cell apoptosis.\nDiagnostic methods\nDiagnosis is based on the clinical examination and on laboratory findings showing leukopenia, severe lymphopenia with low CD3, CD4, and CD8 counts and variable B cell function and immunoglobulin levels. Neutropenia has also been reported. Hallmark diagnostic markers of PNP deficiency include hypouricemia, complete or near complete absence of PNP activity in red blood cell lysate and increased urine or blood levels of inosine, guanosine and their deoxy forms. Diagnosis is confirmed by genetic screening of PNP.\nDifferential diagnosis\nDifferential diagnosis includes aplastic anemias, SCID, severe combined immunodeficiency due to adenosine deaminase deficiency, ataxia-telangiectasia, and viral meningoencephalitis.\nAntenatal diagnosis\nMeasurement of T cell receptor excision circles during newborn screening for SCID can detect some patients suffering from PNP deficiency, although removal of metabolites by maternal PNP may delay the deleterious effects on PNP-deficient lymphocytes. Few newborn screening programs also measure purine metabolites in dried blood spots.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be proposed to affected families informing them of a 25% risk of transmitting the disease where both parents are unaffected carriers.\nManagement and treatment\nSpecific enzyme replacement is not available for PNP deficiency, although frequent red blood cells transfusions rich in PNP have been shown to provide temporary benefit. Hematopoietic stem cell transplantation (HSCT) is the only treatment option for the severe immune deficiency. Transplanted cells deliver the missing enzyme, thereby improving purine homeostasis. Supportive treatment, including intravenous immunoglobulin therapy, prophylaxis for Pneumocystis carinii, and physical, occupational, and speech therapy, reduces the risk of infection and may encourage optimal neurologic development for patients.\nPrognosis\nIf left untreated, prognosis is poor and patients usually die in the first decade of life, often succumbing to infections. Few patients have reached the 2nd and even 3rd decade of life. After HSCT from family or unrelated donors, patients may achieve successful immune reconstitution and are free from infections. Nevertheless, even with HSCT, improvement of neurological deficits is not definite.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Eyal GRUNEBAUM"}
{"Disease Name": "Pustular pyoderma gangrenosum", "Disease Definition": "A rare subtype of pyoderma gangrenosum characterized by multiple painful, sterile pustules with a surrounding erythematous halo, predominantly occurring on the trunk and extensor surfaces of the limbs, and potentially persisting for months. Histopathology shows a dermal neutrophilic infiltrate and subcorneal neutrophilic micropustules. The condition is commonly associated with inflammatory bowel disease.", "ORPHA ID": 538866, "Summary": ""}
{"Disease Name": "Pustulosis palmaris et plantaris", "Disease Definition": "A rare skin disease characterized by chronic eruption of sterile pustules on an erythematous and desquamative background. The lesions are usually painful and affect the palms and soles, sometimes also the lateral aspects of hands and feet. Nail lesions (such as nail pitting, onycholysis, subungual pustules, and nail dystrophy) are also observed. The condition takes a chronic and relapsing course. Typical associations are psoriatic arthritis, thyroid gland dysfunction, and smoking.", "ORPHA ID": 163927, "Summary": ""}
{"Disease Name": "Pycnodysostosis", "Disease Definition": "Pycnodysostosis is a genetic lysosomal disease characterized by osteosclerosis of the skeleton, short stature and brittle bones.", "ORPHA ID": 763, "Summary": "Epidemiology\nIt is very rare, the exact prevalence is unknown but it is less than 1/100,000.\nClinical description\nThe disease is discovered at variable ages, ranging from 9 months to 50 years. The condition is most often diagnosed in childhood, but sometimes the condition is not detected until adulthood, usually as a result of a fracture or a routine examination. The most frequent clinical or radiological manifestations of the disease are osteosclerosis, short stature or dwarfism, acroosteolysis of the distal phalanges, fragile bones associated with spontaneous fractures and dysplasia of the clavicles. Patients present with characteristic cranial malformations: a voluminous skull with wormian bones present and persistence of the anterior fontanelle, and a small mandible. Dental abnormalities such as decayed, poorly located or abnormally shaped (pointed or conical) teeth and delayed tooth eruption may be observed. Nails are sometimes irregular and cracked. Very rarely, the disease is associated with anemia, hepatosplenomegaly, hematologic alterations, respiratory distress and sleep apnea. The short stature is variable but moderate (1.35m to 1.50m).\nEtiology\nPycnodysostosis is due to mutations in the gene encoding cathepsin K (localized to 1q21), a lysosomal enzyme secreted by osteoclasts, which allows the division of proteins of the bone matrix (collagen type I, osteonectin or osteopontin).\nDiagnostic methods\nDiagnosis is clinical and should be confirmed by radiographic examination of the entire skeleton and skull.\nDifferential diagnosis\nDifferential diagnoses include osteoporosis, osteopetrosis, cleidocranial dysplasia and idiopathic acroosteolysis (see these terms).\nGenetic counseling\nInheritance is autosomal recessive.\nManagement and treatment\nManagement is symptomatic and multidisciplinary. It includes orthopedic monitoring, treatment of fractures, of which consolidation is sometimes slow, and static vertebral surveillance to detect frequent spondylolisthesis.\nPrognosis\nThe prognosis is favorable; the disease is not progressive.\n\n                            Last update: \n                            December 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "PYCR2-related microcephaly-progressive leukoencephalopathy", "Disease Definition": "PYCR2-related microcephaly-progressive leukoencephalopathy is a rare, genetic, syndromic intellectual disability disorder characterized by progressive postnatal microcephaly, cerebral hypomyelination and severe psychomotor developmental delayed with absent speech, as well as axial hypotonia, appendicular hypertonia with hyperextensibility of the wrists and ankles, hyperreflexia, severe muscle wasting and failure to thrive. Associated craniofacial dysmorphism includes triangular facies with bitemporal narrowing, down- or upslanting palpebral fissures, malar hypoplasia, large malformed ears with overfolded helices, upturned bulbous nose, long smooth philtrum and thin vermilion borders.", "ORPHA ID": 481152, "Summary": ""}
{"Disease Name": "Pyknoachondrogenesis", "Disease Definition": "A lethal skeletal osteochondrodysplasia characterized by severe generalized osteosclerosis.", "ORPHA ID": 3003, "Summary": "Epidemiology\nThe disease is very rare and only five cases (four males and one female) have been reported in the literature so far.\nClinical description\nPyknoachondrogenesis may be detected prenatally due to the extreme shortening of the limbs and hydrops fetalis, or is recognized at birth. The main clinical manifestations include a large head, palpebral edema, a flat nose, low-set ears, a short neck, a short and wide trunk, a prominent abdomen, and severe micromelic dwarfism.\nEtiology\nEtiology remains unknown. Familial occurrence of affected sibs of both sexes points to an autosomal recessive pattern of inheritance but parental consanguinity has not been reported.\nDiagnostic methods\nDiagnosis is based on clinical findings and typical radiographic features. X-rays show marked sclerosis of the facial bones and extremities, and poor ossification elsewhere.\nDifferential diagnosis\nAchondrogenesis (see this term) is the main differential diagnosis.\nAntenatal diagnosis\nPrenatal diagnosis of pyknoachondrogenesis may be made by ultrasound.\nPrognosis\nPyknoachondrogenesis has a lethal outcome, either prenatally or during the early neonatal period.\n\n                            Last update: \n                            November 2008"}
{"Disease Name": "Pyle disease", "Disease Definition": "A rare bone dysplasia characterized by long bones with wide and expanded metaphyses, thin cortical bone and bone fragility. The metaphyseal widening and undermodeling extends well into the diaphysis and causes in the distal femur the typical ''Erlenmeyer flask'' or ''paddle'' appearance. Bone undermodeling is also seen in the tubular bones of the hands where there is lack of diaphyseal constriction. Common clinical features include genua valga, big clavicles and dental anomalies. Mild hyperostosis of the skull and mild platyspondyly can also be observed on radiographs.", "ORPHA ID": 3005, "Summary": "Epidemiology\nTo date, less than 30 cases have been reported in the literature.\nClinical description\nThe disorder is usually not apparent at birth. Genua valga in childhood is a frequently presenting symptom. Dental anomalies are common and may include malocclusion, caries, delayed eruption or prolonged retention of teeth. Prominent clavicles are a characteristic feature that can help in making the diagnosis. Joint pain, muscle weakness and mild scoliosis are occasionally seen. Height is usually in the higher range of normal. Mild sclerosis of the skull base may be present but this does not result in cranial nerve palsy. There is an increased bone fragility but fracturing is usually not a significant problem. The diagnosis can be made incidentally by radiography performed for a fracture.\nEtiology\nPyle disease is an autosomal recessive disorder caused by biallelic loss-of-function mutations in the SFRP4 gene, located on chromosome locus 7p14.1. SFRP4 codes for secreted frizzled-related protein 4, a soluble Wnt inhibitor that plays a role in bone remodeling by differential inhibition of the canonical and non-canonical Wnt signaling in cortical and trabecular bone.\nDiagnostic methods\nThe diagnosis is suspected based on clinical presentation and radiographic evaluation and can be confirmed by genetic analysis of the SFRP4 gene.\nDifferential diagnosis\nPyle disease should be differentiated from other skeletal dysplasias with osteosclerosis and/or bone undermodeling. The ''Erlenmeyer flask'' deformity (usually to a lesser degree) can also be observed in metaphyseal dysplasia, Braun-Tinschert type; craniometaphyseal dysplasia; frontometaphyseal dysplasia; Gaucher disease; and some forms of dysosteosclerosis (CSF1R-related) or osteopetrosis. Prominent clavicles, dental anomalies and bone undermodeling are also features of metaphyseal dysplasia-maxillary hypoplasia-brachydactyly syndrome (RUNX2-related).\nAntenatal diagnosis\nAntenatal diagnosis is possible in case the biallelic pathogenic variants in SFRP4 have been identified in an affected relative.\nGenetic counseling\nInheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nAffected individuals may be asymptomatic. Genu valgum and/or fractures may require orthopedic intervention. Dental and orthodontic care may be necessary when dental anomalies are present. There is no specific or curative treatment available to date.\nPrognosis\nLife expectancy is normal.\n\n                            Last update: \n                            February 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Geert MORTIER"}
{"Disease Name": "Pyoderma gangrenosum", "Disease Definition": "A rare inflammatory neutrophilic dermatosis characterized by painful cutaneous ulcerations with a violaceous and undermined border affecting the lower extremities; however, any hair-bearing area can be affected.", "ORPHA ID": 48104, "Summary": "Epidemiology\nThe worldwide incidence of pyoderma gangrenosum (PG) is estimated to be between 3-10 cases per million people with an increased incidence in women. The exact prevalence of PG is unknown but has been estimated to be approximately 1 in 17,000 adults. It tends to affect middle-aged individuals (40-60 years).\nClinical description\nClinically, onset occurs with pustules, nodules, or ulcers on the lower extremity with a violaceous, undermined border. Ulcers are primarily sterile but may be complicated by secondary microbial colonization. They can rapidly progress and turn into very painful ulcers of variable depth and size. Other presentations are rarer and include peristomal, pustular, bullous, and vegetative/superficial granulomatous PG as well as extracutaneous manifestations (most commonly pulmonary). The clinical course is unpredictable; it can be mild or severe, chronic, or relapsing with significant morbidity; some patients might heal spontaneously.\nEtiology\nThe etiology has not yet been clearly determined.\nDiagnostic methods\nDiagnosis of PG is based on clinical presentation, exclusion of other causes of ulceration, and can be supported by histopathology showing neutrophilic infiltrate (though this is not specific and may be evident only in acute cases). Tissue culture is often necessary to rule out superinfection. Diagnosis may be assisted with use of existing clinical frameworks, including PARACELSUS score, Delphi criteria, and Mayo Clinic criteria.\nDifferential diagnosis\nPG can occur spontaneously or in association with other autoimmune conditions, including most commonly inflammatory bowel disease (IBD), rheumatologic conditions, hematologic disorders, or in association with autoinflammatory syndromes including PAPA (pyogenic arthritis, PG, and acne), PASH (PG, acne, and suppurative hidradenitis), PAPASH (pyogenic arthritis, acne, PG, and suppurative hidradenitis), PAC (PG, acne, and ulcerative colitis), PsAPASH (psoriatic arthritis, PG, acne and suppurative hidradenitis), PAMI (PSTPIP1-associated myeloid related proteinemia syndrome), and SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis). The most common differential diagnoses in clinical practice are chronic venous ulcers, calciphylaxis, and factitial ulcers. Other entities include vasculitic/vasculopathic ulcers, metastatic Crohn's disease, hidradenitis suppurativa, other neutrophilic dermatoses (e.g., Sweet's Syndrome), infectious (e.g. Leishmaniasis, Buruli ulcer, Lues maligna), Marjolin and neoplastic ulcers.\nManagement and treatment\nTreatment of PG remains challenging and there is currently no FDA-approved medication for its treatment. Prednisolone is approved in Europe by the EMA and adalimumab is approved in Japan by the Pharmaceutical and Medical Devices Agency. In addition to pharmacological interventions, wound and pain management are also necessary. Globally, the cornerstone of treatment remains systemic corticosteroids and cyclosporine, with a step-up to biologics as second line therapies in addition to wound care and pain management.\nPrognosis\nDespite recent advances in therapy, the prognosis of PG remains unpredictable. Recurrence rates have been reported in up to 30% of patients. Patients carry an increased mortality rate, three times higher than that of the general population, which may be due to associated conditions rather than PG itself though this remains to be elucidated.\n\n                            Last update: \n                            June 2024\n\n\n                            - Expert reviewer(s): \n                             Sarah BECKER  - Dr Alex ORTEGA-LOAYZA"}
{"Disease Name": "Pyomyositis", "Disease Definition": "Pyomyositis (PM) is a rare primary bacterial infection of the skeletal muscle, usually resulting from hematogenous spread or due to muscle injury, and characterized by pain and tenderness in the affected muscle, fever and abscess formation.", "ORPHA ID": 764, "Summary": "Epidemiology\nPrevalence is unknown. PM is commonly found in the tropics and is endemic to Eastern Uganda where 400-900 cases are reported annually. Cases in temperate regions such as the U.S. are now increasing in frequency.\nClinical description\nPM occurs in all ages with a male predominance. In tropical regions, it usually presents in otherwise healthy, athletic individuals and affects mainly children (aged 2-5) and young adults, while in temperate regions most patients are immunocompromised (due to malnutrition, chemotherapy, diabetes mellitus, HIV infection) or suffer from chronic renal failure or rheumatoid arthritis. Muscles most commonly involved include the serratus anterior, pectoralis major, biceps, the abdominal and spinal muscles, glutei, iliopsoas, quadriceps and gastrocnemius. There are 3 phases seen in disease development. The invasive stage lasts 1-10 days with manifestations of localized muscle ache/pain and swelling (with a lack of warmth or erythema), along with a low grade fever. Symptoms of appendicitis can be reported in those with iliopsoas pyomyositis. The purulent or suppurative stage follows 2-3 weeks after symptom onset with a progressive febrile illness and a soft tissue mass that is tender and painful when touched. If left untreated, the third stage involves sepsis that can lead to bacteremia, septicemia, metastatic abscess, acute renal failure, septic shock and death.\nEtiology\nThe exact etiology is unknown but muscle trauma or vigorous exercise may facilitate hematogenous access of bacteria to the skeletal muscles (usually resistant to these types of infections). Fibronectin binding receptors on muscle cells have been proposed as a possible entry point for bacteria. In most cases the causative organism is Staphylococcus aureus (SA) (up to 90% of tropical cases, 70% of temperate cases) but infections with various other species (ex. Streptococci) have been reported. Methicillin-resistant SA (MRSA) is increasing in frequency as the infectious agent seen in non-tropical PM.\nDiagnostic methods\nPM is often hard to diagnose. Aspiration of pus from the muscle is usually possible at the purulent stage and can determine a diagnosis. If an abscess is absent, a culture and a muscle biopsy with special staining can equally identify the bacteria responsible and eliminate other possibilities. Diagnostic imaging is useful for diagnosing and treating PM.\nDifferential diagnosis\nDifferential diagnoses include parasitic and viral myositis, leptospirosis, polymyositis, trichinellosis (see these terms), osteomyelitis, cellulitis, necrotizing fasciitis, clostridial myonecrosis, septic arthritis, deep vein thrombosis and muscle contusions, hematomas, ruptures or strains.\nManagement and treatment\nEarly diagnosis and prompt treatment with antibiotics is essential. Due to the increased occurrence of MRSA, vancomycin, teicoplanin, tigecycline, daptomycin, linezolid, or daptomycin are the antibiotics of choice. Treatment with tetracycline or trimethoprim-sulfamethoxisole may be sufficient in some cases. Antibiotics are taken for 3-4 weeks, or longer, in cases of multiple muscle involvement, poorly drained infections, when initiation of treatment is delayed or when due to mycobacteria or Bartonella. If an abscess forms, treatment involves incision, debridement and muscle drainage or in some cases guided aspiration followed by antibiotic therapy. Muscle drainage is required in 40-70% of cases and repeated drainage in 10% of cases. Treatment should continue until a patient is fever-free for 7-10 days, wound is clean and leukocyte count is back to normal.\nPrognosis\nThe prognosis is good when diagnosed and treated properly and there is very little residual deformity of the muscles, if any. When PM is left untreated, the mortality rate is 0.5 - 2%.\n\n                            Last update: \n                            September 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Grigorios MITSIONIS  - Dr Sotiris PLAKOUTSIS"}
{"Disease Name": "Pyramidal molars-abnormal upper lip syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by a variable combination of dental, cutaneous, ocular, and bone abnormalities, including pyramidal and fused molar roots, taurodontism, an abnormal upper lip without a cupid's bow and thickened and wide philtrum, juvenile glaucoma, syndactyly, and clinodactyly. There have been no further descriptions in the literature since 1973.", "ORPHA ID": 2561, "Summary": ""}
{"Disease Name": "Pyridoxal phosphate-responsive seizures", "Disease Definition": "A very rare neonatal epileptic encephalopathy disorder characterized clinically by onset of severe seizures within hours of birth that are not responsive to anticonvulsants, but are responsive to treatment with pyridoxal phosphate.", "ORPHA ID": 79096, "Summary": ""}
{"Disease Name": "Pyridoxine-dependent epilepsy", "Disease Definition": "A rare neurometabolic disease characterized by recurrent intractable seizures in the prenatal, neonatal and postnatal period that are resistant to anti-epileptic drugs (AEDs) but that are responsive to pharmacological dosages of pyridoxine (vitamin B6).", "ORPHA ID": 3006, "Summary": "Epidemiology\nThe prevalence of Pyridoxine-dependent epilepsy (PDE) has been estimated to range from 1/20,000 to 1/783,000 live births. More than 200 cases have been reported in the literature to date.\nClinical description\nOnset is classically fetal/neonatal but a later onset (>2 months) has also been reported. Patients present with epileptic encephalopathy manifesting with intractable seizures along with irritability, crying, poor feeding, gastrointestinal symptoms (emesis, abdominal distention), sleeplessness, facial grimacing and abnormal eye movements. Although prolonged seizures and recurrent episodes of status epilepticus are most common, recurrent self-limiting partial, generalized or atonic seizures, myoclonic events and infantile spasms can also occur. Intellectual disability/developmental delay ranges from mild to severe (particularly affecting the expressive language domain). With treatment, most patients achieve complete seizure control, but 75-80% have some degree of intellectual disability. Atypical features include seizures that initially respond to AEDs and later become intractable, seizures initially unresponsive to pyridoxine but that respond several months later and prolonged seizure-free intervals after the discontinuation of pyridoxine treatment.\nEtiology\nPDE is caused by mutations in the ALDH7A1 gene (5q31) that encodes alpha-aminoadipic semialdehyde dehydrogenase (antiquitin), a multifunctional enzyme which, among other functions, is involved in the catabolism of cerebral lysine.\nDiagnostic methods\nDiagnosis is suspected in patients with early onset epilepsy with a poor response to AEDs. Laboratory testing reveals elevated urinary and plasma concentrations of alpha-aminoadipic semialdehyde and sometimes elevated pipecolic acid in the plasma and cerebrospinal fluid. Electroencephalography findings are non-specific but thinning of the corpus callosum, particularly of the isthmus, is always seen on brain MRI. Molecular genetic testing, identifying homozygous or compound heterozygous ALDH7A1 mutations, confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other causes of neonatal epileptic encephalopathy such as inborn errors of metabolism (e.g. glucose transporter type I deficiency, 4-hydroxybutyric aciduria and molybdenum cofactor deficiency), single gene defects and fetal or neonatal brain injury. Pyridoxal phosphate-responsive seizures, hyperprolinemia type 2 and infantile hypophosphatasia (see these terms) should also be excluded.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease-causing mutation in order to start prophylactic prenatal/postnatal treatment.\nGenetic counseling\nPDE is inherited in an autosomal recessive manner. Genetic counseling is possible in families with a known mutation.\nManagement and treatment\nStandard treatment involves lifelong oral pyridoxine supplementation (15-30mg/kg/day, divided into 3 doses in infants; up to 200mg/day in neonates and 500mg/day in adults) to control seizures, as well as regular clinical follow-up. Initial interruption of status epilepticus requires up to five 100mg doses of pyridoxine administered intravenously while closely monitoring patients for signs of cardio-respiratory arrest. Dietary lysine restriction is also recommended as an adjunct to pyridoxine therapy. In at-risk pregnancies, mothers may take supplemental pyridoxine (100mg/day) during the last half of gestation and newborns should received prophylactic pyridoxine until diagnostic tests are finalized.\nPrognosis\nPrognosis is variable and depends, in part, on genotype, associated abnormalities in brain development, and response to pyridoxine treatment. A delay in diagnosis and initiation of treatment generally confers a poorer prognosis associated with more significant neurodevelopmental disabilities.\n\n                            Last update: \n                            November 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Sidney GOSPE"}
{"Disease Name": "Pyruvate carboxylase deficiency, benign type", "Disease Definition": "Benign pyruvate carboxylase (PC) deficiency (Type C) is a rare, very mild form of PC deficiency characterized by episodic metabolic acidosis and normal or mildly delayed neurological development.", "ORPHA ID": 353320, "Summary": "Epidemiology\nBenign PC deficiency is a very rare form of PC deficiency and has been described in fewer than 10 patients to date. No ethnic predilection has been reported.\nClinical description\nOnset typically occurs during the first year of life with episodic metabolic acidosis associated with lactic acidemia and occasionally with ketoacidosis during metabolic stress. Neurological development is normal or mildly impaired. Other signs include dystonia, episodic ataxia, dysarthria, transitory hemiparesis and seizures.\nEtiology\nType C PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5).\nDiagnostic methods\nBlood lactic acid levels are usually between 2 and 5 mmol/l. The abnormal biochemical parameters found in severe forms of PC deficiency are absent in patients with Type C, although lysine, proline and alanine may be elevated, while citrulline is normal. PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.\nGenetic counseling\nPyruvate carboxylase deficiency is inherited in an autosomal recessive manner.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Darryl DE VIVO  - Dr Dong WANG"}
{"Disease Name": "Pyruvate carboxylase deficiency, infantile type", "Disease Definition": "Infantile pyruvate carboxylase (PC) deficiency (Type A) is a rare, severe form of PC deficiency characterized by infantile-onset, mild to moderate lactic acidemia, and a generally severe course.", "ORPHA ID": 353308, "Summary": "Epidemiology\nThe specific prevalence of type A pyruvate carboxylase deficiency is not known but it has been reported most often in Native Americans from North American Algonquian-speaking groups including the Mi'kmaq, Cree, and Ojibwa tribes. In these groups, the carrier frequency may be as high as 1/10.\nClinical description\nPatients with Type A PC deficiency usually first present with symptoms at the age of two to five months, often after normal early development. Clinical manifestations include mild to moderate metabolic acidosis with acute vomiting and tachypnea, failure to thrive, apathy, delayed intellectual and motor development, hypotonia, pyramidal dysfunction, ataxia, nystagmus and seizures. Renal tubular acidosis has also been reported.\nEtiology\nPC deficiency is caused by mutations in the PC gene (11q13.4-q13.5).\nDiagnostic methods\nBiochemical testing shows hypoglycemia and ketosis, increased alanine and proline levels, but normal citrulline and lysine levels, along with a normal lactate-to-pyruvate ratio despite acidemia, and normal hydroxybutyrate/acetoacetate (H/A) ratio in plasma. Blood lactic acid levels are usually between 2 and 10 mmol/l. PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.\nGenetic counseling\nPC deficiency is inherited in an autosomal recessive manner.\nPrognosis\nMost affected patients die in infancy or in early childhood. Surviving children require special care and schooling.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Darryl DE VIVO  - Dr Dong WANG"}
{"Disease Name": "Pyruvate carboxylase deficiency, severe neonatal type", "Disease Definition": "Severe neonatal pyruvate carboxylase (PC) deficiency (Type B) is a rare, extremely severe form of PC deficiency characterized by severe, early-onset metabolic acidosis, and a generally fatal outcome in early infancy.", "ORPHA ID": 353314, "Summary": "Epidemiology\nThe exact prevalence of Type B pyruvate carboxylase deficiency is not known. The disorder has been reported to be more common in populations of Arab descent (Algerian, Egyptian, and Saudi Arabian). Higher incidence is also reported in France, Germany and the United Kingdom.\nClinical description\nPatients develop clinical manifestations during the first 72 hours of life with severe truncal hypotonia and tachypnea. Subsequent clinical signs include anorexia, failure to thrive, hepatomegaly, myoclonic or generalized tonic-clonic seizures, stupor, pyramidal dysfunction, abnormal movements (high-amplitude tremor and dyskinesia), abnormal limb and ocular movements and severe impairment of mental and motor development. Renal tubular acidosis has been reported.\nEtiology\nPC deficiency is caused by mutations in the PC gene (11q13.4-q13.5).\nDiagnostic methods\nThe biochemical hallmarks of Type B pyruvate carboxylase deficiency include elevated lactate/pyruvate (L/P) ratio, ketoacidosis with low hydroxybutyrate/acetoacetate (H/A) ratio in plasma, hypoglycemia, increased citrulline, proline, lysine and alanine levels, low glutamine, hyperammonemia and hypernatremia. Blood lactic acid levels are usually above 10 mmol/l. PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.\nGenetic counseling\nPyruvate carboxylase deficiency is inherited in an autosomal recessive manner.\nPrognosis\nThe prognosis is very poor with almost all affected infants dying within the first three months of life.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Darryl DE VIVO  - Dr Dong WANG"}
{"Disease Name": "Pyruvate carboxylase deficiency", "Disease Definition": "Pyruvate carboxylase (PC) deficiency is a rare neurometabolic disorder characterized by metabolic acidosis, failure to thrive, developmental delay, and recurrent seizures at an early age in severely affected patients.", "ORPHA ID": 3008, "Summary": "Epidemiology\nThe overall prevalence of PC deficiency is not known and annual incidence has been reported to be 1/250,000 births. The disorder affects males and females equally.\nClinical description\nThree clinical presentations of PC deficiency, probably constituting a continuum, have been described: infantile PC deficiency (type A); severe neonatal PC deficiency (type B); and intermittent/benign PC deficiency (type C). The only common feature is metabolic acidosis. Type A is characterized by infantile onset, generally with a severe course. Type B has a very severe course with a fatal outcome in early infancy, and Type C involves only episodic metabolic acidosis.\nEtiology\nPC deficiency is caused by mutations in the PC gene (11q13.4-q13.5), involved in the conversion of pyruvate to oxaloacetate, an intermediate in the citric acid cycle and gluconeogenesis. Pyruvate carboxylase also participates in a wide range of other metabolic processes. Most cases are familial but some de novo mutations have been reported. Genotype-phenotype correlations have not been clearly established but missense mutations appear to be associated with infantile PC deficiency (Type A), while truncating mutations are more common in patients with the severe neonatal form (Type B).\nDiagnostic methods\nPC deficiency may be suspected in patients with the non-specific clinical signs of the condition. Diagnosis is based on detection of characteristic laboratory test abnormalities in amino acid, organic acid, glucose, and ammonia serum concentrations. A PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.\nDifferential diagnosis\nSeveral inborn errors of metabolism have certain features similar to those of PC deficiency. Similar disorders to consider in the differential diagnosis include biotinidase deficiency, holocarboxylase synthase deficiency, pyruvate dehydrogenase deficiency, as well as respiratory chain disorders, tricarboxylic acid cycle disorder, and gluconeogenic defects.\nAntenatal diagnosis\nPrenatal testing for pregnancies at increased risk is possible and requires identification of both disease-causing alleles in an affected family member.\nGenetic counseling\nPC deficiency follows an autosomal recessive pattern of inheritance. Genetic counseling should be provided to affected families, particularly regarding the risk of recurrence in subsequent pregnancies.\nManagement and treatment\nThe aim of treatment is to provide alternative energy sources and to correct acute metabolic acidosis. Other management and treatment options depend on the type of PC deficiency. Current symptomatic and supportive treatments are generally ineffective.\nPrognosis\nType A patients usually die in infancy or early childhood. Type B most commonly has a fatal outcome within the first three months of life. Type C is mostly a benign form of the disorder with little or no effect on life-expectancy.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Darryl DE VIVO  - Dr Dong WANG"}
{"Disease Name": "Pyruvate dehydrogenase deficiency", "Disease Definition": "Pyruvate dehydrogenase deficiency (PDHD) is a rare neurometabolic disorder characterized by a wide range of clinical signs with metabolic and neurological components of varying severity. Manifestations range from often fatal, severe, neonatal lactic acidosis to later-onset neurological disorders. Six subtypes related to the affected subunit of the PDH complex have been recognized with significant clinical overlap: PDHD due to E1-alpha, E1-beta, E2 and E3 deficiency, PDHD due to E3-binding protein deficiency, and PDH phosphatase deficiency (see these terms).", "ORPHA ID": 765, "Summary": "Epidemiology\nExact prevalence is unknown but hundreds of cases have been reported.\nClinical description\nPDHD may affect fetal development, with poor fetal weight gain and low birth weight being noted. Characteristic facial dysmorphism has only been described in some patients (narrow head, frontal bossing, wide nasal bridge, long philtrum and flared nostrils). Structural brain lesions are commonly observed, especially in females. Other patients develop symptoms soon after birth. Some have a primarily metabolic-type picture (potentially fatal lactic acidosis, occasionally with hyperammonemia, poor feeding, lethargy, tachypnea) and few neurological signs, while others have mainly neurological signs (developmental delay, growth retardation, poor acquisition or loss of motor milestones, hypotonia, seizures, ataxia and dystonia). Symptoms may occur in periods of stress or illness in the less severe, later-onset cases. Many patients have the characteristic clinical presentation, disease course and neuropathological changes of Leigh syndrome (see this term).\nEtiology\nPDHD is caused by a deficiency of one of the components of the PDH complex. The most common cause are mutations in the PDHA1 gene (Xp22.1), which encodes the E1-alpha subunit. Mutations in the genes for the other subunits have been described, but are far less frequent: E1-beta and E2 subunits (PDHB, DLAT); E3 binding protein (PDHX gene); and E3 and PDH phosphatase (DLD andPDP1).\nDiagnostic methods\nPDHD should be considered in cases of early-onset neurological disease and unexplained lactic acidosis, particularly if there are structural cerebral abnormalities. In many cases, lactate concentration in cerebrospinal fluid (CSF) is disproportionately increased compared to blood lactate. Definitive diagnosis is made by demonstrating abnormal enzyme function and immunochemical demonstration of a specific subunit deficiency.\nDifferential diagnosis\nDifferential diagnosis includes other causes of primary lactic acidosis (pyruvate carboxylase deficiency, defects of gluconeogenesis and a wide range of mitochondrial diseases). In patients presenting as Leigh syndrome, the differential diagnosis includes various forms of Complex I deficiency (see this term), cytochrome oxidase deficiency due to mutation in the SURF1 gene and a number of mitochondrial DNA mutations.\nAntenatal diagnosis\nDue to the severity of PDHD, prenatal diagnosis is requested in affected families (chorionic villi or amniocyte testing).\nGenetic counseling\nMost cases are due to mutations in the PDHA1 gene and are thus inherited as an X-linked dominant trait. As patients almost always have severe symptoms and greatly reduced life expectancy, most new cases are sporadic. Inheritance of all other forms of PDHD is autosomal recessive.\nManagement and treatment\nTreatment is generally aimed at stimulating the PDH complex or providing an alternative energy source for the brain. Cofactor supplementation with thiamine, carnitine, and lipoic acid has been recommended. A very small number of patients with mutations in the PDHA1 gene are thiamine-responsive. A ketogenic diet may be indicated especially for those presenting with a dystonic disorder. Dichloroacetate has been used but significant side effects, such as peripheral neuropathy, may limit effectiveness. No treatment has an effect on preventing prenatal development of structural central nervous system anomalies.\nPrognosis\nPrognosis is variable but is generally poor (in terms of impact on development and life expectancy).\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Garry BROWN"}
{"Disease Name": "Pyruvate dehydrogenase E1-alpha deficiency", "Disease Definition": "A disorder that is the most frequent form of pyruvate dehydrogenase deficiency (PDHD) characterized by variable lactic acidosis, impaired psychomotor development, hypotonia and neurological dysfunction.", "ORPHA ID": 79243, "Summary": "Epidemiology\nPrevalence is unknown. Over 200 patients have been reported and while there are approximately equal numbers of males and females, male patients are generally more severely affected.\nClinical description\nPatients present with a range of classic signs and symptoms of PDHD, including lactic acidosis, poor feeding, lethargy, tachypnea, developmental delay, growth retardation, poor acquisition or loss of motor milestones, hypotonia, seizures, ataxia and dystonia. Structural brain lesions including cortical atrophy, dilated ventricles, and incomplete corpus callosum, absence of the medullary pyramids and ectopia of the olivary nuclei are commonly observed, especially in female patients heterozygous for the disease-causing mutations that result in complete deficiency of E1-alpha subunit protein in cells expressing the gene mutation.\nEtiology\nThe disease is caused by deficiency of the E1-alpha subunit of the PDH complex related to mutations in the PDHA1 gene (Xp22.1).\nGenetic counseling\nThe pattern of inheritance is X-linked.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Garry BROWN"}
{"Disease Name": "Pyruvate dehydrogenase E1-beta deficiency", "Disease Definition": "Pyruvate dehydrogenase E1-beta deficiency is an extremely rare form of pyruvate dehydrogenase deficiency (PDHD, see this term) characterized by severe lactic acidosis, developmental delay and hypotonia.", "ORPHA ID": 255138, "Summary": "Epidemiology\nPrevalence is unknown. About 8 cases have been reported to date.\nClinical description\nPatients presented with lactic acidosis and hypotonia at birth and were often from consanguineous families. There are no specific clinical features that distinguish this condition from pyruvate dehydrogenase E1-alpha deficiency.\nEtiology\nThe disorder is caused by mutations in the gene coding for the E1-beta subunit of the PDH complex (PDHB; 3p21.1-p14.2).\nGenetic counseling\nThe pattern of inheritance is autosomal recessive.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Garry BROWN"}
{"Disease Name": "Pyruvate dehydrogenase E2 deficiency", "Disease Definition": "A very rare form of pyruvate dehydrogenase deficiency (PDHD) characterized by variable lactic acidosis and neurological dysfunction, mainly appearing during childhood.", "ORPHA ID": 79244, "Summary": "Epidemiology\nPrevalence is unknown. Only 4 cases have been reported to date.\nClinical description\nPatients with E2 deficiency generally present later in childhood with movement disorders and lesions in the globus pallidus similar to those found in patients with pantothenate kinase-associated neurodegeneration (see this term). Other signs include general hypotonia and delayed psychomotor development. Lactate concentration may be normal in both blood and cerebrospinal fluid.\nEtiology\nThe condition is caused by mutations in the DLATgene (11q23.1) encoding the dihydrolipoamide acetyl transferase E2 subunit of the PDH complex. Parental consanguinity is commonly reported.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Garry BROWN"}
{"Disease Name": "Pyruvate dehydrogenase E3 deficiency", "Disease Definition": "Pyruvate dehydrogenase E3 deficiency is a very rare subtype of pyruvate dehydrogenase deficiency (PDHD, see this term) characterized by either early-onset lactic acidosis and delayed development, later-onset neurological dysfunction or liver disease.", "ORPHA ID": 2394, "Summary": "Epidemiology\nPrevalence is unknown. About 20 cases have been reported to date.\nClinical description\nThe majority of patients have presented with neonatal lactic acidosis or with lactic acidosis, delayed development and hypotonia during infancy. A few patients have presented later in childhood with ataxia and dystonia with normal cognitive development. A separate group of patients, essentially all of Ashkenazi Jewish origin and many homozygous for a common G229C missense mutation, present with episodic vomiting, abdominal pain, encephalopathy and liver cell dysfunction. In some patients, there is evidence of branched chain alpha-ketoacid dehydrogenase deficiency, with elevated concentrations of the branched chain amino acids and their metabolites. However, clinical manifestations in most cases appear to be related to the pyruvate dehydrogenase deficiency.\nEtiology\nThe disorder is caused by mutations in the DLD gene (7q31-q32).\nGenetic counseling\nThe pattern of inheritance is autosomal recessive.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Garry BROWN"}
{"Disease Name": "Pyruvate dehydrogenase E3-binding protein deficiency", "Disease Definition": "Pyruvate dehydrogenase E3-binding protein deficiency is a rare mild form of pyruvate dehydrogenase deficiency (PDHD, see this term) characterized by variable lactic acidosis and neurological dysfunction.", "ORPHA ID": 255182, "Summary": "Epidemiology\nPrevalence is unknown. About 20 cases have been reported to date. The disorder is more frequent than PDHD E2 deficiency but less frequent than E1-alpha deficiency (see these terms).\nClinical description\nPatients usually present with neonatal lactic acidosis or with delayed development and hypotonia during infancy. In contrast to other forms of pyruvate dehydrogenase deficiency, patients with E3 binding protein deficiency often survive well into childhood or adult life as there is some assembly of the pyruvate dehydrogenase complex even with complete deficiency of this protein. Thinning or agenesis of the corpus callosum is a common finding on MRI imaging of the brain.\nEtiology\nPDHD E3 binding protein deficiency is caused by a mutation in the PDHX gene (11p13) encoding the E3 binding protein subunit; also known as component X of the pyruvate dehydrogenase complex.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Garry BROWN"}
{"Disease Name": "Pyruvate dehydrogenase phosphatase deficiency", "Disease Definition": "Pyruvate dehydrogenase phosphatase deficiency is a very rare subtype of pyruvate dehydrogenase deficiency (PDHD, see this term) characterized by lactic acidemia in the neonatal period.", "ORPHA ID": 79246, "Summary": "Epidemiology\nPrevalence is unknown but this form of PDHD appears to be very rare, with only three patients reported.\nClinical description\nAll three patients presented in the newborn period with lactic acidosis and hypotonia. Two siblings from one family have had a prolonged course on a ketogenic diet, surviving into teenage years with exercise intolerance and mild developmental delay. The third patient died at age 6 months.\nEtiology\nThe disorder is caused by mutations in the PDP1 gene (8q22.1) encoding pyruvate dehyrogenase phosphatase isoform 1, an enzyme which regulates the activity of the pyruvate dehydrogenase complex.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive.\n\n                            Last update: \n                            August 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Garry BROWN"}
{"Disease Name": "Q fever", "Disease Definition": "Q fever, caused by Coxiella burnetii, is a bacterial zoonosis with a wide clinical spectrum that can be life-threatening and, in some cases, can become chronic.", "ORPHA ID": 781, "Summary": "Epidemiology\nIn recent years in Europe, there has been an increase in the number of reported cases. In the Netherlands in particular, between 2007 and 2010 there were more than 4,000 cases reported.\nClinical description\nQ fever affects all ages, but is mostly reported in those aged 30-70 years. The incubation period is 2-3 weeks. Approximately 60% of cases are asymptomatic. The most common symptoms of acute Q fever are high fever, severe headache, myalgia, chills, and cough. It may also be associated with pneumonia or hepatitis. Pneumopathy is mostly moderate but pleural effusion or acute respiratory distress may occur. Symptoms may last 10-90 days. Rarely, patients may have neurological (ex. meningitis), cardiac (pericarditis, myocarditis) or dermatological manifestations (maculopapular eruption, erythema nodosum). Children often suffer from gastrointestinal manifestations and skin rash (in up to 50% of diagnosed children). The infection may evolve to a chronic form (<5% of cases) in persons with a predisposition (ex. heart valve or vascular defect), months or years after initial infection. Chronic manifestations include endocarditis, vascular infections and osteomyelitis, or less commonly, fever with hepatitis evolving to hepatic fibrosis or cirrhosis. During pregnancy, a primary infection may cause spontaneous abortion, prematurity, low birth weight, fetus infection or recurrent miscarriages. Chronic Q fever after delivery may be associated with cardiac involvement.\nEtiology\nCoxiella burnetii, is an intracellular gram-negative bacterium now classified in the gamma group of Proteobacteria. Most infections are due to inhalation of aerosols or dust contaminated with dried birth fluids or excreta from infected animals. Less frequent routes of infection include ingesting contaminated milk, tick bite, or fomite transmission. Person-to-person and mother-to-fetus transmission has been reported.\nDiagnostic methods\nDiagnosis of acute Q fever is confirmed by serologic evidence of a fourfold increase in phase II immunoglobulin (Ig) G via an immunofluorescent assay test between paired sera taken 3-6 weeks apart. PCR testing on blood or serum may be useful in the first 2 weeks of symptom onset and before antibiotic administration. A single high serum phase II IgG titer in the convalescent stage may be considered as evidence of probable infection. Confirmation of chronic Q fever is based on an increasing phase 1 IgG titer (typically ≥1:1024) and an identifiable nidus of infection (e.g., endocarditis, vascular infection, osteomyelitis, chronic hepatitis). Liver enzyme levels are commonly increased.\nDifferential diagnosis\nDifferential diagnosis includes any disease with fever and other constitutional symptoms such as Brucellosis (see this term) and influenza.\nManagement and treatment\nProphylactic strategies are based on vaccination (in Australia) and appropriate hygiene measures. Adherence to standard precautions during care of patients prevents transmission. Symptomatic patients with acute Q fever should be treated for 2 weeks with doxycycline. A pregnancy test should be performed before commencing treatment in women of child-bearing age. Children aged younger than 8 with mild illness, pregnant women, and patients allergic to doxycycline can be treated with trimethoprim-sulfamethoxazole. Chronic Q fever is treated with a combination of doxycycline and hydroxychloroquine for a minimum of 18 months.\nPrognosis\nAcute Q fever is often a mild or self-limiting illness with a low risk for death. Untreated chronic Q fever endocarditis or vascular infection is often fatal. In treated patients with chronic Q fever endocarditis, the 10-year mortality rate is 19%.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Alicia ANDERSON"}
{"Disease Name": "Qazi-Markouizos syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder characterized by non-progressive, congenital, marked, central hypotonia, severe psychomotor delay and intellectual disability, chronic constipation, distended abdomen, abnormal dermatoglyphics, delayed and dysharmonic skeletal maturation, and preponderance of type 2 larger-sized muscle fibers. Additional features include narrow and high-arched palate, prominent nasal root, long philtrum, and open mouth with drooling, as well as variably present cryptorchidism, hypertelorism, and tapered fingers. Seizures and/or an abnormal electroencephalograph may also be assoicated. There have been no further descriptions in the literature since 1994.", "ORPHA ID": 3010, "Summary": ""}
{"Disease Name": "QRICH1-related intellectual disability-chondrodysplasia syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of developmental delay and mild chondrodysplasia with short stature and abnormal growth plate morphology. Dysmorphic facial features are variable and may include hypertelorism, upslanting palpebral fissures, broad nose with broad nasal tip, and low-set, cup-shaped ears, among others. Autism spectrum disorder and neurologic abnormalities have also been reported.", "ORPHA ID": 580940, "Summary": ""}
{"Disease Name": "QRSL1-related combined oxidative phosphorylation defect", "Disease Definition": "A rare mitochondrial disease characterized by prenatal or early infantile onset of severe cardiomyopathy, failure to thrive and global developmental delay, sensorineural hearing loss, and severe lactic acidosis. Hepatic involvement and adrenal insufficiency, as well as encephalopathy and anomalies of deep gray matter structures on brain MRI have also been reported.", "ORPHA ID": 570491, "Summary": ""}
{"Disease Name": "Quadricuspid aortic valve", "Disease Definition": "A rare congenital aortic malformation characterized by an aortic valve with four cusps instead of the usual three. The cusps can be equal-sized or vary in size. The malformation is an isolated finding in the majority of cases but may also be associated with other cardiac anomalies. The most common complication is aortic regurgitation. Aortic stenosis is infrequently observed. Patients usually become symptomatic in the fifth to sixth decade of life and may present with palpitations, chest pain, dyspnea, fatigue, pedal edema, and syncope. In severe cases, congestive heart failure can be the presenting symptom.", "ORPHA ID": 542568, "Summary": ""}
{"Disease Name": "Quebec platelet disorder", "Disease Definition": "A rare platelet granule disorder characterized by moderate to severe bleeding after trauma, surgery or obstetric interventions, frequent ecchymoses, mucocutaneous bleeding and muscle and joint bleeds.", "ORPHA ID": 220436, "Summary": ""}
{"Disease Name": "Quinquaud folliculitis decalvans", "Disease Definition": "A rare chronic inflammatory cicatricial alopecia of the scalp occurring in middle-aged adults and characterized by the development of alopecic patches with slowly centrifugal spread predominantly in the vertex and occipital area of the scalp, associated with perifollicular erythema, follicular pustules and hemorrhagic crusts.", "ORPHA ID": 346, "Summary": ""}
{"Disease Name": "Rabies", "Disease Definition": "Rabies is a viral zoonosis leading to a fatal encephalopathy if not treated.", "ORPHA ID": 770, "Summary": "Epidemiology\nEpidemiology depends on the control level of the pathogen and its animal vectors, so the rabies is much more prevalent in the developing world than in developed countries. The WHO estimates that around 50,000 persons die each year from rabies.\nClinical description\nRabies evolution follows a three steps path. After a contact (bite) with an infected animal, incubation lasts 20 to 90 days while patients remain asymptomatic. This duration varies with the quantity and the location of the inoculum. It can extend to several years in rare cases. The second phase, the prodromal period, lasts 2 to 10 days and is characterized by paresthesia or pain at the inoculation site. Other nonspecific symptoms may occur, including malaise, anorexia, headaches, fever, chills, pharyngitis, nausea, emesis, diarrhea, anxiety, agitation, insomnia and depression. The third phase is the most distinctive one, named the acute neurologic period. It is associated to clear central nervous system (CNS) involvement, its duration is 2 to 7 days and it can be of two kinds: the furious rabies or the paralytic rabies. In the first case, patients show agitation, hyperactivity, restlessness, trashing, biting, confusion or hallucinations. Hydrophobia and aerophobia are pathognomonic for rabies and occur in 50% of patients. After hours or days these signs appear by bouts - during less than 5 minutes - alternating with calm phases of lucidity. Seizures may occur. The terminal evolution of this phase is cardiorespiratory arrest or paralysis. In the second case, also named apathetic rabies, paralysis develops from the outset with fever, headache and nuchal rigidity. In both cases, the terminal evolution, if untreated, is coma and death.\nEtiology\nRabies is caused by infection of a virus of the Lyssavirus genus. Infection occurs in a large majority through the bite of a rabid dog and more generally through contact of broken skin or mucous membrane with infected saliva, CNS tissue or aerosolized secretions from infected animals. Lyssavirus are neurotropic viruses that escape immune system invading peripheral nerve ending. Incubation duration depends on the time needed to invade the CNS.\nDiagnostic methods\nDiagnosis is based on clinical examination, early signs being paresthesia or pain at the inoculum site, and firmly relies on PCR detection of viral RNA in the saliva, the cerebrospinal fluid (CSF) or in a nuchal skin biopsy, on blood or CSF serological findings.\nDifferential diagnosis\nTetanus is the main differential diagnosis which also includes other types of encephalomyelitis and neuropaludism.\nManagement and treatment\nStandardized vaccination procedures are established for pre- or post-exposure situations. In case of exposition, rapid washing, antisepsis and vaccine administration could be associated to a serotherapy protocol consisting of immunoglobulins injection at the inoculum site. Each infection has to be declared.\nPrognosis\nIf not treated, rabies is always fatal. Treatment has to be administrated during the incubation period to be efficient.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Hervé BOURHY"}
{"Disease Name": "Rabson-Mendenhall syndrome", "Disease Definition": "A rare syndrome that belongs to the group of extreme insulin-resistance syndromes (which also includes leprechaunism, the lipodystrophies, and the type A and B insulin resistance syndromes).", "ORPHA ID": 769, "Summary": "Epidemiology\nIt is an extremely rare disorder of unknown prevalence.\nClinical description\nEarly onset is marked by intrauterine and postnatal growth retardation, hypotrophy of muscle and adipose tissues, acanthosis nigricans (a skin lesion associated with extreme insulin resistance), dental dysplasia, abnormal hair and nails, hirsutism, and acromegaloid facies. A hypertrophic pineal gland has been reported in some cases.\nEtiology\nAs in leprechaunism (of which Rabson-Mendenhall syndrome may represent a less severe form); the condition is caused by anomalies in both alleles of the insulin-receptor gene (INSR;19p13.3-p13.2).\nDiagnostic methods\nBiologically, infants display fasting hypoglycemia, postprandial hyperglycemia and hyperinsulinemia, which progress to permanent hyperglycemia and recurrent diabetic ketoacidosis.\nDifferential diagnosis\nDifferential diagnoses include early-onset forms of leprechaunism, and moderate and late-onset forms of type A insulin resistance syndrome.\nGenetic counseling\nThe condition is transmitted as an autosomal recessive trait and mainly affects children of consanguineous parents.\nManagement and treatment\nTreatment is problematic and consists of high doses of insulin and/or recombinant insulin-like growth factor 1 (IGF1), sometimes associated with IGFBP3 (IGF binding protein).\nPrognosis\nLife expectancy may reach a few years.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Corinne VIGOUROUX"}
{"Disease Name": "Radial deficiency-tibial hypoplasia syndrome", "Disease Definition": "Radial deficiency-tibial hypoplasia syndrome is a rare, genetic dysostosis syndrome with combined reduction defects of upper and lower limbs characterized by bilateral radial aplasia, absent thumbs and bilateral tibial hypo/aplasia. Additional bone anomalies (including partial toe hypo/aplasia, short fibula and clubhand) may be associated. There have been no further descriptions in the literature since 1996.", "ORPHA ID": 1121, "Summary": ""}
{"Disease Name": "Radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome", "Disease Definition": "Radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome is characterised by symmetric, nonopposable triphalangeal thumbs and radial hypoplasia. It has been described in eight patients (five females and three males) spanning generations of a family. The affected males also presented with hypospadias. The syndrome is inherited as an autosomal dominant trait.", "ORPHA ID": 2252, "Summary": ""}
{"Disease Name": "Radial ray hypoplasia-choanal atresia syndrome", "Disease Definition": "An extremely rare syndrome characterized by radial ray hypoplasia, choanal atresia and convergent strabismus.", "ORPHA ID": 3026, "Summary": "Epidemiology\nIt has been reported in a father and his two daughters.\nClinical description\nThe radial ray involvement varies from absent radius, first metacarpal and thumb to hypoplastic thumb or triphalangeal thumb.\nGenetic counseling\nThe condition is most probably hereditary, transmitted as an autosomal dominant trait.\n\n                            Last update: \n                            January 2011"}
{"Disease Name": "Radiation myelitis", "Disease Definition": "Radiation myelitis is a rare neurological disease characterized by the development of paresthesias, as well as, in severe cases, progressive paresis and paralysis following irradiation of tumors in which the spinal cord is included within the radiation field. Symptoms may develop months or years after radiation therapy was administered.", "ORPHA ID": 90021, "Summary": ""}
{"Disease Name": "Radiation proctitis", "Disease Definition": "Radiation proctitis is a rare rectal disease directly induced by pelvic radiotherapy and characterized by rectal bleeding, change in bowel habits, tenesmus and sepsis.", "ORPHA ID": 70475, "Summary": ""}
{"Disease Name": "Radiation-induced plexopathy", "Disease Definition": "A rare radiation-induced disorder characterized by impairment of the peripheral nervous system at the level of the brachial or lumbosacral plexus following radiation therapy. Onset of symptoms can occur between several months up to decades after the last dose of radiation. Patients with radiation-induced brachial plexopathy typically present with mostly unilateral progressive paresthesia, followed by weakness, atrophy, and pain. Symptoms in radiation-induced lumbosacral plexopathy include more variable combinations of numbness, paresthesia, pain, and weakness, and are more often bilateral.", "ORPHA ID": 521123, "Summary": ""}
{"Disease Name": "Radio-renal syndrome", "Disease Definition": "Radio-renal syndrome is a rare developmental defect during embryogenesis characterized by variable upper limb reduction defects and renal anomalies. Patients typically present absence/hypoplasia of digits, radii and/or ulnae, short stature and mild external ear malformation, as well as kidney agenesis or ectopia. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 3015, "Summary": ""}
{"Disease Name": "Radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome", "Disease Definition": "Radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome is characterised by the association of proximal fusion of the radius and ulna with congenital amegakaryocytic thrombocytopaenia. Less than 10 cases have been reported in the literature so far. The syndrome is transmitted as an autosomal dominant trait and is caused by mutations in the HOXA11 gene (7p15).", "ORPHA ID": 71289, "Summary": ""}
{"Disease Name": "Radioulnar synostosis-developmental delay-hypotonia syndrome", "Disease Definition": "Radioulnar synostosis-developmental delay-hypotonia syndrome, also known as Der Kaloustian-McIntosh-Silver syndrome, is an extremely rare syndrome with synostosis described in about 4 patients to date with clinical manifestations including congenital unilateral radioulnar synostosis, generalized hypotonia, developmental delay, and dysmorphic facial features (long face, prominent nose and ears).", "ORPHA ID": 3270, "Summary": ""}
{"Disease Name": "Radioulnar synostosis-microcephaly-scoliosis syndrome", "Disease Definition": "Radioulnar synostosis-microcephaly-scoliosis syndrome, also known as Guiffré-Tsukahara syndrome, is an extremely rare syndrome characterized by the association of radioulnar synostosis with microcephaly, scoliosis, short stature and intellectual deficit.", "ORPHA ID": 3268, "Summary": ""}
{"Disease Name": "Ramon syndrome", "Disease Definition": "A rare, genetic, primary bone dysplasia syndrome characterized by bilateral, painless swelling of the face extending from the mandible to the inferior orbital margins (cherubism), epilepsy, gingival fibromatosis (possibly obscuring teeth), and intellectual disability. Other associated variable features include hypertrichosis, stunted growth, juvenile rheumatoid arthritis, and development of ocular abnormalities (e.g. pigmentary retinopathy, optic disc pallor, Axenfeld anomaly). Radiological images typically show bilateral multifocal radiolucency involving the body, angle and ramus of the mandible and coronoid process.", "ORPHA ID": 3019, "Summary": ""}
{"Disease Name": "Ramos-Arroyo syndrome", "Disease Definition": "Ramos-Arroyo syndrome (RAS) is a very rare genetic disorder characterized by corneal anesthesia, retinal abnormalities, bilateral hearing loss, distinct facies, patent ductus arteriosus, Hirschsprung disease (see these terms), short stature, and intellectual disability.", "ORPHA ID": 1051, "Summary": "Epidemiology\nPrevalence and incidence are not known. RAS is extremely rare with only six cases reported to date.\nClinical description\nThe phenotype in RAS is variable. Some affected individuals have only mild disease manifestations. Characteristic features include corneal anesthesia, nasolacrimal duct obstruction, absent peripapillary choriocapillaris and retinal pigment epithelium, poor visual acuity, and moderate to severe sensorineural deafness. Developmental delay and intellectual disability are common. Patent ductus arteriosus, Hirschsprung disease, and short stature have also been observed. Affected individuals have a distinct facial appearance with a broad face, prominent forehead, hypertelorism, upslanting palpebral fissures, concave nasal ridge, and underdeveloped midface. Feeding problems and failure to thrive are common in infancy. Challenging behavior has been reported in two cases. Overlap with the group of diseases known as hereditary sensory and autonomic neuropathy (HSAN, see this term) has been suggested.\nEtiology\nThe etiology of this syndrome is not yet known. Mutations in an as of yet unidentified gene, involved in autonomic nervous system function, are suspected.\nGenetic counseling\nRAS follows an autosomal dominant pattern of inheritance, probably with variable expressivity.\n\n                            Last update: \n                            August 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Daniela PILZ"}
{"Disease Name": "Ramsay Hunt syndrome", "Disease Definition": "A rare infectious disease characterized by herpes zoster oticus associated with peripheral facial nerve palsy, often also with other cranial nerve lesions. Patients present with a painful erythematous vesicular rash in and around one ear and facial paralysis on the same side. Other frequent manifestations include hearing loss, tinnitus, vertigo, nausea, vomiting, and nystagmus.", "ORPHA ID": 3020, "Summary": ""}
{"Disease Name": "RAPADILINO syndrome", "Disease Definition": "A rare syndrome for which the acronym indicates the principal signs: RA for radial ray defect, PA for both patellae hypoplasia or aplasia and cleft or highly arched palate, DI for diarrhea and dislocated joints, LI for little size and limb malformations, NO for long, slender nose and normal intelligence.", "ORPHA ID": 3021, "Summary": "Epidemiology\nPrevalence is unknown, but the disease is rare. It was first described in families originating from different parts of Finland, but non-Finnish cases were later identified.\nClinical description\nGrowth delay is both pre- and postnatal. It is aggravated by feeding problems and diarrhea of no known cause.\nEtiology\nRAPADILINO syndrome is caused by mutations of the RECQL4 gene, a member of the family of RecQ-helicase genes which are at the origin of diseases predisposing to cancer.\nDifferential diagnosis\nDifferential diagnoses include Rothmund-Thomson syndrome (RTS) and Baller-Gerold syndrome (see these terms), which show considerable overlap with RAPADILINO syndrome. Mutations of the RECQL4 gene have also been described for these syndromes.The presence of poikiloderma, a major symptom of RTS, distinguishes this syndrome from RAPADILINO. Radial hypoplasia or aplasia, which is constant in RAPADILINO syndrome, is occasional in RTS. Equally, the presence of craniosynostosis in Baller-Gerold syndrome differentiates it from RAPADILINO syndrome. The three syndromes predispose the risk of developing malign pathologies, although this is significantly greater for RTS (mainly osteosarcoma and cutaneous cancers). The clinical differences can be explained by phenotype-genotype correlation, in particular by preservation of helicases in RAPADLINO syndrome.\nGenetic counseling\nRAPADILINO syndrome is transmitted in an autosomal recessive manner.\nManagement and treatment\nOrthopedic and nutritional management is recommended when needed and appropriate investigation is recommended in the event of signs suggestive of osteosarcoma.\n\n                            Last update: \n                            April 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence OLIVIER-FAIVRE"}
{"Disease Name": "Rapid-onset childhood obesity-hypothalamic dysfunction-hypoventilation-autonomic dysregulation syndrome", "Disease Definition": "A rare syndromic endocrine disease characterized by childhood-onset hyperphagia and obesity, alveolar hypoventilation, dysautonomia, hypothalamic dysfunction and neurobehavioral disorders. Central hypothyroidism, endocrine anomalies, electrolyte imbalances and respiratory failure may also be associated.", "ORPHA ID": 293987, "Summary": "Epidemiology\nFewer than 100 cases have been reported in the medical literature to date.\nClinical description\nDisease onset is between 1.5 to 7 years of age with dramatic weight gain (approximately 9-13 kg over a 3-12 month period) associated with alveolar hypoventilation in a previously healthy child. This rapid-onset obesity is considered as the first sign of hypothalamic dysfunction. Other symptoms of hypothalamic dysfunction may include hyperprolactinemia, central hypothyroidism, water balance disorder, abnormal growth hormone response, adrenocortical insufficiency or puberty disorders. Autonomic dysfunction is principally characterized by an alveolar hypoventilation but may also manifest later with thermal dysregulation, excessive sweating, cardiovascular manifestations (arrhythmias or blood pressure dysregulation), strabismus, abnormal pupillary reaction to light, gastrointestinal or sensory disturbances. Some behavioral (such as aggressiveness) or mood disorders may also be present and seem to be linked with a suboptimal ventilation management. The risk of neuroendocrine tumors in patients is estimated at 50%. These tumors typically include ganglioneuromas and ganglioneuroblastoma and are essentially intra-abdominally located. Patients associating neuroendocrine tumors are described as ROHHADNET.\nEtiology\nEtiology is currently unknown. Genetic studies have investigated numerous genes involved in neuronal development as well as candidate genes of hypothalamic and autonomic dysfunction without identifying any specific mutation. Apart from genetic etiologies, other hypotheses include an epigenetic, autoimmune or even paraneoplastic process.\nDiagnostic methods\nDiagnosis is based on the clinical criteria of dramatic weight gain in a previously healthy child in association with alveolar hypoventilation and at least one other sign of hypothalamic dysfunction (e.g. hyperprolactinemia, central hypothyroidism, water balance disorder, abnormal growth hormone response, adrenocortical insufficiency or puberty disorder). Mutation in the PHOX2B gene must be excluded.\nDifferential diagnosis\nThe primary differential diagnosis is Ondine syndrome, which is defined by a congenital absence of central respiratory control, diffuse involvement of the autonomic nervous system and, in 90% of cases, presence of a PHOX2B mutation. Other diagnoses to be considered include Genetic non-syndromic obesity, Cushing syndrome, a hypothalamic tumor or other conditions with hypothalamic dysfunction, such as Narcolepsy type 1.\nManagement and treatment\nSpecific pediatric multidisciplinary approach is required, with regular follow-up by a cardiologist, pulmonologist, endocrinologist, surgeon, psychiatrist, neurologist and sleep medicine physician. Early recognition of the symptoms is essential as management is based on the rapid instauration of the appropriate therapeutic for each symptom. Hypoventilation, the most life-threatening feature, requires either ventilator support during sleep or 24 hour/day support with BPAP (bilevel positive airway pressure) ventilation through a facial mask or a tracheostomy. Cardiac pacemaker is required in cases of severe bradycardia. Specific hormonal therapies are established based on the endocrine disturbances. Oncologic and surgical management is required in cases of neuroendocrine tumors.\nPrognosis\nThe long-term outlook is variable. Children who are diagnosed early and appropriately managed can have a relatively good quality of life. On the contrary, if the diagnosis is delayed or the symptoms are not anticipated, children present an increased risk for sudden death (typically due to respiratory failure or cardiorespiratory arrest) with demise occurring on average around 10 years of age.\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Julie HARVENGT"}
{"Disease Name": "Rapid-onset dystonia-parkinsonism", "Disease Definition": "Rapid-onset dystonia-parkinsonism (RDP) is a very rare movement disorder, characterized by the abrupt onset of parkinsonism and dystonia, often triggered by physical or psychological stress.", "ORPHA ID": 71517, "Summary": "Epidemiology\nThe prevalence is unknown. Fewer than 100 patients have been described worldwide to date.\nClinical description\nRDP typically presents in childhood or early adulthood (but age of onset can range from 4-55 years) with the abrupt onset of dystonia along with parkinsonism (bradykinesia and postural instability) with a rostrocaudal gradient and prominent bulbar symptoms (dysarthria and dysphagia) that do not respond to dopaminergic medication. Symptoms may develop over several minutes to 30 days, after which time they stabilize. Often onset is triggered by physical exertion, fever, extreme heat, childbirth, excessive alcohol consumption or emotional stress. Some patients experience mild upper limb dystonia (mainly in the hands) and cramping before disease onset occurs. In most cases the disease stabilizes, but a few cases have been reported where a second episode of worsening of symptoms occurred 1-9 years after initial onset. In rare cases seizures, anxiety and depression have been reported. Recently, a variant phenotype in infants (<4 years of age) has been reported with initially episodic hypotonia, gait ataxia, motor delay, and speech and swallowing difficulties.\nEtiology\nRDP is caused by several missense mutations in the ATP1A3 gene (19q13.2) encoding the sodium/potassium-transporting ATPase subunit alpha-3 protein, which is important for maintaining the electrochemical gradients of potassium and sodium across the plasma membrane. These mutations are thought to lead to neuronal dysfunction. Other genes, which have not yet been identified, may also be involved.\nDiagnostic methods\nDiagnosis is based on the sudden onset of clinical manifestations (parkinsonism and dystonia), the finding of low homovanillic acid concentrations in cerebrospinal fluid (CSF), normal brain imaging studies and the lack of response to levodopa (L-dopa) therapy. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies show normal dopamine reuptake in dopamine transporters. A mutation in the ATP1A3 gene may confirm diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other forms of dystonia-parkinsonism, such as young adult-onset parkinsonism, dopa-responive dystonia (DRD), dystonia 16 (DYT16) and X-linked dystonia parkinsonism (DYT3). Unlike DYT3 and other forms of young-onset parkinsonism, RDP is not a neurodegenerative disorder.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families where a disease causing mutation is known.\nGenetic counseling\nRDP is inherited in an autosomal dominant manner with reduced penetrance, and genetic counseling is possible and recommended. De novo mutations are also observed.\nManagement and treatment\nThere is no effective treatment for RDP at present. L-dopa is ineffective. Pallidal deep brain stimulation (DBS) has shown limited or no therapeutic effects. If present, seizures, anxiety and depression can be treated with standard therapy. High-dose benzodiazepines and possibly other muscle relaxants may offer some symptomatic relief. All known triggers of RDP should be avoided. Physical therapy is recommended.\nPrognosis\nThere is no effect on life expectancy, but quality of life is severely affected.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "Rapidly involuting congenital hemangioma", "Disease Definition": "Rapidly involuting congenital hemangiomas (RICH) are a distinctive type of congenital hemangioma that are fully formed in utero and differ from non-involuting congenital haemangiomas (NICH; see this term) mainly because they undergo rapid postnatal involution.", "ORPHA ID": 141184, "Summary": "Epidemiology\nPrevalence is unknown but the lesions appear to be rare.\nClinical description\nRICH have long been confused with infantile immature hemangiomas but are now clearly distinguished on the basis of their distinctive clinical, histological and immunephenotypic features. RICH are round or oval-shaped, solitary and raised or infiltrating vascular tumors that are most commonly located close to a joint on the limbs, or on the scalp, forehead or around the ear. They develop in utero but there is no postnatal growth and involution is achieved in about 1 year. RICH located on the scalp seem to originate from the subperiosteal region and may permeate the vault bone during fetal life, a defect that heals after birth as the tumor regresses. The surface of RICH may be mildly or massively telangiectatic, with telangiectasia radiating from the centre in some cases, resulting in varying hues from pink to purple. A ring of pallor of variable size encircles the tumor. A central linear scar, depressed area or necrotic wound may be observed. In a few cases, the overlying skin appears almost normal. After regression, two types of sequelae can occur: lipoatrophy with a white-bluish skin hue, or a telangiectatic plaque. The term hepatic RICH has been applied to a solitary, involuting vascular liver tumor in newborns that, in resected cases, shows similar pathological features to those of external RICH.\nEtiology\nThe etiology of RICH is unknown.\nDiagnostic methods\nImaging studies are useful for diagnosis and should include color Doppler ultrasound (revealing a high-flow vascular tumor), and postnatal, and often antenatal MRI (showing a heterogeneous tumor with cystic aspects and calcifications). When clinical and radiological data are ambiguous, a biopsy is indicated in the newborn. Pathologic studies of RICH reveal large and densely cellular lobules, areas of fibrosis, and other lobules with larger vessels of irregular shape. GLUT1, the phenotypic marker for infantile hemangioma, is negative in RICH.\nDifferential diagnosis\nRICH must be differentiated from other congenital vascular tumors, tufted angiomas and kaposiform hemangioendotheliomas, as well as from other congenital possibly benign (infantile myofibromatosis) or malignant tumors (rhabdomyosarcoma or fibrosarcoma; see these terms). In rare cases, moderate transient thrombocytopenia occurs in the first week of life: this should not be misdiagnosed as Kasabach-Merritt syndrome (see this term).\nAntenatal diagnosis\nAntenatal diagnosis of RICH during prenatal ultrasound follow-up is feasible in the 3rd trimester, and sometimes as early as the 20th week of pregnancy. Elevated rates of arterial supply and venous drainage are associated with these large tumors. They are best imaged with MRI in the 3rd trimester, not only for diagnostic purposes but also to enable decisions to be made concerning a vaginal or caesarean delivery.\nGenetic counseling\nGenetic counseling should not be recommended as the lesion is sporadic.\nManagement and treatment\nManagement is often limited to observation until the end of spontaneous involution. In case of residual lesions, surgical lipofilling can be considered for a bluish atrophoderma, and surgical resection for a reddish-pink plaque. Early resection in the neonatal period is only performed for lesions in selected locations, when there is a risk of hemorrhage (ulceration and fast-flow vessels located underneath the RICH). Occasionally, corticosteroid treatment may be beneficial for very large lesions.\nPrognosis\nThe prognosis is good; however, a few exceptional cases of fatal hemorrhage have been reported.\n\n                            Last update: \n                            September 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Odile ENJOLRAS  - Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Rare adenocarcinoma of the breast", "Disease Definition": "A rare malignant breast tumor disease encompassing special rare types of adenocarcinoma of the breast, i.e. tubular adenocarcinoma, mucinous carcinoma, medullary carcinoma NOS, papillary adenocarcinoma NOS, cribriform carcinoma, apocrine adenocarcinoma, secretory carcinoma, glycogen-rich clear cell carcinoma, lipid-rich carcinoma, and oncocytic carcinoma.", "ORPHA ID": 213528, "Summary": ""}
{"Disease Name": "Rare cutaneous lupus erythematosus", "Disease Definition": "Rare cutaneous lupus erythematosus (CLE) is an autoimmune disease that denotes a heterogeneous spectrum of clinical manifestations affecting the skin and can be divided into 4 categories: acute CLE (ACLE); subacute CLE (SCLE); chronic CLE (CCLE; the most diverse form); and intermittent CLE (ICLE). CLE can either occur alone or associated with systemic lupus erythematosus (SLE).", "ORPHA ID": 535, "Summary": "Epidemiology\nIncidence is estimated to be 1/25,000 in USA, and it affects predominantly women. CLE occurs more in patients with a family history of lupus or other autoimmune diseases.\nClinical description\nCLE usually appears between 20-70 years but it has also been described in children (0-18 years). There are 4 main types of CLE: ACLE which presents as prominent non scarring-rash on cheeks and nose (''butterfly rash'', localized form) or more rarely, by a widespread eruption of red, symmetric, maculopapular lesions with accentuation of the UV-exposed areas (''maculopapular lupus rash'', generalized form); SCLE which presents with red, raised, scaly rash on sun-exposed areas of the body (annular/polycyclic form or papulosquamous form); CCLE which presents either as red to purple, well demarcated, scaly rash on the scalp, face, ears, and other sun-exposed areas (discoid LE; DLE), as frostbites (Chilblain LE; ChLE), or as painful subcutaneous nodules (LE profundus; LEP); and ICLE or LE tumidus (LET) presenting as red, swollen, urticaria-like plaques. Cutaneous manifestations appear in 72-85% of SLE patients.\nEtiology\nEtiology is still elusive but it is thought to be multifactorial, involving a genetic predisposition. The disease is then triggered by UV radiation, infections (cytomegalovirus, hepatitis C, Epstein-Barr virus), hormones (estrogens, prolactin), and exposure to drugs and chemicals, which initiate an inflammatory process. Cytokines and chemokines are involved in propagating inflammatory responses, suppressing tolerogenic components of the immune system. Autoreactive B cells are intrinsic to lupus pathogenesis.\nDiagnostic methods\nDiagnosis is based on family history, clinical and laboratory findings (detection of antibodies anti-nuclear antigens (ANA)), histological examinations of skin biopsy which show superficial and deep perivascular and periadnexal lymphocytic infiltrate, interface-dermatitis and thickening of the basement membrane as a late consequence. The epidermis is atrophic with necrotic keratinocytes. Diagnosis is confirmed by direct immunofluorescence (detects deposits of immunoglobulins and complement component C3 and IgG at the dermo epidermal junction) and photoprovocation.\nDifferential diagnosis\nDifferential diagnosis depends on subtypes and includes: ACLE: dermatomyositis, erythema multiforme, drug-induced photosensitivity, dermatitis (atopic, contact), exanthema (viral, drug-induced), rosacea, seborrheic dermatitis. SCLE: classic mycosis fungoides, pityriasis rubra pilaris, vitiligo, tinea corporis, erythema anulare centrifugum, granuloma annulare, erythema gyratum repens, psoriasis. DLE: sarcoidosis, tuberculosis, leprosy, classic mycosis fungoides, cutaneous pseudolymphoma, granuloma faciale, nummular eczema, psoriasis, squamous and basal cell carcinoma, rosacea, lichen planus. ChLE: frostbites. LEP: subcutaneous panniculitis-like T-cell lymphoma, erythema nodosum. LET: Jessner lymphocytic infiltration of the skin, polymorphous light eruption, reticular erythematosus mucinosis.\nManagement and treatment\nTreatment goals are to improve skin appearance, limit scarring, and prevent new skin lesions. This includes use of UV light protection; topical therapy (corticosteroids and/or calcineurin inhibitors); and antimalarial therapy that may improve CLE and delay progression to SLE. For patients refractory to antimalarials, immunosupressive and immunomodulatory therapy (systemic corticosteroids, methotrexate, oral retinoids) may be proposed.\nPrognosis\nCLE is a chronic skin disease, with significant impact on the patients' quotidian. Risk of SCLE and CCLE patients developing SLE is <10%. ACLE is associated with SLE.\n\n                            Last update: \n                            June 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Marzia CAPRONI  - Dr Carla CARDINALI  - Pr Paolo FABBRI  - Dr Barbara GIOMI"}
{"Disease Name": "Rare disorder potentially indicated for transplant", "Disease Definition": "A group of rare disorders with irreversible organ and/or system dysfunction(s), or the effects of dysfunction after alternative medical and surgical treatments have been utilized, for which the benefits of transplantation outweigh the risk of continuing alternative modalities.", "ORPHA ID": 506207, "Summary": ""}
{"Disease Name": "Rare form of salmonellosis", "Disease Definition": "Rare form of salmonellosis is a group of rare invasive salmonellosis that includes infection with Salmonella enterica typhoidal species (S. typhi and S. paratyphi) that results in enteric fever, and infection by invasive non-typhoidal species (typically strains of S. typhimurium and S. enteritidis) which have a high burden amongst immunocompromised or malnourished individuals, and results in bacteriemia, systemic febrile disease, and variable manifestations including lower respiratory tract infection and splenomegaly.", "ORPHA ID": 795, "Summary": ""}
{"Disease Name": "Rare isolated myopia", "Disease Definition": "Rare isolated myopia is a rare, genetic, refraction anomaly disorder characterized by non-syndromic severe myopia, which may be associated with cataract and vitreoretinal degeneration (retinal detachment) that may lead to blindness.", "ORPHA ID": 98619, "Summary": ""}
{"Disease Name": "Rare lichen planus", "Disease Definition": "Lichen planus (LP) is a common inflammatory dermatosis characterized by the development of pruritic violaceous papules or plaques on mucocutaneous surfaces. Eruptions can involve the face, neck, limbs, back, genitalia, tongue, buccal mucosa, nails, and scalp. LP comprises rare variants affecting the skin and the mucosa. Rare cutaneous LP includes linear LP (referring to blaschkoid and zosteriform distributions of lichenoid lesions), actinic LP, annular LP, atrophic LP, annular atrophic LP, lichen planopilaris (comprising Graham Little-Piccardi-Lassueur syndrome and frontal fibrosing alopecia), lichen planus pigmentosus, and lichen planus pemphigoides (see these terms). Rare mucosal LP includes vulvovaginal gingival syndrome and LP sialadenitis (see these terms).", "ORPHA ID": 254367, "Summary": ""}
{"Disease Name": "Rare non-syndromic intellectual disability", "Disease Definition": "Rare non-syndromic intellectual disability is a rare, hereditary, neurologic disease characterized by early-onset cognitive impairment as a sole disability. The disease may be associated with autism, epilepsy and neuromuscular deficits.", "ORPHA ID": 101685, "Summary": ""}
{"Disease Name": "Rare surgically correctable form of primary aldosteronism", "Disease Definition": "A rare primary hyperaldosteronism characterized by unilateral aldosterone hypersecretion and renin suppression, associated with varying degrees of hypertension and hypokalemia.", "ORPHA ID": 231637, "Summary": "Epidemiology\nThe prevalence of primary aldosteronism in the general population is not known. Its prevalence in referred hypertensive populations is estimated to be between 6 and 13%, of which 1.5 to 5% have an aldosterone-producing adenoma or primary unilateral adrenal hyperplasia. Taking into account referral biases, the prevalence of surgically correctable primary aldosteronism is probably less than 1.5% in the hypertensive population and less than 0.3% in the general adult population.\nEtiology\nnilateral aldosterone hypersecretion is caused by an aldosterone-producing adenoma (also known as Conn's adenoma and aldosteronoma), primary unilateral adrenal hyperplasia and rare cases of aldosterone-producing adrenocortical carcinoma (see these terms). In these forms, unilateral adrenalectomy can cure aldosterone excess and hypokalemia, but not necessarily hypertension.\nDiagnostic methods\nSurgically correctable primary aldosteronism is sought in patients with hypokalemic, severe or resistant forms of hypertension. Recent recommendations suggest screening for primary aldosteronism using the aldosterone to renin ratio. Patients with a raised ratio then undergo confirmatory suppression tests. Once the diagnosis is confirmed, adrenal computed tomography is performed for all patients.\nDifferential diagnosis\nThe differential diagnosis of hypokalemic hypertension with low renin includes mineralocorticoid excess, with the mineralocorticoid being cortisol or 11-deoxycorticosterone, exposure to glycyrrhizic acid and apparent mineralocorticoid excess caused by mutations in the HSD11B2 gene and pseudo-hypermineralocorticoidism in Liddle syndrome (see these terms).\nManagement and treatment\nIf surgery is considered, taking into consideration the clinical context and the desire of the patient, adrenal vein sampling is performed to detect whether or not aldosterone hypersecretion is unilateral.\nPrognosis\nLaparoscopic surgery for unilateral aldosterone hypersecretion is associated with a morbidity of about 8%, with most complications being minor. It generally results in the normalization of aldosterone secretion and kalemia, and in a large decrease in blood pressure, but normotension without treatment is only achieved in half of all cases. Normotension following adrenalectomy is more frequent in young patients with recent hypertension than in patients with long-standing hypertension or a family history of hypertension.\n\n                            Last update: \n                            September 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence AMAR  - Pr Pierre-François PLOUIN  - Dr Olivier STEICHEN"}
{"Disease Name": "RARS-related autosomal recessive hypomyelinating leukodystrophy", "Disease Definition": "A rare, genetic leukodystrophy characterized by developmental delay, increased muscle tone leading later to spasticity, mild ataxia, nystagmus, dysarthria, intentional tremor, and mild intellectual disability. Brain imaging reveals supratentorial and infratentorial hypomyelination.", "ORPHA ID": 438114, "Summary": ""}
{"Disease Name": "RAS-associated autoimmune leukoproliferative disease", "Disease Definition": "RAS-associated autoimmune leukoproliferative disease (RALD) is a rare genetic disorder characterized by monocytosis, autoimmune cytopenias, lymphoproliferation, hepatosplenomegaly, and hypergammaglobulinemia.", "ORPHA ID": 268114, "Summary": "Epidemiology\nPrevalence of this disorder is not known. It is extremely rare with fewer than 20 patients reported to date.\nClinical description\nAge of onset of the clinical signs is invariably in infancy or early childhood. Most patients have atypical features such as elevated counts for cells of myeloid origin (monocytosis and granulocytosis) making their clinical presentation indistinguishable from juvenile myelomonocytic leukemia (JMML; see this term). Many patients undergo repeated bone marrow assessments showing normal cytogenetics despite dysplastic marrow morphology. Lymphoma in adulthood in one patient and only one case of unexplained sudden death in adolescence have been reported. Hypergammaglobulinemia, autoantibodies and expansion of B lymphocytes in peripheral blood have also been noted.\nEtiology\nRALD is caused by somatic mutations in the NRAS (1p13.2) and KRAS (12p12.1) genes encoding RAS proteins involved in regulating cell proliferation causing impairment of the intrinsic apoptosis pathway.\nDiagnostic methods\nDouble-negative T-cells (DNTs) may be mildly elevated in patients with RALD but are usually normal. Apoptosis assay can identify these patients due to their distinct cellular phenotype showing impaired cell death following serum or IL2 withdrawal.\nGenetic counseling\nThe pattern of inheritance for RALD is not known. RAS mutations are considered somatic and limited to the circulating peripheral blood mononuclear cells.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Koneti RAO"}
{"Disease Name": "Rasmussen subacute encephalitis", "Disease Definition": "A rare inflammatory and autoimmune disease with epilepsy characterized by unilateral hemispheric atrophy, associated with drug-resistant focal epilepsy, progressive hemiplegia, and cognitive decline. The disease mainly affects children and begins with a prodromal period with mild hemiparesis or infrequent seizures lasting up to several years. The acute stage is marked by frequent seizures arising from one cerebral hemisphere, followed by a residual stage with persistent severe neurological deficits and relapsing epilepsy.", "ORPHA ID": 1929, "Summary": ""}
{"Disease Name": "Rat-bite fever", "Disease Definition": "Rat-bite fever (RBF) is a systemic bacterial zoonosis occurring in individuals that have been bitten or scratched by Streptobacillus moniliformis or Spirillum minus-infected rats and characterized by high fever, a rash on the extremities, and arthralgia.", "ORPHA ID": 31205, "Summary": "Epidemiology\nThe exact incidence is unknown.\nClinical description\nThe clinical manifestations include high fever followed by headaches, chills, vomiting, a rash generally developing on the palms and soles, and symmetric polyarthritis of the joints that generally restricts movement.\nEtiology\nMost reported cases of rat-bite fever in the USA are caused by S. moniliformis (streptobacillary rat-bite fever), whereas in Asia the disease is mainly due to Spirillum minus (spirillary rat-bite fever; see these terms). Rat-bite fever is also contracted through contact with secretions of infected rats and less often through contact with other S. moniliformis and S. minus hosts, such as gerbils, mice and squirrels. In rare cases, the disease is transmitted through animal hosts such as dogs, cats and ferrets.\nDiagnostic methods\nDiagnosis is mainly based on the clinical symptoms, reported occurrence of a rat bite, clinical course and characteristic growth of the infectious agents in cultures from blood, synovial fluid or wound tissue.\nDifferential diagnosis\nThe differential diagnosis includes Haverhill fever (caused by S. moniliformis but transmitted via the consumption of water, milk or food contaminated by rat excrement; see this term) and several bacterial and viral infections (Lyme disease, leptospirosis, brucellosis, Rocky Mountain spotted fever (see these terms), S. pyogenes and S. pyogenes-associated diseases, S. aureus infection, disseminated gonorrhea, meningococcemia, viral exanthemas, and secondary syphilis).\nManagement and treatment\nManagement requires a prophylactic (avoiding direct or indirect contact with host animals) and therapeutic approach (local treatment and antimicrobial therapy). The most effective antibiotic treatment is penicillin G administration in non-allergic patients, and tetracycline and streptomycin in penicillin-allergic patients.\nPrognosis\nPrognosis is excellent if the disease is treated. If left untreated, RBF presents a mortality rate of approximately 10% due to complications.\n\n                            Last update: \n                            August 2009\n\n\n                            - Expert reviewer(s): \n                            Dr François TREMOLIERES"}
{"Disease Name": "Ravine syndrome", "Disease Definition": "Ravine syndrome is an extremely rare genetic neurological disorder, reported in a small number of patients in a specific community on Reunion Island (Ravine region), characterized by infantile anorexia with irrepressible and repeated vomiting, acute brainstem dysfunction, severe failure to thrive, and progressive encephalopathy with MRI showing vanishing of medulla oblongata and cerebellar white matter and severe atrophy of pons, along with supra-tentorial periventricular white-matter hyperintensities and basal ganglia anomalies.", "ORPHA ID": 99852, "Summary": ""}
{"Disease Name": "Reactive arthritis", "Disease Definition": "A rare spondyloarthritis characterized by acute or chronic sterile synovitis with or without extra-articular manifestations, becoming manifest after an infection.", "ORPHA ID": 29207, "Summary": "Epidemiology\nAnnual incidence for acute reactive arthritis is conservatively estimated between 1/11,000-166,000, although this may be an underestimate. The prevalence of the chronic form is unknown. The disease most commonly affects young adults and is associated with HLA-B27 allele, especially in its chronic form.\nClinical description\nAge of onset varies widely, with a peak at 15-35 years of age. The disease usually occurs within 1-3 weeks after a urogenital or gastrointestinal infection. Urinary symptoms are often the first manifestation. Prostatitis in men, and cervicitis, salpingitis and/or vulvovaginitis in women are frequent findings. Arthritis generally appears several weeks or months after the initial symptoms. It often affects one (knee) or a few major joints (knees, ankles or toes). The tendons and ligaments next to the joints may also be inflamed, particularly the Achilles tendon and the lower back joints. Extraarticular manifestations may involve the eye with conjunctivitis, iritis, or uveitis, as well as the skin with rashes on the hands or feet. Balanitis, nail changes, mucosal ulcers, fever, weight loss, and cardiac manifestations may also occur. In most patients, the symptoms last for 1-6 months, but the disease can also become chronic.\nEtiology\nReactive arthritis is typically triggered by Gram-negative infections (commonly due to Chlamydia, Shigella, Salmonella, or Yersinia) in genetically predisposed individuals.\nDiagnostic methods\nThe diagnosis relies on a compatible clinical scenario and history, the identification of a trigger infection and is supported by HLA-B27 positivity.\nDifferential diagnosis\nDifferential diagnosis includes other spondyloarthritis (ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease-associated spondyloarthropathy, juvenile-onset spondyloarthropathy, and undifferentiated spondyloarthropathy). Septic arthritis, gonococcal infection, and viral arthritis should also be excluded.\nGenetic counseling\nGenetic testing for HLA-B27 is not recommended in the absence of a clinical suspicion.\nManagement and treatment\nManagement aims at eradication of the underlying infection (antibiotics) and reduction of joint pain and inflammation (analgesics, anti-inflammatory drugs, steroids and immunosuppressants), as well as rest and specific treatment of extraarticular manifestations.\nPrognosis\nPrognosis is variable. One-third of patients may develop chronic disease which requires prolonged or life-long treatment. However, the majority of patients have a normal life span and nearly normal lifestyle.\n\n                            Last update: \n                            October 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Francesca MOTTA  - Pr Carlo SELMI"}
{"Disease Name": "Reading seizures", "Disease Definition": "A rare reflex epilepsy characterized by reading-induced seizures which in most cases present with orofacial/jaw myoclonus possibly extending to the upper limbs but can also manifest as dyslexia or alexia and visual symptoms. In both variants secondary generalized tonic-clonic seizures may evolve if the stimulus is not interrupted. The disease typically begins in the second or third decade of life and may be inherited in an autosomal dominant pattern. It usually takes a benign course with little tendency to spontaneous seizures.", "ORPHA ID": 166433, "Summary": ""}
{"Disease Name": "Recessive dystrophic epidermolysis bullosa inversa", "Disease Definition": "A rare subtype of dystrophic epidermolysis bullosa (DEB) characterized by blisters and erosions which from adolescence or early adulthood are primarily confined to flexural skin sites.", "ORPHA ID": 79409, "Summary": "Epidemiology\nLess than 100 cases of recessive dystrophic epidermolysis bullosa inversa (RDEB-I) have been reported to date; it is probably underreported.\nClinical description\nThe disease manifests at birth or shortly thereafter with generalized blistering and superficial erosions of intermediate severity that heal with atrophic scarring and milia formation. From adolescence to early adulthood, blistering tends to localize to folds, particularly axillae, groin, perianal area and natal cleft. Women may present with marked vulvovaginal and inframammary skin blistering. Other predilection sites include the base of the neck, the uppermost back, and the lumbosacral area. Nail dystrophy is typical but of variable severity. Mucosal lesions with blistering and scarring in the mouth are characteristic and can lead to microglossia (loss of lingual papillae and fusion of the tongue to the mouth floor) and ankyloglossia (obliteration of the oral vestibules and progressive restriction of oral aperture). Esophageal involvement is often severe and is associated with a risk of esophageal stricture that can impair intake of nutrients. Lesions of the lowermost portion of the genitourinary tract are also common and may lead to the development of vaginal strictures that may impair normal sexual function. Other less common extracutaneous features include external auditory canal stenosis or complete occlusion with varying degrees of hearing loss; corneal erosions, and anemia. Growth delay is rare. Patients may develop squamous cell carcinomas, with a cumulative risk reaching 23% by age 50 which is much lower than in either of the two generalized forms of RDEB (severe RDEB and intermediate RDEB).\nEtiology\nThe disease is caused by mutations in the type VII collagen gene (COL7A1; 3p21.31). Mutations in this gene lead to an alteration in function or reduced amounts of collagen VII. This impairs collagen VII assembly into anchoring fibrils which anchor the basement membrane to the underlying dermis. This in turn causes reduced skin resistance to minor trauma. Compound heterozygosity for a loss-of-function COL7A1 mutation in combination with a missense mutation is prototypic. Specific glycine and arginine substitutions are implicated to affect the thermostability of type VII and cause this phenotype.\nDiagnostic methods\nDiagnosis is suspected at clinical examination and is confirmed by immunofluorescence antigen mapping and/or transmission electron microscopy on skin samples showing a cleavage plane located below the lamina densa of the cutaneous basement membrane zone. Genetic testing confirms the diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes other forms of epidermolysis bullosa. In the neonatal period also herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, and staphylococcal scalded skin syndrome may need to be considered.\nAntenatal diagnosis\nGenetic prenatal diagnosis may be considered where the mutations have previously been identified in and affected sibling.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment is symptomatic and includes wound management, treatment of pain and pruritus, nutritional supply, and regular examinations of skin and visible mucous membranes to screen for skin cancer.\nPrognosis\nPrognosis is generally good.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Martin LAIMER | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome", "Disease Definition": "Recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome is a rare, genetic, syndromic intellectual disabilty disorder characterized by severe intellectual disability, progressive, postnatal, multiple joint contractures and severe motor dysfunction. Patients present arrest and regression of motor function and speech acquisition, as well as contractures which begin in lower limbs and slowly progress in an ascending manner to include spine and neck, resulting in individuals presenting a specific fixed position.", "ORPHA ID": 280384, "Summary": ""}
{"Disease Name": "Recessive mitochondrial ataxia syndrome", "Disease Definition": "A rare, mitochondrial DNA maintenance syndrome characterized by early-onset cerebellar ataxia, and variable combination of epilepsy, headache, dysarthria, ophthalmoplegia, peripheral neuropathy, intellectual disability, psychiatric symptoms and movement disorders.", "ORPHA ID": 94125, "Summary": ""}
{"Disease Name": "Recessive X-linked ichthyosis", "Disease Definition": "A rare genetic skin disease belonging to the Mendelian Disorders of Cornification (MeDOC) and characterized by generalized hyperkeratosis and scaling of the skin. The condition is rather mild.", "ORPHA ID": 461, "Summary": "Epidemiology\nRXLI affects almost exclusively males. It is the second most common type of ichthyosis with an estimated prevalence of 1/2,000 to 1/6,000 males.\nClinical description\nOnset may occur within the first days of life with the development of generalized non-erythematous, polygonal, loosely adherent scales. These scales later evolve into grayish or blackish adherent scales that are pronounced on the trunk, the extensor and flexor sites of the extremities, and the neck (giving the ''dirty-neck'' appearance). Skin's folds, palms and soles, are normally spared. Scaling improves with age and during summer. Delayed birth (insufficient cervical dilatation) may be observed. Extracutaneous manifestations like testicular maldescent, attention deficit and hyperactivity disorder (ADHD) and/or corneal opacities are possible. Large deletions involving adjacent genes may result in more complex phenotypes (contiguous gene deletion syndromes like Kallman´s syndrome, the recessive form of X-linked chondrodysplasia punctata, short stature, intellectual disability, or central nervous systems anomalies).\nEtiology\nX-linked ichthyosis is an epidermal lipid metabolism anomaly due to inactivating mutations or deletions in the steroid sulfatase STS gene (Xp22.3). STS codes for a lipid hydrolase of the stratum corneum that participates in the regulation of permeability, barrier homeostasis and desquamation by catalyzing the hydrolysis of steroid sulfates (e.g. cholesterol sulfate CSO4, sulfated steroid hormones). STS deficiency leads to increased amounts of CSO4 that inhibit epidermal serine proteases, which in turn results in decreased desquamation of corneocytes with retention hyperkeratosis. There are some much rarer syndromic RXLI cases that are due to contiguous gene deletion affecting neighboring genes of the STS gene.\nDiagnostic methods\nDiagnosis is based on clinical findings and family history (scaling in male relatives, history of delayed birth). It is confirmed by biochemical (serum protein electrophoresis, STS activity test of fibroblasts or leukocytes) and molecular/cytogenetic analyses (polymerase chain reaction (PCR), multiple ligation-dependent probe amplification (MLPA), comparative genomic hybridization/comparative microarray analysis (CMA), fluorescent in situ hybridization (FISH)). Histology or ultrastructure of the skin is helpful for the differentiation of ichthyosis vulgaris.\nDifferential diagnosis\nDifferential diagnosis includes ichthyosis vulgaris, autosomal recessive congenital ichthyosis (ARCI), namely lamellar ichthyosis, syndromic RLXI, or multiple sulfatase deficiency.\nAntenatal diagnosis\nMaternal urine and serum steroid measurements may show decreased estrogen levels. Therefore, RXLI may be detected in utero, when maternal estriol levels are measured for prenatal screening for Down syndrome and other disorders.\nGenetic counseling\nXLRI is transmitted as an X-linked recessive trait: it affects males and is inherited through female carriers. Female patients have rarely been reported.\nManagement and treatment\nTreatment consists in hydrating and softening the skin with the use of lubricating bath oils and emollients containing humectants and keratolytics (e. g. urea, lactic acid, and glycolic acid). For adult patients, systemic retinoids are an option, e. g. during winter, when the ichthyosis is often more severe.\nPrognosis\nRXLI represents a benign form of ichthyosis. The ichthyosis is life-long but hyperkeratosis and scaling may improve with age. Life expectancy is normal.\n\n                            Last update: \n                            December 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Ángela HERNÁNDEZ MARTÍN"}
{"Disease Name": "Recombinant 8 syndrome", "Disease Definition": "Recombinant 8 (rec(8)) syndrome, also known as San Luis Valley syndrome, is a complex chromosomal disorder that is due to a parental pericentric inversion of chromosome 8 and is characterized by major congenital heart anomalies, urogenital malformations, moderate to severe intellectual deficiency and mild craniofacial dysmorphism.", "ORPHA ID": 96167, "Summary": "Epidemiology\nThe prevalence is unknown but the syndrome is rare. Rec(8) syndrome occurs typically in people with Hispanic ancestry from the Southwestern United States and is thought to be due to a single founder who emigrated from Spain to Colorado or New Mexico in the 17th or 18th century.\nClinical description\nRec(8) syndrome is characterized by major congenital heart anomalies, comprising complex conotruncal abnormalities often accompanied by patent ductus arteriosus or persistent left superior vena cava (PLSVC) or nonconotruncal anomalies including pulmonic stenosis, ventricular septal defect (VSD), patent ductus arteriosus and PLSVC; urogenital malformations such as cryptorchidism and hypoplastic scrotum in males; moderate intellectual disability; and mild craniofacial dysmorphism including abnormal hair whorl, low posterior hairline, wide face, hypertelorism, infraorbital creases, anteverted nares, thin upper lip, downturned mouth, gingival hyperplasia, abnormal tooth development, micrognathia, mal-shaped and low-set ears. Other findings include developmental delay, spasticity, leading to orthopedic complications such as scoliosis, seizures and recurring otitis media or hearing loss. Individuals with rec(8) syndrome generally present solid social and nonverbal communication skills and an overall good nature despite their intellectual disability.\nEtiology\nRec(8) syndrome is a complex chromosomal disorder, rec(8)dup(8q)inv(8)(p23.1q22.1) due to a parental pericentric inversion of chromosome 8 [inv(8)(p23.1q22.1)] with presumed constant breaking points in this Hispanic population and variants in other populations.\nDiagnostic methods\nDiagnosis is based on clinical manifestations leading to chromosomal analysis by classical or molecular karyotyping.\nDifferential diagnosis\nDifferential diagnoses include other chromosomal anomalies involving chromosome 8, Bardet-Biedl syndrome, Williams syndrome and Noonan syndrome (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible by amniocentesis or chorionic villus sampling and cytogenetic analysis.\nGenetic counseling\nGenetic counseling is recommended and needs karyotyping of the parents in order to evaluate the risk of recurrence. Segregation analysis has ascertained a 6.2% risk for a carrier parent to have a child with rec(8) syndrome with the transmission rate being higher in carrier mothers (59%) than fathers (42%).\nManagement and treatment\nManagement involves cardiac surgery in case of cardiac malformations and a multidisciplinary approach including hearing screening, evaluation of reflux and constipation and full developmental assessment with periodic follow-up. Regular neurodevelopmental screening and participation in individually adapted therapy programs are recommended. Orthopedic surgery has been shown to give suboptimal results due to the intellectual deficit impeding rehabilitation.\nPrognosis\nPrognosis is variable, depending on the severity of congenital heart disease. Historically, life expectancy past early childhood was very low, however with the increased quality and early treatment intervention the majority may live into adulthood. Exact life expectancy is unknown.\n\n                            Last update: \n                            November 2012\n\n\n                            - Expert reviewer(s): \n                             Laura PICKLER"}
{"Disease Name": "Rectal duplication", "Disease Definition": "A rare, congenital, intestinal malformation morphological anomaly characterized by an egg-like, cystic, mucus-filled mass, composed of intestinal mucosal lining and smooth muscle tissue. Commonly it presents in childhood with symptoms of recurrent urinary tract infections, gastroenteritis, obstruction, perianal sepsis and rectal bleeding. Drainage of mucus or pus from the anus is also a typical presenting sign. The majority are found in the retro-rectal space where they communicate with, or are contiguous to, the rectum.", "ORPHA ID": 171220, "Summary": ""}
{"Disease Name": "Recurrent hepatitis C virus induced liver disease in liver transplant recipients", "Disease Definition": "A rare hepatic disease characterized by recurrence of hepatitis C virus infection after liver transplantation, leading to liver injury with features resembling those observed in the non-transplant graft, and typically developing after three months post-transplantation. The clinical course is highly variable, although patients most commonly develop progressive chronic liver disease with higher viral loads and more rapid fibrosis progression than in the immunocompetent population.", "ORPHA ID": 90052, "Summary": ""}
{"Disease Name": "Recurrent idiopathic neuroretinitis", "Disease Definition": "A rare inflammatory optic neuropathy characterized by recurrent episodes of idiopathic inflammation of the optic nerve head with optic disc edema associated with macular exudate in a star-shaped pattern. Patients present with acute visual loss, most typically in the form of a large central scotoma. Pain is mild or absent. Bilateral involvement is frequent and usually sequential. The interval between attacks is highly variable, ranging from months to several years. Visual loss is cumulative with each attack and often severe.", "ORPHA ID": 499103, "Summary": ""}
{"Disease Name": "Recurrent infections associated with rare immunoglobulin isotypes deficiency", "Disease Definition": "Deficiencies in immunoglobulin (Ig) isotypes (including: isolated IgG subclass deficiency, IgG sublcass deficiency with IgA deficiency and kappa chain deficiency) are primary immunodeficiencies that are often asymptomatic but can be characterized by recurrent, often pyogenic, sinopulmonary infections.", "ORPHA ID": 183675, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nSome patients may show an increased frequency of infections in their second year of life, while for others the onset of infections may be later. There are four subclasses of IgG (IgG1, IgG2, IgG3 and IgG4), the levels of which change with age. Deficiency with IgG subclass 2 is most common in children, whereas after puberty deficiency in subclass 3 is more common. Symptomatic patients experience recurrent sinopulmonary infections, particularly with Streptococcus pneumonia and Haemophilus influenza, which present as repeated ear infections, bronchitis, pneumonia, sinusitis and diarrhea. Patients may also present with meningitis, bronchiectasis and severe, recurrent otitis media, which may lead to hearing loss. Patients with kappa chain deficiency are usually asymptomatic but symptoms can include recurrent respiratory infections and diarrhea.\nEtiology\nThe cause and mode of transmission of deficiencies in IgG subclasses is unknown. Kappa-chain deficiency is produced by mutations in the IGKC gene (2p11).\nDiagnostic methods\nIgG subclass deficiency, with or without IgA deficiency, should be suspected in patients suffering from recurrent or chronic infections with encapsulated bacteria. Diagnosis is based on the number of infections (more than 6 courses of antibiotics per year given for upper and lower respiratory tract infections) and a lack of functional antibodies produced in response to vaccines and, in the case of IgG subclass deficiency, measurement of IgG subclass levels. The most common subclass deficiency is in IgG2, which may be accompanied by decreased IgG4 with or without decreased IgA levels. IgG subclass deficiency may still be a possibility even when the total IgG is normal, therefore measurement of all four IgG subclasses is required for an accurate diagnosis of IgG subclass deficiency. Diagnosis of kappa chain deficiency can be confirmed with genetic testing.\nDifferential diagnosis\nDifferential diagnoses include other primary immunodeficiencies, including 22q11 microdeletion syndrome, HLA class II deficiency and ataxia telangiectasia (see these terms). In general, infections are less severe than those in patients with marked deficiencies of IgG (all subclasses), IgA and IgM (such as X-linked agammaglobulinemia and common variable immunodeficiency; see these terms).\nGenetic counseling\nTransmission is autosomal recessive and point mutations in one family have been described.\nManagement and treatment\nTreatment is based on prophylactic antibiotics and/or polyvalent immunoglobulin replacement in cases with severe or recurrent infections. Asymptomatic cases do not require treatment. Treatment in children is restricted to 8-9 months over winter with attempts to stop treatment totally in the summer in order to see if the deficit has corrected itself. For kappa chain deficiency, oral poliovaccine should not be given because of the risk of paralytic disease.\nPrognosis\nIn children these deficiencies may be transient, while in adults they seem to be permanent. However, there is no evidence at diagnosis to predict their evolution.\n\n                            Last update: \n                            September 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Anne DURANDY  - Pr Alain FISCHER  - Pr Isabelle PELLIER"}
{"Disease Name": "Recurrent infections due to specific granule deficiency", "Disease Definition": "A rare functional neutrophil defect characterized by infantile onset of increased susceptibility to pyogenic infections, especially of the skin, ears, lung, and lymph nodes, with neutrophils lacking specific granules and exhibiting bilobed nuclei on peripheral blood smear. Bone marrow biopsy shows hypercellularity, paucity of neutrophil granulocytes, and progressive myelodysplasia. Additional manifestations may include mild to moderate developmental delay, mild facial dysmorphic features (such as dysplastic ears), and anomalies of bones, teeth, and nails.", "ORPHA ID": 169142, "Summary": ""}
{"Disease Name": "Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome", "Disease Definition": "Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome is a rare, genetic, neurodegenerative disease characterized by episodic metabolic encephalomyopathic crises (of variable frequency and severity which are frequently precipitated by an acute illness) which manifest with profound muscle weakness, ataxia, seizures, cardiac arrhythmias, rhabdomyolysis with myoglobinuria, elevated plasma creatine kinase, hypoglycemia, lactic acidosis, increased acylcarnitines and a disorientated or comatose state. Global developmental delay, intellectual disability and cortical, pyramidal and cerebellar signs develop with subsequent progressive neurodegeneration causing loss of expressive language and varying degrees of cerebral atrophy.", "ORPHA ID": 480864, "Summary": ""}
{"Disease Name": "Recurrent Neisseria infections due to factor D deficiency", "Disease Definition": "Recurrent Neisseria infections due to factor D deficiency is a rare, genetic, primary immunodeficiency disorder characterized by an increased susceptibility to  Neisseria  bacterial infections, resulting from complement factor D deficiency, typically manifesting as recurrent respiratory infections, recurrent meningitis and/or septicemia. Patients typically present fever, purpuric rash, arthralgia, myalgia and undetectable complement factor D plasma concentrations.", "ORPHA ID": 169467, "Summary": ""}
{"Disease Name": "Recurrent respiratory papillomatosis", "Disease Definition": "A rare respiratory disease characterized by the development of exophytic papillomas, affecting the mucosa of the upper aero-digestive tract (with a strong predilection for the larynx), caused by an infection with human papilloma virus. Symptoms at presentation vary with the age of patients and the extent of lesions and include dysphonia, chronic cough and recurrent respiratory infections.", "ORPHA ID": 60032, "Summary": "Epidemiology\nThe prevalence of recurrent respiratory papillomatosis (RRP) is estimated at about 1/70,400 in the United Kingdom. Annual incidence of the disease is about 1/23,300 in children and 1/55,500 in adults in the United States. The adult forms affect males more often than females.\nClinical description\nA trimodal age distribution is characteristic, with peaks around the ages 7, 35 and 64 years. In sub-Saharan Africa the third peak does not exist. Manifestations depend on the extent and progression of the lesions and in the pediatric population include dysphonia (hoarseness and/ or breathiness), cough, wheezing, chronic dyspnea, rarely choking and syncope. The symptoms tend to be more severe in children because of the rapid growth of the lesions and can lead to potentially life-threatening airway compromise. In the adult population symptoms include dysphonia (hoarseness and/ or breathiness), chronic cough and globus. The clinical course is variable ranging from mild disease with spontaneous remission to an aggressive disease or a chronic clinical course, necessitating dozens of surgical interventions.\nEtiology\nRRP is caused by infection by human papillomavirus (HPV) types 6 and 11 which are considered to be ''low-risk'', or generally not associated with malignancy. RRP caused by HPV types 16, 18, 31, and 33 are considered to be premalignant lesions, not true RRP. The virus can be transmitted in utero, as a transplacental or ascending infection or during the passage through an infected birth canal. Following infection in humans, HPV is able to promote a specific immune system dysfunction, hence favoring the development of papillomatosis. It is theorized that such behavior is related to specific virus capabilities and a possible genetic predisposition.\nDiagnostic methods\nLaryngoscopy, followed by histologic examination and HPV genotyping is the most reliable method used to reach a definite diagnosis. Multiple non-necrotic cauliflower-like lesions can be observed on endoscopy. HPV genotyping can be performed by the detection of HPV DNA by polymerase chain reaction with consensus primers and subsequent restriction mapping or hybridization methods.\nDifferential diagnosis\nDifferential diagnosis includes asthma and bronchitis in children, and acute laryngitis, upper respiratory tract infection and other benign or malignant laryngeal tumors in all age groups.\nManagement and treatment\nThe treatment's goal is to secure airway patency (in children) or preserve the underlying laryngeal tissues (in adults), and thus, maintain an acceptable quality of voice. This is accomplished by surgical intervention with the help of either a microscope or an endoscope in order to debulk or remove the papilloma lesions. Postoperative complications include hampered voice due to scarred vocal folds. A minority of patients requires adjuvant therapy. HPV vaccination appears to be effective in reducing the intersurgical interval. Other adjuvant therapies include intralesional cidofovir and systemic bevacizumab.\nPrognosis\nThe prognosis is often good, although it is a potentially lethal disease. Its morbidity is low in most cases, but dozens of surgical interventions are not uncommon. Malignant degeneration can rarely occur. Patients with pulmonary RRP have an increased risk of malignant transformation.\n\n                            Last update: \n                            January 2023\n\n\n                            - Expert reviewer(s): \n                            Pr F.G. [Frederik] DIKKERS | ERN CRANIO*\n\n\n                                * European Reference Network"}
{"Disease Name": "Reducing body myopathy", "Disease Definition": "Reducing body myopathy (RBM) is a rare muscle disorder marked by progressive muscle weakness and the presence of characteristic inclusion bodies in affected muscle fibres.", "ORPHA ID": 97239, "Summary": "Epidemiology\nThe prevalence is unknown: although some sporadic cases have been described, only four families with RBM have been reported in the literature so far.\nClinical description\nThe age of onset, speed of progression and severity of the disease vary significantly between patients, even between affected members of the same family. Although early development is generally normal (up to 2 years of age), onset during infancy or early childhood appears to be associated with severe myopathy, hypotonia and rapidly progressive muscle weakness leading to death due to respiratory insufficiency within the first five years of life. Onset during childhood or adulthood is characterised by mainly proximal muscle weakness, a rigid spine syndrome and a slowly progressive disease course.\nEtiology\nBoth sporadic and familial cases of RBM are caused by mutations in the gene encoding the four-and-a-half LIM domain 1 protein (FHL1; Xq27.2).\nDiagnostic methods\nAs the clinical picture is highly variable (EMG reveals mixed myogenic patterns), diagnosis relies on recognition of the typical histopathological findings at muscle biopsy: the non-membrane-bound inclusions reduce nitro-blue tetrazolium (hence the name `reducing body myopathy') and are located in the cytoplasm, usually close to the degenerating nucleus. Electron microscopy reveals that the inclusions consist of a fine granular material and immunohistochemical analysis reveals the presence of aggresome-like proteins.\nDifferential diagnosis\nThe differential diagnosis should include other disorders with reducing bodies (e.g. acid maltase deficiency) and other congenital myopathies in familial cases (see these terms). Sarcotubular myopathy may also be considered in patients with less severe forms of the disease.\nGenetic counseling\nThe mode of transmission remains unclear. There are no reports of male-to-male transmission in familial cases and cases of severely affected females have been reported. X-linked dominant, semi-dominant and recessive inheritance have been suggested and skewed X-inactivation has not been excluded.\nManagement and treatment\nManagement is supportive and should be multidisciplinary (involving a neurologist, orthopaedic surgeon and physical therapist).\nPrognosis\nThe prognosis is generally severe: disease progression results in loss of ambulation, and death due to respiratory failure occurs even in patients with later-onset slowly progressive forms of the disease.\n\n                            Last update: \n                            April 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Bertrand FONTAINE"}
{"Disease Name": "Reflex epilepsy", "Disease Definition": "Reflex epilepsy refers to epilepsies where recurrent seizures are provoked by a clearly defined extrinsic (most commonly) or intrinsic triggering stimuli such as flashing lights (photosensitive epilepsy), startling noises (startle epilepsy), urinating (micturition induced seizures), exposure to hot-water (hot water epilepsy, see these terms), eating, reading, and thinking, while being associated with an enduring abnormal predisposition to have such seizures (thereby meeting the conceptual definition of epilepsy).", "ORPHA ID": 310, "Summary": ""}
{"Disease Name": "Refractory anemia with excess blasts in transformation", "Disease Definition": "A rare hematologic disease characterized by the presence of 20-29% blasts in the bone marrow, presence of 5-29% blasts in the peripheral blood, and/or presence of Auer rods. Patients show relatively stable peripheral blood counts for weeks or months, with specific cytogenetic and molecular genetic characteristics constituting important prognostic factors.", "ORPHA ID": 168960, "Summary": ""}
{"Disease Name": "Refractory celiac disease", "Disease Definition": "Refractory celiac disease is a rare intestinal disease characterized by persistent or recurrent symptoms and signs of confirmed celiac disease despite a long-term, strict, gluten-free diet, in the absence of other causes of villous atrophy or malignant complications and with or without presence of increased abnormal intraepitelial lymphocytes.", "ORPHA ID": 398063, "Summary": ""}
{"Disease Name": "Refractory cytopenia with multilineage dysplasia", "Disease Definition": "Refractory cytopenias with multilineage dysplasia (RCMD) is a frequent subtype of myelodysplastic syndrome (MDS; see this term) characterized by 1 or more cytopenias in the peripheral blood and dysplasia in 2 or more myeloid lineages.", "ORPHA ID": 86836, "Summary": "Epidemiology\nExact prevalence is unknown but RCMD accounts for about 30% of patients with MDS which has a prevalence estimated to be 1/25,000 to 1/33,000. The disease tends to occur in older adults with a male predominance.\nClinical description\nMost patients are asymptomatic at presentation, and the disorder is detected incidentally. Some patients may have fatigue (anemia), a tendency to bleed or bruise (thrombocytopenia), or susceptibility to infections (neutropenia). Laboratory findings show one or more cytopenias.\nEtiology\nThe etiology is not known but is thought to involve inherited susceptibility or hematopoietic stem cell damage.\nDiagnostic methods\nThe hematological parameters used to define RCMD are as follows: less than 1% blasts in peripheral blood or less than 5% in bone marrow, multilineage dysplasia sometimes with ring sideroblasts, and no Auer rods (abnormal, needle-shaped or round inclusions in the cytoplasm of myeloblasts and promyelocytes).\nPrognosis\nMedian survival of 17 to 33 months has been reported.\n\n                            Last update: \n                            February 2015"}
{"Disease Name": "Refsum disease", "Disease Definition": "A metabolic disease characterized by anosmia, cataract, early-onset retinitis pigmentosa and possible neurological manifestations, including peripheral neuropathy and cerebellar ataxia. Other features can be deafness, ichthyosis, skeletal abnormalities, and cardiac arrhythmia. It is characterized biochemically by accumulation of phytanic acid in plasma and tissues.", "ORPHA ID": 773, "Summary": "Epidemiology\nAbout 60 cases of Refsum disease (RD) have been reported worldwide. Prevalence rates are not known but the disorder may be underdiagnosed. Prevalence has been estimated to be 1/1,000,000 in the United Kingdom. Males and females are affected equally.\nClinical description\nAge of onset ranges is childhood to over 50 years of age but may be difficult to determine. Retinitis pigmentosa is often the first sign and is found in almost all patients. Onset of night blindness in childhood is common. Cataract and nystagmus may be found later on. Anosmia is a universal clinical manifestation. Symmetric mild-to-profound sensorineural hearing loss, ataxia of late onset causing an unsteady gait, and more rarely mild generalized ichthyosis may develop subsequently. Mixed motor and sensory neuropathy may also be found, causing muscular atrophy, weakness, and peripheral sensory disturbances. Autism spectrum disorder and attention deficit-hyperactivity disorder (AD-HD) are also reported. Short metacarpals and metatarsals at birth are found in about 1/3 of cases. Cardiac arrhythmia and cardiomyopathy causing heart failure are also reported.\nEtiology\nRD is caused by mutations in the PHYH gene (10p13) in more than 90% of cases, and mutations in the PEX7 gene (6q21-q22.2) in less than 10%. These genes are involved in lipid metabolism and protein transport. The pathogenic mechanism is related to the accumulation of phytanic acid, which is predominantly (>90%) degraded by alpha-oxidation in peroxisomes.\nDiagnostic methods\nThe diagnosis is based on clinical manifestations including retinitis pigmentosa and variable combinations of the other features. The interval between initial signs and diagnosis may exceed 10 years. All classic disease manifestations are rarely found in a single affected person. Analysis of phytanic acid concentrations in plasma or serum shows abnormal levels generally above 200 micromol/L. Enzymatic fibroblast analysis and molecular genetic testing of the causative genes are required to confirm the diagnosis.\nDifferential diagnosis\nOther causes of retinitis pigmentosa and sensorineural hearing loss should be considered in the differential diagnosis (Usher syndromes, types 1, 2, and 3; Alström syndrome; Kearns-Sayre syndrome; Sjögren-Larsson syndrome). Refsum disease should not be confused with infantile Refsum disease a misnomer that belongs to the Zellweger syndrome spectrum.\nAntenatal diagnosis\nPrenatal diagnosis can be performed if a disease-causing mutation is known in the family.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nPhytanic acid is obtained from the diet, particularly from meat and dairy products. Dietary restriction helps to control sensory neuropathy, myopathy, ataxia and ichthyosis. In acute presentations (arrhythmia, weakness), plasmapheresis or lipapheresis may be useful. Supportive treatment includes hydrating creams, anti-arrhythmics, and cardiac medication. Bilateral cochlear implantation may be considered for severe hearing loss. Cardiac and ophthalmological monitoring is required. Rapid weight loss should be prevented (e.g. during hospital admission) because that can cause rapid increase in plasma phytanic acid levels.\nPrognosis\nPrognosis in the absence of treatment is generally poor. Severe cases or late diagnosis may be life-threatening. The main cause of death is arrhythmia and heart failure.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Dr M. [Marc] ENGELEN  - Pr C.E.M. [Carla] HOLLAK  - Dr M. [Mirjam] LANGEVELD"}
{"Disease Name": "Regional odontodysplasia", "Disease Definition": "A rare orodental disease characterized by localized developmental anomaly of the dental tissues, with enamel and dentin hypomineralization affecting one (odontodysplasia) or several (regional odontodysplasia; ROD) teeth (deciduous and permanent, with teeth of the maxilla more frequently involved).", "ORPHA ID": 83450, "Summary": "Epidemiology\nThe prevalence is unknown but around 180 cases have been reported in the literature so far.\nClinical description\nThe defects involve both primary and permanent dentitions in the majority of the cases. The teeth of individuals with ROD are usually hypoplastic, small and atypically shaped with surface pits and grooves and a yellowish or brownish discoloration. Early loss of primary teeth is described. The condition usually affects the maxilla more than the mandible and is generally unilateral. Other common features include eruption failure or delay, and facial swellings (cellulitis), abscesses or fistulae in the absence of caries. Radiographic examination reveals a lack of contrast between enamel and dentin, with very thin (ghost-like) layers. Both dentin and enamel are hypomineralized. The pulp looks large and pulp stones or denticles can be seen. Histological features include mixed areas of cellular, amorphous and interglobular dentin. The enamel is hypoplastic, and hypocalcified areas and invaginations from the enamel surface into the dentin layer have been observed and may result in bacterial contamination of the pulp, leading to pulpitis or necrosis. The bone itself is not affected.\nEtiology\nThe underlying cause of ROD is still a matter of debate but various etiological factors have been suggested such as local circulatory disorders, viral infections, local trauma, pharmacotherapy during pregnancy, facial asymmetry or a combination of these factors. Some familial cases may also point towards a genetic etiology.\nDiagnostic methods\nDiagnosis should be suspected on the basis of the clinical aspect of the teeth, or upon presentation with failure of eruption, or pulpitis or necrosis in absence of caries. The diagnosis may be confirmed by radiography revealing the typical ''ghost-like'' appearance of the teeth and the presence of enamel and dentin with similar radiodensities.\nDifferential diagnosis\nThe differential diagnosis includes dentinogenesis imperfecta, dentin dysplasia and amelogenesis imperfecta.\nManagement and treatment\nManagement is mainly conservative and includes treatment of the pulpitis and necrosis when necessary, with the aim of trying to maintain the affected teeth as long as possible to permit normal jaw development. If extraction is required, the extracted teeth should be replaced with removable appliances to maintain aesthetic appearance and function, and to avoid overeruption of opposing teeth and preserve the normal vertical dimension. Some patients benefit from autotransplants. Prosthesis and implants can be considered when craniofacial development is complete.\nPrognosis\nThe prognosis for patients is good, especially when the condition is diagnosed and managed during the early stages. Life-long treatment is expected.\n\n                            Last update: \n                            November 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN | ERN CRANIO*\n\n\n                                * European Reference Network"}
{"Disease Name": "Regressive spondylometaphyseal dysplasia", "Disease Definition": "A rare, primary bone dysplasia characterized by mild short stature, rhizomelic shortening of the arms and legs, bowing of long bones with widened and irregular metaphyses, thoracolumbar kyphosis, and metacarpal shortening. A marked improvement of the radiologic skeletal features is typical. Pelger-Huet anomaly (i.e. dumbbell shape bilobed nuclei of neutrophils) is a characteristic hematological feature of this disease.", "ORPHA ID": 448267, "Summary": ""}
{"Disease Name": "Reis-Bücklers corneal dystrophy", "Disease Definition": "Reis-Bücklers corneal dystrophy (RBCD), also known as granular corneal dystrophy type III, is a rare form of superficial corneal dystrophy characterized by bilateral symmetrical reticular opacities in the superficial central cornea, with progressive visual impairment.", "ORPHA ID": 98961, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is not known.\nClinical description\nLesions develop at about 4 to 5 years of age. The opacities assume an irregular ring-shaped pattern of discrete spots and lines that focally elevate the corneal epithelium. RBCD remains asymptomatic until epithelial erosions precipitate acute episodes of ocular hyperemia, pain, and photophobia. Visual acuity eventually becomes reduced during the second and third decades of life following a progressive superficial haze and development of an irregular corneal surface. Compared to other variants of granular corneal dystrophy, RBCD involves earlier onset of symptoms and a higher frequency of recurrent erosions.\nEtiology\nReis-Bücklers corneal dystrophy is caused by a specific mutation in the TGFBI gene (5q31).\nDiagnostic methods\nThe superficial corneal stroma contains deposits of mutated transforming growth factor beta-induced protein that are indistinguishable from those of other forms of granular corneal dystrophies.\nDifferential diagnosis\nRBCD is clinically similar to Thiel-Behnke corneal dystrophy (TBCD, see this term), but generally has a more severe course. Tissue examination or molecular genetic analysis can be used to differentiate RBCD and TBCD.\nGenetic counseling\nAn autosomal dominant pattern of inheritance has been reported.\nManagement and treatment\nIn advanced cases of RBCD, a superficial keratectomy, phototherapeutic keratectomy (PTK) or lamellar keratoplasty (LKP) may improve vision, but a penetrating keratoplasty (PK) is rarely necessary because the pathologic changes only involve the superficial cornea.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "RELA fusion-positive ependymoma", "Disease Definition": "A rare ependymal tumor characterized by the presence of a RELA fusion gene. This supratentorial grade II or III ependymoma most often occurs in children and young adults. Histopathological features are variable, but a distinctive vascular pattern of branching capillaries or clear-cell change are common. Patients may present with focal neurological deficits, seizures, or features of raised intracranial pressure. Prognosis is worse than in other supratentorial ependymomas.", "ORPHA ID": 530792, "Summary": ""}
{"Disease Name": "Relapsing fever", "Disease Definition": "Relapsing fever is an infection caused by bacteria of the genus Borrelia, excluding those responsible for Lyme disease (see this term) belonging to the Borrelia burgdorferi complex.", "ORPHA ID": 91547, "Summary": "Epidemiology\nLouse-borne relapsing fever is a world-wide disease but occurs mainly in localized regions of developing countries. Tick-borne relapsing fever occurs in Africa, the Mediterranean region, Asia and America. Only a few imported cases are seen in Northern European countries.\nClinical description\nThe disease is characterized by cyclic fever (alternating periods of sudden fever followed by remission) associated with a general state of ill health with other rare complications (cardiac, neurologic or ocular manifestations and hemorrhage).\nEtiology\nThe disease may be epidemic and transmitted by lice or endemic and transmitted by soft-bodied ticks (Ornithodoros and Argas).\nDiagnostic methods\nDiagnosis revolves around direct examination of stained blood smears and on PCR analysis of blood samples.\nDifferential diagnosis\nThe principle differential diagnosis is malaria.\nManagement and treatment\nAntibiotic treatment (cycline) is effective. Prevention revolves around eradication of the host vector.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Muriel CORNET  - Dr Elisabeth FERQUEL"}
{"Disease Name": "Relapsing polychondritis", "Disease Definition": "A rare, clinically heterogeneous, multisystemic inflammatory disease characterized by inflammation of the cartilage and proteoglycan rich structures leading to cartilage damage along with joint, ocular and cardiovascular involvement.", "ORPHA ID": 728, "Summary": "Epidemiology\nThe prevalence and annual incidence of Relapsing polychondritis (RP) are not known. The estimated incidence is 1/285,000. The sex ratio appears to be equal and all ethnic groups seem to be affected (with more cases reported among Caucasians).\nClinical description\nOnset is generally sudden and most commonly occurs in the 5th decade of life (age 40 to 55). Cases with early and late onset do occur. RP follows a flaring and remitting course. Clinical manifestations vary from intermittent auricular and nasal chondritis, to occasional organ or life-threatening complications. Unilateral or bilateral external ear inflammation with pain, tenderness, swelling, erythema, and discoloration, limited to the cartilaginous portion of the pinna with characteristic sparing of the lobule, is one of the hallmark features of RP (90-95% of patients). Auricular collapse or inflammation of vestibular structures can lead to conductive or sensorineural hearing loss. Other associated complications include nausea, vomiting, tinnitus, vertigo and ataxia. Nasal chondritis with sudden pain and tenderness is found at some stage of the disease in more than 50% of patients. Nasal cartilage may be severely damaged resulting in saddle nose deformity. Some patients develop potentially serious laryngotracheal involvement with hoarseness, aphonia, stridor and wheezing, dyspnea, or even airway collapse. Joint pain lasting weeks or months is found in most patients (>70%) and is often the presenting feature (30%). Cardiovascular manifestations (25-50%) include large vessel vasculitis, aneurysmal involvement, and aortic or mitral valve disease. Ocular manifestations reported are proptosis, conjunctivitis, ulcerative keratitis, episcleritis/scleritis, uveitis, and periorbital edema. Cutaneous manifestations that may precede chondritis include aphthosis, nodules, purpura, and papules. Neurological manifestations are due to vasculitis of central or peripheral nervous system. Renal involvement is rare. MAGIC syndrome represents a subset of patients with RP who also have mouth and genital ulcers, which are features of Behçet disease.\nEtiology\nThe exact etiopathogenesis of RP is not known but it is thought to be an immune-mediated disease. A complex cytokine network is thought to be involved in the recruitment of infiltrating cells in RP lesions.\nDiagnostic methods\nThere is no single blood or imaging test that can be used to diagnose this condition. The diagnosis is generally based upon the detection of a combination of clinical presentations. According to the most accepted and widely used diagnostic criteria, three of the following six features are required to make a diagnosis of RP: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage.\nDifferential diagnosis\nDifferential diagnoses include granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, Behçet disease, and leprosy.\nManagement and treatment\nTreatment is primarily symptomatic and no standard therapeutic protocol has been established due to the rarity of the disease. In less severe cases, non-steroidal anti-inflammatory drugs, dapsone, and colchicine may be used. In severe cases with organic involvement, systemic corticosteroids (oral prednisolone or rarely intravenous methylprednisolone) are required. Methotrexate, azathioprine, cyclosporine and chlorambucil may constitute an alternative. Use of biological agents like anti TNFs, tocilizumab, anakinra, rituximab and abatacept has been reported with various efficacy in case reports and small case series. A relapsing polychondritis disease activity index (RPDAI) and damage index (RPDAM) has been validated for assessing disease activity and damage respectively.\nPrognosis\nPrognosis is generally good in the majority of cases, but the disease may occasionally follow a severe, life-threatening course, with respiratory complications (tracheal collapse and infections) as the primary cause of mortality. Cardiovascular involvement may also lead to a fatal outcome.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Aman SHARMA"}
{"Disease Name": "REN-related autosomal dominant tubulointerstitial kidney disease", "Disease Definition": "A rare autosomal dominant tubulointerstitial kidney disease (ADTKD) of childhood due to REN mutations and characterized by early onset hypoproliferative anemia, hyperuricemia, gout, and slowly progressive tubulointerstitial kidney disease.", "ORPHA ID": 217330, "Summary": "Epidemiology\nTo date, approximately 35 families have been reported in the medical and scientific literature.\nClinical description\nFor patients with mutations in the promoter or prosegment of the REN gene, disease onset typically occurs from the first year of life, with presentation of hypoproliferative anemia and elevated serum creatinine. The anemia resolves as the child enters adolescence. Dysfunction of the renin-angiotensin system puts children at risk of volume depletion and acute kidney injury (particularly after febrile illness). Acute kidney injury typically resolves with appropriate treatment; however, baseline chronic kidney disease (CKD) may be noted. Individuals also suffer from hyperuricemia and may develop gout in their teenage years. Other occasional features include polyuria, mild hypotension and mild hyperkalemia. Kidney function slowly worsens over time with progression to end-stage kidney disease (ESKD) between 40-70 years of age. Patients with mutations in the segment of the REN gene encoding mature renin present with gout in the late teens and early twenties as well as early CKD which worsens over time and eventually requires renal replacement therapy.\nEtiology\nThe disease is due to heterozygous missense mutations in the REN gene (1q32) and results in reduced renin biosynthesis and secretion, and intracellular accumulation of abnormal protein. These changes lead to accelerated apoptosis, nephron dropout, interstitial fibrosis, and progressive loss of kidney function.\nDiagnostic methods\nThe diagnosis is suspected on clinical and laboratory findings including hypoproliferative anemia and hyperuricemia, decreased fractional excretion of uric acid, and evidence of slowly progressive, chronic tubulointerstitial kidney disease. A family history compatible with ADTKD may assist in diagnosis. Renal ultrasound shows normal or small-sized kidneys with no signs of cyst formation. Plasma renin levels are low. Genetic diagnosis through a multi-gene panel or whole exome sequencing provides a good option for differentiating from similar conditions.\nDifferential diagnosis\nRenal manifestations are similar to that of nephronophthisis; however, nephronophthisis is often associated with other symptoms. For individuals with mutations in the segment encoding the mature part of the REN gene, patients present very similarly to ADTKD-UMOD.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known mutation through molecular genetic testing.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. The risk of inheriting the pathogenic variant is 50% in siblings and offspring of affected individuals. Penetrance is 100%, although the rate of progression of ESKD is variable. Cascade testing should be performed within families, as family members may have been misdiagnosed. Children of a parent with a REN mutation in the promoter or prosegment should have a basic metabolic panel within the first week of life, with genetic testing also performed.\nManagement and treatment\nChildren at risk should be referred to a pediatric nephrologist as early management is likely beneficial. Erythropoiesis-stimulating agents and fludrocortisone can be used for the treatment of anemia and symptomatic hypotension, respectively. Alkali supplementation can also correct metabolic acidosis but may not be as effective or as palatable as fludrocortisone. It is important to normalize serum bicarbonate to maximize growth. Fludrocortisone can potentially aggravate interstitial fibrosis and should not be used in those with declining kidney function, hypertension, hyperkalemia, or edema. Gout is typically prevented with allopurinol or febuxostat and prevention therapy is life-long; treatment with a low sodium diet and nonsteroidal anti-inflammatory drugs is contraindicated. Progression of kidney disease should be monitored by a nephrologist. As kidney disease progresses, renal replacement therapy may be required. Kidney transplantation without prior dialysis is the treatment of choice for kidney failure.\nPrognosis\nThe prognosis is good with suitable, timely treatment. The disorder does not reoccur in transplanted kidneys.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Anthony BLEYER  - Pr Stanislav KMOCH  - Dr Martina ZIVNA"}
{"Disease Name": "Renal agenesis, bilateral", "Disease Definition": "A form of renal agenesis characterized by complete absence of kidney development, absent ureters and subsequent absence of fetal renal function resulting in Potter sequence with pulmonary hypoplasia related to oligohydramnios, which is fatal shortly after birth.", "ORPHA ID": 1848, "Summary": ""}
{"Disease Name": "Renal agenesis, unilateral", "Disease Definition": "A form of renal agenesis characterized by the complete absence of development of one kidney accompanied by an absent ureter.", "ORPHA ID": 93100, "Summary": ""}
{"Disease Name": "Renal agenesis", "Disease Definition": "A rare, congenital renal tract malformation characterized by the complete absence of development of one or both kidneys (unilateral or bilateral renal agenesis respectively), accompanied by absent ureter(s).", "ORPHA ID": 411709, "Summary": "Epidemiology\nThe birth prevalence of unilateral renal agenesis (RA) is estimated at around 1/2,000. Fetal prevalence of bilateral renal agenesis in Europe has been estimated at 1/8,500.\nClinical description\nMost patients with unilateral RA are asymptomatic early in life if the other kidney is fully functional in which case the condition is commonly detected as an incidental finding later in life. However, hypertension, proteinuria and renal failure may develop in the long run (20-50% of cases at the age of 30). Unilateral RA is occasionally associated with additional urogenital tract anomalies on the same side (e.g. seminal vesicle hypoplasia and absence of the vas deferens), cardiac anomalies (such as atrial or ventricular septal defects) and/or gastrointestinal anomalies (such as anal atresia). Bilateral RA is characterized by complete absence of kidney development, absent ureters and subsequent absence of fetal renal function resulting in Potter sequence with pulmonary hypoplasia related to oligohydramnios, which left untreated is fatal shortly after birth.\nEtiology\nRenal agenesis results from a developmental failure of the ureteric bud and the metanephric mesenchyme. Unilateral renal agenesis can be caused by mutations in many genes, such as RET (10q11.2), BMP4 (14q22-q23), FRAS1 (4q21.21), FREM1 (9p22.3), or UPK3A (22q13.31). A few cases of bilateral renal agenesis have been found to be caused by mutations in the RET, FGF20 (8p22) or ITGA8 (10p13) genes. Maternal diabetes mellitus or use of specific drugs during pregnancy may also cause renal agenesis.\nDiagnostic methods\nDiagnosis is based on ultrasonography, showing an empty renal fossa and no ectopic kidney. Additional radiological examinations like MRI (magnetic resonance imaging) and/or DMSA (dimercaptosuccinic acid) scintigraphy may confirm the diagnosis. The contra-lateral kidney may be compensatory hypertrophied.\nDifferential diagnosis\nDifferential diagnoses of an empty renal fossa include kidney ectopia and involution of multi-cystic dysplastic kidneys (MCDK).\nAntenatal diagnosis\nPrenatal diagnosis may be made by prenatal ultrasonography.\nGenetic counseling\nIn familial cases, unilateral RA is typically inherited in an autosomal dominant manner with incomplete penetrance. Bilateral RA is inherited autosomal recessively.\nManagement and treatment\nClinical management of unilateral renal agenesis with fully functioning contra-lateral kidney included routine evaluations of blood-pressure and screening for proteinuria as individuals with RA have an elevated risk of chronic kidney disease.\nPrognosis\nThe prognosis of RA with fully functioning contra-lateral kidney is generally good. Without intensive care, bilateral RA is fatal shortly after birth.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Stefan KOHL | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Renal caliceal diverticuli-deafness syndrome", "Disease Definition": "A rare, syndromic, developmental defect during embryogenesis characterized by urinary tract and kidney anomalies, such as renal pelviocaliceal attenuation with multiple tiny caliceal diverticula, associated with sensorineural hearing loss. There have been no further descriptions in the literature since 1981.", "ORPHA ID": 2838, "Summary": ""}
{"Disease Name": "Renal coloboma syndrome", "Disease Definition": "A genetic condition characterized by optic nerve dysplasia and renal hypodysplasia.", "ORPHA ID": 1475, "Summary": "Epidemiology\nPrevalence and prevalence at birth are not known. 177 mutation-positive cases (90 different families) have been reported. The number of mutation-negative individuals with clinical findings of Renal coloboma syndrome (RCS) is not known. There is no ethnic predilection.\nClinical description\nRCS is characterized primarily by ocular signs (77%) and renal manifestations (92%). Eye anomalies consist of a wide and sometimes excavated dysplastic optic disc with emergence of the retinal vessels from the disc periphery, frequently called optic nerve coloboma or ''morning glory'' anomaly. Associated findings may include a small corneal diameter, retinal coloboma, scleral staphyloma, reduced corneal diameter, optic nerve cyst, microphthalmia, foveal hypoplasia and pigmentary macular dysplasia. Nystagmus and myopia have also been reported. Consequences include decreased visual acuity, blindness, and retinal detachment. Renal malformations and/or insufficiency are frequently the presenting feature and consist of small and abnormally formed kidneys known as renal hypodysplasia. Histologically, kidneys exhibit fewer than normal enlarged glomeruli (oligomeganephronia). Other renal findings include multicystic dysplastic kidney and horseshoe kidney. Consequences include hypertension, proteinuria, vesicoureteral reflux, and renal insufficiency that frequently progresses to end-stage renal disease (ESRD). ESRD may present prenatally with severely hypoplastic or dysplastic kidneys and oligohydramnios resulting in fetal loss due to Potter sequence. Patients can progress to stage 5 chronic kidney disease at any age. High frequency (HF) hearing loss is reported in 7% of patients.\nEtiology\nMutations in thePAX2gene (10q24) have been identified in about 1/2 of patients with renal hypodysplasia and abnormalities of the optic nerve. PAX2 mutations have been identified in about 9% of unselected individuals presenting with renal hypoplasia. The genetic basis of the remaining cases is not known.\nDiagnostic methods\nFormal diagnostic criteria have not been established. However, the disorder should be suspected in patients who have the classical findings of optic nerve dysplasia or coloboma and renal hypodysplasia. Oligomeganephronia is a common histologic finding in renal hypodysplasia but it is not pathognomonic for RCS.\nDifferential diagnosis\nThe differential diagnosis includes conditions where colobomas and renal anomalies have been identified such as CHARGE syndrome and Joubert syndrome with oculorenal defect (see these terms). However these disorders generally have other characteristic findings not found in RCS.\nAntenatal diagnosis\nPrenatal diagnosis or pre-implantation genetic testing is possible if a clearly pathogenic PAX2 mutation has been identified in a family.\nGenetic counseling\nRCS is inherited in an autosomal dominant pattern, though this is complicated by de novo cases, variable expression, incomplete clinical penetrance, and maternal and paternal gonosomal mosaicism.\nManagement and treatment\nManagement involves care for the renal and ophthalmologic manifestations. Patient evaluation should include renal function testing, renal ultrasound, urinalysis (proteinuria), blood pressure measurements and evaluation for vesicouretal reflux if clinically indicated. Long-term follow-up by a nephrologist and ophthalmologist are recommended. Low vision experts may also be called upon if needed. Audiologic evaluation for HF hearing loss is indicated as it may affect verbal communication.\nPrognosis\nPrognosis depends primarily on appropriate specialized treatment. Renal failure can occur at any age requiring dialysis and renal transplantation. Formal longitudinal studies of visual prognosis have not been carried out. However, decreased visual acuity over time has been reported.\n\n                            Last update: \n                            June 2012\n\n\n                            - Expert reviewer(s): \n                             Matthew BOWER  - Pr Lisa SCHIMMENTI"}
{"Disease Name": "Renal dysplasia, bilateral", "Disease Definition": "A form of renal dysplasia (RD), a renal tract malformation, characterized by abnormal or incomplete development of both kidneys. Bilateral RD can be segmental, and of variable severity, with renal aplasia corresponding to extreme RD. Patients may be asymptomatic if the residual kidney function is sufficient. In cases of severe bilateral RD, the risk of renal failure in childhood is high.", "ORPHA ID": 93173, "Summary": ""}
{"Disease Name": "Renal dysplasia, unilateral", "Disease Definition": "A form of renal dysplasia (RD) characterized by abnormal or incomplete development of one kidney. Unilateral RD can be segmental, and of variable severity, with renal aplasia corresponding to extreme RD. Patients may be asymptomatic if the contralateral kidney is functional. Even in cases of severe unilateral RD, i.e. renal aplasia, the risk of renal failure in childhood is minimal; however, patients may develop hypertension, proteinuria and renal failure as adults.", "ORPHA ID": 93172, "Summary": ""}
{"Disease Name": "Renal dysplasia", "Disease Definition": "A rare renal malformation in which the kidney(s) are present but their development is abnormal, leading to malformation of histologic architecture of the kidney and presence of embryological tissue such as mesenchymal collarettes or other forms of undifferentiated and metaplastic tissues. Renal dysplasia can be unilateral or bilateral, segmental, and of variable severity.", "ORPHA ID": 93108, "Summary": "Epidemiology\nPrevalence and incidence are not known due to the highly variable presentation and asymptomatic unilateral cases. In Europe, the prevalence at birth is estimated 1 / 2,300. Renal aplasia/hypoplasia/dysplasia are the most frequent underlying pathology in children requiring renal replacement therapy (13.5%).\nClinical description\nRenal dysplasia is usually asymptomatic, but an abnormal kidney sonographic appearance may be detected during routine antenatal ultrasonography (US), US for urinary tract infections (in children) or renal disease (in children and adults). The severity of dysplasia is variable with renal aplasia at the extreme end. In cases of unilateral renal aplasia, consequences are similar to having a solitary functioning kidney, potentially resulting in hypertension and proteinuria, and possible kidney failure in adulthood. In cases of bilateral renal dysplasia, chronic kidney disease and kidney failure can occur during childhood. Bilateral renal dysplasia may limit kidney function to such an extent that oligohydramnios occurs during pregnancy, which is associated with the Potter sequence. In such cases, neonates may die shortly after birth due to respiratory failure; those with residual renal function may develop complications of chronic kidney disease: failure to thrive, growth retardation, anemia, hypertension, proteinuria and kidney failure.\nEtiology\nThe etiology of renal dysplasia is multi-factorial. Generally, it may occur as an isolated condition or as a component of numerous rare syndromes, either secondary due to antenatal urine obstruction or due to primary maldevelopment of nephrogenic tissues. Isolated renal dysplasia has been reported in families with mutations in HNF1B (17q12). Incomplete penetrance and variable expressivity are very common in CAKUT (congenital anomalies of kidney and urinary tract); thus, genes involved in multi-organ syndromes ( such as EYA1, GATA3, GREBI1L, PAX2, PBX1, SALL1, FRAS1, FREM2, and GRIP1) may possibly lead to an isolated renal phenotype (dysplasia/hypoplasia/agenesis). Other forms of renal dysplasia may be caused by embryotoxic drugs such as angiotensin converting enzyme inhibitors or prenatal programming triggers such as hypoxia or diabetes mellitus.\nDiagnostic methods\nDiagnosis is based on ultrasonography, showing an abnormal appearing kidney with absent or poor corticomedullary differentiation with or without cysts and increased echogenicity. Kidneys may be of normal size or small. Renography shows decreased renal uptake of DMSA-tracer. Histology shows disorganized primitive ducts surrounded by mesenchymal stroma. Genetic analysis may identify variants in one of the previously mentioned genes in a minority of cases.\nDifferential diagnosis\nDifferential diagnoses of an abnormally differentiated kidney on ultrasound include renal hypoplasia, polycystic kidney disease, vascular insults, and renal post-infectious damage. Renal dysplasia may occur as part of recognized syndromes such as Kallmann, Bardet-Biedl, Beckwith-Wiedemann, diGeorge, Fraser, and renal coloboma syndromes as well as HNF1B-related autosomal dominant tubulointerstitial kidney disease.\nAntenatal diagnosis\nAntenatal diagnosis is possible from midway through gestation. The condition is dynamic and can evolve during pregnancy and after birth; therefore, repeated assessments are necessary.\nGenetic counseling\nFamilies may benefit from genetic counseling in case of renal dysplasia as part of a multi-organ syndrome, in familial cases or in bilateral cases with chronic kidney disease. The recurrence risk in families may be elevated, but data remain scarce.\nManagement and treatment\nRegular evaluation of the remaining kidney function is recommended. Due to an increased risk of hypertension and/or proteinuria, a long-term follow-up is recommended. In severe cases, kidney replacement therapy may be needed.\nPrognosis\nInfants with pulmonary hypoplasia show substantial mortality in the neonatal period. Survivors may develop chronic renal failure in childhood. In unilateral renal dysplasia, the risk of kidney failure in childhood is minimal but patients may develop hypertension, proteinuria and kidney failure as adults.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Stefan KOHL | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Renal hypoplasia, bilateral", "Disease Definition": "A form of renal hypoplasia characterized by bilateral small kidneys with a deficit in the number of nephrons present. The condition is typically asymptomatic but may be associated with hypertension, and some excretory functional limitations, as well as eventual chronic renal failure.", "ORPHA ID": 97362, "Summary": ""}
{"Disease Name": "Renal hypoplasia, unilateral", "Disease Definition": "A form of renal hypoplasia characterized by unilateral small kidneys with a deficit in the number of nephrons present. The condition is typically asymptomatic with minimal risk of renal failure in childhood", "ORPHA ID": 97361, "Summary": ""}
{"Disease Name": "Renal hypoplasia", "Disease Definition": "A congenital renal malformation characterized by abnormally small kidney(s) (kidney volume below two standard deviations of that of age-matched normal individuals or a combined kidney volume of less than half of what is normal for the patient's age) with normal corticomedullary differentiation and reduced number of nephrons.", "ORPHA ID": 93101, "Summary": "Epidemiology\nIsolated renal hypoplasia is considered rare and, given the difficulty to distinguish it from renal dysplasia that may also result in small kidneys, its prevalence and incidence are unknown. Both renal dysplasia and renal hypoplasia account for a significant proportion of chronic kidney disease in children and of inborn causes of chronic kidney disease in adults.\nClinical description\nIsolated, unilateral renal hypoplasia is usually asymptomatic. It may be detected in a prenatal ultrasound screening, after a urinary tract infection in children, or with hypertension, proteinuria (generally symptoms of chronic kidney disease) in children and adults. Disease severity depends on the degree of reduction in the number of nephrons, the involvement of the other kidney, and whether other congenital anomalies of the kidney and urinary tract (CAKUT) are present. The disease may lead to glomerular hyperfiltration associated with hypertension, proteinuria and, in the long term, with chronic kidney failure.\nEtiology\nThe occurrence of renal hypoplasia may be caused by mutations in kidney developmental genes (HNF1B, PAX2, PBX1) and/or multiple environmental factors such as intrauterine growth restriction, maternal diseases (diabetes, hypertension), maternal drug intake (inhibitors of the renin-angiotensin system or non-steroidal anti-inflammatory drugs (NSAIDs)) and intoxication (smoking and alcohol). Variants in multiple additional genes or genomic alterations have been linked to kidney hypoplasia or dysplasia but their specific role for hypoplasia is not clearly understood (EYA1, GATA3, GREB1L, SALL1, large copy number variations). Premature birth (before the 36th week) is also a risk factor due to incomplete nephrogenesis. Generally, kidney hypoplasia is seen as a defect in nephron endowment.\nDiagnostic methods\nThe clinical diagnosis is typically based on ultrasonography. On fetal or postnatal ultrasound, renal hypoplasia is defined as a kidney volume of below two standard deviations or a combined kidney volume of less than half of age-related normal kidney volume. Corticomedullary differentiation typically is normal. Postnatal renography with technetium-99m-labeled dimercaptosuccinic acid shows smooth kidney outline.\nDifferential diagnosis\nDifferential diagnoses include all forms of kidney dysplasia. Although the definite differentiation can only be made on histological grounds, in clinical practice ultrasonography is used to distinguish normal appearing small kidneys (hypoplasia) from abnormal appearing small kidneys with disturbed corticomedullary differentiation and/or increased echogenicity, and/or cysts. Oligomeganephronia represents a severe variant of hypoplasia in which nephron number is reduced by 80% and nephrons are markedly hypertrophied\nAntenatal diagnosis\nAntenatal ultrasonographic screening is becoming routine and allows detection of renal hypoplasia from midway through gestation.\nGenetic counseling\nMost cases are sporadic. Familial cases have been observed with an autosomal dominant mode of inheritance with incomplete penetrance and variable expressivity and thus the recurrence risk of is up to 50% in such cases.\nManagement and treatment\nManagement largely depends on the degree of chronic kidney disease and whether or not there are additional CAKUT. Therefore, assessment of renal function (blood pressure, estimate of the glomerular filtration rate and proteinuria) should be obtained to evaluate the function of the remaining nephrons. Due to an increased risk of hypertension and/or proteinuria, individuals with renal hypoplasia deserve long-term follow-up. In extreme cases, kidney replacement therapy may be needed.\nPrognosis\nThe risk of end stage chronic kidney disease in childhood is low but kidney failure may occur in severe cases.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Stefan KOHL | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Renal medullary carcinoma", "Disease Definition": "Renal medullary carcinoma is a rare, aggressive subtype of renal cell carcinoma characterized by a large, white or tan, firm, infiltrative tumor with microabscess-like foci centered in the renal medulla, typically presenting with hematuria, abdominal/flank pain, weight loss and fever. It is associated with sickle cell trait and disease and metastasis to the bones and lungs is common at time of diagnosis.", "ORPHA ID": 319319, "Summary": ""}
{"Disease Name": "Renal nutcracker syndrome", "Disease Definition": "A rare, syndromic renal disease characterized by the entrapment of left renal vein (LRV) between the superior mesenteric artery (SMA) and the abdominal aorta, resulting in increased luminal pressure, renal hilar varices, hematuria and, at the microscopic level, rupture of thin-walled veins into the collecting system in renal fornices.", "ORPHA ID": 71273, "Summary": "Epidemiology\nThe exact prevalence is not known. Most cases have been reported from the Far-East. Women are more commonly affected than men.\nClinical description\nPatients with renal nutcracker syndrome (NCS) are usually asthenic, tall and thin. Many patients remain asymptomatic and are incidentally discovered during radiological imaging for other causes. Symptomatic cases present mostly in second/third decade of life with urological or gynecological symptoms. Urological manifestations include left loibdominal pain, left-sided macroscopic or microscopic hematuria (on endoscopy, varicocele, or lower limb varices. Gynecological symptoms resemble pelvic congestion syndrome and include symptoms of dysmenorrhea, dyspareunia, post-coital ache, lower abdominal pain, dysuria, pelvic/vulvar/gluteal/gonadal or thigh varices, and emotional disturbances. Three types of renal nutcracker syndrome have been defined, according to the site of LRV compression: anterior nutcracker syndrome, posterior nutcracker syndrome and combined nutcracker syndrome.\nEtiology\nNormally SMA separates from the abdominal aorta (AA) at a 90-degree angle. The LRV lies anterior to the aorta in the fork between the SMA and AA. In anterior NCS, the SMA arises from the aorta at an acute angle, compressing the LRV causing left renal venous hypertension. In posterior NCS, the LRV courses posterior to the AA and is compressed between the aorta and the vertebral column. In combined NCS, the anterior branch of the duplicated LRV is compressed between the aorta and the SMA, while the posterior is sandwiched between the aorta and the vertebral column.\nDiagnostic methods\nDiagnosis should be suspected upon presentation with left-sided loin pain and hematuria. Diagnostic tests include urine analysis, ultrasound scan, color Doppler scan, CT or MR angiography, and left renal vein phlebography and manometry. Doppler sonography is usually the first imaging tool, which can detect collateral veins around LRV, whose presence sustains venous hypertension and are a radiological criterion for NCS. The ''gold standard'' for diagnosis remain phlebography, intravascular pressure measurement and intravascular ultrasound through which the venous pressure gradient between LRV and inferior vena cava and the renal vein diameter can be measured. Patients usually show an LRV/inferior vena cava pressure gradient >1 mmHg. Computed tomography venography and magnetic resonance venography are noninvasive evaluation tools which provide good definition of LRV compression and grade of involvement of other organs.\nDifferential diagnosis\nCompression of LRV leading to loin pain and hematuria can be seen in pancreatic neoplasms, paraortic lymphoadenopathy, retroperitoneal masses, overarching testicular artery, lordosis, reduced retroperitoneal and mesenteric fat or too much fibrolymphatic tissue between SMA and AA.\nManagement and treatment\nSurveillance is appropriate in pubertal patients, who may undergo spontaneous remission with physical development and weight gain, and in patients with insignificant symptoms and microscopic hematuria, or intermittent painless gross hematuria with a normal hemogram. Open surgery procedures with good outcomes include vascular transpositions and renal auto transplantation. Extra-vascular stenting can be performed through open or laparoscopic surgery. Intravascular stenting is a treatment option in which a self-expanding metallic stent is deployed in the stenotic region of the LRV.\nPrognosis\nAs this is a benign condition, overall prognosis is excellent. In highly symptomatic patients, with severe pain, frank/recurrent hematuria requiring blood transfusion, active intervention needs to be considered. Prognosis following intervention is excellent.\n\n                            Last update: \n                            March 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Max Christoph LIEBAU | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Renal pseudohypoaldosteronism type 1", "Disease Definition": "A form of pseudohypoaldosteronism type 1 characterized by mild mineralocorticoid resistance that is restricted to the kidneys and that usually improves in early childhood. Typical presentation is in the neonatal period with weight loss, failure to thrive, vomiting and dehydration in association with hyponatremia, hyperkalemia and metabolic acidosis as well as elevated aldosterone and renin levels.", "ORPHA ID": 171871, "Summary": ""}
{"Disease Name": "Renal tubular dysgenesis due to twin-twin transfusion", "Disease Definition": "A rare acquired form of renal tubular dysgenesis that develops in donor fetuses due to the shunting of blood flow to the kidney of the recipient and characterized by absent or poorly developed proximal tubules, persistent oligohydramnios and consequently the Potter sequence (facial dysmorphism with large and flat low-set ears, lung hypoplasia, arthrogryposis and limb positioning defects).", "ORPHA ID": 97367, "Summary": ""}
{"Disease Name": "Renal tubular dysgenesis", "Disease Definition": "A rare disorder of the fetus characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence (facial dysmorphism with large and flat, low-set ears, lung hypoplasia, arthrogryposis and limb positioning defects), and skull ossification defects.", "ORPHA ID": 3033, "Summary": "Epidemiology\nThe incidence of renal tubular dysgenesis is unknown.\nClinical description\nThe clinical picture is of early onset oligohydramnios, skull ossification defects and neonatal pulmonary and renal failure.\nEtiology\nNon-syndromic renal tubular dysgenesis can be acquired during fetal development due to drugs taken by the mother (such as in utero exposure to ACE inhibitors) or in the context of twin-twin transfusion syndrome (TTTS). The genetic form is due to biallelic pathogenic variations in genes encoding either angiotensinogen (AGT; 1q42.2), renin (REN; 1q32.1), angiotensin converting enzyme (ACE ; 17q23.3) or angiotensin 2 receptor type 1(AGTR1; Xq23). Other disorders that can feature renal tubular dysgenesis include severe fetal cardiopathy, congenital hemochromatosis, and severe fetal renal artery stenosis.\nDiagnostic methods\nThe diagnosis is based on renal histology with or without proximal tubule labeling, and molecular genetics.\nDifferential diagnosis\nThe differential diagnosis includes secondary forms of renal tubular dysgenesis and leakage of amniotic fluid.\nAntenatal diagnosis\nDiagnosis may be suspected on routine prenatal ultrasound by presentation of oligohydramnios in the presence of a normal kidney scan. In families with an antecedence, genetic prenatal diagnosis is possible where the pathogenic variations have been previously identified.\nGenetic counseling\nFor the genetic form, transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement is typically expectant. Severe pulmonary hypoplasia is not treatable. Few cases with less severe respiratory disease were treated with peritoneal dialysis, followed by renal transplantation when the weight was sufficient. In cases due to twin-to-twin transfusion, fetoscopic laser photocoagulation, amnioreduction or delivery be suggested.\nPrognosis\nThe prognosis is extremely severe in the majority of cases.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Laurence HEIDET | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Renal tubulopathy-encephalopathy-liver failure syndrome", "Disease Definition": "Renal tubulopathy - encephalopathy - liver failure describes a spectrum of phenotypes with manifestations similar but milder than those seen in GRACILE syndrome (see this term) and that can be associated with encephalopathy and psychiatric disorders.", "ORPHA ID": 254902, "Summary": "Epidemiology\nThe prevalence is unknown. Several cases have been described in Turkey, Spain, New Zealand and Australia.\nClinical description\nDisease presentation is variable. Most of the characteristics of GRACILE syndrome are present (fetal growth restriction, proximal tubulopathy and hepatopathy, as well as lactic acidosis) but they are often less severe. Signs of disturbances in iron metabolism have been described, such as increased serum ferritin levels, but it is unclear whether severe liver iron overload is present. Most infants die during the neonatal period. In those who survive, encephalopathy and psychiatric disorders have been described.\nEtiology\nThis disease is due to different mutations in the BCS1L gene (2q35) encoding a protein essential in the assembly of complex III in the mitochondrial respiratory chain.\nGenetic counseling\nRenal tubulopathy - encephalopathy - liver failure is inherited autosomal recessively and genetic counseling is possible.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Vineta FELLMAN"}
{"Disease Name": "Renal-hepatic-pancreatic dysplasia", "Disease Definition": "Renal-hepatic-pancreatic dysplasia is a rare, genetic, developmental defect during embryogenesis syndrome characterized by the triad of pancreatic fibrosis (and cysts, with a reduction of parenchymal tissue), renal dysplasia (with peripheral cortical cysts, primitive collecting ducts, glomerular cysts and metaplastic cartilage) and hepatic dysgenesis (enlarged portal areas containing numerous elongated binary profiles with a tendancy to perilobular fibrosis). Situs abnormalities, skeletal anomalies and anencephaly have also been associated. Patients that survive the neonatal period present renal insufficiency, chronic jaundice and insulin-dependent diabetes.", "ORPHA ID": 294415, "Summary": ""}
{"Disease Name": "Renin-angiotensin-aldosterone system-blocker-induced angioedema", "Disease Definition": "Renin-angiotensin-aldosterone system (RAAS)-blocker induced angioedema (RAE) is a type of acquired angioedema (AAE, see this term) characterized by acute edema in subcutaneous tissues, viscera and/or the upper airway.", "ORPHA ID": 100057, "Summary": "Clinical description\nLike other forms of AAE it has a later onset than HAE (see this term) and occurs generally in adults.\nEtiology\nThe main causative RAAS-blockers are the angiotensin-converting enzyme inhibitors (ACEIs) which increase levels of bradykinin leading to increased vascular permeability and vasodilation. Angioedema develops in 0.1%-0.5% of patients taking these drugs. Angioedema develops more often at an early phase of treatment, but may also occur with long-term treatment. The same side effect appears more rarely with angiotensin II receptor antagonists (ARAIIs) and direct renin inhibitors (DRIs). Co-administration of ACEI and an antidiabetic agent, dipeptidylptidase-4 (DPP-4) inhibitor, significantly increases the risk of angioedema. This reaction imposes the immediate cessation of these drugs.\nManagement and treatment\nThe orphan drug icatibant or C1-INH concentrate can be effective for acute attack treatment.\n\n                            Last update: \n                            August 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence BOUILLET"}
{"Disease Name": "Renpenning syndrome", "Disease Definition": "Renpenning syndrome is an X-linked intellectual disability syndrome (XLMR, see this term) characterized by intellectual deficiency, microcephaly, leanness and mild short stature.", "ORPHA ID": 3242, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe main clinical manifestations of Renpenning syndrome are usually moderate intellectual deficiency, leanness, microcephaly and short stature (relative to familial target measurements) and sometimes small testes (testicular volumes below 15 ml), that are noticed at puberty. Manifestations are expressed only in males, and female carriers show normal facial features, growth development and intelligence. Small head and brain sizes are noted at birth. Characteristic craniofacial features include long triangular faces with upslanting palpebral fissures, half-depilated eyebrows, large ridged or bulbous nose with overhanging columella, short philtrum, and cupped and laterally protruding ears. Patients are thin and show failure to thrive. Delayed motor and language development is noticed in children from an early age. Moderate to severe intellectual deficiency is seen in two thirds of cases. Muscular atrophy is also observed affecting mostly the spine and back muscles resulting in fall of head, upper back curve loss and an appearance of scapula alata. Metacarpophalangeal ankylosis of the thumb and muscular atrophy of the intrinsic muscles of the hand can occur in some cases. Although uncommon, cardiac malformations (atrial septal defect), cleft palate, ocular colobomas and imperforate anus have been noted in a few patients. Phenotypic variants grouped under Renpenning syndrome include Golabi-Ito-Hall syndrome, Hamel cerebro-palato-cardiac syndrome (see these terms), Porteous syndrome, Sutherland-Haan syndrome, MRX55 and three other XLMR families. Hamel cerebro-palato-cardiac syndrome usually has the most severe manifestations.\nEtiology\nRenpenning syndrome is an X-linked condition caused by mutations in the polyglutamine tract-binding protein 1 (PQBP1) gene, encoding a nuclear protein that regulates pre-mRNA splicing and transcription. Six of the seven mutations discovered in the PQBP1 gene result in a truncated protein whereas a missense mutation that does not affect the length of the mutated protein is seen in Golabi-Ito-Hall syndrome.\nDiagnostic methods\nDiagnosis is based on inheritance of clinical manifestations of Renpenning syndrome. It is often difficult if there is only one male with intellectual deficiency in a family, but it must be suggested even in sporadic cases. Brain magnetic resonance imaging (MRI) shows no obvious gyral reduction, which contrasts with frank microcephaly. PQBP1 gene screening for a mutation can confirm diagnosis.\nDifferential diagnosis\nFragile X syndrome is a differential diagnosis but microcephaly is not a feature. Other causes of microcephaly such as fetal CMV infection, fetal alcohol syndrome, maternal phenylketonuria, autosomal recessive microcephalies and Smith-Lemli-Opitz syndrome (see this term) should be considered.\nAntenatal diagnosis\nIf a mutation is identified, prenatal diagnosis may be proposed to parents for further pregnancies. In sporadic cases, germinal mosaicism should be ruled out on prenatal setting.\nGenetic counseling\nRenpenning syndrome follows an X-linked recessive pattern of inheritance. Genetic testing is possible to identify carrier females and to inform them of the risk of passing on the gene to their offspring.\nManagement and treatment\nManagement for Renpenning syndrome involves early education and intervention by trained therapists and treatment of any associated symptoms (cardiac defect, hypospadias, conductive deafness, strabismus). Children need to attend special education courses at school due to learning disabilities.\nPrognosis\nThere is no cure for Renpenning syndrome but in most cases there is no decrease in life expectancy.\n\n                            Last update: \n                            June 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Vincent DES PORTES"}
{"Disease Name": "RERE-related neurodevelopmental syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, hypotonia, seizures, and autism spectrum disorder. Variable associated features include ophthalmologic anomalies, congenital heart defects, genitourinary defects, and craniofacial dysmorphism (including frontal bossing, epicanthal folds, low-set, posteriorly rotated ears, anteverted nares, and micrognathia). Brain imaging may show thinning of the corpus callosum, white matter abnormalities, ventriculomegaly, and a small cerebellar vermis.", "ORPHA ID": 494344, "Summary": ""}
{"Disease Name": "Resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha", "Disease Definition": "A rare primary congenital hypothyroidism characterized by a markedly reduced T4/T3 ratio, normal levels of thyroid-stimulating hormone, and a highly variable clinical phenotype, which most commonly includes decreased metabolic rate, bradycardia, chronic constipation, neurodevelopmental delay, and delayed bone age and skeletal abnormalities. Dysmorphic craniofacial features, such as macrocephaly, broad face, flat nose, large tongue, and thick lips, have also been reported. Some patients may show only minimal signs and symptoms.", "ORPHA ID": 566231, "Summary": ""}
{"Disease Name": "Resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta", "Disease Definition": "A rare genetic hyperthyroidism characterized by elevated levels of circulating free thyroid hormones, normal or elevated thyroid-stimulating hormone, decreased peripheral tissue responses to iodothyronine action, and a highly variable clinical phenotype which most commonly includes goiter, resting tachycardia, osteoporosis, short stature, and attention deficit disorder. Some patients may be entirely asymptomatic.", "ORPHA ID": 566243, "Summary": ""}
{"Disease Name": "Resistance to thyrotropin-releasing hormone syndrome", "Disease Definition": "Resistance to thyrotropin-releasing hormone (TRH) syndrome is a type of central congenital hypothyroidism (see this term) characterized by low levels of thyroid hormones due to insufficient release of thyroid-stimulating hormone (TSH) caused by pituitary resistance to TRH. It may or may not be observed from birth.", "ORPHA ID": 99832, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nThe clinical manifestations are often subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age.\nEtiology\nResistance to TRH is caused by mutations in the TRH receptor gene (TRHR; 8q23).\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Respiratory bronchiolitis-interstitial lung disease syndrome", "Disease Definition": "Respiratory bronchiolitis - interstitial lung disease is a mild inflammatory pulmonary disorder developed by cigarette smokers and characterized by shortness of breath and cough, pulmonary function abnormalities of mixed restrictive and obstructive lung disease and high resolution CT scanning showing centrilobular micronodules, ground glass opacities and peribronchiolar thickening.", "ORPHA ID": 79127, "Summary": ""}
{"Disease Name": "Restrictive dermopathy", "Disease Definition": "A congenital genodermatosis with skin/mucosae involvement, characterized by very tight and thin skin with erosions and scaling, associated to a typical facial dysmorphism, arthrogryposis multiplex, fetal akinesia or hypokinesia deformation sequence (FADS) and pulmonary hypoplasia without neurological abnormalities.", "ORPHA ID": 1662, "Summary": "Epidemiology\nTo date, approximately 80 children with restrictive dermopathy (RD) have been described in the world literature.\nClinical description\nRD is a congenital disorder and newborns are usually born prematurely (due to premature rupture of membranes with delivery at about 30-32 weeks of gestation). They present at birth with a very typical and recognizable clinical phenotype including tight, thin, rigid and translucent skin with epidermal hyperkeratosis and shedding, erosions and scaling at flexure sites, protruding nipples. Skeletal defects include: bone mineralization defects, large fontanelles, thin dysplastic clavicles, narrow chest, overtubulated long bones, generalized arthrogryposis with rocker-bottom feet. Facial dysmorphism is also characteristic and includes telecanthus, short, down-slanting palpebral fissures, sparse/absent eyelashes and eyebrows, a small and pinched nose, posteriorly rotated low-set ears, retromicrognathism and a small mouth fixed in the ''O'' position with expressionless facies. Additional features may include congenital anonychia, neonatal teeth, ectropion, choanal atresia, patent ductus arteriosus, interatrial septal defects, kyphoscoliosis, camptodactyly, hypospadias (males), ureteral duplication, adrenal hypoplasia. Intrauterine growth retardation (IUGR) with polyhydramnios, and decreased fetal movements are almost always reported. Pulmonary hypoplasia most often leads to respiratory insufficiency and death. Neither structural central nervous system nor visceral defects occur in RD.\nEtiology\nRD can be caused by heterozygous, de novo mutations of the LMNA gene (primary Laminopathy) or, much more frequently, by homozygous or compound heterozygous null mutations of the ZMPSTE24 gene (secondary Laminopathy). Defects in ZMPSTE24 impair the processing of Prelamin A into mature Lamin A, causing the massive intranuclear accumulation of wild type Prelamin A which exerts sytemic toxic effects and leads to the development of RD.\nDiagnostic methods\nThe diagnosis is based upon physical examination at birth and skin histology (flat dermis with paucity/hypoplasia of appendages, abnormally dense collagen bundles parallel to the dermo-epidermic basal lamina and almost total depletion of elastic fibers), cerebral imagery, blood analysis. Molecular genetic testing for mutations confirms the diagnosis and allows genetic counselling.\nDifferential diagnosis\nYunis-varon syndrome, Neu-laxova syndrome, Pena-Shokeir syndrome, cerebrooculofacioskeletal syndrome, Paraná hard-skin syndrome, aplasia cutis congenita, lethal multiple pterygium syndrome.\nAntenatal diagnosis\nEarliest manifestations are only apparent in the late second trimester/early third trimester and include intrauterine growth retardation, decreased fetal movements, eventual joint contractures, and mouth fixed in an 'O' position. However, these signs are too nonspecific to suggest the diagnosis prenatally in cases with no family history.\nGenetic counseling\nThe ZMPSTE24 mutations are inherited recessively, leading to the possibility of genetic counseling and prenatal diagnosis for further pregnancies if the molecular bases of the disease are identified (25% risk of having an affected child for two mutation carriers). The rare dominant mutations in the LMNA gene are de novo and the risk of recurrence of the disorder is very low (eventual germinal mosaicism).\nManagement and treatment\nCorticosteroids are administered for fetal lung maturation. Gavage feeding may be necessary. Supportive treatment consists of mechanical ventilation, broad-spectrum antibiotics, parenteral nutrition, and intravenous analgesia.\nPrognosis\nThe affected babies who are liveborn often die within the first week of life.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                             Annachiara DE SANDRE-GIOVANNOLI"}
{"Disease Name": "Reticular dysgenesis", "Disease Definition": "Reticular dysgenesis is the most severe form of severe combined immunodeficiency (SCID; see this term) and is characterized by bilateral sensorineural deafness and a lack of innate and adaptive immune functions leading to fatal septicemia within days after birth if not treated.", "ORPHA ID": 33355, "Summary": "Epidemiology\nReticular dysgenesis accounts for less than 2% of all SCID cases. The annual incidence has been estimated at 1/3,000,000-1/5,000,000. Both males and females are affected, and consanguinity has been noted in several families.\nClinical description\nThe disease presents earlier than other forms of SCID, at birth or early in the neonatal period, with signs of sepsis, failure to thrive, diarrhea, fever, recurrent infections including upper respiratory tract infections, oral candidiasis, perianal infections and abscesses, and bilateral sensorineural deafness. Despite recurrent infections, no significant lymphoid or tonsillar tissue is evident. Hemoglobin levels are usually within reference ranges at birth, but patients may develop anemia secondary to sepsis and chronic illness.\nEtiology\nReticular dysgenesis is characterized by profound neutropenia and T and natural killer (NK) cell lymphocytopenia, and is caused by mutations in the AK2 gene (1p34). The resulting deficiency in adenylate kinase 2 causes increased apoptosis of myeloid and lymphoid precursors. However, patients without this mutation have been observed implying an alternative cause. An imbalance of growth factor independent-1 transcription repressor (Gfi-1) and/or Gfi-1b has been proposed.\nDiagnostic methods\nDiagnosis is based on evidence of sensorineural deafness in combination with evidence of a marked reduction of T and NK cell counts when compared to age-matched healthy controls. Materno-fetal engraftment is usually present.\nDifferential diagnosis\nDifferential diagnosis includes all other forms of SCID.\nAntenatal diagnosis\nPrenatal diagnosis can be performed in families where there is a family history and where the genetic mutation has been identified.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nThe only curative treatment for this disease is allogenic hematopoietic stem cell transplantation.\nPrognosis\nWithout treatment, patients die from septicemia within days after birth.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Reticular dystrophy of the retinal pigment epithelium", "Disease Definition": "A rare, patterned dystrophy of the retinal pigment epithelium, of progressive course, characterized by the presence of a bilateral hyperpigmented reticular pattern resembling a fishnet with knots, resulting in a slowly progressive loss of vision that often only becomes apparent in old age. This disorder is sometimes associated with scleral staphyloma, choroidal neovascularization, convergent strabismus, spherophakia with myopia and luxated lenses, and partial atrophy of the iris.", "ORPHA ID": 99002, "Summary": ""}
{"Disease Name": "Reticulate acropigmentation of Kitamura", "Disease Definition": "A rare, genetic, hyperpigmentation of the skin disease characterized by childhood to adulthood-onset of reticulate, slightly depressed, sharply demarcated, brown, macular skin lesions without hypopigmentation, affecting the dorsa of the hands and feet, and, occasionally, progressing to involve limbs, neck, forehead and/or trunk. Interrupted dermatoglyphics and palmoplantar pits may be additionally observed. Histologically, hyperpigmented lesions show slightly elongated and thinned rete ridges, mild hyperkeratosis without parakeratosis and absence of incontinentia pigmenti.", "ORPHA ID": 178307, "Summary": ""}
{"Disease Name": "Retiform hemangioendothelioma", "Disease Definition": "A rare vascular tumor characterized by a slowly growing lesion with predominant involvement of the skin and subcutaneous tissue of the distal extremities. Distinctive arborizing blood vessels lined by endothelial cells with characteristic hobnail morphology are a typical feature. Local recurrences are frequent unless wide local excision is performed, while metastasis is rare.", "ORPHA ID": 458763, "Summary": ""}
{"Disease Name": "Retinal capillary malformation", "Disease Definition": "Retinal cavernous hemangioma is a rare, benign, usually unilateral retinal vascular hamartoma that in most cases is asymptomatic but in some patients may present with blurred vision or floaters and that is characterized by the presence of grape-like vacuoles.", "ORPHA ID": 71213, "Summary": ""}
{"Disease Name": "Retinal degeneration-nanophthalmos-glaucoma syndrome", "Disease Definition": "Retinal degeneration-nanophthalmos-glaucoma syndrome is characterized by progressive pigmentary retinal degeneration (with nyctalopia and visual field restriction), cystic macular degeneration and angle closure glaucoma. It has been described in seven members of one family. Patients also have hyperopia and nanophthalmos. The mode of transmission is autosomal recessive.", "ORPHA ID": 1574, "Summary": ""}
{"Disease Name": "Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies", "Disease Definition": "Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies is a rare, genetic, retinal dystrophy disorder characterized by decreased central retinal sensitivity associated with hyper-reflectivity of ganglion cells and nerve fiber layer with loss of optic nerve fibers manifesting with photophobia, optic disc pallor and progressive loss of central vision with preservation of peripheral visual field.", "ORPHA ID": 397758, "Summary": ""}
{"Disease Name": "Retinal dystrophy-optic nerve edema-splenomegaly-anhidrosis-migraine headache syndrome", "Disease Definition": "A rare presumably genetic disorder characterized by idiopathic massive splenomegaly with pancytopenia and childhood-onset chronic optic nerve edema with slowly progressive vision loss. Additional reported features include anhidrosis, urticaria and headaches.", "ORPHA ID": 313800, "Summary": ""}
{"Disease Name": "Retinal ischemic syndrome-digestive tract small vessel hyalinosis-diffuse cerebral calcifications syndrome", "Disease Definition": "A rare systemic disease characterized by progressive hyalinosis involving capillaries, arterioles and small veins of the digestive tract, kidneys, and retina, associated with idiopathic cerebral calcifications, manifesting with severe diarrhea (with rectal bleeding and malabsorption), nephropathy (with renal failure and systemic hypertension), chorioretinal scarring, and subarachnoid hemorrhage. Poikiloderma and premature greying of the hair may be additionally observed.", "ORPHA ID": 3018, "Summary": ""}
{"Disease Name": "Retinal macular dystrophy type 2", "Disease Definition": "Retinal macular dystrophy type 2 is a rare, genetic macular dystrophy disorder characterized by slowly progressive ''bull's eye'' maculopathy associated, in most cases, with mild decrease in visual acuity and central scotomata. Usually, only the central retina is involved, however some cases of more widespread rod and cone anomalies have been reported. Rare additional features include empty sella turcica, impaired olfaction, renal infections, hematuria and recurrent miscarriages.", "ORPHA ID": 319640, "Summary": ""}
{"Disease Name": "Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations", "Disease Definition": "A rare genetic cerebral small vessel disease characterized by progressive loss of visual acuity due to retinal vasculopathy, in combination with more variable neurological signs and symptoms including stroke, cognitive decline, migraine-like headaches, and seizures, among others, typically beginning in middle age. Psychiatric features such as depression and anxiety may also occur. Systemic vascular involvement with Raynaud phenomenon, micronodular liver cirrhosis, and glomerular kidney dysfunction is present in a subset of patients.", "ORPHA ID": 247691, "Summary": ""}
{"Disease Name": "Retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay with mild intellectual disability, short stature, facial dysmorphism (such as sparse hair, high forehead, deep-set eyes, short and upslanting palpebral fissures, short nose, anteverted nares, wide nasal base with broad nasal tip and broad columella, long philtrum, thin upper lip, and low-set, posteriorly rotated ears), and variable onset of sensorineural hearing loss and retinitis pigmentosa. Additional features are other ocular anomalies, abnormalities of the fingers, hypothyroidism, and signs of premature aging. Brain imaging shows cerebellar atrophy and dysmyelination.", "ORPHA ID": 494439, "Summary": ""}
{"Disease Name": "Retinitis pigmentosa-intellectual disability-deafness-hypogonadism syndrome", "Disease Definition": "A rare syndromic retinitis pigmentosa characterized by pigmentary retinopathy, diabetes mellitus with hyperinsulinism, acanthosis nigricans, secondary cataracts, neurogenic deafness, short stature mild hypogonadism in males and polycystic ovaries with oligomenorrhea in females. Inheritance is thought to be autosomal recessive. It can be distinguished from Alstrom syndrome (see this term) by the presence of intellectual disability and the absence of renal insufficiency. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 3085, "Summary": ""}
{"Disease Name": "Retinitis pigmentosa-juvenile cataract-short stature-intellectual disability syndrome", "Disease Definition": "A rare, genetic, syndromic rod-cone dystrophy disorder characterized by psychomotor developmental delay from early childhood, intellectual disability, short stature, mild facial dysmorphism (e.g. upslanted palpebral fissures, hypoplastic alae nasi, malar hypoplasia, attached earlobes), excessive dental spacing and malocclusion, juvenile cataract and ophthalmologic findings of atypical retinitis pigmentosa (i.e. salt-and-pepper retinopathy, attenuated retinal arterioles, generalized rod-cone dysfunction, mottled macula, peripapillary sparing of retinal pigment epithelium).", "ORPHA ID": 436245, "Summary": ""}
{"Disease Name": "Retinitis pigmentosa", "Disease Definition": "Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades.", "ORPHA ID": 791, "Summary": "Epidemiology\nPrevalence of RP is reported to be 1/3,000 to 1/5,000. No ethnic specificities have been reported although founder effects are possible.\nClinical description\nRetinitis pigmentosa is slowly progressive but relentless. There is however broad variability in age of onset, rate of progression and secondary clinical manifestations. Affected individuals generally first develop night blindness (nyctalopia) due to loss of rod function, often in adolescence or earlier. They then develop peripheral visual field impairment, and over time loss of central vision, usually at late stages, often around midlife. Central visual acuity loss may occur at any age as a result of cystoid macular edema or photoreceptor loss. Posterior subcapsular cataracts are common and severity is age dependent. Reduced color vision may also be found. Fundus examination reveals bone spicule pigment deposits, attenuated retinal vessels, retinal atrophy and waxy optic nerve pallor. Severity is partly correlated with the pattern of inheritance with X-linked cases having the most severe course, autosomal recessive and single occurrence cases having intermediate severity, and autosomal dominant the most favorable course.\nEtiology\nMore than 3,000 mutations in over 57 different genes or loci are currently known to cause non-syndromic RP.\nDiagnostic methods\nThe diagnosis of RP is based on peripheral visual field loss, pigment deposits in fundus, loss of photoreceptors at the optical coherence tomography (OCT) scan of the retina and decreased or abolished responses as measured by electroretinography (ERG). Molecular genetic testing using single-gene testing, an RP multi-gene panel or exome sequencing allows for genetic subtype classification.\nDifferential diagnosis\nBesides non syndromic forms, there are syndromic forms of RP of which the most frequent are Usher syndrome (RP and deafness) and BardetBiedl syndrome (RP and metabolic impairment). RP is to be distinguished from macular dystrophies (peripheral visual field is normal) and Leber congenital amaurosis (congenital retinal dystrophy) (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies is possible by DNA analysis following amniocentesis or chorionic villus sampling.\nGenetic counseling\nRP may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. X-linked RP mutations generally only affect men. Genetic counseling should be provided to affected individuals and their families once the mode of inheritance has been determined through family history or molecular testing. Identical mutations may however produce different clinical manifestations. In X-linked familial cases, carrier testing for female relatives can be performed.\nManagement and treatment\nTreatment is primarily aimed at slowing progression of the disease. Vitamin A palmitate and lutein-DHA may be provided as protecting antioxydants. Oral acetazolamide or topical dorzolamide are used to reduce cystoid macular edema. Lens extraction is required when cataracts reduce visual acuity. Sunglasses with short wavelength filtering improve visual performance and optical aids are recommended. Rehabilitation for reading and moving can be proposed in end-stage patients.\nPrognosis\nExcept for mild cases or sectorial RP, most cases progress to legal blindness (visual acuity < 1/20 and visual field < 5 degrees).\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Christian HAMEL"}
{"Disease Name": "Retinitis punctata albescens", "Disease Definition": "A progressive form of familial flecked retinopathy characterized by white punctata throughout the fundus (but sparing the macula in the early stages). Patients present with nightblindness in childhood and may also experience a loss of visual acuity. Significant loss of vision is reported in the 5th and 6th decades of life.", "ORPHA ID": 52427, "Summary": ""}
{"Disease Name": "Retinoblastoma", "Disease Definition": "A rare eye tumor disease representing the most common intraocular malignancy in children. It is a life threatening neoplasia but is potentially curable and it can be hereditary or non hereditary, unilateral or bilateral.", "ORPHA ID": 790, "Summary": "Epidemiology\nRetonoblastoma (RB) has an incidence of approximately 1/15-20,000 in Europe.\nClinical description\nRB manifests most often in young children (90% of cases <3 years old). Early clinical signs are leukocoria and strabismus. RB is most often painless and children rarely complain of visual impairment despite its rapid progression towards loss of vision in the affected eye. Other rare signs include hypopyon, vitreous hemorrhage, non rhegmatogenous retinal detachment, neovascular glaucoma and orbital cellulitis. In later stages, rarely seen in high income countries (HIC), intracranial dissemination and hematagenous metastasis, mainly to bones and bone marrow, are observed and are life-threatening. Most retinoblastomas (60%) are unilateral. Hereditary RB refers to those that arise due to a genetic predisposition (irrespective of family history); most of these patients have a bilateral disease and they are at increased risk to develop secondary tumors, mainly sarcoma but also pineoblastoma/supra-sellar tumor (both named ''trilateral retinoblastoma''), glial tumor, melanoma and carcinoma.\nEtiology\nRB is caused by inactivating mutations of both alleles of RB1 (13q14) with a high (90%) penetrance (RB risk) in most mutations. Some mutations have a low penetrance (asymptomatic carriers or unilateral RB). Some rare unilateral retinoblastoma cases may arise without RB1 gene mutation but with somatic NMYC amplification. Monosomy 13q14 also causes RB.\nDiagnostic methods\nDiagnosis is mainly clinical: Indirect ophthalmoscopy supported by fundal photography. Orbital ultrasound delineates intraocular tumor and usually shows calcification. MRI imaging is used to evaluate intra/extraocular and intracranial extension. Tumor staging (i.e. bone marrow examination, lumbar puncture and/or radionuclide bone scan) should be performed only in patients at risk of extra-ocular metastases.\nDifferential diagnosis\nDifferential diagnoses, particularly in unilateral cases, include anterior chamber or lens abnormalities especially PHPV (persistence of hyperplastic vitreous), toxocariasis, X-linked retinoschisis, uveitis, medulloepithelioma, von Hippel disease, Norrie disease, retinopathy of prematurity and Coats disease (the most difficult differential diagnosis).\nAntenatal diagnosis\nPrenatal and preimplantation genetic diagnoses are available in specialized centers in most HIC.\nGenetic counseling\nPatients with hereditary RB inherit RB1 mutation from a parent and thus the predisposition to RB is transmitted in an autosomal dominant manner. However, more than 75% of predisposed patients do not inherit the mutated RB1 from an affected parent, but might have had a de novo mutation in a parental gamete or post-zygotically. Genetic testing needs to be proposed to all patients and their families, even when retinoblastoma is unilateral.\nManagement and treatment\nTreatment requires a multidisciplinary highly specialized approach. In HIC, conservative treatments for at least one eye are possible in most bilateral cases and increasingly used in unilateral cases. Laser treatment alone or combined with systemic chemotherapy, cryotherapy and brachytherapy are very efficient tools as well as the more recently developped local chemotherapy using intra-arterial and/or intravitreous delivery. Enucleation is still frequently used in large unilateral RB as well as in bilateral with large unilateral tumor. External beam radiotherapy is now avoided (risk of late effects, including second cancers in irradiated field).\nPrognosis\nVital prognosis is excellent in HIC. Visual prognosis is dictated by tumor location and size at diagnosis (macular involvement has a poor visual prognosis). Eye preservation is possible with early diagnosis. After conservative treatment, visual prognosis depends on macular involvement. If not treated promptly, RB may rapidly metastasize and be fatal, which is still frequent in low income countries.\n\n                            Last update: \n                            July 2019\n\n\n                            - Expert reviewer(s): \n                            Pr François DOZ"}
{"Disease Name": "Retinopathy of prematurity", "Disease Definition": "A rare retinal vasoproliferative disease affecting preterm infants characterized initially by a delay in physiologic retinal vascular development and compromised physiologic vascularity, and subsequently by aberrant angiogenesis in the form of intravitreal neovascularization.", "ORPHA ID": 90050, "Summary": "Epidemiology\nThe incidence of Retinopathy of prematurity (ROP) is increasing as higher numbers of premature neonates survive into infancy, particularly in developing countries. Some estimates among preterm birth infants are over 30%. In some countries, ROP accounts for up to 10% of childhood blindness. Higher prevalence has been reported in South East Asia, Latin America, and subSaharan Africa. Incidence rates are similar in Caucasian and Black populations, but progression to severe forms may be more frequent in Caucasians.\nClinical description\nThe degree of prematurity generally correlates with the severity of the clinical manifestations, with the smallest neonates having the highest risks. In affected infants, normal retinal development is incomplete at the time of preterm birth. Subsequently, aberrant angiogenesis in the form of intravitreal neovascularization occurs leading to later cicatricial fibrosis causing partial or complete retinal detachment and possible loss of vision. Patients may also develop ametropia, anisometropia, amblyopia or strabismus. Glaucoma has also been reported in affected individuals.\nEtiology\nThe pathophysiological mechanisms underlying ROP remain poorly understood. Associations with severe ROP include high oxygen at birth and oxygenation fluctuations during the neonatal course, low birth weight and young gestational age, and poor postnatal growth. In candidate gene studies, gene mutations associated with severe ROP have been reported, including NDP (Xp11.4-p11.3), FZD4 (11q14-q21), and LRP5 (11q13.4).\nDiagnostic methods\nNeonates born before 30 weeks of gestation or with a birth weight below 1,500 g should be screened for ROP, but specific guidelines may vary based on regional statistics and characteristics of affected preterm infants world-wide. Diagnosis is based on characterization of ROP severity in preterm infants usually determined by dilated fundus examination with scleral depression but increasingly more with review of photographic images. ROP is categorized into 3 zones and severity in 5 stages (stages 1 to 5, from mild disease to total retinal detachment).\nDifferential diagnosis\nThe main differential diagnostic considerations for early ROP are conditions associated with peripheral avascular retina and intravitreal neovascularization, including familial exudative vitreoretinopathy (FEVR) or incontinentia pigmenti (see these terms). For stage 5 ROP, other conditions causing leukocoria are included (e.g. retinoblastoma, persistent fetal vasculature, toxocariasis, etc.).\nManagement and treatment\nClose work with neonatologists is recommended. All attempts are made to avoid high oxygen at birth (100% oxygen). Optimal monitoring and regulation of oxygen saturation is recommended and is chosen based on gestational age and overall health of the infant. However, the optimum saturation level is not known. Following screening of at-risk infants, monitoring is recommended based on retinal findings. Treatment options include transpupillary or sometimes transscleral laser photocoagulation of the peripheral avascular retina. For the most severe forms of ROP like zone I severe ROP and aggressive posterior ROP, intravitreal treatment with agents that interfere with the bioactivity of vascular endothelial growth factor (VEGF) are being studied and considered. Visual rehabilitation is critical because of the association with myopia and refractive errors. Anisometropia should be corrected and associated amblyopia or strabismus treated. Protective eyewear and low-vision aids may be required.\nPrognosis\nGestational age and birth weight are the main prognostic factors in ROP. Also associated is poor postnatal weight gain. ROP often resolves but if it develops severe characteristics, it can lead to blindness.\n\n                            Last update: \n                            July 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Mary Elizabeth HARTNETT"}
{"Disease Name": "Rett syndrome", "Disease Definition": "A rare severe, X-linked, neurodevelopmental disorder characterized by rapid developmental regression in infancy, partial or complete loss of purposeful hand movements, loss of speech, gait abnormalities, and stereotypic hand movements, commonly associated with deceleration of head growth, severe intellectual disability, seizures, and breathing abnormalities. The disorder has a progressive clinical course and may associate various comorbidities including gastrointestinal diseases, scoliosis, and behavioral disorders.", "ORPHA ID": 778, "Summary": "Epidemiology\nThe disorder affects approximately 1 in 10,000 live female births. The disease has been occasionally reported in males, usually with a lethal course before birth or in early infancy.\nClinical description\nClassic or typical Rett syndrome (RTT) primarily affects girls and is characterized by apparently normal psychomotor development during the first 6-18 months of life followed by developmental stagnation with rapid regression in language and motor abilities, and subsequent long-term plateauing of skills. Repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures (60-80%), and acquired microcephaly. There is a wide variability in the rate of disease progression and severity. A number of males with a phenotype comparable to females with classical RTT have been described.\nEtiology\nPathogenic variants in the X-linked gene methyl CpG-binding protein 2 (MECP2; Xq28) are found in more than 95% of classic RTT cases. The most common mutation involves a C to T transition at CpG dinucleotides; however, the spectrum of mutation types includes missense, nonsense, and frameshift mutations, with over 300 unique pathogenic nucleotide changes described, as well as deletions encompassing whole exons. Different phenotypes to classical RTT have been described in association within MECP2 pathogenic variants in males and females.\nDiagnostic methods\nThe clinical diagnosis of RTT is based on consensus clinical criteria. These include one necessary criteria i.e. presence of regression plus four main criteria that are absolutely required for the diagnosis of typical RTT that include (i) partial or complete loss of acquired purposeful hand skills, (ii) partial or complete loss of acquired spoken language, (iii) gait abnormalities, (iv) stereotypic hand movements. Genetic testing identifies variants in MECP2 in 95-97% of individuals with typical RTT, but is not mandatory for RTT diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes autism spectrum disorder; Angelman syndrome in which early development before 6 months is abnormal; CDKL5 deficient disorders in which early onset seizures are distinctive from RTT; FOXG1 syndrome in which congenital microcephaly and corpus callosum abnormalities are not usually found in RTT.\nAntenatal diagnosis\nPrenatal screening should be discussed in families with a proband having a pathogenic mutation.\nGenetic counseling\nAs pathogenic MECP2 mutations in RTT patients are mostly de novo, the recurrence risk for future pregnancies is low, although germline mosaicism has been reported.\nManagement and treatment\nManagement is mainly symptomatic, focused on optimizing each patient's abilities through a multidisciplinary approach. Attention should be paid to scoliosis and the development of spasticity, as well as to effective communication strategies. Psychosocial support for families is essential. Pharmacological approaches aim at improving sleep disturbances, breathing disturbances, seizures, stereotypic movements and general well-being. As RTT patients have an increased risk of life-threatening arrhythmias associated with a prolonged QT interval, avoidance of a number of drugs is recommended (e.g. macrolide antibiotics).\nPrognosis\nThe clinical picture evolves in stages over a number of years. Patients have been reported to live into middle age and beyond.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Nadia BAHI-BUISSON | EpiCARE* - Dr Andreas BRUNKLAUS | EpiCARE* - Pr Rima NABBOUT | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Reversible cerebral vasoconstriction syndrome", "Disease Definition": "A rare cerebrovascular disorder characterized by severe headaches with or without focal neurological deficits or seizures, and a reversible segmental and multifocal vasoconstriction of cerebral arteries. It may occur spontaneously or be provoked by various precipitating factors, the most common being postpartum and exposure to various vasoactive substances such as illicit drugs and selective serotonin-reuptake inhibitors. The major complication is ischemic or hemorrhagic stroke.", "ORPHA ID": 284388, "Summary": ""}
{"Disease Name": "Revesz syndrome", "Disease Definition": "Revesz syndrome is a rare severe phenotypic variant of dyskeratosis congenita (DC; see this term) with an onset in early childhood, characterized by features of DC (e.g. skin hyper/hypopigmentation, nail dystrophy, oral leukoplakia, high risk of bone marrow failure (BMF) and cancer, developmental delay sparse and fine hair) in conjunction with bilateral exudative retinopathy, and intracranial calcifications.", "ORPHA ID": 3088, "Summary": ""}
{"Disease Name": "Reye syndrome", "Disease Definition": "A rare, systemic disease characterized by persistent vomiting with confusion, lethargy, disorientation, hyperreflexia, hyperventilation, and tachycardia, with rapid progression to seizures, non-inflammatory encephalopathy, coma and death. It typically develops between 12 hours and 3 weeks after recovery from a viral illness, such as upper respiratory tract infection or gastroenteritis. Hepatomegaly, acute hepatic steatosis, fatty liver degeneration and multiple laboratory abnormalities are associated.", "ORPHA ID": 3096, "Summary": ""}
{"Disease Name": "Reynolds syndrome", "Disease Definition": "Reynolds syndrome (RS) is an autoimmune disorder characterized by the association of primary biliary cirrhosis (PBC) with limited cutaneous systemic sclerosis (lcSSc) (see these terms).", "ORPHA ID": 779, "Summary": "Epidemiology\nThe prevalence of systemic sclerosis (SSc) in PBC patients is 5-15%. Conversely, the prevalence of PBC in SSc patients is about 2%. Females are more affected.\nClinical description\nOnset occurs between 30-65 years. RS associates the features of PBC (fatigue, pruritus due to cholestasis, hepatomegaly) with most features of lcSSC (cutaneous calcifications, digital ulcers, facial telangiectasias, calcinosis, Raynaud's phenomenon, esophageal involvement and sclerodactyly). In 50% of cases, symptoms of scleroderma occur prior to those of PBC. About 25-50 % of newly diagnosed RS patients have hyperpigmentation of skin, and jaundice at a later stage. Inflammatory arthropathies are observed in approximately 40% of patients with PBC. In some, RS is associated with other autoimmune diseases such as Sjögren's syndrome, autoimmune hemolytic anemia and (in one case) with thymoma (see these terms). An overlap syndrome between nodular regenerative hyperplasia of the liver (see this term), PBC, and lcSSc may exist.\nEtiology\nThe pathological mechanism of RS has not yet been established, but it is assumed to be an auto-immune disorder. A heterozygous missense mutation in LBR exon 9 was identified in a Caucasian woman with RS. The mutation was predicted to induce a change in Lamin B receptor tertiary structure. Mutations in LBR may either have a direct pathogenic effect or constitute a predisposing factor in conjunction with other genetic and environmental factors.\nDiagnostic methods\nDiagnosis of RS relies on the clinical findings for lcSSc and, for PBC, on the biochemical evidence of cholestasis which is based on marked elevation of serum alkaline phosphatase, gamma-glutamyl transpeptidase enzymes and IgM concentrations, a positive test for serum mitochondrial antibody, histologic evidence of non suppurative destructive cholangitis and destruction of interlobular bile ducts. An elevated serum bilirubin is a poor prognostic sign. Specific autoantibodies associated with both facets of the disease (antimitochondrial antibodies for PBC and anticentromere/antitopoisomerase for SSc), and suggestive microscopical abnormalities in the skin and liver have been found in patients affected with RS. Furthermore, a higher prevalence of clonal populations of CD8+ TCRBV3+ T cells has been found in RS.\nDifferential diagnosis\nThe association with primary sclerosing cholangitis and SSc is extremely rare. Cholestasis in SSc patients may also reflect liver congestion due to right-sided heart failure in cases with severe pulmonary hypertension. Medications (antibiotics, anabolic steroids, birth control pills, chlorpromazine, cimetidine, estradiol) may cause cholestasis similar to that of PBC.\nGenetic counseling\nRS occurs sporadically, but rare familial cases with an unknown inheritance pattern have been observed.\nManagement and treatment\nThere is no cure for RS and management is mainly supportive. It includes physiotherapeutic assistance and treatment of PBC with ursodeoxycholic acid so as to normalize the cholestatic parameters. Potential hepatotoxic drugs such as bosentan monohydrate or methotrexate can be used to treat some SSc manifestations, if transaminases are < 3 fold the upper limit of normal and remains < 3 fold the upper limit of normal over time.\nPrognosis\nNodular regenerative hyperplasia of the liver is a rare complication in those with SSc. Patients usually have a good prognosis, particularly when UDCA treatment is started in the early stages. RS prognosis depends on PBC's severity, but also depends on SSc evolution, as lcSSc has a higher risk of pulmonary arterial hypertension. The regular evaluation of liver function tests is useful for monitoring disease progression. Advanced age, hyperbilirubinemia, low serum albumin and cirrhotic liver biopsy indicate a worse prognosis. Survival of patients with RS seems to be better than that of patients with PBC alone.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Eric HACHULLA"}
{"Disease Name": "RFT1-CDG", "Disease Definition": "RFT1-CDG is a form of congenital disorders of N-linked glycosylation characterized by poorly coordinated suck resulting in difficulty feeding and failure to thrive; myoclonic jerks with hypotonia and brisk reflexes progressing to a seizure disorder; roving eyes; developmental delay; poor to absent visual contact; and sensorineural hearing loss. Additional features that may be observed include coagulation factor abnormalities, inverted nipples and microcephaly. The disease is caused by mutations in the gene RFT1 (3p21.1).", "ORPHA ID": 244310, "Summary": ""}
{"Disease Name": "Rh deficiency syndrome", "Disease Definition": "A rare constitutional hemolytic anemia due to a red cell membrane anomaly characterized by lack or severe reduction of Rh blood group antigens, resulting in increased osmotic fragility of red blood cells and chronic hemolytic anemia of varying severity with stomatocytosis and spherocytosis. Two types of the syndrome arising from independent genetic mechanisms have been distinguished: the regulator type is caused by defects of the Rh associated glycoprotein (encoded by the RHAG gene), while the amorph type is due to mutations at the RH locus itself.", "ORPHA ID": 71275, "Summary": ""}
{"Disease Name": "Rhabdoid tumor", "Disease Definition": "Rhabdoid tumor (RT) is an aggressive pediatric soft tissue sarcoma that arises in the kidney, the liver, the peripheral nerves and all miscellaneous soft-parts throughout the body. RT involving the central nervous system (CNS) is called atypical teratoid rhabdoid tumor (ATRT; see this term).", "ORPHA ID": 69077, "Summary": "Epidemiology\nThe United Kingdom registry estimated that the age-standardized annual incidence of extra-CNS RT is about 1/2,000,000 children, which might be underestimated. Altogether, in infants less than one year, RT may account for 20% of renal cancers, and 15% of soft-part tumors. In the same age range, ATRT may be the most frequent malignant tumor of the posterior fossa.\nClinical description\nRT usually occurs in infancy or childhood (mostly affecting patients < 2 years, with a median of 20 months).In most cases, the first symptoms are linked to the compressive effects of a bulky tumor (such as respiratory distress, abdomen mass, peripheral nerve palsy). Subcutaneous nodular metastases are specifically seen in patients with neonatal tumors. Exceptional cases can occur in adolescents and adults. RT arises in the kidney, liver, peripheral nerve and miscellaneous soft parts. Hypercalcemia may be seen at diagnosis (<1/3 of cases). RT affecting the CNS is called ATRT and constitutes about half of all RTs.\nEtiology\n90% of RT cases have biallelic inactivation of  SMARCB1 (22q11.23), a tumor suppressor gene encoding a member of SWI/SNF chromatin remodeling complex which broadly regulates the expression of the genome. Rare cases are associated with a biallelic mutation of SMARCA4 (19p13.3) (encoding another SWI/SNF chromatin-remodeling complex member).\nDiagnostic methods\nOnce a tumor is evidenced by imaging scans (magnetic resonance and computed tomography), the diagnosis relies on tumor biopsy. The tumor is composed of a diffuse proliferation of rounded or polygonal cells with eccentric nuclei, prominent nucleoli and glassy eosinophilic cytoplasm containing hyaline-like inclusion bodies, arranged in sheets and nests (rhabdoid cells). Tumor cells are usually positive to glypican-3 (50% of cases), vimentin, epithelial markers (keratins, epithelial membrane antigen) and mesenchymal markers (smooth muscle actin, muscle-specific actin, S100 protein). Diagnosis is confirmed by loss of nuclear staining of SMARCB1 (or SMARCA4, exceptionally) protein by immunohistochemistry.\nDifferential diagnosis\nDifferential diagnosis includes all undifferentiated sarcomas, peripheral primitive neuroectodermal tumor in children, epithelioid sarcoma (especially the proximal type) in older patients, extraskeletal myxoid chondrosarcoma, and undifferentiated chordomas (see these terms) in cases with clivus involvement.\nGenetic counseling\nIn 25% of cases, RT is associated with a germline mutation of  SMARCB1. Rarely, germline mutations are inherited from asymptomatic parents, either because of gonadal mosaicism or incomplete penetrant mutations (familial RT; see this term). Adult carriers may develop multiple schwannomas or meningiomas (see these terms).\nManagement and treatment\nNo standard care exists for RT although several prospective trials are now running throughout the world. Treatment includes resection of the tumor mass (as complete as possible), multimodal aggressive chemotherapy and radiotherapy whenever feasible. However, the young age of patients may limit use of radiotherapy.\nPrognosis\nThe survival rate is low with a 5 year survival rate of 20%. Prognostic factors include metastases, young age at diagnosis (< 2years), and incomplete resection.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Franck BOURDEAUT"}
{"Disease Name": "Rhabdomyosarcoma of the cervix uteri", "Disease Definition": "Rhabdomyosarcoma of the cervix uteri is a rare, highly malignant soft tissue sarcoma located in the uterine cervix and arising from primitive mesenchymal cells displaying skeletal muscle differentiation. It most often presents with abnormal vaginal discharge or dysfunctional uterine bleeding, abdominal pain and/or a cervical mass protruding into the vagina. Association with DICER1 syndrome has been reported.", "ORPHA ID": 213802, "Summary": ""}
{"Disease Name": "Rhabdomyosarcoma of the corpus uteri", "Disease Definition": "Rhabdomyosarcoma of the corpus uteri is an extremely rare, highly malignant soft tissue sarcoma located in the uterine body and arising from primitive mesenchymal cells displaying variable degrees of skeletal muscle differentiation. It most often presents with abnormal vaginal discharge or dysfunctional uterine bleeding, abdominal pain and lower abdominal mass. Association with DICER1 syndrome has been reported.", "ORPHA ID": 213615, "Summary": ""}
{"Disease Name": "Rhabdomyosarcoma", "Disease Definition": "A malignant soft tissue tumor which develops from cells of striated muscle. It is the most common form of tumor found in children and adolescents.", "ORPHA ID": 780, "Summary": "Epidemiology\nThe annual incidence is 1/170,000. In children younger than 15 years, the annual incidence is estimated at 1/244,000.\nClinical description\nThe median age of diagnosis is 5 years. Rhabdomyosarcoma can develop anywhere in the body, including in sites where striated muscle does not normally occur. The most frequent locations are: the head and neck (40%), including tumors of the orbit and para-meningeal tumors, the genitourinary tract (20%) including tumors in the bladder and/or prostate, in the uterus and vagina, para-testicular tumors, and tumors in the limbs (20%) and trunk (10%). Rhabdomyosarcoma has a high risk of local relapse, a high risk of local extension to lymph nodes and a lower risk of metastases. There are two main histological subtypes of rhabdomyosarcoma: embryonic (80% of cases) and alveolar (15-20% of cases). Clinically there is little difference between the two types. The alveolar form occurs more readily in the limbs, nearly never in the orbits and more frequently affects the lymph nodes.\nEtiology\nThe cause of rhabdomyosarcoma is unknown, but a translocation t(2;13) is very often associated with the alveolar type.\nDiagnostic methods\nDiagnosis is based on positive muscular markers and immunohistochemistry. The evidence of a translocation t(2;13) leads to diagnosis of alveolar forms.\nDifferential diagnosis\nDifferential diagnoses include small round cell tumors (lymphoma, neuroblastoma, Ewing sarcoma; see these terms). It is possible to distinguish between tumors using immunohistochemistry. Some rhabdomyosarcomas are associated with a genetic predisposition to cancer as part of Li-Fraumeni syndrome or neurofibromatosis type 1 (see these terms).\nManagement and treatment\nTreatment should be managed by a multidisciplinary team, expert in the treatment of childhood cancers. Initial surgery should only be considered if it can be completed, and completed without significant consequences. Chemotherapy is indicated in all other cases from diagnosis. Local treatment is carried out by secondary surgery, often complemented by radiotherapy. Alveolar forms require more intensive treatment than embryonic forms. The objective of current protocols is to avoid radiotherapy, if possible, in order to reduce long term sequelae.\nPrognosis\nSurvival depends on the location of the tumor. In localized forms the survival rate is greater than 80% for tumors of the orbit, bladder, vagina and paratesticular region. The survival rate is in the order of 60-70% for other localized tumors. For patients with metastases at diagnosis the survival rate is lower, and adolescents and patients with osteo-medullar metastases have a survival rate of less than 20%.\n\n                            Last update: \n                            February 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Odile OBERLIN"}
{"Disease Name": "Rheumatic fever", "Disease Definition": "Rheumatic fever (RF) is a multisystem inflammatory disease occurring as a post-infectious, nonsuppurative sequela of untreated streptococcus pyogenes (Group A streptococcus [GAS]) pharyngitis, and mainly occurs in individuals aged 5 to 15 years. The most common presenting signs are fever, migratory polyarthritis and carditis.", "ORPHA ID": 3099, "Summary": "Epidemiology\nThe incidence of RF in industrialized countries, due to sporadic outbreaks, is typically less than 1/20, 000 individuals. In the developing world, the annual incidence is at least 100 times higher with some reports of > 1/200 individuals in select subpopulations, such as Australian Aboriginals. RF remains a major cause of acquired cardiac morbidity and mortality among people under 50 years of age.\nClinical description\nRF usually initially occurs between 5 and 15 years of age, and involves the heart, large joints and skin and is a delayed sequela of untreated GAS pharyngitis. The major diagnostic criteria include migratory polyarthritis (46-66% of cases), most commonly in the knee, ankle, elbow and wrists; carditis (53-68% clinical and additional ''subclinical'' diagnosed by echocardiogram), which is typically inflammation of the mitral (90%) or aortic valve (10%) in isolation, but any combination of all 4 valves have been reported; Sydenham chorea (8-15%); erythema marginatum (1-11%); and subcutaneous nodules on the flexor surfaces (1-8%). Minor criteria include fever (35-75% of cases), arthralgia (35-56%), first degree heart block (prolonged PR interval) (20-29%) and elevated inflammatory markers (53-91%). There is not always a prior clinically apparent GAS infection.\nEtiology\nThere are proposed associations with certain HLA types (most frequently HLA-DR7), but numerous types have been implicated and are not always consistent among different populations. Immunological cross-reactivity is believed to occur through molecular mimicry and has been attributed to the M-protein in the GAS cell membrane. Tumor necrosis factor α and mannose-binding lectin may also be upregulated in individuals with increased RF susceptibility.\nDiagnostic methods\nThe revised Jones criteria require the presence of two major or one major and two minor criteria, as well as evidence of a prior GAS infection. Diagnostic tests include an antistreptolysin O (ASO) titer, erythrocyte sedimentation rate (ESR) or C reactive protein (CRP), electrocardiogram to detect first degree heart block, and echocardiogram to diagnose valvulitis.\nDifferential diagnosis\nThe differential diagnosis includes other causes of febrile polyarthritis in children: juvenile idiopathic arthritis, Lyme disease, mixed connective tissue disease, reactive arthritis, sickle cell anemia, systemic lupus erythematosus (see these terms), and septic arthritis.\nManagement and treatment\nTreatment of RF includes: 1) treatment of pharyngitis to eradicate GAS, with penicillin as first line therapy, 2) anti-inflammatory treatment, usually aspirin in the acute phase, although the use of corticosteroids is sometimes suggested, especially with severe carditis, and 3) secondary antibiotic prophylaxis to prevent recurrence of RF, usually with benzathine penicillin every 3 to 4 weeks.\nPrognosis\nPrognosis is generally good after initial episode of RF and all of the symptoms usually resolve completely with the exception of cardiac valve damage, which can progress over time, especially with subsequent episodes of RF, and require chronic medical management for heart failure and eventual surgical valve replacement.\n\n                            Last update: \n                            April 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Michael SECKELER"}
{"Disease Name": "Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis", "Disease Definition": "A rare form of polyarticular juvenile idiopathic arthritis characterized by childhood-onset chronic arthritis of unknown cause involving five or more joints at disease onset and absence of rheumatoid factor IgM.", "ORPHA ID": 85408, "Summary": "Epidemiology\nRheumatoid factor-negative juvenile polyarthritis represents around 15-20% of cases of juvenile idiopathic arthritis (JIA). Prevalence has been estimated at between 1 and 13 in 22,200 children, with an annual incidence of 1-26 in 700,000 children. Females are affected more often than males, with a female/male ratio of 3:1.\nClinical description\nRheumatoid factor negative juvenile polyarthritis is clinically heterogeneous with two patient groups distinguished by age of onset and distribution of arthritis. The early onset form typically appears between 2 and 6 years of age with asymmetrical pattern of joint involvement, possible eye inflammation (asymptomatic chronic anterior uveitis), and presence of anti-nuclear antibody. This form resembles oligoarticular juvenile idiopathic arthritis. The second group has a later onset around 10 years of age with often symmetrical distribution and distal joint involvement (commonly small joints of the hands, wrist and knees). Patients may be ANA positive or negative. This form closely resembles rheumatoid polyarthritis.\nEtiology\nThe etiology remains unknown but auto-immunity plays a role.\nDiagnostic methods\nRheumatoid factor-negative polyarthritis is defined as the presence of arthritis affecting five or more joints at disease onset. Exclusion criteria are the presence of systemic arthritis or psoriasis in the patient, or a family history of psoriasis in one of the parents or a first-degree relative, HLA B27-positivity in males with onset of arthritis after 6 years of age, and detection of rheumatoid factor IgM in two test samples taken three months apart. Other exclusion criteria include: the presence of ankylosing spondylarthritis, enthesitis and arthritis, sacroiliitis with an inflammatory enteropathy or acute anterior uveitis in the patient, or a family history of one of these conditions in a parent or first-degree relative. It is important to note that these diagnostic criteria were established in 2001 (International League of Associations for Rheumatology, Edmonton) and are currently under revision.\nDifferential diagnosis\nThe differential diagnosis should include other forms of polyarthritis (associated with inflammatory or haemato-oncologic diseases).\nManagement and treatment\nPatients should be managed by a multidisciplinary team, incorporating expertise in pediatric rheumatology, physiotherapy, psychology and infantile orthopedic care. Treatment is based on the association nonsteroidal anti-inflammatory agents (NSAIDS), and disease-modifying antirheumatic drugs; methotrexate is used as first-line treatment and then in case of inefficacy or intolerance. Biologics such as anti-tumor necrosis factor (TNF)-alpha, tocilizumab (anti IL6 receptor) and abatacept (targeting T lymphocyte activation) could be prescribed. Rehabilitation is necessary in case of limited joint motion. Corticotherapy is used at low doses and as rarely as possible. Intraarticular injection of delayed-action corticoids (triamcinolone hexacetonide) may be recommended in case of localized persistent arthritis.\nPrognosis\nThe prognosis is difficult to determine due to the heterogeneity of the condition; but the new therapeutic strategies (initial aggressive and combined therapy) seem able to improve the prognosis and the percentage of remission mainly under treatment.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Chantal DESLANDRE"}
{"Disease Name": "Rheumatoid factor-positive polyarticular juvenile idiopathic arthritis", "Disease Definition": "A rare form of juvenile idiopathic arthritis characterized by distal and symmetrical polyarthritis (more than 5 joints) with presence of rheumatoid factor and possible evolution towards the appearance of erosions and joint destruction.", "ORPHA ID": 85435, "Summary": "Epidemiology\nThe disorder occurs worldwide with regional variation in occurrence; prevalence in juvenile populations ranges from 1/10,000-350,000, and incidence ranges between 1/140,000-1,000,000. The disorder is less frequent in Asian populations. Females are predominantly affect with a female-to-male ratio of 8-9:1.\nClinical description\nThe disease is considered as the childhood onset of seropositive adult rheumatoid arthritis; it represents about 10% of all cases of JIA. Patients are frequently diagnosed in late childhood/adolescence, typically between the 10-12 years of age. As with adult rheumatoid arthritis (RA), patients have a chronic symmetric, erosive polyarticular arthritis. To have polyarticular RF-positive disease, the ILAR classification requires the involvement of 5 or more joints. Also, by definition, patients must have two positive tests for IgM rheumatoid factor (RF). Although anti-cyclic-citrullinated peptide (anti-CCP) antibody status is not part of the ILAR criteria, children with childhood-onset RA also commonly have anti-CCP antibodies.\nEtiology\nRheumatoid factor-positive polyarthritis is an autoimmune inflammatory disease associated with enhanced lymphocyte activity and production of proinflammatory cytokines (IL1, IL6 and TNF alpha).\nDiagnostic methods\nThe international diagnostic criteria rely on the clinical, biological and radiological (joint erosion) features of the disease. Rheumatoid factor-positive polyarthritis is defined as the presence of arthritis affecting five or more joints at disease onset and by detection of rheumatoid factor in two tests carried out in the first six months of the disease course. Exclusion criteria are the presence of systemic arthritis or psoriasis in the patient, or a family history of psoriasis in one of the parents or first-degree relative, and HLA B27-positivity in males with onset of arthritis after 6 years of age. Other exclusion criteria include: the presence of ankylosing spondylarthritis, enthesitis and arthritis, sacroiliitis with an inflammatory enteropathy or acute anterior uveitis in the patient, or a family history of one of these conditions in a parent or first-degree relative.\nDifferential diagnosis\nThe differential diagnosis should include other polyarticular diseases: connective tissue disorders (lupus, dermatomyositis) and hematological diseases (notably, acute leukemia).\nManagement and treatment\nPatients should be managed by a multidisciplinary team, incorporating expertise in pediatric rheumatology, physiotherapy, psychology and infantile orthopedic care. Treatment is based on the association of nonsteroidal anti-inflammatory agents (NSAIDS), disease-modifying antirheumatic drugs (DMARDs) and rehabilitation. Methotrexate is used as first-line treatment and then in case of inefficacy or intolerance , biologics (anti-tumor necrosis factor (TNF)-alpha, tocilizumab (anti-IL6 receptor) or abatacept (targeting T lymphocyte activation) could be prescribed. Corticotherapy, at low doses, can be used while waiting for the effectiveness of DMARDs. Rehabilitation will be associated if necessary to avoid joint limitation or amyotrophy. Intra-articular injection of delayed-action corticoids (triamcinolone hexacetonide) may be recommended in case of persistent localized arthritis.\nPrognosis\nRemission is rare during adulthood (10% of cases). In the vast majority of cases, the disease remains progressive and requires follow-up treatment. The risk of cartilage and bone damage has been significantly reduced with the use of rapid and more aggressive therapeutic strategies.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Chantal DESLANDRE"}
{"Disease Name": "Rhizomelic chondrodysplasia punctata", "Disease Definition": "A rare, primary bone dysplasia characterized by rhizomelic limb shortening, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata) and coronal cleft vertebrae associated with profound postnatal growth deficiency, early-onset cataracts, severe intellectual disability and seizures.", "ORPHA ID": 177, "Summary": "Epidemiology\nRhizomelic chondrodysplasia punctata (RCDP) prevalence is estimated to be lower than 1/100,000. The disorder is pan ethnic.\nClinical description\nPresentation is at birth with severe joint contractures; cataracts may be present or appear in the first few months of life. Respiratory distress and feeding difficulties are commonly observed after birth. Whilst birth parameters (weight, length, and head circumference) are in the lower range from normal, profound postnatal growth retardation ensues. Rhizomelic limb shortening is typically greater in the humerus than the femur. Other skeletal abnormalities include punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata) and coronal cleft vertebrae. Intellectual disability is severe, and the majority of children develop seizures.\nEtiology\nThe disease is caused by defective plasmalogen biosynthesis and impaired peroxisome function. The majority of patients have variants in the PEX7 gene (6q21-q22.2, RDCP type 1) encoding the peroxisomal targeting signal 2 receptor which plays an important role in peroxisomal protein import. Biallelic variants in the GNPAT gene (1q42) encoding dihydroxyacetone phosphate acyltransferase cause RDCP type 2, variants in the AGPS gene (2q31) encoding peroxisomal alkyldihydroxyacetonephosphate synthase cause RDCP type 3, and variants in the PEX5 gene (12p13.31) encoding the peroxisomal targeting signal 1 receptor cause RDCP type 5.\nDiagnostic methods\nDiagnosis is suspected on clinical and radiologic findings and confirmed by either biochemical or molecular testing. Sub-typing requires molecular testing.\nDifferential diagnosis\nThe principle differential diagnosis is Zellweger syndrome. It also includes Warfarin embryopathy, fatty acyl-CoA reductase 1 deficiency, and Chondrodysplasia punctata, tibia-metacarpal type.\nAntenatal diagnosis\nPrenatal diagnosis is feasible for at risk pregnancies where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe disease is transmitted in an autosomal recessive manner. Genetic counseling should be proposed to at risk couples (where both parents are unaffected carriers of the disease) informing them that the risk of having and affected child is 25% for each pregnancy.\nManagement and treatment\nManagement is supportive. Cataract extraction may restore some vision. Physical therapy is recommended to improve contractures; orthopedic procedures may improve function in some individuals. Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with milder forms of RCDP. Gastrostomy tube may be considered for poor weight gain, feeding intolerance, aspiration, and gastroesophageal reflux. Anti-seizure medications may be considered for seizures particularly where seizures are progressive, continuous and apparently painful, or significantly interfering with a child's interaction with the environment.\nPrognosis\nRCDP has a severe prognosis with death generally occurring during the first decade of life, mainly due to respiratory complications; a proportion may die in the neonatal period. Greater than 90% of individuals with RCDP survive the first year of life, and about 75% live to school age. Those with less severe plasmalogen deficiency, had improved survivability compared with those with very low classical plasmalogen levels.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Karen HEATH"}
{"Disease Name": "Rhizomelic dysplasia, Patterson-Lowry type", "Disease Definition": "Rhizomelic dysplasia, Patterson-Lowry type is a rare primary bone dysplasia characterized by short stature, severe rhizomelic shortening of the upper limbs associated with specific malformations of humeri (including marked widening and flattening of proximal metaphyses, medial flattening of the proximal epiphyses, and lateral bowing with medial cortical thickening of the proximal diaphyses), marked coxa vara with dysplastic femoral heads and brachimetacarpalia.", "ORPHA ID": 2831, "Summary": ""}
{"Disease Name": "Rhizomelic syndrome, Urbach type", "Disease Definition": "Rhizomelic syndrome, Urbach type is a rare primary bone dysplasia characterized by upper limbs rhizomelia and other skeletal anomalies (e.g. short stature, dislocated hips, digitalization of the thumb with bifid distal phalanx), craniofacial features (e.g. microcephaly, large anterior fontanelle, fine and sparse scalp hair, depressed nasal bridge, high arched palate, micrognathia, short neck), congenital heart defects (e.g. pulmonary stenosis), delayed psychomotor development and mild flexion contractures of elbows. Radiologic evaluation may reveal flared epiphyses, platyspondyly and/or digital anomalies.", "ORPHA ID": 3098, "Summary": ""}
{"Disease Name": "Rhombencephalosynapsis", "Disease Definition": "A rare cerebellar malformation characterized by congenital complete or partial fusion of the cerebellar hemispheres, dentate nuclei, and middle cerebellar peduncles, and complete or partial absence of the vermis. It may occur as an isolated anomaly or with other malformations of the brain.", "ORPHA ID": 59315, "Summary": "Epidemiology\nMore than 150 cases of rhombencephalosynapsis (RES) have been reported in the literature, 24% of which are reported as an isolated malformation. The prevalence remains unknown.\nClinical description\nOnset is variable as rhombencephalosynapsis (RES) may be detected in the antenatal period or manifest later in childhood. Brain MRI typically reveals an underdeveloped or absent cerebellar vermis associated with a midline fusion of cerebellar hemispheres. Classically, patients with RES present with motor developmental delay, ataxia, and abnormal movements (e.g. diminished movement at birth, head rolling, oculomotor abnormalities, a characteristic ''figure-of-eight'' head shaking). The range of cognitive outcome is very large, from profound intellectual disability to normal IQ. Clinical presentation may vary from a mild phenotype of truncal ataxia with preserved cognition, to a severe form associating cerebral palsy, congenital hydrocephalus and intellectual impairment. Most RES patients without obvious associated malformation and/or obstructive hydrocephaly and/or chromosomal anomaly seem to have preserved intellectual abilities. Attention-deficit/hyperactivity disorder (ADHD) is frequently observed. Other associated brain malformations include aqueductal stenosis, mesencephalosynapsis, holoprosencephaly, corpus callosum dysgenesis, microlissencephaly, pontocerebellar hypoplasia.\nEtiology\nThe genetic etiology of RES remains unknown and no teratogenic effect has been confirmed. Most cases are sporadic, with no chromosomal anomaly. The recurrence risk for a couple is extremely low. Syndromal genetic associations like de novo mutations in MN1 (MN1 C-terminal truncation syndrome; MCTT) or pontocerebellar hypoplasia with RES and microlissencephaly (homozygous variant in EXOSC3) are very rare.\nDiagnostic methods\nDiagnosis is confirmed by brain MRI which shows characteristic dysgenesis or agenesis of the cerebellar vermis, a midline fusion of the cerebellar hemispheres, dentate nuclei and in some cases the superior cerebellar peduncles, as well as variable supratentorial anomalies including absent septum pellicidum, dysplastic corpus callosum, aqueductal stenosis associated with hydrocephalus, dilated third and lateral ventricles, and a keyhole-shaped fourth ventricle. Malformation severity ranges from partial to complete rhombencephalosynapsis and includes an atypical form characterized by absent posterior vermis and residual anterior vermis.\nDifferential diagnosis\nRES sometimes occurs as part of a syndrome such as VACTERL association or the recently described MCTT syndrome. The most common syndrome related to RES is Gomez-Lopez-Hernandez syndrome (GLHS). Differential diagnosis includes other disorders with brain/cerebellar malformations such as holoprosencephaly, Dandy-Walker syndrome and Joubert syndrome.\nAntenatal diagnosis\nAntenatal diagnosis is possible after 21 weeks of gestation, when cerebellar structures are well defined. Ultrasound may reveal enlarged cerebral ventricles, a common indication for fetal MRI which may in turn show typical findings of RES. Follow-up fetal MRI should be considered in uncertain cases. In case of prenatal diagnosis, the prognosis will be defined by the search for associated cerebral or extra-cerebral malformations, chromosomal abnormalities (CGH array) or a pathogenic variant in the MN1 gene.\nGenetic counseling\nRES cases happen sporadically and are not inherited from parents.\nManagement and treatment\nManagement is symptomatic and may include surgical treatment of spasticity (e.g. hamstring release), or hydrocephalus. Neuropsychological assessment should be provided for cases involving intellectual and behavioral impairment.\nPrognosis\nMost RES patients without obvious associated malformation and/or obstructive hydrocephaly and/or chromosomal anomaly seem to have preserved intellectual abilities, which is a crucial point for couples' decision following prenatal diagnosis. Nevertheless, ADHD is frequent. Syndromic cases of RES have a poor prognosis except Gomez-Lopez-Hernandez syndrome.\n\n                            Last update: \n                            November 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Sylvie ODENT | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "RHYNS syndrome", "Disease Definition": "A rare genetic, syndromic retinal disorder characterized by the association of retinitis pigmentosa, hypopituitarism, nephronophthisis, and skeletal dysplasia.", "ORPHA ID": 140976, "Summary": ""}
{"Disease Name": "Riboflavin transporter deficiency", "Disease Definition": "A rare, genetic motor neuron disease characterized by a peripheral and cranial neuropathy, neuronal loss in anterior horns and atrophy of spinal sensory tracts, causing muscle weakness, sensory loss, diaphragmatic paralysis and respiratory insufficiency, and multiple cranial nerve deficits such as sensorineural hearing loss, bulbar symptoms, and loss of vision due to optic atrophy. Depending on the transporter affected, Riboflavin transporter deficiency 2 (RFVT2) and Riboflavin transporter deficiency 3 (RFVT3) are distinguished.", "ORPHA ID": 97229, "Summary": "Epidemiology\nRiboflavin transporter deficiency (RTD) has been reported in more than 100 genetically diagnosed cases to date.\nClinical description\nOnset may occur from early infancy until adulthood, with a more severe presentation at a younger age. The most frequent presenting symptoms are cranial neuropathy, sensory ataxia, muscle weakness and respiratory insufficiency due to diaphragmatic paralysis. The cranial neuropathy leads to sensorineural hearing loss, loss of vision due to optic atrophy, dysarthria, dysphagia, feeding problems, facial weakness and eye movement impairments. Peripheral neuropathy in combination with anterior horn cell dysfunction and atrophy of the sensory tracts in the spinal cord causes muscle weakness with atrophy and (sensory) ataxia. Diaphragmatic paralysis in combination with general muscle weakness may rapidly lead to respiratory insufficiency, especially in infants and young children. Often, feeding through a nasogastric tube or gastrostomy device and artificial ventilation and tracheotomy are required. Sensory ataxia and optic atrophy seem more prevalent in RFVT2 than RFVT3 deficient patients.\nEtiology\nPathogenic biallelic mutations in the genes SLC52A2 and SLC52A3 that encode riboflavin transporter 2 and 3 cause RTD2 and RTD3, respectively. Riboflavin (Vitamin B2) is a water-soluble vitamin that is essential for normal metabolism. The loss of function of the riboflavin transporter results in cellular flavin deficiency in different tissues. As flavins play an important role in mitochondrial function, mitochondrial dysfunction might act as a pathomechanism contributing to neurodegeneration in RTD.\nDiagnostic methods\nDiagnosis is only possible through mutational analysis of all genes coding for riboflavin transporters. Biochemical tests can show abnormalities such as abnormal (MADD-like) plasma acylcarnitine profiles, abnormal urine organic acids and decreased plasma flavin levels; however, approximately 50% of patients have normal results. Magnetic resonance imaging (MRI) is normal in the large majority of RTD patients. Electrophysiological testing (EMG) can show findings consistent with a sensorimotor axonal neuropathy with signs of anterior horn cell dysfunction, but normal results can also be observed.\nDifferential diagnosis\nDifferential diagnosis include neuromuscular diseases, in particular congenital or mitochondrial myopath and rapidly progressive neuropathies.\nAntenatal diagnosis\nPrenatal diagnosis is possible if family mutations in the SLC52A2 or SLC52A3 genes are known.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nRiboflavin supplementations is lifesaving and daily administration of a high dose oral riboflavin supplementation should be started immediately upon suspicion of RTD; treatment is lifelong. In cases with early onset, assisted ventilation, tracheostomy, and maintenance of nutrition via gastrostomy may be required. Regular clinical evaluation is required and includes neurological examination as well as evaluation of hearing and vision, respiratory function and skeletal deformities like scoliosis. Depending on the symptoms, physical and speech therapy should be initiated. Cochlear implants have proven highly successful for hearing loss in RTD.\nPrognosis\nIf untreated, RTD is progressive and often fatal, with respiratory insufficiency as the main cause of death. However, severity and rate of progression vary between patients. When treated with high doses of riboflavin, the majority of patients show improvement over time and early treatment may even result in full recovery and normal development. In contrast, patients with irreversible damage may show stabilization but no improvement of symptoms. No deaths have been reported in riboflavin-treated patients.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr A.M. [Annet] BOSCH  - Dr Eva HOYTEMA VAN KONIJNENBURG  - Dr B. [Bregje] JAEGER"}
{"Disease Name": "Ribose-5-P isomerase deficiency", "Disease Definition": "Ribose-5-P isomerase deficiency is an extremely rare, hereditary, disorder of pentose phosphate metabolism characterized by progressive leukoencephalopathy and a highly increased ribitol and D-arabitol levels in the brain and body fluids. Clinical presentation includes psychomotor delay, epilepsy, and childhood-onset slow neurological regression with ataxia, spasticity, optic atrophy and sensorimotor neuropathy.", "ORPHA ID": 440706, "Summary": ""}
{"Disease Name": "Richards-Rundle syndrome", "Disease Definition": "Richards-Rundle syndrome is an extremely rare neurodegenerative disorder characterized by progressive spinocerebellar ataxia, sensorineural hearing loss, and hypergonadotropic hypogonadism associated with additional neurological manifestations (such as peripheral muscle wasting, nystagmus, intellectual disability or dementia) and ketoaciduria.", "ORPHA ID": 1399, "Summary": ""}
{"Disease Name": "Richieri Costa-da Silva syndrome", "Disease Definition": "Richieri Costa-da Silva syndrome is a rare, genetic, myotonic syndrome characterized by childhood onset of progressive and severe myotonia (with generalized muscular hypertrophy and progressive impairment of gait), short stature, skeletal abnormalities (including pectus carinatum, short, wedge-shaped thoracolumbar vertebrae, kyphoscoliosis, genu valgum, irregular femoral epiphyses), and mild to moderate intellectual deficiency. No facial dysmorphism nor joint limitation is associated. There have been no further descriptions in the literature since 1984.", "ORPHA ID": 3101, "Summary": ""}
{"Disease Name": "Richieri Costa-Pereira syndrome", "Disease Definition": "Richieri Costa-Pereira syndrome is characterized by short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies (including hypoplastic thumbs), and clubfoot. It has been described in 14 Brazilian families and in one unrelated French patient. Prominent low set ears and a highly arched palate were also observed. Transmission is autosomal recessive.", "ORPHA ID": 3102, "Summary": ""}
{"Disease Name": "Ricin poisoning", "Disease Definition": "A rare disorder due to poisoning characterized by acute onset of potentially life-threatening illness following ingestion, inhalation, or injection of ricin, a lectin present in the seeds of Ricinus communis, the castor oil plant. Clinical presentation depends on the route of administration, inhalation being the most toxic route, followed by oral ingestion. Presenting signs and symptoms include nausea, vomiting, diarrhea, hematemesis, and melena (upon ingestion), cough, wheezing, dyspnea, sore throat, and congestion (upon inhalation), and erythema, induration, blisters, capillary leak syndrome, and localized necrosis (upon injection). The condition can progress to seizures, shock, organ failure, pulmonary edema, and respiratory failure.", "ORPHA ID": 570470, "Summary": ""}
{"Disease Name": "Rickettsialpox", "Disease Definition": "A rare, acquired, self-limiting, infectious disease due to the mite-borne bacteria Rickettsia akari characterized by an asymptomatic, 0.5 to 2 cm in diameter papulovesicle that typically ulcerates and forms an eschar, followed by a generalized papulovesicular rash associating variable constitutional symptoms, such as localized lymphadenopathy, fever, malaise, and headaches. Additonal symptoms may include diaphoresis, myalgia and, less frequently, rhinorrhea, pharyngitis, nausea, vomiting, splenomegaly, conjunctival hyperemia, and abdominal pain. Systemic symptoms resolve within 6-10 days.", "ORPHA ID": 83312, "Summary": ""}
{"Disease Name": "RIDDLE syndrome", "Disease Definition": "A rare, genetic, primary immunodeficiency disorder characterized by increased radiosensitivity(R), mild immunodeficiency (ID), dysmorphic features (D), and learning difficulties (LE).", "ORPHA ID": 420741, "Summary": ""}
{"Disease Name": "Rieger anomaly", "Disease Definition": "Rieger's anomaly is a congenital ocular defect caused by anterior segment dysgenesis and is characterized by severe anterior chamber deformity with prominent strands and marked atrophy of the iris stroma, with hole or pseudo-hole formation and corectopia. The term covers the association of these iris and pupil anomalies with the features of Axenfeld’s anomaly (see this term).", "ORPHA ID": 91483, "Summary": ""}
{"Disease Name": "Rift valley fever", "Disease Definition": "Rift Valley fever (RVF), caused by the Rift Valley fever virus (RVFV), is an arbovirus characterized by a usually self-limiting febrile illness but that in some cases can also manifest with thrombosis, vision loss, hemorrhages and/or neurological symptoms.", "ORPHA ID": 319251, "Summary": ""}
{"Disease Name": "Right inferior vena cava connecting to left-sided atrium", "Disease Definition": "A rare vascular anomaly characterized by a congenital anomalous connection between the inferior vena cava and the left atrium. Clinical manifestations depend on the presence and nature of additional cardiac defects and include cyanosis, dyspnea, failure to thrive, clubbing of fingers and toes, and potentially heart failure.", "ORPHA ID": 99119, "Summary": ""}
{"Disease Name": "Right sided atrial isomerism", "Disease Definition": "A rare heterotaxia characterized by complex congenital heart malformations and abnormal lateralization of other thoracic and abdominal organs due to embryonic disruption of the left-right axis development. Cardiac defects include dextrocardia or mesocardia, common atrioventricular valve associated with complete atrioventricular septal defect or common atrium, transposition or malposition of the great arteries, and total anomalous pulmonary venous drainage, among others. Cardiac arrhythmias are frequently observed. Typical abnormalities of other organs are bilateral trilobed lungs, midline liver, and asplenia. Patients present in the newborn period with severe cardiac failure and cyanosis. Prognosis is poor.", "ORPHA ID": 97548, "Summary": ""}
{"Disease Name": "Right superior vena cava connecting to left-sided atrium", "Disease Definition": "A rare, congenital vascular malformation of the major vessels characterized by the right SVC passing medially and dorsally to the aortic root and draining into the left atrium. Patients usually present a right-to-left systemic venous blood shunt which may manifest with arterial hypoxemia, cyanosis, exercise dyspnea, clubbing of the fingers, palpitations, murmurs and/or potentially fatal brain abscess. Association with other cardiac anomalies has been reported.", "ORPHA ID": 99110, "Summary": ""}
{"Disease Name": "Rigid spine syndrome", "Disease Definition": "Rigid spine syndrome (RSS) is a slowly progressive childhood-onset congenital muscular dystrophy (see this term) characterized by contractures of the spinal extensor muscles associated with abnormal posture (limitation of neck and trunk flexure), progressive scoliosis of the spine, early marked cervico-axial muscle weakness with relatively preserved strength and function of the extremities and progressive respiratory insufficiency.", "ORPHA ID": 97244, "Summary": ""}
{"Disease Name": "RIN2 syndrome", "Disease Definition": "RIN2 syndrome, formerly known as macrocephaly, alopecia, cutis laxa and scoliosis (MACS) syndrome, is a very rare inherited connective tissue disorder characterized by macrocephaly, sparse scalp hair, soft-redundant and hyperextensible skin, joint hypermobility, and scoliosis. Patients have progressive facial coarsening with downslanted palpebral fissures, upper eyelid fullness/infraorbital folds, thick/everted vermillion, gingival overgrowth and abnormal position of the teeth. Rarer manifestations such as abnormal high-pitched voice, bronchiectasis, hypergonadotropic hypergonadism and brachydactyly (see this term) have also been reported.", "ORPHA ID": 217335, "Summary": ""}
{"Disease Name": "Ring chromosome 1 syndrome", "Disease Definition": "Ring chromosome 1 syndrome is an autosomal anomaly characterized by variable clinical features, most commonly including significant intrauterine and postnatal growth failure, developmental delay, intellectual disability, microcephaly, and dysmorphic facial features. Some less frequent clinical features are dysgenesis of corpus callosum, atrial septal defect, rocker bottom feet and clinodactyly.", "ORPHA ID": 1437, "Summary": ""}
{"Disease Name": "Ring chromosome 10 syndrome", "Disease Definition": "An autosomal anomaly characterized by variable clinical features, depending on the size and precise location of deleted chromosome segments. Most patients present with developmental delay, intellectual disability, growth retardation, microcephaly, clinodactyly, and dysmorphic features. Congenital heart disease and genitourinary anomalies were reported in some cases.", "ORPHA ID": 1438, "Summary": ""}
{"Disease Name": "Ring chromosome 11 syndrome", "Disease Definition": "A rare autosomal anomaly characterized by variable clinical features, including early growth retardation and short stature, microcephaly, developmental delay, some degree of intellectual disability, facial dysmorphism and café-au-lait spots. In some cases, congenital heart disease and endocrine abnormalities have been reported.", "ORPHA ID": 96175, "Summary": ""}
{"Disease Name": "Ring chromosome 12 syndrome", "Disease Definition": "Ring chromosome 12 syndrome is a rare chromosomal anomaly syndrome with a highly variable phenotype principally characterized by postnatal growth retardation, variable degrees of developmental delay and intellectual disability, microcephaly and facial dysmorphism (incl. epicanthal folds, low-set, cupped ears, prominent nose with flat nasal bridge, high arched palate, micrognathia). Skeletal abnormalities (e.g. pectus excavatum, clinodactyly), congenital heart malformations, cryptorchidism, café-au-lait spots and epilepsy have also been reported.", "ORPHA ID": 1439, "Summary": ""}
{"Disease Name": "Ring chromosome 13 syndrome", "Disease Definition": "A rare chromosomal anomaly of chromosome 13 characterized by a widely variable phenotype (ranging from mild to severe) principally characterized by intrauterine growth retardation, developmental delay, short stature, moderate to severe intellectual deficit, microcephaly, facial dysmorphism (i.e. upslanting palpebral fissures, hypertelorism, abnormal ears, broad nasal bridge, high arched palate, micrognathia, small mouth, and thin lips), hands and feet anomalies, and genital abnormalities. Additional features reported include behavioral problems, hearing and speech disorders, congenital heart defects, cerebral malformations, and anal atresia.", "ORPHA ID": 96176, "Summary": ""}
{"Disease Name": "Ring chromosome 14 syndrome", "Disease Definition": "A rare chromosomal anomalie characterized by intellectual deficit, retinal and skin pigmentation disorders, seizures, and dysmorphic features, including flat occiput, epicanthal folds, downward slanting eyes, flat nasal bridge, upturned nostrils, short neck, and large low set ears.", "ORPHA ID": 1440, "Summary": ""}
{"Disease Name": "Ring chromosome 15 syndrome", "Disease Definition": "A rare chromosomal anomaly syndrome, with a highly variable phenotype, characterized by pre- and/or postnatal growth retardation, variable intellectual disability, short stature, dysmorphic features (microcephaly, triangular facies, frontal bossing, hypertelorism, ear anomaly, broad nasal bridge, highly arched palate, micrognathism), hand and feet anomalies (e.g. brachydactyly, clinodactyly, syndactyly), and multiple hyperpigmented and/or hypopigmented spots. Severe phenotypes present with cardiac abnormalities and/or renal malformations. Other reported features include hypotonia, speech delay, talipes equinovarus, and genital anomalies (cryptorchidism and hypospadias).", "ORPHA ID": 96177, "Summary": ""}
{"Disease Name": "Ring chromosome 16 syndrome", "Disease Definition": "A rare chromosomal anomaly syndrome, resulting from the partial deletion of chromosome 16, characterized by pre- and postnatal growth delay, severe developmental delay, intellectual disability, speech delay, and craniofacial dysmorphism (e.g. microcephaly, hypertelorism, downslanted palpebral fissures, ptosis, telecantus, low set and dysmorphic ears, broad flat nasal bridge, down-turned mouth corners, high palate, retrognathia). Patients may also present congenital cataract, mild synophrys, hypotonia, and poor social contact. Congenital heart anomalies (e.g. ventricular septal defect, patent ductus arteriosus) have also been reported.", "ORPHA ID": 96178, "Summary": ""}
{"Disease Name": "Ring chromosome 17 syndrome", "Disease Definition": "A rare chromosomal anomaly characterized by highly variable manifestations, ranging from a severe phenotype which presents with lissencephaly and severe intellectual disability to a milder phenotype that includes short stature, microcephaly, intellectual disability, seizures (that may be pharmacoresistant), café-au-lait spots, retinal flecks and minor facial dysmorphism, depending on the presence or absence of the Miller-Dieker critical region.", "ORPHA ID": 1441, "Summary": ""}
{"Disease Name": "Ring chromosome 18 syndrome", "Disease Definition": "A rare autosomal anomaly characterized by variable clinical features, most commonly including hypotonia, neonatal feeding and respiratory difficulties, microcephaly, global developmental delay and intellectual disability, growth hormone deficiency, hypothyroidism, hearing loss, aural atresia, dysmorphic facial features and behavioral characteristics.", "ORPHA ID": 1442, "Summary": ""}
{"Disease Name": "Ring chromosome 19 syndrome", "Disease Definition": "Ring chromosome 19 syndrome is a rare chromosomal anomaly syndrome with a highly variable phenotype that may range from normal to patients with profound intellectual disability, developmental delay, learning disability (esp. speech) and mild dysmorphism (incl. micro/macrocephaly, prominent forehead, low-set and posteriorly rotated ears, hypertelorism, high nasal bridge, prominent philtrum, retro/micrognathia). Mild hypotonia and autistic-like mannerisms (e.g. hand opening and closing, head banging) may also be associated. Other anomalies, such as cutis laxa, hearing loss, syndactyly, digital hypoplasia, and talipes equinovarus, have also been reported.", "ORPHA ID": 1443, "Summary": ""}
{"Disease Name": "Ring chromosome 2 syndrome", "Disease Definition": "Ring chromosome 2 syndrome is a rare chromosomal anomaly syndrome with highly variable phenotype principally characterized by intrauterine growth retardation, failure to thrive, developmental delay, hypotonia, mild dysmorphic features (incl. microcephaly, short forehead, upslanting palpebral fissures, hypertelorism, epicanthal folds, wide nasal bridge, broad nasal tip, long philtrum, thin upper lip, micrognathia, short neck), skeletal anomalies (e.g. kyphosis, brachydactyly, clinodactyly, talipes equinovarus) and dermatological features (i.e. café-au-lait spots). Patients may also present ventriculoseptal defects and genital abnormalities (e.g. genital hypoplasia, phimosis, cryptorchidism).", "ORPHA ID": 96171, "Summary": ""}
{"Disease Name": "Ring chromosome 20 syndrome", "Disease Definition": "A rare chromosomal disorder, characterized by childhood onset drug resistant epilepsy with typical electroencephalographic findings (EEG), mild to severe intellectual disability and behavioral problems.", "ORPHA ID": 1444, "Summary": "Epidemiology\nThe overall birth prevalence of ring chromosomes is 1/30-60,000 and ring 20 (r20) is one of the most common and is probably underdiagnosed.\nClinical description\nInitial psychomotor development is usually unaffected. Age of seizure onset varies between 1-24 years (frequently 4-10 years) and are typically recurrent focal motor seizures during sleep or whilst awake with alteration of consciousness, staring, automatisms, ictal visual, affective behavior and periods of intense fear. Seizures can progress to generalized tonic or tonic-clonic seizures. Non-convulsive status epilepticus (NCSE) is common, recognizable by an altered state of vigilance, staring, reduced motor activity and speech. R20 syndrome is considered a developmental epileptic encephalopathy since epilepsy onset is followed by an early cognitive-behavioral decline which seems to be focused on frontal lobe dysfunction. Language and learning disabilities, attention problems, aggressive and obsessive behavior, and apathy are frequently reported. The electroencephalogram (EEG) shows frontal spikes within runs of bilateral slow high voltage activity. Age-related patterns of sleep deterioration, ranging from normal to destructured non-rapid eye movement/rapid eye movement, is also typical. There are no distinct dysmorphisms although microcephaly, strabismus, micrognathia, down-slanting palpebral fissures, ear abnormalities and poor somatic growth can be present. Associated brain, cardiac and renal malformations are rare.\nEtiology\nA ring chromosome is an aberrant chromosome whose ends have fused together. Ring chromosomes are unstable: during mitosis, the ring may be lost or duplicated. Patients carrying a ring chromosome often have mosaic karyotypes with normal cells, cells with a ring chromosome, cells with monosomy and/or cells with reorganized/duplicated rings. Some patients with r20 lose the terminal part of 20q. The epileptogenic mechanism remains unknown. Currently there is no evidence to support a correlation between the level of mosaicism and the severity of the phenotype, although non-mosaic cases present with the most severe symptoms/comorbidities.\nDiagnostic methods\nDiagnosis is suspected in patients with childhood onset recurrent seizures with a cognitive deterioration, behavioral changes and typical EEG findings. As mosaicism is frequent, r20 chromosome should be confirmed by karyotyping with at least 100 metaphases on blood lymphocytes. Diagnosis may be missed using other genetic techniques including aCGH.\nDifferential diagnosis\nDifferential diagnosis includes primarily Lennox Gastaut syndrome. Moreover, frontal lobe epilepsy, continuous spike and wave during slow wave sleep and NCSE of other etiologies should be considered.\nGenetic counseling\nR20 mosaicism could be sporadic or inherited: parent-to child transmission has been reported in a few exceptional families. Genetic counseling is recommended.\nManagement and treatment\nSeizures associated with r20 are often refractory to medications and there is no specific treatment regimen for the disorder. A more favorable outcome has been reported with the combination of valproate and lamotrigine. Ketogenic diet can be helpful, with better results if introduced at seizure onset. Resective brain surgery is not a therapeutic option. Mild improvement with vagus nerve stimulation is reported.\nPrognosis\nPrognosis is generally poor since epilepsy is drug resistant, remaining into adulthood. Cognitive performance can remain locked at the time of epilepsy onset or worsen over time.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Valentina DE GIORGIS | EpiCARE* - Pr Rima NABBOUT | EpiCARE* -  Allison WATSON | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Ring chromosome 21 syndrome", "Disease Definition": "Ring chromosome 21 syndrome is an autosomal anomaly characterized by variable clinical features, most commonly including growth retardation, developmental delay, intellectual disability, epilepsy, microcephaly, short stature, dysmorphic features, hypogammaglobulinemia, thrombocytopenia and unspecific skeletal anomalies (hemivertebrae, clinodactyly, syndactyly). In rare cases, it has been described in phenotypically normal individuals.", "ORPHA ID": 1445, "Summary": ""}
{"Disease Name": "Ring chromosome 22 syndrome", "Disease Definition": "A rare autosomal anomaly characterized by variable clinical features, most commonly including global developmental delay, hypotonia, growth retardation with microcephaly, intellectual disability with severe speech delay, seizures or abnormal EEG, autistic spectrum disorder and other behavioral characteristics.", "ORPHA ID": 1446, "Summary": ""}
{"Disease Name": "Ring chromosome 3 syndrome", "Disease Definition": "Ring chromosome 3 syndrome is a rare chromosomal anomaly syndrome with a highly variable phenotype principally characterized by pre- and postnatal growth retardation, short stature, developmental delay, mild to severe intellectual disability, microcephaly and mild dysmorphic features (incl. triangular face, dysplastic ears, upslanting palpebral fissures, epicanthic folds, broad nasal bridge, full nasal tip, long philtrum, downturned corners of the mouth, and micro/retrognathia). Additional manifestations reported include hypotonia, mild articular limitation, hearing loss, digital anomalies (i.e. clinodacytyly, brachydactyly), café-au-lait patches and hypospadias.", "ORPHA ID": 96172, "Summary": ""}
{"Disease Name": "Ring chromosome 4 syndrome", "Disease Definition": "Autosomal anomaly characterized by variable clinical features, most commonly including significant intrauterine and postnatal growth retardation, developmental delay, intellectual disability, microcephaly, and dysmorphic facial features. Some less frequent features are cleft lip and/or cleft palate, congenital cardiovascular, gastrointestinal and genitourinary system anomalies.", "ORPHA ID": 1447, "Summary": ""}
{"Disease Name": "Ring chromosome 5 syndrome", "Disease Definition": "Ring chromosome 5 syndrome is a rare chromosomal anomaly syndrome, with high phenotypic variability, principally characterized by a neonatal mewing cry, severe developmental delay and intellectual disability, short stature, hypotonia, dysmorphic features (incl. microcephaly, facial asymmetry, hypertelorism, epicanthal folds, abnormal ears, micro/retrognathia), congenital cardiac anomalies (such as atrial and ventricular septal defect, tricuspid insufficiency, hypoplastic aorta) and skeletal abnormalities (e.g. hypoplastic thumbs, anomalous ulna/radius, dysplastic metacarpals and phalanges).", "ORPHA ID": 251043, "Summary": ""}
{"Disease Name": "Ring chromosome 6 syndrome", "Disease Definition": "Ring chromosome 6 syndrome is a rare chromosomal anomaly syndrome with highly variable phenotype principally characterized by prenatal/postnatal growth failure, intellectual disability, developmental delay, craniofacial dysmorphism (incl. microcephaly, microphthalmia, epicanthus, low-set and malformed ears, broad and flat nasal bridge, full lips, micrognathia), central nervous system anomalies (e.g. hydrocephalus, cortical atrophy, ventriculomegaly), short neck, and delayed bone age. Cardiac defects, limb anomalies, hip joint malformations, and seizures have also been reported.", "ORPHA ID": 1448, "Summary": ""}
{"Disease Name": "Ring chromosome 7 syndrome", "Disease Definition": "Ring chromosome 7 syndrome is a rare chromosomal anomaly syndrome, with highly variable phenotype, principally characterized by growth failure, short stature, intellectual disability, dermatological abnormalities (nevus flammeus, dark pigmented nevi, café-au-lait spots), microcephaly and facial dysmorphism (incl. facial asymmetry, small ears, abnormal palpebral fissures, ptosis, epicanthic folds, hyper/hypotelorism). Additional reported features include convulsions, cleft lip and palate, clinodactyly, kyphoscoliosis and genital anomalies (i.e. cryptorchidism, hypospadias, micropenis).", "ORPHA ID": 1449, "Summary": ""}
{"Disease Name": "Ring chromosome 8 syndrome", "Disease Definition": "A rare chromosomal anomaly comprising variable parts of chromosome 8. The phenotype of mosaic or non-mosaic supernumerary r(8)/mar(8) ranges from almost normal to variable degrees of minor abnormalities, and growth and mental retardation overlapping with the well-known mosaic trisomy 8 syndrome.", "ORPHA ID": 1450, "Summary": ""}
{"Disease Name": "Ring chromosome 9 syndrome", "Disease Definition": "A rare autosomal anomaly characterized by variable clinical features, most commonly including developmental delay, some degree of intellectual disability, facial dysmorphism, microcephaly, congenital heart anomalies, and variable genital, limb and skeletal anomalies.", "ORPHA ID": 96173, "Summary": ""}
{"Disease Name": "Ring chromosome Y syndrome", "Disease Definition": "A rare chromosome Y structural anomaly, with a highly variable phenotype, mostly characterized by short stature, partial to total gonadal failure, sexual infantilism, genital anomalies (e.g. ambiguous genitalia, hypospadias, cryptorchidism), and azoospermia or oligozoospermia. Additional reported features include speech delay, obesity, and acanthosis nigricans. Gender dysphoria and comorbid bipolar disorder have also been observed.", "ORPHA ID": 261529, "Summary": ""}
{"Disease Name": "Ring dermoid of cornea", "Disease Definition": "Ring dermoid of cornea is characterised by annular limbal dermoids (growths with a skin-like structure) with corneal and conjunctival extension. Less than 30 cases have been described. Transmission is autosomal dominant and mutations in the PITX2 gene have been suggested as a potential cause of the condition.", "ORPHA ID": 91481, "Summary": ""}
{"Disease Name": "Rippling muscle disease with myasthenia gravis", "Disease Definition": "Rippling muscle disease with myasthenia gravis is a rare, acquired, neuromuscular disease characterized by CAV3 mutation-negative rippling muscle disease in association with acetylcholine receptor antibody-mediated myasthenia gravis. Patients typically present exercise-induced, electrically-silent muscle rippling with myalgia, in combination with generalized myasthenia gravis symptoms (ptosis, diplopia, neck weakness, dysphagia and dyspnea).", "ORPHA ID": 206575, "Summary": ""}
{"Disease Name": "Rippling muscle disease", "Disease Definition": "Rippling muscle disease is a rare, genetic, neuromuscular disorder characterized by muscle hyperirritability triggered by stretch, percussion or movement. Patients present wave-like, electrically-silent muscle contractions (rippling), muscle mounding, painful muscle stiffness and muscle hypertrophy, usually with elevated serum creatine kinase.", "ORPHA ID": 97238, "Summary": ""}
{"Disease Name": "RNF13-related severe early-onset epileptic encephalopathy", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital microcephaly, infantile-onset epileptic encephalopathy, and profound developmental delay. Additional reported features include cortical visual impairment, sensorineural hearing loss, increased muscle tone, limb contractures, scoliosis, and dysmorphic features like midface hypoplasia, narrow forehead, short nose, narrowed nasal bridge, and small chin. Brain imaging may show thin corpus callosum and delayed myelination.", "ORPHA ID": 544503, "Summary": ""}
{"Disease Name": "Roberts syndrome", "Disease Definition": "Roberts syndrome (RBS) is characterized by pre- and postnatal growth retardation, severe symmetric limb reduction defects, craniofacial anomalies and severe intellectual deficit. SC phocomelia is a milder form of RBS.", "ORPHA ID": 3103, "Summary": "Epidemiology\nThe prevalence and incidence are not known. Less than 150 cases have been described in the literature.\nClinical description\nUpper limbs are more frequently and severely affected than lower limbs. The defect is mostly mesomelic with the radius being the most affected in the upper limbs, and the fibula in the lower limbs. The most severe defects result in phocomelia. Aplastic or hypoplastic thumbs, oligodactyly, clinodactyly or syndactyly can also occur. Craniofacial anomalies include microcephaly (more severe in males than in females), hypoplastic nasal alae, malar hypoplasia, hypertelorism, micrognathia, capillary hemangioma, exophthalmos, downslanting palpebral fissures, dysplastic or small ears, cloudy cornea or cataracts, and cleft lip and palate. There is a correlation between the degree of limb and facial malformations. Other malformations such as congenital heart defects, cystic kidney and large genitalia (enlarged phallus or clitoris), may occur. Severe intellectual deficit is observed in patients surviving the newborn period.\nEtiology\nThe disease is caused by mutations in the ESCO2 gene (8p21.1), which encodes a protein belonging to the Eco1/Ctf7 family of acetyltransferases, involved in the establishment of sister chromatid cohesion during S phase. ESCO2 mutations lead to delayed cell division, increased cell death and impaired cell proliferation. The loss of progenitor cells during embryogenesis is likely responsible for the developmental defects observed in RBS.\nDiagnostic methods\nThe diagnosis is based on clinical features and karyotyping (with a characteristic ``railroad track'' appearance of chromosomes due to repulsion of heterochromatic regions and premature centromere separation). Direct sequencing of the ESCO2 gene can confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include thalidomide embryopathy, and the Baller-Gerold, Cornelia de Lange and TAR syndromes (see these terms).\nAntenatal diagnosis\nWhen a previous child in the family is diagnosed with RBS and carries ESCO2 mutations, prenatal diagnosis can be performed through DNA analysis of chorionic villus samples. Otherwise, RBS may be suspected by observation of characteristic RBS anomalies at ultrasonography and can be confirmed by karyotyping.\nGenetic counseling\nThe mode of transmission is autosomal recessive.\nManagement and treatment\nManagement includes surgical correction of facial malformations, surgical and/or orthopedic treatment of limb defects and management of the cognitive disabilities.\nPrognosis\nPrognosis is relatively unfavorable. High mortality in the newborn period or early childhood is due to cardiac or renal malformations.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Sylvie MANOUVRIER-HANU"}
{"Disease Name": "Robin sequence-oligodactyly syndrome", "Disease Definition": "Robin sequence-oligodactyly syndrome is a rare, genetic, developmental defect during embryogenesis syndrome characterized by Robin sequence (i.e. severe micrognathia, retroglossia and U-shaped cleft of the posterior palate) associated with pre- and postaxial oligodactyly. Facial features can include a narrow face and narrow lower dental arch. Clinodactyly, absent phalanx, metacarpal fusions, and hypoplastic carpals have also been reported. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 3104, "Summary": ""}
{"Disease Name": "Robinow syndrome", "Disease Definition": "Robinow syndrome (RS) is a rare genetic syndrome characterized by limb shortening and abnormalities of the head, face and external genitalia.", "ORPHA ID": 97360, "Summary": "Epidemiology\nExact prevalence is unknown. About 200 cases have been reported to date. Cases have been reported primarily from the USA, Arab countries, Turkey, Czech Republic and Slovakia, the Indian subcontinent, and Brazil. Prevalence in other geographic areas is unknown. There is an equal male-to-female ratio.\nClinical description\nTwo forms of the syndrome with different patterns of inheritance and variable frequency of clinical signs have been described: a milder autosomal dominant form (autosomal dominant Robinow syndrome, see this term) and a more severe autosomal recessive form (autosomal recessive Robinow syndrome, see this term). The syndrome has a wide clinical spectrum. Clinical signs such as short stature, characteristic facial features (hypertelorism, midface hypoplasia, large nasal bridge, short upturned nose, and anteverted nares), mesomelic limb shortening, as well as brachydactyly, clinodactyly, gingival hyperplasia, and genital hypoplasia are generally common to both forms. Vertebral segmentation defects are common but more severe in the recessive form: hemivertebrae and scoliosis are more common (75% of cases). Rib fusions appear to be present almost exclusively in the autosomal recessive form. Umbilical hernia and supernumerary teeth appear to be present exclusively in patients with the dominant form. Associated conditions include frequent ear infections, hearing loss, developmental and respiratory disorders, hypotonia, eating difficulties and esophageal reflux.\nEtiology\nAutosomal recessive Robinow syndrome is caused by mutations in the ROR2 gene (9q22). Mutations in the WNT5A gene (3p14.3) have been reported in some patients (< 10%) with autosomal dominant Robinow syndrome.\nDiagnostic methods\nDiagnosis is based on the clinical picture and the characteristic fetal face appearance of patients. Radiological examination is however necessary to confirm the presence of skeletal malformations.\nDifferential diagnosis\nThe main differential diagnosis is RS with a different pattern of inheritance. Syndromes that commonly involve dysmorphic facial features similar to RS, particularly hypertelorism, along with genital hypoplasia such as Aarskog-Scott syndrome and Opitz G syndrome (see these terms) should also be considered. Chromosome abnormalities have occasionally been reported in patients with a Robinow-like phenotype. Similar costovertebral segmentation defects can be found in autosomal recessive spondylocostal dysostosis (ARSD) (see this term).\nAntenatal diagnosis\nPrenatal diagnosis may be performed by fetal ultrasound from the 19th week of pregnancy but the severity of the syndrome is difficult to ascertain. Genetic testing may be performed to confirm the diagnosis in AR cases.\nGenetic counseling\nTransmission is autosomal dominant or recessive. Genetic counseling is recommended. Parents of AD cases should be clinically evaluated to exclude a milder manifestation of the syndrome prior to genetic counseling.\nManagement and treatment\nManagement of the skeletal deformities includes bracing or surgical correction. Growth hormone has been administered to increase the growth rate in children with the syndrome. In patients with wide palpebral fissures, the need for surgical intervention should be evaluated.\nPrognosis\nPrognosis of Robinow syndrome is generally good but the severity of heart disorders may affect life expectancy.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Juliana MAZZEU"}
{"Disease Name": "Rocky Mountain spotted fever", "Disease Definition": "A rare, acquired, life-threatening, infectious disease due to the tick-borne bacteria Rickettsia rickettsii characterized by an acute onset of fever, malaise, and severe headache, variably accompanied by myalgia, anorexia, nausea, vomiting, abdominal pain, and photophobia, associating (2-5 days after fever onset) a typically erythematous, blanching or non-blanching, maculopapluar rash with petechiae, starting on the wrists and ankles and progressing centrifugally to the palms and soles and centripetally to the arms, legs and trunk. Additonal variable features may include conjunctivitis, mucosal ulcers, post-inflammatory hyperpigmentation, jaundice, pneumonia, hepatomegaly, renal failure, meningismus, amnesia, optic disc edema, and ocular arterial occlusion.", "ORPHA ID": 83311, "Summary": ""}
{"Disease Name": "Roifman syndrome", "Disease Definition": "A rare, genetic immuno-osseous dysplasia associated with pre- and post-natal growth retardation, retinopathy, microcephaly, intellectual disability and dysmorphic features.", "ORPHA ID": 353298, "Summary": "Epidemiology\nTo date less than 20 cases have been reported worldwide in the scientific and medical literature.\nClinical description\nRoifman syndrome is characterized by pre- and post-natal growth retardation, hypotonia, borderline to moderate intellectual disability, retinal dystrophy, spondyloepiphyseal dysplasia (epiphyseal dysplasia, epiphyses ossification delay, vertebral changes) and skeletal anomalies (brachydactyly, fifth finger clinodactyly), as well as humoral immunodeficiency, characterized by inability to generate specific antibodies and low circulating B-cells, suggestive of a partial block of B-cell proliferation and maturation. Craniofacial dysmorphism typically includes microcephaly, narrow palpebral fissures, prominent and long eyelashes, a narrow, tubular, upturned nose with hypoplastic alae nasi, long philtrum and thin upper lip. Eczema and mild limitation in hip flexion may be observed. One instance of hypogonadotrophic-hypogonadism and one instance of myocardial noncompaction were reported.\nEtiology\nRoifman syndrome is caused by bi-allelic mutations of RNU4ATAC (2q14.2), a gene encoding a small nuclear RNA involved in minor (U12) splicing. At least one mutation locates in the stem II region of RNU4ATAC. Mutations in the same gene also cause Taybi-Linder syndrome, a more severe disorder in which there are many overlapping features.\nDiagnostic methods\nDiagnosis is suggested based on the clinical, immune and radiological phenotype and confirmed by RNU4ATAC sequencing.\nDifferential diagnosis\nOther syndromes that combine immunodeficiency and skeletal aberrations may be considered and include cartilage hair hypoplasia, primary bone dysplasias with micromelia, severe combined immunodeficiency due to adenosine deaminase deficiency, and Schimke immune-osseous dysplasia.\nAntenatal diagnosis\nThere have been no reports of prenatal diagnosis to date.\nGenetic counseling\nRoifman syndrome is transmitted as an autosomal recessive trait. Genetic counseling should be offered to at risk families (where each parent is an unaffected carrier) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTreatment is supportive only. Particular attention should be given to susceptibility to infections, growth and psychomotor development. Medical care and management should be provided according to recurrent infections and intellectual disability.\nPrognosis\nPrognosis appears to be good with no reported limitation of life expectancy. Infections can be severe and recurrent (pneumonia, septicemia, recurrent herpes reactivation, etc.).\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Patrick EDERY | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer's cramp syndrome", "Disease Definition": "A rare genetic epilepsy syndrome characterized by infantile or childhood onset of focal motor seizures remitting with age, as well as childhood onset of exercise-induced dystonia which often persists into adulthood. Additional reported features include nystagmus and postural tremor of the hands.", "ORPHA ID": 163727, "Summary": ""}
{"Disease Name": "Rolandic epilepsy-speech dyspraxia syndrome", "Disease Definition": "Rolandic epilepsy-speech dyspraxia syndrome is a rare, genetic epilepsy characterized by speech disorder (including a range of symptoms from dysarthria, speech dyspraxia, receptive and expressive language delay/regression and acquired aphasia to subtle impairments of conversational speech) and epilepsy (mostly focal and secondary generalized childhood-onset seizures, sometimes with aura). Mild to severe intellectual disability may also be observed.", "ORPHA ID": 163721, "Summary": ""}
{"Disease Name": "Romano-Ward syndrome", "Disease Definition": "A form of familial long QT syndrome (LQTS) characterized by syncopal episodes and electrocardiographic abnormalities (QT prolongation, T-wave abnormalities and torsade de pointes (TdP) ventricular tachycardia).", "ORPHA ID": 101016, "Summary": "Epidemiology\nThe prevalence of Romano-Ward syndrome (RWS) is estimated at 1/2,500.\nClinical description\nCardiac events occur from infancy through middle age but may manifest as early as the intrauterine stage with possibility of still birth. Most patients develop the symptoms during exercise or in response to stress or emotional disturbances and symptoms rarely occur at rest or during sleep. The syncopal episodes are due to TdP, a polymorphic ventricular tachycardia. TdP often degenerates to ventricular fibrillation and causes cardiac arrest or sudden death. In some patients, cardiac arrest may be the first manifestation of the disease. The electrocardiogram typically shows a prolongation of ventricular repolarization (QTc > 460 ms) and biphasic or notched T-waves in the precordial leads. Beat-to-beat alternation of the T wave (in polarity or amplitude) may be present at rest, but most commonly appears during emotional or physical stress and may precede TdP. The heart rate at rest or during exercise may be slower than normal.\nEtiology\nRWS may result from mutations in genes either encoding subunits of cardiac ion channels or proteins interacting with cardiac ion channels. To date pathogenic mutations have been identified in numerous genes, the most frequently observed causative genes are KCNQ1, KCNH2, SCN5A. The genes CALM1, CALM2 and TRDN have also undisputable evidence as LQTS-causative genes, while the remaining genes have moderate to limited evidence for LQTS causation.\nDiagnostic methods\nDiagnosis is based on typical electrocardiographic findings, clinical manifestations and family history. Genetic diagnosis should always be performed in patients with a clinically suspected diagnosis. It should also be performed on affected family members with normal/borderline QT intervals to identify those at risk of sudden death.\nDifferential diagnosis\nTypical cases are so characteristic that they do not require differential diagnosis. For borderline cases, the following conditions should be considered: catecholaminergic polymorphic ventricular tachycardia (CPVT), Jervell and Lange-Nielsen syndrome and other forms of LQTS, as well as vasovagal syncope, ventricular tachycardia, drug-induced LQTS and epilepsy.\nAntenatal diagnosis\nPrenatal testing may be available for families in which the disease-causing mutation is known.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant and genetic counseling is recommended for affected families. There is a 50% risk of transmitting the pathogenic variant from an affected individual to their offspring. Autosomal recessive transmission has been described in very few cases of RWS, and in some with  TRDN mutations only.\nManagement and treatment\nBeta-adrenergic blockers represent the first choice therapy in symptomatic patients. Whenever syncopal episodes recur despite full-dose beta-blocking therapy, left cardiac sympathetic denervation (LCSD) should be considered and implemented whenever possible. Cardiac pacing is only rarely indicated (e.g. in infants or young children with 2:1 atrioventricular block). Implantable cardioverter defibrillators (ICDs) are always indicated after cardiac arrest, or when requested by the patient, and whenever syncope recurs despite beta-blockade and LCSD. Prophylactic use of beta blockers is indicated in asymptomatic children and adults under age 40 years with LQTS (LQT1, LQT2 or LQT3). LQTS and its variants are leading causes of sudden cardiac death in young, otherwise healthy, subjects and contribute significantly to sudden infant death syndrome (SIDS). As very effective therapies exist, early diagnosis (neonatal ECG screening) is of crucial importance and permits preventive management.\nPrognosis\nThe prognosis is severe for infants with arrhythmic events in the first year of life and for those with mutations in the Calmodulin genes.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Peter SCHWARTZ"}
{"Disease Name": "Rombo syndrome", "Disease Definition": "Rombo syndrome is characterized by vermiculate atrophoderma, milia, hypotrichosis, trichoepitheliomas, peripheral vasodilation with cyanosis and basal cell carcinomas.", "ORPHA ID": 3110, "Summary": "Epidemiology\nIt has been described in four generations of one family and in two additional sporadic cases.\nClinical description\nThe skin lesions become visible between 7 and 10 years of age and are most pronounced on the face. Basal cell carcinomas are frequent and develop at around 35 years of age.\nEtiology\nThe etiology remains unknown.\n\n                            Last update: \n                            September 2009"}
{"Disease Name": "Rosaï-Dorfman disease", "Disease Definition": "A rare non-Langerhans cell histiocytosis characterized by infiltration of lymph nodes or extranodal tissues by non-malignant histiocytes displaying emperipolesis, a non-destructive phagocytosis of lymphocytes or erythrocytes. Most typical presentation is as a massive cervical lymphadenopathy in adolescents and young adults. Most frequent sites of extranodal disease are skin, soft tissue, bones, paranasal sinuses, orbit, salivary glands, and central nervous system. Symptoms are related to mass effect in the affected organs.", "ORPHA ID": 158014, "Summary": ""}
{"Disease Name": "Rosette-forming glioneuronal tumor", "Disease Definition": "Rosette-forming glioneuronal tumor is a rare mixed neuronal-glial tumor characterized by the presence of uniform, rosette- (or pseudorosette-) forming neurocytes with an astrocytic component, together creating a biphasic pattern. It can present with signs of raised intracranial pressure (headache, vomiting, papilledema), hydrocephalus, seizures, ataxia and visual disturbances, or can be diagnosed incidentally in asymptomatic patients. The tumor usually arises in the midline, involving the fourth ventricle or the cerebellum.", "ORPHA ID": 251975, "Summary": ""}
{"Disease Name": "Rothmund-Thomson syndrome type 1", "Disease Definition": "Rothmund-Thomson syndrome type 1 is a subform of Rothmund-Thomson syndrome (RTS; see this term) presenting with a characteristic facial rash (poikiloderma) and frequently associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, and rapidly progressive bilateral juvenile cataracts. In contrast to RTS2 (see this term), patients with RTS1 do not appear to have an increased risk of developing cancer.", "ORPHA ID": 221008, "Summary": "Epidemiology\nAround 300 cases of RTS have been reported in the literature so far, with RTS1 accounting for around one-third of cases.\nEtiology\nRTS is transmitted in an autosomal recessive manner and although mutations in the RECQL4 gene have been found in patients with the RTS2 subform (see this term), the etiology of RTS1 remains unknown.\n\n                            Last update: \n                            February 2010"}
{"Disease Name": "Rothmund-Thomson syndrome type 2", "Disease Definition": "Rothmund-Thomson syndrome type 2 is a subform of Rothmund-Thomson syndrome (RTS; see this term) presenting with a characteristic facial rash (poikiloderma) and frequently associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, congenital bone defects and an increased risk of osteosarcoma in childhood and squamous cell carcinoma later in life.", "ORPHA ID": 221016, "Summary": "Epidemiology\nAround 300 cases of RTS have been reported in the literature so far, with RTS2 accounting for around two-thirds of the cases.\nClinical description\nThe skeletal abnormalities may be overt (such as frontal bossing, saddle nose and congenital radial ray defects), and/or subtle anomalies visible only by radiographic analysis.\nEtiology\nRTS is transmitted as an autosomal recessive trait and RTS2 is caused by homozygous or compound heterozygous mutations in the RECQL4 gene (8q24.3), whereas the etiology of RTS1 (see this term) remains unknown.\n\n                            Last update: \n                            February 2010"}
{"Disease Name": "Rothmund-Thomson syndrome", "Disease Definition": "Rothmund-Thomson syndrome (RTS) is a genodermatosis presenting with a characteristic facial rash (poikiloderma) associated with short stature due to pre- and postnatal growth delay, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to certain cancers.", "ORPHA ID": 2909, "Summary": "Epidemiology\nThe prevalence is unknown, but around 300 cases have been reported so far.\nClinical description\nThe skin is usually normal at birth but erythema develops on the cheeks at 3-6 months of age and subsequently spreads to the extremities and buttocks. The trunk and abdomen are generally spared. During the course of the disease, cutaneous atrophy with reticulated areas of hypo- and hyperpigmentation and persistent telangiectasias develop. Other cutaneous manifestations include dental anomalies, nail dystrophy and palmo-plantar hyperkeratotic lesions. The extracutaneous manifestations are clinically heterogeneous and two subforms of RTS have been defined: RTS type 1 (RTS1; see this term) characterized by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTS type 2 (RTS2; see this term) characterized by poikiloderma, congenital bone defects (frontal bossing, saddle nose and radial ray defects: thumb hypo- or aplasia or radial aplasia) and an increased risk of osteosarcoma (see this term) in childhood and cutaneous squamous cell carcinoma later in life. Gastrointestinal (chronic emesis and diarrhea), respiratory, and benign and malignant hematological manifestations (anemia, neutropenia and myelodysplasia), as well as hypogonadism and osteopenia, have been reported in some patients.\nEtiology\nRTS2 is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (8q24.3; detected in 60-65% of RTS patients), whereas the etiology in RTS1 remains unknown.\nDiagnostic methods\nDiagnosis is based on clinical findings (primarily on the age of onset, spreading and appearance of the poikiloderma) and molecular analysis for RECQL4 mutations. The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes.\nDifferential diagnosis\nThe differential diagnosis should include other causes of childhood poikiloderma and other rare genodermatoses with prominent telangiectasias (including Bloom syndrome, xeroderma pigmentosum, Kindler syndrome, poikiloderma with neutropenia, and dyskeratosis congenita; see these terms), and the allelic disorders, RAPADILINO syndrome (in which radial ray defects are a constant feature, poikiloderma is absent and the risk of malignancy is lower) and Baller-Gerold syndrome (which is associated with craniosynostosis; see these terms).\nGenetic counseling\nRTS is transmitted in an autosomal recessive manner. Genetic counseling should be provided for RTS patients and their families, together with a recommendation for cancer surveillance for all patients with RTS2.\nManagement and treatment\nManagement should include laser treatment for the telangiectatic lesions, annual ophthalmic examinations and a radiological survey in case of bone pain, limping or fractures (indicators of osteosarcoma). RTS patients may show increased susceptibility to the adverse effects of chemotherapy, and a higher risk of a secondary malignancy (5% risk of developing skin cancer).\nPrognosis\nThe prognosis in RTS is variable: life expectancy is normal in the absence of cancer, whereas outcomes in patients with malignant pathologies depend on the quality and frequency of cancer screening and treatment.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence OLIVIER-FAIVRE"}
{"Disease Name": "Rotor syndrome", "Disease Definition": "A benign, inherited liver disorder characterized by chronic, predominantly conjugated, nonhemolytic hyperbilirubinemia with normal liver histology.", "ORPHA ID": 3111, "Summary": "Epidemiology\nRotor syndrome (RT) is a very rare disorder: the exact prevalence is unknown but over 50 cases have been reported in literature so far.\nClinical description\nIt is usually diagnosed in children or adolescents, but mild jaundice is often noted from birth. The main symptom consists of mild-to-moderate, recurrent jaundice without pruritus. Attacks of abdominal pain and low-grade fever can occur but are rare. Total serum bilirubin (mainly in the conjugated form: 50-80%) is elevated, usually between 2 and 5 mg/dl. Hematologic tests (including measurements of liver enzyme activities) and liver histology are normal. However, absolute and relative concentrations of urinary coproporphyrin I are elevated. Hemolysis is not a feature of the syndrome; however, coinheritance of hemolytic disorders, such as G-6-PD deficiency and beta thalassemia (see these terms), has been reported.\nEtiology\nAnalysis of the retention of the cholephilic dyes indicates that RT results from a defect in hepatic storage capacity of conjugated bilirubin and other organic cholephilic anions.\nDiagnostic methods\nAs the genetic basis remains unknown and the clinical, biochemical and histological features are non-specific, RT syndrome remains a diagnosis of exclusion. RT should be considered in all patients exhibiting predominantly conjugated hyperbilirubinemia with no concomitant change in liver enzyme activities (i.e. aminotransferases, alkaline phosphatase, and gamma-glutamyl transpeptidase) and in the absence of any septic condition, ultrasound anomaly of the liver or interfering drug. In this context, elevated (250 to 500% higher than controls) urinary concentrations of both total coproporphyrins and coproporphyrin I are very suggestive, but not completely specific for RT. Taken together with these findings, normal liver histology generally allows the diagnosis to be confirmed.\nDifferential diagnosis\nThe principle differential diagnosis is Dubin-Johnson syndrome (DJS; see this term). DJS and RT can be distinguished on the basis of measurements of urinary coproporphyrin excretion (total coproporphyrin excretion levels are normal in DJS) and liver histology (black-brown liver cell pigmentation is specific to DJS). If liver biopsy is not feasible or is refused, 99mTc-HIDA cholescintigraphy (revealing prominent kidney excretion in RT) or molecular analysis (detection of ABCC2 gene mutations in DJS patients) can be useful for distinguishing between RT and DJS.\nGenetic counseling\nRT appears to be inherited in an autosomal recessive manner, with the parents and siblings of affected individuals showing a pattern of urinary coproporphyrin excretion that is intermediate between that of RT patients and controls.\nManagement and treatment\nAs RT is a benign condition, no specific treatment is recommended or generally required. Affected individuals are advised to avoid alcohol and hepatotoxic drugs.\nPrognosis\nThe prognosis for RT patients is good, highlighting the need for correct diagnosis to avoid unnecessary diagnostic procedures, treatment and follow-up. Unless there is a concomitant chronic liver disease, progression to liver failure, cirrhosis or hepatic fibrosis is not observed.\n\n                            Last update: \n                            January 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Véronique BARBU  - Dr Christophe CORPECHOT"}
{"Disease Name": "Roussy-Lévy syndrome", "Disease Definition": "A rare demyelinating hereditary motor and sensory neuropathy characterized by prominent gait ataxia, pes cavus, tendon areflexia, distal limb weakness, tremor in the upper limbs, distal sensory loss, kyphoscoliosis, and progressive muscle atrophy. The disease becomes symptomatic in infancy or childhood, mode of inheritance is autosomal dominant.", "ORPHA ID": 3115, "Summary": ""}
{"Disease Name": "Rubella panencephalitis", "Disease Definition": "A rare chronic encephalitis developing up to several years after congenital rubella virus infection or rubella infection in childhood, characterized by slowly progressive, wide-spread neurological symptoms, like cognitive decline, cerebellar ataxia, spasticity, and seizures, amongst others. Progredient deterioration of the neurological disease eventually leads to the death of the patient.", "ORPHA ID": 83616, "Summary": ""}
{"Disease Name": "Rubinstein-Taybi syndrome", "Disease Definition": "A rare, genetic malformation syndrome characterized by congenital anomalies (microcephaly, specific facial characteristics, and broad thumbs and halluces), short stature, intellectual disability and behavioral characteristics.", "ORPHA ID": 783, "Summary": "Epidemiology\nBirth prevalence is estimated at around 1/100,000 to 125,000.\nClinical description\nFacial features, which become more prominent with age, include highly arched eyebrows, long eyelashes, downslanting palpebral fissures, convex nasal ridge, low hanging columella, highly arched palate and micrognathia. Talon cusps are very frequent on the permanent incisors. An unusual smile with almost complete closure of the eyes is present in most individuals. Other physical findings may include eye anomalies (nasolacrimal duct obstruction, congenital glaucoma, refractive errors), a variety of congenital heart defects (e.g. ventricular and atrial septal defect, patent ductus arteriosus), joint hypermobility, and skin anomalies (in particular keloid formation). Feeding difficulties are frequently observed in the first year, and respiratory tract infections are very common in infancy and childhood. Constipation is generally a life-long problem, and patients may become overweight during late childhood or early puberty. The children have a marked ability to establish excellent social contacts. In adulthood, sudden mood changes and obsessive-compulsive behavior may gradually become more frequent. Other than previously thought, persons with Rubinstein-Taybi syndrome under the age of 40 have no increased risk of getting malignant tumors. It is unclear whether this risk is increased in the elderly with Rubinstein-Taybi syndrome.\nEtiology\nCauses of Rubinstein-Taybi syndrome include: a microdeletion of chromosome 16p13.3 or chromosome 22q13.2, a variant in CREB-binding protein (CREBBP, 16p13.3) or a variant in E1A-binding protein p300 (EP300, 22q13.2). CREBBP and EP300 show a very high degree of homology and both play important roles as transcriptional coactivators; however, the exact pathogenesis of the syndrome remains uncertain. There is no significant genotype-phenotype correlation, except in the case of individuals with a EP300 mutation who on average have a higher level of functioning, less marked distal limb malformations, and a more pronounced microcephaly.\nDiagnostic methods\nThe diagnosis is in essence based on clinical examination. A cytogenetic or molecular abnormality can be detected in about 65% of individuals.\nDifferential diagnosis\nThe syndrome can sometimes be difficult to differentiate from Saethre-Chotzen syndrome, Floating Harbor syndrome and Cornelia de Lange syndrome.\nAntenatal diagnosis\nIf a cytogenetic or molecular abnormality is found in the affected child, reliable prenatal diagnosis is possible in future pregnancies through chorionic villus biopsy. Prenatal ultrasound only rarely allows a reliable diagnosis.\nGenetic counseling\nThe syndrome is almost always sporadic, most cases resulting from de novo mutations. For a couple with an affected child, accumulating data suggest a recurrence risk of approximately 0.5%. If a person with Rubinstein-Taybi syndrome is able to reproduce, the recurrence risk is 50% as the transmission is autosomal dominant.\nManagement and treatment\nAll individuals should have a cardiac assessment at the time of diagnosis and should be checked for hearing loss or diminished vision (every 3 years in children and every 5 years in adults). Specialized educational programs are required, with early emphasis on psychomotor development and speech therapy. Children should be tested at regular intervals with a systematic developmental assessment starting at age 3-4 years, to ensure adequate educational support compatible with each child's potential. If surgery is required, individuals undergoing general anesthesia should be under the care of an anesthesiologist comfortable with complex airway problems and aware of the increased risk of aspiration and cardiac arrhythmia upon the use of cardioactive drugs.\nPrognosis\nLife expectancy does not seem to be explicitly altered.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Dr L.A. [Leonie] MENKE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Ruvalcaba syndrome", "Disease Definition": "Ruvalcaba syndrome is an extremely rare malformation syndrome, described in less than 10 patients to date, characterized by microcephaly with characteristic facies (downslanting parpebral fissures, microstomia, beaked nose, narrow maxilla), very short stature, narrow thoracic cage with pectus carinatum, hypoplastic genitalia and skeletal anomalies (i.e. characteristic brachydactyly and osteochondritis of the spine) as well as intellectual and developmental delay.", "ORPHA ID": 3121, "Summary": ""}
{"Disease Name": "S-adenosylhomocysteine hydrolase deficiency", "Disease Definition": "A rare, multisystemic inherited metabolic diseases characterized clinically, by a variable spectrum of severity, primarily comprised of psychomotor delay, myopathy and liver dysfunction. Most patients present in infancy, but the onset can be already in utero or in adult age. Hypermethioninemia is frequent, but often absent in infancy. Creatine kinase is elevated in most patients.", "ORPHA ID": 88618, "Summary": "Epidemiology\nApproximately 15 cases of S-adenosylhomocysteine hydrolase (SAHH) deficiency have been described to date.\nClinical description\nDisease onset is typically in infancy, but may occur in utero or in adult age. In infancy, the clinical picture is typically comprised of developmental delay and hypotonia due to myopathy with markedly increased creatine kinase (CK) plasma levels, and more variably with cerebral hypomyelination, coagulation abnormalities and hepatopathy. Microcephaly, strabismus and behavioral changes are frequent. Severe cases may present in utero with fetal hydrops, congenital brain anomalies (pontine and cerebellar hypoplasia, hypoplastic corpus callosum), synthetic liver failure, respiratory insufficiency due to severe muscle weakness and death in early infancy. Specific biochemical findings include markedly increased plasma S-adenosylhomocysteine (AdoHyc) and S-adenosylmethionine (AdoMet) in combination with normal or near normal total homocysteine (tHcy) and hypermethioninemia which is not always present, particularly not in early infancy. Whilst the disease is typically severe with poor developmental outcomes, the phenotype can vary from mild to asymptomatic (one report). The milder phenotype includes later disease onset and milder weakness and developmental delay. Hepatocellular carcinoma was reported in one patient and was possibly present in another.\nEtiology\nThe disease is due to mutations in the gene encoding S-adenosylhomocysteine hydrolase, AHCY (20q11.22), an enzyme involved in methionine metabolism.\nDiagnostic methods\nDiagnosis should be suspected in patients with any combination of the clinical symptoms and in all patients with unexplained hypermethioninemia. Marked elevations of AdoMet and AdoHcy, in combination with normal or near normal tHcy are characteristic for the disease, thus plasma AdoMet and AdoHcy should be measured where there is clinical suspicion for the disease. Since these biochemical assays are poorly available, gene analysis could be a better choice. The latter , as well as enzyme assay of AdoHcy hydrolase, serves also for confirmation of the diagnosis.\nDifferential diagnosis\nBased on the multiorgan clinical presentation, SAHH deficiency has a very wide differential diagnosis, with chronic myopathies, muscular dystrophies, floppy infant syndrome and group of isolated persistent hypermethioninemias being the most important.\nAntenatal diagnosis\nPrenatal testing is possible if a genetic mutation has been previously identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers of the disease, the risk of transmission to offspring is 25%. There is variable disease severity between different families. Intrafamilial variability is also possible.\nManagement and treatment\nWhilst there is little evidence to support specific treatment strategies, the current consensus is on a methionine-restricted diet (with methionine-free amino acid mixture supplementation), which can decrease and sometimes even normalize plasma AdoMet and AdoHcy. Subsequent close clinical and biochemical monitoring seem mandatory. Phosphatidylcholine, creatine and cysteine supplementation may be beneficial. Liver transplantation has resulted in clinical and biochemical improvement in a single case.\nPrognosis\nPrognosis depends on the severity of the disease and ranges from death during the neonatal period to survival into adulthood and possibly normal life span. Functional outcomes in surviving patients are frequently severe, with the most common impact on neurodevelopment and mobility. Long term follow-up is missing in most patients and accurate and precise prognosis is not possible. Whilst dietary management is promising in some cases, it is not effective in all (improving metabolic parameters but not functional outcomes). Evidence on liver graft is limited.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Ivo BARIC"}
{"Disease Name": "Saccharopinuria", "Disease Definition": "A rare autosomal recessive disorder of the lysine catabolism characterized by elevated levels of lysine in the cerebrospinal fluid and blood with variable degrees of saccharopinuria. Some patients present with neurological symptoms such as seizures, spastic diplegia, mild psychomotor delay, intellectual deficit, and behavioral difficulties. However, current findings suggest no causal association between isolated hyperlysinemia and neurological symptoms.", "ORPHA ID": 3124, "Summary": ""}
{"Disease Name": "Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome", "Disease Definition": "Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome is a rare, genetic, neural tube defect malformation syndrome characterized by sacral agenesis and abnormal vertebral body ossification with normal vertebral arches associated with notochord canal persistence on ultrasonography. Additional findings include bilateral clubfoot, oligohydramnios, single umbilical artery and, in some, increased nuchal translucency.", "ORPHA ID": 397927, "Summary": ""}
{"Disease Name": "Saethre-Chotzen syndrome", "Disease Definition": "A syndrome characterized by unilateral or bilateral coronal synostosis, facial asymmetry, ptosis, strabismus and small ears with prominent superior and/or inferior crus, among other less common manifestations.", "ORPHA ID": 794, "Summary": "Epidemiology\nSaethre-Chotzen syndrome (SCS) prevalence ranges from 1/25,000 to 1/50,000 livebirths.\nClinical description\nSCS has a variable spectrum of manifestations. Classic SCS presents at birth with synostosis of coronal (less commonly in conjunction with sagittal, metopic or lambdoid) sutures resulting in abnormal skull shape, facial asymmetry, low frontal hairline, ptosis, strabismus, tear duct stenosis and small ears with prominent crus. Brachydactyly, broad toes, partial cutaneous syndactyly of digits 2 and 3 of the hand, duplicated distal phalanx of the hallux are also often present. Intelligence is normal in most, but mild to severe developmental delay has been reported, primarily in cases with a large genomic deletion. Some may experience conductive and/or sensorineural hearing loss. Less common manifestations include short stature, hypertelorism, cleft palate, bifid uvula, maxillary hypoplasia, lacrimal duct stenosis, parietal foramina, vertebral anomalies, radioulnar synostosis, obstructive sleep apnea and congenital heart malformations. Mild phenotypes include patients with ptosis or blepharophimosis with or without craniosynostosis. Elevated intracranial pressure (ICP) associated with severe cases of synostosis may lead to headaches, visual loss, seizures and death if untreated.\nEtiology\nSCS is due to point mutations or deletions involving (or removing completely) the TWIST1 gene (7p21), which encodes a basic helix-loop-helix (bHLH) transcription factor responsible for cell lineage determination and differentiation. Loss of function mutations in this gene lead to the induction of premature cranial suture fusion. Gene deletions cause more severe phenotypes, usually associated with significant neurocognitive delays.\nDiagnostic methods\nDiagnosis is based mainly on the presence of characteristic clinical findings. CT of the head and radiographs are useful in characterizing abnormalities of the skull, spine and limbs. Molecular genetic testing can identify a TWIST1 mutation or deletion, confirming diagnosis.\nDifferential diagnosis\nAlthough several features (such as 2-3 syndactyly of the hand) are unique to SCS, differential diagnoses include other syndromic forms of craniosynostosis such as Muenke, Baller-Gerold, Pfeiffer, and Crouzon syndromes as well as isolated unilateral coronal synostosis. Robinow-Sorauf syndrome is now considered within the spectrum of SCS, typically with milder features. Mutations in FGFR3, FGFR2, TCF12, RECQL4, and EFNB1 have been reported to cause synostosis conditions that phenotypically overlap with SCS. This is not surprising, as there is evidence that FGFR and TWIST1 may be integrated into overlapping pathways, including in osteoblast differentiation. In addition, TWIST1 mutations have been noted in some cases of isolated single-suture craniosynostosis, including sagittal and unicoronal cases.\nAntenatal diagnosis\nPrenatal testing for a TWIST1 mutation is rare, but it can be performed in families with a known mutation or when an ultrasound shows craniosynostosis of unknown etiology.\nGenetic counseling\nSCS is inherited as an autosomal dominant trait. Genetic counseling is valuable. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nTreatment of SCS requires management by a multidisciplinary craniofacial team with follow-up until young adulthood. In general, patients must undergo cranioplasty in the first year of life to increase the intracranial volume and restore a more normal head shape. Recurrent increased ICP may necessitate further surgical expansion procedures. In childhood, orthodontic care and/or midfacial surgery may be necessary for treatment of airway obstruction and malocclusion. In those with cleft palate, surgical closure can be performed in the context of other malformations, with evaluation for velopharyngeal insufficiency and speech therapy offered as necessary. Routine evaluations of facial growth, hearing loss and psychomotor development are needed, as well as regular ophthalmologic examinations to monitor strabismus, amblyopia or chronic papilledema (that indicates increased ICP). Early intervention programs should be offered to children with developmental delay. Augmentation of hearing and supportive interventions related to deafness should be pursued when indicated.\nPrognosis\nIn most cases, when treated and monitored from an early age, the prognosis is excellent. Developmental prognosis is worse for patients with a TWIST1 deletion, compared to those with point mutations.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Matthew BLESSING  - Dr Michael CUNNINGHAM"}
{"Disease Name": "Sagliker syndrome", "Disease Definition": "A rare bone disease characterized by secondary hyperparathyroidism in patients with chronic renal failure, caused by improper treatment in the early stages of the disease with retention of phosphorus, vitamin D deficiency, and disturbed calcium-phosphorus metabolism, which result in increased parathyroid hormone levels. Patients present with short stature, severe changes of the skull and jaws as well as other skeletal deformities, dental anomalies, ''brown tumors'' in the mouth, hearing loss, and neuropsychiatric disorders.", "ORPHA ID": 300493, "Summary": ""}
{"Disease Name": "Saldino-Mainzer syndrome", "Disease Definition": "Saldino-Mainzer syndrome is characterised by the association of renal disease, retinal pigmentary dystrophy, cerebellar ataxia and skeletal dysplasia.", "ORPHA ID": 140969, "Summary": "Epidemiology\nAround 10 cases have been described in the literature so far.\nClinical description\nMild to moderate short stature has also been reported. Radiologic studies reveal shortened phalanges with cone-shaped epiphysis. Femoral epiphyseal and metaphyseal anomalies are common.\nGenetic counseling\nThe syndrome is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            July 2008"}
{"Disease Name": "Salivary gland type cancer of the breast", "Disease Definition": "Salivary gland type cancer of the breast describes a group of uncommon neoplasms, usually seen in the salivary glands but occurring in the breast, with a variable clinicopathologic spectrum and divided into those with myoepithelial differentiation and those without. This group includes mammary adenoid cystic carcinoma, adenoid cystic carcinoma (see this term), mucoepidermoid carcinoma, acinic cell carcinoma, polymorphous low-grade adenocarcinoma and oncocytic carcinoma.", "ORPHA ID": 213557, "Summary": ""}
{"Disease Name": "Sandhoff disease", "Disease Definition": "A rare autosomal recessive lysosomal disease characterized by accumulation of GM2 gangliosides in the nervous system due to hexosaminidase A and hexosaminidase B deficiency as a consequence of biallelic pathogenic variants in the HEXB gene.", "ORPHA ID": 796, "Summary": "Epidemiology\nThe prevalence of the disease is 1/380,000 live births.\nClinical description\nThe clinical picture is almost identical to that of Tay-Sachs disease: three forms have been described according to age of onset. The infantile form begins at 3-6 months of age for the early infantile (< 12 months) and 12-24 months for the late infantile. The earliest signs are an incessant startle response to noise, and a progressive loss of vision. Psychomotor regression appears during the second semester of life with hypotonia, amaurosis, rapidly pharmacoresistant epilepsy and progressive macrocephaly. A cherry-red macular spot is nearly always present and is strongly evocative even if not specific. Light visceromegaly or cardiomyopathy may be present in infantile Sandhoff disease, contrary to infantile Tay-Sachs disease. Muscular weakness progresses and leads to paralysis. The disorder degenerates into a state of decerebration and is fatal during childhood. Onset of the juvenile form is at 2-10 years of age, with progressive cerebellar ataxia, dystonia, behavioral disorders, and cognitive regression. Death occurs during the second decade. The adult form begins around the age of 10 or later, and is often not diagnosed until adulthood. The onset is insidious with a progressive course. Two initial clinical presentations are described: i) proximal lower limbs weakness with amyotrophy due to a motor neuropathy (mimicking progressive spinal amyotrophy; first complaint: difficulty to climb stairs) that eventually extends to upper limbs and distal parts of the limbs; ii) generalized cerebellar ataxia (more rarely dystonia). In the course of the disease the motor neuropathy almost always occurs, other motor symptoms may occur (dysarthria, swallowing disorder). Cognition is usually preserved.\nEtiology\nThe causative gene HEXB encodes the beta subunit of hexosaminidase A and hexosaminidase B and is located on chromosome 5 (5q13.3).\nDiagnostic methods\nHexosaminidase A and hexosaminidase B enzymatic activities on blood leukocytes is always very low compared to normal values (around 0% for severe infantile form, around 10-15% for adult form). Diagnosis should be confirmed by HEXB gene sequencing. The diagnosis may be firstly suggested by pathogenic variants findings from a panel of genes, or exome or genome sequencing, and should be confirmed by hexosaminidase A and hexosaminidase B enzymatic activities measurement. Abnormal oligosaccharides urinary excretion may be detected in Sandhoff disease.\nDifferential diagnosis\nGM2 gangliosidosis, AB variant (GM2A gene variant), may perfectly mimic Sandhoff or Tay-Sachs diseases, but with normal hexosaminidase A and B enzymatic activities. In adults the differential diagnoses include proximal spinal muscular atrophy and autosomal recessive diseases causing cerebellar ataxia (e.g. Niemann Pick disease type C).\nAntenatal diagnosis\nPrenatal diagnosis is available: a complete study of hexosaminidases A and B activities, and HEXB gene sequencing for the propositus and both parents is requested before prenatal diagnosis may be done for the fetus.\nGenetic counseling\nTransmission is autosomal recessive; at-risk couples (both parents are carriers of a pathogenic variant) have a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThere is no specific and efficient treatment for Sandhoff disease. Treatment is symptomatic.\nPrognosis\nFor the pediatric forms: the severity is correlated to age of onset, with a more rapid regression in the early infantile form leading to death around 2-4 years of age, whereas death occurs in the second decade in the juvenile form. All patients will have pharmacoresistant epilepsy in the advanced stages of the disease. For the adult form: the disease is usually very slow progressive and may last decades. Patients are progressively disabled, may lose the ability to walk and have difficulties for upper limbs utilization, speech, swallowing, and may more rarely have cognitive symptoms.\n\n                            Last update: \n                            October 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Bénédicte HERON | MetabERN* - Dr Yann NADJAR \n\n\n                                * European Reference Network"}
{"Disease Name": "Sandifer syndrome", "Disease Definition": "Sandifer syndrome is a paroxysmal dystonic movement disorder occurring in association with gastro-oesophageal reflux, and, in some cases, hiatal hernia.", "ORPHA ID": 71272, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nOnset usually occurs during infancy or early childhood. The dystonic movements are characterised by abnormal posturing of the head and neck (torticollis) and severe arching of the spine. Episodes usually last for between 1-3 minutes and can occur up to 10 times a day, although they are usually associated with the ingestion of food. Vomiting, poor feeding, anaemia, epigastric discomfort, haematemesis and abnormal eye movements have also been reported. Reflux oesophagitis is common.\nEtiology\nThe dystonic movements are clearly associated with gastro-oesophageal reflux but the pathophysiological mechanism is not clearly understood. Several studies have indicated that the dystonic posturing is a pathological reflex triggered in response to abdominal pain caused by gastroesophageal reflux and oesophagitis. Although conflicting results have been obtained, some authors have suggested that the dystonic posture provides relief from abdominal pain.\nDiagnostic methods\nSandifer syndrome is diagnosed on the basis of the association of gastro-oesophageal reflux with the characteristic movement disorder. Neurological examination is usually normal.\nDifferential diagnosis\nHowever, in the absence of clear indications of gastro-oesophageal reflux, misdiagnosis as infantile spasms, epilepsy or paroxysmal dystonia is common.\nManagement and treatment\nEarly diagnosis of the syndrome is essential, as effective treatment of the gastro-oesophageal reflux (by pharmacological therapy or surgical intervention) leads to resolution of the movement disorder.\nPrognosis\nThe prognosis for patients is good.\n\n                            Last update: \n                            March 2007"}
{"Disease Name": "Sanjad-Sakati syndrome", "Disease Definition": "Sanjad-Sakati syndrome (SSS), also known as hypoparathyroidism - intellectual disability-dysmorphism, is a rare multiple congenital anomaly syndrome, mainly occurring in the Middle East and the Arabian Gulf countries, characterized by intrauterine growth restriction at birth, microcephaly, congenital hypoparathyroidism (that can cause hypocalcemic tetany or seizures in infancy), severe growth retardation, typical facial features (long narrow face, deep-set eyes, beaked nose, floppy and large ears, long philtrum, thin lips and micrognathia), and mild to moderate intellectual deficiency. Ocular findings (i.e. nanophthalmos, retinal vascular tortuosity and corneal opacification/clouding) and superior mesenteric artery syndrome have also been reported. Although SSS shares the same locus with the autosomal recessive form of Kenny-Caffey syndrome (see this term), the latter differs from SSS by its normal intelligence and skeletal features.", "ORPHA ID": 2323, "Summary": ""}
{"Disease Name": "SAPHO syndrome", "Disease Definition": "A rare, pyogenic autoinflammatory disease, characterized by the association of neutrophilic cutaneous involvement and chronic nonbacterial osteomyelitis.", "ORPHA ID": 793, "Summary": "Epidemiology\nAlthough its incidence and prevalence are probably underestimated, SAPHO syndrome (acronym for Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) is considered to be a rare disorder.\nClinical description\nThe age of onset ranges from adolescence to late adulthood, with a median age between 30 and 40 years. SAPHO syndrome encompasses a wide spectrum of anomalies characterized by variable combinations of osteoarticular and cutaneous manifestations of varying degrees of severity. The onset of bone and joint pain, stiffness and swelling is most often insidious. In adults, inflammation occurs mainly in the anterior chest wall but also in the spine, less frequently in the mandible and the iliac bones ; in children it shows a comparable distribution as chronic nonbacterial osteomyelitis (CNO/CRMO) (e.g. long bones, clavicle, spine). When synovitis occurs, it manifests most of the times in the sacro-iliac joint, hips or knees, or the sternoclavicular joints. Depending on severity of symptoms, a limited range of motion may be observed. Dermatological involvement includes severe acne, palmoplantar pustulosis, and pustular psoriasis. Skin manifestations often begin 1-2 years before osseous changes but may appear simultaneously or more than 20 years later. Patients may also suffer from abdominal pain, diarrhea, anal fissures or abscesses, suggesting the possible association with an inflammatory bowel disease (IBD). Most authors regard CNO/CRMO as the pediatric form of SAPHO syndrome. In fact, the frequent occurrence of dermatological disorders or IBD pleads for the inclusion of these two entities in the same spectrum.\nEtiology\nThe etiology is unknown. SAPHO syndrome seems to have a multifactorial origin with genetic, environmental, immunologic, and infectious components. Slow-growing bacteria, such as Propionibacterium acnes, could act as a triggering factor.\nDiagnostic methods\nDiagnosis, suspected upon clinical examination, must be confirmed with imaging procedures (X-rays, CT, MRI) showing a combination of osteolysis and osteosclerosis with secondary hyperostosis, bone marrow edema, endosteal-periosteal inflammation, perifocal myositis, and adjacent arthritis. Bone biopsy often reveals an infiltrate of neutrophils in early stages, progressively replaced by mononuclear cells and associated with sclerosis in later stages. A bacteriological study is sometimes positive for Propionibacterium acnes. Synovial fluid culture is usually negative.\nDifferential diagnosis\nDifferential diagnosis includes infectious osteomyelitis or arthritis, Langerhans cell histiocytosis, and bone tumors such as Ewing sarcoma, osteoblastoma, and osteoid osteoma. Hypophosphatasia may mimic the bone phenotype of SAPHO syndrome.\nGenetic counseling\nMost cases are sporadic. Some familial cases have been reported.\nManagement and treatment\nTreatment is mainly symptomatic and is based on non-steroidal anti-inflammatory drugs, sometimes replaced by corticosteroids (e.g. prednisone). In resistant cases, disease-modifying antirheumatic drugs (e.g. methotrexate) can also be used. Intravenous biphosphonates (pamidronate, zoledronate) can alleviate bone pain. More recently, TNF-inhibitors showed encouraging results in controlling both osteoarticular and cutaneous manifestations. The osteoarticular features may also be treated by sulfasalazine. Acne may be treated with systemic antibiotics, like doxycycline. Palmoplantar pustulosis or pustular psoriasis usually responds well to either topic corticosteroids or PUVA therapy. Physiotherapy is recommended.\nPrognosis\nThe disease usually has a chronic evolution, with alternating periods of remission and relapse, sometimes with the appearance of new osteosclerotic lesions. Spontaneous resolution can occur. Complications include impairment of bone and joint function, vascular compression, chronic pain syndrome, and progression towards classical spondyloarthritis.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Hermann GIRSCHICK"}
{"Disease Name": "Sarcocystosis", "Disease Definition": "A rare parasitic disease characterized by infection with sarcocystis species with humans as definitive (intestinal sarcocystosis) or aberrant intermediate (muscular sarcocystosis with development of sarcocysts in myocytes of skeletal, cardiac, and smooth muscle) host. Enteric infection is often mild or asymptomatic but may cause symptomatic enteritis with nausea, abdominal pain, diarrhea, and vomiting. Symptoms of muscular sarcocystosis include fever, fatigue, headache, cough, myalgia, and arthralgia, among others, with the possibility of a long-lasting, waxing and waning course.", "ORPHA ID": 54368, "Summary": ""}
{"Disease Name": "Sarcoidosis", "Disease Definition": "A rare multisystemic, autoinflammatory disorder of unknown etiology characterized by the formation of immune, non-caseating granulomas in any organ(s), leading to variable clinical symptoms and severity. Clinical presentation is typically with persistent dry cough, eye or skin manifestations, peripheral lymph nodes, fatigue, weight loss, fever or night sweats, and Löfgren syndrome.", "ORPHA ID": 797, "Summary": "Epidemiology\nSarcoidosis is a ubiquitous disease with incidence varying according to age, sex, race and geographic origin. The highest rates are reported in Northern Europe and in African-American individuals, the lowest rates in Asia. In Europe, incidence ranges between 1/625 to 500,000 inhabitants. There is a slight predominance in females.\nClinical description\nPresentation, severity and evolution of sarcoidosis is highly variable. Diagnosis typically occurs in the fourth and fifth decade of life with a second peak of incidence occurring in women older than 50 years of age, but presentation may occur anywhere between childhood and elderly age. The disease is classed as either acute, resolving within 2 years, or chronic, persisting for 3-5 years or longer. The lung and the lymphatic system are predominantly affected, but virtually every organ may be involved. Other severe manifestations result from cardiac, neurological, ocular, kidney or laryngeal localizations. In most cases, sarcoidosis is revealed by persistent dry cough, eye or skin manifestations, peripheral lymph nodes, fatigue, weight loss, fever or night sweats, and Löfgren syndrome (an acute form characterized by fever, bilateral ankle arthritis and/or erythema nodosum and bilateral hilar lymphadenopathy). Abnormal metabolism of vitamin D3 within granulomatous lesions and hypercalcemia are possible. Chest radiography is abnormal in about 90% of cases and shows lymphadenopathy and/or pulmonary infiltrates (without or with fibrosis), defining sarcoidosis stages from I to IV. African-Americans present a more severe disease, and in Scandinavian countries, about one third of cases have Löfgren syndrome.\nEtiology\nThe etiology remains unknown. The prevailing hypothesis is that various, unidentified antigens of either infectious or environmental origin could trigger an exaggerated immune reaction in genetically susceptible hosts.\nDiagnostic methods\nDiagnosis relies on compatible clinical and radiographic manifestations, biopsy showing non-caseating granulomas and exclusion of all other causes of granulomatous disease. Some situations do not require biopsy such as Lofgren's syndrome or the presence of typical asymptomatic bilateral mediastino-hilar adenopathies. Biopsies from easily accessible areas (skin, peripheral lymphadenopathies, conjunctival nodules) should be considered. However, bronchoscopy with bronchial and transbronchial biopsies has a good diagnostic performance. Endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA) provide a high yield in case of mediastino-hilar lymphadenopathies.\nDifferential diagnosis\nDifferential diagnosis includes infections, chronic beryllium disease, common variable immunodeficiency, hypersensitivity pneumonitis, granulomatous polyangiitis, Crohn disease, sarcoid-like reactions (cancer or lymphomas), as well as drug-induced granulomatosis.\nGenetic counseling\nSarcoidosis results from a complex interaction of multiple genes and thus does not require genetic counseling.\nManagement and treatment\nDepending on the evolution and severity of sarcoidosis, patients may not require systemic therapy. Therapy is considered where there is a possibility of severe complications (i.e. functional organ failure) or to reduce persistent symptoms of discomfort that impact on quality of life. Discomfort may be due to fibrosis, para-sarcoidosis syndrome or comorbidities as well as active disease. Treatment is principally with systemic corticosteroids, and generally maintained for 12 months; however, the duration and minimal efficient dose should be adapted to each patient. Patients with repeated relapses may require long-term, low-dose corticosteroid therapy. Other treatments including immunosuppressive drugs (methotrexate, azathioprine, or leflunomide) and aminoquinolins may be useful in case of unsatisfactory response to corticosteroids, poor tolerance or as sparing agents. In some strictly selected cases refractory to standard therapy, specific anti-TNF-alpha agents (infliximab or adalimumab) may offer improvement. Some patients benefit from topical corticosteroids.\nPrognosis\nIn at least half of cases, sarcoidosis resolves spontaneously within 2 years. Remission is less likely where diseases persists for five years after presentation. Mortality is estimated at 6-8% and typically due to organ failure (typically respiratory or cardiac). The extent of pulmonary fibrosis and pulmonary hypertension are predictive of mortality.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Alain CALENDER  - Dr Florence JENY  - Pr Hilario NUNES"}
{"Disease Name": "Sarcosinemia", "Disease Definition": "A rare inborn error of metabolism characterized by increased concentrations of sarcosine in plasma and urine due to sarcosine dehydrogenase deficiency. The condition is considered benign and not associated with any specific clinical phenotype. Mode of inheritance is autosomal recessive.", "ORPHA ID": 3129, "Summary": ""}
{"Disease Name": "SATB2-associated syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by moderate to severe developmental delay/intellectual disability with absent or limited speech development, various behavioral problems (including autistic features, hyperactivity, or aggressiveness), and craniofacial anomalies such as long face, high and prominent forehead, bulbous nose with low-hanging columella, thin vermillion of the upper lip, palatal (cleft palate, high-arched palate, and bifid uvula) and dental (abnormal upper incisors) abnormalities, and micrognathia. Hypotonia and feeding difficulties are frequent. Other supportive findings may include skeletal anomalies with low bone density and abnormal brain imaging.", "ORPHA ID": 576278, "Summary": ""}
{"Disease Name": "Satoyoshi syndrome", "Disease Definition": "Satoyoshi syndrome is a rare, multisystemic autoimmune disease mainly characterized by intermittent painful muscle spasms, alopecia (totalis or universalis in most cases) and long-lasting diarrhea that could lead to malnutrition, growth retardation, and amenorrhea. Secondary bone deformities and various endocrine anomalies may also be associated. Antinuclear antibodies are reported in many cases.", "ORPHA ID": 3130, "Summary": ""}
{"Disease Name": "Say-Barber-Miller syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by microcephaly, developmental delay and intellectual disability, postnatal growth retardation, dysmorphic craniofacial features (including sloping forehead, beaked nose, large and protruding ears, micrognathia, high-arched palate, and craniosynostosis), immunologic abnormalities with transient hypogammaglobulinemia in infancy and defective chemotaxis leading to recurrent infections, as well as autoimmune/autoinflammatory phenomena. Skeletal anomalies and hypogonadism have also been reported.", "ORPHA ID": 3132, "Summary": ""}
{"Disease Name": "Scalp defects-postaxial polydactyly syndrome", "Disease Definition": "A rare syndrome with limb malformations as a major feature characterized by congenital scalp defects and postaxial polydactyly type A. There is a wide variability of expression, with some patients showing only one of the typical manifestations. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 1003, "Summary": ""}
{"Disease Name": "SCALP syndrome", "Disease Definition": "SCALP syndrome is a rare skin disease characterized by the association of sebaceous nevus and aplasia cutis congenita (usually on the scalp and face) in conjunction with limbal dermoid of the eye, a giant congenital melanocytic nevus and variable central nervous system abnormalities, including seizures, hydrocephalus, neurocutaneous melanosis, arachnoid cysts, and diffuse unilateral hemisphere enlargement.", "ORPHA ID": 370052, "Summary": ""}
{"Disease Name": "Scalp-ear-nipple syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by aplasia cutis congenita of the scalp, breast anomalies ranging from hypothelia or athelia to amastia, and anomalies of the external ears. Variable clinical characteristics include nail and dental anomalies, syndactyly and camptodactyly of fingers and/or toes, sparse or absent secondary sexual hair, renal malformations, and facial dysmorphism. Cases with severe hypotonia and developmental delay have been reported.", "ORPHA ID": 2036, "Summary": ""}
{"Disease Name": "Scapuloperoneal spinal muscular atrophy", "Disease Definition": "A rare, genetic motor neuron disease characterized by predominantly motor axonal peripheral neuropathy manifesting with progressive scapuloperoneal muscular atrophy and weakness, laryngeal palsy, congenital absence of muscles, and, in some, skeletal abnormalities.", "ORPHA ID": 431255, "Summary": "Epidemiology\nThe precise prevalence of Scapuloperoneal spinal muscular atrophy (SPSMA) is not available. To date, more than 30 affected individuals have been described worldwide. Males are more severely affected than females.\nClinical description\nOnset is usually congenital or occurs in infancy or early childhood. Clinical hallmarks of SPSMA are muscular atrophy of the shoulders, peroneal and small hand muscles resulting in distal weakness, predominantly of the lower limbs, and pectoral muscle wasting and weakness. Patients present difficulty walking on heels, winged scapulae, and diminished or absent deep tendon reflexes. Other common features reported include vocal cord paralysis, scoliosis, and/or arthrogryposis. Skeletal abnormalities have been described in some patients, including congenital hip dysplasia, short limbs/limb length discrepancy, bilateral congenital clubfoot, metatarsal dysplasia, spondylometaphyseal dysplasia, platyspondyly, metatropic dysplasia, and/or mild short stature. Mildly diminished vibration sense may also be associated. The disease has slow clinical progression and variable pattern of expression, ranging from severe neonatal onset to mild symptoms referred only in adulthood.\nEtiology\nThe causative gene of SPSMA is TRPV4 (12q23-q24.1), which encodes for a calcium, nonselective cation channel thought to be involved in the regulation of systemic osmotic pressure and mechanosensitivity. De novo mutations have also been reported in the literature.\nDiagnostic methods\nDiagnosis is based on clinical manifestations, family history and biopsy findings which reveal severe muscle fiber-type grouping and atrophy, extensive fatty replacement, increased endomysial fibrosis, marked variability of fiber size, fiber splitting, and many fibers with multiple internal nuclei. Pathological changes are particularly severe in the gastrocnemius muscle. Atrophy of both type 1 and type 2 fibers can be observed with ATPase staining. Electroradiography shows reduced compound motor action potentials (cMAPS) but normal sensory action potentials and nerve conduction velocity. Brain and spinal cord sections reveal normal numbers of motor neurons in the motor complex and spinal cord. Genetic testing which reveals a pathogenic mutation confirms diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes Charcot-Marie-Tooth disease type 2C, congenital distal spinal muscular atrophy, neurogenic scapuloperoneal syndrome Kaeser type, and facioscapulohumeral dystrophy.\nAntenatal diagnosis\nPrenatal diagnosis is possible if a pathogenic variant has been previously identified in the family.\nGenetic counseling\nSPSMA has an autosomal dominant pattern of inheritance. Genetic counseling can inform parents of the 50% risk of transmitting the mutation responsible for the disease to their children. Early diagnosis is crucial to prevent the more severe congenital form, as disease tends to be more progressive and severe in succeeding generations.\nManagement and treatment\nThere is no effective treatment to date.\nPrognosis\nThe prognosis is not so poor, even if the problems of ambulation predispose to falls, to the development of arthrosic problems, which together with the dysmorphic aspects and the distal weakness contribute to get worse the motor problems. Generally the respiratory muscles are not involved.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Carmelo RODOLICO"}
{"Disease Name": "SCARF syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by variable skeletal abnormalities (including craniostenosis, pectus carinatum, short sternum, joint hyperextensibility, and anbnormal vertebrae), cutis laxa with excessive skin folds around the cheek, chin and neck, ambiguous genitalia with a micropenis and perineal hypospadia, an umbilical hernia, intellectual disability, premature aged appearance, and cardiac enlargement involving either the ventricles or atria. Facial dysmorphism is variable and can include multiple hair whorls, ptsosis, high and broad nasal root, low set ears and small chin. Enamel hypocalcification, abnormal modelling of tubular bones, and reduced cutis laxa may become apparent later on.", "ORPHA ID": 3134, "Summary": ""}
{"Disease Name": "Scarring in glaucoma filtration surgical procedures", "Disease Definition": "A rare ophthalmic condition characterized by formation of excessive scar tissue between the conjunctiva/Tenon capsule and the sclera at the surgical site following glaucoma filtration surgery. Scarring can occur months or years after surgery, resulting in treatment failure with poor postoperative control of intraocular pressure and, potentially, loss of vision.", "ORPHA ID": 90080, "Summary": ""}
{"Disease Name": "Scedosporiosis", "Disease Definition": "A rare mycosis caused by Scedosporium species, characterized by disparate disease pictures including pneumonia, skin and soft tissue infection, mycetoma, and disseminated infection. Central nervous system infection has also been reported. Infections with this ubiquitous mold can occur in a range of contexts like solid organ transplantation, chemotherapy, chronic lung disease, but also in immunocompetent hosts and near drowning.", "ORPHA ID": 449280, "Summary": ""}
{"Disease Name": "Scheie syndrome", "Disease Definition": "Scheie syndrome is the mildest form of mucopolysaccharidosis type 1 (MPS1; see this term), a rare lysosomal storage disease, characterized by skeletal deformities and a delay in motor development.", "ORPHA ID": 93474, "Summary": "Epidemiology\nPrevalence is estimated at 1/500,000.\nClinical description\nSymptoms commonly occur after the age of 5 years but are so mild that diagnosis is often not considered until adulthood. Patients are of almost normal height and do not show intellectual deficiency. Corneal opacification occurs progressively and diffusely, usually after the age of four years. Glaucoma is more frequent than in Hurler syndrome (see this term). Patients present with mild coarsening of the facial features, including a large mouth with thick lips. Patients may present with nasal secretion, neurosensorial hearing loss, stiff joints, mild skeletal changes and carpal tunnel syndrome. Aortic valve disease may be present. Compression of the cervical spinal cord, caused by glycosaminoglycan infiltration of the dura, may lead to spastic paresis if not corrected by neurosurgical intervention.\nEtiology\nScheie syndrome is caused by mutations in the IDUA gene (4p16.3) leading to partial deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate.\nDiagnostic methods\nEarly diagnosis is difficult because the first clinical signs are not specific, but is very important to allow early treatment. Diagnosis is based on detection of increased urinary secretion of heparan and dermatan sulfate through the 1,9-dimethylmethylene blue (DMB) test and glycosaminoglycan (GAG) electrophoresis, and demonstration of enzymatic deficiency in leukocytes or fibroblasts. Genetic testing is available.\nDifferential diagnosis\nDifferential diagnoses include the more severe forms of mucopolysaccharidosis type 1, Hurler-Scheie syndrome and Hurler syndrome, and mucopolysaccharidosis type VI and mucopolysaccharidosis type II (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible by measurement of enzymatic activity in cultivated chorionic villus or amniocytes and by genetic testing if the disease-causing mutation is known.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling is recommended.\nManagement and treatment\nManagement should be carried out by a multidisciplinary team and should include physiotherapy to maintain range of movement. The enzyme substitute (laronidase) obtained EU marketing authorization as an orphan drug in 2003. Given through weekly infusions it leads to improvement of lung function and joint mobility. Enzyme replacement therapy (ERT) should be started at diagnosis and may be beneficial in patients awaiting hematopoietic stem cell transplantation (HSCT). Early treatment slows the progression of the disease.\nPrognosis\nLife expectancy for patients with Scheie syndrome may only be slightly affected.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Michael BECK"}
{"Disease Name": "Schilbach-Rott syndrome", "Disease Definition": "Schilbach-Rott syndrome (SRS) is an autosomal dominant dysmorphic disorder that is characterized by dysmorphic facies with hypotelorism, blepharophimosis, and cleft palate, and the frequent occurrence of hypospadias in males.", "ORPHA ID": 2353, "Summary": "Epidemiology\nSRS has been described in 18 individuals to date. Its prevalence is unknown.\nClinical description\nFeatures of SRS include a typical facial gestalt characterized by hypotelorism, blepharophimosis, facial asymmetry, small posteriorly angulated ears, a long prominent nose, a small mouth and an array of cleft palate abnormalities. Cutaneous syndactyly of the fingers and toes is a recurrent manifestation. Affected individuals often have a short stature and may present with a mild intellectual disability or learning difficulties. Hypospadias is frequently reported in males with SRS.\nEtiology\nEtiology is unknown.\nGenetic counseling\nTransmission is autosomal dominant with variable expressivity.\n\n                            Last update: \n                            January 2014"}
{"Disease Name": "Schilder disease", "Disease Definition": "Schilder's disease is a progressive demyelinating disorder of the central nervous system.", "ORPHA ID": 59298, "Summary": "Epidemiology\nLess than 20 sporadic cases (predominantly males) have been reported so far.\nClinical description\nThe onset is usually in childhood (age 5-14 years). The disease often occurs shortly after an infectious illness and may manifest with headache, malaise and fever. Variable neurological abnormalities progressively develop and include personality changes, poor attention, dementia, aphasia, headache, vomiting, tremor, seizures, balance instability, incontinence, muscle weakness. Deafness, paralysis of eye movements, nystagmus, optic neuritis and optic atrophy are common. Malnutrition and cachexia are reported in the later chronic stages of illness. Schilder's disease is considered as a variant or borderline form of multiple sclerosis.\nEtiology\nPathologically, it is characterized by bilateral widespread demyelination of the brain hemispheres with varying degrees of axonal injury. Etiology remains unclear.\nDiagnostic methods\nDiagnosis is based on sequential neuroimaging (consistent with subacute or chronic myelinoclastic diffuse sclerosis) and electroencephalographic studies.\nDifferential diagnosis\nDifferential diagnosis includes a wide range of neurodegenerative disorders such as multiple sclerosis, acute disseminated encephalomyelitis, subacute sclerosing panencephalitis, progressive rubella panencephalitis, brucellosis, metachromatic leukoencephalopathy, Churg-Strauss disease, Wegener granulomatosis (see these terms). Schilder's disease often mimics intracranial neoplasm or abscess.\nManagement and treatment\nManagement is mainly symptomatic and supportive (physiotherapy, occupational therapy, nutritional support in the later stages). Corticosteroids have been shown effective in some patients. Additional treatments include beta-interferon and/or immunosuppressive drugs.\nPrognosis\nPrognosis of Schilder's disease is variable. The clinical course is usually progressive, but significant improvement and remissions have also been described. Survival has been reported to be less than ten years after the onset. Patients with a good response to corticosteroids and those with smaller lesions may have a better prognosis.\n\n                            Last update: \n                            July 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Bertrand FONTAINE"}
{"Disease Name": "Schimke immuno-osseous dysplasia", "Disease Definition": "A rare a multisystem disorder characterized by spondyloepiphyseal dysplasia and disproportionate short stature, facial dysmorphism, T-cell immunodeficiency, and progressive, proteinuric steroid-resistant nephropathy.", "ORPHA ID": 1830, "Summary": "Epidemiology\nThe prevalence is unknown. Data from large pediatric registries suggest that it accounts for ~1% of steroid resistant nephrotic syndrome.\nClinical description\nThe main clinical features are spondyloepiphyseal dysplasia, growth retardation both pre- and post-natal, defective cellular immunity and episodic lymphopenia with increased susceptibility to life-threatening infections, and a progressive steroid-resistant nephrotic syndrome that leads to end-stage renal failure. Almost all patients have T-cell deficiency with a normal CD4/CD8 ratio. Hyperpigmented macules, thin hair and dysmorphic facial features (a triangular-shaped face, microdontia, broad depressed nasal bridge, narrow nasal ridge and a broad nasal tip) are common. Neurologic manifestations include atherosclerosis and cerebrovascular disease, which manifest as migraine-like headaches, cerebral ischemia, cardiac dysfunction and cognitive deficiency. Additional features may include hypothyroidism, enteropathy, normocytic or microcytic anemia and thrombocytopenia.\nEtiology\nThe disorder is caused by biallelic pathogenic variants in the SMARCAL1 gene (2q35) which encodes the chromatin remodeling protein, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1.\nDiagnostic methods\nDiagnosis is based on careful clinical, biochemical and radiologic evaluation typically demonstrating osteopenia, ovoid and flattened vertebral bodies, and hypoplastic femoral heads and acetabular roofs. Some patients with progressive proteinuria might be diagnosed incidentally through multigenic mutational screening (next generation sequencing/whole exome sequencing).\nDifferential diagnosis\nCartilage-hair hypoplasia is the main differential diagnosis.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variants) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nTherapy is largely limited to the prophylaxis and management of the various disease manifestations, such as dialysis and renal transplantation, supplementation of hematopoietic growth factors for neutropenia, orthopedic surgery as required, preventive antiviral therapies and vaccinations, anticoagulation, immunosuppressive therapy for those with autoimmune manifestations, and thyroid hormone supplementation.\nPrognosis\nLife expectancy is limited to childhood or early adolescence in most patients, due to stroke, infections, bone marrow failure, and renal failure. Survival into adulthood has been reported for patients with milder late-onset forms of the disease and successful management of the renal manifestations.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Beata LIPSKA-ZIETKIEWICZ | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Schinzel-Giedion syndrome", "Disease Definition": "Schinzel-Giedion syndrome (SGS) is an ectodermal dysplasia syndrome chiefly characterized by a distinctive facial dysmorphism, hydronephrosis, severe developmental delay, typical skeletal malformations, and genital and cardiac anomalies.", "ORPHA ID": 798, "Summary": "Epidemiology\nThe birth prevalence of SGS is not known. More than 50 cases have been reported worldwide to date.\nClinical description\nAt birth, SGS is quite easily characterized by the distinctive facial dysmorphism with a prominent forehead, midface retraction resembling a broadened ''figure-of-eight'' in marked cases, and a short upturned nose, as well as visceral abnormalities and hypertrichosis. Hydronephrosis is present in nearly all affected cases (91%). Cardiac abnormalities, including septal defects, valvular dysplasias, hypoplastic ventricles and patent ductus arteriosus are common (43%), as are other genitourinary abnormalities (76%), such as cryptorchidism, micropenis, hypospadias, hypoplastic uterus, hypoplastic labia minora and majora, deep labial sulcus, and anteriorly displaced anus. Neonates frequently present with short limbs and the following limb malformations: valgus or varus foot deformity, mesomelic brachymelia with hypoplastic and hyperconvex nails and single palmar creases of the hands. Affected neonates suffer from hypotonia and typically present with respiratory failure, with all having a severe developmental delay accompanied by seizures (often refractory), and visual and hearing impairment. Additionally, a higher than normal prevalence for neuroepithelial tumors (17%) in SGS patients has been reported.\nEtiology\nSGS is caused by de novo mutations in the SETBP1 gene (18q21.1), probably resulting in a gain-of-function or dominant-negative effect.\nDiagnostic methods\nDiagnosis is based on clinical findings (including the distinctive facial dysmorphism), the presence of hydronephrosis on ultrasound, and radiographic findings of multiple typical skeletal malformations including sclerotic skull base, wide occipital synchondrosis, increased cortical thickness/density and broad ribs. Under 12 months of age, skull radiographs reveal a gap between the 2 parts of the occipital bone and dense pyramids are also common. Genetic testing for SETBP1 is possible.\nDifferential diagnosis\nOther conditions with the distinctive midface retraction that could be considered in the differential diagnosis include fetal hydantoin, fetal warfarin syndromes, Zellweger syndrome, mucopolysaccharidosis, gangliosidosis, and rhizomelic chondrodysplasia punctata, as well as congenital hypothyroidism (see these terms).\nAntenatal diagnosis\nHydronephrosis is detectable on prenatal ultrasound between the 18th-37th week of pregnancy, in about 40% of affected cases. Genetic testing is possible.\nGenetic counseling\nSGS is an autosomal dominant disorder. Practically all cases occur sporadically, identification of the proband should be undertaken along with genetic counseling for parents.\nManagement and treatment\nManagement is supportive and consists of palliative care. The chief complications are respiratory failure, feeding intolerance, refractory seizures and frequent and recurrent infections such as pneumonia.\nPrognosis\nPrognosis is severe, with most affected patients not surviving infancy due to the progressive neurodegeneration, increased risk of tumors, recurrent infections and respiratory failure, although survival until adolescence has been reported.\n\n                            Last update: \n                            April 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Albert SCHINZEL"}
{"Disease Name": "Schisis association", "Disease Definition": "Schisis association describes the combination of two or more of the following anomalies: neural tube defects (e.g. anencephaly, encephalocele, spina bifida cystica), cleft lip/palate, omphalocele and congenital diaphragmatic hernia (see these terms). These anomalies are associated at a higher frequency than would be expected with random combination rates.", "ORPHA ID": 63862, "Summary": ""}
{"Disease Name": "Schistosomiasis", "Disease Definition": "A rare parasitic disease characterized by infection with trematodes of the genus Schistosoma. Humans become infected when larvae (cercariae) in infested freshwater penetrate the skin, potentially causing cercarial dermatitis. After a few weeks, eggs laid by the adult female worms living in blood vessels become trapped in body tissues, causing progressive organ damage due to inflammation, granuloma formation, and fibrosis. Acute schistosomiasis presents with fever, cough, headache, and urticaria, while chronic manifestations depend on the localization of the eggs and typically include abdominal pain, diarrhea, hepatosplenomegaly, blood in stool or urine, and dysuria, among others.", "ORPHA ID": 1247, "Summary": ""}
{"Disease Name": "Schizencephaly", "Disease Definition": "A rare developmental defect during embryogenesis characterized by the presence of linear clefts containing cerebrospinal fluid lined by abnormal grey matter that extend from the lateral ventricles to the pial surface of the cortex. Schizencephaly can involve one or both cerebral hemispheres and may lead to a variety of neurological symptoms such as epilepsy, motor deficits, and psychomotor retardation.", "ORPHA ID": 799, "Summary": "Epidemiology\nThe birth prevalence is estimated at 1/64,935 in the USA and 1/69,444 in the UK.\nClinical description\nPatients have varying clinical features including epilepsy (50-60% of cases), motor impairment, microcephaly and cognitive and learning disability. The severity of the clinical manifestations depends upon the extent of clefting and on whether other cerebral malformations are present. When a cleft affects one hemisphere alone (unilateral clefts), patients can have a hemiparesis but they may have little or no intellectual disability. Patients with bilateral clefts have a more severe phenotype that may be characterized by severe developmental impairment with spastic quadriplegia and severe intellectual disability. Schizencephaly is often associated with septo-optic dysplasia\nEtiology\nThe disorder usually results from an acquired defect of the cerebral mantle and often becomes apparent only in the second half of pregnancy. Schizencephaly has been linked to a young maternal age and to conditions secondary to vascular disruption such as maternal drug administration (e.g. warfarin), amniocentesis, and infections (cytomegalovirus). Mutations in the COL4A1 gene encoding the major type IV alpha collagen chain of basement membranes have been found responsible of some schizencephaly cases. Other genetic factors have been suggested to play a role in its pathogenesis, such as EMX2, SHH, and SIX3 that could act as susceptibility factors.\nDiagnostic methods\nPostnatally, the diagnosis is made by computed tomography (CT) and/or magnetic resonance imaging (MRI) showing unilateral or bilateral clefting of the brain. There are different classification systems for schizencephaly but a frequently used one refers to clefts as either closed-lip (type I) when the tissue surrounding the clefts are closely opposed, and open-lip (type II) when the tissue is widely separated by cerebrospinal fluid. Cerebral malformations found in association with schizencephaly on neuroimaging studies include optic nerve hypoplasia, enlarged cerebral ventricles, absence of corpus callosum or septum pellucidum, cerebellar hypoplasia, or calcifications. Genetic testing will confirm mutations in the genes associated with susceptibility to the condition but these are rare.\nDifferential diagnosis\nDifferential diagnosis includes porencephaly.\nAntenatal diagnosis\nPrenatal diagnosis can made after 20 weeks of pregnancy by ultrasound examination or on in utero MRI, which demonstrates clefting and abnormalities of the cerebral mantle. The diagnosis may be confirmed post-natally by MRI, which may give additional information about the presence of septo-optic dysplasia and other abnormalities.\nGenetic counseling\nMost cases are sporadic but some familial cases have also been observed with inheritance reported to be either autosomal recessive or autosomal dominant with variable penetrance. Genetic counseling should be proposed to at risk couples informing them that there is either 25% risk of transmitting the disease to offspring in the case of an autosomal recessive inheritance or 50% risk for an autosomal dominant inheritance.\nManagement and treatment\nTreatment consists on administration of anti-epileptic drugs in order to prevent seizures. In drug resistant cases (1/3rd of cases), surgery (e.g. resection of either the schizencephalic cleft alone or the cleft and surrounding epileptogenic tissue, temporal or frontotemporal lobectomy) can be performed. A regular neurologic evaluation is necessary. Physical and occupational therapy are essential.\nPrognosis\nThe prognosis is variable and depends on the degree of clefting and the association with other cerebral malformations. Individuals with schizencephaly can have features of a hemiparesis only but the clinical picture can extend to profound neurological impairment with spastic quadriplegia leading to immobility and to severe learning disability and epilepsy.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Paul GRIFFITHS"}
{"Disease Name": "Schneckenbecken dysplasia", "Disease Definition": "Schneckenbecken dysplasia (or chondrodysplasia with snail-like pelvis) is a prenatally lethal spondylodysplastic dysplasia.", "ORPHA ID": 3144, "Summary": "Epidemiology\nLess than 20 cases have been reported in the literature so far.\nClinical description\nThe typical radiographic finding is the snail-like configuration of the hypoplastic iliac bone. Additional features include flattened hypoplastic vertebral bodies, short ribs, short and wide fibulae, short and broad long bones with a dumbbell-like appearance, and precocious ossification of the tarsus.\nEtiology\nThis syndrome is caused by loss-of-function mutations of the SLC35D1 gene (1p32-p31)\nGenetic counseling\nSchneckenbecken dysplasia is transmitted in an autosomal recessive manner.\n\n                            Last update: \n                            September 2009"}
{"Disease Name": "Schnitzler syndrome", "Disease Definition": "Schnitzler syndrome is a rare, underdiagnosed disorder in adults characterized by recurrent febrile rash, bone and/or joint pain, enlarged lymph nodes, fatigue, a monoclonal IgM component, leukocytosis and systemic inflammatory response.", "ORPHA ID": 37748, "Summary": "Epidemiology\nPrevalence is unknown and about 150 cases have been reported, primarily in Europe.\nClinical description\nThere is a slight male predominance and mean age of disease onset is 51 years. Time to diagnosis often exceeds 5 years. The first clinical sign is usually a mildly or non-pruritic skin rash. Elementary lesions are rose or red macules or slightly elevated plaques, which resolve within 24 hours. Lesions can occur on every body part, though involvement of face and extremities is rare. The frequency and duration of flares are variable. Almost all patients develop intermittent fever and body temperature can rise above 40°C. Fever is usually well tolerated and chills are rare. About 80% of patients experience bone and/or joint pain. Bone involvement is common, and 30 to 40% of patients show bone lesions on imaging studies. IgM levels can remain stable or progressively increase at a rate of about 0.5 to 1 g/L/year. Other signs include elevated erythrocyte sedimentation rate (ESR), inflammatory anemia sometimes with thrombocytosis (up to 50 % of cases), palpable lymph nodes (45%), and hepatic or splenic enlargement (30%). The monoclonal IgM component is a defining feature of the disease. Inflammatory AA amyloidosis may be a serious complication. The disease follows a chronic course.\nEtiology\nEtiology remains unclear but the syndrome is probably an acquired auto-inflammatory disorder. It shares many features with genetically determined auto-inflammatory diseases.\nDiagnostic methods\nDiagnosis is based on a combination of clinical, laboratory and radiological findings and on exclusion of another cause. Histopathological skin findings are noteworthy showing a neutrophilic infiltrate of the dermis, without vasculitis and without significant edema, characteristic of neutrophilic urticarial dermatosis. An immediate and marked response to anakinra treatment is supportive of the diagnosis. The initial work-up should include an examination of bone marrow, immunoelectrophoresis of serum and urinary proteins, and determination of immunoglobulin subtypes. The two latter examinations can then be used for follow-up on a biannual basis. Lymph nodes should be biopsied when they are enlarged.\nDifferential diagnosis\nDifferential diagnosis includes adult-onset Still's disease, hypocomplementic urticarial vasculitis, cryoglobulinemia, hyper IgD syndrome, and acquired C1 inhibitor deficiency (see these terms).\nManagement and treatment\nSome treatments provide only incomplete and/or transient improvement or control of symptoms (steroids, non-steroidal anti-inflammatory drugs, colchicine, dapsone, peflacine, phototherapy) while others are mostly ineffective (anti-histamines, rituximab, intravenous immunoglobulins, TNF-blocking agents, immunosuppressive drugs). In contrast, the IL-1 receptor antagonist anakinra relieves all symptoms within hours after the first injection. Injection-site reactions are frequent with anakinra and sometimes severe, and can be a real concern. The neutrophil count must be monitored.\nPrognosis\nThe overall prognosis depends on the development of lymphoproliferative complications such as lymphoma, IgM myeloma or Waldenström's disease (see these terms). Although these complications have only been reported in about 20% of cases, their incidence may be higher since they generally develop more than 10 to 20 years after the first signs of the syndrome.\n\n                            Last update: \n                            January 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Dan LIPSKER"}
{"Disease Name": "Schnyder corneal dystrophy", "Disease Definition": "Schnyder corneal dystrophy (SCD) is a rare form of stromal corneal dystrophy (see this term) characterized by corneal clouding or crystals within the corneal stroma, and a progressive decrease in visual acuity.", "ORPHA ID": 98967, "Summary": "Epidemiology\nThe prevalence of this form of corneal dystrophy is not known.\nClinical description\nLesions usually develop early in life and are mostly bilateral, but one eye may become affected prior to the other. Some patients complain of glare, which increases with age. Visual acuity gradually decreases. Associated systemic disorders have been commonly reported (hypercholesterolemia, arcus lipoides and genu valgum). Over time, small white opacities develop in the corneal stroma along with a diffuse haze. In about 50% of patients, crystals are not observed clinically.\nEtiology\nSCD is caused by various mutations in the UBIAD1 gene (1p36.22).\nDiagnostic methods\nTypically, a ring-shaped yellow-white opacity composed of innumerable fine needle-shaped crystals forms in Bowman layer and the adjacent anterior stroma of the central cornea. The crystals usually remain in the anterior third of the cornea. The corneal epithelium and endothelium as well as Descemet membrane are spared.\nDifferential diagnosis\nSCD should be differentiated from other lipid keratopathies and particular from lecithin cholesterol acyltransferase disease (LCAT deficiency, see this term).\nGenetic counseling\nAn autosomal dominant pattern of inheritance has been reported.\nManagement and treatment\nThe superficial pathologic corneal tissue needs to be excised.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Schuurs-Hoeijmakers syndrome", "Disease Definition": "A rare genetic syndromic intellectual disability characterized by mild to moderate intellectual disability, developmental delay (with speech and language development more severely affected). Association with infantile hypotonia, seizures, cryptorchidism in males and congenital abnormalities, including cardiac, cerebral or ocular defects, may be observed.", "ORPHA ID": 329224, "Summary": "Epidemiology\nThe prevalence of Schuurs-Hoeijmakers syndrome (also called PACS1-related syndrome) is estimated at <1/1,000,000 birth. To date approximately 60 individuals were reported in the literature, however the disease is most likely under-reported.\nClinical description\nThe disease is characterized by mild-to-severe neurodevelopmental delays. Language skills are more severely affected than motor skills. Feeding difficulty is common, with many of the children requiring gastrostomy tube to maintain appropriate caloric intake. Common facial features include full, arched eyebrows, hypertelorism, down-slanting palpebral fissures, long eyelashes, ptosis, low-set, simple ears, bulbous nasal tip, flat philtrum, wide mouth with downturned corners and thin upper lip and diastema of the teeth. Other common features include short stature and/or low weight, hypotonia, constipation, seizures, autism, behavioral issues, congenital heart anomalies, genitourinary abnormalities, renal issues, and ocular anomalies.\nEtiology\nAlmost all individuals with PACS1-related syndrome have a c.607C>T (NM_018026.3) mutation in the PACS1 gene, within a region thought to be important for the function of the protein. The expression of the PACS1 gene is significant both during embryonic development and after birth. Pathogenic variations in PACS1 lead probably to a dominant-negative mechanism responsible for disrupting protein trafficking in the golgi apparatus.\nDiagnostic methods\nThe diagnosis of PACS1 syndrome is established by molecular genetic testing. All individuals reported to date have the disorder as the result of a de novo pathogenic variant.\nDifferential diagnosis\nThe differential diagnosis includes Winter-Baraitser syndrome and Kabuki syndrome.\nAntenatal diagnosis\nOnce a pathogenic variant has been identified in a family, detection of PACS1 syndrome can be done by amniocentesis and exome sequencing for malformative syndrome screening during pregnancy.\nGenetic counseling\nTransmission of PACS1 syndrome is autosomal dominant with full penetrance (50% risk of transmission at each pregnancy); however, in most situations, the pathogenic variants arise de novo and thus the risk of sibling recurrence is low. Detection of PACS1-related syndrome should be discussed with the parents of an affected individual during subsequent pregnancies.\nManagement and treatment\nManagement requires a lifelong multidisciplinary approach. Regular follow‐up by a clinical geneticist, paediatrician, ophthalmologist, psychologist/psychiatrist, speech therapist, physiotherapist and ophthalmologist will have a major impact on the quality of life and learning at school. Developmental assessments are needed to tailor medical services to each individual's needs. Other specialists can be needed, like a cardiologist, gastroenterologist, nephrologist, otolaryngologists or stomatologist.\nPrognosis\nAutonomy may be limited and affected individuals will sometimes require life-long support from caregivers. There is little data on adults, so it is not currently possible to provide information on the long-term future of PACS1-related syndrome patients.\n\n                            Last update: \n                            November 2023\n\n\n                            - Expert reviewer(s): \n                            Pr David GENEVIEVE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Schwartz-Jampel syndrome", "Disease Definition": "A rare, genetic neuromuscular disease characterized by permanent myotonia, mask-like facies (with blepharospasm, narrow palpebral fissures, small mouth with pursed lips and puckered chin) , and chondrodysplasia (variably manifesting with short stature, pectus carinatum, kyphoscoliosis, bowing of long bones, epiphyseal, metaphyseal, and hip dysplasia).", "ORPHA ID": 800, "Summary": "Epidemiology\nApproximately, 130 cases have been described in the literature to date.\nClinical description\nPresentation is typically by 1 year to 2 years of age, but may occur earlier, with myotonia, maske-like facies, short stature, non-progressive muscle weakness, muscle hypertrophy, progressive restriction of range of motion and paucity of subcutaneous tissue. Facial features consist of blepharospasm, progressive blepharophimosis, pursed lips and a puckered chin. Micrognathia, low-set ears with folded helices and dystopia canthorum have also been reported. The myotonia is characterized by continuous muscle activity recorded on electroneuromyography. Limited joint mobility leads to an unsteady gait. Joint stiffness is progressive, reaching its peak during adolescence The severity of chondrodysplasia is variable and may consist of flattening of the vertebral bodies, hip dysplasia, metaphyseal widening, slender diaphyses, kypho-scoliosis, multiple joint contractures and bowing of long bones. Rarely, myopia, inguinal and umbilical hernias and micro-orchidism have been reported.\nEtiology\nLoss of function mutations in HSPG2 (1p36) are causative. HSPG2  encodes perlecan, a major component of the cellular matrix that plays an important role in maintaining cartilaginous tissue integrity and regulating muscle excitability. The exact pathogenesis is unknown.\nDiagnostic methods\nDiagnosis is established by demonstration of both myotonia via electromyography and chondrodysplasia via radiographs. Genetic testing may confirm diagnosis.\nDifferential diagnosis\nSchwartz-Jampel syndrome (SJS) is non-allelic with Stuve-Wiedemann syndrome, a severe skeletal dysplasia that is typically fatal during the neonatal period and was formerly described as SJS type 2. Other differential diagnosis should include Freeman Sheldon and Marden Walker syndrome and, in cases with minimal skeletal abnormalities, myotonic disorders ( including myotonia congenita, myotonia permamens, and myotonic dystrophy).\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to affected families, informing them that the risk of disease transmission is 25% where both parents are unaffected carriers.\nManagement and treatment\nThe management of patients with SJS is primarily supportive and best offered by a team comprising a neurologist, a geneticist, a physical therapist, an orthopedic surgeon, an ophthalmologist and a psychologist. Medical treatment with muscle relaxants and antiepileptic drugs, such as carbamazepine, phenytoin, or procainamide, aimed to alleviate myotonia has limited usage, although early initiation of treatment may limit the extent of disability. Physical therapy is important to prevent contracture formation and fixed skeletal deformity. Botulinum toxin A injections for blepharospasm has been reported with limited and variable results Rarely, surgical intervention is considered for blepharospasm including orbicularis oculi myectomy or levator aponeurosis resection improve functional and cosmetic outcome. Malignant hyperthermia is a potentially lethal complication of anesthesia.\nPrognosis\nProgressively worsening blepharospasm is an important morbidity that can interfere with vision. The disease appears to stabilize after adolescence and does not affect life span.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Bertrand FONTAINE"}
{"Disease Name": "Schöpf-Schulz-Passarge syndrome", "Disease Definition": "Schöpf-Schulz-Passarge syndrome (SSPS) is a rare autosomal recessive ectodermal dysplasia characterized by multiple eyelid apocrine hidrocystomas, palmoplantar keratoderma, hypotrichosis, hypodontia and nail dystrophy.", "ORPHA ID": 50944, "Summary": "Epidemiology\nMore than 25 cases with SSPS have been described so far.\nClinical description\nSSPS refers to a discrete phenotype of ectodermal dysplasia with a relatively benign course and late diagnosis, often established in adulthood. The onset of symptoms occurs in childhood and early adolescence, but they consist of relatively unspecific features, including various degrees of hypodontia, hypotrichosis, palmoplantar keratoderma and nail dystrophy. Telangiectatic rosacea is a further relatively common feature. Multiple eyelid apocrine hidrocystomas commonly appear in (late) adulthood. Palmoplantar keratoderma with histologic features of eccrine syringofibroadenoma is observed in nearly half of cases and occasionally develops a malignant potential. Other adnexal tumors described include basal cell carcinoma, eccrine poroma, benign acanthoma and follicular infundibulum tumor. Some patients have been described to have a bird-like facies. Within the WNT10A mutational spectrum, odonto-onycho-dermal dysplasia and SSPS are regarded as discrete entities, while an increasing number of patients are described with incomplete phenotypes of the odonto-onychial, tricho-odonto and tricho-odonto-onychial types.\nEtiology\nSSPS is due to homozygous or compound heterozygous mutations in WNT10A. Incomplete/localized disease expression in heterozygous carriers and multiple instances of consanguinity occasionally lead to a pseudodominant transmission.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Marco CASTORI"}
{"Disease Name": "Scimitar syndrome", "Disease Definition": "Scimitar syndrome is characterized by a combination of cardiopulmonary anomalies including partial anomalous pulmonary venous return connection of the right lung to the inferior caval vein leading to the creation of a left-to-right shunt.", "ORPHA ID": 185, "Summary": "Epidemiology\nThe prevalence is estimated at between 1/100,000 and 1/33,333 live births. Females seem to be more frequently affected than males.\nClinical description\nIn the majority of cases, the disease manifests in the first months of life. In the neonatal period, the disease presents with congestive cardiac failure, most commonly due to pulmonary hypertension and respiratory distress. The right lung is most frequently involved. Variable degrees of hypoplasia and malformations of the pulmonary arteries are found in the affected lung, as well as arterial supply from the aorta, which can also arise above or below the diaphragm. The heart itself is usually right-sided. Rarely, the disease may manifest with a small shunt, a cardiac murmur, and recurrent respiratory infections in children and adults. About one-fourth of affected patients have associated congenital heart disease (aortic coarctation, tetralogy of Fallot, patent arterial duct or ventricular septal defect; see these terms). Other reported associated anomalies include bronchogenic cysts, horseshoe lung, accessory diaphragm and hernias.\nEtiology\nThe etiology is not completely understood. In several patients with total anomalous pulmonary venous return, the gene locus has been mapped to chromosome 4q12.\nDiagnostic methods\nThe diagnosis is based on clinical presentation and transthoracic or transesophageal echocardiography, angiography, computed tomography and magnetic resonance angiography. The characteristic feature on chest radiographs, giving the condition its name, is a lesion in the shape of a scimitar (a type of curved Turkish sword).\nDifferential diagnosis\nScimitarsyndrome must be differentiated from pseudoscimitar syndrome (abnormal descending vein draining into the left atrium) and from Kartagener syndrome (see this term).\nAntenatal diagnosis\nPrenatal diagnosis is feasible by fetal echocardiography. Rarely, Scimitar syndrome is diagnosed incidentally in older children and adults who undergo chest radiography for diverse reasons.\nManagement and treatment\nManagement depends on the hemodynamic state. No therapy is required if the amount of blood flowing to the inferior caval vein is small. In case of significant left-to-right shunt and pulmonary hypertension, surgical correction is warranted, and can include repair of the anomalous venous return, ligation of collateral arteries, and right pneumonectomy.\nPrognosis\nWhen diagnosed in infancy, the syndrome is associated with significant mortality due to severe respiratory insufficiency, cardiac failure, and pulmonary infections.\n\n                            Last update: \n                            May 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Robert ANDERSON"}
{"Disease Name": "Scleredema", "Disease Definition": "A rare acquired skin disease characterized by excessive mucin deposition and thickened collagen bundles in the dermis, resulting in woody, non-pitting induration of the skin of the neck, spreading to the shoulders and upper trunk, but sparing hands and feet. According to the association with preceding or underlying conditions, three types can be distinguished: type 1 usually follows a febrile infection, type 2 is associated with paraproteinemia, and type 3 occurs in patients with diabetes mellitus. Especially in types 2 and 3, extracutaneous involvement may be present. Other potentially associated conditions include a variety of endocrinopathies, systemic diseases, and neoplasms.", "ORPHA ID": 352763, "Summary": ""}
{"Disease Name": "Scleroderma", "Disease Definition": "Scleroderma is a rare autoimmune connective tissue disorder characterized by abnormal hardening of the skin and, sometimes, other organs. It is classified into two main forms: localized scleroderma and systemic sclerosis (SSc), the latter comprising three subsets; diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc) and limited SSc (lSSc).", "ORPHA ID": 801, "Summary": "Epidemiology\nThe prevalence is estimated at around 1-9/100,000 for localized scleroderma, and 1/6,500 adults for systemic sclerosis. Women are predominantly affected (F/M sex ratio around 4:1).\nClinical description\nLocalized scleroderma is the cutaneous form of scleroderma characterized by fibrosis of the skin causing cutaneous plaques (morphea) or strips (linear scleroderma). Systemic sclerosis (SSc) is a generalized disorder characterized by fibrosis and vascular obliteration in the skin and organs, particularly, lungs, heart, and digestive tract.\nEtiology\nThe exact cause of scleroderma is unknown. The disease originates from an autoimmune reaction which leads to localized overproduction of collagen. In some cases, the condition is associated with exposure to chemicals. Other suggested causes include genetic and infectious mechanisms.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Eric HACHULLA"}
{"Disease Name": "Scleromyxedema without monoclonal gammopathy", "Disease Definition": "Scleromyxedema without monoclonal gammopathy is a form of atypical lichen myxedematosus (see this term), characterized by a generalized sclerodermoid infiltration of skin studded with multiple, firm papules of 1-3 mm in diameter involving face (leonine appearance), trunk, and limbs, without monoclonal gammopathy. The involvement of the face can be missing and pruritus may be prominent.", "ORPHA ID": 90400, "Summary": ""}
{"Disease Name": "Scleromyxedema", "Disease Definition": "A rare lichen myxedematosus characterized by a progressive, generalized, papular, sclerodermoid cutaneous eruption usually occurring in association with monoclonal gammopathy, but in the absence of thyroid disease. Histological hallmark is the triad of dermal mucin deposition, fibroblast proliferation, and fibrosis. Patients present with relatively sudden onset of numerous closely spaced, waxy, firm papules and plaques predominantly involving the head, neck, trunk, and dorsal aspects of the extremities, on the background of thickened, edematous, erythematous skin with sclerodermoid appearance. Systemic involvement with cardiovascular, gastrointestinal, pulmonary, musculoskeletal, renal, or nervous system complications is common.", "ORPHA ID": 167635, "Summary": ""}
{"Disease Name": "Sclerosteosis", "Disease Definition": "Sclerosteosis is a very rare serious sclerosing hyperostosis syndrome characterized clinically by variable syndactyly and progressive skeletal overgrowth (particularly of the skull), resulting in distinctive facial features (mandibular overgrowth, frontal bossing, midfacial hypoplasia), cranial nerve entrapment causing facial palsy and deafness, and potentially lethal elevation of intracranial pressure.", "ORPHA ID": 3152, "Summary": ""}
{"Disease Name": "Scorpion envenomation", "Disease Definition": "Scorpion envenomation is a rare intoxication caused by a scorpion sting which typically manifests with localized pain, edema, erythema, and paresthesias at the site of the sting and, when severe, progresses to produce systemic symptoms of variable severity that include respiratory difficulties, abnormal systemic blood pressure, cardiac arrhythmia, and a combination of parasympathetic (i.e. excessive salivation and lacrimation, diaphoresis, miosis, frequent urination, diarrhea, vomiting, priapism) and sympathetic (e.g. hyperthermia, hyperglycemia, mydriasis) manifestations. Neurological manifestations may also be associated, such as abnormal eye movements, blurred vision, agitation and restlessness, as well as muscle fasciculations and spasms. Signs and symptoms are highly variable and in most severe cases may lead to cardiogenic shock and pulmonary edema.", "ORPHA ID": 466677, "Summary": ""}
{"Disease Name": "Scott syndrome", "Disease Definition": "Scott syndrome is an extremely rare congenital hemorrhagic disorder characterized by hemorrhagic episodes due to impaired platelet coagulant activity.", "ORPHA ID": 806, "Summary": ""}
{"Disease Name": "Scrub typhus", "Disease Definition": "Scrub typhus is a rare dust mite-borne infectious disease caused by the Orientia tsutsugamushi bacterium and characterized clinically by an eruptive fever which is potentially serious.", "ORPHA ID": 83317, "Summary": "Epidemiology\nPrecise prevalence and incidence rates of scrub typhus are not known. An estimated 1 billion people worldwide are at risk for scrub typhus, and an estimated 1 million cases occur each year. The disease is widespread in rural South and South-East Asia and the Western Pacific (Korea to Australia) as well as from Japan to India and Pakistan. In these regions its annual incidence is approximately 1/4,000. Scrub typhus occurs preferentially in spring and autumn in rural areas and has frequently been reported in individuals who traveled to endemic regions.\nClinical description\nAfter a silent incubation period of 10 days or more, onset is sudden with constant high fever, headache, obtundation, cough, myalgia and nausea. A pale macular rash is common and an inoculation eschar at the site of the mite bite is found in many cases, often with painful satellite lymph nodes. Splenomegaly is observed in 1/3 of cases. Most cases are mild, but pneumonitis, meningoencephalitis, multiorgan failure, bleeding and even death may occur, especially in untreated patients. Relapses after recovery may occur but are usually less severe than the inaugural episode.\nEtiology\nScrub typhus is caused by Orientia tsutsugamushi, an obligate intracellular Gram-negative rod bacteria belonging to the genus Orentia, which is transmitted to humans by the bites of larval thrombiculid mites (chiggers).\nDiagnostic methods\nDiagnosis is based on clinical signs (fever, headache, eschar at the bite site, rash) in an endemic rural zone. Non-specific laboratory test results include increased transaminase levels, thrombocytopenia, leucopenia and CD4/CD8 lymphocyte ratio inversion. A definitive diagnosis can be made by culture of O. tsutsugamushi in a shell vial or molecular biology analysis of sampling (skin, lymph nodes, EDTA blood) using PCR amplification. The organisms stain poorly with the Gimenez method but easily with Giemsa staining. Immunohistochemistry of skin lesions may reveal an O. tsutsugamushi infection. Later serological confirmation is possible by indirect immunofluorescence.\nDifferential diagnosis\nDifferential diagnosis includes typhoid fever, leptospirosis, malaria, and dengue (see these terms), as well as HIV seroconversion and rickettsial diseases (see this term).\nManagement and treatment\nTreatment usually involves drug therapy with doxycycline and chloramphenicol. Doxycycline is administered for a short time (3-7 days) in adults (200 mg/day) and children (2.2 mg/kg, twice daily). All patients with a suspected infection should be treated. Patients with poor response to doxycycline and chloramphenicol, as well as pregnant women, can be treated with rifampicin (600-900 mg/day) or azithromycin (500 mg on the first day, then 250 mg/day).\nPrognosis\nThe disease course may be severe. However, the mortality rate depends on the geographic areas and varies from 3% in Taiwan up to 30% in Northern Japan. The exact reasons for the variable mortality in these regions are not known, but it is likely that different serotypes may account for the varying manifestations of the disease.\n\n                            Last update: \n                            March 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Senaka RAJAPAKSE"}
{"Disease Name": "Sebocystomatosis", "Disease Definition": "Sebocystomatosis is characterized by multiple (100 to 2000) asymptomatic dermal cysts that usually occur on the sternal region, upper back, axillae and proximal parts of the extremities.", "ORPHA ID": 841, "Summary": "Epidemiology\nAt least 30 cases from unrelated families (over three to five generations) and several sporadic cases have been reported.\nClinical description\nSebocystomatosis usually manifests during the first or second decade of life and affects both sexes, with some studies indicating that the prevalence is higher in males.\nEtiology\nSebocystomatosis is caused by mutations in the keratin-17 gene (KRT17, 17q12-q21).\nGenetic counseling\nAn autosomal dominant pattern of inheritance has been suggested.\n\n                            Last update: \n                            September 2009"}
{"Disease Name": "Seborrhea-like dermatitis with psoriasiform elements", "Disease Definition": "A rare, genetic, epidermal disorder characterized by a chronic, diffuse, fine, scaly erythematous rash on the face (predominantly the chin, nasolabial folds, eyebrows), around the earlobes and over the scalp, associated with hyperkeratosis over elbows, knees, palms, soles and metacarpophalangeal joints, in the absence of associated rheumatological or neurological disorders. Cold weather, emotional stress and strenuous physical activity may exacerbate symptoms.", "ORPHA ID": 168606, "Summary": ""}
{"Disease Name": "Seckel syndrome", "Disease Definition": "A rare form of microcephalic primordial dwarfism characterized by a proportionate dwarfism of prenatal onset, a severe microcephaly, a typical dysmorphic face (bird-like), and mild to severe intellectual disability.", "ORPHA ID": 808, "Summary": "Epidemiology\nSeckel syndrome is the most common of the microcephalic osteodysplastic dwarfisms.\nClinical description\nSeckel syndrome is characterized by a proportionate dwarfism of prenatal onset, a severe microcephaly with a bird-headed like appearance and mental retardation. Hematological abnormalities with chromosome breakage have only been found in 15 to 25% of patients.\nEtiology\nBesides to a wide phenotypic heterogeneity between affected patients, genetic heterogeneity has also been proven, with three loci identified to date by homozygosity mapping: SCKL1 (3q22.1-q24, ataxia-telangiectasia and Rad3-related protein (ATR) gene), SCKL2 (18p11.31-q11.2, unknown gene) and SCKL3 (14q23, unknown gene). SCKL3 seems to be the predominant locus for Seckel syndrome. Approaching the function of the ATR gene, the genes with a role in DNA repair are good candidates for SCKL2 and 3.\nDifferential diagnosis\nThe differential diagnosis with microcephalic osteodysplastic dwarfism type II can only be made with a complete radiographic survey in the first years of life.\nGenetic counseling\nSeckel syndrome is an autosomal recessive disorder.\nManagement and treatment\nIntellectual disability is usually severe and families should be helped for social problems. In case of associated hematological abnormalities (anemia, pancytopenia, acute myeloid leukaemia), medical treatment should be provided.\n\n                            Last update: \n                            April 2005\n\n\n                            - Expert reviewer(s): \n                            Pr Valérie CORMIER-DAIRE  - Pr Laurence OLIVIER-FAIVRE"}
{"Disease Name": "Second branchial cleft anomaly", "Disease Definition": "A rare otorhinolaryngological malformation characterized by the presence of a cyst, sinus or fistula occuring along the anterior border of the sternocleidomastoid muscle. Second branchial cleft fistulae and sinuses present with skin opening with chronic discharge and recurrent infections, whereas second branchial cleft cysts present as a painless, nontender, stable in size or slowly enlarging lateral neck masses. Cysts occasionally acutely increase in size during upper respiratory tract infection, leading to respiratory compromise, torticollis, and dysphagia.", "ORPHA ID": 141022, "Summary": ""}
{"Disease Name": "Secondary erythromelalgia", "Disease Definition": "A rare neurologic disease characterized by intermittent pain, erythema, swelling, and heat of the extremities which is aggravated by warming and improved by cooling. Attacks can last between minutes and days and tend to be precipitated by heat, exercise, or physical dependence. The disease may be linked to a variety of underlying conditions including hematological, metabolic, connective tissue or neurological disorders, neoplasia, infections, and certain drug side effects, among others.", "ORPHA ID": 529864, "Summary": ""}
{"Disease Name": "Secondary hypereosinophilic syndrome", "Disease Definition": "A rare hypereosinophilic syndrome characterized by hypereosinophilia produced by reactive/non-clonal eosinophils secondary to an underlying medical condition and persisting for at least six months. The disorder can derive from non-neoplastic conditions (such as chronic infections and infestations, allergic reactions, intoxications, or autoimmune and chronic inflammatory disorders) or from neoplasms including non-myeloid malignancies, among others. It is associated with signs of organ infiltration, dysfunction, and damage. Clinical manifestations are highly variable, depending on the organ systems involved, and most commonly include dermatologic, pulmonary, cardiac, gastrointestinal, and cerebral manifestations.", "ORPHA ID": 314962, "Summary": ""}
{"Disease Name": "Secondary intestinal lymphangiectasia", "Disease Definition": "Secondary intestinal lymphangiectasia is an acquired from of intestinal lymphangiectasia (see this term) manifesting as a protein-losing enteropathy due to another disorder such as Crohn’s disease, congestive heart failure, sarcoidosis, Turner syndrome (see these terms) and often in patients who have undergone a Fontan operation. It is characterized by malabsorption, diarrhea, edema due hypoproteinemia, steatorrhea and serosal effusions.", "ORPHA ID": 90363, "Summary": ""}
{"Disease Name": "Secondary non-traumatic avascular necrosis", "Disease Definition": "A rare osteonecrosis disease characterized by death of bone cellular components secondary to an interruption of the subchondral blood supply, typically manifesting with unilateral or bilateral, unifocal or multifocal lesions usually located on the epiphysis, metaphysis and/or diaphysis of the femoral heads, knees, shoulders, ankles and/or wrists, leading to gradual onset of pain and progressive joint degeneration resulting in loss of function. Association with corticosteroid usage, alcoholism, hyperbaric events, radiation or cytotoxic agent exposure, hemoglobinopathies, and/or underlying autoimmune or metabolic disease, amongst others, has been observed.", "ORPHA ID": 399180, "Summary": ""}
{"Disease Name": "Secondary polyarteritis nodosa", "Disease Definition": "Secondary polyarteritis nodosa (PAN) is a rare serious form of PAN (see this term) characterized by vasculitis in a background of viral infection, primarily with hepatitis B virus (HBV).", "ORPHA ID": 439746, "Summary": ""}
{"Disease Name": "Secondary polycythemia", "Disease Definition": "Secondary polycythemia is an elevated absolute red blood cell mass caused by enhanced stimulation of red blood cell production by an otherwise normal erythroid lineage that may be congenital or acquired (congenital secondary polycythemia and acquired secondary polycythemia; see these terms).", "ORPHA ID": 98428, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nClinical features vary according to the origin of the disease but may include plethora or ruddy complexion, headache and tinnitus. The congenital form may be complicated by superficial or deep vein thrombophlebitis, or present with associated symptoms as in Chuvash erythrocytosis (see this term), or the course of the disease may be indolent. Patients with a specific sub-type of congenital secondary polycythemia, known as Chuvash erythrocytosis, present with lower systolic or diastolic blood pressure, venous varicosities, and vertebral body hemangiomas and may be complicated by cerebrovascular events or mesenteric thrombosis. The acquired form of secondary polycythemia may present with cyanosis, hypertension, clubbing of the fingers and toes and lethargy.\nEtiology\nSecondary polycythemia may be congenital and caused by defects in the oxygen sensing pathway due to autosomal recessive mutations in the VHL, EGLN1 and EPAS1 genes (3p26-p25, 1q42-q43 and 2p21-p16 respectively) which result in enhanced erythropoietin (EPO) production in hypoxic conditions, or by other autosomal dominant congenital defects including high oxygen-affinity hemoglobin and biphosphoglycerate mutase deficiency, which result in tissue hypoxia and a secondary erythrocytosis. Alternatively, secondary polycythemia may be acquired and caused by increased amounts of EPO. This may be due to tissue hypoxia that may be central and caused by pulmonary or cardiac disease or high altitude, or local and caused by hypoxia in the kidney such as renal artery stenosis. EPO production may be pathologic and caused by EPO secreting tumors such as renal cell cancer, hepatocellular carcinoma, cerebellar hemangioblastoma, meningioma and parathyroid carcinoma/adenoma (see these terms). In addition EPO may be administered deliberately to produce erythrocytosis and enhance performance.\nDiagnostic methods\nDiagnosis is based on evidence of increased total red blood cells and normal to high serum EPO levels. Secondary causes of erythrocytosis must be diagnosed individually and will require a comprehensive history.\nDifferential diagnosis\nDifferential diagnoses include polycythemia vera and primary familial polycythemia (see these terms), which can be excluded on the basis of low EPO levels and the presence of a mutation in the JAK2 gene (9p24) for polycythemia vera.\nManagement and treatment\nThere is little evidence to guide management of congenital secondary polycythemia. Phlebotomy or venesection may be of benefit, particularly in patients at increased risk of thrombosis. A target hematocrit (Hct) of 50% may be the most practical. In patients with no specific contraindication, low-dose aspirin may be of benefit. In acquired cases of secondary polycythemia, management is based on treating the underlying condition.\nPrognosis\nPrognosis depends mainly on the associated disease in the acquired forms of secondary erythrocytosis and on the severity of thrombotic complications in the inherited forms such as in Chuvash erythrocytosis.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Jean BRIERE"}
{"Disease Name": "Secondary pulmonary alveolar proteinosis", "Disease Definition": "A rare, acquired, interstitial lung disease, characterized by alveolar surfactant accumulation, cough, progressive dyspnea and respiratory insufficiency. The disease may be secondary to hematological disorder, toxic inhalation, and infection or may occur within the setting of immunosuppression after transplantation.", "ORPHA ID": 420259, "Summary": ""}
{"Disease Name": "Secondary pulmonary hemosiderosis", "Disease Definition": "Secondary pulmonary hemosiderosis is a respiratory disease due to the deposition of hemosiderin-laden macrophages in lungs as a result of repeated alveolar hemorrhage secondary to another disease, especially dysimmunitary disorders (i.e. Heiner syndrome (see this term), autoimmune diseases), thrombotic disorders and cardiovascular disorders such as mitral stenosis. It manifests as a triad of hemoptysis, anemia and diffuse parenchymal infiltrates on chest radiography", "ORPHA ID": 99930, "Summary": ""}
{"Disease Name": "Secondary sclerosing cholangitis", "Disease Definition": "A rare, biliary tract disease characterized by development of sclerosing cholangitis due to a known primary insult to the biliary tree, including infections, autoimmune disease, exposure to toxic agents, obstructive and ischemic injuries. Patients may be initially asymptomatic with only elevated alkaline phosphatase and gamma glutamyltransferase levels. Later presentation includes abdominal pain, jaundice, pruritus, fever and bacterial cholangitis from ascending infection.", "ORPHA ID": 447774, "Summary": ""}
{"Disease Name": "Secondary short bowel syndrome", "Disease Definition": "Secondary short bowel syndrome is an intestinal failure caused by any condition that results in a functional small intestine of less than 200 cm in length and is characterized by diarrhea, nutrient malabsoption, bowel dilation and dysmobility.", "ORPHA ID": 95427, "Summary": ""}
{"Disease Name": "Secondary syringomyelia", "Disease Definition": "Secondary syringomyelia is a rare medullar disease defined as a development of a fluid-filled cavity or syrinx within the spinal cord due to blockage of CSF circulation (e.g., due to basal archnoiditis, meningeal carcinomatosis, various mass lesions), spinal cord injury (e.g., due to trauma, radiation necrosis, hemorrhage, spinal abscess), spinal dysraphism or intramedullary tumours. It presents with neuropathic pain, numbness, muscular weakness, changes in tone or spasticity or autonomic changes (hyperhidrosis, heart rate or blood pressure instability). Selective loss of pain and temperature with relative preservation of dorsal column function (touch and pressure) are classic findings.", "ORPHA ID": 99857, "Summary": ""}
{"Disease Name": "Segmental odontomaxillary dysplasia", "Disease Definition": "A rare oral disease characterized by unilateral enlargement of the right or left maxillary alveolar bone and gingiva in the region distal to the canines towards the maxillary tuberosity. In the enlarged region, dental abnormalities such as missing teeth, abnormal spacing and delayed eruption occur.", "ORPHA ID": 67039, "Summary": "Epidemiology\nThe term segmental odontomaxillary dysplasia (SOD) was introduced by Danforth et al. in 1990. More than 60 cases of SOD have been described. SOD is often diagnosed in childhood both in males and females, with a slight male predominance.\nClinical description\nThe 2022, 5th edition, of the World Health Organization (WHO) Classification of Head and Neck Tumours has added Segmental odontomaxillary dysplasia (SOD) within the group of fibro-osseous lesions. SOD is asymptomatic with onset in 1st-2nd decades that usually halts around puberty. Unilateral facial signs: nonprogressive or slowly progressive overgrowth or undergrowth of soft tissues and/or bones (typically centred on the posterior maxilla, and leading to facial asymmetry), dental anomalies (missing teeth or abnormal dentition), gingival hyperplasia or abnormal gingivae, commissural lip fissures, hypertrichosis, cutaneous hyperpigmentation and/or erythema, cutaneous depression, and lip hypopigmentation. The main clinical features include: 1) an alveolar process characterized by unilateral enlargement of the maxillary alveolar bone and gingiva. Buccal as well as palatal enlargement of the alveolar bone is observed, although it is more pronounced on the buccal side. 2) Dentition is marked by abnormal spacing between erupted primary/permanent molars and adjacent teeth. The first permanent molars are often distally displaced. A depression in the palate can appear in the molar region. The canines erupt normally. Malformations of the primary molars, absence of one or both premolars and delayed eruption of adjacent teeth are regular findings. 3) On radiograph, the bone appears dense and sclerotic with abnormal trabeculation. Decreased size of the maxillary sinus in the affected side is observed. Primary teeth are characterized by enlargement of pulps. 4) Histological findings reveal immature bone with irregular trabecular and basophilic cemental lines resulting from alternating bone resorption and bone formation. Sparse narrow spaces with only a few fat cells are observed. The gingiva shows slight fibrosis without pathological changes. Tubular defects in the coronal dentine are present. An irregular pulp/dentin interface is present. A deficient osteoblast layer and widespread external resorption is also observed. Sometimes homolateral, subtle, cutaneous manifestations (hypertrichosis, cutaneous hyperpigmentation and/or erythema, cutaneous depression) might be present.\nEtiology\nIt is a non-hereditary, unilateral developmental disorder. Somatic mosaic variants in PIK3CA, or ACTB genes have been described.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation.\nDifferential diagnosis\nDifferential diagnosis includes hemimaxillofacial dysplasia (HMD), regional odontodysplasia, fibrous dysplasia (causes enlargement of bone tissue, but in this case affected bone growth is out of proportion with that of unaffected bones, and tooth malformations and missing premolars are not characteristics of the disease), focal cemento-osseous dysplasia (occurring in adults with no gingival enlargement or absence of teeth), and hemifacial hyperplasia (unilateral facial enlargement and precocious eruption and enlarged teeth in the affected region but not report of premolars absence). In HMD, ipsilateral facial hypertrichosis is present in addition to the SOD symptoms. Some authors consider SOD and HMD to be different manifestations of the same syndrome. The incisors and canines of the permanent dentition are commonly involved and agenesis of premolars is not a typical feature.\nGenetic counseling\nIt is a non-hereditary, unilateral developmental disorder.\nManagement and treatment\nMultidisciplinary treatment of SOD should include long-term follow-up as it is important for guidance in the management of this disorder. Implants have been successful in one reported case.\nPrognosis\nLife-long treatment is expected.\n\n                            Last update: \n                            November 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès BLOCH-ZUPAN | ERN CRANIO*\n\n\n                                * European Reference Network"}
{"Disease Name": "Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by progressive, proportionate, asymmetric segmental overgrowth (with soft tissue hypertrophy and ballooning effect) that develops and progresses rapidly in early childhood, arteriovenous and lymphatic vascular malformations, lipomatosis and linear epidermal nevus (arranged in whorls along the lines of Blaschko). Clinical symptoms of Cowden syndrome, such as macrocephaly and progressive development of numerous hypertrophic hamartomatous and neoplastic lesions involving multiple organs and systems, are also associated. Patients present an increased risk of developing cancer.", "ORPHA ID": 137608, "Summary": ""}
{"Disease Name": "Segmental progressive overgrowth syndrome with fibroadipose hyperplasia", "Disease Definition": "A rare PIK3CA-related overgrowth syndrome disease characterized by segmental and progressive overgrowth, predominantly involving the adipose tissue, or a mixture of adipose and fibrous tissue, with variable involvement of subcutaneous and muscular tissue, as well as skeletal overgrowth. Overgrowth severity and range is highly variable, although frequently it is asymmetric and disproportionate, it affects lower extremities more than the upper ones, and progresses in a distal to proximal pattern. Congenital overgrowth is typically associated.", "ORPHA ID": 314662, "Summary": ""}
{"Disease Name": "Seizures-intellectual disability due to hydroxylysinuria syndrome", "Disease Definition": "A rare inborn error of metabolism characterized by infantile onset of global developmental delay, severe intellectual disability, seizures, and movement disorder (including tremor, hyperkinesia, and myoclonus), associated with excessive excretion of hydroxylysine in urine. There have been no further descriptions in the literature since 1970.", "ORPHA ID": 79156, "Summary": ""}
{"Disease Name": "Seizures-scoliosis-macrocephaly syndrome", "Disease Definition": "Seizures-scoliosis-macrocephaly syndrome is a rare, genetic neurometabolic disorder characterized by seizures, macrocephaly, delayed motor milestones, moderate intellectual disability, scoliosis with no exostoses, muscular hypotonia present since birth, as well as renal dysfunction. Coarse facial features (including hypertelorism and long hypoplastic philtrum) and bilateral cryptorchidism (in males) are also commonly reported. Additional manifestations include abnormal gastrointestinal motility (resulting in constipation, diarrhea, gastroesophageal reflux and dysphagia), gait disturbances, strabismus and ventricular septal defects.", "ORPHA ID": 466926, "Summary": ""}
{"Disease Name": "Selective IgM deficiency", "Disease Definition": "A rare primary immunodeficiency characterized by recurrent and/or invasive bacterial, viral, and fungal infections, associated with low to absent blood IgM levels, while IgG, IgG subclasses, and IgA levels, as well as IgG antibody response to vaccinations, are normal. Patients may also present allergic diatheses, and the prevalence of autoimmune diseases is increased.", "ORPHA ID": 331235, "Summary": ""}
{"Disease Name": "Self-healing papular mucinosis", "Disease Definition": "Self-healing papular mucinosis is a rare form of localized lichen myxedematosus (see this term) occurring primarily in children and characterized by the development of mucinous papules on various parts of the body (face, neck, trunk, and limbs) that resolve spontaneously within some weeks to months. Systemic symptoms can be observed such as fever, arthralgias and weakness.", "ORPHA ID": 90397, "Summary": ""}
{"Disease Name": "Self-improving collodion baby", "Disease Definition": "Self-healing collodion baby (SHCB) is a minor variant of autosomal recessive congenital ichthyosis (ARCI; see this term) characterized by the presence of a collodion membrane at birth that heals within the first weeks of life.", "ORPHA ID": 281122, "Summary": "Epidemiology\nThe exact prevalence is unknown. Approximately 25 cases have been reported in the literature.\nClinical description\nAffected babies are born in a collodion membrane. They also display ectropion and eclabium and a limited joint mobility. After the shedding of the membrane, patients present with mild scaling.\nEtiology\nSCHB is due to mutations in the TGM1, ALOXE3 or ALOX12B genes encoding respectively transglutaminase 1, involved in the cornification of the stratum corneum, and arachidonate 3 and 12(R) lipoxygenases involved in lipid metabolism. Transmission is autosomal recessive.\n\n                            Last update: \n                            January 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Juliette MAZEREEUW-HAUTIER"}
{"Disease Name": "Self-improving dystrophic epidermolysis bullosa", "Disease Definition": "A rare dystrophic epidermolysis bullosa (DEB) characterized by generalized blistering at birth that usually regresses within the first 6 to 24 months of life.", "ORPHA ID": 79411, "Summary": "Epidemiology\nPrevalence is unknown. To date, 52 cases have been reported.\nClinical description\nThe disease usually manifests at birth, or soon after. Skin blisters generally affect the whole body. Blisters can also affect the oral cavity. Healing of blisters is associated with mild, mostly atrophic, scarring and milia formation. Disease activity usually ceases within the first 6 to 24 months of life, although there are a few cases with continued blistering past age 3 years. Nail dystrophy and some degree of skin fragility can persist in adulthood. Ultrastructurally, the presence in basal keratinocytes of peculiar cytoplasmic inclusions, known as stellate bodies, filled with unsecreted procollagen VII, is typical of the disease.\nEtiology\nThe disorder is caused by mutations within the type VII collagen gene (COL7A1; 3p21.31). Mutations in this gene lead to reduced amounts or an alteration in function of collagen VII. This impairs its assembly into anchoring fibrils that anchor the basement membrane to the underlying dermis.\nDiagnostic methods\nDiagnosis is based on identification of granular intraepidermal type VII collagen by immunofluorescence mapping and electron-dense stellate bodies on ultrastructural examination. Genetic testing can confirm diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes other types of epidermolysis bullosa.\nAntenatal diagnosis\nBecause of the mild course of the disease, antenatal diagnosis is usually not required.\nGenetic counseling\nGenetic counseling will depend on the mode of inheritance which can be autosomal dominant or recessive.\nManagement and treatment\nTreatment is symptomatic with wound care to prevent secondary infection and reduce scarring.\nPrognosis\nOverall the prognosis is good.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Carmen SALAVASTRU | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Self-limited childhood occipital epilepsy", "Disease Definition": "Benign occipital epilepsy is a rare, genetic neurological disorder characterized by visual seizures and occipital epileptiform paroxysms reactive to ocular opening which present in infancy to mid-adolescence. Vomiting, tonic eye deviation and impairment of consciousness are typically associated with the Panayiotopoulos type, while visual hallucinations, ictal blindness and post-ictal headache are commonly observed in the Gastaut type. Electroencephalographic findings in both types are similar and include bilateral, synchronous, high voltage spike-wave complexes in a normal background activity located predominantly in the occipital lobes.", "ORPHA ID": 25968, "Summary": ""}
{"Disease Name": "Self-limited epilepsy with autonomic seizures", "Disease Definition": "Benign childhood occipital epilepsy, Panayiotopoulos type is a rare, genetic neurological disorder characterized by late infancy to early-adolescence onset of prolonged, nocturnal seizures which begin with autonomic features (e.g. vomiting, pallor, sweating) and associate tonic eye deviation, impairment of consciousness and may evolve to a hemi-clonic or generalized convulsion. Autonomic status epilepticus may be the only clinical event in some cases.", "ORPHA ID": 98815, "Summary": ""}
{"Disease Name": "Self-limited epilepsy with centrotemporal spikes", "Disease Definition": "Rolandic epilepsy (RE) is a focal childhood epilepsy characterized by seizures consisting of unilateral facial sensory-motor symptoms, with electroencephalogram (EEG) showing sharp biphasic waves over the rolandic region. It is an age-related epilepsy, with excellent outcome.", "ORPHA ID": 1945, "Summary": "Epidemiology\nRE is the most common childhood epilepsy and accounts for 8-25% of all childhood epilepsies. Its incidence has been estimated to be approximately 1/5,000 in children within 15 years.\nClinical description\nOnset is between 3 and 12 years, in otherwise normal children (peak of onset is 5-8 years). Seizures typically occur during sleep or drowsy states; they are brief with unilateral sensorimotor (such as numbness, tingling, drooling) that involves pharynx, tongue, face, lips and sometimes hand. Speech arrest often occurs, while comprehension is preserved. Seizures may alternate from one side to the other and may become generalized. Longer attacks can be followed by post-ictal hemiplegia. Some children may have selective neuropsychological impairment affecting language, attention, visuomotor skills and behavior. They usually do not outlast the period of active seizures. Seizure remission occurs within 2-4 years from the onset. The majority of patients have <10 seizures and 10-20% have a single seizure.\nEtiology\nEtiology of RE is still unknown. There is probably a genetic predisposition: an increased rate of RE, febrile seizures, and epilepsy-aphasia spectrum disorders were found among relatives. Pathogenesis seems to be related with the critical and vulnerable phase of brain maturation.\nDiagnostic methods\nDiagnosis of RE relies on the clinical features and on EEG findings that show slow, diphasic, high voltage, centrotemporal spikes, activated by sleep. Brain magnetic resonance imaging (MRI) is normal.\nDifferential diagnosis\nDifferential diagnosis includes other idiopathic focal childhood epilepsies (benign childhood occipital epilepsy, Panayiotopoulos type and Gastaut type. Other etiologies causing similar symptoms are excluded with brain MRI.\nGenetic counseling\nAutosomal dominant transmission has been reported in some cases.\nManagement and treatment\nThe majority of patients, who have a single or few seizures, do not require treatment. Differently, patients with frequent seizures (10-20%) may need treatment for a short time. In such cases, carbamazepine or valproate are preferred even if, in rare cases, carbamazepine may have a paradoxical effect.\nPrognosis\nPrognosis of RE is favorable since nearly 90% of patients remit before puberty. In rare cases (<1%), RE may evolve to atypical RE with linguistic, behavioral and neuropsychological deficits. An aggressive treatment with steroids, in these cases might change the evolution of the disease and a remission of neuropsychological deficits might be seen.\n\n                            Last update: \n                            May 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Nicola SPECCHIO  - Dr Marina TRIVISANO"}
{"Disease Name": "Self-limited infantile epilepsy", "Disease Definition": "Benign familial infantile epilepsy (BFIE) is a genetic epileptic syndrome characterized by the occurrence of afebrile repeated seizures in healthy infants, between the third and eighth month of life.", "ORPHA ID": 306, "Summary": "Epidemiology\nAlthough BFIE cases have been reported worldwide, prevalence and incidence remain unknown. In an Argentinian case series, BFIE have been listed as the third most common type of epilepsy in the first two years of life.\nClinical description\nSeizures usually occur between 3 to 8 months of life, with clusters (8-10 a day) of repeated and brief episodes (2-5 minutes) over a few days. They are usually focal but can sometimes become generalized. Patients present with motor arrest, unresponsiveness, head and/or eye deviation to one side, staring, fluttering of eyelids, grunting, cyanosis, diffuse hypertonia and unilateral or bilateral clonic jerks of the limbs. During the interictal period, patients regain full consciousness and activity. Psychomotor development is normal. A family history of the same epilepsy is a constant finding. A syndrome called familial infantile convulsions and choreoathetosis (ICCA; see this term) has been observed in which BFIE patients present in childhood and/or adolescence with choreoathetotic dyskinetic attacks occurring spontaneously or following diverse stimuli (e.g. exercise, stress). In some rare cases, BFIE has been associated with familial or sporadic hemiplegic migraine.\nEtiology\nBFIE is a genetically heterogeneous disease. In the majority of cases, mutations in the proline-rich transmembrane protein 2 (PRRT2) gene located at 16p11.2 have been found. This gene encodes a membrane protein that interacts with the presynaptic protein SNAP-25. Mutations have also been found in the SCN2A gene (2q24.3) encoding the brain sodium channel NaV1.2 and rarely in the KCNQ2 (20q13.33) and KCNQ3 (8q24) genes both encoding potassium channels. Additionally, three other chromosomal loci have been identified that are mapped to chromosome 19q, 16p and 1p.\nDiagnostic methods\nFamily history can orient the diagnosis which is based on electroencephalography (EEG) and video recordings. Ictal EEG shows that partial seizures originate from the parietal-occipital region and that the side of the hemisphere involved can vary between episodes. Seizures can sometimes spread and involve the entire brain. During a cluster of seizures, postictal EEG shows lateralized occipito-parietal delta waves and spikes. Outside the cluster, waking and sleeping interictal EEG is normal. Interictal neurological examination and brain imaging (brain CT and/or MRI) are normal. Genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes benign familial neonatal-infantile seizures (see this term), an epileptic syndrome with an intermediate onset between the neonatal and infantile age that shares overlapping clinical characteristics with BFIE and that is mainly due to mutations in the SCN2A gene. Other differential diagnoses are benign non-familial infantile seizures, benign infantile seizures associated with mild gastroenteritis and benign infantile focal epilepsy with midline spikes and waves during sleep (BIMSE) (see these terms).\nGenetic counseling\nBFIE is transmitted as an autosomal dominant trait with incomplete penetrance.\nManagement and treatment\nWith anti-epileptic treatment (e.g. carbamazepine, valproate, phenobarbital), symptoms quickly disappear and no other type of epilepsy has been reported to reappear. In patients with a clear familial history the treatment can be interrupted within a few months.\nPrognosis\nPrognosis is good. Seizures normally disappear after the first year of life and patients do not display any neurological sequelae.\n\n                            Last update: \n                            May 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Federico VIGEVANO"}
{"Disease Name": "Self-limited neonatal epilepsy", "Disease Definition": "Benign familial neonatal epilepsy (BFNE) is a rare genetic epilepsy syndrome characterized by the occurrence of afebrile seizures in otherwise healthy newborns with onset in the first few days of life.", "ORPHA ID": 1949, "Summary": "Epidemiology\nPrevalence is currently unknown since this disorder is possibly overlooked. About 100 families have been reported to date.\nClinical description\nSeizure onset is usually between the second and the eighth day of life, in otherwise healthy newborns. Seizures are mostly focal involving alternatively both sides of the body and apnea is frequently associated. Seizures can be isolated or in clusters, are generally brief and last 1-2 minutes. However, they can be very frequent, occurring up to 20 times a day, and may evolve into status epilepticus. Seizures can occur during wakefulness and/or sleep, and are of a mixed type, starting with tonic posture and apnea, and often progressing to clonic movements and motor automatisms. During the interictal period, neonates are neurologically normal, although some degree of sedation can be seen in response to anti-epileptic medications. Although most patients do receive antiepileptic treatment in the neonatal period, seizures have been shown to remit spontaneously after the first months of life, and are usually not seen after the first year of life. However, about 10 to 15% of patients have febrile or afebrile seizures later in childhood. Subsequent psychomotor development is normal.\nEtiology\nBFNE is a genetically heterogeneous disorder due to mutations in the KCNQ2 (20q13.33) and KCNQ3 (8q24) genes that both code for voltage-gated potassium channel subunits. Mutations in KCNQ2 are also responsible for KCNQ2-related epileptic encephalopathy, a severe form of neonatal epilepsy.\nDiagnostic methods\nElectroclinical events are suggestive of the disorder. Asymmetric tonic posturing associated with apnea and followed by focal or bilateral clonic jerking is the typical seizure type. In BFNE, neonates are neurologically normal and neurocognitive development is normal. Ictal electroencephalogram (EEG) may show focal interictal abnormalities, mainly over the central regions, but otherwise the EEG background is normal. The diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes benign familial neonatal-infantile seizures and benign familial infantile epilepsy.\nAntenatal diagnosis\nPrenatal diagnosis is possible if the disease-causing mutation has already been identified in the family.\nGenetic counseling\nTransmission is autosomal dominant with incomplete penetrance. Genetic counseling should be offered to affected families informing them of the 50% risk the offspring has of inheriting the disease-causing mutation and therefore being affected with the disorder. Rare cases are due to de novo mutations.\nManagement and treatment\nThe use of anticonvulsant therapy (e.g. phenobarbital, phenytoin, valproate, carbamazepine) is needed in most cases to stop seizures in the neonatal period, particularly in cases with very frequent seizures or status epilepticus. Usually, patients require treatment for the first 6-12 months of life. However, it is important for clinicians and family to be aware that some patients require treatment beyond 12 months of age.\nPrognosis\nPrognosis is good. Seizures normally disappear during the first year of life and patients do not display any neurological sequelae. Later seizures have been reported, including occasional febrile seizures and idiopathic epilepsy syndromes in childhood, in particular Rolandic epilepsy.\n\n                            Last update: \n                            July 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Maria-Roberta CILIO"}
{"Disease Name": "Self-limited neonatal-infantile epilepsy", "Disease Definition": "Benign familial neonatal-infantile seizures (BFNIS) is a benign familial epilepsy syndrome with an intermediate phenotype between benign familial neonatal seizures (BFNS) and benign familial infantile seizures (BFIS; see these terms). So far, this syndrome has been described in multiple members of 10 families. Age of onset in these BFNIS families varied from 2 days to 6 months, with spontaneous resolution in most cases before the age of 12 months. Like BFNS and BFIS, seizures in BFNIS generally occur in clusters over one or a few days with posterior focal seizure onset. BFNIS is caused by mutations in the SCN2A gene (2q24.3), encoding the voltage-gated sodium channel alpha-subunit Na(V)1.2. Transmission is autosomal dominant.", "ORPHA ID": 140927, "Summary": ""}
{"Disease Name": "Semantic dementia", "Disease Definition": "Semantic dementia (SD) is a form of frontotemporal dementia (FTD; see this term), characterized by the progressive, amodal and profound loss of semantic knowledge (combination of visual associative agnosia, anomia, surface dyslexia or dysgraphia and disrupted comprehension of word meaning) and behavioral abnormalities, attributable to the degeneration of the anterior temporal lobes.", "ORPHA ID": 100069, "Summary": ""}
{"Disease Name": "Semicircular canal dehiscence syndrome", "Disease Definition": "A rare otorhinolaryngologic disease characterized by the uni- or bilateral dehiscence of the bone(s) overlying the superior (most common), lateral or posterior semicircular canal(s). Patients present audiological (autophony, aural fullness, conductive hearing loss, pulsatile tinnitus) and/or vestibular symptoms (sound or pressure-evoked oscillopsia or vertigo, characteristic vertical-torsional eye movements), depending on which semicircular canal is affected. Posterior SCD syndrome is associated with high-riding jugular bulb and fibrous dysplasia, while lateral SCD syndrome is associated with chronic otitis media and cholesteatoma, with or without audiological and vestibular symptoms.", "ORPHA ID": 420402, "Summary": ""}
{"Disease Name": "Semilobar holoprosencephaly", "Disease Definition": "A form of holoprosencephaly characterized by fusion of the left and right frontal and parietal lobes with only a posterior interhemispheric fissure. Craniofacial features variably include ocular hypotelorism, midline cleft lip (complete or partial) and a flat nose.", "ORPHA ID": 220386, "Summary": ""}
{"Disease Name": "Senior-Boichis syndrome", "Disease Definition": "A rare ciliopathy characterized by the association of nephronophthisis and liver fibrosis. Renal manifestations include chronic renal failure, polyuria, polydipsia, anemia, as well as increased echogenicity on renal ultrasound and interstitial fibrosis and tubular dilation on biopsy. Hepatic involvement manifests as hepatosplenomegaly with extensive fibrosis, destruction of the bile ducts, and cholestasis. Mild psychomotor retardation and ocular symptoms, such as strabismus, nystagmus, retinal degeneration, and anisocoria, have been reported in some patients.", "ORPHA ID": 84081, "Summary": ""}
{"Disease Name": "Senior-Loken syndrome", "Disease Definition": "A rare autosomal recessive oculo-renal ciliopathy characterized by the association of nephronophthisis (NPHP), a chronic kidney disease, with retinal dystrophy.", "ORPHA ID": 3156, "Summary": "Epidemiology\nThe worldwide prevalence is estimated at around 1/1,000,000.\nClinical description\nThe disease typically presents in the first two decades of life as a combination of nephronophthisis (NPH) with retinal degeneration. Depending on the genetic background either the visual disorder or chronic kidney disease determine the clinical picture. NPH typically presents with symptoms such as polyuria, polydipsia, secondary enuresis and anemia. Chronic kidney disease usually slowly progresses to end-stage kidney disease (ESKD). Ocular features include congenital or early-onset severe visual loss due to retinal dystrophy (Leber congenital amaurosis) or a milder phenotype determined by a slowly progressing tube-like restriction of visual fields and night blindness (tapeto-retinal degeneration). Funduscopy reveals various degrees of atrophic and pigmentary retinal alterations. In rare occasions, other additional clinical signs may be observed like liver fibrosis, obesity and neurologic disorders.\nEtiology\nSenior-Loken syndrome (SLS) is a genetically heterogeneous ciliopathy. Mutations in 10 different genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, SDCCAG8, WDR19, CEP164 and TRAF3IP1) have been described. These genes encode for proteins of the primary cilia playing key roles in the development and function of several cell types, including retinal photoreceptor and renal tubular epithelial cells. Epistatic interactions, oligogenic inheritance or modifying alleles have been also suggested to influence the expressivity of the different extrarenal phenotypes.\nDiagnostic methods\nComplete renal (kidney function, urinary analysis and abdominal ultrasound) and ophthalmologic (funduscopy, visual acuity test, refraction defects, color vision test, ocular motility and electroretinogram) evaluations are recommended. Hepatic evaluation to exclude liver fibrosis (liver function and abdominal ultrasounds) and neurological examination for infant patients are also highly recommended. Genetic diagnosis of SLS requires the mutational screening of the implicated genes; deletion of the NPHP1 gene is the most common anomaly.\nDifferential diagnosis\nSLS presents genetic and clinical overlap with other ciliopathies, in particular with isolated NPH and Joubert syndrome related diseases (JSRD) such as Joubert syndrome with oculorenal defect, Bardet-Biedl syndrome (BBS) and Alström syndrome. Physical examination should consider the presence of the main clinical signs of JSRD (hypotonia, ataxia and breathing abnormalities in infants) and BBS (polydactyly and obesity). The phenotypic hallmark of JSRD is the presence of a 'molar tooth sign' (a midbrain-hindbrain malformation) on MRI. Other extrarenal signs to consider are nystagmus, psychomotor and learning delay, diabetes mellitus, deafness, hypogonadism, and/or scoliosis.\nAntenatal diagnosis\nPrenatal diagnosis is feasible only when the genetic mutation has been previously identified in another member of the family.\nGenetic counseling\nTransmission of SLS is autosomal recessive and genetic counseling should be offered to affected families. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of an affected individual are obligate carriers.\nManagement and treatment\nRegular follow up by a pediatric nephrologist is recommended with the monitoring of growth, blood pressure, renal function (including urinary concentration and sodium excretion). In order to delay the progression of renal failure and minimize possible complications, early management of NPH is necessary. So far, there is no specific therapy correcting the genetic or functional defects in NPH. Thus, in the early stage of renal disease the main goal is the correction of water and electrolyte imbalances by replacing the ongoing loss of water and salt. Once end-stage renal disease is reached, dialysis and renal transplantation are the therapies of choice. Disease does not recur after kidney transplantation. No treatment is currently available to prevent the progression of visual loss.\nPrognosis\nPrognosis mostly depends on the progression of the disease in the two affected organs (kidney and eye).\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Valentina CAPONE | ERKNet* - Dr Jens KÖNIG | ERKNet* - Pr Giovanni MONTINI | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Sensorineural deafness with dilated cardiomyopathy", "Disease Definition": "Sensorineural deafness with dilated cardiomyopathy is an extremely rare autosomal dominant syndrome described in two families to date and characterized by moderate to severe sensorineural hearing loss manifesting during childhood, and associated with late-onset dilated cardiomyopathy that generally progresses to heart failure.", "ORPHA ID": 217622, "Summary": ""}
{"Disease Name": "Sensorineural hearing loss-early graying-essential tremor syndrome", "Disease Definition": "A rare genetic disease characterized by the triad of adult-onset moderate to severe bilateral sensorineural hearing loss, premature graying of scalp hair, and essential tremor manifesting as involuntary shaking of the head. Additional pigmentation abnormalities have not been reported in this syndrome.", "ORPHA ID": 66633, "Summary": ""}
{"Disease Name": "Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome", "Disease Definition": "A rare mitochondrial disease characterized by adult onset of the triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. Additional signs and symptoms are highly variable and include myopathy, seizures, and hearing loss, among others. Brain imaging may show cerebellar white matter abnormalities and/or bilateral thalamic lesions.", "ORPHA ID": 70595, "Summary": ""}
{"Disease Name": "Sepsis in premature infants", "Disease Definition": "A rare systemic condition affecting neonates born at less than 37 weeks gestational age and characterized by life-threatening organ dysfunction caused by a dysregulated host response to an infection, which may have been acquired shortly before or during birth (resulting in early-onset neonatal sepsis during the first 72 hours of life), or after birth (leading to late-onset neonatal sepsis between 72 hours and three months). Prematurity constitutes one of the primary risk factors for neonatal sepsis. The clinical picture may develop gradually with signs and symptoms like irritability, lethargy, or poor feeding, or progress rapidly to respiratory distress, fever, hypothermia, hypotension, shock, and multiple organ failure.", "ORPHA ID": 90051, "Summary": ""}
{"Disease Name": "Septate vagina", "Disease Definition": "A rare vaginal malformation characterized by the presence of a complete or incomplete longitudinal or transverse septum in the vagina due to disrupted fusion or canalization of the solid vaginal plate during embryogenesis. Signs and symptoms depend on the type of septum.", "ORPHA ID": 180154, "Summary": ""}
{"Disease Name": "Septo-optic dysplasia spectrum", "Disease Definition": "A rare clinically heterogeneous disorder characterized by the classical triad of optic nerve hypoplasia, pituitary hormone abnormalities and midline brain defects.", "ORPHA ID": 3157, "Summary": "Epidemiology\nIncidence is estimated at 1/10,000 live births.\nClinical description\nSeverity varies and only 30% of patients manifest the complete clinical triad with many patients having associated findings. Some patients present at birth with SOD associated with multiple congenital anomalies, whereas others present during childhood with growth failure and/or visual anomalies (most frequently strabismus or nystagmus). The optic nerve hypoplasia can be uni- or bilateral (57% and 32% of cases, respectively) and significant visual impairment occurs in 23% of patients. Hypopituitarism is present in 62-80% of patients and although growth hormone deficiency (leading to short stature in childhood) is the most frequent endocrine anomaly, additional hormone insufficiencies may develop (thyroid-stimulating, adrenocorticotropic and gonadotropin-releasing hormone deficiencies). Midline brain defects include agenesis of the septum pellucidum (60% of cases) and/or corpus callosum. Associated cortical malformations have also been reported (sometimes referred to as SOD-plus syndrome). Intellectual deficit and neurological manifestations (developmental delay, seizures and cerebral palsy) may be present. Additional findings may include diabetes insipidus, sleep disorders, autism, precocious puberty, obesity, thermoregulatory disturbances, anosmia, sensorineural hearing loss and cardiac and digital anomalies.\nEtiology\nThe majority of SOD cases are sporadic but familial cases have been described. Both homozygous (autosomal recessive transmission) and heterozygous (autosomal dominant transmission) HESX1 mutations (3p21.2-p21.1) have been described in familial cases. Three additional genes have been implicated in associated phenotypes that may be considered as part of the SOD spectrum: SOX2 mutations (3q26.3-q27) associated with anophthalmia/microphthalmia and features of SOD; mutations/duplications in the SOX3 gene (Xq26.3) associated with midline brain anomalies and hypopituitarism (although no eye defects have yet been described); and OTX2 mutations (14q21-q22) associated with hypopituitarism and anterior pituitary hypoplasia, with or without eye defects. Mutations in these genes are detected in < 1% of patients and environmental factors (drug and alcohol abuse, young maternal age) may also be involved.\nDiagnostic methods\nClinical diagnosis requires the presence of at least two of the features of the classical triad and can be confirmed by ophthalmological studies, MRI, and dynamic pituitary function tests. SOD should be suspected in newborns with hypoglycemia, jaundice, microphallus (with or without undescended testes) and nystagmus with or without associated midline abnormalities (such as cleft palate).\nDifferential diagnosis\nDifferential diagnoses include congenital hypopituitarism and holoprosencephaly (see these terms).\nAntenatal diagnosis\nOD may be suspected antenatally by ultrasound and subsequent fetal MRI studies.\nGenetic counseling\nGenetic prenatal diagnosis and genetic counseling may be proposed to families in which the disease-causing mutation has been identified, but caution needs to be exercised in cases with autosomal dominant inheritance as the phenotype and penetrance may be highly variable.\nManagement and treatment\nTreatment is symptomatic and SOD patients should be managed by a multidisciplinary team with regular follow-up. Hormone insufficiencies can be treated with hormone replacement therapy but close monitoring is required as the hormone deficiencies evolve with age. Children may benefit from developmental programs for the visually impaired, as well as from physical, and occupational therapies.\nPrognosis\nPrognosis is variable, depending on the severity of the disease. Early diagnosis is associated with a better outcome as it allows timely management of hormone insufficiencies.\n\n                            Last update: \n                            February 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Mehul DATTANI  - Dr Emma WEBB"}
{"Disease Name": "Septopreoptic holoprosencephaly", "Disease Definition": "A rare subtype of holoprosencephaly characterized by midline fusion limited to the septal and/or preoptic regions of the telencephalon without a significant frontal neocortical fusion. Midline craniofacial malformations are generally mild and include solitary median maxillary incisor and pyriform sinus stenosis. Other reported manifestations include language delay, learning difficulties, and behavioral disorders. Imaging reveals abnormal fornix, absent or hypoplasic anterior corpus callosum, and unpaired anterior cerebral artery.", "ORPHA ID": 280195, "Summary": ""}
{"Disease Name": "Serine biosynthesis pathway deficiency, infantile/juvenile form", "Disease Definition": "A rare inborn error of metabolism comprising 3-phosphoglycerate dehydrogenase deficiency, 3-phosphoserine phosphatase deficiency, and phosphoserine aminotransferase deficiency, and characterized by a phenotypic spectrum ranging from congenital microcephaly, psychomotor retardation, and intractable seizures in the infantile forms to milder juvenile forms with moderate developmental delay and intellectual disability.", "ORPHA ID": 583595, "Summary": ""}
{"Disease Name": "SERKAL syndrome", "Disease Definition": "SERKAL (SEx Reversion, Kidneys, Adrenal and Lung dysgenesis) syndrome is characterised by female to male sex reversal and developmental anomalies of the kidneys, adrenal glands and lungs.", "ORPHA ID": 139466, "Summary": "Epidemiology\nThe syndrome is lethal and has been described in three foetuses.\nEtiology\nIt is caused by homozygous missense mutations in the WNT4 gene.\nGenetic counseling\nIt is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            May 2008"}
{"Disease Name": "Seronegative autoimmune hepatitis", "Disease Definition": "A form of autoimmune hepatitis characterized by the features of classic autoimmune hepatitis (i. e. clinical presentation as acute or chronic cryptogenic hepatitis, interface hepatitis on histological examination, elevated serum aspartate aminotransferase and alanine aminotransferase levels, hypergammaglobulinemia/elevated immunoglobulin G, therapeutic response to corticosteroids) in the absence of serum autoantibodies. Clinical manifestations include fatigue, malaise, arthralgia, jaundice, at later stages also signs of advanced chronic liver disease, such as spider nevi, caput medusae, splenomegaly, ascites, and palmar erythema. Presence of concurrent autoimmune diseases is frequently observed.", "ORPHA ID": 563589, "Summary": ""}
{"Disease Name": "Serotonin syndrome", "Disease Definition": "A rare neurologic disease characterized by an excess of serotonin in the central nervous system, associated with the use of various agents, including selective serotonin reuptake inhibitors (SSRIs) and recreational stimulants.", "ORPHA ID": 43116, "Summary": "Epidemiology\nData regarding prevalence in Europe are not available.\nClinical description\nSerotoninergic syndrome may result in muscle rigidity, myoclonus, agitation, confusion, hyperthermia, hyperreflexia as well as dysautonomic symptoms, with a risk of shock with low peripheral vascular resistance, seizures, coma, rhabdomyolysis and/or disseminated intravascular coagulation (DIC).\nEtiology\nSSRIs and monoamine oxidase inhibitors (MAOIs) may be responsible for this syndrome at toxic but also at therapeutic concentrations. The syndrome may appear: a few hours to a few days after the initiation of the treatment; following simultaneous combination (counter-indication) of MAOIs-A (toloxatone, moclobemide) and SSRIs or successive combination with an excessively short pill-free interval; as the result of drug-drug interactions; or in some cases of acute poisoning. Individual susceptibility and severity of clinical effects may be explained by interindividual pharmacokinetic and pharmacodynamic differences. Various recreational stimulants including amphetamines (especially MDMA), synthetic cathinones, and cannabinoids are also increasingly involved.\nDiagnostic methods\nDiagnosis is based on clinical examination and compatible medical history. Additional investigations (electrocardiogram, laboratory examinations, toxicological analysis, electroencephalogram) are essential as clinical manifestations are not specific. Any acute infectious, neurological or metabolic diseases should be first excluded.\nDifferential diagnosis\nDifferential toxicological diagnoses include neuroleptic malignant syndrome, adrenergic or anticholinergic syndromes as well as alcohol withdrawal syndrome.\nManagement and treatment\nTreatment is mainly supportive, based on sedation (benzodiazepines), mechanical ventilation, and even neuromuscular blockade, if necessary. In case of malignant hyperthermia, body cooling is mandatory. Dantrolene was proved inefficient. Cyproheptadine is the specific antidote for serotonin syndrome.\nPrognosis\nPrognosis is generally good if adequate supportive treatments are administered. However, deaths have been reported, due to multiorgan failure or brain anoxia.\n\n                            Last update: \n                            January 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Bruno MÉGARBANE"}
{"Disease Name": "Serotonin-producing neuroendocrine tumor of pancreas", "Disease Definition": "A rare functioning neuroendocrine tumor of pancreas characterized by a typically well-differentiated neoplasm composed of cells expressing serotonin. Patients may present with atypical carcinoid syndrome with abdominal pain, diarrhea, weight loss, and/or flushing. Carcinoid syndrome is usually present only when there are liver metastases. The tumors tend to be larger than non-functioning tumors and are associated with a poorer prognosis because they are almost always metastatic.", "ORPHA ID": 506090, "Summary": ""}
{"Disease Name": "Serous carcinoma of the corpus uteri", "Disease Definition": "A rare high-grade endometrial carcinoma characterized by diffuse, marked nuclear pleomorphism, typically exhibiting complex papillary and/or glandular growth patterns and showing abnormal p53 and diffuse p16 immunohistochemistry. The tumor typically arises in atrophic endometrium or in an endometrial polyp. Most patients present with postmenopausal bleeding. Extrauterine metastasis is present in 40-50% of surgically staged cases, most frequently involving lymph nodes or peritoneal sites and omentum. Patients with extrauterine spread have poor outcomes, while endometrium-limited carcinoma has a better prognosis.", "ORPHA ID": 213726, "Summary": ""}
{"Disease Name": "Serous cystadenocarcinoma of pancreas", "Disease Definition": "A very rare, malignant, epithelial tumor of the pancreas composed of cystic structures lined by glycogen-rich clear cells, associated with local invasiveness often involving the spleen, duodenum and/or stomach and metastatic spread to the liver, peritoneum and/or lymph nodes. Presenting symptoms are variable and usually non-specific and include abdominal and/or flank pain, palpable abdominal mass, upper gastrointestinal bleeding, jaundice or abnormal serum liver enzymes, vomiting, anorexia and/or weight loss.", "ORPHA ID": 424073, "Summary": ""}
{"Disease Name": "Serpiginous choroiditis", "Disease Definition": "A rare non-infectious posterior uveitis characterized by usually bilateral, chronic, progressive, recurrent inflammation of the choroid, retinal pigment epithelium, and choriocapillaris. In the classic or peripapillary geographic type of the disease, infiltrates originating in the peripapillary region progress in an irregular serpentine fashion centrifugally and resolve spontaneously after several weeks, leaving atrophic scars. Multiple recurrences, often with months to years of quiescence in between, result in progressive visual loss in one or both eyes.", "ORPHA ID": 35686, "Summary": ""}
{"Disease Name": "Serrated polyposis syndrome", "Disease Definition": "A rare, genetic intestinal disease characterized by the presence of multiple (usually large) hyperplastic/serrated colorectal polyps, usually with a pancolonic distribution. Histology reveals hyperplastic polyps, sessile serrated adenomas (most common), traditional serrated adenomas or mixed polyps. It is associated with an increased personal and familial (first-degree relatives) risk of colorectal cancer.", "ORPHA ID": 157798, "Summary": ""}
{"Disease Name": "SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by microcephaly, severe global developmental delay and intellectual disability, hypotonia, respiratory insufficiency, failure to thrive, and congenital anomalies affecting the skeleton, eyes, and several organ systems. Seizures and hearing loss are sometimes observed. Independent ambulation and meaningful speech are not attained. Common dysmorphic facial features include small forehead, biparietal narrowing, flat face, hypertelorism, arched eyebrows, short, upslanting palpebral fissures, wide nasal bridge, small, upturned nose, forward facing ears, and micrognathia. Brain imaging shows structural abnormalities in all patients.", "ORPHA ID": 597743, "Summary": ""}
{"Disease Name": "Severe achondroplasia-developmental delay-acanthosis nigricans syndrome", "Disease Definition": "Severe achondroplasia-developmental delay-acanthosis nigricans syndrome is characterised by the association of severe achondroplasia with developmental delay and acanthosis nigricans. It has been described in four unrelated individuals. Structural central nervous system anomalies, seizures and hearing loss were also reported, together with bowing of the clavicle, femur, tibia and fibula in some cases. The syndrome is caused by a Lys650Met substitution in the kinase domain of fibroblast growth factor receptor 3 (encoded by the FGFR3 gene; 4p16.3).", "ORPHA ID": 85165, "Summary": ""}
{"Disease Name": "Severe acute respiratory syndrome", "Disease Definition": "A rare pulmonary disease induced by SARS-CoV coronavirus infection, with a reported incubation period varying from 2 to 7 days. Patients present flu-like symptoms, including fever, malaise, myalgia, headache, diarrhoea, and rigors. Dry, nonproductive, cough and dyspnea are frequently reported. Severe cases evolve rapidly, progressing to respiratory distress and failure, requiring intensive care. Mortality rate is 10%. The disease appeared in 2002 in southern China, subsequently spreading in 2003 to 26 countries. Reported human-to-human transmission occurred in Toronto (Canada), Hong Kong Special Administrative Region of China, Chinese Taipei, Singapore, and Hanoi (Viet Nam).", "ORPHA ID": 140896, "Summary": ""}
{"Disease Name": "Severe autosomal recessive macrothrombocytopenia", "Disease Definition": "A rare isolated hereditary giant platelet disorder characterized by severe thrombocytopenia and thrombopathy due to defects in proplatelet formation and platelet activation in homozygous patients. Clinical manifestation are recurrent bleeding episodes including epistaxis, spontaneous hematomas, and menorrhagia.", "ORPHA ID": 438207, "Summary": ""}
{"Disease Name": "Severe Canavan disease", "Disease Definition": "Severe Canavan disease (CD) is a rapidly progressing neurodegenerative disorder characterized by leukodystrophy with macrocephaly, severe developmental delay and hypotonia.", "ORPHA ID": 314911, "Summary": "Epidemiology\nThe disease has been reported worldwide, but is more frequent in Ashkenazi Jewish population. The incidence of the severe form of CD in the non-Jewish population has been estimated at approximately 1:100,000 births. If both parents are of Ashkenazi Jewish descent, the incidence is 1:6,400 to 1:13,500.\nClinical description\nOnset of severe CD is in infancy. Patients have hypotonia, head lag, and macrocephaly. Developmental delay is most frequently noticed between the 3rd and 5th months of life: patients fail to achieve independent sitting, ambulation and speech. The head circumference increases after the age of 6 months and is usually above the 90th percentile by one year of age. With age, hypotonia progresses to spasticity, seizures may occur and optic atrophy is apparent. Children are often irritable and exhibit sleep disturbance. Gastro-esophageal reflux leads to feeding difficulties, requiring nasogastric feeding or permanent feeding gastrostomy.\nEtiology\nCD is caused by mutations in the ASPA gene (17p13.3), coding for the aspartoacylase enzyme, the only enzyme responsible for the deacetylation of N-acetyl-L-aspartic acid (NAA) in the brain. Enzymatic activity is usually totally absent in severe CD. The most frequent mutations found in Ashkenazi Jews are a missense (E285A) and a nonsense (Y231X) mutation (84% and 13.4%, respectively). In the non-Jewish population the mutations are different and more diverse, the most common being the A305E missense mutation.\nDiagnostic methods\nDiagnosis is suspected based on the clinical findings of hypotonia, macrocephaly and head lag. The urine reveals a very high concentration of NAA. Cerebro-spinal fluid and blood also contain high levels of NAA. Brain CT scan or MRI show diffuse white matter degeneration and leukodystrophy progressing with age. Mutation screening can be performed for molecular diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other neurodegenerative disorders such as Alexander disease, Tay-Sachs disease, metachromatic leukodystrophy, and glutaric acidemia type 1 (see these terms). Spongy degeneration of the brain can be observed in Leigh syndrome and glycine encephalopathy (see these terms) or other mitochondrial disorders and viral infections.\nAntenatal diagnosis\nAntenatal diagnosis is feasible by DNA analysis when the proband mutation is known. Preimplantation diagnosis using a single cell mutation analysis is feasible in an at-risk pregnancy. When mutation analysis is not available, determining the concentration of NAA in the amniotic fluid may be used for the diagnosis.\nGenetic counseling\nCD is an autosomal recessively transmitted disease, recurrence risk is 25%. Carrier molecular genetic testing is available in a clinical setting. Ashkenazi Jewish individuals are tested for the most prevalent mutations. For non-Jewish couples, genotype should be determined using molecular diagnostic techniques.\nManagement and treatment\nThere is no curative treatment for severe CD. Management is supportive and relies on feeding assistance, physical therapy to improve the muscular status, antiepileptic drugs and therapies to improve communication skills. Research for gene therapy and enzyme replacement therapy is ongoing.\nPrognosis\nPrognosis is variable but globally poor. Life expectancy is about one decade, although with advances in medical and nursing care, some patients survive into their adolescence or young adulthood. Morbidity is also severe, with a total dependence for daily living activities.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Kimberlee MATALON  - Dr Reuben MATALON"}
{"Disease Name": "Severe combined immunodeficiency due to adenosine deaminase deficiency", "Disease Definition": "Severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency is a form of SCID characterized by profound lymphopenia and very low immunoglobulin levels of all isotypes resulting in severe and recurrent opportunistic infections.", "ORPHA ID": 277, "Summary": "Epidemiology\nSCID due to ADA deficiency accounts for 10-15% of all cases of SCID. Its annual incidence is estimated to be between 1/200,000 and 1/1,000,000 live births. Both males and females are affected.\nClinical description\nSCID due to ADA deficiency has a variable clinical presentation. The most common form presents in infancy with severe and recurrent opportunistic infections (including respiratory tract infections and candidiasis), failure to thrive, and usually results in early death. Ten to 15% of patients have a delayed clinical onset by age 6-24 months, and a smaller percentage have a partial form of ADA deficiency with later onset between ages 4 years and adulthood, both types showing less severe infections and gradual immunologic deterioration. Patients may also present with extraimmune manifestations (including neurodevelopmental deficits, behavioral disorders, sensorineural deafness, and skeletal and hepatic abnormalities) as a result of the systemic nature of ADA expression.\nEtiology\nSCID due to ADA deficiency is caused by mutations in the ADA gene (20q13.11). The extraimmune manifestations are caused by toxic levels of purine metabolites that result from the deficiency of ADA.\nDiagnostic methods\nDiagnosis is based on evidence of low or undetectable ADA activity in erythrocytes in combination with evidence of a marked reduction of T, B and NK cell counts when compared to age-matched healthy controls. Diagnosis can be confirmed by raised levels of dATP and reduced S-adenosyl homocysteine hydrolase (SAHH) activity in red cells and elevated amounts of deoxyadenosine in urine.\nDifferential diagnosis\nDifferential diagnosis includes all forms of SCID.\nAntenatal diagnosis\nPrenatal diagnosis can be carried out through mutation analysis or measurement of enzyme activity in trophoblasts cultured from chorionic villus sampling or in cultured amniocytes.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment is based on allogenic hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy with pegylated adenosine deaminase enzyme or gene therapy by infusion of CD34+ marrow cells that have been transduced with an ADA-containing vector.\nPrognosis\nPrognosis depends on the severity of the disease. Without treatment, SCID due to ADA deficiency that presents in infancy usually results in early death. Survival rates after allogenic hematopoietic stem cell transplantation or gene therapy are high.\n\n                            Last update: \n                            July 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Severe combined immunodeficiency due to complete RAG1/2 deficiency", "Disease Definition": "Severe combined immunodeficiency due to complete RAG1/2 deficiency is a rare, genetic T-B- severe combined immunodeficiency disorder due to null mutations in recombination activating gene (RAG) 1 and/or RAG2 resulting in less than 1% of wild type V(D)J recombination activity. Patients present with neonatal onset of life-threatening, severe, recurrent infections by opportunistic fungal, viral and bacterial micro-organisms, as well as skin rashes, chronic diarrhea, failure to thrive and fever. Immunologic observations include profound T- and B-cell lymphopenia, normal NK counts and low or absent serum immunoglobulins; some patients may have eosinophilia.", "ORPHA ID": 331206, "Summary": ""}
{"Disease Name": "Severe combined immunodeficiency due to CORO1A deficiency", "Disease Definition": "A rare T-B+ severe combined immunodeficiency characterized by profoundly decreased levels of T-cells, normal B-cells, and low immunoglobulin levels. The thymus is present. Patients typically become symptomatic in infancy or early childhood with recurrent infections. Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative syndrome/lymphoma and mucocutaneous-immunodeficiency syndrome have been reported in association. Some patients may show developmental delay, neurocognitive impairment, and behavioral dysfunction (in particular attention deficit-hyperactivity disorder).", "ORPHA ID": 228003, "Summary": ""}
{"Disease Name": "Severe combined immunodeficiency due to CTPS1 deficiency", "Disease Definition": "A rare primary immunodeficiency disorder due to impaired capacity of activated T- and B-cells to proliferate in response to antigen receptor-mediated activation characterized by early-onset, severe, persistent and/or recurrent viral infections due to Epstein-Barr virus (EBV) and Varicella Zoster virus (VZV, including generalized varicella), as well as recurrent sino-pulmonary bacterial infections due to encapsulated pathogens.", "ORPHA ID": 420573, "Summary": ""}
{"Disease Name": "Severe combined immunodeficiency due to DCLRE1C deficiency", "Disease Definition": "Severe combined immunodeficiency (SCID) due to DCLRE1C deficiency is a type of SCID (see this term) characterized by severe and recurrent infections, diarrhea, failure to thrive, and cell sensitivity to ionizing radiation.", "ORPHA ID": 275, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nPatients present with the classical features of SCID such as failure to thrive, severe infections (pneumonia, gastrointestinal infections, sepsis), recurrent or persistent thrush, and chronic diarrhea. Materno-fetal transfusion-associated graft versus host disease is also associated with the disease. Immunological findings include absence of T and B lymphocytes with normal natural killer (NK) cell count.\nEtiology\nSCID due to DCLRE1C deficiency results from null mutations in the  DCLRE1C gene (10p13) that lead to a defect in the V(D)J recombination and thus to an early arrest of both B and T cell maturation.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            March 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "Severe combined immunodeficiency due to DNA-PKcs deficiency", "Disease Definition": "Severe combined immunodeficiency (SCID) due to DNA-PKcs deficiency is an extremely rare type of SCID (see this term) characterized by the classical signs of SCID (severe and recurrent infections, diarrhea, failure to thrive), absence of T and B lymphocytes, and cell sensitivity to ionizing radiation.", "ORPHA ID": 317425, "Summary": ""}
{"Disease Name": "Severe combined immunodeficiency due to FOXN1 deficiency", "Disease Definition": "A rare, genetic, primary immunodeficiency due to a defect in adaptive immunity characterized by the triad of congenital athymia (resulting in severe T-cell immunodeficiency), congenital alopecia totalis and nail dystrophy. Patients present neonatal or infantile-onset, severe, recurrent, life-threatening infections and low or absent circulating T cells. Additional features reported include erythroderma, lymphoadenopathy, diarrhea and failure to thrive.", "ORPHA ID": 169095, "Summary": ""}
{"Disease Name": "Severe combined immunodeficiency due to IKK2 deficiency", "Disease Definition": "A rare, genetic form of primary immunodeficiency characterized by life-threatening bacterial, fungal and viral infections with the onset in infancy, and failure to thrive. Typically, hypogammaglobulinemia or agammaglobulinemia and normal levels of T and B cells are present.", "ORPHA ID": 397787, "Summary": ""}
{"Disease Name": "Severe combined immunodeficiency due to LAT deficiency", "Disease Definition": "A rare severe combined immunodeficiency characterized by T-cell lymphopenia and absent T-cell proliferative responses, and normal B-cell and natural killer cell counts. Patients present in the first months of life with severe recurrent infections, failure to thrive, hematologic autoimmune disorders, and/or lymphoproliferation with splenomegaly.", "ORPHA ID": 504523, "Summary": ""}
{"Disease Name": "Severe combined immunodeficiency due to LCK deficiency", "Disease Definition": "A rare, combined T- and B-cell immunodeficiency characterized by failure to thrive, severe diarrhea, opportunistic infections, and abnormal T-cell differentiation and function due to LCK deficiency, leading to an important risk factor for inflammation and autoimmunity.", "ORPHA ID": 280142, "Summary": ""}
{"Disease Name": "Severe combined immunodeficiency", "Disease Definition": "Severe combined immunodeficiency (SCID) comprises a group of rare monogenic primary immunodeficiency disorders characterized by a lack of functional peripheral T lymphocytes resulting in early-onset severe respiratory infections and failure to thrive. They are classified according to immunological phenotype into SCID with absence of T cells but presence of B cells (T-B+ SCID) or SCID with absence of both (T-B- SCID) (see these terms). Both of these groups include several forms, with or without natural killer (NK) cells.", "ORPHA ID": 183660, "Summary": "Epidemiology\nOverall incidence is estimated at about 1/50,000 live births, with regional differences and higher incidences among populations with a higher consanguinity rate. The disease affects more males because of the X-linked variant (SCID T-B+ due to gamma chain deficiency; see this term) that represents about 30% of SCID cases in Western countries.\nClinical description\nSCID usually presents within the first few months of life with failure to thrive, severe infections (pneumonia, gastrointestinal infections, sepsis), recurrent or persistent thrush, chronic diarrhea, and/or absent lymph nodes. Patients have an increased susceptibility to opportunistic infections (usually in the respiratory tract and the gut) most often due to P. jiroveci, some viruses (e.g. Cytomegalovirus, adenovirus) and fungi. Alopecia and skin rash may be present depending on the form (e.g. SCID due to gamma chain deficiency or SCID due to JAK3 deficiency; see this term). Patients are unable to produce specific antibodies after vaccination or natural infection. They may also present with extraimmune manifestations like neurodevelopmental deficit, sensorineural deafness, and hepatic abnormalities (SCID due to adenosine deaminase (ADA) deficiency;) with sensorineural deafness (reticular dysgenesis).Others may show microcephaly with neurodevelopmental delay (e.g. LIG4 syndrome; see these terms).\nEtiology\nThe X-linked form is caused by mutations of the IL2RG gene (Xq13) encoding the common gamma chain. Mutations in around 15 genes have been identified to date for the other forms of SCID, which all follow an autosomal recessive mode of inheritance.\nDiagnostic methods\nThe diagnosis is based on evidence of lymphopenia and a marked reduction of T-cell counts. In 50% of cases, transplacental passage of maternally-derived T lymphocytes occurs. In this case, the T cell count may be preserved but the circulating T lymphocytes have an activated phenotype (they express the CD45R0 marker while in normal infants they express CD45RA). Levels of circulating B and NK cells may help to better define the underlying cause of SCID which can then be confirmed with genetic testing. Newborn screening for SCID is now available, and is based on the measurement of levels of T-cell receptor excision circles (TRECs) in dried blood spots collected at birth.\nDifferential diagnosis\nDifferential diagnoses include other combined B-cell and T-cell disorders, 22q11.2 deletion syndrome, congenital TORCH infection, X-linked or autosomal recessive agammaglobulinemia, and other forms of hypogammaglobulinemia (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible and can aid in preparation of a bone marrow transplant.\nGenetic counseling\nGenetic counseling should be offered and, if the genetic defect is known, prenatal testing (by chorionic villus sampling) is recommended.\nManagement and treatment\nTreatment is based on use of continuous antimicrobial prophylaxis, immunoglobulin replacement therapy, and strict hygiene measures. However, permanent cure requires immune reconstitution, most often achieved by allogenic hematopoietic stem-cell transplantation (HSCT). Gene therapy has been shown to be effective for patients with ADA deficiency (as well as enzyme replacement therapy) and X-linked SCID.\nPrognosis\nWithout treatment SCID usually results in severe infection and death in children by age of 2. When performed from an HLA-identical sibling, and in the first few months of life, HSCT can result in a greater than 90% long-term survival rate.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Luigi NOTARANGELO"}
{"Disease Name": "Severe congenital hypochromic anemia with ringed sideroblasts", "Disease Definition": "STEAP3/TSAP6-related sideroblastic anemia is a very rare severe non-syndromic hypochromic anemia, which is characterized by transfusion-dependent hypochromic, poorly regenerative anemia, iron overload, resembling non-syndromic sideroblastic anemia (see this term) except for increased erythrocyte protoporphyrin levels.", "ORPHA ID": 300298, "Summary": "Epidemiology\nIt has been reported in 3 siblings to date.\nEtiology\nSTEAP3/TSAP6-related sideroblastic anemia is caused by a nonsense heterozygous mutation in the STEAP3/TSAP6 gene. Transmission is most likely recessive with a low expression allele.\n\n                            Last update: \n                            July 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Clara CAMASCHELLA"}
{"Disease Name": "Severe congenital nemaline myopathy", "Disease Definition": "Severe congenital nemaline myopathy is a severe form of nemaline myopathy (NM; see this term) characterized by severe hypotonia with little spontaneous movement in neonates.", "ORPHA ID": 171430, "Summary": "Epidemiology\nThe annual incidence of NM has been estimated at 1/50,000 live births and the severe congenital form might represent 10-20% of all cases.\nClinical description\nNeonates have sucking and swallowing difficulties, and gastroesophageal reflux, which leads to failure to thrive. Involvement of diaphragm and intercostal muscles contributes to respiratory insufficiency. Cardiomyopathy and arthrogryposis may occur.\nEtiology\nThe ACTA1 (1q42.13) and NEB (2q22) genes are associated with this form of NM.\nGenetic counseling\nNM is transmitted in an autosomal recessive fashion or occurs sporadically.\nPrognosis\nSurvival after infancy is rare.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Monique RYAN"}
{"Disease Name": "Severe congenital neutropenia due to G6PC3 deficiency", "Disease Definition": "Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency is a rare, genetic, primary immunodeficiency disorder characterized by increased susceptibility to recurrent, life-threatening bacterial infections, in association with typically severe neutropenia in peripheral blood and bone marrow and a prominent ectatic superficial vein pattern, resulting from recessively inherited mutations in the G6PC3 gene. Cardiac malformations (e.g. atrial septal defects, patent ductus arteriosus,valvular defects), urogenital anomalies (incl. cryptorchidism), growth and developmental delay, facial dysmorphism (e.g. frontal bossing, upturned nose, malar hypoplasia), and intermittent thrombocytopenia are frequently associated.", "ORPHA ID": 331176, "Summary": ""}
{"Disease Name": "Severe congenital neutropenia due to JAGN1 deficiency", "Disease Definition": "Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency is a rare, genetic, primary immunodeficiency disorder characterized by early-onset, recurrent, severe bacterial infections, granulopoiesis maturation arrest at the promyelocyte/myelocyte stage and markedly reduced absolute neutrophil counts, resulting from recessively inherited mutations in the JAGN1 gene. Mild facial dysmorphism (i.e. triangular face), short stature, failure to thrive, hypothyroidism, developmental delay, pancreatic insufficiency and coarctation of aorta, as well as bone and urogenital abnormalities, may also be associated.", "ORPHA ID": 423384, "Summary": ""}
{"Disease Name": "Severe congenital neutropenia", "Disease Definition": "Severe congenital neutropenia is an immunodeficiency characterized by low levels of granulocytes (< 200/mm3) without an associated lymphocyte deficit.", "ORPHA ID": 42738, "Summary": "Epidemiology\nThe prevalence in the general population is estimated at 1-1.7/333,300. Annual incidence is around 1/250,000 births.\nClinical description\nThis neutropenia leads to repeated bacterial or mycotic infections in various locations, mostly cutaneo-mucous, ear, nose, and throat, and pulmonary. Stomatological signs are almost always present after 2 years of age and are distinguished by erosive gingivitis, hemorrhage and pain, associated with papilla on the tongue and mucous membranes. Infections may be very severe or even lethal. Around 15% of patients evolve to acute leukemia or a myelodysplastic syndrome.\nEtiology\nTo date, mutations in four genes have been implicated in severe congenital neutropenia. These include the neutrophil elastase gene (ELA2), the GFI1 gene, the HAX1 gene and activation genes of Wiskott Aldrich disease (WASP). The combination of these mutations leads to a deficit in the production of neutrophils.\nDiagnostic methods\nThe defining characteristic is cytology showing profound neutropenia associated with monocytosis. An isolated blockage at the promyelocyte stage of the myeloid series associated with eosinophilia and monocytosis is seen on myelogram.\nDifferential diagnosis\nOn the discovery of these features a complete biological assessment should be conducted to rule out several differential diagnoses, particularly lymphocytic immune deficiencies and autoimmune neutropenia.\nAntenatal diagnosis\nPrenatal diagnosis may be offered if the genotype is known.\nGenetic counseling\nThe four mutations are transmitted differently: ELA2 and GFI1 are autosomal dominant, HAX1 is autosomal recessive, and WASP is X-linked recessive. Genetic counseling is essential and should take into account family history and the causal mutation.\nManagement and treatment\nAll febrile episodes or infections should be reviewed by a hospital and treated actively. Prophylactic antibiotics are used to prevent infections. If this is ineffective, hematopoietic growth factors (G-CSF in particular) can correct both neutropenia and the susceptibility to infections and can be administered either in response to infections or continuously. The dose of G-CSF required varies greatly. Continuous high dose G-CSF (more than 20µg/kg/day) encourages the onset of leukemia in the long term and therefore, in cases requiring continuous high dose treatment, bone marrow transplant should be considered.\nPrognosis\nThe prognosis depends heavily on the quality of care and timeliness of treatment of severe infections, but also on the possibility of a bone marrow transplant, particularly in cases with malignant transformation.\n\n                            Last update: \n                            July 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Jean DONADIEU"}
{"Disease Name": "Severe dermatitis-multiple allergies-metabolic wasting syndrome", "Disease Definition": "A rare genetic epidermal disorder characterized by congenital erythroderma with severe psoriasiform dermatitis, ichthyosis, severe palmoplantar keratoderma, yellow keratosis on the hands and feet, elevated immunoglobulin E, multiple food allergies, and metabolic wasting. Other variable features may include hypotrichosis, nail dystrophy, recurrent infections, mild global developmental delay, eosinophillia, nystagmus, growth impairment and cardiac defects.", "ORPHA ID": 369992, "Summary": ""}
{"Disease Name": "Severe disseminated cytomegalovirus infection in immunocompetent patients", "Disease Definition": "A rare viral disease characterized by fulminant cytomegalovirus infection with multiple organ involvement including the brain, lung, liver, and/or heart, among others, and marked constitutional symptoms in immunocompetent patients. The condition is associated with a high case fatality rate.", "ORPHA ID": 35062, "Summary": ""}
{"Disease Name": "Severe early-childhood-onset retinal dystrophy", "Disease Definition": "Severe early childhood onset retinal dystrophy (SECORD) is an inherited retinal dystrophy characterized by a severe congenital night blindness, progressive retinal dystrophy and nystagmus. Best corrected visual acuity can reach 0.3 in the first decade of life and can pertain well into the second decade of life. Blindness is often complete by the age of 30 years.", "ORPHA ID": 364055, "Summary": "Epidemiology\nThe prevalence is hard to predict as many SECORD patients have been previously diagnosed as Leber congenital amaurosis (LCA) patients.\nClinical description\nSECORD occurs during childhood and covers patients with severe congenital night blindness, nystagmus, a significantly reduced visual acuity (less or equal than 0.3) along with a progressive panretinal dystrophy of diverse extent and affection of the macula. The first symptoms can be recognized in the first year of life. Color vision is impaired in saturated and desaturated tests. An overlap with Leber congenital amaurosis (LCA) occurs when patients are characterized by their visual acuity and panretinal dystrophy. However, compared to LCA, the visual function in SECORD is much better, despite the progressive loss of visual function early in the disease that can lead to blindness in the second to third decade of life, depending on the underlying gene and mutation.\nEtiology\nSECORD is genetically heterogeneous, being caused by many genes including those causing LCA (ABCA4 (1p22), ADAMTS18 (16q23), AIPL1 (17p13.1), BEST1 (11q12), CRB1 (1q31.3), CRX (19q13.3), GUCY2D (17p13.1), IMPDH1 (7q31.3-q32), IMPG1 (6q14.2-q15), IMPG2 (3q12.2-q12.3), IQCB1 (3q21.1), KCNJ13 (2q37), LCA5 (6q14), LRAT (4q32.1), MERTK (2q14.1), NMNAT1 (1p36.22), RDH12 (14q24.1), RPE65 (1p31), RPGR (Xp11.4), RPGRIP1 (14q11.2), SPATA7 (14q31.3), TULP1 (6p21.3)). SECORD has however been primarily associated with mutations in RPE65 (2-10% of SECORD patients) and LRAT.\nDiagnostic methods\nDiagnosis of SECORD includes rod and cone responses below or near threshold in electroretinography. Psychophysical testing predicts cone-rod and rod-cone dystrophies. Patients may show a normal appearing fundus at birth but develop a panretinal dystrophy including the macula later in infancy and early childhood. Corresponding alterations of retinal layers are seen with spectral domain optical coherence tomography. A lack of fundus auto fluorescence is observed from early childhood in a subset of patients with RPE65 or LRAT mutations. Goldmann perimetry reveals severe visual field constriction and central scotomata depending on the type of progression. Bone spicules are usually not detected but pigment accumulations develop with the progress of the disease. Molecular diagnosis is performed by using next generation sequencing panel covering the whole sequence of the known reported genes (90% cases). Identified mutations and segregation analysis in the parents is confirmed by Sanger sequencing.\nDifferential diagnosis\nDifferential diagnosis includes LCA, Alström syndrome, autosomal recessive bestrophinopathy, Bardet-Biedl syndrome, achromatopsia, Stargardt disease, Usher syndrome, Senior-Loken syndrome, Saldino-Mainzer syndrome, Joubert syndrome, abetalipoproteinemia, infantile Refsum disease, neonatal adrenoleukodystrophy, Zellweger syndrome and juvenile neuronal ceroid lipofuscinosis.\nGenetic counseling\nSECORD is usually inherited in an autosomal recessive manner but autosomal dominant (CRX, GUCY2D, IMPDH1, IMPG1, IMPG2) and X-linked inheritance have also been observed.\nManagement and treatment\nSECORD is currently incurable and therapies are being investigated, including gene therapy for RPE65, ABCA4 and MERTK. Retinoid supplementation therapy (9-cis-retinoid) is used for patients with mutations in RPE65 and LRAT. Treatment is supportive and includes correction of refractive error and use of low-vision aids.\nPrognosis\nThe visual performance in bright light permits attendance at regular schools during the elementary years. Due to the genetic heterogeneity, a broad spectrum of progression exists that does not correlate with specific mutations. Useful visual function is frequently preserved beyond the second decade of life and a number of patients retain residual islands of peripheral vision, albeit considerably compromised, in the third decade of life.\n\n                            Last update: \n                            December 2017\n\n\n                            - Expert reviewer(s): \n                            Pr Birgit LORENZ  - Dr Markus PREISING"}
{"Disease Name": "Severe early-onset axonal neuropathy due to MFN2 deficiency", "Disease Definition": "Severe early-onset axonal neuropathy due to MFN2 deficiency is a rare axonal hereditary motor and sensory neuropathy characterized by early onset (<10 years) progressive distal muscle weakness and wasting of the lower limbs and later, to a lesser extent the upper limbs resulting in foot and wrist drop, areflexia, skeletal deformities (kyphoscoliosis, pes cavus with flattening, joint contractures), mild sensory impairment with vibration sense reduced to a greater extent than pain, optic atrophy and hearing loss. Wheelchair dependence by adolescence is usual and respiratory impairment with diaphragmatic paralysis may develop.", "ORPHA ID": 90118, "Summary": ""}
{"Disease Name": "Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency", "Disease Definition": "A rare, genetic form of obesity characterized by severe early-onset obesity, hyperphagia, insulin resistance with hyperinsulinemia, reduced adult final height, delayed speech and language development and a tendency for social isolation and aggressive behavior.", "ORPHA ID": 329249, "Summary": ""}
{"Disease Name": "Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency", "Disease Definition": "A rare, genetic interstitial lung disease characterized by accumulation of lipoproteins in the pulmonary alveoli leading to restrictive lung disease and respiratory failure. Patients present with dyspnea, tachypnea, cough, failure to thrive, and digital clubbing. Liver disease have been described in some cases including hepatomegaly, steatosis, fibrosis or cirrhosis.", "ORPHA ID": 440427, "Summary": ""}
{"Disease Name": "Severe generalized junctional epidermolysis bullosa", "Disease Definition": "A severe form of junctional epidermolysis bullosa (JEB) characterized by blisters and extensive erosions, localized to the skin and mucous membranes.", "ORPHA ID": 79404, "Summary": "Epidemiology\nPrevalence at birth is estimated to range between 1/200,000-2,500,000 worldwide. According to data from U.S. and Italian EB registries, about 20% of patients with JEB have the severe type.\nClinical description\nThe extreme severity of this condition is apparent at birth. Bullae present spontaneously even with a gentle touch, with an onset within the first several months to one to two years of life. After the eruption, blisters lose their roof and remain visible as erosions that do not heal. Exuberant granulation tissue is a characteristic manifestation which arises on such eroded epithelium and may involve the skin (around nail folds, in a mask-like distribution on the face, and at sites of friction, such as shoulders and buttocks), and the upper airways. Involvement of mucous membranes may affect the entire gastrointestinal (GI) tract, genitourinary tract, and respiratory tract to the bronchioles. However, the most significant and frequent mucosal lesions are those in the upper part of the GI and respiratory tracts. The extensive erosions and ulcerations of the oral mucosa severely hamper feeding, and involvement of the laryngotracheal mucosa, manifesting as hoarseness, dyspnea and stridor, may lead to acute respiratory failure requiring tracheostomy. Other consistent features include nail anomalies with paronychia, several degrees of onychodystrophy and nail shedding. Dental abnormalities, when survival enables their observation, include regularly marked hypoplasia or complete absence of enamel. Frequent ocular lesions comprise corneal blisters, erosions and scarring, and ectropion formation. Failure to thrive is an almost constant finding, and multifactorial anemia is also common.\nEtiology\nSevere JEB is caused by mutations in one of the three laminin-332 coding genes: LAMA3 (18q11.2), LAMB3 (1q32) and LAMC2 (1q25-q31). In most cases, null mutations are found on both alleles of the causative gene.\nDiagnostic methods\nIn addition to the finding of a cleavage plane located within the lamina lucida of the cutaneous basement membrane zone, a negative immunofluorescence staining for laminin-332 is typical of severe JEB. However, in rare cases the staining is strongly reduced and thus does not enable differentiation of severe JEB from intermediate JEB. In these cases, genetic testing, showing null mutations in one of the three genes encoding laminin-332, is necessary to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other types epidermolysis bullosa, in particular congenital autoimmune bullous diseases.\nAntenatal diagnosis\nPrenatal diagnosis should always be recommended and diseases-causing pathogenic variants should be disclosed in advance.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nThe approach is multidisciplinary with neonatal pathology units for severely affected patients, antibiotics for pulmonary infections, local antisepsis for slow-healing lesions and advanced dressing for the treatment of ulcers. Nutritional support is mandatory.\nPrognosis\nPrognosis is poor and the most severe JEB patients die in the first few years of life, with the major causes of death being failure to thrive, respiratory failure, sepsis, and pneumonia. Some rare patients with generalized cutaneous and internal disease reach the age of 10-15 years. In addition, squamous cell carcinomas may arise in a minority of severe JEB patients (4.5% according to data from the U.S. National EB Registry).\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Michela BRENA | ERN-Skin* - Dr Sophie GUEZ | ERN-Skin* - Dr Gianluca TADINI | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability characterized by infantile onset of global developmental delay, severe intellectual disability, growth deficiency, microcephaly, strabismus, blue-gray sclerae, and extensive Mongolian spots. Some patients also present with epilepsy. Brain imaging may demonstrate variable abnormalities including cerebral atrophy, thin corpus callosum, ventriculomegaly, or arachnoid cysts.", "ORPHA ID": 488627, "Summary": ""}
{"Disease Name": "Severe hemophilia A", "Disease Definition": "A severe form of hemophilia A characterized by a large deficiency of factor VIII (biological activity <1 IU/dL) leading to frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries, or following trauma, surgery or tooth extraction. It primarily affects males but may also be observed in female carriers of disease-causing mutations.", "ORPHA ID": 169802, "Summary": ""}
{"Disease Name": "Severe hemophilia B", "Disease Definition": "A severe form of hemophilia B characterized by a large deficiency of factor IX (biological activity <1 IU/dL) leading to frequent spontaneous hemorrhage and abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction. It primarily affects males but may also be observed in female carriers of disease-causing mutations.", "ORPHA ID": 169793, "Summary": ""}
{"Disease Name": "Severe hereditary thrombophilia due to congenital protein C deficiency", "Disease Definition": "A rare inherited coagulation disorder characterized by deep venous thrombosis symptoms due to reduced synthesis and/or activity levels of protein C.", "ORPHA ID": 745, "Summary": "Epidemiology\nPrevalence of severe protein C deficiency (homozygous or compound heterozygous forms) is estimated at 1/ 500,000. Partial deficiencies (heterozygous forms) are much more frequent (1/200-1/500). Men and women are equally affected.\nClinical description\nPatients with undetectable protein C levels usually manifest the disease several hours to days after birth, with purpura fulminans (see this term) or massive venous thrombosis. Purpura fulminans is a life-threatening condition involving severe clotting throughout the body and causing necrosis of tissues. Patients with low but detectable protein C levels have milder symptoms generally similar to those of heterozygous individuals. Usually, patients with heterozygous protein C deficiency are asymptomatic until adulthood. Thrombotic episodes are mainly provoked by other risk factors such as surgery, pregnancy or immobilization. Deep vein thrombosis of the lower limbs with or without pulmonary embolism is the most common manifestation of the disease. Cerebral or mesenteric venous thrombosis may also occur.\nEtiology\nProtein C deficiency is caused by mutations in the PROC (2q13-q14) gene controlling the production of protein C. Transmission is autosomal recessive.\nDiagnostic methods\nDiagnosis is based on the measurement of protein C levels. Protein C activity levels range from 0 to 30% in case of severe deficiencies and from 30 to 70% in case of partial defects. There are two biological forms of the disease. Type I deficiency is characterized by concordant reduction in protein C activity and antigen. In type II deficiency, protein C activity is reduced but protein C antigen is normal. Molecular testing is available, but is unnecessary for diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other inherited thrombophilias including antithrombin and protein S deficiencies (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is feasible for families with affected children and is based on the identification of the causal mutation on DNA obtained by chorionic villus sampling.\nManagement and treatment\nAdministration of protein C concentrates or fresh frozen plasma is critical for the initial treatment of neonatal purpura fulminans. Surgical procedures may be required for excision of thrombotic lesions. Patients with thromboses are treated with anticoagulant therapy (heparin, warfarin). Attention should be paid to the risk of coumarin-induced skin necrosis. Preventive treatment is indicated in cases with a strong positive family history of thrombotic diseases, during the peripartum period or perioperatively.\nPrognosis\nPrognosis may be severe in homozygous or compound heterozygous patients. Prognosis is good for heterozygous patients. With adequate treatment and monitoring, the risk of thromboembolic disease is markedly reduced. Mortality may result from pulmonary embolism.\n\n                            Last update: \n                            November 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND"}
{"Disease Name": "Severe hereditary thrombophilia due to congenital protein S deficiency", "Disease Definition": "An inherited coagulation disorder characterized by recurrent venous thrombosis symptoms due to reduced synthesis and/or activity levels of protein S.", "ORPHA ID": 743, "Summary": "Epidemiology\nPrevalence of partial protein S deficiency (heterozygous individuals) is estimated at 0.16-0.21% in the general population. Prevalence of severe protein S deficiency (homozygous or compound heterozygous individuals) is unknown but is probably comparable to that of severe protein C deficiency which is estimated at 1/500,000. Men and women are equally affected.\nClinical description\nIn severe protein S deficiency, the disease manifests several hours to days after birth, with purpura fulminans (see this term) or massive venous thrombosis. Purpura fulminans is a life-threatening condition involving severe clotting throughout the body and causing necrosis of tissues. Severe retinopathy of prematurity (ROP) (see this term) may also occur. Heterozygous patients are usually asymptomatic until adulthood. Thrombotic episodes are mainly provoked by other risk factors such as surgery, pregnancy or immobilization. Deep vein thrombosis of the lower limbs with or without pulmonary embolism is the most common manifestation of the disease. Arterial thrombosis may also occur.\nEtiology\nProtein S deficiency is caused by mutations in the PROS1 gene (3q11-q11.2).\nDiagnostic methods\nDiagnosis is based on the measurement of protein S antigen levels (total protein S or free protein S) and anticoagulant activity. There are three biological forms. Type I and type III are quantitative deficiencies with low free antigen levels (with normal total protein S levels in type III and decreased total protein S levels in type I deficiency). Type II is a qualitative deficiency with normal total and free protein S levels. Molecular testing is available, but is unnecessary for diagnosis.\nDifferential diagnosis\nDifferential diagnoses include other inherited thrombophilias including antithrombin and protein C deficiencies (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is feasible for families with affected children and is based on the identification of the causal mutation on DNA obtained by chorionic villus sampling.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nAdministration of fresh frozen plasma may be required for the initial treatment of neonatal purpura fulminans. Surgical procedures may be required for excision of thrombotic lesions. Patients with thromboses are treated with anticoagulant therapy (heparin, wafarin). Attention should be paid to the risk of coumarin-induced skin necrosis. Preventive treatment is indicated in cases with strong positive family history of thrombotic diseases, during the peripartum period or perioperatively.\nPrognosis\nPrognosis is severe in homozygous or compound heterozygous patients. Prognosis is good for heterozygous patients. With adequate treatment and monitoring, the risk of thromboembolic disease is markedly reduced. Mortality may result from pulmonary embolism.\n\n                            Last update: \n                            November 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND"}
{"Disease Name": "Severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome", "Disease Definition": "Severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome is a rare, genetic, non-dystrophic congenital myopathy disorder characterized by a neonatal-onset of severe generalized hypotonia associated with mild psychomotor delay, congenital strabismus with abducens nerve palsy, and atrial and/or ventricular septal defects. Cryptorchidism is commonly reported in male patients and muscle biopsy typically reveals increased variability in muscle fiber size.", "ORPHA ID": 467176, "Summary": ""}
{"Disease Name": "Severe immune-mediated enteropathy", "Disease Definition": "Severe-immune mediated enteropathy describes a variety of intestinal disorders that can range from a serious, early-onset systemic disease (IPEX; see this term) to a mild isolated gastrointestinal disease. In children it manifests with severe diarrhea and dehydration in the presence of characteristic antibodies (anti-enterocyte and anti-goblet cell) and in adults with chronic diarrhea, malabsorption and weight loss.", "ORPHA ID": 94075, "Summary": ""}
{"Disease Name": "Severe intellectual disability and progressive spastic paraplegia", "Disease Definition": "A rare complex hereditary spastic paraplegia characterized by an early onset hypotonia that progresses to spasticity, global developmental delay, severe intellectual disability and speech impairment, microcephaly, short stature and dysmorphic features. Patients often become non-ambulatory, and some develop seizures and stereotypic laughter.", "ORPHA ID": 280763, "Summary": ""}
{"Disease Name": "Severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by congenital microcephaly, severe intellectual disability, hypertonia at birth lessening with age, ataxia, and specific dysmorphic facial features including hirsutism, low anterior hairline and bitemporal narrowing, arched, thick, and medially sparse eyebrows, long eyelashes, lateral upper eyelids swelling and a skin fold partially covering the inferior eyelids, low-set posteriorly rotated protruding ears, anteverted nares, and a full lower lip. Brain imaging shows partial to almost complete agenesis of the corpus callosum and variable degrees of cerebellar hypoplasia.", "ORPHA ID": 466688, "Summary": ""}
{"Disease Name": "Severe intellectual disability-epilepsy-anal anomalies-distal phalangeal hypoplasia", "Disease Definition": "Severe intellectual disability-epilepsy-anal anomalies-distal phalangeal hypoplasia is characterised by severe intellectual deficit, epilepsy, hypoplasia of the terminal phalanges, and an anteriorly displaced anus. It has been described in two sisters born to consanguineous parents. The syndrome is transmitted as an autosomal recessive trait and appears to be caused by anomalies in to chromosome regions, one localised to chromosome 1 and the other to chromosome 14.", "ORPHA ID": 94066, "Summary": ""}
{"Disease Name": "Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder characterized by global development delay with very limited or absent speech and language, severe intellectual disability, long slender fingers, ocular abnormalities (typically strabismus or hypermetropia), and facial dysmorphism that includes a grimacing facial expression, a tubular-shaped nose with a prominent, broad base and tip, and other variable features, such as broad forehead, hypertelorism, deep-set eyes, narrow palpebral fissures, short philtrum and/or broad mouth.", "ORPHA ID": 363686, "Summary": ""}
{"Disease Name": "Severe intellectual disability-progressive postnatal microcephaly-midline stereotypic hand movements syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability characterized by severe intellectual disability, non-inherited, progressive, post-natal microcephaly, hypotonia, hyperkinesia, absence of speech, strabismus, and midline stereotypic hand movements (e.g. hand washing/rubbing). Additional features include developmental delay, seizures and behavioral disturbances, such as self injury and unexplained crying episodes.", "ORPHA ID": 397933, "Summary": ""}
{"Disease Name": "Severe intellectual disability-progressive spastic diplegia syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder characterized by intellectual disability, significant motor delay, severe speech impairment, early-onset truncal hypotonia with progressive distal hypertonia/spasticity, microcephaly, and behavioral anomalies (autistic features, aggression or auto-aggressive behavior, sleep disturbances). Variable facial dysmorphism includes broad nasal tip with small alae nasi, long and/or flat philtrum, thin upper lip vermillion. Visual impairment (strabismus, hyperopia, myopia) is commonly associated.", "ORPHA ID": 404473, "Summary": ""}
{"Disease Name": "Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability syndrome characterized by severe intellectual disability with limited or absent speech and language, short stature, acquired microcephaly, kyphoscoliosis or scoliosis, and behavioral disturbances that include hyperactivity, stereotypy and aggressiveness. Facial dysmorphism, that typically includes sloping forehead, mild synophrys, deep-set eyes, strabismus, anteverted large ears, prominent nose and dental malposition, is also characteristic.", "ORPHA ID": 391307, "Summary": ""}
{"Disease Name": "Severe lateral tibial bowing-short stature-mild winged scapula-mild facial dysmorphism syndrome", "Disease Definition": "Severe lateral tibial bowing with short stature is a rare, genetic, primary bent bone dysplasia characterized by significant, uni-/bilateral, lateral tibial bowing localized to the distal two-thirds of the tibia, with respective cortical thickening and thinning of the inner and outer tibial curve, loss of normal trabecular bone, bilateral abnormalities of the tibial epiphyses and growth plates, as well as foot abnormalities, including abnormally high arches. Affected individuals have short stature with absence of other skeletal abnormalities.", "ORPHA ID": 324307, "Summary": ""}
{"Disease Name": "Severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome", "Disease Definition": "A rare, multiple congenital anomalies/dysmorphic syndrome characterized by craniofacial dysmorphism, including microbrachycephaly, sloping forehead, micro/anophthalmia, large ears, prominent nasal root, mild micrognathia, and cleft palate, associated with cerebral palsy with choreoathetoid movements, intellectual disability, dextrocardia and longitudinal folding of plantae pedis. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 1236, "Summary": ""}
{"Disease Name": "Severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome", "Disease Definition": "A rare, genetic, neurological disorder characterized by intrauterine growth retardation, failure to thrive, infantile onset of sensorineural deafness, severe global developmental delay or absent psychomotor development, paraplegia or quadriplegia with dystonia and pyramidal signs, microcephaly, ocular abnormalities (strabismus, optic atrophy), mildly dysmorphic features (deep-set eyes, prominent nasal bridge, micrognathia), seizures and abnormalities of brain morphology (hypomyelinating white matter changes, cerebral atrophy).", "ORPHA ID": 369939, "Summary": ""}
{"Disease Name": "Severe myopia-generalized joint laxity-short stature syndrome", "Disease Definition": "A rare developmental defect with connective tissue involvement characterized by joint hyperextensibility and multiple dislocations of large joints, severe myopia, and short stature. Other common features include retinal detachment, iris and chorioretinal coloboma, kyphoscoliosis and other spine deformities, pectus carinatum, talipes equinovarus, and progressive hearing loss.", "ORPHA ID": 527450, "Summary": ""}
{"Disease Name": "Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency", "Disease Definition": "Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency is a rare, hereditary, mitochondrial oxidative phosphorylation disorder characterized by severe neonatal lactic acidosis and deficiency of mitochondrial complexes I, II and III. Clinical features are variable and may include hypotonia, respiratory distress with cyanosis, failure to thrive, feeding difficulties, hypoglycemia, dehydration, vomiting, seizures, and a risk of multiple organ failure.", "ORPHA ID": 397593, "Summary": ""}
{"Disease Name": "Severe neonatal-onset encephalopathy with microcephaly", "Disease Definition": "Severe neonatal-onset encephalopathy with microcephaly is a rare monogenic disease with epilepsy characterized by neonatal-onset encephalopathy, microcephaly, severe developmental delay or absent development, breathing abnormalities (including central hypoventilation and/or respiratory insufficiency), intractable seizures, abnormal muscle tone and involuntary movements. Early death is usual.", "ORPHA ID": 209370, "Summary": ""}
{"Disease Name": "Severe neurodegenerative syndrome with lipodystrophy", "Disease Definition": "A rare, genetic, neurodegenerative disorder characterized by progressive psychomotor and cognitive regression (manifesting with gait ataxia, spasticity, loss of language, mild to severe intellectual disability, pyramidal and extrapyramidal signs and, frequently, development of tretraplegia or tetraparesis) associated with variable degrees of lipodystrophy, hepatomegaly, hypertriglyceridemia and muscular hypertrophy. Hyperactivity, tremor and development of seizures may also be associated.", "ORPHA ID": 363400, "Summary": ""}
{"Disease Name": "Severe neurodevelopmental disorder with feeding difficulties-stereotypic hand movement-bilateral cataract", "Disease Definition": "A rare pervasive developmental disorder characterized by microcephaly, profound developmental delay, intellectual disability, bilateral cataracts, severe epilepsy including infantile spasms, hypotonia, irritability, feeding difficulties leading to failure to thrive, and stereotypic hand movements. The disease manifests in infancy. Brain imaging reveals delay in myelination and cerebral atrophy.", "ORPHA ID": 500545, "Summary": ""}
{"Disease Name": "Severe oculo-renal-cerebellar syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by profound intellectual disability, choreoathetosis, progressive spastic diplegia, progressive tapetoretinal degeneration with loss of retinal vessels, and glomerulopathy resulting in death late in the first or early in the second decade of life. Absence of the cerebellar granular layer has been reported. There have been no further descriptions in the literature since 1982.", "ORPHA ID": 2715, "Summary": ""}
{"Disease Name": "Severe phosphoribosylpyrophosphate synthetase superactivity", "Disease Definition": "A severe form of phosphoribosylpyrophosphate (PRPP) synthetase superactivity, an X-linked disorder of purine metabolism, characterized by early onset hyperuricemia and hyperuricosuria, and clinically manifesting with urolithiasis, gout and neurodevelopmental anomalies consisting of variable combinations of sensorineural hearing loss, hypotonia, and ataxia.", "ORPHA ID": 411543, "Summary": "Epidemiology\nPRPP synthetase superactivity is a rare disorder with 30 families described in the literature. The severe form accounts for approximately 25% of cases. The disorder predominantly affects males.\nClinical description\nThe phenotype varies greatly among patients. The severe form manifests in infancy or early childhood (but may occur earlier) usually with uric acid crystalluria and urinary stones (kidney and/or bladder), followed by the development of gouty arthritis and eventually renal failure as a result of obstructive uropathy from uric acid crystal deposition. This form also shows neurologic impairment, mainly sensorineural hearing loss, hypotonia, ataxia, developmental delay, and /or intellectual disability. Axonal neuropathy with demyelination is also possible (reported in one family).\nEtiology\nThe disease is due to overactivity of PRPP synthetase 1 (PRS-I), an enzyme that catalyzes the synthesis of PRPP, a cofactor involved in the synthesis of purine and pyrimidine nucleotides. PRS-I overactivity results in overproduction of purine nucleotides and uric acid (a waste product of purine breakdown). In the severe form, PRS-I overactivity is due to gain-of-function point mutations in the open reading frame of the PRPS1 gene (Xq22.3), encoding PRS-I, that lead to defective allosteric control of PRS1 isoform activity.\nDiagnostic methods\nDiagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by either molecular genetic testing or a PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes.\nDifferential diagnosis\nDifferential diagnosis includes hypoxanthine-guanine phosphoribosyltransferase deficiency and psychomotor delay due to S-adenosylhomocysteine hydrolase deficiency.\nAntenatal diagnosis\nPrenatal genetic testing in male fetuses is possible where a mutation has previously been identified in a family member.\nGenetic counseling\nSevere PRPP synthetase superactivity is an X-linked recessive disorder with complete penetrance in males. A mother carrying the pathogenic mutation has a 50% chance of transmitting the mutation to any of her offspring, an affected father transmits the mutation only to his daughters. Heterozygous females are typically asymptomatic; however, symptomatic females have been reported, most likely due to X-inactivation. De novo  PRSP1 mutations have also been reported.\nManagement and treatment\nTreatment of uric acid overproduction with xanthine oxidase inhibitors like allopurinol or febuxostat successfully reverses or prevents the consequences of hyperuricemia and hyperuricosuria. A high daily fluid intake is warranted; and, as needed, potassium citrate to alkalinize the urine in order to avoid the formation of kidney stones. A low-purine and low-fructose diet along with regular surveillance of serum urate concentration is essential. Regular audiometric and neurologic evaluations are also recommended.\nPrognosis\nThe prognosis is uncertain in the severe form of the disease. Severe gout can lead to renal impairment, if not properly treated. Of note, the interventions have no known beneficial effect on hearing loss or neurologic impairment.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Arjan DE BROUWER"}
{"Disease Name": "Severe primary trimethylaminuria", "Disease Definition": "A rare inborn error of metabolism characterized by the presence of large amounts of trimethylamine in urine, sweat, and breath, resulting in a fishy body odor in affected individuals. While there are no additional signs and symptoms, the condition can have profound psychosocial consequences.", "ORPHA ID": 468726, "Summary": ""}
{"Disease Name": "Severe X-linked intellectual disability, Gustavson type", "Disease Definition": "A rare, genetic, X-linked syndromic intellectual disability disorder characterized by severe intellectual disability, microcephaly, post-natal growth retardation, severe visual impairment or blindness (due to optic atrophy), severe hearing defect, spasticity, epileptic seizures, restricted large-joint movements and early death (in infancy or early childhood). Facial dysmorphic features (large dysplastic ears and short broad nose) are additionally observed. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 3078, "Summary": ""}
{"Disease Name": "Severe X-linked mitochondrial encephalomyopathy", "Disease Definition": "Severe X-linked mitochondrial encephalomyopathy is an extremely rare mitochondrial respiratory chain disease resulting in a neurodegenerative disorder characterized by psychomotor delay, hypotonia, areflexia, muscle weakness and wasting in the two patients reported to date.", "ORPHA ID": 238329, "Summary": ""}
{"Disease Name": "Sex cord-stromal tumor of testis", "Disease Definition": "A group of rare tumors of testis comprising neoplasms of pure sex cord or pure stromal type, or neoplasms with admixtures of both components in various proportions and degree of differentiation. The tumors usually present as a painless testicular mass, although some may be associated with endocrine manifestations such as precocious puberty, gynecomastia, or erectile dysfunction. Malignant behavior is seen only in a small percentage of these tumors.", "ORPHA ID": 363489, "Summary": ""}
{"Disease Name": "Sheehan syndrome", "Disease Definition": "Sheehan syndrome is a rare, acquired, pituitary hormone deficiency disorder resulting from pituitary necrosis following peri- or postpartum hemorrhage characterized by various symptoms depending on resulting hormone decrease (e.g. failure or difficulty with lactation, oligo- or amenorrhea, hot flashes, decreased libido, weakness, fatigue, anorexia, nausea, vomiting, hypoglycemia, hyponatremia, dizziness, decreased muscle mass, adrenal crisis). Secondary hypothyroidism and secondary adrenal insufficiency may also be presenting signs.", "ORPHA ID": 91355, "Summary": ""}
{"Disease Name": "Sheldon-Hall syndrome", "Disease Definition": "Sheldon-Hall syndrome (SHS) is a rare multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs, triangular face, downslanting palpebral fissures, small mouth, and high arched palate.", "ORPHA ID": 1147, "Summary": "Epidemiology\nEpidemiological data for the prevalence of SHS are not available, but less than 100 cases have been reported in the literature.\nClinical description\nOther common clinical features of SHS include prominent nasolabial folds, high arched palate, attached earlobes, mild cervical webbing, short stature, severe camptodactyly, ulnar deviation, and vertical talus and/or talipes equinovarus. Typically, the contractures are most severe at birth and non-progressive.\nEtiology\nMutations in either MYH3, TNNI2, or TNNT3 have been found in about 50% of cases. These genes encode proteins of the contractile apparatus of fast twitch skeletal muscle fibers.\nDiagnostic methods\nThe diagnosis of SHS is based on clinical criteria.\nDifferential diagnosis\nMutation analysis is useful to distinguish SHS from arthrogryposis syndromes with similar features (e.g. distal arthrogryposis 1 and Freeman-Sheldon syndrome; see these terms).\nAntenatal diagnosis\nPrenatal diagnosis by ultrasonography is feasible at 18-24 weeks of gestation. If the family history is positive and the mutation is known in the family, prenatal molecular genetic diagnosis is possible.\nGenetic counseling\nSHS is inherited in an autosomal dominant pattern but about half the cases are sporadic.\nManagement and treatment\nThere is no specific therapy for SHS. However, patients benefit from early intervention with occupational and physical therapy, serial casting, and/or surgery.\nPrognosis\nLife expectancy and cognitive abilities are normal.\n\n                            Last update: \n                            March 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Michaël BAMSHAD  - Dr Reha TOYDEMIR"}
{"Disease Name": "Shiga toxin-associated hemolytic uremic syndrome", "Disease Definition": "A rare thrombotic microangiopathy characterized by mechanical hemolytic anemia, thrombocytopenia, and renal dysfunction that is usually associated with prodromal enteritis caused by Shigella dysentriae type 1 or E. Coli.", "ORPHA ID": 90038, "Summary": ""}
{"Disease Name": "Shigellosis", "Disease Definition": "Shigellosis is a bacterial infection leading to dysentery and is caused by Shigella, which are small, ubiquitous Gram-negative bacteria belonging to the enterobacteria family. There are four species: S. dysenteriae, S. flexneri, S. boydii and S. sonnei, all of which cause bacillary dysentery and are strictly limited to human hosts.", "ORPHA ID": 810, "Summary": "Clinical description\nClinically, after an incubation period of 2-3 days, dysenteric syndrome appears, with 10-30 glairy, bloody watery stools per day, a high temperature (40°C) and abdominal pain. Examination of the intestinal mucosa with endoscopy shows multiple ulcerations.\nEtiology\nIn western Europe, cases of shigellosis are either imported or limited to small familial epidemics and usually food-borne. They are mostly due to S. sonnei. The virulence of shigellas is a result of their ability to invade the intestinal epithelium by passing between contiguous epithelial cells, leading to the destruction of the intestinal mucosa.\nDiagnostic methods\nDiagnosis is based on evidence of the bacilli in stools.\nManagement and treatment\nTreatment revolves around administration of antibiotics, quinolones and cotrimoxazole, and rehydration to alleviate symptoms. Strict isolation of affected individuals is essential to limit epidemics. The disease is notifiable\n\n                            Last update: \n                            August 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Elisabeth ASLANGUL"}
{"Disease Name": "Shone complex", "Disease Definition": "Shone complex is a rare congenital cardiac malformation characterized by a complex of four obstructive lesions of the left heart: supravalvular mitral membrane, parachute mitral valve, muscular or membranous subvalvular aortic stenosis and coarctation of aorta. Clinical manifestations include heart murmur, shortness of breath and increased load intolerance, left ventricular hypertrophy and dilatation of the left atrium. Partial forms, involving only two or three out of the four specific anomalies, are also described and occasionally other cardiovascular anomalies (e.g. bicuspid aortic valve, patent ductus arteriosus, ventricular septal defect) may be associated.", "ORPHA ID": 99063, "Summary": ""}
{"Disease Name": "Short bowel syndrome", "Disease Definition": "Short bowel syndrome is an intestinal failure due to either a congenital defect, intestinal infarction or extensive surgical resection of the intestinal tract that results in a functional small intestine of less than 200cm in length and is characterized by diarrhea, nutrient malabsoption, bowel dilation and dysmobility.", "ORPHA ID": 104008, "Summary": ""}
{"Disease Name": "Short chain acyl-CoA dehydrogenase deficiency", "Disease Definition": "Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is a very rare inborn error of mitochondrial fatty acid oxidation characterized by variable manifestations ranging from asymptomatic individuals (in most cases) to those with failure to thrive, hypotonia, seizures, developmental delay and progressive myopathy.", "ORPHA ID": 26792, "Summary": "Epidemiology\nApproximately 50 patients have been identified worldwide to date. The Netherlands has an estimated birth prevalence of at least 1/50,000.\nClinical description\nMost infants with SCAD deficiency identified through newborn screening programs have been well at the time of diagnosis and most have remained asymptomatic. In affected individuals manifestations include seizures, developmental delay (delayed sitting/walking and/or speech/social interaction), failure to grow with poor feeding, and usually muscle weakness and hypotonia.\nEtiology\nSymptomatic SCAD deficiency is due to mutations in the acyl-CoA dehydrogenase, C-2 to C-3 short chain ACADS gene (12q24.31) as well as additional as yet unidentified precipitating factors.\nDiagnostic methods\nSCAD deficiency has been defined as the presence of (1) increased butyrylcarnitine (C4) concentrations in plasma and/or increased ethylmalonic acid (EMA) concentrations in urine under non-stressed conditions (on at least two occasions) and (2) biallelic ACADS mutations or susceptibility variants 511C>T and 625G>A. Newborn screening programs in Austria, Hungary and Iceland now usually identify patients with SCAD deficiency at birth. Asymptomatic relatives may meet the diagnostic criteria for SCAD deficiency.\nDifferential diagnosis\nDifferential diagnoses include multiple acyl-CoA dehydrogenase deficiency (MADD), ethylmalonic encephalopathy and acute ackee fruit intoxication (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is not relevant as asymptomatic and symptomatic family members can have the same SCAD genotype.\nGenetic counseling\nSCAD deficiency is inherited in an autosomal recessive manner and genetic counseling is possible.\nManagement and treatment\nMost patients are asymptomatic and no treatment is needed. Some symptomatic patients are given riboflavin and follow a low fat/high carbohydrate diet and avoid fasting. Acute metabolic acidosis can be treated by the administration of high levels of dextrose (with or without insulin) and IV fluids. Seizures can be treated with anticonvulsants but valproate should be avoided. Pregnancies should be monitored for complications such as acute fatty liver of pregnancy and preeclampsia (see these terms). Follow-up at a metabolic clinic should include the regular assessment of growth and development and nutritional status of patients.\nPrognosis\nThe prognosis is good in asymptomatic patients but variable in those who display the disease manifestations.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Simon OLPIN"}
{"Disease Name": "Short fifth metacarpals-insulin resistance syndrome", "Disease Definition": "A rare genetic disease characterized by the association of unilateral or bilateral short fifth metacarpals (defined as a gap of 2 mm or more between the distal end of the fifth metacarpal bone and a tangential line connecting the distal ends of the third and fourth metacarpals), insulin resistance, and spherocytosis. Familial short stature has not been reported as part of the syndrome.", "ORPHA ID": 66518, "Summary": ""}
{"Disease Name": "Short rib-polydactyly syndrome type 5", "Disease Definition": "A rare ciliopathy with major skeletal involvement characterized by short ribs, micromelia, limb bowing, polysyndactyly, absent ossification of the radii, tibiae and fibulae, as well as the bony elements of the hands and feet, and hypoplastic scapulae. Additional hallmarks of ciliopathic disease, such as laterality defects and cystic kidneys, have also been observed.", "ORPHA ID": 498497, "Summary": ""}
{"Disease Name": "Short rib-polydactyly syndrome, Beemer-Langer type", "Disease Definition": "A rare ciliopathy with major skeletal involvement characterized by short ribs and hypoplastic thorax, small iliac bones, short tubular bones with smooth metaphyseal margins, and bowed radii and ulnae. The tibiae are relatively well tubulated and longer than the fibulae. There is a high frequency of brain defects, while post-axial polydactyly is rare. Additional features may include cleft lip, absence of internal genitalia, and renal, biliary, and pancreatic cysts, among others.", "ORPHA ID": 93268, "Summary": ""}
{"Disease Name": "Short rib-polydactyly syndrome, Majewski type", "Disease Definition": "A rare ciliopathy with major skeletal involvement characterized by a hypoplastic thorax with short ribs and protuberant abdomen, micromelia with particularly short tibiae with ovoid configuration, pre- and postaxial polydactyly, brachydactyly, hypoplasia or aplasia of nails, and dysmorphic craniofacial features (such as prominent forehead, low-set and malformed ears, short and flat nose, lobulated tongue, micrognathia, and cleft lip/palate). Additional reported manifestations include urogenital, gastrointestinal, cardiovascular, and cerebral malformations, among others. The condition is fatal in the neonatal period.", "ORPHA ID": 93269, "Summary": ""}
{"Disease Name": "Short rib-polydactyly syndrome, Saldino-Noonan type", "Disease Definition": "A rare ciliopathy with major skeletal involvement characterized by short ribs with an extremely narrow thorax, very short limbs, absent or very small fibulae, severe metaphyseal dysplasia of tubular bones, post-axial polydactyly, and defective ossification in the calvaria, vertebrae, pelvis, and bones of the hands and feet. Congenital anomalies of multiple other organs have also been described, such as polycystic kidneys, transposition of the great vessels, and atretic lesions of the gastrointestinal and genitourinary tract. Hydrops fetalis may be observed at an early gestational age.", "ORPHA ID": 93270, "Summary": ""}
{"Disease Name": "Short rib-polydactyly syndrome, Verma-Naumoff type", "Disease Definition": "A rare ciliopathy with major skeletal involvement characterized by short ribs and extremely narrow thorax, severely shortened tubular bones with round metaphyseal ends and lateral spikes, and anomalies of multiple organs such as the heart, kidneys, liver, pancreas, intestine, and genitalia, with occasional occurrence of situs inversus totalis. Cleft lip/palate and polydactyly may also be present. The syndrome is fatal prenatally or in the perinatal period.", "ORPHA ID": 93271, "Summary": ""}
{"Disease Name": "Short rib-polydactyly syndrome", "Disease Definition": "A group of bone malformations characterized by a narrow thorax and polydactyly (usually preaxial).", "ORPHA ID": 1505, "Summary": "Epidemiology\nPrevalence as a group is unknown.\nClinical description\nThe group is heterogeneous and includes Jeune syndrome and Ellis Van Creveld syndrome (see these terms), neither of which are lethal, together with lethal chondrodysplasias: Saldino-Noonan (type 1), Majewski (type 2), Verma-Naumoff (type 3) and Beemer-Langer (Type 4; see these terms). This classification is based on radiological findings. Visceral malformations are frequent and differ between the syndromes. Some cases do not fit any category.\nEtiology\nCausative genes have been identified for the Ellis Van Creveld syndrome (EVC and EVC2; 4p16) and for a subset of patients with Jeune syndrome (IFT80 gene; 3q25.33).\nGenetic counseling\nAll of these clinically different syndromes are inherited as autosomal recessive traits.\n\n                            Last update: \n                            September 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Short stature due to GHSR deficiency", "Disease Definition": "Short stature due to GHSR deficiency is a rare, genetic, endocrine growth disease, resulting from growth hormone secretagogue receptor (GHSR) deficiency, characterized by postnatal growth delay that results in short stature (less than -2 SD). The pituitary gland is typically without morphological changes, although anterior pituitary gland hypoplasia has been reported.", "ORPHA ID": 314811, "Summary": ""}
{"Disease Name": "Short stature due to growth hormone qualitative anomaly", "Disease Definition": "Short stature due to growth hormone qualitative anomaly is characterised by growth retardation and short stature (despite the presence of normal or slightly elevated levels of immunoreactive growth hormone, GH), low concentrations of insulin-like growth factor-I (IGF-I) and a significant increase in growth rate following recombinant GH therapy. Prevalence is unknown but only a few cases have been reported in the literature. The syndrome is caused by various mutations in the GH1 gene (17q22-q24) that result in structural GH anomalies and a biologically inactive molecule. Transmission is autosomal recessive.", "ORPHA ID": 629, "Summary": ""}
{"Disease Name": "Short stature due to partial GHR deficiency", "Disease Definition": "Short stature due to partial GHR deficiency is a rare, genetic, endocrine disease characterized by idiopathic short stature due to diminished GHR function (decreased ligand binding or reduced availability of receptor), thus resulting in partial insensitivity to growth hormone.", "ORPHA ID": 314802, "Summary": ""}
{"Disease Name": "Short stature due to primary acid-labile subunit deficiency", "Disease Definition": "Short stature due to primary acid-labile subunit (ALS) deficiency is characterized by moderate postnatal growth deficit, markedly low circulating levels of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3), and hyperinsulinemia, in the absence of growth hormone (GH) deficiency or GH insensitivity.", "ORPHA ID": 140941, "Summary": "Epidemiology\nLess than 10 cases have been reported in the literature so far.\nClinical description\nAdditional findings include subnormal IGF-2, IGFBP-1 and IGFBP-2 levels, as well as microcephaly, and delayed puberty and bone maturation in some cases.\nEtiology\nIt is caused by homozygous inactivating mutations of the ALS gene (IGFALS; 16p13.3).\nGenetic counseling\nPrimary ALS deficiency is inherited in an autosomal recessive manner.\n\n                            Last update: \n                            March 2009"}
{"Disease Name": "Short stature, Brussels type", "Disease Definition": "A rare primary bone dysplasia characterized by severe intrauterine and postnatal growth retardation and short stature in association with craniofacial dysmorphism (such as large forehead, triangular face, low-set ears, and micro-retrognathism) and osteochondrodysplastic lesions. Radiographic findings include epiphyseal maturation delay, abnormal metaphyses, a narrow thorax, small pelvis, and short and broad metacarpal bones and phalanges. There have been no further descriptions in the literature since 1996.", "ORPHA ID": 2867, "Summary": ""}
{"Disease Name": "Short stature-advanced bone age-early-onset osteoarthritis syndrome", "Disease Definition": "A rare, primary bone dysplasia characterized by proportional short stature, early cessation of bone growth, accelerated skeletal maturation, variable presence of early-onset osteoarthritis and osteochondritis dissecans, and normal endocrine evaluation. The variable dysmorphic features include mild to relative macrocephaly, frontal bossing, midfacial hypoplasia, flat nasal bridge, brachydactyly, broad thumbs, and lordosis.", "ORPHA ID": 435804, "Summary": ""}
{"Disease Name": "Short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by short stature, conductive hearing loss due to bilateral auditory canal atresia, mandibular hypoplasia and multiple skeletal abnormalities, including bilateral humeral hypoplasia, humeroscapular synostosis, delayed pubis rami ossification, central dislocation of the hips, and proximal femora defects, as well as bilateral talipes equinovarus, proximally implanted thumbs and lumbar hyperlordosis. Associated craniofacial dysmorphism includes micro/scaphocephaly, malar hypoplasia, high-arched palate, and simple, dysplastic pinnae with prearicular pits/tags.", "ORPHA ID": 397623, "Summary": ""}
{"Disease Name": "Short stature-brachydactyly-obesity-global developmental delay syndrome", "Disease Definition": "A rare genetic, multiple congenital anomalies syndrome characterized by short stature, hand brachydactyly with hypoplastic distal phalanges, global development delay, intellectual disability, and more variably seizures, obesity, and craniofacial dysmorphism that includes microcephaly, high forehead, flat face, hypertelorism, deep set eyes, flat nasal bridge, averted nostrils, long philtrum, thin lip vermilion, and short neck.", "ORPHA ID": 464288, "Summary": "Epidemiology\nLess than 15 cases have been reported in the literature to date.\nClinical description\nInitial presentation can be with intrauterine growth retardation or low birthweight. Symptoms of global development delay includes hypotonia, delay in achieving independent sitting and walking and marked language delay. Intellectual disability ranges from mild to severe. Ocular anomalies include strabismus, coloboma, dacryostenosis and blue sclera. Obesity develops in late infancy. Seizures can present in infancy or childhood, are phenotypically variable including absences and febrile convulsions. In addition to hypoplasia of the distal phalanges, the 4th and 5th fingers may show a marked reduction in metacarpal length; brachydactyly of the feet may also be present. Other variable features reported include bilateral absent patellae, sensorineural hearing loss, feeding difficulties in early infancy, dysphagia, kyphosis, eczema, cryptorchidism and laryngomalacia.\nEtiology\nThe malformation is due to a loss of function in the enzyme protein arginine N-methyltransferase 7 (encoded by PRMT7, 16q22.1) resulting in decreased levels of protein arginine methylation.\nDiagnostic methods\nDiagnosis is based on presentation of clinical features, and can be confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis include Albright hereditary osteodystrophies with pseudohypoparathyroidism.\nAntenatal diagnosis\nThere is no definitive antenatal diagnosis available, however ultrasound may show intrauterine growth retardation which should be investigated further.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nGiven that patients with biallelic mutations in PRMT7 present with a spectrum of multisystemic involvement, medical multidisciplinary follow-up is needed. Neurological follow up is indicated with special attention to seizures. Hearing evaluation is recommended at time of diagnosis. Surveillance should also include frequent monitoring of growth and development; regular ophthalmological follow up. Hormonal and phosphocalcic metabolism alterations have been reported in two patients so far, so this should also be tested.\nPrognosis\nDevelopmental delay and intellectual disability had been reported in all patients to date, with variable in severity. Language is more severely affected when hearing impairment is present.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Irene VALENZUELA PALAFOLL | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Short stature-craniofacial anomalies-genital hypoplasia syndrome", "Disease Definition": "A rare developmental defect during embryogenesis mainly characterized by severe intellectual disability, short stature, hypogonadism, and distinct facial dysmorphism (including trigonocephaly, prominent forehead, asymmetric and flat face, hypertelorism, epicanthus, downslanting palpebral fissures, ptosis, low-set angulated ears, small mouth, high-arched/cleft palate crowded teeth, microretrognathia), as well as slender hands and/or feet. Variable additional features may include pterygia, hypoplastic nipples, cardiac anomaly, distal muscular wasting, limb contractures, skeletal anomalies (e.g. scoliosis, pectus excavatum, bilateral clubfeet), hypothyroidism, seizures, and cerebral anomalies. Puberty may be delayed.", "ORPHA ID": 2994, "Summary": ""}
{"Disease Name": "Short stature-deafness-neutrophil dysfunction-dysmorphism syndrome", "Disease Definition": "A rare developmental defect during embryogenesis malformation syndrome characterized by proportionate short stature, sensorineural deafness, mutism, facial dysmorphism and recurrent infections as a result of abnormal neutrophil chemotaxis. There have been no further descriptions in the literature since 1978.", "ORPHA ID": 2866, "Summary": ""}
{"Disease Name": "Short stature-delayed bone age due to thyroid hormone metabolism deficiency", "Disease Definition": "Short stature-delayed bone age due to thyroid hormone metabolism deficiency is a rare, genetic congenital hypothyroidism disorder characterized by mild global developmental delay in childhood, short stature, delayed bone age, and abnormal thyroid and selenium levels in serum (high total and free T4 concentrations, low T3, high reverse T3, normal to high TSH, decreased selenium). Intellectual disability, primary infertility, hypotonia, muscle weakness, and impaired hearing have also been reported.", "ORPHA ID": 171706, "Summary": ""}
{"Disease Name": "Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome", "Disease Definition": "A rare, genetic, primary bone dysplasia disorder characterized by severe pre- and post-natal short stature, facial dysmorphism (incl.dolicocephaly, long triangular face, tall forehead, down-slanting palpebral fissures, prominent nose, long philtrum, small ears), early-onset or postpubertal sparse, short hair and hypoplastic fingernails. Small hands with tapering fingers, bracydactyly and fifth-finger clinodactyly, as well as a high-pitched voice are also associated.", "ORPHA ID": 314394, "Summary": ""}
{"Disease Name": "Short stature-optic atrophy-Pelger-Huët anomaly syndrome", "Disease Definition": "A rare, genetic, developmental defect during embryogenesis malformation syndrome characterized by severe postnatal growth retardation, craniofacial dysmorphism, which includes a progeroid facial appearance, brachycephaly with hypoplasia of the frontal and parietal tubers and a flat occipital area, narrow forehead, prominent glabella, small orbit, slight bilateral exophthalmos, straight nose, hypoplastic cheekbones, long philtrum and thin lips, skeletal abnormalities (i.e. micromelia, brachydactyly, and severe short stature with short limbs), normal intelligence, Pelger-Huët anomaly of leukocytes, loose skin with decreased tissue turgor, and bilateral optic atrophy with loss of color vision and visual acuity. Recurrent liver failure triggered by fever has been occasionally reported. Radiographs may evidence delayed bone age, late ossification and/or osteoporosis.", "ORPHA ID": 391677, "Summary": ""}
{"Disease Name": "Short stature-pituitary and cerebellar defects-small sella turcica syndrome", "Disease Definition": "Short stature-pituitary and cerebellar defects-small sella turcica syndrome is characterised by short stature, anterior pituitary hormone deficiency, small sella turcica, and a hypoplastic anterior hypophysis associated with pointed cerebellar tonsils. It has been described in three generations of a large French kindred. Ectopia of the posterior hypophysis was observed in some patients. The syndrome is transmitted as a dominantly inherited trait and is caused by a germline mutation within the LIM-homeobox transcription factor LHX4 gene (1q25).", "ORPHA ID": 85442, "Summary": ""}
{"Disease Name": "Short stature-skeletal dysplasia-retinal degeneration-intellectual disability-sensorineural hearing loss syndrome", "Disease Definition": "A rare primary bone dysplasia characterized by microcephaly, developmental delay and intellectual disability, sensorineural hearing loss, retinal degeneration, and skeletal dysplasia. Musculoskeletal abnormalities include delayed ossification of epiphyses, spondyloepimetaphyseal dysplasia, short stature, severe spinal deformities, and severe joint laxity resulting in multiple joint dislocations.", "ORPHA ID": 589442, "Summary": ""}
{"Disease Name": "Short stature-valvular heart disease-characteristic facies syndrome", "Disease Definition": "Short stature-valvular heart disease-characteristic facies syndrome is characterised by severe short stature with disproportionately short legs, small hands, clinodactyly, valvular heart disease and dysmorphism (ptosis, high-arched palate, abnormal dentition). It has been described in a mother and two daughters. This syndrome is probably transmitted as an autosomal dominant trait.", "ORPHA ID": 2868, "Summary": ""}
{"Disease Name": "Short stature-webbed neck-heart disease syndrome", "Disease Definition": "Short stature-webbed neck-heart disease syndrome is characterized by short stature, intellectual deficit, facial dysmorphism, short webbed neck, skin changes and congenital heart defects. It has been reported in four Arab Bedouin sibs born to consanguineous parents.", "ORPHA ID": 2865, "Summary": ""}
{"Disease Name": "Short stature-wormian bones-dextrocardia syndrome", "Disease Definition": "A multiple congenital anomalies syndrome characterized by wormian bones, dextrocardia and short stature due to a growth hormone deficiency. Additional manifestations that have been reported include brachycamptodactyly, kidney hypoplasia, bilateral cryptorchidism, midshaft hypospadias, imperforate anus/anorectal agenesis, body asymmetry, mild developmental delay, hemimegalencephaly and facial dysmorphism (hypotelorism, downslanting palpebral fissures, low-set and posteriorly angulated ears, depressed nasal bridge, and microstomia).", "ORPHA ID": 2863, "Summary": ""}
{"Disease Name": "SHORT syndrome", "Disease Definition": "A rare disorder characterized by multiple congenital anomalies. The name is a mneumonic for the common features observed in SHORT syndrome that include; short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay. Other common manifestations of SHORT syndrome are mild intrauterine growth restriction, partial lipodystrophy, delayed bone age, hernias and a recognizable facial gestalt.", "ORPHA ID": 3163, "Summary": "Epidemiology\nThe prevalence of SHORT syndrome is unknown. Less than 50 cases have been reported in the literature to date.\nClinical description\nIndividuals with SHORT syndrome often display mild intrauterine growth restriction. Feeding difficulties and/or failure to thrive present in early childhood and final adult height is shorter than average (155-163 cm in males and 143-160 cm in females). Most patients have a characteristic facial gestalt, often described as progeroid, with triangular face shape, prominent forehead, ocular depression, hypoplastic alae nasi, low-hanging columella, downturned corners of the mouth, micrognathia and prominent (but not typically low-set or posteriorly located) ears. Partial lipodystrophy may be evident in the face at birth and later in the chest and upper extremities (including the hands), but it is usually not reported in the buttocks and legs. Delayed dentition, hypodontia, enamel hypoplasia, malocclusion and multiple dental caries are frequently reported. Ophthalmic anomalies (e.g. Rieger anomaly, Axenfeld anomaly (see these terms), glaucoma) are also characteristic of the disease. Diabetes is seen in approximately 2/3 of individuals with SHORT syndrome after the age of 15 years. Other less common manifestations include hyperextensibility of joints and/or hernias, sensorineural hearing loss and ovarian cysts in females. Intellectual development and cognition are usually unaffected although mild impairment with speech delay has been reported.\nEtiology\nSHORT syndrome is due to mutations in the PIK3R1 gene (5q13.1), encoding phosphatidylinositol 3-kinase regulatory subunit alpha. Mutations are thought to impair the PI3K/AKT/mTOR pathway, which plays an important role in cellular proliferation and growth.\nDiagnostic methods\nDiagnosis is based on the presence of the characteristic features and confirmed by molecular genetic testing identifying a PIK3R1 mutation. The presence of all 5 features of the acronym is not necessary for a positive diagnosis.\nDifferential diagnosis\nDifferential diagnoses include Silver-Russell syndrome, Alagille syndrome, Floating-Harbor syndrome, growth delay due to insulin-like growth factor I resistance, Berardinelli-Seip congenital lipodystrophy and Hutchinson-Gilford progeria syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease-causing mutation.\nGenetic counseling\nSHORT syndrome is inherited in an autosomal dominant manner. Genetic counseling is recommended for at-risk families. De novo cases have also been described. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nTreatment is symptomatic and requires a multidisciplinary team. Screening for insulin resistance is recommended starting in mid-late childhood. Glucose intolerance and diabetes mellitus can be treated with diet, lifestyle, oral medication and insulin, while growth hormone therapy is contraindicated. Ophthalmological management and follow-up (i.e. regular eye examinations) are necessary to reduce and stabilize ocular pressures and to preserve vision. Dental anomalies can be treated using standard methods (e.g. crowns and dental prostheses).\nPrognosis\nIndividuals with SHORT syndrome are considered to have a normal life-expectancy.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Dr David DYMENT  - Dr A.Micheil INNES"}
{"Disease Name": "Short tarsus-absence of lower eyelashes syndrome", "Disease Definition": "Short tarsus - absence of lower eyelashes is a very rare syndrome characterized by the association of thin and short upper and lower tarsus and absence of the lower eyelashes.", "ORPHA ID": 2832, "Summary": "Epidemiology\nIt has been described in 11 patients from a four generation family.\nClinical description\nThere is no other unusual feature.\nGenetic counseling\nInheritance is autosomal dominant.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Short ulna-dysmorphism-hypotonia-intellectual disability syndrome", "Disease Definition": "Short ulna-dysmorphism-hypotonia-intellectual disability syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by mild to severe global development delay, severe intellectual disability, mild hypotonia, a short ulna, hirsutism of the face and extremities, minimal scoliosis, and facial dysmorphism, notably a tall broad forehead, synophrys, hypertelorism, malar hypoplasia, broad nose with thick alae nasi, low-set, small ears, long philtrum, thin upper lip and everted lower lip vermilion.", "ORPHA ID": 357175, "Summary": ""}
{"Disease Name": "Short-limb skeletal dysplasia with severe combined immunodeficiency", "Disease Definition": "An extremely rare type of severe combined immunodeficiency (SCID) characterized by the classical signs of T-B- SCID (severe and recurrent infections, diarrhea, failure to thrive, absence of T and B lymphocytes), associated with skeletal anomalies like short stature, bowing of the long bones and metaphyseal abnormalities of variable degree of severity.", "ORPHA ID": 935, "Summary": ""}
{"Disease Name": "SHOX-related short stature", "Disease Definition": "SHOX-related short stature is a primary bone dysplasia characterized by a height that is 2 standard deviations below the corresponding mean height for a given age, sex and population group, in the absence of obvious skeletal abnormalities and other diseases and with normal developmental milestones. Patients present normal bone age with normal limbs, shortening of the extremities (significantly lower extremities-trunk and sitting height-to-height ratios), normal hGH values, normal karyotype, and Leri-Weill dyschondrosteosis-like radiological signs (e.g. triangularization of distal radial epiphyses, pyramidalization of distal carpal row, and lucency of the distal radius on the ulnar side). Mesomelic disproportions and Madelung deformity are not apparent at a young age, but may develop later in life or never.", "ORPHA ID": 314795, "Summary": ""}
{"Disease Name": "Shprintzen-Goldberg syndrome", "Disease Definition": "A rare genetic disorder characterized by craniosynostosis, craniofacial and skeletal abnormalities, marfanoid habitus, cardiac anomalies, neurological abnormalities, and intellectual disability.", "ORPHA ID": 2462, "Summary": ""}
{"Disease Name": "Shwachman-Diamond syndrome", "Disease Definition": "Shwachman-Diamond syndrome (SDS) is a rare multisystemic syndrome characterized by chronic and usually mild neutropenia, pancreatic exocrine insufficiency associated with steatorrhea and growth failure, skeletal dysplasia with short stature, and an increased risk of bone marrow aplasia or leukemic transformation.", "ORPHA ID": 811, "Summary": "Epidemiology\nWorldwide prevalence is estimated at about 1/350,000 and birth-prevalence at around 1/200,000 live births.\nClinical description\nSDS shows a variable clinical picture, even within families. It generally manifests during infancy or early childhood. The most common anomaly is usually intermittent and moderate neutropenia that is associated with recurrent infections. Mild anemia and thrombocytopenia may also occur. Exocrine pancreatic insufficiency results in failure to thrive, growth retardation, and chronic steatorrhea. Bone involvement is characterized by delayed bone age and maturation with metaphyseal dysplasia resulting in short stature, pectus carinatum, and generalized osteopenia. Other features include cutaneous (e.g. eczema or ichthyosis) and dental anomalies, and psychomotor retardation. Mild or severe intellectual disability (50% of patients) causes learning difficulties. Hematologic manifestations may be complicated by bone marrow aplasia, acute myeloid leukemia or a myelodysplastic syndrome (see these terms). In the neonatal period there are generally no symptoms observed but some cases were reported with pancytopenia, respiratory distress, and severe spondylometaphyseal dysplasia (see this term).\nEtiology\nSDS is caused in 95% of cases by mutations in the SBDS gene (7q11.22) encoding a ribosomal protein involved in ribosomal biogenesis and other cellular processes.\nDiagnostic methods\nDiagnosis is based on clinical, laboratory, and radiologic findings. Blood analysis shows neutropenia (absolute neutrophil count <1500/mL) that can be associated with mild to moderate thrombocytopenia, moderate anemia, and a rise in fetal hemoglobin. Exocrine pancreatic insufficiency can be detected by serum analysis showing low levels of pancreatic isoamylase and/or trypsinogen, stool analysis showing low fecal elastase, and magnetic resonance imaging (MRI) revealing a characteristic pancreatic aspect with fat degeneration (MRI could be normal until the age of 5). Imagery also allows detection, usually after the age of 5, of metaphyseal anomalies and abnormal growth plate development. Bone marrow smears usually reveal varying degrees of hypocellularity with dysgranulopoieisis or dyserythropoieisis. Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnoses include cystic fibrosis, Pearson syndrome, Fanconi anemia, Johanson-Blizzard syndrome, Blackfan-Diamond anemia, celiac disease, and autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is feasible in families in which the disease-causing mutation has already been identified.\nGenetic counseling\nTransmission is autosomal recessive. Recurrence risk is of 25%.\nManagement and treatment\nManagement is multidisciplinary, associating usually a hematologist, a gastroenterologist and other specialists such as a nutritionist, endocrinologist, or orthopedist. Pancreatic insufficiency requires pancreatic enzyme supplementation, adapted to the diet. Antibiotic therapy prophylaxis may be sufficient to avoid infections; otherwise, granulocyte colony-stimulating factor can be proposed. Severe hematological complications require hematopoietic stem cell transplantation. Surgery may be proposed for skeletal anomalies. Patients with learning difficulties require specific educational support.\nPrognosis\nPrognosis is variable. Life-threatening complications include bone marrow aplasia and leukemic transformation, and occasionally viral infections. About 1/3 of patients present such complications, and some can be treated successfully by bone marrow transplant.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Jean DONADIEU"}
{"Disease Name": "Sialidosis type 1", "Disease Definition": "Sialidosis type 1 (ST-1) is a very rare lysosomal storage disease, and is the normosomatic form of sialidosis (see this term), characterized by gait abnormalities, progressive visual loss, bilateral macular cherry red spots and myoclonic epilepsy and ataxia, that usually presents in the second to third decade of life.", "ORPHA ID": 812, "Summary": "Epidemiology\nThe prevalence of ST-1 is unknown but it is less frequent than sialidosis type 2 (ST-2, see this term). The prevalence of sialidosis (types 1 and 2 combined) has been estimated at approximately 1/5,000,000-1/1,500,000 live births.\nClinical description\nThe disease usually presents in adolescence (onset usually between 12 and 25 years) with gait disturbance, walking difficulties and/or a loss of visual acuity. Almost all patients display a cherry-red spot on the retina. They may also have generalized myoclonus, in some cases associated with seizures and ataxia. Color vision progressively diminishes while night blindness appears and, in some cases, corneal opacities and nystagmus are present. Intellectual capacity is normal. In contrast to ST-2, patients do not show facial dysmorphism, bone dysplasia or psychomotor retardation.\nEtiology\nST-1 is due to a mutation of the N-acetyl-alpha-neuraminidase-1 (NEU1) gene (6p21) encoding the lysosomal enzyme neuraminidase, that initiates the degradation of sialoglycoconjugates in lysosomes. Mutations lead to a decrease in enzyme activity and consequently to an accumulation of sialyloligosaccharides in tissues. Disease severity is linked to level of residual neuraminidase activity in vivo and varies between patients.\nDiagnostic methods\nAn ophthalmological examination (fundoscopy) can visualize bilateral cherry-red spots. Magnetic resonance imaging of the brain can reveal diffuse brain atrophy in advanced cases, but is usually normal on first examination. Detection of urinary sialyloligosaccharides can be suggestive of a diagnosis, but excretion levels may be quite low. The diagnosis must be confirmed by the demonstration of deficient neuraminidase activity (in the presence of normal beta-galactosidase activity) in leukocytes or, preferably, in cultured fibroblasts. Diagnosis can be confirmed by molecular genetic testing revealing mutations in the NEU1 gene.\nDifferential diagnosis\nThe main differential diagnosis is galactosialidosis (see this term), which is characterized by deficiencies in both neuraminidase and beta-galactosidase.\nAntenatal diagnosis\nPrenatal diagnosis can be performed by enzyme activity measurement or by molecular genetic analysis if the underlying molecular defect in the family is well established.\nGenetic counseling\nST-1 is inherited in an autosomal recessive manner. Genetic counseling is possible.\nManagement and treatment\nThere is no cure for ST-1 and management should be multidisciplinary to allow for adapted symptomatic treatment, which is essential for improving the quality of life of affected patients. In severe cases, patients may require the use of a wheelchair.\nPrognosis\nThere appears to be no major effect on life expectancy but quality of life can be affected due to myoclonus and resulting mobility issues.\n\n                            Last update: \n                            November 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART  - Dr Nathalie GUFFON-FOUILHOUX"}
{"Disease Name": "Sialidosis type 2", "Disease Definition": "Sialidosis type 2 (ST-2) is a rare lysosomal storage disease, and the severe, early onset form of sialidosis (see this term) characterized by a progressively severe mucopolysaccharidosis-like phenotype (coarse facies, dysostosis multiplex, hepatosplenomegaly), macular cherry-red spots as well as psychomotor and developmental delay. ST-2 displays a broad spectrum of clinical severity with antenatal/congenital, infantile and juvenile presentations.", "ORPHA ID": 87876, "Summary": "Epidemiology\nThe prevalence of ST-2 is unknown. The prevalence of sialidosis (types 1 and 2 combined) has been estimated at approximately 1/5,000,000-1/1,500,000 live births.\nClinical description\nST-2 has a wide range of clinical manifestations and is usually divided into congenital/antenatal, infantile and juvenile forms. The congenital/antenatal form is characterized by non-immune hydrops fetalis, or ascites, presenting in utero or at birth and by the development of a mucopolysaccharidosis (see this term)-like phenotype including coarse facial features, dysostosis multiplex, hepatosplenomegaly, and umbilical and inguinal hernias. Surviving children and patients with the infantile onset form (before 12 months of age) are characterized by a mucopolysaccharidosis-like phenotype that includes coarse facies, dysosotosis multiplex, kyphosis, short stature (with a slowing of growth towards 18 months of age), hepatosplenomegaly, hearing impairment, cherry-red spot on the retina (a constant feature after 3 years of age), corneal opacities (rarely) and speech and developmental delay, followed by psychomotor regression and myoclonus and ataxia in some cases. Renal disease (nephrosialidosis) has been reported in some patients. The juvenile form usually presents after the age of 2 with less pronounced coarse facies, angiokeratoma, myoclonic seizures, macular cherry red spots, and psychomotor regression.\nEtiology\nST-2 is due to a mutation of the N-acetyl-alpha-neuraminidase-1 (NEU1) gene (6p21) encoding the lysosomal enzyme neuraminidase, that initiates the degradation of sialoglycoconjugates in lysosomes. Mutations lead to a deficiency in enzyme activity and consequently to an accumulation of sialyloligosaccharides in tissues. In general, a higher residual neuraminidase activity is associated with milder symptoms and a longer lifespan.\nDiagnostic methods\nAn ophthalmological examination (fundoscopy) can visualize the bilateral macular cherry-red spots. Neuroimaging shows varying degrees of brain and cerebellar atrophy. The diagnosis is suspected by detection of urinary sialyloligosaccharide excretion and must be confirmed by demonstration of the neuraminidase enzyme deficiency (in the presence of normal beta-galactosidase activity) in leukocytes or, preferably, in cultured fibroblasts. Molecular genetic testing revealing causal mutation(s) can also confirm the diagnosis. The presence of echographic signs (such as hydrops, edema, ascites) may aid in diagnosing antenatal forms during pregnancy.\nDifferential diagnosis\nThe main differential diagnoses include galactosialidosis (characterized by deficiencies in both beta galactosidase and neuraminidase) and mucopolysaccharidosis type 1, 2 or 6 (see these terms). Many patients of the juvenile sub-group, in particular, may appear to have a form of galactosialidosis.\nAntenatal diagnosis\nPrenatal diagnosis can be performed by measurement of enzyme activity or by molecular genetic analysis if the underlying molecular defect in the family is well established\nGenetic counseling\nST-2 is inherited in an autosomal recessive manner. Genetic counseling is possible.\nManagement and treatment\nThere is no cure for ST-2 and management is multidisciplinary involving mainly palliative care. Anti-convulsants may be used to treat myoclonic seizures, but are only rarely effective. Hematopoietic stem cell transplantation has not been successful in preventing psychomotor regression, bone changes or nephrosialidosis.\nPrognosis\nThe prognosis depends on the form of ST-2. The congenital form leads to still-birth or death within the first two years of life. For the other forms, life expectancy does not generally exceed two decades.\n\n                            Last update: \n                            November 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Roseline FROISSART  - Dr Nathalie GUFFON-FOUILHOUX"}
{"Disease Name": "Sialidosis", "Disease Definition": "Sialidosis is a lysosomal storage disease, belonging to the group of oligosaccharidoses or glycoproteinoses, with a wide clinical spectrum that is divided into two main clinical subtypes: sialidosis type I (see this term), the milder, non dysmorphic form of the disease characterized by gait abnormalities, progressive visual loss, bilateral macular cherry red spots and myoclonus, that presents in adolescence or adulthood (second or third decade of life); and sialidosis type II (see this term) the more severe, early onset form, characterized by a progressive and severe mucopolysaccharidosis-like phenotype with coarse facies, visceromegaly, dysostosis multiplex, and developmental delay. Bilateral macular cherry red spots are also present. Sialidosis type II has been further divided into congenital (with hydrops fetalis), infantile and juvenile presentations.", "ORPHA ID": 309294, "Summary": ""}
{"Disease Name": "Sialuria", "Disease Definition": "An extremely rare metabolic disorder described in fewer than 10 patients to date and characterized by variable signs and symptoms, mostly in infancy, including transient failure to thrive, slightly prolonged neonatal jaundice, equivocal or mild hepatomegaly, microcytic anemia, frequent upper respiratory infections, gastroenteritis, dehydration and flat and coarse facies. Learning difficulties and seizures may occur in childhood.", "ORPHA ID": 3166, "Summary": ""}
{"Disease Name": "Sickle cell anemia", "Disease Definition": "A severe form of sickle cell disease (SCD) characterized by homozygosity for the sickle hemoglobin (HbS) gene and which acutely manifests with severe anemia, susceptibility to severe bacterial infections, and ischemic vasoocclusive accidents (VOA). It is a red cell disease of genetic origin which manifests with hemolytic disease and loss of red cell deformability leading to other occlusive events.", "ORPHA ID": 232, "Summary": "Epidemiology\nSickle cell anemia (SCA) is the most common form of SCD. Worldwide, it is estimated that there are over 400,000 newborns with sickle cell anemia. The birth prevalence varies according to region, with prevalence greatest in regions affected by holoendemic malaria. In Europe, the pooled birth prevalence is 1/2,300, although this varies between countries.\nClinical description\nThe disease does not manifest during fetal life or up to the first three months of life due to the presence of high levels of fetal hemoglobin. Clinical manifestations evolve with age and are extremely variable between individuals and at different times. In addition to anemia and bacterial infections, VOAs cause hyperalgic focal ischemia (and sometimes infarction) when they occur in the abdomen, chest or skeleton. Over the course of time, VOAs may compromise the integrity of tissues or organs.\nEtiology\nSCA is due to homozygous mutations (rs334) in the beta globin gene, HBB (11p15.4); this variant is termed HbS. There are other forms of sickle cell disease are due to compound heterozygosity for the HbS gene and other hemoglobin (Hb) variants. Under deoxygenated conditions, HbS polymerizes and thereby alters the shape and function of erythrocytes, triggering a cascade of events that leads to hemolysis, vascular occlusion, reduced bioavailability of nitric oxide, and endothelial injury.\nDiagnostic methods\nDiagnosis is based on analysis of hemoglobin using isoelectric focusing or capillary electrophoresis combined with HPLC, solubility test (Itano test) and molecular analysis. Screening of healthy carriers, by family or by population surveys, helps prevention but requires prospective genetic counseling.\nDifferential diagnosis\nDifferential diagnoses include other hereditary hemolytic diseases, and those with recurrent vascular obstruction.\nAntenatal diagnosis\nFollowing genetic counseling, prenatal genetic diagnosis is possible via chorionic villi sampling (before 14 weeks of amenorrhea) or amniotic fluid (from 17 weeks onwards).\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nFrom birth, management should integrate prevention of infections, pain and eventual complications, with social, psycho-educational and nutritional support, within multidisciplinary centers that are equipped with intensive care (immediate access to blood transfusion). Special attention should be paid to pregnant women with SCA. Prospective research of vasculopathies is needed. An orphan drug based on hydroxycarbamide (hydroxyurea) has obtained European marketing authorization for the severe forms of the disease. Regular or occasional transfusions remain an essential therapeutic method. Bone marrow transplantation has its main indication in severe cases, particularly in cases with cerebral vasculopathy. L-glutamine, crizanlizumab and voxelotor are currently in phase III trials.\nPrognosis\nThe prognosis is difficult to predict. Acute bacterial infections, malarial attacks, splenic sequestration, severe VOA or organ failure can be a cause of death.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Frédéric GALACTEROS | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Sickle cell-beta-thalassemia disease syndrome", "Disease Definition": "A rare, genetic hemoglobinopathy that affects red blood cells both in the production of abnormal hemoglobin, as well as the decreased synthesis of beta globin chains. Clinical manifestations depend on the amount of residual beta globin chains production, and are similar to sickle cell disease, including anemia, vascular occlusion and its complications, acute episodes of pain, acute chest syndrome, pulmonary hypertension, sepsis, ischemic brain injury, splenic sequestration crisis and splenomegaly.", "ORPHA ID": 251359, "Summary": ""}
{"Disease Name": "Sickle cell-hemoglobin C disease syndrome", "Disease Definition": "A rare, genetic hemoglobinopathy characterized by anemia, reticulocytosis and erythrocyte abnormalities including target cells, irreversibly sickled cells and crystal-containing cells. Clinical course is similar to sickle cell disease, but less severe and with less complications. Signs and symptoms may include acute episodes of pain, splenic infarction and splenic sequestration crisis, acute chest syndrome, focal segmental glomerulosclerosis, ischemic brain injury, peripheral retinopathy, and osteonecrosis.", "ORPHA ID": 251365, "Summary": ""}
{"Disease Name": "Sickle cell-hemoglobin D disease syndrome", "Disease Definition": "A rare, genetic hemoglobinopathy characterized by all the characteristics of sickle cell anemia (SCA). Clinical course is similar to SCA, including acute episodes of pain, splenic infarction and splenic sequestration crisis, vaso-occlusive crisis, acute chest syndrome, ischemic brain injury, osteomyelitis and avascular bone necrosis. The genotype is characterized by an HbS allele in combination with the HbD variant, beta121Glu>Gln.", "ORPHA ID": 251370, "Summary": ""}
{"Disease Name": "Sickle cell-hemoglobin E disease syndrome", "Disease Definition": "A rare, genetic hemoglobinopathy usually characterized by mild microcytic hemolysis and, very rarely, vaso-occlusive complications. Severe manifestations have been reported, including hematuria, splenic infarction, acute chest syndrome, acute episodes of pain and reversible bone marrow necrosis. The genotype is characterized by an HbS allele in combination with an HbE variant (beta26glu>lys); symptoms are due to the low allelic expression of HbE leading to HbS predominance (65+/-5%).", "ORPHA ID": 251375, "Summary": ""}
{"Disease Name": "Sideroblastic anemia", "Disease Definition": "Sideroblastic anemias (SA) are a group of rare heterogeneous inherited or acquired bone marrow disorders, isolated or part of a syndrome, characterized by decreased hemoglobin synthesis, because of defective use of iron (although plasmatic iron levels may be normal or elevated) and the presence of ringed sideroblasts in the bone marrow due to the pathologic iron overload in mitochondria as visualized by Perls' staining. The group encompasses (idiopathic) acquired sideroblastic anemia and constitutional sideroblastic anemias (see these terms). The latter include syndromic sideroblastic anemias such as Pearson syndrome, mitochondrial mypathy and sideroblastic anemias, x-linked sideroblastic anemia-ataxia, thiamine responsive megaloblastic anemia syndrome and nonsyndromic sideroblastic anemias comprising x-linked and autosomal recessive sideroblastic anemias (see these terms).", "ORPHA ID": 1047, "Summary": ""}
{"Disease Name": "Siegler-Brewer-Carey syndrome", "Disease Definition": "A rare, syndromic, genetic respiratory disease characterized by cataracts, otitis media, intestinal malabsorption, chronic respiratory infections, and failure to thrive. Recurrent pneumonia and progressive azotemia, leading to end-stage renal disease and early death, are additionally observed. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 3167, "Summary": ""}
{"Disease Name": "Silent sinus syndrome", "Disease Definition": "A rare otorhinolaryngologic disease characterized by adult-onset progressive enophthalmos due to collapse of some or all of the maxillary sinus walls and remodeling of the orbital floor.", "ORPHA ID": 71276, "Summary": "Epidemiology\nIts prevalence is unknown but around 550 cases have been reported in the literature so far. Patients typically present at 30-60 years old, with no sex predilection.\nClinical description\nThe progressive enophthalmos may occasionally be associated with hypoglobus, diplopia, headache, and facial pressure/pain. Patients sometimes report a history of remote episodes of sinusitis. The syndrome may be idiopathic or occur following a bony orbital decompression resulting from Graves' ophthalmopathy or orbital floor fracture.\nEtiology\nThe underlying mechanism involves obstruction of the ostiomeatal complex followed by development of hypoventilation and negative maxillary sinus pressure. This negative pressure subsequently collapses the sinus and causes inward bowing of the ipsilateral orbital floor.\nDiagnostic methods\nDiagnosis is made by facial computerized tomography (CT) scanning with coronal reconstructions, showing a collapse of the maxillary sinus wall(s) and opacification of the sinus cavity. The ostium of the maxillary sinus is occluded due to lateral retraction of the uncinate process and apposition against the inferomedial orbital wall. The middle meatus is enlarged.\nDifferential diagnosis\nDifferential diagnosis should include orbital floor 'blow-out' fractures, soft tissue atrophy, primary or secondary malignancy, orbital venous malformations, bone growth arrest following radiation therapy, congenital etiologies (minor forms of hemifacial microsomia, plagiocephaly, microphthalmos etc.) and pseudoenophthalmos (unilateral blepharoptosis, Horner syndrome, contralateral exophthalmos, contralateral high myopia and contralateral eyelid retraction).\nManagement and treatment\nSurgery is the only treatment. Functional endoscopic sinus surgery (FESS) is performed to open the ostiomeatal complex, with complete uncinectomy, and prevent development of negative maxillary pressure. Residual ophthalmic symptoms (e.g., enophthalmos) may be addressed by reconstructing the orbital floor in conjunction or in discontinuity with FESS.\nPrognosis\nImprovement in clinical symptoms, including enophthalmos and hypoglobus, is seen in a majority of patients.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                             Abiri ARASH  - Dr Edward KUAN"}
{"Disease Name": "Sillence syndrome", "Disease Definition": "A rare genetic syndrome with limb malformations as a major feature characterized by brachydactyly and distal symphalangism, pes cavus, scoliosis, and normal stature. There have been no further descriptions in the literature since 1978.", "ORPHA ID": 3168, "Summary": ""}
{"Disease Name": "Silver-Russell syndrome due to maternal uniparental disomy of chromosome 7", "Disease Definition": "Silver-Russell syndrome due to maternal uniparental disomy of chromosome 7 is a genetic malformation syndrome with short stature characterized by severe prenatal and postnatal growth retardation, feeding difficulties, body asymmetry, dysmorphic craniofacial features (triangular-shaped face, relative macrocephaly, frontal bossing, micrognathia, down-turned corners of the mouth) and other anomalies (fifth finger clinodactyly, café au lait macules, male genital anomalies, mild developmental delay and/or speech delay with movement disorders).", "ORPHA ID": 96182, "Summary": ""}
{"Disease Name": "Silver-Russell syndrome", "Disease Definition": "Silver-Russell syndrome is characterized by growth retardation with antenatal onset, characteristic facies and limb asymmetry.", "ORPHA ID": 813, "Summary": "Epidemiology\nThe incidence is evaluated at 1-30/100 000 cases and about 400 cases have been reported in the literature.\nClinical description\nWeight is often more affected than size, with little subcutaneous fat tissue. Bone maturation is delayed, in accordance with small stature. The fontanelle may be late to close. The skull has a normal circumference, which may contrast with the rest of the body and confers a pseudohydrocephalic appearance. The wide prominent forehead contrasts with the small, triangular face with a small pointed chin, a wide mouth with thin lips and down-turned corners, large eyes and bluish sclera. Lateral and usually partial asymmetry of the limbs is observed in 60% to 80% of cases, but is not progressive. Shortness and/or clinodactyly of the fifth fingers is a common finding. Patients may be slow to learn motor skills, and in rare cases, may be mildly intellectually deficient.\nEtiology\nEtiology is heterogeneous. Most cases are sporadic. Maternal uniparental disomy of chromosome 7 is observed in 10% of patients. Approximately 30% of the cases show hypomethylation of the H19 gene, located in the 11p15 imprinted region. Hypomethylation results in most cases from an epigenetic mechanism or a genomic microrearrangement, such as a maternal microduplication of the region.\nDiagnostic methods\nDiagnosis is mainly clinical, as there is no specific biological test, but it can be confirmed by the detection of the underlying molecular anomaly.\nDifferential diagnosis\nDifferential diagnosis includes intrauterine growth retardation due to impaired placental function, structural or mosaic chromosomal abnormalities, neonatal progeria (Wiedemann-Rautenstrauch syndrome), 3M syndrome and Mulibrey dwarfism (see these terms). Genetic counselling depends on the molecular mechanism involved.\nAntenatal diagnosis\nPrenatal diagnosis is not usually possible (as most cases reported so far are sporadic, the potential risk of having an affected child is not anticipated during pregnancy).\nGenetic counseling\nThe recurrence risk is extremely low in cases of uniparental disomy of chromosome 7 or epigenetic anomalies of the 11p15 region.\nManagement and treatment\nTreatment is supportive. Growth hormone therapy can speed up the growth and increases the final height, but does not allow the target height to be reached.\nPrognosis\nBeyond short stature and slender build, long-term prognosis is good. Hemihypotrophy is not associated with an increased tumoral risk.\n\n                            Last update: \n                            September 2007\n\n\n                            - Expert reviewer(s): \n                            Pr Annick TOUTAIN"}
{"Disease Name": "SIM1-related Prader-Willi-like syndrome", "Disease Definition": "A rare Prader-Willi-like syndrome characterized by severe obesity due to SIM1 mutation, in addition to some clinical features of Prader-Willi- syndrome including intellectual disability, developmental delay, behaviour problems and facial dysmorphism. Unlike Prader-Willi syndrome, short stature, hypotonia and hypogonadism may not be observed.", "ORPHA ID": 398079, "Summary": ""}
{"Disease Name": "Simple cryoglobulinemia", "Disease Definition": "Simple (monoclonal) cryoglobulinemia or type I cryoglobulinemia refers to the presence in the serum of one isotype or subclass of immunoglobulin (Ig) that precipitates reversibly below 37°C.", "ORPHA ID": 91139, "Summary": "Epidemiology\nThe prevalence is unknown.\nClinical description\nThis serological disorder is almost invariably associated with well-known hematological disorders, usually B-cell dyscrasias (multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia; see these terms). Type I cryoglobulinemia is frequently asymptomatic per se but patients may develop acrocyanosis, retinal hemorrhage, Raynaud's phenomenon, and arterial thrombosis. These symptoms may be the expression of hyperviscosity syndrome due to high levels of monoclonal cryoglobulins. The cryoprecipitate in type I cryoglobulinemia is usually composed of IgG or IgM, but infrequent cases with IgA and very rarely monoclonal light-chain protein cryoprecipitation have been reported. Type I cryoglobulins lack rheumatoid factor activity (RF) and do not easily activate complement.\nEtiology\nThe pathogenetic processes in simple cryoglobulinemia generally appear to be related to those of the underlying lymphoproliferative diseases. The mechanisms of cryoprecipitation are poorly understood but may be partially related to the structure of the component immunoglobulin heavy and light chains.\nDiagnostic methods\nDiagnosis is based on detection of cryoglobulins through blood sampling, clotting, and serum separation (carried out at 37°C), and cryoglobulin isolation and cryocrit determination (carried out at 4°C). Ig composition is commonly evaluated by simple diffusion on agarose gels or by immunoelectrophoresis (performed at 37°C to avoid precipitation and loss of cryoglobulins during the procedures).\nDifferential diagnosis\nThe principle differential diagnosis is mixed cryoglobulinemia (MC type II-III; see these terms). Type I cryoglobulinemia and MC type II-III are two distinct clinico-serological entities. In contrast to type I cryoglobulinemia, the cryoprecipitate in MC type II-III is composed ofimmune complexes containing polyclonal IgGs and mono- (type II) or polyclonal (type III) IgMs. Patients with simple cryoglobulinemia lack the typical vasculitic manifestations and serological findings (RF positivity and low complement C4) that characterize MC patients. Clinical course, treatment, and prognosis of type I cryoglobulinemia largely depend on the underlying disorder. Patients with a benign monoclonal gammopathy of undetermined significance are generally asymptomatic or present with a mild disorder.\nManagement and treatment\nPlasma exchange treatment, with/without steroids and/or immunosuppressors, is beneficial for simple cryoglobulinemia patients presenting with clinically overt hyperviscosity syndrome. In patients with malignant B-cell neoplasias, the chemotherapy may lead to resolution of this serological manifestation.\n\n                            Last update: \n                            October 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Clodoveo FERRI"}
{"Disease Name": "Simpson-Golabi-Behmel syndrome", "Disease Definition": "A rare X-linked multiple congenital anomalies syndrome characterized by pre- and postnatal overgrowth, distinctive craniofacial features, variable congenital malformations, organomegaly and an increased tumor risk.", "ORPHA ID": 373, "Summary": "Epidemiology\nThe birth prevalence is unknown. Approximately 250 cases have been reported to date.\nClinical description\nSimpson-Golabi-Behmel syndrome (SGBS) manifests a broad clinical picture with varying degrees of severity. It is characterized by pre- and postnatal overgrowth with macrosomia, distinctive craniofacial features (macrocephaly with coarse face, macroglossia, hypertelorism, dental malocclusion, palatal abnormalities), supernumerary nipples, congenital heart defects and arrhythmias, vertebral segmental defects, abdominal visceromegaly (renal dysplasia/nephromegaly, splenomegaly and hepatomegaly), diaphragmatic hernia, diastasis recti/umbilical hernia, limb anomalies (polydactyly/brachydactyly of the hands, cutaneous syndactyly, nail hypoplasia), and genital involvement (cryptorchidism, hypospadias). Involvement of central nervous system presents with variable degrees of intellectual disability, motor delay and speech delay. Patients with SGBS are at increased risk for embryonal tumors (Wilms tumor), hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma.\nEtiology\nSGBS is due to loss-of-function mutations in the GPC3 gene (Xq26), encoding Glypican-3 (GPC3), a cell surface heparin sulfate proteoglycan which acts as a negative regulator of Hedgehog (Hh) signaling during development. Mutations in GPC3 result in the hyperactivation of Hh signaling, that ultimately leads to overgrowth and cancer.\nDiagnostic methods\nDiagnosis is based on clinical findings, family history, genetic testing for GPC3 mutations, and array comparative genomic hybridization (aCGH) analysis of genomic imbalance in Xq26. Imaging techniques help to detect skeletal anomalies and central nervous system involvement. Screening for embryonic tumors is performed by imaging (serial abdominal ultrasonogram and chest X rays), serial measurement of tumor markers and catecholamine metabolites in urine. Kidney function is monitored in cases of kidney involvement.\nDifferential diagnosis\nDifferential diagnosis include overgrowth syndromes such as Beckwith-Wiedemann syndrome and Sotos syndrome, and additional disorders such as fragile X syndrome, Bannayan-Zonana syndrome, PTEN hamartoma tumor syndrome, Marshall syndrome, Nevo syndrome, mosaic trisomy 8 and Pallister-Killian syndrome.\nAntenatal diagnosis\nPrenatal diagnosis and/or pre-implantation genetic testing are possible for at-risk pregnancies when a mutation has previously been identified in the family. Prenatal ultrasound examination can detect disproportionate fetal overgrowth, while elevated maternal serum alpha-fetoprotein (AFP) levels may also be useful to suspect SGBS.\nGenetic counseling\nSGBS follows an X-linked recessive pattern of transmission. In the offspring of an affected male, daughters are heterozygous and sons are unaffected. For each pregnancy, a heterozygous female has a 25% risk of having an affected son and a 25% risk of having a carrier daughter (usually not affected or showing minimal clinical findings due to lyonization). SGBS may also result from de novo mutations (20-30% of cases).\nManagement and treatment\nManagement requires a multidisciplinary approach with pediatric cardiologists, neurologists, orthopedics, and speech therapists. Congenital malformations may require surgery. Special attention should be paid to cardiac abnormalities that are responsible for the increased perinatal and infant mortality. Tumor management and follow-up should be performed.\nPrognosis\nPrognosis depends on the severity of the disease; in the most severe cases, SGBS is life-threatening before birth or in infancy, whereas in milder cases patients often live into adulthood.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Pablo LAPUNZINA | ITHACA* - Dr Jair Antonio TENORIO CASTAÑO \n\n\n                                * European Reference Network"}
{"Disease Name": "Sinding-Larsen-Johansson disease", "Disease Definition": "A rare osteochrondrosis characterized by chronic traction injury of the immature osteotendinous junction where the patellar tendon inserts into the inferior pole of the patella. It is typically seen in active adolescents. Patients present with point tenderness at the inferior pole of the patella associated with focal swelling and restriction of knee joint range of movement. Radiographic features include thickening of the proximal patellar tendon (potentially followed by dystrophic calcification and/or ossification) and fragmentation of the inferior pole of the patella.", "ORPHA ID": 97337, "Summary": ""}
{"Disease Name": "Single-organ polyarteritis nodosa", "Disease Definition": "Single-organ polyarteritis nodosa (PAN) is a rare, often mild form of PAN characterized by limited disease without generalized manifestations, most often affecting the skin (cutaneous PAN; see this term), the brain, eyes, pancreas, testicles, ureter, breasts, or ovaries. Affected patients are often younger than those with systemic PAN (see this term) and relapses appear to be more common.", "ORPHA ID": 439755, "Summary": ""}
{"Disease Name": "Singleton-Merten dysplasia", "Disease Definition": "Singleton-Merten dysplasia is characterized by dental dysplasia, progressive calcification of the thoracic aorta with stenosis, osteoporosis and expansion of the marrow cavities in hand bones. Additional features included generalized muscle weakness and atrophy, and chronic psoriasiform skin eruptions. It has been reported in four unrelated patients (male and female) and in a family with multiple affected members (male).", "ORPHA ID": 85191, "Summary": ""}
{"Disease Name": "Sinoatrial node dysfunction and deafness", "Disease Definition": "Sinoatrial node dysfunction and deafness is a rare genetic disease characterized by congenital severe to profound deafness with no evidence of vestibular dysfunction, associated with sinoatrial node dysfunction with pronounced bradycardia and increased variability of heart rate at rest and episodic syncopes that may be triggered by enhanced physical activity and stress.", "ORPHA ID": 324321, "Summary": ""}
{"Disease Name": "Sirenomelia", "Disease Definition": "A rare, lethal, congenital anomaly that may represent the most severe form of caudal dysgenesia and characterized by fusion of the lower limbs (mermaid-like) always associated with severe genitourinary and gastrointestinal anomalies. Furthermore, there is wide phenotipical variability in the musculoskeletal, central nervous system, cardiopulmonary, anomalies present. Pelvic, sacral and spinal defects , internal and external genitalia defects, renal agenesis, absent bladder, rectal/anal atresia are commonly described. Most cases are stillborn or die during, or shortly after, birth. Sirenomelia can be classified on the basis of limb malformations phenotypes. Due to the similarity, the distinction between sirenomelia and caudal regression syndrome, familial caudal dysgenesis and VACTERL is debated.", "ORPHA ID": 3169, "Summary": ""}
{"Disease Name": "Sitosterolemia", "Disease Definition": "Sitosterolemia is a rare autosomal recessive sterol storage disease characterized by the accumulation of phytosterols in the blood and tissues. Clinical manifestations include xanthomas, arthralgia and premature atherosclerosis. Hematological manifestations include hemolytic anemia with stomatocytosis and macrothrombocytopenia. The disease is caused by homozygous or compound heterozygous mutations in ABCG5 (2p21) and ABCG8 (2p21) genes.", "ORPHA ID": 2882, "Summary": ""}
{"Disease Name": "Situs ambiguus", "Disease Definition": "A rare, genetic, developmental defect during embryogenesis characterized by a partial mirror-image transposition of intra-thoracic and/or intra-abdominal organs across the left-right axis of the body. Intra-organ variations and other malformations, such as ciliary motricity anomalies (e.g. Kartagener syndrome), biliary atresia and cardiac defects, are frequently associated. Left (polysplenia syndrome) or right (asplenia syndrome) isomerism are usually observed.", "ORPHA ID": 157769, "Summary": ""}
{"Disease Name": "Situs inversus totalis", "Disease Definition": "A rare, genetic, developmental defect during embryogenesis characterized by total mirror-image transposition of both thoracic and abdominal viscera across the left-right axis of the body. Congenital abnormalities, such as primary ciliary dyskinesia, Kartagener type, polysplenia syndrome, biliary atresia, congenital heart disease, and midgut malrotation, as well as vascular anomalies (e.g. absence of retrohepatic inferior vena cava, preduodenal portal vein, aberrant hepatic arterial anatomy) and malignancy, are frequently associated.", "ORPHA ID": 101063, "Summary": ""}
{"Disease Name": "SIX2-related frontonasal dysplasia", "Disease Definition": "A rare frontonasal dysplasia characterized by a craniofacial phenotype comprising frontal bossing with high anterior hairline, ptosis, hypertelorism, epicanthus inversus, flat nasal bridge, and broad nasal tip. Large anterior fontanelle, sagittal synostosis, and cranial base anomalies have also been described.", "ORPHA ID": 488437, "Summary": ""}
{"Disease Name": "Sjögren-Larsson syndrome", "Disease Definition": "A rare neurocutaneous disorder caused by an inborn error of lipid metabolism and characterized by congenital ichthyosis, intellectual deficit, and spasticity.", "ORPHA ID": 816, "Summary": "Epidemiology\nPrevalence is estimated at 1/250,000 worldwide, but the syndrome is more common in Sweden due to a founder effect.\nClinical description\nClinical features develop perinatally and during infancy. Patients tend to be born preterm. Hyperkeratosis is usually present at birth and progresses to a generalized ichthyosis, particularly prominent on flexural areas, the nape of the neck, the trunk and the extremities. Pruritus is a prominent feature. Erythematous dermatitis is often present at birth, and then tends to fade with increasing age. Neurological signs appear during the first two years of life and consist of delay in reaching motor milestones due to spastic diplegia or, much less commonly, spastic tetraplegia. Approximately one-half of patients are non-ambulatory. Seizures occur in about 40% of cases. Intellectual deficit varies from mild to severe, although rare patients with normal intellect have been reported. Delayed speech and dysarthria are common. Ophthalmologic involvement is often present and is characterized by retinal crystalline inclusions (so-called glistening white dots) surrounding the fovea. Photophobia and myopia are common.\nEtiology\nSLS is caused by mutations in the ALDH3A2 gene (17p11.2) encoding fatty aldehyde dehydrogenase (FALDH), an enzyme that catalyzes the oxidation of fatty aldehydes to fatty acids. More than 90 mutations in ALDH3A2 have been identified, including amino acid substitutions, deletions, insertions, splicing errors and contiguous gene deletions.\nDiagnostic methods\nSLS is diagnosed based on the clinical features, and by measuring FALDH or fatty alcohol oxidoreductase (FAO) activity in cultured fibroblasts from skin biopsies. DNA-based diagnosis is possible by directly sequencing the ALDH3A2 gene and identifying pathogenic mutations.\nDifferential diagnosis\nIn early infancy, before the onset of spasticity, the differential diagnosis includes other forms of congenital ichthyosis including lamellar ichthyosis and congenital ichthyosiform erythroderma. Once neurologic symptoms appear, the differential diagnosis includes other neuro-ichthyotic syndromes such as neutral lipid storage disease (Chanarin-Dorfman syndrome), ELOVL4 deficiency, multiple sulfatase deficiency and Refsum disease.\nAntenatal diagnosis\nAntenatal diagnosis is possible through biochemical or molecular analysis of amniocytes or chorionic villus cells.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement should be multidisciplinary including neurologists, dermatologists, ophthalmologists, orthopedic surgeons, and physiotherapists. The treatment of ichthyosis consists of topical application of moisturizing creams and keratolytic agents, or use of systemic retinoids. Seizures usually respond to anti-convulsant medications and spasticity is alleviated by botulinum toxin injections or surgical procedures. Special diets with medium-chain fatty acid supplements may help the ichthyosis, but effects are limited.\nPrognosis\nPatients usually survive until adulthood but require life-long care. Minimal progression of the neurologic findings or intellectual deficit occurs after puberty. Patients with early symptoms tend to be more severely affected.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Dr William RIZZO"}
{"Disease Name": "Skeletal dysplasia-epilepsy-short stature syndrome", "Disease Definition": "A rare, genetic dysostosis malformation syndrome characterized by skeletal dysplasia (rabbit ear-shaped iliac alae, delayed bone age, abnormalities of the vertebral bodies and schisis of the vertebral arches), seizures, short stature, cerebral atrophy and moderate to severe intellectual disability. Additional variable manifestations include corneal and retinal abnormalities, cataract, prognathism, dental malocclusion, brachydactyly, clinodactily, slight generalized hypotonia and hyper extensible joints.", "ORPHA ID": 1858, "Summary": ""}
{"Disease Name": "Skeletal dysplasia-T-cell immunodeficiency-developmental delay syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of developmental delay, variable intellectual disability, skeletal dysplasia, and in many cases T-cell immunodeficiency and other immunologic abnormalities. Skeletal findings include short stature, anomalies of the long bones, hands and feet, and pelvis, platyspondyly, cervical malformation, and pectus excavatum. Dysmorphic facial features, such as coarse face, hypertelorism, and broad nasal tip, may be present. Additional reported manifestations are seizures, hyperreflexia, nystagmus, and muscular hypotonia, as well as multiple liver cysts.", "ORPHA ID": 508533, "Summary": ""}
{"Disease Name": "Skeletal Ewing sarcoma", "Disease Definition": "Ewing's sarcoma is a malignant small round cell bone tumor with strong metastatic potential.", "ORPHA ID": 319, "Summary": "Epidemiology\nAnnual incidence is estimated at 1/312,500 in children under the age of 15.\nClinical description\nIt occurs between the ages of 5 and 30 with a peak of incidence between ages 12 and 18. The most frequent symptom is pain. Other symptoms depend on the organs closest to the tumor: motor, sphincteric disorders caused by nervous compression or mechanical disorders are associated with pelvic tumors; respiratory disorders or pleural effusion are associated with costal tumors; medullar or radicular compression are associated with vertebral tumors. The tumor initially develops most frequently in bone, particularly in the pelvis (30%), thorax (rib, clavicle, scapula) (20%), femur (16%), tibia (9%), vertebrae (8%) and humerus (5%). The disease has a high potential for metastases (lung, bone, bone marrow). Neuroepithelioma is a highly differentiated neural variant (see this term). Askin's tumor is a thoracic variant which can be slightly or well differentiated.\nEtiology\nAlthough no specific cause has been identified, a specific translocation involving the EWSR1 gene (22q12.2) is present in 90% of tumors of this type, most often a translocation t(11;22)(q24;q29). Many variants of this translocation have been described (involving the ERG, ETV1, FLI1 and NR4A3 genes).\nDiagnostic methods\nThe diagnosis is suggested after the identification, by PCR (polymerase chain reaction), of these translocations.\nDifferential diagnosis\nDifferential diagnoses include other small round cell tumors: neuroblastoma, embryonal or alveolar rhabdomyosarcoma, non-Hodgkin's lymphoma and mesenchymatous chondrosarcomas (see these terms). The existence of a translocation involving the EWSR1 gene allows these diseases to be ruled out.\nManagement and treatment\nTreatment should be managed by a multidisciplinary team with expertise in treating childhood cancers. Treatment starts systematically with chemotherapy to reduce the size of the primary tumor and to eradicate or prevent metastases. Surgery is recommended whenever the location of the tumor allows. Local radiotherapy is sometimes necessary, either in addition to surgery or alone for inoperable tumors. For more severe forms of the disease (limited response to initial chemotherapy or metastases already present at diagnosis), high dose chemotherapy with stem cell transplantation can be suggested as a last resort treatment. Targeted therapies, for example with anti-IGF-R (insulin-like growth factor receptor), are currently being studied.\nPrognosis\nSurvival without recurrence of localized forms is around 70%. For forms with lung metastases the survival rate is around 50%. Forms with metastases of the bones or bone marrow have a more severe prognosis.\n\n                            Last update: \n                            February 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Odile OBERLIN"}
{"Disease Name": "Skin fragility-woolly hair-palmoplantar keratoderma syndrome", "Disease Definition": "A rare, genetic, ectodermal dysplasia syndrome characterized by persistent skin fragility which manifests with blistering and erosions due to minimal trauma, woolly hair with variable alopecia, hyperkeratotic nail dysplasia, diffuse or focal palmoplantar keratoderma with painful fissuring, and no cardiac abnormalities. Perioral hyperkeratosis may also be associated.", "ORPHA ID": 293165, "Summary": ""}
{"Disease Name": "SLC35A1-CDG", "Disease Definition": "SLC35A1-CDG is an extremely rare form of CDG syndrome (see this term) characterized clinically in the single reported case by repeated hemorrhagic incidents, including severe pulmonary hemorrhage.", "ORPHA ID": 238459, "Summary": ""}
{"Disease Name": "SLC35A2-CDG", "Disease Definition": "A rare, congenital disorder of glycosylation characterized by severe or profound global developmental delay, early epileptic encephalopathy, muscular hypotonia, dysmorphic features (coarse facies, thick eyebrows, broad nasal bridge, thick lips, inverted nipples), variable ocular defects and brain morphological abnormalities on brain MRI (cerebral atrophy, thin corpus callosum).", "ORPHA ID": 356961, "Summary": ""}
{"Disease Name": "SLC39A13-related spondylodysplastic Ehlers-Danlos syndrome", "Disease Definition": "A form of spondylodysplastic Ehlers-Danlos syndrome (EDS) due to variants in the SLC39A13 gene and characterized by the presence of thin and finely wrinkled skin of the hands and feet, hypermobile distal joints, characteristic facial features (downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish sclerae, microdontia or oligodontia), muscular hypotonia, associated with significant short stature of childhood-onset, ocular findings (myopia and keratoconus) and, more rarely, vascular complications. Mild radiographic changes were observed, among which platyspondyly is a useful diagnostic feature.", "ORPHA ID": 157965, "Summary": "Epidemiology\nTo date, 13 individuals with molecularly diagnosed SLC39A13-related spondylodysplastic Ehlers-Danlos syndrome, have been reported.\nClinical description\nThe main features in affected individuals are significant short stature of childhood-onset, characteristic facial features which may be sufficient to suggest the diagnosis (downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish/greyish sclerae, small mouth, and microdontia or oligodontia), connective tissue weakness affecting mainly the skin and peripheral joints, muscular hypotonia and a moderate skeletal dysplasia. The skin is soft, thin and finely wrinkled, especially on the hands and feet, moderately hyperelastic with bruisability and atrophic scars. Affected patients present moderate hypermobility (especially of the small joints) hands with finely wrinkled palms, thenar and hypothenar atrophy, and tapering fingers. Due to muscular hypotonia, motor development may be slightly delayed, but intelligence in reported cases is normal. Body proportions are normal and post-natal short stature seems to be more intrinsic and represents a true growth failure and not a consequence of bone dysplasia. Skeletal radiographs show mild changes, among which platyspondyly of the thoracic and lumbar spine is a useful diagnostic pointer. Other signs are the following: irregular vertebral end plates, with concave conformation, minor epimetaphyseal alterations in appendicular bones, especially of the distal ulna, diaphyseal overconstriction of radius and ulna. Bowing of limbs, pes planus and osteopenia have been described. Hypodontia and oligodontia are particular features of the disorder. Among the eye findings, myopia has been described in various patients, in addition to keratoconus, particularly dangerous due to the possibility of perforation or rupture. Vascular complications, such as varicose veins of the lower legs and cerebral hemorrhage have been described in the 2 elderly patients.\nEtiology\nThe disorder is due to variants of the SLC39A13 gene (11p11.2), encoding for the zinc transporter protein Zrt- and Irt-like protein 13 (ZIP13) which forms a homo-dimer consisting of 8 transmembrane domains and 4 intracellular loops.\nDiagnostic methods\nDiagnosis is based on clinical examination, radiological studies and molecular findings.\nDifferential diagnosis\nDifferential diagnosis includes other spondylodysplastic Ehlers-Danlos syndromes and genetic conditions with significant short stature of childhood-onset, joint hypermobility, and thin and finely wrinkled skin.\nAntenatal diagnosis\nPrenatal diagnosis is possible where a known pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement requires a multi-disciplinary approach. Specific regular follow-up is recommended based on the patient's clinical manifestations. Ophthalmologic investigation should be required in all confirmed cases.\nPrognosis\nWhilst only 3 adult patients have been reported in the literature, data is currently limited with respect to life expectancy. Cerebral hemorrhage has been described in 2 elderly patients; however, it unclear whether this complication is related to the disease and, to date, there are no known reasons to suspect a reduced life expectancy. The functional consequences and quality of life depend on disease severity. The pathology is not progressive.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Livia GARAVELLI | ITHACA* - Dr Gabriele TRIMARCHI | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "SLC39A8-CDG", "Disease Definition": "A rare congenital disorder of glycosylation characterized by infantile onset of global developmental delay, severe intellectual disability, hypotonia, and variable additional features including short stature, cranial asymmetry, seizures, strabismus, recurrent infections, and osteopenia, among others. Laboratory analysis reveals decreased blood levels of zinc and manganese, as well as an abnormal serum transferrin glycosylation pattern with decreased tetrasialo- and increased asialo-, monosialo-, disialo, and trisialo-transferrin, consistent with a type II congenital disorder of glycosylation. Brain imaging shows cerebellar and/or cerebral atrophy.", "ORPHA ID": 468699, "Summary": ""}
{"Disease Name": "Small bowel atresia", "Disease Definition": "A rare, congenital defect of the small intestine characterized by disruption in the normal small intestine continuity, resulting in intestinal obstruction. The malformation may be classified in four different types of small bowel atresia (SBA) based on the anatomical obstruction.", "ORPHA ID": 1201, "Summary": "Epidemiology\nThe prevalence at birth ranges from 1/7,000-25,000 in Europe with equal male/female distribution. About one third of patients are premature. Other congenital anomalies are present in < 10% and occur more frequently with type IIIb or type IV atresia.\nClinical description\nThe type of SBA is important for surgical treatment and prognosis. Type I corresponds to a narrowed intestine with intact walls and mesentery, and a mucous membrane obstructing the lumen. Type II is a true short segment atresia with a fibrous cord between the upper and lower pouch, without a mesenteric defect. Type IIIa consists of a ''V''-shaped mesenteric defect and a blind-ending, dilated proximal pouch without fibrous connection to the distal part. Type IIIb (''apple-peel'', ''Christmas tree'' atresia) is characterized by proximal jejunal atresia, absence of the superior mesenteric artery and a large mesenteric defect with the small bowel assuming a helical configuration around a single perfusing vessel with possible distal type I or II atresia. Type IV is the combination of multiple atresias. Clinical presentation of all types occurs in the first 24-48h of life, depending on the proximity of the first atretic tract to the Treitz ligament, with signs of bowel obstruction (feeding intolerance, bilious vomiting, abdominal distention). Meconium can be passed normally. Complicated cases might present abruptly, with signs of perforation, intussusception, volvulus or internal hernia. Perforation of the proximal dilated bowel can occur in both the antenatal and postnatal life causing meconium peritonitis. In the case of low atresia or incomplete obstruction, clinical manifestations and diagnosis are usually delayed, with failure to thrive and progressive intestinal obstruction.\nEtiology\nThe prevailing hypothesis is that an ischemic insult affecting single or multiple segments of the developed fetal intestine with subsequent necrosis and resorption is the main cause of SBA. Disruption of an embryologic pathway has been suggested for familial forms but no causative genes have yet been identified.\nDiagnostic methods\nDiagnosis relies on clinical evaluation, pre- and post-natal history, together with abdominal X-rays that reveal a distended proximal bowel with no air distally. Abdominal ultrasonography shows dilated small intestinal loops with fluid collection. In case of intestinal perforation free air is present. In children with distal defects and/or poor sucking, radiological and clinical findings can be delayed. A contrast enema can be useful.\nDifferential diagnosis\nDifferential diagnosis includes: colonic atresia, midgut volvulus, meconium ileus, duplication cysts, internal hernias, paralytic ileus, high Hirschsprung´s disease and hypothyroidism.\nAntenatal diagnosis\nAbout 30-50% of cases are suspected antenatally. Dilated bowel loops and polyhydramnios are the typical findings.\nGenetic counseling\nWhilst the majority of cases are sporadic, familial cases have been reported and thus genetic counselling is always recommended. An autosomal recessive pattern of inheritance of multiple atresias has been documented.\nManagement and treatment\nBowel decompression via naso-gastric tube, fluid resuscitation and antibiotics are the bridge to surgical correction (restoration of bowel continuity). Surgery must not be delayed, in order to avoid complications. Preserving the largest amount of small bowel tissue is mandatory during surgery. Resections and tapering must be considered. Prolonged parenteral nutrition is often required, particularly in the case of short bowel syndrome. In children on permanent parenteral nutrition, intestinal lengthening procedures may be considered to decrease the need for parenteral nutrition.\nPrognosis\nThe current survival rate is over 90%. Prognosis mainly depends on the length of the remaining bowel and the subsequent possibility of a short bowel syndrome. Type IIIb and type IV carry a worse prognosis.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Francesco FASCETTI LEON | ERNICA* - Pr Niels QVIST | ERNICA* - Dr Alessandra RANCAN \n\n\n                                * European Reference Network"}
{"Disease Name": "Small cell carcinoma of the bladder", "Disease Definition": "Small cell carcinoma of the bladder (SCCB) is a very rare, poorly differentiated neuroendocrine epithelial bladder tumor characterized clinically by hematuria and/or dysuria and a highly aggressive course.", "ORPHA ID": 284400, "Summary": "Epidemiology\nSCCB is extremely rare with an annual incidence of less than 1-9/1,000,000. Since 1980, fewer than 1,500 cases have been identified. The demographic profile of SCCB is similar to that of patients with bladder transitional cell carcinoma (TCC). The majority of patients are male, with a mean sex ratio of 5:1, and a range between 1:1 to 16:1. The vast majority of cases were reported in the Caucasian population.\nClinical description\nMost knowledge on SCCB is based on retrospective investigations and on a few prospective studies. Mean age at diagnosis is 67 years (range 32 to 91 years). The clinical features of SCCB are similar to those of bladder TCC and reflect the presence of a tumoral mass. The main symptom is gross hematuria (63 to 88% of cases) with dysuria as the second most common symptom. Urinary obstruction, abdominal pain, urinary tract infection and weigh loss are occasionally present. SCCB often occurs with other types of carcinoma and is frequently found combined with other histological forms of bladder cancer: TCC, adenocarcinoma and squamous cell carcinoma. SCCB is generally believed to have a high metastatic potential. Rare cases of paraneoplastic syndromes such as ectopic ACTH secretion and hypercalcemia have also been reported.\nEtiology\nThe etiology of the disease is unknown but a multipotent stem cell anomaly is thought to be a likely mechanism. A history of smoking is found in 65% to 79% of cases.\nDiagnostic methods\nHistology and immunohistochemistry show a tumor that is indistinguishable from small cell lung cancer (SCLC; see this term). Diagnosis of SCCB relies mainly on histopathological data obtained by cystoscopy and transurethral resection of the bladder tumor. Immunochemistry staining is useful in establishing the diagnosis. Light microscopy reveals packed cells having scant cytoplasm containing few organelles. Tumors are composed of nests of small round malignant cells with pyknotic round to oval nuclei and evenly dispersed ''salt and pepper chromatin''. More than 95% of SCCB cases are diagnosed at muscle invasive stage T2 or later.\nDifferential diagnosis\nThe differential diagnosis includes direct invasion of the bladder by SCC of the prostate, metastatic SCC from another source, usually the lung, and primary lymphomas of the bladder.\nManagement and treatment\nThe staging system used is the TNM-staging of bladder transitional cell carcinoma. Treatment is extrapolated from that of SCLC. However, many patients with SCCB undergo radical resection which is rarely performed in SCLC. Patients with surgically resectable disease should be managed with multimodal therapy associating chemotherapy, surgery and/or radiotherapy. Neoadjuvant chemotherapy using 4 chemotherapy cycles followed by radical cystectomy is the most effective therapeutic sequence. Patients with unresectable disease should be managed with palliative chemotherapy based on neuroendocrine-type regimens comprising a platinum drug (cisplatin in fit patients). Prophylactic cranial irradiation should be considered in stages III/IV bladder SCC.\nPrognosis\nThe prognosis of the disease is poor mainly in the case of pure small cell carcinoma.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr NABIL ISMAILI"}
{"Disease Name": "Small cell carcinoma of the ovary", "Disease Definition": "Small cell carcinoma of the ovary is a rare, highly aggressive, poorly differentiated ovarian neoplasm, often associated with paraneoplastic hypercalcemia. It is usually diagnosed in childhood or young adulthood at an advanced stage and presents with abdominal or pelvic mass or, rarely, symptoms related to hypercalcemia. Occasional familial cases have been reported.", "ORPHA ID": 370396, "Summary": ""}
{"Disease Name": "Small cell lung cancer", "Disease Definition": "Small cell lung cancer (SCLC) is a highly aggressive malignant neoplasm, accounting for 10-15% of lung cancer cases, characterized by rapid growth, and early metastasis. SCLC usually manifests as a large hilar mass with bulky mediastinal lymphadenopathy presenting clinically with chest pain, persistent cough, dyspnea, wheezing, hoarseness, hemoptysis, loss of appetite, weight loss, and neurological and endocrine paraneoplastic syndromes. SCLC is primarily reported in elderly people with a history of long-term tobacco exposure.", "ORPHA ID": 70573, "Summary": ""}
{"Disease Name": "SMARCA4-deficient sarcoma of thorax", "Disease Definition": "A rare soft tissue tumor characterized by a compressive mass located in the mediastinum and/or pleura and lung, including prominent lymph node involvement, histologically poorly differentiated and frequently showing rhabdoid features. Loss of SMARCA4 is typically accompanied by SMARCA2-deficiency. Presenting symptoms include dyspnea, cough, chest pain, or dysphagia, among others. The tumors are aggressive with limited response to chemotherapies, rapid local progression, high recurrence rate after surgical resection, and short median survival times. There is a strong association with smoking.", "ORPHA ID": 466962, "Summary": ""}
{"Disease Name": "Smith-Lemli-Opitz syndrome", "Disease Definition": "Smith-Lemli-Opitz syndrome (SLOS) is characterized by multiple congenital anomalies, intellectual deficit, and behavioral problems.", "ORPHA ID": 818, "Summary": "Epidemiology\nSLOS is most common in central and northern Europe with an estimated incidence of around 1/ 20,000 to 1/ 40,000 births.\nClinical description\nThe disease is present at birth, but may be detected in later childhood or adulthood in mild forms. Patients present with growth retardation and intellectual deficit. Behavioral problems include multiple autistic traits, hyperactivity, self-injurious behavior and sleep disturbances. The structural brain anomalies may include hypoplasia or absence of the corpus callosum, and holoprosencephaly. Microcephaly (80% of cases), bitemporal narrowing, ptosis, a broad nasal bridge, short nasal root, anteverted nares (90% of cases), a small chin, and micrognathia are common craniofacial features. Occasionally, cataract, strabismus, and nystagmus are observed. Other clinical features include cleft palate or bifid uvula (1/3 of patients), photosensitivity, rhizomelia and postaxial polydactyly of the hands or feet, syndactyly of the 2nd and 3rd toes (95% of cases), and short and proximally placed thumbs. Genital anomalies (small penis, hypospadias, ambiguous genitalia) are frequent in males (70% of cases). Cardiovascular anomalies (atrial and ventricular septal defects, patent ductus arteriosus, atrioventricular canal) can be present. Gastrointestinal anomalies including poor feeding, gastroesophageal reflux, pyloric stenosis, malrotation, and colonic aganglionosis are frequent.\nEtiology\nSLOS is due to an inborn error of cholesterol synthesis and is caused by mutations in the DHCR7 gene (11q13.4) leading to deficiency of the enzyme 3 beta-hydroxysterol-delta 7-reductase that converts 7-dehydrocholesterol (7DHC) to cholesterol.\nDiagnostic methods\nDiagnosis is based on the detection of elevated 7DHC levels in plasma or tissues. Mutation analysis confirms the diagnosis. Imaging studies (CT, MRI, echocardiogram) may be performed to detect malformations.\nDifferential diagnosis\nhe differential diagnosis includes lathosterolosis, desmosterolosis, Dubowitz syndrome, Cornelia De Lange syndrome, oculo-digito-esophago-duodenal syndrome, Noonan syndrome, Pallister-Hall syndrome, trisomy 13 and trisomy 18 (see these terms), and pseudotrisomy 13.\nAntenatal diagnosis\nPrenatal diagnosis may be suspected at fetal ultrasonography and should be confirmed by analysis of amniotic fluid or chorionic villous samples, measurements of 7DHC content and mutation analysis if DHCR7 mutations have already been identified in the family.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nManagement is symptomatic and most patients are treated with dietary cholesterol supplementation. Treatment trials are underway investigating combined treatment with cholesterol supplementation and a HMG CoA reductase inhibitor (simvastatin). Surgery is proposed in case of secondary problems due to malformations.\nPrognosis\nPrognosis depends on the severity of the disease and on the associated malformations. Heart disease and brain malformations may be lethal. Some individuals live into adulthood. Mildly affected individuals may be able to live and work in a group home setting.\n\n                            Last update: \n                            November 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Simona BIANCONI  - Dr Forbes PORTER"}
{"Disease Name": "Smith-Magenis syndrome", "Disease Definition": "A rare, genetic, neurodevelopmental disorder characterized by cognitive impairment of variable severity, behavioral abnormalities, and sleep disturbance. Patients present with distinctive physical features and a wide range of malformations (e.g. cardiac, renal).", "ORPHA ID": 819, "Summary": "Epidemiology\nSmith-Magenis syndrome (SMS) has an estimated prevalence of 1/15,000-25,000 and has been identified worldwide in all ethnic groups, but is probably underdiagnosed. Males and females are affected equally.\nClinical description\nPatients have a recognizable clinical picture. Craniofacial features include brachycephaly, a broad square-shaped face, synophrys, mildy upslanted palpebral fissures, midface retrusion with relative prognathism with age, and an everted upper lip with a ''tented'' appearance. Short stature is common in young patients, with height typically in the normal range as adults. Excess weight and/or obesity in teens and adults are common. Other skeletal anomalies include brachydactyly, clinodactyly of the 5th finger, 2-3 toe syndactyly and scoliosis. Otolaryngological problems such as velopharyngeal insufficiency, laryngeal anomalies, a hoarse deep voice and otitis media occur frequently. Hearing loss is frequent and may be mild to moderate. Ophthalmologic features (>80%) include strabismus, myopia, iris anomalies and retinal detachment (often resulting from violent behaviors). The majority of individuals function in the mild to moderate range of intellectual disability. Significant speech delay and maladaptive behaviors (outbursts/temper tantrums, nail yanking, insertion of foreign objects into body orifices, self-injurious behaviors, attention seeking, and anxiety) are common. Sleep disturbance is due to an inversion of the circadian rhythm of melatonin. Organ malformations include cardiac, renal and central nervous system abnormalities.\nEtiology\nSMS is typically a sporadic disorder caused either by a 17p11.2 deletion encompassing the retinoic acid-induced 1 (RAI1) gene (90%) or a mutation of the gene (10%). Patients with a mutation can have a less severe phenotype, and manifestations may have a later onset in the least severe cases.\nDiagnostic methods\nDiagnosis is based on initial clinical suspicion followed by molecular confirmation of the genetic defect. Careful history-taking for birth defects, sleep disturbance, delayed milestones, chronic ear infections, self-injurious behaviors, and family history are important to recognize the characteristic features.\nDifferential diagnosis\nDifferential diagnoses include Down syndrome, Williams syndrome, brachydactyly-intellectual deficit syndrome (del 2q37), and Kleefstra syndrome.\nAntenatal diagnosis\nAlmost all cases correspond to a single occurrence in a family, but prenatal testing can be offered for at-risk pregnancies where the genetic alteration has been previously identified in an affected family member.\nGenetic counseling\nThe disorder is autosomal dominant with most cases arising sporadically. Genetic counseling is recommended to affected families due the possibility of vertical transmission, parental germline mosaicism, and complex familial chromosome rearrangements. When a chromosomal deletion is identified, parental chromosomal testing is recommended to rule-out any translocation or other rearrangements that might affect the recurrence risk.\nManagement and treatment\nAppropriate assessment of the degree of cognitive, developmental, and behavioral deficits and of systemic/organ abnormality is essential for appropriate and specific management. Treatment is symptomatic and may include psychotropics intended to increase attention, decrease hyperactivity and stabilize behavior and treatment for sleep disorders. However, no single regimen has shown consistent efficacy. Family psychosocial support is recommended.\nPrognosis\nPrognosis depends on age of diagnosis, disease severity, and precocity of therapeutic interventions.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Laurence PERRIN | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Smith-McCort dysplasia", "Disease Definition": "Smith-McCort dysplasia (SMC) is a rare spondylo-epi-metaphyseal dysplasia characterized by the clinical manifestations of coarse facies, short neck, short trunk dwarfism with barrel-shaped chest and rhizomelic limb shortening, as well as specific radiological features (i.e. generalized platyspondyly with double-humped vertebral end plates and iliac crests with a lace-like appearance) and normal intelligence. The clinical and skeletal features are similar to those seen in the allelic disorder Dyggve-Melchior-Clausen syndrome (DMC; see this term), but can be distinguished from this syndrome by the absence of intellectual deficiency and microcephaly in SMC.", "ORPHA ID": 178355, "Summary": ""}
{"Disease Name": "Smoldering systemic mastocytosis", "Disease Definition": "A rare, slowly progressive form of systemic mastocytosis (SM) characterized by gradual accumulation of neoplastic mast cells in the visceral organs. Patients typically present with splenomegaly, hypercellular marrow and, in most cases, urticaria pigmentosa-like skin lesions.", "ORPHA ID": 158775, "Summary": "Epidemiology\nThe prevalence and incidence is unknown.\nClinical description\nThe age of onset of smoldering systemic mastocytosis (SSM) is in adulthood, with patients tending to be slightly older than those with isolated SM (ISM). The disease is defined by the presence of at least two B-findings, indicative of a high mast cell (MC) burden, and no C findings (organ dysfunction). There is a pronounced MC infiltration (>30% in bone marrow (BM) biopsy), organomegaly and tryptase levels above 200 ng/ml. The clinical course is characterized by slow progression without signs of aggressive disease or an associated hematologic neoplasm (AHN). Patients may remain stable for years or may progress into a more advanced variant (aggressive SM (ASM), mast cell leukemia (MCL) or SM with an AHN).\nEtiology\nAlthough the etiology of SSM is not fully understood, an activating mutation of KIT, usually KIT D816V, is found in the MCs of virtually all SSM cases. This mutation probably accounts for the abnormal accumulation of MCs in organ(s)/tissue(s). Multilineage KIT D816V involvement is constantly found in SSM patients.\nDiagnostic methods\nDiagnosis of SSM is achieved by first establishing a diagnosis of SM, based on the WHO consensus criteria. The disease is then categorized according to the presence of B-findings and C-findings. For SSM, at least two B-findings (but no C-findings) should be present.\nDifferential diagnosis\nDifferential diagnoses include all the other forms of SM, as well as other causes of MC activation syndromes (MCAS): primary (clonal, but not fulfilling SM diagnostic criteria) MCAS; secondary MCAS where an IgE-dependent allergy or another reactive inflammatory disease process is present; and idiopathic MCAS where neither clonal MC nor an IgE-dependent allergy or another underlying condition/disease can be documented. Additional differential diagnoses include other forms of mastocytosis (pure cutaneous mastocytosis, indolent SM, aggressive SM), endocrine disorders (adrenal tumors, VIPoma, gastrinoma), and some gastrointestinal pathologies. Waldenström disease should also be distinguished.\nManagement and treatment\nIn stable SSM patients, symptomatic treatment may be the only therapy. Avoidance of known triggers, prophylactic prescription of an epi-pen, and medications such as antihistamines, antileukotrienes, cromolyn sodium, omalizumab and aspirin may all have a role in the prevention or treatment of MC-mediated symptoms. Regular follow-up and assessment for transformation to more aggressive disease variants is required. Serum tryptase, which may be used to assess disease response, may be evaluated biannually to monitor disease activity and appropriately adjust therapy. In patients who progress to more advanced variants of the disease, introduction of targeted or non-targeted cytoreductive therapy may be discussed. Whilst favorable results have been seen with the current targeted and non-targeted treatment, a consensus on treatment in patients with SSM has not been reached.\nPrognosis\nSome SSM patients may remain stable for years, while others may progress to more advanced variants of the disease (ASM or MCL), with a poorer prognosis. In general, the prognosis of SSM regarding progression-free survival and overall survival is better than that of ASM or MCL, but poorer than in typical ISM.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Michel AROCK"}
{"Disease Name": "Snakebite envenomation", "Disease Definition": "A rare disorder due to poisoning caused by toxins in the bite of a venomous snake. Envenoming can also be caused by spraying of venom into the eyes. Depending on venom composition and other factors, consequences range from local tissue damage to potentially life-threatening systemic effects. Severe manifestations include paralysis, bleeding disorders, kidney failure, or permanent disability and limb amputation due to severe local tissue destruction. Children may suffer more severe effects because of their lower body mass. Immediate medical attention, in particular administration of antivenom, is critical.", "ORPHA ID": 449285, "Summary": ""}
{"Disease Name": "Sneddon syndrome", "Disease Definition": "Sneddon's syndrome (SS) is a rare non-inflammatory thrombotic vasculopathy characterized by the combination of cerebrovascular disease with livedo racemosa.", "ORPHA ID": 820, "Summary": "Epidemiology\nSS has an estimated annual incidence of approximately 1/250,000. The disease predominantly affects women in young adulthood.\nClinical description\nThe mean age of onset of neurological symptoms is 39 years, though the livedo is generally observed up to 10 years earlier and sometimes since childhood. Livedo racemosa is a persistent net-like violaceous-cyanotic, mottled discoloration of the skin affecting primarily the legs and arms, but also involving the buttocks and the trunk, and that is exacerbated by cold or pregnancy. Livedo reticularis, that is limited to the extremities and is visible only in the cold, has also been observed in some cases. Neurological manifestations include recurrent transient ischemic attacks (TIAs) and infarcts, often of the middle cerebral artery territory resulting in contralateral hemiparesis, aphasia, and/or visual field defects. Rarely, spinal strokes or intracranial or subarachnoid hemorrhages occur. Headache and vertigo may precede the onset of livedo racemosa and cerebrovascular manifestations by several years. In the course of the disease, memory disturbances, personality changes, and cognitive decline leading to dementia occur frequently. Rare neurologic symptoms include seizures, chorea, or myelopathies. Secondary hypertension is common, as are valvular heart disease, ocular and kidney involvement.\nEtiology\nWhile about 50% of cases are idiopathic, SS can be associated with autoimmune diseases like systemic lupus erythematosus, antiphospholipid syndrome, Behçet disease, and mixed connective tissue disease (see these terms). The manifestations of SS are caused by a progressive, non-inflammatory arteriopathy, usually of the small to medium arteries, leading to occlusion of these arteries by excessive endothelial proliferation with impaired blood flow and clotting. Genetic factors may play a role in the pathogenesis of SS. Loss-of-function mutations in cat eye syndrome chromosome region candidate 1 CECR1 (22q11.2) encoding adenosine deaminase 2 have been found.\nDiagnostic methods\nSS is suspected on the basis of the clinical picture. It has to be considered in cases of unexplained stroke at a young age, cognitive decline without stroke, and assumed autoimmune-related vasculitis in which immunosuppressive therapy has proven ineffective. Skin biopsy may confirm the diagnosis, revealing occlusion of arterioles by intimal proliferation. MRI typically reveals white matter changes, infarcts, microbleeds or atrophy, and is more sensitive than CT. Laboratory testing for antiphospholipid antibodies may be positive in about 60% of cases.\nDifferential diagnosis\nDifferential diagnoses include reversible cerebral vasoconstriction syndrome, MELAS syndrome, cerebrovascular dementia (see these terms), migraine, the autoimmune diseases with which SS can be associated, and cerebral angiitis.\nGenetic counseling\nMost cases are sporadic but some familial cases with an autosomal dominant inheritance have been reported. In these cases, a genetic susceptibility is likely.\nManagement and treatment\nThe most widely accepted treatment is anticoagulation with warfarin. Some suggest that aPL-negative patients should follow a less aggressive approach consisting of antiplatelet therapy with aspirin, while others recommend warfarin with a higher international normalized ratio (coagulation index) target. Angiotensin-converting enzyme (ACE) inhibitors have been suggested to reduce endothelial proliferation, and prostaglandin to improve microvascular perfusion. Successful intravenous systemic fibrinolysis with tissue plasminogen activator (tpA) has been reported in acute ischemic stroke. While the use of immunosuppressive therapy (azathioprine, cyclophosphamide) doesn't seem effective, there are data indicating that rituximab may be effective in aPL-positive patients.\nPrognosis\nSS is a chronic, intermittent or progressive disease leading to major morbidity. Dementia occurs in 50% of patients resulting in early retirement.\n\n                            Last update: \n                            March 2015\n\n\n                            - Expert reviewer(s): \n                            Pr Peter BERLIT"}
{"Disease Name": "Snowflake vitreoretinal degeneration", "Disease Definition": "Snowflake vitreoretinal degeneration (SVD) is characterised by the presence of small granular-like deposits resembling snowflakes in the retina, fibrillary vitreous degeneration and cataract. The prevalence is unknown but the disorder has been described in several families. Transmission is autosomal dominant and the causative gene has been localised to a small region on chromosome 2q36.", "ORPHA ID": 91496, "Summary": ""}
{"Disease Name": "Solar urticaria", "Disease Definition": "A rare photodermatosis characterized by an abrupt onset of transient erythema, wheals, and pruritus appearing within minutes of exposure to light.", "ORPHA ID": 97230, "Summary": "Epidemiology\nExact, prevalence and incidence of solar urticaria are not known. It is reported as representing only 4-8% of all photodermatosis presentations and estimated to account for only 0.4% of all urticarias. To date, more than 650 cases have been described worldwide. Females are predominantly affected.\nClinical description\nWheal formation and pruritus are characteristic, but other manifestations have been reported such as headaches, general malaise, increased heart rate, low blood pressure and syncope. Symptoms almost always clear within 24 hours. The disease can initially appear in all age groups, although it most commonly presents during the third or fourth decade of life. It is a chronic disease requiring long-term treatment. However, some patients (up to 15%) experience spontaneous remissions.\nEtiology\nThe etiology and pathophysiology are not clearly defined; however, the disease may be caused by an antigen-antibody reaction. There are two possible mechanisms, antibodies are either targeted against an abnormal photoallergen which is generated only in patients with SU, or they are targeted against a normal photoallergen generated both in patients and in normal individuals. The immune response involves a photoallergic reaction resulting in histamine release by mast cells.\nDiagnostic methods\nPhototesting is an important tool for confirming the diagnosis, to assess the responsible wavelengths, the minimal whealing (urticaria) dose (MUD) and the response to therapy.\nDifferential diagnosis\nThe major differential diagnoses to be considered include polymorphic light eruption (which generally appears only 2-3 days after sun exposure and lasts more than 24 hours), lupus erythematosus tumidus (which typically occurs more than a week after sun exposure) and erythropoietic protoporphyria, (an inherited disease that may have similar clinical manifestations).\nManagement and treatment\nTreatment is difficult and referral to a specialist is recommended. Treatment recommendations are based on retrospective studies and small case series. They include broad‐spectrum sunscreens, antihistamines, leucotriene receptor antagonist (LRA), UV phototherapy (hardening), azathioprine, ciclosporin, intravenous immunoglobulins and omalizumab. The European consensus is first-line treatment with non-sedative anti-histamines. If the disease is inadequately controlled, treatment is stepwise with increased dose, followed by omalizumab and then ciclosporin.\nPrognosis\nTherapeutic intervention can significantly improve the quality of life but response is variable. Spontaneous resolution of symptoms may occur in 15% of patients within 10 years. Some patients have to avoid outdoor activities completely, severely impacting their quality of life.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Claes ENK  - Dr Assi LEVI  - Dr Igor SNAST"}
{"Disease Name": "Solid pseudopapillary carcinoma of pancreas", "Disease Definition": "A rare carcinoma of the pancreas characterized by a variable combination of nonspecific signs and symptoms, such as abdominal pain, jaundice, abdominal fullness, anorexia, nausea, vomiting, and weight loss. One-third of the patients are asymptomatic. The tumor has low malignant potential, but can invade locally.", "ORPHA ID": 424065, "Summary": ""}
{"Disease Name": "Solitary bone cyst", "Disease Definition": "A benign non-epithelial bone cavity that is asymptomatic and that is found most commonly in the second decade of life by chance. The long bones are most often affected, but cases involving the jaw bone have been reported.", "ORPHA ID": 83468, "Summary": ""}
{"Disease Name": "Solitary fibrous tumor", "Disease Definition": "A rare soft tissue tumor characterized by a well-circumscribed mass potentially occurring at any anatomical site, histopathologically showing spindled to ovoid cells arranged around a branching and hyalinized vasculature and variable stromal collagen deposition. Immunohistochemistry reveals CD34 and/or STAT6 expression. NAB2-STAT6 gene fusions are pathognomonic for this tumor, which may be malignant or benign. Clinically, most patients present with a slow-growing, painless mass. Large tumors may cause paraneoplastic syndromes such as Doege-Potter syndrome, with the induction of severe hypoglycemia or acromegaloid features.", "ORPHA ID": 2126, "Summary": ""}
{"Disease Name": "Solitary necrotic nodule of the liver", "Disease Definition": "A rare nonmalignant hepatic lesion characterized by a mass with a completely necrotic core often partially calcified, surrounded by a dense hyalinized fibrous capsule containing elastin fibers. Patients are usually asymptomatic but some may suffer from intermittent abdominal pain or discomfort.", "ORPHA ID": 100035, "Summary": ""}
{"Disease Name": "Solitary rectal ulcer syndrome", "Disease Definition": "Solitary rectal ulcer syndrome (SRUS) is a rare rectal disease characterized by rectal bleeding, abdominal pain, passage of mucus, sensation of incomplete evacuation, straining at defecation and rectal prolapsed, secondary to ischemic changes in the rectum.", "ORPHA ID": 209964, "Summary": ""}
{"Disease Name": "Somatomammotropinoma", "Disease Definition": "A rare, mixed, functioning pituitary adenoma characterized by the cosecretion of growth hormone and prolactin, which manifests with signs and symptoms of both acromegaly and hyperprolactinemia.", "ORPHA ID": 314769, "Summary": ""}
{"Disease Name": "Somatostatinoma", "Disease Definition": "Somatostatinoma (SSoma) is an extremely rare pancreatic neuroendocrine tumor or duodenal endocrine tumor (see these terms) that originates either in the pancreas (50%) or the gastrointestinal tract (50%) and mainly presents with non-specific symptoms of abdominal pain, weight loss, jaundice and diarrhea but, in approximately 20% of pancreatic cases, leads to a somatostatin hypersecretion syndrome (somatostatinoma syndrome) characterized by diabetes mellitus, cholelithiasis, steatorrhea and hypochlorhydria.", "ORPHA ID": 97283, "Summary": "Epidemiology\nThe estimated incidence is of 1/40,000,000. Approximately 80 cases of pancreatic SSoma have been reported to date but this is probably an underestimate.\nClinical description\nSSomas usually range in size from 3-11cm. Most SSomas present with non-specific symptoms of abdominal pain, weight loss, painless obstructive jaundice and diarrhea. Somatostatinoma syndrome occurs in those with a functioning pancreatic SSoma with manifestations including diabetes mellitus, cholelithiasis, diarrhea, weight loss, steatorrhea and hypochlorhydria. More than half of all SSomas are malignant and they have often metastasized at the time of diagnosis. Duodenal somatostatinoma is often associated with neurofibromatosis type 1 (NF1; see this term).\nEtiology\nSome SSomas are components of familial endocrine tumor syndromes. The cause of sporadic SSomas is not clear. SSoma hypersecretes stomatostatin, which inhibits the secretion of numerous gastrointestinal hormones (such as gastrin, secretin, insulin, glucagon, and cholecystokinin), resulting in somatostatinoma syndrome\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Run YU"}
{"Disease Name": "Sorsby pseudoinflammatory fundus dystrophy", "Disease Definition": "Sorsby's fundus dystrophy is a rare progressive autosomal dominant macular dystrophy, presenting between the third and sixth decades of life, characterized by retinal atrophy and retinal detachment and leading to loss of central vision, then peripheral vision, and eventually blindness.", "ORPHA ID": 59181, "Summary": ""}
{"Disease Name": "Sotos syndrome", "Disease Definition": "A rare genetic overgrowth syndrome characterized by a typical facial appearance, overgrowth with macrocephaly and variable intellectual impairment.", "ORPHA ID": 821, "Summary": "Epidemiology\nPrevalence at birth is estimated at 1/14,000.\nClinical description\nExcessive growth is evident across life, especially in childhood, and can manifest since fetal life, with final adult height beyond or in the upper part of the normal ranges. Macrocephaly is usually striking and disproportioned with respect to height. The distinct facial appearance is most easily recognized in early childhood (long narrow face, flushed cheeks, prominent forehead with frontotemporal hair scarcity, down-slanting palpebral fissures, hypertelorism, a high arched palate, and pointed chin). Sotos syndrome is associated with mild to severe intellectual disability as well as a wide spectrum of behavioral disorders. Developmental milestones are commonly delayed. Additional features may include in the neonatal period hypotonia and poor feeding and subsequently advanced bone age, scoliosis, prognathia, premature dental eruption, large hands and feet. Seizures and electroencephalogram abnormalities are common. Less common features are conductive hearing loss, and cardiac and genitourinary anomalies. Cancer predisposition is debated: the increased risk, if any, appears to be low.\nEtiology\nSotos syndrome is caused by mutations or microdeletions in the NSD1 gene (5q35) in more than 95% of cases. NSD1 is involved in normal growth and development. Biallelic mutations in the APC2 gene (19p13.3) have also been reported in a few cases.\nDiagnostic methods\nThe diagnosis is based on the major clinical manifestations (characteristic facial features, learning disability, and overgrowth). It can be confirmed by molecular genetic testing of the causative genes. Overlap with other overgrowth syndromes may complicate diagnosis.\nDifferential diagnosis\nThe differential diagnosis should include Malan syndrome, Simpson-Golabi-Behmal syndrome, Weaver syndrome, Tatton-Brown-Rahman syndrome, Bannayan-Riley-Ruvalcaba syndrome, Fragile X syndrome and megalocephalic syndromes associated with mutations in the PI3K-AKT-mTOR pathway. A Sotos-like phenotype has been reported in patients with SETD2 mutations.\nAntenatal diagnosis\nPrenatal diagnosis is possible if the disease-causing mutation has been identified in the family or if there is the strong suspicion of the condition (e.g. macrocephaly).\nGenetic counseling\nSotos syndrome follows an autosomal dominant pattern of inheritance in the rare familial cases associated with NSD1; genetic counseling should be offered to affected individuals informing them that, for every pregnancy, there is a 50% risk of transmitting the disorder to offspring. The vast majority of patients have de novo mutations. In these cases, risk of recurrence is very low.\nManagement and treatment\nThere is no specific treatment for the syndrome. Management of Sotos syndrome requires a multidisciplinary approach.\nPrognosis\nSotos syndrome shows a wide spectrum of intellectual impairment, with functioning from fully independent to fully dependent. Affected individuals are generally healthy with few medical issues.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Alessandro MUSSA | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Southeast Asian ovalocytosis", "Disease Definition": "Southeast Asian ovalocytosis (SAO) is a rare hereditary red cell membrane defect characterized by the presence of oval-shaped erythrocytes and with most patients being asymptomatic or occasionally manifesting with mild symptoms such as pallor, jaundice, anemia and gallstones.", "ORPHA ID": 98868, "Summary": "Epidemiology\nSAO is common in Southeast Asian and Western Pacific countries (i.e. Thailand, Malaysia, Indonesia, Philippines and Papua New Guinea). SAO is very common in malaria-endemic areas (prevalence 1/20-1/4) but in Europe it is very rare.\nClinical description\nSAO can occur at any age. Newborns with SAO might be symptomatic with hemolysis at birth that leads to anemia, pallor or jaundice. Anemia and hyperbilirubinemia in neonates is common together with mild splenomegaly and gallstones. Hemolysis usually disappears in the first three years of life. Adults are asymptomatic or have only minimal hemolytic anemia. Resistance to malaria (see this term) is also noted.\nEtiology\nSAO results from a 27 bp deletion in the SLC4A1 gene, localized on chromosome 17q21.31 (SLC4A1del27 mutation). This gene codes for a band 3 anion transport protein which is the bicarbonate/chloride exchanger in red blood cell membranes and defects in this protein cause membrane rigidity. Heterozygous mutations for the deletion are found in almost all cases, as homozygosity is thought to be lethal to the developing embryo. A homozygous mutation was recently reported in one case of SAO as the primary cause of extremely severe dyserythropoietic anemia associated with distal renal tubular acidosis (see this term), and that which would have been lethal if the fetus had not been transfused in utero. The association of mutation SLC4A1del27 with other mutations in the SLC4A1 gene may result in distal renal tubular acidosis associated with SAO in some cases.\nDiagnostic methods\nDiagnosis is based on the presence on a peripheral blood smear of macro-ovalocytes, some of them stomatocytic with more than one stoma, in the absence of hemolysis. Genetic assays can also be used to identify the mutation in the SLC4A1 gene.\nDifferential diagnosis\nDifferential diagnosis includes all forms of hereditary elliptocytosis and hereditary spherocytosis, and dehydrated hereditary stomatocytosis (see these terms).\nAntenatal diagnosis\nAntenatal diagnosis is possible but not undertaken because of the benign nature of the disease.\nGenetic counseling\nSAO follows an autosomal dominant pattern of inheritance. Genetic counseling is possible.\nManagement and treatment\nMost cases of SAO are asymptomatic and treatment is not necessary.\nPrognosis\nSAO is not life threatening.\n\n                            Last update: \n                            April 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Alberto ZANELLA"}
{"Disease Name": "Spasmus nutans", "Disease Definition": "Spasmus nutans (SN) is a rare eye disease characterized by the clinical triad of asymmetric and pendular nystagmus, head nodding, and torticollis.", "ORPHA ID": 279882, "Summary": "Epidemiology\nThe prevalence of SN is unknown.\nClinical description\nThe age of disease onset ranges from 4-12 months and clinically, SN is characterized by a triad of signs which are nystagmus, head nodding, and abnormal head turn or tilt (torticollis). The nystagmus in SN is typically pendular, intermittent, of small-amplitude, high frequency oscillations (shimmering nystagmus) and is usually bilateral, but it can be monocular, asymmetric, and variable in different positions of gaze. Head nodding is not always present, and often follows the onset of nystagmus. It is usually intermittent and of lower frequency than the nystagmus. Both nystagmus and head nodding can occur in any plane (horizontal (more frequent), vertical, oblique, or torsional). Strabismus and amblyopia may be present while oscillopsia is absent. Optic nerve, retinal, or intracranial abnormalities are generally absent.\nEtiology\nSN is an idiopathic disorder. Head nodding suppresses nystagmus through the vestibular-ocular reflex and aids vision. Similarly, the torticollis has been observed clinically and by electrooculography (EOG) recordings to dampen nystagmus by a hypothesized vestibular mechanism. Low socioeconomic status represents a risk factor for the development of SN.\nDiagnostic methods\nThe diagnosis relies on exclusion of neurological and ophthalmological diseases. Eye movement recordings reveal a fine, high frequency, pendular horizontal nystagmus, which cannot be seen superimposed upon the normal optokinetic response. Visual acuities are generally lower in the eye with the greater nystagmus and vary between 6/6 and 6/24. Optic disc examinations are usually normal. Visual electrophysiology (visual evoked potential (VEP) and electroretinograms (ERG)) should be performed to exclude retinal diseases which can mimic SN.\nDifferential diagnosis\nDifferential diagnosis includes SN-like nystagmus, which is defined as a condition where children have nystagmus, head nodding and abnormal head position similar to SN but symptoms are associated with low vision (for example optic nerve hypoplasia, achromatopsia, congenital stationary night blindness, Bardet-Biedl syndrome), neurologic diseases (optic pathway glioma (chiasmal), arachnoid cyst, opsoclonus-myoclonus syndrome, diencephalic syndrome, and Leigh syndrome (see these terms), or systemic abnormalities. Nystagmus may also be associated with idiopathic infantile nystagmus (see this term). SN may also be misdiagnosed as thalamic neoplasm and empty sella.\nGenetic counseling\nSN is generally sporadic but cases of SN occurring in monozygotic twins have been reported.\nManagement and treatment\nNo cure exists and treatment is mainly supportive. This includes treatment for strabismus, amblyopia and refractive errors.\nPrognosis\nSN is a benign eye motility disorder where patients are usually healthy. The nystagmus has a tendency to decrease in intensity with age and symptoms tend to spontaneously remit within 1 to 5 years of onset with fine, residual nystagmus detectable only on eye movement recording. However, in rare cases, the signs may persist for as long as 8 years.\n\n                            Last update: \n                            January 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Irene GOTTLOB"}
{"Disease Name": "Spastic ataxia with congenital miosis", "Disease Definition": "Spastic ataxia with congenital miosis is a rare hereditary ataxia characterized by an apparently non-progressive or slowly progressive symmetrical ataxia of gait, pyramidal signs in the limbs, spasticity and hyperreflexia (especially in the lower limbs) together with dysarthria and impaired pupillary reaction to light, presenting as a fixed miosis (with pupils that seldom exceed 2 mm in diameter and dilate poorly with mydriatics). Nystagmus may also be present.", "ORPHA ID": 1182, "Summary": ""}
{"Disease Name": "Spastic ataxia-corneal dystrophy syndrome", "Disease Definition": "A rare, hereditary ataxia disorder characterized by the presence of spastic ataxia in association with bilateral congenital cataract, macular corneal dystrophy (stromal with deposition of mucoid material) and nonaxial myopia. Patients present normal intellectual development. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 2572, "Summary": ""}
{"Disease Name": "Spastic ataxia-dysarthria due to glutaminase deficiency", "Disease Definition": "A rare genetic neurometabolic disease characterized by childhood onset of global developmental delay, progressive spastic ataxia leading to loss of independent ambulation, and elevated plasma levels of glutamine. Optic atrophy, tremor, and dysarthria have also been reported. Brain imaging may show cerebellar atrophy.", "ORPHA ID": 557056, "Summary": ""}
{"Disease Name": "Spastic paraparesis-deafness syndrome", "Disease Definition": "A rare neurologic disease characterized by spastic paraparesis presenting in late childhood and hearing loss. Additional features may include retinal anomalies, lenticular opacities, short stature, hypogonadism, sensory deficits, tremor, dysdiochokinesia, elevated cerebrospinal fluid protein, and absent or prolonged somatosensory evoked potentials. Plasma and fibroblast levels of saturated very long-chain fatty acids are normal. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 2815, "Summary": ""}
{"Disease Name": "Spastic paraplegia type 2", "Disease Definition": "A rare, X-linked leukodystrophy characterized primarily by spastic gait and autonomic dysfunction. When additional central nervous system (CNS) signs, such as intellectual deficit, ataxia, or extrapyramidal signs, are present, the syndrome is referred to as complicated SPG.", "ORPHA ID": 99015, "Summary": "Epidemiology\nThe prevalence and incidence of SPG2 have not been reported, but as part of the Pelizaeus-Merzbacher (PMD; see this term) spectrum, SPG2 roughly accounts for about 20 % of cases. There have been approximately 20 cases published on SPG2. SPG2 affects males but some female heterozygotes presenting in adulthood with a milder phenotype have also been reported.\nClinical description\nSPG2 spans a continuum of phenotypes that goes from pure to complicated SPG2. Pure SPG2 manifests as early as infancy or early childhood (<5 years) but may be delayed until early adulthood. It presents with weakness, hyperreflexia, Babinski sign and spastic gait due to spastic paraparesis. Autonomic dysfunction (spastic urinary bladder and possibly bowel, with increased urinary and fecal frequency and incontinence) is frequent. Patients are able to walk and their speech is normal. There is no CNS involvement and no cognitive decline. Complicated SPG2 shares the same features as SPG2 but also shows additional CNS involvement like nystagmus, and ataxia that present in the first years of life. Optic atrophy may be present. Patients can also show a mild intellectual deficit.\nEtiology\nSPG2 is due to missense substitutions affecting the PLP1 gene. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20). SPG2 is allelic to Pelizaeus-Merzbacher disease (PMD; see this term) that is also due to PLP1 mutations.\nDiagnostic methods\nDiagnosis is based on clinical, electrophysiologic, and neuroradiological findings. White matter N-acetyl aspartate levels are reduced. Brain magnetic resonance imaging (MRI) reveals patchy or diffuse hypomyelination on T2-weighted images. Patients with pure SPG2 can have very subtle T2 hyperintensity. Other MR techniques, including MR spectroscopy and diffusion tensor imaging are useful in the diagnosis of the disease. Molecular genetic testing of PLP1 confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other forms of hereditary spastic paraplegia (see this tem). Complicated SPG2 is not clearly distinguishable from mild Pelizaeus-Merzbacher disease (PMD) and null syndrome (see these terms).\nAntenatal diagnosis\nPrenatal genetic testing is possible when a family's underlying PLP1 mutation has been identified.\nGenetic counseling\nTransmission is X-linked recessive.\nManagement and treatment\nA son born to a female carrier has a 50% risk of inheriting the mutation and developing the disease, while a daughter has a 50% risk of being a carrier. All daughters of an affected male will be carriers but none of his sons will be affected. Management is multidisciplinary and involves neurologists, physical therapists, and orthopedic doctors. Treatment may include antiepileptic drugs for seizures, and physical therapy with antispasticity drugs (baclofen, diazepam, tizanidine, botulinum toxin, dantrolene) for spasticity. Regular surveillance is necessary.\nPrognosis\nPure SPG2 patients show a normal life expectancy. In complicated SPG2 cases, patients deteriorate neurologically leading to a shorter life expectancy (between the fourth and seventh decade) typically from aspiration pneumonia, pulmonary embolism and other complications of generalized weakness.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr James GARBERN"}
{"Disease Name": "Spastic paraplegia type 7", "Disease Definition": "A form of hereditary spastic ataxia characterized by an onset usually in adulthood (but ranging from 10-72 years) of progressive bilateral lower limb weakness and spasticity and sometimes predominant cerebellar ataxia. In addition to frequent sphincter dysfunction and decreased vibratory sense at the ankles, manifestations may include optical neuropathy, nystagmus, blepharoptosis, ophthalmoplegia, decreased hearing, scoliosis, pes cavus, motor and sensory neuropathy, muscle atrophy, parkinsonism, and dystonia.", "ORPHA ID": 99013, "Summary": "Epidemiology\nThe worldwide prevalence of autosomal dominant and autosomal recessive spastic paraplegia (SPG) combined is about 1.8 /100.000, the prevalence of SPG type 7 is unknown.\nClinical description\nThe disease onset is typically between the third and fifth decade, even though earlier or later onset are reported (10-72 years). The clinical presentation can be a pure spastic paraplegia (pyramidal syndrome, sphincter dysfunction, lower limbs weakness, diminished vibration sense, pes cavus) mostly associated with, cerebellar ataxia. Optic atrophy, ptosis and oculomotor abnormalities (nystagmus, progressive external ophthalmoplegia, saccadic pursuit) are frequently associated. Additional neurological signs are spastic dysarthria, dysphagia, parkinsonism, dystonia, scoliosis, hearing loss, and cognitive impairment. Brain magnetic resonance imaging nearly always shows a cerebellar atrophy and electromyography can detect a motor and sensory neuropathy.\nEtiology\nThe disease is due to biallelic pathogenic variants in the SPG7 gene (chromosome 16q24.3) coding for paraplegin protein.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and confirmed by genetic testing (panel sequencing of hereditary spastic paraplegia genes, exome or genome analysis).\nDifferential diagnosis\nThe differential diagnosis includes autosomal dominant and recessive spastic paraplegias, spinocerebellar ataxias (e.g. Spinocerebellar ataxia type 28), adrenomyeloneuropathy and other leukodystrophies, amyotrophic lateral sclerosis, and primary progressive multiple sclerosis.\nAntenatal diagnosis\nPrenatal diagnosis is possible if the pathogenic variants are known and present in at risk couples (where both parents are heterozygous carriers).\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. Few cases of dominant transmission are reported, individuals carrying one pathogenic variant could present signs (e. g. mild cerebellar atrophy, peripheral neuropathy) or symptoms (e. g. cerebellar ataxia, brisk deep tendon reflexes).\nManagement and treatment\nThe treatment is symptomatic, including myorelaxants (oral or intrathecal baclofen, dantrolene, intramuscular botulinum toxin, etc.), bladder control medications, anti-parkinsonian drugs (L-Dopa, dopamine-agonists). Physical, occupational, and speech therapy should be proposed in association with medication.\nPrognosis\nThe disease course is variable but often the walking autonomy is decreased requiring the use of a wheelchair. The disease strongly affects the quality of life.\n\n                            Last update: \n                            November 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Giulia COARELLI | ERN-RND* - Pr Alexandra DURR | ERN-RND*\n\n\n                                * European Reference Network"}
{"Disease Name": "Spastic paraplegia-facial-cutaneous lesions syndrome", "Disease Definition": "A complex form of hereditary spastic paraplegia characterized by delays in motor development followed by a slowly progressive spastic paraplegia (affecting mainly lower extremities) associated with a desquamating facial rash with butterfly distribution (presenting at around two months of age) and dysarthria. There have been no further descriptions in the literature since 1982.", "ORPHA ID": 2819, "Summary": ""}
{"Disease Name": "Spastic paraplegia-glaucoma-intellectual disability syndrome", "Disease Definition": "Spastic paraplegia-glaucoma-intellectual disability syndrome is characterized by progressive spastic paraplegia, glaucoma and intellectual deficit. It has been described in two families. The second described sibship was born to consanguineous parents. The mode of inheritance is autosomal recessive.", "ORPHA ID": 2818, "Summary": ""}
{"Disease Name": "Spastic paraplegia-intellectual disability-nystagmus-obesity syndrome", "Disease Definition": "A rare genetic neurological disorder characterized by the association of congenital spastic paraplegia with global developmental delay and intellectual disability, ophthalmologic abnormalities (including nystagmus, reduced visual acuity, or hypermetropia), and obesity. Additional manifestations are brachyplagiocephaly and dysmorphic facial features. Brain imaging may show dilated ventricles, abnormal myelination, and mild generalized atrophy. Homozygous loss-of-function variants of KIDINS220 associated with a fetal lethal phenotype with ventriculomegaly and limb contractures have been reported.", "ORPHA ID": 521390, "Summary": ""}
{"Disease Name": "Spastic paraplegia-nephritis-deafness syndrome", "Disease Definition": "Spastic paraplegia-nephritis-deafness syndrome is a complex form of hereditary spastic paraplegia characterized by progressive, variable spastic paraplegia associated with bilateral sensorineural deafness, intellectual disability, and progressive nephropathy. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 2820, "Summary": ""}
{"Disease Name": "Spastic paraplegia-neuropathy-poikiloderma syndrome", "Disease Definition": "A complex form of hereditary spastic paraplegia characterized by spastic paraplegia, demyelinating peripheral sensorimotor neuropathy, poikiloderma (manifesting with loss of eyebrows and eyelashes in childhood in addition to delicate, smooth, and wasted skin) and distal amyotrophy (presenting after puberty). There have been no further descriptions in the literature since 1992.", "ORPHA ID": 2821, "Summary": ""}
{"Disease Name": "Spastic paraplegia-optic atrophy-neuropathy and spastic paraplegia-optic atrophy-neuropathy-related disorder", "Disease Definition": "A group of rare, genetic, neurodegenerative diseases characterized by an infancy- to childhood-onset of progressive spastic paraplegia (with delayed motor milestones, gait disturbances, hyperreflexia and extensor plantar responses), optic atrophy (which may be accompanied by nystagmus and visual loss) and progressive peripheral neuropathy (with sensory impairment and distal muscle weakness/atrophy in upper and lower extremities). Additional signs may include foot deformities, spinal defects (scoliosis, kyphosis), joint contractures, exaggerated startle response, speech disorders, hyperhidrosis, extrapyramidal signs and intellectual disability. In very rare cases, a variant phenotype with less prominent or absent optic atrophy and/or neuropathy may be observed.", "ORPHA ID": 431320, "Summary": ""}
{"Disease Name": "Spastic paraplegia-optic atrophy-neuropathy syndrome", "Disease Definition": "A rare, complex type of hereditary spastic paraplegia characterized by early-onset progressive spastic paraplegia presenting in infancy, associated with optic atrophy, fixation nystagmus, polyneuropathy occurring in late childhood/early adolescence leading to severe motor disability and progressive joint contractures and scoliosis.", "ORPHA ID": 320406, "Summary": ""}
{"Disease Name": "Spastic paraplegia-Paget disease of bone syndrome", "Disease Definition": "Spastic paraplegia-Paget disease of bone syndrome is an extremely rare, complex form of hereditary spastic paraplegia characterized by a slowly progressive spastic paraplegia (with increased muscle tone, decreased strength in the anterior tibial muscles and hyperreflexia in the lower extremities with Babinski sign) presenting in adulthood, associated with Paget disease of the bone. Cognitive decline, dementia and myopathic changes at muscle biopsy have not been reported.", "ORPHA ID": 329475, "Summary": ""}
{"Disease Name": "Spastic paraplegia-precocious puberty syndrome", "Disease Definition": "Spastic paraplegia-precocious puberty syndrome is a complex form of hereditary spastic paraplegia characterized by the onset of progressive spastic paraplegia associated with precocious puberty (due to Leydig cell hyperplasia) in childhood (at the age of 2 years). Moderate intellectual disability was also reported. There have been no further descriptions in the literature since 1983.", "ORPHA ID": 2826, "Summary": ""}
{"Disease Name": "Spastic paraplegia-severe developmental delay-epilepsy syndrome", "Disease Definition": "Spastic paraplegia-severe developmental delay-epilepsy syndrome is a rare, genetic, complex spastic paraplegia disorder characterized by an infantile-onset of psychomotor developmental delay with severe intellectual disability and poor speech acquisition, associated with seizures (mostly myoclonic), muscular hypotonia which may be noted at birth, and slowly progressive spasticity in the lower limbs leading to severe gait disturbances. Ocular abnormalities and incontinence are commonly associated. Other symptoms may include verbal dyspraxia, hypogenitalism, macrocephaly and sensorineural hearing loss, as well as dystonic movements and ataxia with upper limb involvement.", "ORPHA ID": 464282, "Summary": ""}
{"Disease Name": "Spastic tetraplegia-retinitis pigmentosa-intellectual disability syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder characterized by the association of nonprogressive spastic quadriparesis, retinitis pigmentosa, intellectual disability, and variable deafness. There have been no further descriptions in the literature since 1976.", "ORPHA ID": 3011, "Summary": ""}
{"Disease Name": "Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome", "Disease Definition": "A rare neurometabolic disorder due to serine deficiency characterized by neonatal to infantile onset of global developmental delay, postnatal microcephaly and intellectual disability, which may be associated with slowly progressive spastic tetraplegia mainly affecting the lower extremities, seizures, and brain MRI findings including thin corpus callosum, delayed myelination and cerebral atrophy. Additional symptoms include brisk deep tendon reflexes, extensor plantar responses, behavioral abnormalities (such as irritability, hyperactivity, sleep disorder), abnormal hand movements and stereotypy.", "ORPHA ID": 447997, "Summary": ""}
{"Disease Name": "SPECC1L-related hypertelorism syndrome", "Disease Definition": "A rare autosomal dominant malformation syndrome characterized by hypertelorism, omphalocoele, cleft lip, ear pits, uterine malformation (bicornuate uterus), and more variably by diaphragmatic hernia and congenital heart defects.", "ORPHA ID": 1519, "Summary": "Epidemiology\nUnknown. Less than 40 patients reported with genetic confirmation. The clinical diagnostic is unreliable in older literature due to phenotypic confusion.\nClinical description\nPresentation is typically with characteristic facial dysmorphism: prominent forehead, hypertelorism (>95%) and telecanthus, cleft lip/palate (25%), slightly downslanting palpebral fissures, long philtrum prominent nasal root, and a large nose with a large tip. Malformations include omphalocoele (50%), uterine malformations (>25%), congenital heart malformations (20%), ear pits (30%), dysphagia, reflux and other esophageal problems (30%) and, less commonly, diaphragmatic herniae (10%), inguinal herniae, aortic root dilation, and rarely CNS anomalies (ventriculomegaly, agenesis of the corpus callosum) and craniosynostosis. Learning disability affects 20% of patients, and intellectual disability (ID) is present in 10%.\nEtiology\nThe disorder is due to heterozygous gain of function variants in SPECC1L (Sperm antigen with calponin homology and Coiled-Coil domains 1 Like) located in 22q11.23. The SPECC1L protein is a cytoskeletal protein that associates with both actin and microtubules to affect larger cytoskeletal function. It is involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. Of note, heterozygous loss of function of SPECC1L causes Tessier IV oblique facial cleft.\nDiagnostic methods\nSPECC1L-related hypertelorism syndrome is suspected on clinical findings : ocular hypertelorism and at least one other of the characterstic findings (omphalocoele or diaphragmatic hernia, bicornuate uterus, ear pits). Diagnosis is confirmed by identification of a SPECC1L variant.\nDifferential diagnosis\nOpitz GBBB syndrome is the main differential diagnosis of SPECC1L-related hypertelorism syndrome. Opitz GBBB syndrome has strikingly overlapping craniofacial phenotype, leading to confusion in the past literature between MID1-confirmed Opitz GBBG and various overlapping conditions. Earpits, uterine malformations, omphalocoele, diaphragmatic herniae are specific to SPECC1L, whereas laryngeal and anorectal defects are specific to Optiz GBBB. ID is more common in the latter. Baraitser-Winter cerebrofrontofacial syndrome (ACTB and ACTG1), craniofrontonasal dysplasia (EFNB1), frontonasal dysplasia and Aarskog syndrome (FGD1) share marked hypertelorism.\nAntenatal diagnosis\nPrenatal testing is possible for at-risk pregnancies if a SPECC1L mutation has been previously identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant and genetic counseling is recommended for young adults who are affected. The offspring of an affect individual have a 50% risk of also being affected.\nManagement and treatment\nMultidisciplinary medical support with pediatricians, craniofacial, ENT (ear, nose and throat) and abdominal surgeons, cardiologists, and a medical geneticist is required. Neurodevelopmental support and speech therapy may be necessary. Uterine anomalies may cause fertility issues.\nPrognosis\nPrognosis is variable but usually favorable, depending on the severity of malformations and associated ID.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Spectrin-associated autosomal recessive cerebellar ataxia", "Disease Definition": "Spectrin-associated autosomal recessive cerebellar ataxia is a rare, genetic neurological disease, due to SPTBN2 mutations, characterized by global development delay in infancy, followed by childhood-onset gait ataxia with limb dysmetria and dysdiadochokinesia, mild to severe intellectual disability, development of cerebellar atrophy, and abnormal eye movements (including a convergent squint, hypometric saccades, jerky pursuit movements and incomplete range of movement).", "ORPHA ID": 352403, "Summary": ""}
{"Disease Name": "Spermatocytic seminoma", "Disease Definition": "Spermatocytic seminoma (SS) is an extremely rare form of testicular cancer distinguished from testicular seminomatous germ cell tumors (see this term) by a very low rate of metastasis and lack of an ovarian equivalent.", "ORPHA ID": 99865, "Summary": "Epidemiology\nSS accounts for around 1- 2% of all cases of testicular germ cell tumors (see this term). Annual incidence in Europe is 1/3,300,000.\nClinical description\nSS presents in males in their fifth to sixth decade of life. A painless mass in the scrotum or an interscrotal mass are indicative of disease. A long-standing hydrocele may be noted causing a feeling of heaviness in the testicle. Gynecomastia and back and flank pain are symptoms that are seen in some patients. The invasion of seminoma into the blood vessels, tunica albuginea and epididymus is rarely seen. In extremely rare instances a sarcomatous transformation can occur which causes the tumor size to rapidly increase along with its propensity for metastasis. In the very few cases that metastasis occurs, this aggressive form of tumor is referred to as metastatic spermatocytic seminoma.\nEtiology\nThe etiology of SS is unknown. It is thought to originate from a premeiotic germ cell.\nDiagnostic methods\nClinical findings orientate the diagnosis and measurement of tumor marker levels (alpha-fetoprotein) help in the precision of SS diagnosis. Testicular sonogram is also performed while bone scan and magnetic resonance imaging (MRI) of the central nervous system is only needed when symptoms of involvement in those areas are seen. Histopathological examination of the testicular mass biopsy confirms SS with the presence of three characteristic cell types: small cells (7-8 µm) with dark nuclei, medium sized cells (15 µm) with granular chromatin and eosinophilic cytoplasm in round nuclei and large multinucleated cells (up to 100 µm).\nDifferential diagnosis\nDifferential diagnoses include testicular seminomatous germ cell tumors and all types of lymphoma (see these terms).\nManagement and treatment\nTreatment of SS is similar to that of testicular seminomatous germ cell tumors which involves an orchidectomy. As this form of seminoma rarely metastasizes there is usually no further treatment needed but surveillance following surgery is necessary. Patients with the rare metastatic form are given additional chemotherapy (carboplatin) and radiotherapy but no specific treatment regimen has yet been established. Due to cosmetic and psychological reasons, patients may be offered testicular prostheses after an orchidectomy.\nPrognosis\nThe prognosis for SS is very good as once an orchidectomy is performed most patients are cured.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Hans-Joachim SCHMOLL"}
{"Disease Name": "Spheroid body myopathy", "Disease Definition": "Spheroid body myopathy is a rare form of myofibrillar myopathy characterized by predominantly proximal muscle weakness (that could be either non- or slowly progressive), associated with spheroid body inclusions (composed of myofilamentous material within individual muscle fibers) in skeletal muscle biopsy. Presentation is varied and may range from asymptomatic to severe muscle weakness that manifests with absent Achilles reflexes, gait abnormality and/or other motor incapacitations.", "ORPHA ID": 268129, "Summary": ""}
{"Disease Name": "Spigelian hernia-cryptorchidism syndrome", "Disease Definition": "Spigelian hernia-cryptorchidism syndrome is a rare developmental defect during embryogenesis characterized by a ventral, uni- or bilateral protrusion of extraperitoneal fat, peritoneum and/or intra-abdominal organs through a defect in the spigelian fascia (Spigelian hernia), associated with ipsi- or bilateral undescended testis (usually found within or just beneath the hernial sac) in male neonates. The gubernaculum and/or inguinal canal may be absent.", "ORPHA ID": 314432, "Summary": ""}
{"Disease Name": "Spina bifida and other spinal dysraphisms", "Disease Definition": "A group of rare neural tube defect disorders characterized by improper closure of the spinal column during embryonal development that is usually not associated with other major congenital malformations but may include ventriculomegaly. The extent of the closure defect may vary, ranging from spina bifida occulta, in which the site of the lesion is not exposed (e.g. an isolated posterior vertebral arch defect), to spina bifida aperta, in which the lesion may be conformed of proturding spinal cord and meninges (myelomeningocele) or meninges exposure only (meningocele), with or without a proturding sac at the site of the lesion, to the most severe defect which includes total exposure of the spinal cord along its full length (rachischisis). Depending on the type, size and site of the defect, severe morbidity, typically inlcuding motor, sensory and sphincter dysfunction, and mortality may be associated. Spina bifida occulta may be asymptomatic.", "ORPHA ID": 823, "Summary": ""}
{"Disease Name": "Spina bifida-hypospadias syndrome", "Disease Definition": "Spina bifida-hypospadias syndrome is a rare developmental defect during embryogenesis disorder characterized by the specific association of glandular hypospadias and lumbo-sacral spina bifida. Affected individuals may or may not present additional congenital anomalies, such as hydrocephaly, microstomia, patent ductus arteriosus, cryptorchidism, intestinal malrotation, rocker-bottom feet, and hypertrichosis.", "ORPHA ID": 3176, "Summary": ""}
{"Disease Name": "Spinal arteriovenous metameric syndrome", "Disease Definition": "Cobb syndrome is defined by the association of vascular cutaneous (venous or arteriovenous), muscular (arteriovenous), osseous (arteriovenous) and medullary (arteriovenous) lesions at the same metamere or spinal segment. This segmental distribution may involve one or many of the 31 metameres present in humans. Only 16% of the medullary lesions are multiple and have a clearly metameric distribution.", "ORPHA ID": 53721, "Summary": "Epidemiology\nLess than 100 cases of Cobb syndrome have been reported in the literature. There is no sex predilection. Cobb syndrome represents less than 15% of cases of spinal cord arteriovenous malformations.\nClinical description\nThe neurological symptomatology is comparable to that observed with acute haemorrhagic accidents or with chronic venous congestion of the spinal cord. The extent of the associated deficit depends on the localisation (cervical, thoracic, lumbar or sacral). These manifestations most often involve the lower limbs and are characterised by bilateral motor or sensory asymmetric deficits associated with sphincter anomalies. The morphological manifestations may be partial (appearing incomplete) in cases were some of the localisations at the same metamere are absent. The cutaneous manifestations of the syndrome are most often flat vascular lesions (port-wine stains) but angiokeratomas, angiolipomas and lymphangiomas have been reported. The medullary lesions are arteriovenous malformations. The muscular and osseous lesions may cause nonmechanical localised pain but are often asymptomatic.\nEtiology\nThe syndrome is not familial or hereditary and no chromosomal anomaly has been described. The primitive events causing the disorder occur during early embryogenesis and involve a group of precursor vascular cells before the stage of migration to their definitive cell territories (skin, bone, peripheral nerve or spinal cord). Two consecutive territories may be affected resulting in multimetameric forms of the disease. Recent analysis of Cobb syndrome has led to use of the term Spinal Arteriovenous Metameric Syndrome 1-31 (SAMS 1-31), by analogy with the Cerebrofacial Arteriovenous Metameric Syndromes (CAMS 1-3) and the Cerebrofacial venous metameric syndromes (CVMS1-3).\nDiagnostic methods\nDiagnosis is made by MRI, supplemented by medullary angiography.\nManagement and treatment\nTreatment of the osteomuscular malformations involves embolisation (endovascular navigation and occlusion of the arteries feeding the malformation using a biological glue) and/or surgery. Laser treatment is used for associated superficial cutaneous lesions. Radicular or medullary malformations are treated by embolisation. Indications for classic surgery are restricted to certain localisations and superficial lesions, epidural and paraspinal injections can be used if the endovascular approach fails. Radiotherapy is not indicated. Early diagnosis reduces the extent of the neurological deterioration, in particular paralysis.\nPrognosis\nThe disease course is unpredictable and the lesions may remain asymptomatic for long periods of time.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Hortensia ALVAREZ  - Pr Pierre LASJAUNIAS"}
{"Disease Name": "Spinal atrophy-ophthalmoplegia-pyramidal syndrome", "Disease Definition": "Spinal atrophy-ophthalmoplegia-pyramidal syndrome is a rare, bulbospinal muscular atrophy characterized by generalized neonatal hypotonia, progressive pontobulbar and spinal palsy, pyramidal signs, and deafness. External ophthalmoplegia and bilateral mydriasis are typical signs. There have been no further descriptions in the literature since 1994.", "ORPHA ID": 1217, "Summary": ""}
{"Disease Name": "Spinal dysraphism with a posterior meningocele", "Disease Definition": "A rare spinal dysraphism characterized by the presence of a posteriorly located sac containing cerebrospinal fluid.", "ORPHA ID": 268744, "Summary": ""}
{"Disease Name": "Spinal muscular atrophy with respiratory distress type 1", "Disease Definition": "Spinal muscular atrophy with respiratory distress type 1 is a rare genetic motor neuron disease characterized by severe respiratory distress/respiratory failure in association with diaphragmatic eventration and palsy, as well as progressive, symmetrical, distal-to-proximal muscle weakness and atrophy (in lower limbs especially). Patients typically have a history of intrauterine growth retardation, low birth weight, feeble cry, weak suck and failure to thrive and present with inspiratory stridor, recurrent episodes of dyspnea or apnea, cyanosis and absent deep tendon reflexes. Kyphosis/scoliosis, foot deformities and joint contractures are frequently associated features.", "ORPHA ID": 98920, "Summary": ""}
{"Disease Name": "Spinal muscular atrophy with respiratory distress type 2", "Disease Definition": "Spinal muscular atrophy with respiratory distress type 2 is a rare, genetic, motor neuron disease characterized by progressive early respiratory failure associated with diaphragm paralysis, distal muscular weakness, joint contractures, and axial hypotonia with preserved antigravity limb movements. Phenotype overlaps considerably with SMARD type 1 but is differentiated by a mutation in a different gene.", "ORPHA ID": 404521, "Summary": ""}
{"Disease Name": "Spinal muscular atrophy-Dandy-Walker malformation-cataracts syndrome", "Disease Definition": "A rare neurologic disease characterized by bilateral cataract, Dandy-Walker malformation, and childhood onset of distal spinal muscular atrophy. Patients present with progressively deteriorating symmetrical distal muscle weakness and atrophy of the lower limbs (and, to a much lesser degree, also the upper limbs) and decreased tendon reflexes in the lower and upper limbs.", "ORPHA ID": 73245, "Summary": ""}
{"Disease Name": "Spinal muscular atrophy-progressive myoclonic epilepsy syndrome", "Disease Definition": "Spinal muscular atrophy-progressive myoclonic epilepsy syndrome is characterized by hereditary myoclonus and progressive distal muscular atrophy. Less than 10 cases have been reported. Treatment with clonazepam results in complete and lasting improvement of the myoclonus.", "ORPHA ID": 2590, "Summary": ""}
{"Disease Name": "Spindle cell hemangioma", "Disease Definition": "Spindle cell hemangioma (SCH), also known as spindle cell hemangioendothelioma, is a rare benign vascular tumor either solitary or multiple, characterized by cavernous blood vessels separated by spindle cells reminiscent of those in Kaposi’s sarcoma and located in the dermis and subcutis.", "ORPHA ID": 210584, "Summary": ""}
{"Disease Name": "Spinocerebellar ataxia type 1", "Disease Definition": "Spinocerebellar ataxia type 1 (SCA1) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term) characterized by dysarthria, writing difficulties, limb ataxia, and commonly nystagmus and saccadic abnormalities.", "ORPHA ID": 98755, "Summary": "Epidemiology\nPrevalence is estimated to be 1-2 in 100,000 with significant geographical and ethnic variations.\nClinical description\nThe disease typically presents in the 4th decade (age range = 4-74 years). Ataxia gradually progresses and additional features may emerge including proprioceptive loss, hypoactive reflexes, ophthalmoparesis, and mild optic neuropathy. Initial presentation with blepharospasm, oromandibular dystonia, and retrocollis preceding ataxia has been reported. Cognition is relatively spared early on; however, executive dysfunction and impaired verbal memory may develop in later stages.\nEtiology\nSCA1 is caused by CAG repeat expansions in the ATXN1 gene region on chromosome 6p23.\nPrognosis\nPrognosis is poor. In the late stages of the disease, usually 10 to 15 years following onset, bulbar dysfunction secondary to affection of lower medullary nuclei results in aspiration which is life-threatening.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 10", "Disease Definition": "Spinocerebellar ataxia type 10 (SCA10) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by slowly progressive cerebellar syndrome and epilepsy, sometimes mild pyramidal signs, peripheral neuropathy and neuropsychological disturbances.", "ORPHA ID": 98761, "Summary": "Epidemiology\nPrevalence is unknown. Many kindreds have been found in Mexican and Brazilian populations. SCA10 is the second most common inherited ataxia in these two countries.\nClinical description\nAge of onset ranges from 18 to 45 years (mean age = 32.2 years). The most common type of epilepsy is generalized motor seizures, but partial motor or partial complex seizures can occur.\nEtiology\nSCA10 is caused by an ATTCT pentanucleotide repeat expansion in intron 9 of the ATXN10 gene (22q13). Exact pathogenesis has not been determined but RNA processing may be involved.\nPrognosis\nPrognosis is poor, especially for patients with refractory epilepsy. Exact disease duration is unknown. However, the mean disease duration can be estimated to be about 13 years.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 11", "Disease Definition": "A rare neurologic disease that is characterized by the early-onset of cerebellar signs, eye movement abnormalities and pyramidal signs.", "ORPHA ID": 98767, "Summary": "Epidemiology\nSpinocerebellar ataxia type 11 (SCA11) prevalence is unknown but SCA11 is thought to account for 2% of ADCA type III cases. More than sixty clinically affected members from six families (of British, Pakistani, Danish, Chinese, German and French descent) have been reported to date.\nClinical description\nSCA11 presents between the ages of 11-70 years with a mean age of onset of 25 years. It presents with the cerebellar signs such as dysarthria and progressive ataxia, eventually leading to difficulty walking and loss of balance as well as eye movement abnormalities (jerky pursuit, horizontal and vertical nystagmus and ophthalmoplegia). Pyramidal signs such as hyperreflexia mainly in the lower limbs, with positive Babinski sign are occasionally present. Rarely, dystonia and peripheral neuropathy have been reported. The disease is slowly progressive with dysphagia occurring later in the disease course. Patients usually become wheelchair bound 16 years after the onset of disease symptoms.\nEtiology\nSCA11 is due to mutations in the tau tubulin kinase 2 TTBK2 gene (15q15.2). This gene encodes TTBK2, which is found throughout the brain, and that is essential in stabilizing Purkinje cells and phosphorylating tau protein.\nDiagnostic methods\nDiagnosis is based on the clinical findings of pure cerebellar ataxia as well as molecular findings. Head magnetic resonance imaging (MRI) usually demonstrates the presence of cerebellar atrophy and is helpful in excluding other causes of ataxia. Molecular genetic testing identifies a mutation in the TTBK2  gene, confirming a diagnosis of SCA11.\nDifferential diagnosis\nDifferential diagnoses include other forms of ADCA type III, in particular SCA5, SCA6, SCA26, SCA30 and SCA31.\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with a known disease causing mutation.\nGenetic counseling\nSCA11 is inherited autosomal dominantly and genetic counseling is possible. The disease shows full penetrance. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for SCA11 and treatment is supportive. Language and speech therapy can help patients with dysarthria. Physiotherapy and the use of canes, walkers and wheelchairs can help patients remain mobile. Consultation with an ophthalmologist is recommended and prism glasses can help those with nystagmus. Neurological follow-up is recommended to monitor the progression of ataxia.\nPrognosis\nThe prognosis is fair since the disease progresses very slowly (with disease duration of up to 20 years) and usually does not decrease life expectancy. Quality of life, however, is greatly affected.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 12", "Disease Definition": "Spinocerebellar ataxia type 12 (SCA12) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by the presence of action tremor associated with relatively mild cerebellar ataxia. Associated pyramidal and extrapyramidal signs and dementia have been reported.", "ORPHA ID": 98762, "Summary": "Epidemiology\nPrevalence is unknown. Approximately 40 families have been reported.\nClinical description\nThe age of symptomatic onset ranges from 8 to 55 years with most patients presenting in the 4th decade.\nEtiology\nLike SCA8 the pathogenesis of SCA12 seems to be related to a toxic effect at the RNA level as it is caused by a CAG expansion at the 5' end of the PPP2R2B gene on chromosome 5q31-5q32.\nPrognosis\nPrognosis is essentially good. In many cases progression of the illness is slow and in general life expectancy is not affected.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 13", "Disease Definition": "Spinocerebellar ataxia type 13 (SCA13) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by onset in childhood marked by delayed motor and cognitive development followed by mild progression of cerebellar ataxia.", "ORPHA ID": 98768, "Summary": "Epidemiology\nPrevalence is unknown. Fewer than 20 cases have been reported to date.\nClinical description\nSCA13 is primarily a cerebellar syndrome, but dysphagia, urinary urgency, and bradykinesia have been described in affected patients older than 50.\nEtiology\nEtiology SCA13 has been mapped to chromosome 19q13.3-q13.4 and is known to be associated with two missense mutations in the KCNC3 gene.\nPrognosis\nPrognosis is relatively good. Many patients live beyond 70 years of age.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 14", "Disease Definition": "Spinocerebellar ataxia type 14 (SCA14) is a rare mild subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by slowly progressive ataxia, dysarthria and nystagmus.", "ORPHA ID": 98763, "Summary": "Epidemiology\nThe disease has been reported in more than twenty families from Europe, the United States, and Australia.\nClinical description\nOnset is usually in early adulthood while symptomatic disease onset may be from 10 to 70 years (mean = 33.9 years). In addition to cerebellar signs, hyperreflexia and decreased vibration sense are frequently observed. Some patients have cognitive impairment, parkinsonism characterized by rigidity, as well as focal dystonia, axial myoclonus, facial myokymia, choreic movement of hands and epilepsy.\nEtiology\nSCA14 is caused by missense mutations in the PRKCG gene (19q13.4) encoding protein kinase C gamma (PKC-gamma).\nPrognosis\nPrognosis is good. Some patients need supportive devices such as a cane or wheelchair for gait impairment. However, several affected patients have lived beyond 80 years of age.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 15/16", "Disease Definition": "Spinocerebellar ataxia type 15/16 (SCA15/16) is a rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by cerebellar ataxia, tremor and cognitive impairment.", "ORPHA ID": 98769, "Summary": "Epidemiology\nPrevalence is unknown. Fewer than 80 patients affected by the disease have been identified to date.\nClinical description\nAge of onset is from 20 to 66 years (mean age = 39.6 years).\nEtiology\nGenetic testing has shown that patients originally classified under SCA15 and SCA16 have the same subtype caused by a deletion in the inositol 1,4,5-triphosphate receptor 1 ITPR1 gene (3p26.1).\nPrognosis\nPrognosis is generally good and life-shortening events do not usually occur. Some patients live beyond 80 years of age.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 17", "Disease Definition": "Spinocerebellar ataxia type 17 (SCA17) is a rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by a variable clinical picture which can include dementia, psychiatric disorders, parkinsonism, dystonia, chorea, spasticity, and epilepsy.", "ORPHA ID": 98759, "Summary": "Epidemiology\nWorldwide prevalence is unknown. Local prevalence is 0.47 per 1,000,000 in the Japanese population and 0.16 per 100,000 in North-East England. Fewer than 100 families have been reported to date.\nClinical description\nClinical features overlap with many neurodegenerative syndromes and specifically, Huntington disease (see this term).\nEtiology\nSCA17 is caused by a CAG repeat expansion in the TATA box-binding protein gene TBP (6q27).\nPrognosis\nPrognosis is poor. More than 60% of patients present with dysphagia which frequently results in aspiration and death. Mean disease duration is less than 18 years and a few patients live beyond 60 years of age.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 18", "Disease Definition": "Spinocerebellar ataxia type 18 (SCA18) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by sensory neuropathy and cerebellar ataxia.", "ORPHA ID": 98771, "Summary": "Epidemiology\nPrevalence is unknown. Only 26 cases in a 5-generation American family of Irish ancestry have been reported to date.\nClinical description\nOnset is in the 2nd and 3rd decades of life with symptomatic onset ranging from 13 to 27 years. Patients initially present with axonal sensory neuropathy, while cerebellar ataxia and motor neuron dysfunction develop later.\nEtiology\nSCA18 has been linked to chromosome 7q22-q23 but the responsible gene mutation has not yet been identified.\nDifferential diagnosis\nBoth SCA3 and SCA4 are also associated with a peripheral neuropathy and should be taken into account in the differential diagnosis.\nPrognosis\nPrognosis is unclear. However, mean disease duration from age at onset of illness to age at last examination is about 24 years in the reported cases.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 19/22", "Disease Definition": "Spinocerebellar ataxia type 19 (SCA19) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by mild cerebellar ataxia, cognitive impairment, low scores on the Wisconsin Card Sorting Test measuring executive function, myoclonus, and postural tremor.", "ORPHA ID": 98772, "Summary": "Epidemiology\nPrevalence is unknown. Only 12 cases in a 5-generation Dutch family have been reported to date.\nClinical description\nSCA19 presents in the 3rd decade of life with symptomatic disease onset ranging from 10 to 46 years. Onset symptoms of SCA22 (see this term) overlap significantly with those of SCA19 but with a more narrow age range of 35 to 46 years.\nEtiology\nLinkage to locus 1p21-q21 has been proposed but the gene mutation has not been identified.\nPrognosis\nPrognosis is good. SCA19 does not impact life expectancy to any major extent, and some patients live to over 80 years of age.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 2", "Disease Definition": "Spinocerebellar ataxia type 2 (SCA2) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term) characterized by truncal ataxia, dysarthria, slowed saccades and less commonly ophthalmoparesis and chorea.", "ORPHA ID": 98756, "Summary": "Epidemiology\nPrevalence is estimated to be 1-2 in 100,000 with significant geographical and ethnic variations.\nClinical description\nSCA2 presents in the 3rd or 4th decade (average age = 30 years; age range = 2-65 years). Parkinsonism is also a less common but well-documented manifestation. There is no distinct clinical feature that reliably distinguishes SCA2 from SCA1 although tremor and autonomic dysfunction are more common in SCA2. Disease course is similar in both SCA1 and SCA2 (see this term).\nEtiology\nThe disease is caused by mutations in the ataxin 2 gene ATXN2 (12q23-q24.1). The normal CAG repeat length is 15-24; repeats 35 and longer are associated with the clinical manifestations of SCA2.\nPrognosis\nPrognosis is relatively good in most cases. Cases with disease duration of longer than 20 years have been described. However, in some cases, especially those with younger age of symptomatic disease onset (under 20 years), progression may be rapid.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 20", "Disease Definition": "Spinocerebellar ataxia type 20 (SCA20) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by cerebellar dysarthria as the initial typical manifestation.", "ORPHA ID": 101110, "Summary": "Epidemiology\nPrevalence is unknown. Fewer than 20 cases in a 4-generation Australian family of Anglo-Celtic descent have been reported to date.\nClinical description\nAge of symptomatic disease onset ranges from 19 to 64 years (mean age = 46.5 years). Most affected patients also exhibit palatal tremor and spasmodic dysphonia. Head computed tomography (CT) shows dentate calcifications.\nEtiology\nSCA20 has been linked to chromosome 11q12.2-11q12.3, overlapping with the locus for SCA5 (see this term), though clinical features differ. SCA5 belongs to type III ADCA (see this term) and represents a pure ataxia syndrome with on average earlier age of symptomatic disease onset ranging from 14 to 50 years. Since the causative gene is unknown, SCA20 and SCA5 may be proven genetically to be the same disorder.\nPrognosis\nPrognosis is relatively good. Most patients can walk with or without gait aids and many patients live to more than 60 years of age.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 21", "Disease Definition": "Spinocerebellar ataxia type 21 (SCA21) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by slowly progressive cerebellar ataxia, mild cognitive impairment, postural and/or resting tremor, bradykinesia, and rigidity.", "ORPHA ID": 98773, "Summary": "Epidemiology\nPrevalence is unknown. Fewer than 20 cases in a 4-generation French family have been reported to date.\nClinical description\nMean age of onset is 17.4 years and is relatively early compared to most type I ADCAs. Individuals in successive generations tend to have earlier ages of onset. Parkinsonism was not responsive to L-dopa and magnetic resonance imaging (MRI) revealed cerebellar and brainstem atrophy.\nEtiology\nSCA21 maps to chromosome 7p21.3-p15.1 but the gene and gene mutation have not been identified.\nPrognosis\nThere is insufficient clinical data to draw conclusions concerning prognosis.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 23", "Disease Definition": "Spinocerebellar ataxia type 23 (SCA23) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by gait ataxia, dysarthria, slowed saccades, ocular dysmetria, Babinski sign and hyperreflexia.", "ORPHA ID": 101108, "Summary": "Epidemiology\nThis subtype has only been described in 4 Dutch families. Age of onset is from 43 to 56 years.\nClinical description\nThe clinical features, head magnetic resonance imaging (MRI), and neuropathological findings are indistinguishable from other SCA subtypes.\nEtiology\nSCA23 maps to chromosome region 20p12.3-p13 and missense mutations in the prodynorphin PDYN gene appear to cause the disease.\nPrognosis\nPrognosis may be good in some cases. Disease progression can be slow. Wheelchair dependence can occur more than 20 years after symptomatic disease onset.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 25", "Disease Definition": "Spinocerebellar ataxia type 25 (SCA25) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by cerebellar ataxia and prominent sensory neuropathy.", "ORPHA ID": 101111, "Summary": "Epidemiology\nFewer than 10 cases in a 4-generation French family have been reported to date.\nClinical description\nAge of onset ranges from 1 to 39 years. The clinical features vary widely from sensory neuropathy with little cerebellar ataxia to cerebellar ataxia with little sensory neuropathy. Some patients exhibit gastrointestinal (GI) disorders such as vomiting and abdominal pain as initial symptoms. GI problems can persist. Scoliosis and urinary problems (nycturia or urinary urgency) are also observed. Head magnetic resonance imaging (MRI) shows severe global cerebellar atrophy like in SCA5 and SCA6 (see these terms).\nEtiology\nSCA25 maps to chromosome 2p15-p21. Repeat expansion detection failed to identify CAG repeat expansion.\nPrognosis\nThere is insufficient clinical data to draw conclusions concerning prognosis.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 26", "Disease Definition": "A very rare subtype of autosomal dominant cerebellar ataxia type III (ADCA type III) characterized by late-onset and slowly progressive cerebellar signs (gait ataxia) and eye movement abnormalities.", "ORPHA ID": 101112, "Summary": "Epidemiology\nTo date, only 23 affected patients have been described from one American family of Norwegian descent.\nClinical description\nSpinocerebellar ataxia type 26 (SCA26) onset occurs between the ages of 26-60 with a mean age of onset of 42 years. Slowly progressive gait ataxia and dysarthria were reported in all patients. Nystagmus, impaired pursuit, and dysmetric saccades were described in majority of patitents. Left-sided pyramidal signs (hyperreflexia with positive Babinski sign) were reported in one patient. The disease duration is unknown.\nEtiology\nA candidate gene for SCA26 has recently been identified as the eukaryotic translation elongation factor 2 (EEF2) gene, located on chromosome 19p13.3. Further confirmatory studies are still required in order to determine if a mutation in this gene directly causes SCA26.\nDiagnostic methods\nDiagnosis is based on the clinical findings of pure cerebellar ataxia as well as molecular findings. Head magnetic resonance imaging (MRI) usually demonstrates the presence of atrophy of the cerebellum sparing the brainstem and is helpful in excluding other causes of ataxia. Molecular genetic testing identifies a mutation in the EEF2  gene, confirming a diagnosis of SCA26.\nDifferential diagnosis\nDifferential diagnoses include other forms of ADCA type III, in particular SCA5, SCA6, SCA11, SCA30 and SCA31.\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with a known disease causing mutation.\nGenetic counseling\nSCA26 is inherited autosomal dominantly and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for SCA26 and treatment is supportive. Neurological follow-up is recommended to monitor the progression of ataxia.\nPrognosis\nDisease progression is very slow, but precise prognosis is unknown.\n\n                            Last update: \n                            December 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 27A", "Disease Definition": "Spinocerebellar ataxia type 27 (SCA27) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by early-onset tremor, dyskinesia, and slowly progressive cerebellar ataxia.", "ORPHA ID": 98764, "Summary": "Epidemiology\nFewer than 30 cases have been reported to date.\nEtiology\nThis subtype is caused by a mutation in the fibroblast growth factor 14 FGF14 gene (13q34).\nPrognosis\nPrognosis is relatively good. Patients can walk unassisted until the 7th decade of life. Life-threatening status epilepticus and intractable seizure or severe dysphagia are rare.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 28", "Disease Definition": "Spinocerebellar ataxia type 28 (SCA28) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by juvenile onset, slowly progressive cerebellar ataxia due to Purkinje cell degeneration.", "ORPHA ID": 101109, "Summary": "Epidemiology\nPrevalence is unknown. SCA28 accounts for approximately 1.5% of all European cases of ADCA.\nClinical description\nThe mean age of symptom onset was 19.5 years in the original kindred. Some patients show cognitive impairment. In more advanced stages of the disorder, ophthalmoparesis, slowed saccades, ptosis and pyramidal signs are reported. Patients can walk unassisted until the 7th decade of life. Life-threatening status epilepticus and intractable seizure or severe dysphagia are rare.\nEtiology\nSCA28 is caused by mutations in the AFG3L2 gene located to chromosome 18p11.21.\nGenetic counseling\nSCA28 is inherited autosomal dominantly and genetic counseling is possible.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 29", "Disease Definition": "An autosomal dominant cerebellar ataxia type I that is characterized by very slowly progressive or non-progressive ataxia, dysarthria, oculomotor abnormalities and intellectual disability.", "ORPHA ID": 208513, "Summary": "Epidemiology\nSpinocerebellar ataxia type 29 (SCA29) prevalence is unknown. More than 50 cases have been reported in the literature to date.\nClinical description\nSCA29 presents at birth, or shortly after, with manifestations including very slowly progressive or non-progressive gait and limb ataxia causing delayed walking and frequent falling in children. Mild developmental delay, learning difficulties, and language dysfunction are frequently reported. Other manifestations include nystagmus, dysarthria, dysmetria, and dysdiadochokinesia. Affected patients occasionally present with intention tremor, dystonia, and migraine headaches. Although the disease course is not well established, it appears to range from non-progressive or very slowly progressive ataxia (that does not affect ambulation) to progressively disabling ataxia. A slight improvement in cerebellar signs has been reported in some cases over time.\nEtiology\nSCA29 is due to mutations in the ITPR1 gene (3p26.1), which is also the causal gene of SCA15.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA29 are not specific, diagnosis is only confirmed with the finding of a mutation in the ITPR1 gene.\nDifferential diagnosis\nDifferential diagnosis includes other types of autosomal dominant cerebellar ataxia.\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with a known mutation.\nGenetic counseling\nSCA29 is inherited autosomal dominantly, occasionally autosomal recessively, and genetic counseling is possible.\nManagement and treatment\nThere is no cure for SCA29 and treatment is supportive. Annual neurological examinations are recommended to monitor disease progression.\nPrognosis\nDisease progression is very slow, but precise prognosis is unknown.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 3", "Disease Definition": "Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common subtype of type 1 autosomal dominant cerebellar ataxia (ADCA type 1; see this term), a neurodegenerative disorder, and is characterized by ataxia, external progressive ophthalmoplegia, and other neurological manifestations.", "ORPHA ID": 98757, "Summary": "Epidemiology\nPrevalence is estimated to be 1-2 in 100,000 with significant geographical and ethnic variations: the highest prevalence has been found in the Azores (Flores Island (1/239)), intermediate prevalence rates in Portugal, Germany, the Netherlands, China and Japan, and lower prevalence in North America, Australia and India. Accurate estimates of prevalence are not available. However, SCA3 is the most common form of ADCA1 in most genetically characterized populations and accounts for up to 72 % of families with ataxia. Based on an English language literature review about 600 cases have been published.\nClinical description\nSCA3 is divided into 3 forms. SCA3 type 1 (MJD Type 1, see this term) is associated with ataxia, ophthalmoparesis, pyramidal signs such as spasticity and hyperreflexia, and extrapyramidal signs including dystonia and other movement disorders presenting in adolescence. SCA3 type 2 (MJD Type 2, see this term) presents in middle adulthood with ataxia, spasticity, and dystonia. SCA3 type 3 (MJD Type 3, see this term) occurs after the age of 40 and includes ophthalmoparesis and anterior horn cell disease, i.e. fasciculations, atrophy, and weakness. Parkinsonism can also be a feature of SCA3. A likely overlooked but common feature is impairment of temperature sensation involving the entire body.\nEtiology\nThe disease is associated with a CAG repeat expansion mutation in the ATXN3 gene (14q21) with anticipation phenomenon. The normal repeat length is 13-41 whereas repeat lengths causing SCA3 are greater than 56.\nDiagnostic methods\nDiagnosis is based on the clinical picture, familial history and ultimately on genetic testing.\nDifferential diagnosis\nDifferential diagnosis is broad and includes other types of SCA which may have similar features.\nAntenatal diagnosis\nPrenatal diagnosis and pre-manifestation diagnosis in patients with a family history of SCA can be offered.\nGenetic counseling\nSCA3 follows an autosomal dominant pattern of inheritance with full penetrance and anticipation phenomenon. Genetic counseling is recommended in symptomatic patients or those with a family history of the disorder due to known SCA mutation, and pre-symptomatic testing should be discussed in adults.\nManagement and treatment\nIn the absence of specific treatments to slow or stop disease progression, care is supportive. For example, parkinsonism, restless legs syndrome, spasticity, sleep disorders and depression can be treated pharmacologically. Dystonia and spasticity can be managed with local botulinum toxin injections. Occupational and physical therapy are essential. Speech therapy may also be of benefit for managing dysarthria.\nPrognosis\nPrognosis is poor but patients have been reported to survive for decades after onset of symptoms.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 30", "Disease Definition": "An autosomal dominant cerebellar ataxia type III that is characterized by a slowly progressive and relatively pure ataxia.", "ORPHA ID": 211017, "Summary": "Epidemiology\nSpinocerebellar ataxia type 30 (SCA30) has only been described in 6 patients from one Australian family to date.\nClinical description\nThe age of onset ranges from 45 to 76 years with a mean age of onset of 52 years. It presents with oculomotor dysfunction, moderate dysarthria, and ataxia that progresses slowly and eventually leads to mobility impairment. Some patients have also reported mild hyperreflexia in the lower limbs. Rarer manifestations include gaze-evoked nystagmus and dystonia. Head MRI shows atrophy of cerebellum with preservation of nodulus/uvula and brainstem.\nEtiology\nThe causal gene has not yet been identified but it has been linked to chromosome 4q34.3-q35.1.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical findings and family history of SCA30.\nDifferential diagnosis\nDifferential diagnosis includes other types of autosomal dominant cerebellar ataxia.\nAntenatal diagnosis\nAntenatal diagnosis is not possible, since a causative gene has not yet been identified for SCA30.\nGenetic counseling\nSCA30 is inherited in an autosomal dominant manner and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for SCA30 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. In those with vertigo, vestibular suppressants may be beneficial. Annual neurological examinations are recommended to monitor disease progression.\nPrognosis\nDisease progression is very slow, but precise prognosis is unknown.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 31", "Disease Definition": "An autosomal dominant cerebellar ataxia type III that is characterized by the late-onset of ataxia, dysarthria and horizontal gaze nystagmus, and that is occasionally accompanied by pyramidal signs, tremor, decreased vibration sense and hearing difficulties.", "ORPHA ID": 217012, "Summary": "Epidemiology\nSpinocerebellar ataxia type 31 (SCA31) is the third most common form of ADCA in Japan, where more than 20 families have been reported to date. It is rarely found in other Asian countries and is extremely rare in Western countries.\nClinical description\nThe mean age of disease onset is 58 years but it can present between the ages of 8 to 83 years. Ataxia, dysarthria, and horizontal gaze nystagmus are the common manifestations of SCA31, and the disease duration can be more than 10 years. Less common manifestations include pyramidal signs, tremor, decreased vibration sense, hearing difficulties, and blepharospasm\nEtiology\nSCA31 is due to non-coding pentanucleotide repeat expansions in the BEAN1 gene (16q21), encoding protein BEAN1.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA31 are not specific, diagnosis is only confirmed with the finding of a mutation in the BEAN1 gene\nDifferential diagnosis\nDifferential diagnosis includes other types of ADCA.\nGenetic counseling\nSCA31 is inherited autosomal dominantly with incomplete penetrance and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for SCA31 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. In those with vertigo, vestibular suppressants may be beneficial. Annual neurological examinations are recommended to monitor disease progression.\nPrognosis\nDisease progression is very slow. Life expectancy is not reduced but the quality of life can be significantly affected. According to recent reports, patients can become wheelchair bound at age of 79 years, and died at age of 89 years.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 32", "Disease Definition": "An autosomal dominant cerebellar ataxia type 1 that is characterized by ataxia and cognitive impairment. Azoospermia is a typical feature in affected males.", "ORPHA ID": 276183, "Summary": "Epidemiology\nSpinocerebellar ataxia type 32 (SCA32) has been reported in one Chinese family to date.\nClinical description\nDisease onset occurs in adulthood with females more affected than males. Manifestations include ataxia, cognitive impairment and, in males, azoospermia. Cerebellar atrophy is visible with magnetic resonance imaging.\nEtiology\nThe causal gene of SCA32 has not yet been identified but it is located to chromosome 7q32-q33.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical findings and family history of the disease.\nDifferential diagnosis\nDifferential diagnosis includes other types of ADCA.\nGenetic counseling\nSCA32 is inherited in an autosomal dominant manner and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for SCA32 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. Annual neurological examinations are recommended to monitor disease progression.\nPrognosis\nPrecise prognosis is unknown due to limited number of patients reported. Mean age when aid walking needed is about 34 years.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 34", "Disease Definition": "An autosomal dominant cerebellar ataxia type I that is characterized by papulosquamous, ichthyosiform plaques on the limbs appearing shortly after birth and later manifestations including progressive ataxia, dysarthria, nystagmus and decreased reflexes.", "ORPHA ID": 1955, "Summary": "Epidemiology\nTo date the disorder has been reported in 45 patients including 4 asymptomatic carriers, from one French-Canadian family and three Japanese families.\nClinical description\nDisease onset occurs from shortly after birth to adolescence with the appearance of papulosquamous, ichthyosiform plaques on the limbs, which are often only present in the winter. After the age of 25 years they tend to disappear completely. Progressive ataxia, dysarthria, decreased reflexes, and nystagmus are further clinical signs of the disease that occur after the onset of skin manifestations, generally from the third to fifth decade of life. Patients occasionally present with autonomic dysfunction and pyramidal signs. Cerebellar and pontine atrophy is visible with magnetic resonance imaging (MRI) in individuals who develop cerebellar ataxia.\nEtiology\nThe disorder is due to a mutation in the ELOVL4 gene (6q14).\nDiagnostic methods\nDiagnosis is based on characteristic clinical findings (skin lesions occurring shortly after birth and adult-onset slowly progressive cerebellar ataxia), and on the molecular genetic testing. Mutations in the ELOVL4 gene confirms diagnosis of SCA34. Magnetic resonance imaging usually shows marked atrophy of the cerebellum and pontine which is sometimes accompanied by Hot Cross Bun sign that is common in cerebellar type of multiple system atrophy.\nDifferential diagnosis\nDifferential diagnoses include other forms of autosomal dominant cerebellar ataxia. From the view point of radiological findings, multiple system atrophy is important in differential diagnosis, especially in patients who also develop autonomic dysfunction.\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with a known ELOVL4 mutation.\nGenetic counseling\nThe disorder is inherited in an autosomal dominant manner and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nTreatment is only supportive. Physical activity should be maintained as much as possible with the help of prosthetic devices. Motorized chairs/scooters are eventually necessary. Speech therapy and communication devices should be offered to those with severe dysarthria.\nPrognosis\nDisease progression is slow; the patients require cane or walker in their late 60s, and wheelchair in their 70s.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 35", "Disease Definition": "An autosomal dominant cerebellar ataxia type 1 that is characterized by the adult-onset of progressive gait and limb ataxia, dysarthria, ocular dysmetria, intention tremor of hands, hyperreflexia and spasmodic torticollis.", "ORPHA ID": 276193, "Summary": "Epidemiology\nSpinocerebellar ataxia type 35 (SCA35) has been reported worldwide in less than 30 cases to date.\nClinical description\nDisease onset occurs in adulthood with manifestations of progressive gait and limb ataxia, dysarthria, ocular dysmetria, intention tremor, pseudobulbar palsy, spasmodic torticollis, extensor plantar responses (Babinski sign), reduced proprioception, and hyperreflexia. Cognitive impairment is rare. Patients are usually wheelchair bound 10 years or more after the onset of symptoms. Head MRI shows diffuse cerebellar atrophy without involvement of the brainstem.\nEtiology\nSCA35 is caused by a mutation in the TGM6 gene (20p13) encoding transglutaminase 6 (TG6), a member of the transglutaminase family of enzymes. TG6 is expressed in the kidney, skin, eyes and neurons but the exact process that leads to SCA35 is unknown.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA35 are not specific, diagnosis is only confirmed with the finding of a mutation in the TGM6 gene.\nDifferential diagnosis\nDifferential diagnosis includes other types of ADCA.\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with a known mutation.\nGenetic counseling\nSCA35 is inherited autosomal dominantly and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for SCA35 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Annual neurological examinations are recommended to monitor disease progression.\nPrognosis\nSCA35 is slowly progressive disease, and most of reported patients are usually wheelchair bound 10 years or more after the onset of symptoms.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 36", "Disease Definition": "An autosomal dominant cerebellar ataxia type 1 that characterized by gait and limb ataxia, lower limb spasticity, dysarthria, muscle fasiculations, tongue atrophy and hyperreflexia.", "ORPHA ID": 276198, "Summary": "Epidemiology\nSpinocerebellar ataxia type 36 (SCA36) prevalence is unknown. SCA36 has been described in more than 100 families in Asia (Japan and China) and Europe (France, Italy, Poland, and Spain-Galicia). In a US population, SCA36 accounts for 0.7% of disease in a large undiagnosed ataxia cohort.\nClinical description\nSCA36 presents in adulthood with ataxic dysarthria, truncal ataxia, limb ataxia, general hyperreflexia and variably occurring lower limb spasticity. Motor neuron involvement occurs later in the disease course and manifests with fasciculations and atrophy of the skeletal muscles and tongue. Sensorineural hearing loss may also be present in some. Oromandibular dystonia is a rare manifestation. Only mild cerebellar atrophy is reported.\nEtiology\nSCA36 is due to a pathogenic heterozygous GGCCTG repeat expansion in intron 1 of the NOP56 gene (20p13).\nDiagnostic methods\nDiagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA36 are not specific, diagnosis is only confirmed with the finding of a pathogenic heterozygous GGCCTG repeat expansion in intron 1 of the NOP56 gene.\nDifferential diagnosis\nDifferential diagnosis includes other types of ADCA (Autosomal dominant cerebellar ataxia).\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with a known genetic cause.\nGenetic counseling\nSCA36 is inherited autosomal dominantly and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for SCA36 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Annual neurological examinations are recommended to monitor disease progression.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 37", "Disease Definition": "An autosomal dominant cerebellar ataxia type 1 that is characterized by a cerebellar syndrome along with altered vertical eye movements.", "ORPHA ID": 363710, "Summary": "Epidemiology\nSpinocerebellar ataxia type 37 (SCA37) has been reported in nine members of a Spanish kindred to date.\nClinical description\nDisease onset occurs in adulthood (from the ages of 38-64). Clinical manifestations of SCA37 patients are characterized by slowly progressive cerebellar ataxia (starting with falls, dysarthria and clumsiness followed by other cerebellar signs) along with altered vertical eye movements. Generalized cerebellar atrophy is visible with magnetic resonance imaging.\nEtiology\nSCA37 is due to a pathogenic pentanucleotide ATTTC insertion within the 1p32 5' non-coding regulatory region of the DAB1 gene (1p32.2).\nDiagnostic methods\nDiagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA37 are not specific, diagnosis is only confirmed with the finding of a pathogenic mutation in the DAB1 gene.\nDifferential diagnosis\nDifferential diagnosis includes other types of autosomal dominant cerebellar ataxia.\nAntenatal diagnosis\nPrenatal diagnosis is possible when the ATTTC insertion within the DAB1 gene has been identified in a family member.\nGenetic counseling\nSCA37 is inherited in an autosomal dominant manner and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for SCA37 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Annual neurological examinations are recommended to monitor disease progression.\nPrognosis\nPrecise prognosis is unknown due to small number of patients reported, but disease progression is slow and the patients generally need wheelchair from 10 and 30 years after the disease onset.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 38", "Disease Definition": "Spinocerebellar ataxia type 38 (SCA38) is a subtype of autosomal dominant cerebellar ataxia type 3 characterized by the adult-onset (average age: 40 years) of truncal ataxia, gait disturbance and gaze-evoked nystagmus. The disease is slowly progressive with dysarthria and limb ataxia following. Additional manifestations include diplopia and axonal neuropathy.", "ORPHA ID": 423296, "Summary": ""}
{"Disease Name": "Spinocerebellar ataxia type 4", "Disease Definition": "Spinocerebellar ataxia type 4 (SCA4) is a very rare progressive and untreatable subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term) characterized by ataxia with sensory neuropathy.", "ORPHA ID": 98765, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nSCA4 typically starts in middle-aged adults and presents with cerebellar ataxia, pyramidal signs, and peripheral sensory loss.\nEtiology\nThe disease has been linked to chromosome 16q22.1 in kindreds from Utah (USA) and Germany but the mutation is yet unknown and does not appear to involve trinucleotide repeats.\nPrognosis\nThere is insufficient clinical data to draw conclusions concerning prognosis.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 40", "Disease Definition": "Spinocerebellar ataxia type 40 (SCA40) is a very rare subtype of autosomal dominant cerebellar ataxia type 1, characterized by the adult-onset of unsteady gait and dysarthria, followed by wide-based gait, gait ataxia, ocular dysmetria, intention tremor, scanning speech, hyperreflexia and dysdiadochokinesis.", "ORPHA ID": 423275, "Summary": ""}
{"Disease Name": "Spinocerebellar ataxia type 41", "Disease Definition": "Spinocerebellar ataxia type 41 is a rare autosomal dominant cerebellar ataxia type III disorder characterized by adult-onset progressive imbalance and loss of coordination associated with an ataxic gait. Mild atrophy of the cerebellar vermis has been reported on brain magnetic resonance imaging.", "ORPHA ID": 458798, "Summary": ""}
{"Disease Name": "Spinocerebellar ataxia type 42", "Disease Definition": "A rare, autosomal dominant cerebellar ataxia characterized by pure and slowly progressive cerebellar signs combining gait instability, dysarthria, nystagmus, saccadic eye movements and diplopia. Less frequent clinical signs and symptoms include spasticity, hyperreflexia, decreased distal vibration sense, urinary urgency or incontinence and postural tremor.", "ORPHA ID": 458803, "Summary": ""}
{"Disease Name": "Spinocerebellar ataxia type 43", "Disease Definition": "Spinocerebellar ataxia type 43 is a rare autosomal dominant cerebellar ataxia type I disorder characterized by late adult-onset of slowly progressive cerebellar ataxia, typically presenting with balance and gait disturbances, in association with axonal peripheral neuropathy resulting in reduced/absent deep tendon reflexes and sensory impairment. Lower limb pain and amyotrophy may be present, as well as various cerebellar signs, including dysarthria, nystagmus, hypometric saccades and tremor.", "ORPHA ID": 497764, "Summary": ""}
{"Disease Name": "Spinocerebellar ataxia type 45", "Disease Definition": "A rare autosomal dominant cerebellar ataxia characterized by slowly progressive late-onset gait and limb ataxia, dysarthria, and variable nystagmus. Brain imaging reveals cerebellar atrophy.", "ORPHA ID": 589527, "Summary": ""}
{"Disease Name": "Spinocerebellar ataxia type 46", "Disease Definition": "A rare autosomal dominant cerebellar ataxia characterized by slowly progressive late-onset cerebellar ataxia, variably combined with sensory axonal neuropathy. Patients may present gait and limb ataxia, dysarthria, abnormal oculomotor function, and distal sensory impairment. Cerebellar atrophy is typically mild or absent.", "ORPHA ID": 589522, "Summary": ""}
{"Disease Name": "Spinocerebellar ataxia type 5", "Disease Definition": "An autosomal dominant cerebellar ataxia type III that is characterized by the early-onset of cerebellar signs with eye movement abnormalities and a very slow disease progression.", "ORPHA ID": 98766, "Summary": "Epidemiology\nSpinocerebellar ataxia type 5 (SCA5) prevalence is unknown. Five families (American, French, German, and Japanese) with SCA5 have been reported to date.\nClinical description\nThe mean age of onset is 33 years but it can range from 6 years to 68 years. SCA5 patients clinically present with cerebellar signs (ataxia, dysarthria, tremor), intention tremor, and eye movement abnormalities such as gaze-evoked nystagmus, down beat nystagmus, and impaired smooth pursuit. Occasionally defects of the visual field and horizontal gaze palsy can be also present. Non-cerebellar signs such as facial myokimia, resting tremor, writer's cramp, impaired vibration sense, dysphagia, and brisk deep tendon reflexes have been reported in some patients. SCA5 progresses very slowly with a disease duration of more than 30 years after symptom onset.\nEtiology\nSCA5 is caused by mutations in the SPTBN2 gene (11q13.2) encoding beta-III spectrin, a protein essential for the correct functioning and development of Purkinje cells.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA5 are not specific, diagnosis is only confirmed with the finding of a mutation in the SPTBN2 gene.\nDifferential diagnosis\nDifferential diagnosis includes other types of ADCA (Autosomal dominant cerebellar ataxia).\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with a known mutation.\nGenetic counseling\nThe disease is a rare autosomal dominant spinocerebellar ataxia. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for SCA5 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. Annual neurological examinations are recommended to monitor disease progression.\nPrognosis\nDisease progression is slow, but precise prognosis is unknown.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 6", "Disease Definition": "An autosomal dominant cerebellar ataxia type III that is characterized by late-onset and slowly progressive gait ataxia and other cerebellar signs such as impaired muscle coordination and nystagmus.", "ORPHA ID": 98758, "Summary": "Epidemiology\nSpinocerebellar ataxia type 6 (SCA6) estimated worldwide prevalence is less than 1/100,000. It is most commonly seen in Japan, Korea, the Netherlands and Germany.\nClinical description\nThe mean age of onset is 45 years but can range from the ages of 16 to 72 years. It usually presents with the cerebellar signs of ataxia, dysarthria and dysphagia. Some patients also have episodic vertigo and diplopia. Eye movement abnormalities such as gaze evoked and downbeat nystagmus, impaired smooth pursuit and abnormal vestibulo-ocular reflex are commonly seen in SCA6 patients. Less common presentations include pyramidal tract signs and peripheral neuropathy. Parkinsonism, dystonia, myoclonus, tremor and cognitive impairment have been reported in rare cases. Depression and fatigue have been associated with SCA6. Disease severity seems to increase during pregnancy. SCA6 progresses very slowly with a disease duration that can last over 25 years.\nEtiology\nSCA6 is caused by small expansions of the trinucleotide (CAG) repeat in the CACNA1A gene (19p13) which encodes an alpha 1 subunit of a P/Q-type voltage-gated calcium channel, necessary for proper neural communication in the brain. The expansions in SCA6 patients are usually of 21-29 CAG repeats.\nDiagnostic methods\nDiagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA6 are not specific, diagnosis is only confirmed with the finding of a mutation in the CACNA1A gene.\nDifferential diagnosis\nDifferential diagnosis includes other types of autosomal dominant cerebellar ataxia, familial or sporadic hemiplegic migraine and episodic ataxia type 2.\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with a known mutation.\nGenetic counseling\nSCA6 is inherited autosomal dominantly and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThere is no cure for SCA6 and treatment is supportive. Acetazolamide may help with episodes of ataxia but does not halt the progression of the disease. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Dysphagia should be monitored to decrease the risk of aspiration pneumonia. In those with vertigo, vestibular suppressants may be beneficial. Annual neurological examinations are recommended to monitor disease progression.\nPrognosis\nLife expectancy is not reduced but the quality of life can be significantly affected. Mean age when aid walking needed is about 53 years, and mean age when wheelchair needed is approximately 60 years.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 7", "Disease Definition": "An autosomal dominant cerebellar ataxia type II that is characterized by progressive ataxia, motor system abnormalities, dysarthria, dysphagia and retinal degeneration leading to progressive blindness.", "ORPHA ID": 94147, "Summary": "Epidemiology\nThe worldwide prevalence of the disease is estimated to be less than 1/100,000 and it is thought to account for 2-4 % of all forms of spinocerebellar ataxia (up to 7 % in Asian populations). Higher prevalence is described in some populations such as in Scandinavia or South Africa.\nClinical description\nOnset of Spinocerebellar ataxia type 7 (SCA7) is generally in the second to fourth decade but can range from infancy to the sixth decade of life. Manifestations that present in infancy and early childhood include muscle weakness, wasting, hypotonia, poor feeding, failure to thrive and loss of motor milestones. Changes in visual acuity and color vision (tritanopia) may be the earliest signs of the disease, especially in younger-onset patients. In those where initial symptoms occur before adolescence, the disease progresses much faster and blindness can occur within a few years. In those with adult-onset disease, manifestations include dysmetria, poor coordination and dysdiadokinesia with progression into severe dysarthria, dysphagia and loss of motor control. Visual symptoms (hemeralopia, photophobia, abnormalities in color vision and central visual acuity) may precede, accompany or follow cerebellar ataxia in those with adult-onset SCA7 but progression is slower, with blindness occurring 10 or more years after initial symptom onset. Psychosis and cognitive decline has also been reported in some cases. Patients eventually become bedridden.\nEtiology\nSCA7 is due to a CAG trinucleotide repeat in the ataxin 7 (ATXN7) gene (3p21.1-p12). This mutation leads to degeneration in the cells of the retina, cerebellum and brainstem. A larger CAG-repeat expansion is associated with an earlier onset and more severe disease course.\nDiagnostic methods\nDiagnosis is based on characteristic clinical findings (progressive incoordination and cone-rod retinal dystrophy) as well as molecular genetic testing. A CAG trinucleotide expansion (usually 36 or more CAG repeats) in the ATXN7 gene confirms diagnosis of SCA7. Magnetic resonance imaging usually shows severe atrophy of the cerebellum and the brainstem. Electroretinogram testing reveals rod and cone abnormalities and fundoscopic examination shows macular changes later in the disease course.\nDifferential diagnosis\nDifferential diagnoses include lipid storage diseases (such as neuronal ceroid lipofuscinosis) and Leber hereditary optic neuropathy. Other forms of ADCA should also be considered but can be excluded based on the absence of retinal degeneration, which is unique to SCA7.\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with a known ATXN7 mutation.\nGenetic counseling\nThe disorder is inherited autosomal dominantly and genetic anticipation is observed. Genetic counseling can inform parents with the disease of the 50% risk of passing it on to their children.\nManagement and treatment\nThere is no cure for SCA7 and treatment is supportive. Activity should be maintained as much as possible with the help of canes and walkers. Motorized chairs may eventually be necessary. Speech therapy and communication devices should be offered to those with dysarthria. UV exposure should be limited and sunglasses worn in order to limit damage to the retina. Low vision aids may also be beneficial. Ophthalmological follow-up is essential to monitor visual acuity. Dysphagia must also be monitored and a feeding tube may be required in those with advanced disease, in order to lower the risk of aspiration pneumonia (most common cause of death).\nPrognosis\nThe prognosis depends on the age of symptom onset. An earlier onset is associated with a more severe and rapidly progressive disease. Mean age when aid walking needed is about 35 years, and mean age when wheelchair needed is approximately 37 years.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia type 8", "Disease Definition": "Spinocerebellar ataxia type 8 (SCA8) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term) characterized by cerebellar ataxia and cognitive dysfunction in almost three quarters of patients and pyramidal and sensory signs in approximately a third of patients.", "ORPHA ID": 98760, "Summary": "Epidemiology\nPrevalence is unknown. However, SCA8 accounts for approximately 3% of ADCA cases.\nClinical description\nOther features include dysexecutive disorders and commonly psychiatric disorders.\nEtiology\nSCA8 is caused by a trinucleotide repeat on 13q21 that produces a polyglutamine expansion in the ataxin 8 gene (ATXN8). SCA8 is thought to result from RNA-mediated neurotoxicity.\nPrognosis\nPrognosis is relatively good. Disease usually progresses slowly over decades. Life expectancy is not significantly reduced.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK"}
{"Disease Name": "Spinocerebellar ataxia with axonal neuropathy type 1", "Disease Definition": "Spinocerebellar ataxia with axonal neuropathy type 1 is a rare, genetic neurological disorder characterized by a late childhood onset of slowly progressive cerebellar ataxia. Initial manifestations include weakness and atrophy of distal limb muscles, areflexia and loss of pain, vibration and touch sensations in upper and lower extremities. Gaze nystagmus, cerebellar dysarthria, peripheral neuropathy, stepagge gait and pes cavus develop as disease progresses. Cerebellar atrophy (especially of the vermis) is present in all affected individuals. Additional reported manifestations include seizures, mild brain atrophy, mild hypercholesterolemia and borderline hypoalbuminemia.", "ORPHA ID": 94124, "Summary": ""}
{"Disease Name": "Spinocerebellar ataxia with axonal neuropathy type 2", "Disease Definition": "A rare autosomal recessive cerebellar ataxia (ARCA), characterized by progressive cerebellar ataxia associated with frequent oculomotor apraxia, severe neuropathy and an elevated serum alpha-fetoprotein (AFP) level.", "ORPHA ID": 64753, "Summary": "Epidemiology\nThe prevalence of spinocerebellar ataxia with axonal neuropathy type 2 (SCAN2) in France is estimated to be 1/900,000.\nClinical description\nSCAN2 is mostly an adolescent onset disorder (age at onset ranges between 10 and 25 years), with a mean age of 14-15 years, that manifests as progressive cerebellar ataxia associated with peripheral neuropathy (98%), cerebellar atrophy (96%), occasional oculomotor apraxia (OMA; 51%; inability to coordinate eyes ± head movements: when the head turns toward a lateral target; the head reaches the target before the eyes), pyramidal signs (21%), head tremor (14%), dystonia (14%), strabismus (12%), chorea (10%) and saccadic pursuit without OMA (4.5%).\nEtiology\nSCAN2 results from mutations in SETX gene (9q34), encoding senataxin protein, a DNA/RNA helicase localized in nucleus which is implicated in DNA break repair. Some correlations between genotype and phenotype have been established for example deletions and nonsense mutations are correlated to more severe phenotypes than missense mutations. Mutations in the gene PIK3R5 (17p13.1) have also been implicated in the pathogenesis of SCAN2. PIK3R5 encodes a regulatory subunit that interacts with class 1B phosphoinositide-3-kinase (key enzymes in various signal transduction pathways that regulate cell survival and growth, metabolism, immune, and cardiac functions).\nDiagnostic methods\nDiagnosis is based on clinical features, progressive evolution leading to important motor handicap, absence of extra-neurologic findings and family history. Laboratory findings show an elevated AFP serum level (above 7 µg/L). Electromyography findings reveal axonal sensory-motor neuropathy. Oculographic recordings can demonstrate OMA. Cerebral magnetic resonance imagery displays cerebellar atrophy. Diagnosis is confirmed by molecular analysis of the pathogenic gene.\nDifferential diagnosis\nDifferential diagnosis includes Friedreich ataxia, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia type 1, ataxia-telangiectasia, ataxia-telangiectasia-like disorder, autosomal recessive spastic ataxia of Charlevoix-Saguenay.\nAntenatal diagnosis\nCarrier testing for at-risk family members and prenatal testing are possible if the disease-causing alleles in a family are known.\nGenetic counseling\nTransmission of SCAN2 is autosomal recessive. Genetic counseling is recommended as each sib of an affected individual has 25% risk of being affected, 50% risk of being an asymptomatic carrier, and 25% risk of being neither affected nor a carrier.\nManagement and treatment\nNo specific treatment exists for SCAN2 and management is mainly supportive. It includes physical therapy for cerebellar ataxia and disabilities resulting from peripheral neuropathy; educational support for reading and writing difficulties, speech therapy for dysarthria and cognitive impairment. Routine follow-up with a neurologist or a neurogenetician is recommended.\nPrognosis\nSCAN2 is a progressive neurodegenerative disorder and most patients will become wheelchair bound at a mean age of 29.9 years ± 3.84 after a mean disease duration of 15.3 years ± 3.52.\n\n                            Last update: \n                            May 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Perrine CHARLES"}
{"Disease Name": "Spinocerebellar ataxia with epilepsy", "Disease Definition": "A rare, mitochondrial DNA maintenance syndrome characterized by cerebellar ataxia, sensory peripheral neuropathy, myoclonus, epilepsy, progressive cognitive impairment, late-onset ptosis and external ophthalmoplegia. Liver failure may also occur, most often in association with the use of antiepileptic drug sodium valproate.", "ORPHA ID": 254881, "Summary": ""}
{"Disease Name": "Spinocerebellar ataxia-dysmorphism syndrome", "Disease Definition": "A rare hereditary ataxia characterized by unusual facies (i. e. gross, rough and abundant hair, mild palpebral ptosis, thick lips, and down-curved corners of the mouth), dysarthria, delayed psychomotor development, scoliosis, foot deformities, and ataxia. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 1185, "Summary": ""}
{"Disease Name": "Spinocerebellar degeneration-corneal dystrophy syndrome", "Disease Definition": "A rare, genetic, neurological disorder characterized by the association of slowly progressive spinocerebellar degeneration and corneal dystrophy, manifesting with bilateral corneal opacities (which lead to severe visual impairment), mild intellectual disability, ataxia, gait disturbances, and tremor. Additional manifestations include facial dysmorphism (i.e. triangular face, ptosis, low-set, posteriorly angulated ears, and micrognathia), as well as mild upper motor neuron involvement with hypertonia, lower limb hyperreflexia and extensor plantar responses. There have been no further descriptions in the literature since 1985.", "ORPHA ID": 3177, "Summary": ""}
{"Disease Name": "Spirillary rat-bite fever", "Disease Definition": "Spirillary rat-bite fever (RBF), also known as Sodoku (Japanese for so: rat and doku: poison), is caused by the Gram-negative bacillus Spirillum minus and is transmitted to humans through the bites and scratches of rats. The disease is mostly present in Asia.", "ORPHA ID": 99903, "Summary": "Epidemiology\nThe exact incidence is unknown.\nClinical description\nThe bite is often small and heals quickly. However, after an incubation period of around 14 to 18 days, an inflammation appears at the site of the bite that becomes painful, indurated, edematous and may ulcerate. The inflammation is followed by fever, vomiting and chills and is associated with local lymphadenopathy. In 50% of the cases, a macular rash develops and in rare cases, swollen, red, and painful joints can appear. Occasionally, diarrhea, vomiting, neuralgias and complications, such as endo- and myocarditis, hepatitis and meningitis, can occur.\nEtiology\nSpirillum minus is present in the saliva of rats and is only transmitted through bites and scratches. A few cases of transmission by other animals (monkeys, mice) have been reported.\nDiagnostic methods\nWithout a noticeable bite, diagnosis is based solely on detection of the germ. However, this is difficult due to its poor growth on culture media.\nDifferential diagnosis\nThe differential diagnosis includes streptobacillary RBF and Haverhill fever (see these terms) and several bacterial and viral infections (Lyme disease, leptospirosis, brucellosis, Rocky Mountain spotted fever, malaria, typhoid fever (see these terms), S. pyogenes and S. pyogenes-associated diseases, S. aureus infection, disseminated gonorrhea, meningococcemia, viral exanthems, secondary syphilis, Epstein-Barr virus, and coxsackieviruses).\nManagement and treatment\nManagement requires a prophylactic (avoiding direct or indirect contact with host-animals) and therapeutic approach (local treatment and antimicrobial therapy). Treatment of this form of rat-bite fever is primarily based on penicillin G administration as little is known about the susceptibility of this germ to other antibiotics.\nPrognosis\nWithout treatment, symptoms disappear within 3-4 days but regular relapses can occur 3-10 days later. The initial lesion can become necrotic and can desquamate. The relapses can go on for a year but normally the symptoms disappear within two months. If left untreated, RBF carries a mortality rate of 6.5% due to complications.\n\n                            Last update: \n                            August 2009\n\n\n                            - Expert reviewer(s): \n                            Dr François TREMOLIERES"}
{"Disease Name": "Splenic diffuse red pulp small B-cell lymphoma", "Disease Definition": "Splenic diffuse red pulp small B-cell lymphoma is a rare, indolent B-cell non-Hodgkin lymphoma characterized by abnormal proliferation of small, monomorphous, basophilic B-lymphocytes, with villous cytoplasm, in the splenic red pulp, bone marrow and peripheral blood. It typically presents in the late clinical stages with splenomegaly and moderate lymphocytosis. Cytopenias are rare and likely associated with hypersplenism.", "ORPHA ID": 300869, "Summary": ""}
{"Disease Name": "Splenic marginal zone lymphoma", "Disease Definition": "Splenic marginal zone lymphoma is a rare, indolent B-cell non-Hodgkin lymphoma characterized by abnormal clonal proliferation of mature B-lymphocytes with involvement in the spleen, bone marrow and, frequently, the blood. It usually presents with splenomegaly, lymphocytosis, anemia and/or thrombocytopenia. Hepatitis C virus and autoimmune manifestations, such as autoimmune hemolytic anemia and autoimmune thrombocytopenia, could be associated.", "ORPHA ID": 86854, "Summary": ""}
{"Disease Name": "Splenogonadal fusion-limb defects-micrognathia syndrome", "Disease Definition": "A rare dysostosis syndrome characterized by abnormal fusion of the spleen with the gonad (or more rarely with remnants of the mesonephros), limb abnormalities (consisting of amelia or severe reduction defects leading to upper and/or lower rudimentary limbs) and orofacial abnormalities such as cleft palate, bifid uvula, microglossia and mandibular hypoplasia. It could also be associated with other malformations such as cryptorchidism, anal stenosis/atresia, hypoplastic lungs and cardiac malformations.", "ORPHA ID": 2063, "Summary": ""}
{"Disease Name": "Split cord malformation type I", "Disease Definition": "A rare subtype of split cord malformation characterized by each hemicord contained in its own dural sac, typically with a intervening bony septum.", "ORPHA ID": 1671, "Summary": ""}
{"Disease Name": "Split cord malformation type II", "Disease Definition": "A rare subtype of split cord malformation characterized by both hemicords included in the same single dural sac. An intradural intervening mesenchymal septum may be present.", "ORPHA ID": 573253, "Summary": ""}
{"Disease Name": "Split cord malformation", "Disease Definition": "A rare malformation characterized by localized longitudinal division of the spinal cord into two \"hemicords\". Vertebro-costal anomalies are commonly associated. Classic overlying skin stigmata is a focal hypertrichosis/hairy patch. Split cord malformations may be associated with other dysraphic anomalies (eg: filum lipoma).", "ORPHA ID": 573278, "Summary": ""}
{"Disease Name": "Split hand-split foot-deafness syndrome", "Disease Definition": "Split hand - split foot - deafness is an extremely rare genetic syndrome reported in a few families to date and characterized clinically by split hand/split foot malformation (SHFM; see this term) and mild to moderate sensorineural hearing loss, sometimes associated with cleft palate and intellectual deficit.", "ORPHA ID": 71271, "Summary": ""}
{"Disease Name": "Split-foot malformation-mesoaxial polydactyly syndrome", "Disease Definition": "A rare genetic syndrome with limb malformations as a major feature characterized by unilateral or bilateral split-foot malformation, nail abnormalities of the hand, and bilateral sensorineural hearing impairment. Mesoaxial polydactyly of the foot has also been described.", "ORPHA ID": 488232, "Summary": ""}
{"Disease Name": "SPONASTRIME dysplasia", "Disease Definition": "A rare, genetic, spondyloepimetaphyseal dysplasia disease characterized by short-limbed short stature (more pronounced in lower limbs) associated with characterisitic facial dysmorphism (i.e. relative macrocephaly, frontal bossing, midface hypoplasia, depressed nasal root, small upturned nose, prognathism) and abnormal radiological findings, which include abnormal vertebral bodies (particularly in the lumbar region), striated metaphyses, generalized mild osteoporosis, and delayed ossification of the carpal bones. Progressive coxa vara, short dental roots, hypogammaglobulinemia and cataracts may be occasionally associated.", "ORPHA ID": 93357, "Summary": ""}
{"Disease Name": "Spondylo-megaepiphyseal-metaphyseal dysplasia", "Disease Definition": "A rare, genetic primary bone displasia characterized by disproportionate short stature with short, stiff neck and trunk and relatively long limbs, fingers and toes (which may present flexion contractures), severe vertebral body ossification delay (with frequent pycnodysostosis), markedly enlarged round epiphyses of the long bones, absent ossification of pubic bones and multiple pseudoepiphyses of the short tubular bones in hands and feet. Neurological manifestations resulting from cervical spine instability may be observed.", "ORPHA ID": 228387, "Summary": ""}
{"Disease Name": "Spondylo-ocular syndrome", "Disease Definition": "Spondylo-ocular syndrome is a very rare association of spinal and ocular manifestations that is characterized by dense cataracts, and retinal detachment along with generalized osteoporosis and platyspondyly. Mild craniofacial dysphormism has been reported including short neck, large head and prominent eyebrows.", "ORPHA ID": 85194, "Summary": ""}
{"Disease Name": "Spondylocamptodactyly syndrome", "Disease Definition": "A rare spondylodysplastic syndrome characterized by camptodactyly, cervical platyspondyly, and variable degrees of thoracic scoliosis. There have been no further descriptions in the literature since 1995.", "ORPHA ID": 3180, "Summary": ""}
{"Disease Name": "Spondylocarpotarsal synostosis", "Disease Definition": "A spondylodysplasic dysplasia clinically characterized by postnatal progressive vertebral fusions frequently manifesting as block vertebrae, contributing to an shortened trunk and hence disproportionate short stature, scoliosis, lordosis, carpal and tarsal synostosis and infrequently, club feet.", "ORPHA ID": 3275, "Summary": "Epidemiology\nSpondylocarpotarsal synostosis (SCT) is very rare. To date, less than 40 cases have been reported in the medical literature.\nClinical description\nWhile the clinical onset is postnatal, the diagnosis becomes clinically evident in early in childhood. Primary clinical characteristics of SCT syndrome include progressive vertebral fusions manifesting as block vertebrae leading to a shortened trunk resulting in disproportionate short stature that becomes apparent with physical growth. Scoliosis, lordosis, carpal and tarsal synostosis are frequent with club feet being observed in a minority of cases. A mild facial dysmorphism with a round face with frontal bossing and anteverted nostrils can be evident. Midline cleft palate, conductive hearing loss, joint laxity and dental enamel hypoplasia are uncommonly reported.\nEtiology\nSCT syndrome is due to biallelic mutations in FLNB (localized to 3p14.3) that encodes cytoskeletal protein filamin B. A very similar condition is caused by either monoallelic or biallelic mutations in MYH3.\nDiagnostic methods\nDiagnosis is confirmed by skeletal x-rays and genetic testing. Radiographs demonstrate progressive vertebral fusions and lumbar spine, carpal and tarsal synostosis without rib anomalies. Occasionally, delayed ossification of epiphyses and bilateral epiphyseal femur dysplasia are reported.\nDifferential diagnosis\nDifferential diagnosis may include isolated Klippel-Feil syndrome and other vertebral dysplasias, such as autosomal dominant spondylocostal dysplasia and multiple synostoses syndrome.\nGenetic counseling\nSCT syndrome follows an autosomal recessive inheritance (FLNB, MYH3) or occasionally autosomal dominant inheritance (MYH3). Genetic counseling should be proposed to at risk couples informing them that there is 25% (autosomal recessive) or 50% (autosomal dominant) risk of tranmitting the disease to offspring.\nManagement and treatment\nManagement involves ophthalmologic, audiologic and spine assessments. Scoliosis is treated medically; no effective surgical intervention has been described. The cervical spine should be evaluated for features of instability prior to general anesthesia. Pain management is indispensable as patients suffer from much continuing physical pain due to the spinal deformities and fused block vertebrae.\nPrognosis\nIt has not been formally evaluated if SCT syndrome affects life expectancy.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Stephen ROBERTSON  - Dr Emma WADE"}
{"Disease Name": "Spondylodysplastic Ehlers-Danlos syndrome", "Disease Definition": "A rare connective tissue disorder for which three subtypes exist, either related to the gene B4GALT7, B3GALT6 or SLC39A13, and for which the clinically overlapping characteristics include short stature (progressive in childhood), small joint hypermobility, skin hyperextensibility with soft, doughy skin especially on the hands and feet muscular hypotonia (ranging from congenitally severe to mild with later_onset), skeletal anomalies and, more variably, osteopenia, delayed motor development and bowing of the limbs. Gene-specific features, with variable presentation, are additionally observed in each subtype.", "ORPHA ID": 536471, "Summary": ""}
{"Disease Name": "Spondyloenchondrodysplasia", "Disease Definition": "Spondyloenchondrodysplasia (SPENCD) is a very rare genetic skeletal dysplasia characterized clinically by skeletal anomalies (short stature, platyspondyly, short broad ilia) and enchondromas in the long bones or pelvis. SPENCD may have a heterogeneous clinical spectrum with neurological involvement (spasticity, mental retardation and cerebral calcifications) or autoimmune manifestations, such as immune thrombocytopenic purpura, systemic lupus erythematosus (see these terms) hemolytic anemia and thyroiditis.", "ORPHA ID": 1855, "Summary": ""}
{"Disease Name": "Spondyloepimetaphyseal dysplasia congenita, Strudwick type", "Disease Definition": "Spondyloepimetaphyseal dysplasia congenita, Strudwick type is characterized by disproportionate short stature from birth (with a very short trunk and shortened limbs) and skeletal abnormalities (lordosis, scoliosis, flattened vertebrae, pectus carinatum, coxa vara, clubfoot, and abnormal epiphyses or metaphyses).", "ORPHA ID": 93346, "Summary": "Epidemiology\nThe syndrome has been described in less than 30 patients so far.\nClinical description\nCleft palate and eye abnormalities (severe myopia and retinal detachment) are frequently associated. Arthritis may develop early in life.\nEtiology\nThis condition is caused by mutations in the COL2A1 gene (12q13.11-q13.2).\nGenetic counseling\nIt is inherited in an autosomal dominant manner.\n\n                            Last update: \n                            September 2009"}
{"Disease Name": "Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type", "Disease Definition": "Spondyloepimetaphyseal dysplasia with multiple dislocations is a rare genetic primary bone dysplasia disorder characterized by midface hypoplasia, short stature, generalized joint laxity, multiple joint dislocations (most frequently of knees and hips), limb malalignment (genu valgum/varum) and progressive spinal deformity (e.g. kyphosis/scoliosis). Radiography reveals distinctive slender metacarpals and metatarsals, as well as small, irregular epiphyses, metaphyseal irregularities with vertical striations, constricted femoral necks and mild platyspondyly, among others.", "ORPHA ID": 93360, "Summary": ""}
{"Disease Name": "Spondyloepimetaphyseal dysplasia, aggrecan type", "Disease Definition": "Spondyloepimetaphyseal dysplasia, aggrecan type is a new form of skeletal dysplasia characterized by severe short stature, facial dysmorphism and characteristic radiographic findings.", "ORPHA ID": 171866, "Summary": "Epidemiology\nTo date, three cases have been described, all originating from the same family.\nClinical description\nFacial features include midface hypoplasia with almost absent nasal cartilage, and relative prognathism and macrocephaly. Radiographic findings include irregular epiphyses of long bones with widened metaphyses, platyspondyly, multiple cervical-vertebral clefts and brachydactyly.\nEtiology\nThe disease results from a missense mutation affecting the C-type lectin domain of aggrecan (AGC1 gene; chromosome 15) which regulates endochondral ossification. Transmission is autosomal-recessive.\n\n                            Last update: \n                            October 2009"}
{"Disease Name": "Spondyloepimetaphyseal dysplasia, Geneviève type", "Disease Definition": "Spondyloepimetaphyseal dysplasia, Geneviève type is a rare primary bone dysplasia characterized by severe developmental delay and skeletal dysplasia (including short stature, premature carpal ossification, platyspondyly, longitudinal metaphyseal striations, and small epiphyses), as well as moderate to severe intellectual disability and facial dysmorphism, including prominent forehead, mild synophrys, depressed nasal bridge, prominent bulbous nasal tip and full lips.", "ORPHA ID": 168454, "Summary": ""}
{"Disease Name": "Spondyloepimetaphyseal dysplasia, Handigodu type", "Disease Definition": "Spondyloepimetaphyseal dysplasia, Handigodu type is a rare, genetic, primary bone dysplasia disorder characterized by three distinct phenotypes, namely: 1) patients of average height with painful, osteoarthritic changes of the hip joints and no spinal abnormalities, 2) short-statured patients with predominantly truncal shortening, arm span exceeding height, dysplastic changes of hips and varying degrees of platyspondyly, and 3) patients with dwarfism, various associated skeletal abnormalities (particularly of the knees and hands) and severe epiphyseal dysplasia (of hips, knees, hands, wrists) associated with significant platyspondyly. Most patients cannot walk long distances, and many have decreased joint spaces, as well as sclerotic and cystic changes on imaging.", "ORPHA ID": 99642, "Summary": ""}
{"Disease Name": "Spondyloepimetaphyseal dysplasia, Irapa type", "Disease Definition": "Spondyloepimetaphyseal dysplasia, Irapa type is characterized by disproportionate short-trunked short stature, pectus carinatum, short arms, short and broad hands, short metatarsals, flat and broad feet, coxa vara, genu valgum, osteoarthritis, arthrosis and moderate-to-serious gait impairment.", "ORPHA ID": 93351, "Summary": "Epidemiology\nThe syndrome has been described among Venezuelan Indians of the Yukpa (Irapa) tribe and three sibs from a Mexican mestizo family.\nEtiology\nAutosomal recessive inheritance has been suggested, but the causative gene has not yet been identified.\n\n                            Last update: \n                            November 2009"}
{"Disease Name": "Spondyloepimetaphyseal dysplasia, Isidor-Toutain type", "Disease Definition": "A rare primary bone dysplasia disorder characterized by normal birth length with early postnatal growth deficiency resulting in severe disproportionate short stature (with short trunk and limbs), severe genu varum, flexion contractures in the hips and lumbar hyperlordosis. Radiological findings reveal platyspondyly with central indentation of vertebral endplates, progressive and severe epimetaphyseal abnormalities that primarily affect the lower limbs and include very small, irregular proximal femoral and knee epiphyses, severe coxa vara, delayed ossification of proximal femoral epiphyses, and irregular distal femoral and proximal tibial metaphyses.", "ORPHA ID": 370015, "Summary": ""}
{"Disease Name": "Spondyloepimetaphyseal dysplasia, Maroteaux type", "Disease Definition": "Spondyloepiphyseal dysplasia, Maroteaux type is a very rare type of spondyloepiphyseal dysplasia (see this term) described in fewer than 10 patients to date and characterized clinically by dysplastic epiphyses, short stature appearing in infancy, short neck, short and stubby hands and feet, scoliosis, genu valgum, abnormal pelvis, osteoporosis and osteoarthritis.", "ORPHA ID": 263482, "Summary": ""}
{"Disease Name": "Spondyloepimetaphyseal dysplasia, matrilin-3 type", "Disease Definition": "A rare primary bone dysplasia due to matrilin-3 varaints and characterized by disproportionate early-onset dwarfism, bowing of the lower limbs, short, wide and stocky long bones with severe epiphyseal and metaphyseal changes, lumbar lordosis, hypoplastic iliac bones, flat ovoid vertebral bodies and normal hands.", "ORPHA ID": 156728, "Summary": ""}
{"Disease Name": "Spondyloepimetaphyseal dysplasia, Missouri type", "Disease Definition": "Spondyloepimetaphyseal dysplasia, Missouri type is characterized by moderate-to-severe metaphyseal changes, mild epiphyseal involvement, rhizomelic shortening of the lower limbs with bowing of the femora and/or tibiae, coxa vara, genu varum and pear-shaped vertebrae in childhood.", "ORPHA ID": 93356, "Summary": "Epidemiology\nThe syndrome has been described in a large Missouri (US) kindred with 14 affected members in 4 generations.\nClinical description\nThough some spontaneous improvement of the skeletal defects may occur in adolescence, the affected individuals remained shorter than their age-matched unaffected sibs. Predisposition deformities to osteoarthritis (especially of the knees) have been noted.\nEtiology\nThis condition is caused by mutation in the MMP13 gene (locus 11q22.3) and transmitted in an autosomal dominant manner.\n\n                            Last update: \n                            November 2009"}
{"Disease Name": "Spondyloepimetaphyseal dysplasia, PAPSS2 type", "Disease Definition": "Spondyloepimetaphyseal dysplasia (SEMD), Pakistani type is characterized by short stature, short and bowed lower limbs, mild brachydactyly, kyphoscoliosis, abnormal gait, enlarged knee joints, precocious osteoarthropathy, and normal intelligence.", "ORPHA ID": 93282, "Summary": "Epidemiology\nThe syndrome has been described a large eight-generation consanguineous Pakistani family.\nClinical description\nRadiographic features include delayed epiphyseal ossification at the hips and knees, platyspondyly with irregular end plates and narrowed joint spaces, diffuse early osteoarthritic changes (in the spine and hands), mild brachydactyly, and mild metaphyseal abnormalities (predominantly involving the hips and knees).\nEtiology\nSEMD, Pakistani type is caused by mutations in the PAPSS2 gene (10q22-q24). Mutations in the same gene have been identified in a 14.5-year-old Turkish girl with premature pubarche, hyperandrogenic anovulation, short stature and skeletal dysplasia.\nGenetic counseling\nSEMD, Pakistani type is inherited in an autosomal recessive manner.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Spondyloepimetaphyseal dysplasia, Shohat type", "Disease Definition": "Spondyloepimetaphyseal dysplasia congenita, Shohat type is characterized by severely disproportionate short stature, short limbs, small chest, short neck, thin lips, severe lumbar lordosis, marked genu varum, joint laxity, distended abdomen, mild hepatomegaly and splenomegaly.", "ORPHA ID": 93352, "Summary": "Epidemiology\nThe syndrome has been described in three members of a Jewish family of Iraqi origin and one Mexican boy.\nClinical description\nThe long bone changes in adolescence show general metaphyseal irregularities and significant epiphyseal ossification delay.\nEtiology\nAutosomal recessive inheritance has been suggested, but the causative gene has not yet been identified.\n\n                            Last update: \n                            November 2009"}
{"Disease Name": "Spondyloepimetaphyseal dysplasia-abnormal dentition syndrome", "Disease Definition": "Spondyloepimetaphyseal dysplasia-abnormal dentition syndrome is a rare primary bone dysplasia disorder characterized by the association of dental anomalies (oligodontia with pointed incisors) and generalized platyspondyly with epiphyseal and metaphyseal involvement. Thin tapering fingers and accentuated palmar creases are additional features.", "ORPHA ID": 168451, "Summary": ""}
{"Disease Name": "Spondyloepimetaphyseal dysplasia-hypotrichosis syndrome", "Disease Definition": "Spondyloepimetaphyseal dysplasia-hypotrichosis syndrome is a rare primary bone dysplasia disorder characterized by congenital hypotrichosis associated with rhizomelic short stature (more pronounced in upper limbs than lower limbs), limited hip abduction and mild genu varum. Flared and irregular metaphyses, delayed and irregular epiphiseal ossification and pear-shaped vertebral bodies are characteristic radiologic findings.", "ORPHA ID": 168443, "Summary": ""}
{"Disease Name": "Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome", "Disease Definition": "Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome is a rare, genetic primary bone dysplasia disorder characterized by disproportionate short stature with shortening of upper and lower limbs, short and broad fingers with short hands, narrowed chest with rib abnormalities and pectus excavatum, abnormal chondral calcifications (incl. larynx, trachea and costal cartilages) and facial dysmorphism (frontal bossing, hypertelorism, prominent eyes, short flat nose, wide nostrils, high-arched palate, long philtrum). Platyspondyly (esp. of cervical spine) and abnormal epiphyses and metaphyses are observed on radiography. Atlantoaxial instability causing spinal compression and recurrent respiratory disease are potential complications that may result lethal.", "ORPHA ID": 93358, "Summary": ""}
{"Disease Name": "Spondyloepiphyseal dysplasia congenita", "Disease Definition": "Spondyloepiphyseal dysplasia congenita (SEDC) is a chondrodysplasia characterized by disproportionate short stature, abnormal epiphyses and flattened vertebral bodies.", "ORPHA ID": 94068, "Summary": "Epidemiology\nThe prevalence is approximately 1 per 100,000 live births. Males and females are equally affected.\nClinical description\nClinical manifestations may include short stature with a very short trunk and neck and shortened limbs, clubfoot, coxa vara, cleft palate, flat facial features, hypertelorism, eye abnormalities (nystagmus, congenital cataracts, glaucoma, retinal detachment), decreased hearing, and characteristic radiologic findings (flattened vertebral bodies, flat acetabular roof, delayed ossification of the femoral heads with degenerative changes). Decreased joint mobility and arthritis often develop early in life. Intelligence is usually unaffected.\nEtiology\nSEDC is caused by mutation in the COL2A1 gene (locus 12q13.11-q13.2).\nGenetic counseling\nThe inheritance is autosomal dominant.\n\n                            Last update: \n                            September 2009"}
{"Disease Name": "Spondyloepiphyseal dysplasia tarda, Kohn type", "Disease Definition": "Spondyloepiphyseal dysplasia tarda, Kohn type is characterized by short trunk dwarfism, progressive involvement of the spine and epiphyses and mild-to-moderate intellectual deficit.", "ORPHA ID": 163665, "Summary": "Epidemiology\nThe syndrome has been described in three daughters born to healthy consanguineous parents.\nClinical description\nThe skeletal disorder usually manifests in late childhood. Typical radiographical features include platyspondyly, abnormal lumbar vertebrae and degenerative large joint changes.\nGenetic counseling\nAutosomal recessive transmission has been suggested.\n\n                            Last update: \n                            September 2009"}
{"Disease Name": "Spondyloepiphyseal dysplasia tarda", "Disease Definition": "Spondyloepiphyseal dysplasia tarda (SEDT) is characterized by disproportionate short stature in adolescence or adulthood, associated with a short trunk and arms and barrel-shaped chest.", "ORPHA ID": 93284, "Summary": "Epidemiology\nThe X-linked variant of the disease is most common, with an estimated prevalence of 1 in 150,000-200,000.\nClinical description\nPatients may have normal body proportions at birth. The condition typically manifests around puberty with a short neck, scoliosis or thoracic kyphosis, lumbar hyperlordosis, and early-onset progressive osteoarthritis of the hips and knees. Many patients achieve an adult height of more than 153 cm and true dwarfism may not be present. Radiographic findings appear prior to puberty and may include multiple epiphyseal abnormalities, flattened vertebral bodies, narrow disc spaces, hypoplastic odontoid process, short femoral neck, and coxa vara.\nEtiology\nThe X-linked recessive type is caused by mutations in the TRAPPC2 gene (locus Xp22.2-p22.1).\nGenetic counseling\nSEDT may be transmitted as an X-linked recessive, autosomal recessive or autosomal dominant trait.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Spondyloepiphyseal dysplasia with metatarsal shortening", "Disease Definition": "A rare, genetic, primary bone dysplasia disorder characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and hypoplasia/dysplasia of the third and fourth metatarsals, in the absence of ophthalmologic, cleft palate, and height anomalies.", "ORPHA ID": 137678, "Summary": "Epidemiology\nTo date, fewer than 15 families have been reported worldwide.\nClinical description\nThe first clinical signs appearing in childhood are broad knees and flat nasal bridge, followed in late childhood and adolescence by short 3rd and 4th metatarsals (not always present), joint pain in knees and hips and later osteoarthritis of the spine, shoulder, hips, and knees. Shortening of the metacarpals may also be present. Vertebral abnormalities include mild platyspondyly, irregular end plates, and reduced intervertebral distances. Stature is within average range. Brachydactyly is restricted to metatarsals III, IV and, more variably, V. Progressive hearing loss may be associated and typically starts in early adulthood, although subclinical hearing impairment for high frequencies may be detected in children.\nEtiology\nThe disorder is due to the R275C mutation in the geneCOL2A1 (12q13.11).\nDiagnostic methods\nDisorder is suspected based on family history and clinical presentation, but this may be difficult to detect in early childhood. Skeletal radiographs showing platyspondyly and shortened metatarsals and metacarpals may be helpful in the diagnosis work up. Diagnosis is confirmed by genetic testing for the R275C mutation in COL2A1.\nDifferential diagnosis\nDisorders with early-onset osteoarthritis and polyarticular arthritis form the main differential diagnoses and include juvenile idiopathic osteoarthritis and mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis. Whilst COL2A1 mutations are involved in a spectrum of skeletal dysplasias, this specific disorder is typically distinguished by the absence of cleft palate, ophthalmologic pathology and short stature.\nAntenatal diagnosis\nGenetic prenatal diagnosis is possible when the mutation has been previously identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. The risk of transmission to offspring is 50% and there is full disease penetrance.\nManagement and treatment\nTreatment is symptomatic and frequently includes hip replacement (often by the age of 40), hearing aids for hearing loss, and anti-rheumatic medication for osteoarthritis. Appropriate surveillance of hearing loss and progression of osteoarthritis is required.\nPrognosis\nThe disorder is associated with early-onset, progressive arthritis that is typically associated with significant joint pain and restricted mobility that can adversely impact quality of life. Early joint replacements are often recommended. Longevity does not appear to be different to that of the general population.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Lindsay BURRAGE"}
{"Disease Name": "Spondyloepiphyseal dysplasia, Kimberley type", "Disease Definition": "Spondyloepiphyseal dysplasia, Kimberley type (SEDK) is characterized by short stature and premature degenerative arthropathy.", "ORPHA ID": 93283, "Summary": "Epidemiology\nIt has been described in one multigenerational South African family of English white descent.\nClinical description\nThe main clinical features may include proportionate short stature (<5th percentile for age), stocky habitus and early-onset progressive osteoarthropathy of the weight-bearing joints. Radiographical features are flattened vertebral bodies with sclerosis and prominent endplate irregularity and flattened femoral epiphyses.\nEtiology\nSEDK is caused by mutation in the aggrecan gene (AGC1, locus 15q26.1).\nGenetic counseling\nSEDK is transmitted as an autosomal dominant trait.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Spondyloepiphyseal dysplasia, MacDermot type", "Disease Definition": "Spondyloepiphyseal dysplasia (SED), MacDermot type is characterized by short stature, femoral epiphyseal dysplasia, mild vertebral changes and sensorineural deafness.", "ORPHA ID": 163668, "Summary": "Epidemiology\nThe syndrome has been described in a family in which females in four successive generations were affected.\nClinical description\nMyopia and retinal detachment were present in adult life.\nGenetic counseling\nAutosomal dominant transmission has been suggested.\n\n                            Last update: \n                            September 2009"}
{"Disease Name": "Spondyloepiphyseal dysplasia, Reardon type", "Disease Definition": "Spondyloepiphyseal dysplasia, Reardon type is an extremely rare type of spondyloepiphyseal dysplasia (see this term) described in several members of a single family to date and characterized by short stature, vertebral and femoral abnormalities, cervical instability and neurologic manifestations secondary to anomalies of the odontoid process.", "ORPHA ID": 163662, "Summary": ""}
{"Disease Name": "Spondyloepiphyseal dysplasia, Stanescu type", "Disease Definition": "A rare spondyloepiphyseal dysplasia characterized by progressive joint contractures with premature degenerative joint disease, particularly in the knee, hip, and finger joints. Patients are of normal height and present with gait problems, joint pain, and enlarged joints with joint restriction and contractures. Radiological features include generalized platyspondyly, hypoplastic ilia, epiphyseal flattening with metaphyseal splaying of the tubular bones, and broad, elongated femoral necks with marked coxa valga. Histopathologic examination of cartilage shows PAS-positive cytoplasmic inclusion bodies in chondrocytes.", "ORPHA ID": 459051, "Summary": ""}
{"Disease Name": "Spondyloepiphyseal dysplasia-brachydactyly-speech disorder syndrome", "Disease Definition": "Spondyloepiphyseal dysplasia, Cantu type is an extremely rare type of spondyloepiphyseal dysplasia (see this term) described in about 5 patients to date and characterized by clinical signs including short stature, peculiar facies with blepharophimosis, upward slanted eyes, abundant eyebrows and eyelashes, coarse voice, and short hands and feet (brachymetacarpalia, brachymetatarsalia and brachyphalangia).", "ORPHA ID": 163654, "Summary": ""}
{"Disease Name": "Spondyloepiphyseal dysplasia-craniosynostosis-cleft palate-cataracts-intellectual disability syndrome", "Disease Definition": "Spondyloepiphyseal dysplasia Nishimura type is characterized by spondyloepiphyseal dysplasia, craniosynostosis, cataracts, cleft palate and intellectual deficit.", "ORPHA ID": 163649, "Summary": "Epidemiology\nThe syndrome has been described in four Japanese sibs (three brothers and one sister born to nonconsanguineous parents).\nClinical description\nMost clinical manifestations are evident at birth, but skeletal changes and cataracts may become evident during early childhood.\nGenetic counseling\nAutosomal recessive inheritance has been suggested.\n\n                            Last update: \n                            September 2009"}
{"Disease Name": "Spondylometaphyseal dysplasia, 'corner fracture' type", "Disease Definition": "Spondylometaphyseal dysplasia, 'corner fracture' type is a skeletal dysplasia associated with short stature, developmental coxa vara, progressive hip deformity, simulated 'corner fractures' of long tubular bones and vertebral body abnormalities (mostly oval vertebral bodies).", "ORPHA ID": 93315, "Summary": "Epidemiology\nLess than 30 patients have been reported in the literature.\nClinical description\nTetralogy of Fallot and odontoid hypoplasia have been reported in single patients with this syndrome.\nEtiology\nCurrently, there are no human genes associated with the disease.\nGenetic counseling\nAutosomal dominant inheritance has been suggested.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Spondylometaphyseal dysplasia, A4 type", "Disease Definition": "Spondylometaphyseal dysplasia, A4 type is a rare primary bone dysplasia disorder characterized by disproportionate short stature, severe femoral neck deformity, marked metaphyseal abnormalities and platyspondyly consisting of ovoid vertebral bodies that have an anterior tongue-like deformity.", "ORPHA ID": 168555, "Summary": ""}
{"Disease Name": "Spondylometaphyseal dysplasia, Golden type", "Disease Definition": "Spondylometaphyseal dysplasia, Golden type is a rare primary bone dysplasia disorder characterized by severe short stature, coarse facies, thoracolumbar kyphoscoliosis and enlarged joints with contractures. Psychomotor delay and intellectual disability may also be associated. Radiographic features include flat vertebral bodies, lacy ossification of the metaphyses of long bones and iliac crests, and marked sclerosis of the skull base.", "ORPHA ID": 168544, "Summary": ""}
{"Disease Name": "Spondylometaphyseal dysplasia, Kozlowski type", "Disease Definition": "Spondylometaphyseal dysplasia, Kozlowski type is characterized by short stature (short-trunk dwarfism), scoliosis, metaphyseal abnormalities in the femur (prominent in the femoral neck and trochanteric area), coxa vara and generalized platyspondyly.", "ORPHA ID": 93314, "Summary": "Epidemiology\nPrevalence is estimated at less than one in one million people.\nClinical description\nIntelligence is usually normal.\nEtiology\nThe syndrome is caused by a mutation in the TRPV4 gene (12q24.1) and is transmitted in an autosomal dominant manner.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Spondylometaphyseal dysplasia, Schmidt type", "Disease Definition": "Spondylometaphyseal dysplasia, Schmidt type is characterized by short stature, myopia, ,small pelvis, progressive kypho-scoliosis, wrist deformity, severe genu valgum, short long bones, and severe metaphyseal dysplasia with moderate spinal changes and minimal changes in the hands and feet.", "ORPHA ID": 93316, "Summary": "Epidemiology\nThis condition has been reported in five members of an Algerian family and one Polish boy; the patient reported by Schmidt et al. possibly had this disorder.\nEtiology\nAutosomal dominant inheritance has been suggested, but the causative gene has not yet been identified.\n\n                            Last update: \n                            November 2009"}
{"Disease Name": "Spondylometaphyseal dysplasia, Sedaghatian type", "Disease Definition": "A rare neonatal lethal form of spondylometaphyseal dysplasia characterized by severe metaphyseal chondrodysplasia, mild rhizomelic shortness of the upper limbs, and mild platyspondyly.", "ORPHA ID": 93317, "Summary": "Epidemiology\nNine cases have been reported so far in patients of Iranian, Yemeni and Caucasian origin.\nClinical description\nA lacy appearance of the iliac crests, long fibulae, abnormal tarsal bones, cardiac arrhythmia, and intracranial anomalies have been described. Intrauterine growth is normal. The majority of patients die in the first days of life with symptoms of cardiorespiratory insufficiency. Subacute myocarditis, cortical necrosis of kidneys, adrenal and pulmonary hemorrhage, absence of the corpus callosum and marked frontotemporal pachygyria have been found at autopsy.\nEtiology\nEtiology remains unknown.\nGenetic counseling\nAutosomal recessive inheritance has been suggested.\n\n                            Last update: \n                            September 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Spondylometaphyseal dysplasia-bowed forearms-facial dysmorphism syndrome", "Disease Definition": "A rare, genetic, primary bone dysplasia disorder characterized by short stature, hyperlordosis, protuberant abdomen, mild bilateral genu varum, bowed and shortened forearms with limited elbow extension, and discrete facial dysmorphism (prominent forehead, hypertelorism, flat nasal bridge). Radiographically, moderate platyspondyly, including posterior wedging with anterior bullet-shaped vertebral bodies, with minimal metaphyseal abnormalities are observed.", "ORPHA ID": 168552, "Summary": ""}
{"Disease Name": "Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome", "Disease Definition": "Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome is characterised by the association of spondylometaphyseal dysplasia (marked by platyspondyly, shortening of the tubular bones and progressive metaphyseal irregularity and cupping), with postnatal growth retardation and progressive visual impairment due to cone-rod dystrophy. So far, it has been described in eight individuals. Transmission appears to be autosomal recessive.", "ORPHA ID": 85167, "Summary": ""}
{"Disease Name": "Spondylometaphyseal dysplasia-corneal dystrophy syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay with intellectual disability, postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, abnormalities of the spine, pelvis, and metaphyses, corneal clouding, and patent ductus arteriosus. Dysmorphic facial features include hypertelorism, prominent eyes, depressed nasal bridge, and short upturned nose.", "ORPHA ID": 589435, "Summary": ""}
{"Disease Name": "Spondylometaphyseal dysplasia", "Disease Definition": "Spondylometaphyseal dysplasias are a heterogeneous group of disorders associated with walking and growth disturbances that become evident during the second year of life.", "ORPHA ID": 254, "Summary": "Epidemiology\nPrevalence is estimated at around 1/100,000.\nClinical description\nThe disorders are characterized by platyspondyly (flattened vertebrae) and marked hip and knee metaphyseal lesions. The different forms of spondylometaphyseal dysplasia are distinguished by the localization and severity of involvement of the affected metaphyses. The most common form is the Kozlowski type of spondylometaphyseal dysplasia (see this term). The form of spondylometaphyseal dysplasia referred to as the 'corner fracture' or Sutcliffe type (see this term) results in very severe coxa vara. A rarer form (Algerian or Schmidt type; see this term) appears to have more predominant knee involvement. Lastly, some moderate forms are at present not well classified and other forms have also been identified, including type A4, and an axial type associated with retinitis pigmentosa and optic atrophy (see these terms). Spondylometaphyseal dysplasia may also occur in association with other clinical manifestations such as facial dysmorphism and dentinogenesis imperfecta (see this term).\nEtiology\nKozlowski type of spondylometaphyseal dysplasia results in severe kyphoscoliosis and is caused by mutations in the TRPV4 gene (locus 12q24.1).\nGenetic counseling\nKozlowski type of spondylometaphyseal dysplasia is transmitted in an autosomal dominant manner, as well as the form of spondylometaphyseal dysplasia referred to as the 'corner fracture' or Sutcliffe type and the Algerian (or Schmidt) type. Some moderate forms also generally appear to be transmitted as autosomal dominant traits. Several autosomal recessive forms have also been identified, including type A4 and an axial type associated with retinitis pigmentosa and optic atrophy. A form of spondylometaphyseal dysplasia with X-linked transmission has also been reported (see this term).\n\n                            Last update: \n                            November 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Martine LE MERRER"}
{"Disease Name": "Spondyloperipheral dysplasia-short ulna syndrome", "Disease Definition": "Spondyloperipheral dysplasia-short ulna syndrome is a rare, genetic, primary bone dysplasia, with highly variable phenotype, typically characterized by platyspondyly, brachydactyly type E changes (short metacarpals and metatarsals, short distal phalanges in hands and feet), bilateral short ulnae and mild short stature. Other reported features include additional skeletal findings (e.g. midface hypoplasia, degenerative changes in proximal femora, limited elbow extension, bilateral sacralization of L5, clubfeet), as well as myopia, hearing loss, and intellectual disability.", "ORPHA ID": 1856, "Summary": ""}
{"Disease Name": "Spontaneous intracranial hypotension", "Disease Definition": "A rare headache resulting from a cerebrospinal fluid (CSF) leak with subsequent lowered CSF pressure, characterized clinically by severe headaches which typically worsen upon standing up and get better when lying down. Additional features may include neck stiffness, nausea, vomiting, vertigo, tinnitus, visual disturbances, and cognitive abnormalities, among others, as sagging and displacement of the brain can lead to a variety of lesions and symptoms.", "ORPHA ID": 443180, "Summary": ""}
{"Disease Name": "Spontaneous periodic hypothermia", "Disease Definition": "A rare neurologic disorder characterized by spontaneous periodic hypothermia and hyperhidrosis in the absence of hypothalamic lesions.", "ORPHA ID": 29822, "Summary": "Epidemiology\nSpontaneous periodic hypothermia (SPH) prevalence is unknown but to date more than 50 cases of spontaneous periodic hypothermia have been described in the world literature.\nClinical description\nSPH can occur at any age (ranging from 6 months to 62 years). The clinical manifestations of the disease comprise recurrent episodes of hypothermia (core temperature <35°C) with profuse sweating, nausea and vomiting, that occur in the absence of any detectable infectious or endocrine cause. Periodicity of hypothermic episodes may range from hours to years and the episodes themselves may last from hours to weeks. The sensation is usually experienced as a ''funny feeling'' in the head and is described as powerful, consuming and combined with a sense of weakness, incoordination and gait unsteadiness. Additional features include drowsiness, deep sleep, hypothermic syncope, mild bradycardia, and pale and cool skin. There are usually no associated complaints of diarrhea, confusion, wheezing, rash, seizure activity, shivering or shakiness. Polyuria and polydipsia during the attacks have been described in only one case. Recurrent hypothermia attacks were reported in two siblings.\nEtiology\nThe exact pathophysiological mechanism for this syndrome is still not understood. Postulated mechanisms include hypothalamic dysfunction, neurochemical abnormalities, inflammatory processes, and epileptic activity.\nDiagnostic methods\nDiagnosis includes physical and systemic examinations which show a pale, cold skin and normal blood count and electrolyte levels. Imaging studies may in some cases reveal confluent lesions in the corpus callosum and a circumscribed lesion in the right posterior thalamus. 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) levels in cerebrospinal fluid may be below the normal ranges.\nDifferential diagnosis\nDifferential diagnosis of SPH severe hypothyroidism, hypoglycemia or attacks of diabetic ketoacidosis.\nManagement and treatment\nThere is no cure for SPH. Management is mainly supportive and includes re-warming with a warm blanket. Carbamazepine, clonidine, cyproheptadine, glycopyrrolate, bromocriptine, chlorpromazine, beta1 blockers or sympathectomy are used with varying responses.\nPrognosis\nSPH is a benign disease and may cease spontaneously. Some patients have been reported to have hyperthermia attacks during the course of the disease.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Ozgur DUMAN"}
{"Disease Name": "Sporadic adult-onset ataxia of unknown etiology", "Disease Definition": "A rare non-hereditary degenerative ataxia disease characterized by a slowly progressive cerebellar syndrome (with ataxia of stance and gait, upper limb dysmetria and intention tremor, ataxic speech, and oculomotor abnormalities), presenting in adulthood (at around 50 years of age), that is not due to a known cause. Extracerebellar symptoms (e.g., decreased vibration sense and absent or decreased ankle reflexes), polyneuropathy and mild autonomic dysfunction may also be present. Mild cognitive impairment has also rarely been reported.", "ORPHA ID": 247234, "Summary": ""}
{"Disease Name": "Sporadic Creutzfeldt-Jakob disease", "Disease Definition": "A rare sporadic human prion disease characterized by rapidly progressive cognitive impairment in combination with variable neurologic signs and symptoms including myoclonus, visual or cerebellar problems, pyramidal or extrapyramidal features, or akinetic mutism. Brain imaging may show high signal intensity in caudate, putamen, and/or cortical regions, and a typical EEG pattern consisting of generalized periodic sharp wave complexes is observed in many cases. The disease is invariably fatal within less than two years. Neuropathologic examination reveals deposition of abnormal prion protein in brain tissue, as well as spongiform change and massive neuronal loss and gliosis.", "ORPHA ID": 204, "Summary": ""}
{"Disease Name": "Sporadic fatal insomnia", "Disease Definition": "A rare sporadic human prion disease characterized by adult onset of progredient neurodegeneration presenting as a combination of psychiatric, sleep, and oculomotor disturbances, with development of progressive cognitive impairment (the predominantly affected cognitive domains being memory, temporal and/or spatial orientation, language, executive functions, and attention), postural instability, and sometimes additional motor abnormalities and autonomic hyperactivity, in the course of the disease. Bilateral thalamic hypometabolism on FDG-PET imaging and positive prion seeding activity in the cerebrospinal fluid are present in many cases. The disease is fatal within typically two to three years.", "ORPHA ID": 586130, "Summary": ""}
{"Disease Name": "Sporadic fetal brain disruption sequence", "Disease Definition": "Sporadic fetal brain disruption sequence is a rare, non-syndromic, central nervous system malformation disorder characterized by severe microcephaly (average occipitofrontal circumference -5.8 SD), overlapping sutures, keel-like occipital bone prominence, scalp rugae with normal hair pattern and signs of neurological impairment. Brain imaging may show ventriculomegaly, cortical tissue deficit, and hydranencephaly.", "ORPHA ID": 1665, "Summary": ""}
{"Disease Name": "Sporadic hyperekplexia", "Disease Definition": "A rare neurologic disease characterized by excessive startle response to unexpected auditory, tactile or visual stimuli, associated with hyperreflexia.", "ORPHA ID": 306776, "Summary": ""}
{"Disease Name": "Sporadic infantile bilateral striatal necrosis", "Disease Definition": "Sporadic infantile bilateral necrosis is the sporadic form of infantile bilateral striatal necrosis (IBSN; see this term), a syndrome of bilateral symmetric spongy degeneration of the caudate nucleaus, putamen and globus pallidus characterized by developmental regression, choreoathetosis and dystonia progressing to spastic quadriparesis.", "ORPHA ID": 225147, "Summary": "Epidemiology\nPrevalence has been estimated at 1-9/1,000,000.\nClinical description\nSporadic IBSN can occur any time from the neonatal period through childhood and even in adolescence. Clinical features include choreoathetosis, dystonia, rigidity, spasticity, dysphagia, optic atrophy, intellectual deficit, developmental regression of motor and verbal skills, failure to thrive, myoclonus, quadriparesis, cerebellar ataxia and nystagmus.\nEtiology\nThe disease is associated with abrupt neurologic dysfunction following an acute systemic febrile illness such as a mycoplasma, measles or streptococcus infection.\nDiagnostic methods\nDiagnosis is based on clinical observation of choreoathetoid movements of the face, trunk and extremities and evidence of basal ganglia degeneration on CT and MRI images.\nDifferential diagnosis\nDifferential diagnoses include Wilson's disease, acute disseminated encephalomyelitis, neurodegeneration with brain iron accumulation, Leigh disease, juvenile Huntington chorea, methylmalonic aciduria, guanidinoacetate methyltransferase deficiency, glutaric acidemia I (see these terms), carbon monoxide intoxication, small vessel arteritis and trauma.\nManagement and treatment\nTreatment is based on treatment of the causal infection.\nPrognosis\nPrognosis is variable, with either gradual improvement in symptoms and complete recovery, observed after recovery from the infection, or severe neurological sequelae.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Rachel STRAUSSBERG"}
{"Disease Name": "Sporadic pheochromocytoma/secreting paraganglioma", "Disease Definition": "A rare, isolated, non-familial pheochromocytoma/paraganglioma tumor arising from neuroendocrine chromaffin cells of the adrenal medulla (pheochromocytoma) or from extra-adrenal chromaffin tissue (paraganglioma). The majority of these tumors are benign and the presenting symptoms are typically caused by the increased catecholamine production of the tumor, including hypertension (often paroxysmal), tachycardia, anxiety and/or excessive sweating.", "ORPHA ID": 276621, "Summary": ""}
{"Disease Name": "Sprengel deformity", "Disease Definition": "A rare thoracic malformation characterized by an underdeveloped and abnormally high scapula due to its failure to descend to the regular position during embryonic development. The defect is in most cases unilateral and may be associated with other abnormalities, such as deformities of vertebral bodies, fused or absent ribs, or genitourinary anomalies, among others.", "ORPHA ID": 3181, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of gallbladder and extrahepatic biliary tract", "Disease Definition": "A rare hepatic and biliary tract tumor, arising either in the gallbladder itself or in the epithelium lining the extrahepatic biliary tree, the cystic duct and peribiliary glands. It is characterized by a substantial keratinization with abundant keratohyalin pearls and central deposition of dense keratin material within infiltrative nests and locally aggressive nature. In the early stages of the disease symptoms are vague and nonspecific (abdominal pain, jaundice and vomiting). In the advanced stages it may present with a bulky tumor and symptoms of adjacent organ involvement.", "ORPHA ID": 424996, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of liver and intrahepatic biliary tract", "Disease Definition": "Squamous cell carcinoma of liver and intrahepatic biliary tract is an extremely rare, primary, malignant liver and biliray tract epithelial tumor originating in the intrahepatic bile duct epithelium histologically characterized by the presence of keratinization and/or intracellular bridges. Patients typically present abdominal pain in the right upper quadrant, jaundice, nausea, vomiting, anorexia, weight loss, fever and/or dyspepsia.", "ORPHA ID": 424975, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of pancreas", "Disease Definition": "A rare epithelial tumor of the exocrine pancreas, histologically characterized by presence of keratinization and/or intracellular bridges and lymphovascular and perineural invasion, as well as high metastatic potential. Patients present with upper abdominal and back pain, anorexia, weight loss, nausea, vomiting and jaundice.", "ORPHA ID": 424039, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the anal canal", "Disease Definition": "Squamous cell carcinoma of the anal canal is a rare epithelial intestinal neoplasm, arising from squamous epithelial cells in the anal canal, with variable macroscopic appearance, ranging from small, benign lesions (that mimick fissures, hemorrhoids or anorectal fistulae) to a large, exophytic or ulcerating tumor localized within the anal canal. Patients may be asymptomatic or present difficulty to defecate, anal bleeding, pain and/or discharge, and often have a history of chronic anal fistulae and abscesses, Crohn's disease, hemorrhoids, or, especially in younger patients, immunosuppression (such as HIV infection). Association with HPV infection is commonly reported.", "ORPHA ID": 424019, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the colon", "Disease Definition": "A rare epithelial tumour of the colon arising from squamous cells of the colorectal epithelium without the presence of squamous-lined fistulous tracts or a proximal extension of an anal squamous cell carcinoma. It usually presents with nonspecific symptoms, such as anorexia, weight loss, abdominal pain, changes of bowel habits, hematochesia or melena. Cases of severe, symptomatic hypercalcemia have been reported.", "ORPHA ID": 423994, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the corpus uteri", "Disease Definition": "Squamous cell carcinoma of the corpus uteri is a rare cancer of corpus uteri composed of squamous cells of varying degree of differentiation that usually affects postmenopausal women and presents with abnormal vaginal discharge, dysfunctional bleeding, abdominal pain and distension. It is often associated with cervical stenosis and pyometra.", "ORPHA ID": 213716, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the esophagus", "Disease Definition": "Esophageal squamous cell carcinoma (ESCC) is a type of esophageal carcinoma (EC; see this term) that can affect any part of the esophagus, but is usually located in the upper or middle third.", "ORPHA ID": 99977, "Summary": "Epidemiology\nESCC has an estimated annual incidence of 1/29,400.\nClinical description\nThe average age of onset of ESCC is between the ages of 60 to 70 years and it is more frequently seen in males. It is usually asymptomatic until an advanced disease stage with common presenting symptoms being dysphagia (at first with solids then progressing to fluids) and weight loss. Less commonly odynophagia, hoarseness of voice, coughing, or chest pain can be presenting features. Tumors are typically found in the middle and the upper third of the esophagus.\nEtiology\nThe exact etiology is unknown. Cigarette smoking and alcohol abuse are the principal risk factors. There is also an association with idiopathic achalasia (see this term), a motility disorder of the esophagus.\nDiagnostic methods\nEndoscopy and a biopsy will establish the diagnosis. For staging, a computed tomography (CT) scan of the neck, chest and abdomen, or CT combined with a positron emission tomography (CT-PET) scan will identify the primary tumor in most cases as well as any spread to the lymph nodes and organs such as the liver, lungs and bone. Endoscopic ultrasound (EUS), the combination of an ultrasound probe on an endoscope, is also increasingly used for staging, and is of particular value for early cancers. In upper or mid-esophageal tumors where there is a possibility of invasion of the airway (trachea or bronchi) a bronchoscopy may also be required.\nDifferential diagnosis\nDifferential diagnoses include idiopathic achalasia (see this term), benign esophageal stricture, an esophageal web, and occasionally lung cancer.\nManagement and treatment\nTreatment may be with curative intent when the disease is confined to the esophagus and even when local nodes of the primary tumor are involved, and when the patient is fit enough for treatment. Treatment with palliative intent, targeted on symptom control and quality of life, but not cure, is the mainstay of treatment when the disease is advanced or incurable, or the patient is unfit for therapy due to significant co-morbidities. The traditional treatment of ESCC is surgical resection; this is usually via a transthoracic resection, and occasionally by a neck incision. In some cases a transhiatal esophagectomy is performed. The use of minimally invasive approaches to perform these operations is increasing in use. There is also an increasing use of chemotherapy or of the combination of chemotherapy and radiotherapy before and after surgery. A number of clinical trials support this practice, particularly where the tumor is locally advanced, and this is increasingly the standard of care in Europe and North America. The chemotherapeutic drugs most often used in combination are epirubicin, cisplatin and 5-fluorouracil (known as ECF). Capecitabine and oxaliplatin are less toxic agents that can be used in those with cardiac and renal problems. There is also an increasing use of radical, high-dose radiotherapy and chemotherapy for ESCC which avoids a surgery, and the outcomes are equivalent to surgical or multimodality approaches. For palliative approaches, self-expanding metal stents (SEMS) can relieve dysphagia, and chemotherapy, radiation therapy and laser-based approaches are also considered. Palliation may also involve nutritional support via feeding devices such as percutaneous endoscopic gastrostomy (PEG) tubes.\nPrognosis\nAs ESCC is usually diagnosed at an advanced disease stage, the overall prognosis is poor, with an overall 5-year survival of between 10-20%. In patients treated with curative intent the cure rate currently approaches 40%.\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Claire DONOHOE  - Dr John REYNOLDS"}
{"Disease Name": "Squamous cell carcinoma of the hypopharynx", "Disease Definition": "A rare head and neck tumor characterized by a malignant epithelial neoplasm with evidence of squamous differentiation, most commonly located in the piriform sinus, less frequently the posterior pharyngeal wall or the postcricoid area. The tumor can spread directly to adjacent structures or metastasize via lymphatic and blood vessels to regional lymph nodes, or lung, liver, and bones, respectively. Primary risk factors are tobacco smoking and (to a lesser extent) alcohol consumption. Patients may present with odynophagia, dysphagia, signs and symptoms related to a neck mass, voice changes, otalgia, and constitutional symptoms.", "ORPHA ID": 494547, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the larynx", "Disease Definition": "A rare head and neck tumor characterized by a malignant epithelial neoplasm with evidence of squamous differentiation, most commonly located in the supraglottis or glottis. The tumor can spread directly to adjacent structures or metastasize via lymphatic and blood vessels to regional lymph nodes, or lung, liver, and bones, respectively. Primary risk factors are tobacco smoking and (to a lesser extent) alcohol consumption. Patients may present with hoarseness, dyspnea, stridor, dysphagia, hemoptysis, or odynophagia.", "ORPHA ID": 494550, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the lip", "Disease Definition": "A rare head and neck tumor characterized by a firm infiltrative neoplasm with squamous differentiation, most commonly arising at the vermilion border of the lower lip. Patients present with a usually asymptomatic lesion of variable appearance, such as ulceration, a focus of whitish thickening, a dry atrophic area, or an area of persistent chapping and localized flaking and crusting. Carcinomas of the lower lip tend to progress slowly (as opposed to those of the upper lip). Invasion of adjacent structures, including perineural spread, is typical, with a variable rate of metastasis, depending on the location.", "ORPHA ID": 502366, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the oral cavity", "Disease Definition": "A rare head and neck tumor characterized by a firm infiltrative neoplasm with squamous differentiation, arising from the mucosal epithelium, and most commonly located in the tongue, floor of the mouth, or gingiva, but also the buccal mucosa or any other area of the oral cavity, depending on prevailing risk factors (such as smoking, alcohol consumption, and tobacco chewing). Patients present with a variably white, erythematous, mixed, nodular, or ulcerated lesion, which may cause discomfort, pain, or reduced mobility of the tongue. The tumor is aggressive with a propensity for local invasion and early lymph node metastasis.", "ORPHA ID": 502363, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the oropharynx", "Disease Definition": "A rare head and neck tumor characterized by a malignant epithelial neoplasm with evidence of squamous differentiation, which may arise in association with high-risk HPV in a subset of cases. HPV-positive tumors have a strong predilection for the base of tongue and the palatine tonsils and typically present at an advanced clinical stage with cervical lymphadenopathy. They are associated with significantly better prognosis than HPV-negative tumors, which more commonly involve the soft palate, manifest as sore throat and difficulty in swallowing or a neck mass, and occur in older patients. Smoking and alcohol consumption are important risk factors.", "ORPHA ID": 500478, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the penis", "Disease Definition": "A rare urogenital tumor characterized by origin from squamous epithelial cells of the penis, most commonly the glans or inner surface of the prepuce. Macroscopically, the tumors can appear either papillary or flat and ulcerating. Histological subtypes include usual squamous cell carcinoma as the most common type, as well as basaloid, warty, verrucous, papillary, and mixed carcinomas. Patients may initially be asymptomatic but present with itching, bleeding, discharge, foul odor, and pain, as the disease progresses. Regional lymph node involvement is common, while distant metastases occur only late in the disease. Risk factors include HPV infection, smoking, poor hygiene, and HIV infection. Neonatal circumcision is implicated as strongly protective.", "ORPHA ID": 398058, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the rectum", "Disease Definition": "A rare epithelial tumor of the rectum, arising from squamous cells in the rectal epithelium, without the presence of squamous-lined fistulous tracts in the rectum or a proximal extension of SCC of anal or gynecological origin. The reported symptoms are often nonspecific, such as anorexia, weight loss, lower abdominal pain, rectal bleeding and changes of bowel habits.", "ORPHA ID": 424002, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the small intestine", "Disease Definition": "Squamous cell carcinoma of the small intestine is an extremely rare, malignant, epithelial tumor of the small intestine (most often localized in the duodenum). Presenting symptoms are often nonspecific, such as weight loss, epigastric pain, anorexia, weakness, fatigue, vomiting and abdominal distension, and vary depending on localization of the tumor. Gastrointestinal bleeding and perforation may occur in advanced cases.", "ORPHA ID": 423968, "Summary": ""}
{"Disease Name": "Squamous cell carcinoma of the stomach", "Disease Definition": "A rare epithelial tumour of stomach, defined histopathologically as keratinizing cell masses with pearl formation, mosaic pattern of cell arrangement, intercellular bridges, and high concentrations of sulphydryl or disulphide bonds, arising directly from gastric mucosa, without esophageal involvement. It is characterized by preferential location in the upper third of the stomach, high probability of lymphovascular and serosal invasion and late onset of clinical symptoms associated with poor prognosis including nonspecific symptoms of abdominal pain, dysphagia, vomiting, melena or hematochezia, haematemesis and weight loss.", "ORPHA ID": 418959, "Summary": ""}
{"Disease Name": "SRD5A3-CDG", "Disease Definition": "SRD5A3-CDG is a rare, non X-linked congenital disorder of glycosylation due to steroid 5 alpha reductase type 3 deficiency characterized by a highly variable phenotype typically presenting with severe visual impairment, variable ocular anomalies (such as optic nerve hypoplasia/atrophy, iris and optic nerve coloboma, congenital cataract, glaucoma), intellectual disability, cerebellar abnormalities, nystagmus, hypotonia, ataxia, and/or ichthyosiform skin lesions. Other reported manifestations include retinitis pigmentosa, kyphosis, congenital heart defects, hypertrichosis and abnormal coagulation.", "ORPHA ID": 324737, "Summary": ""}
{"Disease Name": "SSR4-CDG", "Disease Definition": "SSR4-CDG is a form of congenital disorders of N-linked glycosylation characterized by neurologic abnormalities (global developmental delay in language, social skills and fine and gross motor development, intellectual disability, hypotonia, microcephaly, seizures/epilepsy), facial dysmorphism (deep set eyes, large ears, hypoplastic vermillion of upper lip, large mouth with widely spaced teeth), feeding problems often due to chewing difficulties and aversion to food with certain textures, failure to thrive, gastrointestinal abnormalities (reflux or vomiting) and strabismus. The disease is caused by mutations in the gene  SSR4 (Xq28).", "ORPHA ID": 370927, "Summary": ""}
{"Disease Name": "St. Louis encephalitis", "Disease Definition": "An acute arboviral infection caused by a virus of the Flaviviridae family transmitted by an infected mosquito, and characterized by the onset of flulike symptoms such as fever, malaise, headache, cough, and sore throat that can progress to meningitis or encephalitis with symptoms like nausea, vomiting, confusion, stiff neck, disorientation, irritability, tremors, and convulsions. Photophobia, cranial nerve palsies, and even coma may occur.", "ORPHA ID": 83484, "Summary": ""}
{"Disease Name": "STAG1-related intellectual disability-facial dysmorphism-gastroesophageal reflux syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, variable degrees of intellectual disability, and facial dysmorphism (including high nasal bridge, deep-set eyes, and wide mouth), often associated with feeding difficulties and/or gastroesophageal reflux. Additional reported manifestations are seizures, hypotonia, autistic features, and joint laxity. Brain imaging may show non-specific features (such as cerebral atrophy).", "ORPHA ID": 502434, "Summary": ""}
{"Disease Name": "Stapes ankylosis with broad thumbs and toes", "Disease Definition": "Stapes ankylosis with broad thumbs and toes is a very rare genetic bone disorder characterized by ankylosis of stapes, broad thumbs and halluces, conductive hearing loss and hyperopia.", "ORPHA ID": 140917, "Summary": ""}
{"Disease Name": "Staphylococcal necrotizing pneumonia", "Disease Definition": "Staphylococcal necrotizing pneumonia is a rare, bacterial, pulmonary infectious disease, caused by a Panton-Valentine leukocidin-producing Staphylococcus aureus strain, characterized by severe respiratory failure, extensive, rapidly progressing pneumonia and hemorrhagic lung necrosis. Patients typically present with influenza-like symptoms, such as fever, cough, and chest pain, as well as hemoptysis, hypotension, leukopenia, and severe respiratory symptoms that rapidly evolve to acute respiratory distress syndrome and septic shock. High mortality is associated.", "ORPHA ID": 36238, "Summary": ""}
{"Disease Name": "Staphylococcal scalded skin syndrome", "Disease Definition": "A rare staphylococcal toxemia caused by epidermolytic toxins of Staphylococcus aureus and characterized by the appearance of widespread erythematous patches, on which large blisters develop. Upon rupture of these blisters, the skin appears reddish and scalded. The lesions typically begin in the face and rapidly expand to other parts of the body. The disease may be complicated by pneumonia and sepsis. It most commonly affects newborns and infants.", "ORPHA ID": 36236, "Summary": ""}
{"Disease Name": "Staphylococcal scarlet fever", "Disease Definition": "A rare bacterial infectious disease characterized by staphylococcal epidermolytic toxin-mediated scarlatiniform exanthema accentuated in the flexural areas, as well as fever and affection of the general condition. The exanthema progresses to desquamation in large flaps, while blistering is not observed. Enanthema, strawberry tongue or palatal petechiae are absent. The condition has mainly been reported in children and young adults.", "ORPHA ID": 36235, "Summary": ""}
{"Disease Name": "Staphylococcal toxic-shock syndrome", "Disease Definition": "Staphylococcal toxic shock syndrome (staphylococcal TSS) is an acute disease mediated by the production of superantigenic toxins, characterized by high fever, skin rash followed by skin peeling, hypotension, vomiting, diarrhea and potentially leading to multisystem organ failure and caused by a Staphylococcus aureus bacterial infection.", "ORPHA ID": 99919, "Summary": "Epidemiology\nThe incidence of staphylococcal TSS in the United States ranges from 1/192,000 - 1/156,000 people/year. With menstrual TSS now reduced by changes in tampon use, non-menstrual TSS represents up to 50% of staphylococcal TSS cases.\nClinical description\nStaphylococcal TSS is seen most commonly in otherwise healthy adult women. However non-menstrual staphylococcal TSS can also be observed in men and children. Onset is sudden and includes high fever (> 38.9°C), nausea, diarrhea, vomiting, myalgia, abdominal pain and sore throat. Unlike streptococcal TSS (see this term), a generalized rash is seen in most cases of staphylococcal TSS, occurring within the first 2 days of symptom onset and affecting both the mucosa and the skin. Later during convalescence, skin peeling also occurs. More serious manifestations include confusion, shock, renal and myocardial dysfunction and acute respiratory distress syndrome (ARDS; see this term). ARDS is the most common cause of death seen in staphylococcal TSS.\nEtiology\nStaphylococcal TSS is due to an infection with Staphylococcus aureus, that releases toxins and causes a massive immune reaction involving mainly cytokines and chemokines. This reaction is related to the activation of T cells by the production of superantigens that circumvent the normal pathway of antigen presentation. It was originally often associated with high absorbency tampon use, but also intravaginal devices (i.e. barrier contraceptive, menstrual cup) and infections following surgical procedures. Currently, many cases of Staphylococcal TSS are complications of suppurative infections or upper airways colonization.\nDiagnostic methods\nDiagnosis of staphylococcal TSS is suspected when rash followed by skin peeling, shock and involvement of at least three other organs are clinically observed. Laboratory analysis, where staphylococcal superantigens (such as toxic shock syndrome toxin 1) are identified in urine or serum, can aid in confirming diagnosis. Blood cultures are rarely positive for staphylococci.\nDifferential diagnosis\nDifferential diagnoses include streptococcal TSS, Rocky Mountain spotted fever, leptospirosis, dengue fever, typhoid fever (see these terms), peritonitis, pneumonia, pelvic inflammatory disease, pericarditis and acute myocardial infarction, meningococcemia, viral/ drug/allergic rash and septic shock.\nManagement and treatment\nThe onset of staphylococcal TSS is sudden and requires immediate medical treatment in an intensive care unit. Treatment of staphylococcal TSS involves antibiotics (clindamycin) along with supportive therapy (fluid resuscitation, inotropes and vassopressors) and intravenous immunoglobins (IVIGs) that block superantigens. Corticosteroids and recombinant activated protein C (derotrecogin-alpha) can also be helpful in some cases. Dialysis may be necessary for those with renal dysfunction and oxygen supplementation along with mechanical ventilation is required for patients with ARDS. Vancomycin and linezolid can be used in penicillin-allergic patients or when the strain is resistant to the methicillin. Women should refrain from using intravaginal devices, unless necessary, in order to minimize the risk of menstrual related staphylococcal TSS.\nPrognosis\nThe prognosis is usually good. Staphylococcal TSS has a mortality rate of only 1-6%.\n\n                            Last update: \n                            November 2015\n\n\n                            - Expert reviewer(s): \n                             Claude-Alexandre GUSTAVE  - Pr Gerard LINA  - Dr Anne TRISTAN"}
{"Disease Name": "Stargardt disease", "Disease Definition": "A rare ophthalmic disorder that is usually characterized by a progressive loss of central vision associated with irregular macular and perimacular yellow-white fundus flecks, and a so-called ''beaten bronze'' atrophic central macular lesion.", "ORPHA ID": 827, "Summary": "Epidemiology\nThe prevalence is estimated at 1/8,000 - 1/10,000. Both sexes are equally affected.\nClinical description\nThe disease typically presents within the first two decades of life, even though symptoms can also appear during adulthood and as late as the seventh decade. Although disease progression and severity varies widely, Stargardt disease (STGD1) is usually characterized by a progressive loss of central vision causing blurry vision and, occasionally, an increasing difficulty to adapt in the dark. Peripheral vision is usually normal. Most affected individuals also have impaired color vision. Photophobia may be present.\nEtiology\nThe disorder has been linked to mutations in the ABCA4 gene, which encodes an adenosine triphosphate (ATP)-binding cassette transporter (ABCR) expressed specifically in the cones and rods of the retina. Defects in ABCR function cause the accumulation of all-trans-retinal and its cytotoxic derivatives, mainly lipofuscin pigments (e.g., diretinoid-pyridinium-ethanolamine) in photoreceptors and retinal pigment epithelial (RPE) cells, ultimately causing RPE cell death and the subsequent loss of photoreceptors. Mutations in ABCA4 have been linked to a spectrum of phenotypes ranging from STGD1 to cone rod dystrophy and severe early-onset retinal dystrophy.\nDiagnostic methods\nThe clinical diagnosis is based on ophthalmological examinations consisting of visual acuity and visual field testing, ophthalmoscopy, electroretinography (ERG), fluorescein angiography (FA), fundus autofluorescence (FAF), and optical coherence tomography (OCT), revealing macular anomalies (progressive atrophy often in a 'beaten bronze pattern') and yellow-white fishtail flecks that may present only in the central macula but may also extend beyond the vascular arcades. These flecks are hyper autofluorescent on FAF images. Fluorescein angiography reveals the characteristic dark choroid (''silence choroidien'') in aproximately 85% of the patients. Diagnosis can be confirmed by genetic testing of the ABCA4 gene.\nDifferential diagnosis\nDifferential diagnosis includes multifocal pattern dystrophy simulating STGD1 and retinal and/ or macular dystrophies such as central areolar choroidal dystrophy (CACD), achromatopsia, cone dystrophy (CD) and cone rod dystrophy (CRD). In addition, two autosomal dominant types of macular dystrophy exist that resemble STGD1: STGD3 caused by mutations in the ELOVL4 gene and STGD4 associated with mutations in PROM1.\nAntenatal diagnosis\nPrenatal diagnosis is technically possible by means of genetic testing of the ABCA4 gene, but is not used in clinical practice.\nGenetic counseling\nThe disorder is transmitted in an autosomal recessive or an autosomal dominant mode of inheritance. Genetic counseling should be offered to at-risk couples informing them that there is 25% or 50% risk, respectively, of transmitting the disease to offspring.\nManagement and treatment\nPreventive measures for slowing down the progression of the disease include avoidance of overexposure to visible light with sunglasses and no intake of vitamin A supplements. Regular ophthalmologic evaluations are recommended. Currently, various treatment options are being developed. Different oral medical treatments that prevent the accumulation of lipofuscin in Stargardt disease are being tested in phase II/III clinical trials. These medical treatments inhibit the visual cycle by blocking the action of certain enzymes in the retina (RPE65/RBP4/LRAT/RDH5), replace vitamin A with a deuterated form of vitamin A (ALK001) or aid in the removal of lipofuscine by breaking down the lipofuscin (Soraprazan).\nPrognosis\nDue to the high clinical variability, prognosis depends on certain parameters (notably age of onset and electroretinographic findings) that may help the clinician provide the patient with an indication of the course of the disease. STGD1 may progress rapidly over a few months or gradually over several years leading to a severe decrease in visual acuity. Typically, peripheral vision is not affected, although certain patients may progress to a cone-rod phenotype that does affect the peripheral retinal function.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Patty DHOOGE  - Pr C.B. [Carel] HOYNG"}
{"Disease Name": "Startle epilepsy", "Disease Definition": "Startle epilepsy is a rare neurologic disease characterized by frequent and spontaneous epileptic seizures (frequently with symmetrical or asymmetrical tonic features) triggered by a normal startle in response to a sudden and unexpected somatosensory (most frequently auditory) stimulus. Falls are common and can be traumatic. In most cases, the disease is associated with spastic hemi-, di-, or tetraplegia and intellectual disability.", "ORPHA ID": 166427, "Summary": ""}
{"Disease Name": "STAT1-related autoimmune enteropathy and endocrinopathy-susceptibility to chronic infections syndrome", "Disease Definition": "An extremely rare, autosomal dominant immunological disorder characterized by variable enteropathy, endocrine disorders (e.g. type 1 diabetes mellitus, hypothyroidism), immune dysregulation with pulmonary and blood-borne bacterial infections, and fungal infections (chronic mucocutaneous candidiasis) developing in infancy. Other manifestations include short stature, eczema, hepatosplenomegaly, delayed puberty, and osteoporosis/osteopenia.", "ORPHA ID": 391487, "Summary": ""}
{"Disease Name": "STAT3-related early-onset multisystem autoimmune disease", "Disease Definition": "A rare, genetic, lymphoproliferative syndrome characterized by early onset recurrent infections, lymphadenopathy with hepatosplenomegaly and variable autoimmune disorders, including hemolytic anemia, thrombocytopenia, neutropenia, enteropathy, type I diabetes, scleroderma, arthritis, atopic dermatitis, and inflammatory lung disease. Patients commonly have failure to thrive. Variable immunologic findings include decreased regulatory T-cells, hypogammaglobulinemia, and reduction in memory B cells.", "ORPHA ID": 438159, "Summary": ""}
{"Disease Name": "Steatocystoma multiplex-natal teeth syndrome", "Disease Definition": "A rare malformation syndrome characterized by generalized multiple steatocystomas and natal teeth.", "ORPHA ID": 3184, "Summary": "Epidemiology\nIt has been described a five-generation Chinese family with at least 21 affected patients.\nGenetic counseling\nThe same condition has been reported in one additional sporadic case. Autosomal dominant inheritance has been suggested.\n\n                            Last update: \n                            September 2009"}
{"Disease Name": "Steel syndrome", "Disease Definition": "A rare genetic bone disease characterized by short stature, bilateral congenital hip dislocation, radial head dislocation, carpal coalition, scoliosis, pes cavus, and atlantoaxial subluxation. Dysmorphic facial features include broad forehead, broad nasal bridge, hypertelorism, and mild midface hypoplasia. Association with bilateral sensorineural hearing loss has also been described.", "ORPHA ID": 438117, "Summary": ""}
{"Disease Name": "Steinert myotonic dystrophy", "Disease Definition": "A rare genetic multi-system disorder characterized by a wide range of muscle-related manifestations (muscle weakness, myotonia, early onset cataracts (before age 50) and systemic manifestations (cerebral, endocrine, cardiac, gastrointestinal tract, uterus, skin and immunologic involvement) that vary depending on the age of onset. The very wide clinical spectrum ranges from lethal presentations in infancy to mild, late-onset disease.", "ORPHA ID": 273, "Summary": "Epidemiology\nIt is the most frequent adult muscular dystrophy and has an estimated prevalence ranging from 1/215,000 in Taiwan to 1/5,500 in Croatia. It appears to be more prevalent in the Saguenay-Lac-St-Jean region-Quebec, Canada (1/600), suggesting a founder effect. The disease occurs worldwide.\nClinical description\nThe age of onset is highly variable, from prenatal to adulthood. The clinical manifestations also cover a wide range and may differ within and between affected families. Five forms are currently recognized: congenital, early childhood, juvenile, adult-onset and late-onset. Congenital disease (15% of cases) is the most severe form and includes severe generalized weakness at birth with respiratory distress, hypotonia, and feeding difficulty. Patients subsequently develop delayed cognitive and motor milestones intellectual disability, and autism spectrum disorder. The course may be fatal in congenital cases (30-40%). In childhood onset cases (with the age of onset between 1 and 10 years of age), the main clinical manifestations involve muscle weakness (including both proximal and distal muscle group, facial weakness, respiratory and gastrointestinal complications such as respiratory distress, aspiration, dysphagia, constipation and speech disturbances), myotonia, sleep breathing disorders, recurrent infections, cognitive impairment, psychiatric disorders (phobia, depression, anxiety, attention deficit-hyperactivity). The juvenile form with the age of onset between 11 and 20 years of age, is characterized by scholar and behavioral problems and is often under recognized. The classic adult form (75% of cases), which develops between 20 and 40 years of age, is characterized by progressive distal muscle weakness, pain, myotonia and multiorgan involvement (irritable bowel disease, conduction and other cardiac disorders, cataracts, ophthalmoplegia, diabetes mellitus, hypogonadism, hypotestosteronism, and thyroid dysfunction). Intellectual deficit is also present in adult cases. Balding may occur in affected males and females and infertility may be present. Late-onset disease after 40 years of age involves mild myotonia and weakness, daytime sleepiness, and cataracts. A higher cancer risk has been reported in affected patients.\nEtiology\nThe disease is due to abnormal CTG expansion in the non-translating region of the DMPKgene (19q13.3). Disease severity generally correlates with the number of DNA repeats. More than 2000 CTG repeats may be found. The expansion is unstable, which may explain the clinical variability.\nDiagnostic methods\nDiagnosis is suspected on the characteristic clinical manifestations and a consistent family history, and confirmed by molecular genetic testing of the causative gene expansion. Muscle biopsy is not anymore necessary for the diagnosis and is has been replaced by genetic testing, which represents the gold standard.\nDifferential diagnosis\nThere are several overlapping features with myotonic dystrophy type 2; however, the diseases are distinct genetically and have different courses and management requirements.\nAntenatal diagnosis\nEarly-onset cases may be identified prenatally with polyhydramnios and reduced fetal movements.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. Genetic counselling should be provided to affected families. Whilst there is a 50% risk of disease transmission from an affected parent to their offspring, the disease shows variable penetrance.\nManagement and treatment\nNo specific targeted treatment is currently available. Management primarily includes monitoring for complications and supportive care (assistive devices, hormone therapy, pain medication).\nPrognosis\nSome cases are severe and may have an impact on life expectancy, particularly early-onset cases caused by massive gene expansions. The prognosis in adult-onset cases is mainly dependent on the severity of cardiac manifestations. Causes of death include respiratory failure, cardiovascular disease, arrhythmia, and neoplasms.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanni MEOLA"}
{"Disease Name": "Sterile multifocal osteomyelitis with periostitis and pustulosis", "Disease Definition": "Sterile multifocal osteomyelitis with periostitis and pustulosis is a rare, severe, genetic autoinflammatory syndrome characterized by usually neonatal onset of generalized neutrophilic cutaneous pustulosis and severe, recurrent, multifocal, aseptic osteomyelitis with marked periostitis, typically affecting distal ribs, long bones and vertebral bodies. High levels of acute-phase reactants (with no fever associated) and onychosis are frequently observed additional features.", "ORPHA ID": 210115, "Summary": ""}
{"Disease Name": "Sternal cleft", "Disease Definition": "A rare idiopathic congenital thoracic malformation characterized by a sternal fusion defect, that can be complete or partial (either superior or inferior), that is usually asymptomatic in the neonatal period (apart from a paradoxical midline thoracic bulging) but that can lead to dyspnea, cough, frequent respiratory infections and increased risk of trauma-related injury to the heart, lungs and major vessels if left untreated.", "ORPHA ID": 2017, "Summary": ""}
{"Disease Name": "Steroid dehydrogenase deficiency-dental anomalies syndrome", "Disease Definition": "A rare metabolic liver disease characterized by progressive liver disease and early cirrhosis due to accumulation of toxic cholesterol metabolites, which are detectable in bile, plasma, and urine, in association with dental abnormalities such as general hypomineralization and enamel hypoplasia, as well as occurrence of supernumerary teeth. There have been no further descriptions in the literature since 1996.", "ORPHA ID": 3196, "Summary": ""}
{"Disease Name": "Steroid-responsive encephalopathy associated with autoimmune thyroiditis", "Disease Definition": "Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a rare, acquired, neurological disease characterized by encephalopathy associated with elevated antithyroid antibodies, in the absence of other causes. Clinical presentation varies from minor cognitive impairment to status epilepticus and coma, and frequently includes seizures, confusion, speech disorder, memory impairment, ataxia and psychiatric manifestations.", "ORPHA ID": 83601, "Summary": ""}
{"Disease Name": "Stevens-Johnson syndrome", "Disease Definition": "A limited form of Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum characterized by destruction and detachment of the skin epithelium, involving less than 10% of the body surface area, and mucous membranes. Onset usually occurs 4-28 days after administration of the causal medication and is most frequently associated with anticonvulsants, antibacterial sulfonamides, allopurinol, nevirapine, and oxicams (non-steroidal anti-inflammatory drugs), but many other medications have also been implicated. The disease is not induced by medication in 15% of cases. Histology is characterized by an epidermal necrolysis. Multiple disabling long-term sequelae (especially cutaneous, ocular and psychological) are frequent.", "ORPHA ID": 36426, "Summary": ""}
{"Disease Name": "Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome", "Disease Definition": "An intermediate form of Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum characterized by destruction and detachment of the skin epithelium, involving between 10 to 29% of the body surface area, and mucous membranes. Onset usually occurs 4-28 days after administration of the causal medication and is most frequently associated with anticonvulsants, antibacterial sulfonamides, allopurinol, nevirapine, and oxicams (non-steroidal anti-inflammatory drugs), but many other medications have also been implicated. The disease is not induced by medication in 15% of cases. Histology is characterized by an epidermal necrolysis. Multiple disabling long-term sequelae (especially cutaneous, ocular and psychological) are frequent.", "ORPHA ID": 506784, "Summary": ""}
{"Disease Name": "Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum", "Disease Definition": "A rare toxic dermatosis with clinical and histological features characterized by the destruction and detachment of the skin epithelium and mucous membranes.", "ORPHA ID": 95455, "Summary": "Epidemiology\nOn average, the annual incidence is 1/319,000 in Europe; however, it varies worldwide with a higher incidence observed in Asian populations and in the US. Females are more often affected than males.\nClinical description\nOnset may occur at any age, but the risk increases after 40 years. Three subforms have been described according to the percentage of the body surface area affected: Stevens-Johnson syndrome (<10%), toxic epidermal necrolysis (≥ 30%; TEN) and an intermediate form, Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome (10-29%). The initial manifestations are nonspecific: a seemingly banal rash, fever, and a burning sensation involving the eyes, mouth and genitalia. The rash rapidly progresses to become vesicular and bullous on the face and body. The cutaneous vesicles aggregate and rupture under mild friction, revealing denuded red skin with seeping and pain. Mucous membrane lesions are present in 85 to 95% of patients with involvement, in order of frequency, of the oropharynx, eyes, genitalia and anus. Lesions are painful and lead to hypersalivation, feeding problems, photophobia, and burns following urination. High fever is a constant feature. Visceral manifestations are also frequent with hematological, respiratory and digestive involvement.\nEtiology\nIn 85% of cases, the disorder is triggered by a clearly identifiable drug allergy. A dozen high risk drugs have been identified: allopurinol, anti-infective sulphonamide agents, carbamazepine, phenobarbital, phenytoin, lamotrigine, nevirapine, and oxicam-derived nonsteroidal anti-inflammatory drugs. Genetic predisposition is described in some populations. In the other 15% of cases, the disease is associated with infections (in particular, Mycoplasma pneumoniae) or lupus erythematosus (TEN-like lupus). The remaining cases are classed as idiopathic and should be confirmed by skin biopsy.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and confirmed by skin biopsy which will reveal full-thickness epidermal necrosis and the absence of antibody deposits by direct immunofluorescence. Medication history will find a suspect drug in 85% of cases. Allergology work-up may help assessing the culprit in case of multiple suspects, and to find alternatives. Assessing possible genetic predisposition may help identifying the culprit drug in predisposed populations (e.g. Chinese Hans for carbamazepine and allopurinol).\nDifferential diagnosis\nThe differential diagnosis should include chicken pox during the early stages of the disease, staphylococcal epidermolysis, staphylococcal scalded skin syndrome, generalized bullous fixed drug eruption and, more rarely, severe graft versus host disease, and autoimmune bullous diseases (excluded by examination of skin biopsies). The more limited forms of TEN are still often misdiagnosed as erythema multiforme major.\nGenetic counseling\nHLA predisposition should be screened before prescription of carbamazepine (and other aromatic anti-epileptics) and allopurinol in Chinese Hans population; and before prescription of abacavir in all populations.\nManagement and treatment\nPatients should be admitted (according to the severity) to a dermatology or an intensive care or burns unit as soon as the diagnosis is suspected. The causative drug, together with any related compounds should be contraindicated for the patient and their close relatives (in case a genetic predisposition). No disease-modifying drugs have been shown to be efficient in the treatment of this disease. The benefits of general corticotherapy, cyclosporine or anti-TNF administration are still under evaluation. High-dose intravenous immunoglobulins appear to be of limited efficacy. Intensive supportive care is essential: a heated environment, analgesia, daily dressing changes, prevention of infections, and symptomatic intensive care measures (especially hydration, nutrition, analgesics, ocular care).\nPrognosis\nReepithelialization is usually rapid (2-3 weeks). However, the prognosis for patients with extensive forms is poor (20-25% mortality). Sequelae are reported in over 80% of surviving patients with ocular sequelae being the most problematic as they tend to be severe and progressive. Other sequelae (cutaneous, genital, buccal/dental or bronchial problems) are generally easier to detect and treat.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Saskia ORO | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Stickler syndrome", "Disease Definition": "A rare group of genetic connective tissue disorders characterized by ophthalmic, auditory, orofacial and articular manifestations. The two main clinical forms are clinically distinguished by the vitreous phenotype; stickler type 1 by a vestigial vitreous gel in the immediate retrolental space, bordered by a distinct folded membrane, and Stickler type 2 by sparse and irregularly thickened bundles of fibers throughout the vitreous cavity.", "ORPHA ID": 828, "Summary": "Epidemiology\nPrevalence at birth has been estimated at around 1/7,500 to 1/9,000.\nClinical description\nOcular manifestations include a high risk of retinal detachment, congenital abnormalities of vitreous development, congenital myopia and congenital cataract. Retinal paravascular lattice degeneration may develop in adulthood. Orofacial features include Pierre Robin sequence (PRS), cleft palate and midfacial hypoplasia. In addition, congenital high-frequency sensorineural deficit is common and variable conductive hearing loss may also occur. Musculoskeletal problems include spinal abnormalities, hypermobility, epiphyseal dysplasia and premature osteoarthritis. Two other forms are characterized by the ocular-only (autosomal dominant rhegmatogenous retinal detachment) or systemic-only (Stickler syndrome type 3) manifestations.\nEtiology\nStickler syndrome is an inherited connective tissue disorder most commonly caused by mutations in the genes encoding collagen types II (COL2A1, 12q13.11), IX (COL9A1, 6q13; COL9A2, 1p34.2; COL9A3, 20q13.33), and XI (COL11A1, 1p21.1), but rarer non-collagen gene variants have been reported.\nDiagnostic methods\nDiagnosis is made on the basis of clinical and ophthalmic examination and confirmed by molecular genetic analysis. Vitreous phenotyping is helpful in segregating sub-types as many of the other shared clinical features are similar.\nDifferential diagnosis\nDifferential diagnoses includes spondyloepiphyseal dysplasia congenita, spondyloperipheral dysplasia, Kniest dysplasia, Wagner syndrome, Knobloch syndrome, multiple epiphyseal dysplasia, metatropic dysplasia, Marfan syndrome and Marshall syndrome.\nAntenatal diagnosis\nPrenatal diagnosis may be possible. First trimester prenatal diagnosis based on the analysis of linked markers may be possible. In second trimester, ultrasound may be helpful in detecting features such as micrognathia or cleft palate, but their absence does not exclude the diagnosis.\nGenetic counseling\nThe pattern of inheritance for Stickler syndrome type 1 and 2 is autosomal dominant; the risk of disease transmission to offspring is 50%. Autosomal recessive inheritance is rarely observed but should be considered if there is a history of consanguinity. However, there is wide variation in clinical expression of the disease. The disease is highly penetrant but with wide variability in its extraocular phenotype. Affected family members in the high risk sub-groups should be offered prophylactic treatment to reduce the risk of retinal detachment and be offered genetic counselling.\nManagement and treatment\nManagement should be multidisciplinary and as clinical expression is very variable, treatment needs to be adapted to each case. Patients with PRS or cleft palate will require referral to a specialist multidisciplinary cleft team for assessment and management. This may also include speech therapy for patients with sub-clinical or soft palate cleft. Any refractive error should be corrected and prophylactic retinopexy discussed for the high risk variants. For type 1 Stickler syndrome, retinopexy substantially reduces the risk of giant retinal tear detachment. Patients should be warned of the signs and symptoms of retinal detachment and have rapid access to specialist vitreoretinal expertise in the event of such a development. Cataract is common and the surgical management, particularly in the pediatric sub-group requires specialist care. All affected patients should be referred for specialist audiology assessment if this has not already been undertaken by the cleft team. Patients may be unaware of sub-clinical hearing loss, particularly if present from birth. Although intellect is normal, pre-verbal children may need additional educational support with respect to their auditory and visual impairment. Specialist rheumatology and orthopedic management may be required for the associated arthropathy.\nPrognosis\nPrognosis of the disease is generally good. There is no direct reduction on life expectancy. The quality of life will differ depending on clinical expression, age of diagnosis and degree (if any) of associated visual loss, deafness, speech impairment and arthropathy.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Martin SNEAD  - Dr Aijing WANG"}
{"Disease Name": "Stiff person spectrum disorder", "Disease Definition": "A rare neurological disorder comprising fluctuating trunk and limb stiffness, painful muscle spasms, task-specific phobia related to walking, an exaggerated startle response, and often ankylosing deformities such as fixed lumbar hyperlordosis.", "ORPHA ID": 3198, "Summary": "Epidemiology\nThe prevalence is estimated at about 1/1,000,000. Approximately 2/3 of patients are female.\nClinical description\nThe most common form of stiff person spectrum disorders (SPSD) is classic stiff person syndrome (SPS). Age of onset peaks around 45 and symptoms develop over months or years. Progressive muscle stiffness renders the trunk and hips immobile, and the gait becomes stiff and awkward. Superimposed painful spontaneous or reflex-induced muscle spasms may cause serious falls. A specific fear of crossing open spaces (pseudo-agoraphobia) may induce freezing of gait, sudden spasms, and falls. Focal neurological signs are absent. Clinical variants of SPSD include the stiff limb syndrome (SLS) where symptoms affect only one limb, and progressive encephalomyelitis with rigidity and myoclonus (PERM) where stiffness and myoclonic spasms are associated with focal neurological signs. Many patients with SPSD have insulin-dependent diabetes mellitus (30%), autoimmune thyroiditis (10%), atrophic gastritis with pernicious anemia (5%), and some have tumors of the breast, lung, colon or thymus.\nEtiology\nThe presence of antibodies against glutamic acid decarboxylase (GAD-Abs; ~70-80%), glycine receptors (GlyR-Abs; ~10-20%), amphiphysin (~5%) and other, rarer antibodies (e.g. DPPX) in most of cases suggests an autoimmune pathogenesis. The exact immunopathophysiology (idiopathic vs. paraneoplastic; T-cell mediated vs. antibody mediated) varies amongst the different antibody subgroups. In particular for GAD-antibody associated autoimmunity there seems to be a certain genetic predisposition with an association of certain HLA haplotypes (DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype and DRB1*04:01 allele), and genetic variants in genes relevant for immune regulation as risk factors.\nDiagnostic methods\nDiagnosis essentially relies on clinical examination, and is substantiated by detection of associated antibodies in serum and cerebrospinal fluid (CSF), and by characteristic electromyographic abnormalities. Scans of the spinal cord can help to exclude mechanical causes such as a cyst or disc compression of the spinal cord.\nDifferential diagnosis\nDifferential diagnosis includes an atypical manifestation of a spinal cord disease (e.g. multiple sclerosis; tumors), axial dystonia, tetanus, neuromyotonia, acquired hyperekplexia (startle disease), and functional movement disorders.\nManagement and treatment\nBenzodiazepines and baclofen are standard drugs for symptomatic treatment. Immunomodulating therapies (corticosteroids, intravenous immunoglobulin, plasmapheresis, rituximab, cyclophosphamide, autologous hematopoietic stem cell transplantation) have been proposed with variable results. Treatments help to control symptoms in the majority of patients affected by SPSD. PERM is a potentially lethal variant and requires early and consequent immunotherapy. GlyR-antibody mediated disease is often associated with thymomas, which need to be removed. In amphiphysin antibodies-associated SPSD or other paraneoplastic forms, the treatment of the underlying malignancy is of paramount importance.\nPrognosis\nThe prognosis varies widely and depends greatly on the immunological and clinical subtype. While there are monophasic forms (e.g. GlyR-antibody related PERM) in which patients may make a good recovery with adequate treatment, the most common GAD-antibody related form is chronic. Many patients lose their ability to walk independently, and stiffness spreads, leading to an overall decline in the functional status and quality of life. In paraneoplastic SPSD, the prognosis is mainly determined by the underlying malignancy.\n\n                            Last update: \n                            August 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Bettina BALINT"}
{"Disease Name": "Stiff skin syndrome", "Disease Definition": "Stiff skin syndrome is a rare, slowly progressive cutaneous disease characterized by rock-hard skin bound firmly to the underlying tissues (mainly on the shoulders, lower back, buttocks and thighs), mild hypertrichosis and hyperpigmentation overlying the affected areas of skin, as well as limited joint mobility (mainly of large joints) with flexion contractures. Cutaneous nodules, affecting mostly distal interphalangeal joints, as well as extracutaneous manifestations, including diffuse entrapment neuropathy, scoliosis, a tiptoe gait and a narrow thorax, may be associated. Restrictive pulmonary changes, muscle weakness, short stature and growth delay have also been reported. No vascular hyperreactivity, immunologic abnormalities nor visceral, muscular or bone involvement has been described.", "ORPHA ID": 2833, "Summary": ""}
{"Disease Name": "Stimmler syndrome", "Disease Definition": "Stimmler syndrome is characterised by the association of microcephaly, low birth weight and severe intellectual deficit with dwarfism, small teeth and diabetes mellitus. Two cases have been described. Biochemical tests reveal the presence of high levels of alanine in the urine and elevated alanine, pyruvate and lactate levels in the blood.", "ORPHA ID": 3199, "Summary": ""}
{"Disease Name": "STING-associated vasculopathy with onset in infancy", "Disease Definition": "STING-associated vasculopathy with onset in infancy (SAVI) is a rare, genetic autoinflammatory disorder, type I interferonopathy due to constitutive STING (STimulator of INterferon Genes) activation, characterized by neonatal or infantile onset systemic inflammation and small vessel vasculopathy resulting in severe skin, pulmonary and joint lesions. Patients present with intermittent low-grade fever, recurrent cough and failure to thrive, in association with progressive interstitial lung disease, polyarthritis and violaceous scaling lesions on fingers, toes, nose, cheeks, and ears (which are exacerbated by cold exposure) that often progress to chronic acral ulceration, necrosis and autoamputation.", "ORPHA ID": 425120, "Summary": ""}
{"Disease Name": "Stormorken-Sjaastad-Langslet syndrome", "Disease Definition": "Stormorken-Sjaastad-Langslet syndrome is characterized by thrombocytopathy, asplenia, miosis, muscle fatigue, migraine, dyslexia, and ichthyosis. It has been described in six members of one family. It is transmitted as an autosomal dominant trait.", "ORPHA ID": 3204, "Summary": ""}
{"Disease Name": "Straddling and/or overriding mitral valve", "Disease Definition": "A rare, congenital, non-syndromic heart malformation characterized by an abnormal attachment of the mitral chordae to both ventricles. Straddling mitral valve is usually associated with conotruncal anomalies, most commonly double outlet right ventricle or transposition of the great arteries. Overriding mitral valve is characterized by a mitral annulus committed to the two ventricular chambers, where the mitral valve is shared between the ventricles. Straddling and overriding mitral valve can occur together or in isolation.", "ORPHA ID": 99064, "Summary": ""}
{"Disease Name": "Straddling or overriding tricuspid valve", "Disease Definition": "Straddling or overriding tricuspid valve is a rare, congenital, tricuspid valve malformation characterized by the tricuspid valve that overrides the ventricular septum and communicates with both ventricles, as part of the tension apparatus of the valve crosses the ventricular septal defect and is attached in the left ventricle. The anomaly occurs with other congenital heart defects (transposition of great vessels, left ventricle outflow tract obstruction, double outlet right ventricle, hypoplastic right ventricle), which determine the main clinical manifestation.", "ORPHA ID": 95461, "Summary": ""}
{"Disease Name": "Streptobacillary rat-bite fever", "Disease Definition": "Streptobacillary rat-bite fever (RBF) is a systemic zoonosis caused by the aerobic Gram-negative bacterium Streptobacillus moniliformis and is transmitted to humans through the bites and scratches of infected rats.", "ORPHA ID": 99905, "Summary": "Epidemiology\nThe disease is found worldwide, but the exact incidence is unknown.\nClinical description\nHigh fever (up to 40 °C) is the first sign of infection (2-7 days after the bite) and is closely followed by chills, headache, nausea and vomiting. RBF is also associated with a morbilliform or purpuric rash of the extremities (in particular on the palms and the soles) and occasionally hemorrhagic vesicles on the hands and feet that may desquamate. Migratory polyarthralgia of the joints may also occur, generally leading to restricted movement. The bite typically heals quickly. In rare cases, complications are reported including endocarditis, pericarditis, myocarditis, diarrhea and degenerative changes in organs such as the kidneys and liver.\nEtiology\nThe disease is generally contracted by the bites of infected rats and less often by other S. moniliformis hosts (gerbils, squirrels etc.>/i>). It can also be transmitted via ingestion of rat excrement through contaminated water, milk or food, in which case the contracted disease is called Haverhill fever. Streptobacillus moniliformis is predominantly present in the pharynx of the rats, but is also found in blood cultures and on arthritic or skin exudates.\nDiagnostic methods\nDiagnosis is based on characteristic growth, fatty acid profiles obtained by gas-liquid chromatography, blood antibody tests (agglutinating antibodies appearing from the 10th day) and to a lesser extent, on molecular detection of the germ.\nDifferential diagnosis\nThe differential diagnosis includes spirillary RBF (Sudoku; see this term) and several bacterial and viral infections (Lyme disease, leptospirosis, brucellosis, Rocky Mountain spotted fever, malaria, typhoid fever (see these terms), S. pyogenes and S. pyogenes-associated diseases, S. aureus infection, disseminated gonorrhea, meningococcemia, viral exanthemas, secondary syphilis, Epstein-Barr virus and coxsackieviruses).\nManagement and treatment\nManagement requires a prophylactic (avoiding direct or indirect contact with host animals) and therapeutic approach (local treatment and antimicrobial therapy). The most effective antibiotic treatment is penicillin G administration in non-allergic patients and tetracycline and streptomycin in penicillin-allergic patients.\nPrognosis\nPrognosis is excellent if the disease is treated. If left untreated, RBF carries a mortality rate of 13% due to complications.\n\n                            Last update: \n                            August 2009\n\n\n                            - Expert reviewer(s): \n                            Dr François TREMOLIERES"}
{"Disease Name": "Streptococcal toxic-shock syndrome", "Disease Definition": "Streptococcal toxic-shock syndrome (streptococcal TSS) is an acute disease mediated by the production of superantigenic toxins characterized by the sudden onset of fever and other febrile symptoms, pain, multisystem organ involvement and potentially leading to coma, shock and death due to a Streptococcus pyogenes infection.", "ORPHA ID": 99918, "Summary": "Epidemiology\nThe annual incidence is estimated to range between 1/300,000 - 1/1,000,000.\nClinical description\nStreptococcal TSS usually presents with a sudden onset of pain, often mimicking peritonitis or located in the extremities in previously healthy adults. General flu-like symptoms such as high fever, myalgia, nausea, diarrhea and vomiting are signs of streptococcal TSS and most patients develop hypotension soon after hospital admission. Signs of soft tissue infection can also be present manifesting with localized erythema and swelling which can lead to necrotizing fasciitis in some cases. A diffuse scarlatina-like erythema occurs in about 10% of cases. Other serious manifestations include confusion, shock, renal dysfunction, acute respiratory distress syndrome (ARDS; see this term) and coma. In some cases streptococcal TSS can be associated with acute adrenal insufficiency (see this term).\nEtiology\nStreptococcal TSS is caused by an infection with Streptococcus pyogenes, also known as group A streptococcus (GAS), and is usually associated with skin infections, child birth, and surgeries. Infection occurs at a site of trauma or can follow viral infections (influenza or varicella). Streptococcal TSS is the result of toxins released by the bacteria that cause a massive immune reaction involving mainly cytokines and chemokines. This reaction is related to the activation of T cells by the production of superantigens that circumvent the normal pathway of antigen presentation. Group C and G Streptococcus are also rarely associated.\nDiagnostic methods\nClinical symptoms along with laboratory analysis are the basis for diagnosis of streptococcal TSS. Patients with fever, multisystem organ failure and shock are tested for GAS in their blood or a normally sterile site (e.g. cerebrospinal, pleural or peritoneal fluid) and those who test positive are given a diagnosis of streptococcal TSS. Bacteremia is present in most patients with streptococcal TSS (approximately 60%) which is not the case in staphylococcal TSS (see this term) where it is seen in approximately 5% of cases.\nDifferential diagnosis\nDifferential diagnoses include staphylococcal TSS, septic shock, typhoid fever, Rocky Mountain spotted fever, leptospirosis (see these terms), peritonitis, pneumonia, pelvic inflammatory disease, pericarditis, acute myocardial infarction, meningococcemia, viral/ drug/ allergic rash.\nManagement and treatment\nThe onset of streptococcal TSS is sudden and requires immediate medical treatment in an intensive care setting. Treatment involves antibiotics (beta-lactam antibiotics and clindamycin) along with supportive therapy (fluid resuscitation, inotropes and vassopressors) and intravenous immunoglobins that block superantigens. Corticosteroids and recombinant activated protein C (derotrecogin-alpha) can also be helpful in some cases. Dialysis may be necessary for those with renal dysfunction and oxygen supplementation along with mechanical ventilation is required for patients with ARDS. Suspected necrotizing fasciitis may require debridement.\nPrognosis\nThe prognosis varies, with streptococcal TSS having a mortality rate of 30-80% in adults and 5-8% in children.\n\n                            Last update: \n                            November 2015\n\n\n                            - Expert reviewer(s): \n                             Claude-Alexandre GUSTAVE  - Pr Gerard LINA  - Dr Anne TRISTAN"}
{"Disease Name": "Striate palmoplantar keratoderma", "Disease Definition": "Striate palmoplantar keratoderma is an isolated, focal, hereditary palmoplantar keratoderma characterized by linear hyperkeratosis along the flexor aspect of the fingers and on palms, as well as focal hyperkeratosis of the plantar skin. Patients present with painful thickening of the skin on palms and soles, with occasional fissuring, blistering and hyperhidrosis. Rarely, hyperkeratosis on other areas may be seen (knees, dorsal aspects of the digits). Histopatologically, widened intercellular spaces between keratinocytes are observed.", "ORPHA ID": 50942, "Summary": ""}
{"Disease Name": "Stromal corneal dystrophy", "Disease Definition": "The stromal corneal dystrophies refer to a group of rare genetically determined corneal dystrophies (CDs) characterized by lesions affecting the corneal stroma, and variable effects on vision depending on the type of dystrophy.", "ORPHA ID": 98626, "Summary": "Epidemiology\nPrevalence of this group of corneal dystrophies is unknown, but all are rare.\nClinical description\nAge of onset is variable. Eleven subtypes of stromal corneal dystrophy have been identified: Pre-Descemet CD, Type I and Type II lattice CD, Type I and type II granular CD, Macular CD, Schnyder CD, Congenital stromal CD, Fleck CD, Posterior amorphous CD and Central cloudy dystrophy of François (see these terms).\nEtiology\nLike most corneal dystrophies, stromal forms are mostly genetically determined and mutations in the following genes have been identified as causing stromal lesions: TGFBI (5q31), CHST6 (16q22), UBIAD1 (1p36.22), DCN (12q23), and  PIKFYVE (2q34).\nGenetic counseling\nAn autosomal dominant pattern of inheritance has been reported for all subtypes, with the exception of macular CD which is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Stromme syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome usually characterized by microcephaly, ocular anomalies such as microphthalmia, and apple-peel intestinal atresia. Facial dysmorphism is reported in some cases and may include narrow or sloped forehead, hypertelorism, microphthalmia, dysplastic, edematous deep-set eyes, short palpebral fissures, large or low set ears, broad nasal root, anteverted or broad nasal tip, long philtrum, micrognathia, thin upper vermillion, large mouth and skin tag on the cheek. Motor delay and intellectual disability have been reported. Heart, brain, craniofacial abnormalities, renal hypoplasia and other anomalies (e.g. lower limb edema, thrombocytopenia) are variably present. Rarely, cases without intestinal atresia, microcephaly or developmental delay can be found. Severe lethal cases have also been reported.", "ORPHA ID": 506307, "Summary": ""}
{"Disease Name": "Strongyloidiasis", "Disease Definition": "A parasitosis caused by the intestinal nematode Strongyloides stercoralis (round worm).", "ORPHA ID": 76, "Summary": "Epidemiology\nIt affects between 30 and 60 millions people worldwide and is endemic to sub-tropical zones including Africa, the West Indies, Central and South America, the Indian Ocean region, South East Asia.\nClinical description\nAcute infection is characterized by cutaneous manifestations such as serpiginous urticarial rash, cough, dyspnea, gastrointestinal symptoms (including pain and soft stools) and allergic manifestations; however over half of infected individuals remain asymptomatic. Strongyloides hyperinfection syndrome (SHS) may occur in patients with underlying illness such as HTLV1 infection or those undergoing corticosteroids or immunosuppressive treatment and often results in sepsis, shock, and acute respiratory distress syndrome. Respiratory, gastrointestinal, cutaneous, and neurologic symptoms are observed at variable frequencies, but the hallmark of SHS is the severity of organ failure requiring ICU admission.\nEtiology\nThe female nematodes, which measure 2.5 mm in length, live in the small intestine of humans. Eggs laid in the small intestine hatch to release larvae that are normally excreted in the feces. On damp ground, these larvae reach their infectious stage directly or after a phase of sexual reproduction. In this infectious form they can penetrate the skin directly. Evolution towards the infectious stage may also take place within the digestive system, explaining the long duration of parasitosis (more than 30 years) observed in some cases.\nDiagnostic methods\nDiagnosis is made by serological test, agar plate culture or stool examination, the latter of which has low sensitivity and requires a minimum of three samples.\nDifferential diagnosis\nDifferential diagnosis may include ancylostomiasis and other causes of gastritis, enteritis, bronchitis, and dysentery.\nManagement and treatment\nAccess to clean water, footwear, and sanitation is fundamental to preventing new cases of strongyloidiasis. The treatment of choice is ivermectin. Disseminated infections may require intensive care.\nPrognosis\nLifelong infection is possible if left untreated. Most patients remain asymptomatic even with chronic disease, but prognosis depends on development of complications. Disseminated infection is fatal in 60-70% of cases.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Luc PARIS"}
{"Disease Name": "STT3A-CDG", "Disease Definition": "STT3A-CDG is a form of congenital disorders of N-linked glycosylation characterized by developmental delay, intellectual disability, failure to thrive, hypotonia and seizures. STT3A-CDG is caused by mutations in the gene STT3A (11q23.3).", "ORPHA ID": 370921, "Summary": ""}
{"Disease Name": "STT3B-CDG", "Disease Definition": "STT3B-CDG is a form of congenital disorders of N-linked glycosylation characterized by intrauterine growth retardation, microcephaly, failure to thrive, developmental delay, intellectual disability, hypotonia, seizures, optic nerve atrophy and respiratory difficulties. Genital abnormalities (micropenis, hypoplastic scrotum, undescended testes) have also been reported. STT3B-CDG is caused by mutations in the gene STT3B (3p24.1).", "ORPHA ID": 370924, "Summary": ""}
{"Disease Name": "Sturge-Weber syndrome", "Disease Definition": "A rare congenital neurocutaneous syndrome defined by a facial capillary malformation or port-wine birthmark (PWB) associated with cerebral and ocular ipsilateral vascular malformations in most of the cases resulting in variable ocular and neurological complications.", "ORPHA ID": 3205, "Summary": "Epidemiology\nThe birth prevalence in Europe is estimated at around 1/20,000 to 1/50,000.\nClinical description\nThe facial port-wine birthmark is present at birth and covers the forehead and/or the upper eyelid (at risk zone). Glaucoma is the most common ocular complication, affecting 30 to 60% of patients with a risk of early visual impairment. Epilepsy is often the first neurological manifestation. Around 80% of patients develop seizures at a median age of 6 months. First seizures are usually focal motor. Drug resistant seizures are reported in up to 50% of patients and status epilepticus is commonly seen. Fever induced seizures are frequently reported. A pattern of seizure clustering followed by prolonged period of seizure freedom occurs in 40% of cases. The natural history is highly variable but typically marked by seizures in early childhood, stroke-like events, progressive hemiparesis and developmental impairment, glaucoma and visual field defects. Later manifestations include headaches, academic difficulties, behavioral and psychiatric disorders. An increased risk of growth hormone deficiency is reported.\nEtiology\nThe syndrome is caused by a somatic mosaic mutation in GNAQ (9q21) that codes for the protein guanine nucleotide-binding protein G(q) subunit alpha which is critical to the intracellular signaling of a large group of G protein coupled receptors important to vascular development and function. Mutations in GNAQ can also result in an isolated PWB phenotype. The phenotypic presentation is thought to be determined by the developmental time point at which the somatic mutation occurs.\nDiagnostic methods\nDiagnosis is suspected at birth in newborns presenting facial PWB in the at risk zone. The risk of cerebral involvement in such situation ranges between 15 and 40%. Diagnosis can be confirmed by a contrast-enhanced cerebral magnetic resonance imaging showing direct (angioma) and indirect (enlargement of choroid plexus unilaterally) radiological signs of the leptomeningeal angioma. A computer tomography scan can help diagnosis showing localized calcifications and atrophy, although they might develop later during the course of the disease. Electroencephalogram (EEG) recording can show decreased amplitude of the EEG signal on the side of brain involvement.\nDifferential diagnosis\nThe main diagnostic concern is to separate infants with an isolated facial PWB from those with Sturge-Weber syndrome (SWS) brain involvement. Differential diagnosis includes PIK3CA-related overgrowth syndromes, especially megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome.\nAntenatal diagnosis\nPrenatal ultrasounds are usually normal.\nGenetic counseling\nThe disease is sporadic and due to somatic mutations.\nManagement and treatment\nA multidisciplinary approach is needed from onset to monitor disease progression in the skin, eye, and brain. Laser treatment is proposed in infancy to reduce the PWS. Regular ocular monitoring is recommended throughout life. Eye drops are used to lower intraocular pressure but surgical interventions may be required. Parental education for early seizure recognition and individualized emergency plans including the use of rescue benzodiazepine therapy is recommended. Low-dose aspirin might be useful to prevent the stroke-like episodes and possibly seizures but the risk-benefit ratio of such approach is not well established. Antiseizure medications are used to treat epilepsy. Patients with focal drug-resistant seizures should be considered early for pre-surgical evaluation at a reference center. Neuropsychological assessments and rehabilitation are needed and physiotherapy is required for functional deficits.\nPrognosis\nThe prognosis of SWS is highly variable. Early seizure onset, drug-resistant seizures and bilateral intracranial involvement have been associated with poor cognitive outcomes.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Katarzyna KOTULSKA-JOZWIAK | EpiCARE* - Pr Rima NABBOUT | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "STXBP1-related encephalopathy", "Disease Definition": "A rare genetic neurological disorder characterized by a phenotypic spectrum comprising severe intellectual disability, developmental delay, and, in the majority of cases, early-onset epilepsy. The most frequent seizure type are epileptic spasms, but a broad spectrum of seizure types has been reported. Motor disturbances include ataxia, hypotonia, dystonia, tremor, spasticity, and dyskinesia. Some patients may also present with autism/autistic-like features. Older patients have been reported to show signs of parkinsonism, including tremor, bradykinesia, and antecollis.", "ORPHA ID": 599373, "Summary": ""}
{"Disease Name": "Stüve-Wiedemann syndrome", "Disease Definition": "Stüve-Wiedemann syndrome (SWS) is a rare autosomal recessive congenital primary skeletal dysplasia, characterized by small stature, bowing of the long bones, camptodactyly, hyperthermic episodes, respiratory distress/apneic episodes and feeding difficulties that usually lead to early mortality.", "ORPHA ID": 3206, "Summary": "Epidemiology\nSWS is a rare syndrome with few cases reported to date, but the disease is relatively common in the United Arab Emirates, apparently due to a high number of consanguineous unions, with a reported prevalence of approximately 0,5/10,000 births.\nClinical description\nSWS is characterized by short stature, bowing of extremities that affect the lower limbs more than the upper limbs, camptodactyly, respiratory distress/apneic spells and hyperthermic episodes frequently associated with feeding/swallowing difficulties. Other clinical findings are mask-like face, pursed mouth, hypoplastic midface, osteopenia, congenital contractures and muscular hypotonia. The condition is fatal in most cases as a result of respiratory distress or hyperthermia. However, survival beyond one year have been reported in few cases, and patients develop severe spinal deformities, along with streaky osteoporosis and spontaneous fractures, bowing of the lower limbs (with prominent joints) and dysautonomia (including temperature instability, absent corneal and patellar reflexes, and smooth tongue). Motor development is generally delayed but no intellectual deficit has been reported.\nEtiology\nSWS is due to missense or nonsense mutations in the leukemia inhibitory factor receptor (LIFR) gene (5p13.1). These null mutations lead to modifications in the stability of the LIFR transcripts, inhibiting synthesis of the LIFR protein and resulting in alterations in the JAK/STAT3 signaling pathway. In some patients diagnosed for SWS, LIFR mutations were not identified, suggesting that other genes may be involved in the disease.\nDiagnostic methods\nThe diagnosis of SWS is mainly postnatal, based on clinical and radiological findings. Radiographic examination reveals bowed long bones with cortical thickening and rarefaction, wide metaphysis with decreased density and blurred margins, and abnormal trabecular pattern. Other features include flared iliac wings, hypoplasia of the lower ilia. Genetic molecular testing for LIFR mutation may be useful to confirm SWS diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes Crisponi syndrome (cold-induced sweating syndrome) and other skeletal dysplasias, such as Ehlers-Danlos syndrome type IX, Campomelic dysplasia and autosomal dominant Larsen syndrome (see these terms).\nAntenatal diagnosis\nIn some cases, ultrasound examination may be useful to predict the presence of SWS before birth. Prenatal symptoms can sometimes be seen in the late second- or third trimester and include oligohydramnios, intrauterine growth restriction despite normal Doppler findings about the umbilical artery, camptodactyly, bowing of the lower bones affecting the tibia more than the femur, and micromelia.\nGenetic counseling\nSWS is a congenital condition inherited as an autosomal recessive disorder.\nManagement and treatment\nTo date, SWS management is only symptomatic and should include prevention of lung aspirations and chocking while eating (intubation, nasogastric tube feeding and/or gastrostomy often required during the first year of life), physiotherapy and/or surgery for bone malformations, eyes protection from damage to prevent visual loss, and osteopenia or osteoporosis treatment. Predisposition to hyperthermia necessitates caution during procedures requiring anesthesia.\nPrognosis\nSWS is a life-threatening disease which is usually fatal during the neonatal period, due to respiratory distress or hyperthermic episode. However, more patients are surviving for longer (into and, in some cases, beyond adolescence), if diagnosed and monitored appropriately.\n\n                            Last update: \n                            March 2016\n\n\n                            - Expert reviewer(s): \n                            Pr Cheryl JORCYK  - Dr Dawn MIKELONIS  - Pr Julia OXFORD  -  Ken TAWARA"}
{"Disease Name": "Subacute cutaneous lupus erythematosus", "Disease Definition": "A form of cutaneous lupus erythematosus (CLE) that can present either as a non-scarring, annular photo-distributed dermatosis or psoriasiform plaques. This disorder is associated with anti-Ro/SSA antibodies and can be drug-induced.", "ORPHA ID": 163525, "Summary": ""}
{"Disease Name": "Subacute inflammatory demyelinating polyneuropathy", "Disease Definition": "Subacute inflammatory demyelinating polyneuropathy (SIDP) is a subacute progressive symmetric sensorial and/or motor disorder characterized by muscular weakness with impaired sensation, absent or diminished tendon reflexes and elevated cerebrospinal fluid (CSF) proteins. SIDP is an intermediate form between Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP; see these terms).", "ORPHA ID": 206594, "Summary": "Clinical description\nThe time to maximum severity (nadir) and the subsequent course of SIDP differentiate it from GBS and CIDP. Onset can occur at any age but is more common between the 4th and 5th decades. When onset is in childhood, SIDP is rather considered as CIDP. Males are predominantly affected. Patients present a 4 to 8 week history of progression of monophasic demyelinating neuropathy (DN) associated with the occurrence of a symmetric progressive weakness in both proximal and distal muscles with impaired sensation and absent/diminished tendon reflexes. Neuropathy is symmetric and can be either sensorimotor or pure motor in nature. Rarely, cranial nerve dysfunction and respiratory failure may occur.\nEtiology\nSIDP, like CIDP, could be due to an immune reaction, resulting in segmental demyelination which may induce a concomitant axonal loss.\nDiagnostic methods\nDiagnosis is based on clinical and electrophysiological findings. CSF analysis and histological findings can provide additional supportive data but are not mandatory. Four diagnostic criteria allow definite diagnosis: progressive motor and/or sensory dysfunction consistent with neuropathy in more than one limb with time to nadir between 4 to 8 weeks, electrophysiological evidence of demyelination at least in 2 nerves (EMG and nerve conduction study), no other etiology of neuropathy and no relapse on adequate follow-up (in the absence of this last criterion, a probable SIDP is diagnosed). In addition, supportive criteria include raised CSF proteins and segmental and multifocal demyelination in nerve biopsy (in clinically suspected SIDP cases in which electrophysiological proof of demyelination is absent). Cytoalbuminologic dissociation in CSF is characteristic, pointing to nerve root involvement. Occasionally, CSF studies reveal mild lymphocytic pleocytosis and elevated gamma globulins. SIDP presents mostly the same clinical manifestations as CIDP with 3 exceptions: a higher rate of history of infection (about 40% of cases), no relapsing course and a higher rate of recovery to normal.\nDifferential diagnosis\nDifferential diagnosis includes GBS and rarely some other acquired polyneuropathies (monoclonal gammopathy (see this term), infections, or systemic inflammatory or immune-mediated diseases, toxic neuropathies, neuropathy due to nutritional deficiency).\nManagement and treatment\nMost patients respond to steroid therapy (prednisone). A few cases may also require intravenous immunoglobulins (IVIg) and/or plasmapheresis.\nPrognosis\nThe earlier treatment begins in the course of the disease, the higher the rate of recovery to normal (70%) and 30% of patients have partial recovery; some of these cases may progress to CIDP. Rare cases of spontaneous remission have also been reported.\n\n                            Last update: \n                            December 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Michel VALLAT"}
{"Disease Name": "Subacute sclerosing leukoencephalitis", "Disease Definition": "A rare infectious disease characterized by slowly progressive brain disorder caused by a mutant measles virus, typically affecting children and young adults. The condition leads to cognitive decline, myoclonus, vision loss, and eventually a vegetative state.", "ORPHA ID": 2806, "Summary": "Epidemiology\nThe global burden of subacute sclerosing leukoencephalitis (SSPE) is greater in countries with high measles incidence. According to the WHO, there is one case of SSPE every 9,090 to 25,000 measles cases, increasing to one SSPE case every 5,555 measles cases in early childhood. Higher incidences are reported in resource-constrained countries such as India, Pakistan, Papua New Guinea, and Turkey. In high-income countries, fewer cases are seen due to vaccination efforts, though outbreaks can still lead to new SSPE cases. Additionally, the risk of SSPE is twice as high in males.\nClinical description\nIn children, SSPE starts with cognitive decline, poor school performance, forgetfulness, behavioral changes, and gait abnormalities. Verbal output diminishes, progressing to akinesia and mutism. Patients develop pyramidal signs, periodic myoclonus, and eventually enter a vegetative state with autonomic instability. Ophthalmological symptoms, such as chorioretinitis and vision loss, may precede neurological signs. SSPE is almost always lethal. Diagnosis is supported by characteristic electroencephalogram (EEG) findings and elevated measles antibody titers in the cerebrospinal fluid.\nEtiology\nSSPE results from mutant measles virus entry during acute infection. Mutations in the virus genome, particularly in the M and F genes, enable viral persistence and transneuronal spread. The virus enters the brain via infected monocytes, endothelial cells, or the olfactory bulb. Hyperfusogenic properties due to changes in the F protein and defective M protein facilitate viral survival and spread, with genetic susceptibility influencing disease development.\nDiagnostic methods\nEEG reveals characteristic periodic discharges, while neuroimaging shows periventricular white matter abnormalities and significant cerebral atrophy in advanced stages. Diagnosis is confirmed by elevated measles antibody titers in cerebrospinal fluid.\nDifferential diagnosis\nThe differential diagnosis of SSPE includes autoimmune encephalopathies, vitamin B12 deficiency, herpes simplex encephalitis, neurosyphilis, and progressive multifocal leukoencephalopathy in HIV patients. Misdiagnosis can involve psychiatric disorders, autoimmune encephalitis, eclampsia, brain tumors, and acute disseminated encephalomyelitis, potentially leading to incorrect treatments.\nManagement and treatment\nUniversal measles vaccination has significantly reduced the incidence of SSPE. However, treatment remains challenging, with no proven effective therapies currently available. Although various drugs, such as isoprinosine, interferon-alpha, and ribavirin, are used to manage SSPE, there is a lack of randomized clinical trials to support their efficacy. About 6% of patients may experience extended spontaneous remission. Future treatments might involve fusion inhibitor peptides, but universal measles vaccination remains the only proven preventive measure.\nPrognosis\nSSPE is almost always lethal, typically within 1-3 years, with ~60% of patients surviving less than 2 years. Survival rates vary, with some cases experiencing prolonged remission of up to 18 years. In cases of fulminant SSPE, death occurs rapidly, often within 6 months.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Pr Ravindra Kumar GARG"}
{"Disease Name": "Subaortic course of innominate vein", "Disease Definition": "Subaortic course of innominate vein is a rare congential anomaly of the great veins characterized by an anomalous course of the left brachiocephalic vein, passing from left to right below the aortic arch and entering the superior vena cava below the orifice of the azygos vein. Patients are frequently asymptomatic and diagnosed incidentally on imaging studies. Other cardiac malformations may be associated.", "ORPHA ID": 99113, "Summary": ""}
{"Disease Name": "Subaortic stenosis-short stature syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by the association of short stature and progressive discrete subaortic stenosis. Additional variable manifestations include upturned nose, voice and vocal cord abnormalities, obstructive lung disease, inguinal hernia, kyphoscoliosis and, occasionally, epicanthus, strabismus, microphthalmos and widely spaced teeth. There have been no further descriptions in the literature since 1984.", "ORPHA ID": 3191, "Summary": ""}
{"Disease Name": "Subcorneal pustular dermatosis", "Disease Definition": "A rare, acquired, chronic neutrophilic dermatosis characterized by sterile superficial pustules, typically involving the flexural sites of the trunk and proximal extremities.", "ORPHA ID": 48377, "Summary": "Epidemiology\nApproximately 200 cases have been reported worldwide. The disease occurs more frequently in adults (40-60 years of age with a male to female ratio of 4:1).\nClinical description\nSuperficial flaccid grouped pustular lesions, which spread in an annular or gyrate pattern, arise within a few hours and resolve over a few days. Pruritus and irritation occur occasionally. The lesions characteristically evolve to fine scales with crusting and, in rare cases, mild hyperpigmentation. The disease may be associated with IgA monoclonal gammopathy, multiple myeloma or pyoderma gangrenosum. Less frequently associated conditions include rheumatoid arthritis, lupus erythematosus, hyperthyroidism and hypothyroidism, polycythemia rubra vera, SAPHO syndrome.\nEtiology\nThe etiology remains unknown.\nDiagnostic methods\nDiagnosis is confirmed by skin biopsy demonstrating a sterile subcorneal pustule filled with neutrophils, an absence of acantholysis, and negative results from immunofluorescence studies.\nDifferential diagnosis\nDifferential diagnosis includes the subcorneal-type of IgA pemphigus, pemphigus foliaceus, dermatitis herpetiformis, pustular psoriasis, generalized pustulosis, generalized exanthematous pustulosis and bacterial impetigo.\nManagement and treatment\nManagement aims at preventing the complications. A dramatic response to dapsone has been reported but not all patients respond to this drug. In cases refractory to dapsone, other possible treatments (in combination with dapsone or not) include sulfapyridine, oral corticosteroids, tetracycline with niacinamide, retinoids, colchicine, phototherapy, and TNF-alpha inhibitors.\nPrognosis\nThere is no impact on life expectancy for this disease. Dapsone is the drug of choice in most patients; lesions may resolve within weeks of treatment but maintenance doses may be needed to prevent relapses. In addition, addressing the underlying associated conditions has helped to achieve clinical response when done in conjunction with above treatments.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Sung Kyung CHO  - Dr Victoria WERTH"}
{"Disease Name": "Subcortical band heterotopia", "Disease Definition": "A rare, non-syndromic cerebral malformation due to abnormal neuronal migration characterized by variable clinical manifestation depending on the location, size and thickness of subcortical bands. Clinical presentation ranges from mild cognitive deficit to developmental delay with severe intellectual disability, seizures and behavioral problems.", "ORPHA ID": 99796, "Summary": ""}
{"Disease Name": "Subcutaneous panniculitis-like T-cell lymphoma", "Disease Definition": "A rare cytotoxic cutaneous alpha-beta T-cell lymphoma characterized by solitary or multiple erythematous subcutaneous nodules and plaques that can be localized to the lower extremities or generalized. It has been recognized as a distinct subset of peripheral T-cell lymphomas originating and presenting primarily in the subcutaneous fat tissue and often associated with hemophagocytic lymphohistiocytosis.", "ORPHA ID": 86884, "Summary": "Epidemiology\nThe exact incidence is unknown but estimated around 1/10,000,000 individuals per year in Europe. A slight female preponderance has been reported. Median age of diagnosis is around 40 years old, but cases are reported from 1 to 90 years old.\nClinical description\nSubcutaneous panniculitis-like T-cell lymphoma (SPTCL) is characterized by solitary or multiple erythematous subcutaneous nodules and plaques (proliferation of T lymphocytes and macrophages in the subcutaneous fat lobule), which appear in crops and are localized to the lower extremities or may be more generalized. Systemic manifestations include fever, chills, malaise, weight loss, hepatosplenomegaly, mucosal ulcers, and serosal effusions. SPTCL may be accompanied by hemophagocytic syndrome (characterized by the proliferation of histiocytes and phagocytosis of blood elements, hepatosplenomegaly, and coagulopathy and reported in approximately 30-40% of cases), which may be fatal.\nEtiology\nThe etiology is not completely understood. An infectious trigger events has been described in some pediatric cases. Recently, germline homozygous mutation of HAVCR2 has been associated with SPTCL in 32 to 85% of patients.\nDiagnostic methods\nRepeated biopsies may be required to establish the diagnosis. Pathology is characterized by CD8+ T cells expressing alpha-beta T cell antigen receptors (TCRs) and infiltrating subcutaneous adipose tissue, rimming adipocytes in a lace-like pattern, and adipocyte necrosis. The immunophenotype of the lymphoma is CD8+, CD56-, CD30-, granzymeB+, TiA-1, betaF1+. Molecular clonality assay should exclude gamma-delta T cell lymphoma which has a more aggressive course and is considered as a distinct entity.\nDifferential diagnosis\nThe differential diagnosis includes other lymphomas as well as atypical lobular panniculitis and cytophagic histiocytic panniculitis. Lupus panniculitis can be excluded by the frequent MxA staining on lymphocytes, macrophages and on clusters of CD123+CD303+ PDC, and by the presence of lymphoid follicles and B cells.\nGenetic counseling\nTransmission of HAVCR2-associated risk is autosomal recessive with incomplete penetrance. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having a child with heterozygous HAVCR2 variant at each pregnancy.\nManagement and treatment\nSPTCL may be rapidly fatal or indolent. Most patients respond to immunosuppressive drugs (ciclosporin A, corticosteroids, hydroxychloroquine or methotrexate). Systemic chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone) is an available option in severe case or when associated with hemophagocytic lymphohistiocytosis. Allogeneic hematopoietic stem cell transplantation has been proposed in severe cases and is a curative treatment option, especially in HAVCR2-variant cases.\nPrognosis\nSPTCL is a life-threatening disease with a good prognosis in most cases. 2-years overall survival is estimated around 90% and complete remission around 80% with immunosuppressive drugs.\n\n                            Last update: \n                            April 2024\n\n\n                            - Expert reviewer(s): \n                            Pr David MICHONNEAU"}
{"Disease Name": "Subependymal giant cell astrocytoma", "Disease Definition": "A rare low-grade astrocytoma characterized by a benign, slowly growing lesion typically arising in the wall of the lateral ventricles, composed of large ganglioid astrocytes. The tumor corresponds to WHO grade I and typically occurs during the first two decades of life in patients with tuberous sclerosis complex. Most patients present with worsening of epilepsy or symptoms of increased intracranial pressure.", "ORPHA ID": 251618, "Summary": ""}
{"Disease Name": "Subependymoma", "Disease Definition": "Subependymoma is a rare and slow growing type of ependymoma (see this term), often presenting in middle-aged adults, found more commonly in men than in women, usually located in the fourth and lateral ventricles and manifesting with variable symptoms including headache, nausea, and loss of balance. In some cases it can be asymptomatic. It is usually associated with a better prognosis than other forms of ependymoma.", "ORPHA ID": 251639, "Summary": ""}
{"Disease Name": "Subepithelial mucinous corneal dystrophy", "Disease Definition": "Subepithelial mucinous corneal dystrophy (SMCD) is a very rare form of superficial corneal dystrophy characterized by frequent recurrent corneal erosions in the first decade of life, with progressive loss of vision.", "ORPHA ID": 98959, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is unknown. The condition has only been reported in one single family.\nClinical description\nPainful episodes of recurrent corneal erosions occur in the first decade of life but decrease during adolescence. Later in life, patients are reported to develop subepithelial opacities and a corneal haze. SMCD eventually progresses over time leading to corneal opacities and loss of vision.\nEtiology\nThe etiology is unknown but is thought to be genetic. The gene related to SMCD has not been mapped to a particular chromosomal locus.\nDiagnostic methods\nA striking morphologic feature of corneal tissue in this form of corneal dystrophy is the presence of subepithelial mucinous material revealed by special stains.\nGenetic counseling\nAn autosomal dominant pattern of inheritance has been reported.\nManagement and treatment\nSMCD can be treated medically with the aim of healing the epithelial defect and protecting the loosely adherent epithelium. A topical antibiotic, cycloplegic and pressure patch are valuable. A lubricating ointment is useful at night. Hypertonic saline and bandage contact lens therapy may also be beneficial.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Submucosal cleft palate", "Disease Definition": "A rare form of cleft palate characterized by congenital muscular diastasis of the soft palate along the midline with an intact oral and nasal mucosal lining. It is diagnosed by the triad of a bifid uvula, a translucent zone in the soft palate, and a bony notch in the posterior edge of the hard palate, all of which may vary in severity. Velopharyngeal insufficiency in the absence of this triad is classified as occult submucosal cleft palate. Patients may be asymptomatic or present with early feeding problems with fluid reflux through the nose, speech problems, recurrent otitis media with effusions, and hearing loss.", "ORPHA ID": 155878, "Summary": ""}
{"Disease Name": "Succinic semialdehyde dehydrogenase deficiency", "Disease Definition": "A rare neurometabolic disorder of gamma-aminobutyric acid (GABA) metabolism with a nonspecific clinical presentation (ranging from mild to severe) with the most frequent symptoms being cognitive impairment with prominent deficit in expressive language, hypotonia, ataxia, epilepsy, and behavioral dysregulation.", "ORPHA ID": 22, "Summary": "Epidemiology\nApproximately 450 cases have been reported in the literature to date.\nClinical description\nThe mean age of onset is 11 months. Contrary to what is seen in many metabolic encephalopathies, patients do not present with hypoglycemia, hyper-ammonemia, or intermittent lethargy. Infants usually present with a slowly progressive or static encephalopathy manifesting with hypotonia, hyporeflexia, ataxia and delayed acquisition of motor and language developmental milestones in the first two years of life. Seizures occur in more than half of all affected individuals and are usually generalized tonic-clonic or atypical absence. Intellectual disability, psychiatric manifestations (i.e. attention deficit hyperactivity disorder and aggression in early childhood, obsessive-compulsive disorder and anxiety in adolescence and adulthood) and sleep disturbances are commonly observed. Hyperkinetic behavior, self-injurious behaviors and hallucinations are reported in half of all cases. A more fulminating, early-onset presentation occurs in up to 10% of patients and is characterized by extrapyramidal signs and sometimes a progressive disease course.\nEtiology\nSSADH deficiency is due to mutations in the ALDH5A1 gene (6p22), encoding mitochondrial succinate-semialdehyde dehydrogenase, a protein involved in amino-acid degradation. A deficiency of SSADH enzyme activity impairs degradation of GABA, the brain's major inhibitory neurotransmitter, and thereby results in elevated concentrations of a putative toxic metabolite, gamma-hydroxybutyric acid (GHB), which is detectable in physiological fluids including blood, urine, and cerebrospinal fluid.\nDiagnostic methods\nThe key laboratory diagnostic test suggestive of SSADH deficiency is urine organic acid analysis with results of elevated GHB. Findings from plasma analysis include elevated GHB and lymphocytes will display low SSADH enzymatic activity. In cerebrospinal fluid analysis, GHB and GABA will be elevated. Cranial magnetic resonance imaging shows increased bilateral and usually symmetrical T2-weighted signal involving the globus pallidi, as well as the cerebellar dentate nuclei and subthalamic nuclei. Electroencephalogram findings include mainly generalized background slowing and spike discharges. Molecular genetic testing revealing a mutation in the ALDH5A1 gene confirms diagnosis.\nDifferential diagnosis\nThe main differential diagnoses include gamma-aminobutyric acid transaminase deficiency and homocarnosinosis (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease causing mutation.\nGenetic counseling\nSSADH deficiency is inherited in an autosomal recessive fashion. Genetic counseling is recommended.\nManagement and treatment\nAs there is no treatment currently available to effectively address the underlying disorder, long-term management of the phenotype focuses on pharmacologically controlling the most debilitating manifestations (typically seizures and neurobehavioral disorders). Carbamazepine and lamotrigine are effective in controlling seizures. Anxiety, aggressiveness, inattention, and hallucinations may be treated with benzodiazepines, methylphenidate, thioridazine, risperidone or fluoxetine. Physical and occupational therapy, sensory integration, and/or speech therapy may be beneficial in some cases.\nPrognosis\nThe prognosis varies. Although most patients live until adulthood, neuropsychiatric symptoms can be disabling, decreasing quality of life. Early mortality, including sudden unexpected death in epilepsy patients (SUDEP), has been reported.\n\n                            Last update: \n                            February 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Mahsa PARVIZ  - Dr Phillip PEARL"}
{"Disease Name": "Succinyl-CoA:3-oxoacid CoA transferase deficiency", "Disease Definition": "A rare, genetic disorder in ketone body utilization characterized by severe, potentially fatal intermittent episodes of ketoacidosis.", "ORPHA ID": 832, "Summary": "Epidemiology\nOver 30 cases have been reported to date.\nClinical description\nNeonatal onset occurs in half of patients, presenting with a first ketoacidotic attack 2-4 days after birth. Patients with later onset present with an initial episode of ketoacidosis between 6-20 months of age. Initial episodes are often severe, and further episodes may be triggered by metabolic stress, infection or extended periods of fasting. Symptoms include tachypnea, vomiting, lethargy, hypotonia, and, in severe cases, coma. Episode intensity and frequency is variable and severe attacks are potentially fatal. Patients are generally healthy and develop normally between episodes, but infants may present with failure to thrive and poor feeding prior to diagnosis. Cardiomegaly has developed in two cases and may lead to congestive heart failure.\nEtiology\nThis disease is caused by mutations in the OXCT1 gene (5p13) that encodes the mitochondrial enzyme, succinyl-CoA:3-oxoacid CoA transferase, essential for ketone body metabolism in all extrahepatic tissue. Over 30 different mutations to OXCT1 have been identified, all leading to the accumulation of ketone bodies and ketoacidosis during periods of catabolic stress. Partial loss-of-function mutations have been identified that also lead to severe ketoacidosis, but without permanent ketosis.\nDiagnostic methods\nPermanent ketosis or persistent ketouria are pathognomic features; however, some mild cases may not present with these signs. Patients display metabolic acidosis during crises and both serum and urinalysis reveal high levels of ketones, pH levels between 6.8 and 7.12, and HCO3 levels between 3-8 mmol/L may be observed. There is no characteristic organic acid or acylcarnitine profile. The ratio of free fatty acids to total ketone bodies becomes less than 0.3 during a short fast and this may lead one to suspect the disease. Enzyme activity assays using fibroblasts, lymphocytes or platelets reveal a lack, or great reduction, of functional succinyl-CoA:3-oxoacid CoA transferase.\nDifferential diagnosis\nDifferential diagnoses include physiological ketosis (e.g. ketoacidosis due to significant catabolism due to rotavirus infection) and ketoacidosis due to beta-ketothiolase deficiency or monocarboxylate transporter 1 deficiency.\nAntenatal diagnosis\nPrenatal diagnosis by enzyme activity assays is possible using cultured amniocytes.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive and genetic counseling should be offered to affected families. There is a 25% risk of disease transmission to offspring where both parents are unaffected carriers.\nManagement and treatment\nKetoacidotic crises must be treated immediately with intravenous fluid therapy including enough glucose, even when patients show normo- or hyper-glycemia, to suppress ketogenesis. Treatment of metabolic acidosis using sodium bicarbonate is controversial. Minimal usage of sodium bicarbonate is recommended. Patients must avoid prolonged fasting. A fat-rich diet which induces ketogenesis should be avoided. Protein restriction may be not necessary, because the effect of prevention of ketoacidosis is not proven. Home monitoring of urinary ketones helps parents to follow the patient's condition. Carbohydrate-rich food or drink should immediately be provided if ketone levels are higher than usual. If patients become weak or vomit, intravenous glucose infusions should be considered. There is no recommended medication for the chronic phase. The use of oral sodium bicarbonate and L-carnitine have been reported in the literature, but the effect of prevention of ketoacidosis attack is not proven. Affected females should be closely monitored during pregnancy and delivery.\nPrognosis\nRisk of premature death is highest during the neonatal and infantile period due to severe episodes of ketoacidosis. However, the frequency and severity of ketoacidosis decreases after 10 years of age; thus, beyond this period, life expectancy maybe as good as in the general population. Normal growth and development is expected when proper treatment and diet are followed.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Toshiyuki FUKAO  - Dr Hideki MATSUMOTO"}
{"Disease Name": "Sudden infant death-dysgenesis of the testes syndrome", "Disease Definition": "Sudden infant death with dysgenesis of the testes (SIDDT) syndrome is a lethal condition in infants with dysgenesis of testes.", "ORPHA ID": 168593, "Summary": "Epidemiology\nSIDDT syndrome has been described in 21 infants from nine separate sibships among the Old Order Amish.\nClinical description\nInfants with SIDDT syndrome appear normal at birth except that they are often recognized by the unusual staccato sound of their cry. Within the first months of life, they develop signs of viscera-autonomic nerve dysfunction including bradycardia, hypothermia, severe gastroesophageal reflux, laryngospasm, bronchospasm, and abnormal cardiorespiratory patterns during sleep. XY males have testicular dysgenesis and ambiguous genitalia. Female sexual development is normal.\nEtiology\nSIDDT syndrome is caused by homozygous mutation in the testis-specific protein Y-like-1 gene, TSPYL1 on chromosome 6 (6q22.1-q22.31).\nGenetic counseling\nThe syndrome follows an autosomal recessive pattern of inheritance.\nPrognosis\nPrognosis is very poor: infants die before 12 months of age of sudden cardiorespiratory arrest.\n\n                            Last update: \n                            December 2010"}
{"Disease Name": "Sudden sensorineural hearing loss", "Disease Definition": "A rare otorhinolaryngologic condition characterized by sudden hearing loss of at least 30 decibels across three contiguous frequencies, within 72 hours or less, due to acute damage to the cochlear hair cells, resulting from acoustic trauma or mechanical trauma during surgery, or occurring without any known cause. The hearing loss may affect one or both ears. Typical concomitant symptoms are aural fullness, tinnitus, and vertigo. Patients may fully recover or remain with hearing loss of variable intensity.", "ORPHA ID": 90059, "Summary": ""}
{"Disease Name": "Sugarman brachydactyly", "Disease Definition": "Sugarman brachydactyly is a rare, genetic, congenital limb malformation characterized by brachydactyly of fingers, with major proximal phalangeal shortening and immobile proximal interphalangeal joints, as well as dorsally and proximally placed, non-articulating great toes (with or without angulation). Radiographic findings of hands include bilateral double first metacarpals and biphalangeal fifth fingers. There have been no further descriptions in the literature since 1982.", "ORPHA ID": 498602, "Summary": ""}
{"Disease Name": "SUNCT syndrome", "Disease Definition": "A rare primary headache disorder characterized by unilateral trigeminal pain that occurs in association with ipsilateral cranial autonomic symptoms (conjunctival injection and tearing).", "ORPHA ID": 57145, "Summary": "Epidemiology\nThe prevalence is estimated at approximately 1 in 15,000. It is slightly more predominant in males (male-to-female ratio of 1.5:1), with a mean age of onset of around 50 years. A few cases of SUNCT/SUNA syndrome have been reported in children.\nClinical description\nThe disease manifests with strictly unilateral pain attacks of moderate-to-severe or very severe intensity. The pain is described as throbbing, sharp or stabbing. It usually involves the ophthalmic division of the trigeminal nerve and, less commonly, may involve any part of the head. In the majority of cases, the pain attacks are triggered by cutaneous stimuli (and not by alcohol or nitroglycerin). Spontaneous attacks have also been described. The typical SUNCT/SUNA patient may have 50 to 100 short attacks a day, lasting for 1 to 5 minutes. The attacks predominate during the daytime. Prominent, ipsilateral conjunctival injection and lacrimation regularly accompany the attacks. Nasal stuffiness and rhinorrhea are frequent.\nEtiology\nEtiopathology remains unclear. Trauma, arteriovenous malformations and pituitary adenomas may have a causative role.\nDiagnostic methods\nThe diagnosis is made after a careful history with attention to the features of the disorder as set out in the International Classification of Headache Disorders, 3rd Edition, careful physical examination and relevant investigations. Particular features of note are the relative brevity of lateralised attacks, their triggerability and the absence of a refractory period to stimulation.\nDifferential diagnosis\nTrigeminal neuralgia is the major differential diagnosis. It is very important to differentiate SUNCT/SUNA syndrome from other trigeminal autonomic cephalgias such as cluster headache and paroxysmal hemicrania, as each of these syndromes have a highly selective response to treatment.\nManagement and treatment\nThere is no cure for SUNCT/SUNA syndrome. Patients may benefit from administration of lamotrigine, topiramate, gabapentin or carbamazepine. Oxygen, anaesthetic blockades, and sumatriptan or indomethacin therapies, known to be effective in other trigeminal autonomic cephalgias, have little or no effect in SUNCT syndrome. In severe cases, surgical techniques, such as microvascular trigeminal nerve root decompression, have been considered.\nPrognosis\nThe prognosis is guarded in that most patients will continue to have attacks over many years.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Peter GOADSBY"}
{"Disease Name": "Superficial corneal dystrophy", "Disease Definition": "The superficial corneal dystrophies refer to a group of rare genetically determined corneal dystrophies (CDs) characterized by lesions affecting the corneal epithelium and its basement membrane and the superficial corneal stroma, and variable effects on vision depending on the type of dystrophy.", "ORPHA ID": 98625, "Summary": "Epidemiology\nPrevalence of this group of corneal dystrophies is unknown, but all are rare and found mainly in populations carrying the responsible mutated genes.\nClinical description\nAge of onset is variable, between early childhood and the second decade of life. Eight subtypes of superficial corneal dystrophy have been identified: Grayson-Willbrandt CD, Epithelial recurrent erosion dystrophy, Subepithelial mucinous CD, Meesmann CD, Lisch epithelial CD, Gelatinous drop-like CD, Reis-Bücklers CD, and Thiel-Behnke CD (see these terms).\nEtiology\nGenetic heterogeneity has been reported but all superficial corneal dystrophies appear to be genetically determined, and are usually inherited as Mendelian traits. Mutations in four genes:KRT3 (12q13.13), KRT12 (17q11-q12), TGFBI (5q31), and TACSTD2 (1p32), are currently known to cause inherited diseases that are apparently limited to the superficial cornea.\nGenetic counseling\nTransmission is autosomal dominant, autosomal recessive, or X-linked recessive depending on the condition.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Superficial epidermolytic ichthyosis", "Disease Definition": "Superficial epidermolytic ichthyosis (SEI) is a rare keratinopathic ichthyosis (KI; see this term) characterized by the presence of superficial blisters and erosions at birth.", "ORPHA ID": 455, "Summary": "Epidemiology\nLess than 30 families have been reported in the literature.\nClinical description\nClinical features of SEI are similar but milder that those of epidermolytic ichthyosis (EI; see this term). SEI presents at birth or during the neonatal period with mild superficial blistering that is more frequent on flexures, shins, abdomen and extremities. After a few weeks, the skin starts to peel leaving characteristic denuded areas with normal skin (called molting/ mauserung phenomenon). A variable and mild grey rippled hyperkeratosis develops predominantly on the limbs, lower trunk and flexural areas. Blistering diminishes with age but persists through childhood and sometimes into adult life in response to trauma, heat or excessive sweating. Palmoplantar involvement is usually not observed but palmoplantar blistering, usually associated with hyperhidrosis, may sometimes occur. Skin odor is not present.\nEtiology\nSEI is caused by mutations in the KRT2 gene encoding keratin 2. These mutations impair keratin filament formation and weaken the structural stability of the keratinocyte cytoskeleton.\nDiagnostic methods\nDiagnosis is based on clinical and histological examination of skin lesions biopsies revealing acanthosis, a prominent granular layer, epidermolytic changes in the granular and upper spinous layers, hyperorthokeratosis and intracorneal blister formation. On electron microscopic examination, keratinocytes of the granular layer display structural alterations of tonofilaments. Molecular analysis, if available, reveals KRT2 mutations.\nDifferential diagnosis\nDifferential diagnosis includes epidermolytic ichthyosis, peeling skin syndrome, staphylococcal scalded skin syndrome, Alopecia-contractures-dwarfism-intellectual disability syndrome (see these terms), and atopic dermatitis.\nAntenatal diagnosis\nGenetic prenatal diagnosis is available for inherited ichthyoses (see this term) but it is generally not proposed for SEI due to its mild course.\nGenetic counseling\nTransmission is autosomal dominant. Genetic counseling should be offered to affected families. The risk for an affected parent to have an affected child is 50%.\nManagement and treatment\nTreatment is symptomatic. Emollient and mild topical keratolytics may be used to reduce hyperkeratosis. Low dose of oral retinoids may also reduce hyperkeratosis, but must be used with caution because of their side effects and of their effect in the increase of skin fragility. Antibiotic therapy is required to treat secondary infection.\nPrognosis\nSEI is usually a mild disease. Life expectancy is normal and quality of life is not severely impaired.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER"}
{"Disease Name": "Superficial siderosis", "Disease Definition": "Superficial siderosis is a rare neurologic disease characterized by progressive sensorineural hearing loss, cerebellar ataxia, pyramidal signs, and neuroimaging findings revealing hemosiderin deposits in the spinal and cranial leptomeninges and subpial layer. The disease progresses slowly and patients may present with mild cognitive impairment, nystagmus, dysmetria, spasticity, dysdiadochokinesia, dysarthria, hyperreflexia, and Babinski signs. Additional features reported include dementia, urinary incontinence, anosmia, ageusia, and anisocoria.", "ORPHA ID": 247245, "Summary": ""}
{"Disease Name": "Superior limbic keratoconjunctivitis", "Disease Definition": "A rare disorder of the anterior segment of the eye characterized by unilateral or bilateral, chronic and recurrent inflammation affecting the upper tarsal and bulbar conjunctiva, as well as the superior limbus, manifesting as a papillary reaction on the upper tarsal conjunctiva, thickening and folding of redundant superior bulbar conjunctiva, and superficial punctate epithelial keratitis with or without filament formation near the superior corneal limbus. Middle-aged women are most commonly affected and present with foreign body sensation, frequent blinking, burning sensation, and pruritus, among others.", "ORPHA ID": 88633, "Summary": ""}
{"Disease Name": "Supernumerary breasts", "Disease Definition": "A rare breast malformation characterized by the presence of accessory breasts with a complete ductal system, areola, and nipple in addition to two normal breasts. The accessory breast tissue mostly lies along the milk lines. It is often not recognized until puberty, when it begins to respond to regular hormonal fluctuations, and may develop the same changes as normal breasts throughout life.", "ORPHA ID": 180182, "Summary": ""}
{"Disease Name": "Supernumerary nostril", "Disease Definition": "Supernumerary nostril is an extremely rare congenital malformation characterized by the presence of one or more accessory nostrils, with or without accessory cartilage, located medially, above, below or laterally to the other nostrils. Unlike in polyrhinia (see this term) there is no duplication of the nasal septum/cavity. Supernumerary nostril is often associated with other congenital malformations usually of face.", "ORPHA ID": 141096, "Summary": ""}
{"Disease Name": "Supratip dysplasia", "Disease Definition": "Supratip dysplasia is a rare, congenital, non-syndromic, nose and cavum malformation characterized by the presence of a bulbous, soft tissue hypertrophy located in the middle-to-distal third of the nasal dorsum, in association with deformed, slightly laterally- and caudally-placed nasal alae and a scar-like atrophic skin lesion located at the nasal tip. Respiratory function is not affected.", "ORPHA ID": 466695, "Summary": ""}
{"Disease Name": "Supravalvular aortic stenosis", "Disease Definition": "A rare aortic malformation characterized by the narrowing of the aorta lumen (close to its origin) associated or not with stenosis of other arteries (branch pulmonary arteries, coronary arteries). This narrowing of the aorta or pulmonary branches may impede blood flow, resulting in heart murmur and ventricular hypertrophy (left ventricle in case of aorta involvement, right ventricle in case of pulmonary artery involvement).", "ORPHA ID": 3193, "Summary": "Epidemiology\nThe incidence of supravalvular aortic stenosis (SVAS) is estimated at approximately 1 in 25 000 births and the mean prevalence in the general population at 1/7 500.\nClinical description\nClinical manifestations of SVAS include ejection systolic murmur and, in some cases, symptoms of chest pain or syncope. The electrocardiogram may indicate signs of a repolarisation disorder at rest and/or signs of ischemia after a stress test.\nEtiology\nThe narrowing results from a thickening of the artery wall, which is not related to atherosclerosis. SVAS is caused by a mutation in the elastin gene (ELN), which is located on chromosome 7q11.23. In nearly all cases, ELN mutations disrupt elastin protein synthesis, resulting in a production deficit.\nDiagnostic methods\nThe discovery of a systolic murmur may prompt a cardiological examination, potentially showing ventricular hypertrophy. Echocardiogram may indicate a progressive ''hourglass'' narrowing of the aorta and/or pulmonary artery lumen, specific to SVAS. Angiography by retrograde femoral arterial catheterization would allow a more precise diagnosis but it may be associated with risk if the stenosis is significant. Thus, in such cases scanning is preferred. CT scan can show the location and the severity of aorta narrowing.\nDifferential diagnosis\nSVAS can be part of the Williams-Beuren syndrome caused by microdeletion of the 7q11-q23 region, including the elastin and many contiguous genes. SVAS associated with Williams-Beuren syndrome is identical to isolated SVAS, however Williams-Beuren syndrome is also associated with a characteristic face, behavioral disorders and hypercalcemia.\nAntenatal diagnosis\nIn a family affected by SVAS, the progressive nature of the disease makes the identification of mutation carriers important for follow-up. Prenatal ultrasound examination can allow detection of the aortic or pulmonary supravalvular stenosis.\nGenetic counseling\nExcept for the cases with Williams-Beuren syndrome, the disease is either sporadic or familial. In familial cases it is transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity within members of the same family.\nManagement and treatment\nRegular follow-up is recommended (every 6 months for infants and each year in children) in order to monitor the evolution of the stenosis, which can be removed by surgery. Surgical repair is indicated only for significant stenosis.\nPrognosis\nThe prognosis of SVAS depends on the severity of the lesion and on potential associated anomalies located on the aortic valve or coronary arteries. Predictors of worse outcomes and frequent surgical intervention are the presence of diffuse lesions compared to discrete stenosis or presence of associated aortic valve disease.\n\n                            Last update: \n                            September 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Sylvie DI FILIPPO"}
{"Disease Name": "SURF1-related Charcot-Marie-Tooth disease type 4", "Disease Definition": "A subtype of Charcot-Marie-Tooth disease type 4 characterized by childhood onset of severe, progressive, demyelinating sensorimotor neuropathy manifesting with distal muscle weakness and atrophy of hands and feet, distal sensory impairment (vibration and pinprick) of lower limbs, lactic acidosis, areflexia and severely reduced motor nerve conduction velocities (25 m/s or less). Patients may also present kyphoscoliosis, nystagmus, hearing loss, cerebellar ataxia and/or brain MRI abnormalities (putaminal and periaqueductal lesions).", "ORPHA ID": 391351, "Summary": ""}
{"Disease Name": "Susac syndrome", "Disease Definition": "A rare systemic or rheumatologic disease characterized by the triad of central nervous system (CNS) dysfunction, branch retinal artery occlusions (BRAOs) and sensorineural hearing loss (SNHL) due to autoimmune-mediated occlusions of microvessels in the brain, retina, and inner ear.", "ORPHA ID": 838, "Summary": "Epidemiology\nSusac syndrome (SuS) prevalence is still unknown. To date more than 500 cases have been reported worldwide. Young females (20-40 years) are more affected (female: male ratio 3.5:1). The age at onset ranges from 8 to 72 years (mean age: 32 years).\nClinical description\nCharacteristic is a triad of encephalopathy (cognitive and behavioral disturbances, personality changes, psychosis, preceding headaches) and/or focal CNS dysfunction, visual dysfunction due to BRAO and SNHL. The components of the triad may not be concomitantly present and may develop successively. Three major disease courses have been suggested: monocyclic (fluctuating disease that self-limits after a maximum period of 2 years), polycyclic (relapses that continue beyond a 2 years period) and chronic-continuous.\nEtiology\nThe etiology and precise pathophysiology are not yet clear. According to recent data, clonally expanding autoreactive cytotoxic CD8+ T cells cause inflammation-mediated injury of the microvascular endothelium which leads to swelling of endothelial cells, vessel occlusion in the affected organ and finally micro-ischaemic damage and dysfunction.\nDiagnostic methods\nThe diagnosis is based on the demonstration of the typical triad. There is no singular ''marker'' of SuS. Beside the clinical examination, most relevant diagnostic tools are brain magnetic resonance imaging (MRI), retinal fluorescein angiography (FA), and audiometry. In the acute phase, T2 weighted brain MRI often shows blurry lesions in the central fibers of the corpus callosum (''snowball lesions'') which later convert into sharply defined ''punched out'' lesions. Periventricular lesions and involvement of cerebellum, brain stem and deep grey matter nuclei are also often present. FA demonstrates BRAO and fluorescein leakage, often in the retinal periphery (may then be clinically silent). Audiometry analysis reveals uni- or bilateral SNHL. Cerebrospinal fluid analysis often shows mild pleocytosis and moderate protein elevation, oligoclonal bands are uncommon. Anti endothelial cell antibodies have been reported in some cases. An early and reliable diagnosis is facilitated by application of the validated diagnostic criteria of the European Susac Consortium (EUSAC).\nDifferential diagnosis\nInflammatory demyelinating CNS disease (such as multiple sclerosis, acute disseminated encephalitis, neuromyelitis optica spectrum disorders), autoimmune encephalitis, and various other diseases involving CNS, retina, and inner ear (including infections, malignancies, psychotic disorders, cerebrovascular disease, migraine, Meniere disease, isolated BRAO) and a variety of autoimmune diseases such as Cogan syndrome, Eales disease, autoimmune inner-ear disease, polyarteritis nodosa, Wegener granulomatosis, Churg-Strauss syndrome, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren syndrome and Behçet disease.\nManagement and treatment\nNo evidence-based treatment strategies exist. Empirically, pulsed glucocorticosteroid treatment is effective in the acute phase. In severe cases treatment may be complemented by cyclophosphamide and/or intravenous immunoglobulins (ivIG), methotrexate (MTX), azathioprine (AZA) or mycophenolate mofetil (MMF). After stabilization glucocorticosteroids should be very slowly tapered. Long term immunosuppressive treatment by MTX, AZA, MMF, and/or ivIG is usually necessary. More recently, positive experiences have been reported with monoclonal antibodies such as rituximab, natalizumab, and infliximab. Patients with severe hearing loss may benefit from cochlear implants.\nPrognosis\nThe disease usually self-limits after 2-4 years, Late relapses after decades have been reported. The final outcome shows a large variability of disability ranging from unimpairment to dementia, deafness and blindness. The majority of patients retains variable degrees of cognitive, visual and/or hearing deficits.\n\n                            Last update: \n                            January 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Jan-Markus DÖRR"}
{"Disease Name": "Susceptibility to infection due to TYK2 deficiency", "Disease Definition": "A rare primary immunodeficiency characterized by increased susceptibility to intracellular bacterial and viral infection, with or without increased serum IgE. Clinical manifestations are highly variable, depending on the infection type and location, and can include recurrent otitis, sinusitis, pulmonary and cutaneous infections, meningitis and internal abscesses.", "ORPHA ID": 331226, "Summary": ""}
{"Disease Name": "Susceptibility to localized juvenile periodontitis", "Disease Definition": "A rare functional neutrophil defect characterized by increased susceptibility to aggressive periodontitis in otherwise young, healthy individuals, due to impaired polymorphonuclear leukocyte chemotaxis toward bacterial formylpeptides. The periodontitis is rapidly progressive with progredient destruction of periodontal tissue and attachment loss.", "ORPHA ID": 447740, "Summary": ""}
{"Disease Name": "Susceptibility to respiratory infections associated with CD8alpha chain mutation", "Disease Definition": "A rare primary immunodeficiency due to a defect in adaptive immunity characterized by the absence of CD8+ T cells with normal immunoglobulin and specific antibody titres in blood and susceptibility to recurrent respiratory bacterial and viral infections. Symptom severity range from fatal respiratory insufficiency to mild or asymptomatic phenotypes.", "ORPHA ID": 169085, "Summary": ""}
{"Disease Name": "Susceptibility to viral and mycobacterial infections due to STAT1 deficiency", "Disease Definition": "A rare, genetic, primary immunodeficiency due to a defect in innate immunity disorder characterized by impaired intracellular signaling from both type I and type II interferons, leading to early-onset, severe, life-threatening intracellular bacterial (typically mycobacteria) and viral (mainly herpes viruses) infections.", "ORPHA ID": 391311, "Summary": ""}
{"Disease Name": "Sweet syndrome", "Disease Definition": "A rare inflammatory disease characterized by abrupt appearance of painful, edematous and erythematous papules, plaques and nodules on the skin, and frequently accompanied by fever and neutrophilia with a dense infiltration of mature neutrophils that are typically located in the upper dermis. The disease is classically associated with inflammatory disease, pregnancy, infection (mostly of the upper respiratory tract), or vaccination but may be idiopathic, associated with a hematological or visceral malignancy, or drug-induced.", "ORPHA ID": 3243, "Summary": "Epidemiology\nSeveral hundred cases of Sweet syndrome have been published.\nClinical description\nClassical Sweet syndrome (CSS) usually presents in women between the age of 30 and 50 years. It is often preceded by an upper respiratory tract infection and may be associated with inflammatory bowel disease. It is characterized by the abrupt onset of painful erythematous plaques or nodules, but pustules and bullae are also described. Fever is observed in 30 to 80% of cases. Approximately one-third of patients with CSS experience recurrence of the dermatosis. Malignancy-associated Sweet syndrome (MASS) can occur as a paraneoplastic syndrome in patients with an established cancer or individuals whose Sweet syndrome-related hematologic dyscrasia or solid tumor was previously undiscovered; MASS is most commonly related to acute myelogenous leukemia. The dermatosis can precede, follow, or appear concurrently with the diagnosis of the patient's cancer. Hence, MASS can be the cutaneous harbinger of either an undiagnosed visceral malignancy in a previously cancer-free individual or an unsuspected cancer recurrence in an oncology patient. Drug-induced Sweet syndrome (DISS) most commonly occurs in patients who have been treated with granulocyte-colony stimulating factor, however, numerous medications have also be associated with DISS.\nEtiology\nThe pathogenesis may be multifactorial and still remains to be definitively established. Clinical and laboratory evidence suggests that altered expression of inflammatory effector molecules, abnormal neutrophil function and genetic predisposition have an etiologic role.\nDiagnostic methods\nSweet syndrome (SS) is a diagnosis of exclusion and is based on criteria (both of the major and 2 minor criteria are required for diagnosis). Major criteria include 1) abrupt onset of typical cutaneous lesions and 2) histopathology consistent with SS. Minor criteria include 1) lesions preceded by one of the associated infections or vaccinations; accompanied by one of the associated malignancies or inflammatory disorders; associated with drug exposure or pregnancy, 2) presence of fever and constitutional signs and symptoms, 3) leukocytosis, and 4) excellent response to systemic corticosteroids.\nDifferential diagnosis\nDifferential diagnosis includes infectious disorders, inflammatory disorders (e.g. arthropod bites, halogenoderma, other neutrophilic dermatoses, Wells syndrome), and neoplastic disorders (e.g. leukemia cutis, lymphoma cutis, metastatic carcinoma).\nManagement and treatment\nManagement of SS need to take into account any associated-diseases or medications. Systemic corticosteroids are the therapeutic gold standard. After initiation of treatment with systemic corticosteroids, there is a prompt response consisting of dramatic improvement of both the dermatosis-related symptoms and skin lesions. Topical application of high potency corticosteroids or intralesional corticosteroids may be used for treating localized lesions. Other first-line oral systemic agents are potassium iodide and colchicine. Second-line oral systemic agents include indomethacin and dapsone. TNF alpha inhibitors and the IL-1 receptor antagonist (anakinra) have been used in case reports.\nPrognosis\nThe symptoms and lesions may resolve spontaneously, without any therapeutic intervention; however, recurrence may follow either spontaneous remission or therapy-induced clinical resolution.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Emmanuel DELAPORTE"}
{"Disease Name": "Symbrachydactyly of hands and feet", "Disease Definition": "Symbrachydactyly of hands and feet is a rare, non-syndromic limb reduction defect disorder characterized by unilateral or bilateral brachydactyly, cutaneous syndactyly and global hypoplasia of the hand and/or foot, with underlying muscles, tendons, ligaments and bones being affected but without other associated limb anomalies. Patients typically present short, stiff, webbed or missing fingers and/or toes which are often replaced with small stumps (nubbins) with residual nails.", "ORPHA ID": 1570, "Summary": ""}
{"Disease Name": "Symmetrical thalamic calcifications", "Disease Definition": "Symmetrical thalamic calcifications are clinically distinguished by a low Apgar score, spasticity or marked hypotonia, weak or absent cry, poor feeding, and facial diplegia or weakness.", "ORPHA ID": 1314, "Summary": "Epidemiology\nIt is an extremely rare condition, with about 30 cases described in the literature.\nDiagnostic methods\nThe calcifications are revealed by computed tomography scanning.\nPrognosis\nThe prognosis is very poor.\n\n                            Last update: \n                            July 2006"}
{"Disease Name": "Sympathetic ophthalmia", "Disease Definition": "Sympathetic ophthalmia (SO) is a bilateral granulomatous anterior uveitis usually occurring within the three months following trauma or a surgical procedure involving one eye.", "ORPHA ID": 79098, "Summary": "Epidemiology\nSO is reported to affect between 1/1000 and 1/1650 individuals with a history of a penetrating eye wound.\nClinical description\nPatients present with pain, photophobia, paresis of accommodation, metamorphopsia and mild to significant visual loss. The granulomatous anterior uveitis is accompanied by posterior segment findings including moderate to severe vitritis, choroiditis, papillitis, perivasculitis, and yellow-white lesions of the retinal pigment epithelium (Dalen-Fuchs nodules). The inflammation can lead to serous retinal detachment and macular edema. Extraocular symptoms include headache, meningitis or cerebrospinal fluid pleocytosis, hearing loss, poliosis and vitiligo.\nEtiology\nThe etiology of SO is not completely understood. The inflammation is caused by a cell-mediated immune mechanism and autoimmune inflammatory response directed against ocular self-antigens released after the initial injury. The nature of these self-antigens remains controversial. Bacterial infection may potentiate the development of SO and genetic factors may also be implicated as associations with specific major histocompatibility antigens (HLA-DR4, HLA-A11 or HLA-B40) have been reported. SO may occur after ocular trauma (47 to 65 % of patients) or contusions. Wounds involving the ciliary body are associated with the highest risk. Surgical interventions may also trigger SO, with posterior segment surgery carrying a higher risk than anterior segment surgery.\nDiagnostic methods\nDiagnosis of SO is mainly based on patient history and clinical presentation. Imaging studies (fluorescein or indocyanine green angiography, B-scan ultrasonography and optical coherence tomography) may be useful to confirm the diagnosis.\nDifferential diagnosis\nLaboratory analysis can be performed to eliminate infectious uveitis. When a history of trauma has been confirmed, endophthalmitis and other forms of post-traumatic uveitis (lens-induced uveitis, post-traumatic iridocyclitis) should be included in the differential diagnosis. Other diseases associated with granulomatous uveitis, including sarcoidosis and Vogt-Koyanagi-Harada syndrome (see these terms) or uveal effusion syndrome, may also be considered in the absence of a recognized history of ocular trauma.\nManagement and treatment\nPrompt and careful closure of all wounds decreases the risk of SO. The primary treatment is high doses of steroids (for a minimum of 3 months), followed by a taper according to the inflammatory response and maintenance therapy for 6-12 months after resolution. Immunomodulators (cyclophosphamide, azathioprine or cyclosporine) may be considered when the inflammation cannot be controlled by steroids alone. Surgical treatment remains controversial and enucleation or evisceration should only be proposed in cases of blindness or pain in the inciting eye as the visual prognosis of the sympathizing eye is variable. Late enucleation has not been shown to be beneficial.\nPrognosis\nWithout treatment, the visual prognosis is poor with SO leading to bilateral blindness. However, prompt wound closure and efficient medical treatment improve the visual prognosis, which may then be relatively good. However, relapses and complications may occur and long-term follow-up is required.\n\n                            Last update: \n                            March 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Christophe ORSSAUD"}
{"Disease Name": "Symphalangism with multiple anomalies of hands and feet", "Disease Definition": "Symphalangism with multiple anomalies of hands and feet is a rare, genetic, congenital limb malformation disorder characterized by bilateral symphalangism of hands and feet associated with cutaneous syndactyly of digits II-V, unilateral or bilateral brachydactyly type D (i.e. short, broad terminal phalanges of the thumbs), clinodactyly of fifth toes and/or mild hypoplasia of the thenar and hypothenar eminences. There have been no further descriptions in the literature since 1981.", "ORPHA ID": 3246, "Summary": ""}
{"Disease Name": "Symptomatic form of Coffin-Lowry syndrome in female carriers", "Disease Definition": "A rare X-linked syndromic intellectual disability which in symptomatic, female carriers is characterized by a highly variable phenotype including facial dysmorphisms (prominent forehead, hypertelorism, down-slanting palpebral fissures, epicanthic folds, thick lips with everted lower vermilion, thick nasal alae, and septum), short hands with tapering fingers, short stature and skeletal findings (progressive kyphoscoliosis). Intellectual disability is mild to moderate, but intellect can also be normal. A high rate of psychiatric disorders has also been reported.", "ORPHA ID": 276630, "Summary": ""}
{"Disease Name": "Symptomatic form of fragile X syndrome in female carriers", "Disease Definition": "A rare genetic disease characterized by a variable clinical phenotype which includes similar features but is typically less severe than in affected males. Patients may present with mild to borderline intellectual disability, anxiety, social phobia, selective mutism, attention deficit hyperactivity disorder, language deficit, neurologic signs and symptoms (such as seizures, hypotonia, and clonus), ophthalmologic anomalies (strabismus, refractive errors), and facial dysmorphism (including long face, prominent forehead, large, prominent ears, and mandibular prognathism).", "ORPHA ID": 449291, "Summary": ""}
{"Disease Name": "Symptomatic form of HFE-related hemochromatosis", "Disease Definition": "A rare form of hemochromatosis characterized by inappropriately regulated intestinal iron absorption which leads to excessive iron storage in various organs and manifests with a wide range of signs and symptoms, including abdominal pain, weakness, lethargy, weight loss, elevated serum aminotransferase levels, increase in skin pigmentation, and/or arthropathy in the metacarpophalangeal joints. Other commonly associated manifestations include hepatomegaly, cirrhosis, liver fibrosis, hepatocellular carcinoma, restrictive cardiomyopathy and/or diabetes mellitus.", "ORPHA ID": 465508, "Summary": ""}
{"Disease Name": "Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers", "Disease Definition": "A rare, genetic muscular dystrophy affecting female carriers and characterized by variable degrees of muscle weakness due to progressive skeletal myopathy, sometimes associated with dilated cardiomyopathy or left ventricle dilation.", "ORPHA ID": 206546, "Summary": "Epidemiology\nThe prevalence is unknown. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) primarily affect males and only a small percentage of female carriers have been reported to manifest symptoms of these diseases (24% of female carriers from families with DMD and 19% of female carriers from families with BMD).\nClinical description\nSymptomatic female carriers usually present later than males with DMD or BMD. The muscle weakness is generally less severe than in affected males and is usually proximal and, unlike males, has an asymmetric distribution. The upper limbs may be weaker than the lower limbs. Myalgia and cramps have also been reported. The serum creatine kinase level is raised. Some patients may present with cardiac manifestations alone.\nEtiology\nDMD and BMD are both X-linked recessive diseases and are caused by dystrophin deficiency in skeletal and heart muscles due to variants in the DMD gene (Xp21.2). Females with clinical features of DMD and BMD are usually carriers of X-chromosome rearrangements and display skewed X-inactivation.\nDiagnostic methods\nDiagnosis can be confirmed by molecular testing of the DMD gene (Xp21.2-p21.1). Muscle biopsy shows a mosaic pattern of dystrophin expression.\nDifferential diagnosis\nDifferential diagnoses includes Turner syndrome.\nGenetic counseling\nThe pattern of inheritance is X-linked and genetic counseling should be offered to affected families. Female siblings of a proband with DMD or BMD have a 50% risk of being carriers. Female offspring of a female carrier have a 50% risk of becoming a carrier, male offspring have 50% of inheriting DMD or BMD depending on the mutation. In female carriers, the penetrance of symptoms is variable; most carriers are asymptomatic.\nManagement and treatment\nManagement of symptomatic patients should be multidisciplinary, severely affected patients may require treatment with corticosteroids as in DMD. Physiotherapy and orthotics should be used to prevent joint contractures. Respiratory function should be monitored regularly and nocturnal hypoventilation treated with BiPAP (bilevel positive airway pressure). There should be regular cardiac monitoring of all female carriers of BMD and DMD, symptomatic and asymptomatic, with early treatment using ACE inhibitors and or beta-blockers.\nPrognosis\nFemale carriers of DMD and BMD have been shown to be at increased risk of developing dilated cardiomyopathy, although the impact on survival is uncertain.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Shpresa PULA  - Pr Rosaline QUINLIVAN"}
{"Disease Name": "Syndactyly type 1", "Disease Definition": "A rare non-syndromic syndactyly characterized by complete or partial webbing between the 3rd and 4th fingers and/or the 2nd and 3rd toes. Other digits may be involved occasionally. The phenotype varies widely within and between families, sometimes only the hands are affected and sometimes only the feet. Webbing between fingers may be associated with bony fusion of the distal phalanges.", "ORPHA ID": 93402, "Summary": ""}
{"Disease Name": "Syndactyly type 2", "Disease Definition": "A rare non-syndromic syndactyly characterized by a distinctive combination of syndactyly and polydactyly, generally affecting the 3rd and 4th fingers and the 4th and 5th toes, bilaterally, with partial or complete reduplication of a digital ray within the syndactylous web. Additional features include 5th finger clinodactyly, camptodactyly and/or brachydactyly.", "ORPHA ID": 93403, "Summary": ""}
{"Disease Name": "Syndactyly type 3", "Disease Definition": "A rare non-syndromic syndactyly characterized by complete and bilateral syndactyly between the 4th and 5th fingers. In most cases, it is a soft tissue syndactyly, but occasionally the distal phalanges may be fused. The middle phalanx of the fifth finger is usually hypoplastic, and the feet are not affected.", "ORPHA ID": 93404, "Summary": ""}
{"Disease Name": "Syndactyly type 4", "Disease Definition": "A rare non-syndromic syndactyly characterized by complete bilateral cutaneous fusion of all fingers, frequently associated with polydactyly (usually involving six digits and six metacarpals). Phalanges may fuse as a conglomerate mass of bones. Feet are occasionally affected.", "ORPHA ID": 93405, "Summary": ""}
{"Disease Name": "Syndactyly type 5", "Disease Definition": "A rare non-syndromic syndactyly characterized by soft tissue syndactyly of the 3rd and 4th fingers and the 2nd and 3rd toes associated with metacarpal and metatarsal fusion of the 4th and 5th digits. Shortening of fused metacarpals, ulnar deviation of fingers, interdigital cleft, camptodactyly, short distal phalanges, and absent distal interphalangeal creases have also been reported.", "ORPHA ID": 93406, "Summary": ""}
{"Disease Name": "Syndactyly type 6", "Disease Definition": "A rare non-syndromic syndactyly characterized by unilateral fusion of 2nd to 5th fingers, amalgamation of distal phalanges in a knot-like structure, and fusion of the 2nd and 3rd toe. Some individuals present only with webbing between the 2nd and 3rd toes, without involvement of fingers.", "ORPHA ID": 295012, "Summary": ""}
{"Disease Name": "Syndactyly type 8", "Disease Definition": "A rare non-syndromic syndactyly characterized by unilateral or bilateral fusion of the 4th and 5th metacarpals with no other associated abnormalities. Patients present shortened 4th and 5th metacarpals with excessive separation between their distal ends, resulting in marked ulnar deviation of the little finger and an inability to bring the 5th finger in parallel with the other fingers.", "ORPHA ID": 2498, "Summary": ""}
{"Disease Name": "Syndactyly-camptodactyly and clinodactyly of fifth fingers-bifid toes syndrome", "Disease Definition": "A rare, genetic, congenital limb malformation syndrome characterized by a unique combination of bilateral, symmetrical camptodactyly and clinodactyly of 5th fingers, mesoaxial camptodactyly of toes, and ulnar deviation of 3rd fingers. Additional variable manifestations include bifid toes and severe syndactyly, or synpolydactyly, involving all digits of hands and feet.", "ORPHA ID": 357332, "Summary": ""}
{"Disease Name": "Syndactyly-nystagmus syndrome due to 2q31.1 microduplication", "Disease Definition": "A rare, genetic, chromosomal anomaly syndrome resulting from partial duplication of the long arm of chromosome 2 characterized by congenital pendular nystagmus associated with bilateral cutaneous syndactyly between the third and fourth fingers.", "ORPHA ID": 294026, "Summary": ""}
{"Disease Name": "Syndactyly-polydactyly-ear lobe syndrome", "Disease Definition": "A rare, genetic, congenital limb malformation syndrome characterized by complete cutaneous syndactyly between toes 1-2, ulnar polydactyly (ranging from nubbins to an almost complete additional finger) and earlobe malformations. Additionally, abnormalities along the medial border of the foot are observed on X-ray imaging. There have been no further descriptions in the literature since 1976.", "ORPHA ID": 3259, "Summary": ""}
{"Disease Name": "Syndactyly-telecanthus-anogenital and renal malformations syndrome", "Disease Definition": "A rare malformation syndrome characterized by the association of toe syndactyly, facial dysmorphism including telecanthus (abnormal distance between the eyes) and a broad nasal tip, urogenital malformations and anal atresia.", "ORPHA ID": 140952, "Summary": ""}
{"Disease Name": "Syndrome with alpha-thalassemia as a major feature", "Disease Definition": "This term refers to a group of diseases characterized by alpha-thalassemia and an associated disorder. Three conditions are included in this group: alpha thalassemia - X-linked intellectual deficit (or ATR-X syndrome), alpha-thalassemia-intellectual deficit syndrome (or ATR-16 syndrome) and alpha-thalassemia-myelodysplastic disease (or ATMDS).", "ORPHA ID": 232288, "Summary": ""}
{"Disease Name": "Syndromic congenital sodium diarrhea", "Disease Definition": "A rare, genetic, syndromic intestinal disorder, characterized by congenital onset of severe watery diarrhea containing high concentrations of sodium, hyponatremia and metabolic acidosis, and generally, uni- or bilateral choanal atresia, and corneal erosions. Additional congenital malformations may include intestinal atresia, and hexadactyly.", "ORPHA ID": 563708, "Summary": "Epidemiology\nWhilst the prevelence is unknown, less than 50 cases of both the syndromic and non-syndromic form have been reported in the literature.\nClinical description\nPresentation is typically prenatal with polyhydramnios, prominent abdominal distension due to dilated fluid-filled loops of the intestine. A watery diarrhea is present after birth, independent of oral feeding (breast or formula) or nil by mouth. There are increased bowel sounds at examination, and passing of meconium is never reported. The infants become irritable and eventually apathetic, and develop moderate to severe dehydration. Rarely, there is no watery diarrhea noticed either due to severe dehydration or intestinal paralysis. This pseudo-obstruction is caused by dilated fluid-filled loops of intestine, which may result in volvulus, and requires abdominal surgery. Laboratory findings include high stool sodium levels (importantly, this can be normal when the depletion of body sodium has progressed for some time) and low serum sodium levels, metabolic acidosis and alkaline fecal pH, and low urinary sodium excretion. Histological findings reveal characteristic epithelial tufts, small crowding of enterocytes, which are often hard to find. Generally, uni- or bilateral chonal atresia is observed at birth, and most often, episodes of corneal erosions are seen. Additional congenital malformations are observed in some patients, most often intestinal atresia, and hexadactyly. In the case of unrecognized bilateral choanal atresia, aspiration and breathing difficulties can occur postnatally, in addition to the congenital diarrhea; the congenital diarrhea can go unrecognized (as the diarrhea is mistaken for urine), and severe dehydration can occur within the first days of life.\nEtiology\nThe disorder is due to homozygous or compound-heterozygous mutations in serine peptidase inhibitor, Kunitz type 2 (SPINT2; encoded by SPINT2, 19q13.2), resulting in abrogated sodium absorption, enhanced fluid secretion and diarrhea.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation and exclusion of the differential diagnosis. Initial diagnosis might include determination of fecal sodium, chloride and potassium. Separate sampling of watery stool and urine should be performed. Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes the non-syndromic (classical) form of congenital sodium diarrhea (due to NHE3 or GUCY2C mutations) which is typically distinguished by the absence of congenital malformations or corneal erosions. Other differential diagnoses include anatomical bowel obstruction, congenital chloride diarrhea (distinguished by excessive fecal chloride), glucose-galactose malabsorption (which exhibits a diet-induced dehydrating diarrhea with later onset), microvillus inclusion disease and congenital tufting enteropathy (distinguished by histopathology).\nAntenatal diagnosis\nDiagnosis may be suspected on presentation of polyhydramnios in the third trimester. Early, targeted genetic prenatal testing is possible after identifying disease-causing variants in an index patient; however, general concerns to sampling fetal material and diagnosing genetic conditions late in pregnancy would apply.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive (AR) for SPINT2 mutations. The risk of disease transmission to offspring for AR disease is 25% where both parents are unaffected carriers.\nManagement and treatment\nAfter birth, total parenteral nutrition for treatment of dehydration for at least several months is required. Sodium supplementation should be provided for treatment of severe dehydration and to maintain normal body growth by preventing total body sodium depletion. In certain cases, patients may be weaned off total parenteral nutrition. For monitoring adequate sodium supplementation, the fractional excretion of sodium (FENa) should be calculated (normal range reportedly between 0.5%-1.5%). Choanal atresia and anal intestinal atresia require surgical treatment.\nPrognosis\nTotal parenteral nutrition carries the risk of bacteremia, and the risk of acute liver failure in very young children. Affected individuals may continue to have mild-to-moderate watery diarrhea but otherwise tend to lead a normal life. Reported complications include growth delay and hypoaldosteronism. Some patients episodically develop corneal erosions which are associated with pain and visual disturbances, and are treated with hydrating eye drops.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Andreas JANECKE"}
{"Disease Name": "Syndromic diarrhea", "Disease Definition": "A rare gastroenterologic disease manifesting as intractable diarrhea in the first month of life with failure to thrive and associated with facial dysmorphism, hair abnormalities, and, in some cases, immune disorders and intrauterine growth restriction.", "ORPHA ID": 84064, "Summary": "Epidemiology\nSyndromic diarrhea (SD/THE) prevalence is <1/1,000,000. More than 100 cases have been reported worldwide.\nClinical description\nSevere, persistent and intractable diarrhea most often starts within the first month after birth (at latest 6 months) and is accompanied by severe malabsorption resulting in early and relentless protein-energy malnutrition and failure to thrive. SD children in most reported cases (>70%) were below the 10th percentile of birth weight and nearly half were born preterm suffering from intrauterine growth restriction. Patients present with facial dysmorphism including prominent forehead and cheeks, broad nasal root and hypertelorism. Hair is woolly, easily removable and in some cases sparse and poorly pigmented; further analysis reveals trichorrhexis nodosa, pili torti, trichothiodystrophy and aniso- and poikilotrichosis. Liver disease, with extensive fibrosis or cirrhosis and siderosis, affects about half of the patients, and hepatomegaly may be observed. Patients are prone to frequent infections and may fail to produce antibodies upon vaccination or present low immunoglobulin levels. Skin abnormalities including café au lait spots, xerosis and rubbery skin are seen in half of the reported cases and are more prevalent with time. Cardiac abnormalities have been reported in a few cases and mild intellectual deficiency in half of patients.\nEtiology\nAutosomal recessive mutations in SKIV2L (40% of cases) and TTC37 (60% of cases) lead to SD/THE. These genes encode proteins that form the Ski complex, a group of proteins responsible for the 3'-5' degradation of aberrant mRNA. Many different mutations have been identified and are spread along the genes. How Ski complex defects lead to the observed phenotype has yet to be elucidated and no genotype/phenotype correlation has been established to date.\nDiagnostic methods\nDiagnosis is suggested by clinical features. Small intestine biopsy shows non-specific villous atrophy with variable mononuclear cell infiltration of the lamina propria, but no specific histological abnormalities involving the epithelium. Genetic testing confirms these observations.\nDifferential diagnosis\nDifferential diagnoses include all causes of chronic diarrhea, copper and iron deficiencies due to malnutrition, intestinal epithelial dysplasia, and microvillus inclusion disease.\nAntenatal diagnosis\nAntenatal diagnosis should be offered to the parents of an affected child once the molecular defect has been characterized.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nIntractable diarrhea requires parenteral nutrition during a variable period of time ranging from a few months to over a decade. In some cases, the association of enteral with parenteral nutrition can be indicated. Immunoglobulin supplementation may be necessary and antibody production after vaccination should be monitored. Finally, some children can present with a severe liver disease, independent of parenteral nutrition, but which could be worsened by it. In cases of severe liver disease, the only therapeutic option is a liver graft.\nPrognosis\nPrognosis is poor with a mortality rate of up to 50%. The main complications are severe liver disease and infections. Some patients are rapidly weaned off parenteral nutrition but others remain under parenteral dependence for more than 10 years. Most of the children achieve a small final stature and half manifest mild intellectual deficit.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Catherine BADENS  - Dr Alexandre FABRE"}
{"Disease Name": "Syndromic microphthalmia type 5", "Disease Definition": "Syndromic microphthalmia, type 5 is characterized by the association of a range of ocular anomalies (anophthalmia, microphthalmia and retinal abnormalities) with variable developmental delay and central nervous system malformations.", "ORPHA ID": 178364, "Summary": "Epidemiology\nLess than 20 cases have been reported in the literature so far.\nClinical description\nThe clinical picture is highly variable, even between affected members of the same family. Ocular findings ranged from bilateral anophthalmia, to severe or mild bi- or unilateral microphthalmia and retinal dystrophy. MRI may reveal optic nerve aplasia/hypoplasia, hippocampal malformations, structural abnormalities of the pituitary gland, and agenesis of the corpus callosum. Severe developmental delay was noted in some patients, whilst others showed normal cognitive development. Pituitary dysfunction, leading to growth hormone deficiency and short stature, or combined pituitary hormone deficiency (CPHD), has also been reported.\nEtiology\nThe syndrome is caused by heterozygous mutations in the OTX2 gene (14q22.3).\nDifferential diagnosis\nA similar phenotype with bilateral anophthalmia and pituitary abnormalities (with additional findings of limb defects, ear anomalies and facial dysmorphism) is found in patients carrying a deletion encompassing the OTX2 gene. Patients with the full clinical spectrum of ocular anomalies, central nervous system abnormalities and pituitary abnormalities also show significant overlap with septooptic dysplasia (see this term).\n\n                            Last update: \n                            February 2010"}
{"Disease Name": "Syndromic multisystem autoimmune disease due to Itch deficiency", "Disease Definition": "A rare, genetic, systemic autoimmune disease characterized by failure to thrive, global developmental delay, distinctive craniofacial dysmorphism (relative macrocephaly, dolichocephaly, frontal bossing, orbital proptosis, flattened midface with a prominent occiput, low, posteriorly rotated ears, micrognatia), hepato- and/or splenomegaly, and multisystemic autoimmune disease involving the lungs, liver, gut and/or thyroid gland.", "ORPHA ID": 228426, "Summary": ""}
{"Disease Name": "Syndromic orbital border hypoplasia", "Disease Definition": "Syndromic orbital border hypoplasia is a rare disorder observed in two families to date and characterized by agenesis of the orbital margin, varying defects of the lacrimal passages, hypoplasia of the palpebral skin and tarsal plates and atresia of the nasolacrimal duct.", "ORPHA ID": 98606, "Summary": ""}
{"Disease Name": "Syndromic recessive X-linked ichthyosis", "Disease Definition": "A rare genetic skin disease belonging to the Mendelian Disorders of Cornification (MeDOC) characterized by a generally mild cutaneous desquamation in association with extracutaneous manifestations as part of a syndrome.", "ORPHA ID": 281090, "Summary": "Epidemiology\nThe prevalence of syndromic RXLI is estimated at 1/50,000-1/150,000. It affects almost exclusively males.\nClinical description\nCutaneous manifestations include generalized scaling of the skin commonly more pronounced on the extensor surfaces of the limbs (mostly lower extremities). Non-cutaneous manifestations may include cryptorchidism, attention-deficit and hyperactivity disorder (ADHD), and corneal opacity. Manifestations due to contiguous gene syndrome include neurological abnormalities such as epilepsy and hyposmia, intellectual disability and/or short stature. This mechanism can be observed in Kallmann syndrome, hypergonadotropic hypogonadism, ocular albinism type 1, or hypertrophic pyloric stenosis.\nEtiology\nRLXI is due to deletions in the steroid sulfatase STS gene located on chromosome Xp22.3. STS codes for a lipid hydrolase that participates in the regulation of permeability, barrier homeostasis and desquamation. STS mutations result in abnormal desquamation, decreased corneodesmosomal degradation and retention hyperkeratosis.\nDiagnostic methods\nDiagnosis is based on clinical findings and family history (scaling in male relatives, history of delayed birth). It is confirmed by biochemical analysis such as serum protein electrophoresis, and STS activity test of fibroblasts or leukocytes, and molecular/cytogenetic analyses such as polymerase chain reaction (PCR), multiple ligation-dependent probe amplification (MLPA), comparative genomic hybridization/comparative microarray analysis (CMA), and fluorescent in situ hybridization (FISH). Histology and ultrastructure of the skin is helpful for the differentiation of ichthyosis vulgaris.\nDifferential diagnosis\nDifferential diagnosis includes non-syndromic RXLI, ichthyosis vulgaris, autosomal recessive congenital ichthyosis (ARCI), namely lamellar ichthyosis, or multiple sulfatase deficiency.\nAntenatal diagnosis\nMaternal urine and serum steroid measurements may show decreased estrogen levels. Therefore, RXLI may be detected in utero when maternal estriol levels are measured during prenatal screening. Genetic analysis can be performed for families with an identified causing mutation.\nGenetic counseling\nXLRI has an X-linked recessive mode of inheritance: it affects males and is inherited through female carriers. Female patients have rarely been reported.\nManagement and treatment\nCutaneous therapy consists in hydrating and softening the skin with the use of lubricating bath oils and emollients containing humectants and keratolytics (e.g. urea, lactic acid, and glycolic acid). For adult patients, systemic retinoids are an option, e.g. during winter, when the ichthyosis is generally more severe. Additional supportive treatments should be proposed depending on systemic findings.\nPrognosis\nRXLI represents a complex form of ichthyosis whose prognosis depends on the systemic involvement (central nervous system and cognitive impairment are variable). Scaling may improve with age.\n\n                            Last update: \n                            December 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Ángela HERNÁNDEZ MARTÍN"}
{"Disease Name": "Syndromic sensorineural deafness due to combined oxidative phosphorylation defect", "Disease Definition": "A rare mitochondrial disease characterized by a variable phenotype comprising congenital sensorineural deafness, intermittent or persistent hypoglycemia, and hepatic and renal dysfunction potentially progressing to organ failure. Serum lactate levels are variably increased, deficiency of mitochondrial respiratory chain complexes I, III, and IV is observed in the liver and in fibroblasts.", "ORPHA ID": 457223, "Summary": ""}
{"Disease Name": "Syndromic X-linked intellectual disability 7", "Disease Definition": "A rare, X-linked syndromic intellectual disability disorder characterized by mild to moderate intellectual disability, obesity, hypogonadism, tapering fingers and microphallus with small or undescended testes, localized to Xp11.3-Xq23. Additional variable manifestations include alopecia, dental and eyesight anomalies, speech disabilities, and decreased body strength.", "ORPHA ID": 85274, "Summary": ""}
{"Disease Name": "SYNGAP1-related developmental and epileptic encephalopathy", "Disease Definition": "A rare genetic developmental and epileptic encephalopathy (DEE) characterized by developmental delay, generalized epilepsy consisting of eyelid myoclonia with absences and myoclonic-atonic seizures, intellectual disability and autism spectrum disorder (ASD).", "ORPHA ID": 544254, "Summary": "Epidemiology\nThis disorder has an estimated prevalence of <1/1 000 000.\nClinical description\nPresentation is of developmental delay, identified in the first months of life, associated with hypotonia and subsequent neurodevelopmental plateauing or regression. Generalized epilepsy is present in most with seizure onset typically at 2-3 years (ranges from 4 months to 7 years) with a distinctive epilepsy syndrome, combining eyelid myoclonia with absences and myoclonic-atonic seizures. Drop attacks due to eyelid myoclonia evolving to myoclonic-atonic or atonic seizure can be present. Other generalized seizure types, variably combined, and reflex seizures triggered by eating or eyes closure may occur. The spectrum of seizure severity varies, with drug-resistant seizures in about half of patients. Moderate to severe intellectual disability becomes progressively evident in most, associated with ASD in about half of the patients. Behavioral disorders, including oppositional and defiant behavior with aggression, self-injury, and temper tantrums, are seen in most. Subtle dysmorphic facial features may be present in some, including slightly prominent eyebrows with medial flaring, hypertelorism, full nasal tip, slightly upturned nasal tip, short philtrum, cupid bow upper lip, broad mouth with diastemata of the upper teeth, and small pointed chin. Other associated features comprise high pain threshold, eating and sleeping problems, ataxia or gait abnormalities, and orthopedic abnormalities. Brain imaging is usually normal with possible nonspecific findings.\nEtiology\nThe SYNGAP1 gene (6p21.32) encodes the synaptic Ras-GTPase-activating protein 1, mainly expressed in the synapses of excitatory neurons. Loss of function mutations in SYNGAP1 impairs neuronal homeostasis and development. This disorder is caused by heterozygous pathogenc SYNGAP1 variants or chromosome 6p21.32 microdeletions encompassing the SYNGAP1 gene.\nDiagnostic methods\nThe diagnosis is suspected in a patient with developmental delay or intellectual disability, ASD and generalized epilepsy with generalized epileptiform abnormalities on EEG. The genetic identification of pathogenic SYNGAP1 variants (next generation sequencing) or chromosome 6p21.32 microdeletions (aCGH ) confirms the diagnosis.\nDifferential diagnosis\nThe phenotype of SYNPAG1-related encephalopathy might overlap with that of other neurodevelopmental disorders and DEEs. Seizures semiology, trigger factors and EEG patterns can help to differentiate this syndrome and orient the genetic testing.\nAntenatal diagnosis\nOnce a pathogenic SYNGAP1 variant has been identified, prenatal testing is possible for a pregnancy at increased risk.\nGenetic counseling\nThe pattern of inheritance is autosomal dominant. Whilst pathogenic variants occur de novo in almost all cases, parental mosaicism is possible. In such cases, genetic counseling is recommended as the risk of recurrence in affected families is higher than the general population.\nManagement and treatment\nManagement requires a multidisciplinary approach and tailored treatments addressing the specific symptoms. Anti-seizure medications and ketogenic diet are used for the management of seizures. Non-pharmacological interventions comprise physical, occupational, speech, and feeding therapy, as well as individualized educational plans.\nPrognosis\nLife expectancy is unknown due to under diagnosis in adult age. However, adult patients are known, demonstrating that survival into adulthood is possible. Prognosis is poor, resulting in severe cognitive deficits in most, associated with behavioral disorders of variable degree, and persisting seizures in half of the cases.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Sara MATRICARDI  - Pr Rima NABBOUT | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Synovial sarcoma", "Disease Definition": "Synovial sarcoma is an aggressive soft tissue sarcoma (see this term), occurring most commonly in adolescents and young adults (15 to 40 years), usually localized near the large joints of the extremities but also in the head and neck, mediastinum and viscera (lung, kidney etc), clinically presenting as a deep seated swelling or a painful mass often with an initial indolent course and is characterized by its local invasiveness and a propensity to metastasize. The origin of synovial sarcoma is likely from multipotent mesenchymal cells and not synovium (contrary to its name).", "ORPHA ID": 3273, "Summary": ""}
{"Disease Name": "Syringocystadenoma papilliferum", "Disease Definition": "A rare non-malignant adnexal neoplasm that originates from the apocrine or eccrine sweat glands and is characterized histologically by cystic, papillary, and ductal invaginations into the dermis lined by double-layered outer cuboidal and luminal high columnar epithelium and connected to the epidermis. Dilated capillaries and a dense infiltrate of plasma cells are characteristic. Clinically, lesions are asymptomatic with a heterogeneous, non-distinctive appearance ranging from skin-colored to pink papules or plaques, occurring most commonly in the head and neck area.", "ORPHA ID": 840, "Summary": "Epidemiology\nTo date, approximately 730 cases have been reported in the literature. The condition has been reported worldwide.\nClinical description\nSyringocystadenoma papilliferum (SCAP) may be present at birth (50% of cases) or develop around puberty (15-30% of cases). SCAP typically presents as slow developing, non-specific, smooth, skin-colored to pink papule, verruca or nodule, which may be exudative. It may also be seen as hairless plaques, smooth or raised, usually less than 4 cm in diameter, skin-colored to brown. It is rarely pigmented. In the majority of cases, it is asymptomatic, but it may grow progressively and has been occasionally associated with pruritus, pain, and/or bleeding. Three clinical types have been described: the plaque type, the linear type and the solitary nodular type. The plaque type usually presents as an alopecia plaque on the scalp which may increase in size at puberty and often transforms to nodular or verrucous lesions. The linear type consists of multiple pink to reddish, firm papules or umbilicated nodules, 1-10 mm in diameter, and is extremely rare. The solitary type includes dome-shaped, pedunculated nodules, 5-10 mm in diameter, with a predilection for the trunk, shoulder and axillae. Rarely, segmental variants are found. In 75% of cases, SCAP is located on the head or cervical region and less frequent in other regions, or on a postoperative scar. SCAP develops in existing nevus sebaceous in about one-third of cases, 10% of which are associated with he development of basal cell carcinoma and more rarely other carcinomas. SCAP can also be associated with other benign lesions. Transition to malignancy is rare but, possible. Syringocystadenocarcinoma papilliferum is the malignant counterpart to this lesion and may develop in a long-standing case of SCAP.\nEtiology\nThe etiology of SCAP has not been elucidated. It seems to arise from the pluripotent cells with the potential to exhibit either apocrine or eccrine lineage, although apocrine differentiation is more common. The pathogenesis of SCAP remains unclear although, both in sporadic cases and lesions arising in nevus sebaceous, the human papillomavirus (HPV) DNA and mutations in the RAS/mitogen-activated protein kinase signaling pathway have been detected. BRAF V600E mutation or activating mutations in HRAS (or in one case KRAS) have been reported in sporadic forms.\nDiagnostic methods\nDiagnosis is suspected on clinical presentation of non-distinctive lesions and confirmed on biopsy showing the characteristic histology. Immunohistochemically, the tumor cells stains positively for carcinoembryonic antigen. Dermatoscopy is not diagnostic.\nDifferential diagnosis\nThe differential diagnosis is broad, requiring histological confirmation of cases. The main diagnostic issue is the distinction of SCAP from hidradenoma papilliferum. Other conditions to be considered include basal cell carcinoma, cutaneous lymphoma, factitious dermatitis, viral warts, subcutaneous fungal infection, linear verrucous nevus, pyogenic granuloma, warty dyskeratoma, inverted follicular keratosis, as well as eccrine nevus, nevus comedonicus, cylindroma, and basaloid follicular hamartoma.\nManagement and treatment\nTreatment involves complete surgical excision. However, recurrence is common. Carbon dioxide laser treatment can be useful for lesions in anatomic areas not favorable for excision and grafting. SCAP has also been successfully treated with Mohs micrograhic surgery.\nPrognosis\nThe condition is mostly benign but extensive lesions may have an impact on quality of life and transformation to malignancy cannot be ruled out.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Alexander KATOULIS  - Pr Efstathios RALLIS"}
{"Disease Name": "Syringomyelia", "Disease Definition": "A rare medullar disease characterized by cerebrospinal fluid (CSF)-filled cavities (syrinx) inside the spinal cord as a result of an obstruction to CSF flow, either at the craniovertebral junction (Chiari malformation) or in the perimedullary subarachnoid spaces (arachnoiditis).", "ORPHA ID": 3280, "Summary": "Epidemiology\nEstimated prevalence is 8.4/100,000. Cases of autosomal recessive familial syringomyelia have been reported with an estimated incidence of 2% of all syringomyelia cases.\nClinical description\nAlthough syringomyelia can lead to disruption of neural connections in the spinal cord and to neurological damage, 50% of patients (when all types of syrinxes are considered) will experience no or only mild disability. In symptomatic patients, onset is usually marked by pain and sensory disturbances, varying from complete absence of sensation, pins and needles or temperature sensing alterations, to increased sensation to stimuli. Although there are no clear clinical clues at neurological examination, a 'cape-like' sensory dissociation (loss of the ability to distinguish between hot and cold with intact light-touch sensation in the upper limbs and torso), as well as reduced upper limb reflexes, are quite specific initial findings when present. Motor symptoms usually range from varying degrees of weakness to spasticity and loss of autonomy. Alterations in bladder and sexual function may also be present.\nEtiology\nSyringomyelia is due to obstruction of CSF flow either at the craniovertebral junction (e.g. Chiari malformation) or in the perimedullary subarachnoid spaces (e.g. arachnoiditis). Chiari malformations can be associated with other craniovertebral junction malformations (e.g. basilar invagination) or neural tube defects (Chiari II malformation). Spinal arachnoiditis can be either idiopathic or secondary (postinfectious, posttraumatic, posthemorrhagic, postoperative).\nDiagnostic methods\nNeurological examination and MRI are required for diagnosis. MRI is the gold standard and reveals a fluid filled cavity with variable degrees of vertical and horizontal extension within the spinal cord ranging from involvement of one level up to extension over the entire spinal cord. The signal characteristics on MRI are usually quite similar to those of CSF.\nDifferential diagnosis\nThe differential diagnosis includes persistent or dilated central canal (hydromyelia, slits), myelomalacia, tumoral cysts, myelitis, amyotrophic lateral sclerosis and multiple sclerosis.\nManagement and treatment\nManagement consists of long-term follow up and surgery in cases of progressive neurological deterioration. The goal of surgery is to restore CSF flow either at the craniovertebral junction in case of Chiari malformation (foramen magnum decompression) or in the perimedullary subarachnoid spaces in case of arachnoiditis (arachnoidolysis). If not possible, or in case of failure, a shunting procedure can be performed to drain the syrinx, either to the peritoneal space (syringoperitoneal shunt) or pleural space (syringopleural shunt).\nPrognosis\nAround 50% of Chiari malformation type I patients with syringomyelia remain neurologically stable. In cases with progressive deterioration, surgical intervention usually prevents clinical progression. In cases of posttraumatic syringomyelia due to spinal cord compression, reconstruction of the spinal canal appears to yield similar results. Prognosis is worse for cases in which the only surgical option is direct shunting of the syrinx, as this often leads to neurological deficit and recurrence. Persistent or dilated central canal, which is not a syringomyelia, has a benign natural history with usually no progression neither clinically nor radiologically.\n\n                            Last update: \n                            December 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Steven KNAFO  - Dr Silvia MORAR"}
{"Disease Name": "Systemic capillary leak syndrome", "Disease Definition": "Systemic capillary leak syndrome (SCLS) is a severe systemic disease due to increased capillary permeability, characterized by episodes of hypotension, edema and hypovolemia.", "ORPHA ID": 188, "Summary": "Epidemiology\nSCLS has been reported in less than 150 cases since its first description in 1960.\nClinical description\nMean age of onset is 45 and pediatric or geriatric cases are rare. The disease is characterized by alternance of crises and quiescent phases. Delay between crises is a few weeks to several years. They have been reported following infection, mostly of the upper airways, during perimenstrual or post-partum periods and, more rarely, after intense physical effort. They last days or weeks, can be of variable severity, from grade 1 (hypotension responding to oral hydration) to grade 4 (fatal attacks), and have a 3-step evolution. Crises may start with prodromes such as generalized weakness, fatigue, myalgias, orthostatic hypotension, possible digestive (diarrea, abdominal pain) and ENT (rhinorrhea, cough) manifestations, occasional fever and weight gain. The leak phase follows with oliguria, arterial hypotension and rapid development of edema of the face or the upper limbs but sparing the lungs. Hypotension may lead to hypovolemic shock with preserved consciousness. In the post-leak phase, massive edema resorption leads to polyuria and weight loss. Biological features are a characteristic association of hemoconcentration with hypoalbuminemia without albuminuria, hyperleukocytosis and a proteinemia drop in the 350-750 kDa range. Chronic cases have been reported with a continuous generalized edema, visceral effusions, hypotension and hemoconcentration being more subtle. Complications may occur in acute and post-leak phases: in the former, they include compartment syndrome with rhabdomyolysis, cardiac arrythmias, thrombosis, pancreatitis, pericarditis (see this term), seizures, cerebral edema or thickening of the myocardium. Rhabdomyolysis and fatal pericarditis may also occur in the post-leak phase, but cardiovascular overload is more frequent. Fatal acute lung edema has also been reported at this stage. Renal failure may result from hypoperfusion-induced acute tubular necrosis and rhabdomyolysis.\nEtiology\nSCLS is caused by capillary hyperpermeability of unknown etiology. Several physiopathological hypotheses have been considered such as an inflammation-mediated mechanism or a damage of the capillary endothelium by the monoclonal gammopathy.\nDiagnostic methods\nDiagnosis is based on physical and biological examination, recurrence of crises, association of hemoconcentration with hypoalbuminemia being strong indicators. The presence of an anomalous monoclonal immunoglobulin termed paraprotein is suggestive but not diagnostic.\nDifferential diagnosis\nDifferential diagnosis includes sepsis, anaphylaxis, any other cause of capillary leakage and inferior vena cavainterruption (see this term). Chronic cases might be misdiagnosed as Gleich syndrome, venous stasis, protein-losing enteropathy and nephrotic syndrome.\nManagement and treatment\nThere is no curative treatment, thus management is symptomatic and prophylactic. Intravenous fluids administration is not recommended as it fails to increase arterial pressure and worsens edema, furthermore it increases the risk of vascular overload in the post-leak phase. Oral electrolyte-containing fluids can reduce the attack severity if taken early, thus patient education to detect early signs of prodrome is crucial. Beta-adrenergic agonists (terbutaline) and phosphodiesterase inhibitors (theophylline) have shown good results in few cases but have serious side effects; intra-venous immunoglobulines are a promising prophylactic strategy.\nPrognosis\nDespite progress in diagnosis and management that has prolonged the survival of patients, prognosis remains poor as mortality reaches 30-40% after 10 years.\n\n                            Last update: \n                            November 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Zahir AMOURA"}
{"Disease Name": "Systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood", "Disease Definition": "A rare and very aggressive neoplastic disease emerging after a primary acute or chronic active EBV infection. It presents with persisting fever and malaise, hepatosplenomegaly with or without lymphadenopathy, liver failure, severe pancytopenia and a rapid progression towards multi-organ failure and hemophagocytic syndrome with a fatal issue. It is characterized by clonal proliferation of EBV-infected T cells with an activated cytotoxic phenotype.", "ORPHA ID": 364033, "Summary": ""}
{"Disease Name": "Systemic mastocytosis with associated hematologic neoplasm", "Disease Definition": "An advanced form of systemic mastocytosis (SM) characterized by the abnormal accumulation of neoplastic mast cells (MCs) in one or more extracutaneous organs, mainly the bone marrow, associated with another hematologic neoplasm of non MC nature.", "ORPHA ID": 98849, "Summary": "Epidemiology\nSystemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is suggested to represent between 10-40% of all cases of SM, for which the prevalence in Europe is estimated between 1/7,700 and 1/10,400.\nClinical description\nThe disease typically affects adults and the elderly. Although the SM compartment is predominantly of the indolent type (ISM), in rare cases it is aggressive SM (ASM) or mast cell leukemia (MCL). The associated hematologic neoplasms (AHN) most commonly encountered are myeloid neoplasms and are rarely lymphoid neoplasms.When the SM compartment is indolent, the biological and clinical signs, and the prognosis, are dominated by the AHN. In contrast, when the SM compartment is an ASM or MCL, it is difficult to quantify the relative contribution of mastocytosis to typical B- (reflecting a high mast cell burden) and C- (reflecting organ(s) dysfunction(s)) findings. Of note, the SM compartment is often involved in MC mediator-related symptoms such as recurrent syncope, headache, flushing, gastro-intestinal tract symptoms and, in severe cases, life-threatening anaphylactic shock. Skin involvement, mainly with urticaria pigmentosa (UP) is frequently observed.\nEtiology\nIn the vast majority of cases, an acquired and activating mutation in KIT, mostly KITD816V, can be found in the abnormal MCs of the SM compartment as well as in the malignant cells of certain AHN types. However, SM-AHN is often a complex, multi-mutated disease; reported mutations for SM-CMML or SM-MDS include, TET2, ASXL1, and SRSF2 among others.\nDiagnostic methods\nIt is critical to determine the type of the two malignancies (SM and AHN). Diagnosis of the SM compartment is with the WHO consensus criteria. The SM is then categorized as ISM, ASM or MCL, although this may be difficult. Further testing (phenotyping, cytogenetics, molecular biology) are mandatory to characterize the nature of the AHN.\nDifferential diagnosis\nIn the case where the AHN component is of myeloid nature, the two major differential diagnoses are myelomastocytic leukemias and myeloid neoplasms with expression of mast cell lineage antigens or related gene defects. Waldenström macroglobulinemia may be considered in certain circumstances. These diseases do not fulfill the SM criteria.\nGenetic counseling\nThe disease is due to somatic mutations, genetic counseling is not required.\nManagement and treatment\nEach component is treated as per the guidelines for SM and AHN, irrespective of the presence of the other component. Since it is difficult to clearly delineate which component is responsible for the clinical issues/organ damage, all patients with SM-AHN should be treated as having high-risk disease. Midostaurin is approved for treatment in Europe and the USA, and whilst it is promising with partial remission of the SM-compartment, complete remission has not been reported. Patients who achieve a complete remission of their AHN, or exhibit a significant response after treatment, should be considered for allogeneic stem cell transplantation (allo-SCT) to consolidate their response. However, use of allo-SCT is often limited by age, poor performance, or other factors. For these patients, palliative therapy with hydroxyurea is required. MC mediator-related symptoms often requires supportive therapy, including H1 and H2-receptor antagonists.\nPrognosis\nCurrently the overall median survival of 24 months is reported. However, the prognosis of SM-AHN depends both on the nature (aggressiveness) of the SM and the AHN component, with longer median survival reported in SM-MPN patients (31 months) and shorter survival in SM‐CMML (15 months), SM‐MDS (13 months), and SM‐AML (11 months). In addition, multi-mutated disease can negatively impact disease prognosis.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Michel AROCK"}
{"Disease Name": "Systemic mastocytosis", "Disease Definition": "A heterogeneous group of rare, acquired and chronic hematological malignancies related to an abnormal accumulation/proliferation of neoplastic mast cells (MCs) in one or several organs, mainly the bone marrow (BM), associated frequently with skin involvement.", "ORPHA ID": 2467, "Summary": "Epidemiology\nThe prevalence in Europe is estimated between 1/7,700 and 1/10,400. Systemic mastocytosis (SM) preferentially affects Caucasians and there is no sex predominance.\nClinical description\nSM is mainly observed in adults (average age at diagnosis is 60 years) and is very rare in the pediatric population. SM can be divided into five variants: indolent SM (ISM), smoldering systemic mastocytosis (SSM), aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL), the later 3 variants being collectively termed advanced SM (advSM). In ISM, there are no signs of high mast cell burden (B-findings) and no organ dysfunction (C-findings). SSM is a slowly progressive SM with B-findings. By contrast, advSM variants are characterized by (multiple) C-findings.\nEtiology\nMost patients with SM present activating mutations in KIT, the receptor of the stem cell factor, in their neoplastic MCs. Of note, a recurrent KIT mutation (D816V; exon 17 of the KIT gene) located in the phosphotransferase domain of the receptor is detectable in most patients (> 80% of all SM patients), including those with advSM. Other less frequent mutations affect exons 2, 8, and 9 encoding for the extracellular domain or exons 13 and 14 encoding for Kinase Domain 1 of KIT. Whatsoever, the various KIT mutations encountered in SM result in uncontrolled activation of the receptor, making the migration, survival and activation of MCs independent of stem cell factor.\nDiagnostic methods\nConsensus criteria for the diagnosis of systemic mastocytosis established by the WHO include one major criterion - the presence of aggregates of at least 15 MCs identified in BM or other extracutaneous organ biopsies (usually revealed after tryptase staining of biopsies) - and four minor criteria: the presence of more than 25% of MCs with atypical morphology in BM smears (spindle-shaped, degranulated and/or multinucleated MCs); aberrant immunophenotype of MCs which frequently abnormally express non-mast cell markers (CD25 and/or CD2); presence of a point mutation in codon 816 of the KIT gene in BM; peripheral blood or other extracutaneous organs; and increased level of serum tryptase (above 20 ng/mL). For diagnosis of SM, at least the major and one minor criterion or at least three minor criteria are fulfilled. The disease is then categorized, as described above, according to the presence of B-findings and C-findings.\nDifferential diagnosis\nDifferential diagnoses of SM include all the other causes of mast cell activation syndromes (MCAS): primary (clonal, but not fulfilling SM diagnostic criteria) MCAS; secondary MCAS where an IgE-dependent allergy (most cases) or another reactive inflammatory disease process is present (and is considered to be the causative etiology); and idiopathic MCAS where neither clonal MC nor an IgE-dependent allergy or another underlying condition/disease can be documented. As well, differential diagnoses include other forms of mastocytosis (cutaneous mastocytosis, mast cell sarcoma), endocrine disorders (adrenal tumors, VIPoma,, Zollinger-Ellison syndrome), some gastrointestinal pathologies, allergies, other myeloproliferative diseases that affect bone marrow, histiocytosis, hypereosinophilic syndrome and Waldenström macroglobulinemia.\nGenetic counseling\nSM is usually a sporadic disease, although a few familial cases have been reported so far, for which no genetic counseling is available.\nManagement and treatment\nManagement depends on the type of SM. Treatment of ISM and stable SSM is typically symptomatic (antihistamines, corticosteroids or disodium cromoglyylcate). For advanced SM treatment is symptomatic (antihistamines anti-H1 and H2) and antiproliferative with non-targeted (e.g interferon alpha) or targeted cytoreductive therapy with KIT tyrosine kinase inhibitors. Hydroxyurea (HU) is given in patients with SM-AHN. Allogeneic stem cell transplantation (allo-SCT) is rarely used and reserved for fit patients with very aggressive, life-threatening advSM and a suitable donor.\nPrognosis\nPrognosis depends on the type of SM.\n\n                            Last update: \n                            July 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Michel AROCK"}
{"Disease Name": "Systemic monochloroacetate poisoning", "Disease Definition": "Systemic monochloroacetate poisoning is a rare, life-threatening intoxication with monochloroacetic acid (mainly through the skin, but also by inhalation or ingestion). It is characterized by vomiting, diarrhea and central nervous system (CNS)-excitability (disorientation, delirium, convulsions) as early signs of systemic poisoning, followed by CNS-depression, coma and cerebral edema. Additional signs include heart involvement (severe myocardial depression, shock, arrhythmias, nonspecific myocardial damage), severe metabolic acidosis, hypokalemia, hypocalcemia and progressive renal failure leading to anuria. Myoglobinemia and leukocytosis may occur. Manifestations may be delayed for 1-4 hours.", "ORPHA ID": 90069, "Summary": ""}
{"Disease Name": "Systemic polyarteritis nodosa", "Disease Definition": "Systemic polyarteritis nodosa (PAN; see this term) is a chronic systemic necrotizingvasculitis of adults and childrenaffecting small- and medium-sized vessels and characterized by formation of microaneurysms leading to serious generalized disease and multi-organ involvement.", "ORPHA ID": 439762, "Summary": ""}
{"Disease Name": "Systemic primary carnitine deficiency", "Disease Definition": "A rare disorder of carnitine cycle and carnitine transport that is characterized classically by early childhood onset cardiomyopathy often with weakness and hypotonia, failure to thrive and recurrent hypoglycemic hypoketotic seizures and/or coma.", "ORPHA ID": 158, "Summary": "Epidemiology\nSystemic primary carnitine deficiency (SPCD) exact prevalence is unknown and varies depending on ethnicity. The estimated prevalence is 1/20,000 - 1/70,000 newborns in Europe and the USA while the estimated incidence in Japan is 1/40,000 births. In the Faroe Islands, the prevalence is 1/1,300 and the incidence is 1/720.\nClinical description\nDisease onset typically occurs in infancy between the ages of 3 months to 2 years. Infants often present with hypoketotic hypoglycemia, poor feeding, irritability, lethargy, and hepatomegaly, triggered by fasting stress or common illnesses including gastroenteritis and respiratory tract infections. Roughly half of clinically presenting patients present with muscle hypotonia and progressive childhood cardiomyopathy leading to heart failure. Anemia is sometimes observed as carnitine plays a role in red blood cell metabolism. Adulthood presentation is associated with minor symptoms like fatigue and decreased stamina but dilated cardiomyopathy and arrhythmias and sudden cardiac death have also been reported. Asymptomatic adults are also described. During pregnancy, minor symptoms as well as cardiac arrhythmias can worsen.\nEtiology\nSPCD is caused by mutations in the SLC22A5 gene on chromosome 5q31.1 that encodes the plasma membrane sodium-dependent high affinity carnitine transporter (OCTN2) which is expressed in most tissues including cultured fibroblasts, lymphocytes, muscle, kidney, gut and heart. OCTN2 is necessary for L-carnitine transport across the plasma membrane and L-carnitine is necessary for transporting long chain fatty acids into the mitochondria for fatty acid oxidation. When fat cannot be used for fatty acid oxidation due to SPCD, glucose is consumed (resulting in hypoglycemia) and the fat released from adipose tissue accumulates in the liver, heart and skeletal muscle (leading to hepatic steatosis and lipid myopathy).\nDiagnostic methods\nDiagnosis is based on a finding of very low plasma free and total carnitine concentrations (<5-10 micromol/L) and confirmed by demonstrating significantly reduced carnitine transport in skin fibroblasts or biallelic pathogenic mutations in the SLC22A5 gene. There is lipid myopathy with microvesicular lipid accumulation found in the muscle and liver as well as elevated liver transaminases and hyperammonemia. A marked renal loss of carnitine even in the presence of very low plasma and tissue carnitine concentrations is also noted. Newborn screening is available in Austria, Denmark, Hungary, Iceland, Portugal, Spain and Israel.\nDifferential diagnosis\nDifferential diagnoses include other fat oxidation defects such as medium chain acyl-CoA dehydrogenase deficiency and very long chain acyl-CoA dehydrogenase deficiency.\nGenetic counseling\nSPCD is an autosomal recessive disorder and genetic counseling can be offered to families with a known mutation.\nManagement and treatment\nCarnitine therapy is the standard treatment. Oral levocarnitine (L-carnitine) supplementation of 100-400 mg/kg/day in three divided doses is usually required. Oral carnitine treatment is required for lifelong treatment of the disease.\nPrognosis\nThe prognosis is extremely good as long as oral carnitine supplementation is maintained.\n\n                            Last update: \n                            May 2019\n\n\n                            - Expert reviewer(s): \n                             Joanne CROFT  - Dr Simon OLPIN"}
{"Disease Name": "Systemic sclerosis", "Disease Definition": "Systemic sclerosis (SSc) is a generalized disorder of small arteries, microvessels and connective tissue, characterized by fibrosis and vascular obliteration in the skin and organs, particularly the lungs, heart, and digestive tract. There are two main subsets of SSc: diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) (see these terms). A third subset of SSc has also been observed, called limited Systemic Sclerosis (lSSc) or systemic sclerosis sine scleroderma (see these terms).", "ORPHA ID": 90291, "Summary": "Epidemiology\nThe prevalence is estimated at about 1/6,500 adults. Women are predominantly affected (F/M sex ratio around 4:1).\nClinical description\nThe disease usually manifests between 40 and 50 years of age. Raynaud's phenomenon is often the first sign of the disease. The other signs usually appear a few months later in the diffuse cutaneous subset and some years later in the limited cutaneous subset. In the limited cutaneous subset, skin involvement is limited to the hands, face, feet and forearms while in the diffuse subset it rapidly becomes generalized. Esophageal dysmotility is common and provokes gastroesophageal reflux and sometimes dysphagia. Life-threatening complications can occur such as pulmonary fibrosis and, less frequently, pulmonary arterial hypertension. The limited SSc patients have no skin involvement but only Raynaud's phenomenon, and are at risk of organ involvement.\nEtiology\nThe exact cause of SSc is unknown. The disease originates from an autoimmune reaction which leads to overproduction of collagen. In some cases, SSc is associated with exposure to chemicals (including silica, solvents and hydrocarbons).\nDiagnostic methods\nDiagnosis is based on typical clinical manifestations and on evidence of specific microangiopathy with giant loops on capillaroscopy. Blood tests show typical antinuclear autoantibodies. The extent of the disease should be evaluated by computed tomography (CT), electrocardiogram, echocardiography, radiography of the hands and esophageal and gastric fibroscopy if needed.\nDifferential diagnosis\nDifferential diagnoses include Sharp syndrome, systemic lupus erythematosus, antiphospholipid syndrome, polyarteritis nodosa, polymyositis, and rheumatoid arthritis (see these terms).\nManagement and treatment\nManagement is mostly symptomatic. Raynaud's phenomenon can be treated with calcium channel blockers. Proton pomp inhibitors are given for gastric reflux. Low doses of corticosteroids with immunosuppressive agents are needed in cases with recent and severe cutaneous involvement or in progressive lung fibrosis. Pulmonary vasodilators are given in case of pulmonary arterial hypertension. Patients require regular clinical follow-up with early pulmonary function tests and echocardiography.\nPrognosis\nThe prognosis depends on the subset of SSc. The prognosis for limited cutaneous SSc is relatively good (10-year survival rate of 80-90%). However, pulmonary arterial hypertension, which occurs in about 10% of cases, and severe lung fibrosis, may lead to a more severe prognosis. The prognosis for diffuse cutaneous SSc is more severe (10-year survival rate of 60-80%) because of the higher risk of life-threatening complications: renal crisis, severe digestive involvement, severe lung fibrosis, and, sometimes, severe heart involvement and pulmonary arterial hypertension.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                            Pr Eric HACHULLA"}
{"Disease Name": "Systemic-onset juvenile idiopathic arthritis", "Disease Definition": "A rare pediatric rheumatological disease characterized by the variable occurrence of chronic arthritis, intermittent high spiking fever, maculopapular rash during fever episodes, hepatomegaly and/or splenomegaly, lymphadenopathy, and serositis.", "ORPHA ID": 85414, "Summary": "Epidemiology\nJuvenile idiopathic arthritis (JIA) is one of the most common pediatric chronic diseases, with a yearly incidence between 1.6 and 23 new cases per 100,000 children. Systemic-onset JIA accounts for roughly 10-20% of all JIA patients, with incidence estimated at 1/166,000 and prevalence at 1/32,000 in the prediatric population. Frequency is higher in some countries; for example in parts of Asia, sytemic-onset JIA may account for up to 30-40% of all JIA cases.\nClinical description\nOnset usually occurs between 3 and 5 years of age. The clinical signs include fever with oscillating temperatures over a 24-hour period and peaks of over 39°C or more. The fever peaks are associated with the transient occurrence of an evanescent macular rash. Any joint, small or large, may be affected at disease onset, and involvement is nearly symmetrical and may be oligo- or polyarticular. Arthritis tends to increase in severity over time, and thus may not appear until later in the disease course. The course of the disease varies between individuals, ranging from a monocyclic disease course, to recurrent predominantly systemic disease course, to a progressive polyarthritis that could lead to severe and destructive joint disease.\nEtiology\nWhilst the underlying mechanisms and triggering factors are not fully understood, IL-1 and IL-6 play a major role in the pathogenesis of the disease.\nDiagnostic methods\nDiagnosis is based on clinical and biological findings in a child under the age of 16 presenting with fever for at least 3 consecutive days and 2 major criteria (arthritis and evanescent rash) or 1 major and 2 minor criteria ((1) generalized lymph node enlargement and/or hepatomegaly or splenomegaly (2) serositis (3) arthralgias lasting 2 weeks or longer (4) leukocytosis > 15.000/mm3 with neutrophilia) A confirmed diagnosis requires exclusion of other causes of the symptoms.\nDifferential diagnosis\nThe differential diagnoses is extensive and includes bacterial infections (including occult bacterial infection, brucellosis, Lyme disease, cat scratch disease, tuberculosis, and infectious mononucleosis), malaria, malignancies (such as leukemia, lymphoma, and neuroblastoma), viral infections, hereditary recurrent fever syndromes, other inflammatory diseases (such as systemic lupus erythematosus, systemic vasculitis, Kawasaki disease, Behçet disease, inflammatory bowel disease, Sweet syndrome, PFAPA, Takayasu arteritis, Castleman syndrome, rheumatic fever, and polyarteritis nodosa), connective tissue diseases, and periodic fever syndromes.\nManagement and treatment\nManagement by a specialized multidisciplinary team is required. Treatment is typically first with non-steroidal anti-inflammatory drugs (NSAIDs) and, if the inflammation is not controlled, followed by high dose corticosteroids. Treatment with cytokine inhibitors (anakinra, canakinumab, and tocilizumab) has shown to be highly effective. Furthermore, these drugs can help mitigate damage caused by the inflammatory process. Generally, complications such as macrophage activation syndrome, limitations in functional outcome by arthritis and long-term damage from chronic inflammation continue to be a major issue in patients' care, but have decreased since the use of biological treatment.\nPrognosis\nThe disease course is long with major impact on quality of life. The risk of complications due to the illness or medication has been significantly reduced by the early use of biological treatment. Nowadays, osteopenia and osteoporosis, growth impairment, erosive arthritis, and secondary or reactive amyloidosis have almost disappeared. Currently, therapeutic strategies using anakinra (a recombinant IL-1 receptor antagonist), JAK inhibitors, and IL-6 inhibitors are also being studied. In severe case, where these is no response to these treatments or to high-dose corticosteroid therapy, intensive care becomes quickly necessary.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Chantal DESLANDRE"}
{"Disease Name": "Sézary syndrome", "Disease Definition": "Sézary syndrome (SS) is an aggressive form of cutaneous T-cell lymphoma characterized by a triad of erythroderma, lymphadenopathy and circulating atypical lymphocytes (Sézary cells).", "ORPHA ID": 3162, "Summary": "Epidemiology\nSS has an annual incidence rate of 1/10,000,000 and represents 3% of all cutaneous lymphomas.\nClinical description\nSS develops most frequently in men, in most cases during their fifth decade of life and progresses rapidly. SS correspond to stages IVA2 and IVB of T-cell cutaneous lymphoma (see this term). Patients present with a scaling erythroderma and infiltration often manifesting with leonine facies and severe pruritus. Alopecia, ectropium, mild palmoplantar keratoderma and nail onychodystrophy may be present. Lymphadenopathy and hepatosplenomegaly are observed. Patients often shiver and complain of chills and general fatigue.\nEtiology\nSS has been linked to a wide range of chromosomal anomalies, in particular rearrangements in the 6q23-27 region leading to alterations in the MYB proto-oncogene and the interleukin-22 receptor subunit alpha-2 gene (IL22RA2), but its etiology remains unclear.\nDiagnostic methods\nCriteria that define SS are currently the following: an absolute Sézary cell count of 1,000 cells/mm3 or greater (B2 stage); an increase in CD3 or CD4 positive cells resulting in a CD4/CD8 ratio of 10 or greater; aberrant expression of pan T cell markers (i.e. deficient CD7 expression on T cells); increased relative or absolute lymphocyte counts with evidence of an identical T cell clone in the blood and skin by Southern blot or PCR technique. Skin biopsy may be not conclusive.\nDifferential diagnosis\nDifferential diagnosis includes adverse drug reactions, classical mycosis fungoides and other forms of primary cutaneous T cell lymphoma (see these terms) as well as other causes of erythroderma such as psoriasis, atopic dermatitis and pityriasis rubra pilaris (see this term).\nManagement and treatment\nAssessment includes chest X-ray, computed tomography scan, magnetic resonance imaging and PET scan and an initial lymph node biopsy. Bimonthly extracorporeal photopheresis treatment may be combined with low doses of methotrexate, bexarotene or interferon-alpha. In advanced or non-responsive cases, chemotherapy with liposomal doxorubicine, gemcitabine or alemtuzumab may be considered. In cases of relapse, treatment may include total skin electron beam therapy and allogeneic stem cell transplantion.\nPrognosis\nPrognosis is poor, with median survival of patients being approximately 5 years, and is dependent upon initial presentation and evolution.\n\n                            Last update: \n                            August 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Martine BAGOT"}
{"Disease Name": "T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta", "Disease Definition": "A rare T-B+ severe combined immunodeficiency characterized by a T cell-negative, B cell-positive, natural killer (NK) cell-positive immune phenotype. Patients present in infancy or early childhood with recurrent infections. Clinical manifestations may vary in severity depending on the underlying molecular defect, resulting in early death without bone marrow transplantation in some patients.", "ORPHA ID": 169160, "Summary": ""}
{"Disease Name": "T-B+ severe combined immunodeficiency due to CD45 deficiency", "Disease Definition": "A rare T-B+ severe combined immunodeficiency characterized by markedly decreased numbers of T-cells and normal or increased numbers of B-cells and natural killer (NK) cells. Hypogammaglobulinemia has also been reported. Patients generally present in infancy with recurrent infections, failure to thrive, rash, fever, hepatosplenomegaly, lymphadenopathy, and pancytopenia.", "ORPHA ID": 169157, "Summary": ""}
{"Disease Name": "T-B+ severe combined immunodeficiency due to gamma chain deficiency", "Disease Definition": "Severe combined immunodeficiency (SCID) due to gamma chain deficiency, also called SCID-X1, is a form of SCID (see this term) characterized by severe and recurrent infections, associated with diarrhea and failure to thrive.", "ORPHA ID": 276, "Summary": "Epidemiology\nIt accounts for approximately 50% of SCID cases and is the most common form of SCID in Europe. The annual incidence varies among the populations but it is estimated at approximately 1/200,000 births. The disease occurs in males.\nClinical description\nSCID-X1 manifests during the first months of life with severe and often life threatening viral, bacterial or fungal infections (e.g. Pneumocystis jiroveci pneumonitis, disseminated BCG infection if previously vaccinated), and failure to thrive. Chronic diarrhea is a frequent finding. Some patients may have skin rashes and abnormalities of liver function. Materno-fetal transfusion-associated graft versus host disease is also associated with the disease. Immunological findings are lymphopenia with the absence of T and NK cells, hypogammaglobulinemia, and normal or increased B cell count.\nEtiology\nSCID-X1 results from a defect in the IL2RG gene encoding the common gamma chain.\nGenetic counseling\nTransmission is X-linked.\n\n                            Last update: \n                            March 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency", "Disease Definition": "A rare T-B+ severe combined immunodeficiency characterized by markedly decreased numbers of T-cells and normal or increased numbers of B-cells and natural killer (NK) cells. Patients generally present in infancy with recurrent infections, failure to thrive, fever, diarrhea, and dermatitis.", "ORPHA ID": 169154, "Summary": ""}
{"Disease Name": "T-B+ severe combined immunodeficiency due to JAK3 deficiency", "Disease Definition": "Severe combined immunodeficiency (SCID) T-B+ due to JAK3 deficiency is a form of SCID (see this term) characterized by severe and recurrent infections, associated with diarrhea and failure to thrive.", "ORPHA ID": 35078, "Summary": "Epidemiology\nAnnual incidence is between 1/100,000 and 1/1,000,000 live births depending on the population.\nClinical description\nThe disease shares the same clinical picture as SCID due to gamma chain deficiency (see this term). Patients present in the first few months of life with the classical clinical features of SCID, i.e. chronic diarrhea, failure to thrive, recurrent respiratory infections and/or generalized infections due to opportunistic pathogens. Patients may present with skin rash, abnormalities of liver function, and pancytopenia. Materno-fetal transfusion-associated graft versus host disease is also associated with the disease. The disease is characterized by a lack of circulating T and NK (Natural Killer) cells and normal number of B lymphocytes.\nEtiology\nSCID due to JAK3 deficiency results from a defect in the JAK3 gene encoding an intracellular tyrosine kinase, the Janus activating kinase 3 required for cytokine-mediated signaling.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            March 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Andrew GENNERY"}
{"Disease Name": "T-B+ severe combined immunodeficiency", "Disease Definition": "T-B+ severe combined immunodeficiency (SCID; see this term) is a group of rare monogenic primary immunodeficiency disorders characterized by a lack of functional peripheral T lymphocytes with presence of B lymphocytes, resulting in early-onset severe respiratory viral, bacterial or fungal infections, diarrhea and failure to thrive.", "ORPHA ID": 317416, "Summary": ""}
{"Disease Name": "T-B- severe combined immunodeficiency", "Disease Definition": "T-B- severe combined immunodeficiency (SCID; see this term) is a group of rare monogenic primary immunodeficiency disorders characterized by a lack of functional peripheral T and B lymphocytes, resulting in recurrent early-onset severe respiratory viral, bacterial or fungal infections, diarrhea and failure to thrive. Hypersensitivity to ionizing radiation is a characteristic feature of some of its sub-types.", "ORPHA ID": 317419, "Summary": ""}
{"Disease Name": "T-cell immunodeficiency with epidermodysplasia verruciformis", "Disease Definition": "A rare primary immunodeficiency characterized by increased susceptibility to infection by human papillomavirus, presenting in childhood with disseminated flat wart-like cutaneous lesions. Burkitt lymphoma has also been reported. Whilst total T-cell counts are normal, there is impaired TCR signaling, profound peripheral naive T-cell lymphopenia with memory T-cells displaying an exhaustion phenotype.", "ORPHA ID": 324294, "Summary": ""}
{"Disease Name": "T-cell immunodeficiency with thymic aplasia", "Disease Definition": "A rare primary immunodeficiency with autosomal or X-linked recessive inheritance, characterized by thymic aplasia in the absence of other congenital abnormalities, with profound T-cell deficiency, while serum immunoglobulin levels are normal or increased. Patients present with chronic or recurrent infections in infancy including candidiasis, skin, pulmonary and urinary tract infections, chronic diarrhea, and failure to thrive.", "ORPHA ID": 83471, "Summary": ""}
{"Disease Name": "T-cell large granular lymphocyte leukemia", "Disease Definition": "T-cell large granular lymphocyte leukemia (T-cell LGL leukemia) is a lymphoproliferative malignancy that arises from the mature T-cell (CD3+) lineage.", "ORPHA ID": 86872, "Summary": ""}
{"Disease Name": "T-cell prolymphocytic leukemia", "Disease Definition": "A rare mature T-cell neoplasm characterized by proliferation of small to medium-sized prolymphocytes with a mature post-thymic T-cell phenotype, involving the peripheral blood, bone marrow, lymph nodes, liver, spleen, and sometimes the skin. T-cell receptor genes are clonally rearranged. Patients typically present with hepatosplenomegaly, generalized lymphadenopathy, high leukocyte count with normal serum immunoglobulins, anemia, and thrombocytopenia. HTLV-1 serology is negative. The disease course is aggressive with generally poor prognosis.", "ORPHA ID": 86871, "Summary": ""}
{"Disease Name": "T-cell/histiocyte rich large B cell lymphoma", "Disease Definition": "T-cell/histiocyte rich large B cell lymphoma (THRLBCL) is a rare variant of diffuse large B-cell lymphoma (DLBCL; see this term), mainly affecting middle-aged men and often not being discovered until an advanced disease stage, with involvement of the spleen, liver and bone marrow occurring at a greater frequency than in DLBCL. It is often difficult to diagnose due to its similarity with other lymphoid diseases such as classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma (see these terms) and has an aggressive clinical course.", "ORPHA ID": 300857, "Summary": ""}
{"Disease Name": "TAFRO syndrome", "Disease Definition": "A rare systemic disease characterized by acute or subacute onset of thrombocytopenia, anasarca (edema, pleural effusion, ascites), and systemic inflammation (fever and/or elevated C-reactive protein). Minor diagnostic categories are Castleman's disease-like features on lymph node biopsy, reticulin myelofibrosis and/or increased number of megakaryocytes in bone marrow, progressive renal insufficiency, and mild organomegaly including hepatosplenomegaly and lymphadenopathy. Most patients show elevated levels of serum alkaline phosphatase, while marked polyclonal hypergammopathy is rare.", "ORPHA ID": 457077, "Summary": ""}
{"Disease Name": "Takayasu arteritis", "Disease Definition": "A rare predominantly large-vessel vasculitis that is characterized by affected aorta and its major branches, but also other large vessels, causing stenosis, occlusion, or aneurysm.", "ORPHA ID": 3287, "Summary": "Epidemiology\nTakayasu arteritis (TAK) prevalence has been estimated to be 13 to 40 per million habitants. Cases have been reported worldwide but TAK seems to be more frequent in asians. A high female-to-male sex ratio is well documented.\nClinical description\nTAK generally presents before 40 years, although rare pediatric cases are found. Active periods of inflammation may present with non-specific features such as headache, malaise, palpitations, night sweats, polyarthralgia or arthritis, erythema nodosum-like or ulcerating nodular cutaneous lesions, fever, fatigue, and weight loss. Vascular manifestations depend on the location and extent of vessel involvement and occurrence of complications (vascular stenoses, occlusions, and more rarely aneurysms). Clinical features include claudication, rest pain (limbs), hypertension (renal), headache, blurred or double vision, optic atrophy, transient ischemic attack, stroke and seizures. Cardiovascular manifestations include bruit, murmurs, blood pressure difference of extremities, carotidodynia, congestive heart failure, aortic regurgitation or insufficiency, pulmonary hypertension and aortic or arterial aneurysm. Pulmonary artery involvement may result in pulmonary hypertension and coronary or bronchial-pulmonary shunts.\nEtiology\nThe etiology of the inflammatory vasculitis in TAK is unknown. An underlying inflammatory mechanism and genetic factors are thought to play a role. Genetic studies have found HLA B-52 to be related to TAK. Recent GWAS studies revealed association of single nucleotide polymorphisms in IL12B and FCGR2A/3A genes to TAK.\nDiagnostic methods\nThe diagnosis is difficult to establish and is frequently delayed (years or even decades). It is based on the clinical features and physical examination. Vascular manifestations could guide morphologic investigations. However, the main change is related to the use of noninvasive imaging techniques (ultrasound, magnetic resonance imaging, CT angiography and positon emission tomography). Such exams could allow early diagnosis by demonstrating arterial wall thickening or inflammation in the pre-stenotic phase.\nDifferential diagnosis\nThe differential diagnosis of TAK is very broad and may include other inflammatory diseases (atherosclerosis, giant cell arteritis, IgG4 related aortitis), infectious aortitis and fibromuscular dysplasia.\nManagement and treatment\nTreatment and management depend on disease severity and the specific complications. Corticosteroid therapy is the main treatment modality for TAK although it is associated with known long-term adverse effects. Remission following immunosuppressive therapy is achieved in about 60% of cases. Other immunosuppressive agents may be needed to achieve relapse (methotrexate, azathioprine, mycophenolate mofetil, leflunomide, tacrolimus, or cyclophosphamide). Biologic drugs, first of all anti-TNF alpha and probably anti-IL6 could be used in patients resistant or intolerant to conventional treatment. Vascular interventions are used to re-establish vascular patency in stenosed and occluded arteries that cause organ ischemia or hypertension, and for aneurysmal disease.\nPrognosis\nTAK is associated with significant morbidity, especially when diagnosed late, and may be life-threatening in severe cases. Adverse effects from long-term corticosteroid therapy may reduce quality of life.\n\n                            Last update: \n                            April 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Marc LAMBERT"}
{"Disease Name": "Takenouchi-Kosaki syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability characterized by global developmental delay, intellectual disability, macrothrombocytopenia, lymphedema, and dysmorphic facial features (like synophrys, ptosis, eversion of the lateral portion of the lower eyelid, and thin upper lip, among others). Additional reported manifestations include cardiac and genitourinary anomalies, sensorineural hearing loss, ophthalmologic abnormalities, skeletal anomalies, and immunodeficiency. Brain imaging may show enlarged ventricles, cerebellar atrophy, or white matter changes.", "ORPHA ID": 487796, "Summary": ""}
{"Disease Name": "Tako-Tsubo cardiomyopathy", "Disease Definition": "A rare cardiac disease characterized by acute occurrence of heart failure after an emotional or physical trigger; recovery of the wall motion abnormalities are observed within months. Symptoms are similar to acute coronary syndrome (ACS).", "ORPHA ID": 66529, "Summary": "Epidemiology\nTakotsubo syndrome (TTS) is found in about 1-3% of all patients with symptoms of ACS; however, the prevalence is likely underestimated. Around 90% of TTS patients are women, typically postmenopausal but male and younger patients are diagnosed increasingly due to raised awareness of the syndrome.\nClinical description\nIn the acute phase, clinical presentation, electrocardiography (ECG) and cardiac biomarkers are similar to those of ACS. Typical symptoms are acute chest pain or dyspnea. Further symptoms can arise from complications of TTS, e.g. heart failure, cardiogenic shock, or cardiac arrest. New ECG changes or elevated cardiac biomarkers may or may not be present.\nEtiology\nThe underlying mechanisms of this syndrome remain incompletely understood. Recent findings show that specific alterations in neurological response and sympathetic activation after emotional stimuli are present in TTS. These findings confirm the importance of brain-heart interaction in the development of this process. Microcirculatory constriction is also proposed as an underlying mechanism.\nDiagnostic methods\nDiagnosis is often challenging due to the similarity with ACS. Coronary angiography with left ventriculography is considered the gold standard diagnostic tool. The InterTAK (international takotsubo) Diagnostic Criteria have been developed to improve diagnosis and include the following: 1) transient left ventricular dysfunction presenting as either apical, midventricular, basal or focal wall motion abnormalities with possible right ventricular involvement, 2) a preceding emotional, physical, or combined trigger (although not obligatory), 3) neurological disorders can be possible triggers, 4) presence of new ECG abnormalities (ST-segment elevation or depression, T-wave inversion, or QTc prolongation), 5) elevated cardiac markers (especially brain natriuretic peptide), 6) significant coronary artery disease can coexist, 7) absence of myocarditis.\nDifferential diagnosis\nDifferential diagnoses include AMI, myocarditis, spontaneous coronary artery dissection, or peripartum cardiomyopathy.\nManagement and treatment\nDue to difficulty in distinguishing TTS from ACS, patients should be transferred to a chest pain unit upon presentation and receive guideline based treatment of ACS. There are no randomized clinical trials to support specific acute or long term treatment recommendations in TTS. However, the consensus statement from an international TTS expert panel provides recommendations for optimal treatment of TTS patients. Electrocardiogram monitoring is essential as a prolonged QT-interval may trigger malignant ventricular arrhythmias (torsades de pointes) or atrioventricular-block. Cardiogenic shock or post cardiac arrest requires intensive care with treatment according to the presence or absence of pulmonary edema, low left ventricular ejection fraction, hypotension and bradycardia. In all cases, inotropic substances should be avoided. For long term treatment, angiotensin converting-enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) are recommended as they are associated with improved survival and lower recurrence rates. Echocardiography should be performed during the acute phase to exclude right ventricular involvement, left ventricular outflow tract obstruction or intraventricular thrombus. A follow-up echocardiography should be performed after discharge to confirm recovery.\nPrognosis\nThe spectrum of TTS is wide and ranges from low to very high risk. In-hospital mortality and long-term outcome in TTS are similar compared to ACS. Recovery of the left ventricular regional systolic dysfunction is usually observed after 4-8 weeks. The risk of recurrence is around 5%.\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                             Victoria Lucia CAMMANN  - Pr Christian TEMPLIN  - Dr Jelena-Rima TEMPLIN-GHADRI"}
{"Disease Name": "Tall stature-intellectual disability-renal anomalies syndrome", "Disease Definition": "A rare overgrowth syndrome associated with multiple congenital anomalies characterized by tall stature, large hands and feet with large thumbs and halluces, spatulate digits, developmental delay and facial dysmorphism.", "ORPHA ID": 500095, "Summary": "Epidemiology\nTo date only 4 cases from 2 families have been reported in the literature.\nClinical description\nThe overgrowth disorder is characterized by tall stature, large hands and feet with large thumbs/halluces. Facial features include round face with widely spaced and deep-set eyes, epicanthal folds, flat midface, long and downslanting palpebral fissures, large prominent ears, thick lips, macroglossia. Patients exhibit developmental delay. Intellect ranges from normal with learning difficulties to intellectual disability. A range of variable congenital anomalies have been reported and include ocular defects (retinal coloboma or refraction errors), cardiac anomalies (ventricular septal defect, mitral valve prolapse, double chamber right ventricle), kidney malformations (renal malrotation with left bifid ureter, nephromegaly, cystic dysplastic kidneys), connective tissue disorders (inguinal hernia), as well as orthopedic features (talipes equinovarus, internal rotation of the femurs and tibias, bowing of the legs, and spina bifida occulta). Other features may include early-onset varicose veins, transient or chronic benign neutropenia (with normal bone marrow examination), sensorineural hearing loss, Wilms tumor (one patient) and early psychosis (one patient).\nEtiology\nBiallelic loss of function variants in FIBP (11q13.1) are responsible for this phenotype.\nDiagnostic methods\nDiagnosis is with next generation sequencing (exome, genome or panel for developmental disorders).\nDifferential diagnosis\nDifferential diagnosis includes other overgrowth disorders, such as Beckwith-Wiedeman syndrome or Simpson-Golabi-Behmel syndrome in the association with tall stature, nephromegaly, macroglossia, predisposition to Wilms tumor.\nAntenatal diagnosis\nPrenatal diagnosis can be proposed to parents with an affected child.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement is multidisciplinary and depends on the particular manifestations and may include ophthalmological, cardiac, hematological and orthopedic evaluation and follow-up. Social care requirements for learning disability should be assessed. Psychiatric symptoms should be evaluated, in particular in adulthood. Hearing evaluations are required with possible prescription for hearing aids. Surgery may be recommended in cases of inguinal hernia and early-onset varicose veins. Follow-up for Wilms tumor with kidney ultrasound every 3 months from diagnosis to 8-years-old is recommended.\nPrognosis\nThe possible lethality of the disorder has been questioned because of an increased occurrence of stillbirths and miscarriage in one family. A predisposition for Wilms tumor is suspected. Neutropenia does not seem associated with recurrent infections.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence OLIVIER-FAIVRE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Tall stature-long halluces-multiple extra-epiphyses syndrome", "Disease Definition": "Tall stature-scoliosis-macrodactyly of the great toes syndrome is a rare, genetic, overgrowth or tall stature syndrome with skeletal involvement characterized by early and proportional overgrowth, osteopenia, lumbar scoliosis, arachnodactyly of the hands and feet, macrodactyly of the hallux, coxa valga with epiphyseal dysplasia of the femoral capital epiphyses and susceptibility to slipped capital femoral epiphysis.", "ORPHA ID": 329191, "Summary": ""}
{"Disease Name": "Talo-patello-scaphoid osteolysis", "Disease Definition": "Talo-patello-scaphoid osteolysis is an extremely rare form of primary osteolysis (see this term), described in two sisters to date, characterized by bilateral osteolysis of the tali, scaphoids, and patellae (accompanied by periarticular swelling and pain) and short fourth metacarpals (brachydactyly type E; see this term), in the absence of renal disease. Autosomal recessive inheritance has been suggested.", "ORPHA ID": 50809, "Summary": ""}
{"Disease Name": "Tangier disease", "Disease Definition": "A rare, genetic neurometabolic disease characterized biochemically by an almost complete absence of plasma high-density lipoproteins (HDL), and clinically by liver, spleen, lymph node and tonsil enlargement along with multifocal peripheral neuropathy, corneal, skin and nail and, occasionally, cardiovascular disease.", "ORPHA ID": 31150, "Summary": "Epidemiology\nTangier disease (TD) prevalence is unknown. Approximately 200 cases have been described worldwide.\nClinical description\nThe clinical presentation and the severity of symptoms vary widely between patients. Although extremely low plasma HDL cholesterol may be detected fortuitously from birth, the most characteristic finding in children is large tonsils with a particular orange-yellow color due to carotene-enriched low-density lipoprotein (LDL) tissue-accumulation. Patients may also show asymptomatic hepatosplenomegaly, lymph node enlargement, corneal opacities and skin lesions with onset typically in childhood or adolescence. Multi-organ and tissue cholesterol deposition is also observed from biopsies (skin, bone marrow, nerves, muscles, and rectal mucosa). Anemia and thrombocytopenia may be present. Signs of atherosclerosis and cardiovascular disease are not observed before adulthood and when present, are associated with other major cardiovascular risk factors (e.g. high blood pressure or plasma triglycerides, diabetes mellitus, smoking, etc.). Isolated peripheral neuropathy is reported in over 50% of cases under two major phenotypes: a motor and sensory relapsing-remitting mono/polyneuropathy with onset during childhood or adolescence, and a syringomyelia-like syndrome with facial diplegia in adults with a past history of tonsillectomy in childhood. In some cases, patients may also show signs of corneal opacity and skin lesions such as skin ulcer, painless scalds or burn scars.\nEtiology\nThe disease is due to mutations in the ABCA1 gene (9q31) encoding the ATP-binding cassette transporter (ABCA1), a cholesterol-efflux regulatory protein that is able to orient intra-cellular cholesterol and phospholipid trafficking towards the cell surface and to facilitate lipid transfer towards HDL and reverse cholesterol transport. Mutations thus result in very low levels of plasma HDL cholesterol and deposition of cholesteryl, retinyl esters, phospholipids and carotenoids in various non-adipose tissues.\nDiagnostic methods\nThe diagnosis is based on evidence of an abnormal lipoprotein profile characterized by isolated hypoalphalipoproteinemia, extremely low HDL cholesterol (<5 mg/dL) and apolipoprotein A-I (ApoA1) levels (< 5 mg/dL), with only pre beta-1 HDL found by bidimensional electrophoresis in the plasma. Moderate hypertriglyceridemia, decreased LDL cholesterol levels, and occasionally, decreased total- and non-HDL plasma cholesterol are noted together with anemia, thrombocytopenia and mild inflammation. Skin, muscle or rectal mucosa biopsy reveals foam cells in affected tissues. Diagnosis is confirmed by genetic testing.\nDifferential diagnosis\nThe differential diagnosis includes familial Apolipoprotein A-I deficiency, LCAT deficiency and secondary causes of extremely low HDL cholesterol levels that include medications (androgenic steroids, retinoids, paradoxical response to fibrates), liver failure or malignancies. When neuropathic manifestations are present, a plasma lipoprotein profile may rule-out TD diagnosis from other non-uniform demyelinating polyneuropathies, especially when prominent in the upper extremities.\nAntenatal diagnosis\nPrenatal diagnosis is feasible but is usually not performed.\nGenetic counseling\nTransmission is autosomal recessive, although relatives may exhibit lowered plasma HDLC while remaining asymptomatic.\nManagement and treatment\nThe disease has no specific treatment. Tonsillectomy may be required in case of significant tonsillar enlargement. A low-fat diet helps in reducing liver enlargement and preventing atherosclerosis. LDL-lowering drugs are required in patients with cardiovascular risk factors or overt signs of cardiovascular disease, especially when hepato-splenomegaly is absent. Therapies enhancing cellular cholesterol efflux by HDL are developed to reduce cardiovascular risk; anti-inflammatory agents and Miglustat (an iminosugar inhibitory of glycosyl-ceramide synthase) may correct neuropathic and skin manifestations despite being ineffective on plasma lipoprotein profile.\nPrognosis\nPrognosis is usually good and depends mainly on the progression of peripheral neuropathy. TD patients with extremely low plasma HDL cholesterol (<20 mg/dL) have increased risk of coronary artery disease in adulthood and should be offered regular cardiovascular and neurological monitoring.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Pascale BENLIAN"}
{"Disease Name": "TARP syndrome", "Disease Definition": "TARP syndrome is a rare developmental defect during embryogenesis syndrome characterized by Robin sequence (micrognathia, glossoptosis, and cleft palate), atrial septal defect, persistence of the left superior vena cava, and talipes equinovarus. The phenotype is variable, some patients present with further dysmorphic characteristics (e.g. hypertelorism, ear abnormalities) while others do not have any key findings. Additional features, such as syndactyly, polydactyly, or brain anomalies (e.g. cerebellar hypoplasia), have also been reported. The syndrome is almost invariably lethal with affected males either dying prenatally or living just a few months.", "ORPHA ID": 2886, "Summary": ""}
{"Disease Name": "Tarsal kink syndrome", "Disease Definition": "Tarsal kink syndrome is a rare congenital malformation of the tarsus that causes entropion characterized by blepharospasm and absence of an upper eyelid fold that may lead to corneal ulceration caused by the folded edge of the upper tarsus or the inturned eyelashes if not corrected by surgery.", "ORPHA ID": 99170, "Summary": ""}
{"Disease Name": "Tarsal-carpal coalition syndrome", "Disease Definition": "Tarsal-carpal coalition syndrome is characterised by fusion of the carpals, tarsals, and phalanges.", "ORPHA ID": 1412, "Summary": "Epidemiology\nLess than 10 affected families have been described so far.\nClinical description\nAt birth, patients present with stiffness of the proximal interphalangeal joint of the fifth digit, with or without bony synostosis. Proximo-distal progression leads to involvement of the fourth, third and then the second digits. Other anomalies include brachydactyly, humeroradial synostoses and, in some cases, short stature.\nEtiology\nCausative mutations in the NOG gene have recently been identified, showing that this syndrome is an allelic variant of symphalangism.\nDifferential diagnosis\nTarsal-carpal coalition syndrome can be distinguished from multiple synostoses syndrome and proximal symphalangism (see these terms) by the absence of hearing loss.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            September 2007"}
{"Disease Name": "Tatton-Brown-Rahman syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by tall stature due to postnatal overgrowth, mild to moderate intellectual disability, joint hypermobility and subtle distinctive facial features, which often become apparent during adolescence (such as round face, low-set, thick horizontal eyebrows, narrow palpebral fissures and prominent upper-central incisors). Overweight, hypotonia, behavioral and psychiatric problems are common. Other clinical features may involve seizures, cryptorchidism and cardiovascular diseases (including congenital heart disease and aortic root dilatation).", "ORPHA ID": 404443, "Summary": ""}
{"Disease Name": "Tay-Sachs disease", "Disease Definition": "A rare autosomal recessive lysosomal disease characterized by accumulation of GM2 gangliosides in the nervous system due to hexosaminidase A deficiency as a consequence of biallelic pathogenic variants in the HEXA gene.", "ORPHA ID": 845, "Summary": "Epidemiology\nThe prevalence of the disease is 1 case per 320 000 live births. It is more common in the Ashkenazi Jewish and French-Canadian populations.\nClinical description\nThree forms have been described according to age of onset. The infantile form begins between 3 and 6 months of age for the early infantile (before 12 months) and between 12 and 24 months for the late infantile. The earliest signs are an incessant startle response to noise, and a progressive loss of vision. Psychomotor regression appears during the second semester of life with hypotonia, amaurosis, rapidly pharmaco-resistant epilepsy and progressive macrocephaly. A cherry-red macular spot is nearly always present, strongly evocative even not specific. Muscular weakness progresses and leads to paralysis. The disorder degenerates into a state of decerebration and is fatal during childhood. In the juvenile form, onset is between ages 2 and 10 with progressive cerebellar ataxia, leading to dystonia, behavioral disorders, loss of intellectual capacities, and a state of decerebration and death during the second decade. The late-onset form begins around the age of 10 or later, and is often not diagnosed until adulthood. The onset is insidious with a progressive course. Three initial clinical presentations are described: i) proximal lower limbs weakness with amyotrophy due to a motor neuropathy (mimicking progressive spinal amyotrophy; first complaint: difficulty to climb stairs) that eventually extends to upper limbs and distal parts of the limbs; ii) cerebellar ataxia; iii) more rarely psychotic symptoms with mood disorder. In the course of the disease the motor neuropathy almost always occurs, other motor symptoms may occur (dysarthria, swallowing disorder). Cognition is usually preserved.\nEtiology\nThe causative gene HEXA encodes the alpha subunit of hexosaminidase A and is located on chromosome 15(15q23).\nDiagnostic methods\nWhen Tay-Sachs is suspected, hexosaminidase A enzymatic activity on blood leukocytes is always very low compared to normal values (around 0% for the severe infantile form, around 10-15% for the late-onset form). This should be confirmed by HEXA gene sequencing. The diagnosis may be firstly suggested by pathogenic variants findings from a panel of genes, or exome or genome, and should be confirmed by hexosaminidase A enzymatic activity measurement.\nDifferential diagnosis\nGM2 gangliosidosis, AB variant, may perfectly mimic Tay-Sachs disease due to variants in GM2A gene which codes for a protein that activates hexosaminidase enzyme. In this disease, hexosaminidase A enzymatic activity is normal.\nAntenatal diagnosis\nGenetic prenatal and preimplantation testing is available.\nManagement and treatment\nThere is no specific efficient treatment for Tay-Sachs disease. Treatment is symptomatic.\nPrognosis\nFor the pediatric form of Tay-Sachs, the severity is correlated to age of onset, with a more rapid regression in early infantile form leading to death around 2-4 years of age, whereas death occurs in the second decades in the juvenile form. All patients will have pharmaco-resistant epilepsy in the advanced stages of the disease. For the adult form, the disease is usually very slow progressive and may last decades. Patients are progressively disabled, may lost the ability to walk and have difficulties for upper limbs utilization, speech, swallowing, and may more rarely have cognitive symptoms.\n\n                            Last update: \n                            November 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole BAUMANN  - Dr Bénédicte HERON  - Dr Yann NADJAR | MetabERN* - Dr J TURPIN \n\n\n                                * European Reference Network"}
{"Disease Name": "TBCK-related intellectual disability syndrome", "Disease Definition": "TBCK-related intellectual disability syndrome is a rare, genetic, syndromic intellectual disability characterized by usually profound intellectual disability with absent speech, severe infantile hypotonia with decreased or absent reflexes, markedly slow motor development (with no progress beyond the ability to sit independently), early-onset epilepsy, strabismus and post-natal onset of progressive brain atrophy (incl. loss of brain volume, ex vacuo ventriculomegaly, dysgenesis of corpus callosum, white matter abnormalities ranging from non-specific changes to leukodystrophy). Swallowing difficulties, respiratory insufficiency, osteoporosis and variable craniofacial dysmorphisms (incl. plagio/brachicephaly, bitemporal narrowing, high-arched eyebrows, high nasal bridge, anteverted nares, high palate, tented upper lip) may constitute additional clinical features.", "ORPHA ID": 488632, "Summary": ""}
{"Disease Name": "TCR-alpha-beta-positive T-cell deficiency", "Disease Definition": "A rare, hereditary primary immunodeficiency characterized by recurrent respiratory tract infection, otitis media, candidiasis, diarrhea, as well as various signs and symptoms of immune dysregulation (hypereosinophilia, eczema, vitiligo, alopecia areata, autoimmune hemolytic anemia, pityriasis rubra pilaris). Failure to thrive, moderate lymphadenopathy and hepatomegaly have also been reported.", "ORPHA ID": 397959, "Summary": ""}
{"Disease Name": "Teebi-Shaltout syndrome", "Disease Definition": "Teebi-Shaltout syndrome is a rare, genetic, development defect during embryogenesis malformation syndrome characterized by association of characteristic facial features (including abnormal head shape with narrow forehead, hypertelorism, telecanthus, small earlobes, broad nasal bridge and tip, underdeveloped ala nasi, small/wide mouth and high/cleft palate), ectodermal dysplasia (including oligodontia with delayed dentition, slow growing hair and reduced sweating) and skeletal abnormalities including camptodactyly and caudal appendage. Short stature and abnormal palmar creases are additional clinical features.", "ORPHA ID": 3291, "Summary": ""}
{"Disease Name": "Tel Hashomer camptodactyly syndrome", "Disease Definition": "Tel Hashomer camptodactyly syndrome is a rare syndrome characterized by camptodactyly, muscle hypoplasia and weakness, skeletal anomalies, facial dysmorphism and abnormal dermatoglyphics.", "ORPHA ID": 3292, "Summary": "Epidemiology\nUp to 2005, 20 cases had been reported.\nClinical description\nDysmorphic features include facial asymmetry, hypertelorism, broad nasal bridge, long philtrum and a small mouth. Winging scapulae, scoliosis, syndactyly and clinodactyly are commonly observed. The affected patients usually have normal mental development.\nEtiology\nThe molecular basis of the syndrome has not yet been elucidated.\nGenetic counseling\nInheritance is probably autosomal recessive.\n\n                            Last update: \n                            January 2011"}
{"Disease Name": "Telecanthus-hypertelorism-strabismus-pes cavus syndrome", "Disease Definition": "Telecanthus-hypertelorism-strabismus-pes cavus syndrome is characterized by telecanthus, hypertelorism, strabismus, pes cavus and other variable anomalies. It has been described in a father and his son. The son also had hypospadias, bilateral inguinal hernia, clinodactyly and camptodactyly of the fingers, and radiographic findings including flared metaphyses of the long bones and osteopenia.", "ORPHA ID": 3293, "Summary": ""}
{"Disease Name": "Telethonin-related limb-girdle muscular dystrophy R7", "Disease Definition": "A mild subtype of autosomal recessive limb-girdle muscular dystrophy characterized by a variable onset (ranging from infancy to adolescence) of progressive proximal upper and lower limb muscle weakness and atrophy. Mild scapular winging, calf hypertrophy, and lack of respiratory and cardiac involvement are also observed.", "ORPHA ID": 34514, "Summary": ""}
{"Disease Name": "TELO2-related intellectual disability-neurodevelopmental disorder", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and intellectual disability, infantile hypotonia, microcephaly, movement disorder, and impaired balance. More variable manifestations are hearing loss, cortical visual impairment, abnormalities of fingers and/or toes, congenital cardiac anomalies, kyphoscoliosis, dysmorphic facial features, abnormal sleep pattern, and seizures, among others.", "ORPHA ID": 488642, "Summary": ""}
{"Disease Name": "Temperature-sensitive oculocutaneous albinism type 1", "Disease Definition": "An extremely rare form of oculocutaneous albinism type 1 characterized by temperature sensitive hair pigmentation leading to dark hair on the hands, feet, legs, arms and chest (cooler body areas) and white or pale yellow hair on the scalp, axilla and pubic area (warmer body areas). Nystagmus and reduced visual acuity are also noted.", "ORPHA ID": 352737, "Summary": ""}
{"Disease Name": "TEMPI syndrome", "Disease Definition": "TEMPI syndrome is a rare multi-systemic disease characterized by the presence of Telangiectasias, Erythrocytosis with elevated erythropoietin levels, Monoclonal gammopathy, Perinephric-fluid collections, and Intrapulmonary shunting.", "ORPHA ID": 284227, "Summary": "Epidemiology\nLess than 10 cases have been described in the literature.\nClinical description\nTEMPI syndrome manifests in mid-adulthood with the development of telangiectasias mostly on the face, trunk and arms, as well as with erythrocytosis which may cause a red facies and occasionally, headaches. The increased serum erythropoietin levels precede the intrapulmonary shunting. The intrapulmonary shunts cause hypoxia which slowly progresses until the person needs continuous supplemental oxygen. Blood clots, probably due to erythrocytosis, and bleeding in the brain have also been reported in some affected individuals. Monoclonal gammopathy and perinephric fluid collections are usually found incidentally and do not seem to cause any complications. The syndrome has a slow and regular progression.\nEtiology\nThe cause of TEMPI syndrome is currently unknown. The abnormal plasma-cell clone and/or the monoclonal gammopathy are suggested to be triggers of the disease.\nManagement and treatment\nTreatment has reportedly been completely or partially successful with the proteasome inhibitor bortezomib.\n\n                            Last update: \n                            March 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Wilfried SCHROYENS"}
{"Disease Name": "Temple syndrome due to maternal uniparental disomy of chromosome 14", "Disease Definition": "A rare chromosomal anomaly characterized by prenatal and postnatal growth retardation, hypotonia, motor delay, early puberty, obesity, short adult stature, small hands and feet, mild intellectual disability, and mild dysmorphic facial features (frontal bossing, short nose with wide nasal tip, micrognathia, high palate, short philtrum).", "ORPHA ID": 96184, "Summary": ""}
{"Disease Name": "Temple syndrome", "Disease Definition": "A rare, genetic disease characterized by pre-and postnatal growth delay, feeding difficulties, muscular hypotonia, motor developmental delay (with or without mild intellectual disability) and mild facial dysmorphism, such as broad, prominent forehead, short nose with flat nasal root and wide tip, downturned corners of mouth, high-arched palate and micrognathia. Additonal features include childhood-onset central obesity, premature puberty and variable bone abnormalities (e.g. small hands and feet, dolichospondyly, slender long bones and craniofacial disproportion).", "ORPHA ID": 254516, "Summary": ""}
{"Disease Name": "Temple-Baraitser syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies syndrome defined by global developmental delay and severe intellectual disability, epilepsy, hypoplasia/aplasia of the nails of the thumb and great toe, and facial dysmorphism.", "ORPHA ID": 420561, "Summary": "Epidemiology\nTo date, 9 cases have been reported in the literature.\nClinical description\nTemple-Baraitser syndrome (TBS) is defined by the association of developmental delay (neonatal hypotonia, delayed developmental milestones), and intellectual disability which is most often severe. The characteristic finding is the presence of distal hypoplasia of digits (mostly the distal phalanges), which is more pronounced at, and often limited to, the thumbs and halluces; nail aplasia or hypoplasia is observed in all patients. In some patients, thumbs and halluces are broad or elongated, and pseudoepiphysis may be observed on X-ray imaging. Facial dysmorphism is characterized by a pseudo-myopathic appearance. Other reported facial features include high anterior or low frontal hairline with central cowlick, flat forehead, ptosis, hypertelorism, downslanting palpebral fissures, epicanthal folds, thick helices, broad depressed nasal bridge with anteverted nares, short columella, long philtrum, high-arched palate, broad mouth with thick vermilion border of the upper or the lower lip and downturned corners. Seizures are reported in all patients, starting at a various ages. Poor visual contact and autistic behaviour are observed in most patients.\nEtiology\nTBS is due to heterozygous gain of function missense variants in the KCNH1 gene (1q32.2), lowering the activation threshold of the mutant voltage-gated potassium channel and delaying its deactivation. TBS is allelic to Zimmermann-Laband syndrome (ZLS), which differs from TBS by the presence of gingival fibromatosis, coarse facial features, hypertrychosis, hepato-splenomegaly, and more severe digital anomalies. As both syndromes have been described with the same variant, and some patients with KCNH1 variant but without full-blown TBS or ZLS have been reported, it is likely that TBS is part of a broader KCNH1-related disorder.\nDiagnostic methods\nConfirmation of clinical diagnosis is based on KCNH1 sequencing by targeted sanger sequencing, or via NGS (next generation sequencing) multigene panel including KCNH1.\nDifferential diagnosis\nDifferential diagnosis includes DOORS, Lynch Bushby and Zimmermann-Laband syndrome.\nAntenatal diagnosis\nFor parents of an index individual, prenatal diagnosis in subsequent pregnancies should be discussed.\nGenetic counseling\nThe disorder is autosomal dominant; however, most reported KCNH1 variants occur de novo. Mosaicism has been reported in two epileptic, but otherwise unaffected, mothers. Although not known, the recurrence risk to siblings is thus much higher than the usual theoretical 1% estimated risk in the presence of an apparent de novo variant.\nManagement and treatment\nManagement and treatment are based on the phenotype. Antiepileptic drugs, and physical and occupational therapy may be needed. Nutritional and feeding status should be evaluated.\nPrognosis\nPrognosis depends on the severity of the phenotype.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Catheline VILAIN | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Temtamy preaxial brachydactyly syndrome", "Disease Definition": "A rare, genetic, syndromic dysostosis characterized by bilateral, symmetrical, preaxial brachydactyly associated with hyperphalangy, motor developmental delay and intellectual disability, growth retardation, sensorineural hearing loss, dental abnormalities (incuding misalignment of teeth, talon cusps, microdontia), and facial dysmorphism that includes plagiocephaly, round face, hypertelorism, malar hypoplasia, malformed ears, microstomia and micro/retrognathia.", "ORPHA ID": 363417, "Summary": ""}
{"Disease Name": "Temtamy syndrome", "Disease Definition": "A very rare congenital genetic neurological disorder characterized by agenesis/hypoplasia of corpus callosum with developmental abnormalities, ocular disorders, and variable craniofacial and skeletal abnormalities.", "ORPHA ID": 1777, "Summary": "Epidemiology\nThe syndrome is rare and has been reported in more than 7 families to date, representing 56 affected individuals. While generally considered a rare disease, one large cohort of Arab patients (1000 individuals) suggested that start codon mutations in C12ORF57 alone accounts for 1.5% of all cases of intellectual disability, a contribution that rivals that of the much more familiar Fragile‐X syndrome and would make it the single most common cause of recessive intellectual disability/developmental delay in Saudi Arabia. Most affected families are of Middle-Eastern Arab descent, specifically Saudi Arabian. Most reported families have multiplex cases of Temtamy syndrome and almost all are from consanguineous unions. Male and female patients have been reported.\nClinical description\nAge of onset is generally in the neonatal period and in infancy. The manifestations of Temtamy syndrome are variable. The main clinical findings are dysmorphic facies (including elongated face, hypertelorism, prominent nose, low-set ears, and micrognathia), hypotonia, moderate to severe intellectual disability, intractable seizures and autistic features such as absent language or stereotypy. Motor and cognitive delay usually manifests in early childhood. Skeletal anomalies may include brachydactyly of the hands and feet, genu vara, and pes planus. Visual abnormalities include microphthalmia, coloboma of iris, esotropia, and optic atrophy, sometimes leading to progressive loss of vision. Atrial septal defect was also found in some patients. Involvement of other systems was not reported.\nEtiology\nThe pathogenesis of Temtamy syndrome is not known. Various mutations (homozygous, missense, compound heterozygous) in the C12ORF57 gene (12p13.31) have been reported in affected patients. The gene is of unknown function but appears to be required for development of the corpus callosum and the eye. It is expressed primarily in the neurological, visual, and cardiovascular systems. In vitro cellular expression studies indicated that the mutation decreased protein synthesis suggesting the lost-of-function mechanism and phenotypic variability.\nDiagnostic methods\nDiagnosis is based on the specific constellation of clinical signs and brain imaging. Brain magnetic resonance imaging (MRI) of affected patients has shown aplasia, thickening, or hypoplasia of the corpus callosum, thalamic hypoplasia, and rarely colpocephaly.\nDifferential diagnosis\nDifferential diagnoses include muscle-eye-brain disease, Peters-plus, Walker-Warburg, Aicardi, Donnai-Barrow, and Baraitser-Winter syndromes.\nGenetic counseling\nTemtamy syndrome follows an autosomal recessive pattern of inheritance. Genetic counseling should be offered to affected families.\nManagement and treatment\nCurrently, management of the disease is symptomatic.\nPrognosis\nPrognosis and quality of life depend on the severity of disease manifestations.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Elliott SHERR"}
{"Disease Name": "Tenosynovial giant cell tumor", "Disease Definition": "A rare benign proliferative disorder of the synovial membrane primarily affecting young adults (with a peak age of onset in the second to fourth decade of life) characterized by proliferative, locally invasive tumor-like lesions, usually involving a single joint, tendon sheath or bursa (most commonly the joints of the knee and hip and rarely others such as the ankle, shoulder and temporomandibular joints). It presents with pain and limitation of motion along with swelling, heat and tenderness over the involved joint, eventually leading to arthritic degeneration and significant locomotor deficit, if left untreated. PVNS can recur in patients even after treatment.", "ORPHA ID": 66627, "Summary": ""}
{"Disease Name": "Terminal osseous dysplasia-pigmentary defects syndrome", "Disease Definition": "Terminal osseous dysplasia-pigmentary defects syndrome is characterised by malformation of the hands and feet, pigmentary skin lesions on the face and scalp and digital fibromatosis.", "ORPHA ID": 88630, "Summary": "Epidemiology\nIt has been described in 18 females, six of whom came from four different generations of the same family.\nClinical description\nPhenotypic expression is very heterogeneous. In the majority of patients, the bone dysplasia is limited to the hands and feet but shortening and/or bowing of the bones of the arms and legs has been reported in severe cases. The pigmentary lesions and digital fibromatosis appear a few months after birth.\nEtiology\nThe causative gene remains unknown.\nGenetic counseling\nThe syndrome is transmitted as an in utero male-lethal X-linked dominant trait, explaining the large number of miscarriages reported in the affected families.\n\n                            Last update: \n                            September 2007"}
{"Disease Name": "Terrien marginal degeneration", "Disease Definition": "A rare disorder of the anterior segment of the eye characterized by slowly progressive, bilateral, asymmetric, usually non-inflammatory degeneration of the peripheral cornea, resulting in stromal thinning, vascularization, lipid deposition, and against-the-rule astigmatism with decreased visual acuity. Degeneration typically involves the superior aspect of the cornea first and extends circumferentially, leading to circumferential ectasia of the peripheral cornea. Opacification of the central cornea may occur at a very advanced stage. In rare cases, the condition is complicated by perforation.", "ORPHA ID": 519410, "Summary": ""}
{"Disease Name": "Tessier number 4 facial cleft", "Disease Definition": "A rare oblique facial cleft characterized by a congenital unilateral or bilateral oculo-facial defect beginning at the upper lip lateral to the Cupid's bow, then running lateral to the nasal wing, to the lower eyelid lateral to the inferior punctum. Involvement of the facial skeleton begins between the lateral incisors and the canine tooth, involving the maxillary sinus, and ending at the infraorbital rim. Variable involvement of the eye can result in micro- or even anophthalmus.", "ORPHA ID": 141258, "Summary": ""}
{"Disease Name": "Tessier number 5 facial cleft", "Disease Definition": "A rare oblique facial cleft characterized by a congenital unilateral or bilateral defect beginning in the upper lip medial to the oral commissure and extending across the cheek as a groove ending between the middle and lateral third of the lower eyelid (resulting in coloboma). Bone involvement includes an alveolar cleft in the premolar region, extending across the maxilla lateral to the infraorbital nerve and up to the infraorbital rim and orbital floor. The malformation may be associated with Tessier number 3 and number 4 clefts, macrostomia, or anophthalmos.", "ORPHA ID": 141261, "Summary": ""}
{"Disease Name": "Tessier number 6 facial cleft", "Disease Definition": "A rare oblique facial cleft characterized by a defect between the maxilla and the zygomatic bone, opening into the infra-orbital fissure, accompanied by coloboma of the lower eyelid and a vertical furrow on the cheek oriented either laterally to the corner of the mouth or in the direction of the angle of the mandible. The posterior aspect of the maxilla is short with a high palate and choanal atresia. The malformation is typically associated with Treacher-Collins syndrome.", "ORPHA ID": 141265, "Summary": ""}
{"Disease Name": "Tessier number 7 facial cleft", "Disease Definition": "A rare lateral facial cleft characterized by a temporo-zygomatic defect, usually with absence of the zygomatic arch and deformities of the mandibular ramus, condyle, and coronoid process. Associated soft tissue abnormalities include malformations of the ear and hypoplasia or absence of the temporal muscle. Preauricular hair may be absent or divided into two portions. Facial manifestations include macrostomia (with extension of the cleft to the corner of the mouth) and pre-auricular tags. Incomplete clefts may be found in the molar region and between the maxillary tuberosity and pterygoid process.", "ORPHA ID": 141276, "Summary": ""}
{"Disease Name": "Testicular agenesis", "Disease Definition": "A rare 46,XY disorder of gonadal development characterized by congenital complete absence of testicular tissue in an individual with an otherwise normal male phenotype and normal karyotype. In addition, a small penis is a frequent finding in anorchid patients. Typical hormonal characteristics are elevated basal levels of gonadotropins (especially FSH), low concentration of testosterone, and lack of increase of plasma testosterone in response to hCG administration. The GnRH stimulation test induces a prolonged increase in FSH and LH levels.", "ORPHA ID": 325124, "Summary": ""}
{"Disease Name": "Testicular regression syndrome", "Disease Definition": "Testicular regression syndrome (TRS) is a developmental anomaly characterized by the absence of one or both testicles with partial or complete absence of testicular tissue. TRS may vary from normal male with unilateral no-palpable testis through phenotypic male with micropenis, to phenotypic female. The phenotype depends on the extent and timing of the intrauterine accident in relation to sexual development.", "ORPHA ID": 983, "Summary": ""}
{"Disease Name": "Testicular seminomatous germ cell tumor", "Disease Definition": "Testicular seminomatous germ cell tumor is a rare testicular germ cell tumor (see this term), most commonly presenting with a painless mass in the scrotum, with a very high cure rate if caught in the early stages.", "ORPHA ID": 842, "Summary": "Epidemiology\nAnnual incidence in Europe is 1/62,000 people. It accounts for 40% of testicular cancer cases.\nClinical description\nSeminoma usually presents in males between the ages of 30-40. A painless mass in the scrotum is indicative of disease. A long-standing hydrocele may be noted causing a feeling of heaviness in the testicle. Gynecomastia and back and flank pain are symptoms that are seen in some patients. Relapse after surgery can occur, usually (in 97% of cases) in the high iliac or retroperitoneal lymph nodes. Metastasis, although rare, can occur in some cases, affecting the lungs, liver, bones and central nervous system.\nEtiology\nEtiology is unknown but tumors are thought to arise from an embryonic germ cell leading to testicular intraepithelial neoplasia (the precursor to classical seminoma). Cryptorchidism is a risk factor for the development of testicular seminomatous germ cell tumors.\nDiagnostic methods\nUltrasound usually confirms the presence of a testicular mass. Measurement of tumor markers in blood such as alpha-fetoprotein (AFP), beta human chorionic gonadotropin (BHC) and lactate dehydrogenase (LDH) is needed as it can be useful in cases where the tumor is still very small. Classical seminoma does not secrete AFP and patients with raised levels of this tumor marker are given a diagnosis of non-seminoma. After surgical removal of testicle, histopathological characteristics are analyzed and a stage can be assigned. In stage 1 disease the primary tumor is limited to the testis and epididymus with possible invasion of the tunica albuginea, tunica vaginalis, spermatic cord and scrotum but no lymph node or distant metastasis. Stage 2 (2A, 2B and 2C) disease features regional lymph node metastasis and stage 3 has distant metastasis of varying degrees.\nDifferential diagnosis\nTesticular non seminomatous germ cell tumors (see this term) must be excluded.\nManagement and treatment\nTreatment for stage 1 seminoma involves an orchiectomy or partial orchiectomy in some cases. Most patients (88%) do not require any further treatment and only surveillance is necessary. In those cases where follow up is difficult, adjuvant carboplatin or radiotherapy can be applied. Para-aortic and ipsilateral iliac radiotherapy (30 Gy in 2 Gy fractions) is the standard treatment of stage 2A seminoma. Cisplatin, etoposide and bleomycin (PEB) chemotherapy (three cycles) or cisplatin and etoposide (PE) chemotherapy (4 cycles) is an alternative to radiotherapy (but has more acute toxicity). Those with stage 2B, 2C and stage 3 seminomas are given PEB chemotherapy (three or four cycles depending on prognosis). In those with a reduced lung capacity or with emphysema or in severe smokers, 4 cycles of PE is preferred over PEB. Ifosfamide is given instead of bleomycin in certain cases (i.e. patients with existing lung damage). Follow up and sometimes a PET scan is recommended to monitor for residual lesions. Due to cosmetic and psychological reasons, patients may be offered testicular prostheses after an orchidectomy.\nPrognosis\nPrognosis is good but depends on the stage of disease with 5- year survival rates as high as 99% in stage 1 disease. Relapse rates at 5 years depend on risk factors (ex. invasion of the rete testis, tumor size >4cm) present, but is only 12% in those with no risk factors.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Hans-Joachim SCHMOLL"}
{"Disease Name": "Testicular teratoma", "Disease Definition": "A rare neoplastic disease characterized by the presence of a testicular tumor composed of several, well-differentiated or immature, tissues derived from one or more of the 3 germinal layers. Patients typically present unilateral (occasionally bilateral) painless testicular swelling or a palpable testicular nodule/mass.", "ORPHA ID": 363483, "Summary": ""}
{"Disease Name": "Tetanus", "Disease Definition": "A toxin-mediated infection due to the anaerobic bacteria Clostridium tetani and characterized by spasms and contractions of the skeletal muscles, the disease is often lethal.", "ORPHA ID": 3299, "Summary": "Epidemiology\nTetanus has almost disappeared from countries where a vaccination policy is ensured and implemented. Annual incidence in developed countries is less than 1 / 1,000,000 inhabitants, and mainly affects patients over 70 years of age. The annual incidence is 100 to 200 times higher in the poorest countries. There are no international statistics on the number of adult cases. In 2015, the number of newborn deaths recorded was 34,000. In 2018 neonatal and maternal tetanus was eliminated in 14 of the 57 countries deemed to be at high risk.\nClinical description\nTetanus can occur at all ages. The first symptoms appear 4 to 20 days after a wound contamination and begin by a trismus. In a few hours or a few days (depending on the severity), these painful contractures will spread to the whole body; they can be accompanied by dysautonomics disorders. Death can occur from respiratory blockade.\nEtiology\nTetanus caused by Clostridium Tetani, a bacterium found in almost all soils and animal droppings and present as spores. It enters the body through a contaminated wound, and produces a neurotropic toxin which gains, following the nervous axes, the neuromuscular junctions where it attaches, causing spasms and contractures of the striated muscles.\nDiagnostic methods\nDiagnosis is exclusively based on clinical signs.\nDifferential diagnosis\nDifferential diagnosis includes local causes of trismus, muscular dystonia induced by certain drugs, and much more rarely, meningitis or certain forms of hysteria.\nManagement and treatment\nTreatment is symptomatic and aims to control contractures with large doses of muscle relaxant drugs or even prolonged curarization, until the toxin is removed, which often requires respiratory resuscitation. The only effective treatment is vaccination. It is 100% effective and there are almost no contraindications. In practice, a vaccine recipient (three injections and a booster after one year, followed by the scheduled booster) will never get tetanus. For injured individuals whose vaccination status is uncertain, the risk of tetanus is constant, and the systematic administration of specific gamma globulin necessary.\nPrognosis\nThe prognosis is variable. The disease lasts from 2 to 4 weeks, the mortality varying between 20 and 80% depending on the severity of the disease, the age of the patient and the local possibilities of resuscitation.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Dr François TREMOLIERES"}
{"Disease Name": "Tetraamelia-multiple malformations syndrome", "Disease Definition": "An extremely rare mostly lethal congenital disorder characterized by absence of all four limbs and frequent associated major malformations involving the head, face, eyes, skeleton, heart, lungs, anus, urogenital, and central nervous systems. The syndrome has been described in fewer than 20 patients mainly of middle Eastern descent.", "ORPHA ID": 3301, "Summary": ""}
{"Disease Name": "Tetragametic chimerism", "Disease Definition": "A rare, sex chromosome disorder of sex development characterized by the two different haploid sets of maternal and paternal chromosomes and variable phenotype - from normal male or female genitalia, to different degrees of ambiguous genitalia, and often infertility. Also, in the cases of monochorionic dizygotic twins, it can be confined to blood of both twins.", "ORPHA ID": 199310, "Summary": ""}
{"Disease Name": "Tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria", "Disease Definition": "A form of phenylketonuria (PKU), an inborn error of amino acid metabolism, characterized by mild to moderate symptoms of PKU including impaired cognitive function, seizures, and behavioral and developmental disorders, and a marked reduction of elevated phenylalanine concentrations after oral loading with tetrahydrobiopterin (BH4), an essential cofactor of phenylalanine hydroxylase.", "ORPHA ID": 293284, "Summary": ""}
{"Disease Name": "Tetralogy of Fallot", "Disease Definition": "Tetralogy of Fallot is a congenital cardiac malformation that consists of an interventricular communication, also known as a ventricular septal defect, obstruction of the right ventricular outflow tract, override of the ventricular septum by the aortic root, and right ventricular hypertrophy.", "ORPHA ID": 3303, "Summary": "Epidemiology\nThis combination of lesions occurs in 1 of every 35,0000-30,000 live births, and accounts for 7-10% of all congenital cardiac malformations.\nClinical description\nPatients nowadays usually present as neonates, with cyanosis of varying intensity based on the degree of obstruction to flow of blood to the lungs.\nEtiology\nThe aetiology is multifactorial, but reported associations include untreated maternal diabetes, phenylketonuria, and intake of retinoic acid. Associated chromosomal anomalies can include trisomies 21, 18, and 13, but recent experience points to the much more frequent association of microdeletions of chromosome 22. The risk of recurrence in families is 3%.\nDiagnostic methods\nUseful diagnostic tests are the chest radiograph, electrocardiogram, and echocardiogram. The echocardiogram establishes the definitive diagnosis, and usually provides sufficient information for planning of treatment, which is surgical.\nDifferential diagnosis\nDifferential diagnosis includes primary pulmonary causes of cyanosis, along with other cyanotic heart lesions, such as critical pulmonary stenosis and transposed arterial trunks (see these terms).\nAntenatal diagnosis\nApproximately half of patients are now diagnosed antenatally.\nManagement and treatment\nNeonates who present with ductal-dependent flow to the lungs will receive prostaglandins to maintain ductal patency until surgical intervention is performed. Initial intervention may be palliative, such as surgical creation of a systemic-to-pulmonary arterial shunt, but the trend in centres of excellence is increasingly towards neonatal complete repair. Centres that undertake neonatal palliation will perform the complete repair at the age of 4 to 6 months.\nPrognosis\nFollow-up in patients born 30 years ago shows a rate of survival greater than 85%. Chronic issues thatnow face such adults include pulmonary regurgitation, recurrence of pulmonary stenosis, and ventricular arrhythmias. As the strategies for surgical and medical management have progressed, the morbidity and mortality of those born with tetralogy of Fallot in the current era is expected to be significantly improved.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Robert ANDERSON  - Dr Fédérique BAILLIARD"}
{"Disease Name": "Tetramelic monodactyly", "Disease Definition": "Tetramelic monodactyly is a rare, genetic, congenital limb malformation disorder characterized by the presence of a single digit on all four extremities. Malformation is typically isolated however, aplastic and hypoplastic defects in the remaining skeletal parts of hands and feet have been reported. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 2564, "Summary": ""}
{"Disease Name": "Tetraploidy", "Disease Definition": "Tetraploidy is an extremely rare chromosomal anomaly, polyploidy, when an affected individual has four copies of each chromosome, instead of two, resulting in total of 92 chromosomes in each cell. The phenotype is severe with multiple congenital anomalies, including central nervous system, ocular, cardiac, renal, and/or genital malformations and limb defects. Most patients show severe intrauterine growth retardation, hypotonia, failure to thrive and developmental delay. It is usually associated with miscarriage.", "ORPHA ID": 3305, "Summary": ""}
{"Disease Name": "Tetrasomy 12p", "Disease Definition": "Pallister-Killian syndrome (PKS) is a rare multiple congenital anomaly/intellectual deficit syndrome caused by mosaic tissue-limited tetrasomy for chromosome 12p.", "ORPHA ID": 884, "Summary": "Epidemiology\nIncidence is uncertain and is estimated around 1/25,000.\nClinical description\nA number of cases are prenatally diagnosed because of abnormal ultrasonic findings, and abnormal presentation at birth is usual. Most common signs include facial dysmorphism, rhizomelic limb shortness, small hands and feet with nail hypoplasia. Craniofacial manifestations include a ``coarse'' face with flat profile, high forehead with temporo-frontal balding, sparseness of eyebrows and lashes, shallow supraorbital ridges, upslanting palpebral fissures, hypertelorism, flat and broad nasal bridge, short nose with upturned nares, large mouth with downturned corners and prominent upper lip. Macroglossia and pointed chin occur with age. Hypotonia is present at birth with contractures developing with age. A wide range of congenital malformations may be present, the most specific being diaphragmatic and anal defects. Heart defects, mainly ventricular septal defects, are present in 25% of cases. Severe intellectual deficit, pigmentary skin anomalies, deafness and seizures are frequent signs.\nEtiology\nPatients with PKS have mosaïcism for a supernumerary isochromosome 12p, resulting in four copies of the short arm of chromosome 12 instead of the normal two. The isochromosome is mostly of maternal origin. Selection against i(12p) cells is observed in vitro, and probably also occur in vivo. Karyotype is 47, XX or XY, i(12)(p10)/ 46,XX or XY.\nDiagnostic methods\nClinical recognition is very important as the additional chromosome is usually absent from routine blood lymphocytes examination. Cytogenetic diagnosis requires skin biopsy and fibroblast chromosome examination. The isochromosome is usually present in 30-100% of fibroblast metaphases. In situ hybridization with chromosome 12-specific DNA probes can be used to confirm the chromosome identity. Interphase FISH on a buccal smear may allow a fast preliminary diagnosis.\nDifferential diagnosis\nDifferential diagnoses include trisomy 12p and Fryns syndrome (see these terms). Antenatal diagnosis may be possible through ultrasound examination revealing abnormal findings such as diaphragmatic hernia, polyhydramnios, hydrops fetalis, cardiac malformations, short limbs, and other, leading to amniocentesis and chromosomal diagnosis.\nAntenatal diagnosis\nAntenatal diagnosis is also possible after choriocentesis for maternal age.\nGenetic counseling\nAll reported cases of this disorder have been sporadic.\nManagement and treatment\nThere is no specific therapy. Affected children may benefit from early intervention programs and special education.\nPrognosis\nPrognosis is usually poor. Death may occur perinatally, mainly due to diaphragmatic hernias, or during the first years of life in about a half of patients. Intellectual deficit is mostly profound and almost always accompanied with seizures. The manifestations (facial dysmorphism and malformations) progress with age. Some patients with a low level mosaïcism are less severely affected.\n\n                            Last update: \n                            January 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Catherine TURLEAU"}
{"Disease Name": "Tetrasomy 18p", "Disease Definition": "Tetrasomy 18p is a very rare structural chromosomal anomaly affecting multiple body systems and characterized clinically by craniofacial abnormalities, delayed development, cognitive impairment, changes in muscle tone, distinctive facial features, and rarely renal malformations.", "ORPHA ID": 3307, "Summary": ""}
{"Disease Name": "Tetrasomy 21", "Disease Definition": "Tetrasomy 21 is an extremely rare autosomal anomaly resulting from the presence of 4 copies of chromosome 21, characterized by features of trisomy 21 including developmental delay/intellectual disability, muscular hypotonia, short neck with redundant skin, brachycephaly, microcephaly, flat face, epicanthus, upslanted palpebral fissures, small ears, protruding tongue, single transverse palmar crease, brachydactyly, hypoplastic iliac wings, together with additional features such as prematurity, intrauterine growth retardation, high and broad forehead, hypertelorism. Haematological malignancies are also associated and may occur earlier than in trisomy 21.", "ORPHA ID": 96055, "Summary": ""}
{"Disease Name": "Tetrasomy 5p", "Disease Definition": "Tetrasomy 5p is a rare chromosomal anomaly syndrome with variable phenotype principally characterized by developmental delay, growth retardation/short stature, hypotonia, seizures, ventriculomegaly, hand and foot anomalies (e.g. clinodactyly, overlapping toes) and mosaic pigmentary skin changes. Patients may also present minor dysmorphic craniofacial features (incl. macrocephaly, upslanting palpebral fissures, hypertelorism, abnormal auricles, anteverted nasal tip, midface hypoplasia).", "ORPHA ID": 3309, "Summary": ""}
{"Disease Name": "Tetrasomy 9p", "Disease Definition": "Tetrasomy 9p is a rare autosomal anomaly characterized by pre- and postnatal growth retardation, psychomotor delay, mild to moderate intellectual disability, hypotonia, microcephaly, dysmorphic features (ocular hypertelorism, low-set, malformed ears, bulbous/beaked nose, microretrognathia, enophthalmos/micropthalmia, epicanthus, strabismus), cleft lip/palate, skeletal abnormalities (hypoplastic nails/distal phalanges, short stature, short neck, contractures), congenital heart defects, renal and urogenital malformations (renal hypoplasia, genital hypoplasia, cryptorchidism).", "ORPHA ID": 3310, "Summary": ""}
{"Disease Name": "Tetrasomy X", "Disease Definition": "Tetrasomy X is a sex chromosome anomaly caused by the presence of two extra X chromosomes in females (48,XXXX instead of 46,XX).", "ORPHA ID": 9, "Summary": "Epidemiology\nPrevalence is unknown but only around 40 cases have been reported in the literature so far.\nClinical description\nTetrasomy X is associated with delayed speech, learning difficulties, developmental delay and facial dysmorphism. Although disease severity is variable, the learning difficulties and developmental delay are generally mild to moderate. Commonly associated facial features include hypertelorism, upslanting palpebral fissures, epicanthal folds and a flat nasal bridge. Other anomalies may include dental abnormalities, hypotonia and joint laxity, radioulnar synostosis, heart defects, hip dysplasia, and ovarian dysfunction. An increased susceptibility to infections during childhood has also been reported.\nEtiology\nTetrasomy X is generally thought to arise as a result of successive maternal nondisjunction during meiosis.\n\n                            Last update: \n                            January 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Natalie AYARI  - Dr A BERGE  - Dr Susan HOWELL  - Dr Nicole TARTAGLIA"}
{"Disease Name": "TFR2-related hemochromatosis", "Disease Definition": "A form of rare hemochromatosis (HC) characterized by excessive tissue iron deposition of genetic origin and presenting with liver disease, hypogonadism, arthritis, diabetes and skin pigmentation.", "ORPHA ID": 225123, "Summary": "Epidemiology\nLess than 50 cases have been reported in the literature. It is mainly found in Caucasian populations but has also been reported in Asia.\nClinical description\nTFR2-related hemochromatosis concerns middle aged-adults but also adolescents and young adults (<30 years old). It resembles symptomatic HFE-related hemochromatosis and presents with liver disease, hypogonadism, arthritis, diabetes and skin pigmentation. Biochemical abnormalities include elevated serum iron, transferrin saturation and ferritin.\nEtiology\nIt is due to mutations of the transferrin receptor 2 gene (TFR2) on chromosome 7. These mutations lead to hypohepcidinemia which in turn causes iron excess through increased intestinal iron absorption and iron release from spleen macrophages.\nDiagnostic methods\nDiagnosis is based on biochemical testing using serum transferrin saturation and serum ferritin, and on imaging testing for quantifying visceral iron overload (magnetic resonance imaging). Molecular genetic blood testing permits to confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes: a) in younger patients: HJV or HAMP-related hemochromatosis and post-transfusional iron overload in the case of hematological diseases such as thalassemia major, sickle cell disease, and other rare iron-loading anemias b) in older patients: HFE-related hemochromatosis and other adult-onset rare forms of non-HFE-related hemochromatosis (SLC40A1-related HC, for example).\nGenetic counseling\nGenetic counseling should be offered to first-degree relatives of patients with genetically confirmed TFR2-related hemochromatosis. Particular focus should be given to siblings as they are at the highest risk (25%).\nManagement and treatment\nPatients are treated by repeated phlebotomies that are performed weekly until the ferritin level reaches 50 µg/L, after which they are performed every 1-3 months.\nPrognosis\nPrognosis can be considered as good, provided that the patients are treated early, before the development of severe visceral complications (especially cirrhosis).\n\n                            Last update: \n                            August 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Graça PORTO | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Thakker-Donnai syndrome", "Disease Definition": "A rare, genetic, lethal, multiple congenital anomalies/dysmorphic syndrome characterized by facial dysmorphism (including long, downward slanting palpebral fissures, hypertelorism, posteriorly rotated ears, broad nasal bridge, short nose with a bulbous tip and anteverted nares, downturned corners of the mouth) as well as vertebral (occult spina bifida, hemivertebrae), brain (ventricular dilatation, agenesis of corpus callosum), cardiac (tetralogy of Fallot, ventricular septal defect) and gastrointestinal (short esophagus with intrathoracic stomach, small intestine, spleen and pancreas, anal atresia) malformations. There have been no further descriptions in the literature since 1991.", "ORPHA ID": 1780, "Summary": ""}
{"Disease Name": "Thalidomide embryopathy", "Disease Definition": "Thalidomide embryopathy is a group of anomalies presented in infants as a result of in utero exposure (between 20-36 days after fertilization) to thalidomide, a sedative used in treatment of a range of conditions, including morning sickness, leprosy and multiple myeloma (see these terms). Thalidomine embryopathy is characterized by phocomelia, amelia, forelimb and hand plate anomalies (absence of humerus and/or forearm, femur and/or lower leg, thumb anomalies). Other anomalies include facial hemangiomas, and damages to ears (anotia, microtia), eyes (microphthalmia, anophthalmos, coloboma, strabismus), internal organs (kidney, heart, and gastrointestinal tract), genitalia, and heart. Infant mortality associated with thalidomide embryopathy is estimated to be as high as 40%. Thalidomide is contraindicated in pregnancy and pregnancy prevention is recommended in women under treatment.", "ORPHA ID": 3312, "Summary": ""}
{"Disease Name": "Thanatophoric dysplasia type 1", "Disease Definition": "A form of thanatophoric dysplasia characterized by prenatal onset of growth deficiency of the limbs of less than 5%, bowed femurs (like a telephone receiver), shortened ribs, and platyspondyly. Fetal MRI can identify temporal lobe abnormalities and a narrow foramen magnum. Postnatally, distinctive facial features include macrocephaly, large anterior fontanel, frontal bossing, midface hypoplasia, proptosis, and low nasal bridge. Neonates usually die shortly after birth due to respiratory insufficiency and/or spinal cord/brain stem compression.", "ORPHA ID": 1860, "Summary": ""}
{"Disease Name": "Thanatophoric dysplasia type 2", "Disease Definition": "A form of thanatophoric dysplasia characterized by prenatal onset of micromelia with straight femurs, platyspondyly, narrow thorax, and cloverleaf skull with increased risk of hydrocephalus and neurological complications. Fetal MRI can identify temporal lobe abnormalities and a narrow foramen magnum. Postnatally, distinctive facial features include macrocephaly, frontal bossing, midface hypoplasia, low nasal bridge, large anterior fontanel, and proptosis. Neonates usually die shortly after birth due to respiratory insufficiency and/or spinal cord/brain stem compression.", "ORPHA ID": 93274, "Summary": ""}
{"Disease Name": "Thanatophoric dysplasia", "Disease Definition": "A primary bone dysplasia with micromelia characterized by micromelia, macrocephaly, narrow thorax, and distinctive facial features. It includes TD, type 1 (TD1) and TD, type 2 (TD2), that can be differentiated from each other by femur and skull shape.", "ORPHA ID": 2655, "Summary": "Epidemiology\nThanatophoric dysplasia (TD) estimated incidence is about 1/20,000 to 1/50,000 births.\nClinical description\nCharacteristic morphological features are seen on prenatal ultrasounds. Late in the 1st trimester, shortening of the long bones is apparent on ultrasound along with increased nuchal translucency. In the 2nd trimester a marked growth deficiency (limb length below 5th percentile) is noted along with relative macrocephaly, a well mineralized skull, and narrow thorax with flattened vertebral bodies. Bowed ''telephone receiver'' femurs (in TD1), cloverleaf skull (in TD2 and a few cases of TD1) and polyhydramnios can also be seen. Neonates are macrocephalic with a large anterior fontanelle, frontal bossing, severe midface hypoplasia and proptosis. The thorax is narrow and bell-shaped. There is significant micromelia with redundant skin folds and brachydactyly with a trident hand configuration is common. Generalized hypotonia is present. CNS abnormalities can include temporal lobe dysplasia, hydrocephalus, and injury from critical foramen magnum stenosis. Rarely, cardiac and renal abnormalities have been reported as well as seizures.\nEtiology\nTD is caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene (4p16.3) which cause overactivity of the FGFR3 protein, resulting in the disturbances in bone growth and other tissues that are characteristic of TD.\nDiagnostic methods\nDiagnosis is usually made in the 2nd to 3rd trimester but is possible earlier with short limbs identified during standard 1st trimester dimensional ultrasound. Molecular genetic testing can be used to screen for FGFR3 mutations and definitely diagnose TD.\nDifferential diagnosis\nDifferential diagnoses include homozygous achondroplasia, achondrogenesis (types 1A, 1B, and 2), SADDAN, short rib-polydactyly syndromes, osteogenesis imperfecta type 2, platyspondylic lethal skeletal dysplasias, dyssegmental dysplasia Silverman-Handmaker type, and campomelic dysplasia.\nAntenatal diagnosis\nAntenatal diagnosis is usually suspected by prenatal ultrasound and can be confirmed by molecular analysis of amniocytes, or by chorionic villus sampling (CVS), or recently by cell free fetal DNA.\nGenetic counseling\nTD is inherited autosomal dominantly but the majority of cases are due to a de novo mutation in the proband. Genetic counseling allows families who have already had one child with TD to know that recurrence rate is about 2%, so the likelihood of having a healthy child is high.\nManagement and treatment\nPrenatally, treatment aims to avoid potential pregnancy and delivery complications. Postnatally, management should focus on the parents' wishes for provision of comfort-care for the newborn versus aggressive management. Respiratory support with a tracheostomy and ventilation is essential for survival in all infants. Hydrocephaly can be treated with the placement of a shunt. Suboccipital decompression can be done when needed to relieve craniocervical junction constriction. Antiepileptic drugs can be given to those with seizures. Hearing aids can be provided to those with hearing loss.\nPrognosis\nPrognosis is poor with death occurring in utero or shortly after birth in almost all cases. Death is likely due to respiratory insufficiency and/or spinal cord/brain stem compression. A few rare cases have been reported where patients survived into childhood with significant medical intervention.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Elaine PEREIRA"}
{"Disease Name": "Theca steroid-producing cell malignant tumor of ovary, not further specified", "Disease Definition": "A rare malignant sex cord stromal tumor of ovary of unknown histological lineage, occurring in adult women, characterized, in most cases, by manifestations of androgen excess (hirsutism, hair loss, amenorrhea, or oligomenorrhea) and, occasionally, Cushing syndrome.", "ORPHA ID": 99917, "Summary": ""}
{"Disease Name": "Thiamine-responsive encephalopathy", "Disease Definition": "Thiamine-responsive encephalopathy is a Wernicke-like encephalopathy (see this term) characterized by seizures responsive to high doses of thiamine.", "ORPHA ID": 199348, "Summary": "Epidemiology\nTwo cases have been described so far.\nClinical description\nClinical features include epilepsy, nystagmus, ophthalmoplegia and ataxia.\nEtiology\nThe disease results from mutations in the SLC19A3 gene, encoding a thiamine transporter.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            October 2009"}
{"Disease Name": "Thiamine-responsive maple syrup urine disease", "Disease Definition": "Thiamine-responsive maple syrup urine disease (thiamine-responsive MSUD) is a less severe variant of MSUD (see this term) that manifests with a phenotype similar to intermediate MSUD (see this term) but that responds positively to treatment with thiamine.", "ORPHA ID": 268184, "Summary": "Epidemiology\nMSUD has an estimated incidence of 1/150,000 live births. The thiamine-responsive type appears to be very rare.\nClinical description\nThiamine-responsive MSUD is poorly characterized. It appears to usually present after infancy with a phenotype very similar to that seen in intermediate MSUD (see this term). Manifestations include feeding problems, poor growth, maple syrup odor in urine and developmental delay. Older children usually present with learning difficulties. Like classic MSUD (see this term), physiological stress can result in acute decompensation with anorexia, nausea, vomiting (at all ages), ataxia (in infants/toddlers), cognitive impairment, sleep disturbances, hallucinations, hyperactivity, mood swings, acute / focal dystonia and choreoathetosis (in adults) that can progress to stupor, coma and cerebral edema, if untreated. Thiamine (doses of 10-1000 mg per day) has improved the leucine tolerance in the few reported cases of this MSUD subtype, but some dietary branched-chain amino-acid (BCAA) restriction remains necessary.\nEtiology\nMSUD is due to mutations in the genes encoding 3 of the 4 subunits of branched-chain 2-ketoacid dehydrogenase (BCKAD) complex. The genes are BCKDHA (19q13.1-q13.2), encoding E1a; BCKDHB (6q14.1), encoding E1b; and DBT (1p31), encoding E2 respectively. Mutations lead to an accumulation of BCAAs (especially leucine) and branched-chain alpha-ketoacids. In thiamine-responsive MSUD, mutations in DBT predominate.\nGenetic counseling\nInheritance is autosomal recessive and genetic counseling is possible.\n\n                            Last update: \n                            April 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Bridget WILCKEN"}
{"Disease Name": "Thiamine-responsive megaloblastic anemia syndrome", "Disease Definition": "Thiamine-responsive megaloblastic anemia (TRMA) is characterized by a triad of megaloblastic anemia, non-type I diabetes mellitus, and sensorineural deafness.", "ORPHA ID": 49827, "Summary": "Epidemiology\nTRMA syndrome has been reported in less than 80 cases worldwide. Its prevalence and incidence are unknown.\nClinical description\nTRMA can present at any age between infancy and adolescence, although often not all key features are manifested at onset. TRMA is typically characterized by the triad of megaloblastic anemia responding to thiamine, sensorineural deafness, and non-type I diabetes mellitus. Clinical megaloblastic anemia manifestations may comprise hyporexia, lethargy, cephalalgia, pallor, diarrhea, and parasthesia in hands and feet. Other variable clinical signs include retinal dystrophy and optic nerve atrophy; short stature; cardiovascular abnormalities including congenital heart defects such as atrial and/or ventricular septal defect and arrhythmia/conduction anomalies; seizures and strokes. The variable phenotypic presentation of TRMA syndrome may cause a significant delay between the onset of symptoms and an accurate diagnosis.\nEtiology\nTRMA is an autosomal recessive disorder caused by heterogeneous mutations in the high-affinity transporter SLC19A2, located to chromosome 1q23.3. Nearly all patients identified are homozygous for the SLC19A2 mutations, but a small number of heterozygous mutations have been reported.\nDiagnostic methods\nDiagnosis of TRMA is based on clinical findings and can be confirmed by a bone marrow assessment showing megaloblastic anemia in association with erythroblasts with iron-filled mitochondria (ringed sideroblasts) and by molecular genetic analysis of the  SLC19A2 gene. Affected individuals have normal thiamine serum levels. Newborns should be screened by distortion-product otoacoustic emissions (DPOAE) and brainstem evoked response audiometry (BERA).\nDifferential diagnosis\nDifferential diagnosis includes Wolfram syndrome, mitochondrial disorders such as Kearns-Sayre syndrome and Pearson syndrome (see these terms), as well as dietary vitamin B12 or folate deficiency.\nAntenatal diagnosis\nPrenatal diagnosis is possible by amniocentesis or chorionic villus sampling and specific gene analysis.\nGenetic counseling\nThe SLC19A2 mutation is transmitted as an autosomal recessive trait. Genetic counseling should be offered to affected individuals and their families informing them of the possibilities of carrier testing for at-risk family members and the genetic risk for transmission to their children. Many patients are from consanguineous families, so it is difficult to ascertain whether all of the clinical features reported in some families are solely associated with the SLC19A2 mutation.\nManagement and treatment\nTreatment is symptomatic and includes daily significant doses of thiamine (vitamin B1; 25-75 mg per day) to alleviate anemia and to possibly improve diabetes mellitus short-term and long-term outcome. Hearing loss appears irremediable and has a variable timeframe. There is still debate on whether prenatal and early thiamine treatment in affected individuals significantly delays the onset and reduces the hearing defect; several patients diagnosed at a young age have preserved hearing with thiamine treatment since a young age. Hearing aids and palliative care are recommended. Management includes regular hematological monitoring, glucose tolerance, urine, hearing, ophthalmologic and cardiac assessment.\nPrognosis\nPrognosis is variable. Once hearing is lost, it cannot be restored, whereas the anemia is generally reversible and the diabetes is often ameliorated for some time, and to some degree, with treatment. For patients with appropriate treatment and regular follow-up normal life expectancy should be achievable.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Ellis NEUFELD"}
{"Disease Name": "Thickened earlobes-conductive deafness syndrome", "Disease Definition": "Thickened earlobes-conductive deafness syndrome is characterized by microtia with thickened ear lobes, micrognathia and conductive hearing loss due to congenital ossicular anomalies. It has been described in two families. The mode of inheritance is autosomal dominant.", "ORPHA ID": 2405, "Summary": ""}
{"Disease Name": "Thiel-Behnke corneal dystrophy", "Disease Definition": "Thiel-Behnke corneal dystrophy (TBCD) is a rare form of superficial corneal dystrophy characterized by sub-epithelial honeycomb-shaped corneal opacities in the superficial cornea, and progressive visual impairment.", "ORPHA ID": 98960, "Summary": "Epidemiology\nPrevalence of this form of corneal dystrophy is not known. Cases have been reported in Germany, the USA and in other countries.\nClinical description\nCorneal erosions develop in the first and second decade of life and cause ocular discomfort and pain. The erosions recur and vision gradually becomes impaired.\nEtiology\nThiel-Behnke corneal dystrophy appears to be caused by mutation in the TGFBI gene (5q31), like Reis-Bücklers corneal dystrophy. However, there appears to be genetic heterogeneity as another locus has also been identified on chromosome 10 (10q23-q24).\nDiagnostic methods\nHistological examinations reveal a variable thickness of the corneal epithelium. The epithelial basal lamina and Bowman layer display variable degenerative changes. Irregular subepithelial collagenous tissue is also found.\nDifferential diagnosis\nTBCD is clinically similar to Reis-Bücklers corneal dystrophy (RBCD, see this term), but generally has a less severe course. Tissue examination or molecular genetic analysis can be used to differentiate TBCD and RBCD.\nGenetic counseling\nThis entity has an autosomal dominant mode of inheritance.\nManagement and treatment\nThe pathologic corneal tissue can be excised surgically or with an eximer laser.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "Thiemann disease, familial form", "Disease Definition": "A very rare genetic necrotic bone disorder characterized clinically by painless swelling of the proximal interphalangeal joints associated with osteonecrosis of epiphyses followed by osteoarthritic changes, with onset before 25 years of age and often a benign course.", "ORPHA ID": 3314, "Summary": ""}
{"Disease Name": "Thin ribs-tubular bones-dysmorphism syndrome", "Disease Definition": "An extremely rare, lethal, primary bone dysplasia characterized by thin ribs, thin long bones, high-arched palate and facial features of frontal bossing and low-set, posteriorly rotated ears. Bilateral cryptorchidism may be also observed. There have been no further descriptions in the literature since 1990.", "ORPHA ID": 1506, "Summary": ""}
{"Disease Name": "Thinking seizures", "Disease Definition": "Thinking seizures is a rare neurologic disease characterized by seizures induced by specific cognitive tasks, such as calculation or solving arithmetic problems (e.g. Sudoku puzzle), playing thinking games (e.g. Rubik's cube, chess, cards), thinking, making decisions and abstract reasoning. Idiopathic generalized seizures are mainly involved, but partial epilepsies may, in rare cases, be observed.", "ORPHA ID": 166424, "Summary": ""}
{"Disease Name": "Third branchial cleft anomaly", "Disease Definition": "A rare otorhinolaryngeal malformation characterized by a soft, fluctuant mass, abscess or draining tract along the anterior border of the lower half of sternocleidomastoid muscle, occasionally leading to development of retropharyngeal absces, acute suppurative thyroiditis, stridor, respiratory distress, odynophagia,and dysphagia. Anomaly occurs as a tract from the piriform sinus to the thyroid gland. A third branchial cleft fistula passes superficial to both the superior and recurrent laryngeal nerves, which is the main difference in comparison to the fourth branchial cleft fistula.", "ORPHA ID": 141030, "Summary": ""}
{"Disease Name": "THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome", "Disease Definition": "A rare, autosomal recessive, syndromic intellectual disability disorder characterized by global development delay, mild microcephaly, mild to severe intellectual disability and non-specific facial dysmorphism in association with variable multiple congenital anomalies including congenital heart defects, dental anomalies, cryptorchidism, renal and cerebral malformations. Short stature is frequent.", "ORPHA ID": 363444, "Summary": "Epidemiology\nFirst described in two Hutterite families, there are now approximately 20 affected individuals reported worldwide.\nClinical description\nAffected individuals have mild to severe intellectual disability and are non-verbal or have limited speech. The most relevant congenital anomalies include cardiac malformations (atrial and/or ventricular septal defects, patent ductus arteriosus), renal anomalies (unilateral agenesis or ectopic kidney), multiple teeth caries and/or malocclusion, cryptorchidism, anteriorly displaced anus, ventriculomegaly and corpus callosus dysgenesis. Short stature is reported in approximately half of individuals. Several recurrent craniofacial features have been described including mild microcephaly, tall forehead, high anterior hairline, short upslanting palpebral fissures, deep-set eyes, a long nose with low-hanging columella. The facial features are non-specific. More rarely, affected individuals could have hypergonadotropic hypogonadism (in females), seizures, low birth weight, feeding difficulties, hearing loss and/or eye abnormalities.\nEtiology\nThe syndrome is caused by homozygous mutations in THOC6, encoding for a protein of the THO/TREX (transcription/export) complex, which is involved in the transcription of mRNA as well as the export of spliced mRNA from the nucleus; it is supposed to play a crucial role in both embryogenesis and human neurodevelopment.\nDiagnostic methods\nDiagnosis is based on molecular studies: for Hutterite communities, testing the specific c.136G>A variant can be considered; for non-Hutterite individuals, multigene panels for intellectual disability, chromosome microarray analysis, or exome array are indicated.\nDifferential diagnosis\nDue to the non-specific characteristics of the syndrome, all disorders with intellectual disability and without other distinctive features should be investigated.\nAntenatal diagnosis\nPrenatal testing is possible when a pathogenic variant is already known in the family.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. Carrier testing is possible where the pathogenic variant has been previously identified in a family member.\nManagement and treatment\nManagement requires a lifelong multidisciplinary approach, including a pediatrician, neurologist, otorhinolaryngologist (assessment for hearing loss), ophthalmologist, cardiologist, radiologist and gastroenterologist (to evaluate feeding problems and consider gastrostomy). Developmental assessments are needed to tailor medical services, develop an individualized education plan, and promote occupational therapy. Moreover, a behavioral assessment for signs of autism spectrum disorder is recommended. Annual evaluation of renal function should be considered in those with anomaly of kidney/urinary tract. Surgery is required in case of cryptorchidism while females older than 12 require an endocrine consultation. Need for family support (e.g. social work involvement, palliative care, home nursing) should be evaluated at each visit. No specific pharmacological therapy is available.\nPrognosis\nThe course of the disease is non-progressive. Longitudinal data are insufficient to determine life expectancy, although survival into adulthood is possible. Need for life-long support from caregivers depends on the severity of intellectual disability.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Andrea ACCOGLI | ITHACA* - Dr Valeria CAPRA | ITHACA* - Dr Gianluca PICCOLO | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Thomas syndrome", "Disease Definition": "Thomas syndrome is characterised by renal anomalies, cardiac malformations and cleft lip or palate. It has been described in six patients. Transmission was suggested to be autosomal recessive.", "ORPHA ID": 3316, "Summary": ""}
{"Disease Name": "Thomsen and Becker disease", "Disease Definition": "A rare, genetic, skeletal muscle channelopathy characterized by slow muscle relaxation after contraction (myotonia).", "ORPHA ID": 614, "Summary": "Epidemiology\nWorldwide prevalence is estimated at 1/100,000.\nClinical description\nOnset occurs early in life, usually in the first two decades, with myotonia potentially affecting every muscle after contraction, most frequently lower limb and hand muscles. Myotonia usually improves with exercise (e.g. after warm-up). Myotonia congenita may be inherited as an autosomal dominant (Thomsen disease) or recessive (Becker's disease) inheritance, with a more severe and earlier phenotype in recessively inherited disease.\nEtiology\nDisease is caused by loss of function mutations in the gene encoding the chloride channel, CLCN1 (7q34), that plays a role in muscle cell repolarization.\nDiagnostic methods\nThe clinical diagnosis can easily be confirmed by electromyography (EMG), which reveals myotonic discharges in association with hyperexcitation of the muscle fiber membrane. EMG testing under exercise and cold stress allows detailed characterization of the myotonia and helps orientate the molecular diagnosis. Identification of mutations in the chloride channel gene can be considered as diagnostic.\nDifferential diagnosis\nSteinert myotonic dystrophy, proximal myotonic myopathy and sodium channel channelopathies should be always considered in the differential diagnosis. Steinert myotonic dystrophy and proximal myotonic myopathy represent the most relevant differential diagnosis; these diseases present with fixed muscle weakness and wasting, and multisystem involvement, which are usually not associated to Thomsen and Becker disease, and occasionally may present with only myotonia. In addition, some degree of weakness may be observed in Thomsen and Becker disease, especially in later disease stages. Sodium muscle channelopathies may present with myotonia, which may be very similar to that reported in Thomsen and Becker disease or characterized by worsening with exercise, the so-called ''paradoxical myotonia'' (paramyotonia congenita).\nGenetic counseling\nThe mode of transmission may be autosomal dominant (Thomsen myotonia) or autosomal recessive (Becker myotonia). Although some clinical and EMG clues may help distinguish Thomsen from Becker disease, genetic counselling should be proposed and the results of the molecular analysis should be interpreted with care as the same mutations have been associated with both dominant and recessive modes of transmission depending on the family studied.\nManagement and treatment\nTreatment revolves around sodium channel blocking agents such as mexiletine hydrochloride (indication approved in Europe), carbamazepine, phenytoin, ranolazine or lamotrigine.\nPrognosis\nMyotonia congenital prognosis is relatively good, with normal life expectancy. Becker disease is considered more severe than Thomsen disease.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Lorenzo MAGGI  - Dr Renato MANTEGAZZA"}
{"Disease Name": "Thoracic dysplasia-hydrocephalus syndrome", "Disease Definition": "A rare syndromic primary bone dysplasia characterized by short ribs with a narrow chest and thoracic dysplasia, mild rhizomelic shortening of the limbs, communicating hydrocephalus, and developmental delay. There have been no further descriptions in the literature since 1987.", "ORPHA ID": 1861, "Summary": ""}
{"Disease Name": "Thoracic outlet syndrome", "Disease Definition": "Thoracic outlet syndrome (TOS) is a group of disorders characterized by paresthesias, pain and weakness of the upper extremities due to compression, tension or inflammation of the neurovascular bundle as it passes through the thoracic outlet. There are 3 forms of TOS with different clinical pictures and etiologies: neurogenic TOS (NTOS) that can be divided into true or disputed forms, arterial TOS (ATOS) and venous TOS (VTOS) (see these terms).", "ORPHA ID": 97330, "Summary": "Epidemiology\nThe diagnosis of TOS remains controversial so the true incidence is unknown. Neurogenic TOS is the most frequently observed form accounting for 95% of all cases with 99% of these being disputed NTOS.\nClinical description\nCompression typically occurs at the interscalene triangle, the costoclavicular space between the first thoracic rib and clavicle, or the subcoracoid space beneath the pectoralis minor tendon causing pain, paresthesias and weakness in the upper extremities. Patients are unable to maintain the position of opening and closing hands while arms are in an elevated position for 3 minutes (the Roos test).\nEtiology\nDepending on the subtype, TOS is due to subclavian vein obstruction (in VTOS), subclavian artery compression (in ATOS) or lower trunk brachial plexus compression, scarring of scalene muscles, poor posture or a congenital anomaly (in NTOS).\n\n                            Last update: \n                            May 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Joseph FEINBERG  - Dr Paul SCHOLTEN"}
{"Disease Name": "Thoraco-abdominal enteric duplication", "Disease Definition": "Thoraco-abdominal enteric duplication is a rare, syndromic intestinal malformation characterized by single or multiple smooth-walled, often tubular, cystic lesions, which on occasion contain ectopic gastric mucosa, located in the thorax (usually in the posterior mediastinum and to the right of the midline) and in the abdomen. Infants usually present with respiratory distress and older patients with heartburn, abdominal pain, vomiting and/or melena. Vertebral anomalies in the lower cervical spine, with CNS involvement, are frequently present and complications, such as bowel obstruction, perforation and intussusception, have also been reported.", "ORPHA ID": 1759, "Summary": ""}
{"Disease Name": "Thoracolaryngopelvic dysplasia", "Disease Definition": "Thoracolaryngopelvic dysplasia is a short-rib dysplasia characterized by thoracic dystrophy, laryngeal stenosis and a small pelvis.", "ORPHA ID": 3317, "Summary": "Epidemiology\nPrevalence is unknown but less than 10 cases have been reported in the literature so far.\nClinical description\nPatients present with severe respiratory distress (requiring intubation) during the neonatal period. The rib shortening is less severe than in Jeune syndrome (see this term) and the thorax is characteristically small, narrow and bell-shaped. The pelvis is reduced in all dimensions and the combination of the thorax anomalies and the small pelvis give the appearance of a protruding abdomen. Subglottic stenosis has also been described but it remains unclear whether this is a congenital anomaly or is secondary to long-term intubation. In addition, several cases of thoracopelvic dysostosis (without laryngeal involvement) have been described, which could represent heterogeneous expression of the same syndrome or a distinct entity.\nGenetic counseling\nTransmission is autosomal dominant.\n\n                            Last update: \n                            November 2008"}
{"Disease Name": "Thoracomelic dysplasia", "Disease Definition": "A rare primary bone dysplasia disorder characterized by a bell-shaped thorax, disproportionate short stature, pelvic hypoplasia, dislocatable radial heads and elongated distal fibulae. No acetabular spurs nor phalangeal cone-shaped epiphyses are present and osseous manifestations tend to normalize with age. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 1803, "Summary": ""}
{"Disease Name": "Thrombocythemia with distal limb defects", "Disease Definition": "Thrombocythemia with distal limb defects is a rare, genetic syndrome with limb reduction defects characterized by thrombocytosis, unilateral transverse limb defects (ranging from absence of phalanges to absence of hand or forearm) and splenomegaly.", "ORPHA ID": 329319, "Summary": ""}
{"Disease Name": "Thrombocytopenia with congenital dyserythropoietic anemia", "Disease Definition": "Thrombocytopenia with congenital dyserythropoietic anemia (CDA; see this term) is a rare hematological disorder, seen almost exclusively in males, characterized by moderate to severe thrombocytopenia with hemorrhages with or without the presence of mild to severe anemia.", "ORPHA ID": 67044, "Summary": "Epidemiology\nThe prevalence is unknown. At least 3 families have been described with thrombocytopenia with CDA and GATA1 mutations in the literature.\nClinical description\nThe disease affects mainly males as females are usually asymptomatic or have only mild symptoms. It presents in infancy or in neonates (in severe cases) with patients bruising easily along with further manifestations of thrombocytopenia including epistaxis, petechiae, ecchymoses, or splenomegaly. Anemia is often present but can range from mild to severe. Excessive hemorrhage and/or bruising can occur in some patients after trauma or spontaneously in others. Cryptorchidism has also been reported in several cases.\nEtiology\nThe disease is caused by mutations in the GATA1 (Xp11.23) gene encoding GATA1, a transcriptional regulator involved in erythropoiesis and megakaryocytopoiesis. Different mutations found in this gene account for a variable phenotypic spectrum of disorders.\nDiagnostic methods\nDiagnosis is based on family history of the disease and laboratory findings. Blood count reveals thrombocytopenia, in some cases anemia, and very rarely neutropenia. Platelets often have functional abnormalities, shown by a defect in the aggregation response to agonists. Peripheral blood smear shows abnormal erythrocyte size and shape as well as paucity of platelets. Bone marrow biopsy can reveal dyserythropoiesis, dysmorphic erythroblasts, and dysplastic platelets and megakaryocytes. Molecular genetic testing can identify GATA1 mutations.\nDifferential diagnosis\nDifferential diagnosis includes myelodysplastic syndromes, thalassemias, Gilbert syndrome, hereditary spherocytosis, acute erythroid leukemia (see these terms), folate, iron or vitamin B12 deficiencies as well as infections such as AIDS, malaria (see this term), kala-azar or other acquired or inherited thrombocytopenias. Wiskott-Aldrich Syndrome (see this term) should also be excluded.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known GATA1 mutation.\nGenetic counseling\nThe disease is inherited in an X-linked manner and genetic counseling is possible. Most females are asymptomatic carriers.\nManagement and treatment\nThose with very mild symptoms do not require treatment. Thrombocytopenia related manifestations can be treated with platelet transfusions. For short-term mild to moderate bleeding, desmopressin may also be beneficial. Those with severe hydrops fetalis (see this term) related anemia will need an in utero transfusion and transfusions can be required after birth for those with severe anemia. Blood iron levels should be closely monitored in those undergoing regular transfusions. Bone marrow transplantation (BMT) can be considered in those with life-threatening manifestations. Antiplatelet agents, nonsteroidal anti-inflammatory agents and activities with a high risk of trauma should be avoided.\nPrognosis\nPrognosis depends on the severity of the disease. Quality of life may be affected in those with a serious form of the disease, and iron overload due to repeated blood transfusions to treat anemia can be very damaging if left untreated.\n\n                            Last update: \n                            September 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Mayka SÁNCHEZ FERNÁNDEZ"}
{"Disease Name": "Thrombocytopenia-absent radius syndrome", "Disease Definition": "A rare congenital malformation syndrome characterized by bilateral absence/hypoplasia of the radii with presence of both thumbs, and thrombocytopenia. Additional manifestations can include cow's milk allergy, anomalies of the lower limbs, heart and genitourinary system.", "ORPHA ID": 3320, "Summary": "Epidemiology\nThe prevalence of thrombocytopenia-absent radius (TAR) syndrome is estimated at around 1/100,000-200,000 people.\nClinical description\nIndividuals with TAR syndrome almost always have bilateral absence or hypoplasia of the radii. The thumbs are always present, which is highly specific for TAR syndrome. Upper limbs may be more severely affected (hypoplasia or absence of the ulnae and/or humeri, fingers syndactyly, fifth-finger clinodactyly). Lower limbs are affected in almost 50% of cases with variable severity (hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, absence of the patella). The most severe limb involvement is tetraphocomelia. Thrombocytopenia is congenital or develop within the first few weeks to months of life. Usually, platelet counts remain low during the first two years of life; then, they increase but do not normalize. Additional recurrent manifestations include: cardiac anomalies (atrial and/or ventricular septal defect, patent foramen ovale), gastro-intestinal involvement (cow's milk allergy, increased susceptibility to gastro-enteritis), genitourinary anomalies (kidney agenesis or malrotation, horseshoe kidney, hydronephrosis, pyelectasis). Other rare manifestations include Mayer-Rokitansky-Kuster-Hauser syndrome, rib and vertebral anomalies, Langerhans cell histiocytosis, transient leukemoid reaction, acute myeloid or lymphoblastic leukemia. Cognitive development is usually normal.\nEtiology\nTAR syndrome is caused by compound heterozygosity for a null (most often a 1q21.1 deletion including RBM8A) and a hypomorphic RBM8A allele.\nDiagnostic methods\nDiagnosis is made on the clinical signs and confirmed by molecular genetic testing.\nDifferential diagnosis\nThe main differential diagnoses are other disorders associated with radial aplasia, with a genetic etiology (Holt-Oram syndrome, ESCO2-spectrum disorder, Fanconi anemia, RAPADILINO syndrome, SALL4-related disorders), or not (VACTERL association, thalidomide embryopathy, fetal valproate spectrum disorder).\nAntenatal diagnosis\nAntenatal diagnosis may be suspected by fetal ultrasound examination identifying radial anomalies, and confirmed by molecular genetic testing.\nGenetic counseling\nTAR syndrome is inherited in an autosomal recessive manner. Penetrance is complete, with variable expressivity. Several characteristics are unusual in autosomal recessive disorders: null alleles are rare and can occur de novo in the proband, the percentage of affected sibs is consequently lower than expected; hypomorphic alleles are common, therefore an apparent parent-to-child transmission can be observed resulting in pseudo-dominant inheritance. Biallelic carriers of hypomorphic variants are asymptomatic.\nManagement and treatment\nThere is no curative treatment for TAR syndrome. Symptomatic treatment of manifestations and prevention of complications include: early detection of thrombocytopenia, prevention of bleeding and hemorrhage, platelet transfusions in case of severe thrombocytopenia, surgical interventions if required to manage cardiac, urinary or skeletal malformations, avoidance of cow's milk.\nPrognosis\nPrognosis is variable and mainly conditioned by the severity of thrombocytopenia and its complications (intracranial, digestive hemorrhage). Cardiac defects, renal malformations, acute complications of cow's milk intolerance, acute leukemia can also affect the prognosis.\n\n                            Last update: \n                            August 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Simon BOUSSION | ITHACA* - Pr Florence PETIT | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Thrombomodulin-related bleeding disorder", "Disease Definition": "A rare genetic coagulation disorder characterized by marked bleeding tendency and posttraumatic bleeding with easy bruising, soft tissue and muscle bleeding, hemarthroses, and menorrhagia due to an increase of soluble thrombomodulin in plasma with subsequent protein C activation and reduction of thrombin generation within a potential thrombus. Abnormal laboratory findings include markedly elevated plasma thrombomodulin, reduced prothrombin consumption, and decreased thrombin generation.", "ORPHA ID": 436169, "Summary": ""}
{"Disease Name": "Thrombotic thrombocytopenic purpura", "Disease Definition": "An aggressive and life-threatening form of thrombotic microangiopathy (TMA) characterized by profound peripheral thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and organ failure of variable severity and is comprised of a congenital (cTTP) and acquired, immune-mediated (iTTP) form.", "ORPHA ID": 54057, "Summary": "Epidemiology\nThe prevalence of thrombotic thrombocytopenic purpura (including both acquired and congenital forms) is difficult to determine. Worldwide, the incidence for iTTP ranges from 1/165,000-1,000,000 and, in France the prevalence is estimated at 1/77,000. The prevalence of cTTP ranges from 1/ 60,000-2,500,000.\nClinical description\niTTP generally occurs in adulthood, whereas cTTP usually in the neonatal period, during childhood or in the setting of pregnancy. Onset is usually acute but early symptoms may include fatigue, purpura or ecchymoses, abdominal pain, arthralgia and myalgia, resembling a flu-like episode. Disseminated microvascular thrombosis leads to consumptive peripheral thrombocytopenia, MAHA and widespread organ injury associated with cerebral (headache, confusion, altered consciousness, coma, seizures, hemiparesis and visual disturbances), cardiac (arrhythmia, infarction, congestive heart failure and cardiac arrest) and gastrointestinal (nausea, vomiting, abdominal pain and diarrhea) manifestations. Purpura and petechiae are the most common bleeding manifestations. Renal involvement is usually mild. Fever occurs in less than 50% of patients. Patients with iTTP may suffer from only one episode, but relapses can occur in 30 to 40% of cases in the absence of preemptive therapies. A chronic and frequently relapsing disease course is more typical in those with cTTP, without prophylactic treatment.\nEtiology\nTTP is caused by a severely decreased activity (< 10%) of ADAMTS13, a metalloprotease involved in the cleavage of ultra-large von Willebrand factor multimers. In cTTP, ADAMTS13 deficiency is caused by homozygous or compound heterozygous mutations ADAMTS13 (9q34), whereas it is associated with the presence of anti-ADAMTS13 immunoglobulin G (IgG) antibodies in iTTP.\nDiagnostic methods\nFirst, the diagnosis of TMA must be evoked in a patient with MAHA and a negative direct antiglobulin test, associated with a peripheral thrombocytopenia, especially if there is an associated organ failure (cerebral, renal or cardiac involvement, abdominal pain). Once the diagnosis of TMA is made, TTP must be recognized. The diagnosis can be strongly suspected in a patient with TMA when thrombocytopenia is profound (platelet count < 30 x109/L) and when renal involvement is only mild (serum creatinine level < 2.27 mg/dL). However, the diagnosis of TTP can only be ascertained by an undetectable ADAMTS13 activity (activity < 10%). cTTP is characterized by a persistently severe ADAMTS13 deficiency with no identifiable anti-ADAMTS13 antibodies. The sequencing of ADAMTS13 gene then identifies bi-allelic mutations. Acquired, iTTP is associated with anti-ADAMTS13 antibodies in serum. In 20% of cases, antibodies may not be detectable, but ADAMTS13 activity normalizes after the acute phase.\nDifferential diagnosis\nDifferential diagnosis includes other TMAs (hemolytic uremic syndrome, TMA secondary to transplantation, chemotherapy, drug, HIV/AIDS, as well as HELLP syndrome) and other diseases including catastrophic antiphospholipid syndrome, severe sepsis, vitamin B12 deficiency, malignant hypertension and severe disseminated intravascular coagulopathy.\nGenetic counseling\ncTTP is inherited autosomal recessively and genetic counseling is suggested. The risk of inheriting the disease is 25% where both parents are unaffected carriers.\nManagement and treatment\nGiven the severity of the disease and the risk of sudden organ failure, management in intensive care units until platelet count recovery is recommended. The current standard of care consists of plasma exchange replenishing active ADAMTS13 from donors' plasma (and to a lesser extend removing anti-ADAMTS13 antibodies and pro-aggregant substances), immunosuppressive therapies (e.g. glucocorticoids and rituximab) to prevent ADAMTS13 antibody production, and caplacizumab. Caplacizumab is a nanobody that targets von Willebrand factor (VWF) and accelerates platelet count recovery and prevents worse outcomes. After recovery, patients benefit from long-term follow-up with regular assessment of ADAMTS13 activity. Where decreased ADAMTS13 activity is observed, a preemptive infusion of rituximab should be proposed.\nPrognosis\nWith a rapid diagnosis and the current standard of treatment, the prognosis of the disease is usually excellent with a complete recovery in more than 95% of cases. However, in a substantial number of cases patients suffer neurocognitive disorders including chronic fatigue, problems of memory and concentration, as well as depression. These troubles still have no clear explanation, and significantly impact quality of life.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Paul COPPO"}
{"Disease Name": "Thumb deformity-alopecia-pigmentation anomaly syndrome", "Disease Definition": "Thumb deformity-alopecia-pigmentation anomaly syndrome is a rare, genetic, congenital limb malformation syndrome characterized by short stature, sparse scalp hair, hypoplastic, proximally-placed thumbs, and skin hyperpigmentation with areas of 'raindrop' depigmentation. Presence of a single, upper central incisor has also been reported. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 2251, "Summary": ""}
{"Disease Name": "Thumb stiffness-brachydactyly-intellectual disability syndrome", "Disease Definition": "A rare, genetic, congenital limb malformation syndrome characterized by bilateral thumb ankylosis, type A brachydactyly and mild to moderate intellectual disability. Patients present thumb stiffness and abnormalities of the metacarpal bones, frequently associated with mild facial dysmorphism and signs of obesity. There have been no further descriptions in the literature since 1990.", "ORPHA ID": 1078, "Summary": ""}
{"Disease Name": "Thygeson superficial punctate keratitis", "Disease Definition": "A rare disorder of the anterior segment of the eye characterized by chronic recurrent epithelial keratitis manifesting with groupings of small, slightly elevated, ovoid, grayish-white intraepithelial opacities, usually located in the central cornea. Patients present with photophobia, tearing, foreign body sensation, and blurred vision. The condition is typically bilateral, takes a relapsing-remitting course, and is mostly self-limiting after a few years.", "ORPHA ID": 519406, "Summary": ""}
{"Disease Name": "Thymic carcinoma", "Disease Definition": "Thymic carcinoma (TC) is a type of thymic epithelial neoplasm (see this term) characterized by a high malignant potential.", "ORPHA ID": 99868, "Summary": "Epidemiology\nThe exact prevalence or incidence is unknown. It represents 1% of the anterior mediastinal tumors and occurs in all ages but more frequently between the ages of 30 and 60 years. The male to female ratio is 1.5:1.\nClinical description\nPatients can be asymptomatic but more often present with chest-related symptoms (cough, chest pain), phrenic nerve palsy, or superior vena cava syndrome. Contrary to patients with thymoma (see this term), myasthenia gravis or paraneoplastic syndromes are rarely observed.\nEtiology\nEtiology is unknown.\nDiagnostic methods\nDiagnosis is based on clinical findings and on radiological studies. Chest X-rays reveals a mediastinal mass. Computed tomography, magnetic resonance imaging (MRI), magnetic resonance angiography (angio-MRI) and/or positron emission tomography (PET) further evaluate the lesion. Tissue biopsy, usually performed by CT- or ultrasound-guided percutaneous needle-biopsy, is used to confirm a diagnosis of malignancy. Complete excision is required for definitive histologic typing. TC is composed of atypical cells of an invasive nature and lacks immature (or cortical) T cells. Several histologic subtypes are observed: the most common are squamous cell carcinoma, mucoepidermoid carcinoma and lymphoepithelioma-like carcinoma while rarer variants include clear cell carcinoma, basaloid carcinoma, spindle cell carcinoma, and anaplastic carcinoma. Extremely rare variants include papillary carcinoma, adenocarcinoma, and rhabdoid carcinoma. The diagnosis of thymic carcinoma is one of exclusion, as there are no morphologic, immunohistochemical, ultrastructural or cytogenetic/molecular features that are pathognomonic for this tumor. Histologically, the tumors may resemble carcinomas commonly arising in other organs. For this reason, the diagnosis can only be established by exclusion through careful demonstration on clinical history, clinical examination, and radiographic and endoscopic examination of the absence of a primary tumor elsewhere.\nDifferential diagnosis\nDifferential diagnoses include lymphoma, germ-cell tumors (see these terms), and other primary thymic malignancies and metastatic cancers.\nManagement and treatment\nTreatment consists in total thymectomy and complete tumor excision usually accompanied by neoadjuvant or adjuvant therapy consisting of radiotherapy, chemotherapy, or both. In case of metastatic TC, platinum-based chemotherapy is the first-line treatment.\nPrognosis\nPrognosis is poor due to the high frequency of recurrences and metastases in the pleura, lung, lymph nodes, bone, brain, and liver. The survival rate at 5 years is 35%.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Saul SUSTER"}
{"Disease Name": "Thymic epithelial neoplasm", "Disease Definition": "Thymic epithelial neoplasms (TEN) are rare malignancies arising from the epithelium of the thymic gland. They comprise three sub-types: thymoma, thymic carcinoma, and thymic neuroendocrine carcinoma (see these terms).", "ORPHA ID": 3398, "Summary": "Epidemiology\nTENs have an annual incidence of approximately 1/588,000. Thymoma is the most frequent subtype, while thymic carcinoma and thymic neuroendocrine carcinoma represent 1% and 2-4% of the anterior mediastinal tumors, respectively. The two latter have a higher malignant potential than thymoma. TENs usually occur in adults from 30 to 80 years of age, with a median age of 60 years, but they can also occur during childhood.\nClinical description\nMost adult patients are asymptomatic, while in children nearly two thirds present with symptoms that include cough, chest pain, weight loss, fatigue and dyspnea. Many autoimmune syndromes are associated with TENs. Myasthenia gravis (see this term) is observed in 30-50% of thymoma cases. Phrenic nerve palsy and superior vena cava syndrome are usually observed in cases of thymic carcinoma.\nEtiology\nEtiology is unknown.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Saul SUSTER"}
{"Disease Name": "Thymic neuroendocrine carcinoma", "Disease Definition": "Thymic neuroendocrine carcinoma is a type of thymic epithelial neoplasm (see this term) displaying evidence of neuroendocrine differentiation.", "ORPHA ID": 99869, "Summary": "Epidemiology\nThe exact prevalence or incidence is unknown. Thymic neuroendocrine carcinomas represent 2-4% of the anterior mediastinal tumors. More than 300 cases have been reported to date. Men are predominantly affected.\nClinical description\nMany of the patients are asymptomatic but some present with chest-related symptoms such as cough, chest pain, weight loss, fatigue and dyspnea. Cushing's syndrome, multiple endocrine neoplasia, and, rarely, carcinoid syndrome (see these terms) are associated with this type of tumor.\nEtiology\nEtiology is unknown.\nDiagnostic methods\nDiagnosis is based on clinical findings, radiological studies (chest X-rays, computed tomography, magnetic resonance imaging (MRI), angiography (angio-MRI) and/or positron emission tomography (PET)), and on tissue biopsy, usually performed by CT- or ultrasound-guided percutaneous needle-biopsy. Three histological subtypes are observed: well-differentiated neuroendocrine carcinoma (formerly known as ''thymic carcinoid''), moderately-differentiated neuroendocrine carcinoma (formerly known as ''atypical carcinoid''), and poorly-differentiated neuroendocrine carcinoma (also known as small cell carcinoma of the thymus).\nDifferential diagnosis\nDifferential diagnosis includes lymphoma, germ-cell tumors (see these terms), and other primary thymic malignancies and metastatic cancers.\nManagement and treatment\nTreatment consists of total thymectomy and complete tumor excision usually accompanied by post-operative radiotherapy and chemotherapy.\nPrognosis\nThymic neuroendocrine carcinomas are aggressive tumors with a poor prognosis. Prognosis is dependent on the histological subtype with well-differentiated neuroendocrine carcinoma being the least aggressive subtype and poorly-differentiated neuroendocrine carcinoma being the most aggressive subtype with a median survival of 18 months. Recurrences and metastases are frequently observed. The 10-year survival is between 10% and 28% and depends on the treatment.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Saul SUSTER"}
{"Disease Name": "Thymic neuroendocrine tumor", "Disease Definition": "A rare, malignant, primary thymic neoplasm originating from neuroendocrine cells, presenting as a mass within the anterior mediastinum. Patients typically present with nonspecific symptoms, such as chest pain, cough, shortness of breath, or in some cases, superior vena cava syndrome, although patients could be asymptomatic during the early stages or present with multiple endocrine neoplasia type I. Ectopic production of ACTH and serotonin can lead to Cushing syndrome and carcinoid syndrome, respectively.", "ORPHA ID": 97289, "Summary": ""}
{"Disease Name": "Thymic-renal-anal-lung dysplasia", "Disease Definition": "This syndrome is characterised by intrauterine growth retardation, renal dysgenesis and a unilobed or absent thymus.", "ORPHA ID": 3326, "Summary": "Epidemiology\nIt has been described in three girls born to a nonconsanguineous couple.\nGenetic counseling\nThe mode of transmission is unknown but autosomal recessive inheritance was suggested.\n\n                            Last update: \n                            September 2007"}
{"Disease Name": "Thymoma", "Disease Definition": "Thymoma is a thymic epithelial neoplasm (TEN; see this term), a rare malignancy that arises from the epithelium of the thymic gland.", "ORPHA ID": 99867, "Summary": "Epidemiology\nIt is the most common form of TEN and has an annual incidence of approximately 1/769,000. The male to female ratio is 1:1.4. Thymomas usually occur between the age of 30 and 70 years (with a median age of 50 years) but in some rare cases they can also occur during childhood.\nClinical description\nWhile half of the patients are asymptomatic, the other half present with chest related symptoms such as dyspnea, chest pain, upper respiratory infection, fatigue, weight loss, and cough or pneumonia. Thymomas are often associated with myasthenia gravis (see this term), an autoimmune disorder that manifests with diplopia, ptosis, dysphagia, and weakness. Some patients may suffer from other autoimmune diseases such as systemic lupus erythematosus (SLE; see this term) and rheumatoid arthritis, hematologic syndromes such as red cell anaplasia and erythrocytosis, and other chronic diseases such as hypertension, diabetes mellitus, renal insufficiency and coronary artery disease. A history of second tumor may be present in some patients.\nEtiology\nEtiology is unknown.\nDiagnostic methods\nDiagnosis is based on clinical findings, radiological studies and pathologic examination of resected tissues. Chest X-rays may reveal a widened mediastinum or loss of the normal anterior clear space. Computed tomography, magnetic resonance imaging (MRI), magnetic resonance angiography (angio-MRI) and/or positron emission tomography (PET) can be indicated to further evaluate the lesion. Tissue biopsy, usually performed by CT- or ultrasound-guided percutaneous needle-biopsy, is necessary for diagnosis. Thymomas are currently divided according to the World Health Organization (WHO) into four histological subclasses: types A, B, AB, and C. Type A tumors are composed of spindle or oval epithelial cells. Type B tumors consist of round or polygonal epithelial cells and are divided into three subtypes (B1, B2, and B3) based on their various proportions of background lymphocytes and increase in cytologic atypia of the epithelial cells. Type AB tumors consist of type A thymoma features with a variably dense lymphocytic component. Type C tumors are characterized by cytologic atypia and loss of the organotypical characteristics of the thymus; the latter term is synonymous with thymic carcinoma (see this term). On cut section, the tumors are nodular and gray-white, can be multi-cystic and can contain calcifications or hemorrhage. Most of them are encapsulated and some may be invasive.\nDifferential diagnosis\nDifferential diagnoses include lymphoma, germ-cell tumors (see these terms), and metastatic cancers.\nManagement and treatment\nIn early stages, treatment consists of complete surgical excision (usually performed by median sternotomy). In advanced stages (stage II according to Masaoka staging system) and in high-risk histologic subtypes (B3), surgery is accompanied by additional adjuvant therapy (consisting of post-operative radiotherapy) or neoadjuvant therapy. Total thymectomy usually relieves myasthenia gravis symptoms.\nPrognosis\nIn the majority of cases, thymomas have a favorable course and can be removed by complete surgical excision. However, relapses and / or pleural, peritoneal, pulmonary, bone, central nervous or hepatic metastases have often been observed, which highlights that thymomas are all potentially malignant neoplasms. The prognosis seems to depend on the type of treatment and the stage of the tumor at the time of diagnosis.\n\n                            Last update: \n                            March 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Saul SUSTER"}
{"Disease Name": "Thyrocerebrorenal syndrome", "Disease Definition": "A rare syndromic renal disorder characterized by renal, neurologic and thyroid disease, associated with thrombocytopenia. There have been no further descriptions in the literature since 1978.", "ORPHA ID": 3327, "Summary": ""}
{"Disease Name": "Thyroid ectopia", "Disease Definition": "Thyroid ectopia is a form of thyroid dysgenesis (see this term) characterized by an ectopic location of the thyroid gland that results in primary congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth.", "ORPHA ID": 95712, "Summary": "Epidemiology\nPrevalence is estimated at about 1/7,000. Thyroid ectopia causes around two-thirds of thyroid dysgenesis and is twice as common in females as in males.\nClinical description\nClinical manifestations of thyroid ectopia are often subtle or not present at birth, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. Goiter is always absent. More specific symptoms and signs do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age.\nEtiology\nThyroid ectopia refers to an ectopic location of the thyroid gland. This occurs when a thyroid remnant is found along the normal pathway of the thyroglossal duct, which is the path of the developing thyroid as it descends from the base of the tongue to its final location in the neck. Ectopic thyroid tissue has been found inferior and superior to the hyoid bone and above the thyroid cartilage. No specific mutations have been identified in humans, although mutations in FOXE1 (TTF-2; 9q22) are associated with ectopic thyroid glands in mice.\nDiagnostic methods\nImaging studies are required to confirm the diagnosis of ectopia.\nGenetic counseling\nThyroid ectopia is generally thought to be sporadic. However, recent evidence points to the possibility of a genetic component. Around 2% of cases have been shown to be familial.\nPrognosis\nWithout treatment thyroid ectopia results in severe intellectual deficit and short stature.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Thyroid hemiagenesis", "Disease Definition": "Thyroid hemiagenesis is a form of thyroid dysgenesis (see this term) characterized by an absence of half of the thyroid gland that is usually asymptomatic but may result in primary congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth.", "ORPHA ID": 95719, "Summary": "Epidemiology\nThyroid hemiagenesis is estimated to occur in 1/500-1/2,000 individuals.\nClinical description\nIn symptomatic cases, clinical features and signs may include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay may also occur.\nEtiology\nThyroid hemiagenesis has been reported in mice with compound heterozygous FOXE1/NKX2-1 and PAX8 gene (14q13 and 2q12-q14) mutations.\nGenetic counseling\nSome familial cases have been reported, suggesting genetic factors but to date none have been identified in humans.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Thyroid hypoplasia", "Disease Definition": "Thyroid hypoplasia is a form of thyroid dysgenesis (see this term) characterized by incomplete development of the thyroid gland that results in primary congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth.", "ORPHA ID": 95720, "Summary": "Epidemiology\nPrevalence is estimated at around 1/28,000. Thyroid hypoplasia and athyreosis (see this term) combined account for one-third of cases of thyroid dysgenesis.\nClinical description\nClinical manifestations of thyroid hypoplasia are often subtle or not present at birth, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment thyroid hypoplasia results in severe intellectual deficit and short stature.\nEtiology\nFamilial cases of thyroid hypoplasia are caused by mutations in the FOXE1,  NKX2-1, NKX2-5 or PAX8 genes (9q22, 14q13, 5q34 and 2q12-q14). Mutations that result in partial inactivation of the TSHR gene (14q31) can present with thyroid hypoplasia.\nDiagnostic methods\nImaging studies are required to confirm the diagnosis.\nGenetic counseling\nThyroid hypoplasia is generally thought to be sporadic. However, recent evidence points to the possibility of a genetic component. Around 2% of cases have been shown to be familial.\n\n                            Last update: \n                            August 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI"}
{"Disease Name": "Thyroid lymphoma", "Disease Definition": "A rare primary organ-specific lymphoma characterized by primary origin in the thyroid gland, sometimes involving cervical lymph nodes, and infrequently more distant sites. Diffuse large B-cell lymphoma is most common, followed by MALT lymphoma, and follicular lymphoma. More rare types include T-cell lymphomas, Burkitt lymphoma, or classic Hodgkin lymphoma. The condition is usually associated with Hashimoto thyroiditis. Patients typically present with a mass in the thyroid, with or without cervical lymphadenopathy. Hoarseness and dyspnea may occur, while constitutional symptoms are rare. Prognosis is favorable for patients with localized tumors.", "ORPHA ID": 97285, "Summary": ""}
{"Disease Name": "Thyrotoxic periodic paralysis", "Disease Definition": "Thyrotoxic periodic paralysis (TPP) is a rare neurological disease characterized by recurrent episodes of paralysis and hypokalemia during a thyrotoxic state.", "ORPHA ID": 79102, "Summary": "Epidemiology\nIt is most common in Asian males (with male-to-female ratios ranging from 17:1 to 70:1) during the third decade of life: the annual incidence in Chinese and Japanese thyrotoxicosis patients is estimated at around 1/50, whereas it is estimated at 1-2/1,000 among non-Asian thyrotoxicosis patients.\nClinical description\nTPP manifests as recurrent episodes of acute muscular weakness of the four extremities that vary in severity from paresis to complete paralysis. Recovery occurs within 2-72 hours. Attacks typically occur at night and may be preceded by muscle cramps, aches and stiffness. Ocular, bulbar and respiratory involvement has also been reported but is rare. Attacks are triggered by ingestion of a high carbohydrate load or strenuous physical activity followed by a period of rest. Episodes only occur when patients are thyrotoxic but symptoms and classical signs of hyperthyroidism are often absent at the time of the first attack. TPP can occur in association with any cause of hyperthyroidism, but is most commonly associated with Graves' disease.\nEtiology\nThe pathogenesis remains unclear. Genetic predisposition is thought to play a role in the pathogenesis of TPP and single nucleotide polymorphisms (SNPs) of the CACNA1S (1q32) and GABRA3 (Xq28) genes have been associated with TPP susceptibility in some Asian populations. Hypokalemia is the consequence of an extra- to intracellular potassium shift due to an increase in Na/K-ATPase pump activity, either as a direct response to thyroid hormone or indirectly via adrenergic stimulation, insulin or exercise.\nDiagnostic methods\nBiochemical studies are essential for diagnosis, with mild-to-severe thyrotoxicosis and hypokalemia during attacks being the major findings. Other anomalies may include hypophosphatemia and hypomagnesemia, without changes in acid-base balance. EMG reveals myopathic changes during attacks and muscle excitability anomalies after a prolonged exercise test. ECG anomalies are also noted. Thyrotoxicosis is the key finding for distinguishing TPP from other causes of hypokalemic periodic paralysis (HOP), such as familial HOP (FHOP; see this term), and from other hypokalemic disorders with a transcellular potassium shift, and excessive renal potassium wasting or gastrointestinal losses.\nDifferential diagnosis\nThe differential diagnosis may also include Guillain-Barré syndrome, transverse myelitis (see these terms), spinal cord compression and hysteria, as well as muscle weakness and fatigue associated with hyperthyroidism in patients with thyrotoxic myopathy or myasthenia gravis (see this term).\nGenetic counseling\nTPP usually occurs sporadically\nManagement and treatment\nManagement of TPP includes definitive control of hyperthyroidism, prevention of attacks with propranolol and avoidance of precipitating factors. Potassium administration during attacks may prevent cardiac arrhythmias and hasten the recovery from paralysis.\nPrognosis\nThe prognosis for patients is good and TPP resolves when euthyroid status is achieved.\n\n                            Last update: \n                            March 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Savine VICART"}
{"Disease Name": "Tibial aplasia-ectrodactyly syndrome", "Disease Definition": "Tibial aplasia-ectrodactyly syndrome is a rare condition characterized by congenital ectrodactylous limb malformations associated with tibial aplasia or hypoplasia.", "ORPHA ID": 3329, "Summary": "Epidemiology\nThe incidence is estimated to be approximately 1 in 1,000,000 live births.\nClinical description\nThe expression of the phenotype is highly variable and ranges from bilateral aplasia of tibiae and split-hand/split-foot deformity (tetramonodactyly or transverse hemimelia) to the mildest visible manifestation, hypoplastic big toes. Additional malformations may include distal hypoplasia or bifurcation of femora, hypo- or aplasia of ulnae, and minor anomalies such as aplasia of patellae, postaxial and intermediate polydactyly in association with split-hand deformity, and cup-shaped ears.\nEtiology\nTwo susceptibility loci at 1q42.2-q43 and 6q14.1 have been identified, leading to the hypothesis that this syndrome fits the model of digenic inheritance.\nDifferential diagnosis\nOverlap with the Gollop-Wolfgang syndrome (see this term) has been described.\nGenetic counseling\nThe syndrome is generally inherited in an autosomal dominant manner with reduced penetrance. Autosomal recessive inheritance has also been proposed in some families.\n\n                            Last update: \n                            May 2008"}
{"Disease Name": "Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome", "Disease Definition": "Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome is a rare, genetic dysostosis syndrome, with marked inter- and intra-familial variation, typically characterized by triphalangeal thumbs, hand and/or foot polysyndactyly and/or absent/hypoplastic tibiae (associated with duplication of fibulae in some cases), although isolated triphalangeal thumbs have also been reported. It is often accompanied with remarkable short stature and additional features may include radio-ulnar synostosis and hand oligodactyly, as well as abnormal carpal and metatarsal bones.", "ORPHA ID": 988, "Summary": ""}
{"Disease Name": "Tibial muscular dystrophy", "Disease Definition": "Tibial muscular dystrophy (TMD) is a distal myopathy characterized by weakness of the muscles of the anterior compartment of lower limbs, appearing in the fourth to seventh decade of life.", "ORPHA ID": 609, "Summary": "Epidemiology\nTMD is highly prevalent in Finland (1/5,000) due to a founder mutation, making it the most common muscle disease in Finland. The disease has also rarely been identified in families in several other European countries.\nClinical description\nTMD manifests after the age of 35 to 40 (rarely after the age of 60) as slowly progressive weakness and atrophy of the anterior tibial muscles with decreased dorsiflexion. Muscle involvement may remain asymmetrical for many years. After about 10 to 20 years, long toe extensors become involved causing foot drop, tripping and clumsiness while walking. Proximal limb muscles, mainly hamstring muscles, may be involved after the age of 60 to 70 and may necessitate the use of a cane and reduced walking distances. Extensor digitorum brevis muscles are spared and involvement of upper limbs is very rare. Neither cardiomyopathy nor respiratory failure has been encountered. TMD may present in a mild form (may remain unnoticed even in elderly individuals) or as aberrant phenotypic forms in about 9% of cases (proximal leg or posterior lower leg muscle involvement even at onset).\nEtiology\nTMD is linked to mutations in the TTN gene (2q31) encoding the protein Titin. The Finnish founder mutation (FINmaj) is located in the last exon 363(Mex6). Atypical presentations in Finnish patients have recently been explained by modifying second mutations in TTN. Seven other mutations of the TTN gene causing TMD have been identified in non-Finnish populations of which some C-terminal titin mutations can be recessive, manifesting the disease in homozygosity or in compound heterozygosity (usually with recessive truncating titin mutations). FINmaj mutation in homozygosity or in combination with truncating recessive titin mutations causes early onset autosomal recessive limb girdle muscular dystrophy (LGMD2J, see this term).\nGenetic counseling\nMode of inheritance of typical TMD is autosomal dominant, with a 50% risk of transmission to offspring, while some forms of TMD may be autosomal recessive.\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Johanna PALMIO  - Pr Bjarne UDD"}
{"Disease Name": "Tick-borne encephalitis", "Disease Definition": "An infectious disease characterized by central nervous system (CNS) involvement caused by the TBE virus (TBEV) and transmitted to humans principally by the bite of ticks from the Ixodes genus. The symptomatology is often biphasic, with the initial phase being associated with a nonspecific febrile illness and the second phase with meningitis, meningoencephalitis or meningoencephalomyelitis.", "ORPHA ID": 297, "Summary": "Epidemiology\nTBE is the most important tick-borne viral disease in the Northern Hemisphere (Europe and Asia), is endemic in 27 European countries, and represents a considerable disease burden. It is predominantly transmitted to humans by the bite of the Ixodes ricinus and Ixodes persulcatus ticks, or in some cases, by alimentary infection through the milk of infected animals. TBEV is generally restricted to endemic areas where the virus circulates among ticks and reservoir hosts. Over the past two decades, the incidence of TBE has risen across Europe, including at higher altitudes, and in regions previously considered virus-free. The highest incidence rates are reported from the Baltic states and Central Europe (>10/100,000 inhabitants per year). There are wide fluctuations in registered annual cases. Infection rates are elevated in the 45-64 years age group, with a male preponderance.\nClinical description\nClinical presentation partly (but not solely) depends on the TBEV subtype. In the majority of patients infected with the European subtype of TBEV, CNS inflammation is preceded by a febrile illness, resulting in a biphasic course of the disease. The first phase (which corresponds to viremia) presents with fever, fatigue, malaise, headache, and muscle and joint pain which occur in the absence of CNS inflammation. It usually lasts <1 week and is followed by an asymptomatic period lasting several days. The hallmark of the second phase of TBE is CNS involvement. Meningitis is the predominant manifestation in children (70%), whereas approximately 50% of adult patients develop meningitis, 40% meningoencephalitis, and 5-10% meningoencephalomyelitis. The disease is on average milder in children than in adults and has the highest severity in the elderly. The fatality rate in patients infected with the European TBEV subtype is up to 1%. Moreover, 5% of patients have permanent paresis and >30% suffer from postencephalitic syndrome. The Siberian subtype is associated with similar TBE course, but may persist as chronic viral infection. The Far Eastern subtype is associated with a usually more severe disease with monophasic course and higher fatality and neurological sequelae rates.\nEtiology\nTBE is caused by three main subtypes of TBEV (a member of the genus Flavivirus in the family Flaviviridae): European, Siberian and Far Eastern; recently, Baikal and Himalayan TBEV subtypes have also been reported.\nDiagnostic methods\nTBE is suspected on clinical signs and symptoms associated with a living or travel history of the patient in endemic zones. Diagnosis is confirmed by: i) clinical presentation of meningitis or meningoencephalitis; ii) elevated cerebrospinal fluid leukocyte counts (>5×106 cells/L); iii) demonstration of a recent infection with TBEV indicated by the presence of specific serum IgM and IgG antibodies or IgG seroconversion in paired serum samples.\nDifferential diagnosis\nDifferential diagnosis depends on the travel history of the patient and includes other arboviral and tick-borne diseases, as well as meningitis, meningoencephalitis or meningoencephalomyelitis of other etiology.\nManagement and treatment\nTreatment is symptomatic. Vaccination of individuals living in or visiting to TBE endemic regions is recommended.\nPrognosis\nThe fatality rate is up to 1% for the European subtype; 5% of patients have permanent paresis and >30% suffer from postencephalitic syndrome. Various nonspecific symptoms and cognitive and neuropsychiatric sequelae (i.e. apathy, irritability, memory and concentration disorders, altered sleep pattern, headache, hearing defects, visual disturbances, ataxia, and flaccid paresis or paralysis) may affect the patient's quality of life, and sometime require lifestyle changes.\n\n                            Last update: \n                            May 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Petra BOGOVIC  - Pr Franc STRLE"}
{"Disease Name": "Tietz syndrome", "Disease Definition": "Tietz syndrome is a genetic hypopigmentation and deafness syndrome characterized by congenital profound bilateral sensorineural hearing loss and generalized albino-like hypopigmentation of skin, eyes and hair.", "ORPHA ID": 42665, "Summary": "Epidemiology\nTietz syndrome has been reported in 7 families to date.\nClinical description\nAffected cases have a pale skin, blue eyes and light blond to white hair with white eyebrows and eyelashes. They gradually gain some pigmentation often as freckles on sun-exposed areas. Hearing loss is always bilateral, congenital, sensorineural and profound. Psychomotor development is normal.\nEtiology\nThe syndrome is due to a missense mutation or in-frame deletion of one amino acid in the basic domain of the MITF (3p14-p13) gene, coding a basic helix-loop-helix (bHLH) leucine zipper transcription factor, regulating melanocyte development and the biosynthetic melanin pathway. However, these types of mutations give rise to variable phenotype, ranging from Tietz syndrome to Waardenburg syndrome type 2 (see this term), with possible interactions with modifier loci.\nGenetic counseling\nTietz syndrome is an autosomal dominant syndrome. Genetic counseling is recommended.\n\n                            Last update: \n                            November 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Véronique PINGAULT"}
{"Disease Name": "Timothy syndrome", "Disease Definition": "A rare, multiple congenital anomalies syndrome with cardiac involvement as a major feature characterized by QT prolongation, congenital heart defects, syndactyly, facial dysmorphism and neurodevelopmental features. There are three clinical phenotypes recognized, the classical types that present with a prolonged QT interval and either with (TS1) or without (TS2) cutaneous syndactyly of fingers and toes. The atypical form (ATS) causes multi-system health concerns but not necessarily with prolonged QT.", "ORPHA ID": 65283, "Summary": "Epidemiology\nTo date more than 60 cases have been reported worldwide.\nClinical description\nTimothy syndrome (TS) often manifests during the neonatal period. However, in many cases it is diagnosed later, between the ages of 2-4 years old. In TS1, cardiac concerns may become apparent under anesthesia during finger separation surgery. Typical cardiac manifestations in all TS types include a rate corrected QT interval >480 ms, functional 2:1 atrio-ventricular (AV) block associated with bradycardia, tachyarrhythmias and congenital heart defects (patent ductus arteriosus, patent foramen ovale, atrial or ventricular septal defects, tetralogy of Fallot, hypertrophic cardiomyopathy). Facial dysmorphia often includes round face, depressed nasal bridge, low set ears, thin vermilion of the upper lip, and hypoplasic premaxillary. Widely placed teeth with poor enamel is common. Hair is generally sparse. Cutaneous syndactyly is typical of TS1, and often noted in ATS individuals. In TS2, congenital hip abnormalities and/or hypotonia are often noted. Pulmonary health concerns include frequent pneumonia. Gastro-intestinal issues include severe constipation, and in some ATS children, complications of chronic constipation may require surgical removal. Immunodeficiencies are common. Endocrinological concerns includes unusual fluctuations in blood sugar levels resulting in life threatening hypoglycemia, primarily associated with infections, and sleep issues; some children may require growth hormones. Neuronal-developmental concerns can be profound, autism or autistic spectrum disorders are noted, delayed speech and other physical, mental and social developmental milestones are generally delayed.\nEtiology\nTS is due to mutations in the CACNA1C gene (12p13.33). The clinical phenotypes correlate with genotype. TS1 is specifically due to a G406R (c.1216 G>A) change in exon 8A. TS2 has the exact same G406R (c. 1216 G>A) change but in the alternatively spliced exon 8. ATS can be recognized by any CACNA1C change (excluding the G406R change) that causes typical multi-system health concerns.\nDiagnostic methods\nTS diagnosis is based on observed clinical features and molecular genetic testing confirmation.\nDifferential diagnosis\nNon-syndromic autosomal Long QT syndrome, Jervell and Lange-Nielsen syndrome, Andersen-Tawil syndrome, Acquired Long QT syndrome, syndactyly and heart-hand related syndromes, autism associated syndromes.\nAntenatal diagnosis\nEchocardiography can often identify fetal distress secondary to cardiac finding of 2:1 AV Block or bradycardia. When the pathogenic CACNA1C variant has been identified in a family member, prenatal genetic testing is possible for at risk pregnancies.\nGenetic counseling\nMost cases arise de novo; however, in some cases, TS has been identified as an inherited autosomal dominant trait resulting from parental germline mosaicism.\nManagement and treatment\nThe main objective is to prevent ventricular fibrillation (VF) and possible sudden death. Interventions should be considered as early as possible and include the combination of left cardiac sympathetic denervation (LCSD) with an implantable cardioverter-defibrillator (ICD). A pacemaker can be placed during the first days of life to control 2:1 AV block and resultant bradycardia. Beta-blockers and/or other antiarrhythmia drugs can be administered to maintain QT interval and prevent ventricular tachyarrhythmias. Drugs that prolong QT interval should be avoided, and all medical procedures requiring anesthesia should be performed with caution. Additional congenital heart defects, respiratory infections, hypoglycemia, and skeletal/smooth muscle anomalies should be managed according to standard protocols. Drugs and dietary practices that could lead to hypoglycemia should be avoided for patients treated with beta-blockers.\nPrognosis\nWithout prompt and appropriate treatment for cardiac concerns, the disease is usually fatal in infancy and early childhood due to arrhythmias precipitated by infections, severe illnesses, hypoglycemia or from complications associated with anesthesia.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Peter SCHWARTZ  - Dr Katherine TIMOTHY"}
{"Disease Name": "Titin-related limb-girdle muscular dystrophy R10", "Disease Definition": "A form of limb-girdle muscular dystrophy that usually has a childhood onset (but can range from the first to third decade of life) of severe progressive proximal weakness, eventually involving the distal muscles. Some patients may remain ambulatory but most are wheelchair dependant 20 years after onset.", "ORPHA ID": 140922, "Summary": ""}
{"Disease Name": "TMEM165-CDG", "Disease Definition": "TMEM165-CDG is a form of congenital disorders of N-linked glycosylation characterized by a psychomotor delay-dysmorphism (pectus carinatum, dorsolumbar kyphosis and severe sinistroconvex scoliosis, short distal phalanges, genua vara, pedes planovalgi syndrome) with postnatal growth deficiency and major spondylo-, epi-, and metaphyseal skeletal involvement. Additional features include facial dysmorphism (midface hypoplasia, internal strabism of the right eye, low-set ears, moderately high arched palate, small teeth), nephrotic syndrome, cardiac defects, and feeding problems. The disease is caused by mutations in the gene TMEM165 (4q12).", "ORPHA ID": 314667, "Summary": ""}
{"Disease Name": "TMEM199-CDG", "Disease Definition": "A rare congenital disorder of glycosylation characterized by chronic, non-progressive liver disease, manifesting as mild steatosis with elevated serum transaminases and alkaline phosphatase, hypercholesterolemia, and decreased coagulation factors and ceruloplasmin. Transferrin glycosylation pattern is consistent with a type 2 congenital disorder of glycosylation. Liver biopsy may show mild non-progressive fibrosis. Patients usually remain asymptomatic, although delayed psychomotor development and hypotonia have been reported in single cases.", "ORPHA ID": 466703, "Summary": ""}
{"Disease Name": "TMEM70-related mitochondrial encephalo-cardio-myopathy", "Disease Definition": "Mitochondrial encephalo-cardio-myopathy due to TMEM70 mutation is characterized by early neonatal onset of hypotonia, hypetrophic cardiomyopathy and apneic spells within hours after birth accompanied by lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria.", "ORPHA ID": 1194, "Summary": "Epidemiology\nPrevalence is unknown. To date fewer than 100 cases have been reported in the literature.\nClinical description\nNeonatal onset of the disease is frequent and clinical symptoms include low birth weight due to prematurity or intrauterine growth retardation, hypotonia, apneic spells, respiratory failure requiring ventilator support, and hypertrophic cardiomyopathy. Most patients who survive the neonatal period have mild cranio-facial dysmorphism with low set ears, prominent nasal bridge and retrognathia, persisting muscular hypotonia and moderate psychomotor developmental delay. Hypospadias and/or cryptorchidism are present in 50 % of boys. Hypertrophic cardiomyopathy is non-progressive and may even disappear.\nEtiology\nMitochondrial encephalo-cardio-myopathy due to ATP synthase deficiency is a result of an isolated decrease in the tissue content and activity of mitochondrial FoF1 ATP synthase caused by depressed biosynthesis of the enzyme. This enzyme defect is present in all tissues and is due to autosomal recessive mutations in the TMEM70 gene (8q21.11), encoding ancillary factor of ATP synthase biogenesis. The mutation c.317-2A>G is prevalent, particularly in the Roma population.\nDiagnostic methods\nThe most important diagnostic tool for this disease is molecular genetic analysis which confirms the presence of pathogenic mutations in the TMEM70 gene. Diagnosis of the enzyme defect is based on biochemical methods (Blue Native electrophoresis and Western blot analysis) confirming the decreased presence of ATP synthase and/or decreased activity of ATP synthase (both synthetic and hydrolytic activities are decreased) in tissue biopsy or cultivated fibroblasts.\nDifferential diagnosis\nDifferential diagnoses include ATP synthase deficiency due to ATPAF2 mutation and other ATP synthase disorders including NARP/MILS syndrome (see this term). Mitochondrial encephalo-cardio-myopathy due to isolated ATP synthase deficiency should be considered in critically ill neonates, especially in those with early onset of hypotonia and hypertrophic cardiomyopathy accompanied with lactic acidosis and/or hyperammonemia.\nAntenatal diagnosis\nPrenatal diagnosis in affected families is available using molecular genetic testing.\nManagement and treatment\nTreatment is reliant on early diagnosis and includes appropriate intensive care during the neonatal period and optimizing nutrition to prevent catabolism in patients who survive this period.\nPrognosis\nMortality is high, usually in the neonatal period or during early childhood. Most of the patients who survive the neonatal period have persisting muscular hypotonia and moderate intellectual deficit. Treatment may improve the life expectancy of affected patients.\n\n                            Last update: \n                            March 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Josef HOUSTEK  - Pr Stanislav KMOCH"}
{"Disease Name": "TMEM94-associated congenital heart defect-facial dysmorphism-developmental delay syndrome", "Disease Definition": "A rare, genetic, neurodevelopmental disorder characterized by global developmental delay, congenital heart defects, generalized hypertrichosis and dysmorphic facial features, most commonly triangular face, thick arched eyebrows, widely spaced eyes, posteriorly rotated low set ears, depressed nasal bridge, broad nasal root and tip, and pointed chin.", "ORPHA ID": 562569, "Summary": ""}
{"Disease Name": "TNP03-related limb-girdle muscular dystrophy D2", "Disease Definition": "A rare subtype of autosomal dominant limb-girdle muscular dystrophy ,with a variable age of onset, characterized by progressive, proximal weakness and wasting of the shoulder and pelvic musculature (with the pelvic girdle, and especially the ileopsoas muscle, being more affected) and frequent association of calf hypertrophy, dysphagia, arachnodactyly with or without finger contractures and/or distal and axial muscle involvement. Additional features include an abnormal gait, exercise intolerance, myalgia, fatigue and respiratory insufficiency. Cardiac conduction defects are typically not observed.", "ORPHA ID": 55595, "Summary": ""}
{"Disease Name": "Tolosa-Hunt syndrome", "Disease Definition": "Tolosa-Hunt syndrome is an ophthalmoplegic syndrome, affecting all age groups, characterized by acute attacks (lasting a few days to a few weeks) of periorbital pain, ipsilateral ocular motor nerve palsies, ptosis, disordered eye movements and blurred vision usually caused by a non-specific inflammatory process in the cavernous sinus and superior orbital fissure. It has an unpredicatable course with spontaneous remission occurring in some and recurrence of attacks in others.", "ORPHA ID": 64686, "Summary": ""}
{"Disease Name": "Toluene embryopathy", "Disease Definition": "A neurodevelopmental teratologic syndrome due to prenatal exposure to toluene. The disease is characterized by prematurity, low birth weight, dysmorphic features (short palpebral fissures, deep set eyes, low set ears, mid-facial hypoplasia, flat nasal bridge, thin upper lip, micrognathia, spatulate fingertips and small fingernails), central nervous system dysfunctions (intellectual disability, microcephaly, language impairment, hyperactivity, visual dysfunction) and postnatal growth delay. Prenatal exposure to toluene occurs as a result of incidental occupational exposure or solvent abuse during pregnancy. The features of toluene embryopathy often overlap with those seen in fetal alcohol syndrome.", "ORPHA ID": 1920, "Summary": ""}
{"Disease Name": "TOR1AIP1-related limb-girdle muscular dystrophy", "Disease Definition": "A form of limb-girdle muscular dystrophy, presenting in the first or second decades of life, characterized by slowly progressive proximal and distal muscle weakness and atrophy. Additional manifestations include contractures of the proximal and distal interphalangeal hand joints, rigid spine, restricted pulmonary function, and mild cardiomyopathy.", "ORPHA ID": 424261, "Summary": ""}
{"Disease Name": "Toriello-Carey syndrome", "Disease Definition": "Toriello Carey syndrome is a multiple congenital anomaly syndrome characterized by craniofacial dysmorphic features, cerebral anomalies, swallowing difficulties, cardiac defects and hypotonia.", "ORPHA ID": 3338, "Summary": "Epidemiology\nAt least 50 cases have been reported since the first description in 1988.\nClinical description\nMain clinical signs include telecanthus, short palpebral fissures, small nose with anteverted nares, Pierre Robin sequence (micrognathia, glossoptosis and cleft palate), abnormally shaped ears, redundant neck skin and features of midline structural abnormalities with agenesis of corpus callosum, laryngeal anomalies and congenital heart defects. Short hands and hypotonia may also be observed. Patients have a moderate to severe intellectual disability.\nEtiology\nThe etiology of Toriello-Carey syndrome is not fully understood, but there is evidence that this is a heterogeneous condition, with chromosome anomalies identified in approximately 20%, and at least two candidate genes identified: MN1 (22q12.1) which has been reported in a microdeletion and SATB2 (2q33.1), interrupted by a de novo balanced translocation in another patient.\nDiagnostic methods\nImaging studies of the brain to determine if the corpus callosum is abnormal and physical examination paying particular attention to ocular spacing and palatal structure. A chromosomal microarray is indicated in any child with a Toriello-Carey phenotype.\nDifferential diagnosis\nThere are few conditions which include the combination of abnormalities of the corpus callosum and Pierre-Robin sequence. Two such conditions are Aicardi syndrome (in which Robin anomaly is a rare occurrence) and TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistence of the left superior vena cava) (see these terms).\nAntenatal diagnosis\nThe combination of corpus callosum anomalies and micrognathia should suggest the diagnosis.\nGenetic counseling\nIf a chromosomal microdeletion/duplication has been ruled out, inheritance is autosomal recessive and the recurrence risk is likely 25%.\nManagement and treatment\nManagement is supportive.\nPrognosis\nThe syndrome is associated with decreased life span.\n\n                            Last update: \n                            August 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Helga TORIELLO"}
{"Disease Name": "Torsade-de-pointes syndrome with short coupling interval", "Disease Definition": "A rare variant of Torsade de pointes, a polymorphic ventricular tachycardia, which is characterized by a short coupling interval of the first TdP beat on electrocardiogram in the absence of any structural heart disease. It manifests in early adulthood with syncope, often results in ventricular fibrillation and shows a high risk of sudden cardiac death.", "ORPHA ID": 51084, "Summary": ""}
{"Disease Name": "Torticollis-keloids-cryptorchidism-renal dysplasia syndrome", "Disease Definition": "Torticollis-keloids-cryptorchidism-renal dysplasia syndrome is an extremely rare developmental defect during embryogenesis malformation syndrome characterized by congenital muscular torticollis associated with skin anomalies (such as multiple keloids, pigmented nevi, epithelioma), urogenital malformations (including cryptorchidism and hypospadias) and renal dysplasia (e.g. chronic pyelonephritis, renal atrophy). Additional reported features include varicose veins, intellectual disability and musculoskeletal anomalies.", "ORPHA ID": 3341, "Summary": ""}
{"Disease Name": "Townes-Brocks syndrome", "Disease Definition": "A rare genetic disorder characterized by the triad of imperforate anus, dysplastic ears often associated with sensorineural and/or conductive hearing impairment, and thumb malformations. These features are often associated with other signs mainly affecting the kidneys and heart.", "ORPHA ID": 857, "Summary": "Epidemiology\nThe prevalence of TBS is unknown. An estimate of 1/250,000 has been reported. More than 100 cases have been reported to date. Exact prevalence is difficult to determine because of overlap with other similar syndromes.\nClinical description\nThe clinical presentation is variable, even within the same family. Most patients present with imperforate anus (82%), dysplastic ears manifesting as overfolded superior helices and preauricular tags with hearing impairment (65%), and thumb malformations (89%), including triphalangeal thumbs, preaxial polydactyly, and rarely hypoplasia. Other common associated manifestations are renal dysfunction (27%), including end-stage renal disease (ESRD) (42%), with or without structural abnormalities, congenital heart disease (25%), foot malformations (52%) involving flat feet or overlapping toes, and genitourinary malformations such as hypospadias, vaginal aplasia with bifid uterus, bifid scrotum, and cryptorchidism (36%). Rare manifestations are ophthalmological (iris coloboma, microphthalmia, lamellar cataract, and chorioretinal coloboma with loss of vision), renal (kidney agenesis/hypoplasia, polycystic kidneys), and cardiac (atrial or ventricular septal defect, tetralogy of Fallot, lethal truncus arteriosus, pulmonary valve atresia, and persistent ductus arteriosus). Additional rare features are gastrointestinal (anal stenosis, chronic constipation, gastroesophageal reflux) and CNS-related including Duane anomaly (see this term), Type I Arnold-Chiari malformation, intellectual deficit (10%), behavioral disorders, cranial nerve palsy, and hypoplasia of the dorsal part of corpus callosum. Rib and mild vertebral anomalies, growth retardation, and congenital hypothyroidism have been reported in rare cases.\nEtiology\nTBS is caused by mutations in the SALL1 gene (16q12.1). Over 70 nonsense, frameshift, and splice mutations have been identified. Large or full deletions have also been described. Some patients with clinical TBS carry a causative mutation in SALL4 rather than SALL1.\nDiagnostic methods\nThe clinical diagnosis is based on the characteristic clinical findings. However, some patients carry SALL1 mutations but present only with a subset of these anomalies. Identification of a mutation confirms the clinical diagnosis. Corresponding sequencing and qRT-PCR/MLPA techniques are clinically available to detect gene mutations. Array CGH/SNP array is recommended to determine the extent and gene content of larger deletions.\nDifferential diagnosis\nDifferential diagnoses include VACTERL/VATER association, Okihiro syndrome, and Goldenhar syndrome (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis for pregnancies at increased risk is available and usually requires identification of the disease-causing mutation in the family. However, if typical malformations are seen on prenatal ultrasound, complete analysis of the SALL1 gene is also possible from prenatal samples.\nGenetic counseling\nTBS follows an autosomal dominant pattern of inheritance and about 50% of cases are de novo. Genetic counseling should be provided.\nManagement and treatment\nTreatment involves immediate surgery to correct imperforate anus, with subsequent surgery for severe malformations of the hands and feet. Routine management of congenital heart defects is recommended. Hemodialysis and possible kidney transplantation may be required. Early treatment of hearing loss is essential.\nPrognosis\nThe physical prognosis depends on the severity of the associated renal and cardiac signs. A prognosis with respect to intellectual development is not possible.\n\n                            Last update: \n                            October 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Jürgen KOHLHASE"}
{"Disease Name": "Toxic epidermal necrolysis", "Disease Definition": "An extended form of Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum characterized by destruction and detachment of the skin epithelium, involving 30% or more of the body surface area, and mucous membranes. Onset usually occurs 4-28 days after administration of the causal medication and is most frequently associated with anticonvulsants, antibacterial sulfonamides, allopurinol, nevirapine, and oxicams (non-steroidal anti-inflammatory drugs), but many other medications have also been implicated. The disease is not induced by medication in 15% of cases. Histology is characterized by an epidermal necrolysis. Multiple disabling long-term sequelae (especially cutaneous, ocular and psychological) are frequent.", "ORPHA ID": 537, "Summary": ""}
{"Disease Name": "Toxic maculopathy due to antimalarial drugs", "Disease Definition": "Toxic maculopathy due to antimalarial drugs is a rare, acquired eye disease, due to long-term exposure to chloroquinine (CQ) or hydrochloroquinine (HCQ), characterized by a slowly progressive, usually non-reversible, development of bilateral atrophic bull's-eye maculopathy (progressive loss of central vision acuity, reduced color vision and central scotoma), which in severe cases can spread over the entire fundus, leading to widespread retinal atrophy and visual loss.", "ORPHA ID": 279894, "Summary": ""}
{"Disease Name": "Toxic oil syndrome", "Disease Definition": "Toxic oil syndrome is a rare intoxication, due to consumption of a rapeseed oil denatured with aniline 2%, characterized by generalized vascular lesions affecting all organs and vessels (including veins and arteries) and presenting with severe incapacitating myalgias, marked peripheral eosinophilia and pulmonary infiltrates.", "ORPHA ID": 227972, "Summary": "Epidemiology\nSpain is the only country to have reported cases of this disease in the spring of 1981 and patients resided in fourteen Central and North West provinces. Almost 20,000 people have been recorded, with women under the age of 40 years being more frequently and severely affected than men.\nClinical description\nWhile TOS can affect all organs and vessels (such as the lungs, peripheral nerves, muscles, skin, digestive tract, liver and pancreas) the main outcome is fibrosis of the lumen of the vessels, skin, peripheral nerves and intestines. The disease course can be characterized by three clinical phases: i) the acute phase (lasting approximately 2 months) with a presentation of severe lung edema, eosinophilia, rash and myalgia, ii) the intermediate phase (2-3 months) with dysphagia, cramps, severe myalgia, skin edema, pulmonary hypertension, paresthesia, major vessel thromboembolism and severe weight loss, iii) the chronic phase, where the skin edema evolves to scleroderma, and the neuromuscular manifestations into paresis and paralysis due to polyneuropathy. Liver disease and fibrosis in major organs such as the pancreas and intestines are also present in patients with the poorest prognosis.\nEtiology\nThe cause of TOS is the consumption of commercial rapeseed oil denatured with 2% of aniline. It was originally sold for industrial use and during the epidemic of 1981 was marketed fraudulently for human consumption. It still remains unclear whether fatty acid esters of 3-(N-phenylamino)-1, 2-propanediol (PAP) can induce TOS or if they are simply markers of oil toxicity.\nDiagnostic methods\nThe diagnosis is based on clinical findings as there are no laboratory tests available.\nDifferential diagnosis\nIn the initial phase, several interstitial lung diseases should be excluded. Differential diagnoses for the chronic phase of TOS include several autoimmune rare diseases such as idiopathic pulmonary arterial hypertension, scleroderma (see these terms) and inflammatory polyneuropathy. Myalgia-eosinophilia syndrome associated with tryptophan (see this term) is another differential diagnosis that should be considered.\nManagement and treatment\nNo specific treatment is available. Major clinical features, such as lung edema at the earlier phase, can be treated with supportive measures at intensive care clinical units. Steroids are administered for some immunological manifestations, but they are not always effective. Certain major chronic features, such as pulmonary hypertension, are currently treated with modern vasodilators but many patients may require lung and cardiac transplantation. No effective treatments are available for scleroderma or neurological manifestations.\nPrognosis\nThe prognosis is highly variable. Of the 20,000 people affected, more than 300 died during the first few years and around 30% of survivors developed a chronic condition. Other TOS survivors can show a variety of symptoms such as muscle pain, cramps and asthenia, as well as increased cardiovascular risks, while others have recovered with no further health problems.\n\n                            Last update: \n                            June 2016\n\n\n                            - Expert reviewer(s): \n                            Pr Manuel POSADA DE LA PAZ"}
{"Disease Name": "Toxin-mediated infectious botulism", "Disease Definition": "Infectious botulism is a form of botulism (see this term), a rare acquired neuromuscular junction disease, characterized by descending flaccid paralysis caused by botulinum neurotoxins (BoNTs), produced in vivo leading to toxin-mediated infection. Infectious botulism includes wound botulism and intestinal toxemia botulism (infant botulism and adult intestinal botulism; see these terms).", "ORPHA ID": 230800, "Summary": "Epidemiology\nPrevalence is unknown. So far, about 4,000 cases have been reported worldwide, infant botulism being the most frequently reported form.\nClinical description\nClinical manifestations are similar to other forms of botulism, in particular those of foodborne botulism (see this term), except for the lack of gastrointestinal symptoms (nausea and vomiting). Fever may be present in wound botulism.\nEtiology\nInfectious botulism is due to BoNTs produced in vivo after colonization by C. botulinum and, very rarely, by neurotoxigenic strains of C. baratii and C. butyricum. Intestinal botulism is due to intestinal colonization and wound botulism is due to the contamination of a wound, but nowadays affects mainly intravenous drug users (IDUs). After spore germination and toxinogenesis, the toxin is absorbed into the blood stream and distributed throughout the body, causing the typical manifestations of botulism.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Michel POPOFF"}
{"Disease Name": "Toxocariasis", "Disease Definition": "A cosmopolitan zoonotic disease caused in humans by the accidental ingestion of eggs or larvae of the ascarids Toxocara canis or Toxocara cati, the common round worm of dogs and cats respectively. The infestation can be asymptomatic or can present as visceral larva migrans caused by larval migration through major organs such as liver, lungs or central nervous system (manifesting with fever, cough, hepatomegaly, pneumonia or rarely encephalitis), or as ocular larva migrans caused by larval migration to the eye (manifesting as ocular inflammation and retinal scaring).", "ORPHA ID": 3343, "Summary": ""}
{"Disease Name": "Tracheal agenesis", "Disease Definition": "A rare congenital malformation characterized by either completely absent (agenesis), or severely underdeveloped (atresia) trachea. In both cases, the tracheal lumen is absent for at least a portion of its length, with no proximal-distal communication between the larynx and lower airways. Functionally and in terms of management, tracheal agenesis and tracheal atresia are equivalent.", "ORPHA ID": 3346, "Summary": "Epidemiology\nThe prevalence at birth is less than 1 in 50 000. There is a male predominance (2:1 male-to-female ratio).\nClinical description\nAssociated congenital malformations are present in 90% of cases, most frequently affecting the cardiovascular or gastro-intestinal systems and the genito-urinary tract. Prenatal imaging may show signs of CHAOS (congenital high airway obstruction syndrome), including enlarged lungs, flattened or inverted diaphragm, fetal hydrops, and ascites. Polyhydramnios may be present. Tracheoesophageal fistula may also be present and cause decompression of the fetal lungs, which may obscure prenatal imaging signs of airway obstruction or CHAOS. Postnatal signs include aphonia, respiratory effort without air movement on auscultation, and inability to place an endotracheal tube. In patients with tracheoesophageal fistula, esophageal intubation may allow temporary oxygenation. Severity of agenesis may be described using the Floyd classification (type I: proximal tracheal agenesis with distal tracheoesophageal fistula; type II: absent trachea with carina arising from esophagus and leading to bronchi; type III: absent trachea and carina with bilateral mainstem bronchi arising directly from esophagus).\nEtiology\nNo clear genetic cause or environmental contributors have been identified.\nDiagnostic methods\nPostnatally, the condition should be suspected in neonates presenting with polyhydramnios, respiratory distress, cyanosis and no audible cry, and in those in whom tracheal intubation proves impossible due to anatomic airway obstruction at or below the glottis. The diagnosis of TA is confirmed by direct laryngoscopy and a helical computerized tomography (CT) scan of the airway. A failure to perform esophageal intubation or an esophagoscopy may confirm presence of tracheoesophageal fistula; in some cases, a flexible bronchoscope may be passed via the esophagus and fistula into the lower airways.\nDifferential diagnosis\nThe differential diagnosis includes laryngeal atresia, severe glottic web (e.g with 22q11.2 microdeletion syndrome), congenital tracheal stenosis and VATER/VACTERL syndrome.\nAntenatal diagnosis\nTracheal agenesis should be suspected in any fetus with prenatal imaging suggestive of CHAOS, particularly if the proximal airway fluid column on MRI extends into the larynx or proximal trachea. If tracheoesophageal fistula is present, there may be no clear signs of tracheal agenesis on prenatal imaging.\nManagement and treatment\nIf prenatal diagnosis is possible, careful counseling of the parents about the prognosis and typical clinical course is essential. Planned ex utero intrapartum treatment (EXIT) procedure may allow placement of a low or mediastinal tracheostomy if adequate distal trachea is present on prenatal imaging. If a concurrent tracheoesophageal fistula is present, oxygenation and ventilation may be achieved temporarily via esophageal intubation. Reconstruction may use the esophagus as a neotrachea, with or without external splinting or endoluminal stenting; subsequent alimentary tract reconstruction may use gastric pull-up or bowel interposition. Cadaveric tracheal allografts, 3D-printed grafts, and autologous free tissue reconstruction may provide other tracheal reconstructive options once the trachealized esophagus allows somatic growth.\nPrognosis\nThis malformation is usually fatal in newborns; however, very rare cases of survival of several years have been reported with use of the esophagus in tracheal reconstruction.\n\n                            Last update: \n                            August 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Karthik BALAKRISHNAN"}
{"Disease Name": "Tracheobronchopathia osteochondroplastica", "Disease Definition": "A rare idiopathic, benign respiratory disease characterized by submucosal cartilaginous and/or bony nodules presenting in the trachea with or without the involvement of the major bronchi; involvement is potentially anywhere along the anterior and lateral walls of the tracheobronchial tree with sparing the posterior walls.", "ORPHA ID": 3348, "Summary": ""}
{"Disease Name": "TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay or regression, variable congenital heart defects (such as patent ductus arteriosus, atrial or ventricular septal defects, and double outlet right ventricle, among others), and dysmorphic features (including ptosis, epicanthal folds, abnormally set/dysplastic ears, low hairline or excess nuchal skin, wide-spaced/inverted nipples, umbilical hernia or diastasis recti, and digital anomalies). Additional variable manifestations are hyper- or hypotonia, seizures, hearing loss, cortical blindness, and optic atrophy. Brain imaging may show cerebral and cerebellar atrophy and hydrocephalus.", "ORPHA ID": 592570, "Summary": ""}
{"Disease Name": "Transaldolase deficiency", "Disease Definition": "Transaldolase deficiency is an inborn error of the pentose phosphate pathway that presents in the neonatal or antenatal period with hydrops fetalis, hepatosplenomegaly, hepatic dysfunction, thrombocytopenia, anemia, and renal and cardiac abnormalities.", "ORPHA ID": 101028, "Summary": "Epidemiology\nLess than ten cases have been reported in the literature so far, all involving children born to consanguineous parents of Turkish and Arabic origin.\nClinical description\nDysmorphic features (downward-slanting palpebral fissures, low-set ears, and cutis laxa) have also been described. The severity of the symptoms and outcome vary widely.\nEtiology\nThe disorder is caused by mutations in the transaldolase gene (TALDO1, 11p15.5-p15.4).\n\n                            Last update: \n                            March 2009"}
{"Disease Name": "Transcobalamin deficiency", "Disease Definition": "Transcobalamin deficiency (TC) is a disorder of cobalamin transport that usually presents during the first few months of life and is characterized by megaloblastic anemia, failure to thrive, vomiting, weakness and pancytopenia.", "ORPHA ID": 859, "Summary": "Epidemiology\nTo date, more than 40 cases of TC have been described in the literature.\nClinical description\nTC typically manifests in the first few months of life. Patients present with one or more of the following signs: weight loss, failure to thrive, diarrhea, vomiting, lethargy, irritability, pallor, ulcers of oral mucous membranes and impaired development. Myoclonus, decreased reflexes in the lower extremities and toe-walking may be observed. Severe infections (i.e. Pneumocystis carinii, pneumococcal meningitis, Escherichia coli, urinary tract infection, Salmonella sepsis, aseptic meningitis and gastro-enteritis) in the first year of life are also reported. In rare cases, the disease may be asymptomatic. Metabolic stroke and peripheral neuropathy have been observed in one case.\nEtiology\nTC is caused by mutations in the TCN2 gene (22q12.2) which encodes transcobalamin, a transporter of cobalamin (vitamin B12). Cobalamin has an important role in the metabolism of both homocysteine and methylmalonic acid as a cofactor for methionine synthase and methylmalonyl-CoA mutase, respectively. Methionine synthase helps to maintain levels of methionine and its derivative, S-adenosylmethionine, which is required for neurotransmitter synthesis and methylation of DNA, RNA, lipids and proteins. It also prevents accumulation of homocysteine.\nDiagnostic methods\nDiagnosis is based on laboratory findings showing pancytopenia (or isolated megaloblastic anemia or combined anemia and leucopenia) and accumulation of homocysteine and methylmalonic acid. Methionine concentration may be reduced. Serum cobalamin levels are typically not low (most circulating cobalamin bound to haptocorrin). Reduction of unsaturated B12 binding capacity (test must be carried out before starting treatment with vitamin B12) and Holo- TC levels are observed. Diagnosis is confirmed by quantification of total transcobalamin in serum or plasma or by genetic screening of TCN2. Postnatal diagnosis may be achieved by screening newborn serum by tandem mass spectroscopy to detect the presence of C3-carnitines derived from methylmalonic acid.\nDifferential diagnosis\nDifferential diagnosis includes inherited disorders of intestinal cobalamin absorption (Gräsbeck-Imerslund disease and congenital intrinsic factor deficiency); inborn errors of cellular cobalamin metabolism, in particular the forms resulting in combined homocystinuria and methylmalonic aciduria (cblC, cblD, cblF, cblJ and cblX); and pernicious anemia (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is based on genetic screening of TCN2 or incubation of amniocytes in medium lacking any exogenous source of transcobalamin supplemented with radiolabeled cobalamin followed by measurement of transcobalamin-bound cobalamin.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nTreatment of TC involves maintenance of a very high serum cobalamin concentration (1,000-10,000 pg/ml) by intramuscular (IM) administration of hydroxocobalamin. Oral treatment or treatment with cyanocobalamin instead of hydroxocobalamin may result in poorer outcomes. Treatment with IM hydroxocobalamin at least once a week is recommended, with monitoring of biochemical and hematological parameters to ensure that treatment is effective. Follow-up into adulthood for asymptomatic children who continue to have abnormal metabolite excretion is recommended.\nPrognosis\nTC is a severe, life-threatening and rapidly progressing disease. Treatment, started early, is highly effective and reverses the clinical and hematological manifestations of the disease. If left untreated, immunologic deficiency (marked hypogammaglobulinemia with absence of specific antibody production after antigenic stimulation) and neurological problems (severe intellectual disabilities, ataxia, and pyramidal deficit) can develop.\n\n                            Last update: \n                            December 2013\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Transcobalamin I deficiency", "Disease Definition": "A rare, genetic, benign disorder of cobalamin transport, due to variable degrees of transcobalamin I deficiency, characterized by mildly low to almost undetectable plasma transcobalamin I levels and slighly low to absent serum cobalamin levels. Normal methylmalonic acid and homocysteine serum values and absence of megaloblastic anemia are reported. No specific clinical manifestations are associated and patients are typically asymptomatic.", "ORPHA ID": 2967, "Summary": ""}
{"Disease Name": "Transgrediens et progrediens palmoplantar keratoderma", "Disease Definition": "A rare, isolated, diffuse palmoplantar keratoderma disorder characterized by red-yellow, moderate to severe hyperkeratosis of the palms and soles, extending to the dorsal aspects of the hands, feet and/or wrists and involving the skin over the Achilles' tendon (transgrediens), gradually worsening with age (progrediens) to include patchy hyperkeratosis over the shins, knees, elbows and, sometimes, skin flexures. Hyperhidrosis is usually associated. Histologically, either epidermolytic or nonepidermolytic changes may be seen.", "ORPHA ID": 495, "Summary": ""}
{"Disease Name": "Transient erythroblastopenia of childhood", "Disease Definition": "A rare, benign, red cell aplasia of young children or infants characterized by a normocytic normochromic anaemia with severe reticulocytopenia in otherwise normocellular bone marrow, and a complete spontaneous recovery within 1-2 months after diagnosis. Neutropenia and thrombocytosis may be associated findings at diagnosis, and a history of a preceding viral illness is frequent. No organomegaly is observed.", "ORPHA ID": 98871, "Summary": ""}
{"Disease Name": "Transient familial neonatal hyperbilirubinemia", "Disease Definition": "A rare genetic hepatic disease characterized by very high serum bilirubin levels in a newborn, clinically presenting as jaundice during the first few days of life. The condition is usually self-resolving, although in some cases it can lead to kernicterus with corresponding symptoms (including lethargy, high-pitched crying, hypotonia, missing reflexes, vomiting, or seizures, among others), which may result in chronic disability and even death.", "ORPHA ID": 2312, "Summary": ""}
{"Disease Name": "Transient hypogammaglobulinemia of infancy", "Disease Definition": "A rare primary immunodeficiency characterized by a delay in the maturation of immunoglobulin production, leading to prolongation of the physiologic hypogammaglobulinemia of the newborn period beyond six months of age. Patients present recurrent respiratory infections, otitis media, bronchitis, gastroenteritis, or allergic symptoms in the first two to four years of life, before the condition resolves spontaneously. Some children may remain asymptomatic, and severe or life-threatening infections are rare. The capacity to synthesize specific antibodies in response to vaccines is usually normal.", "ORPHA ID": 169139, "Summary": ""}
{"Disease Name": "Transient infantile hypertriglyceridemia and hepatosteatosis", "Disease Definition": "Transient infantile hypertriglyceridemia and hepatosteatosis is a rare, genetic, hepatic disease characterized by massive hepatomegaly, moderate to severe, transient hypertriglyceridemia and hepatic steatosis (followed by fibrosis), manifesting in infancy with failure to thrive, vomiting, an enlarged abdomen and a fatty liver. Reduction or normalization of triglyceride serum levels occurs with advancing age.", "ORPHA ID": 300293, "Summary": ""}
{"Disease Name": "Transient myeloproliferative syndrome", "Disease Definition": "A rare hematologic disease characterized by clinical and morphological findings indistinguishable from those of acute myeloid leukemia, typically occurring in newborns with Down syndrome. Peripheral blood and bone marrow blasts display features suggestive of megakaryoblasts. In addition to trisomy 21, acquired GATA1 mutations are present in blast cells. Patients may be asymptomatic or present with thrombocytopenia, less commonly other cytopenias, leukocytosis, hepatosplenomegaly, jaundice, ascites, respiratory distress, bleeding, and pericardial or pleural effusions. Most patients undergo spontaneous remission within the first three months of life, although some may develop life-threatening hepatic, renal, or cardiac complications.", "ORPHA ID": 420611, "Summary": ""}
{"Disease Name": "Transient neonatal diabetes mellitus", "Disease Definition": "Transient neonatal diabetes mellitus (TNDM) is a genetically heterogeneous form of neonatal diabetes (NDM, see this term) characterized by hyperglycemia presenting in the neonatal period that remits during infancy but recurs in later life in most patients.", "ORPHA ID": 99886, "Summary": "Epidemiology\nThe prevalence of neonatal diabetes is estimated to be between 1/95,000 to 1/400,000 live births. About 50% of NDM cases are transient (TNDM) and 50% permanent (PNDM, see this term). The condition has been reported in all ethnic groups and affects male and female infants equally.\nClinical description\nCardinal clinical manifestations include severe intrauterine growth retardation, hyperglycemia (within the first week of life beginning in the neonatal period and resolving usually by 18 months of age), and dehydration. The most commonly reported congenital abnormalities are macroglossia and umbilical hernia. A wide range of different associated clinical signs including, facial dysmorphism, deafness and neurological (as a rule no epilepsy), cardiac, metabolic, kidney or urinary tract anomalies are reported. Affected infants usually require insulin initially, but the need for insulin gradually declines with time. Developmental delay and learning difficulties may also be observed. Women who have had TNDM as infants are at risk for relapse during pregnancy. Ketoacidosis is generally absent (except in patients with KCNJ11 and ABCC8 mutations).\nEtiology\nTNDM is caused by 6q24 alterations consisting of paternal uniparental disomy, partial duplication of paternal origin, or relaxation of maternal imprinting in 6q24. All these alterations induce overexpression of imprinted genes at the 6q24 locus, most likely PLAGL1 (6q24-q25) and HYMAI (6q24.2). Heterozygous mutations in the KCNJ11 (11p15.1) and ABCC8 (11p15.1) genes account for 26% of cases. Homozygous or compound heterozygous ZFP57 (6p22.1) mutations have also been reported to cause TNDM.\nDiagnostic methods\nDiagnosis is based on the clinical signs of TNDM and hyperglycemia and is confirmed by laboratory findings showing abnormal plasma insulin concentrations and by molecular genetic testing.\nDifferential diagnosis\nDifferential diagnoses include permanent NDM, DEND syndrome (epilepsy, hypotonia, and developmental delay in addition to diabetes mellitus), intermediate DEND, and Wolcott-Rallison syndrome (see these terms) as well as all other syndromic forms of neonatal diabetes mellitus.\nAntenatal diagnosis\nPrenatal diagnosis requires identification of a specific genetic defect in the family and is available clinically on a limited basis.\nGenetic counseling\nThe family tree may be indicative of an imprinting disorder. Sporadic cases with de novo mutations have been reported, as well as autosomal recessive and autosomal dominant patterns of inheritance, complicating genetic counseling. In the case of (partial) uniparental disomy, the recurrence risk is probably close to zero. In partial duplication, there is a risk of recurrence.\nManagement and treatment\nEarly diagnosis and appropriate treatment are crucial. Initial treatment mainly involves rehydration and intravenous insulin. Some infants however do not require insulin therapy. Insulin can rapidly be switched to the subcutaneous route or to continuous insulin pump therapy and discontinued once blood glucose levels have stabilized. During relapse of DM, which is poorly characterized, some patients can be treated with diet alone but others require oral sulfonylurea or insulin.\nPrognosis\nRapid catch-up growth is normally achieved through insulin treatment and normal height and weight is often reached by two years of age. Diabetes may recur in childhood, during puberty, or later in adulthood in about 85% of patients. Prognosis is generally good but is dependent on timely rehydration and adequate control of potential complications.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Michel POLAK"}
{"Disease Name": "Transient neonatal multiple acyl-CoA dehydrogenase deficiency", "Disease Definition": "Transient neonatal multiple acyl-CoA dehydrogenase deficiency describes a very rare condition where a maternal riboflavin deficiency causes an infant to present with manifestations similar to those seen in multiple acyl-CoA dehydrogenase (MAD) deficiency (see this term) such as poor suck, metabolic acidosis and hypoglycemia, but that resolves completely with oral riboflavin. In the one patient described haploinsufficiency of the human riboflavin transporter (hRFT1) was described in the mother.", "ORPHA ID": 329942, "Summary": ""}
{"Disease Name": "Transient neonatal myasthenia gravis", "Disease Definition": "Transient neonatal myasthenia gravis (MG) is a rare form of MG (see this term) occurring in neonates born to mothers who have the disorder or specific circulating autoantibodies.", "ORPHA ID": 391504, "Summary": "Epidemiology\nExact incidence data are not available. The disorder occurs in 10% to 20% of children born to mothers with myasthenia gravis.\nClinical description\nIn some cases, the mother may be asymptomatic. Severity is generally not correlated with maternal disease but possibly with maternal antibody titers. Onset is usually within the first hours of life. Transient neonatal MG manifests as hypotonia, feeding difficulties, weak cry, facial diplegia and respiratory difficulties in affected neonates. With the gradual decrease in maternally-derived antibodies, the symptoms usually resolve. Subsequent births to the same mother are also at risk of this disorder. Risk factors for the condition are currently not clear. Rapid treatment usually enables resolution of the condition by 2 months of age.\nEtiology\nThe disorder is related to passive transplacental transfer of maternal anti-acetylcholine receptorantibodies (anti-AChR) or anti-muscle-specific tyrosine kinase antibodies (anti-MuSK) to the neonate. Circulating autoimmune antibodies are thought to damage the post-synaptic neuromuscular junction. The fetal onset form is related to antibodies directed against fetal AChR.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Sonia BERRIH-AKNIN  - Pr Bruno EYMARD"}
{"Disease Name": "Transient pseudohypoaldosteronism", "Disease Definition": "A rare renal tubulopathy secondary to urinary tract infection (UTI) and/or urinary tract malformation (UTM) characterized by renal tubular resistance to aldosterone, characterized by hyponatremia, metabolic acidosis, hyperkalemia and inappropriately high serum aldosterone concentration and clinically manifesting as dehydration, vomiting, and poor oral intake.", "ORPHA ID": 93164, "Summary": "Epidemiology\nSo far, less than 100 cases have been reported worldwide. Because of its association with underlying UTMs, there is a strong male preponderance with more than 80% of affected infants being males. Due to the non-specific manifestations, the true prevalence of transient pseudohypoaldosteronism (TPHA1) is possibly underestimated.\nClinical description\nTPHA1 occurs exclusively during the neonatal or early infantile period (90 % during the first six months of life). The clinical course is transient, typically resolving with treatment of the UTI, and may range from asymptomatic to life-threatening. The clinical features are non-specific and include nausea, vomiting, poor activity and low oral intake. As a consequence, life-threating salt loss, hyperkalemia and hemodynamic compromise may occur.\nEtiology\nRisk factors for TPHA1 in infants with UTI include male sex, young age and urinary tract malformation. Young age may contribute to the development of TPHA1 through low renal mineralocorticoid receptor expression and physiological partial aldosterone resistance. Urinary tract malformation has been found to be associated with decreased expression of mineralocorticoid receptor and increase in mineralocorticoid receptor resistance. In addition, bacterial factors including bacterial endotoxins and host factors such as TGF-beta, INF-alpha, IL-1 and -6 have also been speculated to involve the pathogenesis of TPHA1 in infants with UTI.\nDiagnostic methods\nThe diagnosis can be confirmed by the findings of inappropriately elevated serum aldosterone in the setting of hyponatremia with renal sodium wasting, hyperkalemia with impaired renal potassium excretion, and non-anion gap metabolic acidosis. Infants should be screened for UTI and UTMs.\nDifferential diagnosis\nThe differential diagnoses include patients with impaired renal function (chronic kidney disease stage III to V), pre-existing electrolyte imbalance, medications (Na channel blockers, mineralocorticoid receptor blockers, calcineurin inhibitors, angiotensin converting enzyme inhibitors) which may cause pseudohypoaldosteronism. In cases of recurrent or persistent pseudohypoaldosteronism, the differential diagnosis should include pseudohypoaldosteronism type 1.\nGenetic counseling\nTPHA1 is not an inherited condition; however, in the cases of recurrent or persistent pseudohypoaldosteronism after treatment, the genetic analysis for the genes responsible for PHA1 may be considered.\nManagement and treatment\nEarly recognition and prompt treatment is crucial for affected infants with life-threatening hyperkalemia, salt wasting, and acidosis. The mainstays of treatment include antibiotics for UTI, volume repletion with salt supplementation for hyponatremia and in some cases bicarbonate for correction of metabolic acidosis. The need for additional therapeutic measures, such as loop diuretics, beta2 agonist, ion exchange resins, and calcium gluconate are determined by the severity of hyperkalemia.\nPrognosis\nThe outcome is typically favorable as TPHA1 resolves with treatment of dehydration and urinary tract infection; however, the prognosis for affected infants with life-threatening hyperkalemia, salt wasting, and acidosis depends on early recognition and prompt treatment.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Martin KONRAD | ERKNet* - Dr MinHua TSENG \n\n\n                                * European Reference Network"}
{"Disease Name": "Transient tyrosinemia of the newborn", "Disease Definition": "A rare disorder of tyrosine metabolism characterized by tyrosinemia, moderate hyperphenylalaninemia, and tyrosiluria that usually resolve after 2 months of age. It shows no clinical symptoms and is detected upon newborn screening. It is often observed in premature infants.", "ORPHA ID": 3402, "Summary": ""}
{"Disease Name": "Transitional cell carcinoma of the corpus uteri", "Disease Definition": "A rare uterine cancer characterized by a usually intracavitary, friable, relatively well-circumscribed tumor located in the corpus uteri, with possible infiltration of the myometrium, composed, microscopically, of cells resembling urothelial transition cells, with a papillary or polypoid growth pattern, typically admixed with another type of carcinoma (frequently endometrial adenocarcinoma), generally manifesting with postmenopausal vaginal bleeding.", "ORPHA ID": 213746, "Summary": ""}
{"Disease Name": "Transketolase deficiency", "Disease Definition": "A rare disorder of pentose phosphate metabolism characterized by developmental delay and intellectual disability, delayed or absent speech, short stature, and congenital heart defects (such as ventricular septal defect, atrial septal defect, and patent foramen ovale). Additional reported features include hypotonia, hyperactivity, stereotypic behavior, ophthalmologic abnormalities (bilateral cataract, uveitis, strabismus), hearing impairment, and variable facial dysmorphism, among others. Laboratory analysis shows elevated plasma and urinary polyols (erythritol, arabitol, and ribitol) and urinary sugar-phosphates (ribose-5-phosphate and xylulose/ribulose-5-phosphate).", "ORPHA ID": 488618, "Summary": ""}
{"Disease Name": "Transverse vaginal septum", "Disease Definition": "A rare vaginal malformation characterized by the presence of a complete or incomplete transverse septum at any level of the vagina (most frequently the upper or middle third), resulting from incomplete fusion between the Müllerian duct component and the urogenital sinus component of the vagina during embryogenesis. The condition is only rarely diagnosed in neonates or infants, unless it causes significant hydromucocolpos. Complete septa present with primary amenorrhea, cyclic pelvic pain, dyspareunia, or a pelvic mass consisting of accumulated menstrual blood, while incomplete septa may lead to dyspareunia and dysmenorrhea.", "ORPHA ID": 180160, "Summary": ""}
{"Disease Name": "TRAPPC11-related limb-girdle muscular dystrophy R18", "Disease Definition": "A form of limb-girdle muscular dystrophy characterized by childhood-onset of progressive proximal muscle weakness (leading to reduced ambulation) with myalgia and fatigue, in addition to infantile hyperkinetic movements, truncal ataxia, and intellectual disability. Additional manifestations include scoliosis, hip dysplasia, and less commonly, ocular features (e.g. myopia, cataract) and seizures.", "ORPHA ID": 369840, "Summary": ""}
{"Disease Name": "Treacher-Collins syndrome", "Disease Definition": "A rare genetic mandibulofacial dysostosis characterized by bilateral symmetrical oto-mandibular dysplasia including underdeveloped cheekbones (malar hypoplasia), a very small low jaw (micrognathia) and downward-slanting palpebral fissures, coloboma of the lower eyelids, microtia, hearing loss and without abnormalities of the extremities. Intelligence is normal.", "ORPHA ID": 861, "Summary": "Clinical description\nChildren present with characteristic facial dysmorphism with bilateral and symmetrical hypoplasia of the malar bones and infra-orbital rim (more than 80% of cases) and of the mandible (78% to 97%) (retrognathia), which results in dental malocclusion, often characterized by a limitation of mouth opening of varying severity. Predominant hypoplasia of soft tissues is observed in the malar bone, inferior orbital rim and cheek. Eye manifestations include downward-slanting palpebral fissures (89%-100%), lower eyelid colobomas between the external and middle thirds (54% to 69%), with absence of eyelashes on the outer third of the lower eyelid. Bilateral conductive hearing loss is frequent (83% to 96%). External ear abnormalities, such as microtia or anotia (77%) are often associated with atresia of the external auditory canals and anomalies of the middle ear ossicles (60%). Breathing and nutrition difficulties may arise during the early years because of the narrowness of the upper respiratory tract and limited mouth opening. Occasionally, there is high palate, cleft palate with or without cleft lip (21% to 33%) and unilateral or bilateral choanal stenosis or atresia (13%-25%). Less common manifestations include salivary gland abnormalities with subsequent dry mucosa, enchondromas and/or pretragal fistulas, spinal and cardiac anomalies. Intellect is typically normal, and disability or delayed motor development has been rarely reported.\nEtiology\nThe syndrome is caused by mutations in the TCOF1 gene (5q32) encoding the nucleolar phosphoprotein, treacle, or in the POLR1C (6p21.1), POLR1D (13q12.2), POLR1B (2q14.1) genes coding for RNA polymerase I and III subunits. Of note, a similar phenotype of acrofacial dystosis has been associated with POLR1A.\nDiagnostic methods\nDiagnosis is based on clinical findings and complementary examinations. Molecular tests confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include Nager syndrome (acrofacial dysostosis) distinguished by limb preaxial defects, Miller syndrome distinguished by limb postaxial defects, oculo-auriculo-vertebral spectrum in its bilateral and slightly asymmetrical form, and Burn-Mckeown syndrome.\nAntenatal diagnosis\nOnce a pathogenic variant is identified in a family, antenatal molecular diagnosis is possible by molecular analysis of chorionic villus samples (CVS) and amniotic fluid. Preimplantation testing is also possible. Antenatal ultrasound may show typical facial dysmorphism and bilateral ear abnormalities.\nGenetic counseling\nTransmission is principally autosomal dominant with 90% penetrance and variable intra- and extra-familial expressivity. The mode of inheritance can be autosomal recessive in case of pathogenic variants in POLR1C and POLR1D genes. Genetic counseling is complicated by the variable expression of the disease and should be discussed with a multidisciplinary antenatal diagnosis team.\nManagement and treatment\nManagement is multidisciplinary. In cases with postnatal respiratory distress, tracheostomy, non-invasive ventilation (NIV) or mandibular distraction should be discussed. Maxillofacial and plastic surgery can correct the soft tissue hypoplasia (facial recontouring with lipostructure), bone hypoplasia (surgical bone distraction, bone grafts), eyelid coloboma and cleft palate (surgical repair). The treatment of the limited opening of the mouth is very difficult. Specialist otorhinolaryngology surgery is required for the abnormalities of the middle ear (functional surgery) and the external ear (reconstruction of the auricles). Management of hearing impairment should be early (hearing aids and functional surgery) to aid normal development.\nPrognosis\nThe prognosis for milder forms of the disease is favorable with adequate treatment.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Corinne COLLET | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Trehalase deficiency", "Disease Definition": "A rare, genetic, intestinal disease characterized by osmotic diarrhea, abdominal pain and increased rectal flatulence after ingestion of trehalose, a disaccharide found mainly in mushrooms, due to intestinal trehalase deficiency. It occurs primarily in the Greenland population, although cases have also been reported elsewhere.", "ORPHA ID": 103909, "Summary": ""}
{"Disease Name": "Tremor-nystagmus-duodenal ulcer syndrome", "Disease Definition": "Tremor-nystagmus-duodenal ulcer syndrome is a rare hyperkinetic movement disorder characterized by mild to severe, progressive essential tremor, nystagmus (principally horizontal), duodenal ulceration and a narcolepsy-like sleep disturbance. Refractive errors and cerebellar signs, such as gait ataxia and adiadochokinesia, may be associated. There have been no further descriptions in the literature since 1976.", "ORPHA ID": 3350, "Summary": ""}
{"Disease Name": "Trench fever", "Disease Definition": "A rare bacterial infectious disease caused by the louse-borne bacterium Bartonella quintana and characterized by a variable clinical picture with acute or insidious onset of a (potentially relapsing) febrile illness, headache, leg pain (most typically the shinbone), endocarditis, and thrombocytopenia. There may also be only non-specific symptoms that mimic other infections. The disease nowadays most commonly affects socially disadvantaged persons in urban areas.", "ORPHA ID": 64694, "Summary": ""}
{"Disease Name": "Trichinellosis", "Disease Definition": "Trichinellosis is a zoonotic parasitic disease caused by the consumption of raw or undercooked meat (pork and wild game) infected by nematodes of the genus Trichinella and that is characterized by an enteral (intestinal) phase, that can be asymptomatic or that can manifests with diarrhea, nausea, vomiting and abdominal pain, and a parenteral (muscular) phase, manifesting with fever, periorbital edema, muscle swelling and pain, weakness, and in some cases, skin rash and peripheral edema. Rarely, potentially fatal cardiac (i.e. myocarditis), pulmonary (i.e. pneumonitis, respiratory failure), and nervous system (i.e. meningoencephalitis) complications may occur.", "ORPHA ID": 863, "Summary": ""}
{"Disease Name": "Tricho-dento-osseous syndrome", "Disease Definition": "Tricho-dento-osseous dysplasia (TDO) belongs to the ectodermal dysplasias and is characterised by curly/kinky hair at birth, enamel hypoplasia with discolouration and molar taurodontism, increased overall bone mineral density (BMD) and increased thickness of the cortical bones of the skull.", "ORPHA ID": 3352, "Summary": "Epidemiology\nThe prevalence is unknown but the disease has been described in at least 8 families with over 30 affected members in some large kindreds.\nClinical description\nThe disease shows significant inter and intrafamilial clinical variation, with enamel hypoplasia and taurodontism being the most consistent features, however, the extent of the enamel defects may also vary between affected family members. The hair and bone manifestations are more variable and age dependent. Curly/kinky hair is present at birth in around 80% of patients, but around half of these patients loose the hair phenotype by adolescence. The BMD measurements show increasing variability with age, particularly in the radius and ulna. In addition, spinal BMD shows an increase with age. Other reported features include flat/brittle fingernails, increased susceptibility for caries and abscesses, delayed dental eruption, tubular sclerosis of the long bones, dolichocephaly (as a result of craniosynostosis), and an absence of mastoid pneumatisation, the frontal sinus and calvarial diploe.\nEtiology\nThe syndrome is caused by mutations in the distal-less homeobox gene (DLX3), located on the long arm of chromosome 17 (17q21.3-q22).\nDiagnostic methods\nDiagnosis can be made by clinical and radiological examination and confirmed by detection of DLX3 mutations.\nDifferential diagnosis\nThe differential diagnosis should include amelogenesis imperfecta, hypomaturation-hypoplastic type, with taurodontism (AIHHT), oculodentoosseous dysplasia (see this term) and the autosomal dominant form of osteopetrosis (see this term).\nGenetic counseling\nThe disease is transmitted as a highly penetrant autosomal dominant trait.\nManagement and treatment\nTreatment is symptomatic and patients require frequent dental follow-up.\nPrognosis\nThe prognosis is good and there appearsto be no predisposition for developing fractures.\n\n                            Last update: \n                            January 2007"}
{"Disease Name": "Tricho-retino-dento-digital syndrome", "Disease Definition": "Tricho-retino-dento-digital syndrome is an autosomal dominant ectodermal dysplasia syndrome, characterized by uncombable hair syndrome (see this term), congenital hypotrichosis and dental abnormalities such as oligodontia (see this term) or hyperdontia, and associated with early-onset cataract, retinal pigmentary dystrophy, and brachydactyly with brachymetacarpia. Furthermore, hyperactivity and a mild intellectual deficit have been reported in affected patients.", "ORPHA ID": 1264, "Summary": ""}
{"Disease Name": "Trichodental syndrome", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by the association of sparse, fine, dry, slow growing hair with variable dental abnormalities including oligodontia, peg-shaped incisors, and shell teeth. Mild intellectual disability, microcephaly, and dysmorphic facial features have also been reported.", "ORPHA ID": 3351, "Summary": ""}
{"Disease Name": "Trichodermodysplasia-dental alterations syndrome", "Disease Definition": "Trichodermodysplasia-dental alterations syndrome is a rare, genetic ectodermal dysplasia syndrome characterized by sparse, thin, brittle scalp hair, as well as sparse eyebrows, eyelashes, axillary and pubic hair, delayed eruption of deciduous teeth and hypodontia of both dentitions. Mild palmoplantar keratosis, café-au-lait spots on back, mild dystrophy of nails, and tibial deflection of toes are also associated. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 3353, "Summary": ""}
{"Disease Name": "Trichodysplasia-amelogenesis imperfecta syndrome", "Disease Definition": "A rare ectodermal dysplasia syndrome characterized by the association of amelogenesis imperfecta and trichodysplasia with symmetrical pits in the cuticles of hair shafts. There have been no further descriptions in the literature since 1993.", "ORPHA ID": 79129, "Summary": ""}
{"Disease Name": "Trichodysplasia-xeroderma syndrome", "Disease Definition": "Trichodysplasia-xeroderma syndrome is an extremely rare, syndromic hair shaft anomaly characterized by sparse, coarse, brittle, excessively dry and slow-growing scalp hair, sparse axillary and pubic hair, sparse or absent eyelashes and eyebrows and dry skin. Hair shaft analysis shows pili torti, longitudinal splitting, grooves, peeling and scaling. There have been no further descriptions in the literature since 1987.", "ORPHA ID": 3361, "Summary": ""}
{"Disease Name": "Trichofolliculoma", "Disease Definition": "A rare benign follicular hamartoma that develops primarily on the face of adults, with a particular predilection for the back of the nose, but also on the neck or scalp. It presents as a solitary hemispheric flesh-colored nodule with a central pore or black dot that may contain a tuft of hair.", "ORPHA ID": 864, "Summary": ""}
{"Disease Name": "Trichomegaly-retina pigmentary degeneration-dwarfism syndrome", "Disease Definition": "Trichomegaly-retina pigmentary degeneration-dwarfism syndrome, also known as Oliver-McFarlane syndrome, is an extremely rare genetic disorder characterized by hair abnormalities, severe chorioretinal atrophy, hypopituitarism, short stature, and intellectual disability.", "ORPHA ID": 3363, "Summary": ""}
{"Disease Name": "Trichoodontoonychial dysplasia", "Disease Definition": "Trichoodontoonychial dysplasia is a rare ectodermal dysplasia syndrome characterized by severe generalized hypotrichosis, parietal alopecia, secondary anodontia resulting from enamel hypoplasia, onychodystrophy, bone deficiency in the frontoparietal region and skin manifestations (incl. nevus pigmentosus, papules, ephelides, palmoplantar keratosis, supernumerary nipples, abnormal dermatoglyphics). There have been no further descriptions in the literature since 1983.", "ORPHA ID": 3355, "Summary": ""}
{"Disease Name": "Trichorhinophalangeal syndrome type 1", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by short stature, sparse and depigmented scalp hair, typical facial characteristics (broad eyebrows, especially the medial portion, broad nasal ridge and tip, underdeveloped nasal alae, long philtrum, thin upper lip vermilion, and protruding ears), and limb anomalies (brachydactyly, short metacarpals and metatarsals, cone-shaped phalangeal epiphyses, dystrophic nails, and hip dysplasia).", "ORPHA ID": 77258, "Summary": "Epidemiology\nThe exact prevalence is unknown. Around 250 cases have been published in the world literature. The disease is infrequently described as mildly affected individuals may go unnoticed.\nClinical description\nThe disease has variable severity and clinical presentation, even between family members. It presents typically with prenatal and postnatal growth delay. The facial characteristics (broad eyebrows, broad nasal ridge and tip, underdeveloped nasal alae, long philtrum, thin upper lip vermilion, and protruding ears) may be noticeable early on but may also remain completely unnoticed, especially as some features such as thin and sparse scalp hair are also common in infants in the general population. As time passes, growth delay, accompanied by increasing hair loss and dental overcrowding, may make the facial features more apparent. The brachydactyly also becomes more visible. Fingers start to deviate due to epiphyseal abnormalities in childhood which continues till adulthood. Increased and/or decreased mobility in the finger joints can occur and may cause pain. Hips abnormalities and associated pain are very common; they may present sometimes in late childhood but almost invariably in adulthood. Radiology typically reveals joint dysplasia, reduced joint space and sclerotic bone. Distal limb mobility problems often develop at a later age. Hip problems can be so severe that hip replacement may be indicated in early adulthood. The term \"trichorhinophalangeal syndrome type 3'' has previously been used to refer to a severe form of type 1 with pronounced facial characteristics, short stature and brachydactyly.\nEtiology\nTRP type 1 is caused by heterozygous pathogenic variants in TRPS1 (8q23.3). Infrequently, inversions and balanced translocation disrupting the function of TRPS1 have been reported. Pathogenic variants are considerably different in type and location, with no clear genotype-phenotype correlation. TRPS1 is a zinc finger transcriptional repressor involved in regulating growth and development of chondrocytes and perichondrium.\nDiagnostic methods\nDiagnosis is typically suspected on clinical presentation and confirmed by genetic testing with sequencing technology.\nDifferential diagnosis\nThe differential diagnosis includes other disorders in which ectodermal manifestations are accompanied by distal limb anomalies and/or an unusual shape of the nose such as oculodentodigital dysplasia, cartilage-hair hypoplasia, and Ellis-Van Creveld syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is possible if a pathogenic variant has been previously identified in a family member. Families should be aware that intra-familial variety in severity can be marked, and the severity of the phenotype cannot be predicted by prenatal testing.\nGenetic counseling\nThe disorder is autosomal dominant with full penetrance. Whilst most cases occur sporadically, genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. Germline mosaicism has been detected in rare cases.\nManagement and treatment\nThe management and treatment are mostly supportive. Ectodermal manifestations of hair, nails and teeth can be managed with esthetic care such as the use of wigs, artificial nails, and extraction of supernumerary teeth. In patients whose growth hormone stimulation tests results are subnornal or abnormal, growth hormone therapy can be considered and may (variably) result in increased growth in height. Physiotherapy and occupational therapy can be beneficial for problems of altered distal limb mobility. Regular simple analgesics (such as NSAID) may be used to treat joint pain. Prosthetic hip implantation should be considered in individuals with severe hip dysplasia, even in early adulthood. If osteopenia is present, bisphosphonates may be considered.\nPrognosis\nLife expectancy is normal. The unusual facial morphology and ectodermal manifestations, combined with the reduced mobility, can have a marked impact on the quality of life. Peer support and counseling by a social scientist can be beneficial.\n\n                            Last update: \n                            March 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM | ITHACA* - Dr S.M. [Saskia] MAAS | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Trichorhinophalangeal syndrome type 2", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by intellectual disability, short stature, sparse and depigmented scalp hair, typical facial characteristics (broad eyebrows, especially the medial portion, broad nasal ridge and tip, underdeveloped nasal alae, long philtrum, thin upper lip vermilion, and protruding ears), limb anomalies (brachydactyly, short metacarpals and metatarsals, cone-shaped phalangeal epiphyses, dystrophic nails, and hip dysplasia) and multiple cartilaginous exostoses.", "ORPHA ID": 502, "Summary": "Epidemiology\nThe prevalence is unknown. Around 100 cases were described in the literature.\nClinical description\nThe disease has variable severity and clinical presentation. The disorder goes along with prenatal and postnatal growth delay which can be the presenting clinical sign. Although the typical facial characteristics are present from early on, they may go unnoticed as facial morphology may differ only mildly from a typical face; thin and sparse scalp hair are also common in infants in the general population. Microcephaly is present in more than half of the affected individuals. Delayed motor and cognitive development is usually the reason for further investigations; this may lead to a decreased ability of the affected individuals to indicate joint problems of the distal limbs and hips, which are however present in a similar way as in trichorhinophalangeal syndrome (TRPS) type 1. The developmental delay vary and may be mild or marked. Multiple exostoses arise in the first five years of life, especially on the limbs but potentially also elsewhere, and become more marked with time. Exostoses may lead to bone deformation, pain, and functional problems. Malignancies are extremely uncommon.\nEtiology\nTRPS type 2 is caused by a microdeletion in chromosome 8q23.3-q24.11 leading to the loss of the genes TRPS1, RAD21 and EXT1 and is therefore a contiguous gene syndrome. Usually the microdeletion occurs de novo but some inherited cases have been reported. A small number of affected individuals have a deletion which involves only RAD21 and EXT1; in these patients, the facial characteristics are similar to those of Cornelia de Lange syndrome. TRPS1 is a zinc finger transcriptional repressor involved in growth regulation and the development of chondrocytes and perichondrium.\nDiagnostic methods\nDiagnosis is typically suspected on clinical presentation and confirmed by genetic testing through chromosomal microarray analysis.\nDifferential diagnosis\nTRPS type 2 needs to be distinguished from other disorders in which intellectual disability and ectodermal manifestations are accompanied by distal limb anomalies and/or an unusual shape of the nose. The phenotype of TRPS type 2 is very characteristic and is usually not confused with any other disorder, except for patients in whom the microdeletion does not involve TRPS1, who may resemble patients with Cornelia de Lange syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is possible if the pathogenic variant has previously been identified in the affected family member. Parental germline mosaicism has not been reported but remains theoretically a possibility.\nGenetic counseling\nThe disorder is autosomal dominant. Most cases occur sporadically. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. Penetrance has been 100% in all reported individuals to date. Somatic mosaicism is extremely uncommon.\nManagement and treatment\nEctodermal manifestations and growth delay are cared for in the same way for individuals both with TRPS type 1 and TRPS type 2, and take into account the developmental level of the affected individual. In patients with a marked developmental disability, joint issues and pain need to be considered as affected individuals may be unable to indicate these by themselves. Exostoses need regular follow-up by an orthopedic specialist, and should be treated in the same way as in those with isolated multiple exostoses.\nPrognosis\nLife expectancy is normal. The reduced mobility and developmental problems can have a major impact on the quality of life.\n\n                            Last update: \n                            March 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM | ITHACA* - Dr S.M. [Saskia] MAAS | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Trichothiodystrophy", "Disease Definition": "A rare, genetic, syndromic hair shaft abnormality disorder characterized by short, dry, sulfur-deficient, brittle hair usually associated with highly variable neuroectodermal manifestations, such as ichthyosis, photosensitivity, and intellectual disability.", "ORPHA ID": 33364, "Summary": "Epidemiology\nAlthough epidemiological data is limited worldwide, the prevalence at birth has been estimated at 1/830,000 in Europe.\nClinical description\nTTD syndromes are numerous syndromes affecting mainly organs derived from the neuroectoderm. The clinical appearance is always characterized by brittle and fragile hair, often combined with congenital ichthyosis and nail abnormalities, growth retardation and intellectual deficit among other symptoms. The abnormalities are generally present at birth, with variable clinical expression. About half of the patients with TTD exhibit marked photosensitivity, due to abnormalities in excision repair of ultraviolet (UV)-damaged DNA. In these patients, the deficiency in DNA excision repair is indistinguishable from that observed in Xeroderma Pigmentosum type D (due to ERCC2 variants), however TTD patients do not have an increased risk of skin cancers.\nEtiology\nPatients with a photosensitive form of TTD carry biallelic mutations within three genes encoding distinct subunits of the multi-protein transcription initiation factor IIH (TFIIH) complex, including most frequently ERCC3, but also GTF2H5 or ERCC2. TFIIH is essential for both transcription initiation and nucleotide excision repair (NER). Seven genes have been identified in the so-called non-photosensitive form of TTD, which encode M-phase-specific PLK1 interacting protein (encoded by MPLKIP), general transcription factor IIE subunit 2 (GTF2E2), the X-linked ring finger protein 113A (RNF113A) and the recently identified cysteinyl-tRNA synthetase (CARS), threonyl-tRNA synthetase 1 (TARS1), alanyl-tRNA synthetase (AARS1) and methionyl-tRNA synthetase (MARS1).\nDiagnostic methods\nThe diagnostic findings of TTD are short, unruly, brittle hair, with alternating dark and light bands under polarizing microscopy (tiger-tail pattern), trichoschisis (or trichorrhexis), and an absent or defective cuticle visualized by scanning electron microscopy. The amino-acid analysis of hair shafts revealed a cystine content commonly reduced to less than half of normal values. Functional testing (Unscheduled DNA synthesis) of the nucleotide excision repair system may help to identify photosensitive forms harboring DNA repair defect activity. The diagnosis may be confirmed molecularly.\nDifferential diagnosis\nTTD is a differential diagnosis in congenital alopecias.\nAntenatal diagnosis\nAntenatal molecular diagnosis is possible only if the molecular diagnosis is made in the index case.\nGenetic counseling\nAll forms of TTD are autosomal recessive disorders except for one X-linked form.\nManagement and treatment\nThere is no specific treatment. Patients should receive regular follow-ups in order to precociously detect any neurological, skin, growth delay, malformation and/or immune deficiency. Early intervention with a multidisciplinary team involving pediatricians, neurologists, physiotherapists, psychologists benefit development of the infant and quality of life. Management of ichthyosis is non-specific and mostly relies on topical application of ointments and keratolytic agents. Photoprotection is mandatory in photosensitive forms of TTD.\nPrognosis\nSevere infections may account for the premature death in patients with TTD, who have a higher mortality compared to the general population.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Fanny MORICE-PICARD | ERN-Skin*\n\n\n                                * European Reference Network"}
{"Disease Name": "Tricuspid atresia", "Disease Definition": "A rare congenital heart malformation characterized by absence of the tricuspid valuvar annulus (absent right atrioventricular connection/junction) or an imperforate tricuspid valve leading to severe hypoplasia of right ventricle (functionally univentricular heart). The malformation is associated with normally related great arteries (70 to 80% of cases) or transposed great vessels, an obligatory interatrial connection that is crucial for survival (patent oval foramen or atrial septal defect ostium secundum type), ventricular septal defect (VSD), pulmonary outflow obstruction (pulmonary atresia, stenosis or hypoplasia), aortic coarctation and/or aortic arch interruption.", "ORPHA ID": 1209, "Summary": "Epidemiology\nIn Europe, the prevalence at birth ranges between 1/11,000-50,000. Tricuspid atresia accounts for around 1% of all congenital heart defects. Both sexes are equally affected.\nClinical description\nAt least 80% of children born with tricuspid atresia are symptomatic during the first month of life. Two main clinical presentations are observed, depending on the anatomy: patients with high pulmonary blood flow, and patients with reduced pulmonary blood flow. Subpulmonary obstruction is due to a restrictive VSD when ventriculo-arterial connections are concordant. Patients with high pulmonary blood flow can have either concordant or discordant ventriculo-arterial connections. In the latter case, coarctation of the aorta can occur if the VSD is restrictive. These patients develop cardiac failure, failure to thrive and recurrent upper respiratory tract infections. Patients with reduced pulmonary blood flow exhibit cyanosis and tachypnea without signs of heart failure.\nEtiology\nEtiology is still largely unknown. Tricuspid atresia results from an arrest in cardiac development at an early stage, when the atrioventricular canal is supported only by the primary (left) ventricle and there is no connection between the right atrium and the developing right ventricle. Tricuspid atresia is found in chromosomal anomalies such as 22q11, 4q31, 8p23 and 3p microdeletions. Some genes have been recognized as potentially involved: ZFPM2, HEY2, NFATC1, NKX2.5, and MYH6. Tricuspid atresia has also been reported in association with Alagille and Ellis Van Creveld syndromes.\nDiagnostic methods\nDiagnosis is suspected on clinical examination of cyanosis and heart murmur, and is confirmed on cross-sectional echocardiography. Echocardiography will assess the position of the great vessels, transposed or not, the magnitude of the shunt between the ventricles and the atria, and the presence of subpulmonary stenosis or coarctation, allowing to plan surgical management.\nDifferential diagnosis\nDifferential diagnosis includes all cyanotic congenital heart defects and non-cardiac causes of neonatal cyanosis in forms with reduced pulmonary blood flow, and other causes of high pulmonary blood flow. It also includes other univentricular hearts.\nAntenatal diagnosis\nLike all other types of univentricular hearts, the prenatal detection rate of tricuspid atresia is high (between 70 and 90%) in countries with antenatal screening policies implemented.\nGenetic counseling\nMost cases of tricuspid atresia occur sporadically as a result of spontaneous genetic mutations. The recurrence risk for tricuspid atresia is low, 1%.\nManagement and treatment\nThe management of neonates with tricuspid atresia depends on the pulmonary blood flow. If pulmonary blood flow is high, pulmonary banding will be indicated to protect the pulmonary vascular bed. If it is reduced, prostaglandin E1 may be needed to maintain the permeability of the arterial duct before a surgical Blalock-Taussig-Thomas systemic-to-pulmonary anastomosis is performed. Rashkind maneuver may be needed if the interatrial shunt is restrictive. The second surgical stage will consist of a partial cavopulmonary connection (superior caval vein to pulmonary artery anastomosis) between 4 and 6 months of age, followed by the Fontan procedure (total cavopulmonary connection, fenestrated or not) between 2 and 4 years of age.\nPrognosis\nFontan procedure is a palliative surgery which does not restore a biventricular circulation. Current pooled survival estimates at 5, 10 and 15 years are 88.4%, 85.7% and 84.1% respectively. Long-term complications include left ventricular dysfunction, atrial arrhythmias, cardiac conduction disorders, thromboembolism, cirrhosis and hepatocellular carcinoma, and protein-losing enteropathy. Many of these patients will ultimately require cardiac transplantation.\n\n                            Last update: \n                            February 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Lucile HOUYEL"}
{"Disease Name": "Tricuspid valve agenesis", "Disease Definition": "A rare, congenital, non-syndromic heart malformation characterized by partial or complete absence of tricuspid valve tissue and its apparatus, with an existing orifice. It can be isolated or associated with other heart anomalies. Clinical presentation is variable and may include syncope, arrhythmias, cyanosis, right heart dilatation and failure.", "ORPHA ID": 95457, "Summary": ""}
{"Disease Name": "Trigeminal neuralgia", "Disease Definition": "A rare acquired peripheral neuropathy characterized by paroxysmal, sharp, stabbing, electric-shock-like orofacial pain, that is restricted to one or more of the trigeminal nerve divisions and mostly unilateral. Attacks are brief (few seconds to a maximum of two minutes), but typically occur repeatedly and periodically, can arise spontaneously or be triggered by innocuous stimuli, and are frequently accompanied by tic-like cramps of facial muscles. The condition affects women more often than men.", "ORPHA ID": 221091, "Summary": ""}
{"Disease Name": "Trigonocephaly-bifid nose-acral anomalies syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by trigonobrachycephaly, facial dysmorphism (including narrow forehead, upward-slanting palpebral fissures, bulbous nose with slightly bifid tip, macrostomia with thin upper lip, micrognathia), and various acral anomalies, such as broad thumbs, large toes, bulbous fingertips with short nails, joint laxity of the hands and fifth finger clinodactyly. Short stature, hypotonia and severe psychomotor delay are also associated. There have been no further descriptions in the literature since 1991.", "ORPHA ID": 3368, "Summary": ""}
{"Disease Name": "Trigonocephaly-broad thumbs syndrome", "Disease Definition": "Trigonocephaly-broad thumbs syndrome is characterized by neonatal trigonocephaly and multiple anomalies including craniosynostosis, shallow orbits, unusual nose, deviation of the terminal phalanges of fingers 1, 2, and 5, and broad toes with duplication of the terminal phalanx. It has been described in a mother and her son. It is transmitted as an autosomal dominant trait.", "ORPHA ID": 3365, "Summary": ""}
{"Disease Name": "Trigonocephaly-short stature-developmental delay syndrome", "Disease Definition": "A rare developmental defect during embryogenesis characterized by premature closure of metopic sutures and/or other sutures, short stature, and developmental delay. Dysmorphic features include trigonocephaly, metopic ridge, narrow forehead, bitemporal narrowing, arched eyebrows, hypotelorism, deep-set eyes, epicanthal folds, strabismus, wide nasal bridge, small pointed nose, anteverted nostrils, long philtrum, low-set ears, malar flattening, narrow mouth, thin lips, high-arched palate, crowded teeth, and micrognathia. Variable additional manifestations may include conductive hearing loss, cerebral (mainly involving the white matter), skeletal (e.g. brachymesophalangy of the fifth fingers), cardiovascular and renal anomalies, inguinal hernia, hypospadias, and seizures.", "ORPHA ID": 3369, "Summary": ""}
{"Disease Name": "TRIM22-related inflammatory bowel disease", "Disease Definition": "A rare genetic gastroenterological disease characterized by infantile or childhood onset of severe gastrointestinal inflammation. Patients present with a variable phenotype including fever, diarrhea, failure to thrive, oral ulcers, fistulating perianal disease, strictures, granulomatous colitis, and recurrent bacterial and viral infections.", "ORPHA ID": 597201, "Summary": ""}
{"Disease Name": "TRIM32-related limb-girdle muscular dystrophy R8", "Disease Definition": "A mild subtype of autosomal recessive limb girdle muscular dystrophy characterized by slowly progressive proximal muscle weakness and wasting of the pelvic and shoulder girdles with onset that usually occurs during the second or third decade of life. Clinical presentation is variable and can include calf psuedohypertrophy, joint contractures, scapular winging, muscle cramping and/or facial and respiratory muscle involvement.", "ORPHA ID": 1878, "Summary": ""}
{"Disease Name": "Triose phosphate-isomerase deficiency", "Disease Definition": "Triosephosphate isomerase (TPI) deficiency is a severe autosomal recessive inherited multisystem disorder of glycolytic metabolism characterized by hemolytic anemia and neurodegeneration.", "ORPHA ID": 868, "Summary": "Epidemiology\nPrevalence of TPI deficiency is unknown and less than 50 cases have been reported in the literature. The frequency of heterozygosity was estimated at 0.4-1% among Caucasians and Asians, and 4% among African Americans. These high values suggest that homozygosity is often lethal in utero. Frequent miscarriages in the affected families support this view.\nClinical description\nTPI deficiency is a congenital disease. Hemolytic anemia occurs with very few exceptions and manifests with jaundice in most cases. Reticulocytosis and hyperbilirubinemia are common. Patients have often recurrent bacterial infections, most frequently affecting the respiratory system. In the classical generalized form of the disease, manifestations of progressive neurologic dysfunction become evident usually after 6-24 months of age, with dystonia, tremor, dyskinesia, pyramidal tract signs, cardiomyopathy and spinal motor neuron involvement with progressive neuromuscular impairment (severe weakness and muscle wasting). Cognitive function is not or mildly/moderately influenced and developmental retardation is more related to motor dysfunction affecting mobility (e.g. walking ability) and speech. Chronic axonal neuropathy was proved by nerve biopsy and peripheral electrophysiologic studies. In one case, severe convulsive microcephalic encephalopathy was also reported. Cerebrospinal fluid has been normal when studied, as have CT brain scans and EEG in two cases.\nEtiology\nTPI deficiency is due to mutations in the gene coding for the triosephosphate isomerase enzyme (TPI1, 12p13.31). The Glu104Asp substitution is the most frequent one, which accounts for approximately 80% of clinical TPI deficiency, and induces the most severe phenotype. However, many other mutations have been identified, mostly in compound heterozygotes coupled with the Glu104Asp mutation. These substitutions seems to result in a lack (Ile170Val, Phe240Leu) or delay (Cys41Tyr, Val231Met) of neurologic degeneration and an increased life expectancy.\nDiagnostic methods\nDiagnosis is based on physical examination and laboratory findings revealing enzymatic activity deficiency (2-30% of the normal values) and 15 to 100-fold accumulation of the toxic substrate dihydroxyacetone phosphate (DHAP) in erythrocytes. Muscle biopsy shows myopathic changes; nerve biopsy can be indicative for chronic axonal neuropathy. Molecular genetics can confirm diagnosis. Identification of genotype is crucial because of the different life expectancies.\nDifferential diagnosis\nAs an autosomal recessive inherited disease, TPI deficiency has a 25% recurrence risk in the case of heterozygous parents.\nAntenatal diagnosis\nAntenatal diagnosis is feasible in the first trimester by chorionic villus DNA analysis or by analysis of fetal red cells.\nManagement and treatment\nThere is no curative treatment for TPI deficiency. Management is based on repetitive red blood cell transfusions. Supportive care, if needed, consists of respiratory assistance. Neurological management is the same as in other progressive neuromuscular diseases.\nPrognosis\nPrognosis of TPI deficiency is poor, especially for patients homozygous for Glu104Asp mutation or heterozygous for a TPI null allele and Glu104Asp. In these cases life expectancy is generally reduced to infancy or early childhood, while patients carrying other mutations show longer survival. The most frequent cause of death is respiratory failure and infection. Central nervous system degeneration and cardiac failure were also reported as causes of death.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Ferenc OROSZ"}
{"Disease Name": "Triphalangeal thumbs-brachyectrodactyly syndrome", "Disease Definition": "A rare genetic syndrome with limb duplication, polydactyly, syndactyly, and/or hyperphalangy characterized by duplication anomalies such as triphalangeal thumbs, phalangeal duplication of other digits, and polydactyly, associated with highly variable combinations of ectrodactyly, brachydactyly, and syndactyly of hands and/or feet. Severe nail dysplasia or absence of nails is also observed.", "ORPHA ID": 2947, "Summary": ""}
{"Disease Name": "Triple A syndrome", "Disease Definition": "Triple A syndrome is a very rare multisystem disease characterized by adrenal insufficiency with isolated glucocorticoid deficiency, achalasia, alacrima, autonomic dysfunction and neurodegeneration.", "ORPHA ID": 869, "Summary": "Epidemiology\nPrevalence is unknown but less than 100 cases have been published since the first description in 1978.\nClinical description\nThe onset of Triple A syndrome varies between infancy and adulthood. When presenting in early childhood, alacrima and, possibly, achalasia are the indicative signs; in childhood and adolescence, onset is characterized by achalasia and adrenal insufficiency; while in adulthood, presentation is predominantly neurological with autonomous and polyneuropathic involvement. Alacrima, when present, is the first clinical sign, manifesting in the first months of life, but achalasia of the cardia, leading to dysphagia, is usually the first relevant symptom leading to diagnosis. Adrenal insufficiency may cause hypoglycemia and seizures. These three cardinal signs may not all be present, or be associated with autonomic dysfunction and other neurological features, leading to the ''double A'' or ''quaternary A'' denomination, respectively. Neurological manifestations are diverse: dysautonomia results in dyshidrosis and digestive, sexual, circulatory and urinary dysfunction; pyramidal syndrome and peripheral neuropathy lead to walking difficulties and sometimes to sensory deficit; and bulbar and facial deficiencies are responsible for velar insufficiency, tongue amyotrophy or paresis, orbicularis oris dysfunction and oropharyngeal dysphagia.\nEtiology\nThe disease is caused by mutations in the AAAS gene (12q13), coding for the ALADIN nuclear pore scaffolding protein.\nDiagnostic methods\nDiagnosis is based on clinical examination and adrenal function testing. It can be confirmed by molecular testing.\nDifferential diagnosis\nGiven that the presence of 2 among the 3 main clinical signs (achalasia, alacrima or adrenal insufficiency) is pathognomonic, differential diagnosis can be considered when only one clinical sign is observed, for example at the onset of the disease. Differential diagnosis thus includes other causes of adrenal insufficiency, achalasia or alacrima such as frequent forms of congenital adrenal hyperplasia (easily excluded with dosage of adrenal hormones precursors), and rare peripheral forms of congenital adrenal insufficiency or adrenoleukodystrophy, which might be associated with neurological features.\nGenetic counseling\nTriple-A syndrome has an autosomal recessive mode of inheritance, thus causing a 25% recurrence risk for parents with an affected child.\nManagement and treatment\nTreatment for Triple A syndrome includes hydrocortisone substitutive therapy, esophageal dilatation or myotomy of the lower esophageal sphincter and artificial tear drops. Management of neurological features is symptomatic.\nPrognosis\nIf untreated, triple A syndrome may have a high morbidity and prognosis can be severe. The appropriate management of the disease ameliorates the prognosis significantly.\n\n                            Last update: \n                            April 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Marc NICOLINO"}
{"Disease Name": "Triploidy", "Disease Definition": "Triploidy is a rare chromosomal anomaly, polyploidy, characterized by early in utero growth restriction, and multiple birth defects, including neural tube defects, facial abnormalities, cleft lip/palate, congenital heart anomalies, genital malformations, and peripheral skeletal abnormalities. It is usually prenatally lethal.", "ORPHA ID": 3376, "Summary": ""}
{"Disease Name": "Trismus-pseudocamptodactyly syndrome", "Disease Definition": "A rare, genetic, distal arthrogryposis characterized by pseudocamptodactyly, mild foot deformities, moderately short stature, and short muscles and tendons resulting in a limited range of motion of the hands, legs, and mouth, the later presenting with trismus.", "ORPHA ID": 3377, "Summary": ""}
{"Disease Name": "Trisomy 10p", "Disease Definition": "Trisomy 10p is a syndrome of mental retardation/multiple congenital malformations (MR-MCA) that is caused by the total or partial duplication of the short arm of chromosome 10.", "ORPHA ID": 171929, "Summary": "Epidemiology\nAround 50 cases have been described in the literature.\nClinical description\nIn complete trisomy 10p, the anomalies are present at birth. Children are usually dolichocephalic with a high and prominent forehead, contrasting with a small face, a distinctive implantation of hair that grows backwards, large sutures and a large anterior fontanelle, eyebrows that are fine, arched and that extend to the temples, a large nasal bridge that becomes prominent. The mouth is triangular, with not very apparent fleshy parts, the chin is round, often small and not well defined. The ears are large and low. A third of cases have a cleft lip and/or palate. Osteoarticular anomalies are frequent, including ligament hyperlaxity, flexion deformations of limbs, and club feet. Cardiac, renal (renal cystic dysplasia), ocular (coloboma, microphthalmia) and bone malformations have been reported. Hypochromic anemia is sometimes observed. Development is affected by severe intellectual and motor deficiency, and muscular hypotonia and hypotrophia.\nEtiology\nThe majority of cases are a result of the malsegregation of a familial balanced translocation. The most frequent break point is located at the level of p11 band, but it can be more distal and result in partial trisomy. Other mechanisms can also be involved (pericentric inversion, duplication de novo, supernumerary chromosome...).\nDiagnostic methods\nThe observation of a developmental anomaly associated with congenital anomalies leads to performing a karyotype which shows total or partial duplication of the short arm of chromosome 10, often associated with another imbalance. The identity of the chromosomal segment can be confirmed using in situ hybridization with probes specific to 10p. The parents' karyotype is essential in order to determine how the disease has occurred.\nDifferential diagnosis\nDifferential diagnoses include other syndromes of developmental delay with dysmorphism and congenital malformations.\nAntenatal diagnosis\nPrenatal diagnosis is possible, after the birth of the first affected child or after warning signs from an ultrasound, by choronic villus sampling (CVS) or amniocentesis in cases of structural anomalies in one of the parents.\nGenetic counseling\nIn cases where the anomaly occurred de novo, the risk of recurrence in siblings is weak. When a structural anomaly is present in one of the parents, the risk will be evaluated depending on the type of anomaly.\nManagement and treatment\nThere is no specific treatment. Early multidisciplinary management and special education is necessary.\nPrognosis\nThe prognosis is severe. A quarter to a third of patients die in the neonatal period. In other cases the progression is marked by severe intellectual and motor deficiency, and muscular hypotonia and hypotrophia. Partial trisomy with a break point at p13 result in similar characteristics but serious malformations are less frequent.\n\n                            Last update: \n                            February 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Catherine TURLEAU"}
{"Disease Name": "Trisomy 12p", "Disease Definition": "A partial autosomal trisomy characterized by developmental delay and intellectual disability, generalized hypotonia, postnatal growth retardation, variable brain and heart anomalies and dysmorphic features, including frontal bossing, round face, full cheeks, low-set ears, broad nasal bridge, short nose with anteverted nares, long philtrum, thin upper lip vermilion, and everted, thick lower lip. Unspecific associated congenital anomalies have also been reported.", "ORPHA ID": 1699, "Summary": ""}
{"Disease Name": "Trisomy 13", "Disease Definition": "A rare chromosomal anomaly characterized by the presence of extra chromosome 13 material and manifesting with severe intellectual disability and multiple congenital anomalies including holoprosencephaly, microcephaly, microphthalmia, scalp defect, cleft lip/palate, congenital heart defects, and postaxial polydactyly. Neurological involvement may lead to seizures and hypotonia.", "ORPHA ID": 3378, "Summary": "Epidemiology\nThe incidence at birth is between 1/3500 and 1/5000. In 1st trimester diagnosis, the rate is 1/1,500 in the Danish register. Risk increases with maternal age.\nClinical description\nIn utero death occurs in over 95% of affected fetuses. Median survival is 7-10 days, and less than 30% survives beyond 1 year. Intrauterine growth retardation (IUGR) is common. Neurological manifestations are severe and present as hypotonia and hyporeactivity with an apparent lack of awareness of surroundings. Holoprosencephaly (resulting from a defect in the division of the brain into two hemispheres) is present in 70% of cases and can be observed as variable degrees of hemisphere fusion on MRI. Facial anomalies are variable and may range in severity from hypotelorism and premaxillary agenesis (80% of cases) to cyclopia. Cleft lip/palate (50-80%), micro- or anophthalmia (40%) eye coloboma, areas of cutaneous aplasia of the vertex (30%), postaxial polydactyly (50%), congenital heart defect (CHD) (80% of cases) and renal malformations (40%) may also be present.\nEtiology\nFree trisomy 13 (T13) is found in around 75% of cases. In 20% of cases, T13 is associated with a Robertsonian translocation in which the supernumerary chromosome 13 becomes attached to another acrocentric chromosome (chromosomes 13, 14, 15, 21 or 22). In rare cases, the syndrome is caused by reciprocal translocation between chromosome 13 and a non-acrocentric chromosome. Mosaic T13 (in which there is both trisomic and normal cell types) has been reported in a few patients with a clinical picture that varies between a normal phenotype and that of classical T13 according to the number of trisomic cells present in the tissues.\nDiagnostic methods\nT13 must be confirmed by conventional karyotyping. Chromosomal microarray will show T13 but may not discriminate free from translocation T13.\nDifferential diagnosis\nThe differential diagnosis includes trisomy 18, Smith-Lemli-Opitz syndrome, CHARGE Syndrome, Meckel syndrome and, in a minority of cases, other ciliopathies like Joubert syndrome and Bardet-Biedl syndrome (which may present with renal anomalies, polydactyly, brain anomalies).\nAntenatal diagnosis\nAnalysis of fetal DNA in maternal blood (non-invasive prenatal testing; NIPT) has high sensitivity (> 97%). Maternal serum screening based on blood markers and nuchal translucency ultrasound scan may detect a proportion of T13 fetuses. Most T13 fetuses can be detected by routine fetal ultrasound scan (holoprosencephaly, polydactyly). Invasive prenatal testing like amniocentesis or chorionic villi sampling (CVS) will confirm any suspicion raised by prenatal screening.\nGenetic counseling\nThe risk of recurrence of trisomy (21, 13 or 18) in families of an index case with T13 is around 1%. However, in families in which T13 is associated with translocation (Robertsonian or balanced) the risk of recurrence is higher if one of the parents is a carrier of a balanced translocation.\nManagement and treatment\nManagement is supportive/palliative only. Follow-up is needed for cardiac, respiratory, neurological, genitourinary, abdominal, otolaryngologic, and orthopedic complications.\nPrognosis\nSurgical treatment of the malformations does little to improve the poor prognosis associated with this syndrome: half of the infants born alive die within the first month of life, 70% die before 1 year of age from cardiac, renal or neurologic complications, and 10% more die before 5 years of age. Prolonged survival (in some cases into adulthood) has been reported and is more common in cases of mosaic or partial trisomy and in the absence of severe brain malformations. In general, non-mosaic patients develop only limited autonomy (absence of speech and ambulation).\n\n                            Last update: \n                            September 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Trisomy 17p", "Disease Definition": "Trisomy 17p is a rare chromosomal abnormality resulting from the duplication of the short arm of chromosome 17 and characterized by pre- and post-natal growth retardation, developmental delay, hypotonia, digital abnormalities, congenital heart defects, and distinctive facial features.", "ORPHA ID": 261290, "Summary": "Epidemiology\nIt has been described in fewer than 15 patients.\nClinical description\nFacial dysmorphism includes microcephaly, receding forehead, down-slanting palpebral fissures, ptosis, hypertelorism, low-set malformed ears, smooth philtrum, micrognathia, high-arched palate and a short broad neck. Digital abnormalities include absent fourth and fifth digits, brachydactyly and fifth finger clinodactyly. Genital hypoplasia in males and hypertrichosis are often observed. Intellectual deficit is severe to profound and the prognosis is poor.\nEtiology\nTrisomy 17p has been reported to be ``pure'', as the result of a de novo 17p duplication or an extra chromosome derived from the 17p arm. It can result from a recombination of a familial pericentric inversion, or from a malsegregation of a translocation, in which case trisomy 17p can be associated with monosomy of the partner chromosome.\nDiagnostic methods\nDiagnosis is based on standard and molecular karyotyping.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "Trisomy 18", "Disease Definition": "Trisomy 18 is a chromosomal abnormality associated with the presence of an extra chromosome 18 and characterized by growth delay, dolichocephaly, a characteristic facies, limb anomalies and visceral malformations.", "ORPHA ID": 3380, "Summary": "Epidemiology\nIncidence is estimated at between 1/6000 and 1/8000 births. In utero death occurs in more than 95% of fetuses with this chromosome anomaly. For unknown reasons, the rate of survival is higher in females than in males, leading to a female predominance among live-born trisomy 18 infants.\nClinical description\nHypotonia, hyporeactivity and feeding problems (poor suction) are present in the first weeks of life and are followed by a progression to hypertonia with infants showing an apparent lack of awareness of their surroundings. Common features are intrauterine and postnatal growth delay, an emaciated appearance with hypotrophy, microcephaly with a narrow skull and dolichocephaly, microretrognathia, hypertelorism, and poorly modeled and angular ears. Foot anomalies include pes equinovarus and/or rocker-bottom feet and the fingers overlap (the fifth and second fingers with the fourth and third). Malformations are common with involvement of the eyes (microphthalmia, coloboma), heart (over 90% of cases) digestive tract (esophageal atresia, anorectal malformations), kidneys and urinary tract (hydronephrosis, uni- or bilateral agenesis). Less frequently, cleft/lip palate, arthrogryposis, radial aplasia, spina bifida and anencephaly, holoprosencephaly and omphalocele are observed.\nEtiology\nThe majority of cases are associated with free trisomy 18. Mosaic trisomy 18 has been detected in a few patients presenting with a clinical picture that varies from classical trisomy 18 to a normal phenotype depending on the number of trisomic cells present in the tissues. The trisomy 18 phenotype appears to be associated with the presence of three copies of the 18q11-q12 interval.\nAntenatal diagnosis\nTrisomy 18 may be suspected during pregnancy from ultrasound findings (growth retardation, malformations, multiple choroid plexus cysts) and can be confirmed by karyotype analysis of the fetus. Serum markers (used for the diagnosis of trisomy 21) may also be abnormal.\nGenetic counseling\nThe risk of recurrence of trisomy (21, 13 or 18) in families of an index case with trisomy 18 is around 1%. However, in families in which trisomy 18 is caused by translocation, the recurrence risk is higher if one of the parents is a carrier of a balanced translocation.\nManagement and treatment\nManagement is supportive only.\nPrognosis\nSurgical treatment of the malformations does little to improve the poor prognosis associated with this syndrome: 90% of infants die within the first year of life from cardiac, renal or neurological complications, or from repeated infections. Prolonged survival (in some cases into adulthood) has been reported, mainly in cases involving mosaic or partial trisomy (resulting from translocation). The majority of non-mosaic patients develop only limited autonomy (absence of speech and ambulation). The growth retardation is significant.\n\n                            Last update: \n                            May 2008\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES"}
{"Disease Name": "Trisomy 18p", "Disease Definition": "A rare partial trisomy of the short arm of chromosome 18 manifesting with a highly variable clinical phenotype which may include variable developmental delay and intellectual disability, epilepsy, and non-specific dysmorphic features, among others.", "ORPHA ID": 1715, "Summary": ""}
{"Disease Name": "Trisomy 1q", "Disease Definition": "Trisomy 1q is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome 1, with a highly variable phenotype principally characterized by intellectual disability, short stature, craniofacial dysmorphism (incl. macro/microcephaly, prominent forehead, posteriorly rotated, low-set ears, abnormal palpebral fissures, microphthalmia, broad, flat nasal bridge, high-arched palate, micro/retrognathia), cardiac defects and urogenital anomalies. Patients may also present cerebral (e.g. ventriculomegaly) and gastrointestinal malformations, as well as dystonic tremor and recurrent respiratory tract infections.", "ORPHA ID": 261344, "Summary": ""}
{"Disease Name": "Trisomy 20p", "Disease Definition": "Trisomy 20p is a chromosomal disorder resulting from duplication of all or part of the short arm of chromosome 20. It is mostly characterized by normal growth, mild to moderate intellectual disability, speech delay, poor coordination and evocative facial features.", "ORPHA ID": 261318, "Summary": "Epidemiology\nTrisomy 20p is rarely reported. To date, fewer than 40 patients have been described.\nClinical description\nClinical manifestations linked to trisomy 20p comprise a variable degree of developmental delay and mild to moderate intellectual disability, poor motor coordination, marked speech delay with difficulties in the articulation of some sounds. Typical facial dysmorphisms include a round face with full cheeks, thick coarse and usually straight hair, laterally arched eyebrows, upward slanting palpebral fissures, flared nostrils, high arched palate, abnormal teeth, occipital flattening and large misshapen ears. Other common features include variable skeletal anomalies including vertebral malformations (fusion of vertebrae, reduction of intervertebral spaces, spina bifida, scoliosis and kyphosis), hip deformity, and malposition of fingers and toes. Osteoporosis/osteopenia is reported in a few patients. Congenital heart defects and non-specific kidney abnormalities are present in some patients. Birth weight and growth pattern are usually normal. Less frequent physical abnormalities include umbilical and/or inguinal hernias and hypospadias. The extent and severity of clinical manifestations described above is contingent on the size and location of the duplication in 20p.\nEtiology\nTrisomy 20p is a chromosomal abnormality resulting from duplication of a fraction of the short arm of chromosome 20, variable in length, with no recurrent breakpoints. It may occur de novo, but most reported cases arise from a reciprocal translocation or, as described in a few cases, a parental inversion. Trisomy 20p is therefore frequently associated with another chromosomal imbalance that may modify the clinical picture. Pure trisomy 20p resulting from isochromosome formation and whole arm translocation has been reported. Precise genotype-phenotype correlations remain elusive due to the small number of patients and heterogeneity of breakpoints.\nDiagnostic methods\nDiagnosis is based on clinical manifestations leading to chromosomal analysis. Depending on their size, partial 20p duplications may be diagnosed by classical or molecular karyotyping. Molecular techniques are necessary for the genetic characterization of the duplication (FISH, MLPA, CGH array).\nAntenatal diagnosis\nPrenatal diagnosis of 20p duplication is possible by amniocentesis or chorionic villus sampling and cytogenetic analysis. Molecular techniques may be required depending on the size of the duplication.\nGenetic counseling\nGenetic counseling is recommended and requires parental karyotyping to evaluate their risk of having another affected child.\nManagement and treatment\nManagement is multi-disciplinary and requires evaluation and treatment by a pediatrician, and appropriate specialists. Patients will benefit from an early assessment and intervention with physiotherapy and occupational therapy.\nPrognosis\nThe prognosis is variable, depending on the size and location of the duplication and on the quality and timing of treatment. Exact life expectancy is unknown, and depends on whether severe congenital anomalies are present. The majority of individuals with trisomy 20p will live into adulthood.\n\n                            Last update: \n                            November 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Catherine TURLEAU"}
{"Disease Name": "Trisomy 4p", "Disease Definition": "Trisomy 4p is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 4, with a highly variable phenotype, typically characterized by pre- and postnatal growth delay, psychomotor developmental delay and craniofacial dysmorphism (microcephaly, prominent glabelle, hypertelorism, enlarged ears with abnormal helix and antihelix, bulbous nose with flat or depressed nasal bridge, long philtrum, retrognathia with pointed chin). Additional features include skeletal (rocker bottom feet, arachnodactyly, camptodactyly) and renal malformations, cardiac defects, ocular abnormalities and abnormal genitalia in males.", "ORPHA ID": 1738, "Summary": ""}
{"Disease Name": "Trisomy 5p", "Disease Definition": "Trisomy 5p is a chromosomal abnormality resulting from the duplication of a segment of variable size of the short arm of chromosome 5, which usually involves the distal band 5p15. The clinical presentation is variable but is always associated with severe intellectual deficit.", "ORPHA ID": 1742, "Summary": "Epidemiology\nTo date, more than 40 cases have been reported, the majority in association with another chromosomal anomaly.\nClinical description\nDuplication of the 5p13 band determines the characteristic phenotype of trisomy 5p (the critical region): dolichocephaly or scaphocephaly with macrocephaly, oval elongated face, epicanthus, absent malar, long philtrum, ogival palate, macroglossia, dysplasic and low-set ears, micrognathia and short neck. Fingers are long. Patients may have microphthalmia or coloboma of the iris. At birth, the fontanelles are wide. Cerebral malformations (hydrocephalus, agenesis of the corpus callosum or Dandy-Walker malformation) are common. Visceral malformations are rare. Hypotonia is severe. There is a marked susceptibility to infections, especially respiratory infections, which can be life-threatening. Intellectual deficit is severe and may be accompanied by epilepsy. Larger duplications (up to the 5p11 band) have similar dysmorphisms, but more often are associated with failure to thrive, visceral and anorectal malformations, diaphragmatic hernia and club feet. Hydramnios may complicate pregnancy.\nEtiology\nThe duplication may extend towards the centromere, to the 5p11 band. The majority of reported patients have a large duplication, visible on the standard karyotype. Small subtelomeric duplications are rare. Duplications that extend to the 5p14 band result in variable intellectual deficit, epilepsy and a specific phenotype. There are no established correlations between genes in the critical region and the phenotype observed. In the majority of patients the 5p duplication is associated with the deletion of another chromosome as part of a translocation (familial or de novo). ``Pure'' duplications are rare. Some patients have been reported with interstitial duplication of 5p or an extra chromosome derived from the 5p arm (possibly in the form of a 5p isochromosome); these patients have a phenotype comparable to classical duplication.\nDiagnostic methods\nDiagnosis is based on standard karyotyping or molecular determination of the karyotype (FISH, MLPA, CGH array).\nGenetic counseling\nIn cases of de novo anomalies, the risk of recurrence is low and can be explained by the possibility of a mosaic germline parent.\nManagement and treatment\nDisease management does not differ from that of other patients with severe intellectual deficit and includes physical and psychomotor therapy. Respiratory infections should be treated aggressively.\nPrognosis\nThe prognosis is poor; many patients die in childhood as a result of neurological complications or respiratory infections.\n\n                            Last update: \n                            April 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Alain VERLOES"}
{"Disease Name": "Trisomy 8p", "Disease Definition": "Trisomy 8p is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 8, with highly variable phenotype ranging from no dysmorphic features and only mild intellectual disability to patients with severe developmental delay, neonatal hypotonia, short stature, profound intellectual disability, mild dysmorphic features (e.g. mild ptosis, hypertelorism, down-slanting palpebral fissures, broad nasal bridge, short, prominent philtrum, abnormal dentition) and structural brain abnormalities. Autism, epilepsy, and spastic paraplegia have also been reported.", "ORPHA ID": 264450, "Summary": ""}
{"Disease Name": "Trisomy 8q", "Disease Definition": "A partial autosomal trisomy characterized by developmental delay, intellectual disability, prenatal and postnatal growth retardation, congenital heart, genitourinary and skeletal anomalies, and dysmorphic facial features, including high and broad forehead, hypertelorism, upslanting palpebral fissures, broad nose, dysplastic and low set ears, micrognathia. Phenotypic features vary in relation to the duplication size.", "ORPHA ID": 1752, "Summary": ""}
{"Disease Name": "Trisomy 9p", "Disease Definition": "Trisomy 9p is a rare chromosomal anomaly syndrome, resulting from a partial or complete trisomy of the short arm of chromosome 9, with a wide phenotypic variablility, typically characterized by intellectual disability, craniofacial dysmorphism (e.g. microcephaly, large anterior fontanel, hypertelorism, strabismus, downslanting palpebral fissures, malformed, low-set, protruding ears, bulbous nose, macrostomia, down-turned corners of mouth, micrognathia), digital anomalies (brachydactyly and clinodactyly), and short stature. Less frequently patients present with cardiopathy and renal, skeletal, and central nervous system malformations.", "ORPHA ID": 236, "Summary": ""}
{"Disease Name": "Trisomy X", "Disease Definition": "Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX).", "ORPHA ID": 3375, "Summary": "Epidemiology\nIt is the most common female chromosomal abnormality occurring in approximately 1 in 1,000 female births. However, as most individuals are only mildly affected or asymptomatic, it is estimated that only 10% of individuals with trisomy X are actually diagnosed.\nClinical description\nThe most common physical features include tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure (POF; see this term) are also associated findings. Children with trisomy X have higher rates of motor and speech delays than in the general poplation, with an increased risk of cognitive deficits and learning disabilities presenting in the school-age years. Psychological problems such as attention deficits, mood disorders (including anxiety and depression), and adjustment disorders are also more common than in the general population.\nEtiology\nTrisomy X most commonly occurs as a result of nondisjunction during meiosis, although postzygotic nondisjunction occurs in approximately 20% of cases. Advanced maternal age (known to be associated with an increased likelihood of nondisjunction events) is noted in approximately 30% of trisomy X cases. Mosaicism (46,XX/47,XXX, 47,XXX/48,XXXX or in combinations including 45,X Turner's syndrome (see this term) cell lines) occurs in approximately 10% of cases. The phenotype in trisomy X is thought to be associated with overexpression of genes on the X-chromosome that escape X-inactivation but specific genotype-phenotype relationships remain to be defined.\nDiagnostic methods\nDiagnosis during the prenatal period by amniocentesis is common. Indications for postnatal diagnosis most commonly include developmental delay or hypotonia, learning disabilities, emotional or behavioral difficulties, or POF.\nDifferential diagnosis\nDifferential diagnosis prior to definitive karyotype results includes fragile X syndrome, tetrasomy X, pentasomy X, and Turner syndrome mosaicism (see these terms).\nAntenatal diagnosis\nPatients diagnosed in the prenatal period should be followed closely for developmental delay so that early intervention therapies can be implemented as needed.\nGenetic counseling\nGenetic counseling is recommended, with families being informed about the sporadic nature of the chromosome anomaly, the wide variability in phenotype, and low risk of recurrence (< 1%-5%).\nManagement and treatment\nFollowing diagnosis, clinical evaluation should be conducted to identify any manifesting features of the disorder. School-age children and adolescents often benefit from a psychological evaluation with an emphasis on identifying and developing an intervention plan for problems in cognitive/academic skills, language, and/or social-emotional development. Fertility in women with trisomy X is generally considered normal, however, adolescents and adult women presenting with late menarche, menstrual irregularities, or fertility problems should be evaluated for hormonal abnormalities that may signal ovarian insufficiency. Patients should be referred to support organizations to receive individual and family support.\nPrognosis\nThe prognosis is variable, depending on the severity of the manifestations and on the quality and timing of treatment.\n\n                            Last update: \n                            June 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Susan HOWELL  - Dr Ashley SUTHERLAND  - Dr Nicole TARTAGLIA  - Dr Callum WILSON  - Dr Rebecca WILSON  - Dr Lennie WILSON"}
{"Disease Name": "Tritanopia", "Disease Definition": "A rare form of colour blindness characterized by a selective deficiency of blue vision.", "ORPHA ID": 88629, "Summary": ""}
{"Disease Name": "Tropical endomyocardial fibrosis", "Disease Definition": "Tropical endomyocardial fibrosis is a restrictive cardiopathy, occuring almost exclusively in children and young adults in tropical and subtropical regions, characterized by endocardial fibrosis, affecting the apices and the inflow tract of the right or left ventricle (or both) and manifesting with a restrictive cardimyopathy and atrioventricular regurgitation leading to severe pulmonary hypertension, very high systemic venous pressure and congestive cardiac failure. Suspected etiologies include helminth and protozoal infestation and malnutrition.", "ORPHA ID": 75565, "Summary": ""}
{"Disease Name": "Tropical pancreatitis", "Disease Definition": "A rare pancreatic disease of juvenile onset occurring mainly in tropical developing countries and characterized by chronic non-alcoholic pancreatitis manifesting with abdominal pain, steatorrhea and fibrocalculous pancreatopathy. It is also commonly associated with the development of pancreatic calculi and pancreatic cancer at a much higher frequency than seen in ordinary chronic pancreatitis.", "ORPHA ID": 103918, "Summary": ""}
{"Disease Name": "Tropical spastic paraparesis", "Disease Definition": "Tropical spastic paraparesis is a chronic systemic immune-mediated inflammatory myeloneuropathy, more frequently reported in women than in men, that usually presents in adulthood with slowly progressive spastic paraparesis of the lower limbs, bladder and bowel dysfunction, and sensory disturbances in the lower extremities (e.g. paresthesia and dysesthesia) and that is associated with a human T-cell lymphotropic virus type 1 (HTLV-1) infection.", "ORPHA ID": 289326, "Summary": ""}
{"Disease Name": "True congenital shoulder dislocation", "Disease Definition": "A rare congenital limb malformation characterized by true congenital dislocation of the shoulder, developing in utero. It can be unilateral or bilateral and is usually associated with other abnormalities of the shoulder girdle, such as in the glenoid, the humeral head, the joint capsule, and the scapula. In addition, it may be accompanied by other malformations, like developmental hip dysplasia or cardiac malformation.", "ORPHA ID": 295030, "Summary": ""}
{"Disease Name": "True unicornuate uterus", "Disease Definition": "A rare, non-syndromic uterovaginal malformation characterized by a crescent-shaped, small-sized uterus containing a single horn and fallopian tube with no rudimentary horn. Urinary tract anomalies are frequently associated.", "ORPHA ID": 180074, "Summary": ""}
{"Disease Name": "TSH-secreting pituitary adenoma", "Disease Definition": "A rare, functioning, pituitary adenoma characterized by the presence of a pituitary mass associated with high levels of circulating, free, thyroid hormones in conjunction with normal to high levels of TSH and unresponsiveness of TSH levels to TRH stimulation and T3 suppression tests, typically manifesting with signs and symptoms of mild to moderate hyperthyroidism (e.g. goiter (most frequently observed), palpitation, excessive sweating, arrhythmia, weight loss, tremor) and/or tumor mass effect (such as headache, visual field defects, hypopituitarism). Occasionally, cosecretion of prolactin and/or growth hormone may cause galactorrhea and/or acromegaly.", "ORPHA ID": 91347, "Summary": ""}
{"Disease Name": "Tuberculosis", "Disease Definition": "Tuberculosis (TB) is a contagious-infectious disease caused mainly by Mycobacterium tuberculosis that in most individuals is usually asymptomatic but that in at risk individuals (e.g. with diabetes or with HIV infection) can cause weakness, fever, weight loss, night sweat, and respiratory anomalies such as chronic cough, chest pain, hemoptysis or respiratory insufficiency.", "ORPHA ID": 3389, "Summary": ""}
{"Disease Name": "Tuberous sclerosis complex", "Disease Definition": "A rare neurocutaneous disorder characterized by multisystem hamartomas, most commonly involving the skin, brain, kidneys, lungs, eye, and heart, and associated with neuropsychiatric disorders.", "ORPHA ID": 805, "Summary": "Epidemiology\nWhilst prevalence has been historically estimated at 1/10,000, more recent data from the UK and Taiwan estimates prevalence at 1/20-25,000 and 1/100,000, respectively. However, current estimates are likely an underestimate given the variability in phenotypic expression, severity and age of onset.\nClinical description\nSkin involvement is almost constantly present, beginning as hypomelanotic macules in the first years of life and evolving to facial angiofibromas by 3-4 years, followed by ungual fibromas, cephalic and lumbar (shagreen patch) fibrous plaques, and ''confetti'' skin lesions appearing in childhood to early adolescence. Brain involvement includes cortical dysplasias (tubers), subependymal nodules, and/or subependymal giant cell astrocytoma (SEGA), and is seen in almost all cases. SEGA affects 10 to 20% of tuberous sclerosis complex (TSC) patients, almost exclusively children and young adults. Early-onset epilepsy (focal seizures and/or infantile spasms) is present in 85% of patients. TSC-Associated Neuropsychiatric Disorders (TAND) include intellectual disability, attention-deficit/hyperactivity disorder, autism spectrum disorders (ASD), psychiatric disorders, neuropsychological deficits, as well as school and occupational difficulties. Renal angiomyolipomas (AML) develop during childhood with a higher risk of growth during adolescence and adulthood and manifest by pain, hematuria/retroperitoneal hemorrhage, abdominal masses, hypertension and renal failure. Lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia and pulmonary cysts develop during adulthood and manifest with dyspnea, pneumothorax, or chylothorax. Cardiac rhabdomyomas appear during the fetal period, are rarely symptomatic, and tend to decrease in size in early childhood. Additional features include retinal and liver hamartomas, dental enamel pitting, intraoral fibromas, skeletal dysplasia, and rarely neuroendocrine tumors.\nEtiology\nTSC is due to mutations in either TSC1 (9q34) or TSC2 (16p13.3) which encode proteins that indirectly inhibit the mTOR pathway. In excess, mTOR causes increased cell growth and proliferation, as well as disproportionate glutamate activity leading to disrupted synaptic plasticity. Expressivity of TSC is variable due to mosaicism and to genetic-epigenetic modifiers.\nDiagnostic methods\nA definite diagnosis is defined as presence of ≥ 2 major features or 1 major and ≥ 2 minor features. Possible TSC is considered in the presence of 1 major or ≥ 2 minor features. The identification of a pathogenic variant, confirms the diagnosis regardless of the clinical findings.\nDifferential diagnosis\nAutosomal dominant polycystic kidney disease type 1 with tuberous sclerosis is seen in up to 5% of patients presenting with TSC and should be excluded. Other differential diagnoses include vitiligo, Ito hypomelanosis, acne, skin rash, cardiac myxoma, isolated brain tumors, pulmonary emphysema, and kidney cysts.\nAntenatal diagnosis\nAntenatal diagnosis is made in two situations: familial cases with genetic diagnosis (amniocentesis, chorionic villus sampling) or de novo cases with the discovery of cardiac rhabdomyoma or less frequently brain abnormalities on routine pregnancy exams.\nGenetic counseling\nThe disorder is autosomal dominant; however, two thirds of cases are the result of a de novo pathogenic variant. In one third of cases, TSC is inherited from one of the parents and, in such cases, genetic counseling is recommended to inform the parents that the risk of having an affected child is 50% for each pregnancy.\nManagement and treatment\nManagement is multidisciplinary and includes frequent clinical follow-up as well as treatment of epilepsy, tumors, and TAND. Early referral to a specialized pediatric epilepsy center is strongly recommended. Epilepsy treatment includes the use of vigabatrin (GABA transaminase inhibitor) for infantile spasms and early onset focal seizures. For pre-symptomatic infants, video electroencephalogram monitoring is recommended to identify subtle or electrographic seizures. If vigabatrin fails, other antiseizure medicine, ketogenic diet, vagal nerve stimulation, or mTOR pathway inhibitor (everolimus) might be helpful. Early identification of candidates for epilepsy surgery is highly recommended. The developing tumors require frequent follow-up and can be treated with mTOR inhibitors or surgery.\nPrognosis\nTSC is a chronic, life-long condition. As patients transition into adulthood, seizures may persist; renal and/or pulmonary issues may become more frequent and clinically significant.\n\n                            Last update: \n                            December 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Alexis ARZIMANOGLOU | EpiCARE* - Pr Katarzyna KOTULSKA-JOZWIAK | EpiCARE* - Pr Rima NABBOUT | EpiCARE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Tubular aggregate myopathy", "Disease Definition": "A rare congenital myopathy characterized ultrastructurally by the presence of tubular aggregates in the subsarcolemmal region of the muscle fiber. It most commonly presents with slowly progressive proximal muscle weakness predominantly of the lower limbs, periodic paralysis, post-exertion muscle cramps, and muscular pain. Ocular anomalies like ophthalmoplegia or pupillary abnormalities may be associated. The intensity of the symptoms is variable, cases with normal muscle strength but myalgia or fatigue, as well as clinically asymptomatic cases have been described.", "ORPHA ID": 2593, "Summary": ""}
{"Disease Name": "Tubular duplication of the esophagus", "Disease Definition": "A rare, non-syndromic, congenital esophageal malformation characterized by a second structure with individual lumen and stratified squamous mucosa and muscularis mucosa lying within or adjacent to the true esophagus causing dysphagia, nausea, vomiting, retrosternal pain and respiratory problems (stridor and recurrent pneumonia) and usually presenting in childhood.", "ORPHA ID": 100048, "Summary": ""}
{"Disease Name": "Tubulinopathy-associated dysgyria", "Disease Definition": "A rare genetic central nervous system malformation characterized by dysplasia of the superior cerebellum (especially the vermis), brainstem asymmetry, dysplasia of the basal ganglia, and cortical irregularities with asymmetric abnormalities in gyral size and orientation, as well as varying sulcal depth, but without lissencephaly, pachygyria, or polymicrogyria. Clinically, patients present global developmental delay with motor development usually being more affected that speech. Variable features are abnormal eye movements including oculomotor apraxia, strabismus, seizures, and behavioral problems.", "ORPHA ID": 467166, "Summary": ""}
{"Disease Name": "Tubulocystic renal cell carcinoma", "Disease Definition": "Tubulocystic renal cell carcinoma is an extremely rare subtype of renal cell carcinoma most frequently characterized by a small, solitary, well-circumscribed, unencapsulated renal tumor composed of multiple small to medium-sized cysts with a white or gray, spongy (\"bubble wrap-like\") cut surface. Patients are usually asymptomatic or could manifest with abdominal pain, abdominal distension and/or hematuria. Progression, recurrence and metastasis rarely occur although lymph node, bone, pleura and liver metastases have been reported.", "ORPHA ID": 319325, "Summary": ""}
{"Disease Name": "Tubulointerstitial nephritis and uveitis syndrome", "Disease Definition": "A rare renal tubular disease characterized by early-onset tubulointerstitial nephritis associated with anterior uveitis.", "ORPHA ID": 91500, "Summary": "Epidemiology\nApproximately 200 cases have been reported in the literature to date, although the disease is likely under-reported. It comprises up to a third of bilateral acute onset acute uveitis in patients younger than 20 years old. Females are predominantly affected with a female:male ratio of 2.5-5:1.\nClinical description\nPresentation is typically in children and adolescents (median age of onset of 15 years old) with either uveitis (U) or tubulointerstitial nephritis (TIN). Symptoms of renal involvement are non-specific and can include polyuria/polydipsia, fever, general malaise, abdominal and flank pain, fatigue, arthralgia, myalgia or a non-specific rash. Ocular signs are eye pain and redness, loss of visual acuity and photophobia, though almost 60% of patients with confirmed uveitis present no symptoms. Uveitis is typically bilateral and anterior, but intermediate or posterior uveitis may occur. Of note, uveitis and TIN may occur synchronously or metachronously.\nEtiology\nThe pathogenesis is unclear, but likely autoimmune in origin. The role of the cellular and humoral immunity is highlighted by studies demonstrating loss of T cell-tolerance and the presence in kidney and ocular tissue of antibodies against modified C-reactive protein. Certain HLA haplotypes are associated with a higher risk of the disease.\nDiagnostic methods\nThere are no specific non-invasive tests to establish the diagnosis. Diagnosis should be suspected in patients with polyuria/polydipsia, rise in serum creatinine, elevated markers of tubular damage (such as low-molecular weight proteins), elevated urinary eosinophils, anemia and elevated erythrocyte sedimentation rate. A definitive diagnosis can be established by renal biopsy.\nDifferential diagnosis\nDifferential diagnoses should include secondary causes of tubulointerstitial nephritis and uveitis, such as infections (ex. TBC, viral infections as EBV or HIV, bacterial infections as chlamydia or mycoplasma; toxoplasmosis, brucellosis, histoplasmosis), granulomatous diseases as sarcoidosis, Sjögren syndrome, systemic lupus erythematosus (SLE), Wegener's granulomatosis and other as Behcet's disease, ankylosing spondylitis and inflammatory bowel diseases. The renal phenotype can be similar to nephronophthisis, which can also be associated with eye manifestations, albeit not in the form of uveitis.\nManagement and treatment\nTreatment is typically with immunosuppression. Oral corticosteroids are the first line therapy and improvement in symptoms is typically seen within days to weeks of commencement. Use of other immunosuppressive therapies, such as cyclophosphamide, cyclosporine, methotrexate or mycophenolate mofetil has been reported. Topical corticosteroids are useful for TINU-associated uveitis. A careful ophthalmological follow-up is required to monitor possible long-term complications.\nPrognosis\nPrognosis is favorable as the disease resolves in most of patients. However, some cases progress to end-stage renal disease. There is a low risk of visual loss; however, ocular complications (such as posterior synechiae, cystoid macular edema, disc edema, elevated intraocular pressure and cataract) have been described in 20% of patients.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Detlef BÖCKENHAUER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Tufted angioma", "Disease Definition": "A rare vascular tumour that may be either congenital or acquired (appearing before the age of 5 years) with slow angiomatous proliferation.", "ORPHA ID": 1063, "Summary": "Epidemiology\nThe prevalence is unknown but around 200 cases have been described in the literature. However, not all cases of tufted angioma are published and a certain number of cases are probably misdiagnosed as noninvoluting congential haemangiomas (NICH).\nClinical description\nTufted angiomas appear as poorly delineated red plaques, sometimes containing scattered deep-red papules. In rare (usually congenital) cases, tumoural masses have been reported. The appearance of the lesions changes with time and they are sensitive upon palpitation, or even painful if subjected to trauma. The angiomas are sometimes covered by a layer of downy hair or encircled by a clear ring of tissue or halo.\nDiagnostic methods\nThe diagnosis relies on the histological findings, which are characterised by a cannonball distribution of tufts of capillaries distributed throughout the dermis in a lobular arrangement. Lymphatic spaces and dermal fibrosis are frequently associated. Tufted angiomas are GLUT1-negative tumours that can be clearly distinguished from infantile haemangiomas.\nManagement and treatment\nGeneral corticotherapy, or therapy with alpha interferon or vincristine may be beneficial in severe cases with an extendedclinical course.\nPrognosis\nAlthough rare cases of spontaneous regression have been reported, the clinical course is often chronic. In some cases, tumours arising in the lower limbs infiltrate and progressively form a hardened (sclerous) tegument. This sclerosis may eventually reach the underlying muscle and joints, leading to significant functional problems. Tufted angiomas may be associated with Kasabach-Merritt syndrome (KMS), in which thrombopaenia can be life-threatening.\n\n                            Last update: \n                            May 2006\n\n\n                            - Expert reviewer(s): \n                            Dr Odile ENJOLRAS  - Pr Marie-Paule VAZQUEZ"}
{"Disease Name": "Tularemia", "Disease Definition": "A rare bacterial infectious disease caused by Francisella tularensis and characterized by six major clinical presentations: ulceroglandular, glandular, oropharyngeal, oculoglandular, pneumonic, or typhoidal, depending on the route of infection. Early flu-like symptoms are common to all forms and are accompanied/followed by either a skin inoculation ulcer with localized lymphadenopathy; isolated lymphadenopathy; chronic pharyngitis with cervical lymphadenopathy; conjunctivitis with localized lymphadenopathy; lung involvement; severe systemic disease with neurological symptoms.", "ORPHA ID": 3392, "Summary": ""}
{"Disease Name": "Tumor necrosis factor receptor 1 associated periodic syndrome", "Disease Definition": "Tumor necrosis factor receptor 1 associated periodic syndrome (TRAPS) is a periodic fever syndrome, characterized by recurrent fever, arthralgia, myalgia and tender skin lesions lasting for 1 to 3 weeks, associated with skin, joint, ocular and serosal inflammation and complicated by secondary amyloidosis (see this term).", "ORPHA ID": 32960, "Summary": "Epidemiology\nAnnual incidence in Germany was estimated at 1/1,785,000 children under 16.\nClinical description\nThe onset of TRAPS is usually in infancy or childhood but rarely in adolescence or adulthood. TRAPS is characterized by recurrent episodes that begin with muscle cramps or migrating myalgia, followed by fever that typically lasts for 1 to 3 weeks along with skin, joint, abdominal and ocular manifestations. These episodes occur either spontaneously or after minor triggers (stress, infection, exercise etc). Skin manifestations include centrifugal, migratory, erysepela-like erythema, edematous plaques and urticarial lesions. Eye involvement can manifest in the form of conjunctivitis, periorbital edema (highly specific feature for TRAPS) or uveitis (see this term). Serosal inflammation (pleuritis, peritonitis) is common. Abdominal pain and arthralgias are frequent symptoms. Secondary amyloidosis with renal and hepatic manifestations may eventually develop. An increased risk of atherosclerosis and acute myocardial infarction has been noted.\nEtiology\nMutations in the TNFRSF1A  (12p13.2) gene encoding TNFR1, that plays a key role in systemic inflammation, have been shown to underlie this condition. More than 70 mutations in the TNFRSF1A gene have been associated with TRAPS; about 50% of the mutations described (known as structural mutations) involve cysteine residues and are associated with a higher disease penetrance.\nDiagnostic methods\nDuring inflammatory episodes, laboratory tests reveal increased indicators of inflammation: raised erythrocyte sedimentation rate, C reactive protein, fibrinogen and haptoglobulin. There may also be an associated leucocytosis along with thrombocytosis, hypo or normochromic anemia and polyclonal hypergammaglobulinemia. The levels of serum amyloid A (SAA) protein and S100A12 correlate closely with disease activity and treatment efficacy. Serum level of soluble p55 TNF receptor (sTNFRSF1A) may be low. Urinary protein analysis helps to monitor evolution of renal amyloidosis. Mutational analyses can help confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other diseases characterized by periodic fever such as familial cold urticaria, juvenile idiopathic arthritis, Behçet disease, PFAPA syndrome, and Muckle-Wells syndrome (see these terms).\nGenetic counseling\nThe disease is transmitted in autosomal dominant manner with genetic heterogeneity and variable penetrance.\nManagement and treatment\nNon steroidal anti-inflammatory agents are used for symptomatic relief. Inflammatory episodes can be controlled by corticosteroids but often increasing doses are required. Etenarcept, a TNF inhibitor has been shown to be effective. However its efficacy tends to wane during the time. IL-1 receptor agonist (anakinra) and monoclonal antibody to IL-1 (canakinumab) have also been used in treating TRAPS, providing an optimal control of the inflammatory manifestations in the long term.\nPrognosis\nWith age, fever attacks may decrease in intensity and a more chronic and fluctuating course can be observed. Secondary amyloidosis complicates the course of the disease.\n\n                            Last update: \n                            September 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Marco GATTORNO"}
{"Disease Name": "Turcot syndrome with polyposis", "Disease Definition": "Turcot syndrome with polyposis or Turcot syndrome type 2 is a form of familial adematous polyposis, characterized by the concurrence of thousands of colonic adenomatous polyposis or colorectal cancer (CRC) and a primary central nervous system tumor (principally medulloblastoma). It is also associated with pigmented ocular fundus lesions.", "ORPHA ID": 99818, "Summary": ""}
{"Disease Name": "Turner syndrome", "Disease Definition": "A rare chromosomal anomaly syndrome characterized by complete or partial loss of an X chromosome in phenotypic females, clinically manifesting with short stature, primary ovarian insufficiency as well as cardiovascular, renal, liver, autoimmune diseases, hearing loss and neurocognitive abnormalities.", "ORPHA ID": 881, "Summary": "Epidemiology\nPrevalence is about 5/10 000 live female births. Incidence among all conceptions is higher, since aneuploidy is a common cause of spontaneous abortion.\nClinical description\nPatients typically present with significant statural growth retardation during childhood and/or primary ovarian insufficiency, often associated with homogeneous X monosomy. However, clinical features are heterogeneous and some may be milder or even absent in front of a 45,X/46,XX mosaic karyotype. Approximately 30% of patients will undergo the first pubertal stages such as breast development, 20% will experience spontaneous menarche and 95% have primary ovarian insufficiency before the age of 40. Around 5-7% are able to have a natural pregnancy. Patients may have a low posterior hairline, webbed neck, broad chest, hypoplastic nails, skeletal anomalies, congenital cardiovascular abnormalities (bicuspid aortic valves, aortic coarctation) as well as acquired vascular features, such as hypertension (50% of adult cases). Monitoring of aortic root diameters indexed to body surface area is recommended, since aortic bicuspidy, coarctation and hypertension may lead to aortic root dilatation and ultimately to aortic dissection. Other manifestations are renal defects, congenital lymphedema, liver steatosis or other hepatic diseases, ophthalmologic problems, hypothyroidism and autoimmune disorders. Intellectual disability is rarely reported, but patients may present impaired social skills and subtle cognitive difficulties. Variable comorbidities include obesity, insulin-resistance, conductive and sensorineural hearing impairment associated with repeated otitis media during childhood, and hyperlipidemia.\nEtiology\nX monosomy is the most common underlying etiology, while some cases have mosaicism or structural X chromosome anomalies. Clinical signs are more severe in patients with 45,X monosomy than in 45,X/46,XX or 45,X/46,XX/47,XXX mosaicism. Patients with an X isochromosome have a higher risk of liver and autoimmune diseases, while those with a ring chromosome are more prone to growth retardation and metabolic disorders. Haploinsufficiency of the SHOX gene is a well-established cause of short stature. The presence of Y material is related to the occurrence of gonadoblastoma.\nDiagnostic methods\nSuggestive clinical findings are confirmed by lymphocytic karyotype, demonstrating a 45,X cell line or deletion of the short arm (Xp) of the X chromosome. A second cell line study, such as buccal or urinary cell FISH analysis, may also be helpful.\nDifferential diagnosis\nDifferential diagnosis includes Noonan syndrome; 46,XX gonadal dysgenesis; 46,XY complete gonadal dysgenesis, SHOX-related short stature, as well as a single deletion of the long arm of the X chromosome downstream of Xq24.\nAntenatal diagnosis\nTypical forms with associated malformations can be diagnosed during ultrasound examination showing fetal abnormalities including diffuse edema, increased nuchal translucency, cystic hygroma, and left-sided obstructive cardiac anomalies. Noninvasive screening of circulating cell-free fetal DNA in maternal serum, amniocentesis or chorionic villus sampling can detect X chromosome abnormalities. Karyotyping must be repeated postnatally to confirm the diagnosis.\nManagement and treatment\nEarly diagnosis is beneficial, as it is recommended to start recombinant growth hormone therapy (GH) around 4-6 years and preferably before 12-13 years in case of growth failure (< 50th percentile) or short stature. This requires monitoring of insulin-like growth factor 1 and glycemia, due to a higher risk of glucose intolerance. A majority of patients require induction of puberty with estrogen replacement therapy at gradually increased doses, followed within 2 years by progestin supplementation to minimize endometrial hyperplasia and the long term risk of endometrial carcinoma. Hormonal replacement therapy with estrogen and progesterone/progestin is prescribed until the mean age of natural menopause (51 yrs). Lifelong follow-up is necessary, especially for the regular evaluation of aortic diameters.\nPrognosis\nEarly diagnosis, timely pubertal induction, successful transition to adult care, and long-term follow-up by a multidisciplinary team are key elements in the achievement of optimal growth, psychosocial milestones and fertility.\n\n                            Last update: \n                            December 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Claude CAREL | Endo-ERN* - Pr Sophie CHRISTIN-MAITRE | Endo-ERN* - Dr Bruno DONADILLE | Endo-ERN* - Pr Juliane LEGER | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Twin to twin transfusion syndrome", "Disease Definition": "Twin twin transfusion syndrome (TTTS) is a rare condition seen in twin monochorionic pregnancies, typically developing during the 15-26 week gestation period and usually due to unbalanced intertwin placental anastomoses, where an unequal exchange of blood between twins causes oligohydramnios in one sac and polyhydramnios in the other which can lead to a high perinatal mortality rate and a high rate of disability in survivors if left untreated", "ORPHA ID": 95431, "Summary": ""}
{"Disease Name": "Typhoid", "Disease Definition": "Typhoid or typhoid fever is a reportable, fecal-oral, potentially fatal infectious disease, caused by the bacteria Salmonella typhi and characterized by a non-focal fever.", "ORPHA ID": 99745, "Summary": "Epidemiology\nThe prevalence of typhoid is unknown but it is most commonly found in Asia, Africa and South America where access to properly treated drinking water may be limited. It is rare in Europe and Western countries and generally only occurs when imported from an endemic location. The annual incidence in Europe is estimated to be less than 1/30,000 persons/year.\nClinical description\nSymptoms usually appear 1-7 days after ingestion of the bacteria and include high fever (39 to 40°C), chills, constipation or diarrhea, headache, stomach pain, malaise, rash of flat rose-colored spots on the chest and hepato-splenomegaly. Temperature rises for 2-3 days and remains elevated for another 10-14 days accompanied by bradycardia and prostration. In severe cases, delirium, stupor and coma can occur. In 1-2% of patients, intestinal lesions can lead to bleeding and death. Others may develop pneumonia in the second to third week. Intestinal hemorrhage and perforation (usually in the terminal ileum) is a serious complication that can occur 2-3 weeks after infection, and usually occurs in developing countries where treatment is not always available. The convalescence period may last several months. Patients can remain carriers after symptoms disappear. With treatment most patients recover after 5-7 days of therapy and death is extremely uncommon.\nEtiology\nTyphoid is caused by several serovars of Salmonella enterica, a Gram-negative bacterium, with S. typhi being the most common. It is transmitted by the fecal-oral route from human to human when food or water is contaminated with feces of infected individuals. There is no known zoonotic reservoir. Once ingested,  S. typhi multiply inside macrophages and spread throughout the body in the bloodstream where they travel to the bone marrow, liver and gallbladder and are shed in the bile and feces. Asymptomatic carriers can spread the disease as a consequence of gallbladder colonization.\nDiagnostic methods\nDiagnosis of typhoid is suspected in patients with fever who have recently travelled to an area where the disease is endemic. The only methodology currently able to categorically confirm a diagnosis of typhoid involves a microbiological culture of blood or bone marrow to detect S. typhi or other typhoidal organisms. The Widal test, an agglutination test, is used only in developing countries as it is rapid, inexpensive and does not require a specialized laboratory, but it lacks sensitivity and specificity.\nDifferential diagnosis\nOther viral, bacterial or parasitic pathogens that cause diseases similar to typhoid include malaria, dengue fever, leptospirosis, typhus group rickettsia (see these terms), and influenza.\nManagement and treatment\nTyphoid is treated with antimicrobials, typically fluoroquinolones, which are essential for bacterial clearance. Patients usually begin to recover after 2-3 days but must complete the course of treatment to prevent relapse or latent retention of the infection. If intestinal perforation occurs, surgical intervention is necessary immediately. When travelling to countries where typhoid is endemic, vaccinations are recommended. The two licensed vaccines currently available are the oral live attenuated vaccine Ty21a and the parenteral Vi polysaccharide vaccine. Travelers should take care to avoid unsafe drinking water and food prepared in unsanitary conditions. Any cases of typhoid should immediately be reported. Food should not be prepared by people who have been infected with typhoid recently as they may still be carriers.\nPrognosis\nPrognosis is good and complications rarely occur if treated quickly with antibiotics. In untreated cases the fatality rate can be as high as 20%.\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                             Stephen BAKER"}
{"Disease Name": "Typical nemaline myopathy", "Disease Definition": "Typical nemaline myopathy is a moderate neonatal form of nemaline myopathy (NM; see this term) characterized by facial and skeletal muscle weakness and mild respiratory involvement.", "ORPHA ID": 171436, "Summary": "Epidemiology\nThe annual incidence of NM has been estimated at 1/50,000 live births and the typical form to represent about 50% of all cases.\nClinical description\nDisease onset is in the neonatal period. Patients have a long face, a high-arched palate and a tented upper lip. Skeletal anomalies may include kyphoscoliosis, pectus carinatum and pes cavus. In the first year of life, hypotonia and facial weakness are present and often contribute to failure to thrive and delayed motor development. Anti-gravity movements are present and respiratory muscle involvement is frequent. Nocturnal hypoxia and hypercarbia and lower respiratory tract infections are common manifestations. Joint hypermobility can be observed. In a minority of children weakness is more distal. Progression is very slow or absent and most patients are able to live an independent active life.\nEtiology\nTypical NM is caused by mutations of the ACTA1 (1q42.13), NEB (2q22) or TPM2 (9p13) genes, and disease transmission can be autosomal recessive or dominant.\n\n                            Last update: \n                            October 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Monique RYAN"}
{"Disease Name": "Tyrosinemia type 1", "Disease Definition": "A rare inborn error of tyrosine catabolism characterized by progressive liver disease, renal tubular dysfunction, porphyria-like crises and a dramatic improvement in prognosis following treatment with nitisinone.", "ORPHA ID": 882, "Summary": "Epidemiology\nBirth incidence is 1/100,000 in most areas but is higher in some regions, notably in Québec, Canada.\nClinical description\nThe disease is clinically heterogenous. Symptoms may start during the first few months (acute type), in second half of the first year (subacute type) or in the following years up to adulthood (chronic type). In the acute type, manifestations of hepatic failure predominate (bleeding diathesis, hypoglycemia, ascites etc) with frequent sepsis and rapid deterioration. Mild proximal tubular disease is usually present. Subacute type manifests a similar but less severe clinical picture presenting usually with hepatomegaly or hypophosphatemic rickets (due to tubular dysfunction). Intercurrent illness may precipitate hepatic crisis. Chronic type presents with hepatomegaly secondary to cirrhosis and often tubulopathy, leading to rickets and renal failure. Neurological crises are infrequent presenting symptoms (in Europe but not in Canada); however, they can complicate any type of the disease when untreated. The crises resemble those of acute intermittent porphyria, manifesting with painful parasthesias (causing patients to assume ophisthotonic position, self mutilation), autonomic signs (hypertension, tachycardia, ileus) and respiratory decompensation. All patients stand a high risk of developing hepatocellular carcinoma (HCC).\nEtiology\nThe deficiency of fumarylacetoacetate hydrolase, FAH(15q23-q25) results in accumulation of fumaryl-,maleyl-acetoacetate and their derivates, succinyl-acetone (SA) and succinyl-acetoacetate (SAA), that cause hepatorenal damage. SA leads to accumulation of delta-aminolevulinate (δ-ALA) resulting in inhibition of porphobilinogen synthesis and porphyria-like crises.\nDiagnostic methods\nLiver synthetic functions are usually severely affected with coagulopathy and hypoalbuminemia. Elevated levels of SA in dried blood spots, plasma or urine are pathognomonic. Other abnormalities include elevated α -fetoprotein, increased plasma levels of tyrosine, phenylalanine and methionine, increased urinary δ-ALA excretion and features of Fanconi tubulopathy. Confirmation of diagnosis is usually by mutation analysis. Newborn screening programs include testing for tyrosinemia type 1 (SA is the recommended marker).\nDifferential diagnosis\nDifferential metabolic diagnoses include classic galactosemia, hereditary fructose intolerance, and fructose 1,6 diphosphatase deficiency, Wilson's disease and some mitochondrial disorders.\nAntenatal diagnosis\nAntenatal diagnosis is possible with chorionic villus sampling and amniocentesis when a mutation has been identified in the family.\nGenetic counseling\nTyrosinemia type 1 is an autosomal recessive disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them there is a 25% chance of having an affected child at each pregnancy.\nManagement and treatment\nAs soon as the diagnosis is confirmed (or even highly suspected) start nitisinone (NTBC) orally in a dose of 1-2 mg/kg a day along with the emergency treatment for acute liver failure if necessary. A protein-restricted diet must also be started in parallel. Patients should be referred to a specialist center for long term management. Liver transplantation should be considered in acutely ill infants (if liver function fails to respond to nitisinone within a week), suspected or diagnosed HCC, and non-compliance or unavailability of medical treatment.\nPrognosis\nNitisinone treatment, combined with a low-protein diet allows most the patients to survive in good health. The prognosis is dominated by the risk of HCC, which increases the later the treatment is started.\n\n                            Last update: \n                            June 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Corinne DE LAET | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Tyrosinemia type 2", "Disease Definition": "A rare inborn error of tyrosine metabolism characterized by hypertyrosinemia with oculocutaneous manifestations and, in some cases, intellectual deficit.", "ORPHA ID": 28378, "Summary": "Epidemiology\nPrevalence is unknown but less than 150 cases have been reported in the literature so far. The disease appears to be more common in Arab and Mediterranean populations.\nClinical description\nSkin lesions occur in 80% of cases, ocular involvement in 75% of cases and neurologic findings and some degree of intellectual deficit in up to 60% of cases. Onset is variable but the ocular symptoms (redness, photophobia, excessive tearing and pain) usually develop in the first year of life. Ocular signs include corneal clouding with bilateral dendritiform corneal lesions (pseudodendritic keratitis), neovascularization, corneal ulceration and scarring, which may lead to decreased visual acuity. Cutaneous manifestations usually begin after the first year of life but may develop at the same time as the ocular symptoms. The skin lesions consist of nonpruritic, hyperkeratotic papules and plaques principally located on the palms and soles (palmoplantar hyperkeratosis). These lesions are painful and progressive and are often associated with hyperhidrosis. Central nervous system (CNS) involvement is highly variable with intellectual deficit (ranging from mild to severe) being the most common manifestation. Other signs of CNS involvement include behavioral problems, nystagmus, tremor, ataxia, and convulsions.\nEtiology\nTyrosinemia type 2 is caused by mutations in the TAT gene (16q22.2) encoding tyrosine aminotransferase (TAT). The elevated levels of tyrosine caused by TAT deficiency appear to result in deposition of tyrosine crystals leading to an inflammatory response and the oculocutaneous findings. Tyrosine crystals were not found in skin lesions; it was suggested that intracellular tyrosine excess interfere with microtubules and tonofilaments. It has also been suggested that there is a correlation between the extent of the CNS involvement and the levels of tyrosine in the plasma.\nDiagnostic methods\nDiagnosis is established on the basis of the clinical findings and detection of high levels of plasma and urinary tyrosine, and elevated levels of urinary tyrosine metabolites (such as 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, 4-hydroxyphenylacetate and N-acetyltyrosine). The confirmation of the diagnosis is done by mutations analysis; TAT assays on liver biopsy samples are usually not necessary. Some patients with tyrosinemia type 2 may be identified through neonatal screening program studies.\nDifferential diagnosis\nAs the ocular findings are often the initial manifestations of the disease, the pseudodendritic keratitis is often mistaken for herpes simplex keratitis. Mutilating palmoplantar keratoderma with periorificial keratotic plaques is also part of the differential diagnosis.\nAntenatal diagnosis\nAntenatal diagnosis is possible with chorionic villus sampling and amnioncentesis when a mutation has been identified in the family.\nGenetic counseling\nTyrosinemia type 2 is an autosomal recessive disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them there is a 25% chance of having an affected child at each pregnancy.\nManagement and treatment\nManagement revolves around dietary restriction of phenylalanine and tyrosine. Oral retinoids may also be administered for treatment of the skin lesions.\nPrognosis\nThe controlled diet results in lowering of plasma tyrosine levels and rapid resolution of the oculocutaneous manifestations. However, the extent to which this controlled diet prevents the CNS involvement is unclear.\n\n                            Last update: \n                            June 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Corinne DE LAET | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Tyrosinemia type 3", "Disease Definition": "A rare inborn error of tyrosine metabolism characterized by mild hypertyrosinemia and increased urinary excretion of 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate and 4-hydroxyphenylacetate.", "ORPHA ID": 69723, "Summary": "Epidemiology\nIt is the least frequent form of tyrosinemia with less than 20 cases reported in the literature so far.\nClinical description\nThe clinical picture is highly variable ranging from asymptomatic in some patients identified through neonatal screening program studies to patients with neurologic manifestations including intellectual deficit, ataxia, tremors and seizures.\nEtiology\nTyrosinemia type 3 is caused by mutations in the HPD gene (12q24.31) encoding 4-hydroxyphenylpyruvate dioxygenase.\nDiagnostic methods\nDetection of elevated tyrosine in the blood and detection of tyrosine derivatives in the urine is suggestive of the disease. The diagnosis is confirmed by enzyme assay, revealing accumulation of 4-hydroxyphenylpyruvate dioxygenase in the liver or kidney, or by mutation testing.\nDifferential diagnosis\nThe differential diagnosis broadly includes neurological disorders with psychomotor and/or intellectual disability of other etiology.\nAntenatal diagnosis\nAntenatal diagnosis is possible when a disease-causing mutation has been identified in the family.\nGenetic counseling\nTyrosinemia type 3 is an autosomal recessive disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them there is a 25% chance of having an affected child at each pregnancy.\nManagement and treatment\nAlthough it has not been clearly established that treatment prevents the onset of symptoms, it is currently recommended that, patients with tyrosinemia type 3 follow a phenylalanine- and tyrosine-restricted diet.\nPrognosis\nTyrosinemia type 3 has no impact on life expectancy. Intellectual disability, usually mild to moderate, may require adaptations to daily life.\n\n                            Last update: \n                            June 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Corinne DE LAET | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Uhl anomaly", "Disease Definition": "Uhl anomaly is characterized by an almost complete absence of the myocardium in the right ventricle resulting in a thin walled nonfunctional right ventricle manifesting with cardiac arrhythmias and right ventricular failure. Cases of partial absence of right ventricular myocardium which remains asymptomatic or mildly symptomatic until adulthood have also been reported. Patients presenting with complete Uhl anomaly should be considered for cardiac transplantation.", "ORPHA ID": 3403, "Summary": ""}
{"Disease Name": "Ulbright-Hodes syndrome", "Disease Definition": "Ulbright-Hodes syndrome is characterised by renal dysplasia, growth retardation, phocomelia or mesomelia, radiohumeral fusion, rib abnormalities, anomalies of the external genitalia and a potter-like facies. The syndrome has been described in three infants (one pair of sibs and an unrelated case), all of whom died shortly after birth from respiratory distress resulting from pulmonary hypoplasia and oligohydramnios caused by renal dysplasia. The mode of transmission appears to be autosomal recessive.", "ORPHA ID": 3404, "Summary": ""}
{"Disease Name": "Ulerythema ophryogenesis", "Disease Definition": "Ulerythema ophryogenesis is characterised by inflammatory keratotic papules occurring on the face, which may be followed by scars, atrophy and alopecia. Prevalence is unknown but the disease, affecting mainly children and young adults, is rare. Erythema with mild hyperkeratosis of the hair follicles resulting in rough papules is observed on the cheeks and lateral aspects of the eyebrows. The disorder occasionally extends to the adjacent scalp, ears and forehead and rarely to the extensor surfaces of the limbs. Symptoms regress with age, although loss of the lateral aspects of the eyebrows can occur. Many cases occur sporadically; autosomal dominant inheritance has also been reported. There is no particular treatment, but patients should avoid sun exposure without UV protection.", "ORPHA ID": 3406, "Summary": ""}
{"Disease Name": "Ullrich congenital muscular dystrophy", "Disease Definition": "A form of congenital muscular dystrophy characterized by congenital weakness, hypotonia, proximal joint contractures, marked hyperlaxity of the distal joints, with a loss of ambulation (if achieved) and uniform respiratory insufficiency during childhood.", "ORPHA ID": 75840, "Summary": "Epidemiology\nA Northern England study of genetic muscle disease reported an estimated prevalence of Ullrich congenital muscular dystrophy (UCMD) of 1/769,231.\nClinical description\nThe first signs noted are typically noted in utero with decreased fetal movement. Characteristic features at birth include hypotonia, torticollis, contractures of the proximal joints, hyperlaxity of the distal joints, kyphoscoliosis, abnormal positioning of the hands (wrist flexion) and feet (ankle dorsiflexion), hip dislocation, and prominent calcanei. Independent walking is not always achieved, and progression of muscle weakness and joint contractures result in loss of ambulation by 10-11 years old. Progressive, severe respiratory insufficiency occurs in all affected individuals by ~11 years old. Congenital kyphoscoliosis may occur. Spinal rigidity with concomitant scoliosis typically manifest at ~7 years, with scoliosis surgical repair performed at ~11 years. Skin manifestations include keratosis pilaris/follicular keratosis, prominently along the extensor surfaces of the arms and legs, keloid scars, and atrophic scars.\nEtiology\nUCMD is caused by heterozygous or biallelic pathogenic variants (PVs) in the genes coding for the alpha chains of the extracellular matrix protein collagen VI (COL6A1, COL6A2, and COL6A3).\nDiagnostic methods\nThe diagnosis is based on clinical signs, muscle imaging (MRI helps to identify characteristic patterns of abnormal muscle signaling), biopsy (revealing degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue), and muscle immunohistochemical features (ranging from absent collagen VI to mislocalized collagen VI) and the identification of a PV or PVs by molecular genetic testing.\nDifferential diagnosis\nThe differential diagnosis includes intermediate COL6-related dystrophy (COL6-RD), Ehlers-Danlos/myopathy overlap syndrome, kyphoscoliotic Ehlers-Danlos syndrome, classic Ehlers-Danlos syndrome, Marfan syndrome, congenital contractural arachnodactyly, TTN-related myopathy, RYR1-related myopathy, SELENON-related myopathy, other forms of congenital muscular dystrophy, and spinal muscular atrophy.\nAntenatal diagnosis\nOnce PV have been identified in an affected family member, prenatal diagnosis for a pregnancy and preimplantation genetic testing are possible.\nGenetic counseling\nUCMD is typically caused by a de novo autosomal dominant PV in COL6A1, COL6A2 or COL6A3, in which case, each child of an affected individual has a 50% chance of inheriting the PV. Less commonly, UCMD is inherited in an autosomal recessive manner; if both parents are carriers of a disease-causing mutation, they should be informed that there is a 25% risk of having an affected child with each pregnancy. Parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in COL6-RDs and should be considered, given the implications for recurrence risk assessment.\nManagement and treatment\nCurrently, there is no curative treatment. Careful pulmonary surveillance and proactive care dramatically improve the quality of life of affected individuals, however. Non-invasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) is necessary by ~11 years. Use of a mechanical insufflator-exsufflator promotes airway clearance. Without adequate respiratory support with NIV, respiratory failure leads to early death in adolescence. Surveillance of the spine and surgical correction of scoliosis, if indicated, should be provided. Physical and occupational therapy are important for providing recommendations for joint stretching, swimming, and aquatherapy. Achilles tendon contractures should be managed with splints and/or tendon release surgery. Feeding and nutrition support should be provided for failure to thrive.\nPrognosis\nUCMD is a severe progressive disorder. Progressive respiratory insufficiency uniformly necessitates the initiation of nocturnal non-invasive ventilation by ~11 years of age. Most patients either are unable to walk or can walk for a period of time, with full-time wheelchair dependence by ~10-11 years of age.\n\n                            Last update: \n                            October 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Carsten G. BONNEMANN  - Dr A. Reghan FOLEY"}
{"Disease Name": "Ulna hypoplasia-intellectual disability syndrome", "Disease Definition": "Ulna hypoplasia - intellectual deficit is a very rare syndrome characterized by mesomelic shortness of the forearms, bilateral clubfeet, aplasia or hypoplasia of all nails and severe psychomotor retardation.", "ORPHA ID": 2249, "Summary": "Epidemiology\nIt has been reported in two sibs.\nGenetic counseling\nThe family is suggestive of autosomal recessive inheritance.\nPrognosis\nPrognosis is poor.\n\n                            Last update: \n                            September 2010"}
{"Disease Name": "Ulnar hypoplasia-split foot syndrome", "Disease Definition": "Ulnar hypoplasia-split foot syndrome is characterised by the association of severe ulnar hypoplasia, absence of fingers two to five, and split-foot. It has been described in four males belonging to two generations of the same family. X-linked recessive inheritance is suggested, but autosomal dominant transmission cannot be excluded.", "ORPHA ID": 1122, "Summary": ""}
{"Disease Name": "Ulnar-mammary syndrome", "Disease Definition": "A rare congenital anomalies syndrome characterized by a variable spectrum of ulnar defects, mammary and apocrine gland hypoplasia and genital anomalies. The most frequent signs include fifth finger and dental anomalies, delayed puberty and mammary hypoplasia. Short stature and obesity are common.", "ORPHA ID": 3138, "Summary": "Epidemiology\nUp to date, approximately 128 cases of Ulnar-mammary syndrome (UMS) have been reported in the literature.\nClinical description\nUpper limb defects are the most common presenting feature of UMS at birth. Whilst the upper limbs can be normal, the limb phenotype is variable and can range from hypoplasia of the distal phalanges of the fifth finger(s), camptodactyly and/or postaxial polydactyly to absent ulnar ray digits, absent or hypoplastic ulna and a reduced humerus at the severe end of the spectrum. Abnormalities may be bilateral but are frequently asymmetric; lower limb defects have not been reported. The variable mammary and apocrine features of UMS may not be apparent until puberty and include mammary gland tissue hypoplasia (leading to absence of breast development and the inability to lactate), areolar or nipple hypoplasia, inverted nipples and apocrine gland hypoplasia (that can result in diminished perspiration and body odor). Absent or reduced axillary hair has also been described. Shared facial features of UMS include a wide face tapering to a prominent chin, a broad nasal tip, a wide nasal base, and a bifid tongue tip. Genital defects can include micropenis, shawl scrotum, cryptorchidism, septate uterus, and imperforate hymen. Delayed puberty is noted, particularly in males (79%), due to hypogonadism. Obesity and short stature are also common in individuals with UMS and a pituitary endocrine deficiency (growth hormone, pituitary hypoplasia) has been suggested as a possible cause. Abnormalities of the teeth with ectopic, hypoplastic or absent canines have been noted in a number of individuals. Cardiac defects (ventricular septal defects or conduction abnormalities), renal and anal anomalies (imperforation, anteposition) have been reported in a few cases.\nEtiology\nUMS is caused by loss-of-function variants in the TBX3 gene (12q24.21). A hotspot of missense variants is observed in the DNA-binding domain of the TBX3 protein. TBX3 is a member of the T-box gene family. These genes encode transcription factors that have been shown to be important in embryologic development and in the morphogenesis of multiple organ systems.\nDiagnostic methods\nDiagnosis of UMS is based on clinical findings and family history. It can be confirmed by molecular genetic analyses of TBX3.\nDifferential diagnosis\nDifferential diagnoses include limb-mammary syndrome (due to TP63 variants) and Poland syndrome (which is sporadic).\nAntenatal diagnosis\nPrenatal testing is based on DNA analysis of amniocentesis and chorionic villus sampling and may be useful to confirm ultrasound and echocardiography findings in families with a known Ulnar Mammary syndrome mutation.\nGenetic counseling\nUMS is an autosomal dominant condition commonly reported in families. There is an important inter- and intra-familial variability in expression; however, there is no obvious phenotypic difference between those who have missense variants and those who have frameshift or stop-gain variants. Genetic counseling is possible for affected individuals, informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement is multidisciplinary and includes geneticists, orthopedic surgeons and pediatric orthopedics, endocrinologists, cardiologists, as well as social support networks.\nPrognosis\nPrognosis is variable. Functional impact in everyday life is based on the type and severity of upper-limb anomalies and of endocrinologic anomalies (short stature, infertility, etc.). Life expectancy is the same as in the general population.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Perrine BRUNELLE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Ulnar/fibula ray defect-brachydactyly syndrome", "Disease Definition": "A rare congenital malformation syndrome characterized by ulnar hypoplasia associated with hypoplastic to absent fourth and/or fifth digits, fibular hypoplasia, short stature and facial dysmorphism.", "ORPHA ID": 52056, "Summary": ""}
{"Disease Name": "Umbilical cord ulceration-intestinal atresia syndrome", "Disease Definition": "A rare syndromic intestinal malformation characterized by ulcer formation in the umbilical cord associated with congenital upper-intestinal atresia, typically presenting with intra-uterine hemorrhaging from the ulcer site and subsequent fetal bradycardia.", "ORPHA ID": 3405, "Summary": "Epidemiology\nWhilst about 66 cases have been described to date in the medical and scientific literature, the entity is probably grossly under-reported due to lack of awareness.\nClinical description\nUmbilical cord ulceration (UCU) occurs in the context of duodenal or jejunal intestinal atresia, developing in 6.5-13.6% of infants with a prenatal diagnosis of congenital upper intestinal atresia (CUIA). Onset of the UCU typically occurs from gestational week 30 onwards. Symptoms of UCU usually begin with the onset of premature labor or rupture of membranes, where the increased intra-uterine pressure causes rupture of the umbilical vessel into the amniotic cavity, triggering massive fetal hemorrhage and subsequent bradycardia. Severe anemia is typically present at birth. The degree of ulceration ranges from only desquamation of the epithelium to exposure of the umbilical artery or vein. Cases that do not significantly hemorrhage, especially lower grade lesions, may go undiagnosed.\nEtiology\nWhilst the exact mechanism of pathogenesis is unclear, it is suspected that UCU is closely related to in-utero regurgitation of bile. Other mechanisms proposed include vascular hyper-reactivity and secondary ischemia, causing simultaneous occurrence of both UCU and CUIA, due to an epithelial abnormality (similar to the association of epidermolysis bullosa with intestinal atresia).\nDiagnostic methods\nPrenatal ultrasound findings of CUIA with polyhydramnios should raise suspicion of associated UCU. However, in these cases, confirmation of diagnosis is most often done postnatally upon examination of umbilical cord.\nDifferential diagnosis\nDifferential diagnoses include absence of Wharton's jelly, omphalomesenteric duct with gastric mucosa, umbilical cord hemangioma, and umbilical hematoma.\nAntenatal diagnosis\nSuggestive ultrasound (US) findings include signs of CUIA and polyhydramnios. Whilst there is an increased risk of UCU in cases of CUIA, prenatal detection of UCU is challenging. In high-risk cases, increased frequency of ultrasound monitoring with a meticulous evaluation of the umbilical cord, especially at the fetal end, is advisable but technically difficult. Findings suspicious of blood in amniotic fluid include observations of bleeding from the umbilical cord by color Doppler or changes in the luminosity of the amniotic fluid indicating the presence of blood. Measurement of bile acid concentration in amniotic fluid can further help in segregation of high-risk cases.\nManagement and treatment\nIt is currently difficult to present a method by which sudden fetal death can be prevented. The risk of UCU must be explained elaborately to the parents of fetuses with CUIA. Daily monitoring of high risk cases with fetal kick chart and non‐stress test (NST) is advisable for early detection of UCU. Termination of pregnancy may be considered when hemorrhage is confirmed via amniocentesis or ultrasound findings are suggestive of blood in amniotic fluid. In cases of polyhydramnios with CUIA, continuous fetal heart monitoring at the onset of premature labor or premature rupture of membranes has been found to improve outcome. Awareness of this association and immediate delivery of fetus at first signs of hemorrhage or hypoxia will help prevent stillbirths and poor neonatal outcomes.\nPrognosis\nPrognosis of Umbilical cord ulceration-intestinal atresia syndrome is poor, with intra-uterine fetal or neonatal death occurring in the majority of cases. Prompt intervention, initiated with immediate delivery at the first signs of fetal hemorrhage/hypoxia, may improve the outcome.\n\n                            Last update: \n                            March 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Sangeeta GUPTA"}
{"Disease Name": "UMOD-related autosomal dominant tubulointerstitial kidney disease", "Disease Definition": "A form of autosomal dominant tubulointerstitial kidney disease (ADTKD) due to UMOD mutations that is clinically characterized by bland urinalysis (absence of blood or protein in the urine), chronic kidney disease (CKD) leading to end-stage kidney disease (ESKD) between 20 and 80 years, and gout occurring in 50% of affected individuals.", "ORPHA ID": 88950, "Summary": "Epidemiology\nWhilst prevalence data is limited, it is estimated at approximately 1/600,000 in Austria and 1/110,000 in the UK. The disease has equal prevalence among all studied racial groups.\nClinical description\nCKD is usually first evident in the early twenties, though many children will have some evidence of mildly decreased kidney function by 18 years. Ten percent of affected individuals develop gout before age 18 years. Many individuals are first recognized with gout or CKD in their twenties. Patients will have slowly progressive loss of kidney function. The mean age of ESKD is approximately 49 years of age, though the age varies widely from 20 to over 70 years, even among family members with the same mutation. The reason for this variation in age of ESKD is unclear. Gout will develop in approximately 50% of affected individuals over time, often preceding significant loss of kidney function.\nEtiology\nThe disorder is caused by mutations in the UMOD gene, resulting in a mutated uromodulin protein that deposits within the endoplasmic reticulum, leading to cell stress, accelerated apoptosis, and progressive chronic kidney disease.\nDiagnostic methods\nDiagnosis is suspected in individuals who have chronic kidney disease, a bland urinary sediment, and a family history of kidney disease. Gout presenting in adolescence or in a young woman is suggestive for ADTKD-UMOD. Mutational analysis is the preferred means of diagnosis, either by direct sequencing if the family has a known UMOD mutation or by multi-gene panel or whole exome sequencing, both of which will identify alternative genetic causes.\nDifferential diagnosis\nADTKD-MUC1 is almost clinically indistinguishable from ADTKD-UMOD except that gout is less prevalent in ADTKD-MUC1 and only occurs after the development of CKD. ADTKD-REN due to mutations in the segment of the gene encoding mature renin is clinically identical to ADTKD-UMOD, with early gout, CKD, and autosomal dominant inheritance. Most other conditions have other associated symptoms, but when these symptoms are less severe or not clinically noted, ADTKD-UMOD may be considered. These include kidney disease related to DNAJB11, IFT140, or HNF1B, and, in rare cases, Alagille syndrome.\nAntenatal diagnosis\nAntenatal diagnosis is possible if there is known mutation in the family.\nGenetic counseling\nThe disorder is autosomal dominant. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. Genetic testing may be performed in children to prevent the risk of gout development with early treatment with allopurinol. If gout is not prevalent in the family, testing in childhood is not recommended. Relatives should be informed of their risk of ADTKD-UMOD, as the disease is often misdiagnosed, and reaching out to family members can prevent the need for kidney biopsy or inappropriate treatment.\nManagement and treatment\nThe only specific treatment for this disease is gout prevention with allopurinol or febuxostat. Gout is lifelong and worsens as CKD worsens, preventative therapy is thus important in patients who develop gout. Patients with ADTKD-UMOD are excellent transplant candidates, as the disease does not recur in the transplanted kidney and most patients do not have other comorbid conditions. The goal should be transplant without ever needing dialysis. Family members should be screened for the familial UMOD mutation to see if they can donate. Major advances are occurring in kidney disease management, with placement of pig kidneys, CRISPR technology to treat genetic disorders, and advances in immunosuppression-free kidney transplantation.\nPrognosis\nWhilst there is wide variation in onset of ESKD, many patients diagnosed today will not develop ESKD for more than two decades, with a current mean age of 49 years. Use of dialysis is variable, ranging from the third decade or as late as the eighth decade of life. Survival post-transplant is comparable to the general ESKD transplant population.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Anthony BLEYER  - Pr Stanislav KMOCH"}
{"Disease Name": "Unclassified myelodysplastic syndrome", "Disease Definition": "Unclassified myelodysplastic syndrome (MDS-U) is a subtype of myelodysplastic syndrome (MDS; see this term) with atypical features of uncertain clinical significance.", "ORPHA ID": 98827, "Summary": "Epidemiology\nPrevalence is unknown but MDS-U appears to account for a very low proportion of MSD cases.\nClinical description\nUnclassified MDS covers cases that cannot be allocated to another subtype of MSD after a full diagnostic work-up has been performed including clinical, morphologic, immunophenotypic, or cytogenetic testing. One or more cytopenias are a standard feature of MDS-U but other clinical features are variable. The following cases are considered to fall into this subtype: features of refractory cytopenia with uni- or multi-lineage dysplasia (RCUD, RCMD, see these terms) but with 1% blasts in peripheral blood, unilineage dysplasia with pancytopenia, and persistent cytopenias without morphological features of MDS associated with characteristic cytogenetic abnormalities.\nEtiology\nThe etiology is not known but is thought to involve inherited susceptibility or hematopoietic stem cell damage.\n\n                            Last update: \n                            February 2015"}
{"Disease Name": "Unclassified myelodysplastic/myeloproliferative disease", "Disease Definition": "A rare myelodysplastic/myeloproliferative neoplasm characterized by clinical, laboratory, and morphological features of both myelodysplastic syndrome and myeloproliferative neoplasm at onset, in the absence of recent cytotoxic or growth factor therapy, and without Philadelphia chromosome, BCR-ABL1 or PCM1-JAK2 fusion, or rearrangement of PDGFRA, PDGFRB, or FGFR1. Cases of a previously well-defined myeloproliferative neoplasm developing dysplastic features are excluded, and the criteria for any other myelodysplastic/myeloproliferative neoplasm, myelodysplastic syndrome, or myeloproliferative neoplasm are not met.", "ORPHA ID": 98825, "Summary": ""}
{"Disease Name": "Unclassified vasculitis", "Disease Definition": "A rare vasculitis characterized by an inflammatory disease of blood vessels which cannot be assigned to any of the known categories of vasculitis. Clinical features are highly variable, depending on the nature and extent of the inflammatory process, as well as the type of vessels and organ systems involved.", "ORPHA ID": 251328, "Summary": ""}
{"Disease Name": "Uncombable hair syndrome", "Disease Definition": "Uncombable hair syndrome (UHS), or pili trianguli et canaliculi, is a rare scalp hair shaft dysplasia.", "ORPHA ID": 1410, "Summary": "Epidemiology\nPrevalence is unknown.\nClinical description\nOnset is usually between ages 3 months and 12 years. Hair becomes progressively silvery-blond or straw-colored, dry and disordered, standing out from the scalp and growing in different directions, and being unmanageable to comb it flat. The quantity of hair stays normal. Microscopic analysis reveals a longitudinal groove of the hair shaft with a triangular or kidney-shaped section. The anomaly is clinically detectable when approximately 50% of hairs are affected. Several conditions have been reported to occur with UHS such as ectodermal dysplasia, retinal dysplasia, retinal pigmentary dystrophy, juvenile cataract, digit abnormalities, tooth enamel anomalies, oligodontia, phalango-epiphyseal dysplasia, alopecia areata, atopic eczema, and ichthyosis vulgaris.\nEtiology\nThe stiffness and brightness of hair are supposed to result from a misshapen dermal papilla inducing an anomaly in the keratinization of the inner root sheath.\nDiagnostic methods\nDiagnosis relies on clinical and microscopic observation, but electron microscopic analysis of hair shaft can eliminate other hair anomalies.\nDifferential diagnosis\nDifferential diagnosis includes Rapp-Hodgkin ectodermal dysplasia, loose anagen hair syndrome, ectrodactyly, cleft/lip palate syndrome, familial tricho-odonto-onchyial ectodermal dysplasia with syndactyly and other ectodermal dysplasias.\nGenetic counseling\nUHS is likely to be an autosomal dominant inherited disease with a variable penetrance but no causal gene has been identified yet.\nManagement and treatment\nUHS spontaneously regresses in late childhood and only gentle care including conditioners, soft brushes and avoidance of harsh treatments cares of the hair are recommended. Biotin treatment as been used in several patients and might be useful to control nail fragility, leading to acclaimed increase in hair growth after 4 months of supplementation.\n\n                            Last update: \n                            January 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Alexander NAVARINI"}
{"Disease Name": "Undetermined colitis", "Disease Definition": "Underterminate colitis designates a rare inflammatory bowel disease that clinically resembles Crohn’s disease and ulcerative colitis (see these terms) but that cannot be diagnosed as one of them after examination of an intestinal resection specimen.", "ORPHA ID": 103920, "Summary": ""}
{"Disease Name": "Undifferentiated carcinoma of esophagus", "Disease Definition": "A rare, aggressive, malignant, epithelial carcinoma of the esophagus characterized, macroscopically, by an exophytic mass with central ulceration located on the esophagus and, histologically, by a sheet-like growth of neoplastic cells without significant glandular, squamous or neuroendocrine differentiation. Patients may present with progressive dysphagia, long-standing history of gastroesophageal reflux, weight loss, anemia, abdominal or chest pain/pressure, dyspnea, and/or hematemesis. Presence or history of Barrett esophagus is frequently associated.", "ORPHA ID": 418951, "Summary": ""}
{"Disease Name": "Undifferentiated carcinoma of liver and intrahepatic biliary tract", "Disease Definition": "Undifferentiated carcinoma of liver and intrahepatic biliary tract is an extremely rare epithelial tumor of the liver and biliary tract which presents heterogenous histological findings and not yet fully defined clinicopathological characterisitcs. Patients usually present with nonspecific signs and symptoms, such as abdominal pain, nausea, vomiting, anorexia, weight loss and/or jaundice. Invasive growth, high metastatic potential and a rapid clinical course are typically associated.", "ORPHA ID": 424970, "Summary": ""}
{"Disease Name": "Undifferentiated carcinoma of stomach", "Disease Definition": "Undifferentiated carcinoma of stomach is a rare epithelial tumour of the stomach that lacks any features of differentiation beyond an epithelial phenotype. The presenting symptoms are usually vague and nonspecific, such as weight loss, anorexia, fatigue, epigastric pain and discomfort, heartburn and nausea, vomiting or hematemesis. Patients may also be asymptomatic. Ascites, jaundice, intestinal obstruction and peripheral lymphadenopathy indicate advanced stages and metastatic spread.", "ORPHA ID": 423786, "Summary": ""}
{"Disease Name": "Undifferentiated carcinoma of the corpus uteri", "Disease Definition": "Undifferentiated carcinoma of the corpus uteri is a rare cancer of corpus uteri presenting as a large, polypoid, intraluminal mass with necrosis, composed of small to intermediate-size, relatively uniform, dyshesive cells displaying no differentiation. It usually presents with dysfunctional bleeding or vaginal discharge and, less often, abdominal pain. Association with Lynch syndrome was reported.", "ORPHA ID": 213721, "Summary": ""}
{"Disease Name": "Undifferentiated carcinoma with osteoclast-like giant cells of pancreas", "Disease Definition": "A rare type of pancreatic ductal adenocarcinoma characterized by composition of non-neoplastic osteoclast-like multinucleated giant cells, a mononuclear histiocytic component, and the neoplastic cells, which vary from spindle-shaped to epithelioid and can be very large and pleomorphic. Clinical features of pancreatic ductal adenocarcinoma include abdominal pain, nausea, weight loss, jaundice, and new-onset diabetes.", "ORPHA ID": 424080, "Summary": ""}
{"Disease Name": "Undifferentiated connective tissue syndrome", "Disease Definition": "A rare systemic autoimmune disease characterized by the presence of signs and symptoms suggestive of a systemic autoimmune disease that do not fulfil the existing classification criteria. The main clinical manifestations are arthritis with arthralgia, Raynaud's phenomenon, xerostomia, xerophthalmia, and leukopenia, while neurologic or renal involvement are virtually absent.", "ORPHA ID": 90002, "Summary": ""}
{"Disease Name": "Undifferentiated embryonal sarcoma of the liver", "Disease Definition": "Embryonal sarcoma of the liver is a rare primary malignant hepatic neoplasm of childhood of mesenchymal origin. It can rarely occur in adults. It is characterized by abdominal mass, right upper quadrant or epigastric pain, nausea, anorexia, intermittent fever or headache.", "ORPHA ID": 178315, "Summary": ""}
{"Disease Name": "Undifferentiated pleomorphic sarcoma", "Disease Definition": "An aggressive sarcoma of soft tissues or bone that can arise from any part of the body, clinically presenting as swelling, mass, pain, pathological fracture and occasional systemic features and is characterized by high local recurrence and significant metastasis.", "ORPHA ID": 2023, "Summary": "Epidemiology\nUPS ranks the 4th most common soft tissue sarcoma with a slight male preponderance. The incidence has been evaluated to be close to 0.8-1 new case per 100000 per year in one European series.\nClinical description\nThe tumor arises most commonly during the sixth and seventh decades of life. The most common sites of involvement include lower extremities (mainly thigh) followed by upper arms, retroperitoneum, viscera, head and neck (in childhood). Primary osseous UPS most commonly occurs in distal femur, proximal tibia, proximal femur and humerus. Patients may present pain, swelling / mass and pathological fractures. In the skin, UPS presents as a relatively painless, rapidly enlarging nodule. Anorexia, malaise, fever and weight loss are present in retroperitoneal and inflammatory forms of UPS. Most UPS recur locally; distant metastases are common (the most frequent is lung). Regional metastases are rare.\nEtiology\nUPS is thought to be derived from a primitive mesenchymal cell capable of differentiating into histiocytes, fibroblasts, myofibroblasts and osteoclasts. The etiology of the tumor remains unknown. Prior radiation therapy is a likely risk factor in some cases.\nDiagnostic methods\nAny tumor mass over 5 cm is suspected to be a sarcoma. Magnetic resonance imaging (MRI) is the imaging method of choice for limbs and shows a high signal on T2 weighted images. Histology of biopsy specimen prior to any treatment is crucial to reach diagnosis and shows pleomorphic spindle cell population with large atypical cells frequently exhibiting numerous irregular mitotic figures, associated regions of hemorrhage and necrosis, associated lymphohistiocytic infiltrate and invasion of dermis. Immunohistochemical staining is negative for S-100, HMB-45, CD34 and cytokeratin which assists in ruling out other soft tissue tumors. Most cases previously diagnosed as malignant fibrous histiocytoma have been reclassified into other histological types of sarcoma.\nDifferential diagnosis\nWhen occurring in skin, UPS is difficult to differentiate from atypical fibroxanthoma or dermatofibrosarcoma protuberans (see this term). Histological differential diagnoses include leiomyosarcoma, rhabdomyosarcoma, lymphoma, and melanoma (see these terms).\nManagement and treatment\nUPS should be referred to an expert/ reference center for primary biopsy, expert pathology review, and multidisciplinary treatment. Immediate surgery of a mass without knowledge of its histological nature is strongly discouraged because it is associated with an increased risk of death due to inappropriate resection and increased risk of relapse. UPS is best treated by wide surgical excision. Sometimes amputation may be necessary to remove the whole lesion. Adjuvant radiotherapy is given for high-grade, large (>5 cm), deep-seated tumors, in limb sparing surgeries and when negative margins are not obtained. For non-operable sarcomas, primary radiation therapy could be an option, but usually doxorubicin containing regimens are preferred options in first-line setting for locally irresectable and/or metastatic lesions. Chemotherapy (CHT) with ifosfamide, trabectedin, dacarbazine, pazopanib have demonstrated efficacy in UPS and are registered and available in most European Union countries.\nPrognosis\nA 5-year overall survival rate of 48% has been reported for patients with head and neck tumors versus 77% for patients with tumors arising on the trunk and extremities. The childhood variant appears have better prognosis.\n\n                            Last update: \n                            June 2014\n\n\n                            - Expert reviewer(s): \n                            Pr Jean-Yves BLAY"}
{"Disease Name": "Unexplained long-lasting fever/inflammatory syndrome", "Disease Definition": "A rare systemic disease characterized by febrile illness (body temperature >38.3°C on several occasions) or inflammation (elevated serum C-reactive protein and erythrocyte sedimentation rate) lasting at least three weeks and for which no specific diagnosis is achieved despite extended diagnostics.", "ORPHA ID": 251332, "Summary": ""}
{"Disease Name": "Unicentric Castleman disease", "Disease Definition": "A rare lymphoid hemopathy characterized by involvement of a single lymph node or a group of lymph nodes in one lymph node station (most commonly in the mediastinum, neck, abdomen, or retroperitoneum). Histopathologically, it may occur as a hyaline vascular subtype with hyaline-vascular follicles and a fibrotic and hypervascular stroma with sinus compression, or a mixed/plasmacytic subtype with dense, interfollicular sheets of (usually polytypic) plasma cells extending to the cortex, and variably sized lymphoid follicles including some with regressive changes. Clinically, most patients are asymptomatic, and lesions are detected incidentally.", "ORPHA ID": 93685, "Summary": ""}
{"Disease Name": "Unicervical bicornuate uterus", "Disease Definition": "A rare non-syndromic uterine malformation characterized by a uterus with two uterine horns and only one cervix, resulting from a failure in the fusion of the two Müllerian structures. Depending on the degree of the fusion deficiency, the malformation may be complete with the cavities separated up to the internal orifice of the cervix and not linked, or partial when there is some linkage. Patients may present recurrent pregnancy loss or preterm labor.", "ORPHA ID": 180114, "Summary": ""}
{"Disease Name": "Unilateral focal polymicrogyria", "Disease Definition": "Unilateral focal polymicrogyria (BFPP) is the mildest sub-type of polymicrogyria (PMG; see this term), a cerebral cortical malformation characterized by excessive cortical folding and abnormal cortical layering, that affects only one small region of the brain and that may show no neurologic involvement.", "ORPHA ID": 268947, "Summary": ""}
{"Disease Name": "Unilateral multicystic dysplastic kidney", "Disease Definition": "A rare form of multicystic dysplastic kidney (MCDK), a congenital anomaly of the kidney and urinary tract (CAKUT), in which one kidney is large, distended by multiple cysts, and non-functional.", "ORPHA ID": 97363, "Summary": "Epidemiology\nUnilateral MCDK is the most common form of MCDK with a birth prevalence estimated at 1/4,300 live births.\nClinical description\nUnilateral MCDK frequently presents antenatally at routine ultrasound scans, with the majority detected around the 20th week of gestation. The large majority of patients are asymptomatic but unilateral MCDK may occasionally present with abdominal obstructive signs (abdominal distention, feeding difficulties, respiratory distress) when the cysts become too large. Patients may also develop hypertension, proteinuria, and renal failure in the long run. The contralateral renal tract has an increased incidence of additional CAKUT such as vesicoureteral reflux and pelvi-ureteric junction obstruction (PUJO). Hypertrophy of the contralateral kidney may occur in 24-46% cases before birth, and in up to 80% in the years after birth.\nEtiology\nUnilateral MCDK results from disrupted nephrogenesis but the exact pathogenic mechanism is still unknown. Disturbed formation of nephrons could result from impaired fetal urine flow early in development. Mutations in the HNF1B gene (17q12), coding for hepatocyte nuclear transcription factor 1beta, associated with renal cysts and diabetes syndrome, have been detected in cases of unilateral MCDK. MCDK is also linked to gestational diabetes and to the use of some medications during pregnancy, such as anti-epileptic drugs.\nDiagnostic methods\nDiagnosis is mainly based on prenatal ultrasound showing large hypoechogenic non-communicating cysts within an irregularly outlined kidney with no visible renal pelvis. A tiny remnant kidney can be observed if the cysts have involuted. Complete prenatal involution has been described in 5% of MCDK, with complete involution in 50% during the first decade of life. Histologic examination shows that cysts are surrounded by undifferentiated and metaplastic cells with occasional residual functional renal tissue with recognizable glomeruli and proximal tubules. Renography with technetium-99m-labeled dimercaptosuccinic acid may show little or no renal uptake. As this has no clinical consequences, renography is not routinely indicated.\nDifferential diagnosis\nDifferential diagnoses include PUJO, in which the largely dilated calices may appear to be cysts, or in case of involuting MCKD, renal hypoplasia or renal agenesis.\nAntenatal diagnosis\nUltrasonographic screening can detect unilateral MCDKs from midway through gestation.\nGenetic counseling\nBoth sporadic and familial cases have been observed. In familial cases, transmission is autosomal dominant with a recurrence risk of 50%.\nManagement and treatment\nPartially based on the supposed increased risk of hypertension and malignancy of which no evidence is found, nephrectomy was performed routinely until recently. Nowadays, in most cases the kidney is left in situ and followed with serial ultrasound. However, nephrectomy may be indicated in case of abdominal obstructive complaints when the cysts become too large. Due to an increased risk of hypertension and/or proteinuria, as a sign of glomerular hyperfiltration or renal dysplasia in the solitary functioning kidney, individuals with unilateral MCDK deserve long-term follow-up. Up to 30% of unilateral cases of MCDK may lead to renal failure at the age of 30 years, at which stage renal replacement therapy is necessary.\nPrognosis\nThe prognosis is influenced by the presence of abnormalities in the contralateral kidney.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr M.F. [Michiel] SCHREUDER | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Unilateral ocular duplication", "Disease Definition": "A rare developmental defect during embryogenesis characterized by unilateral duplication of an eye which may appear as a synophthalmic eye in a single orbit or as two separate unilateral eyes, each in a separate orbit. The malformation is always associated with other anomalies of the central nervous system (such as porencephaly, meningocele, or arachnoidal cysts) and with craniofacial abnormalities. A proboscis is often found. Clinically, moderate mental retardation and epilepsy are typical.", "ORPHA ID": 3374, "Summary": ""}
{"Disease Name": "Unilateral polymicrogyria", "Disease Definition": "Unilateral polymicrogyria is a cerebral cortical malformation characterized by unilateral excessive cortical folding and abnormal cortical layering. It comprises two sub-types depending on the areas affected: unilateral hemispheric and focal polymicrogyria (see these terms).", "ORPHA ID": 268943, "Summary": ""}
{"Disease Name": "Univentricular heart", "Disease Definition": "A severe congenital cardiac malformation characterized by both atria related entirely or almost entirely to one functionally single ventricular chamber. The clinical manifestations include congestive heart failure, failure to thrive, cyanosis, hypoxemia and neurodevelopmental disabilities.", "ORPHA ID": 1464, "Summary": ""}
{"Disease Name": "Unspecified juvenile idiopathic arthritis", "Disease Definition": "Unspecified juvenile idiopathic arthritis is a rare, pediatric, rheumatologic disease, a subtype of juvenile idiopathic arthritis (JIA) characterized by arthritis of an unknown cause that persists for at least 6 weeks, and does not fulfill the criteria for any of the other JIA subtypes, or fulfills criteria for more than one of the other subtypes.", "ORPHA ID": 91140, "Summary": ""}
{"Disease Name": "Unstable hemoglobin disease", "Disease Definition": "A rare hemoglobinopathy characterized by variable degrees of hemolytic anemia, depending on the nature of the hemoglobin variant. In symptomatic patients, clinical manifestations are jaundice, splenomegaly, and, in patients with severe anemia, pallor. Additional features include reticulocytosis, presence of Heinz bodies, and pigmenturia.", "ORPHA ID": 99139, "Summary": ""}
{"Disease Name": "Upington disease", "Disease Definition": "A rare primary bone dysplasia characterized by Perthes-like pelvic anomalies (premature closure of the capital femoral epiphyses and widened femoral necks with flattened femoral heads), arthralgias of hips and knees, and occurrence of enchondromata and ecchondromata. There have been no further descriptions in the literature since 1971.", "ORPHA ID": 3408, "Summary": ""}
{"Disease Name": "Upper limb defect-eye and ear abnormalities syndrome", "Disease Definition": "A rare multiple congenital anomalies syndrome characterized by upper limb defects (hypoplastic thumb with hypoplasia of the metacarpal bone and phalanges and delayed bone maturation), developmental delay, central hearing loss, unilateral poorly developed antihelix, bilateral choroid coloboma and growth retardation.", "ORPHA ID": 2489, "Summary": ""}
{"Disease Name": "Upper limb mesomelic dysplasia, type Fryns", "Disease Definition": "A rare primary bone dysplasia characterized by isolated upper limb mesomelic dysplasia. Patients present with ulnar hypoplasia with severe radial bowing, but normal stature.", "ORPHA ID": 2497, "Summary": ""}
{"Disease Name": "Upper tract urothelial carcinoma", "Disease Definition": "A rare urinary tract tumor characterized by a malignant neoplasm arising from urothelial cells of the pyelocaliceal cavities and ureter. The tumor may be multifocal and bilateral in some cases and is more common in males than in females. Cigarette smoking and occupational exposure are major risk factors. Patients most commonly present with visible or non-visible hematuria and/or flank pain due to obstruction of the flow of urine by tumor tissue, or (less often) to local tumor growth. Systemic symptoms such as anorexia, weight loss, malaise, fatigue, fever, night sweats, or cough can be associated with advanced stages.", "ORPHA ID": 598216, "Summary": ""}
{"Disease Name": "Urachal cyst", "Disease Definition": "Urachal cyst is a congenital urachal anomaly (see this term) characterized by a failure of complete closure of the urachus, in which both ends are closed but the central lumen remains patent. It is typically asymptomatic but may become clinically significant when infected, presenting as a mass in the umbilical region accompanied by abdominal pain and fever.", "ORPHA ID": 488, "Summary": ""}
{"Disease Name": "Urachal diverticulum", "Disease Definition": "Urachal diverticulum is the rarest type of congenital urachal anomaly (see this term) resulting from the failure of the distal urachus to close at its point of connectivity to the bladder that is usually asymptomatic but can be associated with recurrent urinary tract infections and other complications.", "ORPHA ID": 431347, "Summary": ""}
{"Disease Name": "Urachal sinus", "Disease Definition": "Urachal sinus is a type of congenital urachal anomaly (see this term) resulting from the failure of the umbilical end of the urachus to close, without continuity to the bladder, and that is usually asymptomatic but can present with continuous cloudy umbilical discharge, tender midline infraumbilical mass and fever when infected.", "ORPHA ID": 431344, "Summary": ""}
{"Disease Name": "Urban-Rogers-Meyer syndrome", "Disease Definition": "A rare syndromic intellectual disability characterized by intellectual deficit, short stature, obesity, genital abnormalities, and hand and/or toe contractures. The patients also present with generalized osteoporosis and a history of frequent fractures. This syndrome is similar to Prader-Willi syndrome, but the hand contractures and osteoporosis, together with the lack of hypotonia, indicate this is a different entity.", "ORPHA ID": 3409, "Summary": ""}
{"Disease Name": "Urocanic aciduria", "Disease Definition": "A rare histidine metabolism disorder characterized by urocanic aciduria and other variable manifestations including intellectual deficit and intermittent ataxia.", "ORPHA ID": 210128, "Summary": ""}
{"Disease Name": "Urofacial syndrome", "Disease Definition": "A rare syndromic urinary tract malformation characterized by the association of severe voiding dysfunction and inversion of facial expression when the child smiles or cries.", "ORPHA ID": 2704, "Summary": "Epidemiology\nThe prevalence of the syndrome is not known; more than 150 cases, mostly children, have been reported. The majority of cases reported in the literature are from Columbia, although affected families have also been reported worldwide.\nClinical description\nPatients present with incontinence, urinary tract infections and hydro-uretero-nephrosis with progressive renal impairment. Voiding dysfunction is the result of an obstructive uropathy. About two-thirds of the patients have moderate to severe constipation. Cryptorchidism has also been reported. The peculiar facial dysmorphism is related to an unusual inversion of facial expression that occurs when the child smiles or cries. Nocturnal lagophthalmos has recently been described.\nEtiology\nThe disorder is due to recessive mutations in either HPSE2 (10q23-q24) encoding inactive heparanase-2, or LRIG2 (1p13.2) encoding leucine-rich repeats and immunoglobulin-like domains protein 2; however, in up to 16% of patients, no associated mutations have been found.\nDiagnostic methods\nNo formal diagnostic criteria have been published. Diagnosis may be suspected following recognition of the peculiar facial expression during infancy. Ultrasonography, renal scan, voiding cystourethrogram and urodynamics can be used to evaluate the lower urinary tract dysfunction. A genetic diagnosis can be made through different tests including assessment of a single-gene testing (HPSE or LRIG2 gene), exome or genome sequencing.\nDifferential diagnosis\nDifferential diagnoses include Hinman-Allen syndrome (a rare voiding disorder of the bladder of neuropsychological origin), neuropathic bladder (e.g., due to a neurologic lesion such as spina bifida), vescicoureteric reflux, and urethral obstruction.\nAntenatal diagnosis\nThe disorder can be suspected prenatally on ultrasound findings of megabladder, hydroureter, and/or hydronephrosis. However, not all patients will have prenatal manifestations as the onset of symptoms can occur in infancy or even adulthood. Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. The penetrance of the disease is complete, but the clinical expression is variable even in individuals of the same family.\nManagement and treatment\nTreatment is symptomatic and involves bladder re-education, antibiotic prophylaxis, anticholinergic therapy and alpha-blockers. Intermittent catheterization may be needed. Constipation should be treated. Early diagnosis and treatment are essential in order to prevent upper urinary tract deterioration and renal failure.\nPrognosis\nPatients live a normal lifespan. Prognosis depends on the severity of the renal disease and precocity of treatment but is generally good, particularly if appropriate treatment is provided and established early.\n\n                            Last update: \n                            June 2022\n\n\n                            - Expert reviewer(s): \n                            Dr Camilla MEOSSI  - Dr Donatella MILANI | ITHACA* -  Dario MINOLI | EUROGEN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Usher syndrome type 1", "Disease Definition": "A rare ciliopathy characterized by profound congenital deafness, retinitis pigmentosa and vestibular dysfunction. Retinitis pigmentosa results in visual loss and generally manifests as night blindness, progressively constricted visual fields, and impaired visual acuity. Vestibular dysfunction a defining feature of this form, manifests as delayed motor development with affected infants taking longer to sit independently and to walk. Later on, vestibular dysfunction results in difficulty with activities requiring balance.", "ORPHA ID": 231169, "Summary": ""}
{"Disease Name": "Usher syndrome type 2", "Disease Definition": "A rare ciliopathy characterized by congenital moderate-to-severe deafness, retinitis pigmentosa developing in the first or second decade, and normal vestibular function. Congenital bilateral sensorineural hearing loss is mild to moderate in the low frequencies and severe to profound in the higher frequencies. Additional manifestations include night blindness, constricted visual field (tunnel vision), and later on decreased visual acuity sometimes ending with bare light perception.", "ORPHA ID": 231178, "Summary": ""}
{"Disease Name": "Usher syndrome type 3", "Disease Definition": "A rare ciliopathy characterized by progressive hearing and visual loss in the first decades of life and, in some cases, vestibular dysfunction. Patients have normal hearing at birth. Onset of hearing loss is usually in late childhood or adolescence after development of speech. Profound deafness is mostly reported by middle age. Retinitis pigmentosa related visual loss also develops in late childhood or adolescence. Developmental motor milestones are generally normal but vestibular dysfunction may occur in adulthood.", "ORPHA ID": 231183, "Summary": ""}
{"Disease Name": "Usher syndrome", "Disease Definition": "A rare ciliopathy characterized by congenital or childhood onset sensorineural hearing loss (HL) and retinitis pigmentosa (RP) that occurs in a second step with a night blindness and a progressive vision loss and, in some cases, vestibular dysfunction.", "ORPHA ID": 886, "Summary": "Epidemiology\nPrevalence of Usher syndrome (US) is estimated at 1/30,000. It is by far the most common cause of hereditary, combined deafness-blindness.\nClinical description\nSensorineural hearing loss is typically congenital and three clinical entities have been defined according to severity of hearing loss severity. Type 1 (around 40% of cases) is characterized by profound, nonprogressive congenital deafness, typically associated with vestibular areflexia that leads to delayed acquisitions (delayed head control, unassisted sitting and walking). Type 2 (around 60% of cases) is characterized by moderate or severe, congenital hearing loss that is slowly progressive and not associated with vestibular disorders. Type 3 (< 3% of cases, but more frequent in the Finnish and Ashkenazi Jewish populations) is characterized by rapidly progressive hearing loss that is often diagnosed during the first decade; vestibular disorders are associated with half of the cases. Retinitis pigmentosa appears later, mainly in the second or third decades, with characteristic night vision and progressive peripheral visual field impairment. Night blindness can be noted in early childhood. The only reported retinal phenotype is rod cone dystrophy. A central visual impairment can be caused by a macular edema. A cataract is frequently observed before the age of 50 years.\nEtiology\nSo far, mutations in five genes (MYO7A, USH1C, CDH23, PCDH15, USH1G) have been implicated in USH type 1. Mutations in three genes (USH2A, ADGRV1 and WHRN) have been implicated in USH type 2. Mutations in a predominant gene (CLRN1) have been identified for USH type 3. Some genes are called into question: CIB2 and PDZD7 seem eventually to be involved in non syndromic HL.\nDiagnostic methods\nClinical diagnosis is based on findings of a bilateral sensorineural hearing loss associated with a retinitis pigmentosa defined by a night blindness and a peripheral visual field impairment. Multimodal imaging with color, fundus autofluorescence frames (FAF), spectral domain-optical coherence tomography and full-field electroretinogram are required to confirm the diagnosis of rod cone dystrophy. Genetic testing is feasible now based on massively parallel sequencing (gene panels or exomes).\nDifferential diagnosis\nDifferential diagnoses include oculo-acoustic syndromes associated with peroxysomal gene alterations (Heimler syndrome with enamel dysplasia), metabolic genetic inherited diseases (Refsum disease), moderate forms of Alstrom syndrome, or mitochondrial DNA mutations (MIDD, Kearns-Sayre syndrome). Mutations in TUBB4B gene can cause a dominant inherited oculo-acoustic phenotype, Leber congenital amaurosis and early-onset HL. In some patients, HL can coexist independently of RP.\nAntenatal diagnosis\nPrenatal diagnosis is feasible for families in which the disease-causing mutations have already been identified.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling is straightforward but patients should be informed that heterozygous USH2A mutations are relatively frequent in the general population.\nManagement and treatment\nManagement requires a multidisciplinary team with experience in the management of combined deafness and blindness (ENT specialist, ophthalmologist, speech therapist, psychologist, hearing aid specialist, occupational therapist, and all professionals implicated in adapted learning programs for patients with both hearing and visual deficits). Conventional hearing aids may be indicated for patients wit h moderate or severe hearing loss. Cochlear implants, (in most cases bilateral), are now more frequently used for patients with profound congenital hearing loss. Both cochlear implants and hearing aids are more effective when implemented early. Lenses with specialized filters may be recommended for the management of the rod cone dystrophy. A specific treatment with anhydrase carbonic inhibitor can be indicated in case of macular edema. Cataract surgery can be required. Current research is directed towards gene therapy, antisense oligonucleotide therapy (USH2A), neuroprotection and artificial vision systems.\nPrognosis\nThe prognosis mainly depends on the progression of rod cone dystrophy: a severe visual impairment occurs between 50 and 70 years of age in most cases.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Catherine BLANCHET  - Pr Isabelle MEUNIER  - Dr Anne-Françoise ROUX"}
{"Disease Name": "USP18 deficiency", "Disease Definition": "A rare genetic neurological disorder characterized by severe pseudo-TORCH syndrome with signs of brain damage and occasionally systemic manifestations resembling the sequelae of congenital infection, but in the absence of an infectious agent. Characteristic features include microcephaly, white matter disease, cerebral atrophy, cerebral hemorrhage, and calcifications, among others. Affected individuals typically have seizures and respiratory insufficiency and die in infancy.", "ORPHA ID": 481665, "Summary": ""}
{"Disease Name": "Uterine cervical aplasia and agenesis", "Disease Definition": "A rare, non-syndromic, uterovaginal malformation characterized by variable degrees of cervical aplasia, ranging from complete agenesis to the presence of a cervix with a cervical canal that contains a blind end. Patients typically present primary amenorrhea, cyclical abdominal or pelvic pain, dyspareunia and/or reproductive problems.", "ORPHA ID": 180145, "Summary": ""}
{"Disease Name": "Uterine hypoplasia", "Disease Definition": "A rare congenital urogenital tract malformation characterized by a small uterus of regular shape (simple uterine hypoplasia), an elongated uterus with normal fundus (elongated uterine hypoplasia), or an abnormally shaped uterus (malformative uterine hypoplasia). Symptoms may include primary amenorrhea, abdominal pain, and infertility.", "ORPHA ID": 180139, "Summary": ""}
{"Disease Name": "UV-sensitive syndrome", "Disease Definition": "A rare photodermatosis characterized by cutaneous photosensitivity and slight dyspigmentation, without an increased risk of developing skin tumors. Telangiectasia may also be observed, but no other clinical abnormalities. Patients present in infancy or childhood, mode of inheritance is autosomal recessive.", "ORPHA ID": 178338, "Summary": ""}
{"Disease Name": "Uveal coloboma-cleft lip and palate-intellectual disability", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by uveal coloboma (typically bilateral) variably associated with cleft lip, palate and/or uvula, hearing impairment, and intellectual disability. The spectrum of eye involvement is also variable and includes iris coloboma extending to the choroid, disc, and/or macula, microphthalmia, cataract, and extraocular movement impairment.", "ORPHA ID": 1473, "Summary": ""}
{"Disease Name": "Uveal melanoma", "Disease Definition": "Uveal melanoma is a rare tumor of the eye, arising from the choroid in 90% of cases and from the iris and ciliary body in the other 10% of cases, which clinically presents with visual symptoms (including blurred vision, photopsia, floaters, and visual field reduction), a visible mass and pain. Fatal metastatic disease is seen in about half of all patients, with the liver being the most frequent site of metastasis.", "ORPHA ID": 39044, "Summary": ""}
{"Disease Name": "VACTERL with hydrocephalus", "Disease Definition": "A rare multiple congenital anomalies characterized by the association of Vertebral anomalies, Anal atresia, Congenital cardiac disease, Tracheoesophageal fistula, Renal anomalies, and Limb defects (acronym VACTERL) with hydrocephalus. Association with hydrocephalus is relatively rare, may be distinct from VACTERL association in general, and may follow an autosomal recessive pattern of inheritance in some individuals.", "ORPHA ID": 3412, "Summary": ""}
{"Disease Name": "VACTERL/VATER association", "Disease Definition": "A rare multiple congenital anomalies characterized by the presence of at least three of the following malformations: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities.", "ORPHA ID": 887, "Summary": "Epidemiology\nExact prevalence and incidence data are not available due to variable diagnostic criteria, but the association has been reported to occur in 1-9/100,000 infants, and the annual incidence has been reported to be 1/10,000 to 1/40,000 live births. No specific geographic distribution or predominance in certain populations has been found.\nClinical description\nA cluster of congenital malformations may be found prenatally, perinatally, or sometimes later in life, and is usually considered to include at least three component features: vertebral defects (60-80% of patients), commonly accompanied by rib anomalies; imperforate anus/anal atresia (55-90%); cardiac defects (40-80%); tracheo-esophageal fistula (50-80%), with or without esophageal atresia; renal anomalies (50-80%) including renal agenesis, horseshoe kidney, and cystic and/or dysplastic kidneys; and limb abnormalities (40-50%). Limb defects are classically defined as radial anomalies, including thumb aplasia/hypoplasia, and have variable degrees of severity; other types of limb anomalies have also been reported. While the above malformations are considered to be the core component features (some experts consider trachea-esophageal fistula and anal atresia to be especially characteristic), many other malformations have been described in affected patients. These non-typical malformations should be used as clues in considering other possible conditions.\nEtiology\nVACTERL/VATER association can occur due to a variety of genetic and non-genetic causes, and there are many syndromes with overlapping features. In most individuals, the cause is unknown and the association largely occurs sporadically.\nDiagnostic methods\nDiagnosis of VACTERL/VATER association is based on the clinical manifestations, which may be evident prior to or after birth.\nDifferential diagnosis\nDifferential diagnosis, depending on the overall presentation, includes Baller-Gerold syndrome, CHARGE syndrome, congenital vertebral-cardiac-renal anomalies syndrome, Currarino disease, 22q11.2 microdeletion syndrome, Fanconi anemia, Feingold syndrome, Fryns syndrome, MURCS association, oculo-auriculo-vertebral spectrum, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, and VACTERL with hydrocephalus, as well as other conditions.\nAntenatal diagnosis\nThe condition may be suspected prenatally, primarily based on prenatal imaging results.\nGenetic counseling\nThe condition most commonly occurs sporadically, and the underlying causes are not known in most individuals. However, the differential diagnosis is broad, and some conditions with features of VACTERL/VATER association have known inheritance patterns.\nManagement and treatment\nManagement typically centers around surgical correction of the specific congenital anomalies (typically anal atresia, certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae of the congenital malformations.\nPrognosis\nIf optimal surgical correction is achievable, the prognosis can be relatively good, though some patients will continue to be affected by their congenital malformations throughout life. Importantly, patients with VACTERL association do not tend to have neurocognitive impairment, though some conditions with overlapping features can include neurologic (and other) findings.\n\n                            Last update: \n                            October 2023\n\n\n                            - Expert reviewer(s): \n                            Dr Benjamin SOLOMON"}
{"Disease Name": "Vacuolar myopathy with sarcoplasmic reticulum protein aggregates", "Disease Definition": "A rare, genetic vaculolar myopathy characterised by mild myopathy or elevated levels of creatine kinase in the blood without associated symptoms.", "ORPHA ID": 88635, "Summary": ""}
{"Disease Name": "Vaginal atresia", "Disease Definition": "A rare vaginal malformation characterized by congenital uterovaginal outflow tract obstruction due to failure of the urogenital sinus to form the caudal aspect of the vagina, which is then replaced by fibrous tissue. The malformation may occur as an isolated developmental defect or in association with other anomalies, such as cervical agenesis, imperforate hymen, and bicornuate bicervical uterus. Presenting signs and symptoms include primary amenorrhea, cyclic pelvic pain, abdominal pain, dyspareunia, pelvic mass, menstrual disorder, and periodic fever.", "ORPHA ID": 65681, "Summary": ""}
{"Disease Name": "Vaginal carcinoma", "Disease Definition": "A group of rare vaginal tumors comprising HPV-associated and HPV-independent squamous cell carcinoma, glandular tumors (including HPV-associated adenocarcinoma, endometrioid carcinoma, clear cell carcinoma, gastric type and intestinal type mucinous carcinoma, and mesonephric adenocarcinoma), adenocarcinoma of Skene gland origin, adenosquamous carcinoma, and adenoid basal carcinoma. Depending on the type of tumor and disease stage, patients may present with symptoms related to a vaginal mass, vaginal bleeding and/or discharge, postcoital bleeding, urinary symptoms, pelvic pain, and a foreign body sensation within the vagina.", "ORPHA ID": 180247, "Summary": ""}
{"Disease Name": "Van den Bosch syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by intellectual deficit, choroideremia, horizontal nystagmus, severe myopia, acrokeratosis verruciformis-like skin abnormality, anhidrosis, and scapular winging. There have been no further descriptions in the literature since 1959.", "ORPHA ID": 3417, "Summary": ""}
{"Disease Name": "Van den Ende-Gupta syndrome", "Disease Definition": "Van den Ende-Gupta syndrome is a very rare syndrome characterized by blepharophimosis, arachnodactyly, joint contractures, and characteristic dysmorphic features.", "ORPHA ID": 2460, "Summary": "Epidemiology\nTen cases from seven families have been reported in the literature.\nClinical description\nThe dysmorphic features include narrow nose with hypoplastic alae nasi, hypoplastic maxilla, everted lower lip, blepharophimosis, large ears and high-arched or cleft palate. The affected patients can have learning disabilities.\nGenetic counseling\nThe condition is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            October 2010"}
{"Disease Name": "Van der Woude syndrome", "Disease Definition": "Van der Woude syndrome (VWS) is a rare congenital genetic dysmorphic syndrome characterized by paramedian lower-lip fistulae, cleft lip with or without cleft palate, or isolated cleft palate.", "ORPHA ID": 888, "Summary": "Epidemiology\nThe disorder represents the most common single-gene cause of cleft lip/cleft palate, i.e. 2% of all individuals with cleft lip/palate. Estimated incidence at birth is between 1/35,000 and 1/100,000 in European and Asian populations. Males and females are affected equally.\nClinical description\nAt birth, patients with VWS have one or more of the following dysmorphic features: paramedian lower-lip pits (fistulae, usually bilateral), small mounds with a sinus tract leading from a mucous gland of the lip, or cleft lip/cleft palate. Lip pits are the most common sign (>80%) and are mostly asymptomatic although dribbling and infection is possible. The second most frequent sign is cleft lip, followed by cleft palate, with variable clinical repercussions depending on severity. Some patients have cleft lip with or without cleft palate, while others have cleft palate only. Hypodontia and dental hypoplasia are also common. Other non-classic signs include single unilateral lip pits, submucous cleft, bifid uvula, ankyloglossia, limb abnormalities (skin folds, syndactyly), and sensorineural hearing loss. Growth, development and intellectual abilities are normal in VWS patients.\nEtiology\nMutations in the IRF6 gene (1q32.2-q32.3), involved in epidermal development and in regulation of craniofacial development, are found in over 70% of patients with VWS.IRF6 mutations are also causal for popliteal pterygium syndrome (see this term).Whole-gene deletions are a very rare cause of VWS and the frequency of partial-gene deletions is not currently known. Recently, mutations in the gene GRHL3 (1p36), coding for a Grainyhead-like protein 3 homolog, was found in eight families with VWS with no causative mutations in IRF6.\nDiagnostic methods\nThe diagnosis is suspected on the basis of clinical findings and can be confirmed by molecular genetic testing of IRF6. The presence of isolated lip pits, submucous cleft palate, and hypodontia in a parent of a patient with suspected VWS is highly indicative of the diagnosis.\nDifferential diagnosis\nThe main differential diagnosis is autosomal dominant popliteal pterygium syndrome (PPS; see this term). VWS has a milder phenotype; PPS includes popliteal pterygia, syndactyly, and abnormal external genitalia. There is significant overlap in the craniofacial features of the two syndromes. Other conditions to consider include isolated cleft lip and Kabuki syndrome (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis for at-risk pregnancies is possible provided that the disease-causing allele has been identified in the family. Cleft lip can be identified late in pregnancy on prenatal ultrasound.\nGenetic counseling\nVWS is inherited in an autosomal dominant manner. However, penetrance is incomplete and de novo mutations have been reported. Genetic counseling is recommended for affected families.\nManagement and treatment\nIn the neonatal period, patients with cleft lip/palate should be monitored for nutritional intake and weight gain. Cleft lip and/or palate should then be managed by a multidisciplinary team with surgical and orthodontic treatment as needed. Speech therapy and audiological evaluation may also be required. Lip pits may be treated surgically for cosmetic purposes and/or to ensure proper lip function.\nPrognosis\nSuccessful correction of the congenital malformations is the main prognostic factor.\n\n                            Last update: \n                            May 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Olivier ABBO  - Pr Philippe GALINIER"}
{"Disease Name": "Variably protease-sensitive prionopathy", "Disease Definition": "A rare human prion disease characterized by accumulation of abnormal prion protein markedly less protease-resistant than in other prion diseases, depending on the genotype at codon 129 of the prion protein gene. No mutations are found in the coding sequence of the gene. Neuropathological analysis shows spongiform change and prion protein deposition with microplaques in the cerebellum. Patients present with slowly progressive cognitive and motor decline, psychiatric symptoms, ataxia, myoclonus, or tremor, among others. The disease is fatal and transmissible to other individuals.", "ORPHA ID": 454742, "Summary": ""}
{"Disease Name": "Variant ABeta2M amyloidosis", "Disease Definition": "A rare form of amyloidosis characterized by accumulation and extensive visceral deposition of anamyloidogenic variant of beta 2 microglobulin leading to progressive gastrointestinal dysfunction, Sjögren syndrome and autonomic neuropathy.", "ORPHA ID": 314652, "Summary": ""}
{"Disease Name": "Variant Creutzfeldt-Jakob disease", "Disease Definition": "A rare acquired human prion disease characterized by a progressive, invariably fatal neuropsychiatric disorder resulting from transmission via consumption of products from prion-diseased cows or via blood transfusion from an affected individual. Patients typically present early psychiatric symptoms (such as depression, anxiety, apathy, withdrawal, and delusions), as well as persistent painful sensory symptoms, ataxia, myoclonus, chorea, or dystonia, and dementia. Brain MRI often shows bilateral FLAIR hyperintensities involving the pulvinar thalamic nuclei. Neuropathological examination reveals spongiform change and extensive deposition of abnormal prion protein with florid plaques throughout the cerebrum and cerebellum.", "ORPHA ID": 576370, "Summary": ""}
{"Disease Name": "Variegate porphyria", "Disease Definition": "A rare acute hepatic porphyria characterized by neurovisceral attacks and/or skin lesions.", "ORPHA ID": 79473, "Summary": "Epidemiology\nIts prevalence is around 1/330,000 in European countries. Due to a founder effect, it is much higher in South Africa.\nClinical description\nThe disease generally manifests after puberty, predominantly affecting women. In 60 % of cases, patients' only symptoms are skin lesions due to photosensitivity (bullous photodermatitis). Lesions predominantly appear on sun-exposed areas (hands, face) and are characterized by the presence of more or less painful bullae, which usually leave hyperpigmented scars. In 20% of cases, patients present with both skin lesions and neurovisceral attacks. Finally, 20% of patients experience only neurovisceral attacks. Neurovisceral attacks can last several weeks and manifest as severe abdominal pain, neurological disorders and psychological disturbances. Abdominal pain is very often associated with low back pain irradiating to the legs, with nausea, vomiting and severe constipation. Psychological disturbances are variable: irritability, emotional sensitivity, depressive disorder, anxiety and, more rarely, auditory or visual hallucinations, disorientation, and mental confusion. Neurological manifestations can affect both the central and peripheral nervous systems (myalgia, paresis, ascending flaccid paralysis of the limbs or convulsions), and can lead to severe complications such as motor paralysis. Tachycardia and hyponatremia are common during attacks. The attacks are most commonly triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, a low caloric diet, stress), and/or endogenous factors (hormonal, linked to menstrual cycle).\nEtiology\nVariegate Porphyria (VP) is caused by a deficiency in coproporphyrinogen oxidase (PPOX, the penultimate enzyme in the heme biosynthesis pathway), which leads to an accumulation of porphyrins and their precursors (delta aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver. The enzyme deficiency is due to mutations of the PPOX gene (NM_000309.5) coding for PPOX.\nDiagnostic methods\nDiagnosis is based on significantly elevated concentrations of PBG (pathognomonic of acute porphyria attacks) and ALA in urine, and defective PPOX enzyme activity in circulating lymphocytes. Identification of a causal mutation of the PPOX gene confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include acute intermittent porphyria and, particularly, porphyria cutanea tarda. The presence of a fluorometric peak (626-628 nm) in plasma is pathognomonic and allows a definitive diagnosis of variegate porphyria rather than porphyria cutanea tarda.\nAntenatal diagnosis\nAntenatal diagnosis may be offered to families at risk of homozygous porphyria variegata.\nGenetic counseling\nTransmission is autosomal dominant and penetrance is incomplete. Genetic counseling is offered to patients and their families, informing them that there is a 50% risk of transmitting the disease at each pregnancy.\nManagement and treatment\nAcute attacks must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Management includes elimination of one or more triggers, relief of pain (opioids), vomiting, and anxiety, and prevention of episodes (avoidance of triggers, particularly drugs). Phlebotomy and chloroquine are not effective in treating cutaneous signs. Micro-bleeds are beneficial in some patients. Protecting the skin from light is key. In the case of symptomatic iron-deficiency anemia, iron supplementation is likely to cause a skin flare-up and should preferably be administered intravenously.\nPrognosis\nThanks to early diagnosis and management, fatal outcomes from acute attacks are rare. The disease is rarely progressive. On the other hand, VP is a risk factor for the long-term development of hepatocellular carcinoma and chronic renal failure. Annual monitoring is proposed to detect these chronic complications.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Neila TALBI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Vascular Ehlers-Danlos syndrome", "Disease Definition": "A rare genetic connective tissue disorder typically characterized by the association of unexpected organ fragility (arterial/bowel/gravid uterine rupture) with inconstant physical features as thin, translucent skin, easy bruising and acrogeric traits.", "ORPHA ID": 286, "Summary": "Epidemiology\nThe true prevalence of vascular Ehlers-Danlos syndrome (vEDS) is unknown, due to underdiagnosis of both symptomatic and milder forms of the disease. Prevalence estimates range between 1/50 000 and 1/200 000.\nClinical description\nTypical physical signs associated with vEDS are predominantly cutaneous, as easy bruising unrelated to trauma, thin translucent skin predominantly on the upper torso and abdomen, with abnormally visible veins. Wound healing may be delayed and may result in widened, papyraceous scars, particularly over prominent bony pressure points (knee). Extremities, particularly hands may appear prematurely aged (acrogeria). Characteristic facial features are prominent eyes, thin lips, sunken cheeks and a pinched nose. Hair loss, particularly notable in women may also be present. Clinical complications of vEDS typically start to occur in the late teenage years, more rarely during childhood, and may repeat at unpredictable time intervals through the entire adult life. Most common complications are arterial accidents involving medium size arteries, including dissections, aneurysms, arterial rupture and arteriovenous fistulas. Spontaneous carotid-cavernous fistula is almost pathognomic of vEDS. Digestive complications are dominated by spontaneous perforations of the sigmoid colon. Solid organ rupture as liver or spleen, may also occur. Other complications are gravid uterine rupture or arterial rupture in the peripartum period. Spontaneous, often recurrent hemo/pneumothoraces are not uncommon. Varicose veins are also commonly present in vEDS patients at a young age.\nEtiology\nThe disorder is caused by mutations in the COL3A1 gene (2q32.2), which encodes for the pro-alpha1-chains of type III procollagen.\nDiagnostic methods\nDiagnosis is suspected on the base of physical signs and clinical complications in probands, and requires the identification of a pathogenic variant within the COL3A1 gene by molecular genetic testing (single gene testing or multigene panel including COL3A1).\nDifferential diagnosis\nMain differential diagnosis are other forms of Ehlers-Danlos syndromes, notably classical EDS (including COL1A1 variants leading to substitutions of arginine to cysteine residues in the triple helical domain), kyphoscoliotic EDS and periodontal EDS. Other rare connective tissue disorders are: Loeys-Dietz syndromes, polycystic kidney disease, and Marfan syndrome. In children with marked bruising, coagulation disorders and child abuse are sometimes considered.\nAntenatal diagnosis\nPreimplantation and prenatal genetic diagnosis can be considered in families where the mutation is known.\nGenetic counseling\nHalf of vEDS patients have inherited the pathogenic variant from an affected parent. The other half of patients have a de novo pathogenic variant, except for rare cases of parental COL3A1 somatic mosaicism. The pattern of inheritance is typically autosomal dominant, and thus there is a 50% risk of transmitting the disease to offspring. Rare cases of biallelic mutations have been reported. Therefore, genetic counseling should be offered to affected families.\nManagement and treatment\nPatient management requires a multidisciplinary care team, ideally in dedicated centers for vEDS patients. These centers coordinate follow-up of clinically silent patients and implement prophylactic measures. Acute onset, unexplained pain require emergency imaging by appropriate means to exclude arterial rupture. Acute arterial complications commonly require hospitalization with a conservative approach in most cases. Life-saving procedures (arterial rupture, bowel perforation, etc.) may require interventional radiology, vascular or bowel surgery. Medical management includes optimal blood pressure control to minimize arterial stress. Betablockers may be of interest in reducing arterial complications, but only one has been investigated in that indication (celiprolol). Angiotensin receptor blockers might also be beneficial and are currently being investigated.\nPrognosis\nPrognosis is variable and depends in part on the type of pathogenic COL3A1 variant. There is also an important intra- and interfamilial heterogeneity in the age of onset of complications and life expectancy for the same variant. Overall, patients with vEDS are exposed to recurrent organ complications, estimated at a rate of 1.6 events/5 years, 1.3 events/5 years for arterial complications. Overall life-expectancy is reduced to a median 51 years of age, but with an important range in age of survival for individual patients.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Michael FRANK"}
{"Disease Name": "Vasculitis", "Disease Definition": "Vasculitis represents a clinically heterogenous group of diseases of multifactorial etiology characterized by inflammation of either large-sized vessels (large-vessel vasculitis, e.g. Giant-cell arteritis and Takayasu arteritis; see these terms), medium-sized vessels (medium-vessel vasculitis e.g. polyarteritis nodosa and Kawasaki disease; see these terms), or small-sized vessels (small-vessel vasculitis, e.g. granulomatosis with polyangiitis, microscopic polyangiitis, immunoglobulin A vasculitis, and cutaneous leukocytoclastic angiitis; see these terms). Vasculitis occurs at any age, may be acute or chronic, and manifests with general symptoms such as fever, weight loss and fatigue, as well as more specific clinical signs depending on the type of vessels and organs affected. The degree of severity is variable, ranging from life or sight threatening disease (e.g. Behçet disease, see this term) to relatively minor skin disease.", "ORPHA ID": 52759, "Summary": ""}
{"Disease Name": "Vasoproliferative tumor of the retina", "Disease Definition": "Vasoproliferative tumor of the retina is a rare, benign, retinal vascular disease characterized by solitary or multiple, unilateral or bilateral, intra-retinal tumor(s), usually located in the peripheral infero-temporal quadrant, and often associated with sub- and intraretinal exudates, epiretinal membranes, exudative retinal detachment and cystoid macular edema, as well as, occasionally, retinal and vitreous hemorrhage. Patients may present with visual loss, floaters, and/or photopsia. Association with various conditions, such as retinitis pigmentosa, congenital retinal toxoplasmosis, retinopathy of prematurity, or coloboma, has been reported.", "ORPHA ID": 353356, "Summary": ""}
{"Disease Name": "Vegetative pyoderma gangrenosum", "Disease Definition": "A rare subtype of pyoderma gangrenosum disease characterized by a solitary, erythematous, ulcerated plaque, which lacks the violaceous border typically present in classic pyoderma gangrenosum, usually affecting individuals who are otherwise healthy. Histologically, the lesion presents a central layer containing neutrophilic inflamation, surrounded by a palisade of histiocytes, which are rimmed by a lymphocytic infiltrate. In comparison with the other variants of pyoderma gangrenosum, this subtype usually shows a good response to less aggressive treatments and underlying systemic disorders are less frequently associated. It is considered the most benign and uncommon clinical variant of pyoderma gangrenosum.", "ORPHA ID": 538872, "Summary": ""}
{"Disease Name": "Vein of Galen aneurysmal malformation", "Disease Definition": "A rare intracranial congenital high-flow vascular malformation characterized by arteriovenous shunts draining into the median prosencephalic vein of Markowski, embryonic precursor of the vein of Galen, typically presenting in neonates or infants.", "ORPHA ID": 1053, "Summary": "Epidemiology\nAlthough its prevalence is unknown, vein of Galen aneurysmal malformation (VGAM) is thought to account for 30% of all pediatric intracranial arteriovenous malformations.\nClinical description\nClinical presentation differs according to age group. Neonates typically present with congestive heart or multi-organ failure and, in more severe cases, melting brain syndrome. Infants tend to present with hydrovenous disorders (hydrocephalus, macrocrania), collateral maxilla-facial venous circulation, neurodevelopmental delays; children (and exceptionally young adults) commonly present with neurological symptoms (seizures, deficit, headaches or intracranial hemorrhage). Pulsatile bruit can be heard at auscultation of the skull. VGAM can be classified into mural or choroidal types based on their angioarchitecture. The mural type occurs when the fistula is in the wall of the dilated vein itself. The choroidal type consists of multiple shunts into choroidal tributaries draining into the prosencephalic vein of Markowski. Mixed forms combining direct shunts and arterial networks may also occur.\nEtiology\nVGAM is created between the 8th and 11th weeks of gestation. Recent data suggest that genetic dysregulation of RAS signaling pathway is an important driver of VGAM pathogenesis.\nDiagnostic methods\nImaging is essential for diagnosis and include trans-fontanel ultrasonography, magnetic resonance imaging/angiography (MRI/MRA) or computed tomography scan, and digital subtraction angiography (usually coupled with embolization).\nDifferential diagnosis\nIt is important to differentiate VGAM from dilatation of the vein of Galen draining cerebral arteriovenous malformation (AVMs); venous dilatation without arteriovenous shunt can also be observed in developmental venous anomalies or in rare neonatal cases with congenital cardiopathy. In the assessment of neonatal heart failure, VGAM has to be excluded from congenital cardiopathy.\nAntenatal diagnosis\nDiagnosis is most often made during the third trimester of pregnancy with ultrasound and fetal MRI.\nGenetic counseling\nVGAM can occur in the context of capillary malformations AVMs and more rarely in hereditary haemorrhagic telangiectasia. Genetic screening can therefore be proposed to patients depending on the clinical and familial context.\nManagement and treatment\nIf the diagnosis is established antenatally, delivery at a tertiary care center is recommended. The timing of endovascular management depends on the clinical presentation. Ideally, the first intervention should be performed at 5-6 months of age; however, early embolization may be required if there is congestive heart failure refractory to medical management or if cerebral development is impaired. In such cases, partial, rather than complete, obliteration of the shunt is the goal in order to improve hemodynamic situation and allow proper maturation of the brain. A residual shunt will be occluded at later times in sequential procedures. Hydrocephalus may require ventriculocisternostomy (preferred to ventricular shunt which is associated with neurological complications) in association with endovascular treatment of the VGAM.\nPrognosis\nThe neurological prognosis can be satisfactory with early proper treatment; however, the prognosis is poorer for patients with severe neonatal presentation or with cerebral defects or cardiac dysfunction detected prenatally. Patients presenting later in life have better post-operative outcomes.\n\n                            Last update: \n                            July 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Julien COULIE  - Dr Georges RODESCH | VASCERN* - Dr Stanislas SMAJDA | VASCERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "Velo-facial-skeletal syndrome", "Disease Definition": "A very rare multiple congenital anomalies syndrome characterized by short stature, facial dysmorphism (elongated face, hypertelorism, broad and high nasal bridge, mild epicanthus, posteriorly angulated ears, narrow and high-arched palate), skeletal anomalies (mesomelic brachymelia, short broad hands, prominent finger pads, short stubby thumbs, hyperextensibility of small joints, small feet), hypernasality and normal intelligence. Delayed bone age has also been reported.", "ORPHA ID": 3424, "Summary": ""}
{"Disease Name": "Venezuelan hemorrhagic fever", "Disease Definition": "Venezuelan hemorrhagic fever (VHF), caused by the Guanarito virus, is a viral hemorrhagic disease characterized by fever, headache, arthralgia, sore throat, convulsions, and hemorrhagic manifestations.", "ORPHA ID": 319234, "Summary": ""}
{"Disease Name": "Venous thoracic outlet syndrome", "Disease Definition": "Venous thoracic outlet syndrome (VTOS) is a form of thoracic outlet syndrome (TOS; see this term) that manifests as unilateral (rarely bilateral) arm pain and cyanosis.", "ORPHA ID": 357131, "Summary": "Epidemiology\nDetermination of incidence is difficult due to the lack of a confirmatory test for TOS. VTOS accounts for 2%-3% of all cases of TOS.\nClinical description\nVTOS occurs in young adults, usually after excessive arm activity. The characteristic symptoms, caused by venous obstruction, are arm swelling, cyanosis, pain and mild paresthesias. Neck pain and headaches may rarely occur. The forearm fatigues within minutes of use. Visible subcutaneous veins over the shoulder and upper chest are often present.\nEtiology\nRepetitive arm motion and compression of the subclavian vein in the neck (between the clavicle and the first rib) leads to scar tissue that can predispose one to thrombosis due to narrowing of vessels.\nDiagnostic methods\nDiagnosis is based on findings of arm swelling, cyanosis and distended superficial veins. Radiographs may identify compressive sources including an elongated C7 transverse process or anomalous first rib. Subclavian vein stenosis or occlusion on dynamic ultrasonography, magnetic resonance or computed tomography venography supports the diagnosis. Provocative physical exam maneuvers such as the Roos (test is positive when patient is unable to maintain the position of opening and closing hands while arms are in an elevated position for 3 minutes) and Adson (test is positive if radial pulse disappears while turning the head with extended neck following deep inspiration) tests can also be helpful.\nDifferential diagnosis\nDifferential diagnoses include arterial (ATOS) and neurogenic TOS (NTOS) (see these terms), which are differentiated clinically. ATOS presents as upper extremity ischemia due to subclavian artery compression or thrombosis and can be ruled-out with magnetic resonance angiography. True NTOS usually presents as a lower trunk brachial plexopathy and is diagnosed with electrodiagnostics or MRI. Other causes of venous obstruction including tumors, congenital abnormalities and upper extremity deep venous thromboses must also be considered.\nManagement and treatment\nWhen acute, treatment is thrombolytic therapy followed by decompressive surgery (first rib resection, pectoralis minor release or scalenectomy) to decrease recurrences. Angioplasty or surgical bypass is performed to repair damaged veins. If chronic, with heaviness and a swollen limb but with a patent subclavian vein, decompressive surgery, angioplasty or vascular reconstruction is recommended. Physical therapy is not generally helpful in treating VTOS, but may be helpful in less severe cases.\nPrognosis\nPatients undergoing successful thrombolysis followed by decompression have five-year secondary vein patency rates greater than 95% but residual edema may limit function.\n\n                            Last update: \n                            May 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Joseph FEINBERG  - Dr Paul SCHOLTEN"}
{"Disease Name": "Ventilator-induced diaphragmatic dysfunction", "Disease Definition": "A rare respiratory disorder characterized by major reduction of diaphragmatic contractile force together with fiber atrophy in the diaphragm and other respiratory muscles as a consequence of invasive mechanical ventilation. Reduction of diaphragmatic contractile force may be observed even within hours after intubation. The condition can increase weaning time and affects weaning outcome, mortality, and long-term clinical outcomes.", "ORPHA ID": 505395, "Summary": ""}
{"Disease Name": "Ventricular extrasystoles with syncopal episodes-perodactyly-Robin sequence syndrome", "Disease Definition": "This syndrome is characterized by cardiac arrhythmias (ventricular extrasystoles manifesting as bigeminy or multifocal tachycardia with syncopal episodes), perodactyly (hypoplasia and/or agenesis of the distal phalanges of the toes) and Pierre-Robin sequence (see this term).", "ORPHA ID": 3201, "Summary": "Epidemiology\nIt has initially been reported in six patients from three generations of one family. Four affected members of another family manifesting a similar constellation of clinical features have recently been reported.\nClinical description\nAn additional feature may be an antimongoloid slant of the palpebral fissures.\nEtiology\nEtiology remains unknown.\n\n                            Last update: \n                            September 2009"}
{"Disease Name": "Ventriculomegaly-cystic kidney disease", "Disease Definition": "A rare genetic syndrome with a central nervous system malformation as a major feature, characterized by a triad of high alpha-fetoprotein levels in both maternal serum and amniotic fluid, cerebral ventriculomegaly, and renal macro- and microcysts. Variable findings include congenital nephrotic syndrome, aqueductal stenosis, gray matter heterotopias, and cardiac malformations, among others.", "ORPHA ID": 443988, "Summary": ""}
{"Disease Name": "Verloove Vanhorick-Brubakk syndrome", "Disease Definition": "Verloove Vanhorick-Brubakk syndrome is a multiple congenital anomalies/dysmorphic syndrome characterized by multiple skeletal malformations (short femora and humeri, bilateral absence of metatarsal and metacarpal bone in hands and feet, bilateral partial syndactyly of fingers and toes or oligopolysyndactyly, deformed lumbosacral spine), congenital heart disease (truncus arteriosus), lung and urogenital malformations (bilateral bilobar lungs, horseshoe kidney, cryptorchidism), and facial malformations (bilateral cleft lip and palate, micrognathia, small, low-set ears without external meatus). It is lethal in the neonatal period. There have been no further descriptions in the literature since 1981.", "ORPHA ID": 3429, "Summary": ""}
{"Disease Name": "Vernal keratoconjunctivitis", "Disease Definition": "A rare disorder of the anterior segment of the eye, characterized by a severe recurrent allergic reaction affecting the cornea and the conjunctiva. It presents with red eyes, ocular itching, photophobia, foreign body sensation, mucous discharge, blepharospasm, and blurring of vision. The symptoms are typically bilateral but may be asymmetric. Characteristic signs include conjunctival injection, giant papillae mostly on the upper tarsal conjunctiva (cobblestone appearance), limbal gelatinous infiltrates (Horner-Trantas dots), and variable corneal signs. The condition is more prevalent in hot climates and most commonly affects young boys.", "ORPHA ID": 70476, "Summary": ""}
{"Disease Name": "Verrucous hemangioma", "Disease Definition": "A rare vascular anomaly characterized by congenital, solitary or grouped, red-to-purple plaques which may bleed and enlarge over time. The lesions show a predilection for the lower extremities. Histological examination reveals numerous dilated, congested capillaries and venules in the papillary dermis, often with a deep dermal component, and with increased density of variably congested capillaries and venules also in the subcutaneous tissue. The overlying epidermis displays prominent acanthosis, papillomatosis, hyperkeratosis, parakeratosis, and crusting.", "ORPHA ID": 464318, "Summary": ""}
{"Disease Name": "Very long chain acyl-CoA dehydrogenase deficiency", "Disease Definition": "Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid oxidation with a variable presentation including: cardiomyopathy, hypoketotic hypoglycemia, liver disease, exercise intolerance and rhabdomyolysis.", "ORPHA ID": 26793, "Summary": "Epidemiology\nOver 400 cases have been reported worldwide. Prevalence in Germany is of 1/50, 000.\nClinical description\nVLCADD is a clinically heterogeneous disease, with 3 major phenotypes. Severe infantile VLCADD has an early onset, usually within the first 3-12 months of life and as early as the neonatal period, with high mortality and a high incidence of hypoketotic hypoglycaemia, liver disease, cardiac arrhythmias and cardiomyopathy. Pericardial effusion is also reported. Moderately severe infantile/childhood VLCADD has a later onset (early neonatal period to early childhood) and usually presents with hypoketotic hypoglycemia, lower mortality and rarely cardiomyopathy. Late-onset myopathic VLCADD presents in older children and young adults (usually >10 years of age) with isolated skeletal muscle involvement, exercise intolerance, myalgia, rhabdomyolysis and myoglobinuria usually triggered by exercise, fasting, cold/heat and/or stress but viral infection can also precipitate/exacerbate this presentation. In rare cases it can lead to renal failure and can be fatal. Some patients presenting with myopathic disease may have a previous history of hypoglycemia in infancy/childhood.\nEtiology\nVLCADD is caused by mutations in the ACADVL gene (17p13.1). Mutations of this gene lead to dysfunction of mitochondrial beta-oxidation of long-chain fatty acids.\nDiagnostic methods\nAbnormal plasma or blood acylcarnitine profile identifies virtually all patients with the severe/moderately severe phenotypes by demonstrating increased C14:1 and C14:1/C12:1 ratios together with elevations of C12, C16, C16:1, C18 and C18:1 species. Occasionally patients with mainly myopathic disease can give an essentially normal profile when metabolically stable. Crisis urine organic acid analysis generally shows a non-specific abnormal pattern of C6-C14 dicarboxylic and hydroxydicarboxylic acids. Newborn screening is available in Austria, Czech Republic, Denmark, Germany, Hungary, Iceland, Netherlands, Portugal and Spain (milder ''late-onset'' patients may not be detected). VLCADD is confirmed by showing two pathogenic mutations in the ACADVL gene. Fatty acid oxidation flux assays in cultured fibroblasts or direct measurement of VLCAD activity in lymphocytes or fibroblasts can also clarify difficult diagnoses.\nDifferential diagnosis\nDifferential diagnosis includes other long chain fat oxidation defects. Myopathic carnitine palmitoyl transferase II deficiency (see this term) has a presentation identical to the myopathic presentation of VLCADD.\nAntenatal diagnosis\nAntenatal diagnosis is possible when mutation(s) have been identified within the family.\nGenetic counseling\nVLCADD is inherited autosomal recessively and genetic counseling is available.\nManagement and treatment\nDietary treatment along with strict avoidance of fasting is essential in infants/children and involves a low long-chain fat diet in combination with medium chain triglycerides. An emergency regimen should be available for each patient to use when they cannot tolerate their prescribed diet. Medical treatment should be sought immediately if there is evidence of decompensation. Those with a milder phenotype should limit exercise and cold/heat exposure and avoid fasting. Treatment with bezafibrate offers potential benefit in myopathic patients with residual enzyme activity, although this awaits full clinical evaluation.\nPrognosis\nVLCADD can be fatal but thanks to newborn screening programs, the outcome is improving for all phenotypes. Prognosis is much better for milder phenotypes provided that there is adherence to treatment protocols.\n\n                            Last update: \n                            February 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Simon OLPIN"}
{"Disease Name": "Vestibular schwannoma", "Disease Definition": "Vestibular schwannoma is a rare tumor of the posterior fossa originating in the Schwann cells of the vestibular transitional zone of the vestibulocochlear nerve that can be benign, small, slow growing and asymptomatic or large, faster growing and aggressive and potentially fatal, presenting with symptoms of hearing and balance impairment, vertigo, ataxia, headache and fifth, sixth or seventh cranial nerve dysfunction and facial numbness.", "ORPHA ID": 252175, "Summary": ""}
{"Disease Name": "VEXAS syndrome", "Disease Definition": "A rare autoinflammatory syndrome characterized by adult onset of rheumatologic manifestations such as recurrent fever, skin and pulmonary inflammation, ear and nose chondritis, vasculitis, deep vein thrombosis, and arthralgia. Laboratory examination reveals progressive hematologic abnormalities including macrocytic anemia and thrombocytopenia, as well as elevated inflammatory markers. Bone marrow biopsy shows hypercellularity and signs of bone marrow dysplasia. The disease primarily occurs in males and is caused by somatic mutations on chromosome Xp11.", "ORPHA ID": 596753, "Summary": ""}
{"Disease Name": "Vibratory urticaria", "Disease Definition": "Vibratory urticaria is a rare, genetic urticaria characterized by the development of localized, short-lasting (resolving within 1 hour), pruritic, erythematous, edematous hives in response to repetitive frictional or vibratory stimulation of the skin, which in some cases is accompanied by facial flushing, headache or the sensation of a metallic taste. Concomitant local mast cell degranulation and increased histamine serum levels are additional typical findings.", "ORPHA ID": 493342, "Summary": ""}
{"Disease Name": "Vici syndrome", "Disease Definition": "Vici syndrome is a very rare and severe congenital multisystem disorder characterized by the principal features of agenesis of the corpus callosum, cataracts, oculocutaneous hypopigmentation, cardiomyopathy and combined immunodeficiency.", "ORPHA ID": 1493, "Summary": "Epidemiology\nPrevalence is unknown. Only 20 cases have been reported to date.\nClinical description\nVici syndrome is usually diagnosed in the first years of life. The phenotype is variable but the principal diagnostic features are almost always present at onset or evolve over time. Swallowing and feeding difficulties may be noted early on and may lead to failure to thrive. Cataracts are the most frequent ocular abnormality observed but others include optic nerve hypoplasia (see this term), nystagmus and photophobia. Hypopigmentation of eyes and hair is relative to the familial or ethnic background. Cardiomyopathy may evolve over time, leading to progressive heart failure. Most patients suffer from recurrent infections during infancy, often affecting the respiratory, gastrointestinal and urinary tracts, but can also include mucocutaneous candidiasis, conjunctivitis and sepsis. An associated skeletal muscle myopathy with hypotonia and motor developmental delay is common. Some patients can display facial dysmorphism (cleft lip/palate and micrognathia), or rarely, other dysmorphic features (i.e. syndactyly). Sensorineural hearing loss has been reported in some and is probably underdiagnosed. Other structural CNS abnormalities, psychomotor retardation and seizures may also be present. Thymus, thyroid, liver and kidney involvement, as well as hematological abnormalities, have been rarely reported. Death is mainly due to cardiac complications or severe infections.\nEtiology\nVici syndrome is due to mutations in the EPG5 gene (18q12.3) which encodes an important autophagy regulator, ectopic P-granules autophagy protein 5 (epg5). The autophagy pathway involves several tightly regulated steps, evolving from the initial formation of phagophores to autophagosomes, whose fusion with lysosomes results in the final structures of degradation, autolysosomes. Formation of autolysosomes is specifically disturbed by an epg5 deficiency.\nDiagnostic methods\nDiagnosis is based mainly on the presence of the characteristic clinical features. Brain MRI visualizes agenesis of the corpus callosum and an ocular examination (slit lamp exam) can identify any cataracts or ocular abnormalities. Electrocardiogram (ECG) and cardiac ultrasound are useful in assessing cardiac function. Immunological studies are also performed. Molecular genetic testing, identifying mutations in the EPG5 gene, confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses include Marinesco-Sjogren syndrome, Chédiak-Higashi syndrome, Griscelli syndrome, DiGeorge syndrome or ataxia-telegiectasia (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known disease causing mutation.\nGenetic counseling\nInheritance is autosomal recessive and genetic counseling is possible.\nManagement and treatment\nTreatment of Vici syndrome is purely supportive. In patients with seizures, anticonvulsant therapy should be instituted. Tube feeding may be necessary in those with feeding difficulties. Intercurrent infections should receive prompt and aggressive antibiotic treatment. In those with severe immunodeficiency, intravenous immunoglobulin replacement and antimicrobial prophylaxis should be considered. Cardiac function should be monitored regularly and immediate medical treatment instituted in case of evolving cardiac failure. Cataracts can be surgically corrected and hearing aids can be provided as necessary. Thyroid, liver and kidney function should be regularly monitored.\nPrognosis\nThe overall prognosis is poor but may improve if the condition is diagnosed early and if cardiac and immunological aspects of the disease are managed proactively.\n\n                            Last update: \n                            May 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Heinz JUNGBLUTH"}
{"Disease Name": "VIPoma", "Disease Definition": "VIPoma is an extremely rare type of pancreatic neuroendocrine tumor (see this term) that secretes vasoactive intestinal polypeptide (VIP) leading to the manifestations of watery diarrhea, hypokalemia and achlorhydia or hypochhlorhydia (known as WDHA syndrome).", "ORPHA ID": 97282, "Summary": "Epidemiology\nThe incidence of VIPoma in the general population is of less than 1/10,000,000 individuals per year. There is a slight female predominance.\nClinical description\nThe median age of diagnosis is the fifth decade of life but VIPoma can occur at any age. The most common presentation includes chronic watery diarrhea (described as >3L/day, odorless, blood and mucus free and unaffected by fasting), hypokalemia (manifesting with muscle weakness, abdominal muscle cramps, or respiratory depression), and various dietary deficiencies (iron and B12 deficiency) caused by achlorhydia/hypochlorhydia. Other less common manifestations include nausea, vomiting, weight loss, bloating, indigestion, skin rash and facial flushing, backache and lethargy. In 60-80% of cases, metastasis has occurred at the time of diagnosis as symptoms usually only occur once a tumor has reached a certain size. The most common site of metastasis is liver but lung, lymph node and kidney involvement have also been reported. If untreated, prolonged dehydration can lead to renal failure and cardiac arrest. In rare cases, VIPomas are non-functional.\nEtiology\nMost cases are sporadic but VIPomas can also occur in association with multiple endocrine neoplasia type 1 (MEN1; see this term). VIPomas are, in 90% of cases, located in the pancreas (mainly in the body and tail) and are usually solitary with a diameter ranging from 1-7cm. The remainder (10%) originate from non-pancreatic tissue such as the colon, liver and neural crest-derived tissues (mainly pediatric cases). These tumors secrete VIP, which stimulates cyclic adenosine monophosphate (cAMP) production in the intestine, causing increased water and electrolyte secretion into the lumen. VIP also has an inhibitory effect on gastric mucosa parietal cells leading to decreased gastric acid production.\nDiagnostic methods\nDiagnosis is based on clinical, laboratory and imaging findings. Typical blood laboratory findings include elevated VIP levels (>200pg/mL is diagnostic), hypokalemia, hypochlorhydia or achlorhydia, hyperglycemia, hypercalcemia and non-anion gap metabolic acidosis. Computed tomography (CT) and octreotide scans, magnetic resonance imaging (MRI) and endoscopic ultrasound can be used to localize neoplasms, confirming diagnosis. Immunohistochemically, VIPomas stain positively for VIP, synaptophysin, chromagranin A, somatostatin, neuron specific enolase and cytokeratin.\nDifferential diagnosis\nDifferential diagnoses include all other causes of chronic diarrhea such as malabsorption syndrome, Crohn disease, ulcerative colitis, microscopic colitis (see these terms), and gastrointestinal infections.\nManagement and treatment\nInitial treatment focuses on replacing the massive loss of fluids, restoring electrolyte levels and reversing acidosis. Some patients may require intravenous fluid and potassium replacement in a hospital setting. Octreotide (a somatostatin analogue) is successful in controlling diarrhea and reducing VIP hormone levels. Loperamide may also be used. Surgical resection is the standard treatment in those with primary or metastatic VIPoma. Unresectable metastatic disease has been treated with chemotherapy (docorubicin/streptozocin regimen) in some cases.\nPrognosis\nPrognosis is highly variable and is dependent on many factors. In those with benign, surgically resectable tumors, the reported 5-year survival rate is almost 95%.\n\n                            Last update: \n                            November 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Run YU"}
{"Disease Name": "Viral hemorrhagic fever", "Disease Definition": "A rare group of infectious disease characterized by malaise, fever, exhaustion, vascular permeability, decreased plasma volume, coagulation abnormalities and varying degrees of hemorrhage. Severity of hemorrage is affected by a variety of contributing factors (depending on the pathogen and the host, whether it is primary infection or reinfection) and severly ill patients often show signs of bleeding under skin, in internal organs and in orifices. They may develop circulatory collapse, multisystem organ failure, shock, nervous system malfunction, coma, delirium, and seizures. A variety of rashes and ocular manifestations can also be associated with the diseases. They are caused by several different families of RNA viruses, including members of arenaviruses, bunyaviruses, filoviruses and flaviviruses that are capable of causing high morbidity and mortality.", "ORPHA ID": 341, "Summary": ""}
{"Disease Name": "Viral myositis", "Disease Definition": "A rare acquired skeletal muscle disease characterized by sudden onset of muscle weakness, tenderness, and pain during or following recovery from a viral illness. The most commonly reported underlying viral infections are influenza B and A, the latter being the significantly less frequent cause. Most cases occur in children. Symptoms are often limited to the calf muscles, but other muscle groups may be involved as well. The condition is typically self-limiting, resolving within several days, although rhabdomyolysis with renal failure and compartment syndrome have been reported.", "ORPHA ID": 206991, "Summary": ""}
{"Disease Name": "Virus-associated trichodysplasia spinulosa", "Disease Definition": "Virus-associated trichodysplasia spinulosa is a rare infectious skin disease characterized by the development of follicular papules with keratin spicules in various parts of the body, predominantly in the face (e.g. nose, eyebrows, auricles), that is due to polyomavirus infection in immunocompromized patients.", "ORPHA ID": 228379, "Summary": ""}
{"Disease Name": "Visceral calciphylaxis", "Disease Definition": "A rare, life-threatening, non-inflammatory vasculopathy characterized by diffuse precipitation of calcium in viscera (mainly in the heart or lungs, but also in the stomach or kidneys) leading to fibrosis and thrombosis, which eventually causes tissue necrosis. Depending on the affected organ, patients may present with dyspnea, cough and respiratory failure or acute heart block and subsequent sudden cardiac death. The disease predominantly affects patients with end-stage kidney disease (ESKD) on dialysis.", "ORPHA ID": 280068, "Summary": ""}
{"Disease Name": "Visceral neuropathy-brain anomalies-facial dysmorphism-developmental delay syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay, neuropathic visceral dysmotility (resulting in neurogenic megacystis and sometimes chronic intestinal pseudo-obstruction syndrome), intracerebral calcifications, and dysmorphic facial features (including broad forehead, downslanted palpebral fissures, strabismus, protruding and low-set ears, and retrognathia). Microcephaly and renal abnormalities have also been reported.", "ORPHA ID": 73246, "Summary": ""}
{"Disease Name": "Visual snow syndrome", "Disease Definition": "Visual snow syndrome is a rare neurologic disease characterized by persistent continuous bilateral visual experience of flickering snow-like dots throughout the visual field in association with other visual (including palinopsia, enhanced entopic phenomena, nyctalopia, photophobia and photopsia) and non-visual (migraine with or without aura, tinnitus and occasionally tremor) symptoms.", "ORPHA ID": 420556, "Summary": ""}
{"Disease Name": "Vitamin B12-responsive methylmalonic acidemia", "Disease Definition": "An inborn error of vitamin B12 (cobalamin) metabolism characterized by recurrent ketoacidotic comas or transient vomiting, dehydration, hypotonia and intellectual deficit, which responds to vitamin B12. There are three types: cblA, cblB and cblD-variant 2 (cblDv2).", "ORPHA ID": 28, "Summary": "Epidemiology\nTo date, over 120 patients with cblA, 66 patients with cblB and 6 patients with cblDv2 have been reported. Prevalence of 1/48,000-1/61,000 have been reported for methylmalonic acidemia (MA) of all causes in North America, and 1/26,000 in China, but only a subset of this is vitamin B12-responsive MA.\nClinical description\nPatients usually present in infancy or early childhood with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, hepatomegaly and coma. They may also show signs of anemia (not megaloblastic), have potentially life-threatening ketoacidosis and/or hyperammonemia, and developmental delay and intellectual deficit, with metabolic stroke affecting the brain stem. MA frequently leads to end-stage renal failure by adolescence or adulthood. Patients with cblB are usually more severely affected than patients with cblA.\nEtiology\nVitamin B12-responsive MA is caused by defects in the synthesis of adenosylcobalamin (AdoCbl). There are three distinct complementation classes, cblA, B and Dv2. cblA is caused by mutations in the MMAA gene (4q31.1-2); cblB by the MMAB gene (12q24.1); and cblDv2 by the  MMADHC gene (2q23.2). The previously reported cblH disorder has been shown to be cblDv2.\nDiagnostic methods\nDiagnosis is based on increased methylmalonic acid in blood and urine. Neonatal screening for propionylcarnitine and/or increased propionylcarnitine-to-acetylcarnitine ratio in dried blood spots by tandem mass spectrometry (MS/MS) has become common, but specific identification of methylmalonic acid remains crucial.\nDifferential diagnosis\nDifferential diagnoses include MA with homocystinuria (see this term), caused by defects in cblC, D and F, which can be differentiated by the presence of megaloblastic anemia, or vitamin B12-unresponsive MA without homocystinuria (see this term), which also can present early in life (<1 to 4 weeks) with similar symptoms. Complementation analysis can be used to identify the group involved, or sequencing of the causative genes to identify the affected gene.\nAntenatal diagnosis\nAntenatal diagnosis is possible by measurement of methylmalonate in amniotic fluid and maternal urine at mid-trimester and by studies of functional mutase activity and cobalamin metabolism in cultured amniotic fluid cells. Molecular diagnosis is possible if the gene affected and the mutation(s) in the family are known.\nGenetic counseling\nTransmission is autosomal recessive (1 in 4 recurrence risk/pregnancy).\nManagement and treatment\nTreatment involves a protein-restricted diet, which should be instituted as soon as life-threatening manifestations such as ketoacidosis or hyperammonemia have been resolved, and intramuscular injections of vitamin B12, with or without carnitine (mainly effective in cblA). A good response to cobalamin supplementation has been reported in most cblA patients and in nearly half cblB patients. Oral antibiotics may also be useful to reduce propionic acid from gut flora.\nPrognosis\nThe prognosis varies with the complement involved, with cblA patients having the most favorable prognosis (most patients well at ages up to 30 years) and cblB patients less favorable. cblDv2 appears similar to cblA, although the number of patients is small. One complication in long-term surviving patients is chronic renal failure.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Vitamin B12-unresponsive methylmalonic acidemia type mut-", "Disease Definition": "Vitamin B12-unresponsive methylmalonic acidemia type mut- is an inborn error of metabolism characterized by recurrent ketoacidotic comas or transient vomiting, dehydration, hypotonia and intellectual deficit, which does not respond to administration of vitamin B12.", "ORPHA ID": 79312, "Summary": "Epidemiology\nPrevalence of this form of the disorder is not known. More than 450 cases have been reported to date.\nClinical description\nThe disease typically presents very early in life (<1 to 4 weeks), although later onset cases have been observed, with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, developmental delay, intellectual deficit, hepatomegaly and coma. Patients may show signs of anemia. They may also have potentially life-threatening ketoacidosis and/or hyperammonemia, renal and neurological complications, metabolic stroke and cardiomyopathy. mut- is generally less severe than vitamin B12-unresponsive methylmalonic acidemia type mut0 (see this term) and may in some cases respond to vitamin B12 therapy. Long term complications include metabolic stroke and development of end stage renal failure. These complications are more frequent in mut0 than in mut-.\nEtiology\nThe disease is caused by partial deficiency in the activity of the mitochondrial vitamin B12-dependent enzyme methylmalonyl-CoA mutase which is a result of mutations in the MUT gene (6p21).\nGenetic counseling\nIt is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            February 2012\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Vitamin B12-unresponsive methylmalonic acidemia type mut0", "Disease Definition": "Vitamin B12-unresponsive methylmalonic acidemia type mut0 is an inborn error of metabolism characterized by recurrent ketoacidotic comas or transient vomiting, dehydration, hypotonia and intellectual deficit, which does not respond to administration of vitamin B12.", "ORPHA ID": 289916, "Summary": "Epidemiology\nPrevalence of this disorder is not known.\nClinical description\nThe disease typically presents very early in life (<1 to 4 weeks), although rare later onset cases have been observed, with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, developmental delay, intellectual deficit, hepatomegaly and coma. Patients may show signs of anemia. They may also have potentially life-threatening ketoacidosis and/or hyperammonemia, renal and neurological complications, metabolic stroke and cardiomyopathy.\nEtiology\nThe disease is caused by complete deficiency in the activity of the mitochondrial enzyme methylmalonyl-CoA mutase which is a result of mutations in the MUT gene (6p21).\nGenetic counseling\nIt is transmitted as an autosomal recessive trait.\n\n                            Last update: \n                            February 2012\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Vitamin B12-unresponsive methylmalonic acidemia", "Disease Definition": "Vitamin B12-unresponsive methylmalonic acidemia is an inborn error of vitamin B12 (cobalamin) metabolism characterized by recurrent ketoacidotic crises or transient vomiting, dehydration, hypotonia and intellectual deficit, which does not respond to administration of vitamin B12. There are two types of vitamin B12-unresponsive methylmalonic acidemia: mut0 and mut- (see these terms).", "ORPHA ID": 27, "Summary": "Epidemiology\nPrevalence of 1/48,000-1/61,000 has been reported for methylmalonic aciduria of all causes in North America, and 1/26,000 in China, but only a subset of this is vitamin B12-unresponsive methylmalonic acidemia.\nClinical description\nPatients with vitamin B12-unresponsive methylmalonic acidemia without homocystinuria typically present very early in life (<1 to 4 weeks) with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscular hypotonia, hepatomegaly and coma. Later-onset manifestations may include developmental delay and intellectual deficit. Patients may also show signs of anemia which is not megaloblastic. They may also have potentially life-threatening ketoacidosis and/or hyperammonemia, renal and neurological complications, metabolic stroke and cardiomyopathy. Later-onset and milder phenotypes have also been observed, particularly in mut- patients. Long term consequences are neurological damage due to metabolic stroke and end-stage renal failure. These complications are more frequent in mut0 than in mut-.\nEtiology\nVitamin B12-unresponsive methylmalonic acidemia without homocystinuria is caused by complete (mut0) or partial (mut-) deficiency in the activity of the mitochondrial enzyme methylmalonyl-CoA mutase. This deficiency is caused by mutations in the MUT gene (6p21).\nDiagnostic methods\nDiagnosis is based on the finding of increased methylmalonic acid in blood and urine. There is increased propionylcarnitine and/or increased propionylcarnitine-to-acetylcarnitine ratio in dried blood spots by tandem mass spectrometry (MS/MS). Diagnosis can be confirmed by somatic cell studies or molecular genetic testing.\nDifferential diagnosis\nDifferential diagnoses include methylmalonic acidemia with homocystinuria (see this term), caused by defects in cblC, cblD and cblF, which can be differentiated by the presence of megaloblastic anemia, or vitamin B12-responsive methylmalonic acidemia without homocystinuria (see this term), which usually presents slightly later in life (1 month to 1 year). Complementation analysis can be used to identify the cbl or mut complement involved.\nAntenatal diagnosis\nAntenatal diagnosis is possible by measurement of methylmalonate in amniotic fluid and maternal urine at mid-trimester and by studies of functional mutase activity and cobalamin metabolism in cultured amniotic fluid cells. Molecular genetic prenatal diagnosis is also possible when the mutations segregating in the family are known.\nGenetic counseling\nThe disorder is transmitted in an autosomal recessive manner.\nManagement and treatment\nTreatment involves a protein-restricted diet, which should be instituted as soon as life-threatening problems such as ketoacidosis or hyperammonemia have been resolved. Oral antibiotics may also be useful. Liver transplantation has been attempted in a limited number of patients but this does not usually offer complete protection against renal and neurological complications.\nPrognosis\nDespite dietary treatment, patients remain vulnerable to life-threatening metabolic decompensation. Other long-term complications include progressive renal failure, metabolic stroke and other neurological symptoms, as well as cardiomyopathy. Life-expectancy is decreased in mut0 patients compared to mut- patients.\n\n                            Last update: \n                            March 2012\n\n\n                            - Expert reviewer(s): \n                            Dr David ROSENBLATT  - Dr David WATKINS"}
{"Disease Name": "Vitamin K antagonist embryofetopathy", "Disease Definition": "Vitamin K antagonist embryofetopathy is characterized by a group of symptoms that may be observed in a fetus or newborn when the mother has taken oral vitamin K antagonists, such as warfarin during pregnancy. Vitamin K antagonists are anticoagulant drugs that provide efficient thromboprophylaxis and that can cross the placenta. 5-12 % of infants exposed to warfarin between 6-9 weeks gestation present nasal hypoplasia and skeletal abnormalities, including short limbs and digits (brachydactyly), and stippled epiphyses. Warfarin fetopathy with central nervous system abnormalities (hydrocephalus, intellectual disability, spasticity, and hypotonia) or ocular abnormalities (microphthalmia, cataract, optic atrophy), fetal loss, and stillbirth, occurs in infants exposed at later gestations. Additional features that have been reported after in utero warfarin exposure include facial dysmorphism (cleft lip and/or palate, malformed ears), choanal atresia or stenosis, aorta coarctation, situs inversus totalis, bilobed lungs, and ventral midline dysplasia.", "ORPHA ID": 1914, "Summary": ""}
{"Disease Name": "Vocal cord and pharyngeal distal myopathy", "Disease Definition": "Vocal cord and pharyngeal distal myopathy (VCPDM) is a rare autosomal dominant distal myopathy characterized by adult onset of muscle weakness in the feet and hands (slowly progressing to involve proximal limb muscles) combined with vocal or swallowing dysfunction and frequent respiratory muscle involvement in later stages. Normal to mildly elevated creatine kinase (CK) serum levels and rimmed-vacuolated dystrophic muscle fiber changes are associated laboratory and pathologic findings.", "ORPHA ID": 600, "Summary": "Epidemiology\nWorldwide prevalence is unknown but more than 70 patients (of North American, European, and Japanese origin) have been reported to date.\nClinical description\nOnset of muscle weakness is between 30-63 years (mean in the forties) and may initially be asymmetric. It most frequently begins with involvement of ankle and toe extensors with foot drop or may manifest in the hands. Weakness in the ankles renders the gait very unstable resulting in a waddling and steppage gait. In the hands, the extensors of the fingers and the abductor pollicis brevis (with atrophy) are affected to varying degrees. Progression of muscle weakness and wasting to proximal upper and lower limb muscles is common. Bulbar involvement with dysphonia and dysphagia may be initially absent but appear as disease progresses. Initially, voice is usually nasal or hoarse and dysphagia mild (with difficulty swallowing solid food), but progressive vocal cord weakness eventually leads to aspiration. Some patients display respiratory impairment with a low vital capacity that may progress to respiratory failure. Ocular muscle involvement is not observed.\nEtiology\nVCPDM is caused by a c.254C>G mutation in the MATR3 gene (5q31.3) which results in substitution of a conserved amino acid (S85C) in the nuclear protein Matrin-3. It harbors nuclear import and export motifs in addition to several DNA and RNA binding sites. Currently, the mechanism by which S85C alteration in Matrin-3 leads to myopathy remains largely unknown.\nDiagnostic methods\nThe diagnosis of VCPDM is clinical and involves vocal cord examination by laryngoscopy (which reveals bowing of the vocal cords and constantly flowing secretions, resulting from incomplete closure of the glottis and pharyngeal muscle weakness). Needle EMG shows myopathic changes. Muscle biopsies reveal chronic non-inflammatory myopathy with variations in fiber size, fiber splitting and subsarcolemmal rimmed vacuoles, with pathologic changes being scant in the quadriceps and severe in the gastrocnemius. CK serum levels range from normal to an 8 fold increase. Molecular genetic screening revealing mutation in the MATR3 gene confirms diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes Welander distal myopathy, oculopharyngeal muscular dystrophy, and oculopharyngodistal myopathy.\nGenetic counseling\nVCPDM is inherited in an autosomal dominant manner. Genetic counseling can inform affected individuals about the 50% risk of disease transmission to their offspring.\nManagement and treatment\nCurrently, there is no cure for VCPDM. Ankle-foot orthotic braces and/or canes are used to aid in ambulation. For patients suffering from vocal cord weakness, injection of agents that add bulk and act as stiffeners (teflon, gel foam, fat), or bilateral silastic-implant medialization of the vocal folds, may aid in reducing aspiration. Ventilation or oxygen therapy may be needed if patient presents severe respiratory muscle involvement.\nPrognosis\nPrognosis of patients suffering from vocal cord and pharyngeal weakness is highly influenced by the quality of long-term respiratory care, if it is needed. Moreover, as distal upper limb muscles weaken, hand may partially curl closed, leading to a general loss of grip and dexterity. Ambulation is usually preserved.\n\n                            Last update: \n                            September 2018\n\n\n                            - Expert reviewer(s): \n                            Dr Johanna PALMIO  - Pr Bjarne UDD"}
{"Disease Name": "Vogt-Koyanagi-Harada disease", "Disease Definition": "Vogt-Koyanagi-Harada disease is a bilateral, chronic, diffuse granulomatous panuveitis typically characterized by serous retinal detachment and frequently associated with neurological (meningitis), auditory, and dermatological alterations.", "ORPHA ID": 3437, "Summary": "Epidemiology\nAnnual incidence is estimated at 1/400,000. The condition predominantly affects young women and individuals with darker pigmentation (those of Asian, Hispanic, or Native American origin). Children may be affected, but the mean age of onset is about 30 years of age (ranging from 10 to 52 years).\nClinical description\nThe most common clinical manifestations are headaches (67% of cases), ocular involvement with panuveitis, skin vitiligo, alopecia, and inner ear disturbances. The disease can be divided into four clinical stages. The prodromic stage is characterized by nonspecific symptoms such as fever, headaches, nausea and vertigo, and then by neurologic symptoms such as muscle weakness, hemiparesis, hemiplegia, dysarthria and orbital pain. In the ophthalmologic stage, occurring a few days after the prodromic stage, patients complain of blurred vision, ocular pain, and photophobia or central scotoma (bilateral in 80% of cases). Bilateral, serous, non-rhegmatogenous retinal detachment often occurs. Hearing disturbances (75%) and dizziness may also be present. The convalescent stage, occurring within three months of disease onset, is characterized by the apparition of cutaneous signs such as poliosis involving the eyebrows and eyelashes (and sometimes the scalp and body hair), hair loss, and vitiligo (usually perilimbal). Recurrent uveitis and ophthalmologic complications appear in the final stage, the chronic recurrent stage.\nEtiology\nPathogenesis has been linked to immunological disorders targeting the melanocytes, and which involve T-cell-mediated cytotoxicity and apoptosis. However, the etiology is still not completely understood. An association between disease susceptibility and positive blood tests for the HLA-DRB1*0405 haplotype has been reported.\nDiagnostic methods\nDiagnosis is clinical. Cerebrospinal fluid analysis revealing pleocytosis can confirm the diagnosis.\nManagement and treatment\nManagement should involve a multidisciplinary team with dermatologists, ophthalmologists, and neurologists. High doses of corticosteroids usually provide efficient treatment, but immunosuppressors may also be used.\nPrognosis\nWith early and aggressive treatment, the prognosis is usually favorable, but acute hearing and vision alterations may occur.\n\n                            Last update: \n                            March 2009\n\n\n                            - Expert reviewer(s): \n                            Dr Olivier CALVETTI  - Dr Caroline LAURENT-CORIAT  - Pr Michel PAQUES"}
{"Disease Name": "Von Hippel-Lindau disease", "Disease Definition": "A familial cancer predisposition syndrome associated with a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma (RCC), and pheochromocytoma/paraganglioma.", "ORPHA ID": 892, "Summary": "Epidemiology\nPrevalence is estimated at 1/53,000 and annual birth incidence at 1/36,000. Men and women are equally affected. Mean age at diagnosis is 26 years (range: infancy - 7th decade).\nClinical description\nRetinal hemangioblastomas are the most common presenting feature (multiple and bilateral in about 50% of cases). They are usually asymptomatic, but they can cause retinal detachment, macular edema, glaucoma, and vision loss. Central nervous system (CNS) hemangioblastomas are the presenting feature in about 40% and occur overall in 60-80% of patients. They are most often located in the cerebellum, but also in the brainstem and spinal cord. They are benign but cause symptoms by compressing adjacent nervous tissue. In the cerebellum they are most often associated with increased intracranial pressure causing headaches, vomiting, and limb or truncal ataxia (difficulty in controlling fine movements of the arms and legs and unsteadiness in walking). Multiple renal cysts are very common and there is an increased lifetime risk of RCC (up to 70%). Some patients have pheochromocytomas that can be asymptomatic, but may cause hypertension. Epididymal cysts and cystadenomas (60% of male patients) may occur, as well as multiple pancreatic cysts (most patients). Non-secretory pancreatic islet cell tumours occur in a minority (10-15%). Endolymphatic sac tumors (ELST) are also been found (up to 10%) and may cause hearing loss. Head and neck paragangliomas are rare (0.5%). The mean age at diagnosis of tumors (e.g. haemangioblastoma, RCC) in VHL disease is considerably younger than in non-inherited sporadic cases. The clinical manifestations of VHL disease van vary between family members.\nEtiology\nVHL disease is caused by pathogenic variants (mutations) in the VHL gene (3p25.3), a classic tumor suppressor. Most cases are diagnosed via a germline mutation. In addition to VHL disease, pathogenic variants in the VHL gene can also cause, albeit more rarely, predisposition to isolated phaeochromocytoma/paraganglioma and familial erythrocytosis (polycythemia).\nDiagnostic methods\nDiagnosis can be made in the presence of a single typical tumor (e.g. retinal or CNS hemangioblastomas or RCC) and a positive family history of VHL. If there is no family history (about 20% of cases occur de novo), multiple tumors (e.g. two hemangioblastomas or a hemangioblastoma and an RCC) are required for diagnosis. A complete blood count, measurement of urinary or plasma catecholamine metabolites and urinalysis may be indicative of polycythemia, pheochromocytoma/paraganglioma, and RCC bit regular ophthalmology review and MRI scans are the mainstay of surveillance. Imaging studies can be used to detect CNS tumors, pheochromocytoma/paraganglioma, endolymphatic sac tumors, renal tumors, and renal and pancreatic cysts.\nDifferential diagnosis\nDifferential diagnoses include multiple endocrine neoplasia, neurofibromatosis type 1, polycystic kidney disease, tuberous sclerosis, Birt-Hogg-Dube syndrome, and hereditary pheochromocytoma-paraganglioma syndromes associated with succinate dehydrogenase subunit mutations (SDHB, SDHC and SDHD).\nAntenatal diagnosis\nPrenatal diagnosis is possible when a pathogenic variant has been detected in an affected family member.\nGenetic counseling\nInheritance is autosomal dominant with age-dependent penetrance. Most cases are familial and at risk relatives should be identified and offered surveillance and, when available, cascade testing (relatives who test negative can be discharged from follow-up). Surveillance is commenced in early childhood and genetic testing of children can be offered to avoid unnecessary surveillance.\nManagement and treatment\nSurveillance to enable early detection of VHL-related tumors is the mainstay of management. Surveillance (ophthalmologic, MRI brain and abdominal scans, laboratory testing) is lifelong and reduces morbidity and mortality. Tumors detected by surveillance may not require immediate intervention and there are agreed consensus protocols to keep some tumors under surveillance until certain size thresholds are reached (e.g. 3 cm diameter for RCC). When treatment of VHL tumors is indicated surgery has been the most frequently used intervention for abdominal and CNS lesions but recently medical therapy with HIF-2 antagonist (e.g. belzutifan) has become an option in some countries.\nPrognosis\nRegular surveillance and early detection and management of tumors has reduced the morbidity and mortality of VHL disease and recently average life expectancy has been estimated to be ~64 years.\n\n                            Last update: \n                            July 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Eamonn MAHER | ERN GENTURIS*\n\n\n                                * European Reference Network"}
{"Disease Name": "Von Voss-Cherstvoy syndrome", "Disease Definition": "Von Voss-Cherstvoy syndrome is a very rare disorder with phocomelia of upper limbs, encephalocele, variable brain anomalies, urogenital abnormalities, and thrombocytopenia.", "ORPHA ID": 3439, "Summary": "Epidemiology\nLess than 15 cases have been reported.\nClinical description\nThe spectrum of upper limb defects varies from radial agenesis and phocomelia to amelia. A meningoencephalocele is constant. The intellectual development may be normal.\nEtiology\nPathogenesis and cause of this syndrome are unknown.\nGenetic counseling\nParental consanguinity reported in a family suggests an autosomal recessive pattern of inheritance.\n\n                            Last update: \n                            May 2010"}
{"Disease Name": "Von Willebrand disease type 1", "Disease Definition": "A form of von Willebrand disease (VWD) characterized by a bleeding disorder associated with a partial, quantitative plasmatic deficiency of an otherwise structurally and functionally normal von Willebrand factor (VWF).", "ORPHA ID": 166078, "Summary": "Epidemiology\nThe type 1 disease is considered to be the most common form of VWD, accounting for between 50-75% of cases but its prevalence is probably overestimated.\nClinical description\nAge of onset of bleeding anomalies varies, with earlier onset and more severe symptoms being associated with more severe VWF deficiency. The bleeding anomalies are generally characterized by mucocutaneous hemorrhage (menorrhagia, epistaxis, or prolonged bleeding after trauma or a surgical intervention). Hematomas and hemarthrosis are very rare.\nEtiology\nVWD is caused by mutations in the VWF gene (12p13.3). The anomalies responsible for type 1 VWD generally lead to intracellular retention or rapid clearance of VWF from the circulation. However, families have been described in which no mutations in the VWF gene have been detected indicating that other genetic factors are also implicated. To date, the main additional factor associated with the disease is the ABO blood group, with levels of VWF in blood group O being 25-35% lower than in non-O blood groups.\nDiagnostic methods\nThe presence of bleeding manifestations in the patient and in at least one family member is obligatory for diagnosis. Laboratory diagnosis relies on detection of parallel decreases in functional and VWF antigen levels to values below 40% of normal, in the absence of notable anomalies in the distribution or structure of the VWF multimers. Moderate deficiency of factor VIII (FVIII) may also be present.\nDifferential diagnosis\nGiven the variation in VWF levels (particularly among individuals with blood group O) and the occurrence of abnormal bleeding events in the general population, it may be difficult to differentiate between unaffected individuals and those with type 1 VWD. Evaluation of patients using the bleeding score and studies of family history are therefore essential for diagnosis. Differentiation between acquired von Willebrand syndrome (AVWS), which occurs in association with another underlying pathology, and inherited VWD is more problematic, especially if the type 1 VWD is secondary to an increased clearance. Measurements of VWF levels (antigen and functions) generally allow VWD to be distinguished from hemophilia A.\nGenetic counseling\nType 1 VWD is transmitted in an autosomal dominant manner. Genetic counseling should be proposed to inform patients about the severity of the disease and the associated risks (some patients may be carriers for the most severe form type 3), and to allow screening for detection of other affected family members.\nManagement and treatment\nMedication (such as tranexamic acid for ENT (ear, nose and throat) bleeding anomalies and estrogen-progesterone treatment for menorrhagia) provides an effective treatment and may be prescribed alone or as an adjuvant therapy. Desmopressin (which triggers a transitory release of endogenous VWF stored in the epithelial cells) may be administered in cases when a specific curative or preventative treatment is required. The response to desmopressin is usually good for patients with type 1 disease. Substitution therapy with purified human VWF constitutes an alternative treatment in case of major bleeding problems, for patients in which desmopressin is contraindicated, those with a poor response to desmopressin, or those in which tachyphylaxis occurs.\nPrognosis\nType 1 VWD is generally not life-threatening and does not lead to functional VWF impairment.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND  - Pr Sophie SUSEN"}
{"Disease Name": "Von Willebrand disease type 2", "Disease Definition": "A form of von Willebrand disease (VWD) characterized by a bleeding disorder associated with a qualitative deficiency and functional anomalies of the Willebrand factor (VWF). Depending on the type of functional abnormalities, this form is classified as type 2A, 2B, 2M or 2N.", "ORPHA ID": 166081, "Summary": "Epidemiology\nThe subtypes of type 2 VWD account for between 20-45% of cases of VWD; the prevalence wordwide is estimated at 1/107,000.\nClinical description\nAge of onset of the bleeding anomalies varies, with earlier onset being associated with more severe VWF deficiency. Four type 2 VWD subtypes have been described: types 2A, 2B and 2M are characterized by mucocutaneous manifestations (menorrhagia, epistaxis, gastrointestinal hemorrhage etc.); type 2N is mainly characterized by post traumatic soft tissue bleedings. There is an increased risk of abnormal bleeding following an invasive procedure associated with all type 2 subtypes.\nEtiology\nThe VWF gene (12p13.3) anomalies that lead to type 2 VWD involve the well-defined functional domains of the VWF protein. Three of these subtypes are associated with anomalies in the interaction of VWF with platelets and/or the subendothelium, and are caused by decreased affinity for platelets in combination with VWF multimerization anomalies (type 2A), increased VWF affinity for platelets (type 2B), or decreased VWF affinity for platelets or collagen and normal VWF multimerization (type 2M). The fourth subtype (type 2N) is associated with decreased VWF affinity for factor VIII (FVIII); the interactions between the platelets and the vessel walls are often normal and the FVIII deficiency is usually only moderate.\nDiagnostic methods\nFor subtypes 2A, 2B and 2M, diagnosis is suspected following detection of a notably more profound decrease in functional VWF levels than in VWF antigen levels. This discrepancy between the functional VWF levels and VWF antigen levels also allows the type 2 disease to be distinguished from VWD type 1. However, more specific laboratory tests (analysis of the structure and distribution of the multimers) are required to diagnose the exact type 2 subtype. A thrombocytopenia can be observed in type 2B. Diagnosis of type 2N is suspected when the decrease in FVIII levels is much greater than that of VWF, and confirmed by a factor VIII binding assay.\nDifferential diagnosis\nSubtypes 2A, 2B and 2M can be differentiated from acquired von Willebrand syndrome (AVWS), clinically by the onset of bleeding manifestations at a young age, a family history of the disease and the absence of an underlying pathology, and through molecular analysis revealing a mutation in the VWF gene. The factor VIII binding assay, together with molecular analysis of the VWF gene, allows type 2N VWD to be distinguished from mild hemophilia A.\nGenetic counseling\nMost subtypes of type 2 VWD are transmitted in an autosomal dominant manner except for type 2N and some rare forms of type 2A which are autosomal recessive. Genetic counseling should be proposed to inform patients about the severity of the disease and the associated risks, and to allow screening for detection of other affected family members. In case of recessive transmission where both parents are carriers of the disease-causing mutation, the at-risk couple should be informed that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nMedication (such as tranexamic acid for ENT (ear, nose and throat) bleeding anomalies and estrogen-progesterone therapy for menorrhagia) provides an effective treatment and may be prescribed alone or as an adjuvant therapy. The response to desmopressin varies depending on the type 2 subtype, as the endogenous VWF released from the endothelial cells in response to this treatment displays the same functional anomalies as plasmatic VWF. Desmopressin is contraindicated in patients with subtype 2B. Preventative or curative treatment for abnormal bleeding events often involves substitution therapy with purified human VWF. Platelet concentrates may have to be transfused in some patients with type 2B.\nPrognosis\nFor patients managed within specialized hemostasis hospital centers, the prognosis is favorable, even for those with the most severe forms of the disease.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND  - Pr Sophie SUSEN"}
{"Disease Name": "Von Willebrand disease type 2A", "Disease Definition": "A subtype of type 2 von Willebrand disease characterized by a bleeding disorder associated with a decrease in the affinity of the Willebrand factor (VWF) for platelets and the subendothelium caused by a deficiency of high molecular weight VWF multimers. The disease manifests as mucocutaneous bleeding (menorrhagia, epistaxis, gastrointestinal hemorrhage, etc.).", "ORPHA ID": 166084, "Summary": ""}
{"Disease Name": "Von Willebrand disease type 2B", "Disease Definition": "A subtype of type 2 von Willebrand disease characterized by a bleeding disorder associated with increased affinity of the Willebrand factor (VWF) for platelets leading to rapid clearance of both the platelets (increasing the risk of thrombocytopenia) and VWF from the plasma. The disease manifests as mucocutaneous bleeding (menorrhagia, epistaxis, gastrointestinal hemorrhage, etc.).", "ORPHA ID": 166087, "Summary": ""}
{"Disease Name": "Von Willebrand disease type 2M", "Disease Definition": "A subtype of type 2 von Willebrand disease characterized by a bleeding disorder associated with decreased affinity of the Willebrand factor (VWF) for platelets or collagen in the absence of any deficiency of high molecular weight VWF multimers. The disease manifests as mucocutaneous bleeding (menorrhagia, epistaxis, gastrointestinal hemorrhage, etc.).", "ORPHA ID": 166090, "Summary": ""}
{"Disease Name": "Von Willebrand disease type 2N", "Disease Definition": "A subtype of type 2 von Willebrand disease characterized by a bleeding disorder associated with a marked decrease in the affinity of the Willebrand factor (VWF) for factor VIII (FVIII). Abnormal bleeding manifestations are less frequent in this VWD subtype than in other forms of the disease. The disease manifests mainly as soft tissue bleeding (haematoma, post-operative bleeding, etc.).", "ORPHA ID": 166093, "Summary": ""}
{"Disease Name": "Von Willebrand disease type 3", "Disease Definition": "A form of von Willebrand disease (VWD) characterized by a bleeding disorder associated with a total or near-total absence of Willebrand factor (VWF) in the plasma and cellular compartments, also leading to a profound deficiency of plasmatic factor VIII (FVIII). It is the most severe form of VWD.", "ORPHA ID": 166096, "Summary": "Epidemiology\nThe type 3 disease is the rarest form of VWD, accounting for less than 5% of all cases. The average prevalence in Europe and the USA is approximately 1/500,000; however, the prevalence worldwide, including within Europe, can vary depending on the country of origin and the level of consanguinity, and can be as frequent as 1/200,000.\nClinical description\nOnset usually occurs during the neonatal period or in infancy, but later onset has been reported. The bleeding anomalies are mainly characterized by mucocutaneous hemorrhage (epistaxis, menorrhagia, postpartum hemorrhage, gastrointestinal bleeding etc.) and prolonged bleeding after surgical interventions. As in hemophilia patients, hematomas and hemarthrosis may occur in individuals with type 3 VWD due to the severe FVIII deficiency. Cerebral hemorrhage has also been reported.\nEtiology\nThe disease is caused by homozygous or compound heterozygous mutations (mainly missense or large mutations) in the VWF gene (12p13.3) that lead to synthesis of a truncated protein or allele silencing.\nDiagnostic methods\nDiagnosis is straightforward and is based on the absence of detectable VWF measured by all available methods (including functional and immunologic assays and agarose gel electrophoresis), accompanied by a secondary FVIII deficiency with a decrease to between 1 and 10% of normal levels.\nDifferential diagnosis\nMeasurements of VWF levels generally allow VWD type 3 to be distinguished from moderate hemophilia A. Type 3 VWD is also generally easy to distinguish from other hereditary forms of VWD.\nAntenatal diagnosis\nIn at risk pregnancies, when the pathogenic variants have been previously identified in a family member, the identification of underlying VWF mutations may be used for prenatal diagnosis.\nGenetic counseling\nThe pattern of inheritance is autosomal recessive. Genetic counseling should be recommended for at risk couples (where both parents are unaffected carriers) informing them that the risk of having an affected child is 25% for each pregnancy.\nManagement and treatment\nPatients with type 3 VWD do not respond to desmopressin and therefore substitution therapy with purified human VWF associated, at least for the first injection, with FVIII is the principle preventative or curative treatment. Long-term prophylactic treatment with regular injections of purified human VWF may be required for patients with recurrent bleeding events. Some patients (5-10 % of cases) develop alloantibodies against VWF rendering the substitution treatment ineffective; the formation of immune complexes is sometimes associated with an anaphylactic response. In these cases, alternative treatments, such as continuous infusion of recombinant factor VIII or recombinant activated factor VII, should be considered. There are some preliminary reports of use of emicizumab in allo-immunized type 3 patients.\nPrognosis\nType 3 VWD is the most severe form of VWD and, in the absence of appropriate management in specialized hemostasis hospital centers, the manifestations can be life-threatening and lead to functional impairment.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND  - Pr Sophie SUSEN"}
{"Disease Name": "Von Willebrand disease", "Disease Definition": "A rare, inherited bleeding disorder characterized by defective platelet adhesion and secondary coagulation defect that manifests as abnormal bleeding of variable severity occurring either spontaneously or in association with an invasive procedure. Three main subtypes are defined based on the type of von Willebrand factor defect: partial (type 1) or total (type 3) deficiency, and qualitative/functional anomalies (type 2).", "ORPHA ID": 903, "Summary": "Epidemiology\nThe prevalence of Von Willebrand disease (VWD) in the general population is estimated at between 0.6 and 1.3% (including all forms) depending on the study, but the prevalence of symptomatic VWD that requires specific treatment is approximately 1/10 000. Type 3 VWD is much more rare (1/1 000 000).\nClinical description\nAge of onset varies, with earlier onset being associated with more severe VWF deficiency. The disease manifests as abnormal bleeding of variable severity occurring either spontaneously or in association with an invasive procedure. The bleeding anomalies are generally characterized by mucocutaneous hemorrhage (epistaxis, menorrhagia, bleeding from minor wounds, etc.) but hematomas and hemarthrosis may occur in more severe forms.\nEtiology\nVWD is caused by mutations in the VWF gene (12p13.3) encoding the multimeric VWF protein. The VWF protein has an intraplatelet, endothelial and plasmatic localization and plays essential roles both in the interaction of platelets with the injured vessel wall and in the transport and stabilization of factor VIII (FVIII).\nDiagnostic methods\nDiagnosis relies on laboratory tests involving functional and immunological assays of VWF and FVIII levels. Determination of the type of VWD requires other specific tests such as studies of the distribution of VWF multimers.\nDifferential diagnosis\nMeasurements of VWF levels (antigen and functions) generally allow VWD to be distinguished from hemophilia A. However, these tests do not allow differentiation of type 2N VWD, which requires more specific assays. Differentiation between acquired von Willebrand syndrome (AVWS), which occurs in association with another underlying pathology, and inherited VWD is more problematic. The fact that individuals in the general population belonging to blood group O may also have moderately lower levels of VWF should also be taken into consideration in the differential diagnosis.\nAntenatal diagnosis\nIn at risk pregnancies, the identification of underlying VWF mutations may be used for prenatal diagnosis of type 3 VWD.\nGenetic counseling\nVWD is most often transmitted in an autosomal dominant manner, however, the mode of inheritance is autosomal recessive for type 3 VWD and for some of the type 2 subtypes. Genetic counseling should be proposed to inform patients about the severity of the disease and the associated risks, and to allow screening for detection of other affected family members. For couples at risk of having a child with type 3 disease, genetic counseling may be best discussed in a specialized multidisciplinary center.\nManagement and treatment\nManagement depends on the type of VWD. Desmopressin is generally an effective preventative or curative treatment for abnormal bleeding in type 1 VWD. In patients with type 2 disease, the response to desmopressin is variable and substitution therapy with purified human VWF is often required. Desmopressin does not constitute an effective treatment for patients with type 3 disease, and thus these individuals require substitution therapy with purified human VWF associated, at least for the first injection, with FVIII.\nPrognosis\nFor patients managed within specialized hemostasis hospital centers, the prognosis is favorable, even for those with the most severe forms of the disease.\n\n                            Last update: \n                            November 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Jenny GOUDEMAND  - Pr Sophie SUSEN"}
{"Disease Name": "VPS11-related autosomal recessive hypomyelinating leukodystrophy", "Disease Definition": "A rare genetic leukodystrophy identified in families of Ashkenazi Jewish descent, characterized by infancy onset of severe global developmental delay with very limited or absent speech and sometimes complete absence of motor development, hypotonia, spasticity, and acquired microcephaly. Seizures, hearing loss, visual impairment, and autonomic dysfunction have also been described. Brain imaging shows delayed myelination and other white matter abnormalities.", "ORPHA ID": 466934, "Summary": ""}
{"Disease Name": "Vulvar adenocarcinoma", "Disease Definition": "A rare vulvar carcinoma characterized by a malignant epithelial neoplasm of glandular origin and/or with glandular characteristics arising in the vulva, including adenocarcinoma of mammary gland type, sweat gland type, and intestinal type, as well as adenocarcinomas of the Bartholin glands and Paget disease of the vulva. Depending on the type of tumor and disease stage, patients may present with a solitary vulvar mass, bleeding, or (in the case of Paget disease) a pruritic, erythematous, eczematous lesion.", "ORPHA ID": 494454, "Summary": ""}
{"Disease Name": "Vulvar basal cell carcinoma", "Disease Definition": "A rare vulvar carcinoma characterized by a slowly growing ulcer or nodule which is histologically composed of demarcated nests of palisaded basal cells originating at the epidermal-dermal junction. Occasionally, the tumor may be extensively pigmented. Patients most commonly present with pruritus. The lesion is usually treated by local excision, although groin metastases have been reported.", "ORPHA ID": 494451, "Summary": ""}
{"Disease Name": "Vulvar carcinoma", "Disease Definition": "A group of rare tumors of the vulva comprising HPV-associated and HPV-independent squamous cell carcinomas as the most frequent malignant vulvar tumors, basal cell carcinomas, adenocarcinomas, and Bartholin gland carcinomas. Depending on the type of tumor and disease stage, patients may present with a painless vulvar mass or ulcer, or with pruritus, a burning sensation, pain, or bleeding.", "ORPHA ID": 494418, "Summary": ""}
{"Disease Name": "Vulvar intraepithelial neoplasia", "Disease Definition": "A rare vulvovaginal tumor characterized by intraepithelial neoplastic proliferation of the vulvar epithelium, histologically presenting proliferation of atypical basal cells with basal layer involvement, enlarged nuclei, hyperchromasia, pleomorphic cells and increased numbers of mitotic figures. Patients are frequently asymptomatic, although vulvar pruritus/pain/burning, dysuria and/or dyspareunia may be associated. Concurrent anogenital involvement is frequent. Two subtypes, usual type VIN (uVIN) and differentiated type VIN (dVIN) exist, with uVIN typically being associated with HPV infection and presenting multifocal, elevated lesions around the introitus and/or labia majora, and dVIN being related to chronic inflammation and lesions consisting of poorly demarcated pink or white plaques that are often associated with lichen sclerosus or lichen planus. Diffusely positive p16 immunohistochemistry and high Ki-67 proliferation index in uVIN futher differentiates this subtype from dVIN, this latter being consistently negative for p16 while presenting p53 positivity.", "ORPHA ID": 137583, "Summary": ""}
{"Disease Name": "Vulvar squamous cell carcinoma", "Disease Definition": "A rare vulvar carcinoma characterized by an ulcer, nodule, macule, or pedunculated mass which is histologically composed of infiltrating islands of malignant squamous cells. Histological subtypes include keratinizing, non-keratinizing, basaloid, warty, and verrucous carcinomas. Some tumors are associated with human papilloma virus, smoking, high grade squamous intraepithelial lesion, chronic vulvar inflammatory disorders, or differentiated vulvar intraepithelial neoplasia. Patients may present with discharge, bleeding, or pain. Most important prognostic features are tumor depth and lymph node status.", "ORPHA ID": 494448, "Summary": ""}
{"Disease Name": "Vulvovaginal gingival syndrome", "Disease Definition": "A rare, non-malformative vulvovaginal disease characterized by a combination of erosive or desquamative lichen planus (LP) of vulval, vaginal and gingival mucosae, with a high propensity for scarring and stricture formation. Additional sites of involvement are frequently observed (in particular, tongue, buccal mucosae, skin and perianal LP). Patients may be asymptomatic or, more commonly, present with pain, burning, discomfort and bleeding, dyspareunia, and seropurulent vaginal discharge.", "ORPHA ID": 83453, "Summary": ""}
{"Disease Name": "Vulvovaginal rhabdomyosarcoma", "Disease Definition": "Vulvovaginal rhabdomyosarcoma is a rare vulvovaginal tumour, a highly malignant soft tissue sarcoma composed of cells with round to oval or spindle-shaped nuclei and eosinophilic cytoplasm that may show differentiation towards striated muscle cells. It usually affects children and presents with a vulvar or vaginal mass that may be polypoid or grape-like (embryonal subtype) and associated with bleeding and ulceration.", "ORPHA ID": 206492, "Summary": ""}
{"Disease Name": "W syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by moderate to severe intellectual disability, neurologic signs and symptoms (such as seizures, spasticity, strabismus), characteristic dysmorphic facial features (including broad forehead, hypertelorism, downslanting palpebral fissures, broad and flat nasal bridge, midline notch of upper lip, lack of upper central incisors, incomplete oral cleft, and prominent mandible), and acne scars. Hearing impairment, pseudo-bulbar palsy, growth retardation, and skeletal anomalies (camptodactyly, clinodactyly, bilateral cubitus valgus, pes cavus/planus) have also been described.", "ORPHA ID": 2804, "Summary": ""}
{"Disease Name": "Waardenburg syndrome type 1", "Disease Definition": "A subtype of Waardenburg syndrome (WS) characterized by congenital deafness, minor defects in structures arising from neural crest resulting in pigmentation anomalies of eyes, hair, and skin, in combination with dystopia canthorum.", "ORPHA ID": 894, "Summary": "Epidemiology\nThe prevalence of WS1 is unknown; the worldwide prevalence of WS is estimated at around 1/40,000. WS1 is one of the most common types of WS.\nClinical description\nClinical manifestations vary within and between families and frequently include congenital sensorineural deafness, which is often a non-progressive profound bilateral hearing loss, dystopia canthorum, heterochromic or hypoplastic blue irides, white forelock, typically in the midline or early graying of the scalp hair before age 30 years. All these manifestations along with a suggestive family history are major criteria. Minor criteria include congenital leukoderma, synophrys/medial eyebrow flare, broad/high nasal root with prominent columella, hypoplastic alae nasi. Spina bifida can also occur in rare cases.\nEtiology\nWS is genetically heterogeneous. WS1 is caused by a heterozygous mutation in the paired box-containing PAX3 gene on chromosome 2q36.1. This syndrome is secondary due to the absence of melanocytes in the skin, hair, eyes and the striavascularis ductus cochlearis and a consequence of abnormal migration of cells derived from the neural crest.\nDiagnostic methods\nOver 90% of cases who meet diagnostic criteria for WS1 have identifiable mutations in PAX3. WS1 is defined by the association of at least 2 major, or 1 major and at least 2 minor clinical criteria, as delineated by the Waardenburg Consortium criteria, including dystopia canthorum. The distance between the inner canthi, pupils, and outer canthi calculates a W index for the diagnosis of lateral displacement of the inner canthi. A W index of more than 1.95 shows dystopia. Dystopia canthorum may be difficult to characterize in babies but is the most penetrant sign.\nDifferential diagnosis\nDifferential diagnosis includes Waardenburg syndrome type 2, 3 and 4, piebaldism, Tietz syndrome, oculocutaneous albinism, Vogt-Koyanagi-Harada disease(see these terms) and other forms of congenital non-progressive sensorineural hearing loss.\nGenetic counseling\nIn the majority of cases, WS1 is transmitted as an autosomal dominant disorder with a large variable inter- and intrafamilial expressivity. Some affected patients present with a de novo mutation.\nManagement and treatment\nHearing aids to counter hearing loss and effective therapy to improve language, communication, and cognitive skill are recommended. Associated manifestations are treated as appropriate (e.g. cosmetics to manage the pigmentation defects).\nPrognosis\nWith hearing aids, prognosis is good for most WS1 affected individuals.\n\n                            Last update: \n                            October 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Véronique PINGAULT"}
{"Disease Name": "Waardenburg syndrome type 2", "Disease Definition": "An autosomal dominant subtype of Waardenburg syndrome (WS) characterized by varying degrees of deafness and pigmentation anomalies of eyes, hair and skin, but without dystopia canthorum.", "ORPHA ID": 895, "Summary": "Epidemiology\nThe prevalence of WS2 is unknown; the worldwide prevalence of WS is estimated at around 1/40,000. WS2 is one of the most common types of Waardenburg syndrome.\nClinical description\nClinical manifestations for WS2 resemble those of Waardenburg syndrome type 1 (WS1; see this term). Sensorineural hearing loss (77%) and heterochromia iridum (47%) are the two most important clinical features for WS. In addition, individuals with WS2 lack dystopia canthorum and are usually more frequently affected by hearing loss and heterochromia iridum. In some cases (mutation in SOX10 gene), patients may present associated signs of Kallmann syndrome (anosmia, hypogonadism; see this term) and/or neurological defects (neurological Waardenburg syndrome).\nEtiology\nWS2 is genetically very heterogeneous and still much of the etiology of WS2 remains elusive. Mutations have been found in MITF (3p14-p13; subtype designated as WS2A), SNAI2 (8q11.21; WS2D), and SOX10 (22q13.1; WS2E) genes. Furthermore WS2 loci have been mapped to chromosome 1p21-p13.3 (subtype designated as WS2B) and to chromosome 8p23 (designated as WS2C). Digenic inheritance of MITF mutation in combination a TYR mutation (and/or the TYRR402Qhypomorphic allele) has been reported in two families with WS2 and ocular albinism.\nDiagnostic methods\nDiagnosis is determined by the presence of major and minor characteristic clinical features according to the Waardenburg Consortium criteria, as well as by genetic testing.\nDifferential diagnosis\nDifferential diagnosis includes Waardenburg syndrome type 1 and 4, piebaldism, Tietz syndrome, oculocutaneous albinism (see these terms) and other forms of congenital non-progressive sensorineural hearing loss.\nGenetic counseling\nIn the majority of cases, WS2 is transmitted as an autosomal dominant disorder with a large variable inter- and intrafamilial expressivity. Some affected patients present with a de novo mutation.\nManagement and treatment\nHearing aids to counter hearing loss and effective therapy to improve language, communication, and cognitive skill are recommended. Pigmentation defects do not require medical care but cosmetic products are available. Rarely, in case of extended depigmentation, care is taken to protect the skinand eyesfrom the sun.\nPrognosis\nWith hearing aids, prognosis is good for most affected individuals with WS2.\n\n                            Last update: \n                            October 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Véronique PINGAULT"}
{"Disease Name": "Waardenburg syndrome type 3", "Disease Definition": "A very rare subtype of Waardenburg syndrome (WS) that is characterized by limb anomalies in association with congenital hearing loss, minor defects in structures arising from neural crest, resulting in pigmentation anomalies of eyes, hair, and skin.", "ORPHA ID": 896, "Summary": "Epidemiology\nIncidence is unknown, but WS3 is the rarest form of all Waardenburg syndrome types.\nClinical description\nWS3 is characterized by the association of limb anomalies (predominantly involving upper limbs, with hypoplasia of the musculoskeletal system, flexion contractures, fusion of the carpal bones, syndactylia) with features of Waardenburg syndrome (see this term), which include congenital sensorineural hearing loss, hypopigmentation abnormalities of irides, hair and skin and minor facial dysmorphism in combination with dystopia canthorum.\nEtiology\nWS3 is caused by heterozygous or homozygous mutations in the PAX3 (2q36.1) gene.\nDiagnostic methods\nDiagnosis is made through criteria of the association of WS1 manifestations with limb anomalies. PAX3 gene analysis confirms diagnosis resulting in an abnormality of melanocytes of skin, ears and hair.\nAntenatal diagnosis\nAntenatal diagnosis is possible for affected parents.\nGenetic counseling\nThe defects are more severe in homozygous than heterozygous forms. Genetic counseling is recommended.\nManagement and treatment\nHearing aids to counter hearing loss, effective therapy to improve language, communication, and cognitive skill and limbs physiotherapy are recommended. Associated manifestations are treated as appropriate (e.g. skin and eyes protection from the sun).\nPrognosis\nDue to the very few number of cases described so far, information on prognosis and quality of life is limited. Disease progression is variable, with symptoms being more severe in homozygous than in heterozygous forms.\n\n                            Last update: \n                            October 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Véronique PINGAULT"}
{"Disease Name": "Waardenburg syndrome", "Disease Definition": "Waardenburg syndrome (WS) is a disorder characterized by varying degrees of deafness and minor defects in structures arising from neural crest, including pigmentation anomalies of eyes, hair, and skin. WS is classified into four clinical and genetic phenotypes.", "ORPHA ID": 3440, "Summary": "Epidemiology\nThe worldwide incidence is estimated at around 1/40,000. Waardenburg syndrome type 1 (WS1) and type 2 (WS2) are the most common types of Waardenburg syndrome. Waardenburg syndrome type3 (WS3) and type 4 (WS4; see these terms) are rarer, with only a few cases of WS3 described worldwide so far. WS accounts for about 3% of all institutionalized cases of congenital hearing loss.\nClinical description\nClinical manifestations vary within and between families. Frequent clinical manifestations include congenital sensorineural deafness, heterochromic or hypoplastic blue irides, white forelock or early graying of the scalp hair before the age of 30 years. All these manifestations, along with a suggestive family history are major criteria, as is dystopia canthorum in WS1 and WS3. Minor criteria include congenital leukoderma, synophrys/medial eyebrow flare, broad/high nasal root with prominent columella and hypoplastic alae nasi. WS is defined by the association of at least 2 major, or 1 major and at least 2 minor clinical criteria (early graying of the hair is considered either a major or minor criteria depending of the WS type). WS1 combines these criteria with dystopia canthorum. The absence of dystopia canthorum clinically differentiates WS2 from WS1, whereas WS3 is similar to WS1, but additionally includes upper limb abnormalities. WS4 is characterized as WS2 with added characteristics of Hirschsprung disease.\nEtiology\nWS is genetically heterogeneous. To date, mutations in 6 different genes have been identified: PAX3 (2q36.1), MITF (3p14-p13), SNAI2 (8q11.21), SOX10 (22q13.1), EDNRB (13q22.3), and EDN3 (20q13.32). Mutations in PAX3 gene are associated with WS1 and WS3, while MITF gene is mutated in cases of WS2. Digenic inheritance of MITF mutation in combination with a TYR mutation (and/or the TYRR402Q hypomorphic allele) has been reported in two families with WS2 and ocular albinism (see this term). Homozygous SNAI2 deletions have been described in two WS2 patients. SOX10 mutations are found in WS4 and WS2 affected patients. Mutations in EDNRB and EDN3 genes have also been reported in WS4.\n\n                            Last update: \n                            November 2015\n\n\n                            - Expert reviewer(s): \n                            Dr Véronique PINGAULT"}
{"Disease Name": "Waardenburg-Shah syndrome", "Disease Definition": "Waardenburg-Shah syndrome (WSS), also known as Waardenburg syndrome type 4 (WS4) is characterized by the association of Waardenburg syndrome (sensorineural hearing loss and pigmentary abnormalities) and Hirschsprung disease (aganglionic megacolon).", "ORPHA ID": 897, "Summary": "Epidemiology\nPrevalence is unknown. So far, less than 100 cases have been reported in the literature worldwide.\nClinical description\nPatients usually present in the neonatal period with pigmentary anomalies (including white forelock, eyebrows and eyelashes, heterochromia of the irides, possibly retinal pigment abnormalities and/or hypopigmented patches on the skin), neurosensory deafness (frequently bilateral, but can be unilateral) and intestinal obstruction presenting as bilious vomiting, inability to pass meconium and abdominal distension since birth. Depending on the gene involved, morphological abnormalities of the temporal bone (especially utricle and semi-circular canals), anosmia (with or without agenesis of the olfactory bulbs) and hypogonadotropic hypogonadism can be associated. ABCD syndrome is a rare variant expression of WSS, characterized by albinism, black lock, cell migration disorder of the gut neurocytes and deafness.\nEtiology\nWSS is caused by abnormal migration or differentiation of neural crest cells during embryonic development. This syndrome is genetically heterogeneous, composed of three etiological subtypes: WS4-A, WS4-B and WS4-C, caused by mutations in the EDNRB (13q22.3, coding for the endothelin-B receptor), EDN3 (20q13.32, coding for an endothelin receptor ligand) and SOX10 (22q13.1, coding for the SOX10 transcription factor) genes, respectively. These genes are involved in melanocyte development and nerve cells development in the intestine. Heterozygous mutations in EDNRB and EDN3 are often asymptomatic although patients may also present with less severe phenotypes (isolated Hirschsprung disease, isolated deafness, less extended hypopigmentation, or Waardenburg syndrome type 2). Specific mutations in SOX10 (particularly those predicted to truncate the protein at the level of the terminal coding exons) result in a more severe WSS variant with neurologic findings (neurologic Waardenburg-Shah syndrome, also called PCWH).\nDiagnostic methods\nDiagnosis is determined by the presence of major and minor characteristic clinical features according to the Waardenburg Consortium criteria, as well as history and physical examination for Hirschsprung disease utilizing plain abdominal X-ray, barium enema, anorectal manometry and rectal biopsy. Genetic molecular analysis confirms the diagnosis.\nDifferential diagnosis\nThe differential diagnosis includes other forms of Waardenburg syndrome, piebaldism and ermine phenotype, as well as other causes of hearing loss or Hirschsprung disease.\nAntenatal diagnosis\nMolecular prenatal diagnosis may be proposed to families in which the disease-causing mutation has been identified.\nGenetic counseling\nGenetic counseling should be adapted according to the mode of inheritance associated with the detected mutation. SOX10 mutations are inherited in an autosomal dominant manner. EDNRB and EDN3 mutations are inherited in an autosomal recessive manner in most families but are semi-dominant in some (with the index case usually carrying bi-allelic mutations, while heterozygous affected relatives present with isolated or milder signs of the disease).\nManagement and treatment\nManagement is only symptomatic. Surgical treatment is required for Hirschsprung disease. Hearing aids are recommended to ameliorate hearing impairment, as well as to improve language, communication and cognitive skills. Associated manifestations are treated as appropriate (e.g., cosmetics to manage the pigmentation defects, sunblock and sunglasses to protect skin and eyes from the sun).\nPrognosis\nThe prognosis is often good, however, significant morbidity and mortality may be associated due to complications resulting from Hirschsprung disease (related to the size of the aganglionic intestinal segment).\n\n                            Last update: \n                            March 2018\n\n\n                            - Expert reviewer(s): \n                            Dr Véronique PINGAULT"}
{"Disease Name": "WAC-related facial dysmorphism-developmental delay-behavioral abnormalities syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability characterised by several dysmorphic features, hypotonia, developmental delay, intellectual disability, behavioral problems, visual and hearing abnormalities, constipation, and feeding difficulties. Common dysmorphic features include coarse facies, broad forehead, synophrys, bushy eyebrows, deep-set eyes, downslanting palpebral fissures, epicanthus, depressed nasal bridge, bulbous nasal tip, posteriorly rotated ears, full cheeks, thin upper lip, inverted nipples, and hirsutism. Behavioral problems tend to be dominated by ADHD, but anxiety, aggressive outbursts and autistic features may also present.", "ORPHA ID": 466943, "Summary": ""}
{"Disease Name": "Wagner disease", "Disease Definition": "Wagner disease is a rare hereditary vitreoretinopathy characterized by an anomaleous vitreous associated with myopia, cataract, chorioretinal atrophy, and peripheral tractional or rhegmatogenous retinal detachment.", "ORPHA ID": 898, "Summary": "Epidemiology\nAbout 100 patients with Wagner syndrome from only a few pedigrees have been described in the literature.\nClinical description\nAffected patients typically exhibit low or moderate myopia, with only a few suffering from severe myopia. The disease has a juvenile onset with progressive nyctalopia and visual field constriction. Presenile cataract is a frequent cause of reduced central visual acuity. The hallmark of the disease is an optically empty central vitreous cavity and the presence of typical peripheral vitreous changes with fibrillary condensations, avascular strands and veils. The peripheral retina is progressively affected by pigmentary changes and chorioretinal atrophy. An abnormal pattern of dragged central retinal vessels (sometimes referred to as inverted papilla) and eventually pseudoexotropia due to an ectopic fovea are a common finding, usually not attributable to peripheral retinal traction. Retinal detachment is a relatively common complication in Wagner disease, the reported incidence rate varying from 7% to 50%. In a few patients, rhegmatogenous retinal detachment is due to flap tears or atrophic holes and occurs typically at a young age. More frequently, peripheral tractional retinal detachment is observed, occuring typically in middle-aged patients. In some cases, anterior chamber angle dysgenesis is observed.\nEtiology\nWagner disease is a connective tissue disorder affecting the collagen and is associated with mutations in the CSPG2 or VCAN gene (5q13-q14). CSPG2 encodes chondroitin sulfate proteoglycan-2, also known as versican. Versican constitutes 5-15% of the total protein content of the vitreous gel. It is a large proteoglycan that forms large complexes by binding to hyaluronic acid and other vitreous structural molecules. Erosive vitreoretinopathy (ERVR), originally described as a distinct clinical entity, is an allelic disease, and the same intronic mutation in GSPG2 has been found in a family with ERVR and four families with Wagner disease.\nDiagnostic methods\nDiagnosis is based on the clinical picture. Molecular testing of CSPG2 mutations confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes Stickler syndrome, Goldmann-Favre disease, Familial Exudative Vitreoretinopahy, and Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) (see these terms).\nGenetic counseling\nWagner disease is inherited as an autosomal dominant trait with near complete penetrance but variable expressivity.\nManagement and treatment\nRegular ophthalmologic examinations should be performed. Retinal breaks without retinal detachment are treated by prophylactic laser- or cryocoagulation. For rhegmatogenous retinal detachment in a young patient, scleral buckling surgery or, less often, vitrectomy is performed. Tractional retinal detachment in the middle-aged or elderly patient requires often a combined procedure. Presenile cataract is treated by phacoemulsification and implantation of an artificial intraocular lens.\nPrognosis\nOverall prognosis seems to be moderate. In the original pedigree described by Wagner, about 50% of the affected members retained a useful vision of more than 20/40 after the age of 60.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph AMSTUTZ"}
{"Disease Name": "WAGR syndrome", "Disease Definition": "A rare genetic disorder characterized by the association of complete or partial congenital aniridia (and associated eyes abnormalities), genitourinary anomalies (ranging from sexual ambiguity to ectopic testis), variable degrees of intellectual disability and an increased risk of developing Wilms tumors. A minority of patients develop kidney failure. Other variable findings may include obesity and duplicated halluces.", "ORPHA ID": 893, "Summary": "Epidemiology\nThe prevalence of WAGR syndrome is approximately 1/500,000-1,000,000 people. There is no male or female predominance.\nClinical description\nThe disease has a broad range of clinical manifestations; most affected patients present with ≥ 2 clinical features. Onset is at birth, but it may be diagnosed at a later age, as clinical features can be hard to detect or do not show in many patients. Congenital aniridia of variable severity is almost systematically present at birth, and is often associated with other eye abnormalities such as cataract, glaucoma, limbal insufficiency, optic nerve hypoplasia, and corneal opacification/vascularization, leading to visual impairment. Some patients are at risk of developing end-stage renal disease, especially when presenting with Wilms tumor (45-60% of patients). Bilateral synchronous kidney tumors are the most common (4-7% of all Wilms tumors) and generally present at a younger age than unilateral tumors (< 5 years old). Patients may also present with genitourinary anomalies or neurological abnormalities, and variable intellectual disability or behavioral abnormalities. A large number of affected patients develops obesity. However, WAGR syndrome with childhood-onset obesity is called WAGRO syndrome.\nEtiology\nWAGR syndrome is a contiguous gene deletion syndrome involving an interstitial de novo 11p13 microdeletion of variable size (from 1 million to 26.5 million base pairs), which explains the variability of clinical signs. The affected genes include PAX6 and WT1. BDNF deletion can be included and is associated to the WAGRO phenotype.\nDiagnostic methods\nDiagnosis is based on clinical signs and may be delayed as some manifestation develop late or are easier to detect in the adult. Congenital aniridia in infants should prompt genetic testing to detect the specific deletions associated with the patient's phenotype and invalidate or confirm WAGR syndrome.\nDifferential diagnosis\nThe main differential diagnoses are isolated aniridia, anterior segment developmental abnormalities of the eye (e.g. Axenfeld-Rieger syndrome, coloboma of iris), aniridia-cerebellar ataxia-intellectual disability syndrome (also called Gillespie syndrome), Frasier syndrome, and Denys-Drash syndrome.\nAntenatal diagnosis\nPrenatal diagnosis is possible in very rare familial cases when mutations/deletions have been identified.\nGenetic counseling\nMost cases are sporadic. In rare cases, the syndrome can be inherited in an autosomal dominant manner. In such cases, affected individuals should be offered genetic counseling informing them of the 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nManagement and treatment are complex and require a multidisciplinary approach. Supportive measures should be provided for visual impairment and light sensitivity. Medical or surgical intervention may be required for eye abnormalities such as cataract, glaucoma or corneal complications. Surgery, chemotherapy and radiotherapy can be recommended for the treatment of tumors. Patients require lifelong oncological and ophthalmologic monitoring. Transplantation may be required for renal disease. The management of obesity has no specificity. Patients and their family often need psychological support, and patients may be enrolled in special education program.\nPrognosis\nWAGR syndrome is associated with significant morbidity (vision loss and intellectual disability). The development of Wilms tumors is the main factor of early mortality. With early detection and appropriate treatment, the prognosis is improved.\n\n                            Last update: \n                            September 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Dominique BREMOND-GIGNAC | ERN-EYE*\n\n\n                                * European Reference Network"}
{"Disease Name": "Waldenström macroglobulinemia", "Disease Definition": "Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoproliferative disorder characterized by the accumulation of monoclonal cells in the bone marrow and peripheral lymphoid tissues, and associated with the production of serum immunoglobulin M (IgM) monoclonal protein.", "ORPHA ID": 33226, "Summary": "Epidemiology\nWM has an overall incidence of 1/260,000 persons/year in the USA and a prevalence estimate of about 1/102,220 in Europe. It accounts for approximately 2% of all hematological malignancies.\nClinical description\nThe median age at diagnosis is 72 years and it is twice as frequent in men. The main clinical features are hepatosplenomegaly, lymphadenopathy, constitutional symptoms, oronasal bleeding, hyperviscosity syndrome and cytopenia. Fatigue related to normochromic normocytic anemia is the most common presenting symptom. Visceral infiltration is rare but may target the stomach, small bowel, lungs, exocrine glands or skin, accounting for such symptoms as diarrhea, steatorrhea and purpura of the skin. Retinal hemorrhage or serious neurologic complications (mental confusion, stroke) may occur in cases with hyperviscosity syndrome. Peripheral neuropathy is present in up to 38% of WM patients. Nephrotic syndrome has been associated with WM in a few cases. Major complications include bone marrow failure, autoimmune cytopenia, large B-cell lymphoma, immune complex vasculitis and infections.\nEtiology\nExact etiology is unknown. Immune-related factors are thought to be involved and WM clearly has a familial component as first degree relatives of WM patients have an increased risk of developing the disease. No susceptibility genes have yet been identified but susceptibility loci have been mapped to chromosome 6p21.3 and 4q and half of WM patients have 6q deletions on tumor cells. A highly recurrent MYD88 (3p22) somatic mutation (L265P) has recently been identified in 90% of WM patients.\nDiagnostic methods\nDiagnosis is confirmed by the presence of an IgM monoclonal protein in the serum and a bone marrow biopsy (showing ≥10% clonal lymphoplasmacytic cells). WM's pathologic designation is lymphoplasmacytic lymphoma according to the WHO Classification of Tumors. Cells test negative for CD3 and CD103 markers but express pan B cell markers CD19 and CD20. The median hemoglobin value seen at diagnosis is 10g/dL. Serum protein electrophoresis and immunofixation as well as computed tomography (CT) of abdomen and pelvis contribute to diagnosis. Splenomegaly and/ or lymphadenopathies are observed in 30% of the patients.\nDifferential diagnosis\nDifferential diagnoses include multiple myeloma, B-cell chronic lymphocytic leukemia, other forms of non-Hodgkin lymphoma (see these terms), and monoclonal gammapathies of undetermined significance. Infections like hepatitis, AIDS, and various rheumatological disorders also raise IgM levels. The presence of a MYD88 L265P mutation distinguishes WM from other closely-related B-cell chronic lymphoproliferative disorders such as marginal zone lymphoma without IgM spike.\nManagement and treatment\nThere is no cure for WM. Patients in an asymptomatic stage are simply monitored. Treatments given to symptomatic patients depend on many factors (e.g. age, disease progression) and can include alkylating agents, purine nucleoside analogs, rituximab (RT) and bortezomib. Initial treatment is usually an RT-based therapy like RT plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or dexamethasone, RT and cyclophosphamide (DRC). Bortezomib-based therapies are used when rapid disease control is needed or for patients who are candidates for autologous stem cell transplantation (ASCT). For those with profound cytopenias, DRC or RT is preferable. Salvage treatments can involve the use of the initial agents or agents of a different class, alone or combined. A PNA-based regimen or ASCT may be suitable for some as a salvage treatment option. Ibrutinib, a B-cell receptor pathway inhibitor, has recently been approved for symptomatic WM patients as a first-line treatment, particularly for those who are not candidates for chemo-immunotherapy, and in relapsing patients.\nPrognosis\nMedian survival time is 5-6 years after starting treatment but WM can be stable or progress slowly for many years before needing treatment.\n\n                            Last update: \n                            March 2016\n\n\n                            - Expert reviewer(s): \n                            Pr Véronique LEBLOND"}
{"Disease Name": "Walker-Warburg syndrome", "Disease Definition": "A rare form of congenital muscular dystrophy (CMD) associated with severe brain and eye abnormalities. It is the most severe form of CMD.", "ORPHA ID": 899, "Summary": "Epidemiology\nThe incidence is estimated at 1-2/100,000 live births. Walker-Warburg Syndrome (WWS) has a worldwide distribution.\nClinical description\nPatients present with global developmental delay, intellectual disability, generalized severe hypotonia, muscle weakness, seizures, and various eye defects which include microphthalmia, microcornea, lens defects, cataract, shallow anterior chamber, atrophy of the optic nerve, coloboma, glaucoma or buphthalmos. Brain MRI shows type II cobblestone lissencephaly in all cases, and may also show hydrocephalus, encephalocele, severe brainstem, and cerebellar hypoplasia with possible Dandy-Walker malformation. The corpus callosum is absent in some patients. White matter abnormalities can also be observed. Other urogenital or facial dysmorphic features can be found in rare patients.\nEtiology\nThis disease caused by abnormal O-glycosylation of alpha-dystroglycan leading to brain abnormalities and congenital muscular dystrophy. At least 14 genes have been implicated in the etiology of WWS, and others are yet unknown. The most common mutations are found in Protein O-Mannosyltransferase 1 and 2 (POMT1 and POMT) genes, FKTN, and FKRP genes. LARGE and POMGNT1 genes from the alpha-dystroglycan glycosylation pathway were also linked to this disease. A mutation in the COL4A1 gene not directly related to posttranslational modification of dystroglycan has also been identified in some WWS patients without associated muscle involvement.\nDiagnostic methods\nDiagnosis is based on ultrasonography and fetal MRI for ocular and brain abnormalities. Laboratory investigations usually show elevated creatine kinase and myopathic/dystrophic muscle pathology with altered alpha-dystroglycan expression.\nDifferential diagnosis\nDifferential diagnoses include other types of congenital muscular dystrophies and myopathies with type II lissencephaly. Trisomy 13, 18 and many congenital syndromes with malformations of the brain also have similar clinical manifestations. Some in utero infections can also be associated with hydrocephaly, intrauterine growth restriction, and cataract.\nAntenatal diagnosis\nAntenatal diagnosis is possible in families with known mutations. Prenatal ultrasound after 22-25 weeks of gestational age (WGA) and fetal MRI at 30 WGA may be helpful for diagnosis in families where the molecular defect is unknown.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nNo specific treatment is available. Management is only supportive and preventive. Surgery is required in some patients for the treatment of hydrocephalus or encephalocele.\nPrognosis\nWWS is the most severe form of congenital muscular dystrophy. It is generally lethal in the first few months of life with most children dying before the age of three years.\n\n                            Last update: \n                            January 2023\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI | EURO-NMD* - Pr Susana QUIJANO-ROY | EURO-NMD*\n\n\n                                * European Reference Network"}
{"Disease Name": "WARS2-related combined oxidative phosphorylation defect", "Disease Definition": "A rare mitochondrial oxidative phosphorylation disorder characterized by a spectrum of three main clinical phenotypes comprising a severe neonatal phenotype with early fatal lactic acidosis, a more protracted course with early-onset developmental delay, motor weakness, extrapyramidal signs, and with or without epilepsy, and a phenotype with normal early development and Parkinson-like symptoms starting around the age of one year. Additional, variably reported, signs and symptoms include cardiomyopathy, optic anomalies, hepatosplenomegaly, and abnormal brain MRI findings, among others. Deficiencies in mitochondrial oxidative phosphorylation enzymes are inconsistent.", "ORPHA ID": 572798, "Summary": ""}
{"Disease Name": "Warsaw breakage syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by pre- and postnatal growth restriction, microcephaly, mild to severe intellectual disability, sensorineural hearing loss with cochlear abnormalities, and facial dysmorphism (with small and elongated face, bifrontal narrowing, epicanthus, short nose, small nares, dysplastic ears, and short neck). Additional variable features include limb malformations, cardiac anomalies, abnormal skin pigmentation, and recurrent infections, among others.", "ORPHA ID": 280558, "Summary": ""}
{"Disease Name": "Warts-immunodeficiency-lymphedema-anogenital dysplasia syndrome", "Disease Definition": "A rare primary lymphedema characterized by extensive, multisegmental lymphedema, associated with persistent, widespread infections with various genital high- and low-risk human papillomaviruses, resulting in multifocal anogenital dysplasia. Laboratory examination shows abnormalities in lymphocyte subsets, in particular CD4+ T-cells. Epidermal nevi and capillary malformations have also been reported.", "ORPHA ID": 568056, "Summary": ""}
{"Disease Name": "Warty dyskeratoma", "Disease Definition": "A rare, benign, epidermal disease characterized by a solitary, asymptomatic, verrucous, skin-coloured to red-brown papule or nodule, which contains a central pore and keratotic plug, occuring most frequently on the scalp, face and neck (rarely, in the mouth, under the nail plate or on the mons pubis). Occasionally, lesions may be multiple and/or pruritic. Histologically, a well-circumscribed, cup-shaped, keratin-filled invagination, with prominent acantholytic dyskeratosis, suprabasilar clefts and villi projecting into the clefts, is observed.", "ORPHA ID": 69745, "Summary": ""}
{"Disease Name": "Weaver syndrome", "Disease Definition": "Weaver syndrome (WVS) is a rare, multisystem disorder characterized by tall stature, a typical facial appearance (hypertelorism, retrognathia) and variable intellectual disability. Additional features may include camptodactyly, soft doughy skin, umbilical hernia, and a low hoarse cry.", "ORPHA ID": 3447, "Summary": "Epidemiology\nAround 50 cases of Weaver syndrome have been reported to date. Precise prevalence and incidence rates are not available.\nClinical description\nWVS is an overgrowth disorder that covers a very wide clinical spectrum: some affected individuals have only tall stature while others have a classic Weaver clinical picture. Tall stature (≥ two standard deviations above the mean) is found in 90% of mutation-positive individuals and most affected patients have higher than normal birth weight and length. The subtle but characteristic facial appearance is most easily recognized in early childhood when there is ocular hypertelorism, large fleshy ears and retrognathia with the appearance of a ''stuck-on'' chin with associated horizontal skin crease. About 80% of patients have mild intellectual disability. A smaller number have moderate intellectual disability with a greater impact on autonomy, while severe deficits are rare. Other variable features include macrocephaly, joint laxity, mild to severe scoliosis, pectus excavatum, hypo- and/or hypertonia, poor coordination, soft skin, clinodactyly, camptodactyly of the fingers and/or toes, umbilical hernia, and a hoarse low cry in infancy. A slightly higher risk of neuroblastoma is suspected. There is currently no data to support an increased risk of other malignancies.\nEtiology\nWVS is caused by mutations in the EZH2 gene (7q35-q36), a histone methyltransferase involved in transcription control. Currently there are no other known causes of WVS although there has been a single case report of an individual in whom there was a clinical suspicion of WVS and a mutation within EED, which complexes with EZH2.\nDiagnostic methods\nThe clinical suspicion of WVS is confirmed through molecular genetic testing and the identification of a heterozygous germline mutation in EZH2. Given the subtle phenotype associated with WVS, if a germline EZH2 mutation is not identified, alternative diagnoses should be sought.\nDifferential diagnosis\nThe main differential diagnosis is Sotos syndrome (see this term) which has considerable overlap with WVS. Other disorders to consider include Beckwith-Wiedemann, Simpson-Golabi-Behmel, Malan overgrowth, tall stature-intellectual disability-facial dysmorphism and Marfan syndromes (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis in at-risk pregnancies is possible.\nGenetic counseling\nWVS follows an autosomal dominant pattern of inheritance although the majority of cases to date have arisen de novo. Genetic counseling should be provided to affected families.\nManagement and treatment\nThere is no specific treatment for WVS although individual symptom management may be indicated. No specific tumor surveillance is currently recommended but clinical vigilance and early investigation for possible tumor (particularly neuroblastoma)-related symptoms are recommended.\nPrognosis\nWith suitable treatment and support, patients with WVS have a normal life.\n\n                            Last update: \n                            January 2016\n\n\n                            - Expert reviewer(s): \n                            Dr Katrina TATTON BROWN"}
{"Disease Name": "Weaver-Williams syndrome", "Disease Definition": "Weaver-Williams syndrome is a multiple congenital anomalies syndrome characterized by moderate-to-severe intellectual disability, decreased muscle mass, microcephaly, facial dysmorphism (prominent ears, midfacial hypoplasia, small mouth and cleft palate), clinodactyly of the fingers, delayed osseous maturation and generalized bone hypoplasia. The syndrome has been described in a brother and sister and an autosomal recessive mode of inheritance has been suggested. There have been no further descriptions in the literature since 1977.", "ORPHA ID": 3448, "Summary": ""}
{"Disease Name": "Weill-Marchesani syndrome", "Disease Definition": "Weill-Marchesani syndrome (WMS) is a rare condition characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities including microspherophakia, ectopia of the lens, severe myopia, and glaucoma.", "ORPHA ID": 3449, "Summary": "Epidemiology\nThe prevalence is not documented. Short stature (usually below the third percentile) and brachydactyly are present in 98% of patients.\nClinical description\nThe following frequencies of ophthalmological manifestations are observed: myopia 94%, microspherophakia 84%, ectopia lentis 73%, glaucoma 80%, and cataract 23%. Other features include joint limitations, muscular build, thickened skin, and cardiac abnormalities (pulmonary valve stenosis, mitral valve insufficiency, aortic valve stenosis, ductus arteriosus, and ventricular septal defect). Intellectual deficit has been reported in 13% of cases and is always mild.\nEtiology\nBoth autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described. The AR mode of inheritance appears to be more frequent and homozygous mutations within the ADAMTS10 gene (19p13.3-p13.2) have been found. ADAMTS10 is a member of the extracellular matrix protease family and is expressed in skin, fetal chondrocytes, and fetal and adult hearts. Electron microscopy and immunological studies of skin fibroblasts from WMS patients suggest that the syndrome is associated with impairment of the extracellular matrix. Heterozygous mutations within the FBN1 gene (15q21.1) have been identified in patients and are transmitted in an AD manner, giving another example of the large clinical expressivity of fibrillin-1.\nAntenatal diagnosis\nPrenatal diagnosis has never been reported.\nGenetic counseling\nClinical homogeneity has been demonstrated despite the genetic heterogeneity in AR and AD families. However, this leads to difficulties in genetic counseling of sporadic cases. Some heterozygotes for AR WMS present with some mild clinical manifestations of the disease, such as brachydactyly.\nManagement and treatment\nPatients should be followed for ophthalmologic complications in particular, and physiotherapy can be proposed for joint stiffness.\nPrognosis\nPrognosis is good.\n\n                            Last update: \n                            May 2006\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence OLIVIER-FAIVRE"}
{"Disease Name": "Weismann-Netter syndrome", "Disease Definition": "Weismann-Netter syndrome is a rare, genetic, primary, bent bone dysplasia characterized by anterior diaphyseal bowing of the tibia and fibula, broadening of the fibula, posterior cortical thickening of both bones and short stature. Additional skeletal abnormalities include scoliosis with marked lumbar lordosis, horizontal sacrum and square iliac wings and/or, less frequently, vertebral malformations, abnormal shape of the clavicles and ribs, calvarial hyperostosis and delayed eruption of permanent teeth. Delayed ambulation is also frequently associated.", "ORPHA ID": 3344, "Summary": ""}
{"Disease Name": "Weiss-Kruszka Syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome with variable intellectual disability characterized by abnormal head shape/metopic ridging and facial dysmorphism (which may include arched eyebrows, ptosis, downslanting palpebral fissures, epicanthal folds, and short upturned nose). Many patients present variable global developmental delay and/or autism spectrum disorder. Additional reported features are cardiac, skeletal, or urogenital anomalies. Brain imaging may show agenesis of the corpus callosum.", "ORPHA ID": 502430, "Summary": ""}
{"Disease Name": "Well-differentiated fetal adenocarcinoma of the lung", "Disease Definition": "Well-differentiated fetal adenocarcinoma of the lung is a rare, primary, low-grade, bronchopulmonary neoplasm characterized by a well-circumscribed, usually large, pulmonary mass that is histologically composed of glycogen-rich neoplastic glands and tubules that resemble fetal lungs at 10 to 16 weeks of gestation and benign adjacent stroma. It typically presents with chest pain, cough, dyspnea, hemoptysis and/or generalized, non-specific symptoms, such as night sweats, lethargy, poor appetite and weight loss.", "ORPHA ID": 284395, "Summary": ""}
{"Disease Name": "Well-differentiated liposarcoma", "Disease Definition": "Well-differentiated liposarcoma (WDLS), the most common type of liposarcoma (LS; see this term), is a slow growing, painless tumor usually located in the retroperitoneum or the limbs. It is composed of proliferating mature adipocytes.", "ORPHA ID": 99971, "Summary": "Epidemiology\nThe incidence is approximately 1/200,000 per year and it accounts for 30-50% of all liposarcomas.\nClinical description\nWDLS occurs in adulthood, most often between the ages of 50 to 60 years, and it is seen more frequently in males. A slow growing, painless mass presents most often in the retroperitoneum or the limbs but occasionally in the spermatic cord and the mediastinum. The mass can be soft and fleshy or firm. Symptoms of urinary or bowel obstruction may be experienced if the tumor is large and compresses these organs.\nEtiology\nWDLS is characterized by extensive chromosomal aberrations, which in 90% of cases include amplification of the chromosomal region 12q13-15. This amplification causes the overexpression of three genes that promote cell growth: MDM2 (that blocks p53 tumor suppressor function), CDK4 (involved in cell cycle regulation) and  HMGA2.\nDiagnostic methods\nWhen a mass is detected, computed tomography (CT) or magnetic resonance imaging (MRI) is performed. Chest and abdominal lesions do not require pretreatment biopsy unless resection is likely to be incomplete or highly morbid. Extremity lesions are generally removed completely without prior biopsy. WDLS resembles large, cohesive groups of adipocytes of varying cell size. Fluorescent in situ hybridization (FISH) and immunohistochemistry show the overexpression of MDM2 and CDK4. The four morphological subtypes of WDLS are adipocytic (lipoma-like), sclerosing, inflammatory and spindle cell.\nDifferential diagnosis\nDifferential diagnoses include benign lipomas and other types of sarcomas, inflammatory myofibroblastic tumor and Castleman disease (see these terms).\nManagement and treatment\nSurgery is the mainstay of treatment for WDLS. If tumor excision is complete, then no further therapy is recommended, although the patient should be monitored for recurrence. Complete excision is often curative if the tumor is located in an extremity. Lesions in the retroperitoneum and inguinal areas are more difficult to treat and are more likely to recur locally and transform into dedifferentiated liposarcoma (DDLS; see this term). If the tumor is unresectable (or if the excision was incomplete), systemic therapies and radiation can be proposed but have shown little efficacy. Clinical trials are ongoing to assess new therapies in patients with advanced unresectable disease (CDK4 and MDM2 inhibitor trials).\nPrognosis\nWDLS prognosis depends on the tumor location. Extremity WDLS usually has a good prognosis after the tumor has been removed, with low rates of recurrence and essentially no mortality. Retroperitoneal WDLS, however, has a 5-year probability of freedom from recurrence of only 54% and a 5-year disease-specific survival of 80 to 90%.\n\n                            Last update: \n                            January 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Samuel SINGER"}
{"Disease Name": "Wells syndrome", "Disease Definition": "Wells syndrome is characterised by the presence of recurrent cellulitis-like eruptions with eosinophilia.", "ORPHA ID": 901, "Summary": "Epidemiology\nApproximately 80 cases have been described in the literature.\nClinical description\nThe lesions are usually filled with fluid, tender and progress to form hardened plaques of edema and erythema. They usually resolve without scarring.\nDiagnostic methods\nHistological studies reveal flame figures and heavy infiltration of eosinophils and histiocytes.\nGenetic counseling\nThe syndrome is usually sporadic but familial cases have been reported.\n\n                            Last update: \n                            June 2006"}
{"Disease Name": "Werner syndrome", "Disease Definition": "Werner syndrome (WS) is a rare inherited syndrome characterized by premature aging with onset in the third decade of life and with cardinal clinical features including bilateral cataracts, short stature, graying and thinning of scalp hair, characteristic skin disorders and premature onset of additional age-related disorders.", "ORPHA ID": 902, "Summary": "Epidemiology\nThe prevalence among Japanese and Sardinian populations is estimated to be 1/50,000 due to the presence of founder mutations. Prevalence in other populations is unknown, but may be around 1/200,000.\nClinical description\nWS patients are normal at birth and during childhood, apart from the absence of a pubertal growth spurt. WS presents between the ages of 20 and 30 with major symptoms of early onset bilateral cataracts, thinning and graying of the hair, short stature and skin changes (ankle ulceration, hyperkeratosis, tight skin, age spots, ''bird-like'' facies and subcutaneous atrophy). In most cases, additional age-related disorders are seen and include osteoporosis, diabetes mellitus, mesenchymal neoplasms and atherosclerosis. Voice changes are frequent and flat feet are sometimes present. Patients with WS have a high risk of developing cancer, in particular sarcomas of mesenchymal origin and melanomas that are not due to sun exposure. Death is usually due to malignancies or myocardial infarction caused by extensive atherosclerosis.\nEtiology\nWS is caused by a mutation in the WRN gene, located on chromosome 8p11-12. WRN codes for one of the five RecQ helicases in humans. Nonsense mutations, insertions and/or deletions or substitutions in the WRN gene all lead to genome instability. Mutations in the WRN gene are found in approximately 90% of clinically diagnosed WS cases. The other 10% are operationally categorized as atypical Werner syndrome (see this term) and are due to other causes (such as a mutation in the LMNA gene).\nDiagnostic methods\nA clinical diagnosis is based on the presence of all major symptoms (cataracts, skin changes, premature graying/thinning of hair and short stature) and two additional signs (such as osteoporosis or voice change) presenting after adolescence. Molecular analysis can identify most of the mutations in the WRN gene by standard exon sequencing and sequencing of RT-PCR products, in combination with Western blot analysis showing the absence of normal WRN protein.\nDifferential diagnosis\nDifferential diagnoses include mandibuloacral dysplasia (MAD), partial lipodystrophy, Rothmund-Thomson syndrome (RTS) and Hutchinson-Gilford progeria syndrome (HGPS; see these terms). Type 2 diabetes mellitus can also share similarities with WS.\nGenetic counseling\nWS is inherited in an autosomal recessive manner. Once a patient is diagnosed with WS, the patient and family should receive genetic counseling in order to identify those that could develop the disease and those who are carriers. Offspring of a patient with WS are obligate carriers, but unlikely to be affected, given the low likelihood of marrying a carrier unless there is consanguinity.\nManagement and treatment\nThere is no cure for WS and treatment involves a multidisciplinary team. Cataracts can be treated with surgery. Regular physical examinations are needed to check for skin ulcers, diabetes, malignancies or cardiovascular disease. Any malignancies should be treated with surgery, chemotherapy and/or radiation. Smoking should be avoided and a healthy lifestyle, including regular exercise and a diet low in fat, should be followed. Psychological counseling may also be beneficial in supporting patients and family members affected by WS.\nPrognosis\nPatients with WS have a shortened life expectancy but prognosis depends on the age-related diseases present and their severity.\n\n                            Last update: \n                            April 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Fuki HISAMA  - Dr George MARTIN  - Dr Junko OSHIMA"}
{"Disease Name": "West-Nile encephalitis", "Disease Definition": "An acute arboviral infection caused by a virus of the Flaviviridae family transmitted by an infected mosquito, that is asymptomatic in the majority of cases but that can present in rare occasions with mild flulike symptoms such as low-grade fever, arthralgia, myalgia, and/or rash, or with neurologic manifestations including meningitis, encephalitis with mental confusion or disorientation, tremors and acute flaccid paralysis/poliomyelitis.", "ORPHA ID": 83476, "Summary": ""}
{"Disease Name": "Western equine encephalitis", "Disease Definition": "An acute arboviral infection caused by an alphavirus of the Togaviridae family transmitted by an infected mosquito, that more frequently affects children and that is characterized by the presence of mild flulike symptoms (fever, chills, headache, nausea, vomiting, and anorexia) but that can progress to weakness, altered mental status, photophobia, mental confusion, seizures, somnolence, coma and/or even death. The disease can leave neurological sequelae, mainly in infants and children, such as seizures, spasticity or behavioral disorders.", "ORPHA ID": 83593, "Summary": ""}
{"Disease Name": "WHIM syndrome", "Disease Definition": "WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a congenital autosomal dominant immune deficiency characterized by abnormal retention of mature neutrophils in the bone marrow (myelokathexis) and occasional hypogammaglobulinemia, associated with an increased risk for bacterial infections and a susceptibility to human papillomavirus (HPV) induced lesions (cutaneous warts, genital dysplasia and invasive mucosal carcinoma).", "ORPHA ID": 51636, "Summary": "Epidemiology\nWHIM syndrome is extremely rare, with 65 cases reported worldwide to date. The incidence in France between 1990 and 2006 has been estimated at less than 1/ 4,000,000 births.\nClinical description\nWHIM syndrome has a heterogeneous clinical picture. Onset usually occurs during early childhood with recurrent bacterial infections, including pharyngitis, sinusitis, otitis, meningitis and pneumonia, which respond well to antibiotics. The response to vaccination is poor; when measured by the titer of specific antibodies, a low response is initially observed followed by a rapid disappearance of specific antibodies. More than 80% of the patients develop, by the age of 30 years old, widespread HPV-induced warts that are often difficult to treat, generally starting on hands and feet. 25% develop anogenital condylomata acuminata which may progress to intractable multifocal dysplastic HPV-induced lesions and invasive genital cancer. Tetralogy of Fallot (see this term) has been reported in about 1/4 of cases.\nEtiology\nWHIM syndrome is caused by heterozygous gain of function mutations in the CXCR4 gene (2q21) encoding a chemokine receptor expressed on mature leukocytes and involved in signal transduction pathways controlling bone marrow cell adhesion and homing, myelopoiesis and lymphopoiesis. Mutations result in prolonged activation of the receptor that leads to retention of neutrophils and other leukocytes in the bone marrow.\nDiagnostic methods\nDiagnosis is based on the evaluation of clinical signs in addition to the following laboratory findings: cell blood counts usually showing (except in case of acute infection) neutropenia, lymphopenia, and monocytopenia resulting in severe panleukopenia, with normal hemoglobin levels and platelets; serum immunoglobulins G, A and M levels showing mild hypogammaglobulinemia in almost all cases; and bone marrow aspirates demonstrating myelokathexis. Genetic analysis of CXRC4 confirms diagnosis.\nDifferential diagnosis\nDifferential diagnosis of diseases with myelokathexis include autosomal dominant severe congenital neutropenia, autosomal recessive severe congenital neutropenia due to G6PC3 deficiency, epidermodysplasia verruciformis, and monocytopenia with susceptibility to infections (see these terms).\nAntenatal diagnosis\nPrenatal testing by amniocentesis or chorionic villus sampling is possible in case of family history.\nGenetic counseling\nWHIM syndrome is usually transmitted as an autosomal dominant trait. Autosomal recessive or sporadic cases have also been described.\nManagement and treatment\nCurrent treatment is symptomatic. Immunoglobulin replacement therapy and prophylactic antibiotic treatment may prevent infections. Treatment with granulocyte-colony stimulating factor (GCSF) may also be used. Standard methods (cauterization, laser therapy) or more aggressive treatments (surgical removal, Interferon, cidofovir, imiquimod) appear mostly ineffective for the management of HPV induced lesions. A clinical trial using CXCR4 antagonist (Plerixafor) is currently ongoing in the USA, and soon in Europe. Case reports suggest that the HPV vaccine may limit the occurrence of HPV infection.\nPrognosis\nWHIM affected individuals may live well into adulthood. Major risk factors include intractable multifocal dysplastic HPV-induced lesions and invasive genital cancer, and liver failure. By the age of 40, the cancer risk is of about 30%.\n\n                            Last update: \n                            October 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Jean DONADIEU"}
{"Disease Name": "Whipple disease", "Disease Definition": "A rare chronic infectious disorder in which almost all organ systems can be invaded by the rod-shaped bacterium Tropheryma whipplei (TW).", "ORPHA ID": 3452, "Summary": "Epidemiology\nThe annual incidence in Central European countries is estimated to be approximately 1/1,000,000.\nClinical description\nThe disease may occur at any age with diagnosis most frequently made between 50 to 60 years of age. The clinical picture is variable. The following symptoms are frequent but not necessarily observed in each patient: weight loss, polyarthritis, diarrhea/malabsorption, fever, lymphadenopathy, cardiac valvular disease, culture-negative endocarditis, pleuritis, ocular inflammatory disease, and relapsing tenosynovitis. In some cases, complex cerebral manifestations (such as cognitive dysfunction, ophthalmoplegia and myoclonus) can be observed. TW polyarthritis is typically palindromic; however, atypical courses may also occur.\nEtiology\nTW has been found in sewage plant influx and efflux, and can be excreted in the stool of healthy carriers, of sewage plant workers and of people living in precarious hygienic conditions. The circumstances facilitating infection and disease are unknown, but a genetic or acquired immunological predisposition is suspected.\nDiagnostic methods\nThe gold standard for diagnosis was the histological recognition by an experienced pathologist of free or phagocytised rod-shaped bacteria with periodic-acid-SCHIFF (PAS) staining in macrophages from the duodenal mucosa. However, the combination of PAS staining in an intestinal mucosal biopsy plus a validated specific real time polymerase chain reaction (PCR) for TW will raise sensitivity and specificity of the diagnosis. Cooperation with a laboratory, certified for PCR in Whipple's disease and routinely sequencing the amplification product of the PCR is recommended. Specific immunohistochemistry should be available. An isolated positive PCR in an intestinal mucosal biopsy or in a stool specimen is not sufficient for diagnosis. The diagnosis in extraintestinal tissue is always made by PCR. Immunohistochemistry can be very useful. A positive PCR in pulmonary alveolar lavage or from the oral cavity may mean colonization with TW and not necessarily infection. As the majority of patients with infected cerebrospinal fluid (CSF) are asymptomatic at the time of diagnosis, CSF should be examined with PCR in every patient before antibiotic treatment. Synovial fluid or synovial tissue should be examined by PCR for TW in patients with rheumatic symptoms as the intestinal mucosa is not always involved. Positive PAS staining in cerebral tissues should never be accepted as sole diagnostic tool.\nDifferential diagnosis\nThe differential diagnosis includes inflammatory bowel disease, malabsorption syndrome, infectious diarrhea, mesenteric lymphadenitis, seronegative polyarthritis, soft tissue rheumatism, culture-negative endocarditis, vasculitis, lymphoma, cerebrovascular disease, demential processes, HIV infection, atypical mycobacteriosis, sarcoidosis, unclear cutaneous symptoms, exophthalmos and many others.\nManagement and treatment\nAccording to the only available prospective randomized trial, treatment should consist in: 2 g Ceftriaxon daily intravenously for 14 days, followed by Cotrimoxazol twice daily for 12 months. Control examination of CSF, when initially positive, after termination of treatment is strongly suggested. In recurrent or resistant cerebral infection, contact with a TW. specialist is recommended. Expert advice concerning treatment is indispensable in patients who have received immunosuppressive treatment prior to the diagnosis, including oral steroids, or when a clinical response to Ceftriaxone is not apparent within a few days. In such cases, the occurrence of an immune reconstitution inflammatory syndrome in Whipple's disease (IRIS) must be considered. Treatment with immunosuppressive agents may be lifesaving. Lifelong clinical, non-invasive observation is advised in effectively treated patients, as late recurrences or de novo infections can occur.\nPrognosis\nUntreated, the disease is relentlessly progressive and leads to death either by wasting or by central nervous system involvement. The treatment schedule and follow up, detailed above, is mostly successful. Fatal courses can occur in patients with advanced cerebral involvement and in patients with the Immune Reconstitution Inflammatory Syndrome (IRIS).\n\n                            Last update: \n                            October 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Gerhard FEURLE"}
{"Disease Name": "White fibrous papulosis of the neck", "Disease Definition": "White fibrous papulosis of the neck is a rare, acquired, dermal elastic tissue disorder characterized by multiple, 2-3 mm sized, non-confluent, asymptomatic, white or pale-colored, non-follicular, firm papular lesions occurring predominantly on the lateral or posterior aspects of the neck. Other, rarely reported sites include inferior axillae, central mid-back and upper sternal region.", "ORPHA ID": 228290, "Summary": ""}
{"Disease Name": "White forelock with malformations", "Disease Definition": "White forelock with malformations is a multiple congenital anomalies syndrome characterized by poliosis, distinct facial features (epicanthal folds, hypertelorism, posterior rotation of ears, prominent philtrum, high-arched palate) and congenital anomalies/malformations of the eye (blue sclera), cardiopulmonary (atrial septal defect, prominent thoracic and abdominal veins), and skeletal (clinodactyly, syndactyly of the fingers and 2nd and 3rd toes) systems. There have been no further descriptions in the literature since 1980.", "ORPHA ID": 2475, "Summary": ""}
{"Disease Name": "White matter hypoplasia-corpus callosum agenesis-intellectual disability syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by severe white matter hypoplasia, corpus callosum agenesis or extreme hypoplasia, severe intellectual disability, failure to thrive and minor midline facial dysmorphism (including hypertelorism, broad nasal root, micrognathia). There have been no further descriptions in the literature since 1993.", "ORPHA ID": 3207, "Summary": ""}
{"Disease Name": "White platelet syndrome", "Disease Definition": "White platelet syndrome (WPS) is is a platelet granule disorder characterized by thrombocytopenia, increased mean platelet volumes, decreased platelet responsiveness to aggregating agents, and significant defects in platelet ultrastructural morphology leading to prolonged bleeding times and bleeding.", "ORPHA ID": 370131, "Summary": ""}
{"Disease Name": "White sponge nevus", "Disease Definition": "White sponge nevus (WSN) is a rare and autosomal dominant genetic disease in which the oral mucosa is white or greyish, thickened, folded, and spongy. The onset is early in life, and both sexes are affected equally. Other common sites include the tongue, floor of the mouth, and alveolar mucosa.", "ORPHA ID": 171723, "Summary": ""}
{"Disease Name": "White-Sutton syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability disorder characterized by craniofacial features, global developmental delay, intellectual disability and variable neurobehavioral abnormalities (autism spectrum disorder, aggressiveness, and self-injury). Additional features include vision abnormalities and variable sensorineural hearing loss, as well as short stature, hypotonia and gastrointestinal manifestations (e.g. poor feeding, gastroesophageal reflux, constipation).", "ORPHA ID": 468678, "Summary": "Epidemiology\nAbout 50 patients have been reported in the literature to date. Some researchers estimate that this syndrome may account for up to 1/700 cases of intellectual disability associated or not with autism spectrum disorder.\nClinical description\nPresentation may be with neonatal hypotonia or developmental delay during infancy. The main features observed in these patients are developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities (including autism spectrum disorder). Most individuals have been described with mild to moderate ID; but the spectrum ranges from low-normal intelligence to severe ID. Some mild cerebral malformations can be found. Common craniofacial characteristics include microcephaly, high and broad forehead, midface hypoplasia or retrusion, tented or triangular mouth with downturned corners of the mouth, a broad nasal root and flat nasal bridge. Additional features may include hypotonia, seizures, sleep apnea, sensorineural hearing impairment, visual defects (strabismus, refraction errors), tendency to be overweight, short stature and gastrointestinal difficulties.\nEtiology\nThe disorder is caused by heterozygous pathogenic variants in POGZ. POGZ gene mutations are thought to impair the ability of the POGZ protein to bind to chromatin.\nDiagnostic methods\nDiagnosis is usually made by gene panels or exome/genome sequencing in the absence of distinctive features.\nDifferential diagnosis\nThe differential diagnosis includes numerous syndromes with developmental disorders as a feature.\nAntenatal diagnosis\nPrenatal diagnosis can be considered in cases with an affected parent with a 50% recurrence risk, and in couples with a de novo mutation in a first child for a 1% recurrence risk limited to the risk of germline mosaicism.\nGenetic counseling\nThe disorder usually occurs sporadically due to de novo mutations in POGZ. The pattern of inheritance is autosomal dominant. Genetic counseling should be offered to affected individuals informing them of that there is a 50% risk of transmission to offspring, at each pregnancy. In couples with a de novo mutation in a first child, the recurrence risk is 1% due to the possibility of germline mosaicism.\nManagement and treatment\nFollowing the initial diagnosis, a comprehensive physical and neurologic examination, genetics consultation, and developmental/behavioral evaluation should be completed if they have not already been done. Careful neuropsychological evaluation should include intellectual quotient with or without verbal working memory, speed of treatment, attention, divided attention, planning and cognitive flexibility, theory of mind, communication, and executive function. Autism evaluation can be proposed in patients with suspicion of autism spectrum disorder. Follow-up of children by a developmental pediatrician, neurologist, or psychiatrist is required in order to propose appropriate therapies (e.g. physical therapy, occupational therapy, speech therapy, behavioral therapy) and individualized education plans. Methylphenidate can be proposed in patients with attention deficit disorders.\nPrognosis\nThere is currently no data on life expectancy but there is no known complication that could lead to early death. The quality of life and functional consequences are variable, and are highly dependent of the severity of neuropsychological problems and the timing of therapeutic management and education plans. Some individuals are able to live independently whilst others will require significant support.\n\n                            Last update: \n                            October 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Laurence OLIVIER-FAIVRE | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Whooping cough", "Disease Definition": "A rare bacterial infectious disease characterized by severe coughing paroxysms with inspiratory whooping and posttussive vomiting, caused by infection with Bordetella pertussis. After a variable incubation time, the clinical course progresses through a catarrhal stage with sore throat, nasal congestion, rhinorrhea, and mild progressive dry cough, a paroxysmal stage with the typical paroxysmal coughing, and finally convalescence. Disease duration is usually 2-3 months, often with milder presentation in adolescents and adults than in infants and children.", "ORPHA ID": 1489, "Summary": ""}
{"Disease Name": "Wiedemann-Rautenstrauch syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by marked prenatal and postnatal growth retardation, decreased subcutaneous fat, hypotrichosis, relative macrocephaly and an unusual face. Mild to moderate intellectual disability is common.", "ORPHA ID": 3455, "Summary": "Epidemiology\nMore than 30 patients have been reported.\nClinical description\nFacial characteristics include triangular face with a relatively large skull, large anterior fontanelle, prominent veins especially on the scalp, sparse scalp hair, decreased eyebrows and eyelashes, small mouth, and micrognathia. Natal teeth represent a common, but variable finding. The clinical spectrum is broad but intrauterine growth retardation and decreased subcutaneous fat have been reported as cardinal features. Mild to moderate intellectual disability is common. In survivors, a progressive ataxia and tremor develops later on. The syndrome is usually lethal in the first year of life but, on rare occasions, patients have survived into adulthood.\nEtiology\nThe syndrome is caused by bi-allelic variants in POLR3A located at 10q22.3, which encodes a subunit of RNA polymerase III. The syndrome is allelic with 4H leukodystrophy and adolescent-onset progressive spastic ataxia.\nDiagnostic methods\nThe diagnosis can be suspected by the clinical presentation and confirmed by molecular genetic testing.\nDifferential diagnosis\nThe syndrome can resemble the allelic conditions 4H leukodystrophy and adolescent-onset progressive spastic ataxia, and may also resemble endosteal sclerosis-cerebellar hypoplasia syndrome which is caused by variants in POLR3B. Other entities to be considered are Hutchinson-Gilford progeria syndrome, Nestor-Guillermo progeria syndrome, Fontaine syndrome, SHORT syndrome, and Marfan syndrome lipodystrophy type.\nAntenatal diagnosis\nReliable prenatal diagnosis is possible if a pathogenic variant has previously identified in a family member.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.\nManagement and treatment\nNo specific treatment is possible. General supportive care including help in coping with the progressive nature of the disorder is indicated.\nPrognosis\nMany reported patients died in the first year of life; however, survival into adulthood has also been reported. Survival beyond infancy and childhood is likely possible nowadays using careful, supportive care.\n\n                            Last update: \n                            June 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Raoul HENNEKAM | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Wiedemann-Steiner syndrome", "Disease Definition": "A rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by short stature, hypertrichosis (most commonly of the back or elbow regions), facial dysmorphism, behavioral problems, developmental delay and, most commonly, mild to moderate intellectual disability.", "ORPHA ID": 319182, "Summary": "Epidemiology\nThe estimated prevalence, based on germline mutation rates, is 1/25,000 -40,000; although this may be an underestimate due to clinical misdiagnosis with other disorders such as Kabuki syndrome and Rubinstein-Taybi syndrome as well as a subgroup of patients that have only slight or even no apparent developmental delay and therefore often do not undergo genetic evaluation.\nClinical description\nWiedemann-Steiner syndrome (WSS) has a variable clinical phenotype presenting rarely in the prenatal period and more commonly neonatally or in infancy or childhood. Many infants with WSS have hypotonia and some degree of feeding problems, which may require tube feeding. Constipation also often starts from a young age and early eruption of teeth is typical. Hypertrichosis (often on the back and/or cubiti) can be already present in infancy, but can also develop in childhood. Children often have telecanthus, long/dense eyelashes and vertically narrow palpebral fissures, as well as other dysmorphic features. Short stature or relative short stature compared to target height is often present and most commonly develops during the first year of life. Some degree of developmental delay/intellectual disability, usually mild to moderate, is often present, although it can range from very mild to severe. Behavioral problems are common and include features of autism and attention deficit and hyperactivity disorder. Anxiety issues seem to play an increased role with advancing age. Less common features include congenital cardiac abnormalities (usually minor, such as persistent ductus arteriosus), urogenital abnormalities, skeletal abnormalities (mostly of the cervical vertebrae), dental abnormalities and small puffy hands and feet. A minority of individuals have seizures, which are more commonly observed in combination with severe developmental delay/intellectual disability. Also tethered cord, chiari malformation, and dysmotility of the gut are sometimes present. Growth hormone deficiency and immune deficiency (hypogammaglobulinemia) have been reported in some patients.\nEtiology\nWSS is caused by variants in the KMT2A gene (11q23.3). This gene is involved in the regulation of many other genes in the genome.\nDiagnostic methods\nDiagnostic criteria for WSS have not been established. The diagnosis is usually made by DNA-testing. If a mutation is not identified a diagnosis can be suspected by a combination of clinical symptoms and methylation profile (episignature).\nDifferential diagnosis\nThe differential diagnosis includes Kabuki syndrome, Coffin-Siris syndrome, Cornelia de Lange syndrome, Rubinstein-Taybi syndrome, and non-syndromic intellectual disability.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe disorder is autosomal dominant; whilst the large majority of cases occur de novo, genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.\nManagement and treatment\nUltrasound of the urinary tract and heart and immunologic screening (immunoglobulins) should be considered in all pediatric patients. Upon indication, cervical X-rays and imaging of the cerebrum or spinal cord can be considered. Growth hormone therapy is indicated for patients with a growth hormone deficiency and is considered in some countries in WSS patients with short stature, although based on very limited evidence.\nPrognosis\nThere is currently no evidence that life expectancy of individuals with WSS is shortened for the majority of individuals with the disorder. Most individuals have mild to moderate intellectual disability.\n\n                            Last update: \n                            August 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Hans BJORNSSON  - Dr Floor DUIJKERS | ITHACA* - Dr Wendy JONES \n\n\n                                * European Reference Network"}
{"Disease Name": "Wild type ABeta2M amyloidosis", "Disease Definition": "A form of amyloidosis affecting patients with chronic kidney disease (CKD), on long term dialysis characterized by the accumulation of amyloid fibrils consisting of beta 2 microglobulin (β2M) deposits in the musculoskeletal system leading to carpal tunnel syndrome (CTS), chronic arthropathy, cystic bone lesions, destructive osteoarthropathy, and pathologic fractures.", "ORPHA ID": 85446, "Summary": ""}
{"Disease Name": "Wild type ATTR amyloidosis", "Disease Definition": "A common form of systemic amyloidosis characterized by deposition of wild type transthyretin predominantly in the heart and the soft tissues (mainly the carpal tunnel region, lumbar canal and tendons).", "ORPHA ID": 330001, "Summary": "Epidemiology\nThe prevalence of wild type ATTR amyloidosis (ATTRwt amyloidosis) is estimated, on average, at 1/5,800 worldwide. In autopsy studies, fibrillar deposits of transthyretin were found in the heart of 25% of elderly people. Many recent reports evaluated the incidence of this disease in patients with heart failure and preserved ejection fraction. In this subset, the incidence could rise to 13% of cases. The disease is more frequent in males.\nClinical description\nThe disease onset is generally after the age of 60. The clinical picture is dominated by manifestations of cardiac failure as shortness of breath, leg swelling, fatigue, nausea and an irregular heartbeat or palpitations. Progressive renal failure may also occur during the disease history. In some cases, history of carpal tunnel syndrome or lumbar canal stenosis may precede the cardiac failure symptoms by 8-10 years.\nEtiology\nATTRwt amyloidosis is caused by the dissociation of transthyretin (TTR) from tetramers to monomers, which leads to misfolding and aggregation as amyloid fibrils in the heart. Amyloid deposits can infiltrate any cardiac tissue including the conduction system, the myocardium and the vessels and it can translate in severe diastolic or systolic dysfunction.\nDiagnostic methods\nSuspicion of ATTRwt amyloidosis is generally raised by echocardiogram or cardiac magnetic resonance (CMR). Confirmation of diagnosis requires scintigraphy with bone radiotracers, that show increased myocardial and decreased bone uptake of the radiolabeled drug. DNA analysis is also required in order to exclude inherited forms of cardiac ATTR. In patients with a concomitant monoclonal gammopathy or an abnormal serum free light chain ratio, demonstration and typing of amyloid deposits is mandatory. Abdominal fat pad aspirate is non-invasive but has relatively low diagnostic sensitivity in ATTRwt. Endomyocardial biopsy can be considered in selected cases. The severity of the disease should be graded. The combination of cardiac biomarkers, N-terminal pro natriuretic peptide type B (NT-proBNP) and troponin, or NT-proBNP and the estimated glomerular filtration rate (eGFR), accurately predict the prognosis of this disease at the time of diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes other forms of cardiac amyloidosis (light chain, AL and mutated forms of ATTRv) and other types of cardiomyopathy.\nManagement and treatment\nCurrently, the goal of treatment is to manage cardiac dysfunction in order to reduce the burden of symptoms. Treatment of heart failure based on diuretics, has a central role. The only specific approved drug for the treatment of ATTRwt is tafamidis which stabilizes TTR proteins, reduces the misfolding and accumulation of amyloid deposits in tissue, and thereby slows progression of heart failure. Many other disease specific therapeutic agents (other TTR stabilizers, TTR gene silencers and amyloid fibrils degraders) are under investigation in clinical trials.\nPrognosis\nNatural history of the disease is characterized by a slow but inevitable progression of heart failure. The severity of cardiac dysfunction, as assessed by cardiac biomarkers and estimated glomerular filtration rate, is the major prognostic determinant. The impact of the use of specific disease modifier drugs in the real-world setting is still under investigation but it will probably change the course of the disease in the upcoming future.\n\n                            Last update: \n                            September 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Giovanni PALLADINI | EuroBloodNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "Wildervanck syndrome", "Disease Definition": "Wildervanck syndrome is characterized by the triad of cervical vertebral fusion (Klippel-Feil anomaly, see this term), bilateral abducens palsy with retracted eyes (Duane syndrome, see this term) and congenital perceptive deafness.", "ORPHA ID": 3456, "Summary": "Epidemiology\nIt has been described in one family with affected members through 5 generations, almost exclusively females. Single additional sporadic cases have been reported.\nClinical description\nBilateral lens subluxation, facial paralysis, atrial septal defect, scoliosis, cholelithiasis have been found occasionally.\nEtiology\nThe causative gene has not yet been identified.\nGenetic counseling\nMultifactorial inheritance is likely; sex-linked dominance with lethality in the hemizygous male has been discussed.\n\n                            Last update: \n                            November 2009"}
{"Disease Name": "Williams syndrome", "Disease Definition": "A rare genetic multisystemic neurodevelopmental disorder characterized by a distinct facial appearance, cardiac anomalies (most frequently supravalvular aortic stenosis), cognitive and developmental abnormalities, and connective tissue abnormalities (e.g., joint laxity). Facial dysmorphism is characterized by a broad forehead, bitemporal narrowing, periorbital fullness, stellate and/or lacy iris pattern, short upturned nose with bulbous tip, long philtrum, wide mouth, full lips and mild micrognathia.", "ORPHA ID": 904, "Summary": "Epidemiology\nPrevalence is approximately 1/7,500. There is no difference between the sexes.\nClinical description\nAll individuals have facial dysmorphism; in addition to the characteristic features, young children have epicanthal folds, full cheeks, a flat profile and small, widely spaced teeth. Older children and adults often have a narrow face and long neck. The majority of patients (80%) suffer from cardiovascular disease, primarily stenosis of the medium and large arteries (supravalvular aortic stenosis (70%), hypertension (50%), and degeneration of aortic and/or mitral-valve leaflets). Developmental milestones are delayed. A relative strength in language and verbal short-term memory, and a significant weakness in visuospatial construction is characteristic. Intellectual disability is common (75%), and a characteristic cognitive profile with an overly friendly and social personality with enjoyment of music but hypersensitivity to sound is characteristic (90%). Emotional dysregulation is common and many patients (50%) require pharmacologic treatment for anxiety and/or attention deficit hyperactivity disorder. Endocrine abnormalities include hypercalcemia (15-45%), impaired glucose tolerance/type 2 diabetes mellitus (DM), obesity in adolescents/adults, subclinical hypothyroidism (15-30%), and osteopenia or osteoporosis (50%). Other problems include axial hypotonia, peripheral hypertonia with increased deep tendon reflexes in the lower extremities, ataxia and tremor. Growth in children is approximately 75% of normal growth rate. Young children have joint laxity; joint contractures occur in older childredults leading to an awkward gait. Lordosis, kyphosis and scoliosis are common. Other common problems include ocular, auditory and dental anomalies, sleep disorders, feeding difficulties, gastrointestinal problems, bladder diverticula, urinary tract malformation, urinary infection and enuresis.\nEtiology\nWilliams syndrome (WS) is caused by a microdeletion on chromosome 7q11.23, a region containing 26 to 28 genes including ELN.\nDiagnostic methods\nDiagnosis is based on phenotype and genetic testing (fluorescence in situ hybridization (FISH) or chromosome microarray).\nDifferential diagnosis\nThe primary differential diagnosis is familial supravalvular aortic stenosis.\nGenetic counseling\nGenetic counselling should be provided to affected families. Most cases arise de novo, and thus the recurrence risk is low (<1%). Affected individuals have a 50% risk of transmitting the deletion to offspring. A specific inversion polymorphism in the area may increase the risk of having a child with WS.\nManagement and treatment\nA lifelong multidisciplinary approach involving medical monitoring, anticipatory guidance, direct therapies, pharmacotherapy, surgery, and adaptive changes is necessary. Close cardiac follow-up during the first year of life, and close monitoring of serum calcium during the first 2 years of life is recommended, as well as careful pre- and postoperative planning due to increased risk of cardiovascular complications during surgery. Children should be referred to an early intervention program for physical, occupational and speech therapy. Information, education and support groups are recommended for affected patients, families and caregivers.\nPrognosis\nA formal assessment of life expectancy is lacking. Cardiovascular complications are the major cause of death. Cardiovascular stenoses may progress, especially during the first 5 years of life. Peripheral pulmonary stenoses often resolves spontaneously. Most individuals will require lifelong supervision at both their home and their workplace.\n\n                            Last update: \n                            March 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Pernille GREGERSEN | ITHACA* - Dr Mette HANDRUP | ITHACA* - Dr Anne LEEGAARD | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Williams-Campbell syndrome", "Disease Definition": "A rare, respiratory malformation characterized by defective or completely absent bronchial wall cartilage in subsegmental bronchi, leading to distal airway collapse and contributing to the formation of bronchiectasis. The defect is mostly present between the fourth and sixth order bronchial divisions. Clinical manifestation includes recurrent pneumonia, coughing and wheezing.", "ORPHA ID": 411501, "Summary": ""}
{"Disease Name": "Wilson disease", "Disease Definition": "A rare genetic disorder of copper metabolism presenting with non-specific hepatic, neurologic, psychiatric or ophthalmologic manifestations due to impaired biliary copper excretion and consecutive excessive copper deposition in the body.", "ORPHA ID": 905, "Summary": "Epidemiology\nThe estimated prevalence at birth ranges between 1/30,000-110,000 worldwide but may be higher in isolated populations.\nClinical description\nThe clinical spectrum is very wide, even within affected families. Likewise, age of onset is highly variable. Some patients remain asymptomatic for decades while few present symptoms before age 3 to 5. The disease can be observed in children after 3 years and most cases develop by 40 years of age. Late-onset cases after the fifth decade of life have also been described. Clinical presentation depends on gender and age. In children, at an average age of 10 years, hepatic manifestations typically prevail, most often commencing with liver damage. In general, hepatic manifestations (hepatomegaly, subacute or chronic hepatitis, acute liver failure or cirrhosis with portal hypertension) commonly precedes neurologic symptoms. Neurological manifestations (dystonia, intention tremor, dysarthria, coordination difficulties, chorea, choreoathetosis, and gait disorders) can be found in conjunction with hepatic symptoms or might also be the first clinical symptoms. Isolated psychiatric disorders (depression, phobias, compulsive behavior, personality changes, aggressiveness, or emotional instability) are rare and more commonly observed in conjunction with hepatic or neurologic disease. A wide range of other manifestations may also be present in affected patients: acute hemolytic episodes, delayed puberty, amenorrhea, repetitive miscarriage, Kayser-Fleischer rings due to copper deposits in the Descemet membrane, bone pain, arthralgia and osteoporosis, arrythmia, myocardiopathy, hematuria, nephrotic syndrome and renal lithiasis. Hepatocellular carcinoma has been reported in rare cases.\nEtiology\nThe disease is due to chronic copper toxicosis, caused by pathogenic ATP7B (13q14.3) variants which leads to impaired copper elimination and subsequent accumulation in body tissues, particularly in the liver initially and then the brain and other organs.\nDiagnostic methods\nThe variable presentation (hepatic, neurologic, psychiatric) complicates diagnosis which is based primarily on the combination of clinical features, and abnormal laboratory tests (elevated liver enzymes, thrombocytopenia, low serum ceruloplasmin, elevated urinary copper excretion). Liver biopsy may be performed to demonstrate high copper levels. Evaluation of liver copper from biopsies can be helpful. Diagnostic scoring system is commonly applied to establish diagnosis, still the diagnostic approach should start with ceruloplasmin and urinary copper excretion evaluation. Molecular genetic testing most often confirms the diagnosis in 98% of cases. Family screening identifies 20% of cases.\nDifferential diagnosis\nFor the liver presentation, the differential diagnosis includes acute or chronic hepatopathy (viral or autoimmune hepatitis, non-alcoholic steatohepatitis, primary sclerosing cholangitis, primary biliary cirrhosis and alpha-1-antitrypsin); regarding the neurological presentation, it includes essential tremor, early onset Parkinson disease, and dystonia.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling should be offered to at-risk couples if both individuals are carriers of a disease-causing mutation, informing them of the 25% risk of having an affected child at each pregnancy and the existence of an effective treatment.\nManagement and treatment\nThere is currently no cure for Wilson disease. The main aim of current treatment is to establish a negative copper balance with the life-long administration of chelating agents (D-penicillamine, trientine salts) or zinc salt. Treatment helps to improve the manifestations of the disease over time, and its effectiveness depends on strict adherence to it throughout life. Restriction of copper-rich foods may be beneficial. Liver transplantation is the recommended therapy in cases of acute liver failure with encephalopathy or decompensated cirrhosis despite drug therapy.\nPrognosis\nThe prognosis is dependent on timely diagnosis and initiation of treatment, and treatment compliance. If left untreated, the disease is progressive with a severe, life-threatening course but with the correct treatment, long-term prognosis is very good.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Edouardo COUCHONNAL | RARE-LIVER* - Pr Dominique DEBRAY  - Pr Alain LACHAUX | RARE-LIVER* - Dr Aurélia POUJOIS | MetabERN* - Dr Thomas Damgaard SANDAHL | RARE-LIVER* - Pr Piotr SOCHA | RARE-LIVER* - Pr H.J. [Henkjan] VERKADE | RARE-LIVER* - Pr Karl Heinz WEISS | RARE-LIVER*\n\n\n                                * European Reference Network"}
{"Disease Name": "Wilson-Turner syndrome", "Disease Definition": "Wilson-Turner syndrome (WTS) is a very rare X-linked multisystem genetic disease characterized by intellectual disability, truncal obesity, gynecomastia, hypogonadism, dysmorphic facial features, and short stature.", "ORPHA ID": 3459, "Summary": "Epidemiology\nPrevalence of WTS is not known. The syndrome has been described in two families to date: 14 males in the 3 most recent generations of the first family, and 7 males and 7 females in a 5-generation Dutch family.\nClinical description\nAffected males were described as having severe intellectual disability, truncal obesity, gynecomastia, hypogonadism, short stature (in the second family), small hands and feet, tapering fingers and facial dysmorphism including a small head, short ears, prominent supraorbital ridges, deep-set eyes, high malae, broad nasal tip, thin upper vermillion, and retrognathia. In obligate female carriers in the second family, a milder phenotype including learning disorders and recognizable facial features was reported. The described phenotype overlaps with Börjeson-Forssman-Lehmann syndrome, a form of X-linked intellectual disability. Differences between the two described families are small, but there is a possibility that they represent different clinical entities.\nEtiology\nThe syndrome has been linked to a mutation in the consensus donor splice site of the histonedeacetylase 8 HDAC8 gene (Xq13).\nGenetic counseling\nX-linked recessive transmission and X-linked dominant inheritance with absence of male-to-male transmission have been reported.\n\n                            Last update: \n                            October 2015\n\n\n                            - Expert reviewer(s): \n                            Dr J.K. [Hans Kristian] PLOOS VAN AMSTEL"}
{"Disease Name": "Wiskott-Aldrich syndrome", "Disease Definition": "A primary immunodeficiency disease characterized by microthrombocytopenia, eczema, infections and an increased risk for autoimmune manifestations and malignancies.", "ORPHA ID": 906, "Summary": "Epidemiology\nThe incidence of WAS has been estimated at less than 1 in 100,000 live births. The disease almost exclusively affects males.\nClinical description\nWAS usually manifests in infancy but onset may also occur during the neonatal period. In most cases the first clinical features are hemorrhagic manifestations with petechiae, bruising, purpura, epistaxis, oral bleeding, bloody diarrhea and intracranial bleeding. Acute or chronic eczema is the second characteristic finding of WAS. Due to combined immunodeficiency, most patients also have airway, gut or skin infections caused by regular or opportunistic germs. Autoimmune manifestations are seen in approximately 40% of cases and include autoimmune hemolytic anemia, neutropenia, vasculitis, inflammatory bowel disease, renal disease, and arthritis. WAS patients have a higher risk of developing tumors (mainly B-cell lymphomas) at any age.\nEtiology\nWAS is due to hemizygous mutations in the WAS gene (Xp11.4-p11.21), coding for the Wiskott-Aldrich syndrome protein, exclusively expressed in hematopoietic cells and having a major role in the reorganization of the actin cytoskeleton, signal transduction and apoptosis. Usually, hypomorphic mutations in the WAS gene can lead to an attenuated form of WAS called X-linked thrombocytopenia with normal platelets (XLTT; see this term), that is characterized by mild to moderate thrombocytopenia and eczema and a lower risk of autoimmunity and malignancy, but usually showing no immunodeficiency. Recently, a mutation in the WIPF1 gene (WAS/WASL interacting protein family, member 1; 2q31.2), coding for a protein that stabilizes and prevents the degradation of WASp, was also found in a patient who displayed some features of WAS.\nDiagnostic methods\nDiagnosis is based on family history, physical examination and laboratory investigations that reveal severe thrombocytopenia with reduced platelet size with a usually normal number of megakaryocytes, as well as altered antibody production (mainly antipolysaccharidic antibodies). Absent or decreased WAS protein levels and genetic testing confirm the diagnosis.\nDifferential diagnosis\nMain differential diagnosis is acute or chronic idiopathic thrombocytopenia (ITP) or platelet alloimmunization in neonates.\nAntenatal diagnosis\nPrenatal diagnosis is feasible in male fetuses when the causal mutation in the family is known.\nGenetic counseling\nWAS is an X-linked recessive disease. Carrier women have a 50% risk of transmitting the disease to their male progeny. Some de novo mutations might also occur.\nManagement and treatment\nThe only curative treatment to date is hematopoietic stem cell transplantation (HSCT), performed as soon as possible with the best matched HLA donor. In young patients lacking a HLA matched donor, HSCT with a haploidentical donor can lead to a favorable outcome. Gene therapy, still experimental to date, may be a promising approach for patients lacking a suitable donor. Immunoglobulin replacement therapy and oral antibiotics prevent infections. Severe eczema requires treatment with topical or short-term systemic steroids. Treatments that could weaken the immune system (steroids, splenectomy, immunosuppressive agents) should be used with the highest caution by trained medical staff. Agonists of the thrombopoietin receptors (such as romiplostim and eltrombopag) can be used to increase the platelet count in severe refractory thrombocytopenia cases that are awaiting HSCT or gene therapy.\nPrognosis\nHSCT leads to an 80% survival rate, but when no donor is available, the overall prognosis is poor and life expectancy is reduced, especially when malignancy occurs.\n\n                            Last update: \n                            December 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Alain FISCHER  - Dr Nizar MAHLAOUI"}
{"Disease Name": "Witteveen-Kolk syndrome", "Disease Definition": "A rare genetic neurodevelopmental syndrome characterized by mild intellectual disability, developmental delay, dysmorphic facial features, growth- and feeding problems, hypotonia, epilepsy, behavioral problems and a variety of congenital abnormalities.", "ORPHA ID": 500163, "Summary": "Epidemiology\nApproximately 40 individuals with mutations in SIN3A have been reported. Males and females are equally affected.\nClinical description\nIndividuals may present with growth or feeding difficulties, developmental delay and/or intellectual disability. Overall intellectual disability is mild (no cognitive impairment in 25%). Intelligence testing typically shows a disharmonic profile favoring verbal IQ. Facial features include a tall, broad forehead, down-slanting palpebral fissures, triangular face with a pointed chin and a thin upper lip. Half of the patients show epilepsy and/or hypotonia. A third have a psychiatric or behavioral condition, including attention deficit and hyperactivity disorder, autism spectrum disorder, aggressive behavior, obsessive compulsory disorder, depression, psychosis, anxiety and schizoaffective disorder. Other reported manifestations are microcephaly, short stature, palatal defect, hearing loss, ocular abnormalities, and hyperlaxity. Brain abnormalities including ventriculomegaly, anomalies of the corpus callosum, cerebellar atrophy, or Chiari 1 malformation are present in a minority. In a minority of patients, congenital anomalies such as pelvic kidney, atrial/ventricular septal defects (ASD/VSD), cystocele, urethrocele, and thickened aortic valve may occur. Individuals with 15q24 microdeletion syndrome have a more heterogeneous phenotype with moderate to severe intellectual disability and additional features depending on the other genes involved in the deletion.\nEtiology\nThe disorder is either caused by mutations in Switch-insensitive 3 transcription regulator family member A (SIN3A; 15q24.2) or microdeletions, of various sizes, in the chromosome region 15q24 (15q24 microdeletion syndrome). The microdeletions often, but not always, encompass SIN3A.\nDiagnostic methods\nMost cases will be identified by unbiased genetic testing including chromosomal microarray, intellectual disability gene panels, whole exome or whole genome sequencing. Targeted genetic testing is possible.\nDifferential diagnosis\nMost cases are identified using an unbiased diagnostic approach for syndromic forms of neurodevelopmental delay or intellectual disability.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nTransmission is autosomal dominant. Genetic counseling should be offered to parents of affected individuals. The majority of cases are sporadic and thus in these cases the sibling recurrence risk is low. If one of the parents is affected, recurrence risk is 50%.\nManagement and treatment\nA multidisciplinary team approach should be considered including a pediatrician, clinical geneticist, and psychiatrist. Referral to other specialists (e.g. neurologist, ophthalmologist) is indicated when specific problems are suspected. Development should be closely monitored and physical and speech therapy should be considered. Early intervention for psychiatric or behavioral conditions is important to ensure optimal treatment and outcome. Clinicians should be aware that affected individuals will likely have a disharmonic intelligence profile; this easily leads to overestimating of the self-management capabilities of patients. Screening of congenital defects (pelvic kidney, ASD/VSD, cystocele, urethrocele, thickened aortic valve) is recommended after diagnosis. Imaging (e.g MRI) should not be performed routinely, but considered on clinical indication, for instance in the occurrence of seizures.\nPrognosis\nThere is insufficient longitudinal follow-up data to determine life expectancy, although survival into adulthood is typical. Individuals will likely require some degree of support throughout life. Quality of life is greatly influenced by the occurrence of psychiatric and/or neurological conditions.\n\n                            Last update: \n                            December 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Meena BALASUBRAMANIAN  - Pr T. [Tjitske] KLEEFSTRA | ITHACA* - Dr Jet VAN DER SPEK \n\n\n                                * European Reference Network"}
{"Disease Name": "Wolcott-Rallison syndrome", "Disease Definition": "Wolcott-Rallison syndrome (WRS) is a very rare genetic disease, characterized by permanent neonatal diabetes mellitus (PNDM) with multiple epiphyseal dysplasia and other clinical manifestations, including recurrent episodes of acute liver failure.", "ORPHA ID": 1667, "Summary": "Epidemiology\nFewer than 60 cases have been reported to date. Most patients are from consanguineous families. Prevalence may therefore vary significantly between countries.WRS may be underdiagnosed because of early death before diagnosis.\nClinical description\nDiabetes occurs early, generally before six months of age, is permanent and insulin-dependent from the onset. Skeletal dysplasia generally manifests within the 1st or 2nd year of life, and is associated with short stature (dwarfism with short trunk). Deficient mineralization or dysplastic changes, affecting the long bones, pelvis and vertebrae, but usually not the skull, may be seen on radiography as early as diabetes onset. Hepatic dysfunction is a 3rd characteristic feature and the most life-threatening complication, and manifests by elevated hepatic enzymes, liver enlargement and recurrent acute liver failure. Other manifestations vary between patients in type and severity and include renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Clinical course is variable, including within the same sibship.\nEtiology\nWRS is caused by mutations in the EIF2AK3 gene encoding eukaryotic translation initiation factor 2-alpha kinase 3 (PKR-like endoplasmic reticulum kinase; PERK), which plays a key role in translation control during unfolded protein response.\nDiagnostic methods\nDiagnosis should be suspected in any infant with permanent neonatal diabetes and skeletal dysplasia and/or episodes of acute liver failure, and family history of consanguinity and/or neonatal diabetes. Diabetes is not autoimmune as shown by absence of antibodies specific for type 1 diabetes. Radiographs show early signs of multiple epiphyseal dysplasia and deficient mineralization. Molecular genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis is based on clinical presentation and, ultimately, genetic testing. That of NDM (see this term) includes transient NDM, and other PNDMs that may be isolated or syndromic. Differential diagnosis of skeletal dysplasia includes other spondylo-epiphyseal dysplasias such as mucopolysaccharidoses (see these terms) where diabetes may occur independently at an older age.\nAntenatal diagnosis\nAntenatal diagnosis should be offered to parents of a WRS patient with confirmed EIF2AK3 mutation.\nGenetic counseling\nInheritance is autosomal recessive and genetic counseling is possible.\nManagement and treatment\nClose therapeutic monitoring of diabetes should be considered and treatment with an insulin pump is recommended, especially in the first months of life, due to the risk of acute episodes of hypoglycemia. At any age, hypoglycemia should be prevented because the disease can decompensate, even if this requires maintaining the level of glucose above the objectives generally recommended in diabetic children. General anesthesia increases the risk of acute aggravation, because of particular sensitivity of patients to anesthetics, and should be avoided wherever possible. Any drug or vaccine not strictly necessary should be limited, due to the risk of triggering secondary liver and/or kidney failure.\nPrognosis\nPrognosis is poor and most patients die at a young age from multiple-organ failure with predominant liver and renal dysfunction.\n\n                            Last update: \n                            February 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Cécile JULIER  - Pr Marc NICOLINO"}
{"Disease Name": "Wolf-Hirschhorn syndrome", "Disease Definition": "A developmental disorder characterized by typical craniofacial features, prenatal and postnatal growth impairment, intellectual disability, severe delayed psychomotor development, seizures, and hypotonia.", "ORPHA ID": 280, "Summary": "Epidemiology\nThe disease has an estimated birth prevalence of 1/20,000 - 50,000. Wolf-Hirschhorn syndrome (WHS) occurs more frequently in females than in males (2:1).\nClinical description\nMarked intra-uterine growth retardation and slow, postnatal weight gain are observed. The distinctive facies is characterized by a broad nasal bridge continuing to the forehead (which is visible more clearly before puberty), microcephaly, high forehead with prominent glabella, high-arched eyebrows, hypertelorism, epicanthus, poorly formed ears with pits/tags, short philtrum, downturned mouth, micrognathia, and, in some cases, cleft lip/palate. Skeletal anomalies include kyphosis or scoliosis with malformed vertebral bodies, accessory or fused ribs, clubfeet and split hand. Patients suffer from hypotonia with muscle underdevelopment, possibly causing frequent feeding difficulties and failure to thrive. Developmental delay is severe: most children do not achieve sphincter control, self-feeding or dressing, and less than 50% walk, with or without support. Intellectual disability is moderate to severe, rarely mild. Speech is limited to guttural or disyllabic sounds, although a few patients achieve simple sentences. Seizure onset is frequently observed between the neonatal period and 36 months (in up to 95% of patients); seizure type varies and is often triggered by fever. Status epilepticus occurs in half of patients, and children may develop atypical absences (over 30%). Seizures stop in childhood in approximately half of patients. Most patients have structural central nervous system defects, mainly including thinning of the corpus callosum. Other frequent anomalies include congenital heart defects (50%), ophthalmologic, auditory and dental anomalies. Patients may have recurrent respiratory tract infections and otitis media, due to antibodies deficiency (IgA or IgG2 subclass). Urinary tract malformations have been described, and half of male patients have hypospadias and cryptorchidism.\nEtiology\nWHS is due to a deletion in the short arm of chromosome 4 with contribution of genes within a 1.5-1.6 Mb region in the ~0.4-1.9 Mb terminal of 4p16.3. Deletions greater than 3-5 Mb seem to be associated with higher risk of heart defects and cleft palate.\nDiagnostic methods\nDiagnosis is based on physical examination and confirmed by molecular genetics or cytogenetic analysis. Fluorescence in situ hybridization (FISH), and genome-wide chromosomal microarray analysis (CMA) being the methods of choice. Electroencephalographic (EEG) investigations show typical findings in 90% of patients.\nDifferential diagnosis\nDifferential diagnosis includes many syndromes displaying growth failure, intellectual disability and/or facial dysmorphism such as Seckel, CHARGE, Smith-Lemli-Opitz, Opitz G/BBB, Williams, Rett, Angelman and Smith-Magenis syndromes.\nAntenatal diagnosis\nAntenatal testing is feasible when a 4p16.3 chromosome rearrangement is already identified in a family member.\nGenetic counseling\nMost cases are sporadic, but an unbalanced translocation may be inherited from a parent with a balanced rearrangement.\nManagement and treatment\nTreatment is symptomatic and requires multidisciplinary management including diverse rehabilitation programs, appropriate seizure treatment (phenobarbital; valproic acid with or without ethosuccimide; levetiracetam) and feeding therapies.\nPrognosis\nWHS patients survive into adult life. Most individuals require close to total care; about 30% are partly independent requiring supervision on daily routines. More than 65% enjoy overall good health.\n\n                            Last update: \n                            May 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Agatino BATTAGLIA"}
{"Disease Name": "Wolfram syndrome", "Disease Definition": "A rare, genetic, endocrine disorder characterized by type I diabetes mellitus (DM), diabetes insipidus (DI), sensorineural deafness (D), bilateral optical atrophy (OA) and neurological signs.", "ORPHA ID": 3463, "Summary": "Epidemiology\nEstimated prevalence of Wolfram syndrome (WS) is 1/770,000 worldwide.\nClinical description\n2 types of WS may be distinguished: type 1 (WS1) and type 2 (WS2). WS1 has onset in the first decade, with DM (91% of cases) and OA (87%) manifestations. Patients present a progressive reduction of visual acuity and loss of color vision. Less frequent ocular abnormalities include abnormal papillary light reflexes, nystagmus, cataracts, pigmentary maculopathy, retinopathy (pigmentary or diabetic) and glaucoma. 50% of patients also develop DI and some degree of deafness (slowly progressive high frequency). The full phenotype spectrum is observed in 65% of cases. Additional features may include urinary tract abnormalities (hydroureter, urinary incontinence, recurrent infections), neurological involvement (ataxia, myoclonus, epilepsy, hyposmia and cognitive disability) and psychiatric manifestations (depression). Life-threatening complications, including central apnea (due to bulbar dysfunction) are frequent and may lead to recurrent aspiration pneumonia. Other reported symptoms are gastrointestinal disorders (bowel dysmotility, gastroparesis, and bowel incontinence), hypogonadism, and delay/disruption of sexual development. Patients with WS2 present early OA, DM, D, and decreased lifespan, but no DI.\nEtiology\n2 causative genes have been identified: WFS1 (4p16.1) and CISD2 (4q24). WFS1 encodes Wolframin, a protein localized to the endoplasmic reticulum (ER) with roles in calcium homeostasis and unfolded protein response. Mutations in WFS1 are responsible for the majority of the WS phenotypes and account for WS1. CISD2 encodes the ERIS protein, located dynamically between the ER and mitochondria outer membrane, with roles in glucose homeostasis regulation, insulin sensitivity for calcium homeostasis and autophagy. Mutations in CISD2 account for WS2.\nDiagnostic methods\nThe clinical criteria for WS diagnosis are juvenile-onset DM and OA, family history of WS or DM and D. MRI scans show generalized brain atrophy, especially in the cerebellum, medulla, and pons; absence of signal from the posterior pituitary; and reduced signal from the optic nerve. Diagnosis is confirmed by genetic screening.\nDifferential diagnosis\nDifferential diagnosis includes mitochondrial disorders such as Maternally-inherited diabetes and deafness, Leber hereditary optic neuropathy, Mohr-Tranebjaerg syndrome, and Autosomal dominant optic atrophy plus syndrome. Other possible differential diagnoses are X-linked Charcot-Marie-Tooth disease type 5, Friedreich ataxia, Thiamine-responsive megaloblastic anemia, Bardet-Biedl and Alstrom syndromes. An autosomal dominant disorder, referred to as Wolfram-like syndrome, with DM occurring in adulthood, a juvenile onset of OA, and/or associated hearing impairment has also been described.\nAntenatal diagnosis\nIn families with characterized causative mutations, molecular carrier detection and preimplantation or prenatal diagnosis can be performed.\nGenetic counseling\nTransmission is autosomal recessive. Genetic counseling may be offered to at-risk couples carrying mutation either in WFS1 or CISD2 genes. Carrier testing may be possible when the variant associated to WFS1 poses heterozygous individuals at risk of developing low frequency D and DM.\nManagement and treatment\nManagement is supportive and includes an annual screening for DM, vision, D, urodynamic testing, nephropathy and daily insulin injections and a controlled diet to treat DM. Treatment of DI, apnea and urinary disorders (i.e. prophylactic antibiotherapy for urinary infections) is needed. Periodic screening for depression and other psychiatric symptoms is necessary to provide patients with specific medical, emotional and psychological intervention.\nPrognosis\nProgression of the disease to premature death is common, often by respiratory failure.\n\n                            Last update: \n                            August 2019\n\n\n                            - Expert reviewer(s): \n                            Dr Miguel LOPEZ DE HEREDIA"}
{"Disease Name": "Wolfram-like syndrome", "Disease Definition": "Wolfram-like syndrome is a rare endocrine disease characterized by the triad of adult-onset diabetes mellitus, progressive hearing loss (usually presenting in the first decade of life and principally of low to moderate frequencies), and/or juvenile-onset optic atrophy. Psychiatric (i.e. anxiety, depression, hallucinations) and sleep disorders, the only neurologic abnormalities observed in this disease, have been reported in rare cases. Unlike Wolfram syndrome, patients with Wolfram-like syndrome do not report endocrine or cardiac findings.", "ORPHA ID": 411590, "Summary": ""}
{"Disease Name": "Wolman disease", "Disease Definition": "A severe form of lysosomal acid lipase deficiency characterized by rapidly progressive lipid accumulation in organs and tissues that presents in the neonatal or infantile period with massive hepatosplenomegaly, liver failure, diarrhea/steatorrhea and vomiting.", "ORPHA ID": 75233, "Summary": "Epidemiology\nApproximately 50 cases have been reported in the literature.\nClinical description\nThe disease can sometimes present in the fetus (hepatomegaly, ascitis, calcified adrenal glands), but onset more typically occurs in the first weeks of life with abdominal distension and major or even massive hepatosplenomegaly (which can occur in the neonatal period) and sometimes ascites. The presence of calcified adrenal glands (as revealed by radiography), is a common and very characteristic sign. . Children present with significant digestive disorders (such as vomiting and diarrhoea with steatorrhoea), which can lead to a sudden arrest of ponderal growth and progressive psychomotor degradation in the absence of specific neurological signs. Later, severe anemia and cachexia become apparent.\nEtiology\nThe enzymatic deficiency results from severe mutations of the acid lipase gene (LIPAor LAL), localised to 10q24-q25.\nDiagnostic methods\nThe diagnosis can be rapidly confirmed by measuring enzymatic activity in leucocytes or dried blood spots , revealing an almost total deficiency.\nDifferential diagnosis\nDifferential diagnosis includes familial hemophagocytic histiocytosis and other phagocytic syndromes, Gaucher disease type II, Niemann-Pick disease type A, and malignancies such as leukemia or neuroblastoma.\nAntenatal diagnosis\nPrenatal diagnosis can be performed by measuring enzymatic activity or by mutational analysis of chorionic villi or amniocytes.\nGenetic counseling\nThe disease follows an autosomal recessive pattern of inheritance.\nManagement and treatment\nEnzyme replacement therapy with sebelipase lipase is available in the US and the European union and has been shown to prolong survival. Very early bone marrow or cord blood transplant has also been used and has provided some benefit in a limited number of cases.\nPrognosis\nIn the absence of definitive therapy, few children survive beyond one year of age. Enzyme replacement therapy, if started in a timely fashion, may prolong survival but the long term impact remains unknown.\n\n                            Last update: \n                            April 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Barbara BURTON"}
{"Disease Name": "Woodhouse-Sakati syndrome", "Disease Definition": "Woodhouse-Sakati syndrome is a multisystemic disorder characterized by hypogonadism, alopecia, diabetes mellitus, intellectual deficit and extrapyramidal signs with choreoathetoid movements and dystonia.", "ORPHA ID": 3464, "Summary": "Epidemiology\nApproximately 30 patients from consanguineous Middle Eastern families, together with one Caucasian woman and three sibs from an Indian family, have been reported so far.\nClinical description\nThe onset is usually in adolescence. Additional manifestations may include sensorineural deafness, flattened T waves on ECG, seizures, sensory polyneuropathy, dysarthria, various craniofacial abnormalities (high forehead, flat occiput, triangular face, prominent nasal root, hypertelorism, and down-slanting palpebral fissures), scoliosis, hyperreflexia, and camptodactyly.\nEtiology\nWoodhouse-Sakati syndrome is associated with mutations in the DCAF17 gene (2q31.1), encoding a nucleolar protein of unknown function.\nGenetic counseling\nThe disease is transmitted in an autosomal recessive manner.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "Woolly hair nevus", "Disease Definition": "Woolly hair nevus (WHN) is a rare non-familial hair anomaly characterized by kinky, tightly coiled, and hypopigmented fine hair with an average diameter of 0.5 cm, noted, since birth or during the first two years of life, in a localized circumscribed distribution on the scalp. Occassionally, WHN grows in areas observed to be alopecic in the neonatal period. WHN can be associated with features like ocular defects (persistent pupillary membrane, retinal defects), precocious puberty, and epidermal nevi.", "ORPHA ID": 79414, "Summary": ""}
{"Disease Name": "Woolly hair-palmoplantar keratoderma syndrome", "Disease Definition": "Woolly hair-palmoplantar keratoderma syndrome is a very rare, hereditary epidermal disorder characterized by hypotrichosis/woolly scalp hair, sparse body hair, eyelashes and eyebrows, leukonychia, and striate palmoplantar keratoderma (more severe on the soles than the palms), which progressively worsens with age. Pseudo ainhum of the fifth toes was also reported. Although woolly hair-palmoplantar keratoderma syndrome shares clinical similarities with both Naxos disease and Carvajal syndrome, cardiomyopathy is notably absent.", "ORPHA ID": 420686, "Summary": ""}
{"Disease Name": "Woolly hair", "Disease Definition": "A rare congenital skin disease defined as an abnormality of the structure of the scalp hair and characterized by extreme kinkiness of the hair.", "ORPHA ID": 170, "Summary": "Epidemiology\nPrevalence of woolly hair is unknown.\nClinical description\nWoolly hair can either be present at birth or appear in the first months of life. The curls, with an average diameter of 0.5 cm, lie closely together and usually make the hair difficult to comb; in addition, the hair may be more fragile than usual. The hair growth rate is usually normal but the anagen phase may be truncated, with the result that the hair does not grow to be long. Woolly hair either shows a generalized distribution affecting the entire scalp or a localized circumscribed distribution in the form of a woolly hair nevus. A diffuse partial form, manifesting during adolescence and adulthood, have also been described. In many cases, woolly hair is associated with hypotrichosis. Whilst wooly hair may occur as an isolated finding, it is important to exclude manifestations that occur in syndromic forms such as dilated cardiomyopathy and palmoplantar keratoderma (Carvajal syndrome), arrhythmogenic right ventricular cardiomyopathy and palmoplantar keratoderma (Naxos disease), or with growth failure and neurological symptoms (Menkes disease).\nEtiology\nIsolated forms are mostly due to homozygous or sometimes compound heterozygous mutations in the genes lipase H (LIPH, 3q27.2) and lysophosphatidic acid receptor 6 (LPAR6, 13q14.2), that act along a common pathway which plays an important role in the control of hair growth as well as hair texture. In only very few patients, heterozygous mutations have been reported in two keratin genes, namely KRT74 (12q13.13) and KRT71 (12q13.13). Mutations have also been reported in KRT25 (17q21.2 ). Recently, a new gene locus was reported for woolly hair on chromosome 4q35.1-q35.2 with a potential disease gene with one affected family only. The etiology of diffuse partial woolly hair and of sporadically occurring woolly hair nevi is unknown.\nDiagnostic methods\nA thorough dermatological examination with an evaluation of the entire integument should be performed and may also identify any associated manifestations. The examination of the hair shafts by light and electron microscopy reveals an elliptical cross section, variations in caliber, axis rotation and kinked formation, as well as non-homogeneous keratinization. In some cases trichorrexis nodosa is evident. If necessary, the anagen/catagen ratio can be determined using a trichogram. In cases of diffuse partial woolly hair, an increase in intermediate follicles can be detected histopathologically.\nDifferential diagnosis\nDifferential diagnosis includes acquired progressive curling of the hair, allotrichia circumscripta symmetrica, acquired partial kinky hair and drug-induced kinky hair. Syndromes with woolly hair should also be excluded, such as Naxos disease, Carvajal syndrome, Woolly hair-hypotrichosis-everted lower lip-outstanding ears syndrome, woolly-hair-palmoplantar keratoderma syndrome, and skin fragility-woolly hair-palmoplantar keratoderma syndrome.\nGenetic counseling\nGeneralized forms due to KRT74 and KRT71 mutations are autosomal dominant, and forms due to LIPH and LPAR6 mutations are autosomal recessive. Sporadic forms may also occur. Follicular mosaicism is likely, while an autosomal dominant transmission has also been discussed for diffuse partial woolly hair.\nManagement and treatment\nNo treatment is currently available. Depending on their size and location, woolly hair nevi can be excised. Harsh physical and chemical cosmetic treatments should be avoided. If the presence of a syndrome is suspected, an extensive internal investigation, with a detailed cardiological diagnostic examination, is necessary.\nPrognosis\nWoolly hair is most pronounced during childhood; the manifestations often become less severe in adulthood.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Regina BETZ  - Pr Ulrike BLUME-PEYTAVI"}
{"Disease Name": "Wormian bone-multiple fractures-dentinogenesis imperfecta-skeletal dysplasia", "Disease Definition": "A rare skeletal disorder characterized clinically by multiple fractures, wormian bones of the skull, dentinogenesis imperfecta and facial dysmorphism (hypertelorism, periorbital fullness). Although the signs are very similar to osteogenesis imperfecta, characteristic cortical defects in the absence of osteopenia and collagen abnormalities are considered to be distinctive. There have been no further descriptions in the literature since 1999.", "ORPHA ID": 166277, "Summary": ""}
{"Disease Name": "Worster-Drought syndrome", "Disease Definition": "Worster-Drought syndrome (WDS) is a form of cerebral palsy characterized by congenital pseudobulbar (suprabulbar) paresis manifesting as selective weakness of the lips, tongue and soft palate, dysphagia, dysphonia, drooling and jaw jerking.", "ORPHA ID": 3465, "Summary": "Epidemiology\nPrevalence is estimated at around 1/25,000-30,000, with a male predominance (male to female sex ratio: 3:1).\nClinical description\nMean age at diagnosis is 6 years. The main clinical features are spasticity and limited movements around the mouth and throat from an early age, and brisk jaw jerks. In severe cases, the muscles of the pharynx and larynx are also involved. Epilepsy, learning difficulties and behavioral disturbances are common. Mild pyramidal tetraplegia, glue ear, recurrent respiratory infections and aspiration, and gastroesophageal reflux may be present in up to 40% of patients. WDS is associated with bilateral lesions of the corticobulbar tract. Cranial nerves VII, X, and XII are implicated.\nDiagnostic methods\nDiagnosis is made on the basis of patient history, clinical examination and magnetic resonance imaging studies.\nDifferential diagnosis\nThe main differential diagnosis is the bilateral perisylvian polymicrogyria (see this term) which manifests with severe epilepsy Clinical overlap of WDS with congenital bilateral perisylvian polymicrogyria and Foix-Chavany-Marie syndrome (see these terms) has been noted. Some authors propose that these three conditions represent a continuum.\nGenetic counseling\nMost cases are sporadic but several families with more than one affected member have been reported. Inheritance in these families appeared to follow an autosomal dominant pattern with variable expression and penetrance.\nManagement and treatment\nManagement is dependent on the degree of feeding difficulties and speech problems but should include multidisciplinary approach by a pediatrician, speech therapist and educational psychologist. Children with epilepsy are treated with antiepileptic drugs.\nPrognosis\nWDS has a non-progressive course. The overall prognosis is good when nutritional problems, epilepsy and respiratory complications are properly managed.\n\n                            Last update: \n                            October 2009\n\n\n                            - Expert reviewer(s): \n                            Pr Jaime CAMPOS-CASTELLÓ"}
{"Disease Name": "Wound botulism", "Disease Definition": "Wound botulism is a rare infectious form of botulism (see this term), a rare acquired neuromuscular junction disease with descending flaccid paralysis due to botulinum neurotoxins (BoNTs), produced after infection of wounds by Clostridium botulinum.", "ORPHA ID": 178475, "Summary": "Epidemiology\nPrevalence is unknown. So far, about 700 cases have been reported worldwide.\nClinical description\nClinical manifestations are similar to other forms of botulism (symmetrical cranial nerve palsy, followed by symmetrical descending flaccid motor paralysis) in particular those of foodborne botulism (see this term), except for the lack of gastrointestinal symptoms (nausea, vomiting, and diarrhea) and the possible presence of fever. The disease, formerly related to traumatic injury, or rarely to surgery, nowadays affects mainly intravenous drug users (IDUs), mostly adults in the fourth or fifth decade of life with a long history of use of injected (``skin popping'') or inhaled drugs and is related to contaminated material or to contaminated black tar heroin. Wound botulism is an infectious but non communicable disease. The incubation period, in case of traumatic injuries, is considered to be 7 to 14 days, but it is difficult to establish for IDUs, as they may inject drugs several times daily.\nEtiology\nWound botulism is due to the colonization of a wound, boil, abscess, or inoculation site by C. botulinum spores with subsequent germination and BoNT production in vivo, at the site of infection. The toxin reaches the neuromuscular junctions through the blood stream. The reported cases are related to C.botulinum type A and type B but one case has been related to C.botulinum type E.\nDiagnostic methods\nInitial diagnosis of wound botulism is based on clinical suspicion in patients with a recent infected wound or history of drug use. Sometimes lesions are not apparent and the presence of deep-seated abscess or sinusitis should be considered. Definitive diagnosis requires laboratory investigations for the detection of BoNTs in serum and wounds. The detection of BoNT-producing Clostridia/i> in wound cultures is generally satisfactory for laboratory diagnosis. Analysis of stools and food may be useful to exclude other forms of botulism.\nDifferential diagnosis\nDifferential diagnosis includes myasthenia gravis, Guillain-Barré syndrome (Miller-Fisher syndrome), Lambert-Eaton syndrome, and foodborne and adult intestinal botulism (see these terms).\nManagement and treatment\nAntitoxin therapy must be associated with supportive care in an intensive care unit (ICU). Antitoxin therapy is effective when it is administrated at the onset of symptoms. In Europe, the formulation currently available for adults is trivalent (anti A, B, E). A heptavalent (anti A to G) product is also available. In the USA, a bivalent (anti A, B) and a monovalent (anti E) antitoxin are available. Specific management of wound botulism includes surgical debridement of the wound with irrigation to remove the source of the toxin and antibiotic therapy with penicillin and metronidazole. Aminoglycoside and clindamycin should be avoided as they may exacerbate the neuromuscular blockade.\nPrognosis\nWith appropriate intensive care, prognosis is good; death occurs in only 7% of cases and results from respiratory failure. Wound botulism may recur in IDUs.\n\n                            Last update: \n                            April 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Lucia FENICIA"}
{"Disease Name": "Wound myiasis", "Disease Definition": "A rare cutaneous myiasis characterized by infestation of open wounds by dipterous fly larvae. Mucous membranes and body cavity openings can also be affected. The condition may be accompanied by fever, pain, and secondary infections and can lead to massive tissue destruction and even death. Predisposing factors for larval infestation are poor hygiene, advanced or very young age, alcoholism, diabetes, and vascular occlusive disease, among others.", "ORPHA ID": 165955, "Summary": ""}
{"Disease Name": "Wrinkly skin syndrome", "Disease Definition": "Wrinkly skin syndrome (WSS) is characterized by wrinkling of the skin of the dorsum of the hands and feet, an increased number of palmar and plantar creases, wrinkled abdominal skin, multiple skeletal abnormalities (joint laxity and congenital hip dislocation), late closing of the anterior fontanel, microcephaly, pre- and postnatal growth retardation, developmental delay and facial dysmorphism (a broad nasal bridge, downslanting palpebral fissures and hypertelorism).", "ORPHA ID": 2834, "Summary": "Epidemiology\nPrevalence is unknown but only around 30 cases have been reported in the literature so far.\nClinical description\nAlthough the clinical picture is milder, WSS also shows significant overlap with classic features of ARCL2 (also known as Debré-type cutis laxa), leading to the suggestion that WSS and ARCL2 are variable manifestations of the same disorder. The clinical spectrum in WSS also closely resembles that of geroderma osteodysplastica (GO) and to some extent that of De Barsy syndrome (DBS; see these terms).\nEtiology\nAlthough the etiology in some patients remains unknown, mutations in the ATP6V0A2 gene (12q24.31) have been identified both in patients with WSS and in those with autosomal recessive cutis laxa (ARCL) type 2 (see this term). Mutations in the PYCR1 gene (17q25.3) have recently been identified in patients with phenotypes (wrinkly skin, osteopenia and progeroid features) overlapping with ARCL2, GO and DBS.\nDiagnostic methods\nHistological findings are not pathognomonic for WSS (elastic fiber abnormalities may be mild or nonspecific) but may allow WSS to be distinguished from ARCL2 and ARCL1 (see this term).\nGenetic counseling\nWSS is transmitted in an autosomal recessive manner.\nManagement and treatment\nTreatment is symptomatic.\nPrognosis\nPatients with WSS syndrome have a variable outcome. The prognosis depends on the underlying mutation and appears to be most benign in children with a mutation in the ATP6V0A2 gene.\n\n                            Last update: \n                            July 2010\n\n\n                            - Expert reviewer(s): \n                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS"}
{"Disease Name": "WT limb-blood syndrome", "Disease Definition": "A rare constitutional aplastic anemia disorder characterized by severe hypo/aplastic anemia or pancytopenia associated with skeletal anomalies (such as radial/ulnar defects and hand/digit abnormalities) and an increased risk of leukemia. There have been no further descriptions in the literature since 1995.", "ORPHA ID": 3466, "Summary": ""}
{"Disease Name": "Wyburn-Mason syndrome", "Disease Definition": "Wyburn-Mason syndrome or Bonnet-Dechaume-Blanc syndrome is characterized by the association of arteriovenous malformations of the maxilla, retina, optic nerve, thalamus, hypothalamus and cerebral cortex.", "ORPHA ID": 53719, "Summary": "Epidemiology\nThe prevalence is not known but it is very rare: fewer than 100 cases have been reported in the literature to date. The sex ratio is even.\nClinical description\nMalformations appear successively, sometimes over several tens of years. Neurological clinical signs include: progressive neurological deficits depending on the location of the malformation, epilepsy or cephalalgia. These symptoms result in venous congestion and hemorrhage. Psychomotor delay in childhood is not common. The associated maxillofacial lesions lead to asymmetries or deformations of the face, impairment of maxillofacial osseous growth and, in intraosseous maxillo-mandibular locations, serious oral hemorrhages. The visual symptoms are caused by arteriovenous malformations of the retina and depend on the size and location of malformations (retina, optical nerve, chiasma). Partial manifestations of the syndrome (incomplete spectrum) are possible.\nEtiology\nWyburn-Mason syndrome is caused by an anomaly in organogenesis, however the etiology and risk factors are unknown. There are no familial forms of the syndrome. The connection between lesions of the same angio-architectural nature, but in different locations, can be explained by the regionalized origin of cells of the vascular walls in the cephalic region, and their migration. The cells of vessels in the facial, orbital, maxillary or mandibular, and encephalic areas come from three large embryonic regions. An embryonic defect in a cellular group before its migration to its final destination may `spread' vascular lesions along the route of migration. This gives rise to cerebrofacial metameric or segmental syndromes (CAMS) called CAMS1, CAMS2 and CAMS3 according to the region from which the cells depart: CAMS1 (corpus callosum, hypothalamus, olfactory tract, forehead, nose), Wyburn-Mason syndrome that has been renamed CAMS2 (cortex and diencephalon, optic chiasma, optic nerve, retina, sphenoid, maxilla, cheek) and CAMS3 (cerebellum, temporal bone, mandible).\nDiagnostic methods\nMagnetic resonance imaging (MRI) is the best diagnostic instrument and provides information on the extent of the anomalies. An arteriogram then allows a more detailed analysis of the angio-architecture of the lesions, revealing the absence of capillary vessels that normally connect arteries and veins. It is most often impossible to completely treat cerebral vascular malformations because of the extent and architecture of the lesions.\nManagement and treatment\nTargeted partial treatment through the endovascular route aims to isolate the region at risk of malformation. It can be successful in dentoalveolar and cerebral locations if a particular weakness has been identified using MRI or arteriogram. Combined management with embolization and surgery is most often necessary for maxillofacial malformations.\nPrognosis\nThe early appearance of neurological problems is an unfavorable factor for long term prognosis.\n\n                            Last update: \n                            March 2007\n\n\n                            - Expert reviewer(s): \n                            Dr Hortensia ALVAREZ  - Pr Pierre LASJAUNIAS"}
{"Disease Name": "X small rings", "Disease Definition": "X small rings is a rare chromosome X structural anomaly, with highly variable phenotype, principally characterized by developmental delay, intellectual disability, short stature, craniofacial dysmorphism (incl. microcephaly, facial asymmetry, hypertelorism, long palpebral fissures, epicanthus, low-set or malrotated ears, broad nose with a flat nasal bridge, anteverted nares, long philtrum, thin upper lip, high arched palate, micrognathia) and skeletal anomalies (e.g. cubitus valgus, talipes equinovarus). Patients may also present heart malformations (e.g. ventricular septal defects, mitral valve stenosis), sacral dimple, soft tissue syndactyly, pigmented nevi, and seizures.", "ORPHA ID": 96201, "Summary": ""}
{"Disease Name": "X-linked acrogigantism", "Disease Definition": "A rare, genetic pituitary disease characterized by infantile-onset, rapid and excessive acceleration of linear growth and body size due to mixed growth hormone (GH)- and prolactin-secreting adenomas and/or pituitary hyperplasia. Patients present with gigantism and may have associated acromegalic features (e.g. coarse facial features, frontal bossing, prognathism, increased interdental space) as well as marked enlargement of hands and feet, soft tissue swelling, increased appetite and acanthosis nigricans.", "ORPHA ID": 300373, "Summary": "Epidemiology\nTo date, less than 40 cases have been described worldwide. It accounts for 10% of cases of pituitary gigantism with a known genetic cause.\nClinical description\nThe onset of disease is in early infancy and may even be present as early as the neonatal period. Pituitary adenoma and/or hyperplasia leads to hypersecretion of GH and insulin-like growth factor 1 (IGF-1). Prolactin secretion is elevated in almost all cases and approximately one third of patients have elevated circulating levels of hypothalamic growth hormone releasing hormone (GHRH). Elevated GH and IGF-1 lead to increased growth in infants, that is usually apparent in the first 12 months of life, and a diagnosis is made usually by the age of 3 years. Increased height and weight are associated with marked increases in hand and foot sizes. Pituitary adenomas are usually macroadenomas (>10 mm diameter) at diagnosis. Height increases in affected children can be very marked in comparison with their peers (Z scores >+5 to +8.7 SDS).\nEtiology\nThe disorder is caused by a GH and prolactin secreting pituitary adenoma and/hyperplasia. Patients with X-linked acrogigantism have a duplication on chromosome Xq26.3 that includes the gene GPR101, which is highly overexpressed in pituitary adenoma tissue.\nDiagnostic methods\nDiagnostic methods include array comparative genomic hybridization (aCGH) and digital droplet PCR as genetic tests.\nDifferential diagnosis\nIn early childhood pituitary gigantism due to a growth hormone secreting pituitary adenoma can be associated with other conditions like AIP germline mutations, McCune-Albright syndrome, and rarely MEN1 syndrome, or Carney complex. For familial X-LAG, the main differential diagnosis is familial isolated pituitary adenomas (FIPA).\nAntenatal diagnosis\nPrenatal diagnosis is possible.\nGenetic counseling\nThe condition is X-linked dominant; however most cases occur sporadically. X-linked mother-to-son transmission has been reported in three cases; no cases of paternal transmission has been identified to date. Where there is vertical transmission, the Xq26.3 duplication occurs constitutively in the germline; in contrast, sporadic male cases exhibit somatic mosaicism. Genetic counseling should be proposed to individuals having the germline disease-causing Xq26.3 duplication informing them that there is 50% risk of passing the mutation to offspring.\nManagement and treatment\nThe disorder usually requires a multimodal therapeutic approach combining surgery, medical therapy and rarely radiotherapy. As the anterior pituitary can be extensively affected by adenoma and hyperplasia, early effective treatment to lower growth hormone and IGF-1 to normal levels can be challenging. In many cases, radical neurosurgery is required to widely resect affected anterior pituitary tissue. Residual tumor tissue can lead to long-term growth hormone and IGF-1 over-secretion and continued overgrowth; medical therapy with a growth hormone antagonist (pegvisomant) is usually effective. In X-linked acrogigantism, hormonal control with a somatostatin analog therapy is usually unsuccessful. Control of elevated prolactin levels can be achieved using a low-dose dopamine agonist. Hypopituitarism, involving multiple hormonal axes, and diabetes insipidus are possible post-surgical complications.\nPrognosis\nWithout effective intervention, pituitary gigantism worsens in severity and expansion of the pituitary adenoma continues. Early diagnosis and effective treatment in X-linked acrogigantism can lead to normal adult height. Unmanaged hypopituitarism may lead to morbidity.\n\n                            Last update: \n                            November 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Albert BECKERS  - Dr Adrian DALY"}
{"Disease Name": "X-linked adrenal hypoplasia congenita", "Disease Definition": "A rare genetic adrenal disease characterized by primary adrenal insufficiency (AI) and/or hypogonadotropic hypogonadism (HH). Male patients typically present with AI with acute onset in infancy or insidious onset in childhood. Clinical features of AI include hyperpigmentation, vomiting, poor feeding, failure to thrive, seizures, vascular collapse, and sometimes sudden death. HH manifests later as delayed or arrested puberty. In rare cases, patients become symptomatic in early adulthood with delayed-onset AI, partial HH, and/or infertility. Histologically, the adrenal glands lack the permanent adult cortical zone. The remaining cells are larger than fetal adrenal cells (''cytomegalic'') and contain characteristic nuclear inclusions.", "ORPHA ID": 95702, "Summary": ""}
{"Disease Name": "X-linked adrenoleukodystrophy", "Disease Definition": "A rare progressive peroxisomal disorder characterized by endocrine dysfunction (adrenal failure and sometimes testicular insufficiency), progressive myelopathy, peripheral neuropathy and, variably, progressive leukodystrophy.", "ORPHA ID": 43, "Summary": "Epidemiology\nX-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder with an estimated birth prevalence of 1/17,000 (male and female). It has been reported throughout the world.\nClinical description\nX-ALD affects males and females, although symptoms and disease progression differ. The age of onset is highly variable and the rate of progression is unpredictable. Male patients usually present in childhood with signs and symptoms of adrenal failure (80% of male patients develop adrenal failure before the age of 18) or with a rapidly progressive leukodystrophy (40% of male patients before the age of 18, with a lifetime prevalence of 60%). Leukodystrophy is initially clinically silent, but eventually neuropsychiatric symptoms develop, followed by focal deficits like hemiparesis and auditory agnosia, and occasionally epileptic seizures. In early adulthood male patients develop a progressive myelopathy (and peripheral neuropathy) with a gait disorder and incontinence. Progression is slow (over years). Penetrance of this myelopathy is complete, although age of onset and progression are highly variable (some patients require a walking aid whilst others remain ambulatory). Female patients virtually never develop adrenal failure or leukodystrophy. About 90% develop a myelopathy and peripheral neuropathy, but at a later age (after 40 years of age) and with slower progression (over decades) than in males.\nEtiology\nX-ALD is caused by variants of ABCD1 (Xq28), with about 900 different mutations reported. There is no geno-phenotype correlation. The encoded protein peroxisomal transmembrane protein is involved in the transport of very long-chain fatty acid CoA-esters (VLCFA) from the cytosol into the peroxisome. Although the exact pathophysiology is poorly understood, perturbed VLCFA homeostasis in glial cells may contribute to the destabilization of the myelin sheath and impairment of axonal function.\nDiagnostic methods\nIf there is clinical suspicion, the diagnosis is established by determining plasma VLCFA (C26:0 and C26:0/C22:0 ratio) which is increased in all male patients; up to 15% of female patients have normal VLCFA. Recently, C26:0-lysophosphatidylcholine in bloodspots or plasma has been validated as diagnostic marker, and is elevated in all male and virtually all female patients. The diagnosis can be confirmed by ABCD1 mutation analysis. If necessary, functional assays in cultured skin fibroblasts are available. In case of leukodystrophy, the MRI pattern is virtually pathognomonic. Adrenal failure can be established with an ACTH stimulation test. Newborn screening for X-ALD has been recently implemented in certain regions.\nDifferential diagnosis\nTesting for X-ALD is recommended in all males presenting with adrenal failure (especially in cases of isolated glucocorticoid deficiency). In adult men or women presenting with a chronic myelopathy, the differential diagnosis is large and includes both acquired and genetic disorders. There is no relevant differential diagnosis for presentation with leukodystrophy.\nAntenatal diagnosis\nIn case of a positive family history and a fetus at risk, genetic prenatal diagnosis is possible.\nGenetic counseling\nThe disorder is X-linked. Male patients transmit the disorder to all of their daughters, but never to a son. Female patients transmit the disorder to 50% of their sons and daughters. In case a patient is diagnosed, family screening and counseling is recommended.\nManagement and treatment\nAdrenal insufficiency in X-ALD is treated by hydrocortisone (and if needed fludrocortisone) by an endocrinologist. For the progressive myelopathy there is currently no disease modifying treatment available. The leukodystrophy is treatable with allogeneic hematopoietic cell transplant (HCT), although the outcome is only acceptable when treated in the early stages (Loes score < 9). Autologous HCT after ex vivo lentiviral gene therapy is pending approval in the U.S.A and Europe.\nPrognosis\nPre-symptomatic diagnosis permits monitoring for the occurrence of adrenal failure and the onset of cerebral ALD. If appropriate treatment is initiated, severe morbidity and mortality can be prevented. There is currently no treatment to prevent the occurrence or progression of the myelopathy. However, with appropriate supportive care life expectancy is near normal.\n\n                            Last update: \n                            July 2021\n\n\n                            - Expert reviewer(s): \n                            Dr M. [Marc] ENGELEN | ERN-RND*\n\n\n                                * European Reference Network"}
{"Disease Name": "X-linked agammaglobulinemia", "Disease Definition": "A clinically variable form of isolated agammaglobulinemia, an inherited immunodeficiency disorder, characterized in affected males by recurrent bacterial infections during infancy.", "ORPHA ID": 47, "Summary": "Epidemiology\nEstimated prevalence is 1/350,000 to 1/700,000. Annual incidence is not known. The disorder has been reported in various ethnic groups worldwide. Only males are affected and females are asymptomatic carriers.\nClinical description\nAffected individuals are usually healthy in the first few months of life due to residual maternal immunoglobulins. The majority of patients develop recurrent or persistent bacterial infections, most commonly caused by S. pneumoniae and H. influenzae, within the first two years of life,: otitis media, conjunctivitis, sinusitis, respiratory infections, diarrhea and skin infections (impetigo, cellulitis, abscesses, and furuncles). Other severe infections may include empyema, meningitis, sepsis, or septic arthritis. Pyoderma or cellulitis (associated with neutropenia) and pseudomonas or staphylococcal sepsis are frequent presenting findings, particularly in patients less than 12 months of age. Lymph nodes, tonsils, and other lymphoid tissues are unusually small or absent. Rare patients are reported to have vitiligo, erythematous rash, or alopecia totalis. Infections tend to persist throughout adulthood. Affected patients are reported to have a higher susceptibility to severe and chronic enteroviral infections. Growth and development are usually normal. Some patients have a less severe clinical presentation and are not recognized as immunodeficient until 10 years of age or later. Complications of X-linked agammaglobulinemia (XLA) include progressive lung disease, chronic sinusitis, inflammatory bowel disease, arthritis , as well as neurological changes.\nEtiology\nXLA is caused by mutations in the BTK gene (Xq21.33-q22) involved in B lymphocyte differentiation and maturation.\nDiagnostic methods\nA diagnosis of XLA should be considered in patients with recurrent or persistent otitis media, pneumonia, sinusitis, and conjunctivitis starting before age five years or severe bacterial infections such as sepsis, meningitis, cellulitis, or empyema. A family history consistent with X-linked transmission also points to this diagnosis. Suspicion can be confirmed with blood tests showing low serum Ig and markedly reduced B lymphocyte counts. Molecular genetic testing can also be used to establish or confirm the diagnosis.\nDifferential diagnosis\nDifferential diagnoses include autosomal recessive or dominant agammaglobulinemia, common variable immunodeficiency (CVID), hyper IgM syndrome and severe combined immunodeficiency (SCID) (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible following identification of the disease-causing mutation in the family.\nGenetic counseling\nXLA, as the name indicates, follows an X-linked pattern of inheritance. Nearly 50% of cases are familial, while the remainder are thought to be related to de novo mutations. Genetic counseling should be provided to members of affected families.\nManagement and treatment\nThere is no curative treatment for XLA but good disease control can be achieved through consistent gammaglobulin therapy. This can be given intravenously (400-600 mg/kg every 3 to 4 weeks) or subcutaneously (100 mg/kg every week). Therapy should be started as early as possible. Some immunologists advocate chronic prophylactic antibiotics and treatment of acute infections should be prolonged and at maximal doses of antibiotics.\nPrognosis\nMost patients with XLA lead a normal life. Life expectancy may be reduced in some patients as a result of complications such as severe infections and chronic pulmonary damage. Early therapeutic measures and treatment compliance are major prognostic factors.\n\n                            Last update: \n                            December 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Marie Ellen CONLEY"}
{"Disease Name": "X-linked alpha-thalassemia-intellectual disability syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by profound developmental delay, facial dysmorphism, genital abnormalities and alpha thalassemia.", "ORPHA ID": 847, "Summary": "Epidemiology\nMore than 200 patients with X-linked alpha thalassemia intellectual disability (ATR-X) syndrome have been reported. Whilst data is limited worldwide, in Japan the prevalence at birth is estimated at 1/60,000-80,000. Males are predominantly affected.\nClinical description\nAffected neonates may present with hypotonia and feeding difficulties. The distinctive facial appearance is most readily recognized in early childhood. Facial hypotonia is associated with upswept frontal hair, widely spaced eyes with epicanthic folds, a depressed nasal bridge and a small triangular upturned nose. The upper lip is tented and the lower lip full and everted. The frontal incisors are widely spaced and there is prodigious drooling. Language is usually very limited. Motor milestones may be delayed and some children never walk. Seizures occur in about one third of the cases. While many patients are affectionate with their caregivers, some exhibit autistic-like behavior. Genital abnormalities are observed in 80% of children and range from undescended testes to ambiguous genitalia. Microcephaly and short stature are common. Alpha thalassemia is not always present. Female carriers are usually physically and intellectually normal.\nEtiology\nThis syndrome is X-linked recessive and results from mutations in the ATRX gene (Xq21.1). This gene encodes the widely expressed ATRX protein. ATRX mutations cause diverse changes in the epigenetic landscape throughout the genome including the pattern of DNA methylation. These are associated with changes in gene expression which are thought to contribute to the clinical phenotype.\nDiagnostic methods\nThe diagnosis can be established by detection of alpha thalassemia, identification of ATRX gene mutations, characteristic changes in DNA methylation, ATRX protein studies in affected males and X-inactivation studies in carrier females.\nDifferential diagnosis\nThere is phenotypic overlap with Coffin-Lowry syndrome, Angelman syndrome, Smith-Lemli-Opitz syndrome and Pitt-Hopkins syndrome. There are readily available diagnostic tests for these disorders.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.\nGenetic counseling\nThe disorder is an X-linked recessive condition. With the exception of two reported heterozygous females with intellectual disability, female carriers are phenotypically and intellectually normal. Genetic counseling should be offered to mothers and female relatives of affected individuals. For a female who has been identified as a carrier, there is a 50% risk of passing on the disease allele with each pregnancy but, since only males are clinically affected, the risk of having an affected child is 25% for each pregnancy.\nManagement and treatment\nManagement is multidisciplinary. Young children must be carefully monitored for gastro-esophageal reflux as it may cause death through aspiration. Episodes of unexplained persistent distress may have a gastrointestinal cause with volvulus a known cause. Drooling is frequently seen but, because of reduced gastrointestinal motility, anticholinergics should be used with caution. Constipation is common and initial treatment should be standard. The possibility of cryptorchidism should be assessed in all children. Intra-abdominal testes, which are usually dysgenic, should be removed because of the long-term risk of malignancy. Abnormalities of the renal/urinary system are common, can lead to urinary tract infections, and should be investigated at diagnosis. Alpha thalassemia may be present and give rise to a mild hypochromic, microcytic anemia; this does not require treatment. Iron is not indicated unless the iron stores are low. Asplenia is rare, but if confirmed, antibody prophylaxis and vaccination to prevent pneumococcal and menigococcal infections is recommended. Osteosarcoma has been observed in a small number of affected individuals; painful lesions of the bones should be investigated to exclude osteosarcoma.\nPrognosis\nA number of individuals with ATR-X are fit and well in their 30s and 40s.\n\n                            Last update: \n                            October 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Richard GIBBONS"}
{"Disease Name": "X-linked Alport syndrome-diffuse leiomyomatosis", "Disease Definition": "A rare renal disease characterized by the association of X-linked Alport syndrome (glomerular nephropathy, sensorineural deafness and ocular anomalies) and benign proliferation of visceral smooth muscle cells along the gastrointestinal, respiratory, and female genital tracts and clinically manifests with dysphagia, dyspnea, cough, stridor, postprandial vomiting, retrosternal or epigastric pain, recurrent pneumonia, and clitoral hypertrophy in females.", "ORPHA ID": 1018, "Summary": "Epidemiology\nPrevalence of X-linked Alport syndrome-diffuse leiomyomatosis (XLAS-DL) is unknown. It affects both males and females.\nClinical description\nSymptoms of glomerular disease (hematuria, progressive proteinuria and renal impairment) typically appear late in childhood, and in males is more severe with faster progression. Patients also have sensorineural deafness and ocular anomalies (anterior lenticonus, congenital cataracts, corneal opacities, maculopathy, fleck retinopathy and temporal retinal thinning). Diffuse leiomyomatosis is severe in males and in females, and typically involves the esophagus, causing dysphagia, postprandial vomiting and retrosternal or epigastric pain. Tracheobronchial lesions lead to dyspnea, cough, stridor and recurrent pneumonia due to aspiration. Affected females show clitoral hypertrophy and variable involvement of labia majora and uterus. Perirectal or perineal leiomyomas are uncommon and associated with constipation.\nEtiology\nXLAS-DL is due to contiguous gene deletions encompassing the 5' ends of COL4A5 (Xq22.3) and COL4A6 (Xq22.3) genes, which respectively encode the alpha-5 and alpha-6 chain of type IV collagen. COL4A5 is an integral component of the type IV collagen 3,4,5 network, a key component of the glomerular basement membrane (GBM), and COL4A6 is a component of the type IV collagen 5,5,6 network present in Bowman's capsule but not in the healthy GBM.\nDiagnostic methods\nX-linked Alport syndrome is suspected on clinical presentation and family history of hematuria, deafness and/or renal impairment, and is confirmed by genetic analysis of COL4 genes. Histological evaluation of the kidney is valuable in case of equivocal or unavailable genetic testing. Immunohistochemical assays can also be performed on kidney and skin specimens, and electron microscopy provides ultrastructural analysis of basement membranes. An abnormal expression pattern of type IV collagen chains confirms the diagnosis; however, a normal expression does not eliminate diagnosis. The diagnosis of leiomyomatosis requires a biopsy of the affected tissue. Radiological imaging can identify lesions and the associated deformation of the affected tract.\nDifferential diagnosis\nThe differential diagnosis regarding the combination of glomerular disease with deafness includes Fechtner syndrome, MYH9-related disease, MELAS and May-Hegglin thrombocytopenia. The main differential diagnosis for glomerular hematuria is IgA nephropathy, familial benign hematuria and membranoproliferative glomerulonephritis. Leiomyomata can occur as sporadic benign smooth muscle tumors, without AS.\nAntenatal diagnosis\nPrenatal testing for at risk pregnancies is possible where the COL4A5-COL4A6 deletion has been previously identified in a family member, and if a molecular diagnosis of the inherited deletion can be reliably performed.\nGenetic counseling\nXLAS-DL is transmitted as X-linked dominant trait and, thus, heterozygous females will also express the disease. Genetic counseling for affected families is recommended.\nManagement and treatment\nRegular monitoring of blood pressure and urinalysis are important to identify hypertension or microalbuminuria/proteinuria and treat accordingly with angiotensin converting enzyme inhibitors/angiotensin receptor blockers. This additionally permits timely clinical management of chronic kidney disease, including eventual renal replacement therapy with either preemptive transplantation or dialysis. Surgical intervention is required for symptomatic leiomyomas. Ocular manifestations rarely need intervention but an ophthalmologist is helpful for diagnosis since ocular involvement is often asymptomatic. Audiological evaluation should be performed regularly and hearing aids should be prescribed when appropriate.\nPrognosis\nThe prognosis of AS is poor due to the progression to ESRD (often affecting young adults). Renal transplantation is successful in individuals with AS, since development of anti-glomerular basement membrane antibodies is a rare event.\n\n                            Last update: \n                            February 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Laurence HEIDET | ERKNet* - Pr Rachel LENNON | ERKNet*\n\n\n                                * European Reference Network"}
{"Disease Name": "X-linked calvarial hyperostosis", "Disease Definition": "A rare, genetic, primary bone dysplasia with increased bone density disorder characterized by benign, isolated, calvarial thickening, presenting with prominent frontoparietal bones, a high forehead with ridging of the metopic and sagittal sutures, lateral frontal prominences, and facial dysmorphism comprising a flat nasal root and short, upturned nose. Increased intracranial pressure and cranial nerve entrapment are not associated. There have been no further descriptions in the literature since 1986.", "ORPHA ID": 391327, "Summary": ""}
{"Disease Name": "X-linked central congenital hypothyroidism with late-onset testicular enlargement", "Disease Definition": "X-linked central congenital hypothyroidism with late-onset testicular enlargement is a rare, genetic, endocrine disease characterized by central hypothyroidism, testis enlargement in adolescence resulting in adult macroorchidism, delayed pubertal testosterone rise with a subsequent delayed pubertal growth spurt, small thyroid gland, and variable prolactin and growth hormone deficiency.", "ORPHA ID": 329235, "Summary": ""}
{"Disease Name": "X-linked centronuclear myopathy", "Disease Definition": "A rare X-linked congenital myopathy characterized by numerous centrally placed nuclei on muscle biopsy and that presents at birth with marked weakness, hypotonia and respiratory failure.", "ORPHA ID": 596, "Summary": "Epidemiology\nThe birth prevalence of X-linked centronuclear myopathy (XLMTM) is estimated at 1/50,000 males.\nClinical description\nThe disease is characterized by a severe phenotype in males presenting at birth with marked weakness, hypotonia and respiratory failure. Signs of antenatal onset are frequent and comprise reduced fetal movements and polyhydramnios. Thinning of the ribs is observed on chest radiographs of the newborn. Birth asphyxia may be the presenting feature. A family history of either male neonatal deaths or miscarriages is common. Affected infants are often macrosomic, with a body length above the 90th centile and large head circumference. External ophthalmoplegia is commonly associated. Testes are frequently undescended. Pyloric stenosis and cavernous hemangiomas of the liver have been reported in some long-term survivors.\nEtiology\nXLMTM is caused by mutations in the myotubularin (MTM1); Xq27.3-q28) gene.\nDiagnostic methods\nDiagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features. Genetic testing confirms the diagnosis.\nDifferential diagnosis\nThe main differential diagnoses include congenital myotonic dystrophy and other conditions characterized by severe neonatal hypotonia.\nAntenatal diagnosis\nPrenatal diagnosis is possible where the mutation has been previously identified in a family member.\nGenetic counseling\nThe pattern of inheritance is x-linked recessive. Where the female is a carrier, the risk to male offspring inheriting the disease is 50%; female offspring have a 50% risk of being carriers. The degree of disease penetrance depends on skewed X-inactivation; the majority of female disease carriers are asymptomatic but may show signs of only mild muscle weakness or urinary incontinence, indicating smooth muscle involvement. Genetic counseling should be offered to all patients and families.\nManagement and treatment\nThere is currently no curative treatment available. Management is supportive and based on a multidisciplinary approach.\nPrognosis\nIn the majority of cases, the course is fatal within the first months of life. A proportion of affected males may survive into their teens or beyond. In these cases, the survival depends on a substantial degree of medical intervention and often constant ventilation.\n\n                            Last update: \n                            March 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Enrico BERTINI  - Dr Adele D'AMICO  - Pr Fabiana FATTORI"}
{"Disease Name": "X-linked cerebral adrenoleukodystrophy", "Disease Definition": "A progressive peroxisomal disease, characterized by endocrine dysfunction (adrenal failure and sometimes testicular insufficiency), progressive myelopathy and peripheral neuropathy, and leukodystrophy. Age of onset is highly variable, but often in the first decade.", "ORPHA ID": 139396, "Summary": ""}
{"Disease Name": "X-linked cerebral-cerebellar-coloboma syndrome", "Disease Definition": "X-linked cerebral-cerebellar-coloboma syndrome is a rare, genetic syndrome with a cerebellar malformation as major feature characterized by cerebellar vermis hypo- or aplasia, ventriculomegaly, agenesis of corpus callosum and abnormalities of the brainstem and cerebral cortex in association with ocular coloboma. Clinically, patients show hydrocephalus at birth, neonatal hypotonia with abnormal breathing pattern, ocular abnormalities with impaired vision, severe psychomotor delay, and seizures.", "ORPHA ID": 163961, "Summary": ""}
{"Disease Name": "X-linked Charcot-Marie-Tooth disease type 1", "Disease Definition": "A rare genetic peripheral sensorimotor neuropathy characterized by an X-linked dominant inheritance pattern and adolescence onset in males of progressive, distal, moderate to severe muscle weakness and atrophy in lower extremities and intrinsic hand muscles, pes cavus, bilateral foot drop, reduced or absent tendon reflexes, as well as mild to moderate sensory impairment in lower extremities. Females tend to have milder manifestations or may be asymptomatic. Sensorineural deafness and (often transient) central nervous system involvement have also been reported.", "ORPHA ID": 101075, "Summary": ""}
{"Disease Name": "X-linked Charcot-Marie-Tooth disease type 2", "Disease Definition": "A rare genetic peripheral sensorimotor neuropathy characterized by an X-linked recessive inheritance pattern and the infantile-to childhood-onset of progressive, distal muscle weakness and atrophy (more prominent in the lower extremities than in the upper extremities), pes cavus, and absent tendon reflexes. Sensory impairment and intellectual disability has been reported in some individuals.", "ORPHA ID": 101076, "Summary": ""}
{"Disease Name": "X-linked Charcot-Marie-Tooth disease type 3", "Disease Definition": "A rare genetic peripheral sensorimotor neuropathy characterized by an X-linked recessive inheritance pattern and the childhood onset of progressive, distal muscle weakness and atrophy (beginning in the lower extremities and then affecting the upper extremities), as well as distal, pansensory loss in the upper and lower extremities, pes cavus, and absent or reduced distal tendon reflexes. Pain and paresthesia are frequently the initial sensory symptoms.", "ORPHA ID": 101077, "Summary": ""}
{"Disease Name": "X-linked Charcot-Marie-Tooth disease type 4", "Disease Definition": "A rare genetic, axonal, peripheral sensorimotor neuropathy, characterized by an X-linked recessive inheritance pattern and the neonatal- to early childhood-onset of severe, slowly progressive, distal muscle weakness and atrophy (in particular of the peroneal group), as well as sensory impairment (with the lower extremities being more affected than the upper extremities), pes cavus, areflexia and hammertoes. Sensorineural hearing loss and cognitive impairment may also be associated. Females are asymptomatic and do not display the phenotype.", "ORPHA ID": 101078, "Summary": ""}
{"Disease Name": "X-linked Charcot-Marie-Tooth disease type 5", "Disease Definition": "A rare genetic peripheral sensorimotor neuropathy characterized by infancy-to childhood onset of progressive distal muscle weakness and atrophy (first appearing and more prominent in the lower extremities than the upper) which usually manifests with foot drop and gait disturbance, bilateral, profound, prelingual sensorineural hearing loss and progressive optic neuropathy.", "ORPHA ID": 99014, "Summary": ""}
{"Disease Name": "X-linked Charcot-Marie-Tooth disease type 6", "Disease Definition": "A rare genetic peripheral sensorimotor neuropathy characterized by principally axonal, peripheral sensorimotor neuropathy with an X-linked dominant inheritance pattern and the childhood-adolescence-onset of slowly progressive, moderate to severe, distal muscle weakness and atrophy of the lower extremities, as well as distal, panmodal sensory abnormalities, bilateral foot deformities (pes cavus, clawed toes), absent ankle reflexes and gait abnormalities (steppage gait). Females are usually asymptomatic or only present mild manifestations (mild postural hand tremor, mild wasting of hand intrinsic muscles).", "ORPHA ID": 352675, "Summary": ""}
{"Disease Name": "X-linked Charcot-Marie-Tooth disease", "Disease Definition": "A disorder that belongs to the genetically heterogeneous group of CMT peripheral sensorimotor polyneuropathy diseases.", "ORPHA ID": 64747, "Summary": "Clinical description\nCMTX1 is characterized by a slowly progressive course: muscle wasting and weakness of distal limb muscles mainly involving the feet, legs and hands (particularly the thenar eminence), with proximal muscle weakness occurring in severe cases; distal sensory loss; loss of deep tendon reflexes; pes cavus and more rarely scoliosis. Rare instances of transient central nervous system (CNS) dysfunction have been described, with dysarthria, dysphagia, weakness, ataxia, and even aphasia and somnolence. All forms of CMTX are rare and are characterized by intellectual deficit (CMTX2, CMTX4), spastic paraplegia (CMTX3), hearing loss (CMTX4, CMTX5, rarely CMTX1), and optic atrophy (CMTX5).\nEtiology\nCMTX1 is associated with mutations in the GJB1 gene (Xq13.1), encoding connexin 32 (Cx32). Cx32 forms gap-junctions in non-compact myelin produced by myelinating Schwann cells. Cx32 is also expressed in oligodendrocytes, explaining the potential CNS involvement. CMTX5 is associated with mutations in the phosphoribosylpyrophosphate synthetase 1 gene (PRPS1). CMTX1 is transmitted as an X-linked dominant trait and males are more severely affected than females, whereas the other CMTX types are X-linked recessive and female carriers are usually unaffected.\nDiagnostic methods\nDiagnosis is based on family and personal history, clinical examination, nerve conduction studies (NCS), and DNA testing (for CMTX1). NCS show a sensorimotor polyneuropathy with decreased conduction velocities in males (usually in the intermediate range of 30-45 m/s in upper limb motor nerves) and mildly decreased or even normal velocities in females. In contrast with other CMT types, conduction slowing is frequently nonhomogeneous, with temporal dispersion and sometimes conduction blocks, and the median nerve being more severely affected than the ulnar nerve. Nerve biopsy reveals prominent axonal changes, in spite of nerve conduction slowing, with evidence of ultrastructural abnormalities in the paranodal regions. Auditory evoked potentials usually reveal abnormalities of central waves in the brainstem, consistent with frequent subclinical brain involvement in CMTX1.\nDifferential diagnosis\nDifferential diagnosis includes other CMT types and acquired dysimmune neuropathies such as chronic inflammatory demyelinating polyradiculoneuropathy (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis is possible for CMTX1 when the mutation is known.\nGenetic counseling\nAs an X-linked dominant trait, there is no male-to-male transmission; female carriers are usually mildly affected and have a 50% risk of transmitting the disease to their offspring.\nManagement and treatment\nThere is no drug treatment available. Rehabilitation therapy and surgical treatment of skeletal deformities are the only options.\nPrognosis\nCMTX1 is moderately severe for affected males, who may loose ambulation capacity later in life.\n\n                            Last update: \n                            January 2008\n\n\n                            - Expert reviewer(s): \n                            Dr Davide PAREYSON"}
{"Disease Name": "X-linked cleft palate and ankyloglossia", "Disease Definition": "X-linked cleft palate and ankyloglossia is a rare, genetic developmental defect during embryogenesis syndrome characterized by the association of complete, partial or submucous cleft palate and ankyloglossia. Patients may also present abnormal uvula (e.g. absent, bifid, shortened or laterally deviated), short lingual frenulum and dental anomalies (e.g. buccal crossbite, absent and/or misshapen teeth). Digital abnormalities, such as mild clinodactyly and/or syndactyly, have also been reported.", "ORPHA ID": 324601, "Summary": ""}
{"Disease Name": "X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome", "Disease Definition": "X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome is a rare syndromic microphthalmia disorder characterized by microphthalmia with coloboma (which may involve the iris, cilary body, choroid, retina and/or optic nerve), microcephaly, short stature and intellectual disability. Other eye abnormalities such as pendular nystagmus, esotropia and ptosis may also be present. Additional associated abnormalities include kyphoscoliosis, anteverted pinnae with minimal convolutions, diastema of the incisors and congenital pes varus.", "ORPHA ID": 431140, "Summary": ""}
{"Disease Name": "X-linked complicated corpus callosum dysgenesis", "Disease Definition": "A congenital, X-linked, clinical subtype of L1 syndrome, characterized by variable spastic paraplegia, mild to moderate intellectual disability, and dysplasia, hypoplasia or aplasia of the corpus callosum. In this subtype hydrocephalus, adducted thumbs, or absent speech are not observed.", "ORPHA ID": 1497, "Summary": ""}
{"Disease Name": "X-linked complicated spastic paraplegia type 1", "Disease Definition": "A congenital, X-linked, clinical subtype of L1 syndrome, characterized by spastic paraplegia, mild to moderate intellectual disability and normal brain morphology. This subtype represents the milder end of the L1 syndrome spectrum.", "ORPHA ID": 306617, "Summary": ""}
{"Disease Name": "X-linked cone dysfunction syndrome with myopia", "Disease Definition": "X-linked cone dysfunction syndrome with myopia is characterised by moderate to high myopia associated with astigmatism and deuteranopia. Less than 10 families have been described so far. Transmission is X-linked recessive and the locus has been mapped to Xq28.", "ORPHA ID": 90001, "Summary": ""}
{"Disease Name": "X-linked congenital generalized hypertrichosis", "Disease Definition": "X-linked congenital generalized hypertrichosis is an extremely rare type of hypertrichosis lanuginosa congenita, a congenital skin disease, which is characterized by hair overgrowth on the entire body in males, and mild and asymmetric hair overgrowth in females. It is associated with a mild facial dysmorphism (anterverted nostrils, moderate prognathism), and, in a kindred, it was also associated with dental anomalies and deafness.", "ORPHA ID": 79495, "Summary": ""}
{"Disease Name": "X-linked corneal dermoid", "Disease Definition": "X-linked corneal dermoid (X-CND) is an exceedingly rare, benign, congenital, corneal tumor characterized by bilateral opacification of the cornea with superficial grayish layers and irregular raised whitish plaques, as well as fine blood vessels covering the central cornea, and intact peripheral corneal borders. No other ocular or systemic abnormality is noted. The pattern of inheritance described in the affected family is consistent with X-linked transmission.", "ORPHA ID": 1661, "Summary": ""}
{"Disease Name": "X-linked creatine transporter deficiency", "Disease Definition": "X-linked creatine transporter deficiency (CRTR-D) is a creatine deficiency syndrome characterized clinically by global developmental delay/ intellectual disability (DD/ID) with prominent speech/language delay, autistic behavior and seizures.", "ORPHA ID": 52503, "Summary": "Epidemiology\nCRTR-D has been reported in more than 150 individuals worldwide.\nClinical description\nThe onset of symptoms occurs during infancy, usually before the age of 2 years. Males are mainly affected, but females can also have various combinations and severities of disease manifestations. CRTR-D is consistently characterized by mild to severe intellectual deficit, and expressive speech and language delay. Behavioral disorders (mainly autism and hyperactivity) are present in all affected individuals. Affected individuals often experience seizures and may present low weight gain, muscular hypotonia, and poor muscle mass. Subtle dysmorphic features such as midface hypoplasia, long face, and prominent chin have been reported in various affected male patients. Epilepsy and extrapyramidal symptoms may also occur occasionally. In adult patients, cardiac and gastrointestinal disorders have been reported. Carrier females are typically asymptomatic, but learning disabilities have been described in some.\nEtiology\nCRTR-D is mostly due to frameshift and splicing mutations in the creatine transporter gene SLC6A8 (Xq28) that result in a cerebral creatine deficiency. An estimated 20% of SLC6A8 mutations can be accredited to de novo mutations, or germinal or somatic mosaicism events.\nDiagnostic methods\nDiagnosis should be suspected clinically in children with DD/ID plus autistic behavior, as they are considered at risk. Diagnosis is based on the determination of urinary creatine excretion (which is elevated, particularly when measured as urinary creatine to creatinine ratio) and demonstration of creatine deficiency in the brain (as shown by magnetic resonance spectroscopy). These features are less pronounced in females. Diagnosis is confirmed by genetic testing for mutations in the SLC6A8 gene. Creatine uptake studies in cultivated fibroblasts are used to verify the pathogenetic relevance of genetic variants of unclear significance.\nDifferential diagnosis\nDifferential diagnosis includes other disorders of creatine deficiency syndrome like guanidinoacetate methyltransferase deficiency and L-arginine:glycine amidinotransferase deficiency (see these terms). In cases with partial cerebral creatine deficiency, argininosuccinic aciduria, citrullinemia type I, and gyrate atrophy of the choroid and retina (see these terms) should be considered.\nAntenatal diagnosis\nPre-implantation or prenatal genetic diagnosis for at risk couples is possible if the mutation has been identified in an affected family member.\nGenetic counseling\nCRTR-D occurs de novo or is inherited in an X-linked manner, with a carrier female having a 50% risk of transmitting the mutation to her offspring. Carrier testing for at-risk relatives in cases of family history is recommended.\nManagement and treatment\nTreatment with high dosages of creatine monohydrate, alone or combined with L-arginine and glycine, has resulted in clinical improvement of seizures and behavior in some patients, but in most cases, it does not appear to increase cerebral creatine. Treatment may also increase muscle mass and improve motor skills, as observed in a small cohort.\nPrognosis\nCRTR-D is not a life threatening disease; however life expectancy is limited, particularly in those who have severe seizures and associated physical handicaps.\n\n                            Last update: \n                            December 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Sylvia STOCKLER"}
{"Disease Name": "X-linked distal spinal muscular atrophy type 3", "Disease Definition": "X-linked distal spinal muscular atrophy type 3 is a rare distal hereditary motor neuropathy characterized by slowly progressive atrophy and weakness of distal muscles of hands and feet with normal deep tendon reflexes or absent ankle reflexes and minimal or no sensory loss, sometimes mild proximal weakness in the legs and feet and hand deformities in males.", "ORPHA ID": 139557, "Summary": ""}
{"Disease Name": "X-linked dominant chondrodysplasia punctata", "Disease Definition": "A rare genodermatosis disease with great phenotypic variation and characterized most commonly by ichthyosis following the lines of Blaschko, chondrodysplasia punctata (CDP), asymmetric shortening of the limbs, cataracts and short stature.", "ORPHA ID": 35173, "Summary": "Epidemiology\nAnnual incidence of X-linked dominant chondrodysplasia punctata (CDPX2) has been estimated to be at least 1/400,000 births with 95% of patients being female.\nClinical description\nCongenital ichthyosiform erythroderma is the typical neonatal manifestation. Erythema is usually generalized while hyperkeratotic scales generally follow Blaschko's lines and tend to fade during a period of weeks to months. In older children, ichthyosis following Blaschko's lines is the most frequent clinical finding (95% of cases) and it improves with age. Hyperkeratosis, especially involving hair follicles, and late atrophy appear at sites of previous scaling, typically in a follicular pattern (atrophoderma vermiculata). Follicular atrophoderma is particularly common on the trunk, forearms and dorsal aspect of the hands. Patchy areas of cicatricial alopecia are common. Asymmetric shortening of the limbs, usually affecting the humerus and femur, together with CDP, are the most common skeletal abnormalities. Facial dysmorphism (low nasal bridge, frontal bossing, hypertelorism, high arched palate) is common. Joint contractures affecting the hips, hands and feet are frequent. Talus valgus and other deformities may be seen. The vertebral column exhibits moderate to severe scoliosis and short stature is common. Most patients (60%) suffer from cataracts (mainly unilateral), which may be congenital or appear early in life. Microphthalmia, microcornea and epicanthus have been reported. Intelligence is normal.\nEtiology\nCDPX2 is due to mutations in the EBP gene (Xp11.23-p11.22) encoding the emopamil binding protein (EBP), which acts as a delta8-delta7-sterol isomerase that catalyzes the conversion of 8(9)-cholestenol to lathosterol in the distal cholesterol biosynthesis pathway. A deficiency in EBP leads to the accumulation of 8-dehydrocholesterol (8DHC) and 8(9)-cholestenol in the skin, plasma and other body tissues.\nDiagnostic methods\nDiagnosis of CDPX2 relies on clinical, biochemical and genetic tests. CDP, usually consisting of epiphyseal stippling, is the fundamental radiological finding. Biochemical analyses show increased levels of 8(9) cholestenol and 8-dehydrocholesterol. Molecular testing for EBP mutations confirms diagnosis.\nDifferential diagnosis\nDifferential diagnoses include CDPX1; RCDP; chondrodysplasia punctata, tibia-metacarpal type; CHILD syndrome; systemic lupus erythematosus; MEND syndrome, and vitamin K deficiencies.\nAntenatal diagnosis\nPrenatal diagnosis and preimplantation genetic diagnosis may be an option for families with a known disease-causing mutation.\nGenetic counseling\nCDPX2 is inherited in an X-linked dominant manner and genetic counseling is possible. Somatic mosaicism in the father or de novo mutations can explain the occurrence of offspring with CDPX2 when no mutations are found in the mother. Germline mosaicism and anticipation has also been reported in families with CDPX2. In most cases it is lethal in males.\nManagement and treatment\nManagement is multidisciplinary. Treatment of skin lesions includes the use of emollients and keratolytics (i.e. ammonium lactate 12%, petrolatum ointment). Topical administration of lovastatin and cholesterol may be beneficial for ichthyosis. Orthopedic management and surgery may be necessary in those with bone deformities. Cataracts should be extracted and vision correction devices provided. Physical, occupational and speech therapies may be necessary. Regular follow-up with dermatologists and ophthalmologists and orthopedic evaluations are recommended. Hearing aids may be needed.\nPrognosis\nThere is usually no effect on life-expectancy (rarely scoliosis can compromise cardiac and pulmonary function) but quality of life may be severely affected.\n\n                            Last update: \n                            September 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Rogelio GONZÁLEZ SARMIENTO"}
{"Disease Name": "X-linked dominant chondrodysplasia, Chassaing-Lacombe type", "Disease Definition": "X-linked dominant chondrodysplasia Chassaing-Lacombe type is a rare genetic bone disorder characterized by chondrodysplasia, intrauterine growth retardation (IUGR), hydrocephaly and facial dysmorphism in the affected males.", "ORPHA ID": 163966, "Summary": "Epidemiology\nPrevalence is unknown. To date, 10 patients (4 males and 6 females) in a single family have been reported through 4 generations.\nClinical description\nThree male fetuses were diagnosed prenatally on ultrasonography (skeletal abnormalities and hydrocephaly) leading to termination of the pregnancies. The fourth affected male died at 6 days of life. The disease is severe and probably lethal in males, in whom the clinical picture includes short hands, brachydactyly, hydrocephaly and facial dysmorphism, including frontal bossing, low-set ears, short flat nose and microphthalmia. Other signs may include cerebellar hypoplasia and hyperkeratotic skin. X-rays show severe platyspondyly due to delayed ossification of the vertebrae, thin ribs, moderate shortening of the long bones, hypoplastic iliac wings, poorly ossified pubis, brachydactyly of the fingers and/or toes with cupped metacarpals, metatarsals, and phalanges and hypoplastic square calcaneus. The clinical picture in females is less severe and comprises short stature (128-151 cm), rhizomelic shortening of the limbs, short hands, brachymesophalangia of the 3rd and 4th toes, and may be associated with body asymmetry and mild cognitive impairment.\nEtiology\nX-linked dominant chondrodysplasia Chassaing-Lacombe type is due to a mutation in the histone deacetylase 6 HDAC6 gene (Xp11.3-q13.1) that causes a nucleotide substitution in the 3' untranslated region (UTR) of the HDAC6 transcript. This mutation lies in the seed sequence of microRNA-433 (hsa-miR-433) and abolishes the post-transcriptional regulation of HDAC6 expression by hsa-miR-433, resulting in the overexpression of the HDAC6 protein.\nGenetic counseling\nInheritance is X-linked dominant.\n\n                            Last update: \n                            February 2011\n\n\n                            - Expert reviewer(s): \n                            Pr Didier LACOMBE"}
{"Disease Name": "X-linked dyserythropoietic anemia with abnormal platelets and neutropenia", "Disease Definition": "X-linked dyserythropoietic anemia with abnormal platelets and neutropenia is a rare, genetic, constitutional dyserythropoietic anemia disorder characterized by moderate to severe anemia without thrombocytopenia, variable degrees of neutropenia, and bone marrow biopsy findings of trilineage dysplasia and hypocellularity of erythroid and granulocytic lineages. Peripheral blood findings include anisocytosis, macrocytosis, poikilocytosis, elliptocytes, and fragmented erythrocytes.", "ORPHA ID": 363727, "Summary": ""}
{"Disease Name": "X-linked dystonia-parkinsonism", "Disease Definition": "X-linked dystonia-parkinsonism (XDP) is a neurodegenerative movement disorder characterized by adult-onset parkinsonism that is frequently accompanied by focal dystonia, which becomes generalized over time, and that has a highly variable clinical course.", "ORPHA ID": 53351, "Summary": "Epidemiology\nOver 500 cases of XDP have been reported in the literature to date, all occurring in the Philippines (Panay Island). The estimated prevalence in the Philippines is 1/322,000 and in the Province of Capiz it is at its highest with a prevalence of 1/4,000 in the male population.\nClinical description\nXDP affects mainly males, most female carriers are asymptomatic. The disease typically presents in adulthood (mean: 39 years) with either focal dystonia or, more commonly, parkinsonism. Focal dystonia affects mainly the jaw, neck, eyes and trunk, but also rarely the limbs, pharynx, larynx and tongue, leading to various manifestations such as difficulty with jaw opening and closing, blepharospasm, involuntary tongue protrusion, difficulty swallowing, retrocollis, trunk hyperextension, leg spasms, foot flexion, and foot inversion. Within 2-5 years after onset, 50% of patients have generalized dystonia. Parkinsonism manifests with bradykinesia, rigidity, resting tremor, shuffling gait and postural instability, which may be severe and can lead to walking impairment and frequent stumbling. Less common findings include sensory tricks, myoclonus, chorea and myorhythmia. In those with pure parkinsonism, the disease progresses slowly and is usually non-disabling. Most who develop orobuccolingual and cervical dystonia suffer from lethal complications such as infections, aspiration pneumonia and laryngeal stridor, leading to premature death. Mean duration of illness is 13-16 years.\nEtiology\nXDP is due to mutations in the TAF1 gene (Xq13.1) encoding the TAF1 RNA polymerase II, TATA box-binding protein-associated factor, 250kDa.\nDiagnostic methods\nDiagnosis is based on clinical and neuroimaging findings (of postsynaptic striatal and presynaptic nigrostriatal involvement), as well as having a positive family history compatible with X-linked inheritance and maternal Panay Island ancestral roots. MRI usually shows no abnormalities. Molecular genetic testing can confirm the diagnosis by identifying a  TAF1 mutation. Preliminary results from a pilot study indicate olfactory dysfunction in XDP, therefore olfactory testing may also support diagnosis.\nDifferential diagnosis\nDifferential diagnoses include Parkinson's disease, hereditary essential tremor, dopa-responsive dystonia and Parkinson-plus syndromes.\nAntenatal diagnosis\nPrenatal diagnosis is possible in families with a known TAF1 mutation.\nGenetic counseling\nXDP is inherited in an X-linked recessive manner and genetic counseling is recommended. Males with XDP pass the mutation to all of their daughters and none of their sons, whereas female carriers have a 50% risk of passing the mutation to their offspring. Rare de novo mutations have been reported.\nManagement and treatment\nThere is no cure for XDP. Treatment involves the use of pharmacological agents and offers only temporary or partial relief. In the early stages of dystonia, benzodiazepines and anticholinergic agents may be effective, especially in combination. Botulinum toxin injections may relieve focal dystonia. Tetrabenazine and zolpidem can improve dystonia once it becomes generalized or multifocal. Those with pure parkinsonism may be responsive to levodopa. Deep brain stimulation has shown promise in a few cases with advanced disease refractory to medication. Periodic swallowing evaluation is recommended, especially in those with dysphagia. Physical therapy may be helpful. Psychological counseling should be offered to patients and their families.\nPrognosis\nPrognosis is phenotype-dependent. Those with pure parkinsonism have the best prognosis, while those with a combination of parkinsonism followed by the development of orobuccolingual and cervical dystonia, 1-2 years after disease onset, have the worst prognosis, usually becoming bedridden with a reduced life expectancy.\n\n                            Last update: \n                            November 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Christoph KAMM"}
{"Disease Name": "X-linked Ehlers-Danlos syndrome", "Disease Definition": "A rare systemic disease characterized by a severe phenotype in all male patients, combining abnormality of connective tissue typical for Ehlers-Danlos syndrome (including joint hypermobility, scoliosis, soft and doughy skin, hyperextensible skin, abnormal scarring, facial peculiarities, and generalized hypotonia, among others) and eventually lethal congestive heart failure due to polyvalvular disease. Female carriers are affected to a variable degree.", "ORPHA ID": 75497, "Summary": ""}
{"Disease Name": "X-linked endothelial corneal dystrophy", "Disease Definition": "X-linked endothelial corneal dystrophy (XECD) is a rare subtype of posterior corneal dystrophy (see this term) characterized by congenital ground glass corneal clouding or a diffuse corneal haze, and blurred vision in male patients.", "ORPHA ID": 293621, "Summary": "Epidemiology\nPrevalence of this rare corneal dystrophy is unknown. Males are affected more severely than females.\nClinical description\nAffected males are born with clouding ranging from a diffuse haze to a ground-glass, milky appearance, which commonly causes blurred vision, and possible nystagmus. Female patients are asymptomatic but have crater-like endothelial abnormalities. The condition is progressive in males and non-progressive in females. In advanced cases, a subepithelial band keratopathy associated with endothelial changes that resemble moon craters is observed.\nEtiology\nXECD has been mapped to the long arm of the X-chromosome (Xq25) but the causative gene has not been identified.\nDiagnostic methods\nLight microscopy reveals focal discontinuities and degenerative changes in the corneal endothelial cells which underlie the crater-like changes seen clinically. Descemet membrane is irregularly thickened with small pits and excavations. The corneal epithelium and Bowman zone may be irregularly thinned.\nGenetic counseling\nTransmission is X-linked recessive.\nManagement and treatment\nA penetrating keratoplasty may be indicated in males if corneal opacification impairs vision significantly. Procedures for repairing the posterior surface of the cornea, such as a deep lamellar endothelial keratoplasty (DLEK), Descemet stripping endothelial keratoplasty (DSEK), or Descemet stripping automated endothelial keratoplasty (DSAEK) are technically difficult in young children.\n\n                            Last update: \n                            May 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Gordon KLINTWORTH"}
{"Disease Name": "X-linked epilepsy-learning disabilities-behavior disorders syndrome", "Disease Definition": "X-linked epilepsy-learning disabilities-behavior disorders syndrome is characterized by epilepsy, learning difficulties, macrocephaly, and aggressive behaviour. It has been described in males from a four-generation kindred. It is transmitted as an X-linked recessive trait and is likely to be caused by mutations in the gene encoding synapsin I (Xp11.3-q12).", "ORPHA ID": 85294, "Summary": ""}
{"Disease Name": "X-linked erythropoietic protoporphyria", "Disease Definition": "A rare disorder of heme metabolism characterized by severe cutaneous photosensitivity in affected boys and sometimes in girls, manifesting in childhood.", "ORPHA ID": 443197, "Summary": "Epidemiology\nX-linked erythropoietic protoporphyria (XLPP) has been reported with a prevalence <1/1,000,000.\nClinical description\nThe disease manifests in infancy or childhood through the onset of severe acute cutaneous photosensitivity in affected boys, with tingling, burning and itching within few minutes of exposure to sunlight or illumination in the visible spectrum (in particular, in the Soret band [400 - 410 nm]), often accompanied by skin edema and redness. Pain may persist for several hours or days after the initial reaction. As protoporphyrin is a lipophilic molecule excreted by the liver, some XLPP patients may develop biliary lithiasis and liver damage. In heterozygous girls, the phenotypes vary from asymptomatic to severe.\nEtiology\nXLPP is due to gain-of-function mutations in the ALAS2 gene (NM_000032.4) encoding erythrocyte-specific aminolevulinic acid synthase 2.\nDiagnostic methods\nDiagnosis is based on the presence of high concentrations of protoporphyrin in plasma and red blood cells, and the detection of a plasma fluorescence peak at 635 nm. The percentage of zinc-bound protoporphyrin is reduced but remains higher than in autosomal EPP, and FECH enzyme activity is normal. A liver damage analysis is recommended. Genetic analysis (mutations in the ALAS2 gene) and family screening are also recommended.\nDifferential diagnosis\nDifferential diagnosis includes autosomal erythropoietic protoporphyria, phototoxic drug reactions, solar urticaria, contact dermatitis, angioedema, and hydroa vacciniforme.\nAntenatal diagnosis\nAntenatal diagnosis is theoretically possible, but not offered.\nGenetic counseling\nThe transmission pattern is X-linked dominant.\nManagement and treatment\nTreatment is based on preventive measures similar to those proposed for the treatment of autosomal erythropoietic protoporphyria. Since liver disease is the major risk in XLPP, regular monitoring of liver function is recommended. Sequential liver and bone marrow transplant should be considered in the treatment of severe cases with liver damage.\nPrognosis\nThe prognosis of XLPP depends on the progression of liver disease. However, photosensitivity can affect patients' quality of life. In contrast to EPP, oral iron supplementation in XLPP patients with iron deficiency anemia reduces the concentration of protoporphyrins in the blood and improves symptoms.\n\n                            Last update: \n                            March 2024\n\n\n                            - Expert reviewer(s): \n                            Dr Neila TALBI | MetabERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome", "Disease Definition": "A rare syndromic genetic deafness characterized by congenital hearing loss, atresia or stenosis of the external auditory canal, dilated internal auditory canal, malformation of the inner ear (incomplete separation of the cochlea basal turn from the fundus of the internal auditory canal), in combination with abnormal auricular shape and facial dysmorphism (including thick eyebrows, ptosis, broad nasal root, and telecanthus). Intelligence is normal and developmental delay is absent.", "ORPHA ID": 500188, "Summary": ""}
{"Disease Name": "X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, and dysmorphic facial features (such as facial asymmetry, prominent forehead, short palpebral fissures, low nasal bridge, smooth and long philtrum, thin upper lip, and low-set, posteriorly rotated, dysplastic ears), exclusively affecting females. Additional reported manifestations include short stature, choanal atresia, scoliosis, congenital ocular, dental, cardiac, and urogenital anomalies, as well as hypotonia, seizures, and structural brain abnormalities, among others.", "ORPHA ID": 480880, "Summary": ""}
{"Disease Name": "X-linked hereditary sensory and autonomic neuropathy with deafness", "Disease Definition": "A rare peripheral neuropathy characterized by the association of an axonal sensory and autonomic neuropathy with hearing loss.", "ORPHA ID": 139583, "Summary": "Epidemiology\nIt has been described in a large five-generation Chinese family.\nClinical description\nOnset occurred in the second decade of life (with an average age of onset of 13 years) with mild to severe hearing impairment due degeneration of the auditory nerve (type 1 auditory neuropathy), followed by late-onset of a diffuse and progressive peripheral sensory neuropathy.\nEtiology\nThe causative gene was mapped to the AUNX1 locus on chromosome Xq23-27.3.\nGenetic counseling\nTransmission was X-linked recessive.\n\n                            Last update: \n                            January 2009"}
{"Disease Name": "X-linked hypophosphatemia", "Disease Definition": "A rare hereditary renal phosphate-wasting disorder characterized by hypophosphatemia, rickets and/or osteomalacia, and diminished growth.", "ORPHA ID": 89936, "Summary": "Epidemiology\nIt is the most common form of hereditary hypophosphatemia with a prevalence of approximately 1/47,000 worldwide. The disease affects both sexes equally.\nClinical description\nX-linked hypophosphatemia (XLH) manifests during childhood with typical clinical features of rickets such as short stature, bone pain, and skeletal deformities (bowed legs, genu varum, rachitic rosary...). Dental abnormalities (recurrent abscesses, abnormal enamel) are observed in children and adults. Cranial anomalies are also observed due to thickness of parietal and frontal bones and craniosynostosis. In adults, musculoskeletal symptoms are the main feature of the disease with a heavy burden on the patient's quality of life. They include fractures and pseudofractures, pain, joint stiffness, osteoarthritis, enthesopathy, and muscle weakness.\nEtiology\nThe disease is caused by various variants in the PHEX gene (Xp22.1) which encodes an endopeptidase expressed predominantly in bone and teeth. Although the mechanism is unknown, the PHEX variants lead to increased circulating levels of FGF-23, a phosphate-regulating hormone. Through its action on sodium-phosphate cotransporter genes in the proximal renal tubule, as well as CYP271B and CYP24A1, increased FGF-23 ultimately results in reduced renal phosphate reabsorption, and decreased intestinal phosphate and calcium absorption, consequently leading to abnormal bone mineralization.\nDiagnostic methods\nDiagnosis is based on clinical and biochemical findings, and typical rickets/osteomalacia radiographic features. Biochemical findings include elevated circulating levels of FGF-23 associated with hypophosphatemia, hyperphosphaturia, normal serum levels of calcium, increased or normal plasma levels of parathyroid hormone, and increased levels of alkaline phosphatase. Phosphate excretion can be evaluated by measuring the maximum tubular reabsorption per glomerular filtration rate. Molecular genetic testing confirms the diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes autosomal dominant and autosomal recessive hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria (HHRH), fibrous dysplasia of bones, renal Fanconi syndrome, vitamin D deficiency and tumor-induced osteomalacia.\nGenetic counseling\nXLH is transmitted as an X-linked dominant trait with complete penetrance, but variable expressivity. Genetic counseling should be recommended to affected patients.\nManagement and treatment\nMultidisciplinary care by experts in the field of XLH is recommended. Current conventional treatment consists of active vitamin D analogs and phosphate supplementation which respectively enhances digestive absorption of phosphate and compensates renal phosphate wasting. This treatment can be effective in treating rickets and osteomalacia and their associated symptoms, as well as improve dental mineralization; however, it does not correct renal phosphate wasting. Potential complications include hyperparathyroidism and/or nephrocalcinosis. In adults, the benefit of continuing conventional treatment remains debated. Burosumab, an anti-FGF23 humanized antibody approved in Europe and the USA, is an alternative treatment to the conventional treatment that lowers circulating FGF-23 levels and thus corrects renal phosphate wasting, rickets and osteomalacia. Management also includes regular dental and orthodontic care in all patients, neurosurgery in certain cases, possible orthopedic interventions, hearing aids, physiotherapy and nutritional follow-up.\nPrognosis\nWith optimal treatment and multidisciplinary care initiated early in life, prognosis can be good. Skeletal deformities can be avoided or corrected by medical treatment and if necessary corrective orthopedic surgery (preferably at the end of growth). Final height remains compromised. In adults who did not receive optimal care, chronic musculoskeletal symptoms lead to physical disabilities and impaired quality of life.\n\n                            Last update: \n                            August 2022\n\n\n                            - Expert reviewer(s): \n                            Pr Agnès LINGLART | Endo-ERN* - Dr Anya ROTHENBUHLER | Endo-ERN*\n\n\n                                * European Reference Network"}
{"Disease Name": "X-linked immunoneurologic disorder", "Disease Definition": "X-linked immunoneurologic disorder is characterized by immune deficiency and neurological disorders in females, and by neonatal death in males.", "ORPHA ID": 2571, "Summary": "Epidemiology\nThe syndrome has been described in only one family with nine affected individuals (five males and four females) spanning two generations.\nClinical description\nSymptomatic females present slowly progressive proximal muscle weakness, leg hyperreflexia, pes cavus, increased muscle tone in the legs, poor bladder function, static reduced night vision, and frequent sinopulmonary infections associated with IgG2 deficiency. Males present with low birth weight and severe hypotonia that leads to death in the neonatal period.\nEtiology\nThe gene locus has been mapped to Xq26-qter.\nDifferential diagnosis\nThe syndrome should be considered in the differential diagnosis of hereditary spastic paraplegia in females and of other causes of severe neonatal hypotonia in males.\nGenetic counseling\nThe condition is thought to be transmitted in an X-linked dominant manner.\n\n                            Last update: \n                            August 2009"}
{"Disease Name": "X-linked intellectual disability due to GRIA3 mutations", "Disease Definition": "A rare, genetic, X-linked syndromic intellectual disability disorder characterized by moderate to severe intellectual disability associated with epilepsy, short stature, autistic features and behavioral problems, such as self injury and aggressive outbursts. Observed facial dysmorphism includes brachycephaly, prominent supraorbital ridges, and deep set eyes. Additional variable manifestations include malposition of feet, asthenic habitus, hyporeflexia, bowel occlusions, hydronephrosis, ren arcuatus, delayed motor development and disturbed sleep-wake cycle.", "ORPHA ID": 364028, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Abidi type", "Disease Definition": "X-linked intellectual disability, Abidi type is characterized by X-linked intellectual deficit and mild variable manifestations, including short stature, small head circumference, sloping forehead, hearing loss, abnormally shaped ears, and small testes. It has been described in eight affected males from three generations.", "ORPHA ID": 85273, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Armfield type", "Disease Definition": "X-linked intellectual disability, Armfield type is characterised by intellectual deficiency, short stature, seizures, and small hands and feet. It has been described in six males from three generations of one family. Three of them also had cataracts/glaucoma and two of them had cleft palate. The locus has been mapped to the terminal 8 Mb of Xq28.", "ORPHA ID": 85276, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Cabezas type", "Disease Definition": "An X-linked syndromic intellectual disability characterized by developmental delay, intellectual disability (ID) with severe speech impairment, and short stature. Variable additional clinical features have been associated, including behavioral disturbances, gait abnormalities, tremor, seizures, hypogonadism, truncal obesity, unspecific facial dysmorphism, and small hands and feet.", "ORPHA ID": 85293, "Summary": "Epidemiology\nThe prevalence of Cabezas syndrome (CS) is unknown. It is estimated that CS accounts for 3% of X-linked intellectual disability. To date, around 120 cases have been reported in the literature. Males are predominantly affected.\nClinical description\nCS typically presents in childhood and the penetrance of CS is age-dependent, with less specific clinical features in early childhood which progress over time. It is characterized by mild to severe intellectual disability with disproportionate, severe speech impairment. Other neurologic problems include behavioural disturbances (mainly hyperactivity and aggressive behaviour), gait abnormalities, tremors, seizures (more common in young children), and variable and unspecific cerebral abnormalities (such as malformations of cortical development, including polymicrogyria, ventriculomegaly, and decreased white matter volume). Most of the described patients also have short stature, truncal obesity, hypogonadism, and small hands and feet. The facial phenotype is unspecific and evolves with age. The most frequent facial dysmorphisms are prominent lower lip and low-set ears. Additional features include urogenital anomalies (such as undescended and/or small testes, hypospadias, and small penis), gynecomastia, kyphosis, pes cavus and sandal gap. Females are mainly asymptomatic but in rare cases can present learning disability, attention deficit disorder, or tremor.\nEtiology\nThis syndrome is caused by pathogenic variants in CUL4B gene (Xq24), encoding a scaffold protein of the cullin 4B-RING ubiquitin ligase (E3) complex, which is crucial in the regulation of the degradation of cellular proteins.\nDiagnostic methods\nMolecular genetic testing approaches can include a combination of chromosomal microarray and Next Generation Sequencing-based multigene panel or a comprehensive genomic testing (whole-exome sequencing or genome sequencing).\nDifferential diagnosis\nDifferential diagnosis includes Börjeson-Forssman-Lehmann syndrome, Wilson-Turner syndrome and Smith-Fineman-Myers syndrome.\nAntenatal diagnosis\nPrenatal diagnosis can be offered if the disease-causing mutation has been identified in a family member.\nGenetic counseling\nGenetic counselling should be proposed to parents of affected individuals. It is inherited in an X-linked manner. If the mother is a carrier of the pathogenic variant, the chance of transmitting the pathogenic variant at each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. Female carriers are usually asymptomatic but in rare cases can exhibit a mild phenotype.\nManagement and treatment\nManagement is symptomatic and should be multidisciplinary, usually addressing developmental delay. It can include physical, occupational and speech therapy, including nonverbal methods of communication. In patients with seizures, anticonvulsant medication is needed. Medication may also be required in patients with behavioural disturbances and/or hypogonadism.\nPrognosis\nLongitudinal data are insufficient to determine life expectancy. However, it is not a life-threatening condition and survival into adulthood is expected. Autonomy is limited and depends on the severity of intellectual disability.\n\n                            Last update: \n                            January 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Marcia RODRIGUES | ITHACA* - Dr Marta P. SOARES | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "X-linked intellectual disability, Cantagrel type", "Disease Definition": "A rare X-linked intellectual disability characterized by marked neonatal hypotonia, progressive quadriparesia, severely delayed developmental milestones (walking at 3 years of age), gastroesophageal reflux, stereotypic movements of the hands, esotropia and infantile autism.", "ORPHA ID": 85277, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Cilliers type", "Disease Definition": "A rare developmental defect characterized by mild intellectual deficit associated with short stature, hypergonadotropic hypogonadism, microcephaly and mild facial dysmorphism (deep-set eyes, prominent supraorbital ridges, a high nasal bridge and large ears).", "ORPHA ID": 163971, "Summary": "Epidemiology\nIt has been described in four males from one family.\nEtiology\nThe syndrome is mapped to the Xq25-q26 region of the X-chromosome.\nGenetic counseling\nThe syndrome was transmitted in an X-linked recessive manner.\n\n                            Last update: \n                            May 2009"}
{"Disease Name": "X-linked intellectual disability, Golabi-Ito-Hall type", "Disease Definition": "An X-linked intellectual disability syndrome (XLMR) characterized by intellectual deficiency, microcephaly and short stature. It belongs to the group of disorders collectively referred to as Renpenning syndrome.", "ORPHA ID": 93947, "Summary": "Epidemiology\nIt has been reported in only one family, with three affected patients.\nClinical description\nModerate to severe intellectual deficiency (IQ<50) is seen in all cases as are marked facial characteristics (long narrow face with upslanting palpebral fissures). Spastic diplegia is common. Golabi-Ito-Hall syndrome shows atrial septal defects and severe growth restriction (head circumference and length) but unlike other syndromes in the Renpenning group, small testes are not observed.\nEtiology\nIt is caused by a missense mutation in the PQBP1 gene on exon 3 that leads to deregulated splicing that alters an amino acid in the gene's WW domain.\nGenetic counseling\nGolabi-Ito-Hall syndrome follows an X-linked recessive pattern of inheritance. Genetic testing is possible to identify carrier females and to inform them of the risk of passing on the gene to their offspring.\n\n                            Last update: \n                            June 2012\n\n\n                            - Expert reviewer(s): \n                            Pr Vincent DES PORTES"}
{"Disease Name": "X-linked intellectual disability, Hedera type", "Disease Definition": "X-linked intellectual disability, Hedera type is a rare X-linked intellectual disability syndrome characterized by an onset in infancy of delayed motor and speech milestones, generalized tonic-clonic seizures and drop attacks, and mild to moderate intellectual disability. Additional, less common manifestations include scoliosis, ataxia (resulting in progressive gait disturbance), and bilateral pes planovalgus. Physical appearance is normal with no dysmorphic features reported.", "ORPHA ID": 93952, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Miles-Carpenter type", "Disease Definition": "X-linked mental retardation, Miles-Carpenter type is characterised by severe intellectual deficit, microcephaly, exotropia and low digital arches.", "ORPHA ID": 85283, "Summary": "Epidemiology\nIt has been described in four male members of one family.\nClinical description\nJoint hypermobility, distal muscle wasting, hypogonadism and rocker bottom feet were also reported. Low digital arches and exotropia were described in several female members of the family.\nGenetic counseling\nTransmission is X-linked and the causative gene has been mapped to Xq13-q22.\n\n                            Last update: \n                            March 2008"}
{"Disease Name": "X-linked intellectual disability, Najm type", "Disease Definition": "Najm type X-linked intellectual deficit is a rare cerebellar dysgenesis syndrome characterized by variable clinical manifestations ranging from mild intellectual deficit with or without congenital nystagmus, to severe cognitive impairment associated with cerebellar and pontine hypoplasia/atrophy and abnormalities of cortical development.", "ORPHA ID": 163937, "Summary": "Epidemiology\nPrevalence of this rare neurological syndrome is unknown. Up to 35 families have been reported to date.\nClinical description\nPatients (mostly females) have been reported to have variable clinical manifestations including intellectual deficit, severe developmental delay, seizures, unsteady gait, sensorineural hearing loss and postnatal microcephaly (in most cases). Minor facial anomalies include: low or broad forehead, hypertelorism, long philtrum and micrognathia. Ocular findings are also variable and include congenital nystagmus, strabismus, cataracts, myopia or reduced visual acuity. Males appear to be more severely affected.\nEtiology\nPoint mutations and deletions in the CASK gene (Xp11.4) have been found in patients with this syndrome.\nDiagnostic methods\nMagnetic resonance imaging (MRI) generally shows pontocerebellar hypoplasia/atrophy and simplified cortical gyri. Molecular genetic testing is needed to confirm diagnosis.\nGenetic counseling\nTransmission follows an X-linked dominant pattern.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Ginevra ZANNI"}
{"Disease Name": "X-linked intellectual disability, Nascimento type", "Disease Definition": "X-linked intellectual disability, Nascimento type is a rare X-linked intellectual disability syndrome characterized by intellectual disability (with severe speech impairment), a myxedematous appearance, dysmorphic facial features (including large head, synophrys, prominent supraorbital ridges, almond-shaped and deep-set eyes, large ears, wide mouth with everted lower lip and downturned lip corners), low posterior hairline, short, broad neck, marked general hirsutism and abnormal hair whorls, skin changes (e.g. dry skin or hypopigmented spots), widely spaced nipples, obesity, micropenis, onychodystrophy and seizures.", "ORPHA ID": 163956, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Pai type", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by global developmental delay and severe intellectual disability, seizures, and recurrent lower respiratory tract infections, resulting in premature death in affected males. Additional reported manifestations include mild dysmorphic facial features (such as epicanthic folds, high nasal bridge, or small mouth), gait disturbances, brisk tendon reflexes, delayed bone age, and tapering fingers. No evident heterozygous manifestation has been reported in females.", "ORPHA ID": 85322, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Schimke type", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by intellectual deficit, growth retardation with short stature, deafness and ophthalmoplegia. Choreoathetosis with muscle spasticity generally appears during childhood.", "ORPHA ID": 85285, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Seemanova type", "Disease Definition": "X-linked intellectual disability, Seemanova type is characterised by microcephaly, intellectual deficit, growth retardation and hypogenitalism. It has been described in four boys from one family. A characteristic facies and ophthalmologic anomalies were also present and included microphthalmia, microcornea and cataract. Transmission is X-linked.", "ORPHA ID": 85323, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Shashi type", "Disease Definition": "X-linked intellectual disability, Shashi type is characterised by moderate intellectual deficit, obesity, macroorchidism and a characteristic facies (large ears, a prominent lower lip and puffy eyelids). It has been described in nine boys from two families. Transmission is X-linked and the causative gene has been localised to the q21.3-q27 region of the X chromosome.", "ORPHA ID": 85286, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Shrimpton type", "Disease Definition": "An X-linked syndromic intellectual disability characterised by severe intellectual disability, microcephaly and short stature in male patients. Strabismus and spastic diplegia have also been described.", "ORPHA ID": 85324, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Siderius type", "Disease Definition": "X-linked intellectual disability, Siderius type is characterised by mild to borderline intellectual deficit associated with cleft lip/palate. Preaxial polydactyly, large hands and cryptorchidism are sometimes present. The syndrome has been described in seven boys from two families. Transmission is X-linked and the syndrome is caused by mutations in the PHF8 gene, localised to the p11.21 region of the X chromosome.", "ORPHA ID": 85287, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Snyder type", "Disease Definition": "X-linked intellectual disability, Snyder type is a rare X-linked intellectual disability syndrome characterized by hypotonia, asthenic build with diminished muscle mass, severe generalized psychomotor delay, unsteady gait and moderate to severe intellectual disability, as well as a long, thin, asymmetrical face with prominent lower lip, long fingers and toes and nasal, dysarthric or absent speech. Bone abnormalities (e.g., osteoporosis, kyphoscoliosis, fractures, joint contractures) are also characteristic. Myoclonic, or myoclonic-like, seizures and renal abnormalities have been associated in some patients.", "ORPHA ID": 3063, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Stevenson type", "Disease Definition": "X-linked intellectual disability, Stevenson type is characterised by intellectual deficit, hypotonia, absent deep tendon reflexes, tapered fingers and excessive fingerprint arches, genu valgum, a characteristic face and small teeth. It has been described in four males from two generations of one family. The causative gene appears to be located in the q13 region of the X chromosome.", "ORPHA ID": 85325, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Stocco Dos Santos type", "Disease Definition": "X-linked intellectual disability, Stocco Dos Santos type is characterised by severe intellectual deficit with hyperactivity, language delay, congenital hip luxation, short stature, kyphosis and recurrent respiratory infections. Aggressive behaviour and frequent epileptic seizures may also be present. The syndrome has been described in four boys from the same family. Transmission is X-linked and is caused by mutations in the KIAA1202 gene, localised to the Xp11.2 region.", "ORPHA ID": 85288, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Stoll type", "Disease Definition": "X-linked intellectual disability, Stoll type is characterised by intellectual deficit, short stature and characteristic facies (hypertelorism, prominent forehead, frontal bossing, a broad nasal tip and anteverted nares). It has been described in four males from three generations of the same family. Two females from this family also displayed intellectual deficit and the characteristic facies. Transmission is X-linked.", "ORPHA ID": 85326, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Van Esch type", "Disease Definition": "A rare, genetic, syndromic intellectual disability characterized by developmental delay, mild to moderate intellectual disability, low birth weight, moderate to severe short stature, microcephaly and variable hypergonadotropic hypogonadism. Mild facial dismorfism include upslanted palpebral fissures and prominent nasal bridge.", "ORPHA ID": 163976, "Summary": ""}
{"Disease Name": "X-linked intellectual disability, Wilson type", "Disease Definition": "X-linked intellectual disability, Wilson type is characterised by severe intellectual deficit with mutism, epilepsy, growth retardation and recurrent infections. It has been described in three males from three generations of one family. The causative gene has been localised to the 11p region of the X chromosome.", "ORPHA ID": 85290, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-acromegaly-hyperactivity syndrome", "Disease Definition": "X-linked intellectual disability-acromegaly-hyperactivity syndrome is characterised by severe intellectual deficit, acromegaly and hyperactivity. The syndrome has been described in two half-brothers. Dysarthria, aggressive behaviour, a characteristic facies (an acromegalic and triangular face with a long nose) and macroorchidism were also present. The mother displayed moderate intellectual deficit and milder facial anomalies. Central nervous system anomalies were identified in the two boys: subarachnoid cysts and hyperdensity in the pontine region.", "ORPHA ID": 85327, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-ataxia-apraxia syndrome", "Disease Definition": "A rare, X-linked syndromic intellectual disability disorder characterized by non-progressive ataxia, apraxia, variable intellectual disability and/or visuospatial, visuographic and visuoconstructive dysfunctions in male patients. Seizures, congenital clubfoot and macroorchidism have also been associated. Partial clinical expression was noted in obligate female carriers. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 85338, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome", "Disease Definition": "X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome is a rare X-linked syndromic intellectual disability disorder characterized by profound intellectual disability, global developmental delay with absent speech, seizures, large joint contractures, abnormal position of thumbs and middle-age onset of cardiomegaly and atrioventricular valve abnormalities, resulting in subsequent congestive heart failure. Additional features include variable facial dysmorphism (notably large ears with overfolded helix) and large testes.", "ORPHA ID": 324410, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-cerebellar hypoplasia syndrome", "Disease Definition": "X-linked intellectual deficit-cerebellar hypoplasia, also known as OPHN1 syndrome, is a rare syndromic form of cerebellar dysgenesis characterized by moderate to severe intellectual deficit and cerebellar abnormalities.", "ORPHA ID": 137831, "Summary": "Epidemiology\nOPHN1 syndrome is very rare. To date, up to 12 families have been reported.\nClinical description\nAffected male patients present moderate to severe intellectual disability, hypotonia, severe developmental delay, early-onset complex partial or tonic-clonic seizures, strabismus, dysmetria and occasionally ataxia. Cryptorchidism and genital hypoplasia have been reported. Some patients have abnormal behavior and a characteristic facial phenotype (long face, prominent forehead, infraorbital creases, deep-set eyes, upturned philtrum and large ears). Carrier females have been reported to have mild learning disabilities, mild cognitive impairment, strabismus, and subtle facial changes.\nEtiology\nVarious mutations including deletions and splice site mutations in the OPHN1 gene (Xq12) have been reported in patients with this syndrome.\nDiagnostic methods\nNeuroradiological findings include posterior vermis dysgenesis, vermian parasagittal cleft, cerebellar hypoplasia, cortical atrophy, and enlargement of the cerebral ventricles. Molecular genetic testing is needed to confirm diagnosis.\nGenetic counseling\nTransmission appears to follow an X-linked semi-dominant pattern.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Ginevra ZANNI"}
{"Disease Name": "X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, growth retardation, hypotonia, cerebellar symptoms such as ataxia, spondyloepiphyseal dysplasia, and dysmorphic craniofacial features (including microcephaly, dolichocephaly, prominent ears, epicanthus, broad nasal bridge, long and flat philtrum, or small mouth). Additional reported manifestations are epilepsy, retinitis pigmentosa, and urogenital abnormalities, among others. Brain imaging may show cerebellar hypoplasia.", "ORPHA ID": 459070, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-craniofacioskeletal syndrome", "Disease Definition": "X-linked intellectual disability-craniofacioskeletal syndrome is a rare, hereditary, syndromic intellectual disability characterized by craniofacial and skeletal abnormalities in association with mild intellectual disability in females and early postnatal lethality in males. In addition to mild cognitive impairment, females present with microcephaly, short stature, skeletal features and extra temporal lobe gyrus. In males, intrauterine growth impairment, cardiac and urogenital anomalies have been reported.", "ORPHA ID": 163979, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-cubitus valgus-dysmorphism syndrome", "Disease Definition": "X-linked intellectual disability-cubitus valgus-dysmorphism syndrome is characterised by moderate intellectual deficit, marked cubitus valgus, mild microcephaly, a short philtrum, deep-set eyes, downslanting palpebral fissures and multiple nevi. Less than ten individuals have been described so far. Transmission is thought to be X-linked recessive.", "ORPHA ID": 85280, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-Dandy-Walker malformation-basal ganglia disease-seizures syndrome", "Disease Definition": "A rare central nervous system malformation characterized by severe intellectual deficit, early hypotonia with progression to spasticity and contractures, choreoathetosis, seizures, dysmorphic face (long face with prominent forehead), and brain imaging abnormalities such as Dandy-Walker malformation, and iron deposition.", "ORPHA ID": 1568, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-dysmorphism-cerebral atrophy syndrome", "Disease Definition": "An X-linked syndromic intellectual disability characterized by intellectual disability, subcortical cerebral atrophy, dental anomalies, patella luxation, lower back skin dimple, and dysmorphic facial features.", "ORPHA ID": 2958, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome", "Disease Definition": "X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome is characterised by intellectual deficit, epilepsy, facial dysmorphism and progressive joint contractures. It has been described in two boys. Hypotonia and feeding problems at birth were also reported. The mode of transmission is X-linked.", "ORPHA ID": 85319, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-global development delay-facial dysmorphism-sacral caudal remnant syndrome", "Disease Definition": "A rare multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, growth retardation, hearing impairment, characteristic facial dysmorphology (including prominent supraorbital ridges, downslanting palpebral fissures, deep-set eyes, long face, sagging cheeks, anteverted nares, and pointed chin), generalized hypotonia, joint hypermobility, gluteal crease with sacral caudal remnant and sacral dimple, and variable neurological features. Various ophthalmic, cutaneous, musculoskeletal, gastrointestinal, and cardiovascular anomalies have also been described.", "ORPHA ID": 480907, "Summary": "Epidemiology\nDue to the small number of known affected individuals, the prevalence of this condition remains unknown. Globally, some 30 cases are known.\nClinical description\nThe main clinical features include growth retardation, delayed speech and language development, delayed gross motor development, generalized hypotonia, intellectual disability and symptoms of autism spectrum disorder. Microcephaly, facial dysmorphism, hearing impairment, variable brain morphological abnormalities, and congenital heart defects, hypospadias and cryptorchidism have also been reported.\nEtiology\nThe disorder is caused by pathogenic mutations in the TAF1 gene (Xq13.1). The encoded protein, transcription initiation factor TFIID subunit 1, is a part of the transcription factor II D complex that participates in the initiation of the transcription of RNA polymerase II transcription-dependent genes.\nDiagnostic methods\nDiagnosis is based on clinical examination and genetic testing.\nDifferential diagnosis\nThe main differential diagnosis options include other X-linked intellectual disability syndromes that involve similar symptoms or clinical findings.\nAntenatal diagnosis\nAntenatal diagnosis is possible if a familial pathogenic variant has been identified.\nGenetic counseling\nThe pattern of inheritance is X-linked. Where the female is a carrier, at risk couples should be informed that for each pregnancy the male offspring have a 50% risk of being affected and female offspring have a 50% risk of being a carrier. Females may rarely be affected due to skewed X chromosome inactivation.\nManagement and treatment\nManagement is symptomatic. After initial diagnosis, evaluation by a pediatric urologist, pediatric cardiologist, pediatric neurologist, otorhinolaryngologist or other relevant specialist may be warranted to rule out associated congenital abnormalities.\nPrognosis\nStudies suggest that the symptoms are generally not progressive; however, individual cases with progressive symptomatology have been reported. Longitudinal data regarding life expectancy is currently unavailable due to the small number of known cases.\n\n                            Last update: \n                            October 2021\n\n\n                            - Expert reviewer(s): \n                            Dr Outi KUISMIN | ITHACA* - Dr Leila SOIKKONEN | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by moderate intellectual disability, dysmorphic facial features (such as prominent glabella, synophrys, and prognathism), generalized hirsutism, bilateral single palmar creases, and seizures. Additional reported manifestations include slowly progressive neurological deterioration with muscular weakness and impaired gait and balance, as well as hypogammaglobulinemia with specific absence of plasma and/or secretory IgA, among others. Brain imaging may show mild cerebellar atrophy and thin corpus callosum.", "ORPHA ID": 85317, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome", "Disease Definition": "X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome is a rare X-linked intellectual disability syndrome characterized by intellectual disability associated with short stature, obesity, primary hypogonadism and an ichthyosiform skin condition. There have been no further descriptions in the literature since 1982.", "ORPHA ID": 3055, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-hypotonia-facial dysmorphism-aggressive behavior syndrome", "Disease Definition": "A rare X-linked syndromic intellectual disability characterized by severe to profound intellectual disability, muscular hypotonia in childhood, delayed walking, delayed or minimal/absent speech, behavioral abnormalities including aggressiveness, agitation, and self-injurious behavior, and dysmorphic facial features (such as triangular face with high forehead, prominent ears, and small, pointed chin). Additional reported manifestations include microcephaly, short stature, and seizures, among others.", "ORPHA ID": 85329, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-hypotonia-movement disorder syndrome", "Disease Definition": "A rare, genetic, syndromic intellectual disability characterized by mild to severe intellectual disability associated with variable features, including hypotonia, dyskinesia, spasticity, wide-based gait, microcephaly, epilepsy and behavioral problems. MRI imaging may show a corpus callosum hypoplasia or ventricular enlargement. Other variable features, such as joint hyperlaxity, skin pigmentary abnormalities, and visual impairment, have also been reported.", "ORPHA ID": 457260, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-limb spasticity-retinal dystrophy-arginine vasopressin deficiency", "Disease Definition": "X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome is a rare genetic neurometabolic disease characterized by severe intellectual disability, spastic quadraparesis, Leber´s congenital amaurosis and diabetes insipidus. Additional manifestations include facial dysmorphy (dolichocephalic skull, hypertelorism, deep-set eyes, hypoplastic nares, low-set ears), short stature, truncal hypotonia and axial hypertonia. Brain anomalies (e.g. thin corpus callosum with lack of isthmus and tapered splenium, hypoplasia or atrophy of the optic chiasm, prominent lateral ventricles, diminished white matter), described on magnetic resonance imaging, have been reported. High prenatal α-fetoprotein and intrauterine growth restriction is observed in routine pregnancy examination.", "ORPHA ID": 423479, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-macrocephaly-macroorchidism syndrome", "Disease Definition": "An X-linked syndromic intellectual disability characterized by intellectual disability, macrocephaly, macroorchidism, prominent eyebrows and jaws and abnormal ears. Males are predominantly affected, some females show lower cognitive abilities.", "ORPHA ID": 85320, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-plagiocephaly syndrome", "Disease Definition": "A rare, syndromic intellectual disability characterized by severe intellectual deficit, brachycephaly, plagiocephaly, and prominent forehead in male patients. Females may display moderate intellectual deficit without craniofacial dysmorphism. There have been no further descriptions in the literature since 1992.", "ORPHA ID": 2898, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-psychosis-macroorchidism syndrome", "Disease Definition": "An X-linked syndromic intellectual disability characterized by developmental delay, variable degree of intellectual disability, speech delay or absent speech, pyramidal signs, tremor, macroorchidism and variable mood and behavior problems, including psychosis and autistic-like behavior. Males are predominantly affected, some females show lower cognitive abilities.", "ORPHA ID": 3077, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-retinitis pigmentosa syndrome", "Disease Definition": "X-linked intellectual disability-retinitis pigmentosa syndrome is characterized by moderate intellectual deficit and severe, early-onset retinitis pigmentosa. It has been described in five males spanning three generations of one family. Some patients also had microcephaly. It is transmitted as an X-linked recessive trait.", "ORPHA ID": 85332, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-seizures-psoriasis syndrome", "Disease Definition": "A rare, X-linked syndromic intellectual disability disorder characterized by severe intellectual disability, psychomotor developmental delay, generalized seizures, and psoriasis. Mild craniofacial dysmorphism, such as hypertelorism, broad nasal bridge, anteverted nares, macrostomia, highly arched palate and large ears, is also associated. There have been no further descriptions in the literature since 1988.", "ORPHA ID": 3052, "Summary": ""}
{"Disease Name": "X-linked intellectual disability-short stature-overweight syndrome", "Disease Definition": "X-linked intellectual disability-short stature-overweight syndrome is a multiple congenital anomalies syndrome characterized by borderline to severe intellectual disability, speech delay, short stature, elevated body mass index, a pattern of truncal obesity (reported in older males), and variable neurologic features (e.g. hypotonia, tremors, gait disturbances, behavioral problems, and seizure disorders). Less common manifestations include microcephaly, microorchidism and/or microphallus. Dysmorphic features have been reported in some patients but no consitent pattern has been noted.", "ORPHA ID": 457240, "Summary": ""}
{"Disease Name": "X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome", "Disease Definition": "A rare genetic disease characterized by congenital contractures of the distal interphalangeal joints, progressive stiffness of the shoulders and neck, keloid scarring, increased optic cup-to-disc ratio, and renal stones. Additional reported features include arthritis, osteoporosis, hypoplastic flexion creases, clinodactyly, anxiety, and facial dysmorphism (such as sloping forehead, prominent supraorbital ridges, downslanting palpebral fissures, prominent ears, and high arched palate). Female carriers exhibit a variable, milder phenotype.", "ORPHA ID": 482606, "Summary": ""}
{"Disease Name": "X-linked lethal multiple pterygium syndrome", "Disease Definition": "X-linked lethal multiple pterygium syndrome is a rare, genetic, developmental defect during embryogenesis characterized by the typical lethal multiple pterygium syndrome presentation (comprising of multiple pterygia, severe arthrogryposis, cleft palate, cystic hygromata and/or fetal hydrops, skeletal abnormalities and fetal death in the 2nd or 3rd trimester) with an X-linked pattern of inheritance.", "ORPHA ID": 79447, "Summary": ""}
{"Disease Name": "X-linked lissencephaly with abnormal genitalia", "Disease Definition": "A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by lissencephaly, agenesis of the corpus callosum and other cerebral structural anomalies, early-onset intractable seizures, and ambiguous genitalia. Consequences of hypothalamic dysfunction, such as disturbed temperature regulation, may be observed. Additional anomalies including dysmorphic craniofacial features have been reported. The disease is fatal in infancy or childhood in males, while female carriers may be unaffected or show a milder phenotype with developmental delay, behavioral abnormalities, and seizures.", "ORPHA ID": 452, "Summary": ""}
{"Disease Name": "X-linked lymphoproliferative disease due to SAP deficiency", "Disease Definition": "A rare, genetic, primary immunodeficiency disorder characterized by an abnormal immune response to Epstein-Barr virus (EBV) infection, caused by hemizygous mutations in the X-linked SH2D1A gene, resulting in B cell lymphoproliferation and manifesting with various phenotypes which include EBV-driven severe or fulminant mononucleosis, hemophagocytic lymphohistiocytosis (presenting with fulminant hepatitis, hepatic necrosis, bone marrow hypoplasia, and neurological involvement), hypogammaglobulinemia, and B-cell lymphoma. Additional variable manifestations include vasculitis, lymphomatoid granulomatosis, aplastic anemia, and chronic gastritis. Occasionally, T-cell lymphoma may be observed. Laboratory findings include normal or increased activated T cells and reduced memory B cells.", "ORPHA ID": 538931, "Summary": ""}
{"Disease Name": "X-linked lymphoproliferative disease due to XIAP deficiency", "Disease Definition": "A rare, genetic, primary immunodeficiency disorder characterized by an abnormal immune response to Epstein-Barr virus (EBV) infection, caused by hemizygous mutations in the X-linked XIAP gene, resulting in B cell lymphoproliferation and manifestating with various phenotypes which include EBV-driven hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, recurrent splenomegaly, hepatitis, colitis, and intestinal bowel disease with features of Crohn's disease. Additional manifestations include variable auto-inflammatory symptoms such as uveitis, arthritis, skin abscesses, erythema nodosum, and nephritis. Neurological involvement is rare and lymphoma is never observed. Laboratory findings include normal or increased activated T cells, low or normal iNKT cells, and normal or reduced memory B cells.", "ORPHA ID": 538934, "Summary": ""}
{"Disease Name": "X-linked mandibulofacial dysostosis", "Disease Definition": "X-linked mandibulofacial dysostosis is an extremely rare multiple congenital abnormality syndrome that is characterized by microcephaly, malar hypoplasia with downslanting palpebral fissures, highly arched palate, apparently low-set and protruding ears, micrognathia, short stature, bilateral hearing loss, and learning disability. Occasionally, additional features have been observed such as bilateral cryptorchidism, cardiac valvular lesions, body asymmetry, and pectus excavatum.", "ORPHA ID": 1131, "Summary": ""}
{"Disease Name": "X-linked mendelian susceptibility to mycobacterial diseases", "Disease Definition": "X-linked (XR) Mendelian susceptibility to mycobacterial diseases (MSMD; see this term) describes a rare group of immunodeficiencies due to specific mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG) or the cytochrome b-245, beta polypeptide (CYBB) genes. They are characterized by mycobacterial infections, occuring in males.", "ORPHA ID": 319605, "Summary": "Epidemiology\nThe prevalence is unknown. Six male patients have been reported with XR-MSMD deficiency due to IKBKG mutations and seven male patients have been reported with XR-MSMD deficiency due to CYBB mutations.\nClinical description\nXR-MSMD due to IKBKG deficiency affects otherwise healthy male patients. The most common infections seen are Mycobacterium avium, Mycobacterium bovis  BCG and Mycobacterium tuberculosis. An invasive Haemophilus influenza type b infection was reported in one patient. In two cases, mild signs of anhidrotic ectodermal dysplasia (AED; see this term), limited to conical deciduous incisors, were observed. Patients with XR-MSMD due to CYBB deficiency present with disseminated tuberculosis mycobacterial disease (such as BCG or M. tuberculosis). They do not suffer from any other infectious diseases.\nEtiology\nXR-MSMD is due to hemizygous mutations in the IKBKG or CYBB genes. IKBKG (Xq28) encodes the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma. This mutation causes defects in T-cell dependant IL-12 production and consequently IFN-gamma production. The mutations disturb the plasticity of the leucine zipper domain (LDZ) helix of IKBKG interfering selectively with the CD40-NEMO-NFkB signaling pathway. These hypomorphic mutations are associated with impaired NF-kB activation of c-Rel containing proteins in response to CD40. The CYBB gene (Xp21.1) encodes the gp91-phox subunit of the phagocyte NADPH oxydase. These mutations do not impair the respiratory burst in granulocytes and monocytes, but they impair macrophages and B-cell lines selectively.\nDiagnostic methods\nDiagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA. Low levels of IFN-gamma and IL-12 production by the patients' mononuclear cells upon phytohemagglutinin (PHA) are detected in those with an IKBKG mutation. In addition, an impaired IL-12 production by monocytes upon PHA stimulation by activated T cells is shown. Impaired NADPH activity is demonstrated in vitro in macrophages and B-cell lines in those with a CYBB mutation. A mutational analysis is necessary to identify the exact causative genes involved allowing for the implementation of a specific treatment plan.\nDifferential diagnosis\nDifferential diagnoses include other diseases caused by IKBKG mutations such as EDA with immunodeficiency (see this term). It is important to exclude the diagnosis of chronic granulomatous disease (CGD; see this term) caused by CYBB mutations. Other genetic forms of MSMD should also be excluded.\nAntenatal diagnosis\nThis immunodeficiency is not severe and antenatal diagnosis is not necessary.\nGenetic counseling\nThe occurrence of mycobacterial diseases in maternally-related males suggests an X-linked recessive form of MSMD. Genetic counseling is possible when a known mutation is present in the family.\nManagement and treatment\nBCG vaccination should be avoided in those with a known XR-MSMD mutation. Treatment usually involves IFN-gamma therapy in addition to antibiotics.\nPrognosis\nThe prognosis is good.\n\n                            Last update: \n                            February 2013\n\n\n                            - Expert reviewer(s): \n                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA"}
{"Disease Name": "X-linked microcephaly-growth retardation-prognathism-cryptorchidism syndrome", "Disease Definition": "X-linked microcephaly-growth retardation-prognathism-cryptorchidism syndrome is a rare syndromic intellectual disability characterized by hypotonia, microcephaly, severe developmental delay, seizures, intellectual disability, growth retardation, cardiac septal defects, cryptorchidism, hypospadias, and dysmorphic features - prominent ears, prognathism, thin upper lip, dental crowding.", "ORPHA ID": 435938, "Summary": ""}
{"Disease Name": "X-linked myopathy with excessive autophagy", "Disease Definition": "X-linked myopathy with excessive autophagy is a childhood-onset X-linked myopathy characterised by slow progression of muscle weakness and unique histopathological findings.", "ORPHA ID": 25980, "Summary": "Epidemiology\nIt has been described in about fifteen families.\nClinical description\nThe first manifestations appear typically in children around 5-10 years of age and include difficulty climbing stairs and running.\nEtiology\nThe Xq28 locus has been associated with the disease.\nDiagnostic methods\nMuscle fibres are not necrotic but they show excessive autophagic activity and exocytosis of the phagocytosed material.\nGenetic counseling\nTransmission is X-linked recessive; female carriers are asymptomatic or only mildly affected.\nPrognosis\nProgression is very slow, longevity is not altered. Many patients need a wheelchair in their 6th decade of life.\n\n                            Last update: \n                            June 2006"}
{"Disease Name": "X-linked myopathy with postural muscle atrophy", "Disease Definition": "A rare progressive muscular dystrophy characterized by an adult-onset scapulo-axio-peroneal myopathy. Clinical presentation includes shoulder girdle atrophy, scapular winging, axial muscular atrophy of postural muscles combined with a generalized hypertrophy. Typically, neck rigidity, rigid spine, Achilles tendon shortening, and respiratory insufficiency later in disease course are present.", "ORPHA ID": 178461, "Summary": ""}
{"Disease Name": "X-linked myotubular myopathy-abnormal genitalia syndrome", "Disease Definition": "X-linked myotubular myopathy-abnormal genitalia syndrome is a rare chromosomal anomaly, partial deletion of the long arm of chromosome X, characterized by a combination of clinical manifestations of X-linked myotubular myopathy and a 46,XY disorder of sex development. Patients present with severe form of congenital myopathy and abnormal male genitalia.", "ORPHA ID": 456328, "Summary": ""}
{"Disease Name": "X-linked neurodegenerative syndrome, Bertini type", "Disease Definition": "An X-linked syndromic intellectual disability characterized by congenital ataxia and generalized hypotonia, global developmental delay with intellectual disability, myoclonic encephalopathy, progressive neurological deterioration, macular degeneration, and recurrent bronchopulmonary infections.", "ORPHA ID": 85334, "Summary": ""}
{"Disease Name": "X-linked neurodegenerative syndrome, Hamel type", "Disease Definition": "An X-linked syndromic intellectual disability characterized by a few months of normal development, followed by progressive neurodegenerative course with gradual loss of vision, development of spastic tetraplegia, convulsions, microcephaly, failure to thrive, and early death.", "ORPHA ID": 85336, "Summary": ""}
{"Disease Name": "X-linked non progressive cerebellar ataxia", "Disease Definition": "X-linked non progressive cerebellar ataxia is a rare hereditary ataxia characterized by delayed early motor development, severe neonatal hypotonia, non-progressive ataxia and slow eye movements, presenting normal cognitive abilities and absence of pyramidal signs. Frequently patients also manifest intention tremor, mild dysphagia, and dysarthria. Brain MRI reveals global cerebellar atrophy with absence of other malformations or degenerations of the central and peripheral nervous systems.", "ORPHA ID": 314978, "Summary": ""}
{"Disease Name": "X-linked osteoporosis with fractures", "Disease Definition": "A rare, genetic, primary bone dysplasia with decreased bone density disorder characterized by childhood-onset osteoporosis associated with recurrent, multiple, osteoporotic, long bone fractures and/or vertebral compression fractures, significant height loss in adulthood, low bone mineral density scores, and otherwise no other abnormalities. Heterozygote females may be unaffected or have a milder phenotype.", "ORPHA ID": 391330, "Summary": ""}
{"Disease Name": "X-linked parkinsonism-spasticity syndrome", "Disease Definition": "A rare, genetic, neurological disorder characterized by parkinsonian features (including resting or action tremor, cogwheel rigidity, hypomimia and bradykinesia) associated with variably penetrant spasticity, hyperactive deep tendon reflexes and Babinski sign.", "ORPHA ID": 363654, "Summary": ""}
{"Disease Name": "X-linked progressive cerebellar ataxia", "Disease Definition": "A rare X-linked cerebellar ataxia, characterized by a combination of upper and lower motor neuron signs, with an age of onset in the first or second decade, slow progression, and normal intelligence. Typical features of cerebellar dysfunction include gait and limb ataxia, intention tremor, dysmetria, dysdiadochokinesia, dysarthria, nystagmus, and hyperreflexia. Further phenotypic features are pes cavus, scoliosis, muscle atrophy, and peripheral sensory and motor nerve abnormalities.", "ORPHA ID": 1175, "Summary": ""}
{"Disease Name": "X-linked recessive ocular albinism", "Disease Definition": "X-linked recessive ocular albinism (XLOA) is a rare disorder characterized by ocular hypopigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity in males.", "ORPHA ID": 54, "Summary": "Epidemiology\nThe estimated birth prevalence is from 1/60,000 to 1/150,000 live male births.\nClinical description\nNystagmus, sometimes associated with head nodding, usually develops in affected males within the first 3 months of life. It can diminish with time but rarely completely disappears. Best-corrected visual acuity is usually between 20/40 and 20/200, and often improves during childhood. Most patients have photodysphoria, strabismus and absent or reduced stereoacuity. Ocular findings include iris translucency, foveal hypoplasia, hypopigmentation of the fundus and excessive crossing of the nerves from the eye to the brain. Some males have irregular hypopigmented spots on the extremities, but they escape clinical notice. Carrier women, in the vast majority of cases, are asymptomatic. XLOA is less severe in those with dark constitutive skin pigmentation than those who are more lightly pigmented.\nEtiology\nXLOA is caused by a mutation in the G-protein coupled receptor 143 GPR143 gene located at Xp22.3 that encodes for a membrane glycoprotein found in melanosomes. The few cases where females displayed the same phenotypes as males are thought to have been due to either a homozygous mutation in GPR143, partial monosomy of the X chromosome or X-chromosome inactivation.\nDiagnostic methods\nDiagnosis is based on the presence of characteristic ocular findings and molecular genetic testing. A family history consistent with X-linked inheritance provides further evidence of XLOA. A GPR143 mutation is found in 90% of affected males. Melanin macroglobules (macromelanosomes) are usually found on skin biopsy but are not pathognomonic. Female obligate carriers are identified by finding patchy mottling or streaking of pigment in the midperipheral retina (pigmentary mosaicism), representing random X inactivation.\nDifferential diagnosis\nDifferential diagnoses include various types of oculocutaneous albinism (OCA), blue cone monochromatism, congenital stationary night blindness, ocular albinism with sensorineural deafness, cone dystrophy with supernormal rod response, Leber congenital amaurosis, complete and incomplete achromatopsia, X-linked congenital nystagmus (see these terms), and autosomal dominant infantile nystagmus syndrome.\nAntenatal diagnosis\nPrenatal testing can be performed when women are known carriers of the GPR143 mutation, using chorionic villus sampling or amniocentesis. Preimplantation genetic diagnosis may be available.\nGenetic counseling\nXLOA is inherited in an X-linked recessive manner so genetic counseling is possible. Affected males do not transmit the disease causing mutation to their sons but all of their daughters become carriers. Female carriers have a 50% risk of transmitting the mutation to their offspring, whether male or female; however, only sons with the mutation will display the disease. Carrier testing can be offered to at-risk individuals.\nManagement and treatment\nAnnual ophthalmologic examinations are recommended for patients under the age of 16, and after that every 2-3 years. Treatment consists of visual correction with eyeglasses or contact lenses. Sunglasses, photochromic lenses or special filter glasses can help to relieve photodysphoria. Extraocular muscle surgery can be performed to restore alignment and/or improve a head posture that is compensatory for nystagmus. Visual aids, changing electronic font size, and special education for the visually impaired may be needed. Patients should wear hats/caps, clothing, and sunscreen on sun-exposed skin to prevent burning and skin cancer.\nPrognosis\nXLOA is not life threatening. The reduced visual acuity and the social consequences of albinism can however have an impact on a patient's daily life.\n\n                            Last update: \n                            April 2013\n\n\n                            - Expert reviewer(s): \n                             Gail SUMMERS"}
{"Disease Name": "X-linked reticulate pigmentary disorder", "Disease Definition": "X-linked reticulate pigmentary disorder is an extremely rare skin disease described in only four families to date and characterized in males by diffuse reticulate brown hyperpigmentated skin lesions developing in early childhood and a variety of systemic manifestations (recurrent pneumonia, corneal opacification, gastrointestinal inflammation, urethral stricture, failure to thrive, hypohidrosis, digital clubbing, and unruly hair and flared eyebrows), while in females, there is only cutaneous involvement with the development in early childhood of localized brown hyperpigmented skin lesions following the lines of Blaschko. This disease was first considered as a cutaneous amyloidosis, but amyloid deposits are an inconstant feature.", "ORPHA ID": 85453, "Summary": ""}
{"Disease Name": "X-linked retinal dysplasia", "Disease Definition": "A rare genetic eye disease characterized by abnormal proliferation of retinal tissue resulting in the formation of retinal folds, thereby causing gliosis and, clinically, variable degrees of visual impairment. No clinical findings other than those associated with the eyes have been demonstrated.", "ORPHA ID": 1852, "Summary": ""}
{"Disease Name": "X-linked retinoschisis", "Disease Definition": "A rare disorder involving multiple structure of the eye characterized by reduced visual acuity in males due to juvenile macular degeneration. Clinical features such as vitreous hemorrhage, retinal detachment, and neovascular glaucoma can be observed in advanced stages.", "ORPHA ID": 792, "Summary": "Epidemiology\nX-linked retinoschisis prevalence is estimated to range between 1/5,000-1/25,000 males worldwide.\nClinical description\nXLRS is a symmetrical bilateral macular disorder with onset in the first decade of life. It manifests with poor vision and reading difficulties. In severe cases, nystagmus may also be observed. Severe cases involve full-thickness retinal detachment that leads to impaired vision or blindness. In more advanced stages of the disease, vitreous hemorrhage, retinal detachment, and neovascular glaucoma, which may induce severe loss of vision, can be seen. Correlation exists between visual acuity, patient age, and OCT features. There is clinical variability. Female carriers rarely have any vision impairment.\nEtiology\nThe disease is caused by mutations on the RS1 gene (Xp22.2-p22.1), including missense, nonsense, frameshift, and splice site mutations, deletions, and insertions. RS1 codes for retinoschisin, an adhesive protein, localized in photoreceptors and bipolar cells, and secreted in the extracellular matrix. In the adult retina, retinoschisin is essential for maintaining the structural and functional integrity of the retina and participates in molecular pathways at the photoreceptor bipolar synapse.\nDiagnostic methods\nThe diagnosis of XLRS can be made clinically, based on fundus appearance. Fundus examination shows microcystic changes of the macular region of the retina and areas of splitting within the nerve fiber layer, or schisis (spoked-wheel pattern), and vitreous veils. Electroretinogram (ERG) usually shows generalized cone system dysfunction with a reduction in the amplitude of the beta-wave and a relative preservation of the negative alpha-wave in scotopic ERG (electronegative rods and mixed ERG) and a normal photopic ERG. Optical coherence tomography (OCT) shows schisis areas in the macular region. There is also a family history consistent with X-linked inheritance. Molecular genetic analysis by direct sequencing of the RS1 gene detects mutations in approximately 90% of patients. NGS panels for Inherited Retinal dystrophies, including the RS1 gene represent also an appropriate approach.\nDifferential diagnosis\nDifferential diagnosis includes retinitis pigmentosa and Goldmann-Favre syndrome. The presence of an autosomal recessive inheritance, severe nyctalopia, pigmentary retinopathy, and reduced alpha- and beta-waves on the electroretinogram (ERG) help to differentiate Goldmann-Favre syndrome from XLRS.\nGenetic counseling\nThere are more than 290 mutations described in RS1, most missense (~51%). Nonsense, splicing, small indels and CNVs variants have also been reported. XLRS is inherited in an X-linked manner, with a carrier female having a 50% risk of transmitting the mutation to her offspring. Carrier testing for at-risk female relatives and prenatal diagnosis for pregnancies at increased risk are possible if a RS1 mutation is identified in an affected family member.\nManagement and treatment\nManagement includes periodic ophthalmologic examination to monitor progression of XLRS. Additionally, patients are informed about possible ophthalmic complications that can be surgically treated (i.e., retinal detachment, vitreous haemorrhage, cataracts or strabismus). Therefore, patient education and close follow-up are the only clinical alternatives to early identification and treatment of vision-threatening complications.\nPrognosis\nIn XLRS, vision slowly decreases until adolescence, and then in most patients remains relatively stable during young adulthood. The disease does not progress again until the fourth or fifth decade of life, when a significant decline in visual acuity typically occurs.\n\n                            Last update: \n                            August 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen AYUSO  - Dr Marta CORTON PÉREZ  -  Marta DEL POZO VALERO  - Dr José María MILLÁN SALVADOR"}
{"Disease Name": "X-linked scapuloperoneal muscular dystrophy", "Disease Definition": "A rare, genetic, muscular dystrophy disease characterized by the co-occurrence of late onset scapular and peroneal muscle weakness, principally manifesting with distal lower limb and proximal upper limb weakness and scapular winging.", "ORPHA ID": 431272, "Summary": ""}
{"Disease Name": "X-linked severe congenital neutropenia", "Disease Definition": "X-linked severe congenital neutropenia is an immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia. It has been described in five males spanning three generations of one family. It is transmitted as an X-linked recessive trait and is caused by mutations in the WAS gene, encoding the WASP protein.", "ORPHA ID": 86788, "Summary": ""}
{"Disease Name": "X-linked sideroblastic anemia and spinocerebellar ataxia", "Disease Definition": "A rare syndromic, inherited form of sideroblastic anemia characterized by mild to moderate anemia (with hypochromia and microcytosis) and early-onset, non- or slowly progressive spinocerebellar ataxia.", "ORPHA ID": 2802, "Summary": "Epidemiology\nX-linked sideroblastic anemia and ataxia (XLSA-A) prevalence is unknown. Less than 20 genetically confirmed patients have been reported to date.\nClinical description\n.XLSA-A usually presents before the age of 3 years. Anemia is usually asymptomatic. In males, spinocerebellar symptoms are apparent in childhood and can include delayed walking, predominantly truncal ataxia, dysmetria and dysdiadochokinesis. Dysarthria and intention tremor are sometimes present. Ataxia may improve over time, but in the fifth to sixth decade of life a slow deterioration of walking is noted. Upper motor neuron signs in the legs such as equivocal or extensor plantar responses, brisk deep tendon reflexes and unsustained ankle clonus are sometimes present. Strabismus, as well as mild learning disability and depression, have also been reported in some, but intellectual abilities are generally within the normal range. Hepatic and systemic iron overload does not occur. Females are clinically asymptomatic.\nEtiology\nXLSA-A is caused by mutations in the ABCB7 gene (Xq13.3), encoding a mitochondrial ATP-binding cassette (ABC) transporter protein, which plays a role in heme production and iron homeostasis. A pathogenic variant in this gene alters the availability of reduced iron and therefore disrupts heme biosynthesis. The ABCB7 gene is highly expressed in both the bone marrow and the cerebellum, which may explain ataxia.\nDiagnostic methods\nDiagnosis is based on the presence of characteristic neurological and blood test findings. Mild to moderate hypochromic, microcytic anemia is noted in all males and both whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) are elevated. Bone marrow examination demonstrates the presence of increased iron stores with ring sideroblasts and peripheral blood smear reveals Pappenheimer bodies. In the majority of cases magnetic resonance imaging (MRI) shows cerebellar atrophy/hypoplasia. Female carriers display hematological abnormalities. Molecular genetic testing identifies a ABCB7 gene variation, confirming the diagnosis.\nDifferential diagnosis\nThe main differential diagnosis includes other forms/causes of ataxia that typically present before the age of 3 years such as ataxia-telangiectasia, infantile-onset spinocerebellar ataxia, congenital disorder of glycosylation, and cerebellar malformations (e.g. Dandy-Walker malformation). Ataxia with vitamin E deficiency, Friedreich ataxia, ataxia - oculomotor apraxia type 1 and 2, and X linked sideroblastic anemia , the most common form of congenital sideroblastic anemia (without ataxia), should also be excluded.\nAntenatal diagnosis\nPrenatal testing is possible in families with a known ABCB7 mutation.\nGenetic counseling\nThe pattern of inheritance is X-linked recessive and gentic counselling should be offerend to affected families. Where the female is a carrier, the risk to male offspring inheriting the disease is 50%, female offspring have a 50% risk of being carriers. Where a male is affected, female offspring are obligate carriers, and male offspring do not inherit the pathogenic mutation.\nManagement and treatment\nThere is no cure for XLSA-A and treatment is symptomatic. Anemia does not require treatment. Early physical therapy may aid in the acquisition of gross motor skills. Ankle fixation orthoses and walkers may be required to aid with mobility. Weighted eating utensils promote independent skills in children. Speech therapy is recommended for those with dysarthria. Crutches or a wheelchair may be needed by some patients.\nPrognosis\nWhile prognosis information is limited due to very few existing reports, XLSA-A does not appear to have a significant impact on life expectancy. Quality of life, however, can be significantly affected.\n\n                            Last update: \n                            June 2020\n\n\n                            - Expert reviewer(s): \n                            Pr Soumeya BEKRI"}
{"Disease Name": "X-linked sideroblastic anemia", "Disease Definition": "X-linked sideroblastic anemia is a constitutional microcytic, hypochromic anemia of varying severity that is clinically characterized by manifestations of anemia and iron overload and that may respond to treatment with pyridoxine and folic acid.", "ORPHA ID": 75563, "Summary": "Epidemiology\nPrevalence is unknown. Around 200 cases and fewer than 100 unrelated probands are described in the literature.\nClinical description\nThe anemia can present at any age from birth to the 9th decade. Some patients are asymptomatic and are detected incidentally by hematological screening or through a family study. Clinical features are those of anemia and/or iron overload such as pallor, fatigue, weakness. Breathlessness, mild splenomegaly, cardiac problems, abnormal liver function, hyperglycemia, glucose intolerance and skin hyperpigmentation are seen more rarely.\nEtiology\nSA is due to inherited or de novo mutations in the ALAS2 gene (Xp11.21) encoding the erythroid form of delta amino levulinic acid synthase (ALAS2), which altered function leads to impaired heme synthesis. The increased ineffective and expanded erythropoiesis leads to increased absorption of dietary iron and a risk of iron overload. Female carriers are usually unaffected, however, one quarter of probands are female who have X-chromosome inactivation skewed against the unaffected allele and almost half of the female probands have macrocytic rather than microcytic red blood cells due to the heterozygous inheritance of a severe/null allele.\nDiagnostic methods\nDiagnosis requires a full blood and reticulocyte count, measurement of iron stores, exclusion of thalassemia as a cause, bone marrow aspirate showing ringed sideroblasts, and mutation analysis of the ALAS2 gene.\nDifferential diagnosis\nThe differential diagnosis should include other types of inherited sideroblastic anemia and in case of macrocytic red cells in females also acquired myelodysplasia (refractory anemia with ringed sideroblasts or RARS (see these terms). Most female carriers show some evidence of microcytic, hypochromic red blood cells but hematological parameters cannot be relied upon for genetic counseling purposes and DNA analysis is required\nAntenatal diagnosis\nPrenatal diagnosis is rarely indicated or requested, but should be offered in case of family history.\nGenetic counseling\nGenetic counseling for the family of affected individuals is recommended, as early diagnosis in a child may be of great benefit for treatment of anemia and prevention of iron overload, the main cause of early death in the past.\nManagement and treatment\nTreatment is supportive and involves hematological monitoring, the surveillance of iron levels, lifetime pyridoxine supplementation in those who respond and folic acid supplementation. Pyridoxine response varies in degree and is rarely complete. Prophylactic occasional phlebotomy can be performed to prevent iron overload, if anemia is very mild or corrected by pyridoxine. If iron overload has already developed, phlebotomy, iron chelation or a combination of both can be used to normalize iron levels. In some cases iron depletion may simultaneously increase the hemoglobin level. Blood transfusions may be needed on occasion but are only required on a regular basis for those most severely affected.\nPrognosis\nPrognosis is variable but for patients with pyridoxine-responsive anemia whose iron stores are kept low, normal life expectancy should be achievable\n\n                            Last update: \n                            July 2013\n\n\n                            - Expert reviewer(s): \n                            Pr Clara CAMASCHELLA"}
{"Disease Name": "X-linked skeletal dysplasia-intellectual disability syndrome", "Disease Definition": "A rare genetic syndrome characterized by skeletal anomalies, including short stature, ridging of the metopic suture, a fusion of cervical vertebrae, thoracic hemivertebrae, scoliosis, sacral hypoplasia, short middle phalanges. Patients also had a moderate intellectual disability and abducens palsies. Glucose intolerance and imperforate anus were also described.", "ORPHA ID": 1436, "Summary": ""}
{"Disease Name": "X-linked spastic paraplegia type 16", "Disease Definition": "A complex, hereditary, spastic paraplegia characterized by delayed motor development, spasticity, and inability to walk, later progressing to quadriplegia, motor aphasia, bowel and bladder dysfunction. Patients also present with vision problems and mild intellectual disability. The disease affects only males.", "ORPHA ID": 100997, "Summary": ""}
{"Disease Name": "X-linked spastic paraplegia type 34", "Disease Definition": "X-linked spastic paraplegia type 34 is a pure form of hereditary spastic paraplegia characterized by late childhood- to early adulthood-onset of slowly progressive spastic paraplegia with spastic gait and lower limb hyperreflexia, brisk tendon reflexes and ankle clonus. Lower limb pain and reduced lower limb vibratory sense is also reported in some older adult patients.", "ORPHA ID": 171607, "Summary": ""}
{"Disease Name": "X-linked spasticity-intellectual disability-epilepsy syndrome", "Disease Definition": "A rare ARX-related epileptic encephalopathy characterized by infantile onset of myoclonic epilepsy with generalized spasticity, severe global developmental delay, and moderate to profound intellectual disability. Obligate female carriers show subtle, generalized hyperreflexia. Late onset progressive spastic ataxia has also been reported.", "ORPHA ID": 3175, "Summary": ""}
{"Disease Name": "X-linked spinocerebellar ataxia type 3", "Disease Definition": "X-linked spinocerebellar ataxia type 3 is a form of spinocerebellar degeneration characterized by onset in infancy of hypotonia, ataxia, sensorineural deafness, developmental delay, esotropia, and optic atrophy, and by a progressive course leading to death in childhood. It has been described one family with at least six affected males from five different sibships (connected through carrier females). It is transmitted as an X-linked recessive trait.", "ORPHA ID": 85297, "Summary": ""}
{"Disease Name": "X-linked spinocerebellar ataxia type 4", "Disease Definition": "A rare X-linked spinocerebellar ataxia characterized by ataxia, pyramidal tract signs and adult-onset dementia. The disease manifests during early childhood with delayed walking and tremor. The pyramidal signs appear progressively and by adulthood memory problems and dementia gradually become apparent.", "ORPHA ID": 85292, "Summary": ""}
{"Disease Name": "X-linked spondyloepimetaphyseal dysplasia", "Disease Definition": "A rare, genetic primary bone dysplasia disorder characterized by disproportionate short stature with mesomelic short limbs, leg bowing, lumbar lordosis, brachydactyly, joint laxity and a waddling gait. Radiographs show platyspondyly with central protrusion of anterior vertebral bodies, kyphotic angulation and very short long bones with dysplastic epiphyses and flarred, irregular, cupped metaphyses.", "ORPHA ID": 93349, "Summary": ""}
{"Disease Name": "Xanthinuria type I", "Disease Definition": "Type I xanthinuria, a type of classical xanthinuria (see this term), is a rare autosomal recessive disorder of purine metabolism (see this term) characterized by the isolated deficiency of xanthine dehydrogenase, causing hyperxanthinemia with low or absent uric acid and xanthinuria, leading to urolithiasis, hematuria, renal colic and urinary tract infections, while some patients are asymptomatic and others suffer from kidney failure. Less common manifestations include arthropathy, myopathy and duodenal ulcer.", "ORPHA ID": 93601, "Summary": ""}
{"Disease Name": "Xanthinuria type II", "Disease Definition": "Type II xanthinuria, a type of classical xanthinuria (see this term), is a rare autosomal recessive disorder of purine metabolism (see this term) characterized by the deficiency of both xanthine dehydrogenase and aldehyde oxidase, leading to the formation of urinary xanthine urolithiasis and leading, in some patients, to kidney failure. Other less common manifestations include arthropathy, myopathy and duodenal ulcer, while some patients remain asymptomatic.", "ORPHA ID": 93602, "Summary": ""}
{"Disease Name": "Xanthoma disseminatum", "Disease Definition": "A rare, systemic disease characterized by normolipidemic mucocutaneous xanthomatosis with histiocytic cells proliferation and secondary deposition of lipid in the dermis. Clinically, multiple, grouped, coalescent, yellowish red to brown papulonodular lesions in the skin and mucous membranes are present. Less often internal organs are affected, in particular pituitary gland and/or hypothalamus. Patients present with characteristic mucocutaneous lesions, diabetes insipidus, dysphagia, dyspnea, hoarseness of voice, and blurred vision.", "ORPHA ID": 158003, "Summary": ""}
{"Disease Name": "Xeroderma pigmentosum variant", "Disease Definition": "Xeroderma pigmentosum variant is a milder subtype of xeroderma pigmentosum (XP; see this term), a rare genetic photodermatosis characterized by severe sun sensitivity and an increased risk of skin cancer.", "ORPHA ID": 90342, "Summary": "Epidemiology\nIt is observed in approximately 20% of XP patients and approximately 50 cases have been reported in the literature.\nClinical description\nIt is often diagnosed in the late teens or early 20s. Patients present with skin lesions, generally at the sun-exposed parts of the body which develop into skin cancer at about 20-30 years of age with a 1,000 times higher frequency than that of the general population. No neurological manifestations are observed.\nEtiology\nThe disease is due to mutations in the POLH gene (XPV) (6p21.1-p12) encoding the error-prone DNA-polymerase eta (pol-eta) which performs trans-lesion synthesis past ultraviolet (UV) photoproducts.\nGenetic counseling\nTransmission is autosomal recessive.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Hiva FASSIHI"}
{"Disease Name": "Xeroderma pigmentosum-Cockayne syndrome complex", "Disease Definition": "Xeroderma pigmentosum/Cockayne syndrome complex (XP/CS complex) is characterized by the cutaneous features of xeroderma pigmentosum (XP) (see this term) together with the systemic and neurological features of Cockayne syndrome (CS; see this term).", "ORPHA ID": 220295, "Summary": "Epidemiology\nLess than 30 cases have been described to date.\nClinical description\nThe disease manifests during infancy. Patients present with cutaneous UV-sensitive lesions that generally develop into skin cancer, and also develop characteristic CS manifestations such as microcephaly, hydrocephalus, cachexia, premature aging, dwarfism, skin atrophy, arteriosclerosis, progressive hearing loss, cognitive deficit, spasticity, ataxia, pigmentary retinopathy and optic atrophy. In contrast to the neurological abnormalities of XP which are predominantly secondary to neuronal degeneration, in XP/CS complex, dysmyelination typical of CS is observed.\nEtiology\nAffected individuals have mutations in one of three XP genes: ERCC3 (2q21), ERCC2 (19q13.3), or ERCC5 (13q22-q34). Recently, one patient with XP/CS complex and additional features of Fanconi anemia (see this term) was reported with a mutation in the ERCC4 gene (16p13.3).\nGenetic counseling\nTransmission is autosomal recessive and genetic counseling is possible.\n\n                            Last update: \n                            March 2014\n\n\n                            - Expert reviewer(s): \n                            Dr Hiva FASSIHI"}
{"Disease Name": "Xeroderma pigmentosum", "Disease Definition": "Xeroderma pigmentosum (XP) is a rare genodermatosis characterized by extreme sensitivity to ultraviolet (UV)-induced changes in the skin and eyes, and multiple skin cancers. It is subdivided into 8 complementation groups, according to the affected gene: classical XP (XPA to XPG) and XP variant (XPV) (see these terms).", "ORPHA ID": 910, "Summary": "Epidemiology\nIt has an estimated prevalence of 1/1,000,000 in the USA and Europe, with higher figures in other countries (e.g. Japan, North Africa and Pakistan), particularly in communities with a high degree of consanguinity.\nClinical description\nThe severity of the clinical manifestations and the age of onset are extremely variable and are in part dependent on exposure to sunlight and the complementation group. Approximately 50% of affected individuals have acute sun sensitivity from the first few months of life, presenting with severe sunburn and/or persistent erythema which takes weeks to resolve. Others do not show any sunburn reaction and gradually develop marked freckling at sun exposed sites. Individuals have dry skin and hypo- or hyperpigmented lesions. There is a greater than 10,000-fold increased risk of non-melanoma skin cancers, and a 2,000 fold increased risk of melanoma under the age of 20 when compared to the general population. Patients with classical XP develop skin cancer generally before the age of 20, while patients with XP variant start to develop skin cancer at about 20-30 years of age. Ocular abnormalities include keratitis resulting in corneal opacification and vascularization. Photophobia is common. Ocular squamous cell carcinoma and melanoma are common. Neurologic abnormalities of varying severity have been reported in about 30% of cases. These include acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, spasticity, ataxia, seizures and progressive cognitive impairment. De Sanctis-Cacchione syndrome is a term that was originally attributed to XP cases with severe neurological abnormalities but it is no longer in general use.\nEtiology\nXP is caused by mutations in 8 genes involved in DNA repair. Seven of these genes, XPA to XPG (ERCC5), are involved in nucleotide excision repair (NER). XPV, or POLH, encodes the DNA polymerase eta, which is required to replicate DNA containing UV-induced damage.\nDiagnostic methods\nDiagnosis is based on clinical symptoms and is confirmed by cellular tests for defective DNA repair (e.g. unscheduled DNA synthesis (UDS) test in cultured skin fibroblasts) and UV hypersensitivity. Reduced UDS and hypersensitivity to UV-induced killing confirm the diagnosis of XP. A normal UDS and specific sensitivity to UV in the presence of caffeine confirm the diagnosis of XP variant.\nDifferential diagnosis\nDifferential diagnoses include trichothiodystrophy, Cockayne syndrome, cerebrooculofacioskeletal syndrome (COFS), UV-sensitive syndrome, erythropoietic protoporphyria, and Rothmund-Thomson syndrome (see these terms).\nAntenatal diagnosis\nPrenatal diagnosis through measurement of UDS in cultured chorionic villus cells or amniocytes has been reported.\nGenetic counseling\nTransmission is autosomal recessive.\nManagement and treatment\nPatients must avoid sun exposure (application of sun cream, UV protective clothing, indoor protection with UV blocking films). Management requires a multidisciplinary approach. Regular skin and eye review and appropriate management of any cancerous lesions is essential. Vitamin D deficiency is common and supplements should be prescribed.\nPrognosis\nThere is no cure for XP but sun avoidance and regular follow-up to assess and treat any skin cancers increases life expectancy. For those with no neurological disease and rigorous UV protection, the prognosis is good. However the neurological abnormalities are progressive and can result in a shortened lifespan.\n\n                            Last update: \n                            May 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Hiva FASSIHI"}
{"Disease Name": "XK aprosencephaly syndrome", "Disease Definition": "A rare syndromic type of cerebral malformation characterized by aprosencephaly (absence of telencephalon and diencephalon), oculo-facial anomalies (i.e. ocular hypotelorism or cyclopia, malformatiobsence of nasal structures, cleft lip), preaxial limb defects (i.e. hypoplastic hands, absent halluces) and various other anomalies including ambiguous genitalia, imperforate anus, and vertebral anomalies. The syndrome is thought to have an autosomal recessive mode of inheritance.", "ORPHA ID": 3469, "Summary": ""}
{"Disease Name": "XMEN", "Disease Definition": "X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia is a rare combined T and B cell immunodeficiency characterized by recurrent sinopulmonary and viral infections, persistent elevated Epstein-Barr virus (EBV) viremia and increased susceptibility to EBV-associated B-cell lymphoproliferative disorders. Immunological analyses show normal lymphocyte count or mild to moderate lymphopenia, inverted CD4:CD8 T-cell ratio and hypogammaglobulinemias.", "ORPHA ID": 317476, "Summary": ""}
{"Disease Name": "Xp21 deletion syndrome", "Disease Definition": "A rare chromosomal anomaly characterized by complex glycerol kinase deficiency, congenital adrenal hypoplasia, intellectual disability and/or Duchenne muscular dystrophy that usually affect males. The clinical features depend on the deletion size and the number and type of involved genes.", "ORPHA ID": 261476, "Summary": ""}
{"Disease Name": "Xp22.13p22.2 duplication syndrome", "Disease Definition": "A rare syndromic intellectual disability characterized by developmental delay and intellectual disability, learning and behavioral problems, short stature, thin and sparse hair, mild dysmorphic features, tapering fingers and later onset of scoliosis, obesity and cardiovascular problems (cardiomegaly and cardiomyopathy). Females have normal intelligence.", "ORPHA ID": 284180, "Summary": ""}
{"Disease Name": "Xp22.3 microdeletion syndrome", "Disease Definition": "Xp22.3 microdeletion syndrome is a microdeletion syndrome resulting from a partial deletion of the chromosome X. Phenotype is highly variable (depending on length of deletion), but is mainly characterized by X linked ichthyosis, mild-moderate intellectual deficit, Kallmann syndrome, short stature, chondrodysplasia punctata and ocular albinism. Epilepsy, attention deficit-hyperactivity disorder, autism and difficulties with social communication can be associated.", "ORPHA ID": 1643, "Summary": ""}
{"Disease Name": "Xq12-q13.3 duplication syndrome", "Disease Definition": "Xq12-q13.3 duplication syndrome is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the long arm of chromosome X, characterized by global developmental delay, autistic behavior, microcephaly and facial dysmorphism (including down-slanting palpebral fissures, depressed nasal bridge, anteverted nares, long philtrum, down-slanting corners of the mouth). Seizures have also been reported in some patients.", "ORPHA ID": 314389, "Summary": ""}
{"Disease Name": "Xq21 microdeletion syndrome", "Disease Definition": "An X-linked retinal dystrophy characterized by choroideremia, causing in affected males progressive nyctalopia and eventual central blindness. Obesity, moderate intellectual disability and congenital mixed (sensorineural and conductive) deafness are also observed. Female carriers show typical retinal changes indicative of the choroideremia carrier state.", "ORPHA ID": 1435, "Summary": ""}
{"Disease Name": "Xq25 microduplication syndrome", "Disease Definition": "A rare, X-linked, multiple congenital anomalies/dysmorphic malformation-intellectual disability syndrome characterized by developmental delay, mild to moderate intellectual disability, speech disturbance, behavioral problems (such as anxiety, hyperactivity, and aggressiveness) and mild facial dysmorphism (including facial hypotonia, thin arched eyebrows, ectropion, epicanthus, malar flatness, thick vermillion of the lips and prognathia). Additional variable manifestations include short stature, skeletal and genital anomalies, seizures, and autism spectrum disorders. Brain imaging may reveal cerebellar vermis hypoplasia, thin corpus callosum, and enlarged subarachnoid spaces.", "ORPHA ID": 521258, "Summary": ""}
{"Disease Name": "Xq27.3q28 duplication syndrome", "Disease Definition": "Xq27.3q28 duplication syndrome is a recently described syndrome characterized by short stature, hypogonadism, developmental delay and facial dysmorphism.", "ORPHA ID": 261483, "Summary": "Epidemiology\nIt has been clinically and molecularly characterized in 3 male members from the same family.\nClinical description\nFacial features include deep-set eyes, bulbous nasal tip and thin lips. Hypogonadism is due to primary gonadal failure. Patients also had some features which are probably caused by testosterone deficiency such as a high-pitched voice, sparse body hair and small hands and feet. Carrier females present with a short stature and early menopause.\nEtiology\nThis syndrome is caused by an Xq27.3q28 interstitial duplication encompassing the FMR1 and AFF2  genes but not the MECP2 gene. This duplication was characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH).\nGenetic counseling\nTransmission is X-linked.\n\n                            Last update: \n                            July 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Nicole MORICHON-DELVALLEZ"}
{"Disease Name": "XY type gonadal dysgenesis-associated anomalies syndrome", "Disease Definition": "A rare syndrome with 46,XY difference of sex development characterized by mild developmental delay and streak gonads associated with short stature, cardiac, renal, musculoskeletal, and ectodermal abnormalities (the latter including scalp defects and unusual hair whorls), and dysmorphic facial features (such as preauricular pits, short columella, and small nares). There have been no further descriptions in the literature since 1980.", "ORPHA ID": 1770, "Summary": ""}
{"Disease Name": "XYLT1-CDG", "Disease Definition": "A rare congenital disorder of glycosylation characterized by moderate intellectual disability, short stature, mild skeletal changes and distinctive facial features with coarse face, synophyrs and deep nasolabial ridges. Skeletal features include broad ribs, stocky long bones, short femoral necks with coxa valga, clinodactyly and broad thumbs.", "ORPHA ID": 370930, "Summary": ""}
{"Disease Name": "Yellow fever", "Disease Definition": "Yellow fever (YF), caused by YF virus, is a zoonotic disease characterized by fever and constitutional symptoms, with the potential to progress to severe and fatal viral hemorrhagic fever with shock and multi-organ system failure.", "ORPHA ID": 99829, "Summary": "Epidemiology\nYF is endemic to the tropics of the Americas and Africa, where collectively an estimated 5,000-200,000 clinical cases and 30,000 deaths occur annually, the vast majority in Africa.\nClinical description\nMost infections are mild or asymptomatic. After an incubation period of 3-6 days, patients typically present with the abrupt onset of non-specific signs and symptoms including fever, malaise, headache, chest pain, and myalgia/arthralgia, followed rapidly by gastrointestinal (nausea, vomiting, diarrhea) symptoms. Most cases will then resolve. In a minority, after a quiescent period of a few days, more severe manifestations ensue, including jaundice, hepato-renal failure, hemorrhage, shock, and meningoencephalitis. Disease is usually mild in children. Clinical laboratory findings typically include elevated hepatic transaminases and proteinuria.\nEtiology\nOver 25 different viruses cause viral hemorrhagic fever. YF virus is a member of the virus family Flaviviridae, genus Flavivirus. The virus is maintained in a cycle between monkeys and forest canopy mosquitoes. Sporadic cases occur when humans are bitten by these mosquitoes (sylvatic YF). Larger outbreaks occur when humans bring the virus back to more settled environments, where the urban container-breeding mosquito Aedes aegypti can spread YF virus directly between humans (urban YF). Sanitation and mosquito control measures have virtually eliminated urban yellow fever in the Americas, but urban outbreaks continue to be noted in Africa, where 90% of all YF virus infections occur.\nDiagnostic methods\nCommon diagnostic modalities include cell culture, serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories.\nDifferential diagnosis\nYF is difficult to distinguish from a host of other febrile illnesses, at least early in the course of disease. Other viral hemorrhagic fevers, malaria, typhoid fever, leptospirosis, rickettsial infection (see these terms), viral hepatitis and meningococcemia need to be excluded.\nManagement and treatment\nAs there is presently no antiviral drug available for YF, treatment is supportive, following the guidelines for treatment of severe septicemia. Insecticide-treated bed nets and/or room screens should be used in open-air settings to prevent further transmission. The YF-17D live attenuated vaccine is highly efficacious, conferring long-term protection in over 95% of recipients within 10 days. YF-17D is indicated for persons over 9 months of age who are traveling to or living in YF endemic areas. Vaccination is contraindicated in children <4 months old and pregnant women and caution is advised in persons with egg allergy, the immunocompromised, children 4-9 months of age and elderly persons, especially if the risk is minimal, such as trips restricted to attending conferences in modern urban hotels with no rural exposure.\nPrognosis\nCase fatality rates in symptomatic cases are 20-50%. Shock, tachycardia, bleeding, oliguria, proteinuria and azotemia confer a poor prognosis. Although convalescence may be prolonged, survivors usually have no lasting sequelae.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Daniel BAUSCH  -  Andrew BENNETT"}
{"Disease Name": "Yellow nail syndrome", "Disease Definition": "A rare, syndromic nail anomaly disease characterized by the variable triad of characteristic yellow nails, chronic respiratory manifestations, and primary lymphedema.", "ORPHA ID": 662, "Summary": "Epidemiology\nPrevalence and incidence rates are not known, but Yellow nail syndrome (YNS) is considered a rare condition. To date, approximately 400 cases have been reported, mainly as single case reports. The disorder affects males and females equally.\nClinical description\nMost cases of YNS are of late onset, after 50 years of age, but the disease has also occasionally been observed in neonates and children. Patients generally complain of slowed or arrested nail growth: the nails become thickened and opaque, with yellowish or green discoloration. The cuticles are absent and the proximal nail fold swollen. Increased transverse curvature is another feature, which may lead to nail plate shedding. Both fingernails and toenails are affected, but severity may vary. Only 1/3 of the patients with nail changes have associated lymphedema and respiratory tract involvement. Nail changes may precede the development of lymphedema or respiratory manifestations by years. Lymphedema is the most consistent associated finding and usually affects the lower limbs. Respiratory conditions include cough, bronchitis, tracheobronchitis, bronchiectasis, chronic sinusitis, chronic respiratory infections, and pleural effusions. YNS may exceptionally be a paraneoplastic disorder (lung cancer).\nEtiology\nThe etiology of YNS has not been elucidated. Impaired lymphatic drainage not due to anatomical abnormalities, but rather to a functional disorder, appears to have a central role.\nDiagnostic methods\nNail changes in YNS are pathognomonic and the presence of typical nail alterations is an absolute requirement for the diagnosis. This is because the three main signs (i.e. nail changes, respiratory disorders, and lymphedema) may not be present all at once in the patient.\nDifferential diagnosis\nThe most important nail differential diagnoses include chronic paronychia, which shares absence of the cuticle and nail thickening and discoloration, and onychomycosis of the toenails, which produces thickening and onycholysis. Onychogryphosis and acquired pachyonychia should also be considered.\nManagement and treatment\nSpontaneous improvement in nail signs is reported in up to 30% of cases. Oral α‐tocopherol (vitamin E) at high doses, 600 to 1200 international units (IU) daily has been reported to be effective in about half of patients.\nPrognosis\nSome patients recover fully, but the respiratory condition and the associated symptoms are often chronic. Serious lymphedema and respiratory complications may affect quality of life and periodic follow-up is mandatory. Patients with YNS present several comorbidities other than the respiratory ones, possibly due to their older age, therefore they tipically have a lower life expectancy when compared to the general population.\n\n                            Last update: \n                            June 2019\n\n\n                            - Expert reviewer(s): \n                            Pr Bianca Maria PIRACCINI"}
{"Disease Name": "Yolk sac tumor", "Disease Definition": "A rare germ cell tumor characterized by multiple patterns reflecting endodermal extraembryonal differentiation (secondary yolk sac and allantois) or endodermal somatic tissues (intestine, liver, and mesenchyme). The tumors most commonly occur in the second or third decade of life. They are typically located in the gonads, occasionally also in other regions. Patients present with a pelvic mass and/or abdominal pain (females) or an often painless, unilateral testicular mass (males). Elevated serum alpha fetoprotein is a common laboratory finding.", "ORPHA ID": 876, "Summary": ""}
{"Disease Name": "Young adult-onset distal hereditary motor neuropathy", "Disease Definition": "Young adult-onset distal hereditary motor neuropathy is a rare autosomal recessive distal hereditary motor neuropathy characterized by slowly progressive muscular weakness, hypotonia and atrophy of the lower limbs, more pronounced distally, leading to paralysis, and loss of tendon reflexes. Additional features may include pes cavus and mild dysphonia. The upper limbs are relatively spared.", "ORPHA ID": 314485, "Summary": ""}
{"Disease Name": "Young syndrome", "Disease Definition": "A rare respiratory disease characterized by recurrent sinopulmonary infections and bronchiectasis predominantly in the lower lung fields, as well as azoospermia with reduced fertility, due to production of thick, viscous mucus which causes mild airflow obstruction in the respiratory tract and obstruction of sperm transport in the genital tract. Patients commonly present in adulthood. Sweat gland and pancreatic function are normal. The cause of the syndrome is unknown, however mercury exposure had been proposed as a potential cause.", "ORPHA ID": 3471, "Summary": ""}
{"Disease Name": "Young-onset Parkinson disease", "Disease Definition": "A rare, genetic, parkinsonian disorder characterized by an age of onset between 21-45 years, rigidity, painful cramps followed by tremor, bradykinesia, dystonia, gait complaints and falls, and other non-motor symptoms. A slow disease progression and a more pronounced response to dopaminergic therapy are also observed in most forms of this disease.", "ORPHA ID": 2828, "Summary": "Epidemiology\nPrevalence of Young onset Parkinson disease (YOPD) in Europe is estimated to be 1/5,000-8,000 (5-10 % of all PD patients). Males are more affected than females (1.7:1). Women develop the disease 2 years later than men.\nClinical description\nThe age at onset of motor symptoms lies between 21-45 years. The predominant initial motor symptoms include rigidity and painful cramps which may be followed by tremor, bradykinesia, gait complaints and falls. Compared to PD, a lower risk of developing falls and freezing of gait but a higher risk of dystonia, motor fluctuations, and levodopa induced dyskinesia (LID) have been reported. YOPD patients report higher prevalence of non-motor symptoms including apathy, anxiety disorders (including panic disorders, generalized anxiety disorder, and social phobia), depression, psychosis (hallucinations), behavioral disturbances (agitation or impulse control disorder), dementia, and higher concentration difficulties than patients with sporadic or more typical form of PD. Women are more likely to present with tremor or to develop apathy, anxiety, depression, or LID. Likewise, untreated YOPD patients may present with cramps and dystonic postures more often than older PD patients.\nEtiology\nThe exact etiology of YOPD is still unknown. Symptoms of YOPD are thought to result from degeneration of the dopamine producing neurons in the substantia nigra secondary to infectious diseases, pharmacotherapy, or genetic. Mutations in  PRKN (6q25.2-q27), PINK1 (1p36.12), PARK7 (1p36.23), and VPS13C (15q22.2), (21q22.11) genes have also been implicated in some cases of YOPD. The genes PODXL (7q32.3), DNAJC6 (1p31.3) and SYNJ1 (21q22.11) have been implicated in both YOPD and Atypical juvenile parkinsonism.\nDiagnostic methods\nDiagnosis relies on presence of the clinical symptoms with tremor present in 85% of YOPD patients, an early age at onset, a family history of PD and a positive response to dopaminergic therapy. Diagnosis is confirmed by genetic analysis and cerebral scintigraphy of the dopamine transporters. Final diagnosis is usually made by the presence of lewy bodies in the brain during autopsy.\nDifferential diagnosis\nDifferential diagnosis includes atypical juvenile parkinsonism, late onset PD, hereditary essential tremor, Wilson disease, Gaucher disease type 3, Pantothenate kinase-associated neurodegeneration, juvenile Huntington disease and central basal ganglia lesions.\nGenetic counseling\nIn most cases, YOPD is sporadic. However, familial cases have been reported in which an autosomal recessive mode of inheritance have been suggested.\nManagement and treatment\nFor symptomatic therapy, an initial treatment with a dopamine receptor agonist maintained at a very low threshold is advised. A switch to or addition of levodopa (L-DOPA) is recommended in cases where treatment response is suboptimal or if problematic adverse effects develop. However, after 5 years of treatment with L-DOPA, 30-40% of patients (59-100% by 10 years) develop dyskinesias and motor fluctuations. Some dopamine receptor agonists may also have antidepressive efficacy. Additional treatments include subthalamic nucleus deep brain stimulation and stereotactic surgery (fetal transplantation, pallidal stimulation, pallidotomy, thalamotomy or both).\nPrognosis\nThe survival rate is favorable, with a median survival age of 30 years. YOPD is also associated with slower disease progression and less cognitive decline until later ages. However, YOPD patients are more likely to have earlier motor complications such as violent and disabling dyskinesias, painful dystonia, and unpredictable and severe motor fluctuations with a greater frequency of occurrence. Poorer quality of life has also been noted resulting from social and psychosocial disturbances.\n\n                            Last update: \n                            July 2020\n\n\n                            - Expert reviewer(s): \n                            Dr Coro PAISAN-RUIZ"}
{"Disease Name": "Yunis-Varon syndrome", "Disease Definition": "A rare, genetic, multiple congenital malformation syndrome, characterized by cleidocranial dysplasia (wide fontanelles, calvaria dysostosis, absent or hypoplastic clavicles), absent thumbs and halluces, hypoplastic distal and medial phalanges of fingers, pelvic dysplasia with hip dislocations. Dysmorphic features include sparse scalp hair, protruding eyes, low-set ears, anteverted nares, midfacial hypoplasia, tented upper lip, high arched palate, and micrognathia. Brain malformations are frequently associated. From birth, affected individuals tend to be significantly hypotonic and present with global developmental delay, and respiratory, feeding and swallowing difficulties.", "ORPHA ID": 3472, "Summary": ""}
{"Disease Name": "Zebra body myopathy", "Disease Definition": "Zebra body myopathy is a benign congenital myopathy, characterised by congenital hypotonia and weakness. Prevalence is unknown. Less than ten patients have been described so far. Muscle biopsy shows zebra bodies and other myopathic changes. Mutations of the alpha-skeletal actin (ACTA1) gene may be involved.", "ORPHA ID": 97240, "Summary": ""}
{"Disease Name": "Zechi-Ceide syndrome", "Disease Definition": "A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by occipital atretic cephalocele associated with a specific facial dysmorphism (consisting of prominent forehead, narrow palpebral fissures, midface deficiency, narrow, malformed ears, broad nose and nasal root, grooved nasal tip and columella, laterally angulated, hypoplastic nares, short philtrum, thin upper lip, clift lip/palate, severe oligodontia, prominent chin) and large feet with sandal gap. Intellectual disability, developmental delay and hypoplastic finger and toenails have also been reported.", "ORPHA ID": 217017, "Summary": ""}
{"Disease Name": "Zellweger syndrome", "Disease Definition": "A rare peroxisome biogenesis disorder (the most severe variant of Peroxisome biogenesis disorder spectrum) characterized by neuronal migration defects in the brain, dysmorphic craniofacial features, profound hypotonia, neonatal seizures, and liver dysfunction.", "ORPHA ID": 912, "Summary": "Epidemiology\nThe birth prevalence of Peroxisome biogenesis disorder (PBD) is estimated to be around 1/50,000 in North America, and around 1/500,000 in Japan. The highest incidence of Zellweger syndrome (ZS) was reported in the Saguenay-Lac St Jean region of Quebec (around 1/12,000).\nClinical description\nOnset is in the neonatal period, reflecting both organ malformations that occurred in utero and progressive disease due to ongoing peroxisome dysfunction. Infants present with characteristic dysmorphic craniofacial features (flattened facies, large anterior fontanel, split sutures, prominent high forehead, flattened occiput, upslanting palpebral fissures, epicanthal folds, and broad nasal bridge), profound hypotonia and seizures. Macrocephaly or microcephaly, high arched palate, micrognathia and redundant neck skin folds may be present. Skeletal abnormalities (chondrodysplasia punctata, most often in the patella and hips) and subcortical renal cysts are frequent. There is often failure to thrive, hepatomegaly, jaundice, and coagulopathy. Eye findings include cataracts, glaucoma, pigmentary retinopathy, nystagmus, corneal clouding and optic nerve atrophy. Visual changes and loss are progressive. Sensorineural hearing loss may be present. Cryptorchidism and hypospadias (male) and clitoromegaly (female) may occur. CNS function is severely affected and infants have profound psychomotor delay.\nEtiology\nPBD is caused by mutations in one of 13 PEX genes encoding peroxins. Mutations in these genes lead to abnormal peroxisome biogenesis.\nDiagnostic methods\nZS is often suspected on physical examination and confirmed with biochemical evaluation. Plasma very-long-chain fatty acid (VLCFA) levels indicate defects in peroxisomal fatty acid metabolism with elevated plasma concentrations of C26:0 and C26:1 and elevated ratios of C24/C22 and C26/C22. Erythrocyte membrane concentrations of plasmalogens C16 and C18 are reduced. Plasma pipecolic acid levels are increased. Sequence analysis of the 13 PEX genes can be performed. MRI can be used to identify perisylvian polymicrogyria, and other developmental brain malformations.\nDifferential diagnosis\nThe main differential diagnoses include Usher syndrome I and II, other PBD disorders (see these terms), single enzyme defects in peroxisome fatty acid beta-oxidation, and disorders that feature severe hypotonia, neonatal seizures, liver dysfunction or leukodystrophy.\nAntenatal diagnosis\nPrenatal screening for VLCFA levels and plasmalogen synthesis can be performed on cultured amniocytes and chorionic villus sampling in suspected or high-risk pregnancies. If disease causing alleles in the carrier parents have been identified, prenatal diagnosis by DNA testing can be performed as well as preimplantation genetic diagnosis.\nGenetic counseling\nZS is inherited in an autosomal recessive manner, so genetic counseling is possible.\nManagement and treatment\nThere is no cure for ZS. Standard epileptic drugs are used for seizure control. Hepatic coagulopathy can be treated with vitamin K supplementation while cholestasis may require the provision of all fat soluble vitamins. A gastrostomy tube may be needed to allow for adequate calorie intake. Foods rich in phytanic acids (i.e. cow's milk) should be restricted. Supplementation of mature bile acids, cholic and chenodeoxycholic acid may help improve liver disease in infants with severe hepatopathy. As ZS patients cannot biosynthesize DHA, it can also be provided.\nPrognosis\nRegardless of interventions, prognosis is poor with most infants dying within the first year of life secondary to respiratory compromise related to infection or intractable epilepsy.\n\n                            Last update: \n                            December 2012\n\n\n                            - Expert reviewer(s): \n                            Dr Nancy BRAVERMAN"}
{"Disease Name": "Zellweger-like syndrome without peroxisomal anomalies", "Disease Definition": "A rare mitochondrial disorder characterized by facial dysmorphism similar to that seen in Zellweger syndrome (see this term), such as frontal bossing, high forehead, upslanting palpebral fissures, hypoplastic supraorbital ridges, and epicanthal folds, and in addition, pale skin, profound hypotonia, developmental delay, and minor metabolic anomalies. No peroxysomal defects, however, have been reported. Transmission is thought to be autosomal recessive.", "ORPHA ID": 50812, "Summary": ""}
{"Disease Name": "Zika virus disease", "Disease Definition": "Zika virus disease is an emerging Aedes mosquito-born virus disease characterized by a clinical course that may be asymptomatic or mild with fever, conjunctivitis, muscle and joint pain, headache, exanthema, but may also be associated with severe neurological (meningitis, meningoencephalitis and myelitis) and auto-immune (Guillain-Barre syndrome) complications, as well as a potential increase of birth defects (microcephaly) if the infection occurs during pregnancy.", "ORPHA ID": 448237, "Summary": ""}
{"Disease Name": "Zimmermann-Laband syndrome", "Disease Definition": "A rare genetic multiple congenital anomalies syndrome characterized by gingival fibromatosis, coarse facial appearance, and absence or hypoplasia of nails or terminal phalanges of hands and feet.", "ORPHA ID": 3473, "Summary": "Epidemiology\nAbout 50 patients have been reported to date.\nClinical description\nZimmermann Laband (ZLS) is characterized by the presence of a progressive, diffuse, gingival hypertrophy, often with multiple unerupted teeth and skeletal deformities of maxillary arches; a coarse facial appearance which includes a bulbous, soft nose, thickened lips, thick and floppy ears; and absence or hypoplasia of the terminal phalanges and nails of hands and feet. More variable features include hyperextensibility of joints, hepatosplenomegaly, mild hirsutism, and hearing loss. Intellectual disability is occasional and usually mild to moderate. The overgrown gingival tissues can affect the ability to speak.\nEtiology\nZLS is genetically heterogeneous. Heterozygous gain of function missense variants in KCNH1 (1q32.2), and KCNN3 (1q21.3) genes have been described and, more rarely, recurrent missense variants in the ATP6V1B2 (8p21.3) gene. Zimmermann-Laband syndrome is allelic to Temple Baraitser syndrome (TBS) which is also caused by gain-of-function mutations in the KCNH1 gene, and is characterized by global developmental delay and severe intellectual disability, epilepsy, hypoplasia/aplasia of the nails of the thumb and great toe, and facial dysmorphism. As both syndromes have been described with the same variant, and some patients with KCNH1 variants are reported without full-blown TBS or ZLS, it is likely that TBS, and ZLS are part of a broader KCNH1-related disorder.\nDiagnostic methods\nConfirmation of the clinical diagnosis is based on KCNH1, KCNN3, and ATP6V1B2 sequencing by targeted sanger sequencing, or via NGS (next generation sequencing) multigene panel including KCNH1, KCNN3, and ATP6V1B2, as well as other genes that may be part of the differential diagnosis.\nDifferential diagnosis\nZLS has overlapping features with a few different diseases which include : FHEIG syndrome (characterized by facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) resulting from gain-of-function KCNK4 variants, Cantú syndrome, and DOORS syndrome as well as other defined syndromes of hirsutism and coarsening of the face. Some ATP6V1B2 variants are responsible for autosomal dominant deafness-onychodystrophy (DDOD) syndrome, a syndromic form of deafness which shares features with ZLS, such as anomalies of digits, nails, and teeth. Variants in ATP6V1B2 have also been reported in patients with epilepsy, intellectual disability and mild gingival and nail abnormalities. Some patients with ABCC9 variants also have gingival hypertrophy and, rarely, hypoplasia of terminal phalanges. Isolated gingival fibromatosis has been documented as a dominantly transmissible trait.\nAntenatal diagnosis\nFor parents of an index individual, prenatal diagnosis in subsequent pregnancies should be discussed.\nGenetic counseling\nAlthough familial aggregation with different inheritance patterns has been reported, all genetically confirmed ZLS to date follow an autosomal dominant mode of in inheritance, most cases resulting from a de novo mutation.\nManagement and treatment\nManagement and treatment are based on the phenotype. Orthodontic treatment may be needed.\nPrognosis\nPrognosis depends on the phenotype. The syndrome is not life-threatening.\n\n                            Last update: \n                            April 2021\n\n\n                            - Expert reviewer(s): \n                            Pr Catheline VILAIN | ITHACA*\n\n\n                                * European Reference Network"}
{"Disease Name": "Zinc-responsive necrolytic acral erythema", "Disease Definition": "A rare skin disease characterized initially by erythematous patches with superficial necrosis, at later stages by hyperkeratotic plaques with a rim of dusky erythema, of exclusively acral distribution with a predilection for the lower extremities, and universal association with hepatitis C virus infection. Patients typically experience pruritus or pain. Serum zinc levels may or may not be decreased, although oral zinc supplementation often improves the condition.", "ORPHA ID": 439196, "Summary": ""}
{"Disease Name": "Zollinger-Ellison syndrome", "Disease Definition": "Zollinger-Ellison syndrome (ZES) is characterized by severe peptic disease (ulcers/esophageal disease) caused by hypergastrinemia secondary to a gastrinoma resulting in increased gastric acid secretion.", "ORPHA ID": 913, "Summary": "Epidemiology\nAnnual incidence is estimated at 1-2 cases per million. The condition is slightly more common in females than males (sex ratio of 1.3:1).\nClinical description\nZES is usually diagnosed in the fifth decade of life. Abdominal pain (typically in the upper abdomen) and diarrhea are the most frequent manifestations. Heartburn is often present (44% of cases). Other signs include nausea, vomiting, malabsorption, and weight loss. Some patients present with ulcer complications (gastrointestinal bleeding, perforation and penetration).\nEtiology\nZES is caused by a gastrin-secreting tumor (gastrinoma), usually located in the duodenum (50-85% of cases), pancreas, abdominal lymph nodes or, in rare cases, ectopic locations (heart, ovary, liver etc.). ZES can be sporadic (75% of cases) or associated with multiple endocrine neoplasia type 1 (MEN1; see this term), which is transmitted in an autosomal dominant manner. MEN1 is caused by mutations in the MEN1 gene (11q13) encoding menin, a protein which binds and regulates the activity of numerous transcription factors.\nDiagnostic methods\nDiagnosis of ZES is first suspected on the basis of the clinical manifestations. Elevated fasting serum gastrin (FSG) levels are almost invariably present. FSG levels 10 times higher than normal and a gastric pH of <2 confirm the diagnosis. If the FSG level is elevated less than 10 fold and the gastric pH is <2, secretin stimulation (abnormal: increase >120 pg/ML) and basal acid (abnormal: >15 mEq/hr-basal) tests need to be done. Imaging studies (somatostatin receptor scintigraphy, CT scan, abdominal or endoscopic ultrasound) are required to localize the gastrinoma. Esophagogastroduodenoscopy may be indicated to detect duodenal ulcerations.\nDifferential diagnosis\nDifferential diagnoses include other causes of increased acid output and elevated FSG levels: Helicobacter pylori infections, retained gastric antrum, gastric outlet obstruction, renal failure, antral G cell syndromes, idiopathic gastroesophageal reflux or peptic ulcer disease, and physiological causes of hypergastrinemia (atrophic gastritis, pernicious anemia, or use of potent antisecretory drugs).\nAntenatal diagnosis\nAntenatal genetic testing may allow prenatal diagnosis of MEN1 but not gastrinomas.\nGenetic counseling\nGenetic counseling should be offered to ZES patients with MEN1.\nManagement and treatment\nGastric acid hypersecretion must be controlled both in the short- and long-term. Oral H(+)-K(+)-ATPase inhibitors (proton-pump inhibitors; PPIs) are now the drugs of choice because of their long duration of action and potency (administered in once- or twice-a-day doses). Intravenous PPIs are effective when oral drugs cannot be taken. Histamine H2-receptor antagonists can also be effective but frequent high doses are needed by many patients. Management also includes treatment directed at the tumor itself as 60-90% of tumors are malignant. For localized disease in non-MEN1 patients, surgery is recommended. For advanced metastatic disease, numerous antitumor therapies are used including chemotherapy, biotherapy (somatostatin/interferon analogues), embolization of hepatic metastases and aggressive surgery. A number of newer treatments (including somatostatin receptor-mediated radiotherapy, novel chemotherapeutic agents and growth factor/tyrosine kinase inhibitors) are under investigation.\nPrognosis\nIn the absence of liver metastases, the prognosis is favorable (10-year survival rate of 90-100%). Patients with liver metastases (65-75% of patients) have a 10-year survival rate of 20-40%. Patients with MEN1 are rarely cured surgically due to the presence of multiple tumors and lymph node metastases, however, only 15% pursue an aggressive course and 10 year survival is 80-98%.\n\n                            Last update: \n                            May 2009\n\n\n                            - Expert reviewer(s): \n                             Robert JENSEN"}
{"Disease Name": "Zygomycosis", "Disease Definition": "A rare mycosis caused by ubiquitous, opportunistic fungi of the order Mucorales, characterized by tissue infarction and necrosis due to invasion of the vasculature by hyphae. The spectrum of clinical manifestations depends on the route of infection and includes rhinocerebral, pulmonary, cutaneous, gastrointestinal, renal, and disseminated forms. The disease is usually rapidly progressive and associated with high mortality.", "ORPHA ID": 73263, "Summary": ""}
{"Disease Name": "Åland Islands eye disease", "Disease Definition": "An X-linked recessive retinal disease characterized by fundus hypopigmentation, decrased visual acuity, nystagmus, astigmatism, progressive axial myopia, defective dark adaptation and protanopia.", "ORPHA ID": 178333, "Summary": "Epidemiology\nAIED is a very rare disease originally reported in a family from Aland islands in the Bothnia sea. Some other cases from the Baltic area and other origins have been reported but the clinical features of these cases overlap with X-linked incomplete congenital stationary night blindness (CSNB2; see this term).\nClinical description\nAIED is characterized by hypopigmented eye fundus, foveal dysplasia with no foveal reflex that leads to decreased visual acuity, progressive axial myopia, latent nystagmus, astigmatism, night blindness and protan color vision defect. The hypopigmentation is most pronounced in the posterior pole and in the peripapillary region. Female carriers may show slight disturbances of color discrimination and subtle nystagmus.\nEtiology\nAIED is caused by mutations in the CACNA1F gene. Some mutations in CACNAF1 are associated with CSNB2 suggesting allelism of the two disorders.\nDiagnostic methods\nPatients with a clinical suspicion of AIED should undergo a complete ophthalmologic examination including funduscopy, visual acuity, refraction defects, electroretinogramm (ERG) and color vision test. Mutation screening of CACNA1F gene including the presence of large deletions in the gene can help the clinical diagnosis.\nDifferential diagnosis\nDifferential diagnosis includes X-linked ocular albinism (OA1; see this term) and CSNB2. The lack of misrouting of optic nerve axons excludes OA1 whereas CSNB2 is apparently stationary with a normal fovea and, usually, no color defects.\nGenetic counseling\nAIED is an X-linked disorder, with a carrier female having a 50% risk of transmitting the mutation to her offspring. Carrier testing for at-risk female relatives is possible. Genetic counseling of the family is recommended.\nManagement and treatment\nNo treatment is available except for correction of the myopia.\nPrognosis\nExcept for progression of axial myopia, the disease presents a stationary course.\n\n                            Last update: \n                            December 2011\n\n\n                            - Expert reviewer(s): \n                            Dr Carmen AYUSO  - Dr Teresa JAIJO  - Dr José María MILLÁN SALVADOR"}
{"Disease Name": "Neonatal diabetes mellitus", "Disease Definition": "Neonatal diabetes mellitus presents as hyperglycemia, failure to thrive and, in some cases, dehydration and ketoacidosis which may be severe with coma, in a child within the first months of life.", "ORPHA ID": 224, "Summary": "Epidemiology\nTransient (TNDM) and Permanent (PNDM) neonatal diabetes are rare conditions occurring in 1:300,000-400,000 live births.\n\nClinical description\nTNDM infants develop diabetes in the first few weeks of life but go into remission in a few months, with possible relapse to a permanent diabetes state usually around adolescence or as adults. The pancreatic dysfunction may be maintained throughout life, with relapse initiated at times of metabolic stress such as puberty or pregnancy. Patients with TNDM are more likely to have intrauterine growth retardation and less likely to develop ketoacidosis than patients with PNDM. In TNDM, patients are younger at the diagnosis of diabetes and have lower initial insulin requirements. In PNDM, insulin secretory failure occurs in the late fetal or early post-natal period and does not go into remission. Considerable overlap occurs between the two groups, so that TNDM cannot be distinguished from PNDM based on clinical features. Very early onset diabetes mellitus seems to be unrelated to autoimmunity in most instances.\n\nEtiology\nA number of conditions are associated with PNDM, some of which have been elucidated at the molecular level. Among these, the very recently elucidated mutations in the KCNJ11 and ABCC8 genes, encoding the Kir6.2 and SUR1 subunit of the pancreatic KATP channel involved in regulation of insulin secretion, account for one third to half of the PNDM cases.\n\nDiagnostic methods\nMolecular analysis of chromosome 6 anomalies, and the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1, provides a tool to identify TNDM from PNDM in the neonatal period. This analysis also has potentially important therapeutic consequences leading to transfer some patients, those with mutations in KCNJ11 and ABCC8 genes, from insulin therapy to sulfonylureas.\n\nDifferential diagnosis\n\nAntenatal diagnosis\n\nGenetic counseling\n\nManagement and treatment\nRecurrent diabetes is common in patients with 'transient'' neonatal diabetes mellitus and, consequently, prolonged follow-up is imperative. Insulin pump may offer an interesting therapeutic tool in this age group in experienced hands.\n\nPrognosis"}